CN110105200A - 用于治疗纤维化的经取代的芳族化合物及相关方法 - Google Patents
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Abstract
本发明涉及如下化合物,或其药学上可接受的盐,和包含其的组合物以及使用其用于预防或治疗受试者的各种纤维化疾病及病状,包括肺纤维化、肝纤维化、皮肤纤维化、肾纤维化、胰腺纤维化、全身性硬化、心脏纤维化或黄斑变性的方法,其中A为C5烷基、C6烷基、C5烯基、C6烯基、C(O)‑(CH2)n‑CH3或CH(OH)‑(CH2)n‑CH3,其中n为3或4;R1为H、F或OH;R2为C5烷基、C6烷基、C5烯基、C6烯基、C(O)‑(CH2)n‑CH3或CH(OH)‑(CH2)n‑CH3,其中n为3或4;R3为H、F、OH或CH2Ph;R4为H、F或OH;Q为1)(CH2)mC(O)OH,其中m为1或2,2)CH(CH3)C(O)OH,3)C(CH3)2C(O)OH,4)CH(F)‑C(O)OH,5)CF2‑C(O)OH,或6)C(O)‑C(O)OH。
Description
本申请是申请日为2014年3月14日、申请号为201480013578.9、发明名称为“用于治疗纤维化的经取代的芳族化合物及相关方法”的中国发明专利申请的分案申请。
发明领域
本发明涉及经取代的芳族化合物、其制备、包含其的组合物以及使用其用于预防或治疗受试者的各种纤维化疾病及病状,包括肺纤维化、肝纤维化、皮肤纤维化、肾纤维化、胰腺纤维化、全身性硬化、心脏纤维化或黄斑变性的方法。
发明背景
纤维化
纤维化为特征在于细胞外基质(ECM)过度积聚从而导致所涉及组织变硬和/或瘢痕形成的慢性和进行性过程。其经由复杂细胞、细胞外基质、细胞因子和生长因子相互作用而发展。涉及到不同的细胞类型,诸如常驻间质细胞(纤维母细胞和肌纤维母细胞)及源自上皮和内皮细胞的ECM产生细胞(经由称为上皮-间质转化及内皮-间质转化的过程)、局部或骨髓源干细胞(纤维细胞)。肌纤维母细胞长久以来已被视为正常伤口愈合中所涉及的主要细胞类型,且作为纤维生成的关键效应细胞。其可高度合成胶原和其他ECM组分,且特征为α-平滑肌肌动蛋白(α-SMA)的重新表现(于Scotton C.J.和Chambers R.C.,2007中评述)。纤维化动物模型中的纤维化损伤中肌纤维母细胞的存在与活性纤维化的发展有关,且其持续存在及对于人类疾病中纤维化位点的定位与疾病进展有关(Kuhn C.及McDonaldJ.A.,1991;及Zhang等人,1994)。肌纤维母细胞也展现增强的迁移表型(Suganuma等人,1995)且能够释放众多促纤维化介体。
纤维化疾病
纤维化疾病,包括肺纤维化、全身性硬化、肝硬化、心血管疾病、进行性肾脏疾病及黄斑变性,为发病率和死亡率的首要原因且可影响所有组织及器官系统。纤维化组织重塑也可影响癌症转移且于移植受者中加速慢性移植排斥反应。具有多个/单个器官表现的原发性(特发性)和继发性纤维化病症的实例列于表1中。然而,尽管其对人类健康影响巨大,但目前尚未批准有直接针对纤维化机制的治疗。
表1:具有多个/单个器官表现的原发性(特发性)和继发性纤维化病症的实例
改编自Vettori S,Gay S,Distler O.Role of MicroRNAs in Fibrosis,TheOpen Rheumatology Journal,2012,6,(增刊1:M9)130-139。
肺纤维化
肺纤维化(也称为肺部纤维化(pulmonary fibrosis))为一种涉及肺组织瘢痕形成的严重医学病状。当肺泡和肺间质组织发炎且在组织上形成瘢痕以试图自我修复时,出现此病状。肺纤维化涉及正常肺实质与纤维化组织(纤维瘢痕)的逐渐交换。正常的肺经瘢痕组织置换造成氧扩散能力不可逆地下降。目前,尚未有可逆转肺组织的此瘢痕形成的治疗措施或手段。
可以造成肺纤维化的许多病状包括慢性炎性过程(结节病、韦格纳氏肉芽肿病(Wegener's granulomatosis))、感染、环境剂(石棉、二氧化硅、暴露于某些气体)、暴露于电离辐射(诸如治疗胸部肿瘤的辐射疗法)、慢性病状(狼疮),以及某些药物治疗(例如胺碘酮(amiodarone)、博莱霉素(bleomycin)、平阳霉素(pingyangmycin)、白消安(busulfan)、甲氨喋呤(methotrexate)和呋喃妥因(nitrofurantoin))。
在称为过敏性肺炎的病状中,针对吸入有机粉尘或职业化学物质的免疫反应提高后可形成肺的纤维化。此病状最通常起因于吸入受细菌、真菌或动物产品污染的粉尘。
在一些受试者中,在无可鉴别原因的情况下形成慢性肺部炎症和纤维化。大部分这些受试者具有称为特发性肺纤维化(IPF)的病状。IPF为一种病因不明的慢性进行性肺纤维化。泼尼松(prednisone)为IPF的常用治疗,但其可用目标在于减少作为肺纤维化前奏的炎症的其他免疫抑制疗法来治疗。尽管泼尼松对改善肺功能具有适度可测量的作用,但对于其长期功效的证据缺乏以及关于其安全性的担忧限制了其使用。实际上大部分免疫抑制药物很少有治疗作用并且肺移植可能为必要的。遗憾的是,末期肺病患者中的移植成功率有限且患者的中位存活时间为诊断后四至六年。因而,需要新颖但有效的IPF治疗。
关于特异性处理肺中纤维化的抑制或减缓的候选药物(诸如干扰素-γ(IFN-γ)及吗替麦考酚酯(mycophenolate mofetil))的一些临床试验正在进行中。其他实例包括:吡非尼酮,其作用机制并不明确,但似乎减少CTGF且已在临床阶段中显示一些成果;经取代的联苯羧酸,其充当溶血磷脂酸受体拮抗剂且在标准肺纤维化小鼠模型(博莱霉素诱发的肺纤维化)中显示显著的抗纤维化活性。因而,据报导此化合物正处于IPF治疗的临床试验中。用口服活性候选药物抑制蛋白激酶或用口服活性抗氧化剂进行治疗提供两种对于肺纤维化的治疗方法:多重受体酪氨酸激酶抑制剂(诸如尼达尼布(nintedanib))及JNK(激酶)抑制剂(诸如坦兹替布(tanzisertib))。此外,IPF候选药物包括抗氧化剂N-乙酰基半胱氨酸。然而,迄今为止,由于毒性和/或功效问题,蛋白激酶抑制剂和抗氧化剂的发展对于治疗IPF一直是值得商榷的。在正常和病变细胞群体中普通存在蛋白激酶及相关受体,因此特别在迅速增殖的细胞群体中抑制作用会导致产生毒性。
另外,关于靶向用于治疗IPF的不同促纤维化蛋白(细胞因子(CTGF、TGF-β、MCP-1、IL-4及IL-13)、整合素(αvβ6)和酶(赖氨酰氧化酶样2)的单克隆抗体的临床试验正在进行中。然而,许多相关问题与用于治疗IPF的单克隆抗体(其应用于其他重组蛋白)的发展和使用相关,包括毒性(包括蛋白免疫原性)、制造难度(批次一致性、扩大规模、费用)和施用难度(需要冷藏,而非口服活性)。
此外,虽然研究试验正在进行,但无证据表明任何药物治疗可显著有助于此病状。肺移植为重度情况下唯一可用的治疗选择。遗憾的是,末期肺病患者中的移植成功率有限。因而,需要新颖但有效的IPF治疗。因此,需要新颖但方便施用(口服活性)的有效的合成(容易制造)化合物。
肝纤维化
肝纤维化(Liver fibrosis或hepatic fibrosis))为细胞外基质蛋白(包括胶原)的过度积聚以及后续瘢痕形成过程,其发生于大多数慢性肝病中。随着时间推移,晚期肝纤维化导致肝硬化。肝硬化为慢性肝病的最终阶段并且一般长期预后不良且不可逆。在晚期阶段,唯一选择为肝移植。肝硬化所伴随的肝癌风险显著增加且肝硬化可视为癌前病状(肝细胞癌)。实际上,肝硬化及肝癌皆属于全世界范围内前十大死亡原因。因而,需要新颖但有效的对肝纤维化和后续肝硬化的治疗。遗憾的是,可用治疗选择很少且最通常治疗由处理肝硬化的病因和/或症状组成。尚无治疗可治愈肝纤维化后续的瘢痕形成和肝硬化。肝移植为晚期纤维化患者唯一可用的治疗。因此,需要侵入性较小的替代性方法来治愈肝纤维化、治疗肝纤维化、减缓肝纤维化的进展或预防肝纤维化。
腹部流体(腹水)积聚为与肝硬化相关的常见问题。治疗选择包括低钠饮食、利尿剂以及通过插入针于腹腔(穿刺术)中来移除流体。肝硬化由酒精滥用、病毒性肝炎(B、C和D)、与肥胖症相关的非酒精性脂肪肝病(NAFLD)、糖尿病、蛋白质营养不良、冠状动脉疾病、皮质类固醇、自身免疫性肝炎、遗传性疾病(囊性纤维化、α-1-抗胰蛋白酶缺乏症等)、原发性胆汁性肝硬化、药物反应及暴露于毒素引起。
关于特异性处理肝纤维化的抑制或减缓的候选药物的有限数目的临床试验正在进行中。然而,这些试验针对特定肝病,诸如NASH(非酒精性脂肪肝炎)。NASH是指脂肪肝(NAFLD)与炎症的组合且发生于饮酒很少或不饮酒的受试者中。半胱胺为有效的肝抗氧化剂谷胱甘肽的前驱体且据信谷胱甘肽的体内产生增加提供NASH相关肝病的改善。因而,半胱胺正在NASH儿童患者中进行临床试验评估。其他抗氧化剂诸如维生素E和硒正在进行评估,但其用于治疗NASH的效用是未知的。此外,处于NASH治疗评估中的是甚至在不具有糖尿病的患者中使用抗糖尿病药物。此方法处理了大多数NASH患者具有胰岛素抗性的事实。再次,需要新颖但方便施用(口服活性)的用于治疗肝纤维化、后续瘢痕形成及肝硬化的有效化合物。
皮肤纤维化
皮肤纤维化(skin fibrosis或dermal fibrosis)为皮肤的过度瘢痕形成,且为病理性伤口愈合反应的结果。存在广泛多种纤维化皮肤疾病:硬皮病、肾源性纤维化皮肤病、混合性结缔组织疾病、硬化性黏液水肿、硬肿病和嗜酸性筋膜炎。暴露于化学物质或物理因素(机械创伤、烧伤创面)也为纤维化皮肤疾病的潜在原因。皮肤纤维化可由免疫、自身免疫性和炎症机制驱动。胶原产生与由纤维母细胞降解的平衡在皮肤中的纤维化过程的病理生理学中起关键作用。某些细胞因子促进伤口愈合和纤维化,诸如转化生长因子-β(TGF-β)和白介素-4(IL-4),而其他细胞因子抗纤维化,诸如干扰素-γ(IFN-γ)和肿瘤坏死因子-α(TNF-α)。正常皮肤的纤维母细胞处于静止状态。其合成受控量的结缔组织蛋白且具有低增殖活性。在皮肤损伤后,这些细胞变得活化,即其增殖、表达α-平滑肌肌动蛋白(α-SMA)且合成大量结缔组织蛋白。这些活化细胞通常称为肌纤维母细胞。
在皮肤纤维化期间,从美容观点来看,作为伤口愈合过程的一部分且伴随着纤维化的瘢痕形成为特别不合需要的,尤其当瘢痕形成于面部和/或身体的其他暴露部分上时。硬皮病(scleroderma)是指皮肤纤维化;sclera表示硬且derma表示皮肤。然而,皮肤纤维化可能具有重要的健康问题,尤其当其为全身性硬皮病的一部分时。全身性硬皮病是指具有自身免疫性病因的结缔组织疾病。局限皮肤型硬皮病受限于面部上和足部上的皮肤,而弥漫皮肤型硬皮病覆盖更多皮肤且可发展至内脏器官。
