WO1993014745A1

WO1993014745A1 - Use of 5-ht4 receptor antagonists as medicaments for treating migraine

Info

Publication number: WO1993014745A1
Application number: PCT/GB1993/000130
Authority: WO
Inventors: Alberto Julio Kaumann
Original assignee: Smithkline Beecham Plc
Priority date: 1992-01-23
Filing date: 1993-01-20
Publication date: 1993-08-05
Also published as: AU3361693A

Abstract

Use of 5-HT4 receptor antagonists in the treatment of migraine.

Description

SE OF 5-HT4 RECEPTOR ANTAGONISTS AS MEDICAMENTS FOR TREATING MIGRAINE

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,

879-885 and 102 : 98P; Kaumann, Naunyn-Schmiedeberg's Arch. Pharmacol. (1990) 342 : 619-622 and (1991) 344, 150-159). There are also reports of the existence of neuronal 5HT4 receptors in the guinea pig ileum (Craig and Clarke, ( 1990) J. Pharmacol. Exp. Ther., 252 : 1378-1386) and in the rat oesophagus smooth muscle (Baxter et al., (1991) Naunyn- Schmiedeberg's Arch. Pharmacol. 343 : 439-446). In the present specification the aforementioned receptors will collectively be referred to as 5-HT4 receptors and compounds which antagonise them as 5-HT4-antagonists.

The compound ICS 205930 (3α-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).

The present applicants believe that a 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.

Examples of 5-HT4 receptor antagonists 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); (3α-tropanyl)-lH-indazole-3-carboxylic acid ester (EPA 200444); and the compounds described in EPA 501322, which have the general formula :

Formula (I)

wherein

R! represents a hydrogen or a halogen atom, or a Ci .galkyl, Cμ^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,

C(O)Cι_₆alkyl, C(O)C₆H₅, -CONR^RO, -NR^COR⁶, -SO₂NR5R6 ₀r -NR*5S0₂R⁶ (wherein each of R- and R^ independently represent a hydrogen atom, a Cj.^alkyl or phenyl group);

and quaternary ammonium derivatives, piperidine N-oxides and pharmaceutically acceptable salts and solvates thereof.

Specific compounds of formula (I) include :

[l-[2-(methylsulphonyl)amino]ethyl]-4-piperidinyl]methyl 1 -methyl- lH-indole-3- carboxylate;

[l-(2-hydroxyethyl)-4-piperidinyl]methyl 1 -methyl- lH-indole-3-carboxylate;

[l-[2-(methylamino)sulphonyl]ethyl]-4-piperidinyl]methyl 1 -methyl- lH-indole-3- carboxylate;

[l-(2-methoxyethyl)-4-piperidinyl]methyl 1 -methyl- 1 H-indole-3-carboxylate; [l-(3-amino-3-oxopropyl)-4-piperidinylJmethyl 1 -methyl- lH-indole-3-carboxylate;

[l-(2-cyanoethyl)-4-piperidinyl]methyl 1 -methyl- lH-indole-3-carboxylate;

[l-[2-(methylsulphonyl)amino]ethyl]-4-piperidinyl]methyl lH-indole-3-carboxylate;

[l-[2-(methylsulphonyl)amino]ethyl]-4-piperidinylJmethyl 2-methoxy-lH-indole-3- carboxylate; f l-r2-(acetylamino)ethyπ-4-piperidinyl]methyl 1 -methyl- lH-indole-3-carboxylate:

[l-[3-[(methylsulphonyl)aminoJpropyl)-4-piperidinylJmethyl 1 -methyl- lH-indole-3- carboxylate;

[l-[2-[(methylsulphonyl)aminolethyl]-4-piperidinyl]methyl 5-fluoro-lH-indole-3- carboxylate; [l-[2-[(methylsulphonyl)amino]ethyl]-4-piperidinyl]methyl 5-fluoro-2-methoxy-lH-indole- 3-carboxylate; f l-f2-f(methylsulphonyl)amino]ethyl]-4-piperidinyl]methyl 2-methoxy-l -methyl- lH-indole- 3-carboxylate;

[l-[2-[(phenylsulphonyl)amino|ethyl]-4-piperidinyl)methyl 1 -methyl- lH-indole-3- carboxylate;

