CN112022856A - 用于治疗青光眼和眼压过高的前列腺素偶联物和衍生物 - Google Patents
用于治疗青光眼和眼压过高的前列腺素偶联物和衍生物 Download PDFInfo
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Abstract
公开了前列腺素偶联物和衍生物以及其用于治疗青光眼和/或降低眼内压的方法。另外，公开了可用于治疗眼病如青光眼和眼内压升高的眼科药物组合物。这类组合物包含有效量的本发明的前列腺素偶联物或衍生物。
Description
本申请是申请号为201580056402.6(PCT/US2015/055766)、申 请日为2015年10月15日、发明名称为“用于治疗青光眼和眼压过高 的前列腺素偶联物和衍生物”的中国发明专利申请的分案申请。
相关申请的交叉引用
本申请要求2014年10月14日提交的美国临时申请62/064,193的 优先权，其内容通过引用纳入本文。
技术领域
本发明涉及前列腺素偶联物和衍生物及其用于治疗青光眼和升高 的眼内压的用途。本发明具体涉及曲伏前列素偶联物和衍生物及其用 于降低和/或控制正常或升高的眼内压(IOP)和治疗青光眼的用途。
背景技术
称为青光眼的疾病状态的特征在于因视网膜神经的不可逆破坏所 致的视觉功能的永久性丧失。几种形态或功能不同的青光眼类型一般 特征为升高的IOP，其被认为与疾病的病因有因果关系。眼压过高是 一种病症，其中眼内压升高，但是没有产生明显的视觉功能丧失；这 类患者被认为处于最终发展到与青光眼相关的视觉丧失的高度风险 中。一些具有青光眼性视野丧失的患者有较低的眼内压。这些压力正 常或低压力的青光眼患者也可受益于降低并控制IOP的药剂。如果在 早期检测到青光眼或眼压过高并用有效降低升高的眼内压的药物及时 治疗，一般可消除视觉功能丧失或其进行性退化。
已经证明有效降低眼内压的药物疗法包括减少房水产生的药剂和 增加流畅系数(outflow facility)、葡萄膜巩膜和常规流出的药剂。此 类疗法一般通过两种可能途径之一给予，局部(直接施用至眼)或口 服。然而，药学上的眼部抗高压方法已经显示各种不希望的副作用。 例如，缩瞳药如匹鲁卡品可能导致视力模糊、头痛、和其他负面视觉 副作用。全身给予的碳酸酐酶抑制剂也可能导致恶心、消化不良、疲 劳和代谢酸中毒。某些前列腺素会导致充血、眼部瘙痒、以及眼眶周 围皮肤和睫毛暗化。另外，某些β-阻断剂日益与各种严重肺部副作用 相关，可归因于其对肺部组织中β-受体的作用。拟交感神经药导致心 动过速、心律失常和高血压。这类负面副作用可能导致降低的患者顺 应性或治疗终止，使得正常视觉持续劣化。另外，存在用某些现有青 光眼疗法进行治疗时完全没有响应的个体。因此，存在对降低并控制 IOP的其他治疗剂的未满足的医学需求。
发明内容
本发明涉及本文所述的前列腺素偶联物和衍生物及其用于治疗青 光眼和/或降低眼内压的用途。下述的式(I)的对象化合物可用于在 恒温动物，包括人中降低和/或控制与正常眼压性青光眼、眼压过高、 和/或青光眼相关的IOP。在某些实施方式中，当用于治疗正常眼压性 青光眼或眼压过高时，化合物可配制成适于局部递送至眼的药学上可 接受的组合物。
本发明的另一个实施方式考虑可用于治疗青光眼和控制眼内压的 眼科药物组合物，包含有效量的下述式(I)的化合物。
本发明的另一个实施方式包括降低眼内压的方法，包括向人或其 他哺乳动物的受影响的眼睛施用治疗有效量的可用于治疗青光眼并控 制眼内压的眼科药物组合物，其中该组合物包含有效量的下述式(I) 的化合物。
之前的简述广义描述了本发明的某些实施方式的特征和技术优 势。将在下面的本发明的详述中描述其他特征和技术优势。
发明详述
在本发明的实施方式中公开并采用的化合物具有下式：
式(I)
其中A选自以下：
其中：
n是1-6；
R1，R2，R3独立地＝OH或O-NO2；
R4，R5独立地＝H、烷基、或杂烷基；或R4和R5可联合形成环烷 基或环杂烷基；并且
