WO1995001170A2

WO1995001170A2 - Use of phenethanolamine derivatives in the treatment of gastrointestinal disorders

Info

Publication number: WO1995001170A2
Application number: PCT/EP1994/002106
Authority: WO
Inventors: Richard Storer; Michael Walter Foxton; Charles David Hartley; Richard Howard Green; Stuart Travers
Original assignee: Glaxo Group Limited
Priority date: 1993-07-01
Filing date: 1994-06-29
Publication date: 1995-01-12
Also published as: GB9313574D0; JPH08512038A; WO1995001170A3; AU7384094A; EP0706386A1

Abstract

The use of compounds of formula (I) in which: R0 is hydrogen, methyl or hydroxymethyl; R1 is substituted alkyl; R?2 and R3¿ are each hydrogen, halogen, hydroxy, alkoxy, carboxy, alkoxycarbonyl, alkyl, nitro, haloalkyl group, or substituted alkyl; X is oxygen or sulphur; and Ar is optionally substituted phenyl or naphtyl; and pharmaceutically acceptable salts thereof in the treatment of gastrointestinal disorders is described.

Description

USE OF PHENETHANOLAMINE DERIVATIVES IN THE TREATMENT OF GASTROINTESTINAL DISORDERS

This invention relates to a new medical use for certain phenethanolamine derivatives and to pharmaceutical compositions containing them. In particular, the invention relates to the use of such compounds which act as agonists at atypical beta-adrenoceptors (also known as beta-3-adrenoceptors). Such receptors have been described for example by J R S Arch et. al., Nature, 309, 163-165 (1984); C Wilson et. al., Eur. J. Pharmacol., 100, 309-319 (1984); L J Emorine et. al., Science, 245, 1118-1121 (1989); and A. Bianchetti et. al. Br. J. Pharmacol., 100, 831-839 (1990).

Atypical beta-adrenoceptors belong to the family of adrenoceptors which mediate the physiological actions of the hormones adrenaline and noradrenaline. Sub-types of the adrenoceptors, - -, α-2-, βι~, &2" and &3- (atypical) can be identified on the basis of their pharmacological properties and physiological effects. Chemical agents which stimulate or block these receptors (but not >2) are widely used in clinical medicine. More recently, emphasis has been placed upon specific receptor selectivity in order to reduce side effects caused, in part, by interactions with other receptors.

Atypical beta-adrenoceptors are known to occur in adipose tissue and the gastrointestinal tract. Compounds which act as agonists at atypical beta- adrenoceptors may be identified using standard tests (see for instance C Wilson et. al., supra).

A particular class of phenethanolamine compounds have been described in European Patent Specification No. 0 543 662-A which describes compounds of the general formula (I)

wherein

R° is a hydrogen atom, a methyl group or a hydroxymethyl group; R¹ is a substituted C^^alk l group which group is substituted by at least one of the substituents A, defined below; R² and R³ are each selected from a hydrogen atom, a halogen atom, a hydroxyl group, a C.,..₅alkoxy group, a carboxy group, a C₂_₇alkoxycarbonyl group, a Chalky! group, a nitro group, a haloC^alkyl group, or a substituted C₁_₁₂alkyl group which group is substituted by at least one of substituents A, defined below; X is an oxygen atom or a sulphur atom; and Ar is a group of formula (C) or (D):

in which:

R⁴ is a hydrogen atom, a halogen atom, a hydroxy group, a hydroxymethyl group, a C^alkoxy group, a C^alkyl group, an aliphatic carboxylic C₁^acyloxy group, a nitro group, a cyano group, an aralkyloxy group in which the aralkyl part is as defined below, an aryloxy group in which the aryl part is as defined below, an aryl group as defined below, or a haloC^alkyl group;

R⁵ is a hydrogen atom, a halogen atom, a hydroxy group, a C-^alkoxy group, a Chalk ! group, or a nitro group;

R⁶ is a hydrogen atom, a halogen atom, a hydroxy group, a C-^alkoxy group, or a C^alkyl group; said aralkyl part is a C^alkyl group which group is substituted by 1 or 2 aryl groups as defined below; said aryl groups are carbocyclic C₆_₁₀aryl groups which are unsubstituted or are substituted by at least one of substituents B, defined below; said substituents A are selected from carboxy groups, C₂_7alkoxycarbonyl groups, aryloxycarbonyl groups in which the aryl part is as defined above, aralkyloxycarbonyl groups in which the aralkyl part is as defined above, C^ alkylcarbamoyl groups, dialkylcarbamoyl groups in which each alkyl part has from 1 to 4 carbon atoms, carbamoyl groups, hydroxycarbamoyl groups, hydroxy groups, carboxylic acyloxy groups having from 1 to 6 carbon atoms, and

2,4-dioxothiazolidin-5-yl groups; and said substituents B are selected from halogen atoms, C_1. alkyl groups, C-^alkoxy groups, nitro groups, haloC^alkyl groups, and hydroxy groups; and pharmaceutically acceptable salts thereof.

