CN1086940C - 用于治疗肺病的二核苷酸 - Google Patents

用于治疗肺病的二核苷酸 Download PDF

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CN1086940C
CN1086940C CN96195028A CN96195028A CN1086940C CN 1086940 C CN1086940 C CN 1086940C CN 96195028 A CN96195028 A CN 96195028A CN 96195028 A CN96195028 A CN 96195028A CN 1086940 C CN1086940 C CN 1086940C
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M·J·斯图兹三世
R·C·小保彻尔
E·R·拉萨罗斯基
C·A·格里
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Abstract

本发明公开了式(I)化合物或其药学上可接受的盐。在式(I)化合物中，n为1-6；n优选为2-4，最优选为4。X为-OH或-SH，优选-OH。A和B各自独立地选自(a)和(b)，其中R为H或Br。该化合物可用于治疗气道疾病如囊纤维变性。另外公开了包含药学上可接受的载体(例如固体或液体载体)和上述式(I)化合物的药物制剂。还公开了水化需要治疗的患者肺中的粘液分泌物的方法，包含给予该患者的肺部上述式(I)化合物。给药步骤可以通过吸入来完成。

Description

用于治疗肺病的二核苷酸
                        发明领域
本发明涉及某种二核苷酸，含有其的药物制剂，以及通过给患者服用二核苷酸而从该患者的肺中去除残留粘液分泌物的方法。
                        发明背景
本发明是以由国家健康学会授予的Grant No.MHLBIHL34322的政府资助形式完成的。政府对本发明拥有一定权利。
在囊纤维变性中，气道上皮的几项机能是异常的，CL-转运和Na+吸收方面的缺陷已在文献中详细记载。参见，例如：Knowles等人，科学221，1067(1983)；Knowles等人，临床研究杂志71，1410(1983)。调整离子转运对以上皮离子转运异常为特征的肺病如囊纤维变性可能会有潜在的治疗效果。
在囊纤维变性和其他肺病中的一个治疗目的是，改变粘液的水含量使肺粘液分泌物水化，以便该分泌物随后可以更容易地通过mucociliaryaction或简单的咳嗽而从肺中除去。美国专利No.4,501,729中公开了利用烟雾化的阿米洛利来水化粘液分泌物。阿米洛利似乎可阻断Na+通过气道上皮细胞重吸收，并由此抑制水从粘液中的吸收。
涉及ATP或UTP给药的技术例举了水化肺粘液分泌物的不同治疗方法，它们似乎刺激了呼吸上皮细胞的氯化物分泌。参见，例如：Boucher的美国专利No.5,292,498.
考虑到大量受囊纤维变性困扰的病人，非常需要一种新的方法，以提供水化肺粘液分泌物的方法并由此促进肺粘液的清除。
                        发明概述
本发明的第一个方面是式(I)化合物或其药学上可接受的盐：
Figure C9619502800071
在式I化合物中：
n为1-6。n优选为2-4，最优选为4。
X为-OH或-SH，优选-OH。
A和B各自独立地选自下列成员：
Figure C9619502800072
其中R为H或Br。
本发明的第二个方面是药物制剂，其包含处于药学上可接受的载体(例如固体或液体载体)中的、有效量的可水化肺粘液分泌物的上述式(I)化合物或其药学上可接受的盐。任意地，该药物制剂可以进一步包含选自下列成员的化合物：有效量的阿米洛利、苯沙明和非那明，以抑制水从肺粘液分泌物中的重吸收。
本发明的第三个方面是水化需要治疗的患者的肺中的粘液分泌物的方法，包括给予该患者的肺有效量的可水化肺粘液分泌物的上述式I化合物或其药学上可接受的盐。
本发明的第四个方面是上述式I化合物或其药学上可接受的盐在制备用于水化需要治疗的患者的肺中的粘液分泌物的药剂中的用途。
