CN1310702A - 特殊药物的硝酸酯和硝酸盐 - Google Patents

特殊药物的硝酸酯和硝酸盐 Download PDF

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CN1310702A
CN1310702A CN99809042A CN99809042A CN1310702A CN 1310702 A CN1310702 A CN 1310702A CN 99809042 A CN99809042 A CN 99809042A CN 99809042 A CN99809042 A CN 99809042A CN 1310702 A CN1310702 A CN 1310702A
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nitrate
salt
shi
solution
compound
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CN1264828C (zh
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P·德尔索尔达托
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Nicox SA
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Nicox SA
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Abstract

本发明公开了在呼吸系统疾病治疗中具有药物活性的硝酸盐。

Description

特殊药物的硝酸酯和硝酸盐
本发明涉及系统或非系统使用的用于带有或不带有传染性发病基础的呼吸系统疾病治疗的化合物或其药物组合物，所述疾病具体地为慢性肺病(慢性阻塞性肺病(COPD))，如哮喘、支气管炎、enphisema、血栓栓塞，与目前用于治疗这些疾病的药物相比，具有较低的副作用。
现有技术中已知用于治疗这些疾病的最常用的产品是沙丁胺醇、沙美特罗等。参见例如“Textbook of Therapeutics-Drugs andDisease Management-6th 1996”685页。这些产品是有效的，但有产生副作用的缺点，尤其对于心血管系统。所述产品向患有心血管疾病的患者给药时必须小心。
本身或作为其它药物的辅药用于这些疾病的其它产品是例如氨溴索和溴己新，它们的给药同样伴随着胃肠系统的副作用，例如烧灼和胃感受性。
人们感到需要获得在治疗呼吸系统疾病中是有效的，而对于心血管系统和/或胃肠系统具有较低副作用的化合物和它们的药物组合物。
申请人出乎意料和惊奇地发现特殊化合物和它们的组合物解决了上述技术问题。
本发明的目的是提供用于治疗呼吸系统疾病，尤其是慢性肺病(慢性阻塞性肺病(COPD))，如哮喘、支气管炎、enphisema、血栓栓塞、传染性肺病的化合物的硝酸盐或其药物组合物，所述化合物的特征在于它们含有至少一个能够用硝酸盐化的反应基团，所述化合物选自如下之一：
-式(Ⅰ)的沙丁胺醇：-式(Ⅱ)的塞(西)替利嗪(cetrezin)：-式(Ⅲ)的氯雷他定：
Figure A9980904200093
-式(Ⅳ)的特非那定：
Figure A9980904200094
-式(Ⅴ)的依美司汀：
Figure A9980904200101
-式(Ⅵ)的酮替芬：
Figure A9980904200102
-式(Ⅶ)的奈多罗米：-式(Ⅷ)的氨溴索：-式(Ⅸ)的溴己新：
Figure A9980904200111
-式(Ⅹ)的右美沙芬：
Figure A9980904200112
-式(Ⅺ)的右啡烷：
Figure A9980904200113
-式(Ⅻ)的甲硝唑：-式(ⅩⅢ)的异烟肼：-式(ⅩⅣ)的红霉素：
Figure A9980904200121
-式(ⅩⅤ)的阿昔洛韦：-式(ⅩⅥ)的吡嗪酰胺：
Figure A9980904200123