These compounds are described as being of use in the treatment or prophylaxis of diabetes, obesity, hyperlipemia, hyperglycaemia, complications of diabetes, obesity related hypertension and osteoporosis.

In general, atypical beta-adrenoceptor agonists have been found to be particularly useful as thermogenic anti-obesity agents and as anti-diabetic agents. Compounds having atypical beta-adrenoceptor agonist activity have also been described as being useful in the treatment of hyperglycaemia, as animal growth promoters, as blood platelet aggregation inhibitors, as positive inotropic agents and as antiathereosclerotic agents, and as being useful in the treatment of glaucoma.

It has now been found that the compounds of general formula (I) which act as agonists at atypical beta-adrenoceptors may be useful for the treatment of gastrointestinal disorders, especially inflammatory gastrointestinal disorders including peptic ulceration, oesophagitis, gastritis and duodenitis (including that induced by H. pylori), intestinal ulcerations (including inflammatory bowel disease, especially, ulcerative colitis, ileitis, Crohn's disease and proctitis) and gastrointestinal ulcerations, especially when induced by non-steroidal anti- inflammatory drugs (NSAIDs) or corticosteroids.

A preferred sub-class of the compounds of the general formula (I) for use according to the present invention is that defined by formula (II)

and physiologically acceptable salts and solvates thereof, wherein one of R¹¹ and R¹² represents a hydrogen atom and the other of R¹¹ and R¹² represents the group -CH₂CO₂H; and

R¹⁴ represents a chlorine, fluorine or bromine atom or a methyl or trifluoromethyl group.

It will be appreciated that the above compounds of formulae (I) and (II) are optically active. The use of both the individual, isolated isomers and mixtures thereof, including racemates, is also considered to be within the scope of the present invention. Particularly preferred compounds of formulae (I) and (II) for use according to the present invention are those wherein the asymmetric carbon atoms in the -CH(OH)- group and the -CH(CH₃)- group are in the (R)-configuration.

Another preferred group of compounds of formula (II) is that wherein R¹¹ represents the group -CH₂CO₂H.

A particularly preferred compound of general formula (I) for use according to the present invention is:

(R,R)-[4-[2-[2-[(3-chlorophenyl)-2-hydroxy-ethylamino]propoxy]phenyl]acetic acid; or a physiologically acceptable salt or solvate thereof.

Suitable physiologically acceptable salts of the compounds of general formula (I) include acid addition salts derived from inorganic and organic acids, such as hydrochlorides, hydrobromides, sulphates, phosphates, benzoates, naphthoates, hydroxynaphthoates, p-toluenesulphonates, methanesulphonates, sulphamates, ascorbates, tartrates, citrates, oxalates, maleates, salicylates, fumarates, succinates, lactates, glutarates, glutaconates, acetates or tricarballyates. The compounds may also form salts with suitable bases. Examples of such salts include alkali metal (e.g. sodium or potassium), alkaline earth metal (e.g. calcium, or magnesium), ammonium and substituted ammonium.

It will be appreciated that, for pharmaceutical use, the salts referred to above will be physiologically acceptable, but other salts may find use, for example, in the preparation of the compounds of general formula (I) and the physiologically acceptable salts thereof.

The present invention provides a method of treatment of a human or non-human mammal, suffering from or susceptible to a inflammatory gastrointestinal disorder, such as peptic ulceration, oesophagitis, gastritis, duodenitis, intestinal ulcerations and gastrointestinal ulcerations, which method comprises administering to said mammal an effective amount of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof.

In a preferred aspect of the present invention, there is provided a method of treatment of a human or non-human mammal, suffering from a condition of intestinal ulcerations wherein said condition is an inflammatory bowel disease, such as ulcerative colitis, ileitis, Crohn's disease or proctitis, which method comprises administering to said mammal an effective amount of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof.

In a particularly preferred aspect of the present invention, there is provided a method of treatment of a human or non-human mammal, suffering from a condition of gastrointestinal ulcerations wherein said condition is induced by non-steroidal anti-inflammatory drugs, which method comprises administering to said mammal an effective amount of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof.

References in this specification to treatment include prophylactic treatment as well as the alleviation of symptoms.

In a further aspect, the present invention provides a therapeutic agent which comprises an effective amount of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in medicine, particularly human medicine, for the treatment of inflammatory gastrointestinal disorders such as peptic ulceration, oesophagitis, gastritis, duodenitis, intestinal ulcerations and gastrointestinal ulcerations.

In a further preferred aspect of the present invention, there is provided a therapeutic agent which comprises an effective amount of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment of a condition of intestinal ulcerations wherein said condition is an inflammatory bowel disease such as ulcerative colitis, ileitis, Crohn's disease or proctitis.

In a further particularly preferred aspect of the present invention, there is provided a therapeutic agent which comprises an effective amount of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment of a condition of gastrointestinal ulcerations wherein said condition is induced by non-steroidal anti-inflammatory drugs.

In a yet further aspect, the invention provides for the use of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of inflammatory gastrointestinal disorders such as peptic ulceration, gastritis, duodenitis, intestinal ulcerations and gastrointestinal ulcerations.

