WO2000076500A2 - Compound for use as a medicament for treatment of disorders involving bronchocontraction - Google Patents

Compound for use as a medicament for treatment of disorders involving bronchocontraction Download PDF

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Publication number
WO2000076500A2
WO2000076500A2 PCT/SE2000/001267 SE0001267W WO0076500A2 WO 2000076500 A2 WO2000076500 A2 WO 2000076500A2 SE 0001267 W SE0001267 W SE 0001267W WO 0076500 A2 WO0076500 A2 WO 0076500A2
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WO
WIPO (PCT)
Prior art keywords
bronchocontraction
compound
receptor
brl
medicament
Prior art date
Application number
PCT/SE2000/001267
Other languages
French (fr)
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WO2000076500A8 (en
WO2000076500A3 (en
Inventor
Staffan Skogvall
Original Assignee
Respiratorius Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from SE9902251A external-priority patent/SE9902251D0/en
Priority claimed from SE9902252A external-priority patent/SE9902252D0/en
Priority claimed from PCT/SE2000/000819 external-priority patent/WO2000064441A2/en
Priority to JP2001502833A priority Critical patent/JP2003501462A/en
Priority to EP00944534A priority patent/EP1185263A2/en
Priority to AU58619/00A priority patent/AU5861900A/en
Application filed by Respiratorius Ab filed Critical Respiratorius Ab
Priority to PCT/SE2000/002613 priority patent/WO2001095903A1/en
Priority to AU2001225663A priority patent/AU2001225663A1/en
Priority to PCT/SE2000/002612 priority patent/WO2001095902A1/en
Priority to AU2001225664A priority patent/AU2001225664A1/en
Publication of WO2000076500A2 publication Critical patent/WO2000076500A2/en
Publication of WO2000076500A3 publication Critical patent/WO2000076500A3/en
Publication of WO2000076500A8 publication Critical patent/WO2000076500A8/en

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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
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    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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Definitions

  • 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.
  • Receptors of the 5-HT (serotonin; 3- ( ⁇ -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
  • 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.
  • the present invention is based on the novel finding that certain 5-HT receptors are of utmost importance in regulating bronchocontraction.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • disorders 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.
  • 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) .
  • SRI serotonin uptake inhibitor
  • 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.
  • said medicament is intended for treatment of asthma and disorders related thereto.
  • 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 :
  • 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 having the structural formula:
  • 5-HT 4 agonists can be divided in certain groups, wherein each group contains a common structural element.
  • 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:
  • 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.
  • 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 :
  • amide group has been replaced with an esther group.
  • esther group examples are ML 10302, RS 57639, and SR 59768.
  • 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
  • the amide fuction may also be replaced with an oxa- diazol ring.
  • BIMU 1 e.g. BIMU 1
  • BIMU 8 DAU 6215
  • DAU 6236 DAU 6236
  • Some indols are olso useful as 5-HT 4 agonists, e.g. 5-methoxytryptamine, 2-methylserotonine, and 5-hydroxy- N,N-di-methyltryptamine .
  • the most preferred 5-HT 4 receptor agonist is RS 67333.
  • 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 .
  • 5-HT3 receptor antagonists are at the same time 5-HT4 receptor agonists.
  • 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.
  • 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
  • 5-HT4 agonists e.g. benzamides
  • zatosetron LY 277359, ADR 851
  • 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.
  • Another group is the isoquinoline-1-ones
  • quinoline-4-carboxylates are active antagonists
  • MDL 72222 which also is a specific 5-HT 3 antagonist
  • 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.
  • 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.
  • said method relates to treatment of asthma and disorders related thereto.
  • 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.
  • FEV1 Forced Expiratory Volume
  • the expiratory capacity for a patient can be compared to his own FEV1 during periods of relatively little obstructive problems. As appears from Fig.
  • 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.
  • 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.
  • 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.
  • the medicament prepared according to present invention in each embodiment may op- tionally include two or more of the above outlined compounds .
  • 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.
  • said medicament is preferably administered via the respiratory tract in the form of e . g . an aerosol or an air- suspended fine powder.
  • 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.
  • 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 .
  • 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.
  • 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.
  • the preparations instead display a strong, smooth type of tone.
  • 5-HT serotonin
  • 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.
  • 5-HT or 5-HT analogues may be useful in the treatment of bronchoob- structive diseases.
  • the 5-HT i.e. serotonin
  • the 5-HT may be of use as an addition to standard beta2 receptor stimulation.
  • 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) .
  • a 5-HT analogue that lacks the 5-HT 3 activating properties is given, the relaxing effect is persistent, and not transient .
  • 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.
  • the compounds used according to the present invention have only low or no agonist activity to 5-HT 3 re- ceptors.
  • 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.
  • 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.

