CN116077489A - 用于治疗及/或预防纤维化疾病的吲哚啉衍生物 - Google Patents
用于治疗及/或预防纤维化疾病的吲哚啉衍生物 Download PDFInfo
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Abstract
本发明涉及用于治疗及/或预防纤维化疾病的吲哚啉衍生物、吲哚啉衍生物的用途,及其用于预防及/或治疗纤维化疾病的有效剂量。所述化合物可有效预防及/或治疗纤维化疾病且无细胞毒性或遗传毒性。
Description
本申请是申请日为2015年10月27日、申请号为“201580084223.3”、名称为“用于治疗及/或预防纤维化疾病的吲哚啉衍生物”的发明专利申请的分案申请。
技术领域
本发明涉及一种治疗及/或预防纤维化疾病的方法或用途。特别地,所述方法使用吲哚啉衍生物来治疗及/或预防纤维化疾病且无细胞毒性及遗传毒性。
背景技术
纤维化是于器官或组织通常由于受伤或长期发炎而在修复或反应过程(例如愈合)中形成过量纤维性结缔。纤维化导致受影响组织硬化及/或肿胀并减少流体流动通过此等组织。因此,一些组织会纤维化且纤维化组织会无法正常发挥作用。例如,肝脏纤维化是过于旺盛的创伤愈合,其中于肝脏中建立过量结缔组织。慢性肝病可导致肝纤维化,其病因是慢性病毒性B型肝炎及酒精性肝病。肺纤维化(字面意思“肺部瘢痕”)是呼吸疾病,其中瘢痕是于肺组织中形成,从而导致严重呼吸问题。瘢痕形成,过量纤维性结缔组织的累积(所述过程称为纤维化)导致壁增厚,从而导致血液中的氧供应减少。因此患者罹患永久性呼吸急促。肾脏纤维化是胞外基质的过量累积的必然结果,其几乎出现于各种类的慢性肾疾病中。肠道纤维化是发炎性肠病(IBD)的常见并发症并可出现于溃疡性结肠炎(UC)及克隆氏症(CD)二者中,然于CD中更加盛行。纤维化亦可出现于心脏中,例如心脏纤维化可呈心瓣膜的增厚出现。
组织蛋白去乙酰酶(HDAC)是依据以下四种类型分类:类型I(HDAC1、2、3及8);类型IIa(HDAC4、5、7及9)及类型IIb(HDAC6及10);类型III(SIRT1-7)及类型IV(HDAC11)。此等涉及核心组织蛋白及非组蛋白蛋白质的转译后修饰。US 8,846,748揭示特定吲哚基或吲哚啉基羟肟酸盐化合物作为具有有效抗癌活性的HDAC抑制剂。Masahiro Yoshikawa等人于人类RPTEC(Masahiro Yoshikawa等人,J Am Soc Nephrol 18:58-65,2007)中指出HDAC抑制剂预防肝脏、皮肤及肺的纤维化,然大部分其潜在机制仍有待阐明,并提出诱导几个TGF-β1信号的抑制因子的TSA(HDAC抑制剂),诸如Id2及BMP-7。Maoyin Pang及Shougang Zhuang指出一些慢性病的显现及进展是通过纤维化表征,包括慢性肾疾病、心脏肥大及自发性肺纤维化(Maoyin Pang及Shougang Zhuang,The Journal of Pharmacology and ExpermentalTherapeutics,第355卷,编号2,第266至272页,2010)。
然而,已经充分开发认定为纤维化的HDAC抑制剂的潜在候选非常少。因此,仍然需要开发抗纤维化药物。
发明内容
本发明提供一种预防及/或治疗个体的纤维化疾病的方法,其包括向个体投与有效量的本文所述的化合物作为活性成分。优选地,有效量是n,针于个体为约1.5mg/kg/天至约20mg/kg/天的范围内。于一些实施例中,所述有效量的活性成分于以下的范围内:约1.5mg/kg/天至约15mg/kg/天、约1.5mg/kg/天至约13mg/kg/天、约1.5mg/kg/天至约12mg/kg/天、约1.5mg/kg/天至约10mg/kg/天、约2.0mg/kg/天至约20mg/kg/天、约2.0mg/kg/天至约15mg/kg/天、约2.0mg/kg/天至约13mg/kg/天或约2.0mg/kg/天至约12mg/kg/天、约5mg/kg/天至约20mg/kg/天、约5mg/kg/天至约15mg/kg/天或约5mg/kg/天至约10mg/kg/天。于一些实施例中,本发明方法的活性成分是进一步与第二抗纤维化药剂组合投与。优选地,第二抗纤维化药剂是ESBRIET(吡非尼酮(pirfenidone))、OFEV(尼达尼布(nintedanib))、LOXL2抗体(诸如辛图单抗(simtuzumab))、IL-13抗体(罗氏单抗(lebrikizumab))、αVβ6抗体(诸如STX-100)、CTGF抗体(诸如FG-3019)、泰鲁司特(tipelukast)(诸如MN-001)或气雾剂吡非尼酮(诸如GP-101)。于一些实施例中,纤维化疾病是皮肤纤维化、肺纤维化、肾脏纤维化、肝脏纤维化、肠道纤维化、囊肿纤维化、心脏纤维化、子宫平滑肌瘤或子宫肌腺症。于另一实施例中,肺纤维化是自发性肺纤维化。
