RECEPTOR AGONISTS AND ANTAGONISTS

Abstract: The present invention relates to a compound having agonist activity to the 5-HT4 receptor for use as a medicament and to the use of said compounds in the manufacture of a medicament for use in therapeutic or prophylactic treatment of disorders involving bronchocontraction of a human or animal body, as well as methods of treatment, wherein said compounds are administered. The present invention also relates to a compound having antagonist activity to the 5-HT3 receptor for use as a medicament and to the use of said compound in the manufacture of a medicament for use in therapeutic or prophylactic treatment of disorders involving bronchocontraction of a human or animal body, as well as methods of treatment, wherein said compounds are administered.

Description: RECEPTOR AGONISTS AND ANTAGONISTS Field of the Invention The present invention relates to a compound having agonist activity to the 5-HT 4 receptor for use as a medicament and to the use of said compound in the manu- facture of a medicament for therapeutic or prophylactic treatment of disorders involving bronchocontraction of a human or animal body, as well as methods of treatment, wherein said compound is administered. The present invention also relates to a compound having antagonist activ- ity to the 5-HT 3 receptor for use as a medicament and to the use of said compound in the manufacture of a medicament for therapeutic or prophylactic treatment of disorders involving bronchocontraction of a human or animal body, as well as methods of treatment, wherein said com- pound is administered. Background of the Invention Receptors of the 5-HT (serotonin; 3- (β-aminoethyl) - 5-hydroxyindole) type are well known and occur throughout the body, e.g. in the airways, and their relevance has mainly been reported in conjunction v/ith treatment of CNS, muscle and gastric disorders, as disclosed in e.g. WO 98/18458 and US 5 246 935. In such treatments, compounds having agonist activity to a 5-HTι type receptor are often used. As examples of other 5-HT receptors, men- tion can be made of receptors of the 5-HT 2 , 5-HT 3/ 5-HT 4 , 5-HT 5 , 5-HT 6 and 5-HT 7 type. For a recent review of 5-HT receptors, see Gerhardt, C.C., van Heerikhuizen, H. , Eur. J. Pharm. , 334, 1-23 (1997), which is incorporated herein by reference. A review of typical agonists and antagonists of various 5-HT receptors is disclosed in R.A. Glennon, Neu- roscience and Biobehavioral Reviews, 14, 35-47 (1990), the whole content of which is incorporated herein by reference . SU 1 701 320 Al discloses the use of serotonin for treatment of acute asthma attacks. This reference does not suggest any receptor mechanism for serotonin, which is a compound with both a contracting and a relaxing ef- feet on the airways, as is further discussed herein below. In the RBI Handbook or Receptor Classification and Signal Transduction, 3 rd Edition, 1998, RBI, One Strathmore Road, Natick, MA 01760-2447, USA, Editor: Keith J. Watling are compounds having agonist or antagonist activity to various receptors disclosed. Disclosure of the Invention The present invention is based on the novel finding that certain 5-HT receptors are of utmost importance in regulating bronchocontraction. In summary, it is disclosed herein that compounds having agonist activity to the 5-HT 4 receptor bring about a bronchorelaxing action upon administration thereof, and are therefore suitable as agents for treatment of bronchocontraction disorders. It is also disclosed herein that compounds having antagonist activity to the 5-HT 3 receptor, are suitable agents in the treatment of bronchocontraction disorders. Methods for treatment of bronchocontraction disorders are also disclosed. As used herein, the expression bronchocontraction disorder refers to an abnormal increase of the force development of the smooth muscle, resulting in a reduced diameter in some or all of the airways of the lungs and/- or the extrapulmonary airways. Said expression also re- fers to reduction of airflow caused by swelling, oedema, plasma extravasation or mucous secretion caused by e. g. asthma or any other disorder related thereto. Accordingly, the present invention relates, in one of its aspects, to a compound having agonist activity to the 5-HT 4 receptor for use as a medicament. In another aspect it relates to use of said compound in the manufacture of a medicament for therapeutic or prophylactic treatment of a human or animal body, wherein the medicament is intended for treatment of disorders involving bronchocontraction, such as asthma. In a preferred embodiment, the invention relates to the use of a compound having agonist activity to the 5-HT 4 receptor in the manufacture of a medicament for therapeutic or prophylactic treatment of disorders involving bronchocontraction, wherein said agonist has the capacity of reducing the pathological