CN104185472A - 4-孕甾烯-11β-17-21-三醇-3,20-二酮衍生物的药物组合物和使用方法 - Google Patents
4-孕甾烯-11β-17-21-三醇-3,20-二酮衍生物的药物组合物和使用方法 Download PDFInfo
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- CN104185472A CN104185472A CN201280066021.2A CN201280066021A CN104185472A CN 104185472 A CN104185472 A CN 104185472A CN 201280066021 A CN201280066021 A CN 201280066021A CN 104185472 A CN104185472 A CN 104185472A
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Abstract
本发明涉及包含4-孕甾烯-11β-17-21-三醇-3,20-二酮衍生物的药物组合物,以及它们作为药物、作为糖皮质激素受体(GR)和/或盐皮质激素受体(MR)的调节剂的用途。本发明特别涉及这些化合物和它们的药物组合物用以治疗与糖皮质激素受体(GR)和/或盐皮质激素受体(MR)相关的眼部病症的用途。
Description
相关申请案
本申请要求2011年11月11日提交的美国临时申请序列号61/558,775的权益,其公开内容由此以引用方式以其整体并入本文。
发明领域
本发明涉及包含4-孕甾烯(pregenen)-11β-17-21-三醇-3,20-二酮衍生物的药物组合物,以及它们作为药物、作为糖皮质激素受体(GR)和/或盐皮质激素受体(MR)的调节剂的用途。本发明特别涉及这些化合物和它们的药物组合物用以治疗与糖皮质激素受体(GR)和/或盐皮质激素受体(MR)相关的眼部病症的用途。
发明背景
糖皮质激素(GC)激动剂代表了一类抗炎化合物,其可用于治疗多种眼部病症,包括眼内压升高,青光眼,葡萄膜炎,视网膜静脉阻塞,黄斑变性,糖尿病性视网膜病变,各种形式的黄斑水肿,术后炎症,睑结膜和球结膜、角膜、和眼球前段的炎性病症,诸如过敏性结膜炎,眼红斑痤疮,干眼症,睑缘炎,视网膜脱离,睑板腺功能障碍(MGD),浅层点状角膜炎,带状疱疹性角膜炎,虹膜炎,睫状体炎,选择感染性结膜炎(selected infective conjunctivitis),由于化学品、辐射或热灼伤、异物渗入、过敏症、或其组合的角膜损伤。
传统GC激动剂疗法(例如,醋酸肤轻松(fluocinolone acetonide))的潜在使用限制和威胁视力的副作用是高眼压症,其可能是由房水流过小梁网的阻力增大产生的。GC激动剂诱导的流出阻力和随后的高眼压症的机制还不是很清楚。
正因为如此,本领域中需要不导致眼内压升高或其他副作用的、通过GC受体的激动剂或拮抗剂活性的GC调节,并在本文中描述。
发明概要
已经发现一组4-孕甾烯-11β-17-21-三醇-3,20-二酮衍生物作为有效和选择性糖皮质激素受体(GR)和/或盐皮质激素受体(MR)的用途。因此,本文所述的化合物可用于治疗多种与糖皮质激素受体(GR)受体或盐皮质激素受体(MR)的调节有关的病症。本文所用的术语“调节剂”包括但不限于:受体激动剂、拮抗剂、反向激动剂、反向拮抗剂、部分激动剂、部分拮抗剂。
本发明涉及可用于治疗一种或多种眼部病症的包含4-孕甾烯-11β-17-21-三醇-3,20-二酮衍生物的药物组合物。还公开了治疗一种或多种眼部病症的方法。使用本文所述的化合物和/或制剂治疗的眼部病症包括眼内压升高,青光眼,葡萄膜炎,视网膜静脉阻塞,黄斑变性,糖尿病性视网膜病变,各种形式的黄斑水肿,术后炎症,睑结膜和球结膜、角膜、和眼球前段的炎性病症,诸如过敏性结膜炎,眼红斑痤疮,干眼症,睑缘炎,视网膜脱离,睑板腺功能障碍(MGD),浅层点状角膜炎,带状疱疹性角膜炎,虹膜炎,睫状体炎,选择感染性结膜炎,由于化学品、辐射或热灼伤、异物渗入、过敏症、或其组合的角膜损伤。