本发明亦提供一种医药组合物,其包含以一或多个单位剂型的于约100mg至约1,400mg的范围内的日剂量的3-(1-苯磺酰基-2,3-二氢-1H-吲哚-5-基)-N-羟丙烯酰胺或医药上可接受的盐、溶剂化物或前药作为活性成分。
图式简单说明
图1(A)、图1(B)及图1(C)显示TMU-C-0012、地塞米松(dexamethasone)及吡非尼酮对小鼠的经博莱霉素诱导的肺纤维化的抗纤维化效应。于预防模型中,结果显示TMU-C-0012以剂量相依方式抑制经BLM诱导的肺纤维化(A)且TMU-C-0012的抑制功效高于地塞米松(B)。于治疗模型中,结果显示TMU-C-0012以剂量相依方式抑制经BLM诱导的肺纤维化(A)且TMU-C-0012的抑制功效高于吡非尼酮(C)。
图2显示TMU-C-0012及SAHA于小鼠中对经博莱霉素诱导的肺纤维化的抗纤维化效应。
图3显示TMU-C-0012及地塞米松于小鼠中对经OVA诱导的肺纤维化的抗纤维化效应。
图4显示TMU-C-0012于小鼠中对经硅石诱导的肺纤维化的抗纤维化效应。
图5显示TMU-C-0012及吡非尼酮于小鼠中对经CCl4诱导的肝脏纤维化的抗纤维化效应。
具体实施方式
本发明是(至少部分)基于发现使用吲哚啉衍生物及其有效剂量来预防及/或治疗纤维化疾病。所述化合物可有效地预防及/或治疗纤维化疾病且无细胞毒性或遗传毒性。
如本文所用,除语境中另有需要外,术语“包括”及术语的变化,诸如“包括(comprising/comprise/comprised)”不希望排除其他添加剂、组分、整数或步骤。
如本文所用,除语境中另有需要外,所揭示的方法步骤不希望受限制其也不希望表示每个步骤对所述方法而言必要的或每个步骤必须以所揭示的顺序出现。
如本文所用,除非另有说明,否则使用的“或”意为“及/或”。于文中多个附属申请专利范围中,使用的“或”是指仅在所述备择方案中多于一个先前独立或者附属申请专利范围。
如本文所用,所有数字是近似的,且可变化地说明测量误差及有效位数的舍入。于某些测量的量前使用的“约”包括由于样品杂质、测量误差、人为误差及统计变异以及有效位数的舍入的变化。
如本文所用,术语“医药上可接受的盐”是指彼等在合理医药判断范围内适于与人体及低等动物组织接触且无异常毒性、刺激、过敏反应等,且符合合理效益/风险比值的盐。医药上可接受的盐是此项技术中所熟知。例如Berge等人详细地于J.PharmaceuticalSciences,1977,66,1-19中描述医药上可接受的盐,所述文章以引用的方式并入本文中。本发明化合物的医药上可接受的盐包括彼等衍生自合适无机及有机酸及碱者。医药上可接受的实例,无毒酸添加盐是用无机酸诸如氢氯酸、氢溴酸、磷酸、硫酸及过氯酸或用有机酸诸如乙酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸或丙二酸或通过使用此项技术中已知的其他方法诸如离子交换来形成的胺基的盐。其他医药上可接受的盐包括己二酸盐、海藻酸盐、抗坏血酸盐、天冬胺酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷丙酸盐、双葡萄醣酸盐、十二烷基硫酸盐、乙磺酸盐、蚁酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚酸盐、已酸盐、氢碘化物、2-羟基-乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟碱酸盐、硝酸盐、油酸盐、草酸盐、软脂酸盐、双羟萘酸盐、果胶酯酸盐、过氧硫酸盐、3-苯丙酸盐、磷酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一烷酸盐、戊酸盐及类似者。衍生自适当碱的盐包括碱金属、碱土金属及铵盐。典型碱或碱土金属盐包括钠、锂、钾、钙、镁及类似者。其他医药上可接受的盐包括(当适当时)使用抗衡离子诸如卤离子、氢氧离子、羧酸根离子、硫酸根离子、磷酸根离子、硝酸根离子、低碳烷基磺酸根离子及芳基磺酸根离子形成的无毒铵、四级铵及胺类阳离子。
术语“溶剂化物”是指通常通过溶剂分解反应而与溶剂缔合的化合物形式。此物理缔合可包括氢键结。习知溶剂包括水、甲醇、乙醇、乙酸、DMSO、THF、乙醚及类似者。本文所述的化合物可制备成,例如,结晶形式及可溶剂化。合适溶剂化物包括医药上可接受的溶剂化物且进一步包括化学计量溶剂化物及非化学计量溶剂化物。在某些情况中,所述溶剂化物可单离,例如,当将一或多种溶剂分子合并至结晶固体的晶格中时。“溶剂化物”涵盖溶液相及可单离溶剂化物。典型溶剂化物包括水合物、乙醇化物及甲醇化物。
术语“前药”是指具有可裂解基团及通过溶剂分解作用或在生理条件下变为本文所述的化合物,包括本文所述的化合物的衍生物,其等在体内成医药活性。此等实例包括,但不限于,胆碱酯衍生物及类似者、N-烷基吗啉酯及类似者。本发明化合物的其他衍生物在酸及酸衍生物形式下皆具有活性,但在酸敏感形式下,经常提供关于溶解度、组织相容性或在哺乳动物中延迟释放的优点(参见,Bundgard,H.,Design of Prodrugs,第7至9页,第21至24页,Elsevier,Amsterdam 1985)。前药包括本技艺从业人员熟知的酸衍生物,如例如,通过母体酸与合适醇的反应所制备的酯,或通过母体酸化合物与经取代或未经取代的胺的反应所制备的酰胺,或酸酐,或混合酸酐。
