IE46825B1

IE46825B1 - Pyrrole derivatives

Info

Publication number: IE46825B1
Application number: IE942/78A
Authority: IE
Original assignee: Beecham Group Ltd
Priority date: 1977-05-10
Filing date: 1978-05-09
Publication date: 1983-10-05
Also published as: CH640225A5; CA1100142A; ES469631A1; FR2390431B1; FR2390431A1; NL7804942A; IL54642A0; AU3599078A; JPS53141268A; IE780942L; IL54642A; DE2819463A1; DK204078A; AU526256B2; SE7805282L

Abstract

The compounds of the formula: and pro-drugs therefor wherin R1 is a hydrogen atom or a methyl group; Ar is a phenyl group or is a phenyl group substituted by one or two moieties selected from fluorine, chlorine, bromine, methyl, methoxyl or trifluoromethyl or is a thienyl group; and X is a CO or CHOH group have antiinflammatory activity.

Description

The present invention relates to pyrrole derivatives, to ; ί a process for their preparation and to compositions containing I them.

Tolmetin, a clihically used anti-inflammatory and analgesic 5 agent of the formula (I): (I) has been reported in J. Pharmacol. Exptl. Therap. 1973, 185. 127-138 to possess anti-inflammatory activity. Tolmetin and related compounds have also been described in British Patent Specification No: 1195628. It has been found that tolmetin causes gastric irritancy in test animals at doses not greatly exceeding the therapeutic dose. A group of anti-inflammatory and analgesic compounds has now been found which have reduced propensity to cause gastric irritancy. These compounds may be thus used in pharmaceutical compositions for the treatment of 1-$ * inflammatory or painful conditions such as rheumatism, arthritis or the like.

The present invention provides the compounds of the formula (II): Ar-CO CHtLjCHg-X-CH^ (II) ch3 - 2 46825 Wherein R^ is a hydrogen atom or methyl group; Ar is a phenyl group or a phenyl group substituted by one or two groups selected from fluorine, chlorine, bromine, methyl, methoxyl or trifluoromethyl or is a thienyl group; X is a CO or CHOH group; and pro-drugs thereof.

Suitably Ar is a phenyl or substituted phenyl group.

More suitably Ar is a phenyl or mono-substituted phenyl group.

Particularly apt groups Ar include the phenyl, methylphenyl, fluoromethyl chlorophenyl dichlorophenyl and the methoxyphenyl group.

A favoured group Ar is the phenyl group. A further favoured group Ar is the 4-methylphenyl. Another favoured group Ar is the 4-chlorophenyl group. Yet a further favoured group Ar is the 4-fluorophenyl group. Yet another favoured group Ar is the 4-methoxyphenyl group.

Other suitable values for Ar include di-halogenated phenyl such as di-chlorophenyl, for example 2,4-dichlorophenyl.

Suitably Ar is a thienyl group. A favoured group Ar is the 2-thienyl group. A further favoured group Ar is the 3-thienyl group.

Suitably R^ in the preceeding compounds represents a hydrogen atom.

Suitably R^ in the preceeding compounds represents a methyl group.

Suitably X in the preceeding compounds is a CO group.

Suitably X in the preceeding compounds is a CHOH group. - 5 4G82S When used herein the term 'pro-drug' means a compound metabolised in-vivo to or via a compound of the formula (II).

The pro-drugs will be compounds containing deriva5 tives of the group X, for example those wherein the CHR^CHg-X-CH^ side chain hereinafter referred to as 'Q' is the .subrformulae (a) - (d): R1 (a) V. (b) (c) (d) wherein R^ is a hydrogen atom or a methyl group; Rg is a group CO.Rg wherein Rg is the residue of a pharmaceutically acceptable carboxylic acid of up to 9 carbon atoms of the formula RgCOOH; Rg is a C1-4 alkyl group or a CO.Rg group; R4 is a methyl, ethyl or propyl group and R^ is a methyl, ethyl or propyl group or Rg is joined to R^ so that they together represent a CHgCHg or CHgCHgCHg group. -446 825 A favoured side chain Q in the preceeding compounds is the Ci^.CI^.CO.CH^ group.

Another favoured side chain Q in the preceeding compounds is the ΟΗ^ΟΗ,,.ΟΗΟΗ.ΟΗ^ group.

Further favoured gide chains Q are those of the formula CH2.CH2.CH(0.C0.Rg)CH^ wherein Rg is as defined in relation to sub-formula (a).

