CN102070631B - 戊乙奎醚光学异构体的季铵盐、药物组合物及其医药用途 - Google Patents
戊乙奎醚光学异构体的季铵盐、药物组合物及其医药用途 Download PDFInfo
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- CN102070631B CN102070631B CN200910223255.3A CN200910223255A CN102070631B CN 102070631 B CN102070631 B CN 102070631B CN 200910223255 A CN200910223255 A CN 200910223255A CN 102070631 B CN102070631 B CN 102070631B
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- ammonium salt
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Abstract
本发明涉及式I所示的季铵盐类化合物,或其药学可接受的盐或溶剂合物。本发明还涉及所述化合物作为选择性M受体拮抗剂特别是选择性M3受体拮抗剂的用途,以及包含所述化合物的药物组合物。
Description
技术领域:
本发明涉及式I所示的季铵盐类化合物,或其药学可接受的盐或溶剂合物。本发明还涉及所述化合物作为选择性M受体拮抗剂特别是选择性M3受体拮抗剂的用途,以及包含所述化合物的药物组合物。
背景技术:
M胆碱受体是十分重要的药物治疗靶标。M受体拮抗剂类的抗胆碱药具有支气管扩张作用、分泌抑制作用和降低迷走神经张力的作用,可有效治疗慢性阻塞性肺病;通过抑制呼吸道腺体分泌,有效减轻感冒的流涕及鼻充血症状;M受体拮抗剂还能够减少呼吸道分泌,保持呼吸道通畅,常用于吸入麻醉前的术前用药。因此从M受体拮抗剂中开发治疗药物已成为世界各大医药公司新药研究的热点。
但是,非选择性M受体拮抗剂,会产生口干、心动过速、便秘、尿潴留、散瞳及中枢神经系统症状等副作用;甚至同一组织中M受体的不同亚型具有不同的药理学性质。在呼吸道,M2受体的功能与M1和M3受体的功能截然相反。因此,对不同亚型的M受体的选择性是决定抗胆碱药物应用前景的关键。
盐酸戊乙奎醚[英文名:Penehyclidine Hydrochloride;化学名:
3-(2′-羟基-2′-环戊基-2′-苯基乙氧基)奎宁环烷盐酸盐],其结构如下式所示:
盐酸戊乙奎醚结构式
盐酸戊乙奎醚是一种新型结构的M受体拮抗剂类的抗胆碱药物(林永煅等.军事医学科学院院刊,1987,11,356.),临床已经成功用于救治有机磷农药中毒等方面,其抗毒效价高,作用持久、不良作用较少(曾繁忠等.中华内科杂志.1993,32,838;乔建忠等.中国药学杂志.2003,38,942.)。在抗胆碱作用的评价研究中,与工具药QNB(3-Quinuclidinebenziate)相比具有同等剂量水平的抗神经毒剂作用,其抗槟榔碱所引起的震颤和流诞作用分别比QNB强10倍和2倍(沈淑英等.中国药理学报.1985,6,158.)。盐酸戊乙奎醚分子中含有两个手性中心,为具有4个光学异构体的混合物。
中国发明专利CN1951938A公开了下式(A)所示的戊乙奎醚的季铵盐:
中国发明专利CN1769286A公开了下式(B)所示的治疗鼻分泌过度和慢阻肺的化合物:
中国发明专利CN1257903C公开了式(B)所示的含有季铵基团的奎宁类化合物,CN1257903C还通过硅胶板分离得到了N-甲基戊乙奎醚溴化物(式B中R1为环戊基、R2为甲基、X为溴)的两对消旋体。
未见有关戊乙奎醚单一光学异构体的季铵盐的结构、理化性质及生物活性的报道。
手性药物的不同光学异构体是两个不同的化学实体。由于药物作用靶点和药物代谢酶结构的立体特异性,手性药物的不同光学异构体在药理学活性上可能表现为:1)两个对映体一个有活性,另一个没有活性;2)两个对映体的生物活性不同;3)两个对映体具有相同或相似的生物活性;4)两种异构体相互拮抗;5)两个对映体一个有活性,另一个产生毒副作用;6)两种异构体在体内相互转化;7)两种异构体具有药物相互作用等多种情况。
根据现阶段本领域掌握的知识,无法预测哪一个异构体将有效或是无效;也无法断言其中的一个光学异构体一定具有比消旋体更好的生物学性质。
发明内容
本发明的研究者经过深入细致的研究发现,式I所示的戊乙奎醚光学异构体,即3-(R)-[2′-(R)-2′-羟基-2′-环戊基-2′-苯基乙氧基]-奎宁环烷的季铵盐具有高于消旋体的M受体拮抗作用;本发明的研究者更意外的发现,式I所示的戊乙奎醚光学异构体季铵盐具有比消旋体更高的M3受体选择性;本发明的研究者还意外的发现,在等效剂量下,式I所示的戊乙奎醚光学异构体季铵盐对心脏的副作用小于消旋体。
发明概述
本发明一方面提供式I所示的戊乙奎醚光学异构体的季铵盐或其药学可接受的盐或溶剂合物。
式I中,R代表甲基、乙基、丙基、异丙基或环丙基;X代表卤原子。
根据本发明第一方面上述或下述任一项所述的化合物,其光学纯度大于90%,优选大于95%,优选大于98%,优选大于99%,优选大于99.5%。
根据本发明第一方面上述或下述任一项的化合物,其可用作选择性M受体拮抗剂,优选可用作选择性M3受体拮抗剂。
根据本发明第一方面上述或下述任一项所述的化合物,其可用作治疗慢性阻塞性肺病的药物、治疗感冒的药物、和/或麻醉前给药的药物。