用于治疗皮肤纤维化的最流行的方法为使用免疫抑制疗法。基本原理在于,自身免疫性病因造成疾病的炎症方面以及后续组织损伤和纤维化。所研究的药物包括甲胺喋呤、吗替麦考酚酯、环磷酰胺和环孢菌素。尽管已观察到免疫抑制疗法的一些改进,但关于药物安全性的担忧以及确定的临床数据和可证实的功效的缺乏仍然存在。
需要开发用于治疗皮肤纤维化、纤维化皮肤疾病和皮肤的病理性瘢痕形成的有效药物制剂。
肾纤维化
肾为一种结构复杂的器官,其已进化为执行许多重要功能:排泄代谢废物、调节身体水分和盐分、维持适当的酸平衡,以及分泌多种激素和内分泌物。肾脏疾病与其结构一样复杂,但可通过按照其对四个基本形态组成部分:肾小球、肾小管、间质和血管的作用对它们分类来促进其研究。遗憾的是,一些病症会影响一个以上的结构且肾脏结构的解剖学相互依赖性意味着对一个结构的损伤几乎总是继发性影响其他结构。因此,无论起源如何,存在所有形式的肾病最后皆破坏肾脏的所有四个组成部分且最终导致慢性肾衰竭的倾向。例如,在诸如糖尿病的自身免疫性疾病中,肾脏为遭受组织损伤或病变的首要目标。肾切除或肾移除为有时对肾癌(例如肾细胞癌)患者实施的程序且可能对剩余肾脏的肾功能产生不利影响。化学疗法和免疫抑制疗法也为有害影响肾脏的来源。所有这些肾损伤在大多数情况下皆导致肾纤维化。术语“肾纤维化”意指细胞过度增殖、组织硬化和瘢痕形成。肾纤维化也可由肾衰竭后的透析和导管置放引起,例如,腹膜和血管通路纤维化。肾纤维化也可由诸如肾小球疾病(例如肾小球硬化、肾小球肾炎)、慢性肾功能不全、急性肾损伤、末期肾病和肾衰竭的肾病引起。无论病因如何,所有的慢性肾病患者皆显示肾功能随时间进行性下降。纤维化(所谓的瘢痕形成)为此病理生理学的关键原因。纤维化涉及细胞外基质(主要由胶原组成)过度积聚且当正常组织经瘢痕组织置换时通常导致功能损失。该过程在很大程度上不可逆,不可避免地导致末期肾衰竭,其为需要终身透析或肾移植的病状。近来的重大进展已导致对肾纤维化(或肾小管间质纤维化)更好的理解,但仍存在许多问题。对于为何一些伤口愈合而其他伤口形成瘢痕知之甚少,以及有多少假定的抗纤维化剂起作用也知之甚少。
需要开发用于治疗肾纤维化的有效药物制剂。
心脏纤维化
心脏纤维化(心脏疾病的标志)被认为促进心脏性猝死、心室性心动过速、左心室(LV)功能障碍和心脏衰竭。心脏纤维化的特征在于心肌细胞死亡后发生的原纤化胶原的不相称积聚、炎症、工作负荷增强、肥厚,以及受多种激素、细胞因子和生长因子的刺激。
心脏纤维化也可指心脏瓣膜由于心脏纤维母细胞的不当增殖而引起的异常增厚,但更通常指心肌中纤维母细胞的增殖。纤维细胞通常分泌胶原,且用于对心脏提供结构支撑。当过度活化时,此过程造成瓣膜增厚和纤维化,其中白色组织主要聚集于三尖瓣上,但也存在于肺动脉瓣上。增厚和柔性损失最终可导致瓣膜功能不全和右侧心脏衰竭。
用于心脏瓣膜纤维化或其他部位纤维化的最明显治疗由停用刺激性药物或产生血清素组成。在一些患者中有必要为严重狭窄(阻塞血流)进行手术三尖瓣置换。此外,已发现红葡萄酒中存在的化合物白藜芦醇(resveratrol)可减缓心脏纤维化的发展。[Olson等人,(2005)“Inhibition of cardiac fibroblast proliferation and myofibroblastdifferentiation by resveratrol”.American journal of physiology.Heart andcirculatory physiology 288(3):H1131-8;Aubin等人,(2008)“Female rats fed ahigh-fat diet were associated with vascular dysfunction and cardiac fibrosisin the absence of overt obesity and hyperlipidemia:Therapeutic potential ofresveratrol”.The Journal of Pharmacology and Experimental Therapeutics 325(3):961-8。]正在于动物模型中测试抵抗心脏纤维化的更先进方法如微RNA抑制(例如miR-21)。
市面上不存在用于预防或治疗心脏纤维化的药物且需要开发有效的药物制剂。
胰腺纤维化
慢性胰腺炎(CP)为进行性胰腺发炎疾病,其特征为不可逆的形态变化和腺体的逐渐纤维化置换。外分泌和内分泌功能损失由实质性纤维化引起。CP的主要症状为腹痛及消化不良。胰腺大概有可能增大或萎缩,存在或不存在囊肿或钙化或肿瘤。导管可能扩张、不规则或狭窄。基本病理特征包括腺泡组织的不规则和片状损失、慢性炎症、导管变化和纤维化。这些总体变化为与以下相关的复杂致病机制的最终表现:基因突变(包括但不限于囊性纤维化、阳离子胰蛋白酶原基因、特发性急性和慢性胰腺炎中的CFTR基因突变、胰腺分泌型胰蛋白酶抑制剂基因、胰凝乳蛋白酶原C基因和钙敏感受体基因、α-1抗胰蛋白酶缺乏症)、代谢性(酒精、吸烟、高钙血症、高脂质血症、慢性肾衰竭)、环境因素(营养因素如微量营养素缺乏(锌、铜和硒);以及辐射后暴露)、阻塞性(肿瘤)、缺血性(血管疾病),以及自身免疫性,或原发性硬化性胆管炎、肖格伦综合征(syndrome)、原发性胆汁性病症及1型糖尿病。由于诊断和治疗上的挑战,需要跨学科管理策略。
黄斑变性
造成灾难性视力丧失的大多数疾病(例如黄斑变性)由于通常响应于组织缺血或炎症的异常血管生成和伤口愈合而产生此后果。由血管渗漏、出血和伴随的纤维化而造成的眼睛中高度有序组织结构的破坏可导致视轴机械破坏和/或生物机能不良。CNS以多种方式高度专一化,包括存在的炎症细胞和伤口愈合细胞的类型。由于视网膜为CNS的一部分,所以其对于损伤的反应利用与大脑其余部分中所观察非常类似的机制;不仅对于伤口愈合反应,且也对于在此高度组织化组织的神经元和血管成分的发育过程中有效的迁移信号的利用而言,此皆为事实(Friedlander M.;Fibrosis and diseases of the eye,J.Clin.Invest.2007)。如下文所述,眼睛前部对于伤口愈合的反应相比于眼睛后部中的这些事件更密切类似于非CNS组织的反应。因此,I是指在前部中的这些伤口愈合事件如纤维化,而视网膜中的类似事件被称为神经胶质增生。尽管此类区别在某种程度上为人为的,但其可用于区分实现伤口愈合和瘢痕形成事件的纤维母细胞和神经胶质细胞。对于炎症、伤口愈合和血管生成的理解增加已导致开发出可有效调节此等生物过程且在某些情形下保全视力的药物。遗憾的是,这些药理学干预往往过小,过迟,且经常发生视力丧失的进展。
需要用安全且有效的药物来预防或治疗各纤维化疾病。
发明概述
更具体而言,本发明涉及如下文的式所定义的新颖的经取代的芳族化合物。与已知芳族化合物相比,本发明化合物在位置R2具有较长的链;且本发明化合物的此特殊性已表明对活性具有有利且令人惊讶的影响。因此,本发明涉及一种由下式定义的化合物:
或其药学上可接受的盐,其中
A为C5烷基、C6烷基、C5烯基、C6烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n为3或4;或优选为C5烷基、C5烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n为3;或优选为C6烷基、C6烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n为4;
R1为H、F或OH;或优选为H或OH;
R2为C5烷基、C6烷基、C5烯基、C6烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n为3或4;或优选为C5烷基、C5烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n为3;或优选为C6烷基、C6烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n为4;
R3为H、F、OH或CH2Ph;或优选为H、F或OH;或优选为H或OH;
R4为H、F或OH;或优选为H或OH;
Q为
1)(CH2)mC(O)OH,其中m为1或2,
2)CH(CH3)C(O)OH,
3)C(CH3)2C(O)OH,
4)CH(F)-C(O)OH,
5)CF2-C(O)OH,或
6)C(O)-C(O)OH。
在一优选实施方案中,化合物的药学上可接受的盐为钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、锰盐、锌盐、铁盐或铜盐。优选的化合物的药学上可接受的盐为钠盐。
根据本发明的优选化合物为下列化合物之一:
本发明也涉及一种用于减少细胞中的胶原产生的方法,其包括使所述细胞与治疗有效量的本发明化合物接触。该胶原优选为胶原1。该胶原产生优选为胶原mRNA表达和胶原蛋白产生。根据一优选实施方案,细胞处于培养中,为器官的一部分或为完全为活动物的一部分的器官的一部分,其中所述动物包括但不限于小鼠、大鼠或人类。在细胞为完全为活动物的一部分的器官的一部分的情况下,使细胞与治疗有效量的本发明化合物接触的步骤等效于向动物施用化合物。在细胞为完全为活动物的一部分的器官的一部分且活动物为人类的情况下,化合物的治疗有效量对应于优选约0.01%至约10%(w/w)、或约0.1%至10%(w/w)、或约1.0%至约10%(w/w)、约0.1%至约5%(w/w)、或约1.0%至约5%(w/w)的局部施用量,或对应于优选约1mg/kg至约50mg/kg、或约1mg/kg至25mg/kg、或约1mg/kg至约10mg/kg、约5mg/kg至约25mg/kg、或约10mg/kg至约20mg/kg的经口施用量。在培养细胞的情况下,化合物的治疗有效量对应于0.01mM至0.5mM,且优选为约0.2mM。
本发明进一步涉及一种用于在有需要的受试者中预防纤维化疾病和/或减缓纤维化疾病的进展和/或治疗纤维化疾病的方法,其包括施用治疗有效量的本发明化合物。在本发明的一优选实施方案中,所述纤维化疾病为肺纤维化、肝纤维化、皮肤纤维化、肾纤维化、胰腺纤维化、全身性硬化、心脏纤维化或黄斑变性。