优选化合物是沙丁胺醇，也称为阿布叔醇、塞替利嗪、依美司汀、氨溴索。
本发明的硝酸盐还可以通过使用上述种类的上述化合物得到，它选择性地含有通过如下二价连接桥之一共价键合到分子的一个或多个-ONO2基团：
-YO,其中Y是直链或支链C1-C20亚烷基，如果可能，优选2-5个碳原子，或选择性地取代的5-7个碳原子的环亚烷基；
-Y1选自：
Figure A9980904200131
其中n3是0-3的整数；
Figure A9980904200133
Figure A9980904200134
其中nf’是1-6的整数，优选2-4；
Figure A9980904200135
其中R1f=H、CH3和nf是1-6的整数；优选2-4。
含有通过上述二价连接桥之一共价键合到分子的-ONO2基团的这些化合物如以申请人名义申请的专利申请WO95/30641中描述制备，所述申请列为本文参考文献。
在本发明的组合物中，还可以使用上述化合物的可能的一种或多种异构体(包括旋光异构体)。
异构体的实例是顺-、反-、旋光异构体D和L或外消旋体、对映体。通常一种异构体形式相对于其它的形式，例如D型相对于L型具有较高活性，反之亦然。
本发明的化合物每摩尔母体含有至少一摩尔硝酸盐离子，硝酸盐离子摩尔与母体摩尔之间的比率优选是归一的。当在分子中存在其它其碱性足以与硝酸根阴离子形成离子键的氨基时，可得到具有较高摩尔比率的盐。
本发明的盐根据本领域已知的方法，与常用赋形剂一起配制在相应药物组合物中，参见例如“Remington's Pharmaceutical Sciences15a Ed.”卷。
属于上述种类的盐的母体根据“Index Merek 14a Ed.”卷中所述的方法制备，列为本文参考文献。
本发明的盐可根据如下方法中的一种得到。
如果用于形成本发明的盐的母体作为游离碱得到或相应的盐得到，两者都溶解于优选在分子中不含有羟基的有机溶剂，例如乙腈、乙酸乙酯、四氢呋喃等，则硝酸盐通过将物质或其盐以优选等于或高于10％w/v的浓度溶解在溶剂中，随后加入所需数量的浓硝酸制备，在加入前优选在上述溶解化合物的相同溶剂中稀释，优选在加入过程中和加完后，将混合物冷却至20℃-0℃的温度，产物通常通过过滤和选择性地用相同的冷冻溶剂洗涤固体回收。
当物质或其可得到的盐微溶解于上述溶剂时，将羟基化溶剂加入上述溶剂中以增加溶解性。该羟基化溶剂的实例是甲醇、乙醇和水。在加完硝酸后，用非质子溶剂稀释所得到的混合物可加速沉淀。
当母体用氢卤酸盐化时，其硝酸盐可通过将硝酸银加入在上述溶剂中的卤化物溶液中制备，在过滤去卤化银后，浓缩溶液和冷却通过沉淀回收硝酸盐。
当起始产物是其中阴离子不是氯的母体盐时，优选通过用碳酸或碳酸氢钠或钾的饱和溶液，或用氢氧化钠或钾稀溶液处理上述盐的水溶液，随后用合适的有机溶剂(例如卤代溶剂、酯、醚)提取水相，随后脱水和蒸发有机溶剂，随后将得到的残余物溶解于不含有羟基的上述溶剂，例如乙腈或所述溶剂与羟基溶剂的混合物中，随后按照上述制备方法。
本发明的盐和组合物可用于系统给药，例如它们可通过口服途径给药，例如作为祛痰药；通过肌内、静脉内途径等；或它们可用于非系统给药，例如作为气溶胶或局部应用。通常本发明的盐用于与母体的相同治疗应用。
与母体相比，本发明的硝酸盐具有增加的一般安全。
给药剂量是与母体相同的，然而由于本发明的产物显示优于母体的治疗效果，它们还可以以高于母体的剂量使用，而不会产生副作用。
本发明产物的其它应用是作为tokolitics(镇痉剂)，例如子宫肌内镇痉剂、肠肌肉镇痉剂；抗组胺药(抗变态反应药)，例如用于眼睛；用于传染性呼吸疾病的止咳、抗菌剂。它们可如上所述系统或非系统地给药，或是眼药组合物的形式，例如洗眼液等。
给出如下实施例仅用以举例说明本发明，它们不是限制本发明。
实施例1氨溴索硝酸盐制备
氨溴索溶液(4g,20.6mmol)通过将其溶液在乙腈(30ml)和四氢呋喃(10ml)的混合物中制备，在低温(4℃)下加入在乙腈中稀释的硝酸(3.5ml通过将乙腈加入2.7ml65％的硝酸，随后用乙腈使最终体积为10ml得到的溶液)。在30分钟后，在相同的温度(4℃)下缓慢加入乙醚(100ml)，过滤形成的沉淀，用乙醚洗涤，真空干燥，得到白色无定形固体，元素分析结果相应于氨溴索的硝酸盐：
