CN114641289A - 补体成分C5a受体的游离碱晶型 - Google Patents
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Abstract
本文提供具有化合物1式的补体成分5a受体的游离碱晶型。本文还提供了使用本文所述的化合物1的结晶游离碱形式的药物组合物和治疗方法。
Description
相关申请的交叉引用
本申请要求2019年11月8日提交的美国临时申请序列号62/932652享有U.S.C§119(e)35项下的优先权,该申请的全部公开通过引用并入本发明。
关于联邦政府资助研发的发明权利的声明
不适用。
引用的“序列表”、表格或计算机程序列表附录在光盘上提交
不适用。
发明背景
补体系统在免疫复合物的清除和对感染因子、外来抗原、病毒感染细胞和肿瘤细胞的免疫反应中起核心作用。补体系统的不适当或过度激活,会由于严重的炎症和由此产生的组织破坏,而导致有害的甚至可能危及生命的后果。这些后果在临床上表现为各种疾病,包括败血性休克;心肌以及肠缺血/再灌注损伤;移植排斥;器官衰竭;肾炎;病理性炎症;和自身免疫性疾病。
补体系统由一组通常以非活性状态存在于血清中的蛋白质组成。补体系统的激活主要包括三种不同的途径,即经典途径、替代途径和凝集素途径(V.M.Holers,临床免疫学:原理与实践,编辑.R.R.Rich,莫斯比出版社;1996,363-391):1)经典途径是钙/镁依赖性级联反应,通常由抗原-抗体复合物的形成激活。它还可以通过与配体复合的C反应蛋白的结合,以及包括革兰氏阴性菌在内的许多病原体以不依赖抗体的方式激活。2)替代途径是依赖镁的级联反应,其通过C3在某些易感表面(例如酵母和细菌的细胞壁多糖,以及某些生物聚合物材料)上的沉积和活化而被激活。3)凝集素途径涉及甘露糖结合凝集素的初始结合和随后的C2和C4激活,这是经典途径所共有的(Matsushita,M.等人,实验医学杂志。176:1497-1502(1992);Suankratay,C.等人,免疫学杂志.160:3006-3013(1998))。
补体途径的激活产生补体蛋白的生物活性片段,例如C3a、C4a和C5a过敏毒素和C5b-9膜攻击复合物(MAC),所有这些都通过影响白细胞趋化性来介导炎症反应;激活巨噬细胞、中性粒细胞、血小板、肥大细胞和内皮细胞;并增加血管通透性、细胞溶解和组织损伤。
补体C5a是补体系统最有效的促炎介质之一。(以摩尔计,过敏性C5a肽在引发炎症反应方面的效力是C3a的100倍。)C5a是C5的活化形式(190kD,分子量)。C5a在人血清中的含量约为80μg/ml(Kohler,P.F.等人,免疫学杂志.99:1211-1216(1967))。它由两条多肽链α和β组成,分别具有大约115 kD和75kD的分子量(Tack,B.F.等人,生物化学18:1490-1497(1979))。C5被生物合成为单链前分子,在加工和分泌过程中被酶分解成双链结构。裂解后,两条链通过至少一个二硫键以及非共价相互作用连接在一起(Ooi,Y.M.等人,免疫学杂志.124:2494-2498(1980))。
最近的研究发现了(2R,3S)-2-(4-(环戊基氨基)苯基)-1-(2-氟-6-甲基苯甲酰基)-N-(4-甲基-3-(三氟甲基)苯基)哌啶-3-甲酰胺,化合物1可用于治疗C5a介导的疾病。尽管如此,化合物1的生物相关量的有效递送仍然具有挑战性。
因此,需要鉴定化合物1的固体形式,其可以改善重要的生物学特性,例如溶解度、溶出速率和生物利用度,并且不牺牲稳定性和效力。本公开解决了这些需求并且还提供了相关的优点。
发明内容
本发明提供了化合物1的游离碱晶型、使用其的方法以及使用化合物1的游离碱晶型制备的药物组合物。
在一些方面,本发明提供的是(2R,3S)-2-(4-(环戊基氨基)苯基)-1-(2-氟-6-甲基苯甲酰基)-N-(4-甲基-3)的游离碱晶型-(三氟甲基)苯基)哌啶-3-甲酰胺,化合物1
化合物1的游离碱晶型可以使用各种技术表征,包括但不限于X射线粉末衍射(XRPD)和差示扫描量热法(DSC)。本发明进一步描述了来自所列技术的相关表征特征。
附图简要说明
图1显示了实施例1中描述的游离碱晶型的X射线粉末衍射(XRPD)图。
图2显示化合物1的游离碱晶型的差示扫描量热法(DSC)热分析图。
发明详述
I通用
本发明提供化合物1的游离碱晶型。该形式适用于制备药物组合物,包括口服固体剂型如片剂、胶囊、软胶囊,口服液体剂型如溶液和混悬剂,局部剂型如半固体剂、软膏、糊剂、乳膏和凝胶剂,吸入剂型和肠胃外剂型,例如IV、IM和SC;但不限于上述剂型。
II定义
如本发明用于修饰数值的术语“约”和“左右”表示围绕该明确值的紧密范围。如果“X”是该值,“约X”或“X左右”将表示从0.9X到1.1X的值,更优选地,从0.95X到1.05X的值。任何提及“约X”或“X左石”具体至少表示值X、0.95X、0.96X、0.97X、0.98X、0.99X、1.01X、1.02X、1.03X、1.04X和1.05X。因此,“约X”和“X左右”旨在教导和提供对权利要求限制的书面描述支持,例如“0.98X”。
“化合物1”是一种化合物,其IUPAC名称为(2R,3S)-2-(4-(环戊基氨基)苯基)-1-(2-氟-6-甲基苯甲酰基)-N-(4-甲基-3-(三氟甲基)苯基)哌啶-3-甲酰胺,结构如下所示:
“基本上不含”是指10%或更少的另一种形式,优选8%、5%、4%、3%、2%、1%、0.5%或更少的另一种形式的量。