Apt values forRg include phenyl, alkyl of 1-4 carbon atoms, and alkyl of 1-4 carbon atoms substituted by phenyl, or one of the aforementioned groups substituted by a hydroxyl, acetoxyl, methoxyl, acetamido, optionally salted amino or alkylamino or optionally salted carboxyl group.

Favoured values for r g include the methyl, ethyl, n-propyl, iso-propyl, t-butyl, phenyl, benzyl, phenylethyl, acetoxymethyl, methoxymethyl, hydroxymethyl optionally salted aminoethyl, α-acetoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl and 3,4, 5-trimethoxyphenyl groups.

Particularly suitable values for R g include the methyl, ethyl, benzyl, 2-methoxyphenyl, phenyl and 3,4,5-trimethoxyphenyl group.

A preferred group Rg is the methyl group.

From the foregoing it will be realised a further favoured 2- position side chain is the CHg.CI^.CHiO.CO.CH^CH^ group.

One group of favoured side chains Q is that of the formula CH2CH2X1CH3 where X1 is a CO, CHOH or CHOCOR? group where R? is an alkyl group of 1-4 carbon atoms. Most suitably Ry is a methyl group. - 5 46825 These compounds of the formula (II) wherein R1 is a methyl group may he in the form of an isolated optical isomer or may be presented as a mixture of isomers, for example the R, S ox* RS form.

These compounds of the formula (II) wherein X is a CHOH or CHORg group may be in the form of an isolated optical isomer or may be presented as a mixture of isomers, for example as the R, S or RS form.

Certain particularly effective compounds of this invention 10 include those of the formula (IV): CH.

(IV) wherein R^ is a hydrogen atom or methyl group and X is a CO, CHOH ., or CH.OCOCH^ group. ·. - In the compounds of formula (IV) Rq is suitably a hydrogen atom. In the compounds of the formula (IV) R^ is suitably a methyl group.

In the compounds of the formula (IV) X is suitably a CO group. In the compounds of the formula (IV) X is suitably a CHOH group. In the compounds of the formula (IV) X is suitably a CHOCOCH^ group. - 6 46825 Certain other particularly effective invention include those of the formula (V) compounds of this CH5 wherein R^ is a hydrogen atom or a methyl group and X is a CO, CHOH or CH.O.CO.CH^ group, In the compounds of the formula (V) R^ is suitably a hydrogen atom. In the compounds of the formula (V) R^ is suitably a methyl group.

Suitably in the compounds of the formula (V) X is a CO group. Suitably in the compounds of the formula (V) X is a CHOH group. Suitably in the compounds of the formula (V) X is a CHOCOCH^ group.

Certain further particularly effective compounds of this invention include those of the formula (VI): wherein R^ is a hydrogen atom or a methyl group and X is a CO, CHOH or CHOCOCH^ group.

In the compounds of the formula (VI) R^ is suitably a hydrogen atom. In the compounds of the formula (VI) is suitably a methyl group.

' In the compounds of the formula (VI) X is suitably a t CO group. In the compounds of the formula (VI) X is suitably a CHOH group. In the compounds of the formula (VI), X is suitably a CHOCOCH^ group.

Particularly suitable compounds of this invention include: 4-(1 -m ethyl-5-p-toluoyl-2-pyrryl)butan-2-one; 2-a cetoxy-4- (1 -methyl-5-p-toluoyl (-2- pyrpyl) butane; 4-(1-methyl- 5-p-chlorobenzoyl-2-pyrryl)butan-2-one; 4-(1-methyl- 5-p-chlorobenzoyl-2-pyrxyl)butan-2-ol; 2-a.cetoxy-4-(i-m ethyl- 5-p-chlorobenzoyl-2-pyrryl)butane; 4-(1-methyl-5-thien-2 ’-oyl-2-pyrryl)butan-2-one; 4-(1 -methyl-5-thien-2*-oyl-2-pyrryl)butan-2-ol; 2-a,cetoxy-4-(1-m ethyl-5-thien-2 ’-oyl-2-pyrryl)- butane. 4-(1-methyl-5-p-toluoyl-2-pyrryl)butan-2-ol. '7 - 8 46825 In a further aspect this invention provides a pharmaceutical composition which comprises a compound of the formula (II) and a pharmaceutically acceptable carrier.

The compositions of this invention are useful in treating rheumatic and arthritic conditions because of their anti-inflammatory and analgesic properties. The compositions may be adapted for administration via the oral, rectal or injection routes but since the compositions of this invention do not excessively irritate the gastro-intestinal tract it is preferred that they are adapted for oral administration.