本发明第二方面提供了本发明第一方面任一项所述化合物在制备作为选择性M受体拮抗剂,优选作为选择性M3受体拮抗剂的药物中的用途。
本发明第三方面提供了本发明第一方面任一项所述化合物在制备作为治疗慢性阻塞性肺病的药物、治疗感冒的药物、和/或麻醉前给药的药物中的用途。
本发明第四方面提供了一种药物组合物,其包含作为活性成分的治疗有效量的本发明第一方面任一项所述的化合物,和任选的药学可接受的载体或赋形剂。本发明的药物组合物可用于作为选择性M受体拮抗剂,优选作为选择性M3受体拮抗剂的药物。本发明的药物组合物还可用于作为治疗慢性阻塞性肺病的药物、治疗感冒的药物、和/或麻醉前给药的药物。
根据本发明第四方面上述或下述任一项所述的药物组合物,其中所述式I所示光学异构体或其药学可接受的盐或溶剂合物的光学纯度大于95%,优选大于98%,优选大于99%,优选大于99.5%。
根据本发明第四方面上述或下述任一项所述的药物组合物,其为片剂、胶囊剂、注射剂、喷雾剂、气雾剂、滴鼻剂或粉雾剂。
发明详述
下面对本发明的特征和优点作进一步的描述。
本发明一方面提供了基本光学纯的式I化合物。术语“基本光学纯的”是指本发明式I所示光学异构体是基本上纯净的,以致于其光学纯度大于90%,即式I所示光学异构体所占重量百分数在90%以上,优选大于95%,优选大于98%,优选大于99%,优选大于99.5%。虽然本发明在制备所述式I化合物时获得了光学纯度在98%以上产物;但是,本领域技术人员清楚,通过适宜的方法,例如分级结晶、手性柱色谱层析等,可以进一步获得更高光学纯度的式Ia或者式Ib化合物以及其药学可接受的盐或溶剂合物。当然,本领域技术人员清楚,获得光学纯度大于90%的式I化合物也是容易的,并且也是有其应用价值的,例如光学纯度约大于90%的式I化合物可用于制备其盐或溶剂合物并在制备该盐或溶剂合物过程中进一步纯化,以获得更高纯度的光学异构体。
M受体具有本领域最广泛的含义,并且通常是指M1受体、M2受体、M3受体、M4受体、M5受体,在本发明中特别是指M3受体。
如用于本文的,术语“药学可接受的”通常是指可用于制药学上或医学上可用的,或者虽然不能直接用于制药学或医学,但是可作为制备制药学或医学产品中间体时可以利用,并在最后用于制药学或医学之前通过适宜的方法脱除的。例如药学可接受的盐,不但包括可用于临床的药用盐,还包括不能直接用于临床,但可在制备本发明化合物时使用并在随后的工艺过程中脱除的盐。
如用于本文的,术语“药学可接受的载体或赋形剂”是指制剂工业领域常用的药用辅料,例如在罗明生,等.药剂辅料大全,四川科学技术出版社,1995中列举的。
根据本发明的药物组合物,其可以是例如以下的剂型:片剂例如但不限于速释片、缓缓片、控释片、薄膜衣片、糖衣片、口含片、舌下片、生物粘附片等;胶囊剂例如但不限于硬胶囊剂、软胶囊剂等;注射剂例如但不限于无菌的或含抑菌剂的水性注射液、油性注射液、冷冻干燥粉针剂、注射用微球等;喷雾剂例如但不限于口腔喷雾用、鼻腔喷雾用、局部皮肤喷雾用等的喷雾剂;气雾剂例如但不限于肺吸入用气雾剂、局部皮肤用气雾剂等;滴鼻剂例如但不限于滴鼻用溶液、滴鼻用凝胶等;粉雾剂例如但不限于口腔用粉雾剂、鼻腔用粉雾剂、局部皮肤用粉雾剂等。这些制剂的制备工艺是本领域技术人根据其已有知识或参考相关教科书或工具书而可以制备的。
虽然本发明药物组合物的每单位剂量中所包含的活性成分的量可以参考式I化合物的临床用药剂量确定,但是在本发明的具体情况下,该活性成分的量显然是可以作进一步的扩展的,以适合于发明实施。
如本文所述的,慢性阻塞性肺疾病(COPD)是指一组以基本不可逆的慢性气道阻塞为特征的临床疾病。COPD支气管阻塞的主要病理生理机制包括由迷走神经控制的粘膜高分泌以及由胆碱能机制诱发的支气管平滑肌张力增加。抗胆碱药具有支气管扩张作用、分泌抑制作用和降低迷走神经张力的作用,可有效改善COPD患者的肺功能、运动耐力、生活质量减少急性加重频率(韩伟。抗胆碱药在COPD治疗中的作用。世界临床药物,2003,24(2):85-88。)。
如本文所述的,感冒是最常见的人类疾病。由于缺乏有效的预防手段和抗病毒药物,对感冒的主要治疗方法为对症治疗,即通过使用抗组胺药物抑制、镇咳药物或外周血管收缩药物抑制流涕、抑制咳嗽或解除鼻腔充血来减轻感冒症状。抗胆碱药物如异丙托溴铵能够通过抑制呼吸道腺体分泌,有效减轻流涕及鼻充血症状(Hayden FG,Diamond L,WoodPB,Korts DC,Wecker MT.Effectiveness and safety of intranasalipratropiumbromide in common colds.A randomized,double-blind,placebo-controlledtrial.Ann Intern Med 1996;125:89-97.)。
如本文所述的,术语“麻醉前用药”是指通过在麻醉前使用安定镇静药、催眠药、镇痛药和/或抗胆碱药等使病人情绪安定,减少麻醉药的用量,减少副作用,减少上呼吸道的分泌物,抑制恶心与呕吐,增强麻醉效果。抗胆碱药如阿托品和东莨碱等能减少呼吸道分泌,保持呼吸道通畅,常用于吸入麻醉前的术前用药。
本发明的一个方面涉及含有式所示的戊乙奎醚光学异构体的季铵盐作为活性成分的药物组合物。该药物组合物可根据给药途径配成各种适宜的剂型。使用一种或多种生理学上可接受的载体,包含赋形剂和助剂,它们有利于将活性化合物加工成可以在药学上使用的制剂。适当的制剂形式取决于所选择的给药途径,可以按照本领域熟知的常识进行制造。