术语“治疗”或“疗法”包括改善疾病的治疗和对症治疗,其中任何一种都可以是预防性的(即,在症状出现之前,以预防、延迟或减轻症状的严重性)或治疗性的(即,在症状出现后,以减少症状的严重程度和/或持续时间)。
如本发明所用,如果C5a受体活性的调节导致C5a受体的不适当活性降低,则认为病症“对C5a受体调节有反应”。
术语“个体”是指哺乳动物,包括灵长类动物(尤其是人类)、驯养的伴侣动物(如狗、猫、马等)和家畜(如牛、猪、羊等)。如本发明所述的剂量。在一些实施例中,术语“个体”是指人。
III实施方案的详细描述
A.化合物1的游离碱晶型
在一些方面,本发明提供了基本上不含化合物1的其他形式的游离碱晶型化合物1。
在一些实施方案中,化合物1的游离碱晶型以X射线粉末衍射图案为特征,其包括8.1、8.4、14.1、16.9和19.0度2θ(±0.2度2θ)处的峰。在一些实施方案中,化合物1的游离碱晶型进一步由X射线粉末衍射图案表征,其包括12.4度、15.2度、16.1度、24.4度和24.7度2θ(±0.2度2θ)处的峰。在一些实施方案中,化合物1的游离碱晶型由基本上符合图2的X射线粉末衍射图案表征。
差示扫描量热法(DSC)也可用于表征化合物1的游离碱晶型。在一些实施方案中,化合物1的游离碱晶型通过差示扫描量热法(DSC)表征,该差示扫描量热法(DSC)包括216℃左右的吸热峰。在一些实施方案中,化合物1的游离碱晶型通过差示扫描量热法(DSC)确定的约213℃的熔点起始来表征。在一些实施方案中,化合物1的游离碱晶型通过基本上符合图2的差示扫描量热法(DSC)热谱图进行表征。
B.化合物1的游离碱晶型的制备方法
可以按先前所述制备化合物1。例如,参见WO2010/075257,每个文件的内容均通过引用完整合并,用于所有目的。
本文所述的游离碱晶型可以按提供的实施例中所述制备。应当理解,可能有不止一种结晶方法会产生所描述的游离碱晶型。
C.药物组合物
本发明提供了包含化合物1的游离碱晶型的药物组合物,或使用化合物1的游离碱晶型制备的液体药物组合物。药物组合物将包括一种或多种药学上可接受的赋形剂。
含有化合物1的游离碱晶型的药物组合物可以是适合口服使用的形式,例如片剂、含片(troches)、锭剂(lozenges)、液体制剂、水性或油性混悬剂、可分散粉剂或颗粒剂、乳剂和如在美国专利申请2002-0012680中描述的自乳化剂、硬胶囊或软胶囊、糖浆剂、酏剂、溶液剂、口腔贴剂、口服凝胶、口香糖、咀嚼片、泡腾粉和泡腾片。可根据本领域已知的用于制备药物组合物的任何方法制备旨在用于口服的组合物,并且此类组合物可包含一种或多种选自甜味剂、调味剂、着色剂、抗氧化剂和防腐剂的试剂以提供药学上典雅和可口的制剂。片剂含有化合物1的游离碱晶型,并与适用于制造片剂的无毒药学上可接受的赋形剂混合。这些赋形剂可以是例如惰性稀释剂,例如纤维素、二氧化硅、氧化铝、碳酸钙、碳酸钠、葡萄糖、甘露醇、山梨糖醇、乳糖、磷酸钙或磷酸钠;造粒和崩解剂,例如玉米淀粉或海藻酸;粘合剂,例如PVP、纤维素、PEG、淀粉、明胶或阿拉伯胶,以及润滑剂,例如硬脂酸镁、硬脂酸或滑石。片剂可以是未包衣的,或者它们可以通过已知技术被包衣(肠溶或其他)以延迟在胃肠道中的崩解和吸收,从而提供更长时间的持续作用。例如,可以使用诸如单硬脂酸甘油酯或二硬脂酸甘油酯的延时材料。它们也可以通过美国专利第4,256,108号;4,166,452;和4,265,874中描述的技术进行包衣,以形成用于控制释放的渗透治疗片剂。
口服制剂也可以以硬明胶胶囊形式提供,其中化合物1的游离碱晶型与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合,或以软明胶胶囊形式提供,其中化合物1的游离碱晶型与水或油介质混合,例如花生油、液体石蜡或橄榄油。此外,乳液可以用非水混溶性成分如油制备并用表面活性剂如甘油二酯、PEG酯等稳定。
用于口服使用的水性混悬剂含有化合物1的游离碱晶型,并与适用于制造水性混悬剂的赋形剂混合。这样的赋形剂是悬浮剂,例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、羟丙基纤维素、海藻酸钠、聚乙烯吡咯烷酮、黄蓍胶和阿拉伯树胶;分散剂或润湿剂可以是天然存在的磷脂,例如卵磷脂,或环氧烷与脂肪酸的缩合产物,例如聚氧乙烯硬脂酸酯,或环氧乙烷与长链脂肪醇的缩合产物,例如十七亚乙基氧十六醇,或环氧乙烷与衍生自脂肪酸和己糖醇的偏酯例如聚氧乙烯山梨糖醇单油酸酯的缩合产物,或环氧乙烷与衍生自脂肪酸和己糖醇酐的偏酯例如聚山梨糖醇单油酸酯以及其他泊洛沙姆的缩合产物(例如泊洛沙姆F-68)。水性悬浮液还可包含一种或多种防腐剂,例如对羟基苯甲酸乙酯或正丙酯,一种或多种着色剂,一种或多种调味剂,和一种或多种甜味剂,例如蔗糖或糖精。
因此,本发明提供了包含化合物1的游离碱晶型和至少一种赋形剂的水性悬浮液。在一些实施方案中,至少一种赋形剂是如上所述的至少一种悬浮剂和/或至少一种润湿剂。
可通过将化合物1的游离碱晶型悬浮在植物油例如花生油、橄榄油、芝麻油或椰子油中,或在矿物油例如液体石蜡中来配制用于口服使用的油性混悬剂。油性悬浮液可以含有增稠剂,例如蜂蜡、硬石蜡或鲸蜡醇。可以添加诸如上述那些的甜味剂和调味剂以提供可口的口服制剂。这些组合物可以通过添加抗氧化剂如抗坏血酸来保存。
