CN1461216A - 用作治疗有关支气管收缩的机能障碍的药物的化合物 - Google Patents

用作治疗有关支气管收缩的机能障碍的药物的化合物 Download PDF

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CN1461216A
CN1461216A CN00808617A CN00808617A CN1461216A CN 1461216 A CN1461216 A CN 1461216A CN 00808617 A CN00808617 A CN 00808617A CN 00808617 A CN00808617 A CN 00808617A CN 1461216 A CN1461216 A CN 1461216A
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chemical compound
bronchoconstriction
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S·斯克戈瓦尔
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Respiratorius AB
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Abstract

本发明涉及用作药物的、对5－HT4受体具有激动活性的化合物，和所述化合物在药物制备中的用途，该药物用于人或动物体有关支气管收缩的机能障碍的治疗或预防，以及将所述化合物给药的治疗方法。本发明还涉及用作药物的、对5－HT2A受体具有拮抗活性的化合物，和所述化合物在药物制备中的用途，该药物用于人或动物体有关支气管收缩的机能障碍的治疗或预防，以及将所述化合物给药的治疗方法。

Description

用作治疗有关支气管收缩的机能障碍的药物的化合物
发明领域
本发明涉及用作药物的、对5-HT4受体具有激动活性的化合物，和所述化合物在药物制备中的用途，该药物用于人或动物体有关支气管收缩的机能障碍的治疗或预防，以及将所述化合物给药的治疗方法。本发明还涉及用作药物的、对5-HT2A受体具有拮抗活性的化合物，和所述化合物在药物制备中的用途，该药物用于人或动物体有关支气管收缩的机能障碍的治疗或预防，以及将所述化合物给药的治疗方法。
发明背景
5-HT(血清素；3-(β-氨基乙基)-5-羟基吲哚)型受体是熟知的，存在于身体各处，例如在气道中，人们主要报道了它们与CNS、肌肉和胃机能障碍治疗的相关性，例如WO98/18458和US5,246,935。在这类治疗中，经常使用对5-HT1型受体具有激动活性的化合物。作为其他5-HT受体的实例，可以提到5-HT2、5-HT4、5-HT5、5-HT6和5-HT7型。关于5-HT受体的最新评论，参见Gerhardt，C.C.，van Heerikhuizen，H.《欧洲药理学杂志》(Eur.J.Pharm.)，334，1-23(1997)，引用在此作为参考文献。
5-HT2型受体也是熟知的，例如US5,869,947、US5,705,519和US5,246,935。人们已经报道了5-HT2型受体例如与CNS和神经元机能障碍的相关性。这类机能障碍经常用对5-HT2A、5-HT2B或5-HT2C型受体具有拮抗活性的化合物加以治疗。这类化合物的实例是利坦色林和萘呋胺。各种5-HT受体的典型激动剂和拮抗剂公开在R.A.Glennon《神经科学与生物行为评论》(Neuroscience andBiobehavioral Reviews)，14，35-47(1990)，其全部内容引用在此作为参考文献。
SU1,701,320A1公开了血清素用于急性哮喘发作治疗的用途。这篇文献没有提出任何关于血清素的受体机理，血清素是一种对气道既具有收缩效应也具有松弛效应的化合物，下文对此作进一步讨论。