本发明涉及治疗与糖皮质激素受体(GR)受体和/或盐皮质激素受体(MR)的调节有关的病症的方法,其包括施用治疗有效量的包含4-孕甾烯-11β-17-21-三醇-3,20-二酮衍生物的组合物。根据本发明的化合物因此具有在医学中的用途,例如,在治疗患有由糖皮质激素或盐皮质激素受体调节减轻的疾病和病症的人中的用途。
在一个方面,本发明提供选自表1的化合物组的4-孕甾烯-11β-17-21-三醇-3,20-二酮衍生物的药物组合物:
表1
术语“药学上可接受的盐”是指这样的盐或复合物,其保留上文确定的化合物的期望生物活性并呈现最小或不呈现非期望的毒理学效应。根据本发明的“药学上可接受的盐”包括表1化合物能够形成的具有治疗活性、无毒碱或酸的盐形式。
以其游离形式作为碱出现的本发明化合物的酸加成盐,可通过用合适的酸处理游离碱而获得,诸如无机酸,例如盐酸、氢溴酸、硫酸、磷酸、硝酸等;或有机酸,例如乙酸、羟基乙酸、丙酸、乳酸、丙酮酸、丙二酸、富马酸、马来酸、草酸、酒石酸、琥珀酸、苹果酸、抗坏血酸、苯甲酸、鞣酸、双羟萘酸、柠檬酸、甲磺酸、乙磺酸、苯磺酸、甲酸等(Handbook of Pharmaceutical Salts,P.Heinrich Stahal&Camille G.Wermuth(编辑),Verlag Helvetica Chemica Acta-Zürich,2002,329-345)。
以其酸形式出现的本发明化合物的碱加成盐,可通过用合适的碱处理酸而获得,诸如无机碱,例如氢氧化钠、氢氧化镁、氢氧化钾、氢氧化钙、氨水等;或有机碱,例如L-精氨酸、乙醇胺、甜菜碱、二苄基乙二胺(benzathine)、吗啉等(Handbook of Pharmaceutical Salts,P.Heinrich Stahal&Camille G.Wermuth(编辑),Verlag HelveticaChemica Acta-Zürich,2002,329-345)。
本发明的化合物和其盐可以是溶剂化物的形式,这包括在本发明的范围之内。此类溶剂化物包括,例如水合物、醇化物等。
本文所述的化合物可用于治疗多种眼部病症,包括但不限于眼内压升高,青光眼,葡萄膜炎,视网膜静脉阻塞,黄斑变性,糖尿病性视网膜病变,各种形式的黄斑水肿,术后炎症,睑结膜和球结膜、角膜、和眼球前段的炎性病症,诸如过敏性结膜炎,眼红斑痤疮,干眼症,睑缘炎,视网膜脱离,睑板腺功能障碍(MGD),浅层点状角膜炎,带状疱疹性角膜炎,虹膜炎,睫状体炎,选择感染性结膜炎,由于化学品、辐射或热灼伤、异物渗入、过敏症、或其组合的角膜损伤。
在本发明的又一个实施方案中,提供了用于治疗与糖皮质激素受体(GR)和/或盐皮质激素受体(MR)调节相关的病症的方法。例如,可通过向需要其的受试者施用治疗有效量的至少一种表1化合物,或任何其组合,或其药学上可接受的盐。
在另一个实施方案中,提供了包括在药学上可接受的载体中的至少一种表1化合物的药物组合物。
本文所述的化合物可以药学有效的剂量施用。通常此类剂量是实现期望治疗效果所需的最小剂量。一般而言,此类剂量将在约1mg/天至约1000mg/天的范围内;更优选在约10mg/天至约500mg/天的范围内。在另一个示例实施方案中,一种化合物或多种化合物可以约0.5mg/kg/天至约100mg/kg/天或约1mg/kg/天至约100mg/kg/天的范围存在于组合物或制剂中。然而,在任何给定情况下要施用的化合物的实际量将通过医生考虑到相关的情况,诸如患者的年龄和体重、患者的一般身体状况、眼部病症的严重程度、以及施用途径而确定。在一些情况下,依据个案来估计剂量。