如本文所用的术语“投与(administer/administering/administration)”是指向个体植入、吸收、摄取、注射、吸入或者引入本发明化合物或其医药组合物。
如本文所用,术语“病况”、“疾病”及“病症”可交换地使用。
本文所述的化合物的“有效量”是指足以引出所需的生物反应(即治疗病况)的量。如一般技术者应了解本文所述的化合物的有效量可端视如所希望的生物学终点、化合物的药物动力学、治疗的病况、投药的模式及个体的年龄与健康状况等因素而变化。有效量涵盖治疗及预防性治疗。
本文所述的化合物的“治疗有效量”是足以在病况治疗中提供治疗效益或延迟或最小化一或多种与病况相关的症状的量。化合物的治疗有效量意为治疗药剂单独或与其他疗法的组合在病况治疗中提供治疗效益的量。术语“治疗有效量”可涵盖改良整体疗法,减少或避免症状或病因,及/或增强另一治疗药剂的治疗功效的量。
本文所述的化合物的“预防有效量”是足以预防病况或一或多种与病况相关的症状或预防其复发的量。化合物的预防有效量意为治疗药剂单独或与其他疗法的组合在病况预防中提供预防效益的量。术语“预防有效量”可涵盖改良整体预防法或增强另一预防药剂的预防功效的量。
如本文所用,术语“医药上可接受的载剂”是指此项技术中习知的用于与治疗药剂投与给个体的固体、半固体或液体充填剂、稀释剂、囊封物质、调配助剂或载剂。医药上可接受的载剂所用的剂量及浓度是对接受者无毒的并与调配物的其他成分相容。医药上可接受的载剂部分通过经投与的特定组合物以及通过投与组合物所用的特定方法来决定。
如本文所用,本文中定义的术语“个体”包括动物,诸如:哺乳动物,包括(但不限于)灵长类动物(例如,人)、乳牛、绵羊、山羊、马、狗、猫、兔、大鼠、小鼠及类似者。于某些实施例中,所述个体为人。术语“个体”及“患者”于本文中以引用方式可交换使用,例如,哺乳类个体,诸如人。
如本文所用,术语“治疗(treat/treating/treatment)”是指疾病或病症,或一或多种与疾病或病症相关的症状的根除或改善。于某些实施例中,这些术语是指向具有疾病或病症的个体投与一或多种预防或治疗药剂所造成的此疾病或病症的传布或恶化最小化。于一些实施例中,这些术语是指于特定疾病的诊断或症状开始之后,投与本文中提供的化合物或剂型并有或无一或多种另外活性药剂。
如本文所用,术语“预防(prevent/preventing及prevention)”是指预防疾病或病症,或一或多种其的症状的开始、复发或传布。于某些实施例中,这些术语是指于症状开始之前,尤其针对本文中提供的疾病或病症的高风险患者使用本文中提供的化合物或抗体或剂型并有或无一或多种另外活性药剂来治疗或投药。这些术语涵盖特定疾病的症状的抑制或减少。就此而言,术语“预防”可与术语“预防性治疗”交换使用。
如本文所用,除非另有指示,否则术语“组合投与”及“与……组合”包括两或多种治疗药剂于无具体时间限制下同时、并行、分开或依序投与。于一实施例中,治疗药剂是相同组合物或单位剂型。于其他实施例中,治疗药剂是分开组合物或单位剂型。
于一态样中,本发明提供一种预防及/或治疗个体的纤维化疾病的方法,其包括向个体投与有效量的式(I)化合物或其医药上可接受的盐、溶剂化物或前药作为活性成分;
其中n为0、1或2;
R1为SO2Ra,其中Ra为烯基、炔基、苯基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基;
R2为烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基、杂环烯基、卤基、氰基、硝基、ORb、SRb、S(O)Rb、NHC(O)-CH=CH-C(O)Rb、NHC(O)-CH=CH-C(O)NRcRd、SO2NRcRd、OC(O)Rb、C(O)NRcRd、NRcRd、NHC(O)Rb、NHC(O)NRcRd或NHC(S)Rc,其中Rb、Rc及Rd各自独立地为H、羟基、烷氧基、芳氧基、杂芳氧基、烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基;及
R3、R4、R5及R6各自独立地为H、烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基、杂环烯基、卤基、氰基、硝基、ORb、SRb、S(O)Rb、CH=CH-C(O)NRcRd、NHC(O)-CH=CH-C(O)Rb、NHC(O)-CH=CH-C(O)NRcRd、SO2NRcRd、OC(O)Rb、C(O)NRcRd、NRcRd、NHC(O)Rb、NHC(O)NRcRd或NHC(S)Rc,其中Rb、Rc及Rd各自独立地为H、羟基、烷氧基、芳氧基、杂芳氧基、烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基。