R6独立地＝H、O2、有机硝酸酯、有机亚硝酸酯、金属-NO复合 物、硝普钠(SNP)、二亚硝酰基铁硫醇复合物(dinitrosyl iron thiol complex)(DNIC)、N-亚硝胺、N-羟基-N-亚硝胺、N-亚硝亚胺、亚 硝亚胺(nitrosimine)、C-亚硝基、二氮杂环丁烯二氧化物、氧化呋咱环(furoxan)、苯并氧化呋咱环(benzofuroxan)、噁三唑-5-亚胺、 斯德酮亚胺(sydnonimine)、肟、羟胺、N-羟基胍、或羟基脲。
本文所用术语“烷基”是指具有至多20个碳原子的完全饱和的支 链，包括单或多支链，或直链烃部分。除非另外说明，烷基是指具有 1-16个碳原子、1-10个碳原子、1-7个碳原子、或1-4个碳原子的烃部 分。烷基的代表性示例包括，但不限于、甲基、乙基、正丙基、异丙 基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、 正己基、3-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、正庚基、正 辛基、正壬基、正癸基等。
本文所用“芳基”表示具有6-20个碳原子、6-15个碳原子、或6-10 个碳原子的芳基碳环系统。其可以是单环、双环或三环，并且可任选 地根据定义取代。6-15碳芳基的示例包括但不限于苯基、亚苯基、苯 三基、茚满基、萘基、亚萘基、萘三基和蒽基。
本文所用术语“杂烷基”是指直链或支链烷基，其优选在链上具有 2-14个碳、更优选2-10个碳、2-7个碳原子、或1-4个碳原子，其中 的一个或多个已被选自S、O、P和N的杂原子取代。示例性的杂烷 基包括烷基醚、仲烷基胺和叔烷基胺、酰胺、烷基硫化物等。该基团可以是端基或桥连基团。
本文所用术语“环烷基”是指3-12个碳原子的饱和或部分不饱和单 环、双环或三环烃基。除非另外说明，环烷基是指具有3-10个环碳原 子或3-7个环碳原子的环烃基。
本文所用术语“环杂烷基”是指3-7元单环或7-10元饱和或部分饱 和环或环系，其含有至少一个选自N、O和S的杂原子，其中N和S 也任选地被氧化成各种氧化态。环杂烷基可在杂原子或碳原子处接合 并且可包括稠合或桥联的环。
术语“有机硝酸酯”表示任何常见的含碳硝酸酯。该术语是指硝酸 的多元醇酯。有机硝酸酯具有一般结构式RONO2，其中R是芳基或 烷基。在这组有机硝酸酯中包括三硝酸甘油酯(或硝基甘油)和单硝 酸异山梨醇酯作为非限制性示例。
术语“有机亚硝酸酯”或“亚硝酸酯”表示任何常见的含碳亚硝酸 酯。有机亚硝酸酯是亚硝酸的酯并且含有亚硝酰基官能团。有机亚硝 酸酯具有一般结构式RONO，其中R是芳基或烷基。
认识到式(I)的化合物可含有一个或多个手性中心。本发明考虑 全部对映异构体、非对映异构体、及其混合物。另外，本发明的某些 实施方式包括式(I)的化合物的药学上可接受的盐。
合成：
可使用下述一般和具体示例与本领域技术人员可得的信息一起合 成式(I)的化合物。本文引用的所有出版物通过引用全文纳入本文。
方案1。前列腺素偶联物和衍生物的O-亚硝基化的合成示例。
O-亚硝基化参考：
Baker,J.W.等，Chem.Ind.1954,465
方案2。二醇二氮烯鎓前列腺素偶联物和衍生物的合成示例。
二醇二氮烯鎓参考：
1.Drago,R.S.等，J.Am.Chem.Soc.1960,82,96-98
2.Drago,R.S.等，J.Am.Chem.Soc.1961,83,1819-1822
3.Margos,C.M.等，J.Med.Chem.1991,34,3242-3247
4.Saavedra,J.E.等，J.Med.Chem.2000,43,261-269
5.Konter,1等，Bioorg.Med.Chem.Lett.2008,16,8294-8300
6.Saavedra,J.E.等，J.Org.Chem.1992,57,6134-6138
以下实施例显示了式(I)的选择化合物的合成并且提供了可用于 式(I)的其他化合物的合成的方法。
实施例1
