WO1994000113A2 - Medicaments containing 5-ht4 receptor antagonists - Google Patents

Medicaments containing 5-ht4 receptor antagonists Download PDF

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Publication number
WO1994000113A2
WO1994000113A2 PCT/GB1993/001330 GB9301330W WO9400113A2 WO 1994000113 A2 WO1994000113 A2 WO 1994000113A2 GB 9301330 W GB9301330 W GB 9301330W WO 9400113 A2 WO9400113 A2 WO 9400113A2
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WO
WIPO (PCT)
Prior art keywords
receptor antagonist
treatment
prophylaxis
emesis
gastrointestinal disorders
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Application number
PCT/GB1993/001330
Other languages
French (fr)
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WO1994000113A3 (en
Inventor
Gareth John Sanger
Original Assignee
Smithkline Beecham Plc
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Publication date
Priority claimed from GB929213708A external-priority patent/GB9213708D0/en
Priority claimed from GB929214399A external-priority patent/GB9214399D0/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to JP6502163A priority Critical patent/JPH07508276A/en
Priority to AU43504/93A priority patent/AU4350493A/en
Publication of WO1994000113A2 publication Critical patent/WO1994000113A2/en
Publication of WO1994000113A3 publication Critical patent/WO1994000113A3/en

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    • 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
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • 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
    • 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
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
    • 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
    • A61K31/452—Piperidinium derivatives
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics

Definitions

  • This invention relates to a method of treatment of gastrointestinal disorders and emesis in mammals, including humans.
  • EP-A-501322 (Glaxo Group Limited), WO 93/02677, WO 93/03725, WO 93/05038, WO 93/05040 and PCT/GB93/00506 (SmithKline Beecham pic) describe compounds having 5-HT4 receptor antagonist activity.
  • 5-HT3 receptor antagonists have been disclosed as of potential use in the treatment of gastrointestinal disorders associated with upper gut motility (see EP-A-226266 (Glaxo Group Ltd.) and EP-A- 189002 (Sandoz Limited)).
  • 5-HT 3 receptor antagonists are also well known antiemetics, such as ondansetron, granisetron and tropisetron (Drugs of the Future 1989, .14 (9) p.875 - F.D. King and G.J. Sanger).
  • 5-HT4 receptor antagonists are tested in a model of total body irradiation in the ferret (Bermudez et.al. Br. . Cancer 1988, at 58, 644) at a dose determined from the in vitro activity, to determine antiemetic effects.
  • Gastro-oesophageal reflux disease (GERD/GORD) is thought to be due to hypersensitivity of the stomach to distension, and distension evokes a vago-vagal reflex causing transient relaxation of the lower oesophageal sphincter and hence, reflux (Gut 1988, 29, 1020-1028 and Gastroenterology 1986, 1, 890-5). Agents which desensitise the vagus nerve are therefore of potential use in treating GERD/GORD.
  • the invention therefore provides a method for the treatment and/or prophylaxis of gastrointestinal disorders associated with upper gut motility and/or emesis in mammals, including humans, which method comprises administering to the mammal in need of such treatment and/or prophylaxis, an effective and/or prophylactic amount of a 5-HT4 receptor antagonist.
  • 5-HT4 receptor antagonists may be identified according to standard methods, such as that described hereinafter, and the methods described in Naunyn-Schmiedeberg's Arch Pharmacol. 342, 619-622 and 2, 439-446, and J. Pharamcol. Exp. Ther. (1990) 252. 1378-1386.
  • 5-HT4 receptor antagonists examples include R 50 595 (Janssen), which is described in FR76530 and Eur . Pharmacol., 181 119-125 (1990), SDZ 205-557, which is described by K.H. Buchheit and R. Gamse in Naunyn-Schmiedeberg's Arch. Pharmacol., 242 (Suppl.), R101 (1991) and 345, 387-393 (1992), DAU 6215 (Br. J. Pharmacol. (1991), JjQ4, Proc. Supp. 47P, DAU 6285 (Naunyn-Schmiedeberg's Arch. Pharmacol, 245; 264-269 (1992), RS 23597-190 (Syntex - British Pharmacology
  • ICS 205-930 (tropisetron), which is described in GB 2125398 A (Sandoz Limited) is also a 5-HT4 receptor antagonist, but is far more potent as a 5-HT3 receptor antagonist.
  • 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 in substantially pure pharmaceutically acceptable form.
  • the administration of the 5-HT4 receptor antagonist may be by way of oral, sublingual, transdermal or parenteral administration.
  • a unit dose will normally contain 0.1 to 50 mg for example 0.5 to 10 mg, of the 5-HT4 receptor antagonist.
  • 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 -i-
  • / ⁇ kg adult ot 0.1 to 50 mg, for example 0.1 to 5 mg, that is in tne range ot approximately 0.001 to 1 mg/kg/day, more usually 0.005 to 0.2 mg/kg/day.
  • the 5-HT4 receptor antagonist is administered in the form of a unit-dose composition, such as a unit dose oral or parenteral composition.
  • compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or 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, disinte grants, 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.
  • 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 art.
  • 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 rj-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 monoole
  • 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.
  • the present invention also provides the use of a 5-HT4 receptor antagonist in the manufacture of a medicament for use in the treatment and/or prophylaxis of gastrointestinal disorders associated with upper gut motility and as antiemetics.
  • a 5-HT4 receptor antagonist in the manufacture of a medicament for use in the treatment and/or prophylaxis of gastrointestinal disorders associated with upper gut motility and as antiemetics.
  • Such treatment and/or prophylaxis may be ' carried out as hereinbefore described.
  • the present invention further provides a pharmaceutical composition for use in the treatment and/or prophylaxis of gastrointestinal disorders associated with upper gut motility and/or emesis which comprises a 5-HT4 receptor antagonist, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for use in the treatment and/or prophylaxis of gastrointestinal disorders associated with upper gut motility and/or emesis which comprises a 5-HT4 receptor antagonist, and a pharmaceutically acceptable carrier.
  • Such compositions may be prepared in the manner as hereinbefore described.
  • guinea-pigs Male guinea-pigs, weighing 250-400g were used. Longitudinal muscle-myenteric plexus preparations, approximately 3cm long, were obtained from the distal colon region. These were suspended under a 0.5g load in isolated tissue baths containing Krebs solution bubbled with 5% CO2 in O2 and maintained at 37°C. In all experiments, the Krebs solution also contained methiothepin 10 " ⁇ M, methysergide 2X10 " 7M and granisetron lO' ⁇ M.
  • a concentration of 5-HT is selected so as to obtain a contraction of the muscle approximately 40-70% maximum(10-9M approx).
  • the tissue is then alternately dosed every 15min with this concentration of 5-HT and then with an approximately equi-effective concentration of the nicotine receptor stimulant (dimethylphenyl piperazinium) DMPP.
  • increasing concentrations of a putative 5-HT4 receptor antagonist are then added to the bathing solution. The effects of this compound are then determined as a percentage reduction of the contractions evoked by 5-HT or by DMPP. From this data, IC50 values are determined, being defined as the concentration of antagonist which reduced the contraction by 50%.
  • a compound which reduced the response to 5-HT but not to DMPP is believed to act as a 5-HT4 receptor antagonist.
  • Compounds are administered to ferrets at a suitable dose e.g.lOmg kg ⁇ l p.o., 15 min before total body irradiation (Bermudez et al, Br J. Cancer 1988, 58, p644).
  • a suitable dose e.g.lOmg kg ⁇ l p.o., 15 min before total body irradiation (Bermudez et al, Br J. Cancer 1988, 58, p644).

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Abstract

A method for the treatment and/or prophylaxis of gastrointestinal disorders associated with upper gut motility and/or emesis in mamals, including humans, which method comprises administering to the mammal in need of such treatment and/or prophylaxis, and effective and/or prophylactic amount of a 5-HT4 receptor antagonist.