在另一个示例实施方案中,提供了包括在药学上可接受的载体中的至少一种化合物的药物组合物。药物组合物可以固体、溶液、乳液、分散体、胶束,脂质体等形式使用,其中所得的组合物包含与适合于肠内或肠胃外应用的有机或无机载体或赋形剂混合的、作为活性成分的本文所述的一种或多种化合物。例如,可以将一种或多种化合物与通常无毒的、药学上可接受的载体组合,用于片剂、丸剂、胶囊剂、栓剂、溶液、乳液、混悬剂、以及适合使用的任何其他形式。可使用的载体包括葡萄糖、乳糖、阿拉伯树胶、明胶、甘露醇、淀粉糊、三硅酸镁、滑石、玉米淀粉、角蛋白、胶体二氧化硅、马铃薯淀粉、脲、中等链长度的甘油三酯、葡聚糖、以及适用于生产呈固体、半固体或液体形式的制剂的其他载体。另外,可以使用助剂、稳定剂、增稠剂和着色剂以及香料。本文所述的化合物以足以对进程或疾病状况产生期望的效果的量包含在药物组合物中。
在另一个实施方案中,本文所述的化合物可以经口以任何可接受的形式诸如片剂、液体、胶囊剂、粉剂等施用。然而,其他途径可以是理想的或必要的,特别是当病人感到恶心时。此类其他途径可以包括,但不限于,透皮、肠胃外、皮下、鼻内、鞘内、肌内、静脉内、以及直肠内递送模式。此外,可将制剂设计为在一段给定时间内延缓释放活性化合物,或小心地控制在治疗过程期间于给定的时间释放的药物量。
适合于经口应用形式的药物组合物,例如以片剂、锭剂(troch)、糖锭(lozenge)、水性或油性混悬剂、可分散性粉剂或颗粒、乳剂、硬或软胶囊剂、或者糖浆剂或酏剂施用。
可以根据本领域已知的用于生产药物组合物的任何方法制备旨在用于经口应用的组合物,并且此类组合物可包含一种或多种试剂以提供药学上美观和可口的制剂,所述试剂选自甜味剂诸如蔗糖、乳糖或糖精,调味剂诸如薄荷、冬青油或樱桃油,着色剂,以及防腐剂。也可通过已知方法生产包含与无毒的药学上可接受的赋形剂混合的本文所述的化合物的片剂。
药物组合物可以为无菌可注射混悬剂的形式。该混悬剂可以使用合适的分散剂或润湿剂以及悬浮剂根据已知方法进行配制。无菌可注射制剂还可以为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或混悬液,例如作为1,3-丁二醇中的溶液。常规采用无菌的不挥发油作为溶剂或悬浮介质。为此目的,可以采用任何温和的不挥发性油,包括合成的甘油单酯或甘油二酯,脂肪酸(包括油酸),天然存在的植物油如芝麻油、椰子油、花生油、棉籽油等,或合成脂肪酸媒介,如油酸乙酯等。可根据需要掺入缓冲剂、防腐剂、抗氧化剂等。
本发明化合物也可以栓剂形式施用,以用于直肠施用药物。这些组合物可通过将本发明化合物与适宜的非刺激性赋形剂混合而制备,所述赋形剂诸如,可可脂、聚乙二醇的合成甘油酯(其在常温下为固态,但在直肠腔内液化和/或溶解以释放药物)。
在任何给定情况下要施用的化合物的实际量将通过医生考虑到相关的情况,诸如病症的严重程度、患者的年龄和体重、患者的一般身体状况、病症的原因、以及施用途径而确定。
本文描述的是能够调节糖皮质激素受体(GR)和/或盐皮质激素受体(MR)的化合物。与诸如皮质醇的化合物相比,所描述的化合物可具有更大的GR活化和/或结合效能。正因如此,该化合物可有效地治疗眼部适应症。该化合物可进一步通过眼内酯酶被代谢以形成天然激动剂皮质醇,从而降低高眼压症的风险。保留在眼睛和身体内的皮质醇通过天然存在的脱羟基酶和其他酶被进一步代谢为无活性化合物,使之成为安全的治疗途径。
在患者中,当通过滴眼液局部施加时,与合成的GC诸如地塞米松、泼尼松龙以及氟米龙相比,天然存在的内源性GC激动剂皮质醇(氢化可的松)对眼内压具有极小的影响(Cantrill等,1975)。皮质醇作为治疗剂的整体优异安全性的进一步支持是多种外用氢化可的松制剂目前在柜台直接向消费者出售的事实。
不希望受限于任何具体理论的束缚,惊奇地发现的是,由于对皮质醇分子的17-位的修饰,目前所描述的化合物可具有比皮质醇更多的糖皮质激素受体调节。
如本文所用的术语“治疗有效量”意指将引起需要其的受试者的为研究者、兽医、医生或其他临床医生正在寻求的生物学或医学响应的药物组合物的量。在一些实施方案中,需要其的受试者为哺乳动物。在一些实施方案中,哺乳动物为人。
所用的赋形剂可以为例如,(1)惰性稀释剂诸如碳酸钙、乳糖、磷酸钙或磷酸钠;(2)成粒剂和崩解剂,诸如玉米淀粉、马铃薯淀粉或褐藻酸;(3)粘合剂,诸如黄蓍胶、玉米淀粉、明胶或阿拉伯树胶,以及(4)润滑剂,诸如硬脂酸镁、硬脂酸或滑石。片剂可以是未包衣的或其可以通过已知技术包衣,以延缓在胃肠道内的崩解和吸收,从而在较长的时间内提供持续作用。例如,可以采用延时材料诸如单硬脂酸甘油酯或二硬脂酸甘油酯。
