CN1120841C - 新颖药物组合物及其用途 - Google Patents
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Abstract
(内,顺式)-(-)-3-(3-羟基-1-氧基-2-苯丙氧基)-8-甲基-8-(甲基乙基)-8-氮鎓二环[3,2,1]辛烷的L-(-)-对映体由于具有显著强力和持久的效果,适于作为以吸入方式给药以治疗呼吸道的活性物质。
Description
本发明是关于(内,顺式)-(-)-3-(3-羟基-1-氧基-2-苯丙氧基)-8-甲基-8-(甲基乙基)-8-氮鎓二环[3,2,1]辛烷盐类的吸入治疗的用途。这些化合物可用作具有高效、并特别是长期有效的支气管解痉剂。本发明也关于该盐类在制备治疗气喘制剂中的用途。
上述化合物的消旋物(以溴的形式)是以溴化异丙托品的名称作为抗胆碱能药物的活性物质销售。
目前已发现并且令人惊讶的是,该消旋物、左旋和右旋对映体的活性性质明显不同,并且在实质上具有许多与基准基本不同的特性。正对映体(eutomer)(即具有所希望的或要找寻的活性的对映体)是L-(-)-对映体。CHO-HM受体上的受体结合研究已表明L-(-)-对映体的亲和力大约为消旋物的2倍。这比率相当于在观察比较对映体和消旋物的效果时常常得到的。
然而,我们意外地发现在本情况下,对狗(已麻醉)以吸入方式摄入重量比为1∶2的正对映体和消旋物后所进行的比较,它表明正对映体不仅具有较高效力,而且其活性期也相当地长。
图1中的曲线图表明抑制支气管痉挛百分比和时间的函数图。虚线(曲线B)代表(内,顺式)-(-)-3-(3-羟基-1-氧基-2-苯丙氧基)-8-甲基-8-(甲基乙基)-8-氮鎓二环[3,2,1]辛烷的曲线图,而实线(曲线A)则是使用相应溴化氢的消旋物的曲线图。由于给药5μg纯L-(-)-对映体,因此消旋物给药量为1.0μg。该实验对五只试验动物使用纯L-(-)-对映体(BIIM 150 BR),而消旋物则给药七只试验动物而进行的。
图1表示对狗施用溴化异丙托品烟雾剂以抑制乙酰胆碱所诱发的支气管痉挛(曲线A),在约10分钟后达到约55%的峰值,而在60分钟后回复到其最初量。相同量的正对映体,如包含在消旋物中,(曲线B)在约10分钟后达到60%的抑制作用,而在180分钟后并不回复到其起始量。
测量半衰期表示该正对映体BIIM 150 BR的活性时间约为4倍之久。
由消旋物通过结合使用高压液体色谱法和再结晶后,所获得的正对映体实际上的纯度很高。使用于本发明目的的“正对映体”一词也包括L-(-)-对映体的高度浓缩产物(约90%以上),优选含有约95%以上,而97%以上特佳。阴离子和起始化合物的相当。若有需要,可以进行互换。
以下实例是说明L-(-)-和D-(+)-对映体的制备:
使用高压液相色谱法,在Chiralcel OD柱(250×20mm)上,以由600己烷、250甲醇、150乙醇和1饱和NaBr醇溶液(V∶V∶V∶V,通流速率6毫升/分钟,波长254nm;敏感度0.5A.U.F.S.,含有1克溴化异而托品/5毫升乙醇+5毫升流动相+2.5毫升浓醋酸)组成的流动相,分离出18克溴化异丙托品。
使用重复色谱法和再结晶作用由乙醇获得熔点为239-40℃(分解)旋光率[α]20 D=-24.06°(c=1.014;H2O),对映体纯度97.4%(HPLC)的白色L-(-)-对映体晶体,以及熔点为238-39℃(分解),旋光率[α]20 D=+24.06°(c=1.018;H2O),对映纯度98.9%(HPLC)的白色D-(+)-对映体晶体。元素分析和光谱都表明这些化合物是存在的。
各种盐类型态的L-(-)-正对映体由于是抗胆碱能的,因此适于以吸入方式治疗慢性阻塞性支气管炎和气喘,而且没有副作用。
关于用途方面,该活性物质可以和已知的赋形剂和/或载剂处理而形成传统的盖仑制剂,例如用于吸入的溶液,液化推进器气体中的悬浮液,含有脂质体或原脂质体的制剂,和供传统吸入器用的吸入的粉末(必要时在胶囊中)。
制剂实例(用量以重量百分比计算):1.计量烟雾剂
本发明的活性物质 0.005
山梨聚糖三油酸酯 0.1
一氟三氯甲烷和
二氟二氯甲烷2∶3 加至100
将该悬浮液转移到有计量阀的一般烟雾剂容器内。例如,每次启动释放50μl悬浮液。若有需要,该活性物质也可以以较高剂量存在(例如0.02重量百分比)。
除了氯化推进器气体外,也可使用其它的推进器气体,如TG 134a(1,1,1,2-四-氟乙烷)和/或TG 227(1,1,1,2,3,3,3-七-氟丙烷)。2.吸入用粉末
将微粉化的活性物质粉末(颗粒度为0.5至7μm)与微粉化的乳糖混合,并必要时和其它添加物一起装入硬凝胶胶囊内。例如,每一胶囊内装入0.01毫克活性物质和5毫克乳糖。使用一般吸入器,例如DE-A 3345772所述即可吸入该粉末。3.吸入用溶液
也可以使用该活性物质的水溶液,例如,根据WO 91/14468的装置制造烟雾剂。例如,每次喷射剂量可给药0.005毫克活性物质。
根据本发明的活性物质也可以和其它活性物质一起而有利地使用于呼吸道的治疗。需要特别注意β2-拟似物;这些拟似物的结合用量是其单独使用时的50-100%的剂量。
下列物质也必须加以注意:班布特罗(Bambuterol)双甲苯喘定(Bitolterol)脲喘宁(Carbuterol)双氯醇胺(Clenbuterol)酚丙喘宁(Fenoterol)福莫特罗(Formoterol)双喘定(Hexoprenaline)三丁喘宁(Ibuterol)吡丁醇(Pirbuterol)异丙喹喘宁(Procaterol)瑞普特罗(Reproterol)舒喘宁(Salbutamol)沙美特罗(Salmeterol)磺丁喘宁(Sulfonterol)叔丁喘宁(Terbutaline)叔丁氯喘通(Tulobuterol)1-(2-氟-4-羟苯基)-2-[4-(1-苯并咪唑基)-2-甲基-2-丁氨基]乙醇赤-5′-羟基-8′-(1-羟基-2-异丙氨基丁基)-2H-1,4-苯并噁嗪基-3-(4H)-酮1-(4-氨基-3-氯-5-三氟甲基苯基)-2-叔丁氨基)-乙醇1-(4-乙氧羰氨基-3-氰基-5-氟苯基)-2-(叔-丁氧基)-乙醇
