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WO1993014745A1 - Utilisation d'antagonistes de recepteur de 5-ht4 comme medicaments pour traiter la migraine - Google Patents

Utilisation d'antagonistes de recepteur de 5-ht4 comme medicaments pour traiter la migraine Download PDF

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Publication number
WO1993014745A1
WO1993014745A1 PCT/GB1993/000130 GB9300130W WO9314745A1 WO 1993014745 A1 WO1993014745 A1 WO 1993014745A1 GB 9300130 W GB9300130 W GB 9300130W WO 9314745 A1 WO9314745 A1 WO 9314745A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
indole
carboxylate
amino
piperidinyl
Prior art date
Application number
PCT/GB1993/000130
Other languages
English (en)
Inventor
Alberto Julio Kaumann
Original Assignee
Smithkline Beecham Plc
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 GB929201484A external-priority patent/GB9201484D0/en
Priority claimed from GB929219318A external-priority patent/GB9219318D0/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Publication of WO1993014745A1 publication Critical patent/WO1993014745A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine

Definitions

  • the present invention relates to the use of compounds which are antagonists at 5-HT4 receptors in therapy. More particularly the invention relates to the use of compounds which are 5-HT4 antagonists in the treatment and prophylaxis of migraine.
  • 5-HT4 receptors which are positively coupled with adenylyl cyclase in the central nervous system (CNS) have been identified in mouse embryo colliculi neurons, (Dumuis et al, Naunyn-Schmiedeberg's Arch. Pharmacol. (1989) 340 : 403-410) and in guinea pig hippocampal membranes (Bockaert et al, (1990) Mol. Pharmacol. 37 : 408-1 1).
  • 5-HT receptors which have similar properties, including that of mediating an increase in cyclic AMP levels, have been identified in the atrial myocardium of man and piglet and are designated as '5-HT4-like' receptors (Kaumann et al., Br. J. Pharmacol. (1990) 100,
  • ICS 205930 (3 ⁇ -tropanyl-lH-indole-3-carboxylic acid) which is known as a 5-HT3 receptor antagonist, has recently been described as an antagonist at 5-HT4 receptors, but other known 5-HT3 receptor antagonists were reported to be ineffective at 5-HT4 receptors (Dumuis et al., Molecular Pharmacology, 34 : 880-887 and Naunyn- Schmiedeberg's Arch. Pharmacol, 1989, 340 : 403-410). Although ICS 205930 has been described as having a variety of potential clinical uses, including migraine, mediated via -HT3 receptors, no clinical utility which is mediated by blockade of 5-HT4 receptors has been proposed for this compound.
  • a class of 3-piperidinylmethylcarboxylate substituted indole 5-HT4 antagonists is described in EPA 501 322 (Glaxoi. There is no disclosure 01 ' their use in migraine.
  • Migraine sufferers often undergo situations of anxiety and emotional stress that precede the appearance of headache (Sachs, (1985) Migraine, Pan Books, London). It has been observed that during and within 48 hours of a migraine attack cyclic AMP levels are considerably increased in the cerebrospinal fluid (Welch et al., (1976) Headache 1 , 160- 167).
  • migraine attack including the prodromal phase and the associated increased levels of cyclic AMP are related to stimulation of 5-HT4 receptors.
  • the present invention therefore provides a 5-HT4 receptor antagonist for use in therapy, in particular in the treatment of conditions associated with increased levels of cyclic AMP levels in the CNS, for example in the treatment or prophylaxis of migraine.
  • 5-HT4 receptor antagonists may be identified according to standard methods, such as that described hereinafter, and that described in Naunyn-Schmiedeberg's Arch Pharmacol. 342, 619-622.
  • 5-HT4 receptor antagonists examples include ICS205-930 (tropisetron), which is described in the above mentioned patent references; R 50 595 (Janssen), which is described in FR76530 and Eur. J. Pharmacol., 181 119-125 (1990); SDZ 205-557, which is described by K.H. Buchheit and R. Gamse in Naunyn-Schmiedeberg's Arch. Pharmacol., 343 (Suppl.), R101 (1991); (3 ⁇ -tropanyl)-lH-indazole-3-carboxylic acid ester (EPA 200444); and the compounds described in EPA 501322, which have the general formula :