药物组合物可以是无菌可注射或可输注的水性或油性溶液或悬浮液的形式。该溶液或悬浮液可以根据已知技术使用上文提及的那些合适的分散剂或润湿剂和悬浮剂来配制。无菌可注射制剂也可以是在无毒的肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或悬浮液,例如作为在1,3-丁二醇中的溶液。可以使用的可接受的载体和溶剂包括水、林格氏溶液、等渗氯化钠溶液、等渗水性缓冲溶液,以及盐水、崩解剂如PEG(例如PEG 200、PEG400、PEG 800等)和非离子表面活性剂如吐温80的混合物。此外,无菌的不挥发油通常用作溶剂或悬浮介质。为此目的,可以使用任何温和的不挥发油,包括合成的甘油单酯或甘油二酯。此外,脂肪酸如油酸可用于制备注射剂和输注剂。用于可注射或可输注给药的组合物任选地包括局部麻醉剂,例如利多卡因,以减轻注射部位的疼痛。成分可以预先混合或单独提供,在使用前不久混合成分。在一些实施方案中,需要在使用前不久混合以利用化合物1的游离碱晶型在某些液体制剂混合物中的高初始溶解度。
可注射或可输注的组合物包括但不限于静脉内给药、肌肉内给药以及皮下或胸骨内注射。因此,在一些实施方案中,本发明提供了包含化合物1和至少一种润湿剂或溶剂的可注射或可输注溶液,其中使用本文所述化合物1的游离碱晶型制备静脉内药物组合物。在一些实施方案中,可注射或可输注溶液被制备为用于静脉内给药。在一些实施方案中,可注射或可输注的溶液被制备为用于肌肉内给药。在一些实施方案中,可注射或可输注的溶液被制备为用于皮下注射。在一些实施方案中,可注射或可输注的溶液被制备为用于胸骨内注射。在一些实施方案中,可注射或可输注药物组合物中的至少一种润湿剂或溶剂包括盐水、崩解剂和非离子表面活性剂。
可注射或可输注的组合物可以在方便医师或使用者的任何时间制备;这包括使用前不久或大大提前于使用。在一些实施方案中,组合物在使用前不久制备。使用前不久包括使用前0-24小时、使用前0-10小时、使用前0-5小时或使用前0-1小时。在一些实施方案中,可注射或可输注组合物在使用前0-5小时制备。大大提前通常是指使用前一天或多天。因此,本发明还提供了制备可注射或可输注溶液的方法。该方法包括用至少一种润湿剂或溶剂将化合物1的游离碱晶型溶解以制备可注射或可输注的溶液;以及将所述可注射或可输注溶液施用于有需要的受试者。
适用于通过添加水制备含水口服制剂或口服混悬剂的可分散粉末和颗粒提供与分散剂或润湿剂、悬浮剂和一种或多种防腐剂混合的化合物1的游离碱晶型。合适的分散剂或润湿剂和悬浮剂例如上面已经提到的那些。也可以存在其他赋形剂,例如甜味剂、调味剂和着色剂。
本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油如橄榄油或花生油,或矿物油如液体石蜡或这些的混合物。合适的乳化剂可以是天然存在的树胶,例如阿拉伯树胶或黄蓍胶,天然存在的磷脂,例如大豆、卵磷脂,以及衍生自脂肪酸和己糖醇酐的酯或偏酯,例如脱水山梨糖醇单油酸酯,以及缩合所述偏酯与环氧乙烷的产物,例如聚氧乙烯脱水山梨糖醇单油酸酯。乳液还可以含有甜味剂和调味剂。
糖浆和酏剂可以用甜味剂配制,例如甘油、丙二醇、山梨糖醇或蔗糖。这样的制剂还可以包含缓和剂、防腐剂以及调味剂和着色剂。口服溶液可以与例如环糊精、PEG和表面活性剂组合制备。
本发明的化合物也可以以用于药物的直肠给药的栓剂的形式给药。这些组合物可以通过将化合物1的游离碱晶型与合适的无刺激性赋形剂混合来制备,该赋形剂在常温下为固体但在直肠温度下为液体,因此将在直肠中熔化以释放药物。这种材料包括可可脂和聚乙二醇。此外,化合物可以通过溶液或软膏的方式通过眼部递送来给药。更进一步,主题化合物的透皮递送可以通过离子电渗贴片等来实现。对于局部使用,使用含有本发明化合物的乳膏剂、软膏剂、凝胶剂、溶液剂或混悬剂等。如本发明所用,局部应用也意味着包括使用漱口水和漱口液。
本发明的化合物还可以与作为可靶向药物载体的合适聚合物的载体偶联。此类聚合物可包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟基-丙基-甲基丙烯酰胺-苯酚、聚羟乙基-天冬酰胺-苯酚或被棕榈酰基残基取代的聚环氧乙烷-聚赖氨酸。此外,本发明的化合物可以与载体偶联,该载体是可用于实现药物控制释放的一类生物可降解聚合物,例如聚乳酸、聚乙醇酸、聚乳酸和聚乙醇酸的共聚物、聚ε-己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二氢吡喃、聚氰基丙烯酸酯和水凝胶的交联或两亲嵌段共聚物。聚合物和半透性聚合物基质可以形成成形制品,例如瓣膜、支架、管、假体等。在本发明的一个实施方案中,本发明的化合物与形成为支架或支架移植装置的聚合物或半透性聚合物基质偶联。
D.治疗方法
本发明还提供了治疗患有对C5a受体调节有反应的病症的个体的方法。
在一些方面,本发明提供了治疗患有或易患涉及C5a受体病理活化的疾病或病症的个体的方法,包括向个体施用有效量的化合物1的游离碱晶型或包含如本发明所述的化合物1的药物制剂。
在一些实施方案中,本发明所述化合物1的游离碱晶型用于治疗患有对C5a受体调节有反应的病症的患者。
C5a调节可以治疗的病症:
自身免疫性疾病——例如,类风湿性关节炎、系统性红斑狼疮、格林巴利综合征、胰腺炎、C3肾小球病(C3G)、化脓性汗腺炎(HS)、狼疮性肾炎、狼疮性肾小球肾炎、免疫球蛋白A(IgA)肾病、牛皮癣、克罗恩病、血管炎、肠易激综合征、皮肌炎、多发性硬化、支气管哮喘、天疱疮、类天疱疮、硬皮病、重症肌无力、自身免疫性溶血和血小板减少症、肺出血肾炎综合征(以及相关的肾小球肾炎和肺出血)、免疫血管炎、组织移植排斥、移植器官超急性排斥反应;诸如此类。
