CN110177549A - 治疗局灶性节段性肾小球硬化的方法 - Google Patents
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Abstract
提供了用式I的化合物治疗局灶性节段性肾小球硬化的方法。FSGS可以是原发性的(未知原因)或继发性的。继发性FSGS可能与感染或病毒例如HIV、疾病例如镰状细胞疾病或狼疮、毒素或药物例如促蛋白合成类固醇、海洛因或帕米膦酸盐、肾单元损失和超过滤相关,例如与慢性肾盂肾炎和反流、病态肥胖或糖尿病相关。
Description
本申请要求2016年11月23日提交的美国临时申请号62/425,832的优先权。该优先权申请的公开内容通过引用以其全部并入本文。
技术领域
本公开描述了用式I的化合物治疗局灶性节段性肾小球硬化(FSGS)的方法。FSGS包括一组以肾脏病变为特征的病症,其在光学显微镜下显示仅涉及一些(局灶性)肾小球以及所涉及的肾小球的仅一部分(节段性)。FSGS可能发生在遗传风险因素(遗传性FSGS)、apoL1的风险变异的杂合性或纯合性(apoL1 FSGS)、暴露于病毒(病毒性FSGS)、提高的肾单位过滤需求(自适应性FSGS,如可能发生在肾单位损失、高血压、肥胖、其它病症的设定下)、暴露于毒素或药物(中毒性FSGS)的情况下,在其它肾脏或全身性疾病的情况下(继发性FSGS,如可能发生在糖尿病、狼疮肾炎和其它疾病的设定下),在公认或未公认的循环因素的情况下,或可能是特发性的(原发性FSGS)。
FSGS可能是原发性的(未知原因)或继发性的。继发性FSGS可能与感染或病毒(例如HIV)、疾病(例如镰状细胞疾病或狼疮)、毒素或药物(例如促蛋白合成类固醇、海洛因或帕米膦酸盐(pamidronate))、肾单位损失和超过滤相关,例如与慢性肾盂肾炎和反流、病态肥胖或糖尿病相关。
发明背景
FSGS用于描述以原发性足细胞损伤为特征的疾病和在任何类型的慢性肾脏病(CKD)中继发性发生的病变二者。其通过光学显微镜由部分(节段性)或一些肾小球(局灶性)中存在硬化来定义。FSGS可以在没有可识别原因的情况下被发现(“原发性”或“特发性”FSGS占病例的80%)或响应先前的肾小球损伤,例如高血压或肥胖被发现(“继发性”FSGS占病例的20%)。
FSGS最常见的表现是亚肾病性(subnephrotic)至肾病性水平范围的蛋白尿(大量蛋白尿(heavy proteinuria)、低白蛋白血症和高脂血症)。大量蛋白尿导致肾脏功能的进行性丧失(肾小球硬化症)和肾衰竭。其占终末期肾病(ESRD)的~15%。大量蛋白尿(massiveproteinuria)(>10-15克/天)导致肾脏功能的迅速恶化,并在2-3年内进展为ESRD。具有大量蛋白尿的FSGS患者的存活率仅为45%。
局灶性节段性肾小球硬化被美国国立卫生研究院(NIH)的罕见疾病办公室(ORD)列为“罕见疾病”,且目前尚无批准用于FSGS的药物。在美国每年大约5400名患者被诊断患有FSGS,但是病例数量比肾病综合征的任何其它原因增加得更多。每年大约1,000名FSGS患者接受肾移植。但是,在肾移植后的几小时至几周内,FSGS在大约30-40%的患者中复发。现行护理标准包括使用类固醇、钙调神经磷酸酶抑制剂、ACE抑制剂或ARB、免疫抑制药物、利尿剂、血浆去除术、饮食改变和他汀类药物。但是,仅有20%的患者在治疗5年后实现完全缓解,且40%的患者显示无缓解(Focal and Segmental Glomerulosclerosis: Definitionand Relevance of a Partial Remission. Troyanov等人, J Am Soc Nephrol 16:1061-1068, 2005)。因此,仍需要开发新的有效药物来治疗该疾病。
发明概述
本公开涉及治疗需要其的患者中的局灶性节段性肾小球硬化(FSGS)的方法,其包括向该患者施用有效量的式I的化合物:
式I
或其药学上可接受的盐,
其中
R1是卤素或C1-6烷基;
R2是氢、卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基或-CN;
R3是氢、卤素或C1-6烷基;
R4是氢、卤素或C1-6烷基;
各R5独立地为C1-6烷基、-OH或-NH2;
n为0、1、2或3;且
A1、A2和A3各自为-CH-或-N-,其中A1、A2或A3中的至少一个是-N-。
附图简述
图1显示在5/6残肾模型中在具有和不具有化合物3治疗的情况下在基线、第1周和第2周的UACR值。
图2显示在5/6残肾模型中在具有和不具有化合物3治疗的情况下作为总面积百分比的巨噬细胞含量。
图3显示在具有和不具有化合物3治疗的情况下在5/6残肾模型中肾间质巨噬细胞的代表性图像。
图4显示在5/6残肾模型中在具有和不具有化合物3治疗的情况下每个肾小球横截面的足细胞数量。
图5显示在具有和不具有化合物3治疗的情况下在5/6残肾模型中足细胞的代表性图像。
图6显示在健康对照小鼠中和在5/6残肾模型中在具有和不具有化合物3治疗的情况下5/6肾切除小鼠中具有系膜溶解的肾小球的百分比。
图7显示具有系膜溶解的肾小球的代表性图像。
图8显示在阿霉素肾病模型中与载体相比在用化合物1、坎地沙坦以及化合物1与坎地沙坦的组合治疗后第1、2和3周的UACR水平。
图9显示在阿霉素肾病模型中与载体相比在用化合物1、坎地沙坦以及化合物1与坎地沙坦的组合治疗后第1、2和3周的UAER水平。
图10显示在5/6残肾模型中在化合物3治疗、坎地沙坦治疗以及化合物3与坎地沙坦的组合治疗的情况下在基线、第1、2和3周的UAER值。
图11显示在5/6残肾模型中在化合物3治疗、坎地沙坦治疗以及化合物3与坎地沙坦的组合治疗的情况下在基线、第1周和第2周的UACR值。
发明详述
缩写和定义
当描述本公开的化合物、组合物、方法和过程时,除非另行说明,以下术语具有以下含义。
“烷基”本身或作为另一取代基的一部分是指可以是具有指定碳原子数(即C1-8表示一至八个碳原子)的直链、环状或支链或其组合的烃基团。烷基的实例包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、环己基、环戊基、(环己基)甲基、环丙基甲基、双环[2.2.1]庚烷、双环[2.2.2]辛烷等等。除非另行说明,烷基是未取代的。取代烷基的实例包括卤代烷基、硫代烷基、氨基烷基等等。
“烷氧基”是指-O-烷基。烷氧基的实例包括甲氧基、乙氧基、正丙氧基等等。
“烯基”是指可以是直链、环状或支链或其组合的不饱和的烃基团。具有2-8个碳原子的烯基是优选的,尽管烯基可以具有超过8个碳原子。烯基可以含有1、2或3个碳-碳双键。烯基的实例包括乙烯基、正丙烯基、异丙烯基、正丁-2-烯基、正己-3-烯基、环己烯基、环戊烯基等等。除非另行说明,烯基是未取代的。
“炔基”是指可以是直链、环状或支链或其组合的不饱和的烃基团。具有2-8个碳原子的炔基是优选的。炔基可以含有1、2或3个碳-碳三键。炔基的实例包括乙炔基、正丙炔基、正丁-2-炔基、正己-3-炔基等等。除非另行说明,炔基是未取代的。
“芳基”是指具有单个环(单环)或多个环(双环)的多不饱和的芳族烃基团,所述多个环可以稠合在一起或共价连接。具有6-10个碳原子的芳基是优选的,其中该碳原子数可以表示为例如C6-10。芳基的实例包括苯基和萘-1-基、萘-2-基、联苯(基)等等。除非另行说明,芳基是未取代的。
“卤代”或“卤素”本身或作为取代基的一部分是指氯、溴、碘或氟原子。
“卤代烷基”作为取代的烷基是指单卤代烷基或多卤代烷基,最通常被1-3个卤素原子取代。实例包括1-氯乙基、3-溴丙基、三氟甲基等等。
“杂环基”是指含有至少一个选自氮、氧或硫的杂原子(通常1至5个杂原子)的饱和或不饱和的非芳族环。杂环基环可以是单环或双环的。优选地,这些基团含有0-5个氮原子、0-2个硫原子和0-2个氧原子。更优选地,这些基团含有0-3个氮原子、0-1个硫原子和0-1个氧原子。杂环基团的实例包括吡咯烷、哌啶、咪唑烷、吡唑烷、丁内酰胺、戊内酰胺、咪唑啉酮、乙内酰脲、二氧戊环、邻苯二甲酰亚胺、哌啶、1,4-二氧杂环己烷、吗啉、硫代吗啉、硫代吗啉-S-氧化物、硫代吗啉-S,S-二氧化物、哌嗪、吡喃、吡啶酮、3-吡咯啉、噻喃、吡喃酮、四氢呋喃、四氢噻吩、奎宁环等等。优选的杂环基团是单环的,尽管它们可以稠合或共价连接到芳基或杂芳基环体系上。
“杂芳基”是指含有至少一个杂原子的芳族基团,其中该杂芳基可以是单环或双环的。实例包括吡啶基、哒嗪基、吡嗪基、嘧啶基、三嗪基、喹啉基、喹喔啉基、喹唑啉基、噌啉基、酞嗪基、苯并三嗪基、嘌呤基、苯并咪唑基、苯并吡唑基、苯并三唑基、苯并异噁唑基、异苯并呋喃基、异吲哚基、吲嗪基、苯并三嗪基、噻吩并吡啶基、噻吩并嘧啶基、吡唑并嘧啶基、咪唑并吡啶、苯并噻唑基、苯并呋喃基、苯并噻吩基、吲哚基、氮杂吲哚基、氮杂吲唑基、喹啉基、异喹啉基、异噻唑基、吡唑基、吲唑基、蝶啶基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、噻二唑基、吡咯基、噻唑基、呋喃基或噻吩基。优选的杂芳基是具有至少一个芳基环氮原子的那些,例如喹啉基、喹喔啉基、嘌呤基、苯并咪唑基、苯并吡唑基、苯并三唑基、苯并噻唑基、吲哚基、喹啉基、异喹啉基等等。优选的6-环杂芳基体系包括吡啶基、哒嗪基、吡嗪基、嘧啶基、三嗪基等等。优选的5-环杂芳基体系包括异噻唑基、吡唑基、咪唑基、噻吩基、呋喃基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、噻二唑基、吡咯基、噻唑基等等。
杂环基和杂芳基可以在任何可用的环碳或杂原子处连接。各杂环基和杂芳基可以具有一个或更多个环。当存在多个环时,它们可以稠合在一起或共价连接。各杂环基和杂芳基必须含有至少一个选自氮、氧或硫的杂原子(通常1至5杂原子)。优选地,这些基团含有0-5个氮原子、0-2个硫原子和0-2个氧原子。更优选地,这些基团含有0-3个氮原子、0-1个硫原子和0-1个氧原子。除非另行说明,杂环基和杂芳基是未取代的。对于取代的基团,该取代可以在碳或杂原子上。例如,当该取代是氧代(=O或-O-)时,所得基团可以具有羰基(-C(O)-)或N-氧化物(-N+-O-)。
