CN101400261B - 使用三唑化合物治疗炎症异常 - Google Patents
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- CN101400261B CN101400261B CN2007800090970A CN200780009097A CN101400261B CN 101400261 B CN101400261 B CN 101400261B CN 2007800090970 A CN2007800090970 A CN 2007800090970A CN 200780009097 A CN200780009097 A CN 200780009097A CN 101400261 B CN101400261 B CN 101400261B
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- triazole compounds
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- rambazole
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Abstract
本发明涉及三唑化合物在降低炎症和治疗炎症相关异常中的应用。
Description
发明人
马利纳·库尔斯和马赛尔·鲍格斯
发明领域
本发明涉及三唑化合物，以及使用三唑化合物治疗炎症和炎症相关异常的方法。
发明背景
炎症是身体对损伤、过敏或疾病的第一反应。其急性形式的特征在于疼痛、发热、发红、肿胀和功能缺失的典型症状。例如，刺激性皮炎是由于直接接触引起刺激性物质所引起的皮肤炎症，其特征在于血流的提高、发红和经表皮失水(TEWL)。
前列腺素在炎症进程中发挥了主要作用，抑制前列腺素的产生，特别是PGG2、PGH2和PGE2的产生已经成为发现抗炎药物的共同目标。然而，在降低前列腺素所诱导的与炎症过程相关的疼痛和肿胀中发挥作用的常见非类固醇抗炎药物(NSAIDs)也能够在影响其他与炎症过程不相关的前列腺素调节的过程中发挥作用。因此，使用高剂量的一些最常见的NSAIDs可产生严重的副作用，例如威胁生命的溃疡，这限制了它们的治疗潜能。NSAID的一种替代是使用皮质类固醇，其具有更强的副作用，特别是在采用长期治疗时。
肿瘤坏死因子(TNF)、白介素-12(IL-12)和白介素(IL-1)是重要的生物实体，这些被统称作促炎细胞因子。这些分子连同一些其他相关分子介导了与传染剂的免疫识别相关的炎症反应。这些炎症反应在限制和控制致病致病性感染中发挥着重要作用。
促炎细胞因子的水平提高还与许多自身免疫相关的疾病有关，例如中毒性休克综合征、类风湿性关节炎、骨关节炎、糖尿病和炎性肠病(Dinarello等人，Rev.Infect.Disease6，51(1984))。通常，炎症的慢性提高引起或加剧这些疾病中所观察到的许多症状。例如，炎症细胞攻击类风湿性滑液组织，导致对软骨和骨的破坏(Koch等人，J.Invest.Med.43，28-38(1995))。促炎细胞因子如TNF(其被分泌的无细胞形式也被称作TFNα)和IL-1β的减少代表了一种用于这些疾病中的可接受的潜在的药物干涉的治疗方法。目前在临床试验中有许多抗细胞因子疗法。在许多自身免疫疾病中已经证明了使用针对TFNα的单克隆抗体的效果，例如类风湿性关节炎、克罗恩氏病(Crohn′s disease)以及溃疡性结肠炎(Rankin，E.C.C.，等人，British J. Rheum.35，334-342(1997)和Stack等人，Lancet349，521-524(1997))。
IL-1已经被认为是许多疾病过程中的免疫效应分子。已经证明了IL-1受体拮抗剂治疗类风湿性关节炎的功效(Antril，Amgen)。在人类临床试验中已经显示IL-1受体拮抗剂降低了感染性休克综合征患者的死亡率(Dinarello，Nutrition11，492(1995))。在滑液和骨关节的软骨基质中已经检测到IL-1。IL-1的拮抗剂已经显示在多种关节炎实验模型中减少软骨基质组分的降解(Chevalier，Biomed Pharmacother.51，58(1997))。
人干扰素诱导蛋白10(IP-10)是趋化因子CXC超家族的成员，并吸引T-淋巴细胞和自然杀伤细胞。在牛皮癣中IP-10上调。特别地，牛皮癣损伤的表皮角质细胞表达增高水平的IP-10。激活的角质细胞IP-10表达和分泌的抑制能够代表对炎性皮肤病症治疗性干涉的新靶标。
IL-12是促炎性细胞因子，是由免疫效应细胞例如激活的单核细胞/巨噬细胞和树突细胞、以及由角质细胞所产生的，其在诱导和维持I型T辅助细胞变体(Th1)介导的多种皮肤疾病中发挥了关键作用。因此，在激活的单核细胞中的抑制代表了治疗性干涉的新靶标。