在一些情况下,经口应用的制剂可以为硬明胶胶囊剂形式,其中将化合物与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合。它们也可以为软明胶胶囊剂形式,其中将化合物与水或油介质例如花生油、液体石蜡或橄榄油混合。
本文所述的化合物还可作为眼科可接受的制剂或组合物施用。配制眼科可接受的液体使得其可以局部施用至眼睛。虽然有时出于配制的考虑(例如,稳定性)而无法达到最佳的舒适性,但应尽可能使舒适性最大化。在不能使舒适性最大化的情况下,应配制所述液体使得其对于局部眼用为患者可耐受的。另外,眼科可接受的液体可以被包装以供单次使用,或者含有防腐剂以在多次使用时免遭污染。
对于眼科应用,通常使用生理盐水溶液作为主要媒介物制备溶液或药剂。应优选用合适的缓冲体系使眼用溶液保持在舒适的PH值。制剂中还可包含常规的药学上可接受的防腐剂、稳定剂和表面活性剂。
可用于本文所述的眼用组合物中的防腐剂包括但不限于,苯扎氯铵、氯丁醇、硫柳汞、醋酸苯汞和硝酸苯汞。可用的表面活性剂是例如吐温80。同样,各种可用的媒介物可使用于本文所述的眼用制剂中。这些媒介物包括但不局限于,聚乙烯醇、聚乙烯吡咯酮、羟丙基甲基纤维素、泊洛沙姆(poloxamer)、羧甲基纤维素、羟乙基纤维素和纯净水。
如果需要或为了方便,可加入张力调节剂。它们包括但不局限于,盐,特别是氯化钠、氯化钾,甘露醇和甘油,或任何其他合适的眼科可接受的张力调节剂。
可使用各种用于调节pH的缓冲剂和方法,只要所得的制剂是眼科可接受的。因此,缓冲剂包括乙酸盐缓冲剂、柠檬酸盐缓冲剂、磷酸盐缓冲剂和硼酸盐缓冲剂。按需要可使用酸或碱调节这些制剂的PH。
在一个示例实施方案中,如本文所述的眼用组合物可具有于表2中所列的以下量使用的成分。
表2
成分 | 量(%w/v) |
活性成分 | 约0.001-5 |
防腐剂 | 0-0.10 |
媒介物 | 0-40 |
张力调节剂 | 1-10 |
缓冲剂 | 0.01-10 |
pH调节剂 | q.s.pH4.5-7.5 |
抗氧化剂 | 根据需要 |
表面活性剂 | 根据需要 |
纯化水 | 根据需要加至100% |
在其他实施方案中,眼科可接受的液体可配制成用于眼内注射。本文所述化合物可配制为液体、凝胶膏剂、霜剂、油。另外,化合物可配制成包含可生物降解聚合物诸如聚乳酸、聚乙醇酸、其组合等的缓释或控释眼内植入剂。
一些示例性组合物可包括两种或更多种本文所述的化合物的组合。可根据正被治疗的具体眼部病症或一组病状来配制不同比例的化合物。
由于各个受试者在症状严重度方面可能存在很大差异,并且每种组合物具有其独特的治疗特性,因此用于每位受试者的精确的施用方式和剂量交由医师判定。
详述
应当理解,前文一般性描述和下文详细描述均仅仅为示例性和阐释性的,而不限制受权利要求书保护的本发明。如本文所用,除非另外具体指明,否则单数的使用包括复数。
以下实施例仅为了进行示意性的说明,而非意在也不应视为以任何方式限制本发明。本领域的技术人员将会知道,可在不超出本发明的精神或范围的情况下对以下实施例作出变化和修改。
对本领域技术人员显而易见的是,各个同分异构形式可通过以常规方式分离其混合物而获得。例如,就非对映异构体而言,可以采用色谱分离。
实施例1
皮质醇和17-酯衍生物的糖皮质激素受体反式激活效能
使用含有MMTV-bla报道基因的HeLa细胞系(加利福尼亚州,卡尔斯巴德(Carlsbad),Invitrogen Corp.的MMTV-bla HeLa)评价糖皮质激素受体(GR)激活效能。该细胞系在先前鉴定为糖皮质激素受体响应元件的MMTV响应元件的控制下用含有β-内酰胺酶cDNA的表达构建体稳定地转染。