在Keith J.Watling编著的《RBI受体分类与信号转导手册》(RBI Handbook of Receptor Classification and SignalTransduction)第3版，1998，RBI，One Strathmore Road，Natick，MA01760-2447，USA中，公开了对各种受体具有激动或拮抗活性的化合物。
发明的公开
本发明基于这样一种新颖的发现，某些5-HT受体在调节支气管收缩中是极为重要的。总之，本文公开了对5-HT4受体具有激动活性的化合物在其给药后带来支气管松弛作用，因此适合作为药物，用于支气管收缩障碍的治疗。本文还公开了对5-HT2受体、尤其是5-HT2A受体具有拮抗活性的化合物是适用于支气管收缩障碍治疗的药物。还公开了用于支气管收缩障碍治疗的方法。
本文所用的表达方式支气管收缩障碍指的是平滑肌力异常增加，导致部分或全部肺气道和/或肺外气道的直径减小。所述表达方式也指例如由哮喘或任何其他与之有关的障碍所致肿胀、水肿、血浆外渗或黏膜分泌而导致的气流减少。
因此，本发明在其一方面涉及用作药物的、对5-HT4受体具有激动活性的化合物。另一方面涉及所述化合物在药物制备中的用途，该药物用于人或动物体的治疗或预防，其中该药物打算用于有关支气管收缩的机能障碍、例如哮喘的治疗。
在优选的实施方式中，本发明涉及对5-HT4受体具有激动活性的化合物在药物制备中的用途，该药物用于有关支气管收缩的机能障碍的治疗或预防，其中所述激动剂能够减少病理性支气管收缩达至少30％，优选为至少60％，最优选为至少90％。
本发明在另一方面还涉及用作药物的、对5-HT2A受体具有拮抗活性的化合物。另一方面涉及所述化合物在药物制备中的用途，该药物用于人或动物体的治疗或预防，其中该药物打算用于有关支气管收缩的机能障碍、例如哮喘的治疗。
在优选的实施方式中，本发明涉及对5-HT2A受体具有拮抗活性的化合物在药物制备中的用途，该药物用于有关支气管收缩的机能障碍的治疗或预防，其中所述拮抗剂能够减少病理性支气管收缩达至少30％，优选为至少60％，最优选为至少90％。
所述支气管收缩还可能存在于这样的机能障碍中，例如肺气肿、慢性支气管炎、慢性阻塞性肺病、抑郁、食欲缺乏性或食欲过盛性进食障碍、焦虑或各种精神病状态，包括精神分裂症。
本发明还涉及对5-HT2A受体具有拮抗活性的化合物与对5-HT4受体具有激动活性的化合物的组合在药物制备中的用途，该药物用于有关支气管收缩的机能障碍的治疗或预防。在优选的实施方式中，所述具有激动活性的化合物是对5-HT4受体具有激动活性的血清素或其衍生物。5-HT2A受体拮抗剂与该激动剂的这种组合增加体内血清素的传递，特别是在血清素摄取抑制剂(SRI)的存在下更是如此。进而，按照本发明所使用的、对5-HT4受体具有激动活性的化合物还可用于本组合实施方式。确切地说，所述药物打算用于哮喘和与之有关的障碍的治疗。
按照本发明，若干已知物质惊人地能够刺激5-HT4受体，且不激活收缩性5-HT2A受体，从而对支气管收缩产生松弛效应。这类激动性化合物选自SC53116、ML10302、RS67506和BIMU8，它们是如下定义的，以及更加非特异性的5-酰氨基色胺，和它们的具有相同或实质上相同松弛效应的衍生物和药学上可接受的盐。
本发明还涉及一种或多种上述激动性化合物在药物制备中的用途，该药物用于有关支气管收缩的机能障碍的治疗或预防：SC53116，即4-氨基-5-氯-N-[[(1S，7aS)-六氢-1H-pyrrolizin-1-基]甲基]-2-甲氧基-苯甲酰胺，结构式如下：
Figure A0080861700091
ML10302，即4-氨基-5-氯-2-甲氧基-苯甲酸-2-(1-哌啶基)乙酯，结构式如下：
RS67506，即N-[2-[4-[3-(4-氨基-5-氯-2-甲氧基苯基)-3-氧代丙基]-1-哌啶基]乙基]-1-甲磺酰胺一盐酸盐，结构式如下：
BIMU8，即2，3-二氢-N-[(3-内)-8-甲基-8-氮杂二环[3.2.1]辛-3-基]-3-(1-甲基乙基)-2-氧代-1H-苯并咪唑-1-酰胺一盐酸盐，结构式如下：
5-酰氨基色胺，结构式如下：
Figure A0080861700101