本发明的另一个方面涉及含有式I所示的戊乙奎醚光学异构体的季铵盐及其药学可接受的盐作为活性成分的药物组合物作为慢性阻塞性肺病治疗药物、感冒治疗药物、麻醉前用药等的医药用途。可以通过口服、非肠道或局部给药的方式给药。可以口服的药物制剂包括胶囊剂和片剂等;病人吞咽有困难时,也可以采用舌下片或者其他非吞咽的方式给药。非肠道剂型可以是注射剂或粉针剂。局部给药的剂型可以使喷雾剂、滴剂或粉雾剂。
本发明的化合物可以以非溶剂合物和溶剂合物的形式存在,包括水合形式,例如半水合物。一般来说,对于本发明的目的,与药学可接受的溶剂如水、乙醇等的溶剂合物形式与非溶剂合物形式相当。
本发明的化合物还可形成药学可接受的盐,例如酸加成盐。例如,氮原子可与酸成盐。用于成盐的合适酸的实例是盐酸、硫酸、磷酸、乙酸、柠檬酸、草酸、丙二酸、水杨酸、苹果酸、富马酸、琥珀酸、抗坏血酸、马来酸、甲磺酸、氢溴酸、酒石酸、葡萄糖酸、对甲苯磺酸、苯甲酸、乳酸和本领域技术人员公知的其他矿物酸和羧酸。这些盐是通过以常规方式使游离碱形式与足量的所需酸相接触而产生盐来制备的。用合适的稀碱水溶液如氢氧化钾、碳酸钾、氨水和碳酸氢钠的稀水溶液处理所得的盐,可使游离碱形式再生。各游离碱形式与它们各自的盐形式在某些物理性质(如在极性溶剂中的溶解度)上稍有不同,但对于本发明目的,各酸式盐与它们各自的游离碱形式相当。(参见例如S.M.Berge,etal.,“Pharmaceutical Salts,”J.Pharm.Sci.,66:1-19(1977),其通过引用并入本文。
本文所用的术语“组合物”意指包括包含指定量的各指定成分的产品,以及直接或间接从指定量的各指定成分的组合产生的任何产品。
本发明的化合物可以以衍生自无机酸或有机酸的药物可接受盐的形式使用。词语“药学可接受的盐”指在可靠的医学判断范围内,适合用于与人类和低等动物的组织接触而不出现过度的毒性、刺激、过敏反应等,且与合理的效果/风险比相称的盐。药学可接受的盐是本领域公知的。例如,S.M.Berge等在J.Pharmaceutical Sciences,1977,66:1中对药学可接受的盐进行了详细描述。所述盐可通过使本发明化合物的游离碱官能度与合适的有机酸反应,在本发明化合物的最终分离和纯化过程中原位制备或者单独制备。代表性的酸加成盐包括但不限于乙酸盐、己二酸盐、海藻酸盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、二葡糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、富马酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐(异硫代硫酸盐,isothionate)、乳酸盐、马来酸盐、甲磺酸盐、烟酸盐、2-萘磺酸盐、草酸盐、棕榈酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、磷酸盐、谷氨酸盐、碳酸氢盐、对甲苯磺酸盐和十一烷酸盐。同样,碱性含氮基团可用以下物质季铵化:低级烷基卤化物如甲基、乙基、丙基和丁基的氯化物、溴化物和碘化物;硫酸二烷基酯如硫酸二甲酯、二乙酯、二丁酯和二戊酯;长链卤化物如癸基、十二烷基、十四烷基和十八烷基的氯化物、溴化物和碘化物;芳基烷基卤化物如苄基溴和苯乙基溴及其他。因此得到可溶于或分散于水或油的产品。可用来形成药学可接受的酸加成盐的酸实例包括无机酸如盐酸、氢溴酸、硫酸和磷酸,以及有机酸如草酸、马来酸、琥珀酸和柠檬酸。
供局部给予本发明化合物的剂量形式包括散剂、喷雾剂、软膏剂和吸入剂。在无菌条件下将活性化合物与药学可接受的载体和任何所需的防腐剂、缓冲剂或推进剂混合。眼用制剂、眼软膏剂、散剂和溶液剂也被考虑在本发明范围内。
可改变本发明药物组合物中各活性成分的实际剂量水平,以便所得的活性化合物量能有效针对具体患者、组合物和给药方式得到所需的治疗反应。剂量水平须根据具体化合物的活性、给药途径、所治疗病况的严重程度以及待治疗患者的病况和既往病史来选定。但是,本领域的做法是,化合物的剂量从低于为得到所需治疗效果而要求的水平开始,逐渐增加剂量,直到得到所需的效果。
当用于上述治疗或其他治疗时,治疗有效量的一种本发明化合物可以以纯形式应用,或者以药学可接受的盐、酯或前药形式(在存在这些形式的情况下)应用。或者,所述化合物可以以含有该目的化合物与一种或多种药物可接受赋形剂的药物组合物给药。词语“治疗有效量”的本发明化合物指以适用于任何医学治疗的合理效果/风险比治疗障碍的足够量的化合物。但应认识到,本发明化合物和组合物的总日用量须由主诊医师在可靠的医学判断范围内作出决定。对于任何具体的患者,具体的治疗有效剂量水平须根据多种因素而定,所述因素包括所治疗的障碍和该障碍的严重程度;所采用的具体化合物的活性;所采用的具体组合物;患者的年龄、体重、一般健康状况、性别和饮食;所采用的具体化合物的给药时间、给药途径和排泄率;治疗持续时间;与所采用的具体化合物组合使用或同时使用的药物;及医疗领域公知的类似因素。例如,本领域的做法是,化合物的剂量从低于为得到所需治疗效果而要求的水平开始,逐渐增加剂量,直到得到所需的效果。
本发明还提供包含与一种或多种无毒药物可接受载体配制在一起的本发明化合物的药物组合物。所述药物组合物可特别专门配制成以固体或液体形式供口服给药、供胃肠外注射或供直肠给药。