可吸入使用的类固醇,例如丁地去炎松,氯地米松(或17,21-二丙酸酯),地塞米松-21-异烟酸酯,9-去氟肤轻松和抗过敏的药剂,如色甘酸二钠盐,奈多罗米(Nedocrolmil),依匹斯汀(Epinastine)也可以是结合使用时的成份。这些组合成份也可以按其单独使用时相同或较小的剂量给药。
Claims (8)
1.一种对映体纯度为90至100%的(内,顺式)-(-)-3-(3-羟基-1-氧基-2-苯丙氧基)-8-甲基-8-(1-甲基乙基)-8-氮 二环[3,2,1]辛烷的盐类。
2.根据权利要求1的盐类,其对映体纯度为95-100%。
3.根据权利要求1或2的盐类,它包含BrΘ,ClΘ或CH3CO2Θ作为阴离子。
4.一种适用于吸入形态的药物制剂,其特征在于,它包含权利要求1-3之一的盐类,需要时可与通用的赋形剂和/或载体和/或其它活性物质相组合。
5.根据权利要求4的药物制剂,其特征在于,除了权利要求1-3之一的化合物,还包含有效剂量的β2-拟似物,一种可吸入使用的类固醇或可吸入使用的抗过敏药剂。
6.根据权利要求5的药物制剂,其特征在于,使用的β2-拟似物是
班布特罗
双甲苯喘定
脲喘宁
双氯醇胺
酚丙喘宁
福莫特罗
双喘定
三丁喘宁
吡丁醇
异丙喹喘宁
瑞普特罗
舒喘宁
沙美特罗
磺丁喘宁
叔丁喘宁
叔丁氯喘宁
1-(2-氟-4-羟苯基)-2-[4-(1-苯并咪唑基)-2-甲基-2-丁氨基]乙醇
赤-5′-羟基-8′-(1-羟基-2-异丙氨基丁基)-2H-1,4-苯并嗪基-3-(4H)-酮
1-(4-氨基-3-氯-5-三氟甲基苯基)-2-叔-丁氨基)-乙醇或
1-(4-乙氧羰氨基-3-氰基-5-氟苯基)-2-(叔-丁氨基)-乙醇
而所用的类固醇是丁地去炎松,氯地米松(或17,21-二丙酸酯),地塞米松-21-异烟酸酯,9-去氟肤轻松和抗过敏的药剂,如色甘酸二钠盐,奈多罗米,及依匹斯汀。
7.根据权利要求1-3之一的化合物用于制备治疗呼吸道病症用的药物中的应用。
8.根据权利要求7的应用,其中使用β2-拟似物、类固醇或抗过敏药剂作为组合物的成份。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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DE19528145.4 | 1995-08-01 | ||
DE19528145A DE19528145A1 (de) | 1995-08-01 | 1995-08-01 | Neue Arzneimittel und ihre Verwendung |
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CN1191535A CN1191535A (zh) | 1998-08-26 |
CN1120841C true CN1120841C (zh) | 2003-09-10 |
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CN96195701A Expired - Lifetime CN1120841C (zh) | 1995-08-01 | 1996-07-31 | 新颖药物组合物及其用途 |
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US (1) | US6299861B1 (zh) |
EP (1) | EP0843676B1 (zh) |
JP (1) | JPH11510150A (zh) |
KR (1) | KR100445016B1 (zh) |
CN (1) | CN1120841C (zh) |
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AT (1) | ATE208390T1 (zh) |
AU (1) | AU6739796A (zh) |
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CO (1) | CO4750836A1 (zh) |
CZ (1) | CZ291998B6 (zh) |
DE (2) | DE19528145A1 (zh) |
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EE (1) | EE04614B1 (zh) |
ES (1) | ES2167592T3 (zh) |
HK (2) | HK1013597A1 (zh) |
HR (1) | HRP960365B1 (zh) |
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IL (1) | IL118986A (zh) |
MX (1) | MX9800864A (zh) |
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NO (1) | NO317561B1 (zh) |
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PL (1) | PL183789B1 (zh) |
PT (1) | PT843676E (zh) |
RO (1) | RO120260B1 (zh) |
RU (1) | RU2171258C2 (zh) |
SI (1) | SI0843676T1 (zh) |