适合于取代的烷基、取代的烯基和取代的炔基的取代基包括卤素、-CN、-CO2R’、-C(O)R’、-C(O)NR’R’’、氧代(=O或-O-)、-OR’、-OC(O)R’、-OC(O)NR’R’’-NO2、-NR’C(O)R’’、-NR’’’C(O)NR’R’’、-NR’R’’、-NR’CO2R’’、-NR’S(O)R’’、-NR’S(O)2R’’’、-NR’’’S(O)NR’R’’、-NR’’’S(O)2NR’R’’、-SR’、-S(O)R’、-S(O)2R’、-S(O)2NR’R’’、-NR’-C(NHR’’)=NR’’’、-SiR’R’’R’’’、-N3、取代或未取代的C6-10芳基、取代或未取代的5-至10-元杂芳基和取代或未取代的3-至10-元杂环基。可能的取代基数量在零至(2m’+1)范围内,其中m’是此基团中的碳原子总数。
适合于取代的芳基、取代的杂芳基和取代的杂环基的取代基包括卤素、-CN、-CO2R’、-C(O)R’、-C(O)NR’R’’、氧代(=O或-O-)、-OR’、-OC(O)R’、-OC(O)NR’R’’、-NO2、-NR’C(O)R’’、-NR’’’C(O)NR’R’’、-NR’R’’、-NR’CO2R’’、-NR’S(O)R’’、-NR’S(O)2R’’、-NR’’’S(O)NR’R’’、-NR’’’S(O)2NR’R’’、-SR’、-S(O)R’、-S(O)2R’、-S(O)2NR’R’’、-NR’-C(NHR’’)=NR’’’、-SiR’R’’R’’’、-N3、取代或未取代的C1-8烷基、取代或未取代的C2-8烯基、取代或未取代的C2-8炔基、取代或未取代的C6-10芳基、取代或未取代的5-至10-元杂芳基和取代或未取代的3-至10-元杂环基。可能的取代基数量在零至芳族环体系上开放价态的总数范围内。
如上文所用,R’、R’’和R’’’各自独立地是指多种基团,包括氢、取代或未取代的C1-8烷基、取代或未取代的C2-8烯基、取代或未取代的C2-8炔基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的杂环基、取代或未取代的芳基烷基、取代或未取代的芳氧基烷基。当R’和R’’连接到同一氮原子上时,它们可以与该氮原子组合以形成3-、4-、5-、6-或7-元环(例如,-NR’R’’包括1-吡咯烷基和4-吗啉基)。此外,R’和R’’、R’’和R’’’或R’和R’’’可以与它们连向的原子一起形成取代或未取代的5-、6-或7-元环。
在芳基或杂芳基环的相邻原子上的两个取代基可以任选被式-T-C(O)-(CH2)q-U-的取代基替代,其中T和U独立地为-NR’’’’-、-O-、-CH2-或单键,并且q是0至2的整数。或者,在芳基或杂芳基环的相邻原子上的两个取代基可以任选被式-A’-(CH2)r-B’-的取代基替代,其中A’和B’独立地为-CH2-、-O-、-NR’’’’-、-S-、-S(O)-、-S(O)2-、-S(O)2NR’’’’-或单键,并且r是1至3的整数。如此形成的新环的单键之一可以任选被双键替代。或者,在芳基或杂芳基环的相邻原子上的两个取代基可以任选被式-(CH2)s-X-(CH2)t-的取代基替代,其中s和t独立地为0至3的整数,并且X是-O-、-NR’’’’-、-S-、-S(O)-、-S(O)2-或-S(O)2NR’-。R’’’’选自氢或未取代的C1-8烷基。
“杂原子”表示包括氧(O)、氮(N)、硫(S)和硅(Si)。
“高于天然同位素丰度”是指自然测量的化学元素的同位素的丰度。
“药学上可接受的”载体、稀释剂或赋形剂是与制剂的其它成分相容并对其接受者无害的载体、稀释剂或赋形剂。
“药学上可接受的盐”是指可接受用于施用于患者,例如哺乳动物的盐(例如对给定剂量方案具有可接受的哺乳动物安全性的盐)。此类盐可以衍生自药学上可接受的无机碱或有机碱以及衍生自药学上可接受的无机酸或有机酸,取决于在本文所述的化合物上发现的特定取代基。当本公开的化合物含有相对酸性的官能团时,可以通过将此类化合物的中性形式与足量的所需碱(纯净的或在合适的惰性溶剂中)接触来获得碱加成盐。衍生自药学上可接受的无机碱的盐包括铝、铵、钙、铜、铁、亚铁、锂、镁、三价锰、二价锰、钾、钠、锌盐等等。衍生自药学上可接受的有机碱的盐包括伯、仲、叔和季胺的盐,包括取代的胺、环胺、天然存在的胺等等,例如精氨酸、甜菜碱、咖啡因、胆碱、N,N’-二苄基乙二胺、二乙胺、2-二乙氨基乙醇、2-二甲氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺、氨基葡糖、组氨酸、海巴明(hydrabamine)、异丙胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等等的盐。当本公开的化合物含有相对碱性的官能团时,可以通过将此类化合物的中性形式与足量的所需酸(纯净的或在合适的惰性溶剂中)接触来获得酸加成盐。衍生自药学上可接受的酸的盐包括乙酸、抗坏血酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡糖酸、葡糖醛酸、谷氨酸、马尿酸、氢溴酸、盐酸、羟乙磺酸、乳酸、乳糖酸、马来酸、苹果酸、扁桃酸、甲磺酸、粘酸、萘磺酸、烟酸、硝酸、双羟萘酸、泛酸、磷酸、琥珀酸、硫酸、酒石酸、对甲苯磺酸等等的盐。
还包括氨基酸的盐,例如精氨酸盐等等,以及有机酸如葡糖醛酸或半乳糖醛酸等等的盐(参见,例如Berge, S.M.等人, “Pharmaceutical Salts”, J. PharmaceuticalScience, 1977, 66:1-19)。本公开的某些具体化合物含有碱性官能团和酸性官能团二者,其使得该化合物能够转化为碱加成盐或酸加成盐。
该化合物的中性形式可以通过使盐与碱或酸接触并以常规方式分离母体化合物来再生。该化合物的母体形式在某些物理性质(例如在极性溶剂中的溶解度)方面不同于各种盐形式,但是另外对本公开的目的而言,盐与化合物的母体形式等效。
除了盐形式之外,本公开提供了呈前药形式的化合物。本文中描述的化合物的前药是在生理条件下容易发生化学变化以提供本公开的化合物的那些化合物。此外,前药可以通过化学或生物化学方法在体外环境中转化为本公开的化合物。例如,当放置在含有合适的酶或化学试剂的透皮贴剂储库中时,前药可以缓慢地转化为本公开的化合物。
“治疗有效量”是指当施用于需要治疗的患者时足以实现治疗的量。
如本文中所用的“治疗”(“treating”或“treatment”)是指治疗患者例如哺乳动物(特别是人或伴侣动物)的疾病或病况(medical condition),其包括改善疾病或病况,即,消除患者的疾病或病况或引起其消退;抑制疾病或病况,例如缓解或阻止患者的疾病或病况的发展;或减轻患者的疾病或病况的症状;或预防疾病发展。
“UACR”是指尿白蛋白与肌酐的比率。
“UAER”是指尿白蛋白排泄率。
本公开的某些化合物可以以非溶剂化形式以及溶剂化形式(包括水合形式)存在。通常,溶剂化形式和非溶剂化形式二者均意在包含在本公开的范围内。
对本领域技术人员将显而易见的是,本公开的某些化合物可以以互变异构形式存在,该化合物的所有此类互变异构形式都在本公开的范围内。本公开的某些化合物具有不对称碳原子(光学中心)或双键;外消旋物、非对映异构体、几何异构体和单独的异构体(例如单独的对映异构体)全部意在包括在本公开的范围内。
可以制备化合物,使得任何数量的氢原子被氘(2H)同位素取代。本公开的化合物还可以在构成此类化合物的一个或更多个原子上含有非天然比例的原子同位素。非天然比例的同位素可以定义为从自然界中发现的量至由考虑中的原子的100%所组成的量的范围。例如,化合物可以混入放射性同位素,如,例如氚(3H)、碘-125(125I)或碳-14(14C),或非放射性同位素,例如氘(2H)或碳-13(13C)。此类同位素变体(isotopic variation)可以为本申请中其它地方描述的那些提供附加的效用。本公开的化合物的所有同位素变体(无论是否具有放射性)都意在包括在本公开的范围内。例如,本公开的化合物的同位素变体可以找到附加的效用,包括但不限于作为诊断和/或成像试剂,或作为细胞毒性/放射毒性治疗剂。此外,本公开的化合物的同位素变体可以具有改变的药代动力学和药效学特性,这可有助于在治疗期间提高安全性、耐受性或功效。
治疗FSGS的方法
本公开提供了在患者中治疗FSGS的方法,其包括向需要其的患者施用有效量的式(Ia)的化合物:
(Ia)
或其药学上可接受的盐,其中
Ar1选自取代或未取代的C6-10芳基和取代或未取代的5-至10-元杂芳基;
R1a选自氢、取代或未取代的C1-8烷基、取代或未取代的C2-6烯基、取代或未取代的C2-6炔基和取代或未取代的3-至10-元杂环基;
Y1选自-CR2a-、-N-和-N+(O)--;
Y2选自-CR2b-、-N-和-N+(O)--;
Y3选自-CR2c-、-N-和-N+(O)--;
R2a、R2b和R2c各自独立地选自氢、卤素、-CN、-C(O)R3a、-CO2R3a、-C(O)NR3aR4a、-OR3a、-OC(O)R3a、-OC(O)NR3aR4a、-SR3a、-S(O)R3a、-S(O)2R3a、-S(O)2NR3aR4a、-NO2、-NR3aR4a、-NR3aC(O)R4a、-NR3aC(O)OR4a、-NR3aS(O)2R4a、-NR3aC(O)NR4aR5a、取代或未取代的C1-8烷基、取代或未取代的C2-8烯基、取代或未取代的C2-8炔基、取代或未取代的3-至10-元杂环基、取代或未取代的C6-10芳基和取代或未取代的5-至10-元杂芳基;
R3a、R4a和R5a各自独立地选自氢、取代或未取代的C1-8烷基、取代或未取代的C2-8烯基、取代或未取代的C2-8炔基、取代或未取代的C6-10芳基、取代或未取代的5-至10-元杂芳基和取代或未取代的3-至10-元杂环基;
R3a和R4a、R4a和R5a或R3a和R5a可以与它们连向的原子一起形成取代或未取代的5-、6-或7-元环;