9种化合物和对照化合物地塞米松的以一式两份进行的一个实验的结果总结于表3中。使用以100nM最大化合物浓度开始的一半对数倍数稀释系列,进行所有试验作为10点剂量反应。将化合物温育5小时。内源性GR的激活导致报道基因β-内酰胺酶的表达,其通过FRET底物在比率计量试验形式中的转化来检测。该功能性试验允许测量化合物对受体的激动作用并且可用于测定化合物效能和选择性。通过计算未处理的相对于最大激发的Z'值测定试验再现性。Z'值大于0.6,表明试验形式的良好再现性。
数种化合物表现出GR信号通路的剂量依赖性激发(表3)。表1化合物表现出与母体分子皮质醇相比约30倍的效能。
表3:糖皮质激素受体效能。示出以激动剂方式测试的对照化合物、地塞米松以及所述化合物的EC50(nM)和Z'值。
实施例2
皮质醇和17-酯衍生物的盐皮质激素受体反式激活效能
使用含有UAS-bla报道基因的HEK293T细胞系(UAS-bla HEK293T)评价盐皮质激素受体(MR)激活效能。该细胞系在GAL4上游激活剂序列(UAS)和另一种编码融合蛋白GAL4(DBD)-MR(LBD)的表达构建体的控制下用含有β-内酰胺酶cDNA的表达构建体稳定地转染。9种化合物和对照化合物醛甾酮的以激动剂方式一式两份进行的一个实验的结果总结于表4中。使用以100nM最大化合物浓度开始的一半对数倍数稀释系列,进行所有试验作为10点剂量反应。将化合物温育16小时。GAL4(DBD)-MR(LBD)的激活导致报道基因β-内酰胺酶的表达,其通过FRET底物在比率计量试验形式中的转化来检测。该功能性试验允许测量化合物对受体的激动作用并且可用于测定化合物效能和选择性。通过计算未处理的相对于最大激发的Z'值测定试验再现性。Z'值大于0.6,表明试验形式的良好再现性。数个化合物表现出MR信号通路的剂量依赖性激发(表4)。
表4.盐皮质激素受体效能。示出以激动剂方式测试的对照化合物、醛甾酮以及所有10种化合物的EC50(nM)和Z'值。
表4
实施例3
治疗眼内压升高
一位58岁的男性拜访他的眼科医生以进行例行检查。该医生发现患者表现出眼内压升高并且面临未来并发症的高风险。患者被指导对每只眼睛施用含有表1中的化合物之一的外用液体制剂,每天一次。
三个月后患者返回进行随访。在测量眼内压之后,注意到的是,患者现在表现出眼内压降低。
实施例4
治疗眼部刺激
一位38岁的男性拜访他的眼科医生,抱怨他的右眼受到刺激。医生发现患者的右眼发炎且发红。患者被指导对右眼施用含有表1中的化合物之一的外用液体制剂,每天两次。
一周后患者返回进行随访。在检查右眼之后,注意到的是,患者的右眼不再发红,并且患者指出刺激消失了。
除非另有指示,否则说明书和权利要求书中用于表示成分、性能例如分子量、反应条件等的量的全部数值被理解为在全部的情况中是用术语“约”修饰的。
因此,除非有相反指示,否则在说明书和所附权利要求书中阐明的数值参数是近似的,其可以根据本发明寻求获得的期望性能而变化。绝非并且也不打算将本申请限制到权利要求书范围的等价物的条框中,每个数值参数应当至少根据所报告的有效数字的个数并通过使用通常的舍入技术来解释。
虽然阐明本发明的宽的范围的数值范围和参数是近似的,但是在具体实施例中所阐明的数值是尽可能精确地报告的。然而,任何数值都固有地包含了必然来自于在它们各自的测试测量中出现的标准偏差的某些误差。
术语“一个(a)”、“一种(an)”以及“该”和类似表述在描述本发明的上下文中(特别是在所附的权利要求书的上下文中)的使用应当被理解为涵盖了单数和复数,除非本文明确指出或者与上下文明显冲突。本文数值范围的的引述仅仅意图作为单独地引用落入到该范围内的每个单独值的速记方法。除非本文另有指示,否则每个单独值都结合到说明书中,就好像每个值被单独引用。本文所述的所有方法可以任何适合的顺序实行,除非本文另有指示或与上下文明显冲突。这里提供的任何及所有的实施例或示例性语言(例如,“诸如”)仅仅意图更好地说明本发明,而不是对于本发明的范围施加限制,除非另外要求保护。在本说明书中的语言不应被理解为表示任何未要求保护的元件对于本发明的实施来说是必不可少的。