(Z)-7-((1R,2R,3R,5S)-3,5-双(硝氧基)-2-((R,E)-3-(硝氧基)-4-(3-(三 氟甲基)苯氧基)丁-1-烯-1-基)环戊基)庚-5-烯酸异丙酯：将曲伏前列素 (928mg，1.85mmol)溶解在DCM(12mL)中并使用冰浴冷却至0℃。 乙酸酐(2.3mL，5V于硝酸)冷却至0℃并且向乙酸酐中小心添加白 色发烟硝酸(699mg，472μL，6.0当量，>99％纯度)并混合5分钟。 在4分钟内向曲伏前列素的DCM溶液中滴加硝酸/乙酸酐溶液。反应 混合物搅拌10分钟，用DCM(50mL)稀释并且用碳酸氢钠溶液(12 mL水，12mL饱和碳酸氢钠溶液)猝灭。分离各相，并且有机层依 次用饱和碳酸氢钠水溶液和盐水(25mL)洗涤，在MgSO4上干燥， 过滤并真空浓缩。粗产物在二氧化硅上层析分离并得到无色油状的标 题化合物(1.03g，88％)。XH NMR(400MHz,CDC13)δppm 7.42 (t,J＝8.0Hz,1H),7.28-7.26(m,1H),7.12(s,1H),7.08-7.06(m,1H), 5.96-5.90(m,1H),5.79-5.73(m 2H),5.48-5.42(m,1H),5.34-5.26 (m,2H),5.16(ddd,J＝8.7,7.0,3.5Hz,1H),5.03-4.93(m,1H),4.21- 4.17(m,2H),2.78-2.66(m,2H),2.27-2.20(m,2H),2.17-1.93(m, 5H),1.67-1.58(m,2H),1.21(dd,J＝6.3,2.8Hz,6H)；13CNMR(100 MHz,CDC13)δ173.1,158.1,135.7,132.5(q,2JCF＝32Hz)132.1, 130.4,126.3,126.1,124.2(q,1JCF＝H\Hz),118.6(q,3JCF＝4.0Hz), 118.2,1 11.5(q,3JCF＝4.0Hz),85.5,82.5,80.5,67.7,67.5,50.8,47.6, 37.3,34.0,26.6,24.8,24.6,22.0；19F NMR(376MHz,CDC13)δ-62.73； IR(KBr)v 2981,1720,1638,1450,1330,1275,1127,855；MS(ES+) m/z 636.20(M+H)+,653.29(M+NH4)+,658.26(M+Na)+,573.35 (M-NO3).
实施例2
吡咯烷NO-亲核复合体(NONOate)：向置于玻璃内衬的2L压 力容器中的吡咯烷(55mL，46.8g，657mmol)添加甲醇中25重量 ％甲醇钠溶液(172mL，756mmol，1.15当量)，之后添加MeCN(165 mL，3V)和MTBE(165mL，3V)。用氮气吹扫顶部空间并且用氮 气对溶液进行脱气。用NO气体吹扫顶部空间，然后加压至3巴。然 后在搅拌下运行反应混合物。观察到伴随放热(28℃)的快速气体摄 入。压力保持在3巴并且在4小时后没有观察到进一步的摄入。容器 放空并用氮气吹扫。所得白色沉淀经过滤和用MTBE(20mL)洗涤 以提供72g(72％)白色固体的所需产物。
(Z)-2-((甲硫基)甲氧基)-l-(吡咯烷-l-基)二氮烯1-氧化物：在氮气气 氛下向干500mL RBF中添加无水碳酸钠(7.42g，70.0mmol，0.7当 量)、无水DMF(200mL，13V)和氯甲基甲硫醚(10.0mL，120.0 mmol，1.2当量)。反应混合物在环境温度下搅拌6小时。用NO-亲核复合体(15.3g，100.0mmol)处理反应，产生从黄色到粉色的颜色 变化。反应混合物在25℃下搅拌16小时，用EtOAc(50mL)稀释 并在硅藻土上过滤。滤液用水(100mL)稀释，并用MTBE(2x 200 mL)萃取。合并的有机层用10％盐水洗涤(3x 200mL)，在MgSO4上干燥，过滤并浓缩。通过自动化快速色谱纯化粗材料以得到淡黄色 油状的所需产物(3.97g，21％)。1HNMR(400MHz,CDC13)δppm 5.18(s,2H),3.55-3.51(m,4H),2.23(s,3H),1.93-1.90(m,4H).
