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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WIPO (PCT)
Prior art keywords
bronchocontraction
compound
receptor
brl
medicament
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Application number
PCT/SE2000/001267
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English (en)
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WO2000076500A3 (fr
WO2000076500A8 (fr
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.)
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Publication date
Priority claimed from SE9902251A external-priority patent/SE9902251D0/xx
Priority claimed from SE9902252A external-priority patent/SE9902252D0/xx
Priority claimed from PCT/SE2000/000819 external-priority patent/WO2000064441A2/fr
Priority to JP2001502833A priority Critical patent/JP2003501462A/ja
Priority to AU58619/00A priority patent/AU5861900A/en
Priority to EP00944534A priority patent/EP1185263A2/fr
Application filed by Respiratorius Ab filed Critical Respiratorius Ab
Priority to PCT/SE2000/002612 priority patent/WO2001095902A1/fr
Priority to PCT/SE2000/002613 priority patent/WO2001095903A1/fr
Priority to AU2001225663A priority patent/AU2001225663A1/en
Priority to AU2001225664A priority patent/AU2001225664A1/en
Publication of WO2000076500A2 publication Critical patent/WO2000076500A2/fr
Publication of WO2000076500A3 publication Critical patent/WO2000076500A3/fr
Publication of WO2000076500A8 publication Critical patent/WO2000076500A8/fr

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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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    • A61K31/404—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
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    • 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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    • A61K31/517—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

La présente invention concerne un composé qui présente une activité d'agoniste du récepteur 5-HT4 et qui est destiné à être utilisé comme médicament, l'utilisation dudit composé dans la fabrication d'un médicament destiné à être utilisé dans le cadre d'un traitement thérapeutique ou prophylactique de troubles impliquant une bronchoconstriction chez l'homme ou chez l'animal, et des méthodes de traitement basées sur l'administration desdits composés. La présente invention concerne également un composé qui présente une activité d'antagoniste du récepteur 5-HT3 et qui est destiné à être utilisé comme médicament, l'utilisation dudit composé dans la fabrication d'un médicament destiné à être utilisé dans le cadre d'un traitement thérapeutique ou prophylactique de troubles impliquant une bronchoconstriction chez l'homme ou chez l'animal, et des méthodes de traitement basées sur l'administration desdits composés.
PCT/SE2000/001267 1999-06-15 2000-06-15 Compound for use as a medicament for treatment of disorders involving bronchocontraction WO2000076500A2 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
JP2001502833A JP2003501462A (ja) 1999-06-15 2000-06-15 受容体アゴニストおよびアンタゴニスト
AU58619/00A AU5861900A (en) 1999-06-15 2000-06-15 Receptor agonists and antagonists
EP00944534A EP1185263A2 (fr) 1999-06-15 2000-06-15 Agonistes et antagonistes de recepteurs
AU2001225664A AU2001225664A1 (en) 2000-06-15 2000-12-20 5-ht3 receptor antagonists for treatment of disorders involving airway constriction
AU2001225663A AU2001225663A1 (en) 2000-06-15 2000-12-20 A composition comprising a combination of receptor agonists and antagonists
PCT/SE2000/002612 WO2001095902A1 (fr) 2000-06-15 2000-12-20 Composition contenant une association d'agonistes et d'antagonistes d'un recepteur
PCT/SE2000/002613 WO2001095903A1 (fr) 2000-06-15 2000-12-20 Antagonistes du recepteur 5-ht3 destines au traitement de troubles englobant la constriction des voies aeriennes

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SE9902251A SE9902251D0 (sv) 1999-06-15 1999-06-15 Medicinskt preparat
SE9902251-9 1999-06-15
SE9902252-7 1999-06-15
SE9902252A SE9902252D0 (sv) 1999-06-15 1999-06-15 Medicinskt preparat
US13963399P 1999-06-17 1999-06-17
US13963299P 1999-06-17 1999-06-17
US60/139,633 1999-06-17
US60/139,632 1999-06-17
SEPCT/SE00/00819 2000-04-28
PCT/SE2000/000819 WO2000064441A2 (fr) 1999-04-28 2000-04-28 Medicament

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WO2001095903A1 (fr) * 2000-06-15 2001-12-20 Respiratorius Ab Antagonistes du recepteur 5-ht3 destines au traitement de troubles englobant la constriction des voies aeriennes
WO2002036113A1 (fr) * 2000-11-01 2002-05-10 Respiratorius Ab Composition comprenant des agonistes (5ht-4) et des antagonistes (5ht-2, 5ht-3) recepteurs de la serotonine
WO2004006902A1 (fr) * 2002-07-10 2004-01-22 Warner-Lambert Company Llc Combinaison d'un inhibiteur allosterique ou metalloproteinase matricielle-13 a inhibiteur selectif de cyclooxygenase-2 autre que celecoxib ou vadecoxib
US6986901B2 (en) 2002-07-15 2006-01-17 Warner-Lambert Company Llc Gastrointestinal compositions
WO2006133104A3 (fr) * 2005-06-07 2007-04-26 Theravance Inc Composes de benzoimidazolone-carboxamide en tant qu'agonistes du recepteur 5-ht4
WO2010086387A1 (fr) 2009-01-30 2010-08-05 Movetis Nv Inhibiteurs de 5-ht4 pour traiter des maladies des voies aériennes, en particulier l'asthme
US10603272B2 (en) 2015-02-27 2020-03-31 Kindred Biosciences, Inc. Stimulation of appetite and treatment of anorexia in dogs and cats

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001095903A1 (fr) * 2000-06-15 2001-12-20 Respiratorius Ab Antagonistes du recepteur 5-ht3 destines au traitement de troubles englobant la constriction des voies aeriennes
WO2001095902A1 (fr) * 2000-06-15 2001-12-20 Respiratorius Ab Composition contenant une association d'agonistes et d'antagonistes d'un recepteur
WO2002036113A1 (fr) * 2000-11-01 2002-05-10 Respiratorius Ab Composition comprenant des agonistes (5ht-4) et des antagonistes (5ht-2, 5ht-3) recepteurs de la serotonine
WO2004006902A1 (fr) * 2002-07-10 2004-01-22 Warner-Lambert Company Llc Combinaison d'un inhibiteur allosterique ou metalloproteinase matricielle-13 a inhibiteur selectif de cyclooxygenase-2 autre que celecoxib ou vadecoxib
US6986901B2 (en) 2002-07-15 2006-01-17 Warner-Lambert Company Llc Gastrointestinal compositions
WO2006133104A3 (fr) * 2005-06-07 2007-04-26 Theravance Inc Composes de benzoimidazolone-carboxamide en tant qu'agonistes du recepteur 5-ht4
US7317022B2 (en) 2005-06-07 2008-01-08 Theravance, Inc. Benzoimidazolone-carboxamide compounds as 5-HT4 receptors agonists
US7772239B2 (en) 2005-06-07 2010-08-10 Theravance, Inc. Benzoimidazolone-carboxamide compounds as 5-HT4 receptor agonists
WO2010086387A1 (fr) 2009-01-30 2010-08-05 Movetis Nv Inhibiteurs de 5-ht4 pour traiter des maladies des voies aériennes, en particulier l'asthme
US10603272B2 (en) 2015-02-27 2020-03-31 Kindred Biosciences, Inc. Stimulation of appetite and treatment of anorexia in dogs and cats

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CN1355698A (zh) 2002-06-26
AU5861900A (en) 2001-01-02

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