已有显示细胞因子可提高COX-2的表达，并且相信环氧合酶的同工型是造成炎症的原因(O′B anion等人，Proc.Natl.Acad.Sci.U.S.A..89，4888(1992))。因此，细胞因子如IL-1的抑制剂被认为表现出针对那些目前使用COX抑制剂例如常见的非类固醇抗炎药(NSAID)治疗的疾病的效力。这些疾病包括急性和慢性疼痛以及炎症症状和心血管疾。
在活跃的炎症性肠病(IBD)的过程中，已经证实多种细胞因子的升高。在IBD患者中已经显示存在肠内IL-1和IL-1受体拮抗剂的粘膜失衡。内源性IL-1受体拮抗剂的生产不足可能会造成IBD的发病(Cominelli等人，Aliment.Pharmacol.Ther.10，49(1996))。IL-1受体拮抗剂显示了与急性炎症事件、以及与HIV感染病理学的不同疾病阶段的的明确联系，(Kreuzer等人，Clin.Exp.Immunol.109，54(1997))。
促炎性细胞因子如TFNα和IL-1α也是重要的败血性休克和相关的心肺功能障碍、急性呼吸窘迫综合征(ARDS)和多器官功能衰竭的重要介体。在对在医院表现出败血症的患者的研究中，发现了TFNα和IL-6水平与败血并发症之间的联系(Terregino等人，Ann.Emerg.Med.35，26(2000))。
IL-1也显示出诱导大鼠中的葡萄膜炎，这可以被IL-1阻断剂所抑制(Xuan等人，J.Ocular Pharmacol，and Ther..14，31(1998))。IL-1已经显示对于刺激性和过敏性接触皮炎的发展是重要的。可以通过在表皮施加过敏原之前施用抗IL-1单克隆抗体来防止表皮过敏(Muller等人，Am.J.Contact Dermat.7.177(1996))。
三唑化合物已经被用作治疗药物。参见例如美国专利6,124,330；6,265,425和6,486,187。
本发明还涉及降低哺乳动物包括人体内炎症相关疾病的方法，包括对所述哺乳动物施用一定量的能调节一种或多种细胞因子包括趋化因子表达和/或活性的三唑化合物。在某些实施方式中，所述炎症相关疾病是炎性皮肤疾病。在某些实施方式中，所述表达和/或活性被抑制。在另一实施方式中，细胞因子是IL-1和/或IL-12。
发明内容
本发明的一个方面是一种预防或降低哺乳动物内炎症的方法，其包括对哺乳动物施用三唑化合物，其量能有效降低炎症。
本发明的另一方面是治疗与哺乳动物内细胞因子水平提高相关的疾病状态的方法，其包括对需要治疗的哺乳动物施用三唑化合物，其量能够有效地降低对于治疗疾病状态所必需的细胞因子表达和/或活性。在示范性的实施方式中，细胞因子是IL-1。在另一个示范性的实施方式中，细胞因子是IL-12。
本发明的另一方面包括治疗哺乳动物中炎症相关疾病的方法，其包括对所述哺乳动物包括人施用一种药物组合物，所述药物组合物包含一定量的三唑化合物，其能够调节所述哺乳动物中一种或者多种促炎性细胞因子的表达和/或活性。在某些实施方式中，所述炎症相关疾病是炎性皮肤疾病。在另一个实施方式中，细胞因子是IL-1，或者与IL-1具有相同活性的细胞因子。在某些实施方式中，细胞因子是IL-12或与IL-12具有相同活性的细胞因子。通过多种机制可以实现对细胞因子表达和/或活性的抑制和/或阻止，其包括但不限于抑制此类细胞因子的转录、翻译和转导等。
本发明的另一方面是治疗需要治疗的哺乳动物中炎症相关疾病的方法，其包括对哺乳动物施用有效治疗疾病的充分量的三唑化合物。
本发明的另一方面是使用三唑化合物治疗哺乳动物中炎症相关疾病的方法或联合疗法。
本发明的另一方面是包含三唑化合物的组合物，其用于防止或减少哺乳动物中的炎症，或者治疗哺乳动物中与增高水平的IL-1或IL-12相关的疾病。
本发明的另一方面是包含三唑化合物的组合物，其用于防止和/或治疗哺乳动物中炎症相关疾病。
在本发明的一个方面中，所述三唑化合物选自式I，或其药物上可以接受的盐：
式I
其中X是N、O或S，每个R1和每个R3独立地选自C1～8烷基、氨基、烷基氨基、卤素、羟基、烷氧基、芳基、芳氧基、-CF3、-OCF3、-CORa、-COORa、-CONRaRb、-NHCORaRb、-NHSO2Ra、-SO2Ra、-SO3Ra或-SO2NRaRb，其中Ra和Rb独立地是氢、烷基、环烷基、芳基或芳烷基；R2选自H、C1～6烷基和-SO2Ra，且R4选自C1-8烷基，任选地R4被选自氨基、烷基氨基、卤素、羟基、烷氧基、-CF3、-OCF3、-CORa、-COORa和-CONRaRb的至少一种基团所取代。
本发明的另一方面是选自式I的三唑化合物或其药物上可以接受的盐
式I
其中，