于一些实施例中,R4为CH=CH-C(O)NRcRd、NHC(O)-CH=CH-C(O)Rb或NHC(O)-CH=CH-C(O)NRcRd;优选R4为C(O)NHOH、CH=CH-C(O)NHOH、NHC(O)-CH=CH-C(O)OH或NHC(O)-CH=CH-C(O)NHOH;更优选R4为CH=CH-C(O)NHOH。
于一些实施例中,R1为SO2Ra及Ra为视情况经卤基、羟基、烷氧基、胺基、氰基或硝基取代的杂芳基或苯基。
于一些实施例中,R2为NHC(O)-CH=CH-C(O)Rb或NHC(O)-CH=CH-C(O)NRcRd;且R3、R5及R6独立地为CH=CH-C(O)NRcRd、NHC(O)-CH=CH-C(O)Rb或NHC(O)-CH=CH-C(O)NRcRd。
于另一些实施例中,R2为NHC(O)-CH=CH-C(O)OH或NHC(O)-CH=CH-C(O)NHOH;R3、R5及R6独立地为CH=CH-C(O)NHOH、NHC(O)-CH=CH-C(O)OH或NHC(O)-CH=CH-C(O)NHOH;R1为SO2Ra,其中Ra为视情况经卤基、羟基、烷氧基、胺基、氰基或硝基取代的杂芳基或苯基。
于另一实施例中,式(I)化合物是选自由以下组成的群:
或其医药上可接受的盐、溶剂化物或前药。
于另一实施例中,式(I)化合物为3-(1-苯磺酰基-2,3-二氢-1H-吲哚-5-基)-N-羟丙烯酰胺或其医药上可接受的盐、溶剂化物或前药。3-(1-苯磺酰基-2,3-二氢-1H-吲哚-5-基)-N-羟丙烯酰胺的结构是如下所示。
于一实施例中,有效量为约1.5mg/kg/天至约20mg/kg/天的范围内。于另一实施例中,针对人类的有效量为约2.0mg/kg/天至约15mg/kg/天的范围内。另一方面,本发明亦提供一种有效量的本文所述的化合物或医药上可接受的盐、溶剂化物或前药作为活性成分的用途,其用于制造预防及/或治疗纤维化疾病的药剂。
如本文所述的式(I)化合物及其制备已经揭示于US 8,846,748中,所述案是以引用的方式并入本文中。
于另一些实施例中,本发明所用的有效量的活性成分于以下的范围内:约1.5mg/kg/天至约15mg/kg/天、约1.5mg/kg/天至约13mg/kg/天、约1.5mg/kg/天至约12mg/kg/天、约1.5mg/kg/天至约10mg/kg/天、约2.0mg/kg/天至约20mg/kg/天、约2.0mg/kg/天至约15mg/kg/天、约2.0mg/kg/天至约13mg/kg/天或约2.0mg/kg/天至约12mg/kg/天、约5mg/kg/天至约20mg/kg/天、约5mg/kg/天至约15mg/kg/天或约5mg/kg/天至约10mg/kg/天。于另一实施例中,本发明所用的有效量为约2.3mg/kg/天至约11mg/kg/天。
针对治疗纤维化疾病,有效量的活性成分于以下的范围内:约5mg/kg/天至约20mg/kg/天、约5mg/kg/天至约18mg/kg/天、约5mg/kg/天至约15mg/kg/天、约5mg/kg/天至约13mg/kg/天、约5mg/kg/天至约11mg/kg/天或约5mg/kg/天至约10mg/kg/天。
针对预防纤维化疾病,有效量的活性成分于以下的范围内:约1.5mg/kg/天至约10mg/kg/天、约1.5mg/kg/天至约8mg/kg/天、约2mg/kg/天至约10mg/kg/天、约4.0mg/kg/天至约8mg/kg/天或约6.0mg/kg/天至约8.0mg/kg/天。
于一实施例中,本发明的活性成分进一步与第二抗纤维化药剂组合投与。优选地,第二抗纤维化药剂是ESBRIET(吡非尼酮)、OFEV(尼达尼布)、LOXL2抗体(诸如辛图单抗)、IL-13抗体(罗氏单抗)、αVβ6抗体(诸如STX-100)、CTGF抗体(诸如FG-3019)、泰鲁司特(诸如MN-001)或气雾剂吡非尼酮(诸如GP-101)。于另一实施例中,组合投与是同时、分开或依序投与。
于一些实施例中,纤维化疾病是皮肤纤维化、肺纤维化、肾脏纤维化、肝脏纤维化、肠道纤维化、囊肿纤维化、心脏纤维化、子宫平滑肌瘤或子宫肌腺症。于另一实施例中,肺纤维化是自发性肺纤维化。于又另一实施例中,治疗肺纤维化的方法进一步包括与肺移植、高压氧疗法(HBOT)、肺复健的组合投与疗法。
于另一态样中,本发明提供一种医药组合物,其包含以一或多个单位剂型的于约100mg至约1,400mg的范围内的日剂量的如上文所述的式(I)化合物或医药上可接受的盐、溶剂化物或前药作为活性成分。于一实施例中,本发明医药组合物包含约140mg至约1,050mg的范围内的日剂量。