L选自键、-O-、-S-、-S(O)-、-S(O)2-、-CR6R7-、-NR8-、-C(O)-和-NR8C(O)-;
R6和R7各自独立地选自氢、卤素、取代或未取代的C1-8烷基、取代或未取代的3-至10-元杂环基、取代或未取代的C2-6烯基、取代或未取代的C2-6炔基、-CN、-OR9、-NR10R11、-S(O)R9和-S(O)2R9;
R6和R7可以与它们连向的碳原子一起形成取代或未取代的C3-8环烷基或取代或未取代的3-至10-元杂环;
R9选自氢、取代或未取代的C1-8烷基、取代或未取代的C2-8烯基、取代或未取代的C2-8炔基、取代或未取代的C6-10芳基、取代或未取代的5-至10-元杂芳基和取代或未取代的3-至10-元杂环基;
R10和R11各自独立地选自取代或未取代的C1-8烷基、取代或未取代的3-至10-元杂环基、取代或未取代的C6-10芳基、取代或未取代的5-至10-元杂芳基、取代或未取代的C2-8烯基和取代或未取代的C2-8炔基;
-NR10R11的R10和R11可以与氮一起形成取代或未取代的C3-8环烷基或者取代或未取代的3-至10-元杂环基;
R8选自氢、C(O)R12、S(O)2R12、CO2R12、取代或未取代的C1-8烷基、取代或未取代的3-至10-元杂环基、取代或未取代的C2-6烯基和取代或未取代的C2-6炔基;
R12选自取代或未取代的C1-8烷基、取代或未取代的C2-6烯基、取代或未取代的C2-6炔基、取代或未取代的3-至10-元杂环基、取代或未取代的C6-10芳基和取代或未取代的5-至10-元杂芳基;
Z1选自取代或未取代的C6-10芳基、取代或未取代的5-至10-元杂芳基、取代或未取代的3-至10-元杂环基和-NR13R14;
R13和R14各自独立地选自氢、取代或未取代的C1-8烷基、取代或未取代的C2-8烯基、取代或未取代的C2-8炔基、取代或未取代的3-至10-元杂环基、取代或未取代的C6-10芳基、取代或未取代的5-至10-元杂芳基、取代或未取代的(C1-4烷基)-(C6-10芳基)和取代或未取代的(C1-4烷基)-(5-至10-元杂芳基);
R13和R14可以与氮一起形成取代或未取代的4-、5-、6-或7-元杂环基;
Y4选自-N-和-N+(O)--。
在一些实施方案中,从式(Ia)中排除式CC的化合物:
其中X14选自-Cl、-NO2、-OCH3、-CH3、-NHC(O)CH3和-CH2CH2-(苯基);
R65选自氢、取代或未取代的C1-4烷基和取代或未取代的-SO2(苯基);和
R60选自-NR61CH2CH2OR62、-NR61CH2CH2NR63R64、-NR61CH2CH2SR62、和;
其中R61选自氢和取代或未取代的苯基;
R62选自取代或未取代的苯基和取代或未取代的C1-4烷基;和
R63和R64各自独立地选自氢、取代或未取代的C1-8烷基、取代或未取代的苯基、取代或未取代的-SO2(苯基)、-C(O)CH3、-C(O)C(O)OH和-C(O)2C(CH3)3。
在一些实施方案中,Z1是取代或未取代的5-至10-元杂芳基。
在一些实施方案中,L是-C(O)-。
在一些实施方案中,Y1是-CR2a-;Y2是-CR2b-;Y3是-CR2c-;且R2a、R2b和R2c各自独立地选自氢、卤素、取代或未取代的C1-8烷基。
在一些实施方案中,R1a选自氢或者取代或未取代的C1-8烷基。
在一些实施方案中,Ar1是取代或未取代的C6-10芳基。在一些实施方案中,Ar1是被1至3个选自卤素、C1-6烷基和C1-6卤代烷基的取代基取代的C6-10芳基。在一些实施方案中,Ar1是被1至3个选自卤素、C1-3烷基和C1-3卤代烷基的取代基取代的苯基。
在一些实施方案中,Y4是-N-。
在一些实施方案中,Z1是取代或未取代的5-至10-元杂芳基;L是-C(O)-;Y1是-CR2a-;Y2是-CR2b-;Y3是-CR2c-;R2a、R2b和R2c各自独立地选自氢、卤素、取代或未取代的C1-8烷基;R1a选自氢或者取代或未取代的C1-8烷基;Ar1是取代或未取代的C6-10芳基;且Y4是-N-。
在一些实施方案中,Z1是未取代的9-至10-元杂芳基;L是-C(O)-;Y1是-CR2a-;Y2是-CR2b-;Y3是-CR2c-;R2a、R2b和R2c各自独立地选自氢、卤素和C1-8烷基;R1a选自氢或C1-8烷基;Ar1是被1至3个选自卤素、C1-6烷基和C1-6卤代烷基的取代基取代的苯基;且Y4是-N-。
本公开还提供了治疗需要其的患者中的局灶性节段性肾小球硬化(FSGS)的方法,其包括向患者施用有效量的式I的化合物:
式I
或其药学上可接受的盐,其中
R1是卤素或C1-6烷基;
R2是氢、卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基或-CN;
R3是氢、卤素或C1-6烷基;
R4是氢、卤素或C1-6烷基;
各R5独立地为C1-6烷基、-OH或-NH2;
n为0、1、2或3;且
A1、A2和A3各自为-CH-或-N-,其中A1、A2或A3的至少一个是-N-。
在一些实施方案中,R1是卤素或甲基;
R2是卤素或C1-3卤代烷基;
R3是卤素或C1-3烷基;
R4是氢;
n为0;
A2是-CH-;且
A3是-N-。
在一些实施方案中,该化合物是:
,
或其药学上可接受的盐。
在一些实施方案中,该化合物是
,
或其药学上可接受的盐。
在一些实施方案中,该化合物是
或其药学上可接受的盐。
在一些实施方案中,治疗FSGS的方法包括预防、减少或消除FSGS的症状或并发症。
在一些实施方案中,治疗FSGS的方法包括预防、消除或延迟患者的终末期肾病的发作。
在一些实施方案中,FSGS是原发性FSGS。
在一些实施方案中,FSGS是继发性FSGS。在一些实施方案中,继发性FSGS与感染或病毒、疾病、暴露于毒素或药物、或肾单位损失和超过滤相关。在一些实施方案中,FSGS与HIV、镰状细胞疾病、狼疮、暴露于促蛋白合成类固醇、海洛因或帕米膦酸盐、慢性肾盂肾炎和反流、病态肥胖或糖尿病相关。
在一些实施方案中,该方法包括以下的一种或更多种:减少蛋白尿、减缓蛋白尿的增加、降低UACR、减缓尿白蛋白肌酐比率(UACR)的提高、降低UAER、减缓UAER的提高、减少白蛋白尿(albuminuria)、减缓白蛋白尿的增加、提高肾小球足细胞密度、防止或减缓肾小球基底膜(GBM)增厚、降低肾小球面积、减少肾间质巨噬细胞数量、降低或减缓肾组织纤维化、停止或减少肾脏炎症、停止或减少巨噬细胞对肾脏引起的损害、增加或正常化估算的肾小球滤过率(eGFR)、减弱eGFR的下降、减少肾小球硬化症、停止或减少肾小球细胞外基质的扩张、停止或减少透明团块(hyaline masses)的沉积、停止或减少肾小球上皮增生病变(EPHL)和停止或减少淋巴细胞浸润。
在一些实施方案中,该化合物或其药学上可接受的盐口服施用。
在一些实施方案中,该化合物或其药学上可接受的盐每天施用两次。
在一些实施方案中,该化合物或其药学上可接受的盐每天施用一次。
在一些实施方案中,该化合物或其药学上可接受的盐不与任何其它治疗化合物一起施用。在一些实施方案中,该化合物或其药学上可接受的盐不与任何其它治疗化合物同时或依次施用。在一些实施方案中,该化合物或其药学上可接受的盐单独施用。在一些实施方案中,该化合物或其药学上可接受的盐不与血管紧张素受体II阻滞剂(ARB)一起施用。在一些实施方案中,该化合物或其药学上可接受的盐不与血管紧张素受体II阻滞剂(ARB)同时或依次施用。
在一些实施方案中,该方法进一步包括向患者施用一种或更多种附加的治疗化合物。在一些实施方案中,所述一种或更多种附加的治疗化合物选自以下的一种或更多种:抗高血压药、他汀类药物、血管舒张药、类固醇、细胞毒类药物、利尿剂、非甾体抗炎药(NSAID)、胆固醇或甘油三酯降低剂和免疫抑制药物。
在一些实施方案中,所述一种或更多种附加的治疗化合物选自血管紧张素转化酶(ACE)抑制剂和血管紧张素受体II阻滞剂(ARB)。在一些实施方案中,所述一种或更多种附加的治疗化合物选自雷米普利、培哚普利、赖诺普利、培哚普利精氨酸盐、卡托普利、螺普利、喹那普利、依那普利、咪达普利、福辛普利、佐芬普利、贝那普利、群多普利、维拉帕米、贝那普利、氨氯地平、群多普利、P-003、西拉普利、地拉普利、莫昔普利、喹那普利、福辛普利、替莫普利、氯沙坦、坎地沙坦、厄贝沙坦、替米沙坦、奥美沙坦、缬沙坦、阿齐沙坦、替米沙坦、非马沙坦、EMA-401、阿齐沙坦酯钾盐、司帕生坦(sparsentan)、坎地沙坦酯、奥美沙坦酯、TRV-027、氯沙坦钾、YH-22189、阿齐沙坦三甲基乙醇胺盐(azilsartantrimethylethanolamine)、阿利沙坦酯和依普沙坦。在一些实施方案中,所述一种或更多种附加的治疗化合物是坎地沙坦。在一些实施方案中,所述一种或更多种附加的治疗化合物是厄贝沙坦。
在一些实施方案中,该化合物或其药学上可接受的盐与血管紧张素转化酶(ACE)抑制剂同时或依次施用。
在一些实施方案中,该化合物或其药学上可接受的盐与血管紧张素受体II阻滞剂(ARB)同时或依次施用。
在一些实施方案中,所述一种或更多种附加的治疗化合物选自内皮素ET-A拮抗剂、B-淋巴细胞抗原CD20抑制剂、钠-葡萄糖转运蛋白-2抑制剂、T细胞表面糖蛋白CD28抑制剂;细胞毒性T-淋巴细胞蛋白-4刺激物、38 MAP激酶抑制剂、N-乙酰甘露糖胺激酶刺激物、促肾上腺皮质激素配体、整合素α-V/β-3拮抗剂;结缔组织生长因子配体抑制剂和TGFβ拮抗剂。
在一些实施方案中,所述一种或更多种附加的治疗化合物选自利妥昔单抗、达格列净(dapagliflozin)、司帕生坦、阿巴西普、DMX-200、丙帕锗、厄贝沙坦、洛吡莫德(losmapimod)、X-M74、阿克撒凝胶(Acthar Gel)、VAR-200、西仑吉肽、潘瑞鲁单抗(pamrevlumab)、DEX-M74、夫苏木单抗(fresolimumab)和SHP-627。