X是N、O或S，每个R1和每个R3独立地选自C1～8烷基、氨基、烷基氨基、卤素、羟基、烷氧基、芳基、芳氧基、-CF3、-OCF3、-CORa、-COORa、-CONRaRb、-NHCORaRb、-NHSO2Ra、-SO2Ra、-SO3Ra或-SO2NRaRb，其中Ra和Rb独立地是氢、烷基、环烷基、芳基或芳烷基；R2选自H、C1～6烷基和-SO2Ra，且R4选自C1-8烷基，任选地R4被选自氨基、烷基氨基、卤素、羟基、烷氧基、-CF3、-OCF3、-CORa、-COORa和-CONRaRb的至少一种基团所取代，条件是当没有R1基团、没有R3基团、且R2＝H和R4＝
X＝O或N时。
在示范性的实施方式中，式I的三唑是拉美唑(rambazole的音译)，其具有下列结构：
附图说明
本发明的附图是为了举例说明的目的，并且代表本发明的示范性实施方式。因此，这些附图不能被认为是限制所述发明的范围。
图1显示rambazole(作为示范性的RAMBA)的局部凝胶制剂与安慰剂相比对生物标志物白介素-1α(IL-1)表达的影响。
图2显示与视黄酸对IL-1α表达的影响相比，rambazole对IL-1α表达的影响。
图3显示各种浓度的rambazole对酵母聚糖或19kDa脂蛋白激活的单核细胞培养的影响。这些结果显示通过施用rambazole抑制IL-12。
图4显示各种浓度的rambazole对IFNγ-激活的正常人表皮角质细胞中IP-10表达和分泌的影响。
图5显示在施用口服rambazole的12周定量给药中，炎症损伤频率的结果。
图6显示在施用口服rambazole的16周定量给药中，非炎症损伤频率的结果。
图7显示在为患有中度至严重面部寻常性痤疮的患者口服施用rambazole的16周定量给药中，涉及皮肤视黄酸的副作用的发生。
图8显示在双盲安慰剂对照的研究中，局部rambazole对UVB的影响。
图9显示局部rambazole对患有轻度至中度面部寻常性痤疮的患者的影响。
图10显示在患有寻常性痤疮的志愿者中单次和多次施用局部rambazole和在健康志愿者中口服定量给药之后，rambazole的血浆水平。
图11显示在患有寻常性痤疮的志愿者中单次和多次施用局部rambazole和在健康志愿者中口服定量给药之后，视黄酸的血浆水平。
图12显示rambazole对十二烷基硫酸钠(SLS)所引起的刺激性皮炎的影响，其是通过对发红(12a)、色度(12b)和TEWL(12c)进行视觉评分而测定的。
发明详述
定义
正如这里所定义的，“有效量的”是指充分但无毒量的活性药物用于提供所期望的治疗效果。在本发明的一个方面中，有效量包括降低细胞因子和/或趋化因子表达和/或活性所需要的式I的三唑化合物的量，以便治疗与高水平的细胞因子和/或趋化因子相关的疾病状态。在另一个方面中，靶细胞因子是IL-1或IL-12。
正如这里所定义的，“局部给药”是指直接为个体的皮肤或粘膜施用局部药物或药理活性药物。
正如这里所定义的，“细胞因子”是指由炎性白细胞和一些非白细胞细胞分泌的非抗体蛋白质，其作为炎症的细胞间介质。
正如这里所定义的，“趋化因子”是指促炎性细胞因子类蛋白质，其具有吸引和激活白细胞的能力。根据共有半胱氨酸单元的变化，它们能够被分成至少三种结构分支：c(趋化因子，c)、cc(趋化因子，cc)和cxc(趋化因子，cxc)。
正如这里所定义的，“IL-1(白介素-1)”是指由单核细胞、巨噬细胞或辅助细胞所分泌的可溶性蛋白质(17kDa，152个氨基酸)，其参与激活T淋巴细胞和B淋巴细胞并促进它们与抗原或促分裂原的反应。其生物学作用包括代替T细胞激活所需要的巨噬细胞的能力，以及影响多种其它细胞类型的能力。至少两种IL-1基因是有活性的，并且IL-1的α和β形式可被识别。其在免疫系统应答中早期由单核细胞和巨噬细胞所释放，并且刺激T细胞增殖和蛋白质合成。
正如这里所定义的，“IL-2”(白介素-2)是75kD的异二聚体细胞因子，其由二硫键连接的40kD和35kD亚基构成，其最初是通过其诱导细胞毒性效应细胞的能力而得以鉴定的，其中细胞毒性效应细胞与低于最佳浓度的白介素-2协同发挥作用。其是由巨噬细胞响应于感染所释放的，并且促进细胞介导的免疫作用的激活。特别地，IL-12引发ThI CD4细胞的成熟、特异性的细胞毒性T淋巴细胞应答、以及NK细胞活性的提高，因而IL-12是细胞介导的免疫的引发剂。IL-12增强NK细胞的裂解活性，诱导干扰素的产生，刺激活化的T细胞和NK细胞的增殖，并且是由人类B淋巴样干细胞(NC37)所分泌。IL-12在控制免疫球蛋白同种型分泌中发挥作用，因为它还抑制IgE的合成(即使存在抗IFN单克隆抗体时)，并作为活化的CD4+和CD8+T细胞的生长因子，而不依赖白介素-2，作为CD56+NK细胞的生长因子，而不使得外周血单核细胞休眠，或者使得扁桃体B细胞休眠或激活。从前，IL-12被称作细胞毒性淋巴细胞成熟因子。