bronchocontraction by at least 30%, preferably at least 60%, and most preferably at least 90%. The present invention also relates, in another aspect, to a compound having antagonist activity to the 5-HT 3 receptor for use as a medicament. In another aspect it relates to use of said compound in the manufacture of a medicament for therapeutic or prophylactic treatment of a human or animal body, wherein the medicament is intended for treatment of disorders involving bronchocontraction, such as asthma. In a preferred embodiment, the invention relates to the use of a compound having antagonist activity to a 5-HT 2a receptor in the manufacture of a medicament for therapeutic or prophylactic treatment of disorders involving bronchocontraction, wherein said antagonist has the capacity of reducing the pathological bronchocontraction by at least 30%, preferably at least 60%, and most preferably at least 90%. Said bronchocontraction may also occur in conjunction with such disorders as e . g. emphysema, chronic bron- chitis, chronic obstructive pulmonary disease, depression, anorectic or bulimic eating disorders, anxiety or various psychotic conditions, including schizophrenia. The present invention also relates to the use of a compound having antagonist activity to a 5-HT 3 receptor in combination with a compound having agonist activity to the 5-HT 4 receptor in the manufacture of a medicament for therapeutic or prophylactic treatment of disorders in- volving bronchocontraction. In a preferred embodiment said compound having agonist activity is serotonin or a derivative thereof having agonist activity to the 5-HT 4 receptor. This combination of the 5-HT 3 receptor antago- nist and the agonist increases the beneficial effect of serotonin, particularly in the presence of a serotonin uptake inhibitor (SRI) . Further, the compounds having agonist activity to the 5-HT 4 receptor to be used according to the present invention are also useful in the pres- ent combination embodiment. In particular, said medicament is intended for treatment of asthma and disorders related thereto. According to the present invention several known substances are able to stimulate the 5-HT 4 receptor, without activating the contracting 5-HT 3 receptor, thereby, surprisingly, generating a relaxing effect on the bronchocontraction. Such agonist compounds are selected from the group comprising the substances SC 53116, ML 10302, RS 67506 and BIMU 8, which are defined below, as well as the more unspecific 5-carboxamidotryptamine, and derivatives and pharmaceutically acceptable salts thereof having the same or essentially the same relaxation effect. The invention also relates to the use of one or more of the above-mentioned agonist compounds: SC 53116, i.e. 4-amino-5-chloro-N- { [IS, 7aS) -hexahydro-lH-pyrrolizin-1- yl] methyl] -2 - ethoxy-benzamide, having the structural formula: ML 10302, i.e. 4-amino-5-chloro-2-methoxy-benzoic acid-2- (1-piperidinyl) ethylester, having the structural formula : RS 67506, i.e. N- [2- [4 - [3 - (4-amino-5-chloro-2- methoxyphenyl) -3 -oxopropyl] -1-piperidinyl] ethyl] - methanesulfonamide monohydrochloride, having the structural formula: BIMU 8, i.e. 2 , 3-dihydro-N- [ (3-endo) -8 -methyl- 8- azabicyclo [3.2.1] oct-3-yl) -3- (1-methylethyl) -2-oxo-lH- benzimidazole-1-carboxamide monohydrochloride, having the structural formula: 5-carboxamidotryptamine (5-CT) having the structural formula: ADR932, BIMU 1, BRL 20627, BRL 24682, BRL 24924, Cinita- prid, Cisapride, DAU 6215, DAU 6236, 5-HT, 5-hydroxy-N,N-dimetyltryptamin, 3-Me-8-OH-DPAT, ML-1035, 5-metoxytryptamin, Metoclopramide, Mosapride, 8-OH-DPAT (8-hydroxy-2-dipropylaminotetralin) , Prucalopride, R 076186, R 093877 (prucalopride) , Renza- pride, RS 17017, RS 23597-190, RS 56532, RΞ 57639, RS 67333, RS 67532, RU 28253 SB 204070, SB 205149, SC-52491, SC-49518, SK-951, SDZ 216-454, SR59768, TKS159, VB20B7, Y-34959, YM-47813, YM-53389, YM-09151, Zacopride, Zelmac (SDZ HTF919; tega- serod) and derivatives and pharmaceutically acceptable salts thereof having essentially the same relaxing effect, in the manufacture of a medicament for therapeutic or prophylactic treatment of disorders involving bronchocontraction, wherein said agonist has the capacity of re- ducing the bronchocontraction by at least 30%, preferably at least 60%, most preferably at least 90%. Most of the different 5-HT 4 agonists can be divided in certain groups, wherein each group contains a common structural element. The largest group, and also the basis for several others, are the benzamides . They all contain the structural element 4-amino-5-chloro-2-methoxy benza- mide and are further developments of the first 5-HT 4 agonist, metoclopramide . These compounds are also potent 5-HT3-antagonists: 3-(4-Allylpiperazin-l-yl)-2-quinoxalinecarbonitrile 5-[(Dimethylammo)methyl] -3 -(1 -methyl- 1 H-indol-3 -yl)-l ,2,4-oxadizole 3-(l -Pipeτa-zinyl)-2-quinoxalinecarbonitrile Granisetron RS-25259-197 SEC-579, Mirisetron SC-52491 KB-6933 BRL 46470, Ricasetron Lerise ron KAE-393/ΥM-114 AS-5370 DAT-582 N-3256 SDZ 214-322 KF-20170 Lurosetron Galdansetron ONO-3051 CP-93318 Batanopride GR 67330 SDZ 206-830 QICS 205-930 BRL 24682 LY 258-458 Zacopride, S(-)Zacopride, R(+)Zacopride RP 62203 SDZ 206-792 BRL 47204 SDZ 210-204 LY-21 1-000 MCPP MK 212 i ianserin SDZ 210-205 Bufotenine Pitozifen Indalptne Cizapride Cyproheptadine 2-Methyl-5HT Amitriptyline LY 278-989 Imipramine Phenylbiguanide TFMPP 5,7-DHT RU 24969 Ritanserin NA -190 Mepyramine Metergoline Methysergide These compounds are also potent 5-HT4-agonists: Bufotenine 5-MeO-N,N,DMT GR 113,808 α-Metyl-5HT Another common feature is a basic nitrogen in a side chain from the amide nitrogen. This basic nitrogen is often a part of a sterically locked system. Examples of substances from this group are: BRL 20627, BRL 24682, BRL 24924, Cisapride, Metoclo- pramide, ML-1035, Mosapride, R076186, Renzapride, RS 67506, Cinitapride, SB 205149, SC-49518, SC-52491, SC- 53116, TKS 159, Y-34959, YM-09151, YM-47813, Zacopride. Thus, a structure-activity relation study performed indicates that a benzene ring and a basic nitrogen in the same plane as the ring and at a distance of 8±1 A from the center of the benzene ring is required. The nitrogen should be locked in that position with a view to obtaining selectivity against other 5-HT receptors. A lipo- philic group on the basic nitrogen also seems to be important for the agonistic action. Further, a heteroatom having a free electron pair close to the indole nitrogen in tryptamine seems to give a positive effect. Benzoic acid esthers are modifications of the benza- mide theme : The only difference is that the amide group has been replaced with an esther group. Examples are ML 10302, RS 57639, and SR 59768. Another variant of the basic theme is to introduce the methoxy group into a ring, thereby arriving at a 2,3- dihydro-bensofuran-7-karboxamide group. Examples are ADR 932, Prucalopride (=R 093877); and SK-951. Benzofuranes and benzotiophenes are also contemplated, as well as the benzodioxan Still another variant is based on the discovery that the benzoic acid antagonist RS 23597 (an esther) was transformed to an agonist if it was converted to a ketone , e.g. RS 67333 and RS 17017. The basic concept also applies for naphtalimides , Benzindolones are also contemplated The amide fuction may also be replaced with an oxa- diazol ring. Benzimidazolone-1-carboxamides , e.g. BIMU 1, BIMU 8, DAU 6215, and DAU 6236, are also contemplated . The carboamides are also contemplated. Some indols are olso useful as 5-HT 4 agonists, e.g. 5-methoxytryptamine, 2-methylserotonine, and 5-hydroxy- N,N-di-methyltryptamine . Other tested substances useful as 5 -HT4 agonists according to the present invent ion are SDZ 216-454 Zelmac=SDZ HTF 19 NB20B7 It should be noted that many of these substances may be quaternized on the nitrogen in the side chain without losing the activity. The most active agonist at present seems to be Zelmac . Benzokinolinones Further 5-HT4 agonist structures useful according to the present invention 2-piperidinmethylethers , particularly kinolines , particularly , particularly bensopyranes The most preferred 5-HT 4 receptor agonist is RS 67333. According to the present invention several known antagonist compounds are, surprisingly, able to influence the 5-HT 3 receptor, thereby generating a contraction reducing effect, i.e. a relaxation effect, and are selected from a group comprising 4-Ph-N-Me-quipazine, ADR-851, ADR-882, Alosetron, Anpirtoline, Azasetron (=Y 25130), BIMU 1, BMY 33462, BRL 24924, BRL 43694, BRL 46470 A, CF 109203 (=BIM) , Chlorpromazine , Cilansetron (=KC 9946) , Cisapride, Clozapine, Cyameazine, DAT-582 (= (R) AS-5370) , Diltiazem, Dolasetron (=MDL 74156) , Dolasetron esilat (=MDL 73147 EF) , Droperidol , FK 1052, Fluphenazone, Gala- nolactone, GK 128, GR 38032 F, GR 65630, Gramisetron (=Kytril=BRL 43694), GR-H, GYKl-48903, ICI 169369, ICS 205-930, Ifenprodil, Iodophenpropit , Itasetron (=DAU 6215), KB-6922, KB-R 6933, KF 17643, KF 18259, L-683877, Litoxetine, LY 278584, McNeil-A-343 , MDL 72222, MDL 72699, Metoclopramid, Mirtazapine, Mosapride, N-3389, N-metylquipazin, Ondansetron (=GR 38032 F) , Palonosetron, Pancopride, Perphenazine , Prochlorperazine (=Stemetil), Quipazine, QX 222, (R) -zacopride , Ra osetron (=YM 060), Renzapride, RG 12915, RS-25259, RS 42358-197, RS 56532, RS-056812-198, RS-25259-197 , RS-56812, S-apomorfin, SC- 53116, SDZ 216-525, SDZ 322, SN-307, Talipexole, Thioper- amide, TMB 8, Trifluoperzine , Trimebutine, Tropisetron (=ICS 205-930=Rifenserin) , VA 21 B 7, Way 100289, WAY- 100579, WAY-SEC-579, Y 2513, YM 114 (=KAE-393), Zatose- tron (=LY 277359) and pharmaceutically acceptable salts thereof having the same or