本发明的药物组合物可通过口服、直肠、胃肠外、池内、阴道内、腹膜内、局部(如通过散剂、软膏剂或滴剂)、口颊给予人类和其他哺乳动物,或者作为口腔喷雾剂或鼻腔喷雾剂给予。本文所用术语“胃肠外”指包括静脉内、肌肉内、腹膜内、胸骨内、皮下和关节内注射和输液的给药方式。
在另一个方面,本发明提供包含本发明成分和生理可耐受稀释剂的药物组合物。本发明包括一种或多种上述化合物,其与一种或多种无毒生理可耐受或可接受的稀释剂、载体、辅料或媒介物(本文将它们统称为稀释剂)一起配制成组合物,以供胃肠外注射、鼻内传递、以固体或液体形式口服给药、直肠或局部给药等等。
适合于胃肠外注射的组合物可包括生理上可接受的无菌含水或非水溶液剂、分散剂、混悬剂或乳剂,及供重构成无菌可注射溶液剂或分散剂的无菌散剂。合适的含水或非水载体、稀释剂、溶剂或媒介物的实例包括水、乙醇、多元醇(丙二醇、聚乙二醇、甘油等)、植物油(如橄榄油)、可注射有机酯如油酸乙酯及它们的合适混合物。
这些组合物也可含有辅料,如防腐剂、湿润剂、乳化剂和分散剂。通过各种抗细菌剂和抗真菌剂,例如尼泊金酯类、三氯叔丁醇、苯酚、山梨酸等,可确保防止微生物的作用。还期望包括等渗剂,例如糖类、氯化钠等。通过使用能延迟吸收的物质,例如单硬脂酸铝和明胶,可达到可注射药物形式的延长吸收。
混悬剂中除活性化合物外还可含有悬浮剂,例如乙氧基化异十八醇、聚氧乙烯山梨醇和聚氧乙烯失水山梨糖醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂和黄蓍胶或者这些物质的混合物等。
在一些情况下,为延长药物的作用,期望减慢皮下或肌内注射药物的吸收。这可通过使用水溶性差的晶体或无定形物质的液体混悬剂来实现。这样,药物的吸收速度取决于其溶解速度,而溶解速度又可取决于晶体大小和晶型。或者,胃肠外给药的药物形式的延迟吸收通过将该药物溶解于或悬浮于油媒介物中来实现。
可注射贮库制剂形式可通过在生物可降解聚合物如聚丙交酯-聚乙交酯(polylactide-polyglycolide)中形成药物的微胶囊基质来制备。可根据药物与聚合物之比和所采用的具体聚合物的性质,对药物释放速度加以控制。其他生物可降解聚合物的实例包括聚原酸酯类(poly(orthoesters))和聚酐类(poly(anhydrides))。可注射贮库制剂也可通过将药物包埋于能与身体组织相容的脂质体或微乳中来制备。
可注射制剂可例如通过用滤菌器过滤或通过掺入无菌固体组合物形式的灭菌剂来灭菌,所述固体组合物可在临用前溶解或分散于无菌水或其他无菌可注射介质。
供口服给药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,活性化合物可与至少一种惰性的药物可接受赋形剂或载体如柠檬酸钠或磷酸二钙和/或以下物质混合:a)填充剂或增量剂如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇和硅酸;b)粘合剂如羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯树胶;c)保湿剂如甘油;d)崩解剂如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐和碳酸钠;e)溶液阻滞剂如石蜡;f)吸收加速剂如季铵化合物;g)湿润剂如鲸蜡醇和甘油单硬脂酸酯;h)吸附剂如高岭土和膨润土以及i)润滑剂如滑石粉、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠和它们的混合物。在胶囊剂、片剂和丸剂的情况下,所述剂型中也可包含缓冲剂。
相似类型的固体组合物使用赋形剂例如乳糖及高分子量聚乙二醇等,也可用作软胶囊和硬胶囊中的填充物。
片剂、糖衣丸剂(dragees)、胶囊剂、丸剂和颗粒剂的固体剂型可与包衣和壳料如肠溶衣材和医药制剂领域公知的其他衣材一起制备。这些固体剂型可任选含有遮光剂,且其组成还可使其只是或优先地在肠道的某个部位任选以延迟方式释放活性成分。可以使用的包埋组合物的实例包括高分子物质和蜡类。
如果适合,活性化合物也可与一种或多种上述赋形剂配成微囊形式。
供口服给药的液体剂型包括药学可接受的乳剂、溶液剂、混悬剂、糖浆剂和酏剂。液体剂型除含有活性化合物外还可含有本领域常用的惰性稀释剂,例如水或其他溶剂,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、油类(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(tetrahydrofurfuryl alcohol)、聚乙二醇和脱水山梨糖醇的脂肪酸酯及它们的混合物。
口服组合物除包含惰性稀释剂外还可包含辅料,例如湿润剂、乳化和悬浮剂、甜味剂、矫味剂和香味剂。
供直肠或阴道给药的组合物优选是栓剂。栓剂可通过将本发明化合物与合适的非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,它们在室温下为固体,但在体温下则为液体,因此可在直肠腔或阴道腔内熔化而释放出活性化合物。
本发明化合物也可以脂质体形式给药。如本领域所公知,脂质体通常用磷脂或其他脂类物质制得。脂质体由分散于含水介质中的单层或多层水化液晶所形成。任何能够形成脂质体的无毒、生理上可接受和可代谢的脂质均可使用。脂质体形式的本发明组合物除含有本发明化合物外,还可含有稳定剂、防腐剂、赋形剂等。优选的脂类是天然和合成的磷脂和磷脂酰胆碱(卵磷脂),它们可单独或者一起使用。形成脂质体的方法是本领域公知的。参见例如Prescott,Ed.,Methods in Cell Biology,Volume XIV,Academic Press,NewYork,N.Y.(1976),p.33。