本发明被认为包括式I所有化合物的对映体、非对映体和互变异构形式，以及它们的外消旋混合物。另外，式I所表示的某些化合物是药物前体，即发挥作用的药物的衍生物，与发挥作用的药物相比，其具有较好的传输能力以及治疗价值。通过体内酶处理或化学处理，药物前体被转化成活性药物。
正如这里所定义的，除非特别说明，“烷基”是指线性和支链基团，其由最高达到12个碳原子构成，包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、己基、异己基、庚基、辛基、2，2，4-三甲基戊基、壬基、癸基、十一烷基和十二烷基。在示范性的实施方式中，“烷基”是C1-6基团，其包括一个碳单元(即甲基)，最高达到六个碳单元(即己基)。在另一个示范性实施方式中，“烷基”是C1-8基团，其包括一个碳单元(即甲基)，最高达到8个碳单元(即己基)。
正如这里所定义的，术语“氨基”是指NH2。
正如这里所定义的，术语“氨基烷基”是指连接到烷基链上的任一碳原子的至少一个伯氨基团或仲氨基团。
正如这里所定义的，“卤素”是指氟、氯、溴或碘。
正如这里所定义的，“羟基”是指OH。
正如这里所定义的，“烷氧基”是指含有最高达到12个碳原子的直链或支链基团，除非特别说明，其连接到氧原子上。例子包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基。
正如这里所定义的，“芳基”是指单环或双环芳香环系统，其环中含有6～12个碳，并任选地，被1～3个取代基所取代，其中所述取代基选自烷氧基、烷基、卤素和羟基。例子包括苯基、联苯基和萘。
正如这里所定义的，术语“芳氧基”是指连接到氧原子的芳基。例子是苯氧基。
正如这里所定义的，术语“芳烷基”是指含有芳基取代基的C1～6烷基。例子包括苄基、苯乙基或2-萘甲基。
正如这里所定义的，术语“环烷基”是指由3～8个碳原子构成的环。烷基取代基可任选地出现在环上。例子包括环丙基、1，1-二甲基环丁基、1，2，3-三甲基环戊基和环己基。
除非特殊说明，所有其他描述或者化学功能基团的列举均是为了具有本领域技术人员最通常赋予的意义。
在本发明的一个方面中，本发明的三唑化合物可以与治疗性唑结合使用，所述治疗性唑例如但不限于酮康唑、伊曲康唑、唑啉、咪康唑、甲硝唑、利阿唑、苯并咪唑、苯并噻唑、联苯苄唑、硝酸丁康唑、氯咪巴唑、克霉唑、氯康唑、依柏康唑、益康唑、酮康唑、芬替康唑、氟康唑、氟地咪唑(flutimazole)、异康唑、拉诺康唑、萘替康唑、奥莫康唑、硝酸奥昔康唑、舍他康唑、硝酸硫康唑、噻康唑、噻唑、特康唑和伊曲康唑。
炎症相关的疾病状态包括但不限于与炎症细胞因子和/或趋化因子的增高表达相关的疾病，例如炎性皮肤疾病、关节炎、毒性休克综合征、糖尿病和炎性肠病。炎性皮肤疾病包括但不限于特应性皮炎、接触性皮炎、脂溢性皮炎、酒渣鼻、湿疹、牛皮癣、痤疮和荨麻疹。牛皮癣包括但不限于斑块状牛皮癣(寻常型牛皮癣或慢性斑块状牛皮癣)。关节炎包括但不限于类风湿性关节炎、牛皮癣关节炎、骨关节炎、痛风、狼疮和纤维肌痛。糖尿病包括但不限于II型糖尿病。炎性肠病包括但不限于克罗恩病。
如图2所述，出乎预料地观察到rambazole降低IL-1的表达。相反，之前已经显示视昔酸提高IL-1在人表皮中的表达(Bernard等人，Exp Dermatol.11(1)，59-74(2002))。因此，施用视黄酸(以含有霜剂Retacnyl的商业化维A酸的形式)以及可能其它的类维生素A会导致炎症增强，而施用本发明的三唑化合物则会导致炎症降低。同样出乎预料地，rambazole治疗的损伤(例如牛皮癣损伤)在不连续治疗后持续改善并显示降低的炎症特征至少3个月。而且，与类维生素A如异维A酸不同，rambazole治疗的炎症损伤在治疗的头4周内快速反应。这一发现支持了除了对增殖和分化的典型影响外，还有rambazole的抗炎症功能。
本发明的用于治疗目的组合物和方法可以在体内应用，通常在哺乳动物中，例如人、羊、马、牛、猪、狗、猫、大鼠和小鼠，或者在体外应用。本发明用于治疗人类受试者是特别有用的。
用于局部施用三唑化合物的适当药物制剂包括例如药膏、油膏、霜剂、凝胶、洗液、敷料剂、洗发精、酊剂、糊剂和粉末。本发明组合物的施用也可以是通过气雾剂，例如使用推进剂如氮气、二氧化碳、氟里昂，或者不使用推进剂如泵式喷雾、滴液、洗液或半固体如可以通过药签施用的增稠组合物。另外，三唑组合物也可以作为透皮贴剂。
其他适当的制剂包括花露水、膏药(packs)、美容涂敷剂、乳液或牛奶洗液。这些制剂通常包括治疗上无活性的组分如油、脂肪、蜡、表面活性剂、湿润剂、增稠剂、抗氧化剂、粘性稳定剂、螯合剂、缓冲剂、防腐剂、香料、染料、低级醇等。如果期望，可以在本发明的组合物中加入其他成分例如抗炎药物、杀菌剂、抗真菌剂、消毒剂、维生素、遮光剂、抗生素或抗痤疮药物。