[l-[2-[(methylsulphonyl)amino]ethyl]-4-piperidinyl]methyl 5-fluoro-l -methyl- lH-indole-3- carboxylate; [l-f2-[(methylsulphonyl)amino)ethyl]-4-piperidinyllmethyl 5-methyl-lH-indoIe-3- carboxylate; ll-[2-[(methylsuIphonyl)aminolethyl]-4-piperidinyl]methyl 2-methoxy-5-methyl-lH-indole- 3-carboxyIate; [ l-[2-fmethyl(methylsulphonyl)amino]ethyl]-4-piperidinyIJmethyl 1 -methyl- lH-indole-3- carboxylate;

[ l-[2-f (methylsuIphonyl)aminoJethyl]-4-piperidinyIJmethyI 5-fluoro-2-methoxy- 1 H-indole- 3-carboxylate N-oxide; l-methyl-4-[[[(l-methyl-lH-indol-3-yl)carbonyl]oxyJmethylJ-l-[2-[(methylsuIphonyl)- amino]ethyl]piρeridinium iodide;

4-[[[(2-methoxy-lH-indol-3-yl)carbonyl]oxy]methyI]-l-methyl-l-f2-[(methylsuIphonyl)- amino]ethyl]-piperidinium iodide; and

pharmaceutically acceptable salts, more particularly the hydrochloride, methanesulphonate and maleate salts, and solvates thereof.

Preferably 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.

An amount effective to treat the disorder hereinbefore described depends on the usual factors such as the nature and severity of the disorder being treated and the weight of the mammal. However, 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. In general, 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.

Such 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.

Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating. For parenteral administration, 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. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, 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. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.

As is common practice, the compositions will usually be accompanied by written or printed directions for use in the treatment concerned.

5-HT4 receptor antagonist activity

PIGLET SPONTANEOUS BEATING ATRIA SCREEN

Method (see A. J. Kaumann 1990, Naunyn-Schmiedeberg's Arch. Pharmacol 342, 619- 622)

Piglets of either sex, 2 to 5 days old, were anaesthetised with halothene; their hearts rapidly removed and washed free of blood with warm solution containing (mM):120 Na⁺, 5 K⁺, 2.25 Ca²⁺, 0.5 Mg²⁺, 98.5 Or, 0.5 SO4²-, 34 HCO3-, 1 HPO4²-, 0.04 EDTA, deionised and double distilled water in glass, equilibrated with 95% O₂ and 5% CO₂.

After dissection of the right atrium in warm solution, the tissue was set up in an apparatus with a 50 ml. bath (Blinks, 1965 J. Appl. Physiol. 20, 755-757), containing the solution

_ described above supplemented with (mM): 15 Na , 5 fumarate, 5 pyruvate, 5 L-glutamate, 10 glucose. Experiments were carried out at 37°C. For the study of positive chronotropic effects (increase in heart rate), the spontaneously beating right atrium was suspended at a resting tension just sufficient for measurable development of tension (to avoid tachycardia induced by stretching the sinoatrial node - Blinks, 1956 Amer. J. Physiol. 186, 299-303). The tissue was attached to a Swema SG4-45 strain gauge transducer by means of a stainless steel wire and force recorded on a Watanabe polygraph.

To avoid possible indirect β-adrenoceptor-mediated effects due to release of noradrenaline all experiments were carried out in the presence of 400 nM (±)-propranolol (about 100 x Kβ for (±)-propranolol). To reduce tissue capture of 5-HT, all experiments were carried out in the presence of 6 μ M cocaine (cocaine potentiates the effects of 5-HT on human atrium; Kaumann et al., Br. J. Pharmacol. 100, 879-885 (1990)). To decrease oxidation of 5-HT the physiological solution and all dilutions of 5-HT contained 0.2 mM ascorbate.

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.

Results

A - ICS 205930, commercially available.

B - (3α-tropanyl-lH-indazole-3-carboxylic acid ester, prepared by the procedures described in EP-A-200444.

The preliminary screening results shown in table 1 indicate that compounds A and B are competitive antagonists of 5-HT4 receptors.

TABLE 1

Blocking potencies of antagonists on piglet right atrial preparations

pK_B

Claims

Claims :

1. The use of a 5-HT4 receptor antagonist in the manufacture of a medicament for the treatment and/or prophylaxis of migraine.