              C        H         N         Br
计算值    35.40％    4.34％    9.53％    36.23％
实验值    35.37％    4.31％    9.57％    36.26％
实施例2沙丁胺醇硝酸盐的制备
由在乙腈(30ml)和四氢呋喃(10ml)中的沙丁胺醇溶液(4g,16.7mmol)和用4ml在乙腈中的硝酸溶液，并采用实施例1的相同方法，得到无定形固体，元素分析结果相应于沙丁胺醇的硝酸盐：
           C           H         N
计算值    51.65％    7.32％    9.27％
实验值    51.54％    7.38％    9.22％
药理学试验
实施例3本发明盐的急性毒性研究
产物以2％wt羧甲基纤维素的悬浮液形式向10只一组的鼠给药。
盐急性毒性通过向10只一组的鼠口服给药增加到100mg/kg单剂量的化合物评价。
动物保持观察14天，记录死亡率和中毒症状的出现。
在给药100mg/kg剂量后，未观察到明显中毒的症状。
实施例4在豚鼠中沙丁胺醇和沙丁胺醇硝酸盐对实验支气管缩小的效果研究
根据Del Soldato等J.Pharmacol.Methods 5 279 1981中的方法准备用于心脏呼吸活性测量的动物。每组由8只动物组成，给动物静脉注射0.1ml辣椒辣素盐水溶液(1μg/kg)。在全部15分钟内，从辣椒辣素注射前5分钟到注射后10分钟，向每组动物通过静脉输注给药沙丁胺醇(0.3nmol/分钟)、或相应的硝酸盐(0.3nmol/分钟)或仅仅载体。
用如上Del Soldato参考文献中所述改进的连接多种波动记录仪系统的Konzett装置测量辣椒辣素给药前后的潮气变化。
采用常用方法用心电图描记器测定心率，结果记录在表1中。在给药赋形剂后心率的平均值是每分钟188±7次，反应表示为相对于对照组的百分数值。
如表Ⅰ所示，沙丁胺醇硝酸盐在抑制辣椒辣素引起的支气管缩小反应方面与沙丁胺醇同样有效，但相对于沙丁胺醇，盐更好地被忍受(无心动过速反应)。
                                  表Ⅰ
处理 支气管缩小(％) 心动过速(％)
载体沙丁胺醇硝酸盐沙丁胺醇     10000     10097116
实施例5塞替利嗪硝酸盐制备
盐通过将1.23ml如实施例1中所述的在乙腈中的硝酸溶液加入在乙腈(10ml)和四氢呋喃(5ml)的溶剂混合物中的塞替利嗪(2g,5.14mmol)溶液中制备，得到无定形固体，元素分析结果相应于塞替利嗪的硝酸盐：
             C         H         N         Cl
计算值    55.18％    5.79％    9.29％    7.84％
实验值    55.84％    5.75％    9.22％    7.83％
实施例6氯雷他定(Loratidine)硝酸盐制备
盐通过将0.63ml如实施例1中所述的在乙腈中的硝酸溶液加入在乙腈(7ml)和四氢呋喃(3ml)的溶剂混合物中的氯雷他定(1g,2.61mmol)溶液中制备，得到固体，元素分析结果相应于氯雷他定的硝酸盐：
             C         H         N        Cl
计算值    59.26％    5.42％    9.42％    7.95％
实验值    59.24％    5.38％    9.42％    7.93％
实施例7特非那定硝酸盐制备
盐通过将0.76ml如实施例1中所述的在乙腈中的硝酸溶液加入在乙腈(15ml)和四氢呋喃(5ml)的溶剂混合物中的特非那定(1.5g,3.18mmol)溶液中制备，得到固体，元素分析结果相应于特非那定的硝酸盐：
            C          H         N
计算值    71.88％    7.91％    5.23％
实验值    71.90％    7.88％    5.24％
实施例8依美司汀(Emedastine)硝酸盐制备