In a yet further preferred aspect of the present invention, there is provided the use of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of a condition of intestinal ulcerations wherein said condition is an inflammatory bowel disease such as ulcerative colitis, ileitis, Crohn's disease or proctitis.

In a yet further particularly preferred aspect of the present invention, there is provided the use of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of a condition of gastrointestinal ulcerations wherein said condition is induced by non-steroidal anti-inflammatory drugs.

It will be appreciated that where a compound of general formula (I) or a physiologically acceptable salt or solvate thereof is used for the treatment of a condition of gastrointestinal ulcerations induced by non-steroidal anti- inflammatory drugs (NSAID's) it may be preferable to co-adminster the compound of general formula (I) together with the NSAID. The active ingredients may be employed in the form of separate pharmaceutical formulations or a combined formulation may be used. In such a combined formulation, the active ingredients must of course be stable and mutually compatible in the particular formulation employed.

Pharmaceutical compositions which comprise at least one compound of general formula (I) or a physiologically acceptable salt or solvate thereof and at least one non-steroidal anti-inflammatory drug, together with at least one physiologically acceptable carrier or excipient are believed to be novel compositions and constitute a further aspect of the present invention.

It will be appreciated that similar combined formulations may be utilised for the treatment of a condition of gastrointestinal ulcerations induced by corticosteroids.

The compound of general formula (I) and their physiologically acceptable salts and solvates may be formulated for administration in any convenient way, and the present invention also includes within its scope pharmaceutical compositions comprising at least one compound of general formula (1) or a physiologically acceptable salt or solvate thereof adapted for use in human or veterinary medicine. Such compositions may be presented for use in a conventional manner in admixture with one or more physiologically acceptable carriers or excipients. The carrier(s) or excipient(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

Thus the compounds for use according to the present invention may be formulated for oral, buccal, parenteral, rectal or transdermal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or the nose).

For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl- β-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to give controlled release of the active compound.

For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.

The compounds for use according to the present invention may be formulated for parenteral administration by injection e.g. by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.

The compounds for use according to the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously, transcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds for use according to the present invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

A proposed dose of the compounds for use according to the present invention for administration to a human (of approximately 70kg body weight) is 0.1 mg to 1g, preferably to 1mg to 100mg of the active ingredient per unit dose, expressed as the weight of free base. The unit dose may be administered, for example, 1 to 4 times per day. The dose will depend on the route of administration. It will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient as well as the severity of the condition to be treated. The precise dose and route of administration will ultimately be at the discretion of the attendant physician or veterinarian.

The compounds of general formula (I) for use according to the present invention may be prepared by a number of processes which are well known in the art for the preparation of phenethanolamine derivatives. Suitable methods are described, for instance, in European Patent Specification No. 0 543 662-A.

The following, non-limiting, examples illustrate the synthesis of compounds of general formula (I) for use according to the present invention.

Temperatures are in °C. Thin layer chromatography (T.l.c.) was carried out over SiO₂ unless otherwise specified, and "dried" refers to drying using magnesium sulphate except where otherwise stated.

Intermediate 1 Methane sulfonic acid, (R)-(2-benzyloxycarbonylamino)-propyl ester

To a stirred solution of (R)-1-(2-hydroxy-1-methylethyl)carbamic acid, benzyl ester (14.95g) in dichloromethane (200ml) maintained at -10° was added triethylamine (7.9g) followed by methanesulphonyl chloride (8.93g), which was added dropwise, maintaining the temperature of the reaction at -10°. The reaction was stirred at this temperature for 1.5h, then concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate, and the aqueous phase was extracted further with ethyl acetate. The combined organic extracts were washed successively with N hydrochloric acid, aqueous sodium bicarbonate solution, and saturated brine, dried and evaporated to give the title compound as a colourless solid (18.81g), which was used without purification. n.m.r. (CDCI₃): δ 1.27(d, 3H), 2.99 (s, 3H), 4.07 (m, 1 H), 4.16 (m, 1 H) and 4.27 (m, 1H), 4.86 (br.s, 1H), 5.11 (s, 2H), 7.3-7.4 (m, 5H).

Intermediate 2 (R)-2-f4-f(2-Benzyloxycarbonylamino)propoxylphenyllacetamide

Sodium hydride (60% dispersion in oil, 2.86g) was added cautiously to a stirred solution of 4-hydroxyphenylacetamide (10.4g) in dry N,N-dimethylformamide (150ml) under an atmosphere of nitrogen. The mixture was stirred for 3h, a solution of Intermediate 1 (18.77g) was added and the mixture was heated at 60° for 3.5h, then allowed to stand at ambient temperature for 72h. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was separated, washed with water, dried, and evaporated. A portion of this residue (10g) was chromatographed on silica, eluting with 10% methanol in chloroform. Concentration of the appropriate fractions gave the title compound as a cream- coloured solid (2.71 g, contains an impurity). n.m.r. (DMSO-d₆): δ 1.14 (d, 3H), 3.32 (s, 2H), 3.48 (m, 1 H), 3.75-3.95 (m, 2H), 5.01 (s, 2H), 6.80-6.88 (m, 2H), 7.12-7.18 (m, 2H), 7.28-7.45 (m, 5H).