于一些实施例中,本发明医药组合物是呈一或多种胶囊型或锭剂型。于另一实施例中,本发明医药组合物于单锭剂中包含约100mg至约300mg、约150mg至约300mg、约150mg至约250mg、约200mg to 250mg、约220mg至约280mg、约220mg至约250mg或约200mg至约220mg的活性成分;优选,于单锭剂中约200mg或220mg。于又另一实施例中,本发明医药组合物于单胶囊中包含约100mg至约500mg、约150mg至约500mg、约180mg至约500mg、约200mg至约500mg、约150mg至约350mg、约150mg至约300mg、约200mg至约400mg、约200mg至约350mg、约200mg至约300mg、约250mg至约500mg、约250mg至约400mg、约250mg至约350mg或约250mg至约300mg的活性成分;优选,于单胶囊中约250mg的活性成分。
于一实施例中,本发明医药组合物包含第二抗纤维化药剂。优选地,第二抗纤维化药剂是ESBRIET(吡非尼酮)、OFEV(尼达尼布)、LOXL2抗体(诸如辛图单抗)、IL-13抗体(罗氏单抗)、αVβ6抗体(诸如STX-100)、CTGF抗体(诸如FG-3019)、泰鲁司特(诸如MN-001)或气雾剂吡非尼酮(诸如GP-101)。
虽然本发明化合物可以化学原料投与,其亦可能以医药调配物存在。相应地,本发明提供一种医药调配物或组合物,其包含化合物或其医药上可接受的盐、前药或溶剂化物,与一或多种其医药上可接受的载剂或视情况一或多种其他治疗成分。载剂应为“可接受”意为可与调配物的其他成分相容且对其接受者不会造成伤害。恰当的调配物是取决于所选择的给药途径。调配物可为以下的形式:锭剂、丸剂、胶囊、半固体、粉末、持续释放调配物、溶液、悬浮液、酏剂、气雾剂或任何其他适当组合物;及包含至少一种与至少一种医药上可接受的赋形剂组合的本发明化合物。合适赋形剂为一般技术者所熟知,且其与调配组合物的方法可于此参考标准中发现如Remington:The Science and Practice of Pharmacy,A.Gennaro编辑,第20版,Lippincott,Williams&Wilkins,Philadelphia,Pa。合适液体载剂,尤其可注射溶液包括水、盐水注射液、葡萄糖水溶液及二醇类。本发明医药组合物可以本身为人已知的方式制造,例如通过习知的混合、溶解、粒化、制造糖衣锭、磨细(levigating)、乳化、囊封、包埋或压缩制程。
调配物包括彼等适于口服、非口服(包括皮下、皮内、肌内、静脉内、关节内及髓内)、腹膜内、经黏膜、经皮、直肠及局部(包括皮肤、颊、舌下及眼内)投药者,尽管最合适途径可取决于接受者的病况及病症。口服投药法是优选途径。调配物可合宜地以单位剂型存在及可通过药学技术中任何熟知的方法制备。所有方法包括以下步骤:使本发明化合物或其医药上可接受的盐、前药或溶剂化物(活性成分)与组成一或多种附加成分的载剂缔合。一般而言,调配物是通过使活性成分与液体载剂或微细固体载剂或二者均匀地及紧密地缔合,且随后(若需要)将产品成形为所需调配物而制得。
针对口服投药,合适本发明医药组合物包含粉末、颗粒、丸剂、锭剂、菱形锭、嚼锭、凝胶及胶囊以及液体、糖浆、悬浮液、酏剂及乳液。此等组合物亦可包含抗氧化剂、矫味剂、防腐剂、悬浮、增稠及乳化剂、着色剂、调味剂及其他医药上可接受的添加剂。用于口服投药的调配物可经调配为立即释放或经修改的释放,其中经修改的释放包括延迟、持续、脉冲、受控、靶向及规画释放。
针对非口服投药,本发明化合物经由静脉内、动脉内、腹膜内、肌内、皮下或其他注射或输液直接投与至血流、肌肉、或器官。非口服调配物可制备成水性注射液,其可含有(除本发明化合物外)缓冲剂、抗氧化剂、抑菌剂、盐、碳水化合物及常用于此等溶液中的其他添加剂。非口服投药可是立即释放或经修改的释放(诸如注射或植入式储存物)。
本发明化合物或组合物亦可经局部、皮(内)或经皮投与至皮肤或黏膜。典型调配物包括凝胶、水凝胶、洗剂、溶液、乳霜、软膏、敷料、泡沫剂、皮肤贴片、糯米纸囊剂、植入物及微乳液。本发明化合物或组合物亦可经由吸入或鼻内投药来投与,诸如干粉末、气雾剂喷雾或如滴剂。本发明化合物的另外投药途径包括阴道内及直肠(通过栓剂、子宫托或灌肠剂)及眼睛及耳。
所述剂量方案可经调整以提供最佳的治疗反应。例如,几个分剂量可每日投与或剂量可如通过治疗情况的紧急性指示来按比例减少。
尤其有利的是以单位剂型调配化合物以易于投药及剂量的均匀性。如本文所用的单位剂型是指适于待治疗个体的单位剂量的物理离散单元;各自含有治疗有效量的化合物及至少一种医药赋形剂。药物产品包括于贴有或伴随指示所需治疗方法的标签的容器内的单位剂型。
应了解前述实例仅是说明本发明。可制成所用的物品及/或方法的某些修改并仍达成本发明的目标。这些修改是预期于本发明的范围内。
实例
实例1 3-(1-苯磺酰基-2,3-二氢-1H-吲哚-5-基)-N-羟丙烯酰胺的遗传毒性的安氏(Ames)测试