本文所公开的本发明的可选元件或实施方案的分组不应该解释为限定。可以涉及每组构件并单独或与该组的其他构件或本文发现的其他元件的任意结合要求保护。可以预期到由于方便和/或可专利性的原因,一组的一个或多个构件可以包括在一组中或从一组中删除。当任何此类包含或删除发生时,本说明书认为包含经过修饰的组,由此满足所附权利要求书中用到的所有马库什组的书面描述。
本文描述了本发明的某些实施方案,包括发明人已知的、用于执行本发明的最佳模式。当然,在阅读了前述说明之后,这些描述的实施方案的变化对于本领域的普通技术人员来说是显而易见的。发明人希望本领域的技术人员适当使用这些变化,并且发明人希望本发明以并非本文具体描述的方式实施。因此,本发明包括本发明所附的被适用法律允许的权利要求书中引用的主题的所有修改和等同变化。另外,除非另有说明或者与上下文明显冲突,否则本发明将包含上述元件的任何组合的所有可能变化。
最后,应该理解的是本文所公开的本发明的实施方案是对本发明的原理的示例性说明。可以使用的其他修改在本发明的范围内。因此,通过实例,但是为非限制性的,可以根据本文的教导利用本发明的可选配置。因此,本发明并不局限于明确示出和描述的内容。
Claims (14)
1.一种治疗与糖皮质激素和/或盐皮质激素受体调节相关的眼部病症的方法,其包括向需要其的患者施用药物组合物,所述药物组合物包含治疗有效量的至少一种选自以下化合物的化合物:
苯乙酸(8S,9S,10R,11S,13S,14S,17R)-17-乙醇酰基-11-羟基-10,13-二甲基-3-氧代-2,3,6,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环戊并[a]菲-17-基酯;
丁酸(8S,9S,10R,11S,13S,14S,17R)-17-乙醇酰基-11-羟基-10,13-二甲基-3-氧代-2,3,6,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环戊并[a]菲-17-基酯;
丙酸(8S,9S,10R,11S,13S,14S,17R)-17-乙醇酰基-11-羟基-10,13-二甲基-3-氧代-2,3,6,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环戊并[a]菲-17-基酯;
辛酸(8S,9S,10R,11S,13S,14S,17R)-17-乙醇酰基-11-羟基-10,13-二甲基-3-氧代-2,3,6,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环戊并[a]菲-17-基酯;
己酸(8S,9S,10R,11S,13S,14S,17R)-17-乙醇酰基-11-羟基-10,13-二甲基-3-氧代-2,3,6,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环戊并[a]菲-17-基酯;
苯甲酸(8R,9R,10S,11R,13R,14R,17S)-17-乙醇酰基-11-羟基-10,13-二甲基-3-氧代-2,3,6,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环戊并[a]菲-17-基酯;
庚酸(8S,9S,10R,11S,13S,14S,17R)-17-乙醇酰基-11-羟基-10,13-二甲基-3-氧代-2,3,6,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环戊并[a]菲-17-基酯;
2-甲基丙酸(8S,9S,10R,11S,13S,14S,17R)-17-乙醇酰-11-羟基-10,13-二甲基-3-氧代-2,3,6,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环戊并[a]菲-17-基酯;以及
rel-环戊羧酸(8R,9R,10S,11R,13R,14R,17S)-17-乙醇酰基-11-羟基-10,13-二甲基-3-氧代-2,3,6,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环戊并[a]菲-17-基酯。