The compositions of this invention may contain diluents, binders, fillers, disintegrants, flavouring agents, colouring agents, lubricants or preservatives in conventional manner. These conventional excipients may be employed in conventional manner, for example as in the preparation of compositions of ketoprofen, indomethacin, naproxen, acetylsalicylic acid or other anti-inflammatory analgesic agent.

Most suitably the composition of this invention will be in the form of a unit dose such as a tablet, capsule or reconstitutable powder in a sachet. Such unit doses will generally contain from 20mg to lOQmg and more suitably will contain from about 30mg to 500mg for example 50mg to 250mg of active agent, for example about 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500mg. These compositions may be administered once or more times a day , for example 2, 3 or 4 times daily, so that the total - 9 46825 daily dose for a 7OKg adult will usually be in the range 200 ' to 400mg and more usually in the range 300 to 3000mg for example 500 to 2000mg. Alternatively the unit dose may contain from 2-20mg of active agent and may be administered in multiples if desired to give the preceeding daily dose.

A favoured form of the composition of this invention is a hard gelatin capsule containing the active agent. The active agent may be in the form of a powder, pr granulate and may advantageously be in intimate mixture with a lubricant 10 such as magnesium stearate.

A further favoured form of the composition of this invention is a tablet containing the active agent. The active agent may be in the form of a recompressed granulate-of the active ingredient in intimate mixture with a lubricant such as magnesium staarate,a filler such as microcrystalline cellulose and a disintegrant such as sodium starch glycollate.

The present invention also provides a method of treating inf lanmatcmy and/or painful conditions in non-human mammals which comprises administering per day from 200 to 4000mg of a compound of this invention and more usually from 300 to 3000mg for example from 500 to 2000mg of a compound of this invention.

Non-human manmals which may be thus treated include domestic animals such as dogs, cats or horses. - 10 4 6 8 2 5 Most suitably the medicament will be administered orally as 2, 3, or 4 doses per day at the dose level previously indicated.

Often the condition treated will be arthritis.

The present invention provides a process for the preparation of a compound of the formula (il) or a pro-drug thereof which process comprises the reaction of a compound of the formula (VII): Ar.CO.Cl (VII) cr an equivalent agent- for the acylation of nucleophilic aromatic nuclei wherein Ar is as defined in relation to formula (II), with a cotpound of the formula (IX): ch3 wherein Q;is a group of the sub-formulae (a) - (d) as hereinbefore 15 defined or a group of the sub-formula (e): -CHR1-CH2-CO-CH3 (e) wherein R^ is a hydrogen atom or a methyl group; and thereafter if desired reducing the carbonyl present in a group of the subformula (e) to a CHOH group.

The present invention also provides a process for the preparation of the compounds of the formula (II) which process comprises the reaction of.a compound of the formula (VII): Ar.CO.Cl (VII) or an equivalent agent far the acylation of nucleophilic aranatic nuclei wherein Ar is as defined in relation to formula (II), with a canpound of the formula (X): CHR1 - CH2 - CO - CH^ (X) wherein is as defined in relation to formula (II) arid thereafter if desired reducing the carbonyl group X to a CHOH group X and/or thereafter converting the CO or CHOH group X to a pro-drug thereof.

The present invention also provides a process for the preparation of the pro-drugs of the compounds of the formula (II) which process comprises the reaction of a compound of the . formula (VII) as hereinbefore defined or an equivalent agent for the acylation of nucleophilic aromatic nuclei with a compound of the formula (XI): (XI) CH, ί wherein Q is a group of the sub-formulae (a) - (d) as hereinbefore defined. - 12 46825 Suitable equivalents of the compounds of the formula (VII) for acylation include the corresponding bromide and anhydride for example the corresponding azide or mixed anhydride.

The reaction of the compounds of the formulae (VII) and 5 (IX), (X) or (XI) takes place in an inert solvent or under conventional Friedel-Crafts acylation conditions, for example in an inert solvent and optionally in the presence of a Lewis acid such as aluminium chloride.

The acylation reaction is normally carried out at a non10 extreme temperature for example from 5°c to 5o°c and more usually from 1O°C to 3O°C if a Lewis acid is used. If no catalyst is used the acylation reaction is normally carried out at a higher temperature than 5O°C e.g. 1OO°C.

Suitable solvents for carrying out the acylation include tetrachloroethylene, chloroform, dichloromethane, dichloroethane, chlorobenzene or benzene, toluene or nitrobenzene.