化合物3-(1-苯磺酰基-2,3-二氢-1H-吲哚-5-基)-N-羟丙烯酰胺(下文称为“TMU-C-0012”)是使用安氏测试来评估以评定潜在致突变性。使用鼠伤寒沙门杆菌的两个组胺酸营养缺陷突变体(TA98及TA100)。测试菌株是自冰冻加工储备瓶并于室温下解冻来获得。将0.2mL等分试样接种至25mL营养肉汁培养基中及然后于振动(120rpm)下,在35至37℃下培养16至18小时。将测试物质溶解于DMSO,以10倍稀释以获得于30,000、3,000、300及30μg/mL的4种储备浓度。制备大鼠肝脏微粒体酵素均质物(S9)混合物,其含有8mM MgCl2、33mMKCl、4mM NADP、5mM葡萄糖-6-磷酸盐、100mM NaH2PO4(pH 7.4)及4%(v/v)Aroclor 1254-诱导的雄性大鼠肝脏微粒体酵素均质物(S9)。将0.2mL等分试样的测试化合物储备溶液与0.1mL菌株培养液及0.5mL大鼠肝脏微粒体酵素均质物(S9)混合物或0.5mL PBS组合及然后将混合物于振动(120rpm)下,在35至37℃下培养20min。添加熔融顶层琼脂(2mL含有0.05mM组胺酸及0.05mM生物素)及然后将混合物倒入最小葡萄糖琼脂板(30mL的底层琼脂/培养皿)的表面上以获得3000、300、30及3μg/培养皿的最终测试物质浓度。将培养皿于37℃下培养72小时及然后对His+反变种菌落的数量进行计数。相较于媒液对照结果为增加3倍(≥3×)的反变种菌落的处理被视为致突变的。减少至≤50%的媒液对照的菌落计数的处理被视为细胞毒性的。进行三重复测定。
下表显示安氏测试结果,其显示化合物TMU-C-0012的遗传毒性是阴性。
-:无显著致突变性或细胞毒性
+:显著致突变性或细胞毒性
实例2活体外哺乳动物细胞微核测定
活体外微核(MNvit)测定使用经培养的人体细胞通过侦测非整倍体诱发剂及染色体异常诱发剂二者来提供研究活体外染色体损害可能性的综合基础。所述测定在肌动蛋白聚合抑制剂细胞松弛素B(Cyto B)下进行,依据化学品测试的OECD准则-TG 487,In VitroMammalian Cell Micronucleus Test(MNvit)(2014)。
下表显示测定的结果及展示化合物TMU-C-0012的遗传毒性是阴性。
PREC:于显微镜下可观测的沉淀物
CYTO:导致不足够数量的评分细胞的高细胞毒性(≥80%细胞毒性)
注释:
'+'通过t-测试得的p<0.05且微核细胞%至少比背景水平高3倍。
'+/-'通过t-测试得的p<0.05且微核细胞%至少比背景水平高2倍。
实例3活体内功效:经博莱霉素(BLM)诱导的肺纤维化小鼠模型测定
于预防模型中,通过气管内投与博莱霉素(BLM,0.05U/50μL)或PBS(50μL)处理C57BL/6JNarl小鼠(8周)。于BLM处理后自第1天至第21天使经博莱霉素处理的小鼠口服TMU-C-0012(25、50、100mg/kg/天,每天一次)及地塞米松(0.5mg/kg/天,每天一次)。于第21天,处死小鼠并通过苏木精-伊红(hematoxylin-eosin(H&E))染色(原始放大率,x100)进行肺组织的组织学分析。于治疗模型中,通过气管内投与博莱霉素(BLM,0.05U/50μL)或PBS(50μL)处理C57BL/6JNarl小鼠(8周)。于BLM处理后自第10天至第38天使经博莱霉素处理的小鼠口服TMU-C-0012(25、50、100mg/kg/天,每天一次)及吡非尼酮(200mg/kg/天,每天一次)。于第39天,处死小鼠并通过苏木精-伊红(H&E)染色(原始放大率,x100)进行肺组织的组织学分析。
图1(A)、图1(B)及图1(C)显示TMU-C-0012、地塞米松及吡非尼酮对小鼠的经博莱霉素诱导的肺纤维化的抗纤维化效应。于预防模型中,结果显示TMU-C-0012以剂量相依方式抑制经BLM诱导的肺纤维化(参见图1(A))且TMU-C-0012的抑制功效高于地塞米松(参见图1(B))。于治疗模型中,结果显示TMU-C-0012以剂量相依方式抑制经BLM诱导的肺纤维化(参见图1(A))且TMU-C-0012的抑制功效高于吡非尼酮(参见图1(C))。
此外,通过气管内投与博莱霉素(BLM,0.05U/50μL)或PBS(50μL)处理C57BL/6JNarl小鼠(8周)。于BLM处理后自第10天至第38天使经博莱霉素处理的小鼠口服TMU-C-0012(25mg/kg/天,每天一次)及SAHA(25mg/kg/天,每天一次)。于第39天,处死小鼠并通过苏木精-伊红(H&E)染色(原始放大率,x100)进行肺组织的组织学分析。图2显示TMU-C-0012及SAHA对小鼠的经博莱霉素诱导的肺纤维化的抗纤维化效应。
实例4活体内功效:OVA肺纤维化小鼠模型测定
通过腹腔注射OVA(50μg/50μl/天)或PBS(50μL/天)处理C57BL/6JNarl小鼠(8周)4周。然后将小鼠暴露于OVA(5%气雾剂暴露)或PBS(气雾剂暴露)8周。自第4周至第12周使注射OVA的小鼠口服TMU-C-0012(25mg/kg/天,每天一次)及地塞米松(25mg/kg/天,每天一次)。于第12周,处死小鼠并通过苏木精-伊红(H&E)染色(原始放大率,x100)进行肺组织的组织学分析。图3显示TMU-C-0012及地塞米松对小鼠的经OVA诱导的肺纤维化的抗纤维化效应。结果显示TMU-C-0012以剂量相依方式抑制经OVA诱导的肺纤维化及TMU-C-0012的抑制功效高于地塞米松。