(Z)-2-(氯甲氧基)-l-(吡咯烷-l-基)二氮烯1-氧化物：向装配测温器、 氮气入口和加料漏斗的250mL三颈烧瓶中添加(Z)-2-((甲硫基)甲氧 基)-l-(吡咯烷-l-基)二氮烯1-氧化物(3.97g，20.7mmol)。反应容器 充入DCM(100mL)并且使反应混合物冷却至-78℃，之后滴加DCM 中的1M磺酰氯溶液(25mL DCM中3.35g，2ml，24.8mmol，1.2 当量)。加入完成后，使该反应混合物升温至环境温度，并搅拌3小 时。依次使用水(50mL)、饱和碳酸氢钠水溶液(50mL)和盐水(50 mL)清洗反应混合物。有机物在MgSO4上干燥，过滤，并真空浓缩 以得到棕色油(3.61g，90％)。3/4NMR(400MHz,CDC13)δppm 5.83 (s,2H),3.64-3.62(m,4H),1.99-1.96(m,4H)；ljC NMR(100MHz, CDC13)δ79.6,50.6,23.1；MS(ES+)180.1(M+H)+.
(Z)-2-((((Z)-7-((1R,2R,3R,5S)-3,5-二羟基-2-((R,E)-3-羟基-4-(3-(三 氟甲基)苯氧基)丁-1-烯-1-基)环戊基)庚-5-烯酰基)氧基)甲氧基)-1-(吡 咯烷-1-基)二氮烯1-氧化物：依次用三乙胺和MeCN(8mL)中(Z)-2-(氯 甲氧基)-1-(吡咯烷-1-基)二氮烯1-氧化物(1.6g，8.9mmol，1.2当量) 溶液处理MeCN(22mL)中的曲伏前列素酸(3.4g，7.41mmol)。 在25℃下将所得溶液搅拌16小时。减压去除溶剂。所得残留物收集 在水(35mL)中，用EtOAc(2x 50mL)萃取。合并的有机物用盐 水(25mL)洗涤，在MgSO4上干燥，过滤并真空浓缩。通过柱色谱 纯化粗材料以得到淡黄色油状的所需产物(1.42g，40％)。XHNMR (400MHz,CDC13)δppm 7.41-7.37(m,1H),7.22-7.20(m,1H),7.15 (s,1H),7.10-7.08(m,1H),5.77-5.64(m,4H),5.46-5.27(m,2H), 4.54(m,1H),4.18-4.17(m 1H),4.03-3.93(m,3H),3.58-3.55(m, 4H),2.69-2.68(m,1H,可交换羟基),2.62-2.60(m,1H,可交换羟基), 2.41-2.04(m,9H),1.98-1.91(m,4H),1.79-1.76(m,1H),1.72-1.64 (m 2H),1.58-1.51(m,1H)；13C NMR(100MHz,CDC13)δ172.5, 158.7,135.3,131.9(q,2JCF＝32.4Hz),130.1,129.5,129.5,129.3,123.9 (q,1JCF＝272.3Hz),118.1,117.8(q,3JCF＝3.8Hz),111.5(q,3JCF＝3.9 Hz),87.3,78.0,73.0,72.1,70.8,56.0,50.7,50.4,42.9,33.3,26.4,25.7, 24.4,23.0；19F NMR(376MHz,CDCI3)δ-62.67；MS(ES-)m/z 646 (M+45)"[M+甲酸酯].