所述化合物优选经口施用。所述受试者优选为人类。当化合物经口施用且受试者为人类时,治疗有效量优选为约1mg/kg至约50mg/kg、或约1mg/kg至约25mg/kg、或约5mg/kg至约25mg/kg、或约1mg/kg至约20mg/kg、或约1mg/kg至约10mg/kg、或约10mg/kg至约20mg/kg。
根据本发明的一优选实施方案,纤维化疾病为肺纤维化。肺纤维化优选为特发性肺纤维化、结节病、囊性纤维化、家族性肺纤维化、硅肺病、石绵沉着病、煤矿工人尘肺病、碳尘肺病、过敏性肺炎、由吸入无机粉尘引起的肺纤维化、由感染物引起的肺纤维化、由吸入有毒气体、气溶胶、化学粉尘、烟雾或蒸气引起的肺纤维化、药物诱发的间质性肺病或肺性高血压。
在一实施方案中,纤维化疾病为肝纤维化。根据本发明的一优选实施方案,肝纤维化由慢性肝病、乙型肝炎病毒感染、丙型肝炎病毒感染、丁型肝炎病毒感染、血吸虫病、酒精性肝病或非酒精性脂肪肝炎、肥胖症、糖尿病、蛋白质营养不良、冠状动脉疾病、自身免疫性肝炎、囊性纤维化、α-1-抗胰蛋白酶缺乏症、原发性胆汁性肝硬化、药物反应及暴露于毒素引起。
在一实施方案中,纤维化疾病为皮肤纤维化。根据本发明的一优选实施方案,皮肤纤维化为瘢痕形成、增生性瘢痕形成、瘢痕瘤、皮肤纤维化病症、伤口愈合、伤口延迟愈合、银屑病或硬皮病。所述瘢痕形成可能源自烧伤、创伤、手术损伤、辐射或溃疡。所述溃疡可为糖尿病性足溃疡、静脉性腿溃疡或压力性溃疡。
当纤维化疾病为皮肤纤维化时,所述化合物优选经局部或经口施用。当所述化合物经局部施用且所述受试者为人类时,本发明化合物的治疗有效量优选为约0.01%至约10%(w/w)、或约0.1%至10%(w/w)、或约1.0%至约10%(w/w)、或约0.1%至约5%(w/w)、或约1.0%至约5%(w/w)。当经口施用时,本发明化合物的治疗有效量优选为约1mg/kg至约50mg/kg、或约1mg/kg至25mg/kg、或约1mg/kg至约10mg/kg、约5mg/kg至约25mg/kg、或约10mg/kg至约20mg/kg,且受试者为人类。
在一实施方案中,纤维化疾病为肾纤维化。根据本发明的一优选实施方案,肾纤维化由肾衰竭后的透析、导管置放、肾病变、肾小球硬化、肾小球肾炎、慢性肾功能不全、急性肾损伤、末期肾病或肾衰竭引起。
根据一优选实施方案,本发明也涉及一种用于拮抗哺乳动物的器官(诸如肺、肝脏、皮肤或心脏)中的胶原分泌或胶原沉积的方法,其包括向所述有需要的哺乳动物施用治疗有效量的本发明化合物,其中所述器官为肾脏、肺、肝脏、皮肤或心脏。有需要的哺乳动物为在诸如肾脏、肺、肝脏、皮肤或心脏的器官中经受过多胶原分泌或胶原沉积的哺乳动物。通常,器官中的过多胶原分泌或胶原沉积由损伤或伤害引起。此类损伤和伤害具有器官特异性且于本文详细描述于背景技术部分和整个说明书中。上文详细描述的治疗有效量也适用于拮抗器官中的胶原分泌或胶原沉积的本方法。本文所述的施用途径也适用于本方法。所述化合物优选经足够时段施用以完全或部分拮抗器官中的胶原沉积水平。本文所用的术语“拮抗”欲意指“降低”或“减少”。足够时段可为在一周内、或1周至1个月、或1至2个月、或2个月以上。对于慢性病状,本发明化合物有利地为终生施用。
在一实施方案中,纤维化疾病为心脏纤维化。在此实施方案中,治疗有效量优选为约1mg/kg至约50mg/kg,且优选为或约1mg/kg至25mg/kg、或约1mg/kg至约10mg/kg、约5mg/kg至约25mg/kg、约5mg/kg至约20mg/kg、或约10mg/kg至约20mg/kg。所述化合物优选经口施用。所述受试者优选为人类。
在另一优选实施方案中,本发明化合物可与治疗有效量的第二化合物组合施用,其中所述第二化合物优选为已知可有效预防或治疗或潜在预防或治疗纤维化疾病的治疗剂。根据本发明的一实施方案,所述化合物可与治疗有效量的第二化合物组合施用,所述第二化合物为免疫抑制药物、抗炎药、细胞因子、单克隆抗体、多重受体酪氨酸激酶抑制剂、抗氧化剂、酶抑制剂、整合素抑制剂、高血压抑制剂、脂质受体调节剂或噻唑啉二酮。
除先前剂量实施方案之外,对于所有上述纤维化疾病,当本发明化合物经口施用人类时,化合物的治疗有效量优选对应于约0.01%至约10%(w/w)、或约0.1%至10%(w/w)、或约1.0%至约10%(w/w)、约0.1%至约5%(w/w)、或约1.0%至约5%(w/w)。在所有上述纤维化疾病中,当本发明化合物经口施用人类时,化合物的治疗有效量优选对应于约1mg/kg至约50mg/kg、或约1mg/kg至25mg/kg、或约1mg/kg至约10mg/kg、约5mg/kg至约25mg/kg、或约10mg/kg至约20mg/kg。
本发明也涉及一种用于在有需要的受试者中预防纤维化疾病和/或减缓纤维化疾病的进展和/或治疗纤维化疾病的试剂盒。所述试剂盒包含由下式表示的化合物:
或其药学上可接受的盐,其中
A为C5烷基、C6烷基、C5烯基、C6烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n为3或4;或优选为C5烷基、C5烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n为3;或优选为C6烷基、C6烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n为4;
R1为H、F或OH;或优选为H或OH;
R2为C5烷基、C6烷基、C5烯基、C6烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n为3或4;或优选为C5烷基、C5烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n为3;或优选为C6烷基、C6烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n为4;
R3为H、F、OH或CH2Ph;或优选为H、F或OH;或优选为H或OH;
R4为H、F或OH;或优选为H或OH;
Q为
1)(CH2)mC(O)OH,其中m为1或2,
2)CH(CH3)C(O)OH,
3)C(CH3)2C(O)OH,
4)CH(F)-C(O)OH,
5)CF2-C(O)OH,或
6)C(O)-C(O)OH;
以及关于向罹患所述纤维化疾病的受试者施用治疗有效量的所述化合物的说明书。在本发明的一优选实施方案中,所述纤维化疾病为肺纤维化、肝纤维化、皮肤纤维化、肾纤维化、胰腺纤维化、全身性硬化、心脏纤维化或黄斑变性。所述试剂盒也可包含关于施用任何上文公开的治疗有效量的经口施用化合物的说明书。
对于所有纤维化疾病,所述试剂盒优选进一步包含关于向人类受试者每天经口施用约1mg/kg至约50mg/kg化合物的说明书。
当纤维化疾病为皮肤纤维化时,所述试剂盒优选进一步包含表明向人类受试者每天经局部施用约0.01%至约10%(w/w)的化合物的说明书;或表明向人类受试者每天经口施用约1mg/kg至约50mg/kg化合物的说明书。
附图简述
图1展示db/db糖尿病小鼠相比于C57BL/6小鼠(对照小鼠)的肾小球滤过率(GFR)功能,以及在db/db糖尿病小鼠中在用剂量为10mg/kg和50mg/kg的化合物1经口处理后的肾小球滤过率(GFR)功能。
发明详述
如本文所用,术语“烷基”意欲包括具有五个或六个碳原子的支链和直链饱和脂族烃基。上文定义的烷基的实例包括但不限于正戊基、正己基、异戊基、异己基、叔戊基和叔己基。类似地,如本文所用,术语“烯基”意欲包括具有五个或六个碳原子且其中至少两个碳原子由双键彼此键结且具有E或Z区域化学及其组合的不饱和直链或支链烃基。上文定义的烯基的实例包括但不限于1-戊烯基、2-戊烯基、1-己烯基和2-己烯基。
本发明化合物或其药学上可接受的盐可含有一个或多个不对称中心、手性轴及手性平面,且因此可产生对映异构体、非对映异构体和其他立体异构形式,随后可根据绝对立体化学诸如(R)-或(S)-进行定义。因此本发明意欲包括所有此类可能的异构体,以及其外消旋和光学纯形式。光学活性(+)和(-)、(R)-和(S)-或(D)-和(L);异构体可使用手性合成子或手性试剂制备或使用常规技术诸如反相HPLC拆分。外消旋混合物可经制备且随后分离为个别光学异构体或这些光学异构体可通过手性合成来制备。对映异构体可通过本领域技术人员已知的方法拆分,例如,通过形成非对映异构盐,其随后可通过结晶、气相-液相或液相层析分离,或使一种对映异构体与对映异构体特异性试剂选择性反应。
如本文所用,术语“药学上可接受的盐”欲意指保持游离酸的生物效能和特性且在生物学上或在其他方面非不合需要的那些盐。这些盐衍生自无机碱或有机碱与有机酸的加成。由无机碱制备的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、锰盐、锌盐、铁盐、铜盐及其类似物。由有机碱制备的盐包括但不限于以下各物的盐:伯胺、仲胺和叔胺、经取代的胺(包括天然存在的经取代的胺)、环胺和碱性胺基酸(赖氨酸、精氨酸及组氨酸)。药学上可接受的盐的实例也描述于例如Berge等人,“Pharmaceutical Salts”,J.Pharm.Sci.66,1-19(1977)中。本发明化合物的优选盐为钠盐、钾盐、锂盐、铵盐、钙盐及镁盐;且更优选为钠盐。药学上可接受的盐可通过常规化学方法由含有酸部分的母体化合物合成。一般而言,此类盐通过使这些化合物的游离酸形式与化学计算量的适当碱于水中或于有机溶剂中或于水性/有机溶剂混合物中反应来制备。盐可在化合物的最终分离或纯化期间就地制备或通过分别使游离酸形式的经纯化本发明化合物与所需相应碱反应且分离产物盐来制备。
如上文所指示及下文所例示,本发明化合物具有有益的药用特性并且可具有用于预防和/或治疗受试者的各种纤维化疾病及相关病状的药物应用。本发明人所预期的药学及药物应用包括但不限于处理肺纤维化、肝纤维化、皮肤纤维化、肾纤维化、胰腺纤维化、全身性硬化、心脏纤维化或黄斑变性的那些应用。
术语“受试者”包括可能发生纤维化疾病或易于患上此病状的活有机体。术语“受试者”包括动物,诸如哺乳动物或鸟类。受试者优选为哺乳动物。受试者更优选为人类。受试者甚至更优选为需要治疗的人类患者。
如本文所用,“预防”欲指至少降低获得疾病或病症的风险(或易感性)的可能性(即,在可能患上或易患上疾病但尚未经历或显示该疾病的症状的患者中造成该疾病的至少一种临床症状未出现)。用于鉴别此类患者的生物及生理参数提供于本文中且也为医师所熟知。