  • R! represents a hydrogen or a halogen atom, or a Ci .galkyl, C ⁇ alkoxy or hydroxy group
  • R- represents a hydrogen atom or a Ci .galkyl, -CH2C2-5 l enyl or group
  • R*-- represents a hydrogen atom or a Ci . ⁇ al yl or C ⁇ alkoxy group: n represents 2 or 3
  • R represents a group selected from cyano, hydroxyl, Ci .galkoxy, phenoxy,
  • salts more particularly the hydrochloride, methanesulphonate and maleate salts, and solvates thereof.
  • the 5-HT4 receptor antagonist is a more potent antagonist at 5-HT4 receptors than at 5-HT3 receptors.
  • the 5-HT4 receptor antagonist is preferably in substantially pure pharmaceutically acceptable form.
  • the 5-HT4 receptor antagonist may be administered by any convenient route, for example by way of oral, sublingual, rectal, transdermal or parenteral administration.
  • a unit dose will normally contain 0.05 to 500 mg for example 0.5 to 100 mg, of the active ingredient.
  • Unit doses will normally be administered once or more than once a day. for example 2. 3. or 4 times a day. more usually 1 to 3 times a day. such that the total daily dose is normally in the range, for a 70 kg adult of 0.1 to 1000 mg, for example 0.1 to 500 mg, that is in the range of approximately 0.001 to 20 mg/kg/day. more usually 0.005 to 1.0 mg/kg day.
  • a compound for use according to the invention will be administered in the form of a pharmaceutical composition, comprising a 5-HT4 antagonist and a pharmaceutically acceptable carrier.
  • compositions are generally prepared by admixture of the active ingredient with one or more pharmaceutically acceptable carriers or exipients. They may be adapted for administration by any convenient route; suitable dosage forms include tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions, and suppositories.
  • Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents.
  • the tablets may be coated according to well known methods in the art.
  • Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
  • Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate.
  • Suitable lubricants include, for example, magnesium stearate.
  • Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
  • Such solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the an.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate
  • Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating.
  • fluid unit dose forms are prepared containing the 5-HT4 receptor antagonist and a sterile vehicle.
  • the compound depending on the vehicle and the concentration, can be either suspended or dissolved.
  • Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.
  • compositions will usually be accompanied by written or printed directions for use in the treatment concerned.
  • a single cumulative concentration-effect curve was determined by the sequential addition of 5-HT or other agonists to the bath in amounts that increased the total concentration in steps of -A log unit. Enough time was allowed for each effect to reach equilibrium. The experiments were terminated by the administration of a saturating concentration of (-)- isoprenaline (0.2 mM). The time of incubation with an antagonist was at least 1 hr before a concentration-effect curve for an agonist was determined. The blocking potency of the test compounds, expresed as the pKg, is shown in Table 1 below.
  • a - ICS 205930 commercially available.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Utilisation d'antagonistes de récepteur de 5HT4 pour le traitement de la migraine.
PCT/GB1993/000130 1992-01-23 1993-01-20 Utilisation d'antagonistes de recepteur de 5-ht4 comme medicaments pour traiter la migraine WO1993014745A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB929201484A GB9201484D0 (en) 1992-01-23 1992-01-23 Medicaments
GB9201484.4 1992-01-23
GB9219318.4 1992-09-11
GB929219318A GB9219318D0 (en) 1992-09-11 1992-09-11 Medicaments

Publications (1)

Publication Number Publication Date
WO1993014745A1 true WO1993014745A1 (fr) 1993-08-05