递送模式：
式(I)的化合物可纳入各种类型的眼科制剂中用于递送。可使用 本领域普通技术人员熟知的技术将式(I)的化合物直接递送至眼(例 如：局部滴眼液或乳膏；植入结膜囊或与巩膜相邻植入或植入眼内的 缓释装置如药物递送海绵；眼周，结膜，筋膜下，房内，玻璃体内， 或管内注射)或全身(例如：口服，静脉内，皮下或肌内注射；胃肠 外，皮肤或经鼻递送)。还考虑，本发明的药剂可配制到眼内惰性物 或植入装置中。
式(I)的化合物优选纳入局部眼科制剂中用于递送至眼。该化合 物可与眼科可接受的防腐剂、表面活性剂、粘度增强剂、渗透增强剂、 缓冲剂、氯化钠、和水结合以形成水性、无菌眼科悬浮液或溶液。可 通过将化合物溶解在生理上可接受的等张水性缓冲液中来制备眼科溶 液制剂。另外，眼科溶液可包含眼科上可接受的表面活性剂以辅助溶 解化合物。另外，眼科溶液可含有药剂以增加粘度，如羟甲基纤维素、 羟乙基纤维素、羟丙基甲基纤维素、甲基纤维素、聚乙烯吡咯烷酮等， 以改善制剂在结膜囊内的保留。也可使用胶凝剂，包括但不限于结冷 胶和黄原胶。为了制备无菌眼科乳膏制剂，活性成分与防腐剂在合适 载剂如矿物油、液体羊毛脂、或白凡士林中组合。可通过在亲水性基 底中悬浮化合物来制备无菌眼科凝胶制剂，该基底从以下组合制备： 例如卡波普-974(carbopol-974)等，按照类似眼科制备的公开制剂；可 纳入防腐剂和等张剂。
式(I)的化合物优选配制成局部眼科悬浮液或溶液，pH为约4-8。 所述化合物以足够在经历升高的IOP患者中降低IOP和/或在青光眼 患者中维持正常IOP水平的量包含在所述组合物中。这种量在本文中 称为“有效控制IOP的量”或简称“有效量”。这些制剂中含有的化合物 的量通常为0.0001至5重量/体积百分比(“w/v％”)，但优选地是0.001 至2w/v％并且最优选0.01至1.0w/v％。因此，对于局部呈递，每天 1-4次将1-2滴这些制剂递送至眼的表面，按照本领域技术人员的判断。
式(I)的化合物也可与其他青光眼治疗剂联用，诸如但不限于， β-阻断剂、前列腺素类似物、碳酸酐酶抑制剂、α2激动剂、rho激酶 抑制剂、缩瞳药、和神经保护剂。
提供以下实施例以说明本发明某些实施方式，但不应对权利要求 构成任何限制。实施例1-4中的术语“式(I)的化合物”表示相应实施 例中所述的制剂被认为适用于式(I)的任何化合物。
组合物实施例1
组合物实施例2
组合物实施例3
组合物实施例4
已经详述了本发明及其实施方式。然而，本发明的范围不是旨在 限制于本说明书所述的形式、化合物、手段、方法和/或步骤的任何过 程、制造、组合物的具体实施方式。可对公开的材料进行各种修饰、 取代和变化而不偏离本发明的精神和/或必要特征。因此，本领域普通 技术人员将易于从本公开理解与本文所述的实施方式执行基本相同的 功能或实现基本相同的结果的后来修饰、取代和/或变化将可按照本发 明的这类相关实施方式应用。因此，以下权利要求旨在将对本文所述 的形式、化合物、手段、方法和/或步骤的过程、制造、组合物的修饰、 取代和变化包括在其范围内。
Claims (21)
1.一种可用于治疗青光眼和控制眼内压的眼科药物组合物，包含有效量的式(I)化合物或其药学上可接受的盐，
式(I)
其中A选自以下基团组成的组：
其中：
n是1-6；
R1，R2，R3独立地＝OH或O-NO2；
R4，R5独立地＝H、烷基、或杂烷基；或R4和R5可联合形成环烷基或环杂烷基；并且
R6独立地＝H、NO2、有机硝酸酯、有机亚硝酸酯、金属-NO复合物、硝普钠(SNP)、二亚硝酰基铁硫醇复合物(DNIC)、N-亚硝胺、N-羟基-N-亚硝胺、N-亚硝亚胺、亚硝亚胺、C-亚硝基、二氮杂环丁烯二氧化物、氧化呋咱环、苯并氧化呋咱环、噁三唑-5-亚胺、斯德酮亚胺、肟、羟胺、N-羟基胍、或羟基脲；以及
用于其的药学上可接受的载剂。
2.如权利要求1所述的组合物，包含式(I)化合物的药学上可接受的盐。
3.如权利要求1所述的组合物，还包含选自下组的化合物：眼科可接受的防腐剂、表面活性剂、粘度增强剂、渗透增强剂、胶凝剂、疏水性基底、载剂、缓冲剂、氯化钠、和水。
4.如权利要求1所述的组合物，其中所述组合物包含多种青光眼治疗剂。
5.如权利要求4所述的组合物，其中至少一种青光眼治疗剂选自下组：β-阻断剂、前列腺素类似物、碳酸酐酶抑制剂、α2激动剂、缩瞳药、rho激酶抑制剂、5-羟色胺能激动剂、和神经保护剂。
6.如权利要求1所述的组合物，其中所述组合物包含约0.01重量/体积百分比至约5重量/体积百分比的所述化合物。
7.如权利要求1所述的组合物，其中所述组合物包含约0.05重量/体积百分比至约2重量/体积百分比的所述化合物。
8.式(I)化合物或其药学上可接受的盐在制备用于治疗青光眼的药物中的用途：
式(I)
