CN110790787B - 一类水溶性前药、其制备方法及其作为药物的用途 - Google Patents
一类水溶性前药、其制备方法及其作为药物的用途 Download PDFInfo
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- CN110790787B CN110790787B CN201911103451.7A CN201911103451A CN110790787B CN 110790787 B CN110790787 B CN 110790787B CN 201911103451 A CN201911103451 A CN 201911103451A CN 110790787 B CN110790787 B CN 110790787B
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- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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Abstract
本发明涉及一类通式(I)所示的新型水溶性前药、其制备方法及含有该前药的药物组合物作为制备预防或/和治疗由水通道蛋白介导的疾病或病症的药物中的用途,所述疾病如脑或脊髓水肿、器官移植等。
Description
技术领域
本发明涉及与水通道蛋白介导的疾病相关的药物学领域,具体涉及一种新的水溶性前药、其制备方法及含有该前药的药物组合物作为制备预防或/和治疗由水通道蛋白介导的疾病或病症的药物中的用途。本发明中涉及的水溶性前药在该领域中具有明显的新颖性和创造性,较现有技术有显著改善。
背景技术
水通道蛋白是细胞膜转运水分子的特异性通道蛋白,在维持机体水平衡中发挥重要作用。水通道蛋白(aquaporin,AQPs)是最近几年研究较多的与水通透性相关的一类跨膜蛋白。至今在哺乳动物体内共发现13种水通道蛋白(AQP0-AQP12),其中AQP4是脑组织中分布最广泛的一种水通道蛋白。近年来研究表明AQP4在各种颅脑疾病(脑血管病、脑外伤、脑肿瘤、炎症等)所致的脑水肿形成和消散中起着关键作用。脑水肿为液体过度聚集在脑实质内(脑组织细胞内或细胞间隙中),可认为当脑组织中的含水量超过其正常含量的80%时就是脑水肿。神经***各种疾病所致的脑水肿主要为细胞毒性和血管源性脑水肿。细胞毒性脑水肿多是由于细胞代谢功能紊乱,导致钠钾泵、钙泵等功能失调,无法正常调节水和离子,导致细胞内水超载的一种病理性水肿,主要发生于脑缺血、缺氧、中毒等损伤因素,主要特点为星形胶质细胞发生肿胀而血脑屏障是完整的。近年来神经***发病率越来越高,其病理改变-脑水肿,是导致病人致残致死的主要原因。目前治疗脑水肿的药物仅局限于对症治疗(激素、甘露醇、高渗液等),但疗效不佳且副作用明显,该领域亟需安全有效的药物。
移植是从供体到受体的组织或器官的转移,移植受体面临长期的免疫抑制治疗和因排斥反应而损害新器官的风险,此外,免疫抑制剂抑制所有免疫应答,并且促成移植后并发症,包括由于感染导致的死亡。虽然移植过程中已经进行了改进,但移植后排斥仍然是常见的并发症。移植过程中的器官保存和运输期间是影响血运重建后移植物结果的主要因素,仍然需要高效的组织器官保存方法提高器官移植的有效性。
N-[3,5-双(三氟甲基)苯基]-5-氯-2-羟基苯甲酰胺是典型的AQP4抑制剂,能够治疗脑水肿,但由于水溶性差,不宜制备成静脉注射剂用于脑水肿、器官移植等紧急治疗,需要制备成易溶于水的前药。中国专利发明201380033198.7、201480061066.X、201580073130.0及201780042780.8(均为国外同族专利)均报道了水溶性前药2-{[3,5-双(三氟甲基)苯基]氨甲酰基}-4-氯苯基二氢磷酸酯作为脑水肿和器官移植药物,但发明专利201480061066.X也同样指出,即使以固态形式存在,2-{[3,5-双(三氟甲基)苯基]氨甲酰基}-4-氯苯基磷酸氢单钠盐、2-{[3,5-双(三氟甲基)苯基]氨甲酰基}-4-氯苯基磷酸双钠盐、2-{[3,5-双(三氟甲基)苯基]氨甲酰基}-4-氯苯基磷酸双乙醇胺盐都能以每天约1%固态水解的速度降解成难溶的原药N-[3,5-双(三氟甲基)苯基]-5-氯-2-羟基苯甲酰胺,因此,对药物的储运条件要求极高,且用药剂量将会难以把握,更严重的是,储运过程中降解产生的难溶性原药作为静脉注射剂有极大的安全性风险,因此,现有公开技术仍然存在极大的缺陷,亟需予以改良。
本发明人完全通过自身大量研究、实践和经验,优选得到一类水溶性前药,极大地增强了前药在储运过程中的稳定性,从而能够极大地降低储运成本,提高医护人员用药剂量的准确性,更重要的是,由于储运过程中降解产生的难溶性原药量大大减少,极大地提高了静脉注射剂的用药安全性,较现有技术有显著改善,相比于现有技术具有明显的新颖性和创造性。