术语受试者的“治疗”包括向受试者施加或施用本发明化合物(或向来自受试者的细胞或组织施施加或施用本发明化合物),目的在于延迟、减缓、稳定化、治疗、治愈、缓解、减轻、改变、医治、减少恶化、改善、改进或影响疾病或病状、疾病或病状的症状、或疾病或病状的风险(或易感性)。术语“治疗”是指损伤、病变或病状的治疗或改善成功的任何指示,包括任何客观或主观参数,诸如消除;缓解;恶化速率减小;疾病严重程度减小;稳定化、减轻症状或使受试者更耐受损伤、病变或病状;减缓恶化或衰退的速率;使恶化终点的衰弱程度较小;或改善受试者的身体或精神健康状况。
本发明涉及用于预防和/或治疗纤维化疾病的方法、化合物、组合物及试剂盒。
术语“纤维化疾病”意指特征为细胞外基质(主要由胶原组成)过度积聚且当正常组织经瘢痕组织置换时的任何纤维化或疾病。纤维化疾病包括但不限于肺纤维化、肝纤维化、皮肤纤维化、肾纤维化、胰腺纤维化、全身性硬化、心脏纤维化及黄斑变性。
术语“肺纤维化”意指肺中形成或产生过多纤维结缔组织(纤维化),从而导致产生瘢痕化(纤维化)组织。更确切地说,肺纤维化为造成肺泡和肺间质组织肿胀和瘢痕形成的慢性疾病。瘢痕组织置换健康组织且造成炎症。此慢性炎症又为纤维化的前奏。此类对肺组织的损伤造成肺变硬,随后使呼吸愈来愈困难。
肺纤维化为可由许多不同原因引起的复杂疾病,所述原因包括因吸入小粒子(石棉、磨细石料、金属粉尘、香烟烟雾中存在的粒子、二氧化硅粉尘等)诱发的肺部微观损伤。或者,肺纤维化可作为其他疾病(自身免疫性疾病、病毒性或细菌性感染等)的副作用而出现。某些药物,诸如细胞毒性剂(例如博莱霉素、白消安和甲胺喋呤)、抗生素(例如呋喃妥因、柳氮磺胺吡啶)、抗心律失常药(例如胺碘达隆(amiodarone)、妥卡胺(tocainide))、抗炎药(例如金、青霉胺)、违禁药物(例如霹雳可卡因、海洛因),也可造成肺纤维化。然而,当在无已知原因下出现肺纤维化时,将其称为“特发性”或特发性肺纤维化(IPF)。
肺纤维化病症被认为是起始于肺实质的急性损伤,其导致慢性间质性炎症,随后纤维母细胞活化及增殖,且最终发展为肺纤维化及组织破坏的常见终点。当前研究表明,炎症在IPF中不太重要,IPF似乎主要为响应一些未知触发的纤维母细胞活化和增殖病症。广义而言,纤维化肺部疾病的表现可以归纳如下:其可为慢性、隐伏性及缓慢进行性的;其可为亚急性的,具有消散性、缓解性、复发性或进行性过程;以及其可为急性的,具有爆发性、进行性、缓解性或消散性过程。具有慢性、隐伏性和缓慢进行性过程的病症为临床上类似于IPF且通常有共同病理学者(即UIP)。许多结缔组织疾病(例如类风湿性关节炎;CREST综合征(皮肤钙沉着症、雷诺氏综合征(Raynaud's syndrome)、食管运动障碍、指硬皮病及毛细管扩张症);综合征/进行性全身性硬皮病;全身性红斑狼疮;混合性结缔组织疾病;尘肺病(例如石绵沉着病、硅肺病);慢性过敏性肺炎;和药物相关的肺纤维化(例如由于博莱霉素))一般属于此类别。与职业暴露相关的临床上明显的肺部疾病(例如尘肺病)的发展一般在暴露后很多年才出现。辐射性纤维化通常在辐射暴露后数月至数年才出现。在使用肺毒性药物与产生纤维化疾病之间可能出现数月或数年的滞后时间。该作用可为剂量依赖性(例如博莱霉素),但在其他情况下,关系不甚明显。结缔组织疾病的肺部表现可能在关节疾病发作之前、同时或很多年后才出现。肺部结节病尽管有时急性或亚急性发作,但在一些情况下可能随时间隐伏存在。具有可变过程的亚急性表现以隐源性机化肺炎(COP)为代表。COP通常在流感样疾病发作后数周或数月才出现。该过程为可变的且可自发缓解或进展。该病症被认为对类固醇疗法极具反应性,但当类固醇类撤除或逐渐减少时其可再次出现。在一些情况下,COP可进展为末期纤维化肺部疾病。具有急性发作的病症以急性间质性肺炎(AIP)为代表,其为重度肺损伤的特发形式。组织病理学为具有弥漫性肺泡损伤的成人呼吸窘迫综合征的组织病理学。患者不具有早先肺病史或存在潜在间质性疾病的加速期的一部分。大多数患者迅速进展为呼吸衰竭。一些患者可用类固醇类或其他免疫抑制疗法进行改善。
术语“肝纤维化”意指肝脏中形成或产生过多纤维结缔组织(纤维化),从而导致产生瘢痕化(纤维化)组织。瘢痕化组织通过纤维化过程置换健康组织且导致后续肝硬化及肝细胞癌。
术语“皮肤纤维化”意指上皮细胞或纤维结缔组织的过度增殖(纤维化),从而导致产生瘢痕化(纤维化)组织。瘢痕化组织通过纤维化过程置换健康组织且可为全身性硬皮病的前奏。皮肤纤维化意欲涵盖任何皮肤组织及上皮细胞的纤维化,包括但不限于血管和静脉、器官或腺体的内腔诸如下颌下、胆囊、甲状腺毛囊、汗腺管、卵巢、肾脏的导管;齿龈、舌、腭、鼻、喉、食道、胃、肠、直肠、肛门和阴道的上皮细胞;真皮、瘢痕、皮肤和头皮。本发明化合物可有效促进伤口愈合且具有一种或多种下列活性:
-改善胶原组织化和/或减少所述伤口中的伤口多孔性;
-减少所述伤口中由纤维母细胞和上皮细胞产生的胶原过度产生;
-减少所述伤口中的上皮间质转化;
-减少所述伤口中的纤维母细胞迁移及活化;
-减少和/或抑制所述伤口中的皮肤增厚;
-减少和/或抑制炎性细胞向所述伤口的募集。
一般而言,预防性和治疗性用途包括向有需要的受试者、优选人类患者施用如本文所述的化合物。根据本发明的化合物可与治疗有效量的第二化合物组合施用,所述第二化合物可包括于相同的药物组合物中或第二药物组合物中。所述第二化合物有利地为免疫抑制药物,包括但不限于环孢菌素、硫唑嘌呤、环磷酰胺或吗替麦考酚酯;抗炎药,包括但不限于皮质类固醇(例如泼尼松);细胞因子,包括但不限于干扰素-α、干扰素-γ、白介素12;单克隆抗体,包括但不限于CTGF、TGF-β、MCP-1、IL-4和IL-13;多重受体酪氨酸激酶抑制剂,包括但不限于尼达尼布和JNK(激酶)抑制剂坦兹替布(CC-930);抗氧化剂,诸如但不限于N-乙酰基半胱氨酸、吡非尼酮(pirfenidone)、维生素E、S-腺苷甲硫氨酸或青霉胺;酶抑制剂,包括但不限于赖氨酰氧化酶样2(LOXL2酶);整合素抑制剂,例如但不限于αvβ6;脂质受体调节剂,包括但不限于溶血磷脂酸受体拮抗剂;吡非尼酮或噻唑啉二酮。
本发明的相关方面涉及包含一种或多种本文所述的本发明化合物的药物组合物及试剂盒。如上文所指示,本发明化合物可用于预防和/或治疗纤维化疾病。
本发明的相关方面涉及与纤维化疾病有关的化合物的预防性和治疗性用途。
肺纤维化可导致若干严重并发症。因为纤维化的肺部的氧摄入能力受损,所以可能产生低血氧含量(低血氧症)。氧缺乏可能影响整个身体。肺纤维化的另一并发症为肺性高血压(肺动脉高血压)。肺部瘢痕组织可使得血液更难以流过。压力增加使得心脏负荷更大且导致心脏衰弱并扩张,使其泵送效率降低并产生心脏衰竭。当人们产生腹部流体积聚、腿部肿胀或颈静脉脉动显著时,疑似此病症。
肝纤维化可导致严重的肝脏机能不良且可导致肝脏完全失去功能。
在因手术或事故造成的皮肤损伤后,皮肤纤维化可导致杂乱印记、永久伤痕和瘢痕,造成严重的美观问题和皮肤变硬。
如本文所用,术语“治疗有效量”意指当施用受试者用于治疗或预防特定病症、疾病或病状时,足以实现该病症、疾病或病状的此类治疗或预防的化合物量。剂量和治疗有效量可例如根据多种因素而改变,所述因素包括所用特定剂的活性、受试者的年龄、体重、一般健康状况、性别和饮食、施用时间、施用途径、排泄速率、及任何药物组合(若适用)、专业人员希望化合物对受试者的作用及化合物的特性(例如,生物利用度、稳定性、效能、毒性等),以及受试者所罹患的特定病症。另外,经静脉内施用的治疗有效量可取决于受试者的血液参数,例如脂质概况、胰岛素含量、血糖或肝脏代谢。治疗有效量也将根据疾病状态的严重程度、器官功能或潜在的疾病或并发症而改变。可使用任何可用的测定(包括本文所述的测定)来确定此类适当剂量。当一种或多种本发明化合物欲施用于人类时,医师可例如首先规定相对低的剂量,随后增大剂量直至获得适当的反应。在人类中,根据本发明的化合物在人类中的经口施用剂量为1mg/kg至50mg/kg、优选5mg/kg至20mg/kg、更优选5mg/kg至15mg/kg、此外更优选约1mg/kg至10mg/kg。本发明化合物在人类中的局部施用剂量为0.01%至10%(w/w)、优选0.1%至5%(w/w)且更优选1%至5%。小鼠代谢比人类代谢更快地消除任何化合物,因此对于化合物于小鼠中的测试,剂量可倍增10倍至20倍。
如本文所用,术语“药物组合物”是指存在至少一种根据本发明的化合物及药学上可接受的媒介物。
“药学上可接受的媒介物”是指与化合物一起施用之稀释剂、佐剂、赋形剂或载体。术语“药学上可接受的”是指适用于与人类和低等动物的组织接触而无不当毒性、不兼容性、不稳定性、刺激性、过敏反应及其类似特性且与合理的效益/风险比相称的药物、药剂、惰性成分等。其优选是指已由或可由联邦或州政府的管理机构批准或列于美国药典或其他公认药典中用于动物且更具体而言用于人类的化合物或组合物。药学上可接受的媒介物可为溶剂或分散介质,其包含例如水、乙醇、多元醇(例如甘油、丙二醇和液体聚乙二醇)、其合适混合物以及植物油。药学上可接受的媒介物的其他实例包括但不限于:注射用水USP;水性媒介物,诸如但不限于氯化钠注射液、林格氏注射液、右旋糖注射液、右旋糖/氯化钠注射液及乳酸化林格氏注射液;水可混溶性媒介物,诸如但不限于乙醇、聚乙二醇及聚丙二醇;及非水性媒介物,诸如但不限于玉米油、棉籽油、花生油、芝麻油、油酸乙酯、肉豆蔻酸异丙酯及苯甲酸苄酯。可通过添加抗细菌剂和抗真菌剂(例如对羟基苯甲酸酯、氯丁醇、苯酚、抗坏血酸、硫柳汞及其类似物)来达成微生物作用的预防。在许多情况下,组合物中包括等渗剂,例如糖、氯化钠或多元醇诸如甘露糖醇及山梨糖醇。可通过在组合物中包括延迟吸收剂(例如单硬脂酸铝或明胶)来产生可注射组合物的延长吸收。
在一些实施方案中,本发明组合物包含有效量的具有上文的式的化合物。尤其优选为2-[3,5-二戊基苯基]乙酸钠盐。
在一些实施方案中,本发明涉及用于预防和/或治疗肺纤维化、肝纤维化、皮肤纤维化、肾纤维化、胰腺纤维化、全身性硬化、心脏纤维化或黄斑变性的药物组合物。
本发明化合物可在施用之前使用可用技术和程序配制成药物组合物。例如,可以适于通过局部、经口、静脉内(iv)、肌肉内(im)、储库式肌肉内(depo-im)、皮下(sc)、储库式皮下(depo-sc)、舌下、鼻内、鞘内局部或直肠途径施用的方式配制药物组合物。