实例5TMU-C-0012对小鼠的经硅石诱导的肺纤维化的效应
通过气管内投与硅石(硅石,2.5mg/50μL)或PBS(50μL)处理C57BL/6JNarl小鼠(8周)。于硅石处理后自第1天至第21天使经硅石处理的小鼠口服TMU-C-0012(100mg/kg/天,每天一次)。于第21天,处死小鼠并通过苏木精-伊红(H&E)染色(原始放大率,x100)进行肺组织的组织学分析。图4显示TMU-C-0012对小鼠的经硅石诱导的肺纤维化的抗纤维化效应。
实例6TMU-C-0012对小鼠的经CCl4诱导的肝脏纤维化的效应
通过腹腔注射CCl4(1μL/μg/BW,每周一次)或PBS(1μL/μg/BW,每周一次)处理C57BL/6JNarl小鼠(8周)6周。自第2周至第6周使注射CCl4的小鼠口服TMU-C-0012(25、50、100mg/kg/天,每天一次)及吡非尼酮(250mg/kg/天,每天一次)。于第43天,处死小鼠并通过IHC染色(原始放大率,x100)进行肝脏组织的α-SMA分析。图5显示TMU-C-0012及吡非尼酮对小鼠的经CCl4诱导的肝脏纤维化的抗纤维化效应。如图5所示,TMU-C-0012对经CCl4诱导的肝脏纤维化的抑制剂量相依的及TMU-C-0012的抑制功效高于吡非尼酮。
Claims (9)
1.一种预防及/或治疗个体的纤维化疾病的方法,其包括投与医药组合物,其中所述医药组合物包含以一或多个单位剂型的于约100mg至约1,400mg的范围内的有效量的包含约日剂量的式(I)化合物的化合物或医药上可接受的盐、溶剂化物或前药作为活性成分:
其中n为0、1或2;
R1为SO2Ra,其中Ra为烯基、炔基、苯基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基;
R2为烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基、杂环烯基、卤基、氰基、硝基、ORb、SRb、S(O)Rb、
NHC(O)-CH=CH-C(O)Rb、NHC(O)-CH=CH-C(O)NRcRd、SO2NRcRd、
OC(O)Rb、C(O)NRcRd、NRcRd、NHC(O)Rb、NHC(O)NRcRd或NHC(S)Rc,其中Rb、Rc及Rd各自独立地为H、羟基、烷氧基、芳氧基、杂芳氧基、烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基;及
R3、R4、R5及R6各自独立地为H、烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基、杂环烯基、卤基、氰基、硝基、ORb、
SRb、S(O)Rb、CH=CH-C(O)NRcRd、NHC(O)-CH=CH-C(O)Rb、
NHC(O)-CH=CH-C(O)NRcRd、SO2NRcRd、OC(O)Rb、C(O)NRcRd、NRcRd、
NHC(O)Rb、NHC(O)NRcRd或NHC(S)Rc,其中Rb、Rc及Rd各自独立地为H、羟基、烷氧基、芳氧基、杂芳氧基、烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基。
2.如权利要求1的方法,其中所述医药组合物系呈一或多种胶囊型或锭剂型。
3.如权利要求1的方法,其中所述医药组合物包含以一或多个单位剂型的于约140mg至约1,050mg的范围内的日剂量的所述活性成分。
4.如权利要求1的方法,其中所述医药组合物于单锭剂中包含约100mg至约300mg的所述活性成分。
5.如权利要求1的方法,其中所述医药组合物于单胶囊中包含约100mg至约500mg的所述活性成分。
6.如权利要求1的方法,其中所述医药组合物用于与第二抗纤维化药剂组合。
7.如权利要求6的方法,其中所述第二抗纤维化药剂为吡非尼酮、尼达尼布、LOXL2抗体、辛图单抗、IL-13抗体、罗氏单抗、αVβ6抗体、STX-100、CTGF抗体、FG-3019、泰鲁司特、MN-001、气雾剂吡非尼酮或GP-101。
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CN201580084223.3A Active CN108368043B (zh) | 2015-10-27 | 2015-10-27 | 用于治疗及/或预防纤维化疾病的吲哚啉衍生物 |
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JP (2) | JP7302120B2 (zh) |
CN (2) | CN116077489A (zh) |
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RS (1) | RS65201B1 (zh) |
TW (1) | TWI663973B (zh) |
WO (1) | WO2017074317A1 (zh) |