发明内容
针对现有技术存在的缺陷和未满足的临床需求,本发明的目的是提供一类更优的水溶性前药,为预防或/和治疗由水通道蛋白介导的疾病或病症提供一类新的潜在药物。
本发明所述的水溶性前药,是含有有效量的通式(I)所示的化合物或其可药用的盐:
其中:
R1和R2各自独立选自氢、烷基,其中所述烷基任选进一步被一个或多个选自卤素、羟基、氰基、硝基、烷基、烷氧基、环烷基的基团所取代。
更优选的通式(I)所示的化合物或其可药用的盐:
R1和R2各自独立选自氢、C1-6烷基,其中所述C1-6烷基任选进一步被一个或多个选自羟基、烷基、烷氧基、环烷基的基团所取代。
更优选的本发明化合物包括,但不限于以下化合物:
本发明的另一方面涉及一种药物组合物,其含有治疗有效剂量的所述化合物或其可药用的盐及适当的载体、稀释剂或赋形剂。本发明涉及的药物组合物可与一种水溶液混合,如无菌注射用水或乳酸林格氏液。
本发明同时涉及所述化合物或其可药用的盐或其药物组合物在制备预防或/和治疗由水通道蛋白介导的疾病或病症的药物中的用途,所述疾病或病症如由水失衡引起的脑或脊髓水肿,或头部外伤、缺血性中风、脑胶质瘤、脑膜炎、急性高原病、癫痫、感染、代谢障碍、缺氧、水中毒、肝功能衰竭、肝性脑病、糖尿病酮症酸中毒、脓肿、子痫、克雅氏病、狼疮脑炎、心脏骤停、微重力和/或辐射暴露、创伤性中枢神经***手术等因素引起的脑水肿,或其他脏器水肿如视网膜水肿、视神经水肿、心脏水肿等疾病中至少一种疾病的药物中的用途。
本发明还涉及所述化合物或其可药用的盐或其药物组合物在制备用于器官移植相关的药物中的用途。
发明的详细说明
除非另有说明,否则下列用在说明书和权利要求书中的术语具有下述含义。
“烷基”指饱和的脂族烃基团,包括1至20个碳原子的直链和支链基团。优选含有1至10个碳原子的烷基,较优选含有1至6个碳原子的烷基,更优选含有1至3个碳原子的烷基,最优选为甲基。非限制性实施例包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、己基等,及其各种支链异构体等。烷基可以是取代的或未取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,优选为一个或多个以下基团,独立地选自卤素、羟基、氰基、硝基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的基团所取代。
“环烷基”指饱和或部分不饱和单环或多环环状烃取代基,其包括3至20个碳原子,优选包括3至12个碳原子,更优选环烷基环包含3至10个碳原子。单环环烷基的非限制性实施例包含环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等
“烷氧基”指-O-(烷基)和-O-(未取代的环烷基),其中烷基的定义如上所述。非限制性实施例包含甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。烷氧基可以是任选取代的或未取代的,当被取代时,取代基优选为一个或多个以下基团,独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基的基团所取代。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生,该说明包括该事件或环境发生或不发生地场合。“取代的”指基团中的一个或多个氢原子,优选为最多5个,更优选为1~3个氢原子彼此独立地被相应数目的取代基取代。不言而喻,取代基仅处在它们的可能的化学位置,本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本发明所述化合物或其可药用的盐,或其前药与其他化学组分的混合物,其他化学组分例如可药用的载体和赋形剂。药物组合物的目的是促进生物体对活性成分的吸收,利于活性成分在生物体内发挥生物活性。
具体实施方式
下面结合实施例对本发明作进一步说明。需要说明的是,下述实施例仅是用于说明,而并非用于限制本发明。本领域技术人员根据本发明的教导所做出各种变化均应在本申请权利要求的保护范围之内。
实施例1
(2-(((3,5-双(三氟甲基)苯基)氨甲酰基)-4-氯苯氧基)甲基二氢磷酸(I-1)
第一步
将氢氧化钠(1.2g,30mmol)和溴氯甲烷(9.9g,76.5mmol)加入到氮气保护下1a(5.9g,15.3mmol)(1a的合成方法参考中国发明专利201480061066.X)的四氢呋喃溶液中,加热至40℃反应6小时,随后冷却至室温,过滤,滤液真空浓缩得到中间体2a 4.7g,收率71%,ESI-MS m/z:432.0[M+H]+.