其中A选自以下基团组成的组：
其中：
n是1-6；
R1，R2，R3独立地＝OH或O-NO2；
R4，R5独立地＝H、烷基、或杂烷基；或R4和R5可联合形成环烷基或环杂烷基；并且
R6独立地＝H、NO2、有机硝酸酯、有机亚硝酸酯、金属-NO复合物、硝普钠(SNP)、二亚硝酰基铁硫醇复合物(DNIC)、N-亚硝胺、N-羟基-N-亚硝胺、N-亚硝亚胺、亚硝亚胺、C-亚硝基、二氮杂环丁烯二氧化物、氧化呋咱环、苯并氧化呋咱环、噁三唑-5-亚胺、斯德酮亚胺、肟、羟胺、N-羟基胍、或羟基脲。
9.如权利要求8所述的式(I)化合物在制备用于治疗青光眼的药物中的用途，其中所述药物是包含约0.01重量/体积百分比至约5重量/体积百分比的式(I)化合物的组合物，并且每天1-4次施用1-2滴所述组合物。
10.如权利要求9所述的式(I)化合物在制备用于治疗青光眼的药物中的用途，其中所述药物进一步包含至少一种青光眼治疗剂，选自下组：β-阻断剂、前列腺素类似物、碳酸酐酶抑制剂、α2激动剂、缩瞳药、rho激酶抑制剂、5-羟色胺能激动剂、和神经保护剂。
11.如式(I)表示的化合物或其药学上可接受的盐：
式(I)
其中A选自以下基团组成的组：
其中：
n是1-6；
R1，R2，R3独立地＝OH或O-NO2；
R4，R5独立地＝H、烷基、或杂烷基；或R4和R5可联合形成环烷基或环杂烷基；并且
R6独立地＝H、NO2、有机硝酸酯、有机亚硝酸酯、金属-NO复合物、硝普钠(SNP)、二亚硝酰基铁硫醇复合物(DNIC)、N-亚硝胺、N-羟基-N-亚硝胺、N-亚硝亚胺、亚硝亚胺、C-亚硝基、二氮杂环丁烯二氧化物、氧化呋咱环、苯并氧化呋咱环、噁三唑-5-亚胺、斯德酮亚胺、肟、羟胺、N-羟基胍、或羟基脲。
12.如权利要求11所述的化合物，其中所述化合物为式(I)化合物的药学上可接受的盐。
13.可用于治疗青光眼和控制眼内压的眼科药物组合物，包含：有效量的(Z)-7-((1R,2R,3R,5S)-3,5-双(硝氧基)-2-((R,E)-3-(硝氧基)-4-(3-(三氟甲基)苯氧基)丁-1-烯-1-基)环戊基)庚-5-烯酸异丙酯或其药学上可接受的盐，以及用于其的药学上可接受的载剂。
14.如权利要求13所述的组合物，还包含选自下组的化合物：眼科可接受的防腐剂、表面活性剂、粘度增强剂、渗透增强剂、胶凝剂、疏水性基底、载剂、缓冲剂、氯化钠、和水。
15.如权利要求13所述的组合物，其中所述组合物进一步包含至少一种青光眼治疗剂，选自下组：β-阻断剂、前列腺素类似物、碳酸酐酶抑制剂、α2激动剂、缩瞳药、rho激酶抑制剂、5-羟色胺能激动剂、和神经保护剂。
16.如权利要求13-15任一项所述的组合物，其中所述组合物包含约0.01重量/体积百分比至约5重量/体积百分比的所述化合物。
17.如权利要求13-15任一项所述的组合物，其中所述组合物包含约0.05重量/体积百分比至约2重量/体积百分比的所述化合物。
18.(Z)-7-((1R,2R,3R,5S)-3,5-双(硝氧基)-2-((R,E)-3-(硝氧基)-4-(3-(三氟甲基)苯氧基)丁-1-烯-1-基)环戊基)庚-5-烯酸异丙酯或其药学上可接受的盐在制备用于治疗青光眼的药物中的用途，其中所述药物是包含该化合物以及用于其的药学上可接受的载剂的组合物。
19.如权利要求18的用途，其中所述组合物包含0.01重量/体积百分比至5重量/体积百分比的该化合物。
20.如权利要求18或19所述的用途，其中所述药物进一步包含至少一种青光眼治疗剂，选自下组：β-阻断剂、前列腺素类似物、碳酸酐酶抑制剂、α2激动剂、缩瞳药、rho激酶抑制剂、5-羟色胺能激动剂、和神经保护剂。
21.化合物，其为(Z)-7-((1R,2R,3R,5S)-3,5-双(硝氧基)-2-((R,E)-3-(硝氧基)-4-(3-(三氟甲基)苯氧基)丁-1-烯-1-基)环戊基)庚-5-烯酸异丙酯或其药学上可接受的盐。
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| AU4057189A (en) * | 1988-08-23 | 1990-03-23 | Aktiebolaget Hassle | Treatment of glaucoma and related disorders in the human eye with pyridinylmethyl (sulfinyl or thio)benzimidazoles |
| US5510383A (en) * | 1993-08-03 | 1996-04-23 | Alcon Laboratories, Inc. | Use of cloprostenol, fluprostenol and their salts and esters to treat glaucoma and ocular hypertension |