essentially the same contraction reducing effect. The present invention also relates to the use of one or more of the above-mentioned 5-HT 3 antagonist compounds and to derivatives and pharmaceutically acceptable salts thereof having essentially the same contraction reducing effect, in the manufacture of a medicament for therapeutic or prophylactic treatment of disorders involving bronchocontraction, wherein said antagonist has the capacity of reducing the pathological bronchocontraction by at least 30%, preferably at least 60%, and most preferably at least 90%. The 5-HT3 receptor is a ligand modulated ion channel . The known anxiety repressing bensodiazepines influence not only 5-HT3 but also several other receptors for different neurotransmittors . Several potent specific 5- HT3 antagonists exist today, of which ondansetron, tro- pisetron, granisetron, and dolasetron are commercial pharmaceuticals, however, not against disorders involving bronchocontraction . Some of the 5-HT3 receptor antagonists are at the same time 5-HT4 receptor agonists. However, for a substance to be active as a 5-HT3 receptor antagonist, the distance from the aromatic center to the basic nitrogen should be about 7,5 A and no large substituents are tolerated on the basic nitrogen. In contrast, for 5-HT4 receptor agonists the corresponding distance is about 8 A, and a large lipophilic group may be bound to the basic notrogen, thereby obtaining a better binding to 5-HT4. The 5-HT3 antagonist may be divided in certain classes with the basis on the chemical structure. Some are unspecific, benzazepines , e.g. mirtazapine benztiazephines , e . g . diltiazem and fentiazines e.g. perphenazine, chlorpromazine, stemetil Some are 5-HT4 agonists, e.g. benzamides , - and 2 , 3 -dihydro-benzof uran- 7 -carboxamides (e.g. zatosetron=LY 277359, ADR 851) 1 , 4 -bensoxazin- 8 -carboxamides e.g. azasetron (=Y25130) benzimidazolones e.g. itasetron (=DAU 6215) indazol -3 -carboxamides , e.g. N 3389, LY 278584, DAT 582 The latter group reminds most of the specific 5-HT3 antagonists, which after contains the group in different forms, such as ondansetron cilansetron alosetron ramosctron GR 65630 tropisetron dolasetron RS 56812 L 683877 In one group of substances the structure has been inverted and the carbonyl group has been placed on the indoline nitrogen This substance is unique by being an antagonist against both 5-HT 3 and 5-HT 4 . BRL 46470A binds to two different positions of the recep- tor. A further development is the so-called bisindoles Another group is the isoquinoline-1-ones palonosetron ( =RS 25259 - 197 ) RS 42358 - 197 and the quinoline-3-carboxarrtides WAY-SEC 579 Mirisetron (=WAY 100579) Also the quinoline-4-carboxylates are active antagonists e.g. KF 18259 Other compounds are benzimidazolones e.g. droperidol (neurolidol, etc.) , itasetron (DAU6215) , and the naphtimides , e.g. RS 56532 A unique single structure is MDL 72222, which also is a specific 5-HT 3 antagonist Other specific structures are Talipexole Galnπolakfon 30 35 iodophenr-vv-opit thioperamide , and 2-piperidin- and 2-piperazin- benzimidazoles . The most preferred 5-HT 3 receptor antagonist is tro- panyl -3 , 5 -dimethylbenzoate . The present invention also relates to a method for treatment of disorders involving bronchocontraction, wherein said method comprises administering to a human or animal patient a therapeutically effective amount of the compound according to the present invention having agonist activity to the 5-HT 4 receptor. Preferably, said method relates to the treatment of asthma and disorders related thereto. The present invention also relates to a method for treatment of disorders involving bronchocontraction, wherein said method comprises administering to a human or animal patient a therapeutically effective amount of a compound according to the present invention having antagonist activity to a 5-HT 3 receptor. Preferably, said method relates to treatment of asthma and disorders related thereto. Further, the present invention relates to a method for treatment of disorders involving bronchocontraction, wherein the above-mentioned combination of agonist (s) and antagonist (s) is administered. The expression "has the capacity of reducing the pathological bronchocontraction by at least ....