BIMU1、BIMU8、BRL24924、西沙必利、DAU6236、5-羟基-N，N-二甲基色胺、ML-1035、ML10302、5-甲氧基色胺、甲氧氯普胺、莫沙必利、8-OH-DPAT(8-羟基-2-二丙氨基四氢化萘)、普鲁卡罗必利(Prucalopride)、R076186、R093877、伦扎必利、RS17017、RS56532、RS57639、RS67333、RS67506、RS67532、SB204070、SB205149、SC-53116、SC-49518、SK-951、SDZ216-454、SR59768、TKS159、VB20B7、YM-47813、YM-53389、YM-09151、扎考必利、泽玛克(Zelmac)和它们的具有实质上相同松弛效应的衍生物和药学上可接受的盐，其中所述激动剂能够减少病理性支气管收缩达至少30％，优选为至少60％，最优选为至少90％。
按照本发明，若干已知的拮抗性化合物惊人地能够影响5-HT2A受体，从而产生收缩减少效应，即松弛效应，它们选自酮色林、AMI-193或MDL100，907，和它们的具有相同或实质上相同收缩减少效应的衍生物和药学上可接受的盐。
因而，本发明还涉及一种或多种上述化合物在药物制备中的用途，该药物用于有关支气管收缩的机能障碍的治疗或预防，也就是：
酮色林，即7-叠氮基-3-[2-[4-(4-氟苯甲酰基)-1-哌啶基]乙基]-1-6-碘-2，4(1H，3H)-喹唑啉二酮，结构式如下：
Figure A0080861700102
AMI-193，即8-[3-(4-氟苯氧基)丙基]-1-苯基-1，3，8-三氮杂螺[4，5]癸-4-酮，结构式如下：
Figure A0080861700111
ALEPH-2、安哌齐特、安麦角、芳氧基烷基咪唑啉、1-芳基-4-丙基哌嗪、BIMT17、1-3-[4-(3-氯苯基)-1-哌嗪基]丙基-6-氟二氢吲哚-2(1H)-酮、CGS18102A、可乐定、赛庚啶、德伦环烷、去甲基-WAY100635、多他利嗪、DV7028、野麦角碱、法南色林、8-[3-(4-氟苯甲酰基)丙基]-1-甲基-1，3，8-三氮杂螺[4，5]癸-4-酮、FG5893盐酸盐、FG5974、FG5983、六氢咔唑、(3H)WAY100635、ICI169,369、8-[3-(4-碘苯甲酰基)丙基]-1-甲基-1，3，8-三氮杂螺[4，5]癸-4-酮、酮色林、LEK-8804、LSD、LU111995、(S，S)-LY-53，857、(R，S)-LY-53，857、(S，R)-LY-53，857、(R，R)-LY-53，857、LY-53，857游离碱、LY215840、MDL-11，939、MDL28133A、MDL100，151、MDL100，907、美舒麦角、甲麦角林、1-3-[4-(2-甲氧基苯基)-1-哌嗪基]丙基二氢吲哚-2(1H)-酮、美西麦角、米安色林、NE-100、奈法唑酮、N-乙氧羰基-2-乙氧基-1，2-二氢喹啉、NRA0045、奥氮平、昂丹司琼、1-(2-嘧啶基)哌嗪衍生物、苯噻啶、雷氯必利、罗克吲哚、利培酮、利坦色林、RP62203，
沙格雷酯及其活性代谢产物(M-1)，血清素再摄取抑制剂，象氟西汀、YM992、美地沙明、西立氯胺、丙米嗪、伊普吲哚、BIMT17、西酞普兰、帕罗西汀、舍曲林、氟伏沙明、被3-(二甲氨基)-丙基链N-取代的螺吲哚，
螺哌隆、SR46349B、WAY100635、WY-50，324、MDL100，907和它们的具有实质上相同收缩减少效应的衍生物和药学上可接受的盐，其中所述拮抗剂能够减少病理性支气管收缩达至少30％，优选为至少60％，最优选为至少90％。
关于用作药物的5-HT2A受体拮抗性化合物的实施方式排除酮色林。
本发明还涉及有关支气管收缩的机能障碍的治疗方法，其中所述方法包括将治疗学上有效量的、对5-HT4受体具有激动活性的本发明化合物对人或动物患者给药。优选地，所述方法涉及哮喘和与之有关的障碍的治疗。
本发明还涉及有关支气管收缩的机能障碍的治疗方法，其中所述方法包括将治疗学上有效量的、对5-HT2A受体具有拮抗活性的本发明化合物对人或动物患者给药。优选地，所述方法涉及哮喘和与之有关的障碍的治疗。