Intermediate 3

(R)-2-f4-(2-Amino-1-propoxy)phenvπacetamide

A suspension of Intermediate 2 (2.7g), 10% palladium on charcoal (280 mg) and dry ammonium formate (1.67g) in methanol (230 ml) was stirred and heated under reflux under an atmosphere of nitrogen for 4h. The catalyst was filtered off, and the filtrate was concentrated. The residue was chromatographed on silica, eluting with chloroform:methanol:0.880 ammonium hydroxide (60:10:1 ). Evaporation of the appropriate fractions gave the title compound (contaminated with 4-hydroxyphenylacetamide) as a colourless solid (1.51g). n.m.r. (DMSO-d₆ + D₂O): δ 1.05 (d, 3H), 3.12 (m, 1 H), 3.28 (s, 1 H), 3.66-3.74 (m, 2H), 6.86 (d, 2H), 7.15 (d, 2H). Intermediate 4

(R,R)-2-r4-f2-r2-(3-Chlorophenyl)-2-hydroxy-ethylaminolpropoxy1-phenvn acetamide

A solution of Intermediate 3 (1.4g) and trimethylsilylacetamide (0.95g) in dimethylsulphoxide (5ml) were stirred under an atmosphere of nitrogen for 2h, then (R)-3-chlorophenyloxirane (1.03g) was added, and the solution was maintained at 70° for 6 days. The solution was poured into a mixture of 2N hydrochloric acid and ethyl acetate; the phases were separated, and the aqueous phase was washed with more ethyl acetate. The aqueous phase was basified and extracted with ethyl acetate. The combined organic extracts were dried and evaporated, and the residue was chromatographed on silica, eluting with 10% methanol in chloroform. Concentration of the appropriate fractions gave the title compound as a colourless solid (0.645mg), m.p. 122- 125° [α^D] -16.1° (c 0.4 MeOH).

Assay Found: C 62.8; H 6.5; N 7.85% C19H2₃CIN2O3 requires: C 62.9; H 6.4; N 7.85%

Example 1 (R,R)-f4-r2-r2-(3-Chlorophenyl)-2-hvdroxy-ethylaminolpropoxy1phenvnacetic acid

Intermediate 4 (490mg) in 2N hydrochloric acid (14ml) was heated under reflux for 70 min. The mixture was cooled and evaporated. The residue was dissolved in water, the solution was filtered, and the filtrate freeze-dried to give a cream-coloured solid (504mg). A solution of this solid in water was chromatographed on Amberlite XAD-2, eluting with aqueous ethanol. The appropriate fractions were combined, concentrated, and freeze-dried to give the title compound (147mg) as a colourless solid. Assay Found: C 60.1 ; H 6.0; N 3.95% Cι₉H₂₂CINO₄.H₂O requires: C 59.8; H 6.3; N 3.7% n.m.r. (DMSO-d₆): δ 1.10 (d, 3H), 2.81 (m, 2H), 3.12 (m, 1 H), 3.50 (s, 2H), 3.85 (m, 2H), 4.69 (m, 1 H), 6.87 (d, 2H) 7.16 (d, 2H), 7.27-7.44 (m, 4H).

Atypical beta-adrenoceptor agonists are compounds which demonstrate a pharmacological response (in vitro or in vivo) mediated at atypical beta-adrenoceptors. This activity has been be measured as the ability to stimulate lipolysis by rat adipocytes at sub-micromolar concentrations, in a response that is resistant to blockade by standard beta-adrenoceptor blocking drugs such as propranolol.

Another useful means of identifying an atypical beta-adrenoceptor agonist involves the measurement of agonist activity at atypical beta-adrenoceptors in the rat isolated lower oesophagus. A suitable assay is .described below as Method 1. Typically in this assay, a compound of general formula (I) for use according to the present invention has an equipotent molar ratio (EPMR) relevant to isoprenaline of less than 30.

The rat oesophagus assay is based upon that described by Ford et. al., Br. J.

Pharmacol., 105(supplΛ 235P, 1992, the method of which is described below as Method 1 :

Method 1

The lower oesophagus is removed from male AH/A rats (100-150g). The overlying serosal muscle is removed from the oesophagus to leave the tunis muscularis mucosa. Tissues are then placed in Kreb's solution containing the β2-antagonist ICI 118,551 (lO^M), the β-| -antagonist atenolol (10"⁵M), the phosphodiesterase inhibitor isobutyl methyl xanthine (IBMX; 3x1 O^M) and the prostaglandin synthesis inhibitor indomethacin (3x1 O^M), and the tissues suspended under a resting tension of 0.5g.

Subsequently, tissues are contracted with a submaximal concentration of carbachol (10^"^M) and, when a stable increase in tension has been achieved, a cumulative concentration effect curve to isoprenaline is constructed. Following washout with fresh Kreb's solution, tissues are recontracted with carbachol (lO^M) and a cumulative concentration effect curve to test agonist is constructed.