优选地,本发明化合物可经口施用或局部施用。制剂有利地以单位剂型呈现且可通过药学技术中熟知的任何方法制备。制备这些制剂或组合物的方法包括使本发明化合物与药学上可接受的媒介物(例如,惰性稀释剂或可同化的食用载体)及任选地一种或多种辅助成分缔合的步骤。一般而言,通过使本发明化合物与液体载体或细粉状固体载体或两者均匀且紧密地缔合以及随后必要时使产品成形来制备制剂。所述治疗上有用的组合物中的治疗剂的量使得可获得合适剂量。
适于经口施用的本发明制剂可呈以下形式:胶囊(例如硬壳或软壳明胶胶囊)、扁囊剂、丸剂、锭剂、口含锭、散剂、颗粒剂、锭片(pellet)、糖衣丸(例如有包衣(例如肠溶包衣)或无包衣),或于水性或非水性液体中的溶液或悬浮液,或水包油或油包水乳液,或酏剂或糖浆,或片剂或漱口剂以及其类似形式,其各自含有预定量的本发明化合物作为活性成分。本发明化合物也可以大丸剂、舐剂或糊剂形式施用,或直接并入受试者的饮食中。此外,在某些实施方案中,这些锭片可经配制以(a)提供瞬时或快速药物释放(即其上面无涂层);(b)经包覆例如以随时间提供持续药物释放;或(c)包覆肠溶包衣以提供更好胃肠耐受性。可通过常规方法达成包衣包覆,典型地为pH或时间依赖性包衣,以使得本发明化合物于所需位置附近释放,或在多个时间释放以延长所需作用。此类剂型典型地包括但不限于邻苯二甲酸乙酸纤维素、聚乙酸乙烯酯邻苯二甲酸酯、邻苯二甲酸羟丙基甲基纤维素、乙基纤维素、蜡及虫胶中的一或多者。
在用于经口施用的固体剂型中,本发明化合物可与一种或多种药学上可接受的载体混合,诸如柠檬酸钠或磷酸二钙,或下列中的任一者:填充剂或增量剂,诸如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇或硅酸;粘合剂,例如羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯啶酮、蔗糖或阿拉伯胶;保湿剂,诸如甘油;崩解剂,诸如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐及碳酸钠;溶解阻滞剂,诸如石蜡;吸收促进剂,诸如季铵化合物;湿润剂,例如鲸蜡醇及单硬脂酸甘油酯;吸收剂,诸如高岭土及膨润土;润滑剂,诸如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠及其混合物;以及着色剂。在胶囊、锭剂及丸剂的情况下,药物组合物也可包含缓冲剂。相似类型的固体组合物也可用作使用诸如乳糖或奶糖以及高分子量聚乙二醇及其类似物的赋形剂的软填充明胶胶囊和硬填充明胶胶囊中的填充剂。
经口组合物典型地包括液体溶液、乳液、悬浮液及其类似物。适于制备此类组合物的药学上可接受的媒介物为本领域中所熟知。用于糖浆、酏剂、乳液及悬浮液的典型载体组分包括乙醇、甘油、丙二醇、聚乙二醇、液体蔗糖、山梨糖醇及水。对于悬浮液而言,典型的悬浮剂包括甲基纤维素、羧甲基纤维素钠、黄蓍胶及海藻酸钠;典型的湿润剂包括卵磷脂及聚山梨醇酯80;且典型的防腐剂包括对羟基苯甲酸甲酯及苯甲酸钠。经口液体组合物也可含有一种或多种组分,诸如上文公开的甜味剂、调味剂及着色剂。
适于注射用途的药物制剂可包括无菌水溶液(为水溶性时)或分散体及用于临时制备无菌可注射溶液或分散体的无菌粉末。在所有情况下,组合物必须无菌且必须为流体以便存在易注射性。其在制造及储存条件下必须稳定且必须抵抗诸如细菌及真菌的微生物的污染作用。可通过将所需量的治疗剂与所需要的上文所列成分中的一者或组合并入适当溶剂中,接着过滤灭菌来制备无菌可注射溶液。一般而言,通过将治疗剂并入含有基本分散介质及来自上文所列成分的所需其他成分的无菌媒介物中来制备分散体。在用于制备无菌可注射溶液的无菌粉末的情况下,制备方法为真空干燥和冷冻干燥,其得到活性成分(即治疗剂)加来自其先前无菌过滤溶液的任何额外所需成分的粉末。
也提供适于以气雾剂形式通过吸入施用的药物制剂。这些制剂包含具有任何本文的式的所需化合物或此类化合物的多个固体粒子的溶液或混悬液。例如,预期本发明化合物的金属盐具有可用于制备用于通过吸入施用的活性药学成分(API)的精细粒子而非这些化合物的游离酸形式的物理化学特性。所需制剂可置于小腔中且喷雾。可通过压缩空气或通过超音能量来实现喷雾以形成多个包含试剂或盐的液滴或固体粒子。所述液滴或固体粒子应具有约0.5至约5微米范围内的粒径。可通过以本领域中已知的任何适当方式、诸如通过微米尺寸化加工具有任何本文所述式的固体试剂或其盐来获得固体粒子。固体粒子或液滴的尺寸应为例如约1至约2微米。在此方面,商业喷雾器可用于达成此目的。适于以气雾剂形式施用的药物制剂可为液体形式,该制剂应于包含水的载体中包含具有任何本文所述式的水溶性剂或其盐。可存在表面活性剂,当进行喷雾时,该表面活性剂充分降低制剂的表面张力以导致形成在所需尺寸范围内的液滴。
本发明组合物也可经局部施用于受试者,例如,通过将组合物直接放置于受试者的表皮或上皮组织上或使组合物在受试者的表皮或上皮组织上扩散,或经由“贴片”经皮施用。这些组合物包括例如洗剂、乳膏、溶液、凝胶、乳液及固体。这些局部组合物可包含有效量、通常约0.01%至约10%(w/w)、或约0.1%至约5%(w/w)、或约1%至约5%(w/w)的本发明化合物。适于局部施用的载体典型地以连续膜形式原位保留于皮肤上,且抵抗因排汗或浸于水中而移除。一般而言,载体为有机性质且能够于其中分散或溶解治疗剂。所述载体可包括药学上可接受的润肤剂、乳化剂、增稠剂、溶剂及其类似物。载体可包括胎脂(vernix)。局部制剂包括一种或多种赋形剂,诸如但不限于保护剂、吸附剂、缓和剂、润肤剂、防腐剂、抗氧化剂、保湿剂、缓冲剂、增溶剂、皮肤渗透剂及表面活性剂。合适的保护剂及吸附剂包括但不限于粉尘剂、硬脂酸锌、火棉胶、二甲聚硅氧烷、聚硅酮、碳酸锌、芦荟凝胶及其他芦荟产品、维生素E油、尿囊素(allatoin)、甘油、矿脂及氧化锌。合适的缓和剂包括但不限于安息香、羟丙基纤维素、羟丙基甲基纤维素及聚乙烯醇。合适的润肤剂包括但不限于动物及植物脂肪及油、肉豆蔻醇、明矾及乙酸铝。合适的防腐剂包括但不限于季铵化合物,诸如氯化苯甲烃铵、苄索氯铵、西曲溴铵(cetrimide)、地喹氯铵(dequalinium chloride)及氯化十六烷基吡啶鎓;汞剂,诸如硝酸苯汞、乙酸苯汞及硫柳汞;醇剂,例如氯丁醇、苯乙醇及苄醇;抗细菌酯,例如对羟基苯甲酸酯;及其他抗微生物剂,诸如氯己定(chlorhexidine)、氯甲酚、苯甲酸及多粘菌素。合适的抗氧化剂包括但不限于抗坏血酸及其酯、亚硫酸氢钠、丁基化羟基甲苯、丁基化羟基苯甲醚、生育酚,及螯合剂如EDTA及柠檬酸。合适的保湿剂包括但不限于甘油、山梨糖醇、聚乙二醇、尿素及丙二醇。适于本发明使用的缓冲剂包括但不限于乙酸盐缓冲剂、柠檬酸盐缓冲剂、磷酸盐缓冲剂、乳酸缓冲剂及硼酸盐缓冲剂。合适的增溶剂包括但不限于季铵氯化物、环糊精、苯甲酸苄酯、卵磷脂及聚山梨醇酯。合适的皮肤渗透剂包括但不限于乙醇、异丙醇、辛基苯基聚乙二醇、油酸、聚乙二醇400、丙二醇、N-癸基甲基亚砜、脂肪酸酯(例如,肉豆蔻酸异丙酯、月桂酸甲酯、单油酸甘油酯及丙二醇单油酸酯);及N-甲基吡咯啶酮。
可用于获得药剂于受试者中的全身性传递的其他组合物可包括舌下、经颊及经鼻剂型。此类组合物典型地包含一种或多种可溶性填充剂物质,诸如蔗糖、山梨糖醇及甘露糖醇;及粘合剂,诸如阿拉伯胶、微晶纤维素、羧甲基纤维素及羟丙基甲基纤维素。也可包括上文公开的助流剂、润滑剂、甜味剂、着色剂、抗氧化剂及调味剂。
根据本发明的化合物也可胃肠外、经腹膜内、经脊柱内或经脑内施用。对于此类组合物,本发明化合物可于甘油、液体聚乙二醇及其混合物中以及于油中制备。在普通储存及使用条件下,此制剂可含有防腐剂以防止微生物的生长。
对于预防纤维化疾病/减缓纤维化疾病的进展/治疗纤维化疾病的方法,本发明的方法也可包括共同施用至少一种根据本发明的化合物或其药学上可接受的盐以及施用另一种治疗有效剂用于预防纤维化疾病和/或减缓纤维化疾病的进展和/或治疗纤维化疾病。因此,本发明也涉及一种用于预防、减少或消除上述疾病或病状中的任一者的症状或并发症的方法。所述方法包括向有需要的受试者施用包含至少一种本发明化合物的第一药物组合物和包含一种或多种其他活性成分之第二药物组合物,其中所有活性成分以足以抑制、降低或消除欲治疗的疾病或病状的一种或多种症状或并发症的量施用。在一个方面中,第一药物组合物与第二药物组合物的施用短暂间隔至少约两分钟。第一试剂优选为式I化合物。第二试剂可选自上文给出化合物的清单。
本发明不意欲局限于本文所示的实施方案,但符合与本文公开的原理及新颖特征一致的最广泛范围。
除非上下文另外明确指示,否则单数形式“一个/种(a/an)”和“该(the)”包括相应的多个指示物。
除非另外指示,否则本说明书及权利要求中所用的所有表示成分量、反应条件、浓度、性质等的数目应理解为在所有情形下皆由术语“约”修饰。最起码,每个数值参数应当至少按照所报导的有效数字的数目且通过应用普通舍入技术理解。因此,除非相反指示,否则本说明书及随附权利要求中所述的数值参数为近似值,其可能根据欲获得的特性而改变。尽管阐述实施方案的宽泛范畴的数值范围及参数为近似值,但特定实施例中阐述的数值尽可能精确地报导。然而,任何数值皆固有地含有由实验、测试测量、统计分析及此类的变化而产生的某些误差。
本领域技术人员应仅使用常规实验可认识到或能够确定本文所述的具体程序、实施方案、权利要求及实施例的众多等效物。此类等效物视为在本发明的范畴内且由其随附权利要求所涵盖。本发明由下列实施例进一步说明,这些实施例不应理解为进一步限制本发明。
实施例
下文阐述的实施例提供由式I涵盖的某些代表性化合物的代表性制备方法。一些实施例提供某些代表性本发明化合物的代表性用途。也提供用于测定本发明化合物的功效的代表性方法。
下文阐述的实施例提供由通式I涵盖的某些代表性化合物的代表性制备方法。一些实施例提供某些代表性本发明化合物的代表性用途。也提供用于测定本发明化合物的体外及体内功效的代表性方法。
仪器:
所有HPLC色谱图和质谱记录于HP 1100 LC-MS Agilent仪器上,其中使用分析型C18柱(250×4.6mm,5微米),以3分钟内含0.01%TFA的50-99%CH3CN-H2O的梯度作为洗脱剂,接着3分钟内等度洗脱且流速为2mL/min。
实施例1:用于制备2-[3,5-二戊基苯基]乙酸钠(化合物1)的实验程序
步骤1:
在0℃下在氮气下用三乙胺(1.68ml,12.1mmol)处理2-[3,5-二羟基苯基]乙酸甲酯(1.00g,5.49mmol)及N-苯基-双(三氟甲基磺酰基)酰亚胺(4.31g,12.1mmol)于二氯甲烷(20ml)中的悬浮液。形成澄清溶液。将反应物随后在0℃下在氮气下搅拌2小时,且在室温下搅拌21小时。用乙酸乙酯(100ml)稀释反应物,且溶液用0.5M氢氧化钠水溶液(2×100ml)和饱和氯化钠水溶液(75ml)洗涤;随后经硫酸钠干燥;过滤且于真空中蒸发,得到粗产物。利用以乙酸乙酯/己烷0:1至1:9洗脱的BiotageTM40iM柱(二氧化硅)纯化,得到呈灰白色油状物的2-[3,5-双(三氟甲基磺酰氧基)苯基]乙酸甲酯(2.23g,91%)。1H NMR(400MHz,CDCl3):δ7.32(d,J=2.2Hz,2H),7.18(dd,J=2.2,2.2Hz,1H),3.72(s,5H);19F NMR(377MHz,CDCl3):δ-73.20(s,3F);13C NMR(101MHz,CDCl3):δ170.05,149.48,139.01,122.95,118.87(q,JCF=320.5Hz),114.42,52.62,40.29。
步骤2:
用碳酸钠(1.59g,15.0mmol)于水(8ml)中的溶液处理双(三氟甲磺酸)芳基酯(2.23g,4.99mmol)及(E)-1-戊烯-1-基硼酸酸频哪醇酯(2.45g,12.5mmol)于1,2-二甲氧基乙烷(25ml)中的溶液。用氮气使溶液脱氧,且随后用四(三苯基膦)钯(0.58g,0.50mmol)处理。将混合物于密封管中在90℃下加热17小时。将反应物冷却至室温且分配于乙酸乙酯(200ml)与1M盐酸水溶液(150ml)之间。有机相用5%碳酸氢钠水溶液(150ml)和饱和氯化钠水溶液(150ml)洗涤;随后经硫酸钠干燥;过滤且于真空中蒸发,得到粗产物。利用以乙酸乙酯/己烷0:1至3:97洗脱的BiotageTM40iL柱(二氧化硅)纯化,得到与过量(E)-1-戊烯-1-基硼酸酸频哪醇酯呈不可分离的10:4混合物形式的2-[3,5-二[(E)-1-戊-1-烯基]苯基]乙酸甲酯(1.12g,61%)。1H NMR(400MHz,CDCl3):δ7.21(s,1H),7.10(d,J=1.3Hz,2H),6.34(d,J=15.8Hz,1H),6.22(dd,J=15.8,6.7Hz,1H),3.65(s,3H),3.55(s,2H),2.18(tdd,J=6.8,6.8,1.0Hz,2H),1.49(qt,J=7.4,7.2Hz,2H),0.96(t,J=7.4Hz,3H);13C NMR(101MHz,CDCl3):δ172.04,138.59,134.47,131.34,129.97,125.57,122.75,52.07,41.32,35.39,22.77,13.97。
步骤3:
用钯/碳(10%w/w Pd;0.12g)处理所述不饱和化合物(1.12g,78.5%w/w,3.07mmol)于乙酸乙酯(1ml)和甲醇(1ml)中的溶液。用氢气使混合物脱气,且在室温下在1atm氢气下搅拌22小时。将反应物过滤且于真空中蒸发,得到与戊基硼酸酸频哪醇酯呈不可分离的10:4混合物形式的2-[3,5-二戊基苯基]乙酸甲酯(0.86g,76%)。1H NMR(400MHz,CDCl3):δ6.93(s,3H),3.70(s,3H),3.59(s,2H),2.58(t,J=7.9Hz,2H),1.58-1.66(m,2H),1.32-1.38(m,4H),0.91(t,J=6.8Hz,3H)。
步骤4:
用氢氧化锂(0.28g,11.7mmol)于水(6ml)中的溶液处理所述甲酯(0.86g,79%w/w,2.34mmol)于乙腈(24ml)中的溶液,且在室温下搅拌反应物22小时。用1M盐酸水溶液(55ml)淬灭反应,随后用乙酸乙酯(100ml)萃取。有机萃取物用饱和氯化钠水溶液(50ml)洗涤;随后经硫酸钠干燥;过滤且于真空中蒸发,得到粗产物。利用以乙酸乙酯/己烷0:1至1:4洗脱的SiliaSep二氧化硅柱纯化,得到呈无色油状的2-[3,5-二戊基]苯基]乙酸(0.55g,84%)。1H NMR(400MHz,CDCl3):δ6.99(s,3H),3.65(s,2H),2.63(t,J=7.8Hz,2H),1.64-71(m,2H),1.36-1.44(m,4H),0.97(t,J=6.9Hz,3H);13C NMR(101MHz,CDCl3):δ178.96,143.55,133.21,127.93,127.06,41.47,36.13,31.94,31.47,22.86,14.34。
步骤5:
用碳酸氢钠(0.15g,1.75mmol)于水(3ml)中的溶液处理所述酸(0.48g,1.75mmol)于乙醇(12ml)中的溶液,且将反应物在室温下搅拌3天。在真空中蒸发乙醇,且残余水性糖浆状物用水(50ml)稀释,过滤(PES,0.2μm),且冻干,得到呈白色固体状的2-[3,5-二戊基苯基]乙酸钠(0.52g,定量)。熔点225-230℃;1H NMR(400MHz,CD3OD+D2O):δ6.92(s,2H),6.76(s,1H),3.41(s,2H),2.50(t,J=7.5Hz,2H),1.52-1.59(m,2H),1.23-1.33(m,4H),0.85(t,J=6.9Hz,3H);13C NMR(101MHz,CD3OD+D2O):δ179.99,142.66,137.63,126.66,126.16,45.11,35.61,31.36,31.19,22.41,13.47;LRMS(ESI):m/z 277.5(w,[M-Na++2H+]),231.1(100%,来自羧基损失的托品鎓离子);HPLC:3.0分钟。
化合物2:2-(3,5-二己基苯基)乙酸的钠盐
如关于化合物1所述自(E)-己-1-烯基硼酸酸频哪醇酯制备上述化合物。白色固体;1H NMR(400MHz,CD3OD):δ6.96(s,2H),6.79(s,1H),3.43(s,2H),2.54(d,J=7.7Hz,4H),1.55-1.63(m,4H),1.28-1.36(m,12H),0.89(t,J=6.8Hz,6H);13C NMR(101MHz,CD3OD):δ179.68,142.38,137.82,126.55,126.07,45.30,35.87,31.83,31.67,29.02,22.61,13.42;LRMS(ESI):m/z 322.0(100%,M-Na++H++NH4 +)及259.0(35%,M-CO2Na);UPLC(系统A):8.9分钟。UPLC系统A:移动相A=10mM碳酸氢铵水溶液;移动相B=乙腈;固相=HSS T3柱;梯度=含5-100%B的A,经10分钟。
化合物3:2-(2-羟基-3,5-二戊基苯基)乙酸的钠盐
步骤1
用氰化钠(2.5g,50.0mmol)的溶液处理2,4-二溴-6-(溴甲基)苯酚(3.5g,10.0mmol)于乙腈(17ml)中的溶液并且将反应物在100℃下回流加热1小时。将反应混合物冷却至室温且倾倒入水(100ml)中。用1M盐酸水溶液将pH自10调节至8,且用乙酸乙酯(3×250ml)萃取混合物。经合并的萃取物用1M盐酸水溶液(250ml)和饱和氯化钠水溶液(250ml)洗涤;经硫酸钠干燥;过滤且在真空中蒸发,得到粗产物。用丙酮萃取;过滤;且在真空中蒸发,得到2-(3,5-二溴-2-羟基苯基)乙腈(2.6g,90%)。1H NMR(400MHz,d6-丙酮):δ8.75(brs,1H),7.69(d,J=2.3Hz,1H),7.54(d,J=2.3Hz,1H),3.92(s,2H);13C NMR(101MHz,d6-丙酮):δ151.31,134.51,131.92,122.80,117.43,111.89,111.53,18.70。
步骤2
用硫酸(2.5ml)、乙酸(2.5ml)和水(2.5ml)的混合物处理2-(3,5-二溴-2-羟基苯基)乙腈(2.6g,9.0mmol),且将反应物在125℃下回流加热2小时。将反应混合物冷却至室温且倾倒入冰(50ml)与水(50ml)的混合物中,随后搅拌直至冰融化。用乙酸乙酯(250ml)萃取混合物;且随后萃取物用水(100ml)和饱和氯化钠水溶液(100ml)洗涤;经硫酸钠干燥;过滤且在真空中蒸发,得到粗制2-(3,5-二溴-2-羟基苯基)乙酸(3.1g)。此物质不经进一步纯化或表征即直接用于下一步骤中。
步骤3
用硫酸(0.43ml,8.1mmol)处理粗制2-(3,5-二溴-2-羟基苯基)乙酸(3.1g,9.0mmol)于甲醇(17ml)中的溶液且在环境温度下搅拌反应物16小时。在真空中蒸发甲醇,且将残余物溶解于乙酸乙酯(270ml)中。溶液用水(2×200ml)和饱和氯化钠水溶液(130ml)洗涤;经硫酸钠干燥;过滤且在真空中蒸发,得到粗产物。利用以含0-20%乙酸乙酯的己烷洗脱的BiotageTMSP1系统(120g二氧化硅筒)纯化,得到2-(3,5-二溴-2-羟基苯基)乙酸甲酯(1.4g,49%)。1H NMR(400MHz,CDCl3):δ7.52(d,J=2.2Hz,1H),7.23(d,J=2.2Hz,1H),6.42(br s,1H),3.72(s,3H),3.65(s,2H);13C NMR(101MHz,CDCl3):δ172.06,150.60,133.74,133.50,123.94,112.62,111.77,52.78,36.61。
步骤4
用碳酸钾(0.26g,1.86mmol)、碘化钾(0.05g,0.32mmol)及苄基溴(0.20ml,1.7mmol)处理2-(3,5-二溴-2-羟基苯基)乙酸甲酯(0.5g,1.54mmol)于丙酮(5ml)中的溶液,且在室温下搅拌反应物1小时。在真空中蒸发丙酮,且残余物分配于乙酸乙酯(50ml)与1M盐酸水溶液(50ml)之间。有机相用饱和氯化钠水溶液(50ml)洗涤;经硫酸钠干燥;过滤且在真空中蒸发,得到粗产物。利用以含0-10%乙酸乙酯的己烷洗脱的BiotageTMSP1系统(40g二氧化硅筒)纯化,得到2-(2-(苄氧基)-3,5-二溴苯基)乙酸甲酯(0.6g,95%)。1H NMR(400MHz,CDCl3):δ7.67(d,J=2.4Hz,1H),7.48-7.51(m,2H),7.37(d,J=2.4Hz,1H),7.34-7.43(m,3H),4.99(s,2H),3.66(s,3H),3.60(s,2H);13C NMR(101MHz,CDCl3):δ171.26,153.79,136.56,135.38,133.57,132.04,128.82,128.64,128.52,118.69,117.56,75.53,52.50,35.86。
步骤5