Description

MEDICAMENTS CONTAINING 5-HT4 RECEPTOR ANTAGONISTS
This invention relates to a method of treatment of gastrointestinal disorders and emesis in mammals, including humans.
European Journal of Pharmacology 146 (1988), 187-188, and Naunyn- Schmiedeberg's Arch. Pharmacol. (1989) 340:403-410, describe a non classical 5-hydroxytryptamine receptor, now designated the 5-HT4 receptor.
EP-A-501322 (Glaxo Group Limited), WO 93/02677, WO 93/03725, WO 93/05038, WO 93/05040 and PCT/GB93/00506 (SmithKline Beecham pic) describe compounds having 5-HT4 receptor antagonist activity.
Some 5-HT3 receptor antagonists have been disclosed as of potential use in the treatment of gastrointestinal disorders associated with upper gut motility (see EP-A-226266 (Glaxo Group Ltd.) and EP-A- 189002 (Sandoz Limited)). 5-HT3 receptor antagonists are also well known antiemetics, such as ondansetron, granisetron and tropisetron (Drugs of the Future 1989, .14 (9) p.875 - F.D. King and G.J. Sanger).
We have now discovered that a compound which acts as an antagonist at 5-HT4 receptors is of potential use in the treatment of such disorders, especially the nausea and gastric symptoms of gastro-oesophageal reflux disease and dyspepsia, and as antiemetics per se.
5-HT4 receptor antagonists are tested in a model of total body irradiation in the ferret (Bermudez et.al. Br. . Cancer 1988, at 58, 644) at a dose determined from the in vitro activity, to determine antiemetic effects.
Since cytotoxic-evoked emesis is known to be vagus-dependent, this suggests that 5- HT4 receptors are associated with the vagus nerve. Gastro-oesophageal reflux disease (GERD/GORD) is thought to be due to hypersensitivity of the stomach to distension, and distension evokes a vago-vagal reflex causing transient relaxation of the lower oesophageal sphincter and hence, reflux (Gut 1988, 29, 1020-1028 and Gastroenterology 1986, 1, 890-5). Agents which desensitise the vagus nerve are therefore of potential use in treating GERD/GORD.
The invention therefore provides a method for the treatment and/or prophylaxis of gastrointestinal disorders associated with upper gut motility and/or emesis in mammals, including humans, which method comprises administering to the mammal in need of such treatment and/or prophylaxis, an effective and/or prophylactic amount of a 5-HT4 receptor antagonist.
5-HT4 receptor antagonists may be identified according to standard methods, such as that described hereinafter, and the methods described in Naunyn-Schmiedeberg's Arch Pharmacol. 342, 619-622 and 2, 439-446, and J. Pharamcol. Exp. Ther. (1990) 252. 1378-1386.
Examples of 5-HT4 receptor antagonists include R 50 595 (Janssen), which is described in FR76530 and Eur . Pharmacol., 181 119-125 (1990), SDZ 205-557, which is described by K.H. Buchheit and R. Gamse in Naunyn-Schmiedeberg's Arch. Pharmacol., 242 (Suppl.), R101 (1991) and 345, 387-393 (1992), DAU 6215 (Br. J. Pharmacol. (1991), JjQ4, Proc. Supp. 47P, DAU 6285 (Naunyn-Schmiedeberg's Arch. Pharmacol, 245; 264-269 (1992), RS 23597-190 (Syntex - British Pharmacology
Society Meeting, September 1992), SC 53606 (Searle - 2nd International Symposium on Serotonin, Houston, USA , - September 1992) and GR113808 (Glaxo - EP -A- 501322).
ICS 205-930 (tropisetron), which is described in GB 2125398 A (Sandoz Limited) is also a 5-HT4 receptor antagonist, but is far more potent as a 5-HT3 receptor antagonist.
In a particular aspect, the 5-HT4 receptor antagonist is a more potent antagonist at 5- HT4 receptors than at 5-HT3 receptors.
Preferably, the 5-HT4 receptor antagonist is in substantially pure pharmaceutically acceptable form.
The administration of the 5-HT4 receptor antagonist may be by way of oral, sublingual, transdermal or parenteral administration.
An amount effective to treat the disorders 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 0.1 to 50 mg for example 0.5 to 10 mg, of the 5-HT4 receptor antagonist. 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 -i-
/υ kg adult ot 0.1 to 50 mg, for example 0.1 to 5 mg, that is in tne range ot approximately 0.001 to 1 mg/kg/day, more usually 0.005 to 0.2 mg/kg/day.
For oral or parenteral administration, it is greatly preferred that the 5-HT4 receptor antagonist is administered in the form of a unit-dose composition, such as a unit dose oral or parenteral composition.
Such compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or 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, disinte grants, 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.
These 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 art.
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 rj-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.
The present invention also provides the use of a 5-HT4 receptor antagonist in the manufacture of a medicament for use in the treatment and/or prophylaxis of gastrointestinal disorders associated with upper gut motility and as antiemetics. Such treatment and/or prophylaxis may be' carried out as hereinbefore described.
The present invention further provides a pharmaceutical composition for use in the treatment and/or prophylaxis of gastrointestinal disorders associated with upper gut motility and/or emesis which comprises a 5-HT4 receptor antagonist, and a pharmaceutically acceptable carrier. Such compositions may be prepared in the manner as hereinbefore described. 5-HT4 receptor antagonist activity
Male guinea-pigs, weighing 250-400g were used. Longitudinal muscle-myenteric plexus preparations, approximately 3cm long, were obtained from the distal colon region. These were suspended under a 0.5g load in isolated tissue baths containing Krebs solution bubbled with 5% CO2 in O2 and maintained at 37°C. In all experiments, the Krebs solution also contained methiothepin 10"^M, methysergide 2X10"7M and granisetron lO'^M.
After construction of a simple concentration-response curve with 5-HT, using 30s contact times and a 15min dosing cycle, a concentration of 5-HT is selected so as to obtain a contraction of the muscle approximately 40-70% maximum(10-9M approx). The tissue is then alternately dosed every 15min with this concentration of 5-HT and then with an approximately equi-effective concentration of the nicotine receptor stimulant (dimethylphenyl piperazinium) DMPP. After obtaining consistent responses to both 5-HT and DMPP, increasing concentrations of a putative 5-HT4 receptor antagonist are then added to the bathing solution. The effects of this compound are then determined as a percentage reduction of the contractions evoked by 5-HT or by DMPP. From this data, IC50 values are determined, being defined as the concentration of antagonist which reduced the contraction by 50%. A compound which reduced the response to 5-HT but not to DMPP is believed to act as a 5-HT4 receptor antagonist.
In Vivo Test For Antiemetic Activity
Compounds are administered to ferrets at a suitable dose e.g.lOmg kg~l p.o., 15 min before total body irradiation (Bermudez et al, Br J. Cancer 1988, 58, p644).