炎症性疾病和相关病症——例如,中性粒细胞减少症、败血症、败血性休克、阿尔茨海默病、多发性硬化症、中风、炎症性肠病(IBD)、年龄相关性黄斑变性(AMD,湿性和干性形式)、与严重烧伤相关的炎症、肺损伤和缺血再灌注损伤、骨关节炎,以及急性(成人)呼吸窘迫综合征(ARDS)、慢性肺阻塞性疾病(COPD)、全身炎症反应综合征(SIRS)、特应性皮炎、牛皮癣、慢性荨麻疹和多器官功能障碍综合征(MODS)。还包括与以下相关的病理后遗症:胰岛素依赖型糖尿病(包括糖尿病视网膜病变)、狼疮性肾病、海曼肾炎、膜性肾炎和其他形式的肾小球肾炎、接触敏感性反应以及血液与可引起补体激活的人造表面接触引起的炎症,例如在血液的体外循环期间(例如,在血液透析期间或通过例如与血管手术如冠状动脉旁路移植术或心脏瓣膜置换术相关的心肺机)发生,或与与其他人造血管或容器表面(例如心室辅助装置、人造心脏机器、输液管、血液储存袋、血浆置换术、血小板置换术等)接触有关。还包括与缺血/再灌注损伤相关的疾病,例如由移植引起的疾病,包括实体器官移植,以及诸如缺血再灌注损伤、缺血性结肠炎和心脏缺血等综合征。本发明所述的化合物1的游离碱晶型也可用于治疗年龄相关性黄斑变性(Hageman等人,美国国家科学院报。102:7227-7232,2005)。
心血管和脑血管疾病——例如心肌梗塞、冠状动脉血栓形成、血管闭塞、手术后血管再闭塞、动脉粥样硬化、外伤性中枢神经系统损伤和缺血性心脏病。在一个实施方案中,可以将有效量的本发明所述化合物1的游离碱晶型施用于有心肌梗塞或血栓形成风险的患者(即,具有一种或多种公认的心肌梗塞或血栓形成风险因素的患者,例如但不限于肥胖、吸烟、高血压、高胆固醇血症、心肌梗塞或血栓形成的既往史或遗传病史),以降低心肌梗塞或血栓形成的风险。
血管炎疾病——血管炎疾病的特征是血管发炎。白细胞的浸润导致血管壁的破坏,补体途径被认为在启动白细胞迁移以及在炎症部位表现出的由此产生的损伤中起主要作用(血管炎,第二版,由Ball和Bridges编辑,牛津大学出版社,第47-53页,2008年)。本发明所述的化合物1的游离碱晶型可用于治疗血管炎,包括抗中性粒细胞胞质抗体相关血管炎(或ANCA相关血管炎,其包括显微镜下多血管炎、嗜酸性肉芽肿性多血管炎和肉芽肿性多血管炎,也称为韦格纳病)、查格-施特劳斯综合征、过敏性紫癜、结节性多动脉炎、急进性肾小球肾炎(RPGN)、冷球蛋白血症、巨细胞动脉炎(GCA)、白塞士病和高安氏动脉炎(TAK)。
HIV感染和AIDS——本发明所述化合物1的游离碱晶型可用于抑制HIV感染、延缓AIDS进展或降低症状或HIV感染和AIDS的严重性。
神经退行性病症和相关疾病——在进一步的实施方案中,本发明描述的化合物1的游离碱晶型可用于治疗与心肺旁路手术和相关程序有关的阿尔茨海默病、多发性硬化和认知功能下降。
癌症——本发明所述的化合物1的游离碱晶型也可用于治疗受试者的癌症和癌前病变。可以治疗的特定癌症包括但不限于肉瘤、癌和混合肿瘤。可根据本发明治疗的示例性病症包括纤维肉瘤、脂肪肉瘤、软骨肉瘤、成骨肉瘤、血管肉瘤、淋巴管肉瘤、滑膜瘤、间皮瘤、脑膜瘤、白血病、淋巴瘤、平滑肌肉瘤、横纹肌肉瘤、鳞状细胞癌、基底细胞癌、腺癌、乳头状癌、囊腺癌、支气管癌、黑色素瘤、肾细胞癌、肝细胞癌、移行细胞癌、绒毛膜癌、精原细胞瘤、胚胎癌、威尔姆氏瘤、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。
在一些实施方案中,本发明所述的化合物1的游离碱晶型可用于治疗选自下组的疾病:败血症(和相关病症)、COPD、类风湿性关节炎、狼疮性肾炎和多发性硬化症。
在一些实施方案中,本发明所述的化合物1的游离碱晶型可用于治疗选自下组的疾病:抗中性粒细胞胞质抗体相关(ANCA)血管炎、C3肾小球病、化脓性汗腺炎和狼疮性肾炎。
本发明提供的治疗方法通常包括向患者施用有效量的化合物1的游离碱晶型。合适的患者包括患有或易患(即预防性治疗)本发明鉴定的病症或疾病的那些患者。用于本发明所述治疗的典型患者包括哺乳动物,特别是灵长类动物,尤其是人类。其他合适的患者包括驯养的伴侣动物如狗、猫、马等,或家畜如牛、猪、羊等。
一般而言,本发明提供的治疗方法包括向患者施用有效量的本发明所述化合物1的游离碱晶型。本发明的药物组合物的确切配方、给药途径和剂量可以由个体医生根据患者的状况来选择。(参见例如,Fingl等人。1975,在“治疗学的药理学基础”中,其通过引用整体并入本发明,特别是参考第1章,第1页)。在一些实施方案中,本发明所述的化合物1的游离碱晶型口服给予患者(例如人)。在一些实施方案中,本发明所述的化合物1的游离碱晶型通过静脉内、肌内或通过皮下或胸骨内注射施用于患者(例如人)。有效量可以是足以调节C5a受体活性的量和/或足以减轻或减轻患者呈现的症状的量。优选地,给药量足以产生足够高的化合物(或其活性代谢物,如果该化合物是前药)的血浆浓度以在体外可检测地抑制白细胞(例如,嗜中性粒细胞)趋化性。
对于通过口服给药治疗大多数疾病,本领域技术人员可以确定合适的给药频率。在一些实施方案中,优选每天4次或更少的给药频率。在一些实施方案中,使用每天2次的剂量方案。在一些实施方案中,使用每日一次给药。可以在进食或禁食状态下给患者施用化合物1的游离碱晶型。在一些实施方案中,患者将游离碱晶型化合物1与食物一起服用。在一些实施方案中,患者在没有食物的情况下服用化合物1的游离碱晶型。
对于通过静脉内、肌肉内给药或通过皮下或胸骨内注射治疗大多数疾病,本领域技术人员可以确定合适的给药频率。在一些实施方案中,给药频率约为每两周一次。在一些实施方案中,给药频率约为每周一次。在一些实施方案中,给药频率约为每周3次。在一些实施方案中,给药频率约为每周2至5次。在一些实施方案中,给药频率约为每隔一天一次。在一些实施方案中,给药频率约为一天一次。