本文所用的术语“药学可接受的前药”代表本发明化合物的前药,其在可靠的医学判断范围内适合用于与人类和低等动物的组织接触而不出现过度的毒性、刺激、过敏反应等,与合理的效果/风险比相称且对其预定用途有效,在可能的情况下还代表本发明化合物的两性离子形式。本发明的前药可例如通过在血液中水解而在体内快速转化成上式的母体化合物。充分讨论提供于T.Higuchi and V.Stella,Pro-drugs as NovelDeliverySystems,V.14 of the A.C.S.Symposium Series以及Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,AmericanPharmaceutical Associationand Pergamon Press(1987),其通过引用并入本文。
本发明式I的光学异构体优选地可以参考以下路线来合成:
以(R)-扁桃酸为手性模板,用三氟甲磺酸(TfOH)作为催化剂,在30~35℃下,扁桃酸分子中的羟基首先与特戊醛(Pivaldehyde)进行羟醛缩合,形成的半缩醛分子中的羟基再与羧基进行分子内的缩合,反应5~10小时,立体选择性得到内酯产物(2R,5R)-2-特丁基-5-苯基-1,3-二噁烷-4-酮(II),溶剂用正戊烷。接着,环戊酮与烯醇形式的II在-78℃下进行立体控制性的Michael加成反应,加入金属锂试剂(优选的使用二(三甲硅基)氨基锂,LHMDS),得到加成产物III;化合物III经脱水、脱保护、氢化反应后,得到(R)-α-苯基-α-环戊基-α-羟基乙酸(VI);VI在四氢呋喃中用LiAlH4还原,得到双羟基化合物VII;VII与对甲苯磺酰氯反应合成对甲苯磺酸单酯,经分子内的关环反应,得到光学纯度在98%以上的合成关键中间体(R)-1-苯基-1-环戊基-1,2-环氧乙烷(IX);IX在氢化钠作用下,与3-(R)-奎宁环醇反应,得到光学异构体3-(R)-[2′-(R)-2′-羟基-2′-环戊基-2′-苯基乙氧基]-奎宁环烷(X),X与卤代烷反应,得到相应的季铵盐I。
虽然本发明提供了上述优选的合成方案,但是,本领域技术人员清楚,本发明并不排除任何其它可行的方式。
具体实施方式
下面通过具体的实施例进一步说明本发明,但是,应当理解为,这些实施例仅仅是用于更详细具体地说明之用,而不应理解为用于以任何形式限制本发明。
本发明对试验中所使用到的材料以及试验方法进行一般性和/或具体的描述。虽然为实现本发明目的所使用的许多材料和操作方法是本领域公知的,但是本发明仍然在此作尽可能详细描述。本领域技术人员清楚,在下文中,如果未特别说明,本发明所用材料和操作方法是本领域公知的。
实施例1、(R)-α-苯基-α-环戊基-1,2-环氧乙烷(IX)的制备
1.1、(2R,5R)-2-特丁基-5-苯基-1,3-二噁烷-4-酮(II)的制备
将R-扁桃酸20g(0.13mol)加入200mL正戊烷中,然后加入特戊醛21.2mL(含量80%,0.16mol,购自Fluka公司),再加入三氟甲磺酸0.5mL,使该混合物回流6小时。用分水器除去生成的水。冷却至室温,加入8%碳酸氢钠溶液100mL,减压蒸馏,除去正戊烷,过滤,得到(2R,5R)-2-特丁基-5-苯基-1,3-二噁烷-4-酮(II),产量27.1g,熔点100-102℃,产率95%,元素分析,理论值%:C 70.89,H 7.32;实验值%:C 70.81,H 7.39。1H-NMR,δ(ppm,CDCl3):1.10(s,9H),5.25(s,1H),5.38(s,1H),7.47(m,5H)。
1.2、(2R,5S)-2-特丁基-5-苯基-5-(环戊基-1-羟基)-1,3-二噁烷-4-酮(III)的制备
将10g(45mmol)的(2S,5S)-2-特丁基-5-苯基-1,3-二噁烷-4-酮(II)溶于70mL干燥四氢呋喃中,冷却至-78℃,加入60mL的二(三甲硅基)氨基锂(在四氢呋喃中的溶液,1.0M)。搅拌下滴加环戊酮65mmol,将反应搅拌2小时,滴加15mL饱和磷酸氢钠溶液和200mL饱和氯化铵溶液。分离有机层,水层用乙酸乙酯萃取。将合并的有机层干燥,蒸馏,除去溶剂,得到(2R,5S)-2-特丁基-5-苯基-5-(环戊基-1-羟基)-1,3-二噁烷-4-酮(III),产量10.5g,产率74%。1H-NMR,δ(ppm,CDCl3):0.88(s,9H),1.52-2.06(m,8H),5.52(s,1H),7.31(m,3H),7.78(dd,J=1.5,8.3Hz,2H)。
1.3、(2R,5R)-2-特丁基-5-苯基-5-(1-环戊烯基)-1,3-二噁烷-4-酮(IV)的制备
将3.6g(10mmol)的(2S,5R)-2-特丁基-5-苯基-5-(环戊基-1-羟基)-1,3-二噁烷-4-酮(III)溶于70mL干燥四氢呋喃溶液中,冷却到0℃,加入2mL氯化亚砜和3mL吡啶,将反应搅拌1小时。加入60mL饱和氯化铵溶液,分出有机层,水层用乙酸乙酯萃取,合并有机层,干燥,蒸馏,除去溶剂,得到(2R,5R)-2-特丁基-5-苯基-5-(1-环戊烯基)-1,3-二噁烷-4-酮(IV),产量3.7g,产率95%。1H-NMR,δ(ppm,CDCl3):1.07(s,9H),1.92-2.50(m,6H),5.22(s,1H),6.03(m,1H),7.25(m,4H),7.59(m,1H)。