The relative potency of each test agonist (EPMR) is compared to isoprenaline as follows: EC50 agonist EPMR =

EC50 isoprenaline

wherein EC50 is the molar concentration of agonist which produces 50% of the maximum possible response for that agonist.

Using the non-selective beta-adrenoceptor agonist isoprenaline as a reference agonist, compounds selective for atypical beta-adrenoceptors should preferably be a minimum of 10-30 times less potent than isoprenaline at

or β2~ adrenoceptors and, more preferably, 300-1000 times less potent than isoprenaline at β-|- or β2-adrenoceptors.

An experimental model in which atypical beta-adrenoceptor agonists may be shown to be of use in the treatment of gastrointestinal disorders is described below as Method 2. The procedure is based upon that described by H. Satoh et al., Gastroenterology, 8_1, 719-725 (1981) in which the effect of compounds on indomethacin-induced gastric antral lesions in the re-fed rat is investigated. Indomethacin is an example of the class of compound known as non-steroidal anti-inflammatory drugs (NSAIDs), the use of which is frequently associated with gastrointestinal ulcers.

Method 2 Food (but not water) is withheld from female random hooded rats (70-120g) for 24 hours and then the rats are re-fed with Rat and Mouse No. 1 Maintenance Diet. After 1 hour of access to food, the rats are dosed orally with either the test compound or solvent (0.5% w/v methyl cellulose in water). 30 minutes later, indomethacin (60mg/kg; dissolved in 1 % w/v NaHCOβ in saline) is administered as a single subcutaneous injection at the back of the neck. Subsequently, the rats are allowed food, but water is withheld, and the animals are humanely killed by cervical dislocation at 6 hours post dose. Control animals received a single subcutaneous dose of the appropriate solvent.

The rat's stomach is removed (with a small amount of duodenum attached), opened along the greater curvature and the contents removed by washing with 0.9% w/v sodium chloride solution (saline). The opened stomach is pinned out (mucosal surface uppermost) on a polystyrene mat and the area of damage assessed by placing a grid (composed of 1 mm squares) over the antral region. Antral damage appears as discrete black or dark brown ulcers. The total area of antral damage is then expressed as a percentage of the total surface area of the antrum.

The protective effect of the test compound on indomethacin-induced antral damage is calculated as a percentage using the following equation:

% area of damage — % area of damage with NSAID with NSAID + test compound 100 x

% area of damage with NSAID

Results

The gastro-protective effects of (R,R)-[4-[2-[2-(3-chlorophenyl)-2-hydroxy- ethylamino]propoxy]phenyl]acetic acid (Example 1) administered as a single intravenous (i.v.) dose or oral (p.o.) dose 30 minutes before indomethacin, is shown by the following data:

i.v. administration p.o. administration

ED 50 dose protection ED 50 dose protection

(mg/kg) (mg/kg) (%) (mg/kg) (mg/kg) (%)

0.12 1.0 90 1.0 1.0 57

TABLETS FOR ORAL ADMINISTRATION

Tablets may be prepared by the normal methods such as direct compression or wet granulation. The tablets may be film coated with suitable film forming materials, such as hydroxypropyl methylcellulose, using standard techniques. Alternatively the tablets may be sugar coated.

Direct Compression Tablet mq/tablet

(i) Active Ingredient 4.688

Calcium Hydrogen Phosphate BP* 83.06

Croscarmellose Sodium NF 1.8

Magnesium Stearate BP 0.45

Compression weight 90.0

* of a grade suitable for direct compression.

The active ingredient is passed through a 60 mesh sieve, blended with the calcium hydrogen phosphate, croscarmellose sodium and magnesium stearate. The resultant mix is compressed into tablets using a Manesty F3 tablet machine fitted with 5.5mm, flat bevelled edge punches.

mg/tablet

(ii)Active Ingredient. 0.31 Anhydrous Lactose USNF 131.99 Pregelatinised Starch USNF 7.0

Magnesium Stearate BP (X7

Compression weight 140.0

The active ingredient is passed through a 60 mesh sieve, and blended with the lactose, pregelatinised starch and magnesium stearate. The resultant mix is compressed into tablets using a Manesty F3 tablet machine fitted with 7.5mm normal concave punches.

SYRUP This may be either a sucrose or sucrose free presentation.

A. Sucrose Syrup mg/5ml dose

Active Ingredient 2.5 Sucrose BP 2750.0 Glycerine BP 500.0 Buffer )

Flavour )

Colour ) as required

Preservative ) Purified Water BP to 5.0ml

The active ingredient, buffer, flavour, colour and preservative are dissolved in some of the water and the glycerine is added. The remainder of the water is heated to dissolve the sucrose and is then cooled. The two solutions are combined, adjusted to volume and mixed. The syrup is clarified by filtration.