如化合物I步骤2所述使2-(2-(苄氧基)-3,5-二溴苯基)乙酸甲酯(0.3g,0.73mmol)与(E)-戊-1-烯基硼酸酸频哪醇酯(0.4g,1.79mmol)偶联,得到2-(2-(苄氧基)-3,5-二((E)-戊-1-烯基)苯基)乙酸甲酯(0.21mg,72%)。1H NMR(400MHz,CDCl3):δ7.50(d,J=7.2Hz,2H),7.44(dd,J=7.2,7.2Hz,2H),7.43(d,J=2.1Hz,1H),7.38(dd,J=7.2,7.2Hz,1H),7.18(d,J=2.1Hz,1H),6.72(d,J=15.8Hz,1H),6.39(d,J=15.8Hz,1H),6.32(dt,J=15.8,7.0Hz,1H),6.22(dt,J=15.8,6.8Hz,1H),4.87(s,2H),3.69(s,3H),3.67(s,2H),2.20-2.29(m,4H),1.50-1.60(m,4H),1.01(t,J=7.3Hz,3H),1.00(t,J=7.4Hz,3H);13C NMR(101MHz,CDCl3):δ172.49,153.59,137.58,134.35,132.91,131.91,130.84,129.53,128.78,128.32,128.30,128.24,127.26,125.21,123.89,75.89,52.21,35.94,35.74,35.42,22.87,22.77,14.07,14.06。
步骤6
如化合物I步骤3所述使2-(2-(苄氧基)-3,5-二((E)-戊-1-烯基)苯基)乙酸甲酯(0.2g,0.53mmol)氢化,得到2-(2-羟基-3,5-二戊基苯基)乙酸甲酯(0.12g,73%)。1H NMR(400MHz,CDCl3):δ7.37(s,1H),6.92(d,J=2.1Hz,2H),6.77(d,J=2.1Hz,1H),3.76(s,3H),3.67(s,2H),2.65(t,J=7.8Hz,2H),2.51(t,J=7.8Hz,2H),1.58-1.66(m,4H),1.31-1.41(m,8H),0.93(t,J=7.0Hz,3H),0.92(t,J=6.9Hz,3H);13C NMR(101MHz,CDCl3):δ175.01,151.27,135.14,131.48,129.92,128.52,120.30,52.95,38.35,35.34,32.15,31.86,31.74,30.61,30.03,22.87,22.83,14.34,14.31。
步骤7
如化合物I步骤4所述使2-(2-羟基-3,5-二戊基苯基)乙酸甲酯(0.2g,0.53mmol)水解,得到与丙酮化物质混合的粗产物。利用以含0-100%乙酸乙酯的己烷洗脱的BiotageTMSP1系统(120g二氧化硅筒)纯化一小份,得到2-(2-羟基-3,5-二戊基苯基)乙酸(13.5mg)。1H NMR(400MHz,CDCl3):δ10.5(br s,1H),6.89(d,J=2.2Hz,1H),6.78(d,J=2.2Hz,1H),6.32(br s,1H),3.66(s,2H),2.58(t,J=7.9Hz,2H),2.48(t,J=7.8Hz,2H),1.52-1.63(m,4H),1.26-1.37(m,8H),0.90(t,J=7.0Hz,3H),0.88(t,J=6.8Hz,3H)。
步骤8
如化合物I步骤5所述使2-(2-羟基-3,5-二戊基苯基)乙酸(13.5mg,0.046mmol)转化为钠盐,得到2-(2-羟基-3,5-二戊基苯基)乙酸钠(11mg,77%)。1H NMR(400MHz,CD3OD):δ6.72(d,J=2.0Hz,1H),6.69(d,J=2.0Hz,1H),3.46(s,2H),2.56(t,J=7.6Hz,2H),2.44(t,J=7.6Hz,2H),1.50-1.61(m,4H),1.25-1.37(m,8H),0.90(t,J=6.8Hz,3H),0.88(t,J=7.0Hz,3H);13C NMR(101MHz,CD3OD):δ180.33,151.94,133.47,130.37,128.21,127.81,123.99,42.90,34.97,31.81,31.60,31.40,30.25,29.88,22.51,22.45,13.29,13.24;LRMS(ESI负模式):m/z 291.2(100%,M-Na+);UPLC(系统B):7.7分钟。UPLC系统B:移动相A=0.1%甲酸水溶液;移动相B=含0.1%甲酸的乙腈;固相=HSS T3柱;梯度=含5-100%B的A,经10分钟。
化合物4:2-(3,5-二己基-2-羟基苯基)乙酸的钠盐
如关于化合物3所述使用(E)-己-1-烯基硼酸酸频哪醇酯制备上述化合物。1H NMR(400MHz,CD3OD):δ6.72(d,J=2.0Hz,1H),6.69(d,J=2.0Hz,1H),3.46(s,2H),2.56(t,J=7.6Hz,2H),2.44(t,J=7.5Hz,2H),1.50-1.60(m,4H),1.27-1.37(m,12H),0.89(t,J=6.6Hz,3H),0.88(t,J=6.80Hz,3H);LRMS(ESI负模式):m/z 319(100%,M-Na+);UPLC(系统B):8.7分钟。ULC系统B:移动相A=0.1%甲酸水溶液;移动相B=含0.1%甲酸的乙腈;固相=HSS T3柱;梯度=含5-100%B的A,经10分钟。
化合物5:2-(4-羟基-3,5-二戊基苯基)乙酸的钠盐
如关于化合物3所述自2-(3,5-二溴-4-羟基苯基)乙酸制备上述化合物。1H NMR(400MHz,CD3OD):δ6.87(s,2H),3.33(s,2H),2.55(t,J=7.7Hz,4H),1.53-1.61(m,4H),1.31-1.37(m,8H),0.90(t,J=7.0Hz,6H);LRMS(ESI负模式):m/z 291.1(100%,M-Na+);UPLC(系统B):6.8分钟。UPLC系统B:移动相A=0.1%甲酸水溶液;移动相B=含0.1%甲酸的乙腈;固相=HSS T3柱;梯度=含5-100%B的A,经10分钟。
化合物6:2-(3,5-二己基-4-羟基苯基)乙酸的钠盐
如关于化合物3所述自2-(3,5-二溴-4-羟基苯基)乙酸及(E)-己-1-烯基硼酸酸频哪醇酯制备上述化合物。1H NMR(400MHz,CD3OD):δ6.72(d,J=2.0Hz,1H),6.69(d,J=2.0Hz,1H),3.46(s,2H),2.56(t,J=7.6Hz,2H),2.44(t,J=7.5Hz,2H),1.50-1.60(m,4H),1.27-1.37(m,12H),0.89(t,J=6.6Hz,3H),0.88(t,J=6.8Hz,3H);LRMS(ESI负模式):m/z319.1(100%,M-Na+);UPLC(系统B):7.6分钟。UPLC系统B:移动相A=0.1%甲酸水溶液;移动相B=含0.1%甲酸的乙腈;固相=HSS T3柱;梯度=含5-100%B的A,经10分钟。
化合物7:2-(4-氟-3,5-二己基苯基)乙酸的钠盐
如关于化合物3所述以3,5-二溴-4-氟苄基溴和(E)-己-1-烯基硼酸酸频哪醇酯为起始物质来制备上述化合物。通过在80℃下于乙腈中用N-溴代丁二酰亚胺及偶氮双异丁腈使3,5-二溴-4-氟甲苯溴化来制备3,5-二溴-4-氟苄基溴。1H NMR(400MHz,CD3OD):δ6.98(d,JHF=7.0Hz,2H),3.38(s,2H),2.57(t,J=7.7Hz,4H),1.54-1.61(m,4H),1.28-1.37(m,12H),0.89(t,J=6.7Hz,6H);19F NMR(377MHz,CD3OD):δ-132.17(d,JHF=6.6Hz,1F);13CNMR(101MHz,CD3OD):δ179.44,158.11(d,JCF=239.8Hz),133.26(d,JCF=3.8Hz),128.73(d,JCF=5.4Hz),128.56(d,JCF=16.9Hz),44.52,31.69,30.35(d,JCF=1.5Hz),28.98,28.97(d,JCF=3.1Hz),22.51,13.29;LRMS(ESI负模式):m/z 321.0(100%,M-Na+);UPLC(系统B):9.2分钟。UPLC系统B:移动相A=0.1%甲酸水溶液;移动相B=含0.1%甲酸的乙腈;固相=HSS T3柱;梯度=含5-100%B的A,经10分钟。
化合物8:2-(4-氟-3,5-二戊基苯基)乙酸的钠盐
如关于化合物3所述以3,5-二溴-4-氟苄基溴为起始物质来制备上述化合物。1HNMR(400MHz,CD3OD):δ6.98(d,JHF=6.8Hz,2H),3.37(s,2H),2.57(t,J=7.6Hz,4H),1.54-1.62(m,4H),1.28-1.37(m,8H),0.90(t,J=7.0Hz,6H);19F NMR(377MHz,CD3OD):δ-132.34(d,JHF=6.6Hz,1F);13C NMR(101MHz,CD3OD):δ179.41,158.10(d,JCF=239.8Hz),133.26(d,JCF=3.8Hz),128.72(d,JCF=4.6Hz),128.56(d,JCF=16.9Hz),44.51,31.54,30.07,28.92(d,JCF=3.1Hz),22.38,13.22;LRMS(ESI负模式):m/z 293.0(100%,M-Na+);UPLC(系统B):8.4分钟。UPLC系统B:移动相A=0.1%甲酸水溶液;移动相B=含0.1%甲酸的乙腈;固相=HSS T3柱;梯度=含5-100%B的A,经10分钟。
实施例2:在TGF-β诱导的纤维母细胞及上皮细胞中本发明化合物对纤维化标志物α-SMA及胶原1的抗纤维化作用
纤维化为特征在于细胞外基质(ECM)过度积聚从而导致所涉及组织变硬和/或瘢痕形成的慢性及进行性过程。其经由复杂细胞、细胞外基质、细胞因子及生长因子相互作用而发展。涉及到不同的细胞类型,诸如常驻间质细胞(纤维母细胞及肌纤维母细胞)和源自上皮及内皮细胞的ECM产生细胞(经由称为上皮-间质转化及内皮-间质转化的过程)、局部或骨髓源干细胞(纤维细胞)。肌纤维母细胞长久以来已被视为正常伤口愈合中所涉及的主要细胞类型,且作为纤维生成的关键效应细胞。其可高度合成胶原和其他ECM组分,且特征为α-平滑肌肌动蛋白(α-SMA)的重新表达(于Scotton C.J.和Chambers R.C.,2007中综述)。纤维化动物模型中的纤维化损伤中肌纤维母细胞的存在与活性纤维化的发展有关,且其持续存在及对于人类疾病中纤维化位点的定位与疾病进展有关(Kuhn C.及McDonaldJ.A.,1991;及Zhang等人,1994)。肌纤维母细胞也展现增强的迁移表型(Suganuma等人,1995)且能够释放众多促纤维化介体。