Claims

Claims
1. A method for the treatment and/or prophylaxis of gastrointestinal disorders associated with upper gut motility and/or emesis in mammals, including humans, which method comprises administering to the mammal in need of such treatment and/or prophylaxis, an effective and/or prophylactic amount of a 5-HT4 receptor antagonist.
2. The use of a 5-HT4 receptor antagonist in the manufacture of a medicament for use in the treatment and/or prophylaxis of gastrointestinal disorders associated with upper gut motility and/or emesis.
3. A pharmaceutical composition for use in the treatment and/or prophylaxis of gastrointestinal disorders associated with upper gut motility and/or emesis, which comprises a 5-HT4 receptor antagonist, and a pharmaceutically acceptable carrier.
4. A method, use or composition according to claim 1, 2 or 3 wherein the 5-HT4 receptor antagonist is more potent at 5-HT4 receptors than at 5-HT3 receptors.
5. A method, use or composition according to claim 4 for the treatment of gastrointestinal disorders associated with upper gut motility.
6. A method, use or composition according to claim 5 for the treatment of emesis.
7. A method, use or composition according to claim 1, 2 or 3 wherein 5-HT4 receptor antagonist is R 50 595, SDZ 205-557, DAU 6285, RS 23597-190, SC 53606 or GR 113808.
8. A method, use or composition according to claim 1, 2 or 3 wherein the
5-HT4 receptor antagonist is a compound described in relation to WO 93/02677, WO 93/03725, WO 93/05038, WO 93/05040 and PCT/GB 93/00506 (SmithKline Beecham pic).
PCT/GB1993/001330 1992-06-27 1993-06-24 Medicaments containing 5-ht4 receptor antagonists WO1994000113A2 (en)

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US6117882A (en) * 1997-10-07 2000-09-12 Eli Lilly And Company 5-HT4 agonists and antagonists
EP2585066A2 (en) * 2010-06-24 2013-05-01 Alkermes Pharma Ireland Limited Prodrugs of nh-acidic compounds: ester, carbonate, carbamate and phosphonate derivatives
JP2013541494A (en) * 2010-06-24 2013-11-14 アルカーメス ファーマ アイルランド リミテッド Prodrugs of NH acidic compounds: derivatives of esters, carbonates, carbamates and phosphonates
EP2585066A4 (en) * 2010-06-24 2014-06-11 Alkermes Pharma Ireland Ltd Prodrugs of nh-acidic compounds: ester, carbonate, carbamate and phosphonate derivatives
US9072788B2 (en) 2010-06-24 2015-07-07 Alkermes Pharma Ireland Limited Prodrugs of NH-acidic compounds: ester, carbonate, carbamate and phosphonate derivatives

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