在一些实施方案中,所述一种或更多种附加的治疗化合物选自法尼酯X受体激动剂、G-蛋白偶联胆汁酸受体1激动剂、内皮素ET-A拮抗剂、内皮素ET-1拮抗剂、内皮素ET-2拮抗剂、内皮素ET-3拮抗剂、内皮素ET-B1拮抗剂、内皮素ET-B2拮抗剂、内皮素ET-C拮抗剂、B-淋巴细胞刺激因子配体抑制剂、甲状旁腺激素配体抑制剂、DNA聚合酶抑制剂、B-淋巴细胞抗原CD20抑制剂、细胞毒性T-淋巴细胞蛋白-4刺激物、T细胞表面糖蛋白CD28抑制剂、MEKK-5蛋白激酶抑制剂、结缔组织生长因子配体抑制剂、甘露聚糖结合凝集素丝氨酸蛋白酶-2抑制剂、Syk酪氨酸激酶抑制剂、钠-葡萄糖转运蛋白-2抑制剂、红细胞生成素受体激动剂、肌苷单磷酸脱氢酶抑制剂;PurH嘌呤生物合成蛋白抑制剂、C5基因抑制剂、核苷类逆转录酶抑制剂、细胞周期蛋白依赖性激酶-4抑制剂;细胞周期蛋白依赖性激酶-6抑制剂;视网膜母细胞瘤相关蛋白调节剂、胰岛素增敏剂、激肽释放酶1调节剂、钾通道抑制剂、Raf B蛋白激酶抑制剂、促肾上腺皮质激素配体、补体C1s亚成分抑制剂、盐皮质激素受体拮抗剂、Jak1酪氨酸激酶抑制剂、Jak酪氨酸激酶抑制剂、Jak2酪氨酸激酶抑制剂、P2Y12嘌呤受体拮抗剂、补体C5因子抑制剂、生长激素受体拮抗剂、醛糖还原酶抑制剂、丝氨酸蛋白酶抑制剂、胰蛋白酶抑制剂、生长抑素受体激动剂、NADPH氧化酶1抑制剂、NADPH氧化酶4抑制剂、ANP激动剂、利钠肽受体B激动剂、I-κB激酶抑制剂、NFE2L2基因刺激物、核因子κB抑制剂、STAT3基因抑制剂、加压素V2拮抗剂、钙调神经磷酸酶抑制剂、醛固酮拮抗剂、盐皮质激素受体拮抗剂、肿瘤坏死因子配体13抑制剂、血栓烷A2拮抗剂、表皮生长因子拮抗剂、Erbb2酪氨酸激酶受体抑制剂、Erbb3酪氨酸激酶受体抑制剂、Erbb4酪氨酸激酶受体抑制剂、肾素抑制剂、半乳凝素-3抑制剂、盐皮质激素受体拮抗剂、FGF受体拮抗剂、PDGF受体拮抗剂、TGFβ拮抗剂、p38MAP激酶抑制剂、肌球蛋白刺激物、β2肾上腺素受体激动剂、糖皮质激素激动剂、毒蕈碱型受体拮抗剂、淀粉样蛋白沉积抑制剂、载脂蛋白基因刺激物、含溴区结构域蛋白4抑制剂、肝细胞生长因子激动剂、高级糖基化产物受体拮抗剂、GHR基因抑制剂;IGF1基因抑制剂、CACNA2D3钙通道亚基调节剂、C型利钠肽配体、树眼镜蛇属利钠蛋白配体、耐热肠毒素受体激动剂、利钠肽受体A激动剂、利钠肽受体B激动剂、利钠肽受体C激动剂、骨形态发生蛋白-7配体调节剂、环加氧酶1抑制剂、加压素V1激动剂、N-乙酰甘露糖胺激酶刺激物、血管紧张素转化酶2刺激物、PPARγ激动剂、前列腺素类受体拮抗剂、血栓烷A2拮抗剂、蛋白酪氨酸磷酸酶β抑制剂、Tek酪氨酸激酶受体刺激物、骨形态发生蛋白-7配体、半胱天冬酶抑制剂、前列环素激动剂、醛糖还原酶抑制剂、细胞周期蛋白依赖性激酶-2抑制剂、细胞周期蛋白依赖性激酶-7抑制剂、细胞周期蛋白依赖性激酶-9抑制剂、MCL1基因抑制剂、硬骨素抑制剂、补体C5a受体拮抗剂、免疫球蛋白γFc受体IIB拮抗剂、前列环素激动剂、p38 MAP激酶抑制剂、血红蛋白调节剂、碱性磷酸酶刺激物、NFE2L2基因调节剂、NFKB基因调节剂、ρ相关蛋白激酶抑制剂、CX3CR1趋化因子拮抗剂、PDGF受体β调节剂、肝素激动剂、弹性蛋白酶刺激物、生长激素配体;生长激素受体激动剂、黄嘌呤氧化酶抑制剂、细胞外基质蛋白调节剂;蛋白多糖调节剂、盐皮质激素受体拮抗剂、单核细胞趋化蛋白1配体抑制剂、组蛋白去乙酰化酶抑制剂、肝细胞生长因子激动剂、白蛋白激动剂、铜胺氧化酶膜抑制剂(membrane copper amineoxidase inhibitor)、整合素α-V/β-3拮抗剂、生长抑素受体激动剂、细胞周期蛋白依赖性激酶抑制剂、溶质载体家族12A1抑制剂、肝细胞生长因子配体调节剂、干扰素γ受体拮抗剂、苯丙氨酸羟化酶刺激物、肾尿素转运蛋白调节剂、Xa因子拮抗剂、低分子量肝素、多巴胺D1受体激动剂、血管紧张素转化酶(ACE)和中性肽链内切酶(EP)的双重抑制剂、噻嗪类利尿剂、保钾利尿剂、碳酸酐酶抑制剂、中性肽链内切酶抑制剂、醛固酮合成酶抑制剂;肾素抑制剂;钙通道阻滞剂、钾通道激活剂、β-肾上腺素能阻断药物、α-肾上腺素能阻断药物、硝酸盐、一氧化氮供体化合物、降脂剂、胆固醇吸收抑制剂、烟酸受体激动剂、烟酸受体部分激动剂、代谢改变剂、α葡糖苷酶抑制剂、二肽基肽酶抑制剂、麦角生物碱和磷酸二酯酶-5(PDE5)抑制剂。
在一些实施方案中,所述一种或更多种附加的治疗化合物选自内皮素ET-A拮抗剂、内皮素ET-1拮抗剂、内皮素ET-2拮抗剂、内皮素ET-3拮抗剂、内皮素ET-B1拮抗剂、内皮素ET-B2拮抗剂、内皮素ET-C拮抗剂、B-淋巴细胞刺激因子配体抑制剂、B-淋巴细胞抗原CD20抑制剂、细胞毒性T-淋巴细胞蛋白-4刺激物、T细胞表面糖蛋白CD28抑制剂、MEKK-5蛋白激酶抑制剂、结缔组织生长因子配体抑制剂、甘露聚糖结合凝集素丝氨酸蛋白酶-2抑制剂、Syk酪氨酸激酶抑制剂、钠-葡萄糖转运蛋白-2抑制剂、红细胞生成素受体激动剂、肌苷单磷酸脱氢酶抑制剂;C5基因抑制剂、胰岛素增敏剂、钾通道抑制剂、盐皮质激素受体拮抗剂、Jak1酪氨酸激酶抑制剂、Jak酪氨酸激酶抑制剂、Jak2酪氨酸激酶抑制剂、P2Y12嘌呤受体拮抗剂、补体C5因子抑制剂、钙调神经磷酸酶抑制剂、醛固酮拮抗剂、盐皮质激素受体拮抗剂、肾素抑制剂、盐皮质激素受体拮抗剂、FGF受体拮抗剂、PDGF受体拮抗剂、TGFβ拮抗剂、p38 MAP激酶抑制剂、肌球蛋白刺激物、β2肾上腺素受体激动剂、糖皮质激素激动剂、毒蕈碱型受体拮抗剂、载脂蛋白基因刺激物、环加氧酶1抑制剂、加压素V1激动剂、血管紧张素转化酶2刺激物、PPARγ激动剂、前列腺素类受体拮抗剂、CX3CR1趋化因子拮抗剂、PDGF受体β调节剂、肝素激动剂、细胞外基质蛋白调节剂、盐皮质激素受体拮抗剂、血管紧张素转化酶(ACE)和中性肽链内切酶(EP)的双重抑制剂以及二肽基肽酶抑制剂。
在一些实施方案中,所述一种或更多种附加的治疗化合物选自INT-767、贝利木单抗、西那卡塞、利妥昔单抗、氯沙坦、阿巴西普、坎地沙坦、司隆色替(selonsertib)、六磷酸肌醇、PBI-4050、OMS-721、福他替尼(fostamatinib)、厄贝沙坦、卡格列净、甲氧基聚乙二醇-依泊汀β、吗替麦考酚酯、ALN-CC5、奥比妥珠单抗(obinutuzumab)、renamezin、哌柏西利(palbociclib)、波生坦、DM-199、布地奈德、阿米吡啶(amifampridine)、磷酸阿米吡啶、达拉菲尼(dabrafenib)、达格列净、达格列净丙二醇、促皮质素、TNT-009、去纤苷酸、非奈利酮(finerenone)、巴瑞替尼(baricitinib)、替卡格雷(ticagrelor)、安立生坦、依库珠单抗、培维索孟、依帕司他、卡莫司他甲磺酸盐、奥曲肽、醋酸奥曲肽、GKT-831、乌拉立肽、巴多索隆、甲基巴多索隆、托伐普坦、奥美沙坦酯、他克莫司、MT-3995、厄贝沙坦+丙帕锗、阿塞西普、伊非曲班、伊非曲班钠、阿法替尼、阿曲生坦、TAK-272、AST-120、非马沙坦、GR-MD-02、CS-3150、吡非尼酮、美卡奥美坎替(omecamtiv mecarbil)、奥美坎替(omecamtiv)、倍氯米松、二丙酸倍氯米松、阿贝他酮(apabetalone)、司帕生坦、ChronSeal、阿齐瑞格(azeliragon)、潘瑞鲁单抗、阿替西生(atesidorsen)、加巴喷丁酯、加巴喷丁、咪达普利、森德立肽(cenderitide)、BMP-7、GLY-230、重组红细胞生成素刺激蛋白、2MD、特利加压素、吡哆胺二盐酸盐、吡哆胺、DEX-M74、GSK-2586881、SER-150-DN、克拉生坦、布利莫德(blisibimod)、AKB-9778、依托特明α、贝那普利、恩利卡生(emricasan)、依前列醇、DW-1029M、苄达赖氨酸、塞利西利(seliciclib)、BPS-804、阿伐可泮(avacopan)、ALLO-ASC-DFU、SM-101、帕洛利珠单抗(plozalizumab)、贝前列素钠、贝前列素、洛吡莫德、PEG-bHb-CO、重组人碱性磷酸酶、CXA-10、SAR-407899、BI-655088、BOT-191、舒洛地特、伏帕尼酶、生长激素、托匹司他、SB-030、SHP-627、KBP-5074、EA-230、培戈-依玛替卡(emapticappegol)、苯丁酸钠、BB-3、Hemalb、替拉扎特、ASP-8232、VPI-2690B、醋酸奥曲肽、EPO-018B、托拉塞米、大黄酸、PHN-033、依普沙坦、KP-100IT、NCTX、ERC-124、沙丙蝶呤、帕肝素钠、帕肝素、非诺多泮和维生素D。
在一些实施方案中,还对患者施以体外血液净化、同种异体移植术和/或干细胞疗法。
在一些实施方案中,所述一种或更多种附加的治疗化合物同时或依次进行施用。
在一些实施方案中,所述一种或更多种附加的治疗化合物与式I或(Ia)的化合物、化合物1、化合物2或化合物3一起作为单一药物组合物施用,或作为单独的药物组合物施用。
调节CCR2活性的化合物
本公开提供了调节CCR2活性的化合物。趋化因子受体是与细胞外配体(例如趋化因子)相互作用并介导细胞对配体的反应(例如趋化性、提高的细胞内钙离子浓度等等)的膜内在蛋白质。因此,调节趋化因子受体功能,例如干扰趋化因子受体配体相互作用,将调节趋化因子受体介导的反应,并治疗或预防趋化因子受体介导的病症或疾病。调节趋化因子受体功能包括功能的诱导和抑制二者。实现的调节类型将取决于化合物(即拮抗剂或全部、部分或反向激动剂)的特性。
不意欲受任何特定理论的束缚,据信本文中提供的化合物干扰趋化因子受体与一种或更多种同源配体之间的相互作用。特别地,据信该化合物干扰CCR2与CCR2配体(例如MCP-1)之间的相互作用。本公开设想的化合物包括,但不限于本文中提供的示例性化合物及其盐。
本公开的化合物被认为通过特异性调节或抑制趋化因子受体功能来干扰不适当的T-细胞运输。本公开设想的可用于治疗FSGS的化合物包括,但不限于本文中提供的示例性化合物及其药学上可接受的盐,以及US 8,519,135、US 2006/0173019、US 2014/0031348、US 7,622,583、US 7,884,110和US 8,093,247(其通过引用由此并入)中提供的化合物。