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-HT4 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-HT3 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-HT2, 5-HT3/ 5-HT4, 5-HT5, 5-HT6 and 5-HT7 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, 3rd 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-HT4 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-HT3 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-HT4 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-HT4 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-HT3 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-HT2a 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-HT3 receptor in combination with a compound having agonist activity to the 5-HT4 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-HT4 receptor. This combination of the 5-HT3 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-HT4 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-HT4 receptor, without activating the contracting 5-HT3 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:
Figure imgf000006_0001
ML 10302, i.e. 4-amino-5-chloro-2-methoxy-benzoic acid-2- (1-piperidinyl) ethylester, having the structural formula :
Figure imgf000006_0002
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:
Figure imgf000006_0003
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:
Figure imgf000007_0001
5-carboxamidotryptamine (5-CT) having the structural formula:
Figure imgf000007_0002
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-HT4 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-HT4 agonist, metoclopramide .
Figure imgf000008_0001
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 :
Figure imgf000011_0001
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.
Figure imgf000012_0001
Benzofuranes and benzotiophenes are also contemplated,
Figure imgf000012_0002
as well as the benzodioxan
Figure imgf000012_0003
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
Figure imgf000013_0001
, e.g. RS 67333 and RS 17017.
The basic concept also applies for naphtalimides ,
Figure imgf000013_0002
Benzindolones are also contemplated
The amide fuction may also be replaced with an oxa- diazol ring.
Figure imgf000013_0003
Benzimidazolone-1-carboxamides
Figure imgf000014_0001
, e.g. BIMU 1, BIMU 8, DAU 6215, and DAU 6236, are also contemplated .
The carboamides
Figure imgf000014_0002
are also contemplated.
Some indols are olso useful as 5-HT4 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
Figure imgf000015_0001
SDZ 216-454
Figure imgf000015_0002
Zelmac=SDZ HTF 19
Figure imgf000015_0003
NB20B7
Figure imgf000015_0004
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
Figure imgf000015_0005
Further 5-HT4 agonist structures useful according to the present invention
Figure imgf000016_0001
2-piperidinmethylethers
Figure imgf000016_0002
, particularly
Figure imgf000016_0003
kinolines
Figure imgf000016_0004
, particularly
Figure imgf000016_0006
Figure imgf000016_0005
Figure imgf000017_0001
Figure imgf000017_0002
, particularly
Figure imgf000017_0003
Figure imgf000017_0004
bensopyranes
Figure imgf000017_0005
The most preferred 5-HT4 receptor agonist is RS 67333.
According to the present invention several known antagonist compounds are, surprisingly, able to influence the 5-HT3 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-HT3 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,
Figure imgf000019_0001
benzazepines , e.g. mirtazapine
Figure imgf000019_0002
benztiazephines , e . g . diltiazem
Figure imgf000020_0001
and fentiazines
Figure imgf000020_0002
e.g. perphenazine, chlorpromazine, stemetil
Some are 5-HT4 agonists, e.g. benzamides
, -
Figure imgf000020_0003
and
Figure imgf000020_0004
2 , 3 -dihydro-benzof uran- 7 -carboxamides
Figure imgf000021_0001
(e.g. zatosetron=LY 277359, ADR 851)
1 , 4 -bensoxazin- 8 -carboxamides
Figure imgf000021_0002
e.g. azasetron (=Y25130)
benzimidazolones
Figure imgf000021_0003
e.g. itasetron (=DAU 6215) indazol -3 -carboxamides
Figure imgf000022_0001
, e.g. N 3389, LY 278584, DAT 582
The latter group reminds most of the specific 5-HT3 antagonists, which after contains the group
Figure imgf000022_0002
in different forms, such as
ondansetron
Figure imgf000022_0003
Figure imgf000022_0004
cilansetron alosetron
Figure imgf000023_0001
ramosctron GR 65630
Figure imgf000023_0002
Figure imgf000023_0004
Figure imgf000023_0003
tropisetron dolasetron
Figure imgf000023_0005
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
Figure imgf000024_0001
This substance is unique by being an antagonist against both 5-HT3 and 5-HT4.
Figure imgf000024_0002
BRL 46470A binds to two different positions of the recep- tor.
A further development is the so-called bisindoles
Figure imgf000024_0003
Another group is the isoquinoline-1-ones
Figure imgf000024_0004
palonosetron ( =RS 25259 - 197 ) RS 42358 - 197 and the quinoline-3-carboxarrtides
Figure imgf000025_0001
WAY-SEC 579 Mirisetron (=WAY 100579)
Also the quinoline-4-carboxylates are active antagonists
Figure imgf000025_0002
Figure imgf000025_0003
e.g. KF 18259
Other compounds are benzimidazolones
Figure imgf000025_0004
e.g. droperidol (neurolidol, etc.) , itasetron (DAU6215) , and the naphtimides
Figure imgf000026_0001
, e.g. RS 56532
A unique single structure is MDL 72222, which also is a specific 5-HT3 antagonist
Figure imgf000026_0002
Other specific structures are
Figure imgf000026_0003
Talipexole
Figure imgf000026_0004
Figure imgf000027_0001
Figure imgf000028_0001
Galnπolakfon
30
35 iodophenr-vv-opit
Figure imgf000029_0001
thioperamide , and
Figure imgf000029_0002
2-piperidin- and 2-piperazin- benzimidazoles .
The most preferred 5-HT3 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-HT4 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-HT3 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-HT3 receptor is not affected; only the relaxing 5-HT4 receptor is activated. In the case of antagonists to the 5-HT3 receptor, this effect is achieved due to direct blocking of the 5-HT3 receptor, whereby the unspecific agonists to the 5-HT4 receptor, such as 5-HT, can act without also causing contraction by the 5-HT3 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-HT3 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-HT4 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-HT4 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-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 as well as on 5-HT2 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-HT2a 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-HT3 receptor. This is clear, because activation of the relaxing 5-HT4 receptor by a substance that lacks 5- HT3 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-HT3 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-HT4 receptor results in a relaxing effect, whereas agonist action on 5-HT3 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-HT4 receptor as well as on the contracting 5-HT3 receptor.
It was also deduced from these experiments that compounds having agonist activity to the 5-HT4 receptor, while having only low or no agonist activity to a 5-HT3 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-HT4 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-HT3 re- ceptors.
In the above mentioned experiments it has also been shown that compounds having antagonist activity to a 5-HT3 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-HT3 receptor. The compounds accord- ing to the present invention having antagonist activity to the 5-HT3 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-HT3 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-HT3-receptor and a compound having agonist activity to the 5-HT4 receptor, in the manufacture of a medicament for therapeutic or prophylactic treatment of disorders involving bronchocontraction.