%" used throughout the present patent application means that the compound in question reduces the contraction in the airways caused (1) either by the underlying disease (asthma etc) or (2) by the administration of 5-HT or other substances with 5 -HT3 -activating properties. The level of contraction in the airways can, for instance, be deter- mined by spirometric measurements of the Forced Expiratory Volume (FEV1) , compared to the normal value for healthy people. Alternatively, the expiratory capacity for a patient can be compared to his own FEV1 during periods of relatively little obstructive problems. As appears from Fig. 1, the contractile component often manifests itself as a reduction or a complete elimination of the 5-HT induced relaxation, rather than in an increase of force from the control (pre-exposure) level. In the case of "specific" agonists to the 5-HT receptor, this sustained relaxing effect is achieved because the contractile 5-HT 3 receptor is not affected; only the relaxing 5-HT 4 receptor is activated. In the case of antagonists to the 5-HT 3 receptor, this effect is achieved due to direct blocking of the 5-HT 3 receptor, whereby the unspecific agonists to the 5-HT 4 receptor, such as 5-HT, can act without also causing contraction by the 5-HT 3 receptor. It should be noted that the medicament prepared according to present invention in each embodiment may op- tionally include two or more of the above outlined compounds . Further, in the embodiment when the compound having 5-HT 3 antagonist activity is administered, optionally together with complementary serotonin or derivatives thereof, a serotonin uptake inhibitor can be added with a view to amplifying the relaxing effect. The typical daily dose of the medicament prepared according to the invention varies within a wide range and will depend on various factors such as the individual requirement of each patient and the route of administra- tion. Said medicament may be prepared as a composition adapted either for administration via the respiratory tract or for oral, intravenous, topical, intraperitoneal or subcutaneous administration, in association with one or more pharmaceutically acceptable carriers, diluents or adjuvants that are well known in the art. Moreover, said medicament is preferably administered via the respiratory tract in the form of e . g . an aerosol or an air- suspended fine powder. However, in some cases a useful alternative to administration via the respiratory tract may be oral, topical, parenteral, subcutaneous, transdermal or rectal administration, wherein e . g. tablets, capsules, powders, microparticles , granules, syrups, suspensions, solutions, transdermal patches or sup- positories are utilized. Brief Description of the Drawing Fig. 1 depicts the effects of 5-HT and the selective 5-HT 4 agonist RS 67333 on the spontaneous tone in human in vitro preparations. Note that 5-HT only gives a tran- sient relaxation, while selective 5-HT 4 agonists give a strong sustained relaxing effect . Detailed Description The subject-matter of the present invention was inter alia deduced from animal experiments, where a spe- cific behavior of the airway smooth muscle called "spontaneous tone" was examined. The spontaneous tone, which involves a spontaneous continuous contraction in the airway smooth muscle, was studied due to a suspicion that defective regulation of the spontaneous tone could be an important cause of the bronchoconstriction observed in asthmatic patients. The examinations of the spontaneous tone were performed in accordance with the methods disclosed in the thesis "Regulation of spontaneous tone in guinea pig tra chea " by S.Skogvall, Department of Physiological Sciences, Lund University, 1999, which is incorporated herein by reference. As evidenced by these examinations, the airways normally display a highly regular type of oscillating tone if exposed to physiological conditions, and the oscillating tone can be reversibly affected by administration of various substances. When the epithelium is removed, the preparations instead display a strong, smooth type of tone. In short, the animal experiments in said thesis showed that the spontaneous tone to a large degree is controlled by powerful regulating factors released from neuroepithelial endocrine (NEE) cells. Later experiments, not included in the thesis, have revealed that one of the regulating factors is serotonin, also called 5-HT, which exerts agonist action on the receptors 5-HTι, 5-HT 3 , 5-HT 4 , 5-HT 5 , 5-HT 6 and 5-HT 7 as well as on 5-HT 2 receptors. Additional experiments have shown that when 1 μM serotonin was added to denuded airway smooth muscle preparations from the guinea-pig displaying a strong, smooth spontaneous tone, the average force level was increased significantly, i.e. a contraction was observed. A contractile effect of serotonin on airway smooth muscle has been reported in e . g. Skogvall, S., Korsgren, M. , Grampp, W., J. Appl . Phys . , 86:789-798, 1999. However, when 10 μM of serotonin was added, the spontaneous tone was signifi- cantly suppressed to a level of about half the force observed in control (drug-free) conditions. The spontaneous tone returned to approximately its normal level when the preparations were again exposed to control conditions. Thus, it has now surprisingly been shown that serotonin brings about contraction of the airways at low concentrations and relaxation at high concentrations, consequently having a dual