在一些实施方案中,本公开的化合物是CCR2的选择性抑制剂。
组合物
本公开设想施用包含式I、式(Ia)的化合物、化合物1、化合物2或化合物3的药学上可接受的组合物用于治疗需要其的患者中的局灶性节段性肾小球硬化(FSGS)。该药学上可接受的组合物可以包含一种或更多种附加的治疗化合物。所述一种或更多种附加的治疗化合物可以选自具有治疗FSGS或肾病的功效的化合物。
该药学上可接受的组合物可以经口、直肠、胃肠外、脑池内、阴道内、腹膜内、局部(如通过散剂、软膏剂或滴剂)、颊含、作为口腔或鼻腔喷雾等等施用于人和其它动物。
用于口服施用的液体剂型包括,但不限于药学上可接受的的乳剂、微乳剂、溶液、混悬剂、糖浆剂和酏剂。除了活性化合物之外,液体剂型可以含有本领域常用的惰性稀释剂,如,例如水或其它溶剂、增溶剂和乳化剂例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇和失水山梨糖醇的脂肪酸酯,及其混合物。除惰性稀释剂之外,该口服组合物还可以包含佐剂,例如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和芳香剂。
可注射制剂,例如无菌可注射水性或油质混悬剂可以根据已知技术使用合适的分散剂或润湿剂和悬浮剂来配制。该无菌可注射制剂还可以是在无毒的胃肠外可接受的稀释剂或溶剂中的无菌可注射溶液、混悬剂或乳剂,例如作为在1,3-丁二醇中的溶液。可以采用的可接受的载体和溶剂之中有水、林格氏溶液、U.S.P.和等渗氯化钠溶液。此外,无菌的固定油通常用作溶剂或悬浮介质。出于此目的,可以采用任何温和的固定油,包括合成的甘油单酯或甘油二酯。此外,在可注射产品中可以混入脂肪酸例如油酸。可注射制剂可以例如通过经细菌截留过滤器过滤、或通过混入无菌固体组合物形式的灭菌剂(其可以在使用前溶解或分散在无菌水或其它无菌可注射介质中)来进行灭菌。
为了延长本公开的化合物的效果,通常合意的是减缓来自皮下或肌肉内注射的化合物的吸收。这可以通过使用水溶性不佳的结晶或非晶材料的液体混悬剂来实现。化合物的吸收速率由此取决于其溶解速率,而溶解速率又可取决于晶体尺寸和晶形。或者,通过将化合物溶解或悬浮在油性载体中来实现胃肠外施用的化合物形式的延迟吸收。通过以生物可降解聚合物(例如聚丙交酯-聚乙交酯)形成化合物的微胶囊基质来制造可注射的储库形式。取决于化合物与聚合物的比率和所采用的特定聚合物的性质,可以控制化合物释放的速率。其它生物可降解聚合物的实例包括聚原酸酯和聚酸酐。还通过在与身体组织相容的脂质体或微乳液中包埋该化合物来制备可注射储库制剂。
用于直肠或阴道施用的组合物优选是栓剂,其可以通过将本公开的化合物与合适的无刺激性赋形剂或载体(例如可可脂、聚乙二醇或栓剂蜡)混合来制备,所述赋形剂或载体在环境温度下为固体,但是在体温下为液体,并因此在直肠或阴道腔内熔化并释放活性化合物。
用于口服施用的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在此类固体剂型中,活性化合物与至少一种惰性的、药学上可接受的赋形剂或载体例如柠檬酸钠或磷酸二钙和/或(a)填料或增量剂例如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇和硅酸,(b)粘合剂如,例如羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶,(c)保湿剂例如甘油,(d)崩解剂例如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐、和碳酸钠,(e)溶解延缓剂(solution retarding agent)例如石蜡,(f)吸收加速剂例如季铵化合物,(g)润湿剂如,例如鲸蜡醇和单硬脂酸甘油酯,(h)吸收剂例如高岭土和膨润土,以及(i)润滑剂例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠,及其混合物混合。在胶囊剂、片剂和丸剂的情况下,该剂型还可以包含缓冲剂。
类似类型的固体组合物也可以在软和硬填充明胶胶囊中用作填料,所述胶囊使用诸如乳糖(lactose或milk sugar)以及高分子量聚乙二醇等等的赋形剂。片剂、糖衣丸、胶囊剂、丸剂和颗粒剂的固体剂型可以制备具有包衣和外壳,例如肠溶包衣和药物配制领域中熟知的其它包衣。它们可以任选含有遮光剂,并还可以具有它们仅仅或优选在肠道某一部分中任选以延迟方式释放活性成分的组成。可以使用的包埋组合物的实例包括聚合物质和蜡。类似类型的固体组合物也可以在软和硬填充明胶胶囊中用作填料,所述胶囊使用诸如乳糖以及高分子量聚乙二醇等等的赋形剂。
本公开的化合物或其药学上可接受的盐可以使用纳米技术来配制。基于它们独特的特征,例如它们大于其它颗粒的表面积与质量比率、它们的量子性质以及它们吸附和负载其它化合物的能力,纳米颗粒对医学目的是有吸引力的。纳米颗粒可以具有低于0.1μm或100 nm的尺寸。或者,如将足够量的药物负载到颗粒上所需那样,药物组合物可以包含相对大(尺寸>100 nm)的纳米颗粒。此外,对于药物递送,不仅可以使用工程化颗粒作为载体,而且药物本身可以以纳米尺度配制,并随后充当其自身的载体。工程化纳米颗粒的组成可以改变。源材料可以具有生物来源如磷脂、脂质、乳酸、右旋糖酐、壳聚糖,或具有更多化学特性,如各种聚合物、碳、二氧化硅和金属。尤其在聚合物来源的工程化纳米颗粒领域中,化学组成具有广泛的可能性。参见,例如Martins等人, Nanoparticle Drug DeliverySystems: Recent Patents and Applications in Nanomedicine, Recent Patents onNanomedicine, 2013, 3(2), 第1-14页。
本公开的化合物或其药学上可接受的盐还可以呈含有一种或更多种如上所述的赋形剂的微囊化形式。片剂、糖衣丸、胶囊剂、丸剂和颗粒剂的固体剂型可以制备具有包衣和外壳,例如肠溶包衣、控释包衣和药物配制领域中熟知的其它包衣。在此类固体剂型中,活性化合物可以与至少一种惰性稀释剂(例如蔗糖、乳糖或淀粉)混合。如通常的做法那样,此类剂型还可以包含不同于惰性稀释剂的附加物质,例如压片润滑剂和其它压片助剂例如硬脂酸镁和微晶纤维素。在胶囊剂、片剂和丸剂的情况下,该剂型还可以包含缓冲剂。它们可以任选含有遮光剂,并还可以具有它们仅仅或优选在肠道某一部分中任选以延迟方式释放活性成分的组成。可以使用的包埋组合物的实例包括聚合物质和蜡。
本公开的化合物的用于局部或透皮施用的剂型包括软膏剂、糊剂、乳膏剂、洗剂、凝胶剂、散剂、溶液、喷雾剂、吸入剂或贴剂。活性组分在无菌条件下与药学上可接受的载体和任何所需防腐剂或缓冲剂(可能需要的)混合。眼用制剂、滴耳剂和滴眼剂也设想在本公开的范围内。此外,本公开设想使用透皮贴剂,其具有提供化合物向身体的受控递送的附加优点。通过在合适的介质中溶解或分散该化合物来制备此类剂型。吸收促进剂也可以用于提高化合物穿过皮肤的通量。可以通过提供速率控制膜或通过在聚合物基质或凝胶中分散该化合物来控制速率。
本公开的化合物和组合物可以通过经口、胃肠外(例如肌肉内、腹膜内、静脉内、ICV、脑池内注射或输注、皮下注射、或植入)、吸入、经鼻、阴道、直肠、舌下或局部施用途径来施用,并可以在含有适于各施用途径的常规无毒药学上可接受的载体、佐剂和赋形剂的合适剂量单位制剂中单独或一起配制。本公开还设想了以储库制剂施用本公开的化合物和组合物。
式(I)、式(Ia)的化合物、化合物1、2或3或其药学上可接受的盐的合适的剂量水平将通常为每天每千克患者体重大约0.001至100 mg(其可以以单剂量或多剂量施用)。优选地,该剂量水平将为每天大约0.01至大约25 mg/kg;更优选每天大约0.05至大约10 mg/kg。合适的剂量水平可以为每天大约0.01至25 mg/kg、每天大约0.05至10 mg/kg、或每天大约0.1至5 mg/kg。在该范围内,该剂量可以为每天0.005至0.05、0.05至0.5、0.5至5.0、或5.0至50 mg/kg。对于口服施用,该组合物优选以含有1.0至1000毫克活性成分、特别是1.0、5.0、10.0、15.0、20.0、25.0、50.0、75.0、80.0、90.0、100.0、110.0、120.0、130.0、140.0、150.0、160.0、170.0、180.0、190.0、200.0、250.0、300.0、400.0、500.0、600.0、750.0、800.0、900.0和1000.0毫克活性成分的片剂形式提供,以便对症调节用于待治疗患者的剂量。对于口服施用,在一些实施方案中,该组合物以含有150 mg活性成分的片剂形式提供。对于口服施用,在一些实施方案中,该组合物以含有10 mg活性成分的片剂形式提供。对于口服施用,在一些实施方案中,该组合物以含有5 mg活性成分的片剂形式提供。该化合物可以以每天1至4次、优选每天一次或两次的方案进行施用。
但是,将理解的是,对于任何特定患者的具体剂量水平和给药频率可以改变,并将取决于多个因素,包括所采用的具体化合物的活性、代谢稳定性和该化合物的作用时长、年龄、体重、遗传特性、总体健康、性别、饮食、施用模式与时间、排泄率、药物组合、特定病症的严重程度以及接受治疗的宿主。
本公开的化合物和组合物可以与具有预防和治疗FSGS的相关效用的其它化合物和组合物组合。用于组合疗法的适当药剂的选择可以由本领域普通技术人员作出。治疗剂的组合可以协同作用以实现各种病症的治疗或预防。采用这种方法,可能够以较低剂量的各药剂实现治疗功效,由此降低不良副作用的可能性。
本公开的化合物与另一活性成分的重量比可以改变,并将取决于各成分的有效剂量。通常,将使用各自的有效剂量。由此,例如,当将本公开的化合物与第二治疗化合物组合时,本公开的化合物与第二治疗化合物的重量比将通常在大约1000:1至大约1:1000、优选大约200:1至大约1:200范围内。