2. Use according to claim 1 wherein the 5-HT4 receptor antagonst is a compound of formula (I) :

Formula (I)

wherein

R-* represents a hydrogen or a halogen atom, or a Cj.galkyl, C_j.^alkoxy or hydroxy group;

R² represents a hydrogen atom or a C_j.galkyl, -CH₂C₂_5alkenyl or -CH C₂_5alkynyl group;

R3 represents a hydrogen atom or a Cj.galkyl or C galkoxy group; n represents 2 or 3;

R represents a group selected from cyano, hydroxyl, Cj.^alkoxy, phenoxy,

C(O)Cι_₆alkyl, C(O)C₆H₅, -CONR5R6, -NR^COR⁶, -SO₂NR5R⁶ or -NR5S0₂R6 (wherein each of R$ and R6 independently represent a hydrogen atom, a C 1.^alkyl or phenyl group);

or a quaternary ammonium derivative, piperidine N-oxide or pharmaceutically acceptable salt or solvate thereof.

3. Use according to claim 1 or claim 2 wherein the 5-HT4 receptor antagonist is a compound of formula (I) selected from :

[l-l2-(methylsulphonyl)aminojethylJ-4-piperidinylJmethyl 1 -methyl- lH-indole-3- carboxylate; [l-(2-hydroxyethyl)-4-piperidinyl]methyl 1 -methyl- lH-indole-3-carboxy late:

[l-[2-(methylamino)sulphonyl]ethyl]-4-piperidinyl]methyl 1 -methyl- lH-indole-3- carboxylate; [l-(2-methoxyethyl)-4-piperidinyI]methyl I -methyl- 1 H-indole-3-carboxylate;

[l-(3-amino-3-oxopropyl)-4-piperidinyl]methyl 1 -methyl- lH-indole-3-carboxyIate;

[l-(2-cyanoethyl)-4-piperidinyl]methyl l-methyl-lH-indole-3-carboxylate;

[l-[2-(methylsulphonyl)amino]ethyl]-4-piperidinyl]methyl lH-indole-3-carboxylate; [l-[2-(methylsulphonyl)amino]ethyl]-4-piperidinyI]methyl 2-methoxy-lH-indole-3- carboxylate;

[l-[2-(acerylamino)ethyl]-4-piperidinyl]methyl 1 -methyl- 1 H-indole-3-carboxyIate;

[l-[3-[(methylsuIphonyl)amino]propyl]-4-piperidinyI]methyl l-methyl-lH-indole-3- carboxylate; [l-[2-[(methylsulphonyl)aminoJethyl]-4-piperidinylJmethyl 5-fluoro-lH-indole-3- carboxylate;

[l-[2-[(methylsulphonyl)amino]ethyl]-4-piperidinyI]methyI 5-fluoro-2-methoxy-lH-indoIe- 3-carboxylate;

[ l-[2-[(methylsuIphonyl)amino]ethyl]-4-piperidinylJmethyl 2-methoxy- 1 -methyl- 1 H-indole- 3-carboxylate;

[l-[2-[(phenylsulphonyl)amino]ethyl]-4-piperidinyI]methyl 1 -methyl- lH-indole-3- carboxylate;

[l-[2-[(methylsulphonyl)amino]ethyI]-4-piperidinyl]methyI 5-fluoro-l-methyI-lH-indole-3- carboxylate; [l-[2-[(methylsulphonyI)amino)ethyl]-4-piperidinyl]methyl 5-methyl-lH-indole-3- carboxylate;

[l-[2-[(methyIsulphonyI)amino]ethyl]-4-piperidinyllmethyI 2-methoxy-5-methyl-lH-indole- 3-carboxyIate;

[l-[2-[methyl(methylsulphonyl)amino]ethyl]-4-piperidinyI]methyl l-methyl-lH-indole-3- carboxylate;

[l-[2-[(methylsulphonyi)amino]ethyl]-4-piperidinyl]methyl 5-fluoro-2-methoxy-lH-indole- 3-carboxylate N-oxide: l-methyl-4-[[[(l-methyl-lH-indol-3-yl)carbonyl]oxy]methyl]-l-[2-[(methylsulphonyl)- amino]ethyl]piperidinium iodide; 4-[[[(2-methoxy-lH-indol-3-yl)carbonyl]oxy]methyl]-l-methyl-l-[2-[(methylsulphonyl)- amino]ethyl]-piperidinium iodide; or a pharmaceutically acceptable salt or solvate thereof.

4. A method for the treatment and/or prophylaxis of migraine in a mammal, which method comprises administering to a mammal in need thereof, a therapeutically or prophylactically effective amount of a 5-HT4 receptor antagonist.