本发明的药物组合物还可以任选地包括其他载体、稳定剂、防腐剂或佐剂。对于这些化合物类型的典型例子，参见Remington：The Science andPractice of Pharmacy.Lippincott，Williams&Wilkins(2005)，此处通过参考将其全文引入。
在一个示范性的实施方式中，可将所述三唑化合物配制成凝胶。在另一个实施方式中，凝胶是无水凝胶。凝胶可以包含醇和多元醇。适当的醇包括但不限于甲醇、乙醇、丙醇、异丙醇、异丁醇或其组合。适当的多元醇包括但不限于聚乙二醇、聚丙二醇、乙二醇、糖或其组合。所述醇的量可以为大约5-70％的重量百分数，例如大约10-50％的重量百分数。类似地，多元醇的量可以为大约15-80％的重量百分数，例如大约25-65％的重量百分数。在一个示范性的实施方式中，所述三唑化合物被配制为口服凝胶，而不是局部凝胶。在一个示范性实施方式中，口服凝胶制剂含有与聚乙二醇400组合的0.20mg或0.5mg或0.75mg或1.0mg或1.5mg或2.0mgrambazole。在某些实施方式中，所述口服凝胶制剂可以是软凝胶胶囊的形式。
在组合治疗组合物或单独给药中的三唑化合物的有效量在大约0.01-25％的重量百分比范围内。适当的是单独或在组合治疗中在一天中以适当的间隔，每日施用1次、2次、3次、4次或更多次亚剂量的三唑化合物。亚剂量可以被配制成单元剂型，例如每单元剂型含有0.001mg～500mg活性成分。
还可以通过口服施用三唑化合物。对于口服施用，可以通过将它们与本领域公知的药物上可以接受的载体进行组合而容易配制三唑。这些使得本发明的化合物能够被配制成药品、药丸、糖衣丸、胶囊、液体、凝胶、糖浆剂、膏剂、悬液等，用于由所治疗的患者进行口服摄入。可以通过将三唑化合物与固体赋形剂进行组合获得口服应用的药物制剂，可任选地将所得到的混合物进行研磨，并处理所得到的颗粒混合物，如果期望，可以加入适当的辅助材料，以得到药片或糖衣丸核心。适当的赋形剂包括例如填充剂如糖包括乳糖、蔗糖、甘露醇或山梨醇；纤维素制剂例如玉米淀粉、小麦淀粉、米淀粉、马铃薯淀粉、明胶、黄蓍树胶、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠和聚乙烯吡咯烷酮(PVP)。如果期望，可以加入分解剂，例如交联的聚乙烯吡咯烷酮、琼脂、海藻酸或其盐，如海藻酸钠。
三唑化合物的药物上可以接受的盐类包括从无机或有机酸或碱形成的常规的无毒盐或季铵盐。这些酸加成盐的例子包括乙酸盐、己二酸盐、苯甲酸盐、苯磺酸盐、柠檬酸盐、樟脑酸盐、十二烷基硫酸盐、盐酸盐、氢溴酸盐、乳酸盐、马来酸盐、甲烷磺酸盐、硝酸盐、草酸盐、特戊酸盐、丙酸盐、琥珀酸盐、硫酸盐和酒石酸盐。碱盐包括铵盐、碱金属盐如钠盐和钾盐、碱土金属盐如钙盐和镁盐，有机碱盐如二环己胺盐和氨基酸盐如精氨酸盐。碱性的含氮基团也可以用例如卤烃类将其季铵化。
在式I的三唑化合物中，可以没有R1基团，或者1个R1基团，或者2个独立选择的R1基团或者3个独立选择的R1基团，或者4个独立选择的R1基团。
在式I的三唑化合物中，可以没有R3基团，或者1个R3基团，或者2个独立选择的R3基团或者3个独立选择的R3基团，或者4个独立选择的R3基团。
在式I的三唑化合物中，可以没有R3基团，或者1个R3基团，或者2个独立选择的R3基团或者3个独立选择的R3基团，或者4个独立选择的R3基团。
正如本领域技术人员所熟知的，三唑化合物的精确剂量、给药频率和持续时间依赖所使用的具体唑，所治疗的具体疾病状态，被治疗疾病的严重程度，具体患者的年龄、体重和整体身体状况、以及患者所采用的的其他药物。而且，明显的是联合治疗给药的有效频率可以根据被治疗的患者的反应和/或根据开出此所使用的治疗性药物的医生的评估而降低或提高。
三唑化合物可以和其他治疗药物结合使用，例如但不限于抗炎药物(例如布洛芬、非诺洛芬、酮基布洛芬、萘普生、双氯芬酸、依托度酸、甲氯芬钠酸钠、保泰松、消炎痛、吡罗昔康、舒林酸和托美汀)、抗增殖药物(例如吗替麦考酚酯和吴茱萸碱)、抗痤疮药物(例如维A酸、异维A酸、水杨酸、过氧化苯甲酰和壬二酸)、止痒剂(例如氮卓斯丁、西替立嗪、苄氯菊酯和林丹)、防衰老药物及其组合。
不需要进一步描述，相信本领域技术人员通过上面的描述和后面的说明性实施例能够制造和利用本发明的化合物并实施所请求保护的方法。后面的实施例描述了本发明的实施方式，并不能解释为以任何方式限制所公开的其余内容。
实施例
实施例1：使用rambazole治疗牛皮癣