在又一方面,本公开提供了治疗或预防FSGS的方法,其通过向患有此病症或疾病的受试者施用治疗有效量的本公开的任何化合物来进行。用于本方法的化合物包括根据式(I)、式(Ia)的那些化合物、化合物1、2或3或其药学上可接受的盐、作为实施方案提供的那些、具备本文中的特定结构的那些、以及US 8,519,135、US 2006/0173019、US 2014/0031348、US 7,622,583、US 7,884,110和US 8,093,247(其通过引用由此并入)中提供的化合物。该化合物可用于治疗需要治疗的受试者。“受试者”在本文中被定义为包括动物,例如哺乳动物,包括但不限于灵长类动物(例如人)、牛、绵羊、山羊、马、狗、猫、兔、大鼠、小鼠等等。在优选的实施方案中,受试者是人。
如本文中所用的短语“治疗有效量”表示将引起研究人员、兽医、医师或其它治疗提供者所寻求的细胞、组织、系统或动物(例如人)的生物或医学反应的主题化合物的量。
在一个实施方案中,本公开提供了治疗或预防FSGS的方法,其包括向受试者施用有效量的本公开的化合物或组合物,其中该施用是口服、胃肠外、直肠、透皮、舌下、经鼻或局部施用。
调节剂
提供以下实施例以例示而非限制本公开。
本专利中公开的某些分子可以以不同的对映异构体和非对映异构体形式存在,并且这些化合物的所有此类变体都在本公开的范围内。
观察到的具体药理学反应可以根据并取决于所选择的特定活性化合物或是否存在药物载体,以及所采用的制剂类型和施用模式而变化,并且根据本公开的实践设想了此类预期变化或结果的差异。
尽管在本文中详细例示和描述了本公开的具体实施方案,但是本公开不限于此。提供以上详细描述作为本公开的示例,并且其不应被解释为构成对本公开的任何限制。对于本领域技术人员而言,修改将是显而易见的,并且不偏离本公开的精神的所有修改都意在包括在所附权利要求的范围内。
附加组合
本公开的化合物可以单独提供,或与一种或更多种用于治疗FSGS的其它药物结合提供。
可以与本公开的化合物或组合物组合的治疗剂(分开施用或以同一药物组合物施用)的实例包括,但不限于:CCR1、CCR2、CCR3、CCR4、CCR5、CCR6、CCR7、CCR8、CCR9、CCR10、CCR11、CXCR1、CXCR2、CXCR3、CXCR4、CXCR5、CXCR6、CXCR7、CX3CR1、ChemR23、C5aR、C5a和C5的调节剂,或其任意组合。在一些实施方案中,该调节剂是拮抗剂。
可以与本公开的化合物或组合物组合的治疗剂(分开施用或以同一药物组合物施用)的实例包括,但不限于:CCX354、CCX9588、CCX140、CCX872、CCX598、CCX6239、CCX9664、CCX2553、CCX2991、CCX282、CCX025、CCX507、CCX430、CCX765、CCX224、CCX662、CCX650、CCX832、CCX168和CCX168-M1或其任意组合。
可以与本公开的化合物或组合物组合的其它治疗剂(分开施用或以同一药物组合物施用)的实例包括,但不限于:治疗性抗体、双特异性抗体和“抗体样”治疗蛋白(例如DARTs®、Duobodies®、Bites®、XmAbs®、TandAbs®、Fab衍生物)、抗体-药物缀合物(ADC)、病毒、溶瘤病毒、基因修饰器或编辑器,例如CRISPR(包括CRISPR Cas9)、锌指核酸酶或合成核酸酶(TALEN)、CAR(嵌合抗原受体)、T-细胞免疫治疗剂、细胞因子、疫苗和疫苗佐剂。
试剂盒和套装
术语“试剂盒”和“药物试剂盒”是指在一个或更多个合适的容器中包含一种或更多种药物组合物以及其使用说明书的商业试剂盒或套装。在一个实施方案中,提供了包含式(I)或(Ia)的化合物、或化合物1、2或3、或其药学上可接受的盐,以及其施用说明书的试剂盒。在一个实施方案中,提供了包含式(I)或(Ia)的化合物、或化合物1、2或3、或其药学上可接受的盐,结合一种或更多种(例如一种、两种、三种、一种或两种、或一种至三种)附加治疗剂,以及其施用说明书的试剂盒。
在一个实施方案中,将本公开的化合物配制成包装在单个包装中的施用单元。该单个包装涵盖,但不限于瓶子、儿童安全瓶、安瓿和管。在一个实施方案中,将本公开的化合物和任选的附加治疗剂配制成施用单元,并且将每个单个施用单元独立地包装在单个包装中。此类独立包装的单元可以含有任何形式的药物组合物,所述形式包括,但不限于液体形式、固体形式、粉末形式、颗粒形式、泡腾粉末或片剂、硬或软胶囊剂、乳剂、混悬剂、糖浆剂、栓剂、片剂、糖锭(troche)、锭剂(lozenge)、溶液、口腔贴剂、薄膜、口服凝胶剂、咀嚼片剂、口香糖和一次性注射器。此类单独包装的单元可以组合在由纸、卡纸板、纸板、金属箔和塑料箔中的一种或更多种制成的包装(例如泡罩包装)中。一个或更多个施用单元可以一天施用一次或数次。一个或更多个施用单元可以一天施用三次。一个或更多个施用单元可以一天施用两次。可以在第一天施用一个或更多个施用单元,并且可以在接下来的几天中施用一个或更多个施用单元。
其它疾病
单独或组合使用的式(I)、(Ia)的化合物、化合物1、化合物2或化合物3、或其药学上可接受的盐和/或前药、或其组合物可用于治疗其它疾病。这些疾病包括,但不限于慢性肾脏病、糖尿病肾病、终末期肾病、肾小球疾病、肺出血肾炎综合征、肾小球肾炎、肾小球硬化症、igA肾病、膜性增生性肾小球肾炎、膜性肾小球肾炎、韦格纳肉芽肿病、血管炎、Anca血管炎、肾衰竭、肾纤维化、巴特氏病、肾钙沉着症、肾盂积水、肾积脓、肝肾综合征、溶血性尿毒症综合征、肾炎、尿崩症、肾性尿崩症、肾功能不全、神经源性尿崩症、沃尔弗拉姆综合征、肾病综合征、微小病变肾病、肾周炎、丹特病、吉特曼氏综合征、肾硬化、肾小管疾病、肝肾综合征、氮质血症、尿毒症、奥尔波特综合征、肾小球肾炎、狼疮肾炎、肾盂炎、肾盂肾炎、肾盂膀胱炎、肾小球损伤、多囊肾病、获得性多囊肾病、常染色体显性多囊肾病、常染色体隐性多囊肾病、阿博赫登-考夫曼-利尼亚克氏综合征(肾病性胱氨酸病)、腹腔间隔室综合征、对乙酰氨基酚引起的肾毒性、急性肾衰竭、急性肾损伤、急性叶性肾炎、急性磷酸盐肾病、急性肾小管坏死、腺嘌呤磷酸核糖基转移酶缺乏、腺病毒肾炎、奥尔波特综合征、淀粉样变、血管平滑肌脂肪瘤、镇痛药性肾病、抗磷脂综合征、抗TNF-α治疗相关性肾小球肾炎、APOL1突变、表观盐皮质激素过多综合征、马兜铃酸肾病、中草药肾病、巴尔干地方性肾病、甜菜尿、β-地中海贫血肾病、胆汁管型肾病、自体肾中的BK多瘤病毒肾病、膀胱括约肌协同失调、膀胱填塞、跨境者肾病(border-Crossers' Nephropathy)、波旁病毒和急性肾损伤、急性肾功能障碍、百泌达(Byetta)、C1q肾病、大麻素剧吐急性肾衰竭、心肾综合征、卡非佐米引起的肾损伤、CFHR5肾病、沙-马-图病伴肾小球病、胆固醇栓塞、查格-施特劳斯氏综合征、乳糜尿、粘菌素肾毒性、胶原纤维性肾小球病、萎陷性肾小球病、CMV相关性萎陷性肾小球病、先天性肾病综合征、锥形骨骺肾病综合征(conorenal syndrome)(迈因策尔-萨尔迪诺综合征或萨尔迪诺-迈因策尔病)、造影剂肾病、硫酸铜中毒、肾皮质坏死、克唑替尼相关性急性肾损伤、冷球蛋白血症、结晶球蛋白引起的肾病、囊性肾病、获得性胱氨酸尿症、致密沉积物病、透析平衡失调综合征、糖尿病肾病、弥漫性肾小球膜硬化症、多重输尿管(duplicated Ureter)、EAST综合征、埃尔德海姆-切斯特病、法布里病、家族性低尿钙性高钙血症、范科尼综合征、弗雷泽综合征、纤连蛋白肾小球病、原纤维性肾小球肾炎和免疫类晶团聚体性肾小球病、弗雷利综合征(Fraley syndrome)、局灶性硬化、局灶性肾小球硬化症、加洛韦-莫厄特综合征(Galloway Mowat syndrome)、肾脏参与的巨细胞(颞)动脉炎、肾小球肾小管反流(glomerular Tubular Reflux)、糖尿、汉坦病毒感染足细胞病、热应激肾病、血尿、非典型溶血性尿毒症综合征(aHUS)、噬血细胞综合征、出血性膀胱炎、流行性肾病、含铁血黄素尿、含铁血黄素沉着症、肾小球病、肝肾小球病(hepathic glomerulopathy)、肝静脉闭塞病、肝窦阻塞综合征、丙型肝炎相关性肾病、肝肾综合征、HIV相关性肾病(HIVAN)、HNF1B相关性常染色体显性肾小管间质性肾病、马蹄形肾(肾融合)、亨纳溃疡、高醛固酮症、高钙血症、高钾血症、高镁血症、高钠血症、高草酸尿、高磷酸盐血症、低钙血症、低补体血症性荨麻疹性血管炎综合征(hypocomplementemic urticarial Vasculitic Syndrome)、低钾血症、低钾血症引起的肾功能障碍、低钾血性周期性麻痹、低镁血症、低钠血症、低磷酸盐血症、IgA肾病、IgG4肾病、免疫检查点治疗相关性间质性肾炎、间质性膀胱炎、膀胱疼痛综合征、间质性肾炎、伊韦马克综合征、氯胺酮相关性膀胱功能障碍、肾石、肾结石、康普茶毒性、铅性肾病和铅相关性肾毒性、钩端螺旋体病肾病、轻链沉积病、单克隆免疫球蛋白沉积病、利德尔综合征、莱-奥二氏综合征、脂蛋白肾小球病、锂肾毒性、LMX1B突变引起的遗传性FSGS、腰痛血尿、狼疮、系统性红斑狼疮、狼疮肾病、狼疮肾炎、狼疮肾炎伴抗中性粒细胞胞浆抗体血清阳性、狼疮足细胞病、莱姆病相关性肾小球肾炎、溶菌酶肾病、疟疾肾病、恶性肿瘤相关性肾病、恶性高血压、软斑病、尿道口狭窄、髓质囊性肾病、尿调素相关性肾病(Urolodulin-Associated Nephropathy)、青少年高尿酸血症肾病1型、髓质海绵肾、巨输尿管、三聚氰胺肾脏毒性(Melamine Toxicity and the Kidney)、膜性增生性肾小球肾炎、膜性肾病、膜样肾小球病伴隐匿性IgG κ沉积、中美洲肾病、代谢性酸中毒、代谢性碱中毒、甲氨蝶呤相关性肾衰竭、显微镜下型多血管炎、乳碱综合征、微小病变肾病、MDMA(摇头丸(Molly/Ecstacy);3,4-亚甲基二氧基甲基苯丙胺)性肾衰竭(MDMA (Molly; Ecstacy; 3,4-Methylenedioxymethamphetamine) and Kidney