Claims

1. Compound having agonist activity to a 5-HT4 receptor, and derivatives and pharmaceutically acceptable salts thereof having agonist activity to the 5-HT4 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 :
Figure imgf000036_0001
ML 10302 , i . e . 4 -amino- 5 -chloro-2 -methoxy-benzoic acid-2 - ( 1 -piperidinyl ) ethylester, having the structural formula :
Figure imgf000036_0002
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 :
Figure imgf000037_0001
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:
Figure imgf000037_0002
5-carboxamidotryptamine (5-CT) , having the structural formula :
Figure imgf000037_0003
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-HT4 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:
Figure imgf000039_0001
ML 10302, i.e. 4-amino-5-chloro-2-methoxy-benzoic acid-2- (1-piperidinyl) ethylester, having the structural formula:
Figure imgf000039_0002
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 :
Figure imgf000039_0003
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:
Figure imgf000040_0001
5-carboxamidotryptamine (5-CT) , having the structural formula :
Figure imgf000040_0002
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-HT3 receptor, and derivatives and pharmaceutically acceptable salts thereof having antagonist activity to the 5-HT3 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-HT3 receptor, and derivatives and pharmaceutically acceptable salts thereof having antagonist activity to the 5-HT3 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-HT4 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-HT4 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.
PCT/SE2000/001267 1999-06-15 2000-06-15 Compound for use as a medicament for treatment of disorders involving bronchocontraction WO2000076500A2 (en)

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JP2003501462A (en) 2003-01-14
CN1355698A (en) 2002-06-26
WO2000076500A3 (en) 2001-07-12

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