Sucrose-free Svrup mo75ml dose

Active Ingredient 2.5

Hydroxypropylmethylcellulose USP

(viscosity type 4000) 22.5

Buffer )

Flavour )

Colour ) as required

Preservative )

Sweetener )

Purified Water BP to 5.0ml

The hydroxypropylmethylcellulose is dispersed in hot water, cooled and then mixed with an aqueous solution containing the active ingredient and the other components of the formulation. The resultant solution is adjusted to volume and mixed. The syrup is clarified by filtration. INJECTION FOR INTRAVENOUS ADMINISTRATION

uq/ml

(i) Active Ingredient 800

Dilute Hydrochloric Acid BP to pH 3.5 Sodium Chloride Injection BP to 1ml

The active ingredient is dissolved in a suitable volume of Sodium Chloride Injection BP, the pH of the resultant solution is adjusted to pH3.5 with dilute hydrochloric acid BP then the solution is made to volume with sodium chloride injection BP and thoroughly mixed. The solution is filled into Type I clear glass 5ml ampoules which are sealed under a headspace of air, by fusion of the glass then sterilised by autoclaving at 120^ for not less than 15 minutes.

ug/ml

(ii) Active ingredient 56.2

Sodium Chloride BP as required Water for Injection BP to 1.0ml

Sodium chloride may be added to adjust the tonicity of the solution and the pH may be adjusted, using acid or alkali, to that of optimum stability and/or facilitate solution of the active ingredient. Alternatively, suitable buffer salts may be used.

The solution is prepared, clarified and filled into appropriate size ampoules sealed by fusion of the glass. The injection is sterilised by heating in an autoclave using one of the acceptable cycles. Alternatively, the solution may be sterilised by filtration and filled into sterile ampoules under aseptic conditions. The solution may be packed under an inert atmosphere of nitrogen or other suitable gas.

SUPPOSITORY FOR RECTAL ADMINISTRATION Active ingredient 49.0 mg

Witepsol^* H15 to 1.0g

*a proprietary grade of Adeps Solidus Ph.Eur.

A suspension of the active ingredient in molten Witepsol is prepared and filled using suitable machinery, into 1g size suppository moulds.

Claims

1. A method of treatment of a human or non-human mammal suffering from or susceptible to an inflammatory gastrointestinal disorder which method comprises administering to said mammal an effective amount of compound of formula (I):

AΓ- (I)

wherein

R° is a hydrogen atom, a methyl group or a hydroxymethyl group; R¹ is a substituted C^^alkyl group which group is substituted by at least one of the substituents A, defined below;

R² and R³ are each selected from a hydrogen atom, a halogen atom, a hydroxyl group, a C^alkoxy group, a carboxy group, a C₂_₇alkoxycarbonyl group, a

Chalky! group, a nitro group, a haloC₁^alkyl group, or a substituted C^^alkyl group which group is substituted by at least one of substituents A, defined below;

X is an oxygen atom or a sulphur atom; and

Ar is a group of formula (C) or (D):

in which:

R⁴ is a hydrogen atom, a halogen atom, a hydroxy group, a hydroxymethyl group, a C-^alkoxy group, a C,_₅alkyl group, an aliphatic carboxylic C^acyloxy group, a nitro group, a cyano group, an aralkyloxy group in which the aralkyl part is as defined below, an aryloxy group in which the aryl part is as defined below, an aryl group as defined below, or a haloC^alkyl group;

R⁵ is a hydrogen atom, a halogen atom, a hydroxy group, a C^alkoxy group, a C_halky! group, or a nitro group; R⁶ is a hydrogen atom, a halogen atom, a hydroxy group, a C-^alkoxy group, or a C-^alkyl group; said aralkyl part is a C-^alkyl group which group is substituted by 1 or 2 aryl groups as defined below; said aryl groups are carbocyclic C_6.10aryl groups which are unsubstituted or are substituted by at least one of substituents B, defined below; said substituents A are selected from carboxy groups, C₂_₇alkoxycarbonyl groups, aryloxycarbonyl groups in which the aryl part is as defined above, aralkyloxycarbonyl groups in which the aralkyl part is as defined above, C-^ alkylcarbamoyl groups, dialkylcarbamoyl groups in which each alkyl part has from 1 to 4 carbon atoms, carbamoyl groups, hydroxycarbamoyl groups, hydroxy groups, carboxylic acyloxy groups having from 1 to 6 carbon atoms, and 2,4-dioxothiazolidin-5-yl groups; and said substituents B are selected from halogen atoms, C^alkyl groups, C-^alkoxy groups, nitro groups, haloC₁_₄alkyl groups, and hydroxy groups; and pharmaceutically acceptable salts thereof. or a physiologically acceptable salt or solvate thereof.

2. A method as claimed in Claim 1 wherein the compound of formula (I), or physiologically acceptable salt or solvate thereof, is selected from compounds of formula (II)

3. A method as claimed in Claim 2 wherein R¹¹ is -CH₂CO₂H.

4. A method as claimed in any one of Claims 1 to 3 wherein the compound of formula is (I) (R,R)-[4-[2-[2-[(3-chlorophenyl)-2-hydroxy-ethylamino]propoxy] phenyljacetic acid.