然而,应当理解,任何特定患者的具体剂量水平和治疗方案将取决于多种因素,包括年龄、体重、一般健康状况、性别、饮食、给药时间、给药途径、排泄速率、药物组合(即给予患者的其他药物)和接受治疗的特定疾病的严重程度,以及开药执业者的判断。通常,优选使用足以提供有效治疗的最小剂量。通常可以使用适合被治疗或预防的病症的医学或兽医标准来监测患者的治疗效果。
每天每千克体重约0.1mg至约140mg量级的剂量水平可用于治疗或预防涉及致病性C5a活性的病症(每人每天约0.5mg至约7g)。可与载体材料组合以产生单一剂型的化合物1的游离碱晶型的量将根据所治疗的宿主和特定的给药方式而变化。剂量单位形式通常含有约1mg至约500mg的化合物1的游离碱晶型。当口服、经皮、静脉内或皮下给药时,优选给药足量的化合物的游离碱晶型1以达到5ng(纳克)/mL-10μg(微克)/mL血清的血清浓度,更优选应给予足够的化合物以达到20ng-1μg/ml血清的血清浓度,最优选应给予足够的化合物以达到50ng/ml-200ng/ml血清的血清浓度。对于直接注射到滑膜中(用于治疗关节炎),应给予足够量的化合物1的游离碱晶型以达到约1微摩尔的局部浓度。
E.联合疗法
本发明公开的方法可包括与一种或多种用于治疗、预防、抑制或改善涉及C5a受体病理激活的疾病或状况的另外的治疗剂的联合治疗。这种一种或多种另外的治疗剂可通过常用于其的的途径和量与化合物1的游离碱晶型同时或顺序施用。当化合物1的游离碱晶型与附加治疗剂同时使用时,优选除了化合物1的游离碱晶型之外还含有此类其他药物的药物组合物。因此,本发明的药物组合物包括除化合物1的游离碱晶型之外还含有一种或多种其他活性成分或治疗剂的组合物。
一种或多种另外的治疗剂的实例是皮质类固醇、类固醇、免疫抑制剂、免疫球蛋白G激动剂、二肽基肽酶IV抑制剂、淋巴细胞功能抗原-3受体拮抗剂、白介素-2配体、白介素-1β配体抑制剂、IL-2受体α亚基抑制剂、HGF基因刺激剂、IL-6拮抗剂、IL-5拮抗剂、α1抗胰蛋白酶刺激剂、大麻素受体拮抗剂、组蛋白去乙酰化酶抑制剂、AKT蛋白激酶抑制剂、CD20抑制剂、Abl酪氨酸激酶抑制剂、JAK酪氨酸激酶抑制剂、TNFα配体抑制剂、血红蛋白调节剂、TNF拮抗剂、蛋白酶体抑制剂、CD3调节剂、Hsp70家族抑制剂、免疫球蛋白激动剂、CD30拮抗剂、微管蛋白拮抗剂、1-磷酸鞘氨醇受体1激动剂、结缔组织生长因子配体抑制剂、半胱天冬酶抑制剂、促肾上腺皮质激素配体、Btk酪氨酸激酶抑制剂、补体C1s亚组分抑制剂、促红细胞生成素受体激动剂、B淋巴细胞刺激物配体抑制剂、细胞周期蛋白依赖性激酶2抑制剂、P-选择素糖蛋白配体1刺激剂、mTOR抑制剂、延伸因子2抑制剂、细胞粘附分子抑制剂、因子XIII激动剂、钙调神经磷酸酶抑制剂、免疫球蛋白G1激动剂、肌苷一磷酸脱氢酶抑制剂、补体C1s亚组分抑制剂、胸苷激酶调节剂、细胞毒性T淋巴细胞蛋白4调节剂、血管紧张素II受体拮抗剂、血管紧张素II受体调节剂、TNF超家族受体12A拮抗剂、CD52拮抗剂、腺苷脱氨酶抑制剂、T细胞分化抗原CD6抑制剂、FGF-7配体、二氢乳清酸脱氢酶抑制剂、Syk酪氨酸激酶抑制剂、I型干扰素受体拮抗剂、干扰素α配体抑制剂、巨噬细胞迁移抑制因子抑制剂、整合素α-V/β-6拮抗剂、半胱氨酸蛋白酶刺激物、p38 MAP激酶抑制剂、TP53基因抑制剂、志贺样毒素I抑制剂、岩藻糖基转移酶6刺激剂、白细胞介素22配体、IRS1基因抑制剂、蛋白激酶C刺激剂、蛋白激酶Cα抑制剂、CD74拮抗剂、免疫球蛋白γFc受体IIB拮抗剂、T细胞抗原CD7抑制剂、CD95拮抗剂、N乙酰甘露糖胺激酶刺激剂、心机营养素-1配体、白细胞弹性蛋白酶抑制剂、CD40配体受体拮抗剂、CD40配体调节剂、IL-17拮抗剂、TLR-2拮抗剂、甘露聚糖结合凝集素丝氨酸蛋白酶2(MASP-2)抑制剂、B因子抑制剂、D因子抑制剂、C3aR调节剂、C5aR2调节剂、T细胞受体拮抗剂、PD-1抑制剂、PD-L1抑制剂、TIGIT抑制剂、TIM-3抑制剂、LAG-3抑制剂、VISTA抑制剂、STING激动剂、IDO抑制剂、腺苷受体调节剂、CD39抑制剂、CD73抑制剂、趋化因子受体(尤其是CXCR1、CXCR2、CXCR3、CXCR4、CXCR7、CCR1、CCR2、CCR3、CCR4、CCR5、CCR7、CCR7、CCR9、CX3CR1和CXCR6)的拮抗剂,以及它们的组合。
在一些实施方案中,本发明治疗方法中使用的另外的治疗剂选自下组:奥比努珠单抗(obinutuzumab)、利妥昔单抗、奥雷利珠单抗(ocrelizumab)、托西妥单抗(tositumomab)、奥比努珠单抗(obinutuzumab)、伊布妥单抗(ibritumomab)、环磷酰胺、强的松、氢化可的松、醋酸氢化可的松、醋酸可的松、新戊酸替可的松、泼尼松龙、甲基泼尼松龙、曲安奈德、曲安奈德醇、莫米松、安西奈德、布地奈德、地奈德、氟轻松、醋酸氟轻松、哈西奈德、倍他米松、倍他米松磷酸钠、地塞米松、地塞米松磷酸钠、氟考龙、氢化可的松-17-戊酸盐、卤米松、二丙酸阿氯米松、倍氯米松、戊酸倍他米松、二丙酸倍他米松、泼尼卡酯、氯倍他松-17-丁酸酯、氯倍他索-17-丙酸酯、己酸氟考龙、丙戊酸氟考龙、醋酸氟泼尼丁、氢化可的松-17-丁酸酯、氢化可的松-17-醋丙酯、氢化可的松-17-丁乙酸酯、环索奈德和泼尼卡酯、GB-0998、免疫球蛋白、贝格洛单抗(begelomab)、阿列法西普(alefacept)、阿地白介素、吉伏基珠单抗(gevokizumab)、达利珠单抗、巴利昔单抗(basiliximab)、伊洛单抗、贝霉素基因质粒(beperminogene