进而，本发明涉及有关支气管收缩的机能障碍的治疗方法，其中将上述激动剂与拮抗剂的组合给药。
本专利申请所用的表达方式“能够减少病理性支气管收缩达至少……％”表示，该化合物减少由(1)所患疾病(哮喘等)或者(2)5-HT或其他具有5-HT2A-激活性质的物质给药所导致的气道收缩。气道收缩的水平例如可以这样测定，进行用力呼吸体积量(FEV1)的肺活量测定，并与健康人的正常值比较。或者，可以比较患者的呼气容量与其自身在相对少的阻塞性问题期间的FEV1。
如图1所示，收缩性成分经常引起5-HT诱发松弛的减少或完全消除，而不引起对照(处理前)水平力量的增加。在5-HT4受体“特异性”激动剂的情况下，实现了这种持续的松弛效应，因为收缩性5-HT2A受体不受影响；仅有松弛性5-HT4受体被激活。在5-HT2A受体拮抗剂的情况下，由于直接阻滞5-HT2A受体而实现了这种效应，由此5-HT4受体非特异性激动剂、例如5-HT可以发挥作用，且不导致由5-HT2A受体引起的收缩。
应当注意，按照本发明各实施方式制备的药物可以可选地包括两种或多种上述化合物。
进而，在将具有5-HT2A激动活性的化合物以及可选的补充性血清素或其衍生物给药的实施方式中，为了增强松弛效应，可以加入血清素摄取抑制剂。
按照本发明制备的药物的典型每日剂量可以是一个宽的范围，这将取决于各种因素，例如每名患者的个别需要和给药的途径。
所述药物可以制成适合于经由呼吸道给药的组合物或者适合于口服、静脉内、局部、腹膜内或皮下给药的组合物，连同本领域熟知的、一种或多种药学上可接受的载体、稀释剂或助剂。
而且，所述药物优选地经由呼吸道给药，剂型例如气雾剂或空气悬浮的微粉。不过，在有些情况下，可以用于替代经由呼吸道给药的是口服、局部、肠胃外、皮下、透皮或直肠给药，其中例如采用片剂、胶囊剂、粉剂、微粒剂、颗粒剂、糖浆剂、悬液、溶液、透皮贴剂或栓剂。
附图的简要说明
图1描绘5-HT和选择性5-HT4激动剂体外制剂对人自发性音调的效应。注意到5-HT仅给出短暂的松弛，而选择性5-HT4激动剂给出强烈的持续的松弛效应。
详细说明
本发明的主题尤其是从动物实验推导而来的，其中检查了气道平滑肌的特定行为，称为“自发性音调”。自发性音调涉及气道平滑肌的自发性连续收缩，研究它的理由是怀疑自发性音调的调节缺陷可能是在哮喘患者中观察到的支气管缩小的一个重要原因。
按照论文“豚鼠气管自发性音调的调节”(Regulation ofspontaneous tone in guinea pig trachea)，S.Skogvall，Department of Physiological Sciences，Lund University，1999所公开的方法进行自发性音调的检查，引用在此作为参考文献。正如这些检查所证明的，如果处于生理条件下，气道通常表现非常规则的振动音，各种物质给药能够可逆地影响振动音。当除去上皮后，制备物代之以表现强烈的平滑的音调。
简而言之，所述论文中的动物实验显示，自发性音调在很大程度上受到从神经上皮内分泌(NEE)细胞释放的强大调节因子的控制。
没有包括在该论文中的以后的实验已经揭示，这些调节因子之一是血清素，也称5-HT，它对5-HT1、5-HT4、5-HT5、5-HT6和5-HT7受体以及5-HT2受体发挥激动作用。
另有实验已经显示，当向从豚鼠剥脱的气道平滑肌制备物加入1μM血清素后，表现强烈的平滑的自发性音调，平均力量水平显著增加，也就是观察到收缩。血清素对气道平滑肌的收缩效应例如已经报道在Skogvall，S.，Korsgren，M.，Grampp，W.《应用生理学杂志》(J.Appl.Phys.)，86：789-798，1999。不过，当加入10μM血清素后，自发性音调被显著抑制到在对照(不含药物)条件下所观察到的力量水平的大约一半。当制备物再次处于对照条件下，自发性音调恢复至大约其正常水平。因而，现已惊人地显示，血清素在低浓度下引起气道收缩，在高浓度下引起松弛，所以对气道具有双重效应。