17名牛皮癣面积和严重程度指数(PASI)评分为至少5(中度至严重的斑块状牛皮癣)的患者每日接受口服剂量为1mg的rambazole。PASI评分的评估是在治疗1、2、4和8周后，以及两周的追踪期结束时进行的监测。整体上，对完成8周治疗的受试者的PASI评分的平均降低为51.4％。副作用倾向于轻微到中等，并且治疗似乎是良好耐受的。提取来自损伤的活体样品，并分析表面标志物。参见表2。
实施例2：使用口服rambazole治疗寻常性痤疮
16位患有中度至严重面部寻常性痤疮的患者接受每日口服剂量为1mg的rambazole，持续12周。如表1所示，研究中的所有的患者(100％)在治疗12周后炎症损伤的降低等于或高于50％。平均损伤降低为79％。其他的个人数据参见表3至表7。图5和6分别为炎症损伤治疗与非炎症损伤对治疗应答的比较。没有报道严重的副作用。参见图7
表1：rambazole治疗达到了炎症损伤的降低50％以上
| 4周 | 8周 | 12周 | 16周(追踪) | |
| 受试者数目 | 16 | 16 | 16 | 16 |
| 应答者数目 | 5 | 9 | 16 | 14 |
| 应答者百分比 | 31％ | 56％ | 100％ | 88％ |
实施例3：使用局部rambazole治疗寻常性痤疮
患有轻微至中度寻常性痤疮的50位患者接受每日0.35％rambazole的局部剂量持续12周。如图9(a)所示，在治疗12周后，研究中的患者在整体评估评分具有大约40％的降低。图9(b)显示rambazole和载体(即所测试rambazole制剂的赋形剂组分)成功率的比较。图9(c)显示rambazole和载体之间炎症损伤的降低的比较。
实施例4：局部0.35％rambazole对UVB的影响
在双盲、安慰剂对照的研究中，将局部0.35％rambazole施用到志愿者的皮肤上9天，接着使用UVB诱导炎症5天。在该研究中，将阿达帕林用作标准的抗炎药物。色谱所评估的结果显示没有光毒性的症状。参见图8。
实施例5：局部0.35％rambazole对刺激性皮炎的影响
在4天内施用0.35％rambazole凝胶作为预处理。通过在两小时内向12位健康志愿者手臂上的环内施用2％的SLS来诱导炎症，每日一次持续5天。在诱导炎症的5天内，施用0.35％rambazole凝胶。在每次施用SLS之后24小时，和最后一次施用SLS之后72小时对未处理和rambazole凝胶处理的皮肤位置的皮肤反应进行检验(发红的视觉评分，色谱，TEWL)。图12(a)-(c)所示出的结果显示rambazole凝胶抑制由施用SLS所诱导的炎症反应。
实施例6：rambazole对白介素12分泌水平的影响
通过在Ficoll-Hypaque Plus上进行密度梯度离心从健康供体分离外周血单核细胞(PBMC)，并通过粘附选择单核细胞。在补充有刺激性FBS的RPMI1640中过夜培养后，使用Zymosan或19kDa脂蛋白激活单核细胞18小时，并通过ELISA检测上清中的IL-12p40。图3中所示的结果显示rambazole剂量依赖性地抑制IL-12分泌。
实施例7：rambazole对IP-10分泌的影响
将第4代的正常人表皮角质细胞以2,000细胞/孔接种在低钙离子KSFM中。培养3天后，达到60％的汇合，除去培养液，并使用50U/mL IFNγ对细胞进行刺激，与10-5M～3x10-8M的rambazole进行孵育18个小时。使用IP-10夹心型ELISA测定培养液中的干扰素诱导蛋白(IP-10)表达，并根据细胞数进行校正。将数值表示为相对于药物溶剂对照的平均百分比±SD(n＝4)。图4所示的结果显示rambazole剂量依赖性地下调IP-10的表达和分泌。
实施例8：rambazole对IL-1在健康志愿者皮肤中表达的影响
在该随机、双盲、左右、安慰剂对照的试验中，在每日一次在未受损皮肤施用两种不同浓度的rambazole(0.35％或0.07)之后，对15个健康受试者的皮肤中白介素-1(IL-1)的表达进行评估。使用实时PCR分析IL-1生物标志物。观察到使用rambazole的治疗剂量依赖性地降低IL-1表达。参见图1。在9天的治疗中，除了一个受试者报告在使用0.35％rambazole治疗8天后的一天内有轻微的发痒外，没有出现发痒、刺激、灼烧或起泡。
除非特别说明，这里的所有技术和科学术语具有本发明所属技术领域技术人员通常理解的相同含义。尽管在本发明的实施和测试中可以使用任何与这里所述的方法和材料类似的或等同的方法和材料，但这里描述的是优选的方法和材料。将所有提到的专利、其他出版物和专利申请通过参考并入此处。
Claims (18)
1.选自式I的三唑化合物或其药物上可接受的盐在制备减少或预防哺乳动物中炎症的药物中的用途，其包括为哺乳动物施用降低炎症有效量的选自式I的三唑化合物或其药物上可接受的盐，其中所述三唑化合物为：