Failure)、MUC1肾病、多囊性肾发育不良、多发性骨髓瘤、骨髓增生性肿瘤和肾小球病、指甲-髌骨综合征、肾钙沉着症、肾性系统性纤维化、浮肾(游动肾、肾下垂)、肾病综合征、神经源性膀胱、结节性肾小球硬化、非淋菌性尿道炎、胡桃夹综合征、肾单位稀少巨大症、口面指综合征、乳清酸尿症、直立性低血压、直立性蛋白尿、渗透性利尿、渗透性肾变病、卵巢过度刺激综合征、草酸盐肾病、Page肾、肾乳头坏死(papillary necrosis)、乳头肾综合征(papillorenal Syndrome)(肾缺损综合征、孤立肾发育不良)、腹膜-肾综合征、后尿道瓣膜、感染后性肾小球肾炎、链球菌感染后肾小球肾炎、结节性多动脉炎、多囊肾病、后尿道瓣膜、先兆子痫、异丙酚输注综合征、增生性肾小球肾炎伴单克隆IgG沉积(纳斯病)、蜂胶相关性肾衰竭、蛋白尿、假性高醛固酮症、假性低重碳酸盐血症(pseudohypobicarbonatemia)、假性甲状旁腺功能减退症、肺-肾综合征、肾盂肾炎、肾积脓、放射性肾病、再喂养综合征、反流性肾病、急进性肾小球肾炎、肾脓肿、肾周脓肿、肾不发生、肾弓状静脉微血栓相关性急性肾损伤、肾动脉瘤、肾动脉狭窄、肾细胞癌、肾囊肿、肾性低尿酸血症伴运动引起的急性肾衰竭、肾梗塞、肾性骨营养不良、肾小管性酸中毒、肾素突变和常染色体显性肾小管间质性肾病、肾素分泌瘤(肾小球旁细胞瘤)、渗透稳定器重设(reset osmostat)、腔静脉后输尿管、腹膜后纤维化、横纹肌溶解、与减肥手术有关的横纹肌溶解、类风湿性关节炎相关性肾病、结节病肾病、盐消耗、血吸虫病和肾小球疾病、schimke免疫-骨发育不良、硬皮病肾危象、蛇形腓骨-多囊肾综合征、埃克斯纳综合征、镰状细胞肾病、斯耶格伦氏综合征、合成大麻素使用和急性肾损伤、造血细胞移植后的肾病、与干细胞移植有关的肾病、薄基底膜病、良性家族性血尿、膀胱三角区炎、结核病、结节性硬化症、肾小管发育不全、近端小管刷状缘侧的自身抗体造成的免疫复合物肾小管间质性肾炎、肿瘤溶解综合征、尿毒症、尿毒症性视神经病变、囊性输尿管炎、输尿管脱垂、尿道肉阜、尿道狭窄、尿失禁、尿路感染、尿路梗阻、尿调素相关性肾病、血管运动性肾病、膀胱肠瘘、膀胱输尿管反流、希佩尔-林道病、瓦尔登斯特伦巨球蛋白血症肾小球肾炎、华法林相关性肾病、韦格纳肉芽肿病、肉芽肿伴多血管炎、西尼罗河病毒、温德利希综合征、泽尔韦格综合征、脑肝肾综合征、黑色素瘤、胶质母细胞瘤、食管肿瘤、鼻咽癌、葡萄膜黑色素瘤、淋巴瘤、淋巴细胞性淋巴瘤、原发性CNS淋巴瘤、T-细胞淋巴瘤、弥漫性大B-细胞性淋巴瘤、原发性纵隔大B-细胞性淋巴瘤、前列腺癌、去势难治性前列腺癌、慢性粒细胞性白血病、卡波西肉瘤纤维肉瘤、脂肪肉瘤、软骨肉瘤、骨源性肉瘤、血管肉瘤、淋巴管肉瘤、滑膜瘤、脑脊膜瘤、平滑肌肉瘤、横纹肌肉瘤、软组织肉瘤、肉瘤、败血症、胆管肿瘤、基底细胞癌、胸腺肿瘤、甲状腺癌、甲状旁腺癌、子宫癌、肾上腺癌、肝脏感染、梅克尔细胞癌、神经肿瘤、滤泡中心淋巴瘤、结肠癌、霍奇金病、非霍奇金淋巴瘤、白血病、慢性或急性白血病,包括急性髓细胞白血病、慢性髓细胞白血病、急性成淋巴细胞白血病、慢性淋巴细胞白血病、多发性骨髓瘤、卵巢肿瘤、骨髓增生异常综合征、皮肤或眼内恶性黑色素瘤、肾细胞癌、小细胞肺癌、肺癌、间皮瘤、乳腺癌、鳞状非小细胞肺癌(SCLC)、非鳞状NSCLC、结肠直肠癌、卵巢癌、胃癌、肝细胞癌、胰腺恶性肿瘤、胰腺癌、胰腺导管腺癌、头颈部鳞状细胞癌、头或颈部癌症、胃肠道、胃癌、骨癌、皮肤癌、直肠癌、肛区癌、睾丸癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、食管癌、小肠癌、内分泌系统癌症、尿道癌、阴茎癌、膀胱癌、肾癌、输尿管癌、肾盂癌、中枢神经系统(CNS)肿瘤、肿瘤血管发生、脊柱轴肿瘤、脑干胶质瘤、垂体腺瘤、表皮样癌、石棉肺、癌、腺癌、乳头状癌、囊腺癌、支气管源性癌、肾细胞癌、移行细胞癌、绒膜癌、精原细胞瘤、胚胎性癌、维尔姆斯瘤、多形性腺瘤、肝细胞乳头状瘤、肾小管腺瘤、囊腺瘤、乳头状瘤、腺瘤、平滑肌瘤、横纹肌瘤、血管瘤、淋巴管瘤、骨瘤、软骨瘤、脂肪瘤和纤维瘤。对于这些疾病中的任何种,可以将本公开的化合物与其它治疗剂(包括本公开中公开的那些)组合。
实施例
残肾模型和阿霉素药物诱导模型是通常用于FSGS的啮齿动物模型(de Mik SM.等人, Pathophysiology and treatment of focal segmental glomerulosclerosis: therole of animal models. BMC Nephrol. 2013年4月1日; 14:74)。5/6残肾模型代表继发性FSGS,而阿霉素肾病模型代表原发性FSGS。
实施例1:5/6残肾模型
该5/6残肾129X1/SvJ小鼠获自杰克逊实验室(Jackson Laboratories)。该小鼠保持标准饮食并可自由获取水。小鼠手术分两个阶段进行。在异氟烷麻醉下,切除左肾质量的三分之二。在7至10天后,进行右侧单侧肾切除术。在5/6肾切除术后6周,将小鼠随机化进行研究。将化合物3及其载体每天一次以100 mg/kg皮下给药,其在1% HPMC中配制。每组使用6只动物。
通过将小鼠单独容纳在代谢笼中18小时,在第1周和第2周收集尿样品。通过ELISA(Bethyl Labs, Montgomery, TX)测量尿白蛋白,并以每24小时的微克数的形式计算尿白蛋白排泄率(UAER)。通过质谱法测量尿肌酐。以每毫克肌酐的白蛋白毫克数的形式计算白蛋白与肌酐的比率(ACR)。在实验结束时(治疗2周后),收集肾脏,将其在福尔马林中固定,包埋在石蜡中,并切成3 µm厚的切片。通过用维尔姆斯瘤蛋白1抗体(Abcam, Cambridge,MA)的免疫组织化学对切片进行足细胞染色。每只小鼠在20-30个肾小球中测定肾小球横截面积和足细胞数量。使用Weibel法由免疫组织化学数据计算肾小球体积和足细胞密度。通过常规方法在2 µm厚的石蜡切片上通过六亚甲四胺银染色来测量系膜扩张。
图1显示化合物3在第1周和第2周在5/6残肾模型中减少了严重的(profound)蛋白尿。
图2显示化合物3在5/6残肾模型中减少了肾间质巨噬细胞的数量。
图3显示在具有和不具有化合物3治疗的情况下在5/6残肾模型中肾间质巨噬细胞的一些代表性图像。
图4显示化合物3提高了5/6残肾模型中的足细胞数量。
图5显示在具有和不具有化合物3治疗的情况下在5/6残肾模型中足细胞的代表性图像。
图6显示在5/6残肾模型中化合物3对具有系膜溶解的肾小球的百分比具有有益效果。
图7显示具有系膜溶解的肾小球的代表性图像。
实施例2:阿霉素肾病模型
该实验在雌性Balb/c小鼠(杰克逊实验室)中进行。该小鼠保持标准饮食并可自由获取水。在第0天,在异氟烷麻醉的动物的尾静脉中注射7.5 mg/kg阿霉素(Selleck Chemicals)或盐水(对照)。将化合物1及其载体(1% HPMC)每天一次以90 mg/kg皮下给药,其在1% HPMC中配制。坎地沙坦及其载体(H2O)每日口服给药一次。每组使用12只动物。
通过将小鼠单独容纳在代谢笼中18小时,在第1周和第2周收集尿样品。通过ELISA(Bethyl Labs, Montgomery, TX)测量尿白蛋白,并以每24小时的微克数的形式计算尿白蛋白排泄率(UAER)。通过质谱法测量尿肌酐。以每毫克肌酐的白蛋白毫克数的形式计算白蛋白与肌酐的比率(ACR)。
图8显示作为单一试剂和与坎地沙坦(CST)组合的化合物1导致UACR水平降低。
图9显示与坎地沙坦(CST)组合的化合物1导致UAER水平降低。
实施例3:采用联合治疗的5/6残肾模型
该5/6残肾129X1/SvJ小鼠获自杰克逊实验室。该小鼠保持标准饮食并可自由获取水。小鼠手术分两个阶段进行。在异氟烷麻醉下,切除左肾质量的三分之二。在7至10天后,进行右侧单侧肾切除术。在5/6肾切除术后3至6周,将小鼠随机化进行研究(n=12/组)。化合物3及其载体每天一次以100 mg/kg皮下给药,其在1% HPMC中配制。坎地沙坦(AK Scientific)及其载体(H2O)以5 mg/kg每日口服给药一次。对每组两只动物在第1、2和3周实施安乐死以进行组织学和IHC。
通过将小鼠单独容纳在代谢笼中18小时,在第1周、第2周和第3周收集尿样品。通过ELISA (Bethyl Labs, Montgomery, TX)测量尿白蛋白,并以每24小时的微克数的形式计算尿白蛋白排泄率(UAER)。通过质谱法测量尿肌酐。以每毫克肌酐的白蛋白毫克数的形式计算白蛋白与肌酐的比率(ACR)。
图10显示在5/6残肾模型中,在仅用化合物3治疗、仅用坎地沙坦治疗、以及用化合物3和坎地沙坦的组合治疗的情况下,在第1、2和3周UAER值的降低。
图11显示在5/6残肾模型中,在仅用化合物3治疗、仅用坎地沙坦治疗、以及用化合物3和坎地沙坦的组合治疗的情况下,在第1周和第2周UACR值的降低。
化合物1是:
。
化合物2是:
。
化合物3是:
。
观察到的具体药理学反应可以根据并取决于所选择的特定活性化合物或是否存在药物载体、以及所采用的制剂类型和施用模式而变化,并且根据本公开的实践设想了此类预期变化或结果的差异。
尽管在本文中详细例示和描述了本公开的具体实施方案,但是本公开不限于此。提供以上详细描述作为本公开的示例,并且其不应被解释为构成对本公开的任何限制。对于本领域技术人员而言,修改将是显而易见的,并且不偏离本公开的精神的所有修改都意在包括在所附权利要求的范围内。
Claims (26)
1.一种治疗需要其的患者中的局灶性节段性肾小球硬化(FSGS)的方法,其包括向所述患者施用有效量的式I的化合物:
式I
或其药学上可接受的盐,
其中
R1是卤素或C1-6烷基;
R2是氢、卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基或-CN;
R3是氢、卤素或C1-6烷基;
R4是氢、卤素或C1-6烷基;
各R5独立地为C1-6烷基、-OH或-NH2;
n为0、1、2或3;且
A1、A2和A3各自为-CH-或-N-,其中A1、A2或A3中的至少一个是-N-。
2.权利要求1所述的方法,其中
R1是卤素或甲基;