1.4、(R)-α-苯基-α-环戊基-α-羟基乙酸(VI)的制备
将2.34g(8.18mmol)的(2R,5R)-2-特丁基-5-苯基-5-(1-环戊烯基)-1,3-二噁烷-4-酮(IV)溶于20mL甲醇和10mL水的混合溶液中。加入4.58g的KOH,在搅拌下使反应回流3小时。冷却至室温,用正庚烷萃取,水相用1N HCl酸化,再用乙酸乙酯萃取,干燥,蒸馏,除去溶剂,得到(R)-α-苯基-α-环戊烯基-α-羟基乙酸(V),产量1.64g,产率92%,1H NMR,δ(ppm,CDCl3):1.81(m,2H),2.29(m,4H),5.59(s,1H),7.24(t,J=6.8Hz,1H),7.32(t,J=7.1Hz,2H),7.48(d,J=7.8Hz,1H)。将1.16g(5.3mmol)的(R)-α-苯基-α-环戊烯基-α-羟基乙酸(V)溶于50mL甲醇中,加入0.2g的10%Pd/C,在1atm下用H2还原8小时。过滤,减压蒸馏,除去溶剂,得到(R)-α-苯基-α-环戊基-α-羟基乙酸(VI)1.08g,收率93%。(MeOH,c=3),熔点:118-119℃。
1.5、(R)-α-苯基-α-环戊基-α-羟基对甲苯磺酸乙酯(VIII)的合成
在N2保护下,将含有2.2g(0.01mol)的(R)-α-苯基-α-环戊基-α-羟基乙酸(VI)的10mL无水THF溶液缓慢滴加到含LiAlH4(0.02mol)的20mL无水THF溶液中,搅拌下缓慢升温至回流,反应3h。冷却,小心滴加2mL饱和NaHCO3溶液,再滴加10mL的2N的NaOH溶液。分离有机相,水相用乙醚提取。将合并的有机相用饱和食盐水洗涤,用无水硫酸钠干燥。减压蒸馏,除去溶剂,得到(R)-α-苯基-α-环戊基-α-羟基乙醇(VII)为无色针状晶体,2.06g,收率100%,熔点:49-50℃。1H NMR,δ(ppm,CDCl3):1.23-1.71(m,8H),2.02(brs,1H),2.20-2.28(m,1H),3.76(d,J=11Hz,1H),3.94(d,J=11Hz,1H),7.23-7.27(m,1H),7.34-7.44(m,4H)。
在干燥的100mL三口瓶中,加入1.89g的(R)-α-苯基-α-环戊基-α-羟基乙醇(VII)与50mL干燥的CH2Cl2,冷却至0℃,加入对甲苯磺酸3.42g(18mmol)。搅拌下滴加三乙胺2.43g(24mmol)。滴加完毕,在0℃下搅拌2h,反应混和液略呈黄色。然后小心加入饱和NaHCO3溶液,将反应旋转蒸发以除去CH2Cl2,用乙醚萃取,干燥,石油醚重结晶,得到(R)-α-苯基-α-环戊基-α-羟基对甲苯磺酸乙酯(VIII)为白色絮状固体,2.61g,收率79%。1H NMR,δ(ppm,CDCl3):1.21-1.27(m,2H),1.35-1.70(m,6H),2.17(s,1H),2.24(m,1H)2.40(s,3H),7.21-7.27(m,8H),7.58(d,J=8Hz 2H)。
1.6、(R)-1-苯基-1-环戊基-1,2-环氧乙烷(IX)的制备
在干燥的50mL三口瓶中,加入1.0g的(R)-α-苯基-α-环戊基-α-羟基对甲苯磺酸乙酯(VIII)和20mL无水甲醇。在搅拌下,加入过量无水K2CO3。在室温下将反应搅拌30min,加水稀释,用乙醚萃取,干燥,蒸除溶剂,得到(R)-1-苯基-1-环戊基-1,2-环氧乙烷(IX),无色液体,0.5g,收率100%。1H NMR,δ(ppm,CDCl3):1.25-1.68(m,8H),2.58-2.63(m,1H),2.66(d,J=5Hz,1H),2.97(d,J=5Hz,1H),7.23-7.40(m,5H)。
实施例2、3-(R)-[2′-(R)-2′-羟基-2′-环戊基-2′-苯基乙氧基]-奎宁环烷(X)的制备
在氮气保护下,将0.6g(15mmol)的NaH置于干燥的三口烧瓶中,加入10mL的无水DMSO,搅拌5min后,滴加含有3-(R)-奎宁环醇1.8g(14.2mmol)的10mL DMSO溶液,在60℃下将反应搅拌1h。冷至室温,缓慢滴加(R)-α-苯基-α-环戊基-1,2-环氧乙烷(IX)2.61g(14mmol)在10mL的DMSO中的溶液。在50℃下将反应搅拌3h,冷却,小心滴加20mL水。用乙醚提取,用水洗涤,再用10%盐酸溶液洗涤醚层,合并水相;用40%的NaOH碱化所得的盐酸提取液,用乙醚萃取,用无水硫酸钠干燥,蒸馏,除去溶剂,得到X的无色液体,2.84g,收率65%,(MeOH,c=0.35)。1H NMR,δ(ppm,CDCl3):1.23-1.75(m,13H),1.96-1.99(m,2H),2.26-2.32(m,1H),2.52-2.77(m,5H),2.71(s,-OH,1H),2.89-2.95(m,1H),3.35-3.38(m,1H),3.58(d,J=9Hz,1H),3.71(d,J=9Hz,1H),7.29-7.42(m,5H)。
实施例3、N-甲基-3-(R)-[2′-(R)-2′-羟基-2′-环戊基-2′-苯基乙氧基]-奎宁环烷溴化物(I1)的制备