5. A method as claimed in any one of Claims 1 to 4 wherein the inflammatory gastrointestinal disorder is an inflammatory bowel disease selected from ulcerative colitis, ileitis, Crohn's disease and proctitis.

6. A method as claimed in any one of Claims 1 to 4 wherein the inflammatory gastrointestinal disorder is a condition of gastrointestinal ulcerations, said condition induced by non-steroidal anti-inflammatory drugs.

7. A therapeutic agent which comprises an effective amount of a compound of formula

wherein

R² and R³ are each selected from a hydrogen atom, a halogen atom, a hydroxyl group, a C^alkoxy group, a carboxy group, a C₂__.7alkoxycarbonyl group, a

C^alkyl group, a nitro group, a haloC^alkyl group, or a substituted C-^alkyl group which group is substituted by at least one of substituents A, defined below;

X is an oxygen atom or a sulphur atom; and

Ar is a group of formula (C) or (D):

in which:

R⁴ is a hydrogen atom, a halogen atom, a hydroxy group, a hydroxymethyl group, a C-^alkoxy group, a C.,_₅alkyl group, an aliphatic carboxylic C-^acyloxy group, a nitro group, a cyano group, an aralkyloxy group in which the aralkyl part is as defined below, an aryloxy group in which the aryl part is as defined below, an aryl group as defined below, or a haloC₁^alkyl group;

R⁵ is a hydrogen atom, a halogen atom, a hydroxy group, a C-^alkoxy group, a

C^alkyl group, or a nitro group; R⁶ is a hydrogen atom, a halogen atom, a hydroxy group, a C-^alkoxy group, or a C-^alkyl group; said aralkyl part is a C₁_₃alkyl group which group is substituted by 1 or 2 aryl groups as defined below; said aryl groups are carbocyclic C₆.₁₀aryl groups which are unsubstituted or are substituted by at least one of substituents B, defined below; said substituents A are selected from carboxy groups, C₂.₇alkoxycarbonyl groups, aryloxycarbonyl groups in which the aryl part is as defined above, aralkyloxycarbonyl groups in which the aralkyl part is as defined above, C^ alkylcarbamoyl groups, dialkylcarbamoyl groups in which each alkyl part has from 1 to 4 carbon atoms, carbamoyl groups, hydroxycarbamoyl groups, hydroxy groups, carboxylic acyloxy groups having from 1 to 6 carbon atoms, and 2,4-dioxothiazolidin-5-yl groups; and said substituents B are selected from halogen atoms, C^alkyl groups,

C^alkoxy groups, nitro groups, haloC^alkyl groups, and hydroxy groups; or a physiologically acceptable salt or solvate thereof for use in the treatment of an inflammatory gastrointestinal disorder.

8. A therapeutic agent as claimed in Claim 7 wherein the compound of formula (I), or physiologically acceptable salt or solvate thereof, is selected from compounds of formula (II):

and physiologically acceptable salts and solvates thereof, wherein one of R¹¹ and R¹² represents a hydrogen atom and the other of R¹¹ and R¹² represents the group -CH₂C0₂H; and

9. A therapeutic agent as claimed in Claim 8 wherein R¹¹ is -CH₂CO₂H.

10. A therapeutic agent as claimed in any one of Claims 7 to 9 wherein the compound of formula (I) is (R,R)-[4-[2-[2-[(3-chlorophenyl)-2-hydroxy- ethylamino]propoxy]phenyl]acetic acid.

11. A therapeutic agent as claimed in any one of Claims 7 to 10 wherein the inflammatory gastrointestinal disorder is an inflammatory bowel disease selected from ulcerative colitis, ileitis, Crohn's disease and proctitis.

12. A therapeutic agent as claimed in any one of Claims 7 to 10 wherein the inflammatory gastrointestinal disorder is a condition of gastrointestinal ulcerations, said condition induced by non-steroidal anti-inflammatory drugs.

13. The use of a compound of formula (I):

wherein

R° is a hydrogen atom, a methyl group or a hydroxymethyl group; R¹ is a substituted C₁_₁₂alkyl group which group is substituted by at least one of the substituents A, defined below;

R² and R³ are each selected from a hydrogen atom, a halogen atom, a hydroxyl group, a C-^alkoxy group, a carboxy group, a C₂.₇alkoxycarbonyl group, a

C_halky! group, a nitro group, a haloC^alkyl group, or a substituted C^-^alkyl group which group is substituted by at least one of substituents A, defined below;

X is an oxygen atom or a sulphur atom; and

Ar is a group of formula (C) or (D):

in which:

R⁴ is a hydrogen atom, a halogen atom, a hydroxy group, a hydroxymethyl group, a C,_₅alkoxy group, a C^alkyl group, an aliphatic carboxylic C₁-₆acyloxy group, a nitro group, a cyano group, an aralkyloxy group in which the aralkyl part is as defined below, an aryloxy group in which the aryl part is as defined below, an aryl group as defined below, or a haloC₁-₄alkyl. group; R⁵ is a hydrogen atom, a halogen atom, a hydroxy group, a C^alkoxy group, a C^alkyl group, or a nitro group; R⁶ is a hydrogen atom, a halogen atom, a hydroxy group, a C-^alkoxy group, or a C₁.₅alkyl group; said aralkyl part is a C^alkyl group which group is substituted by 1 or 2 aryl groups as defined below; said aryl groups are carbocyclic C₆.₁₀aryl groups which are unsubstituted or are substituted by at least one of substituents B, defined below; said substituents A are selected from carboxy groups, C₂_7alkoxycarbonyl groups, aryloxycarbonyl groups in which the aryl part is as defined above, aralkyloxycarbonyl groups in which the aralkyl part is as defined above, C^ alkylcarbamoyl groups, dialkylcarbamoyl groups in which each alkyl part has from 1 to 4 carbon atoms, carbamoyl groups, hydroxycarbamoyl groups, hydroxy groups, carboxylic acyloxy groups having from 1 to 6 carbon atoms, and 2,4-dioxothiazolidin-5-yl groups; and said substituents B are selected from halogen atoms, C₁_ alkyl groups, C_1.3alkoxy groups, nitro groups, haloC^alkyl groups, and hydroxy groups; or a physiologically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of an inflammatory gastrointestinal disorder.

14. The use as claimed in Claim 13 wherein the compound of formula (I), or physiologically acceptable salt or solvate thereof, as selected from compounds of formula (II).

15. The use as claimed in Claim 4 wherein R¹¹ is -CH₂CO₂H.

16. The use as claimed in any one of Claims 13 to 15 wherein the compound of formula (I) is (R,R)-[4-[2-[2-[(3-chlorophenyl)-2-hydroxy-ethylamino]ρropoxy] phenyljacetic acid;

17. The use as claimed in any one of Claims 13 to 16 wherein the inflammatory gastrointestinal disorder is an inflammatory bowel disease selected from ulcerative colitis, ileitis, Crohn's disease and proctitis.

18. The use as claimed in any one of Claims 13 to 16 wherein the inflammatory gastrointestinal disorder is a condition of gastrointestinal ulcerations, said condition induced by non-steroidal anti-inflammatory drugs.

19. A pharmaceutical composition comprising a compound of formula (I)

wherein

R° is a hydrogen atom, a methyl group or a hydroxymethyl group; R is a substituted C₁.₁₂alkyl group which group is substituted by at least one of the substituents A, defined below;

R² and R³ are each selected from a hydrogen atom, a halogen atom, a hydroxyl group, a C^alkoxy group, a carboxy group, a C₂.₇alkoxycarbonyl group, a C-^alkyl group, a nitro group, a haloC^alkyl group, or a substituted C^^alkyl group which group is substituted by at least one of substituents A, defined below;

X is an oxygen atom or a suiphur atom; and Ar is a group of formula (C) or (D):

in which:

R⁴ is a hydrogen atom, a halogen atom, a hydroxy group, a hydroxymethyl group, a C-^alkoxy group, a Chalky! group, an aliphatic carboxylic C^acyloxy group, a nitro group, a cyano group, an aralkyloxy group in which the aralkyl part is as defined below, an aryloxy group in which the aryl part is as defined below, an aryl group as defined below, or a haloC₁_₄alkyl group;

R⁵ is a hydrogen atom, a halogen atom, a hydroxy group, a C-^alkoxy group, a C-^alkyl group, or a nitro group;

R⁶ is a hydrogen atom, a halogen atom, a hydroxy group, a C-^alkoxy group, or a Chalky! group; said aralkyl part is a C-^alkyl group which group is substituted by 1 or 2 aryl groups as defined below; said aryl groups are carbocyclic C₆_₁₀aryl groups which are unsubstituted or are substituted by at least one of substituents B, defined below; said substituents A are selected from carboxy groups, C₂.₇alkoxycarbonyl groups, aryloxycarbonyl groups in which the aryl part is as defined above, aralkyloxycarbonyl groups in which the aralkyl part is as defined above, C-^ alkylcarbamoyl groups, dialkylcarbamoyl groups in which each alkyl part has from 1 to 4 carbon atoms, carbamoyl groups, hydroxycarbamoyl groups, hydroxy groups, carboxylic acyloxy groups having from 1 to 6 carbon atoms, and 2,4-dioxothiazolidin-5-yl groups; and said substituents B are selected from halogen atoms, C^alkyl groups, C-^alkoxy groups, nitro groups, haloC^alkyl groups, and hydroxy groups; or a physiologically acceptable salt or solvate thereof, a non-steroidal anti- inflammatory drug and a physiologically acceptable carrier therefor.

20. A pharmaceutical composition as claimed in Claim 20 wherein the compound of formula (I), or physiologically acceptable salt or solvate thereof, is selected from compounds of formula (II):

21. A pharmaceutical composition as claimed in Claim 20 wherein R¹¹ is - CH₂CO₂H.

22. A pharmaceutical composition as claimed in any one of Claims 19 to 21 wherein the compound of formula (I) is (R,R)-[4-[2-[2-[(3-chlorophenyl)-2- hydroxy-ethylaminojpropoxy] phenyljacetic acid.