perplasmid)、西鲁单抗(sirukumab)、托珠单抗、克拉扎基珠单抗(clazakizumab)、美波利珠单抗、芬戈莫德、帕诺比诺司他(panobinostat)、三氯立宾(tricirbine)、尼罗替尼、伊马替尼、托法替尼(tofacitinib)、莫米洛替尼(momelotinib)、培非替尼(peficitinib)、依他西尼(itacitinib)、英夫利昔单抗(infliximab)、PEG-bHb-CO、依那西普、伊沙唑米布(ixazomib)、硼替佐米、莫那布(muromonab)、奥特利昔单抗(otelixizumab)、胍立莫司、本妥昔单抗、波尼莫德(Ponesimod)、KRP-203、FG-3019、埃米卡桑(emricasan)、促肾上腺皮质激素、伊布替尼、辛利泽(cinryze)、康奈司他(conestat)、甲氧基聚乙二醇促红素β、贝利单抗(belimumab)、布利西比莫德(blisibimod)、阿塞西普(atacicept)、塞利昔单抗(seliciclib)、内胡利珠单抗(neihulizumab)、依维莫司、西罗莫司、地尼白介素(denileukin diftitox)、LMB-2、纳他珠单抗、卡曲得考(catridecacog)、环孢素、他克莫司、沃克罗斯林(voclosporin)、沃克罗斯林(voclosporin)、康那单抗(canakinumab)、霉酚酸酯、咪唑立宾、CE-1145、TK-DLI、阿巴西普、贝拉西普、奥美沙坦酯、sparsentan、TXA-127、BIIB-023、阿伦单抗(alemtuzumab)、喷司他丁(pentostatin)、利珠单抗(itolizumab)、帕利替明(palifermin)、PR0-140、cenicriviroc、福斯他马替尼(fostamatinib)、阿尼呋单抗(anifrolumab)、西法利单抗(sifalimumab)、BAX-069、BG-00011、洛斯马普莫德(losmapimod)、QPI-1002、志贺mAb、TZ-101、F-652、瑞帕利新(reparixin)、拉达利新(ladarixin)、PTX-9908、阿加尼森(aganirsen)、APH-703、索他牛磺酸(sotrastaurin)、索他牛磺酸、米拉妥珠单抗(milatuzumab)、SM-101、T-Guard、APG-101、DEX-M74、心肌营养素-1、替普雷司他(tiprelestat)、ASKP-1240、BMS-986004、HPH-116、KD-025、OPN-305、TOL-101、去纤苷、泊马度胺、兔抗胸腺免疫球蛋白(Thymoglobulin)、拉喹莫德(laquinimod)、remestemcel-L、马抗胸腺细胞免疫球蛋白、斯坦普尔(Stempeucel)、LIV-γ、Octagam 10%、t2c-001、司他比锝[99mTc]、克拉里格(Clairyg)、普罗索巴(Prosorba)、泊马度胺、拉喹莫德、替利组单抗(teplizumab)、FCRx、索那肽(solnatide)、福雷芦单抗(foralumab)、ATIR-101、BPX-501、ACP-01、ALLO-ASC-DFU、厄贝沙坦+丙帕锗、载脂细胞(ApoCell)、大麻二酚、RGI-2001、乳清酸、抗CD3二价抗体-白喉毒素偶联物、NOX-100、LT-1951、OMS721、ALN-CC5、ACH-4471、AMY-101、Acthar凝胶和CD4+CD25+调节性T细胞、MEDI7814、P32、P59、帕博利珠单抗(pembrolizumab)、纳武单抗(nivolumab)、阿特珠单抗、阿维鲁单抗(avelumab)、德瓦鲁单抗、CCX354、CCX721、CCX9588、CCX140、CCX872、CCX598、CCX6239、CCX587、CCX624、CCX282、CCX025、CCX507、CCX430、CCX765、CCX758、CCX771、CCX662、CCX650,及其组合。
IV.实施例
提供以下实施例以帮助说明所描述的发明并且不旨在限制发明人认为他们的发明的范围。
实施例1:制备化合物1的晶型
粗化合物1基本上如WO 2016/053890中所述制备。
通过在40℃加热下将18g粗化合物1溶解在50mL丙酮中来制备化合物1的晶型(浓度约为~0.36g/mL)。温热溶液通过10μm聚乙烯过滤器。然后将溶液装入30℃浴温和180rpm转速下的旋转蒸发器中。收集的固体在45℃烘箱中进一步干燥1小时。晶型的XRPD数据显示在图1中。测量的峰表列于下表1。
表1:化合物1游离碱晶型的显著峰
实施例2:化合物1的游离碱晶型的差示扫描量热法(DSC)和热重分析(TGA)
为了评估化合物1的游离碱晶型的物理特性,收集了差示扫描量热法数据。使用TAInstruments~Waters LLC的DSC25型差示扫描量热仪。将样品称重至标准铝盘中,并用带针孔的标准铝盖密封。在氮气吹扫下,以10℃/min的扫描速度完成测量。DSC分析确定,游离基晶型在约213℃的温度下融化(开始),在216℃左右的温度下出现吸热峰。DSC热谱图如图2所示。
尽管为了清楚理解的目的已经通过说明和示例的方式对前述发明进行了一些详细的描述,但是本领域技术人员将理解在所附权利要求的范围内可以实施某些改变和修改。此外,本发明提供的每篇参考文献均以引用方式全文并入,其程度与每篇参考文献单独以引用方式并入的程度相同。在本申请与本发明提供的参考文献之间存在冲突的情况下,应以本申请为准。