effect on the airways. Furthermore, it has been shown that when the contracting 5-HT 2a receptor was blocked with ketanserin, the 5-HT, i.e. serotonin, induced almost no contraction, but instead only a significant relaxation. Similar experi- ments have also been performed on human in vitro preparations, from patients undergoing lobecotomy or pulmectomy due to lung cancer. It was found that in this tissue, 5-HT was even more potent in relaxing the airway smooth muscle than in guinea pig. In human tissue, already 1 μM 5-HT induces a significant relaxation of the spontaneous tone . Human airways are generally considered to display only a weak contraction when exposed to 5-HT. Nevertheless, examinations on spontaneous tone on human in vitro preparations have shown that 5-HT indeed has a contractile component also in this tissue. However, this contraction takes a longer time to develop than in guinea pig and the contractile effect is seen as a termination of the relaxation, rather than an increase of tone from the baseline. In guinea pig trachea, the contraction reaches a maximum after approximately 10 min, and this is followed by a considerable reduction of tone. However, human preparations instead induce a maximum relaxing effect after 5-10 min, which disappears gradually during the following 30-45 min (see Fig 1) . The transient nature of the 5-HT relaxation is most likely caused by a simultaneous activation of the fast, relaxing 5-HT receptor, and a slower activation of the contracting receptor, which in human airways surprisingly has been found to be the 5-HT 3 receptor. This is clear, because activation of the relaxing 5-HT 4 receptor by a substance that lacks 5- HT 3 receptor activating properties (such as RS 67333), results in a relaxation that is persistent and not transient (see Fig. 1) . It has previously been suggested that 5-HT or 5-HT analogues may be useful in the treatment of bronchoob- structive diseases. In SU 1 701 320 it is suggested that the 5-HT, i.e. serotonin, may be of use as an addition to standard beta2 receptor stimulation. However, from our experiments it seems clear that 5-HT is not effective or useful as the only treatment for e.g. asthmatic disor- ders, because of the transient relaxing effect by 5-HT (see Fig. 1) . If instead, as we propose herein, a 5-HT analogue that lacks the 5-HT 3 activating properties is given, the relaxing effect is persistent, and not transient . In summary, it has now been discovered that agonist action on the 5-HT 4 receptor results in a relaxing effect, whereas agonist action on 5-HT 3 receptors results in a contractile effect. In conclusion, the dual effect of serotonin is most likely a result of its agonist ac- tion on the relaxing 5-HT 4 receptor as well as on the contracting 5-HT 3 receptor. It was also deduced from these experiments that compounds having agonist activity to the 5-HT 4 receptor, while having only low or no agonist activity to a 5-HT 3 receptor, therefore are useful as agents for treatment of bronchocontraction disorders. Thus, the present invention relates to the use of compounds having agonist activity to the 5-HT 4 receptor in the manufacture of a medicament intended for treatment of bronchocontraction disorders, whereby said compounds have the strong bronchorelaxing effect of serotonin but have substantially no contractile effect. As mentioned above, the compounds used according to the present invention have only low or no agonist activity to 5-HT 3 re- ceptors. In the above mentioned experiments it has also been shown that compounds having antagonist activity to a 5-HT 3 receptor are useful as agents for treatment of bronchocontraction disorders, since they are capable of blocking the contractile effect of a compound having agonist activity to a 5-HT 3 receptor. The compounds accord- ing to the present invention having antagonist activity to the 5-HT 3 receptor may even be administered together with serotonin in the form of a complement to the serotonin content already present in the body with a view to obtaining an amplified contracting effect; or with any other substance having agonist activity to the 5-HT 3 receptor; or with a serotonin uptake inhibitor. Said administration can be simultaneous or sequential, and a powerful relaxing effect on the bronchi can be achieved in this manner. Thus, the present invention also relates to the combined use of a compound having antagonist activity to a 5-HT 3 -receptor and a compound having agonist activity to the 5-HT 4 receptor, in the manufacture of a medicament for therapeutic or prophylactic treatment of disorders involving bronchocontraction.