R2是卤素或C1-3卤代烷基;
R3是卤素或C1-3烷基;
R4是氢;
n是0;
A2是-CH-;且
A3是-N-。
3.权利要求1和2中任一项所述的方法,其中所述化合物是:
或其药学上可接受的盐。
4.权利要求1和2中任一项所述的方法,其中所述化合物是
或其药学上可接受的盐。
5.权利要求1和2中任一项所述的方法,其中所述化合物是
或其药学上可接受的盐。
6.权利要求1至5中任一项所述的方法,其中治疗FSGS的方法包括预防、减少或消除FSGS的症状或并发症。
7.权利要求1至6中任一项所述的方法,其中治疗FSGS的方法包括预防、消除或延迟所述患者的终末期肾病的发作。
8.权利要求1至7中任一项所述的方法,其中所述FSGS是原发性FSGS。
9.权利要求1至7中任一项所述的方法,其中所述FSGS是继发性FSGS。
10.权利要求9所述的方法,其中所述继发性FSGS与感染或病毒、疾病、暴露于毒素或药物、或肾单位损失和超过滤相关。
11.权利要求10所述的方法,其中FSGS与HIV、镰状细胞疾病、狼疮、暴露于促蛋白合成类固醇、海洛因或帕米膦酸盐、慢性肾盂肾炎和反流、病态肥胖或糖尿病相关。
12.权利要求1至11中任一项所述的方法,其中所述方法包括以下的一种或更多种:减少蛋白尿、减缓蛋白尿的增加、降低UACR、减缓尿白蛋白肌酐比率(UACR)的提高、降低UAER、减缓UAER的提高、减少白蛋白尿、减缓白蛋白尿的增加、提高肾小球足细胞密度、防止或减缓肾小球基底膜(GBM)增厚、降低肾小球面积、减少肾间质巨噬细胞数量、降低或减缓肾组织纤维化、停止或减少肾脏炎症、停止或减少巨噬细胞对肾脏引起的损害、增加或正常化估算的肾小球滤过率(eGFR)、减弱eGFR的下降、减少肾小球硬化症、停止或减少肾小球细胞外基质的扩张、停止或减少透明团块的沉积、停止或减少肾小球上皮增生病变(EPHL)和停止或减少淋巴细胞浸润。
13.权利要求1至12中任一项所述的方法,其中所述化合物或其药学上可接受的盐口服施用。
14.权利要求1至13中任一项所述的方法,其中所述化合物或其药学上可接受的盐每天施用两次。
15.权利要求1至14中任一项所述的方法,其中所述化合物或其药学上可接受的盐每天施用一次。
16.权利要求1至15中任一项所述的方法,其进一步包括向所述患者施用一种或更多种附加的治疗化合物。
17.权利要求16所述的方法,其中所述一种或更多种附加的治疗化合物选自以下的一种或更多种:抗高血压药、他汀类药物、血管舒张药、类固醇、细胞毒类药物、利尿剂、非甾体抗炎药(NSAID)、胆固醇或甘油三酯降低剂和免疫抑制药物。
18.权利要求16所述的方法,其中所述一种或更多种附加的治疗化合物选自血管紧张素转化酶(ACE)抑制剂和血管紧张素受体II阻滞剂(ARB)。
19.权利要求18所述的方法,其中所述一种或更多种附加的治疗化合物选自雷米普利、培哚普利、赖诺普利、培哚普利精氨酸盐、卡托普利、螺普利、喹那普利、依那普利、咪达普利、福辛普利、佐芬普利、贝那普利、群多普利、维拉帕米、贝那普利、氨氯地平、群多普利、P-003、西拉普利、地拉普利、莫昔普利、喹那普利、福辛普利、替莫普利、氯沙坦、坎地沙坦、厄贝沙坦、替米沙坦、奥美沙坦、缬沙坦、阿齐沙坦、替米沙坦、非马沙坦、EMA-401、阿齐沙坦酯钾盐、司帕生坦、坎地沙坦酯、奥美沙坦酯、TRV-027、氯沙坦钾、YH-22189、阿齐沙坦三甲基乙醇胺盐、阿利沙坦酯和依普沙坦。
20. 权利要求16所述的方法,其中所述一种或更多种附加的治疗化合物选自B-淋巴细胞抗原CD20抑制剂、钠-葡萄糖转运蛋白-2抑制剂、T细胞表面糖蛋白CD28抑制剂;细胞毒性T-淋巴细胞蛋白-4刺激物、38 MAP激酶抑制剂、N-乙酰甘露糖胺激酶刺激物、促肾上腺皮质激素配体、整合素α-V/β-3拮抗剂;结缔组织生长因子配体抑制剂和TGFβ拮抗剂。
21.权利要求16所述的方法,其中所述一种或更多种附加的治疗化合物选自利妥昔单抗、达格列净、司帕生坦、阿巴西普、DMX-200、丙帕锗、厄贝沙坦、洛吡莫德、X-M74、阿克撒凝胶、VAR-200、西仑吉肽、潘瑞鲁单抗、DEX-M74、夫苏木单抗和SHP-627。
22. 权利要求16所述的方法,其中所述一种或更多种附加的治疗化合物选自内皮素ET-A拮抗剂、内皮素ET-1拮抗剂、内皮素ET-2拮抗剂、内皮素ET-3拮抗剂、内皮素ET-B1拮抗剂、内皮素ET-B2拮抗剂、内皮素ET-C拮抗剂、B-淋巴细胞刺激因子配体抑制剂、B-淋巴细胞抗原CD20抑制剂、细胞毒性T-淋巴细胞蛋白-4刺激物、T细胞表面糖蛋白CD28抑制剂、MEKK-5蛋白激酶抑制剂、结缔组织生长因子配体抑制剂、甘露聚糖结合凝集素丝氨酸蛋白酶-2抑制剂、Syk酪氨酸激酶抑制剂、钠-葡萄糖转运蛋白-2抑制剂、红细胞生成素受体激动剂、肌苷单磷酸脱氢酶抑制剂;C5基因抑制剂、胰岛素增敏剂、钾通道抑制剂、盐皮质激素受体拮抗剂、Jak1酪氨酸激酶抑制剂、Jak酪氨酸激酶抑制剂、Jak2酪氨酸激酶抑制剂、P2Y12嘌呤受体拮抗剂、补体C5因子抑制剂、钙调神经磷酸酶抑制剂、醛固酮拮抗剂、盐皮质激素受体拮抗剂、肾素抑制剂、盐皮质激素受体拮抗剂、FGF受体拮抗剂、PDGF受体拮抗剂、TGFβ拮抗剂、p38 MAP激酶抑制剂、肌球蛋白刺激物、β2肾上腺素受体激动剂、糖皮质激素激动剂、毒蕈碱型受体拮抗剂、载脂蛋白基因刺激物、环加氧酶1抑制剂、加压素V1激动剂、血管紧张素转化酶2刺激物、PPARγ激动剂、前列腺素类受体拮抗剂、CX3CR1趋化因子拮抗剂、PDGF受体β调节剂、肝素激动剂、细胞外基质蛋白调节剂、盐皮质激素受体拮抗剂、血管紧张素转化酶(ACE)和中性肽链内切酶(EP)的双重抑制剂以及二肽基肽酶抑制剂。
23.权利要求16所述的方法,其中所述一种或更多种附加的治疗化合物选自INT-767、贝利木单抗、西那卡塞、利妥昔单抗、氯沙坦、阿巴西普、坎地沙坦、司隆色替、六磷酸肌醇、PBI-4050、OMS-721、福他替尼、厄贝沙坦、卡格列净、甲氧基聚乙二醇-依泊汀β、吗替麦考酚酯、ALN-CC5、奥比妥珠单抗、renamezin、哌柏西利、波生坦、DM-199、布地奈德、阿米吡啶、磷酸阿米吡啶、达拉菲尼、达格列净、达格列净丙二醇、促皮质素、TNT-009、去纤苷酸、非奈利酮、巴瑞替尼、替卡格雷、安立生坦、依库珠单抗、培维索孟、依帕司他、卡莫司他甲磺酸盐、奥曲肽、醋酸奥曲肽、GKT-831、乌拉立肽、巴多索隆、甲基巴多索隆、托伐普坦、奥美沙坦酯、他克莫司、MT-3995、厄贝沙坦+丙帕锗、阿塞西普、伊非曲班、伊非曲班钠、阿法替尼、阿曲生坦、TAK-272、AST-120、非马沙坦、GR-MD-02、CS-3150、吡非尼酮、美卡奥美坎替、奥美坎替、倍氯米松、二丙酸倍氯米松、阿贝他酮、司帕生坦、ChronSeal、阿齐瑞格、潘瑞鲁单抗、阿替西生、加巴喷丁酯、加巴喷丁、咪达普利、森德立肽、BMP-7、GLY-230、重组红细胞生成素刺激蛋白、2MD、特利加压素、吡哆胺二盐酸盐、吡哆胺、DEX-M74、GSK-2586881、SER-150-DN、克拉生坦、布利莫德、AKB-9778、依托特明α、贝那普利、恩利卡生、依前列醇、DW-1029M、苄达赖氨酸、塞利西利、BPS-804、阿伐可泮、ALLO-ASC-DFU、SM-101、帕洛利珠单抗、贝前列素钠、贝前列素、洛吡莫德、PEG-bHb-CO、重组人碱性磷酸酶、CXA-10、SAR-407899、BI-655088、BOT-191、舒洛地特、伏帕尼酶、生长激素、托匹司他、SB-030、SHP-627、KBP-5074、EA-230、培戈-依玛替卡、苯丁酸钠、BB-3、Hemalb、替拉扎特、ASP-8232、VPI-2690B、醋酸奥曲肽、EPO-018B、托拉塞米、大黄酸、PHN-033、依普沙坦、KP-100IT、NCTX、ERC-124、沙丙蝶呤、帕肝素钠、帕肝素、非诺多泮和维生素D。
24.权利要求1至23中任一项所述的方法,其中还对所述患者施以体外血液净化、同种异体移植术和/或干细胞疗法。
25.权利要求16至23中任一项所述的方法,其中所述一种或更多种附加的治疗化合物同时或依次施用。
26.权利要求16至23中任一项所述的方法,其中所述一种或更多种附加的治疗化合物与式I的化合物一起作为单一药物组合物施用,或作为单独的药物组合物施用。
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US20220226294A1 (en) | 2022-07-21 |
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BR112019010375A2 (pt) | 2019-08-27 |
CA3044621A1 (en) | 2018-05-31 |
CL2019001381A1 (es) | 2019-10-04 |
KR20190088513A (ko) | 2019-07-26 |
EP3544602A4 (en) | 2020-07-08 |
EP4134080A1 (en) | 2023-02-15 |
EP3544602A1 (en) | 2019-10-02 |
WO2018098353A1 (en) | 2018-05-31 |
AU2017363299B2 (en) | 2022-12-22 |
JP2019535776A (ja) | 2019-12-12 |
RU2022102328A (ru) | 2022-04-01 |
IL266751B (en) | 2022-07-01 |
IL294410B2 (en) | 2024-02-01 |
IL294410B1 (en) | 2023-10-01 |
RU2019119129A3 (zh) | 2021-03-26 |
IL294410A (en) | 2022-08-01 |
US20200323832A1 (en) | 2020-10-15 |
MX2019005810A (es) | 2019-09-11 |
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