Claims (28)
2.如权利要求1所述的游离碱晶型,其特征在于,X射线粉末衍射(XRPD)图包括在8.1、8.4、14.1、16.9和19.0度2θ(±0.2度2θ)处的峰。
3.如权利要求2所述的游离碱晶型,其特征还在于,XRPD峰在12.4、15.2、16.1、24.4和24.7度2θ(±0.2度2θ)处。
4.如权利要求1所述的游离碱晶型,其特征在于,X射线粉末衍射图基本上与图1一致。
5.如权利要求1至4中任一项所述的游离碱晶型,其特征还在于,差示扫描量热热分析图(DSC)包括在约216℃的吸热峰。
6.如权利要求1至4中任一项所述的游离碱晶型,其特征还在于,通过差示扫描量热法热分析图(DSC)测定的约213℃的起始熔点。
7.如权利要求1至4中任一项所述的游离碱晶型,其特征还在于,基本上与图2一致的DSC。
8.一种药物组合物,包含根据权利要求1至7中任一项所述的化合物1的游离碱晶型和至少一种药学上可接受的赋形剂。
9.一种水性悬浮液,包含根据权利要求1至7中任一项所述的化合物1的游离碱晶型和至少一种赋形剂。
10.如权利要求9所述的水性悬浮液,其中所述至少一种赋形剂是至少一种助悬剂和/或至少一种润湿剂。
11.一种治疗患有或易患涉及C5a受体病理性活化的疾病或病症的个体的方法,包括向个体施用有效量的如权利要求1至7中任一项所述的化合物1的游离碱晶型。
12.如权利要求11所述的方法,其特征在于,所述疾病或病症是炎性疾病或病症。
13.如权利要求12所述的方法,其特征在于,所述疾病或病症选自下组:中性粒细胞减少症、败血症、败血性休克、阿尔茨海默病、多发性硬化症、中风、炎性肠病、年龄相关性黄斑变性、慢性阻塞性肺病、烧伤相关的炎症、肺损伤、骨关节炎、特应性皮炎、慢性荨麻疹、缺血再灌注损伤、急性呼吸窘迫综合征、全身炎症反应综合征、多器官功能障碍综合征、组织移植排异、癌症和移植器官的超急性排斥。
14.如权利要求11所述的方法,其特征在于,所述疾病或病症是心血管或脑血管病症。
15.如权利要求14所述的方法,其特征在于,所述疾病或病症选自下组:心肌梗塞、冠状动脉血栓形成、血管闭塞、手术后血管再闭塞、动脉粥样硬化、外伤性中枢神经系统损伤和缺血性心脏病。
16.如权利要求11所述的方法,其特征在于,所述疾病或病症是自身免疫病症。
17.如权利要求16所述的方法,其特征在于,所述疾病或病症选自下组:类风湿性关节炎、C3肾小球病(C3G)、化脓性汗腺炎(HS)、系统性红斑狼疮、格林-巴利综合征、胰腺炎、狼疮性肾炎、狼疮性肾小球肾炎、银屑病、免疫球蛋白A(IgA)肾病、克罗恩病、血管炎、肠易激综合征、皮肌炎、多发性硬化症、支气管哮喘、天疱疮、类天疱疮、硬皮病、重症肌无力、自身免疫性溶血和血小板减少状态、肺出血肾炎综合征、免疫血管炎、组织移植排斥和移植器官的超急性排斥反应。
18.如权利要求11所述的方法,其特征在于,所述疾病或病症是与以下组相关的病理后遗症:胰岛素依赖型糖尿病、糖尿病、狼疮肾病、海曼肾炎、膜性肾炎、肾小球肾炎、接触敏感性反应,以及因血液与人工表面接触而引起的炎症。
19.如权利要求11所述的方法,其特征在于,所述疾病或病症选自下组:抗中性粒细胞胞质抗体相关(ANCA)血管炎、C3肾小球病、化脓性汗腺炎和狼疮性肾炎。
20.如权利要求11所述的方法,其特征在于,所述疾病或病症是抗中性粒细胞胞质抗体相关(ANCA)血管炎。
21.如权利要求11所述的方法,其特征在于,所述疾病或病症是肉芽肿性多血管炎。
22.如权利要求11所述的方法,其特征在于,所述疾病或病症是显微镜下多血管炎。
23.如权利要求11所述的方法,其特征在于,所述疾病或病症是C3肾小球病。
24.如权利要求11所述的方法,其特征在于,所述疾病或病症是化脓性汗腺炎。
25.如权利要求11所述的方法,其特征在于,所述疾病或病症是狼疮性肾炎。
26.如权利要求11至25中任一项所述的方法,还包括向所述个体施用有效量的一种或多种另外的治疗剂。
27.如权利要求26所述的方法,其特征在于,所述一种或多种另外的治疗剂是利妥昔单抗。
28.如权利要求26所述的方法,其特征在于,所述一种或多种另外的治疗剂是环磷酰胺。
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102264227A (zh) * | 2008-12-22 | 2011-11-30 | 凯莫森特里克斯股份有限公司 | C5aR拮抗剂 |
CN103068385A (zh) * | 2010-06-24 | 2013-04-24 | 凯莫森特里克斯股份有限公司 | C5aR拮抗剂 |
CN106999481A (zh) * | 2014-09-29 | 2017-08-01 | 凯莫森特里克斯股份有限公司 | 制备C5aR拮抗剂的方法和中间体 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2005289635A1 (en) * | 2004-09-27 | 2006-04-06 | Acadia Pharmaceuticals Inc. | Salts of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide and their preparation |
US20110275639A1 (en) | 2008-12-22 | 2011-11-10 | Chemocentryx, Inc. | C5aR ANTAGONISTS |