The solvent system used for the process of this invention will be homogenous and will advantageously comprise an inert component and a tertiary amine. In general the inert component 2o will predominate, for example it will comprise 60%-90% v/v of the total system and more usually from 80% to 92% v/v. Toluene and tetrachloroethylene are favoured inert solvents. Suitable tertiary amines include conventional weak tertiary amines such as pyridine, When the solvent system employed, contains a tertiary amine it is frequently advantageous not to employ a Lewis acid catalyst as acceptable yields are obtained in the absence of said catalyst. This form of the reaction may be performed at a low, ambient or elevated temperature but in general it is preferred to use a somewhat elevated temperature to ensure that the reaction is over in a reasonably short period. Thus, for example, a temperature of 40-140°C is generally suitable, for example 80-120°C.

The product produced by acylation in the presence of a Lewis acid may be isolated in conventional manner, for example I by diluting with an aqueous acid, extracting into an organic I solvent, washing and drying the organic phase and thereafter evaporating the solvent? The resulting ketone may then be purified by chromatography and/or recrystallisation.

The product produced by acylation in the absence of a Lewis acid may often be obtained simply by the evaporation of the solvents. If the resulting product is required in a purer form it - may normally be further purified by chromatography in conventional manner.

The diketones of the formula (II) may be converted to the corresponding compounds wherein X is a CHOH hy careful reduction with a complex hydride such as sodium borohydride. The resulting compound may be separated by conventional methods of column chromatography from any contaminant resulting from reduction of the aromatic ketone. - 14 4 6 8 2 5 The compounds wherein X is a CHOH group may be acylated in conventional manner, for example, by reaction with the acid R2C0,H in the presence of a condensation promoting agent such as dieyclohexylcarbodiimide in an aprotic solvent such as dichloromethane or tetrahydrofuran or by reaction with an acyl halide in the presence of an acid acceptor such as pyridine.

The conventional pro-drugs of the compounds of the formula (II) may be prepared from the compounds of the formula (II) In conventional manner.

Thus, for example, those compounds containing a side chain Q of the sub-formula (a) may be prepared by the acylation of a corresponding compound containing a side chain of the sub-formula Suitable methods of acylation include those described in 15 Belgian Patent No: 854429.

Also for example, those compounds containing a side chain q of the sub-formulae (b), (c) or (d) may be prepared by the enol acylation or enol etherification of a corresponding compound containing a side chain of the sub-formula (f): R Suitable methods of enol acylation or enol etherification include those described in West German Application P2647966.3. - 15 46825 Description 1 4-(1-Methyl-2-pyrryl )-butan-2-one I A mixture of 4-;(1-Methyl-2-pyrryl)-but-3-en-2-one (2.98g) and 10% palladium on charcoal (0.2g) was hydrogenated in ethyl acetate (50ml) at room temperature and. atmospheric pressure.

The catalyst was removed by filtration the solvent evaporated, and the resulting oil left overnight to solidify in a refrigerator.

The long, colourless needles which formed were washed with cold 60-80° petrol to give 4-(1-Methyl-2-pyrryl)-butan-2-one (2.46g). - 16 46825 Example 1 4-(1-Methyl-5-P~toluovl-2-pyrryl)butan-2-one To a solution of 4-(1-Methyl-2-pyrryl)-butan-2-one (2.46g) in 5 dichloroethane (10ml) at room temperature was added over 40 minutes a solution of dichloroethane (10ml) containing aluminium chloride (2.17g: 0.016 mole) and p-toluoyl chloride (2.52gi0.0l6 mole). After a further 20 minutes the mixture was treated with dilute hydrochloric acid (5N, 10ml) and extracted with dichloro10 methane (50ml). The organic layer was washed with water (20ml), aqueous unsymmetrical-dimethylethylenediamine (20% 20ml), dilute hydrochloric acid (5N, 10ml) and extracted with dichloromethane (50ml). The organic layer was washed with water (20ml), aqueous unsymmetrical-dimethylethylenediamine (20% 20ml), dilute hydrochloric acid (1N.20ml) and finally brine (20ml). After drying (NagSO^) the mixture was concentrated to give a dark oil which was then chromatographed on alumina (150g) using benzene as eluant. Recrystallisation of the solid fraction from 60-80° petrol gave pure 4-(1-methyl-5-p-toluoyl-2-pyrryl)20 butan-2-one, m.p. 103-4°.