盐通过将0.7ml如实施例1中所述的在乙腈中的硝酸溶液加入在乙腈(10ml)和四氢呋喃(7ml)的溶剂混合物中的依美司汀(2g,5.47mmol)溶液中制备，得到固体，元素分析结果相应于依美司汀的硝酸盐：
            C          H          N
计算值    55.87％    7.44％    19.15％
实验值    55.84％    7.43％    19.18％
实施例9溴己新硝酸盐制备
盐通过将1.24ml如实施例1中所述的在乙腈中的硝酸溶液加入在乙腈(10ml)和四氢呋喃(10ml)的溶剂混合物中的溴己新(2g,5.17mmol)溶液中制备，得到固体，元素分析结果相应于溴己新的硝酸盐：
            C          H          N         Br
计算值    38.29％    4.81％    12.57％    36.39％
实验值    38.31％    4.84％    12.77％    36.41％
实施例10右美沙芬硝酸盐制备
通过将硝酸银(0.96g,5.68mmol)加入右美沙芬氢溴酸盐(2g,5.68mmol)在乙腈(20ml)中的溶液制备，溶液在室温下搅拌30分钟，随后过滤以除去溴化银沉淀。向透明溶液中加入乙醚(110ml)，形成沉淀，过滤，用乙醚洗涤和真空干燥.得到固体，元素分析结果相应于右美沙芬的硝酸盐：
             C         H          N
计算值    65.65％    7.83％    12.65％
实验值    64.68％    7.85％    12.54％
实施例11酮替芬硝酸盐制备
盐通过将0.78ml如实施例1中所述的在乙腈中的硝酸溶液加入在乙腈(10ml)和四氢呋喃(5ml)的溶剂混合物中的酮替芬(1g,3.23mmol)溶液中制备，得到固体，元素分析结果相应于酮替芬的硝酸盐：
             C          H         N         S
计算值    61.27％    5.40％    11.28％    9.51％
实验值    61.24％    5.43％    11.27％    8.60％
实施例12奈多罗米硝酸盐制备
盐通过将0.64ml如实施例1中所述的在乙腈中的硝酸溶液加入在乙腈(7ml)和四氢呋喃(5ml)的溶剂混合物中的奈多罗米(1g,2.69mmol)溶液中制备，得到固体，元素分析结果相应于奈多罗米的硝酸盐：
            C          H          N
计算值    52.54％    4.17％    9.67％
实验值    52.56％    4.19％    9.63％
实施例13右啡烷硝酸盐制备
通过将硝酸银(0.50g,2.96mmol)加入右啡烷氢溴酸盐(1g,2.96mmol)在乙腈(17ml)中的溶液制备，溶液在室温下搅拌30分钟，随后过滤以除去溴化银沉淀。向透明溶液中加入乙醚(100ml)，形成沉淀，过滤，用乙醚洗涤和真空干燥。得到固体，元素分析结果相应于右啡烷的硝酸盐：
            C          H          N
计算值    63.73％    7.54％    13.11％
实验值    63.71％    7.55％    13.10％病理学试验
实施例14在豚鼠中塞替利嗪硝酸盐和塞替利嗪盐酸盐的抗组胺活性-实验支气管缩小的研究
根据Del Soldato等J.Pharmacol.Methods 5 279 1981中的方法准备用于心脏呼吸活性测量的动物。向动物静脉注射0.1ml组胺盐水溶液(2μg/kg)，将动物分为3组，每组由8只。以77μmol/μg的剂量静脉给药塞替利嗪硝酸盐、塞替利嗪盐酸盐或仅仅载体。
用如上Del Soldato参考文献中所述改进的连接多种波动记录仪系统的Konzett装置测量辣椒辣素给药前后的潮气变化。
如下表Ⅱ中，每个处理组的动物反应表示为相对于对照组的百分数值。
如表Ⅱ中所示，与塞替利嗪盐酸盐相比塞替利嗪硝酸盐具有改善的抗组胺活性。
                表Ⅱ