TW202128623A (zh) * | 2019-11-08 | 2021-08-01 | 美商卡默森屈有限公司 | 補體成分C5a受體之鹽形式 |
WO2022078269A1 (zh) * | 2020-10-16 | 2022-04-21 | 苏州科睿思制药有限公司 | Avacopan的晶型及其制备方法和用途 |
-
2020
- 2020-11-06 KR KR1020227018961A patent/KR20220098179A/ko not_active Application Discontinuation
- 2020-11-06 EP EP20884944.8A patent/EP4054577A4/en active Pending
- 2020-11-06 CN CN202080077446.8A patent/CN114641289A/zh active Pending
- 2020-11-06 JP JP2022525889A patent/JP2022554019A/ja not_active Withdrawn
- 2020-11-06 US US17/091,019 patent/US11026935B2/en active Active
- 2020-11-06 WO PCT/US2020/059287 patent/WO2021092292A1/en unknown
- 2020-11-06 BR BR112022007488A patent/BR112022007488A2/pt unknown
- 2020-11-06 AU AU2020378061A patent/AU2020378061A1/en active Pending
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- 2020-11-06 CA CA3155596A patent/CA3155596A1/en active Pending
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-
2021
- 2021-05-04 US US17/307,865 patent/US20220096453A1/en not_active Abandoned
-
2022
- 2022-05-04 CL CL2022001173A patent/CL2022001173A1/es unknown
-
2023
- 2023-04-24 US US18/305,611 patent/US20230381167A1/en active Pending
- 2023-05-25 ZA ZA2023/05622A patent/ZA202305622B/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102264227A (zh) * | 2008-12-22 | 2011-11-30 | 凯莫森特里克斯股份有限公司 | C5aR拮抗剂 |
CN103068385A (zh) * | 2010-06-24 | 2013-04-24 | 凯莫森特里克斯股份有限公司 | C5aR拮抗剂 |
CN106999481A (zh) * | 2014-09-29 | 2017-08-01 | 凯莫森特里克斯股份有限公司 | 制备C5aR拮抗剂的方法和中间体 |
Non-Patent Citations (1)
Title |
---|
LIU H,等: "Orthosteric and allosteric action of the C5a receptor antagonists", NAT STRUCT MOL BIOL, vol. 25, no. 6, 4 June 2018 (2018-06-04), pages 472 - 481, XP036518029, DOI: 10.1038/s41594-018-0067-z * |
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AU2020378061A1 (en) | 2022-05-26 |
US11026935B2 (en) | 2021-06-08 |
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BR112022007488A2 (pt) | 2022-07-12 |
EP4054577A4 (en) | 2023-11-29 |
MX2022005403A (es) | 2022-05-24 |
KR20220098179A (ko) | 2022-07-11 |
ZA202305622B (en) | 2024-01-31 |
CL2022001173A1 (es) | 2023-02-10 |
IL292317A (en) | 2022-06-01 |
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EP4054577A1 (en) | 2022-09-14 |
US20220096453A1 (en) | 2022-03-31 |
US20210137907A1 (en) | 2021-05-13 |
US20230381167A1 (en) | 2023-11-30 |
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