在下面的说明书中详细解释了本发明的上述及其他目的和方面。
                        附图说明
图1显示二核苷酸A2P4对预先用弗司扣林治疗的气道上皮的腔表面上CL-分泌物的作用。
图2显示A2P4给药对预先用UTP刺激的气道上皮中CL-分泌物的作用。
                        发明详述
本发明方法可用于促进(即增强、加速、帮助)粘液分泌物从因为各种原因而需要治疗的患者的肺中的清除，包括(但不限于)由于气管疾病如囊纤维变性、慢性支气管炎、哮喘、支气管扩张、手术后肺膨胀不全(手术后气道被残留的分泌物堵塞)和卡塔格内综合征等而产生的残留分泌物。
本发明主要与人的治疗有关，但也可为了兽医的目的而用于其他哺乳动物如狗和猫的治疗。
式I化合物及其药学上可接受的盐(即活性化合物)可以按照本文中描述的技术和对本领域技术人员来说对其做了显然的改变后的方法来制备。例如，UppppU(U2P4)的合成可以通过利用水溶性碳化亚胺EDC(1-乙基-3-〔3-二甲基-氨-丙基〕-碳化亚胺盐酸化物)来缩合UDP而完成。参见：K.E.Ng和L.E.Orgel，核酸研究15(8)，3572-80(1987)。
阿米洛利及其在水化肺粘液分泌物中的用途是已知的，并公开于Boucher和Knowles的美国专利NO.4,501,729中(本文中引用的所有专利文献都是以其全部内容结合于本文中作为参考的)。苯沙明(也称作3，5-二氨基-6-氯-N-〔苄氨基氨基亚甲基〕吡嗪羰酰胺)和非那明(也称作3，5-二氨基-6-氯-N-〔苯氨基氨基亚甲基〕吡嗪羰酰胺)是已知化合物并公开于E.Cragoe的美国专利No.3,313,813中。本文中所用的术语“苯沙明”、“非那明”和“阿米洛利”包括其药学上可接受的盐(即上述盐)，例如(但不限于)盐酸阿米洛利、盐酸苯沙明或盐酸非那明。
如上所述，本发明的活性化合物可以制备成其药学上可接受的盐。药学上可接受的盐是能保留该化合物预期的生物活性且不会产生不希望的毒性作用的盐。这样的盐的实例是：(a)与无机酸例如盐酸、硫酸、磷酸、硝酸等形成的酸加成盐；与有机酸诸如乙酸、草酸、酒石酸、琥珀酸、马来酸、富马酸、葡糖酸、柠檬酸、苹果酸、抗坏血酸、苯甲酸、单宁酸、棕榈酸、藻酸、聚谷氨酸、萘磺酸、甲磺酸、对甲苯磺酸、萘二磺酸、聚半乳糖醛酸等形成的盐；和(b)从元素阴离子如氯、溴和碘形成的盐。
本文中公开的活性化合物可以通过任何适宜的方式给予患者的肺，但优选通过由该活性化合物组成的可呼吸的颗粒的气溶胶悬液形式给药，患者将其吸入。该可呼吸的颗粒可以是液体或固体。
包含活性化合物的液体粒子的气溶胶可通过任何适宜的方式生产，如用压力驱动的气溶胶喷雾器或超声波喷雾器。参见，例如：美国专利No.4,501,728。喷雾器是商业上可获得的设备，它通过一个窄的文氏管口加速压缩气体、一般空气或氧气，或通过超声波搅动而将活性成分的溶液或悬液转化为治疗气溶胶雾。用于喷雾器的合适的制剂由处于液体载体中的活性成分组成，包含的活性成分最多为该制剂40％W/W，但优选小于20％W/W。该载体通常为水(最优选无菌、无焦精水)或稀释的醇水溶液，优选通过添加例如氯化钠而制成与体液等渗压的。如果该制剂不是无菌制备的话，则任意的添加剂包括防腐剂例如羟基苯甲酸甲酯，还包括抗氧化剂、调味剂、挥发油、缓冲剂和表面活性剂。
包含活性化合物的固体颗粒的气溶胶可用任何固体颗粒药剂气溶胶发生器进行同样的制备。用于患者固体颗粒药剂给药的气溶胶发生器生成如上所解释的可呼吸的颗粒，并以适于人给药的速度产生含有预定剂量药剂的气溶胶体积。固体颗粒气溶胶发生器的一个直观类型是吹入器。适于通过吹入给药的制剂包括精细粉碎的粉末，它可利用吹入器传送或以嗅的方式进入鼻腔。在吹入器中，粉末(例如定量的、可有效进行本文所述治疗的粉末)被包含在一般由明胶或塑料制成的胶囊或盒中，它们可就地贯穿或打开并通过吸气设备或以人工操作的抽气机方式通过抽气而传送该粉末。应用于吸入器中的粉末可以仅由活性成分组成，或由包含活性成分、合适的粉末稀释剂如乳糖以及任意的表面活性剂的粉末搀和物组成。包含的活性成分一般为该制剂的0.1-100W/W。气溶胶发生器的第二种直观类型包括定量吸入器。定量吸入器是压缩气溶胶分配器，一般含有处于液体推进剂中的活性成分的悬液或溶液制剂。在使用这些设备过程中，通过适于传送预定体积，一般是10-150μL的阀门排出该制剂以产生含有活性成分的细颗粒雾。合适的推进剂包括某些含氯氟烃化合物，例如二氯二氟甲烷，三氯氟甲烷，二氯四氟乙烷及其混合物。该制剂还可含有一种或多种共溶剂例如乙醇，表面活性剂如油酸或脱水山梨醇三油酸，抗氧化剂和合适的调味剂。