处理 支气管缩小(％)
载体塞替利嗪硝酸盐塞替利嗪盐酸盐     100040
实施例15在豚鼠中右美沙芬盐酸盐、右美沙芬硝酸盐、右啡烷盐酸盐和右啡烷硝酸盐的镇咳活性
如Braga等在Al.Arzneim.Forsch./Drug Res.43,550,1993中所述处理豚鼠(体重：430+20)。
在病理学实验中，使用5组动物，每组8只，一组未处理，作对照组。
将每个动物放置在带有管子的cilindrical玻璃容器中，管子通过两个圆形平板的表面，所述管子分别用于气溶胶入口和出口，出口管子连接多种波动记录仪。
气溶胶由按重量计7.5％的柠檬酸水溶液形成。
在气溶胶引起的咳嗽发作前后监测玻璃容器内的空气变化，1小时后，以110微摩尔/千克的剂量腹膜内给药右美沙芬盐酸盐、右美沙芬硝酸盐、右啡烷盐酸盐和右啡烷硝酸盐在生理盐水中的溶液。在注射后30分钟，动物用气溶胶处理，重新记录10分钟时间内咳嗽发作的次数。在如下表Ⅲ中报导了每组处理动物的平均反应，对于对照组设定为100％。表Ⅲ
处理     咳嗽发作(％)
载体右美沙芬硝酸盐右美沙芬盐酸盐右啡烷硝酸盐右啡烷盐酸盐     100030040
如表中所示，右美沙芬和右啡烷硝酸盐比相应的盐酸盐是更有效的镇咳药。
实施例16在鼠中氨溴索硝酸盐和氨溴索盐酸盐的mucolitic活性
在雄性鼠中的mucolitic活性根据Engler和Zselenyi的方法，J.Pharm.Methods 11,151 1984评价。采用该方法，测定在气管分泌中酚红的质量。动物首先以500mg/Kg的剂量腹膜给药溶解在生理盐水中的染料，共3组鼠(体重18±2g)，每组8只用染料腹膜处理。一组为对照组，两个处理组在上述注射之前10分钟分别接受264微摩尔/千克氨溴索硝酸盐和氨溴索盐酸盐的腹膜注射。在酚红注射后30分钟，杀死动物。由周围组织中取出气管，切开并在3ml重量生理溶液中洗涤30分钟。随后在生理溶液中加入0.1ml的1M氢氧化钠，洗涤物在3000rpm下离心15分钟。对上清液进行分光光度分析以测定在生理溶液中的酚红的浓度。mucolitic活性以设定为100％的对照组样品吸收的变化％确定。
得到的结果示于表Ⅳ中。
表Ⅳ
处理 Mucolitic活性(％)
载体氨溴索硝酸盐氨溴索盐酸盐     100030
表中显示，氨溴索硝酸盐的mucolitic活性高于相应盐酸盐。
实施例17甲硝唑硝酸盐制备
盐通过将1.40ml如实施例1中所述的在乙腈中的硝酸溶液加入在乙腈(8ml)和四氢呋喃(5ml)的溶剂混合物中的甲硝唑(1g,5.84mmol)溶液中制备，得到固体，元素分析结果相应于甲硝唑的硝酸盐：
             C         H          N
计算值    30.77％    4.30％    24.03％
实验值    30.74％    4.28％    24.00％
实施例18异烟肼硝酸盐制备
盐通过将3.50ml如实施例1中所述的在乙腈中的硝酸溶液加入在乙腈(20ml)和四氢呋喃(10ml)的溶剂混合物中的异烟肼(2g,14.58mmol)溶液中制备，得到固体，元素分析结果相应于异烟肼的硝酸盐：
            C          H         N
计算值    36.00％    4.02％    27.99％
实验值    35.97％    4.00％    28.01％
实施例19红霉素硝酸盐制备
盐通过将0.65ml如实施例1中所述的在乙腈中的硝酸溶液加入在乙腈(23ml)和四氢呋喃(17ml)的溶剂混合物中的红霉素(2g,2.72mmol)溶液中制备，得到固体，元素分析结果相应于红霉素的硝酸盐：
             C         H         N
计算值    57.72％    8.89％    3.63％
实验值    57.75％    8.90％    3.65％
实施例20阿昔洛韦硝酸盐制备
盐通过将1.06ml如实施例1中所述的在乙腈中的硝酸溶液加入在乙腈(10ml)和四氢呋喃(10ml)的溶剂混合物中的阿昔洛韦(1g,4.44mmol)溶液中制备，得到固体，元素分析结果相应于阿昔洛韦的硝酸盐：