将X 3.15g(10mmol)溶于20ml丙酮,加入溴甲烷1.04g(11mmol)搅拌,50-60℃反应3-10小时,点板,至原料点消失,停止反应,降温至10-20℃,缓缓滴加无水乙醚至无固体析出,抽滤,真空干燥,得I13.89g,收率95%,(EtOH,c=0.01)。1H-NMR,δ(ppm,D2O):7.32(m,2H),7.21(m,2H),7.11(m,1H),4.28(m,1H),3.79(d,1H),3.71(br t,1H),3.46(d,1H),3.38(m,1H),3.11(m,1H),2.99(m,2H),2.84(m,2H),2.65(s,3H),2.24(m,1H),2.16(br,1H),1.80(m,1H),1.20-1.61(m,9H),0.94-1.09(m,2H)。
实施例4、N-乙基-3-(R)-[2′-(R)-2′-羟基-2′-环戊基-2′-苯基乙氧基]-奎宁环烷溴化物(I2)的制备
将X 3.15g(10mmol)溶于20ml丙酮,加入溴乙烷1.19g(11mmol)搅拌,50-60℃反应3-10小时,点板,至原料点消失,停止反应,降温至10-20℃,缓缓滴加无水乙醚至无固体析出,抽滤,真空干燥,得I23.99g,收率94%,(EtOH,c=0.01)。1H-NMR,δ(ppm,D2O):7.32(m,2H),7.21(m,2H),7.11(m,1H),3.78(d,1H),3.70(br t,1H),3.46(d,1H),3.29(m,1H),2.72-3.10(m,7H),2.25(m,1H),2.15(br s,1H),1.79(m,1H),0.98-1.60(m,11H),0.96(t,3H)。
实施例5、N-丙基-3-(R)-[2′-(R)-2′-羟基-2′-环戊基-2′-苯基乙氧基]-奎宁环烷溴化物(I3)的制备
将X 3.15g(10mmol)溶于20ml丙酮,加入溴丙烷1.34g(11mmol)搅拌,50-60℃反应3-10小时,点板,至原料点消失,停止反应,降温至10-20℃,缓缓滴加无水乙醚至无固体析出,抽滤,真空干燥,得I3,称重4.02g,收率92%,(EtOH,c=0.01)。1H-NMR,δ(ppm,D2O):7.32(m,2H),7.21(m,2H),7.11(m,1H),3.76(d,1H),3.67(br,1H),3.42(d,1H),3.27(m,1H),2.92-3.04(m,2H),2.70-2.80(m,4H),2.22(m,1H),2.11(brs,1H),1.74(m,1H),0.90-1.61(m,13H),0.64(t,3H)。
实施例6、N-环丙基-3-(R)-[2′-(R)-2′-羟基-2′-环戊基-2′-苯基乙氧基]-奎宁环烷溴化物(I4)的制备.
将X 3.15g(10mmol)溶于20ml丙酮,加入溴代环丙烷1.33g(11mmol)搅拌,50-60℃反应3-10小时,点板,至原料点消失,停止反应,降温至10-20℃,缓缓滴加无水乙醚至无固体析出,抽滤,真空干燥,得I4,称重4.02g,收率92%,(EtOH,c=0.01)。1H-NMR,δ(ppm,D2O):7.32(m,2H),7.21(m,2H),7.11(m,1H),4.28(m,1H),3.79(d,1H),3.71(br t,1H),3.46(d,1H),3.38(m,1H),3.11(m,1H),2.99(m,2H),2.84(m,2H),2.70(m,1H),2.24(m,1H),2.16(br,1H),1.80(m,1H),1.20-1.61(m,9H),0.94-1.09(m,2H),0.84(m,2H),0.56(m,2H).
实施例7、戊乙奎醚季铵盐B的制备
取盐酸戊乙奎醚0.5克,加水20ml溶解,然后以氨水碱化,用乙醚提取3次,每次20ml。合并提取液,蒸干,得到戊乙奎醚游离碱。
参照实施例4的方法,用戊乙奎醚游离碱与溴乙烷反应,得到戊乙奎醚的季铵盐B,收率85%。1H-NMR,δ(ppm,D2O):7.32-7.28(m,2H),7.20-7.25(m,2H),7.06-7.10(m,1H),3.78(d,0.5H),3.753d,0.5H),3.69(br t,1H),3.50(d,0.5H),3.47(d,0.5H),3.32-3.30(m,1H),2.70-3.08(m,7H),2.23-2.21(m,1H),2.14(br s,1H),1.79-1.76(m,1H),0.97-1.60(m,11H),0.94-0.91(m,3H);(乙醇为溶剂)。
实施例8、戊乙奎醚消旋体季铵盐B1和B2的制备
取盐酸戊乙奎醚0.5克,加水20ml溶解,然后以氨水碱化,用乙醚提取3次,每次20ml。合并提取液,蒸干,将残留物用甲醇溶解,点样于25X25cm的制备硅胶板上,用二氯甲烷∶甲醇∶氨水=8∶2∶0.1的混合溶剂展开,得到两条分离良好的色谱带;分别小心刮取两色谱带,分别用含1%氨水的甲醇溶液洗脱,得到戊乙奎醚消旋体C1(硅胶薄层层析Rf=0.65,展开剂:二氯甲烷∶甲醇∶氨水=8∶2∶0.1)0.16克和C2(硅胶薄层层析Rf=0.59,展开剂:二氯甲烷∶甲醇∶氨水=8∶2∶0.1)0.15克。
参照实施例4的方法,用C1与溴乙烷反应,得到戊乙奎醚消旋体C1的季铵盐B1,收率91%,1H-NMR,δ(ppm,D2O):7.30(m,2H),7.23(m,2H),7.08(m,1H),3.75(d,1H),3.69(br t,1H),3.48(d,1H),3.32(m,1H),2.70-3.08(m,7H),2.22(m,1H),2.14(br s,1H),1.78(m,1H),0.97-1.60(m,11H),0.94t,3H);(乙醇为溶剂)。