Claims: CLAIMS 1. Compound having agonist activity to a 5-HT 4 receptor, and derivatives and pharmaceutically acceptable salts thereof having agonist activity to the 5-HT 4 receptor for use as a medicament for treatment of disorders involving bronchocontraction. 2. Compound according to claim 1, wherein said compound has the capacity of reducing pathological bronchocontraction by at least 30%, preferably at least 60%, and most preferably at least 90%, and wherein said compound is chosen from the group comprising SC 53116, i.e. 4- amino-5-chloro-N- [ [IS, 7aS) -hexahydro-lH-pyrrolizin-1- yl] methyl] -2 -methoxy-benzamide, having the structural formula : ML 10302 , i . e . 4 -amino- 5 -chloro-2 -methoxy-benzoic acid-2 - ( 1 -piperidinyl ) ethylester, having the structural formula : RS 67506, i.e. N- [2- [4- [3- (4-amino-5-chloro-2- methoxyphenyl) -3-oxopropyl] -1-piperidinyl] ethyl] - methanesulfonamide monohydrochloride, having the structural formula : BIMU 8, i.e. 2 , 3-dihydro-N- [ (3 -endo) - 8 -methyl -8- azabicyclo [3.2.1] oct-3-yl) -3- (1-methylethyl) -2-oxo-lH- benzimidazole-1-carboxamide monohydrochloride, having the structural formula: 5-carboxamidotryptamine (5-CT) , having the structural formula : ADR932, BIMU 1, BRL 20627, BRL 24682, BRL 24924, Cinita- prid, Cisapride, DAU 6215, DAU 6236, 5-HT, 5-hydroxy-N,N-dimetyltryptamin, 3-Me-8-OH-DPAT, ML-1035, 5-metoxytryptamin, Metoclopramide, Mosapride, 8-OH-DPAT (8-hydroxy-2-dipropylaminotetralin) , Prucalopride, R 076186, R 093877 (prucalopride) , Renza- pride, RS 17017, RS 23597-190, RS 56532, RS 57639, RS 67333, RS 67532, RU 28253 SB 204070, SB 205149, SC-52491, SC-49518, SK-951, SDZ 216-454, SR59768, TKS159, VB20B7, Y-34959, YM-47813, YM-53389, YM-09151, Zacopride, Zelmac (SDZ HTF919; tega- serod) . 3. Compound according to claim 2 , wherein said bronchocontraction appears in asthma and disorders related thereto, emphysema, chronic bronchitis, chronic obstructive pulmonary disease, depression, anorectic or bulimic eating disorders, anxiety or various psychotic conditions including schizophrenia. 4. Use of one or more compounds according to claims 1 and 2 having agonist activity to a 5-HT receptor, and derivatives and pharmaceutically acceptable salts thereof having agonist activity to the 5-HT 4 receptor, in the manufacture of a medicament for therapeutic or prophylactic treatment of disorders involving bronchocontraction, optionally together with a serotonin uptake inhibitor. 5. Use according to claim 4, wherein said one or more compounds has/have the capacity of reducing the pathological bronchocontraction by at least 30%, preferably at least 60%, and most preferably at least 90%, and wherein said compound (s) is/are chosen from the group comprising SC 53116, i.e. 4-amino-5-chloro-N- [ [IS, 7aS) - hexahydro-lH-pyrrolizin-1-yl] methyl] -2-methoxy-benzamide, having the structural formula: ML 10302, i.e. 4-amino-5-chloro-2-methoxy-benzoic acid-2- (1-piperidinyl) ethylester, having the structural formula: RS 67506, i.e. N- [2 - [4- [3 - (4 -amino-5-chloro-2- methoxyphenyl) -3-oxopropyl] -1-piperidinyl] ethyl] - methanesulfonamide monohydrochloride, having the structural formula : BIMU 8, i.e. 2 , 3-dihydro-N- [ (3-endo) -8-methyl-8- azabicyclo [3.2.1] oct-3-yl) -3- (1-methylethyl) -2-oxo-lH- benzimidazole-1-carboxamide monohydrochloride, having the structural formula: 5-carboxamidotryptamine (5-CT) , having the structural formula : ADR932, BIMU 1, BRL 20627, BRL 24682, BRL 24924, Cinita- prid, Cisapride, DAU 6215, DAU 6236, 5-HT, 5-hydroxy-N,N-dimetyltryptamin, 3-Me-8-OH-DPAT, ML-1035, 5-metoxytryptamin, Metoclopramide, Mosapride, 8-OH-DPAT (8-hydroxy-2-dipropylaminotetralin) , Prucalopride, R 076186, R 093877 (prucalopride) , Renza- pride, RS 17017, RS 23597-190, RS 56532, RS 57639, RS 67333, RS 67532, RU 28253 SB 204070, SB 205149, SC-52491, SC-49518, SK-951, SDZ 216-454, SR59768, TKS159, VB20B7, Y-34959, YM-47813, YM-53389, YM-09151, Zacopride, Zelmac (SDZ HTF919; tega- serod) . 6. Use according to claims 4 and 5, wherein said disorder having pathological bronchocontraction is asthma and disorders related thereto, emphysema, chronic bronchitis, chronic obstructive pulmonary disease, depres- sion, anorectic or bulimic eating disorders, anxiety or various psychotic conditions including schizophrenia. 7. A method for treatment of disorders involving bronchocontraction, wherein said method comprises administering to a human or animal patient a thera- peutically effective amount of a compound according to claim 1. 8. Compound having antagonist activity to a 5-HT 3 receptor, and derivatives and pharmaceutically acceptable salts thereof having antagonist activity to the 5-HT 3 re- ceptor for use as a medicament for treatment of disorders involving bronchocontraction. 