式I。
2.根据权利要求1所述的用途，其中所述炎症是由选自炎性皮肤病、关节炎、中毒性休克综合征、糖尿病和炎性肠病的疾病状态所造成的。
3.根据权利要求2所述的用途，其中所述炎性皮肤病选自特应性皮炎、接触性皮炎、脂溢性皮炎、酒渣鼻、湿疹、牛皮癣、痤疮和荨麻疹。
4.根据权利要求2所述的用途，其中所述关节炎选自类风湿性关节炎、牛皮癣关节炎、骨关节炎、痛风、狼疮和纤维肌痛。
5.根据权利要求2所述的用途，其中所述炎性肠病是克罗恩病。
6.根据权利要求2所述的用途，其中所述糖尿病是II型糖尿病。
7.根据权利要求1所述的用途，其中将所述三唑化合物口服给药或局部给药。
8.根据权利要求7所述的用途，其中将所述三唑化合物口服给药。
9.根据权利要求8所述的用途，其中所述三唑化合物的给药量在每日0.05mg～1g范围内。
10.根据权利要求9所述的用途，其中所述范围为每日0.5mg～500mg。
11.根据权利要求10所述的用途，其中所述范围为每日1mg～300mg。
12.根据权利要求7所述的用途，其中将所述三唑化合物局部给药。
13.根据权利要求12所述的用途，其中所述三唑化合物的给药浓度在0.02％～1％的范围内。
14.根据权利要求13所述的用途，其中所述三唑化合物的给药浓度在0.05％～0.80％的范围内。
15.根据权利要求14所述的用途，其中所述三唑化合物的给药浓度是0.07％。
16.根据权利要求14所述的用途，其中所述三唑化合物的给药浓度是0.35％。
17.根据权利要求1所述的用途，其中所述哺乳动物是人。
18.根据权利要求1所述的用途，其中所述有效量是降低IL-1表达和/或活性所必需的三唑化合物的量。
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| GB0811091D0 (en) * | 2008-06-17 | 2008-07-23 | Cancer Rec Tech Ltd | CYP26 Inhibitors |
| PL2730564T3 (pl) | 2010-11-19 | 2018-09-28 | Ligand Pharmaceuticals Inc. | Heterocykliczne aminy i ich zastosowania |
| US9144538B2 (en) | 2013-02-08 | 2015-09-29 | The Procter & Gamble Company | Cosmetic compositions containing substituted azole and methods for alleviating the signs of photoaged skin |
| US9138393B2 (en) | 2013-02-08 | 2015-09-22 | The Procter & Gamble Company | Cosmetic compositions containing substituted azole and methods for improving the appearance of aging skin |
| US10807983B2 (en) | 2015-03-16 | 2020-10-20 | Ligand Pharmaceuticals, Inc. | Imidazo-fused heterocycles and uses thereof |
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| US6124330A (en) * | 1996-06-27 | 2000-09-26 | Janssen-Cilag S.A. | N-[4-(Heteroarylmethyl)phenyl]-heteroarylamines |
| CN1272493A (zh) * | 1999-04-15 | 2000-11-08 | 阿迪尔公司 | 新的氨基三唑化合物,其制备方法及包含它们的药物组合物 |
| US6787555B2 (en) * | 2001-04-30 | 2004-09-07 | The Procter & Gamble Company | Triazole compounds useful in treating diseases associated with unwanted cytokine activity |