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Application Number Title Priority Date Filing Date
PCT/GB1993/000130 WO1993014745A1 (fr) 1992-01-23 1993-01-20 Utilisation d'antagonistes de recepteur de 5-ht4 comme medicaments pour traiter la migraine

Country Status (2)

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AU (1) AU3361693A (fr)
WO (1) WO1993014745A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993024117A2 (fr) * 1992-05-23 1993-12-09 Smithkline Beecham Plc Medicaments pour le traitement de l'anxiete
US5726187A (en) * 1992-10-16 1998-03-10 Smithkline Beecham Plc N-alkylpiperidinyl-4-methyl carboxylic esters/amides of condensed ring systems as 5-HT4 receptor antagonists
US5852014A (en) * 1992-03-12 1998-12-22 Smithkline Beecham P.L.C. Condensed indole derivatives as 5HT4 -receptor antagonists
US5998409A (en) * 1992-03-12 1999-12-07 Smithkline Beecham Plc Condensed indole derivatives as 5HT4 -receptor antagonists
AU760056B2 (en) * 1997-02-04 2003-05-08 Eli Lilly And Company Sulphonamide derivatives

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0200444A2 (fr) * 1985-04-27 1986-11-05 Beecham Group Plc Azabicyclononyl-indazole carboxamide ayant une activité antagoniste de la 5-HT
EP0433043A1 (fr) * 1989-12-13 1991-06-19 Glaxo Group Limited Médicaments
EP0507650A1 (fr) * 1991-04-03 1992-10-07 Synthelabo Dérivés de pipéridine, leur préparation et leur application en thérapeutique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0200444A2 (fr) * 1985-04-27 1986-11-05 Beecham Group Plc Azabicyclononyl-indazole carboxamide ayant une activité antagoniste de la 5-HT
EP0433043A1 (fr) * 1989-12-13 1991-06-19 Glaxo Group Limited Médicaments
EP0507650A1 (fr) * 1991-04-03 1992-10-07 Synthelabo Dérivés de pipéridine, leur préparation et leur application en thérapeutique

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CEPHALALGIA vol. 9/SUP, no. 10, 1989, pages 346 - 7 *
DIALOG INFORMATION SERVICES, FILE 155, MEDLINE, ACCESSION NUMBER 07615935, & 'TUMORI' vol. 76, no. 6, 1990, pages 595 - 8 *
HEADACHE vol. 31, no. 5, 1991, pages 296 - 7 *
NAUNYN-SCHMIEDEBERG'S ARCH PHARMACOL. vol. 342, 1990, pages 619 - 22 cited in the application *
WINDHOLZ ET AL. 'The Merck Index' 1987 , US, RAHWAY, MERCK & CO. *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5852014A (en) * 1992-03-12 1998-12-22 Smithkline Beecham P.L.C. Condensed indole derivatives as 5HT4 -receptor antagonists
US5998409A (en) * 1992-03-12 1999-12-07 Smithkline Beecham Plc Condensed indole derivatives as 5HT4 -receptor antagonists
WO1993024117A2 (fr) * 1992-05-23 1993-12-09 Smithkline Beecham Plc Medicaments pour le traitement de l'anxiete
WO1993024117A3 (fr) * 1992-05-23 1994-04-14 Smithkline Beecham Plc Medicaments pour le traitement de l'anxiete
US5763459A (en) * 1992-05-23 1998-06-09 Smithkline Beecham P.L.C. Medicaments for the treatment of anxiety
US5726187A (en) * 1992-10-16 1998-03-10 Smithkline Beecham Plc N-alkylpiperidinyl-4-methyl carboxylic esters/amides of condensed ring systems as 5-HT4 receptor antagonists
AU760056B2 (en) * 1997-02-04 2003-05-08 Eli Lilly And Company Sulphonamide derivatives
US7135487B2 (en) 1997-02-04 2006-11-14 Eli Lilly And Company Sulphonamide derivatives

Also Published As

Publication number Publication date
AU3361693A (en) 1993-09-01

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