9. Compound according to claim 8, wherein said compound has the capacity of reducing pathological bronchocontraction by at least 30%, preferably at least 60%, and most preferably at least 90%, and wherein said compound is chosen from the group comprising 4-Ph-N-Me-quipazine, ADR-851, ADR-882, Alosetron, Anpirtoline, Axasetron (=Y 25130), BIMU 1, BMY 33462, BRL 24924, BRL 43694, BRL 46470 A, CF 109203 (=BIM) , Chlorpromazine, Cilanse- tron (=KC 9946) , Cisapride, Clozapine, Cyameazine, DAT- 582 (=(R)AS-5370) , Dilalazem, Dolasetron (=MDL 74156), Dolasetron mesilat (=MDL 73147 EF) , Droperidol, FK 1052, Fluphenazone, Galanolactone, GK 128, GR 38032 F, GR 65630, Gramisetron (=Kytril=BRL 43694) , GR-H, GYKl-48903, ICl 169369, ICS 205-930, Ifonprodil, Iodophenpropit , Itasetron (=DAU 6215), KB-6922, KB-R 6933, KF 17643, KF 18259, L-683877, Litoxetine, LY 278584, McNeil-A-343 , MDL 72222, MDL 72699, Metoclopramid, Mirtazapine, Mosapride, N-3389, N-metylquipazin, Ondansetron (=GR 38032 F) , Palonosetron, Pancopride, Perphenazine, Prochiorperazine (=Stemetil) , Quipazine, QX 222, (R) - zacopride, Ramosetron (=YM 060) , Renzapride, RG 12915, RS-25259, RS 42358-197, RS 56532, RS-056812 -198 , RS- 25259-197, RS-56812, S-apomorfin, SC-53116, SDZ 216-525, SDZ 322, SN-307, Talipexole, Thioperamide, TMB 8, Triti- uoperzine, Trimebutine, Tropisetron (=ICS 205- 930=Rifenserin) , VA 21 B 7, Way 100289, WAY-100579, WAY- SEC-579, Y 2513, YM 114 (=KAE-393), Zatosetron (=LY 277359), preferably tropanyl-3 , 5-dimethylbenzoate . 10. Compound according to claim 9, wherein said bronchocontraction appears in asthma and disorders re- lated thereto, emphysema, chronic bronchitis, chronic obstructive pulmonary disease, depression, anorectic or bulimic eating disorders, anxiety or various psychotic conditions including schizophrenia. 11. Use of one or more of the compounds according to claims 8 and 9 and including ketanserin having antagonist activity to a 5-HT 3 receptor, and derivatives and pharmaceutically acceptable salts thereof having antagonist activity to the 5-HT 3 receptor, in the manufacture of a medicament for therapeutic or prophylactic treatment of disorders involving bronchocontraction, optionally together with a serotonin uptake inhibitor. 12. Use according to claim 11, wherein said one or more compounds has the capacity of reducing the pathological bronchocontraction by at least 30%, preferably at least 60%, and most preferably at least 90%, and wherein said compound (s) is/are chosen from the group comprising 4-Ph-N-Me-quipazine, ADR-851, ADR-882, Alosetron, Anpir- toline, Axasetron (=Y 25130), BIMU 1, BMY 33462, BRL 24924, BRL 43694, BRL 46470 A, CF 109203 (=BIM) , Chlor- promazine, Cilansetron (=KC 9946) , Cisapride, Clozapine, Cyameazine, DAT-582 (= (R) AS-5370) , Dilalazem, Dolasetron (=MDL 74156) , Dolasetron mesilat (=MDL 73147 EF) , Droperidol, FK 1052, Fluphenazone, Galanolactone, GK 128, GR 38032 F, GR 65630, Gramisetron (=Kytril=BRL 43694), GR-H, GYK1-48903, ICl 169369, ICS 205-930, Ifonprodil, Iodophenpropit, Itasetron (=DAU 6215), KB-6922, KB-R 6933, KF 17643, KF 18259, L-683877, Litoxetine, LY 278584, McNeil-A-343 , MDL 72222, MDL 72699, Metoclo- pramid, Mirtazapine, Mosapride, N-3389, N-metylquipazin, Ondansetron (=GR 38032 F) , Palonosetron, Pancopride, Per- phenazine, Prochiorperazine (=Stemetil) , Quipazine, QX 222, (R) -zacopride, Ramosetron (=YM 060), Renzapride, RG 12915, RS-25259, RS 42358-197, RS 56532, RS-056812- 198, RS-25259-197, RS-56812, S-apomorfin, SC-53116, SDZ 216-525, SDZ 322, SN-307, Talipexole, Thioperamide, TMB 8, Tritiuoperzine, Trimebutine, Tropisetron (=ICS 205- 930=Rifenserin) , VA 21 B 7, Way 100289, WAY-100579, WAY- SEC-579, Y 2513, YM 114 (=KAE-393), Zatosetron (=LY 277359), preferably tropanyl-3 , 5-dimethylbenzoate . 13. Use of one or more compounds according to claims 11 and 12 in combination, either simultaneously or se- quentially, with a compound having agonist activity to the 5-HT 4 receptor in the manufacture of a medicament for therapeutic or prophylactic treatment of disorders involving bronchocontraction, optionally together with a serotonin uptake inhibitor. 14. Use according to claim 13, wherein said compound having agonist activity to the 5-HT 4 receptor is serotonin and derivatives thereof or a compound according to claims 1 and 2. 15. Use according to claims 11-14, wherein said dis- order having pathological bronchocontraction is asthma and disorders related thereto, emphysema, chronic bronchitis, chronic obstructive pulmonary disease, depression, anorectic or bulimic eating disorders, anxiety or various psychotic conditions including schizophrenia. 16. A method for treatment of disorders involving bronchocontraction, wherein said method comprises administering to a human or animal patient a therapeutically effective amount of a compound according to claims 11-14. 17. Composition comprising a combination of the compounds defined in claims 13 and 14 for use as a medicament for treatment of disorders involving bronchocontraction.

Inventors: SKOGVALL STAFFAN, SKOGVALL, STAFFAN
Applicants: RESPIRATORIUS AB, SKOGVALL STAFFAN, SKOGVALL, STAFFAN
Application year: 2000
Main classification: A61K31
IPC codes: A61K31, A61K45, A61P11