N.m.r. (CDClj) $= 7.65 (2H, d, £ = 8Hz), 7.17 (2H, d, £ = 8Hz), 6.6 (1H, d, J = 4Hz), 5.87 (1H, d, J = 4Hz), 3.92 (3H, s), 3.0 2.7 (4H, m), 2.38 (3H, s), 2.17 (3H, s). - 17 4 6825 Example 2 ϊ 4-(1-Metfayl-5-P-toluoyl-2-pyrryl)butan-2-one 4-(1-Methyl-2-pyrryl)-butan-2-one (15g) and. p-toloyl chloride (37.5 ml) were dissolved in toluene (200ml) and pyridine (30ml). The mixture was heated under reflux for 7 hours. The resulting mixture was filtered and the filtrate evaporated ( 50°C 15mm/Hg) to leave an oil. The oil was extracted into hot 60-80°C petrol (4 x 250ml) and the solution cooled (-30°C)causing a solid to precipitate. This solid was purified hy column chromatography (detection by t.l.c. using u.v.) to yield after evaporation of the solvent the desired 4-(1-methyl-5-p-toluoyl~2-pyrryl)-butan10 2-one (40% yield) as a white solid, m.p. 1O3-1O4°C.

N.m.r. - as described in Example 1.

(The chromatographic system employed 300g silica eluting with / ethyl acetate/60-80°petrol mixtures. The initial eluting solvent contained 10% ethyl acetate and brought through the benzophenone impurity. Increasing the concentration of the ethyl acetate to 20% then brought through the desired product). - 18 46825 Example 5 4-(1-Methyl-5-p-chlorobenzoyl-2-pyrryl)butan-2-one CHz CH, The title compound was prepared by the process as described in Example 2 except that p-chlorobenzoyl chloride was used as acylating agent and tetrachloroethylene as solvent. The crude product was purified by passage through alumina using methylene chloride as solvent, followed by recrystallisation from carbon tetrachloride to give pure 4-(1-methyl~5-p-chlorobenzoyl-2-pyrryl) butan-2-one as colourless needles, m.p. 108-109 C.

N.m.r. (CDC15) S= 7.7 (2H, d, J=9Hz), 7.35 (2H, d, J=9Hz), 6.53 (1H, d, J=4Hz), 5.85 (1H, d, J=4Hz), 5.93 (3H, s), 3.0-2.7 (4H, m), 2.15 (3H, s). - 19 46825 Example 4 4-(1-Methyl-5-thien-2 i-oyl-2-pyrryl)butan-2-one ch2ch2coch3 CH, •Nf CH, :h2ch2coch.

The title compound was prepared by the process described in Example 3 except that thien-2-oyl chloride was used as acylating agent. Recrystallisation from diethyl ether gave pure 4-(1methyl-5-thien-2,-oyl-2-pyri,yl)butan-2-one as rhombic crystals, m.p. 78-79°C.

N.m.r. (CDC13) S= 8.1-6.9 (4H, m), 6.92 (1H, d, J = 4Hz), 3.87 (3H, s), 3.0-2.7 (4H, m), 2.19 (3H, s). - 20 46825 Example 5 4-(1-Me thvJ.-5-p-toluoyl-2-pyrryl)butan-2-ol A mixture of 4-(1-methyl-5-p-toluoyl-2-pyrryl)-butan-2-one (2.35g), sodium borohydride (0.4g) and ethanol (350ml) was stirred for 1 hour at room temperature before being treated with a saturated, aqueous solution of ammonium chloride (20ml). This mixture was concentrated and then partitioned between water (50ml) and methylene chloride (100ml). The aqueous layer was extracted with methylene chloride (3 x 50 ml) and the combined organic layers were then washed with water (50ml), dried (Na2S0^) and concentrated to afford somewhat crude 4-(1-methyl-5-p-toluoyl-210 pyrryl)butan-2-ol as a pale purple oil (2.06g). ^6 8 25 Example 6 2-Acetoxy-4-(1-in3thyl-5-P-toluoyl-2-pyrryl )butane The product of Example 5 was taken up in toluene (100ml) containing pyridine (4ml), treated dropwise at 5°C with acetyl chloride (2ml) and then stirred at room temperature for 1 hour. The resulting mixture was added to cold water (100ml) and extracted with diethyl ether (3 x 100ml). The combined organic layers· were washed with 1N HCl (50ml)and water (2x50ml)and dried (NagSO^) and concentrated to give a pale purple oil which slowly solidified on standing. Recrystallisation of this · solid from diethyl ether gave pure 2-acetoxy-4-(l-methyl-5-p10 toluoyl-2-pyrryl)butane as colourless needles, m.p. 88-89°.