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| WO2000051978A1 (en) * | 1999-03-01 | 2000-09-08 | Nitromed, Inc. | Nitrosated and nitrosylated prostaglandins, compositions and metods of use |
| WO2007000641A2 (en) * | 2005-06-29 | 2007-01-04 | Pfizer Inc. | Prostaglandin derivatives |
| WO2007044963A2 (en) * | 2005-10-13 | 2007-04-19 | Novokin Biotech Inc. | Development of prodrugs possessing a nitric oxide donor diazen-1-ium-1,2-diolate moiety using in vitro/in silico predictions |
| AU2009236356A1 (en) * | 2008-04-16 | 2009-10-22 | Allergan, Inc. | Combination therapy for glaucoma |
| CA2777352A1 (en) * | 2009-11-05 | 2011-05-12 | Biocon Limited | A novel process for the preparation of prostaglandins and intermediates thereof |
| EP2567689A1 (en) * | 2011-09-12 | 2013-03-13 | Visiotact Pharma | Ophthtalmic compositions comprising prostaglandin F2 alpha derivatives and hyaluronic acid |
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| WO2013163219A1 (en) * | 2012-04-24 | 2013-10-31 | Allergan, Inc. | Prostaglandin and vasoconstrictor pharmaceutical compositions and methods of use |
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| CN107106573A (zh) | 2017-08-29 |
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| JP6654757B2 (ja) | 2020-02-26 |
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| BR112017007095B1 (pt) | 2023-03-14 |
| CA2964364A1 (en) | 2016-04-21 |
| EP3206693A1 (en) | 2017-08-23 |
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| WO2016061370A1 (en) | 2016-04-21 |
| KR20170066427A (ko) | 2017-06-14 |
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| MX2020012011A (es) | 2022-04-19 |
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| AU2015332447B2 (en) | 2018-10-25 |
| US20160108012A1 (en) | 2016-04-21 |
| US9604949B2 (en) | 2017-03-28 |
| AU2015332447A1 (en) | 2017-04-27 |
| RU2712221C2 (ru) | 2020-01-27 |
| JP2020023556A (ja) | 2020-02-13 |
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