第二步
将2a 4.5g溶于10.0g 60%的磷酸中,加入三乙胺(6.2g,61mmol)和四丁基溴化铵(4.6g,14mmol),加热至100℃反应1小时,随后浓缩掉部分溶剂,加入100mL水,用6M盐酸溶液调节pH值至1.5,用***(3×40mL)萃取,有机相以饱和食盐水洗涤、干燥、过滤之后减压蒸除有机溶剂,残余物再加入50mL水,冷却下用氢氧化钠溶液调节pH值至9,用甲苯(2×30mL)洗涤之后,浓缩掉25mL水,加入100mL异丙醇,冷却至0℃,过滤,真空干燥得到双钠盐I-2。
第三步
双钠盐I-2以稀盐酸调节pH值至1.5左右,用***(3×20mL)萃取,有机相以饱和食盐水洗涤、干燥、过滤之后减压蒸除有机溶剂得I-12.5g,收率79%。
1H NMR(300MHz,CD3OD)δ:8.39(s,2H),7.80(s,1H),7.72(s,1H),7.56-7.49(m,1H),7.45-7.41(m,1H),6.65(s,2H).
实施例2
(2-(((3,5-双(三氟甲基)苯基)氨甲酰基)-4-氯苯氧基)甲基磷酸双钾盐(I-3)
(2-(((3,5-双(三氟甲基)苯基)氨甲酰基)-4-氯苯氧基)甲基二氢磷酸(1当量),于冰浴冷却下分批加入至1M KOH(2当量)溶液中,混合后于室温反应2小时,所得溶液过滤并冷冻干燥得到白色固体双钾盐I-3,收率97%。
实施例3
(2-(((3,5-双(三氟甲基)苯基)氨甲酰基)-4-氯苯氧基)甲基磷酸双乙醇胺盐(I-4)
(2-(((3,5-双(三氟甲基)苯基)氨甲酰基)-4-氯苯氧基)甲基二氢磷酸(1当量)溶于甲醇中,于冰浴冷却下将乙醇胺(2当量)加入至上述溶液中,混合后于室温反应2小时,减压蒸除溶剂得到白色固体双乙醇胺盐I-4,收率87%。
1H NMR(300MHz,CD3OD)δ:8.37(s,2H),7.81(s,1H),7.71(s,1H),7.55-7.48(m,1H),7.46-7.42(m,1H),6.61(s,2H),4.15(t,4H),3.46(t,4H).
实施例4
1-(2-(((3,5-双(三氟甲基)苯基)氨基甲酰基)-4-氯苯氧基)乙基二氢磷酸(I-5)
参照I-1的制备方法,得到1-(2-(((3,5-双(三氟甲基)苯基)氨基甲酰基)-4-氯苯氧基)乙基二氢磷酸(I-5)2.6g,产率为48%。
1H NMR(300MHz,CD3OD)δ:8.38(s,2H),7.82(s,1H),7.74(s,1H),7.55-7.48(m,1H),7.46-7.43(m,1H),5.87(q,1H),1.58(d,3H).