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US8158589B2 (en) * | 2003-08-22 | 2012-04-17 | Proyecto Biomedicine Cima, S.L. | Peptides with the capacity to bind to transforming growth factor β1 (TGF-β1) |
CA2708004C (en) | 2006-12-04 | 2015-12-01 | Promedior, Inc. | Conjoint therapy for treating fibrotic diseases |
EP2100879A1 (en) * | 2008-03-13 | 2009-09-16 | 4Sc Ag | Novel N-substituted tetrahydroisoquinoline/isoindoline hydroxamic acid compounds |
TWI429628B (zh) * | 2010-03-29 | 2014-03-11 | Univ Taipei Medical | 吲哚基或吲哚啉基羥肟酸化合物 |
JP6180417B2 (ja) | 2011-09-15 | 2017-08-16 | タイペイ メディカル ユニバーシティ | 心不全またはニューロン損傷の治療剤製造のための化合物の使用 |
KR102197524B1 (ko) * | 2012-03-27 | 2020-12-31 | 제넨테크, 인크. | 특발성 폐 섬유증의 예후, 진단 및 치료 방법 |
EP2914575B1 (en) * | 2012-10-31 | 2020-10-14 | The Regents Of The University Of Michigan | Plasminogen activator-1 inhibitors and methods of use thereof |
JP2016537375A (ja) | 2013-11-24 | 2016-12-01 | タイペイ メディカル ユニバーシティ | 神経変性疾患または認知障害を治療するためのインドリルおよびインドリニルヒドロキサメートの使用 |
US20150368195A1 (en) * | 2014-06-20 | 2015-12-24 | Taipei Medical University | Indoline compounds for treatment and/or prevention of inflammation diseases |
EP3368512B1 (en) * | 2015-10-27 | 2023-12-06 | Taipei Medical University | Indoline derivatives for treatment and/or prevention of fibrosis diseases |
JP6965362B2 (ja) * | 2017-03-01 | 2021-11-10 | チェンドゥ フイタイ バイオメディスン カンパニー リミテッドChengdu Huitai Biomedicine Co., Ltd. | ポリペプチド、ポリペプチド断片及びその誘導体、並びに応用 |
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JP2018531959A (ja) | 2018-11-01 |
US11278523B2 (en) | 2022-03-22 |
EP3368512A1 (en) | 2018-09-05 |
JP7302120B2 (ja) | 2023-07-04 |
TWI663973B (zh) | 2019-07-01 |
EP3368512C0 (en) | 2023-12-06 |
US20180243264A1 (en) | 2018-08-30 |
CN108368043A (zh) | 2018-08-03 |
RS65201B1 (sr) | 2024-03-29 |
TW201714614A (zh) | 2017-05-01 |
EP3368512A4 (en) | 2019-06-26 |
ES2965877T3 (es) | 2024-04-17 |
EP3368512B1 (en) | 2023-12-06 |
CN108368043B (zh) | 2022-11-29 |
WO2017074317A1 (en) | 2017-05-04 |
JP2021119190A (ja) | 2021-08-12 |
US20220184032A1 (en) | 2022-06-16 |
HRP20240306T1 (hr) | 2024-05-10 |
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