此外，已经显示，当收缩性5-HT2A受体被酮色林阻滞后，5-HT、即血清素几乎不诱发收缩，但是仅代之以显著的松弛。也已经利用体外制备物对人进行了类似的实验，因患肺癌患者已接受叶切除术或肺切除术(pulmectomy)。发现在该组织中，5-HT在松弛气道平滑肌上甚至比对豚鼠更有力。在人的组织中，1μM 5-HT就已经诱发自发性音调的显著松弛。
一般认为，当与5-HT接触后，人的气道仅表现微弱的收缩。无论如何，体外制备物的人自发性音调检查已经显示，5-HT的确在该组织中也具有收缩性成分。不过，这种收缩需要比豚鼠更长的时间才能形成，并且见到该收缩效应是松弛的结束，而不是基线水平音调的增加。在豚鼠气管中，收缩在大约10分钟后达到最大值，继之以音调的明显降低。不过，人的制备物代之以在5-10分钟后诱发最大松弛效应，在随后的30-45分钟内逐渐消失(见图1)。5-HT松弛的短暂性原因最有可能是快速松弛性5-HT4受体的同时活化和收缩性5-HT2A受体的较慢活化。这是明确无误的，因为松弛性5-HT4受体被缺乏5-HT2A受体激活性质的物质(例如5-酰氨基色胺或SC53116)激活，导致持久而非短暂的松弛(见图1)。
以前已经有人提出，5-HT或5-HT类似物可以用于支气管阻塞性疾病的治疗。SU1,701,320提出，5-HT、即血清素可以用以添加标准β2受体的刺激作用。不过，我们的实验明确了由于5-HT的短暂松弛效应，5-HT作为例如哮喘性障碍的唯一治疗不是有效的或有用的(见图1)。相反，正如我们在本文中所建议的，如果给以缺乏5-HT2A激活性质的5-HT类似物，那么松弛效应就是持久性的，而不是短暂性的。
总之，现已发现，对5-HT4受体的激动作用导致松弛效应，而对5-HT2A受体的激动作用导致收缩效应。最后，血清素的双重效应最有可能是其对松弛性5-HT4受体以及对收缩性5-HT2A受体的激动作用的结果。
从这些实验也可以推断，对5-HT4受体具有激动活性、对5-HT2A受体仅具有低的或者没有激动活性的化合物因此作为药物，可用于支气管收缩障碍的治疗。
因而，本发明涉及对5-HT4受体具有激动活性的化合物在药物制备中的用途，该药物打算用于支气管收缩障碍的治疗，其中所述化合物具有强烈的血清素的支气管松弛效应，但是基本上不具有收缩效应。如上所述，按照本发明所用的化合物对5-HT2A受体仅具有低的或者没有激动活性。
上述实验还显示，对5-HT2A受体具有拮抗活性的化合物作为药物，可用于支气管收缩障碍的治疗，因为它们能够阻滞对5-HT2A受体具有激动活性的化合物的收缩效应。为了获得增强的收缩效应，对5-HT2A受体具有拮抗活性的本发明化合物甚至可以与血清素一起给药，作为体内已经存在的血清素成分的补充；或者与任何其他对5-HT2A受体具有激动活性的物质一起给药；或者与血清素摄取抑制剂一起给药。
所述给药可以是同时或先后进行的，以这种方式可以实现对支气管的强大松弛效应。因而，本发明还涉及对5-HT2A受体具有拮抗活性的化合物与对5-HT4受体具有激动活性的化合物联合在药物制备中的用途，该药物用于有关支气管收缩的机能障碍的治疗或预防。按照本发明进一步有用的5-HT4激动剂结构
Figure A0080861700161
具体地是
Figure A0080861700163
1-哌啶乙醇的芳基氨基甲酸酯衍生物4-氨基-5-氯-2-甲氧基苯甲酸酯，例如ML10302、RS57639和SR597684-氨基-5-氯-2-甲氧基-N-((2S，4S)-1-乙基-2-羟甲基-4-吡略烷基)苯甲酰胺，例如TKS159噻吩酰胺衍生物3(a-j)5.氮杂二环(x.y.z)衍生物2-哌嗪基苯并噁唑衍生物2-哌嗪基苯并噻唑衍生物，例如VB20B7氯波必利Sandoz化合物1b
，具体地是
Figure A0080861700165
Figure A0080861700166
，具体地是
Figure A0080861700167
Figure A0080861700171
Figure A0080861700172
，具体地是
Figure A0080861700173

Claims (17)

1、用作药物的、对5-HT4受体具有激动活性的化合物及其对5-HT4受体具有激动活性的衍生物和药学上可接受的盐，该药物用于有关支气管收缩的机能障碍的治疗。