实施例5
(2-(((3,5-双(三氟甲基)苯基)氨甲酰基)-4-氯苯氧基)甲基一氢磷酸单钠盐(I-6)
(2-(((3,5-双(三氟甲基)苯基)氨甲酰基)-4-氯苯氧基)甲基二氢磷酸(1当量),于冰浴冷却下分批加入1MNaOH(1当量)溶液,混合后于室温反应2小时,所得溶液过滤并冷冻干燥得到白色固体单钠盐I-6,收率93%。
实施例6 溶解度测定
以待测纯品作为标准品,用甲醇配置成一系列浓度的标准液,以HPLC测定其峰面积,做成标准曲线,同时制备待测化合物纯品的饱和水溶液,离心取上清以HPLC测定峰面积,计算得出待测化合物的水溶解度,结果表明:现有公开的水溶性前药2-{[3,5-双(三氟甲基)苯基]氨甲酰基}-4-氯苯基磷酸双钠盐的水溶解度为10.3mg/mL,本发明水溶性前药(2-(((3,5-双(三氟甲基)苯基)氨甲酰基)-4-氯苯氧基)甲基磷酸双钾盐、双钠盐、双乙醇胺盐的水溶解度分别为:9.3、10.5、9.7mg/mL,表明本发明水溶性前药的水溶解度与现有技术相当,能够满足静脉注射剂的溶解度要求。
实施例7 储存稳定性研究
将待测化合物置于室温干燥环境下密闭保存,于储存第5,10,20天分别取样,溶解,以HPLC测定化合物降解程度,结果表明:现有技术的水溶性前药2-{[3,5-双(三氟甲基)苯基]氨甲酰基}-4-氯苯基磷酸双钠盐能够以平均每天0.65%的速率降解,而本发明水溶性前药(2-(((3,5-双(三氟甲基)苯基)氨甲酰基)-4-氯苯氧基)甲基磷酸双钾盐、双钠盐、双乙醇胺盐在放置10天后分别降解了1.3%,0.6%,0.8%;放置20天后分别降解了2.9%,1.4%,2.1%,平均每天降解速率分别为0.15%,0.07%,0.11%。综上所述,本发明中的水溶性前药的储存稳定性远远高于现有技术,从而能够极大地降低储运成本,提高医护人员用药剂量的准确性,更重要的是,由于储运过程中降解产生的难溶性原药量大大减少,极大地提高了静脉注射剂的用药安全性,较现有技术有显著改善,相比于现有技术具有明显的新颖性和创造性。
实施例8 改善水中毒模型存活率
12周龄雄性ICR小鼠随机分组,每组十只,空白组腹腔注射生理盐水,给药组腹腔注射1mg/kg待测化合物,15分钟后,所有小鼠注射其体重20%的水,记录给水后3小时内小鼠的状态和存活情况。结果表明,空白对照组3小时后仅有2只小鼠存活,且状态较差,而本发明水溶性前药(2-(((3,5-双(三氟甲基)苯基)氨甲酰基)-4-氯苯氧基)甲基磷酸双钠盐给药组3小时后小鼠存活6只,且小鼠状态明显好于空白对照组。表明本发明水溶性前药能够明显改善水中毒模型的存活率。
实施例9 改善水中毒模型脑水肿程度
12周龄雄性ICR小鼠随机分组,每组6只,空白组腹腔注射生理盐水,给药组腹腔注射1mg/kg待测化合物,15分钟后,所有小鼠注射其体重20%的水,30分钟后,处死小鼠取全脑,电子天平称取脑湿重,电热恒温箱内70℃烘烤72h,称取脑干重。以(湿重-干重)/湿重×100%计算脑含水量,评价脑水肿程度。结果表明,本发明水溶性前药(2-(((3,5-双(三氟甲基)苯基)氨甲酰基)-4-氯苯氧基)甲基磷酸双钠盐给药组相比于模型对照组能够减少9.6%的脑含水量,表明其能显著改善水中毒模型的脑水肿程度。
Claims (6)
3.一种药物组合物,含有权利要求1-2之一所述的化合物或其可药用盐及适当的载体或赋形剂。
4.权利要求1-3所定义的化合物或其可药用的盐或其药物组合物在制备预防或/和治疗由水通道蛋白介导的疾病或病症的药物中的用途,所述疾病或病症由水失衡引起的脑或脊髓水肿,或头部外伤、缺血性中风、脑胶质瘤、脑膜炎、急性高原病、癫痫、感染、代谢障碍、缺氧、水中毒、肝功能衰竭、肝性脑病、糖尿病酮症酸中毒、脓肿、子痫、克雅氏病、狼疮脑炎、心脏骤停、微重力和/或辐射暴露、创伤性中枢神经***手术引起的脑水肿,或其他脏器水肿。
5.权利要求1-3所定义的化合物或其可药用的盐或其药物组合物在制备用于器官移植相关的药物中的用途。
6.权利要求1-3所定义的化合物或其可药用的盐或其药物组合物在制备预防或/和治疗脑或脊髓水肿相关疾病的药物中的用途。
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