参照实施例4的方法,用C2与溴乙烷反应,得到戊乙奎醚消旋体C2的季铵盐B2,收率89%,1H-NMR,δ(ppm,D2O):7.31(m,2H),7.21(m,2H),7.10(m,1H),3.78(d,1H),3.69(br t,1H),3.45(d,1H),3.28(m,1H),2.71-3.10(m,7H),2.23(m,1H),2.14(br s,1H),1.76(m,1H),0.98-1.60(m,11H),0.96(t,3H);(乙醇为溶剂)。
实施例9、M受体的竞争性结合实验
利用稳定表达M1至M5受体亚型的CHO细胞制备膜蛋白,以[3H]-N-甲基东莨菪碱(NMS)为配基进行竞争性结合实验,测定戊乙奎醚光学异构体季铵盐及消旋体季铵盐竞争抑制作用的IC50,比较其对不同亚型M受体的亲和力,其实验结果见表1所示。
表1戊乙奎醚光学异构体及消旋体季铵盐
对不同亚型M受体的竞争性结合实验结果(IC50,M)
实验结果表明,化合物I1-I4对M3亚型受体表现出较高的亲和性,而对其它亚型的M受体,特别是对在心脏分布较高的M2受体的亲和力较小,显示出较高的选择性,将具有较小的心脏副作用;戊乙奎醚季铵盐B及消旋体季铵盐B1和B2对不同亚型的M受体选择性较小。
实施例10、对气管平滑肌收缩的抑制作用
以豚鼠气管螺旋条作标本,用MedLab生物信号仪记录气管条的张力变化。用溴化乙酰胆碱诱发气管条收缩,然后给予戊乙奎醚光学异构体及消旋体的季铵盐,测量它们抗气管平滑肌收缩作用。
表2戊乙奎醚光学异构体及消旋体季铵盐
对ACh诱导豚鼠气管平滑肌收缩的抑制作用
实施例11、对唾液腺分泌的抑制作用
取昆明种小鼠,雌雄各半,体重18-22g,随机分组,每组10只。预先注射不同剂量的戊乙奎醚光学异构体及消旋体的季铵盐,15min后,皮下给予氧化震颤素(3mg/kg),观察小鼠唾液腺分泌的有无(给药后15-40min内,用滤纸沾小鼠口唇部,以滤纸变湿为阳性指标),对照组只给予相同体积的生理盐水及同等剂量氧化震颤素,Bliss法计算ED50。
表3戊乙奎醚光学异构体及消旋体季铵盐
对氧化震颤素致小鼠唾液分泌的抑制作用
实施例12、对大鼠心率和血压的影响
将Wistar大鼠随机分组,10只/组,雌雄各半,用30mg/kg戊巴比妥钠溶液静脉注射麻醉。分离左侧股总动脉作动脉插管,连接动脉压力探头,右上、右下及左下肢皮下插入针状电极。皮下注射戊乙奎醚光学异构体的季铵盐或其消旋体的季铵盐,剂量分别为其抑制唾液分泌作用的ED50(I2:0.12mg/kg,B:0.81mg/kg,B1:1.4mg/kg,B2:0.37mg/kg)。记录给药后30分钟的血压和心率。以60s内平均值作为评价指标,试验在室温22~23℃进行。
表4戊乙奎醚光学异构体及消旋体季铵盐对大鼠心率和血压的影响
测定指标 | 溶剂 | I2 | B | B1 | B2 |
心率(次/秒) | 343±58 | 339±36 | 314±35 | 282±25 | 296±30 |
收缩压(mmHg) | 138±13 | 137±13 | 130±9 | 121±11 | 129±10 |
舒张压(mmHg) | 94±12 | 93±11 | 94±8 | 93±15 | 95±13 |
由表4的结果可见,在抑制唾液分泌的等效剂量(为相应化合物的ED50值)下,戊乙奎醚季铵盐B及消旋体季铵盐B1和B2能够显著降低大鼠的心率和收缩压,光学异构体的季铵盐I2对心率和收缩压无显著影响;三者对舒张压均无显著影响。因此,光学异构体的季铵盐作为M3受体拮抗剂的心脏副作用较小。
实施例13、对阈下催眠剂量戊巴比妥钠中枢抑制作用的影响
昆明种小鼠,雌雄各半,体重18-22g,随机分组,每组10只。提前15min灌胃给药戊乙奎醚光学异构体或其季铵盐,腹腔给予阈下催眠剂量戊巴比妥钠(30mg/kg),以小鼠30min内的翻正消失作为观察指标,对照组只给予相同体积的生理盐水及阈下催眠剂量戊巴比妥钠,Bliss法计算ED50±95%CL(95%可信限)。
表5戊乙奎醚光学异构体及季铵盐
对阈下催眠剂量戊巴比妥钠中枢抑制作用的影响
可见由表可以看出,戊乙奎醚光学异构体的季铵盐没有中枢抑制作用。
Claims (9)
1.戊乙奎醚光学异构体的季铵盐,其选自:
N-乙基-3-(R)-[2′-(R)-2′-羟基-2′-环戊基-2′-苯基乙氧基]-奎宁环烷溴化物(I2);
N-丙基-3-(R)-[2′-(R)-2′-羟基-2′-环戊基-2′-苯基乙氧基]-奎宁环烷溴化物(I3);和
N-环丙基-3-(R)-[2′-(R)-2′-羟基-2′-环戊基-2′-苯基乙氧基]-奎宁环烷溴化物(I4)。
2.权利要求1所述的化合物,其用作选择性M受体拮抗剂。
3.权利要求2所述的化合物,其用作选择性M3受体拮抗剂。
4.权利要求1所述的化合物,其用作治疗慢性阻塞性肺病的药物、治疗感冒的药物、和/或麻醉前给药的药物。
5.权利要求1所述化合物在制备作为选择性M受体拮抗剂的药物中的用途。
6.权利要求5的用途,其中所述药物作为选择性M3受体拮抗剂。
7.权利要求1所述化合物在制备作为治疗慢性阻塞性肺病的药物、治疗感冒的药物、和/或麻醉前给药的药物中的用途。
8.一种药物组合物,其包含作为活性成分的治疗有效量的权利要求1所述化合物,和任选的药学可接受的载体或赋形剂。
9.权利要求6所述的药物组合物,其为片剂、胶囊剂、注射剂、喷雾剂、气雾剂、滴鼻剂或粉雾剂。
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