气溶胶，无论固体还是液体粒子形成，都可由气溶胶发生器生产，速率为每分钟大约10-150升，更优选每分钟约30-150升，最优选每分钟约60升。含较大量药剂的气溶胶可更快进行。
式I化合物或其药学上可接受的盐的剂量将根据所治疗的病情和患者的状态而变化，但一般该量应足以使活性化合物在患者的气道表面上达到的溶解浓度为约10-7-约10-3摩尔/升，更优选约10-6-约3×10-4摩尔/升。根据所给药活性化合物的颗粒制剂的溶解度，日剂量可以分为一个或几个单位剂量给药。根据患者的年龄和病情，以用于人的可呼吸颗粒计，日剂量可以是约1-20mg(重量)。与式I化合物或其盐同时给药的阿米洛利、苯沙明或非那明的剂量可以与式I化合物或其盐的剂量相同。
含有本发明活性剂的固体或液体粒子药物制剂应包括可呼吸的颗粒，也就是说，颗粒的尺寸应足够小以随着吸气而通过嘴和喉并进入支气管和肺泡。一般说来，大小为1-5微米(更特别是小于约4.7微米)的颗粒是可呼吸的。包括于气溶胶中的不可呼吸大小的颗粒容易沉积在咽和喉中，不可呼吸大小的颗粒在气溶胶中的数量优选减至最小值。对于鼻腔给药来说，颗粒大小优选为10-500μm以确保其保留在鼻腔中。
在本发明制剂的制造中，活性剂或其生理上可接受的盐或游离碱，除了别的物质以外，一般是与可接受的载体混合在一起的。当然，该载体必须是在与制剂中的任何其他成分相容的意义上可接受的，且必须是对病人无害的。该载体可以是固体或液体或两者都有，并优选与化合物配制成单位剂量制剂，例如胶囊，它可含有0.5％-99％(重量)的活性化合物。在本发明的制剂中可以掺合一种或多种活性化合物，制剂可以利用任何一种已知的主要由将各成分混合而组成的制药技术来制备。
通过用研钵和研杵来研磨活性化合物可以制得含有活性化合物的可呼吸的干燥颗粒的组合物，然后将该微粉化的组合物通过400目筛以分散或分离出大的烧结物。
用于制备本发明组合物的阿米洛利、苯沙明和非那明可以选择以苯沙明或非那明的药学上可接受的游离碱形式存在。因为该化合物的游离碱的溶解性小于盐，应用游离碱组合物可使苯沙明或非那明更持久地释放进肺部。以还未进入溶液的微粒形式存在于肺中的阿米洛利、苯沙明或非那明是不可能产生生理应答的，但可作为逐渐进入溶液中的生物可利用药物的保管处。
药物组合物可任意含有用来促进气溶胶形成的分散剂。合适的分散剂是乳糖，它可以任何适宜的比例(例如重量比1∶1)与苯沙明或非那明混合。
在下面非限制性实施例中将更加详细地解释本发明。
实施例1二核苷酸A2P4对氯(CL-)分泌物的作用
在可渗透的支持体上培养普通气道细胞并按照M.J.Stutts等人，美国生理学杂志267，C1442-C1451(1994)中描述的方法测定CL-分泌物。给予二核苷酸A2P4(Sigma Chemicals，St.Louis，MO)后测定CL-分泌物。加入阿米洛利以阻断气道上皮的钠吸收。当接触气道上皮处理的底外侧表面时，A2P4只有很小的作用，但对已用弗司扣林治疗过的腔表面则在气道上皮中刺激出更多CL-分泌物。这一结果显示于图1。因为弗司扣林最大地活化了CFTR介导的cAMP调节的气道上皮的CL-通道，这一结果表明A2P4刺激了腔purigenic P2U受体。
此外，A2P4给药对于事先用已知可活化非CFTR CL-通道的UTP刺激的气道上皮中的CL-分泌物没有影响。显示于图2中的这些结果表明，可通过A2P4调节受purigenic受体控制的非CFTR CL-通道，并进一步表明：A2P4刺激了与通过P2U受体起作用的UTP相同的气道上皮CL-通道。这一受体的激发是某些肺病包括囊纤维变性的治疗策略。
上述实施例是对本发明的举例说明，而对本发明没有限制作用。通过下述权利要求定义了本发明，相当于该权利要求包括在本文中。