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| FR2609026B1 (fr) * | 1986-12-31 | 1989-03-31 | Cird | Amides de l'acide eicosatetraynoique et leur application en pharmacie et en cosmetique |
| GB9506188D0 (en) * | 1995-03-27 | 1995-05-17 | Fujisawa Pharmaceutical Co | Amidine derivatives |
| DE69827295T2 (de) | 1997-12-19 | 2006-02-09 | Janssen Pharmaceutica N.V. | Kombination von einem den retinoinsäure metabolismus blockierenden arzneimittel und einem tocopherol |
| GB9919413D0 (en) * | 1999-08-18 | 1999-10-20 | Zeneca Ltd | Chemical compounds |
| US7582670B2 (en) * | 2001-12-13 | 2009-09-01 | Natrogen Therapeutics, Inc. | Methods of treating an inflammatory-related disease |
| DE10337942A1 (de) * | 2003-08-18 | 2005-03-17 | Merck Patent Gmbh | Aminobenzimidazolderivate |
| AU2004287281A1 (en) * | 2003-11-11 | 2005-05-19 | Veckis Industries Ltd. | Disinfecting composition and methods of making and using same |
| US7659284B2 (en) * | 2004-09-15 | 2010-02-09 | Janssen Pharmaceutica Nv | Thiazolopyridine kinase inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6124330A (en) * | 1996-06-27 | 2000-09-26 | Janssen-Cilag S.A. | N-[4-(Heteroarylmethyl)phenyl]-heteroarylamines |
| CN1272493A (zh) * | 1999-04-15 | 2000-11-08 | 阿迪尔公司 | 新的氨基三唑化合物,其制备方法及包含它们的药物组合物 |
| US6787555B2 (en) * | 2001-04-30 | 2004-09-07 | The Procter & Gamble Company | Triazole compounds useful in treating diseases associated with unwanted cytokine activity |
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| HK1129275A1 (en) | 2009-12-18 |
| EP1981343A2 (en) | 2008-10-22 |
| US20090298897A1 (en) | 2009-12-03 |
| EP1981343B1 (en) | 2015-05-13 |
| EP1981343B8 (en) | 2015-06-24 |
| JP5685364B2 (ja) | 2015-03-18 |
| AU2007207607B2 (en) | 2012-04-19 |
| WO2007084542A2 (en) | 2007-07-26 |
| CA2637590C (en) | 2014-03-18 |
| CA2637590A1 (en) | 2007-07-26 |
| EP1981343A4 (en) | 2010-12-15 |
| WO2007084542A3 (en) | 2007-11-29 |
| MX2008009215A (es) | 2008-12-10 |
| AU2007207607A1 (en) | 2007-07-26 |
| JP2009523803A (ja) | 2009-06-25 |
| CN101400261A (zh) | 2009-04-01 |
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