             C         H          N
计算值    33.33％    4.19％    29.17％
实验值    33.30％    4.20％    29.18％
实施例21吡嗪酰胺硝酸盐制备
盐通过将1.95ml如实施例1中所述的在乙腈中的硝酸溶液加入在乙腈(10ml)和四氢呋喃(10ml)的溶剂混合物中的吡嗪酰胺(1g,8.12mmol)溶液中制备，得到固体，元素分析结果相应于吡嗪酰胺的硝酸盐：
             C         H         N
计算值    48.78％    3.25％    30.10％
实验值    48.80％    3.24％    30.13％

Claims (14)

1．化合物的硝酸盐，所述化合物选自如下之一：-式(Ⅰ)的沙丁胺醇：-式(Ⅱ)的塞替利嗪：
Figure A9980904200022
-式(Ⅲ)的氯雷他定：
Figure A9980904200023
-式(Ⅳ)的特非那定：-式(Ⅴ)的依美司汀：-式(Ⅵ)的酮替芬：
Figure A9980904200032
-式(Ⅶ)的奈多罗米：
Figure A9980904200033
-式(Ⅷ)的氨溴索：-式(Ⅸ)的溴己新：
Figure A9980904200035
-式(Ⅹ)的右美沙芬：
Figure A9980904200041
-式(Ⅺ)的右啡烷：-式(Ⅻ)的甲硝唑：-式(ⅩⅢ)的异烟肼：
Figure A9980904200044
-式(ⅩⅣ)的红霉素：
Figure A9980904200051
-式(ⅩⅤ)的阿昔洛韦：
Figure A9980904200052
-式(ⅩⅥ)的吡嗪酰胺：
Figure A9980904200053
2．权利要求1的硝酸盐，其中化合物是沙丁胺醇、塞替利嗪、依美司汀、氨溴索。
3．权利要求1-2的硝酸盐，其中化合物含有通过如下二价连接桥之一共价键合到分子的一个或多个-ONO2基团：
-YO，其中Y是直链或支链C1-C20亚烷基，如果可能，优选2-5个碳原子，或选择性地取代的5-7个碳原子的亚环烷基；
-Y1选自：其中n3是0-3的整数；
Figure A9980904200064
其中nf’是1-6的整数，优选2-4；
Figure A9980904200065
其中R1f=H、CH3和nf是1-6的整数；优选2-4。
4．权利要求1-3的硝酸盐，其含有所示化合物的一种或多种异构体。
5．权利要求1-4的硝酸盐，其中所述化合物的盐含有每摩尔化合物至少一摩尔硝酸盐离子。
6．权利要求1-5的硝酸盐的药物组合物。
7．权利要求1-6的硝酸盐和药物组合物用作药物。
8．权利要求7的盐和组合物在制备用于治疗呼吸系统疾病的药物中的应用。
9．权利要求7的盐和组合物在制备用作tokolitic的药物中的应用。
10．权利要求7的盐和组合物在制备用作抗变态反应药，优选用于眼睛的药物中的应用。
11．一种制备权利要求1-5的硝酸盐的方法，其中当要被盐化的母体可作为游离碱得到或相应的盐得到，它们都可溶解于不含有羟基的有机溶剂时，则盐通过将该物质或其盐以等于或高于10％w/v的浓度溶解在所述溶剂中，随后加入所需数量的浓硝酸以形成相应的盐，在加入过程中和加完后，冷却至20℃-0℃的温度，通过过滤回收产物制备。
12．权利要求11的方法，其中当化合物或其可得到的盐微溶解于上述溶剂时，将羟基化溶剂加入上述溶剂中以增加溶解性，在加完硝酸后，用非质子溶剂稀释所得到的混合物以加速沉淀。
13．权利要求11-12的方法，其中当起始产品用氢卤酸盐化时，硝酸盐可通过将硝酸银加入卤化物溶液中，过滤去卤化银，浓缩和冷却溶液，通过沉淀回收硝酸盐制备。
14．一种制备权利要求1-5的硝酸盐的方法，其中当起始母体盐的阴离子不是氯时，用碳酸钠或钾或碳酸氢钠或钾的饱和溶液，或用氢氧化钠或钾稀溶液处理上述盐的水溶液，随后用有机溶剂提取水相，脱水和蒸发有机溶液，随后将得到的残余物溶解在有机溶剂中，随后按照权利要求11或12的硝酸盐的制备方法。
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