在纤维母细胞中,已进行分析来测定优选的本发明化合物对正常大鼠肾纤维母细胞(NRK-49F)上TGF-β诱导的α-SMA(纤维化标志物)mRNA表达的影响。NRK-49F以浓度为10ng/ml的TGF-β处理且变得活化(肌纤维母细胞)并表达α-SMA。通过定量实时PCR测定促纤维化标志物α-SMA的表达。如表2中所示,本发明化合物在TGF-β诱导的NRK-49F细胞中抑制α-SMA的表达。
表2:在TGF-β诱导的NRK-49F细胞中化合物对α-SMA mRNA表达的抑制
在组织损伤期间导致器官纤维化(胶原、弹性蛋白、细胞粘合素(tenacin)及其他基质分子的沉积)的EMT作用变得日益清晰。关于与进行性肾脏疾病、肺、皮肤、心脏以及肝脏相关的EMT存在大量此类证据。举例而言,在肾脏中,新兴证据表明,肾小管上皮细胞可在病理条件下经历上皮-间质转化(EMT)而变为产生基质的纤维母细胞(Strutz F.,MüllerG.A.,2000;及Yang J.,Liu Y.,2001)。此表型转化不仅说明成熟的分化肾上皮细胞的显著塑性,且也在根本上牵涉于广泛多种慢性肾病的发病机制中(Iwano M.等人,2002;Yang J.等人,2002;Zeisberg M.等人,2001;及Yang J.,Liu Y.,2002)。近来的研究提供令人信服的证据,即纤维化的肾脏中很大比例之间质纤维母细胞经由EMT源自肾小管上皮细胞(Iwano M.等人,2002)。同样,肾小管EMT的选择性阻断由于在tPA-/-小鼠中保持了肾小管基底膜完整性而保护肾脏免于在阻塞性损伤后产生纤维化损伤(Yang J.等人,2002)。这些观察结果强调肾小管EMT在慢性肾纤维化(其最终导致末期肾衰竭)的发作和进展中的关键重要性。在不同的体外和体内模型中,已表明若干因子为EMT的潜在起始剂(Yang J,LiuY.,2001;Kalluri R.,Neilson E.G.,2003;Okada H.等人,1997;Fan J.M.等人,2001;Strutz F.等人,2002;Ha H.,Lee H.B.,2003;Lan H.Y.,2003;Lee J.M.等人,2006;和Zavadil J.,E.P.,2005)。除CTGF之外,这些介体各自需要诱导TGF-β以完成EMT过程(Yang J.,Liu Y.,2001;Liu Y.,2004;及Lan H.Y.,2003)。
在上皮细胞中,进行分析以测定本发明化合物对人类近端肾小管上皮细胞(HK-2)上TGF-β诱导的胶原1(纤维化标志物)的影响。HK-2细胞为来自人类肾脏的永生化近端肾小管上皮细胞,用浓度为10ng/mL的TGF-β处理,通过定量实时PCR测定促纤维化标志物胶原1的表达。如表3中所示,化合物1和2抑制TGF-β诱导的HK-2细胞中胶原的表达。
表3:在TGF-β诱导的HK-2上皮细胞中胶原mRNA表达的抑制
实施例3.本发明化合物对皮肤纤维化的抗纤维化作用
也使用正常人类皮肤纤维母细胞(NHDF)研究本发明化合物1对皮肤纤维化的作用。
进行体外分析以测定化合物I对正常人类皮肤纤维母细胞(NHDF)上TGF-β诱导的CTGF和α-SMA(纤维化标志物)的影响。通过定量实时PCR测定促纤维化标志物(CTGF)及纤维化标志物(α-SMA)的表达。如表4中所示,化合物1对α-SMA和CTGF的mRNA的表达的抑制率分别为99%和85%。
表4:在TGF-β诱导的NHDF细胞中α-SMA和CTGF mRNA表达的抑制
实施例4:肾纤维化模型中化合物1的抗纤维化活性
小鼠或大鼠中的典型肾纤维化实验模型包括db/db肾病小鼠(糖尿病性肾病模型)且反映在人类中观察到的肾病。在db/db小鼠模型中评估化合物1对糖尿病性肾病的作用。简言之,在第0天进行右肾完全切除术,自第1天起用媒介物或化合物1(10mg/kg和50mg/kg,每天一次经口)处理db/db小鼠(6周龄)且在第119天测量肾小球滤过率(GFR)作为肾功能的直接量度。图1展示db/db糖尿病小鼠相比于C57BL/6小鼠(对照小鼠)的GFR降低,明确显示与糖尿病相关的肾病。用10mg/kg和50mg/kg经口处理使肾脏GFR功能增加至正常(C57BL/6)小鼠水平,如图1中所示。此结果明确指示,用化合物1处理减少糖尿病db/db小鼠的肾脏的肾病和纤维化。
本文提及或引用的所有专利、专利申请案、临时申请案和公开案都以全文引用的方式并入,包括所有图式及表格,引用程度使得其与本说明书的明确教示没有不一致。
应理解,本文所述的实施例和实施方案仅为说明性目的且根据其的各种修改或变化应为本领域技术人员所想到且包括于本申请案的精神及范围内。
Claims (32)
1.一种由下式表示的化合物或其药学上可接受的盐:
其中
A为C5烷基或C6烷基;
R1为H;
R2为C5烷基或C6烷基;
R3为H;
R4为H或OH;和
Q为(CH2)mC(O)OH,其中m为1。
2.根据权利要求1所述的化合物或药学上可接受的盐,其为:
或其药学上可接受的盐。
3.根据权利要求2所述的化合物或药学上可接受的盐,其为化合物1或其药学上可接受的盐。
4.根据权利要求2所述的化合物或药学上可接受的盐,其为化合物2或其药学上可接受的盐。
5.根据权利要求2所述的化合物或药学上可接受的盐,其为化合物3或其药学上可接受的盐。
6.根据权利要求1至5中任一项所述的化合物或药学上可接受的盐,其中所述药学上可接受的盐为钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、锰盐、锌盐、铁盐、铜盐或伯胺盐。
7.根据权利要求6所述的化合物或药学上可接受的盐,其中所述药学上可接受的盐为钠盐。
8.根据权利要求6所述的化合物或药学上可接受的盐,其中所述药学上可接受的盐为伯胺盐。
9.权利要求1至8中任一项所述的化合物或其药学上可接受的盐在制备用于减少细胞中的胶原生成的药物中的用途。
10.权利要求1至8中任一项所述的化合物或其药学上可接受的盐在制备用于预防患有纤维化疾病的受试者中的纤维化和/或减缓患有纤维化疾病的受试者中的纤维化的进展和/或治疗患有纤维化疾病的受试者中的纤维化的药物中的用途。
11.根据权利要求10所述的用途,其中所述纤维化疾病为肺纤维化、肝纤维化、皮肤纤维化、肾纤维化、胰腺纤维化或心脏纤维化。
12.根据权利要求11所述的用途,其中所述纤维化疾病为肺纤维化。
13.根据权利要求11或12所述的用途,其中所述纤维化疾病为特发性肺纤维化、结节病、囊性纤维化、家族性肺纤维化、硅肺病、石绵沉着病、煤矿工人尘肺病、碳尘肺病、过敏性肺炎、由吸入无机粉尘引起的肺纤维化、由感染物引起的肺纤维化、由吸入有毒气体、气溶胶、化学粉尘、烟雾或蒸气引起的肺纤维化、药物诱发的间质性肺病、肺性高血压或慢性阻塞性肺病。
14.根据权利要求11所述的用途,其中所述纤维化疾病为肝纤维化。
15.根据权利要求14所述的用途,其中所述肝纤维化由慢性肝病、乙型肝炎病毒感染、丙型肝炎病毒感染、丁型肝炎病毒感染、血吸虫病、酒精性肝病或非酒精性脂肪肝炎、肥胖症、糖尿病、蛋白质营养不良、冠状动脉疾病、自身免疫性肝炎、囊性纤维化、α-1-抗胰蛋白酶缺乏症、原发性胆汁性肝硬化、药物反应及暴露于毒素引起。
16.根据权利要求15所述的用途,其中所述肝纤维化由非酒精性脂肪肝炎引起。
17.根据权利要求11所述的用途,其中所述纤维化疾病为肾纤维化。
18.根据权利要求17所述的用途,其中所述肾纤维化由肾衰竭后的透析、导管置放、或肾病引起。
19.根据权利要求17所述的用途,其中所述肾纤维化由肾小球硬化、肾小球肾炎、慢性肾功能不全、急性肾损伤、慢性肾病、末期肾病或肾衰竭引起。
20.根据权利要求9至19中任一项所述的用途,其中所述化合物以1mg/kg至50mg/kg的治疗有效量经口施用给所述受试者,且所述受试者为人。
21.根据权利要求20所述的用途,其中所述治疗有效量为1mg/kg至20mg/kg。
22.根据权利要求11所述的用途,其中所述纤维化疾病为皮肤纤维化。
23.根据权利要求22所述的用途,其中所述皮肤纤维化为瘢痕形成、增生性瘢痕形成、瘢痕瘤、皮肤纤维化病症、伤口愈合、伤口延迟愈合、银屑病或硬皮病。
24.根据权利要求23所述的用途,其中所述瘢痕形成源自烧伤、创伤、手术损伤、辐射或溃疡。
25.根据权利要求24所述的用途,其中所述溃疡为糖尿病性足溃疡、静脉性腿溃疡或压力性溃疡。
26.根据权利要求22至25中任一项所述的用途,其中所述化合物以0.01%至10%(w/w)的治疗有效量经局部施用给所述受试者,且所述受试者为人。
27.权利要求1至8中任一项所述的化合物或其药学上可接受的盐在制备用于拮抗哺乳动物的器官中的胶原分泌或胶原沉积的药物中的用途,其中所述器官为肺、肝脏、肾脏、胰脏、皮肤或心脏。
28.根据权利要求9至27中任一项所述的用途,其中所述化合物与治疗有效量的第二化合物组合施用,所述第二化合物为免疫抑制药物、抗炎药、细胞因子、单克隆抗体、多重受体酪氨酸激酶抑制剂、抗氧化剂、酶抑制剂、整合素抑制剂、高血压抑制剂、脂质受体调节剂或抗糖尿病药物。
29.一种用于预防患有纤维化疾病的受试者中的纤维化和/或减缓患有纤维化疾病的受试者中的纤维化的进展和/或治疗患有纤维化疾病的受试者中的纤维化的试剂盒,其包含权利要求1至8中任一项所述的化合物或其药学上可接受的盐,以及用于向所述受试者施用治疗有效量的所述化合物或其药学上可接受的盐的说明书。
30.根据权利要求29所述的试剂盒,其中所述纤维化疾病为肺纤维化、肝纤维化、皮肤纤维化、肾纤维化、胰腺纤维化或心脏纤维化。
31.根据权利要求29或30所述的试剂盒,其包含用于向所述受试者每天经口施用1mg/kg至50mg/kg的所述化合物或其药学上可接受的盐的说明书,其中所述受试者为人。
32.根据权利要求29或30所述的试剂盒,其包含用于向所述受试者每天经局部施用0.01%至10%(w/w)的所述化合物的说明书,其中所述受试者为人,且所述纤维化疾病为皮肤纤维化。
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