Claims (15)

1.式(I)化合物或其药学上可接受的盐：
Figure C9619502800021
其中：n为1-6；
  X为-OH或-SH；
  A和B各自独立地选自下列成员：
Figure C9619502800022
其中R为H或Br。
2.按照权利要求1的化合物，其中n为4。
3.按照权利要求1或2的化合物，其中A和B选自尿苷和5-溴尿苷。
4.按照权利要求1或2的化合物，其中A和B为腺苷。
5.按照权利要求1、2、3或4的化合物，其中X为-0H。
6.一种药物制剂，包含处于药学上可接受的载体中的、有效量的可水化肺粘液分泌物的式(I)化合物或其药学上可接受的盐：其中：n为1-6；
  X为-OH或-SH；
  A和B各自独立地选自下列成员：其中R为H或Br。
7.按照权利要求6的药物制剂，进一步包含以有效量给予所述患者的可抑制水从肺粘液分泌物中重吸收的化合物，其选自下列成员：阿米洛利、苯沙明和非那明。
8.按照权利要求6或7的药物制剂，其中所述载体为液体载体。
9.按照权利要求6或7的药物制剂，其中所述载体为固体微粒载体。
10.式(I)化合物或其药学上可接受的盐在用于水化需要治疗的患者肺中的粘液分泌物的药剂的制备中的用途：
Figure C9619502800041
其中：n为1-6；
  X为-OH或-SH；
  A和B各自独立地选自下列成员：其中R为H或Br。
11.式(I)化合物或其药学上可接受的盐在用于治疗囊纤维变性病人的药剂的制备中的用途：其中：n为1-6；
  X为-OH或-SH；
  A和B各自独立地选自下列成员：
Figure C9619502800051
其中R为H或Br；其用量为可水化所述患者肺中残留肺粘液分泌物的有效量，并由此使该残留粘液分泌物更容易地经粘睫作用而从肺部除去。
12.一种产生气溶胶的方法，其特征在于所述气溶胶包含权利要求1-5中任一项所述的化合物。
13.按照权利要求11的用途，其中包含于所述气溶胶中的粒子选自固体粒子和液体粒子。
14.按照权利要求11的用途，其中所述气溶胶由粒子大小为1-5微米的粒子组成。
15.按照权利要求10的用途，其中所述气溶胶进一步包含以有效量给予所述患者的可抑制水从肺粘液分泌物中重吸收的化合物，其选自下列成员：阿米洛利、苯沙明和非那明。
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