SK (1) | SK283260B6 (zh) |
TR (1) | TR199800121T1 (zh) |
TW (1) | TW449597B (zh) |
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WO (1) | WO1997005136A1 (zh) |
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ES2257152B1 (es) * | 2004-05-31 | 2007-07-01 | Laboratorios Almirall S.A. | Combinaciones que comprenden agentes antimuscarinicos y agonistas beta-adrenergicos. |
PE20060826A1 (es) * | 2004-12-06 | 2006-10-08 | Smithkline Beecham Corp | Derivado oleofinico de 8-azoniabiciclo[3.2.1]octano y combinacion farmaceutica que lo comprende |
WO2006114379A1 (de) * | 2005-04-23 | 2006-11-02 | Boehringer Ingelheim International Gmbh | Arzneimittelkombination für die inhalation enthaltend neben einem anticholinergikum ein betamimetikum und ein steroid |
US20060239935A1 (en) * | 2005-04-23 | 2006-10-26 | Boehringer Ingelheim International Gmbh | Compositions for inhalation |
EP2100598A1 (en) | 2008-03-13 | 2009-09-16 | Laboratorios Almirall, S.A. | Inhalation composition containing aclidinium for treatment of asthma and chronic obstructive pulmonary disease |
EP2100599A1 (en) | 2008-03-13 | 2009-09-16 | Laboratorios Almirall, S.A. | Inhalation composition containing aclidinium for treatment of asthma and chronic obstructive pulmonary disease |
EP2510928A1 (en) | 2011-04-15 | 2012-10-17 | Almirall, S.A. | Aclidinium for use in improving the quality of sleep in respiratory patients |
TW201311649A (zh) * | 2011-09-05 | 2013-03-16 | Everlight Chem Ind Corp | 用於太陽能電池電解液之化合物及其製法、含有該化合物之電解液及太陽能電池 |
CN111751454B (zh) * | 2019-03-29 | 2023-12-08 | 天津药业研究院股份有限公司 | 一种异丙托溴铵中间体i的含量和有关物质的检测方法 |
CN110361494B (zh) * | 2019-06-26 | 2023-08-15 | 四川普锐特药业有限公司 | 异丙托溴铵气雾剂中杂质g的检测方法 |
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US3505337A (en) * | 1967-12-22 | 1970-04-07 | Boehringer Sohn Ingelheim | N - hydrocarbyl-substituted noratropinium,haloalkylates and o-acyl derivatives thereof |
DE2903957A1 (de) * | 1979-02-02 | 1980-08-07 | Boehringer Sohn Ingelheim | Mittel zur behandlung der nasalen hypersekretion |
US5225183A (en) * | 1988-12-06 | 1993-07-06 | Riker Laboratories, Inc. | Medicinal aerosol formulations |
DE4140861C2 (de) * | 1991-12-11 | 2003-12-11 | Boehringer Ingelheim Kg | Verfahren zur Gewinnung von quartären Tropasäurealkaloiden |
WO1994013263A1 (en) * | 1992-12-09 | 1994-06-23 | Jager Paul D | Stabilized medicinal aerosol solution formulations |
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1995
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