2.根据权利要求1所述的方法,其中所述眼部病症选自以下病症:眼内压升高,青光眼,葡萄膜炎,视网膜静脉阻塞,黄斑变性,糖尿病性视网膜病变,各种形式的黄斑水肿,术后炎症,睑结膜和球结膜、角膜、和眼球前段的炎性病症,诸如过敏性结膜炎,眼红斑痤疮,干眼症,睑缘炎,视网膜脱离,睑板腺功能障碍,浅层点状角膜炎,带状疱疹性角膜炎,虹膜炎,睫状体炎,选择感染性结膜炎,由于化学品、辐射或热灼伤、异物渗入、过敏症、及其组合的角膜损伤。
3.根据权利要求1所述的方法,其中所述眼部病症选自眼红斑痤疮,干眼症,睑缘炎,睑板腺功能障碍。
4.一种药物组合物,包含载体和根据权利要求1所述的化合物。
5.根据权利要求1所述的药物组合物,其用于局部眼科用途。
根据权利要求1所述的药物组合物,其向被施用其的患者提供治疗益处。
6.根据权利要求1所述的方法,其中所述化合物为:
苯甲酸(8R,9R,10S,11R,13R,14R,17S)-17-乙醇酰基-11-羟基-10,13-二甲基-3-氧代-2,3,6,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环戊并[a]菲-17-基酯。
7.根据权利要求1所述的方法,其中所述化合物为:
己酸(8S,9S,10R,11S,13S,14S,17R)-17-乙醇酰基-11-羟基-10,13-二甲基-3-氧代-2,3,6,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环戊并[a]菲-17-基酯。
8.根据权利要求1所述的方法,其中所述化合物为:
辛酸(8S,9S,10R,11S,13S,14S,17R)-17-乙醇酰基-11-羟基-10,13-二甲基-3-氧代-2,3,6,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环戊并[a]菲-17-基酯。
9.根据权利要求1所述的方法,其中所述化合物为:
苯乙酸(8S,9S,10R,11S,13S,14S,17R)-17-乙醇酰基-11-羟基-10,13-二甲基-3-氧代-2,3,6,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环戊并[a]菲-17-基酯。
10.根据权利要求1所述的方法,其中所述化合物为:
丁酸(8S,9S,10R,11S,13S,14S,17R)-17-乙醇酰基-11-羟基-10,13-二甲基-3-氧代-2,3,6,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环戊并[a]菲-17-基酯。
11.根据权利要求1所述的方法,其中所述化合物为:
丙酸(8S,9S,10R,11S,13S,14S,17R)-17-乙醇酰基-11-羟基-10,13-二甲基-3-氧代-2,3,6,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环戊并[a]菲-17-基酯。
12.根据权利要求1所述的方法,其中所述化合物为:
庚酸(8S,9S,10R,11S,13S,14S,17R)-17-乙醇酰基-11-羟基-10,13-二甲基-3-氧代-2,3,6,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环戊并[a]菲-17-基酯。
13.根据权利要求1所述的方法,其中所述化合物为:
2-甲基丙酸(8S,9S,10R,11S,13S,14S,17R)-17-乙醇酰-11-羟基-10,13-二甲基-3-氧代-2,3,6,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环戊并[a]菲-17-基酯。
14.根据权利要求1所述的方法,其中所述化合物为:
rel-环戊羧酸(8R,9R,10S,11R,13R,14R,17S)-17-乙醇酰基-11-羟基-10,13-二甲基-3-氧代-2,3,6,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环戊并[a]菲-17-基酯。
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UA116622C2 (uk) * | 2011-11-11 | 2018-04-25 | Аллерган, Інк. | Похідні 4-прегенен-11ss-17-21-тріол-3,20-діону для лікування хвороб очей |
EP2592078A1 (en) | 2011-11-11 | 2013-05-15 | Almirall, S.A. | New cyclohexylamine derivatives having beta2 adrenergic agonist and M3 muscarinic antagonist activities |
US9518050B2 (en) | 2012-12-18 | 2016-12-13 | Almirall, S.A. | Cyclohexyl and quinuclidinyl carbamate derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activity |
TWI643853B (zh) | 2013-02-27 | 2018-12-11 | 阿爾米雷爾有限公司 | 同時具有β2腎上腺素受體促效劑和M3毒蕈鹼受體拮抗劑活性之2-氨基-1-羥乙基-8-羥基喹啉-2(1H)-酮衍生物之鹽類 |
TWI641373B (zh) | 2013-07-25 | 2018-11-21 | 阿爾米雷爾有限公司 | 具有蕈毒鹼受體拮抗劑和β2腎上腺素受體促效劑二者之活性的2-胺基-1-羥乙基-8-羥基喹啉-2(1H)-酮衍生物之鹽 |
TW201517906A (zh) | 2013-07-25 | 2015-05-16 | Almirall Sa | 含有maba化合物和皮質類固醇之組合 |
KR20160098338A (ko) * | 2013-12-13 | 2016-08-18 | 알러간, 인코포레이티드 | 코르티솔 17-알파-벤조에이트의 다형성 및 비결정성 형태들, 및 그 조제 방법들 및 용도 |
TW201617343A (zh) | 2014-09-26 | 2016-05-16 | 阿爾米雷爾有限公司 | 具有β2腎上腺素促效劑及M3蕈毒拮抗劑活性之新穎雙環衍生物 |
WO2016141098A1 (en) * | 2015-03-05 | 2016-09-09 | Allergan, Inc. | Self-emulsifying drug delivery system (sedds) for ophthalmic drug delivery |
US20190216726A1 (en) * | 2016-09-16 | 2019-07-18 | Kala Pharmaceuticals, Inc. | Particles, Compositions and Methods for Ophthalmic and/or Other Applications |
WO2019055028A1 (en) * | 2017-09-15 | 2019-03-21 | Kala Pharmaceuticals, Inc. | PARTICLES, COMPOSITIONS AND METHODS FOR OPHTHALMIC APPLICATIONS AND / OR OTHER APPLICATIONS |
CN116023425B (zh) * | 2023-03-28 | 2023-06-20 | 南京师范大学 | 曲安西龙衍生物及其医药用途 |
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