2、根据权利要求1的化合物，其中所述化合物能够减少病理性支气管收缩达至少30％，优选为至少60％，最优选为至少90％，其中所述化合物选自5-酰氨基色胺、BIMU1、BIMU8、BRL24924、西沙必利、DAU6236、5-羟基-N，N-二甲基色胺、ML-1035、ML10302、5-甲氧基色胺、甲氧氯普胺、莫沙必利、8-OH-DPAT(8-羟基-2-二丙氨基四氢化萘)、普鲁卡罗必利、R076186、R093877、伦扎必利、RS17017、RS56532、RS57639、RS67333、RS67506、RS67532、SB204070、SB205149、SC-53116、SC-49518、SK-951、SDZ216-454、SR59768、TKS159、VB20B7、YM-47813、YM-53389、YM-09151、扎考必利和泽玛克。
3、根据权利要求2的化合物，其中所述支气管收缩出现在哮喘和与之有关的障碍、肺气肿、慢性支气管炎、慢性阻塞性肺病、抑郁、食欲缺乏性或食欲过盛性进食障碍、焦虑或各种精神病状态，包括精神分裂症。
4、根据权利要求1和2的、对5-HT4受体具有激动活性的一种或多种化合物及其对5-HT4受体具有激动活性的衍生物和药学上可接受的盐的用途，可选择性地与一种血清素摄取抑制剂一起用于药物的制备，该药物用于有关支气管收缩的机能障碍的治疗或预防。
5、根据权利要求4的用途，其中所述一种或多种化合物能够减少病理性支气管收缩达至少30％，优选为至少60％，最优选为至少90％，其中所述化合物选自5-酰氨基色胺、BIMU1、BIMU8、BRL24924、西沙必利、DAU6236、5-羟基-N，N-二甲基色胺、ML-1035、ML10302、5-甲氧基色胺、甲氧氯普胺、莫沙必利、8-OH-DPAT(8-羟基-2-二丙氨基四氢化萘)、普鲁卡罗必利、R076186、R093877、伦扎必利、RS17017、RS56532、RS57639、RS67333、RS67506、RS67532、SB204070、SB205149、SC-53116、SC-49518、SK-951、SDZ216-454、SR59768、TKS159、VB20B7、YM-47813、YM-53389、YM-09151、扎考必利和泽玛克。
6、根据权利要求4和5的用途，其中所述具有病理性支气管收缩的机能障碍是哮喘和与之有关的障碍、肺气肿、慢性支气管炎、慢性阻塞性肺病、抑郁、食欲缺乏性或食欲过盛性进食障碍、焦虑或各种精神病状态，包括精神分裂症。
7、有关支气管收缩的机能障碍的治疗方法，其中所述方法包括将治疗学上有效量的根据权利要求1的化合物对人或动物患者给药。
8、用作药物的、对5-HT2A受体具有拮抗活性的化合物及其对5-HT2A受体具有拮抗活性的衍生物和药学上可接受的盐，该药物用于有关支气管收缩的机能障碍的治疗。
9、根据权利要求8的化合物，其中所述化合物能够减少病理性支气管收缩达至少30％，优选为至少60％，最优选为至少90％，其中所述化合物选自AMI-193、MDL100，907、ALEPH-2、安哌齐特、安麦角、芳氧基烷基咪唑啉、1-芳基-4-丙基哌嗪、BIMT17、1-3-[4-(3-氯苯基)-1-哌嗪基]丙基-6-氟二氢吲哚-2(1H)-酮、CGS18102A、可乐定、赛庚啶、德伦环烷、去甲基-WAY100635、多他利嗪、DV7028、野麦角碱、法南色林、8-[3-(4-氟苯甲酰基)丙基]-1-甲基-1，3，8-三氮杂螺[4，5]癸-4-酮、FG5893盐酸盐、FG5974、FG5983、六氢咔唑、(3H)WAY100635、ICI169，369、8-[3-(4-碘苯甲酰基)丙基]-1-甲基-1，3，8-三氮杂螺[4，5]癸-4-酮、酮色林、LEK-8804、LSD、LU111995、(S，S)-LY-53，857、(R，S)-LY-53，857、(S，R)-LY-53，857、(R，R)-LY-53，857、LY-53，857游离碱、LY215840、MDL-11，939、MDL28133A、MDL100，151、MDL100，907、美舒麦角、甲麦角林、1-3-[4-(2-甲氧基苯基)-1-哌嗪基]丙基二氢吲哚-2(1H)-酮、美西麦角、米安色林、NE-100、奈法唑酮、N-乙氧羰基-2-乙氧基-1，2-二氢喹啉、NRA0045、奥氮平、昂丹司琼、1-(2-嘧啶基)哌嗪衍生物、苯噻啶、雷氯必利、罗克吲哚、利培酮、利坦色林、RP62203，