5. Method according to claim 4 wherein the 5-HT4 receptor antagonist is a compound of formula (I) :

Formula (I)

wherein R! represents a hydrogen or a halogen atom, or a Ci .βalkyl, C^alkoxy or hydroxy group; R² represents a hydrogen atom or a Cj.galkyl, -CH₂C2-5alkenyl or -CH C₂-5alkynyl group; R3 represents a hydrogen atom or a C galkyl or Cι_₍-,alkoxy group; n represents 2 or 3; R represents a group selected from cyano, hydroxyl, C^*ι .galkoxy, phenoxy,

C(O)C₁.₆alkyl, C(O)C₆H₅, -CONR^R⁶, -NR^COR⁶, -SO₂NR5R6 ₀r -NR5SO₂R⁶

(wherein each of R^ and R^ independently represent a hydrogen atom, a Cj.galkyl or phenyl group);

6. Method according to claim 5 or claim 6 wherein the 5-HT4 antagonist is compound formula (I) selected from : [l-[2-(methylsulphonyl)amino]ethyl]-4-piperidinyl]methyl 1 -methyl- lH-indole-3- carboxylate;

[l-(2-hydroxyethyl)-4-piperidinyl]methyl 1 -methyl- lH-indole-3-carboxylate; [ l-r2-(methylamino)sulphonylJethyl]-4-piperidinyl]methyl 1 -methyl- 1 H-indoIe-3- carboxylate;

[l-(2-methoxyethyl)-4-piperidinyl]methyl l-methyl-lH-indole-3-carboxyIate;

[ 1 -(3-amino-3-oxopropyl)-4-piperidinyl]methyl 1 -methyl- 1 H-indole-3-carboxylate; [l-(2-cyanoethyl)-4-piperidinyl]methyl l-methyl-lH-indole-3-carboxylate;

[l-[2-(methylsulphonyl)amino]ethyl]-4-piperidinyl]methyl lH-indole-3-carboxyIate;

[l-[2-(methylsulphonyl)amino]ethyl]-4-piperidinyl]methyl 2-methoxy-lH-indoIe-3- carboxylate;

[l-[2-(acetylamino)ethyl]-4-piperidinyl]methyl 1 -methyl- lH-indoIe-3-carboxylate; [l-[3-[(methylsulphonyl)amino]propyl]-4-piperidinyI]methyl 1 -methyl- 1 H-indole-3- carboxylate;

[l-[2-[(methylsulphonyl)aminoJethyI]-4-piperidinyl]methyl 5-fluoro-lH-indole-3- carboxylate;

[l-[2-[(methylsuIphonyl)amino]ethyl]-4-piperidinyl]methyl 5-fluoro-2-methoxy-lH-indoIe- 3-carboxyIate;

[l-[2-[(methylsulphonyl)amino]ethyl]-4-piperidinyl]methyl 2-methoxy-l-methyI-lH-indole- 3-carboxylate;

[l-[2-[(phenylsuIphonyl)amino]ethyl]-4-piperidinyIJmethyI 1 -methyl- 1 H-indole-3- carboxylate; [l-[2-[(methylsulphonyl)amino]ethyl]-4-piperidinyl]methyl 5-fluoro- 1 -methyl- 1 H-indole-3- carboxylate;

[l-[2-[(methylsulphonyI)amino)ethyl]-4-piperidinyl]methyl 5-methyl- 1 H-indole-3- carboxylate;

[l-[2-[(methylsulphonyl)amino]ethyl]-4-piperidinyl]methyl 2-methoxy-5-methyl-lH-indole- 3-carboxylate;

[l-[2-[methyl(methylsulphonyl)aminolethylJ-4--ιjperidinyllmethyl 1 -methyl- lH-indole-3- carboxylate;

[l-[2-[(methylsuIphonyl)amino]ethyl]-4-piperidinyl]methyl 5-fluoro-2-methoxy-lH-indole- 3-carboxylate N-oxide; l-methyl-4-[[[(l-methyl-lH-indol-3-yl)carbonyl]oxy]methyl]-l-[2-l(methylsulphonyI)- amino]ethyl]piperidinium iodide: 4-[[[(2-methoxy-lH-indol-3-yl)carbonyl)oxy|methyl|-l -methyl- 1-[2-[ (methylsulphonyl)- amino]ethyl]-piperidinium iodide;

or a pharmaceutically acceptable salt or solvate thereof.