沙格雷酯及其活性代谢产物(M-1)，血清素再摄取抑制剂，象氟西汀、YM992、美地沙明、西立氯胺、丙米嗪、伊普吲哚、BIMT17、西酞普兰、帕罗西汀、舍曲林、氟伏沙明、被3-(二甲氨基)-丙基链N-取代的螺吲哚，
螺哌隆、SR46349B、WAY100635和WY-50，324。
10、根据权利要求9的化合物，其中所述支气管收缩出现在哮喘和与之有关的障碍、肺气肿、慢性支气管炎、慢性阻塞性肺病、抑郁、食欲缺乏性或食欲过盛性进食障碍、焦虑或各种精神病状态，包括精神分裂症。
11、根据权利要求8和9的、包括酮色林的对5-HT2A受体具有拮抗活性的一种或多种化合物及其对5-HT2A受体具有拮抗活性的衍生物和药学上可接受的盐的用途，可选择性地与一种血清素摄取抑制剂一起用于药物的制备，该药物用于有关支气管收缩的机能障碍的治疗或预防。
12、根据权利要求11的用途，其中所述一种或多种化合物能够减少病理性支气管收缩达至少30％，优选为至少60％，最优选为至少90％，其中所述化合物选自酮色林、AMI-193、MDL100，907、ALEPH-2、安哌齐特、安麦角、芳氧基烷基咪唑啉、1-芳基-4-丙基哌嗪、BIMT17、1-3-[4-(3-氯苯基)-1-哌嗪基]丙基-6-氟二氢吲哚-2(1H)-酮、CGS18102A、可乐定、赛庚啶、德伦环烷、去甲基-WAY100635、多他利嗪、DV7028、野麦角碱、法南色林、8-[3-(4-氟苯甲酰基)丙基]-1-甲基-1，3，8-三氮杂螺[4，5]癸-4-酮、FG5893盐酸盐、FG5974、FG5983、六氢咔唑、(3H)WAY 100635、ICI169，369、8-[3-(4-碘苯甲酰基)丙基]-1-甲基-1，3，8-三氮杂螺[4，5]癸-4-酮、酮色林、LEK-8804、LSD、LU111995、(S，S)-LY-53，857、(R，S)-LY-53，857、(S，R)-LY-53，857、(R，R)-LY-53，857、LY-53，857游离碱、LY215840、MDL-11，939、MDL28133A、MDL100，151、MDL100，907、美舒麦角、甲麦角林、1-3-[4-(2-甲氧基苯基)-1-哌嗪基]丙基二氢吲哚-2(1H)-酮、美西麦角、米安色林、NE-100、奈法唑酮、N-乙氧羰基-2-乙氧基-1，2-二氢喹啉、NRA0045、奥氮平、昂丹司琼、1-(2-嘧啶基)哌嗪衍生物、苯噻啶、雷氯必利、罗克吲哚、利培酮、利坦色林、RP62203，
沙格雷酯及其活性代谢产物(M-1)，血清素再摄取抑制剂，象氟西汀、YM992、美地沙明、西立氯胺、丙米嗪、伊普吲哚、BIMT17、西酞普兰、帕罗西汀、舍曲林、氟伏沙明、被3-(二甲氨基)-丙基链N-取代的螺吲哚，
螺哌隆、SR46349B、WAY100635和WY-50，324。
13、根据权利要求11和12的一种或多种化合物的用途，同时或先后与对5-HT4受体具有激动活性的化合物结合，可选择性地与一种血清素摄取抑制剂一起用于药物的制备，该药物用于有关支气管收缩的机能障碍的治疗或预防。
14、根据权利要求13的用途，其中所述对5-HT4受体具有激动活性的化合物是血清素及其衍生物或根据权利要求1和2的化合物。
15、根据权利要求11-14的用途，其中所述具有病理性支气管收缩的机能障碍是哮喘和与之有关的障碍、肺气肿、慢性支气管炎、慢性阻塞性肺病、抑郁、食欲缺乏性或食欲过盛性进食障碍、焦虑或各种精神病状态，包括精神分裂症。
16、有关支气管收缩的机能障碍的治疗方法，其中所述方法包括将治疗学上有效量的根据权利要求11-14的化合物对人或动物患者给药。
17、用作药物的组合物，包含如权利要求13和14所定义的化合物的组合，该药物用于有关支气管收缩的机能障碍的治疗。
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