7. A pharmaceutical composition for use in the treatment and/or prophylaxi of migraine associated with stimulation of 5-HT4 receptors, which comprises a 5-HT4 antagonist and a pharmaceutically acceptable carrier.

8. A composition according to claim 7 wherein the 5-HT4 receptor antagonist is a compound of formula (I) :

Formula (I)

wherein

R! represents a hydrogen or a halogen atom, or a Cj.^alkyl, Cj.galkoxy or hydroxy grou

R² represents a hydrogen atom or a Ci.galkyl, -CH C₂_5alkenyl or -CH2C₂.5alkynyl group; R- represents a hydrogen atom or a Cj.galkyl or Cj.^alkoxy group; n represents 2 or 3; R represents a group selected from cyano, hydroxyl, C ^alkoxy, phenoxy,

QOC salkyl, C(O)C6H₅, -CONR⁵R⁶, -NR⁵COR⁶, -SO₂NR⁵R⁶ or -NR5S0₂R

(wherein each of R-5 and R^ independently represent a hydrogen atom, a C_j.^alkyl phenyl group);

9. A composition according to claim 7 or claim 8 wherein the 5-HT4 receptor antagonist is a compound of formula (I) selected from :

[l-[2-(methylsulphonyl)amino]ethyl]-4-piperidinyl]methyI 1-methyl- 1 H-indole-3- carboxylate;

[l-(2-hydroxyethyl)-4-piperidinyl]methyl 1 -methyl- lH-indole-3-carboxy late;

[l-(2-methoxyethyI)-4-piperidinyl]methyl 1 -methyl- lH-indole-3-carboxy late; [l-(3-amino-3-oxopropyl)-4-piperidinyI]methyl 1 -methyl- lH-indole-3-carboxylate:

[l-(2-cyanoethyl)-4-piperidinyl]methyl l-methyI-lH-indole-3-carboxyiate;

[l-[2-(methylsuIphonyl)amino]ethyl]-4-piperidinyl]methyl lH-indoIe-3-carboxylate;

[l-[2-(methylsulphonyl)amino]ethyl]-4-piperidinyl]methyl 2-methoxy- 1 H-indoIe-3- carboxylate; [l-[2-(acetylamino)ethyl]-4-piperidinyl]methyl l-methyl-lH-indole-3-carboxylate;

[l-[3-[(methylsuIphonyl)amino]propyl]-4-piperidinyl]methyl l-methyl-lH-indole-3- carboxylate;

[l-[2-[(methyIsulphonyl)amino]ethyl]-4-piperidinyl]methyl 5-fluoro-lH-indole-3- carboxylate; [l-[2-[(methylsulphonyl)amino]ethyl]-4-piperidinyl]methyl 5-fluoro-2-methoxy-lH-indole- 3-carboxylate;

[l-[2-[(methylsulphonyl)amino]ethyl]-4-piperidinyl]methyl 2-methoxy-l-methyl-lH-indole- 3-carboxylate;

[l-[2-[(phenylsulphonyl)amino]ethyl]-4-piperidinyl]methyl 1 -methyl- lH-indole-3- carboxylate;

[l-[2-[(methylsulphonyl)amino]ethyl]-4-piperidinyl]methyl 5-fluoro- 1 -methyl- 1 H-indole-3- carboxylate:

[l-[2-[(methylsulphonyl)amino)ethyl]-4-piperidinyl]methyl 5-methyl-lH-indoIe-3- carboxylate; [ l-[2-[(methylsulphonyl)amino]ethyl]-4-piperidinyIJmethyl 2-methoxy-5-methyl-lH-indole- 3-carboxylate; [l-[2-[methyl(methylsulphonyI)aminoJethyl]-4-piperidinyl]methyl 1 -methyl- lH-indole-3- carboxylate;

[l-[2-l(methylsulphonyl)aminojethyl]-4-piperidinylJmethyl 5-fluoro-2-methoxy-lH-indole- 3-carboxylate N-oxide; 1 -methyl-4-[[[( 1 -methyl- 1 H-indol-3-yl)carbonyl]oxy]methyl ]- 1 -f 2-[ (methylsulphonyl)- amino]ethyl]piperidinium iodide;

4-[[[(2-methoxy- 1 H-indol-3-yl)carbonyl]oxy] methyl]- 1 -methyl- 1 - [ 2- [ (methy lsulphonyl)- amino]ethyl]-piperidinium iodide; or a

pharmaceutically acceptable salt or solvate thereof.