N.m.r. (CDClj) S= 7.65 (2H, d, J = 8Hz), 7.2 (2H, d, J = 8Hz), _ 6.64 (1H, d, J = 4Hz), 5.94 (1H, d, J=4Hz), 4.97 (1H, q, J=6Hz), 3.91 (3H, s), 2.9-1.7 (4H, m), 2.34 (3H, s), 2.03 (3H, s), 1.27 (3H, d, J= 6Hz). - 22 46825 Example γ 2-Methyl-2-[2-(1-methyl-5-P-toluoyl-2-pyrryl)ethyl]-1,g-dioxolane A mixture of 4-(1-Methyl-5-p-toluoyl-2-pyrryl)butan-2-one (1.0g), ethylene glycol (6ml), p-toluene-sulphonic acid (40mg) and benzene (100ml) was refluxed for 5 hours with constant separation of HgO by means of a Dean-Stark trap. The mixture was cooled to room temperature, basified with 1N sodium bicarbonate solution (20ml) and extracted with chloroform (3 x 50ml). The organic layer was washed with H20 (2 x 50ml), dried (NagSO^) and concentrated to give a purple oil. This was chromatographed on alumina using ether as eluant to give pure 2-methyl-2-[2-(1methyl-5-p-toluoyl-2-pyrryl)ethyl]1,3-dioxolane as a colourless oil.

N.m.r. x(CDC13), d= 7.69 (2H, d, J = 8Hz), 7.20 (2H, d, J=8Hz), 6.64 (1H. d, J=4Hz), 5.95 (1H, d,z J= 4Hz), 3.99 (4H, s), 3.95 (3H, s), 3.ΟΙ.8 (4H, m), 2.40 (3H, s), 1.39 (3H, s). - 23 4 6825 Example 8 Compositions (a) Tablets of the following composition may be prepared: 4-(1-Methyl-5-p-toluoyl2-pyrryl)butan-2-one 25 mg Microcrystalline cellulose 123 mg 5 Magnesium Stearate 2 mg (b) Hard gelatin capsules may be prepared containing the following: 4-(1-Methyl-5-p-toluoyl2-pyrryl)butan-2-one 50 mg 10 Lactose 75 mg Sodium lauryl sulphate 5 mg - 24 46825 Example 9 Compositions (a) Tablets of the following composition may be prepared: 4-(1-Methyl-5-p-chlorobenzoyl2-pyrryl)butan-2-one 25 mg Microcrystalline cellulose 123 mg Magnesium Stearate 2 mg (b) Hard gelatin capsules may be prepared containing the following: 4-(1-Methyl-5-thien-2’-oyl2-pyrryl)butan-2-one 50 mg Lactose 75 mg Sodium lauryl sulphate 5 mg (c) Hard gelatin capsules may bs prepared containing the following: 4-(1-Methyl-5-p-chlorobenzoyl2-pyrryl)butan-2-one 100 mg Lactose 25 mg Sodium lauryl sulphate 5 mg - 25 4 6 8 2 5' Demonstration 1 a. When tested on a conventional phenylquinone induced writhing test for analgesic activity, the compound of Example 1 and tolmetin produced the following values when administered orally to mice: COMPOUND ED5o (mg/kg) Test A_Test B Comp. Example 1 6.7 5.3 Tolmetin 4.3 2.3 These results indicate that the compound of Example 1 is about half as potent as tolmetin as an analgesic agent. b. . Groups of 10 rats were starved overnight and then dosed orally with the test compound suspended in 0.7% methylcellulose.

After a 4 hour contact time the animals were killed and the stomachs removed, inflated with 0.9% saline, cut open ? after 30 minutes and examined for erosions. The following results, expressed as the number of animals in each group showing damage, were obtained: Dose (mg/kg) No. of Animals Showing Erosions Tolmetin . 90 30 10 10 6 2 Compound of Example 1 270 1 90 1 30 0 - 26 - This test indicates that tolmetin is probably at least 10 times as gastric irritant as the compound of Example 1. c. When tested on a conventional carrageenin induced oedema test for anti-inflamnatcry activity, the compound of Example 1 was classed as active at 10mg/kg per oral in rats (as compared to about 5mg/kg for tolmetin). d. No drug-induced lethalities have been observed with the compound of Example 1 during testing in rats at dosages up to 100mg/kg per day for 6 days. The compound did not reduce body weight increase at this dose nor did it increase thymus weight. - 27 4 68 2 6 Demonstration 2 When tested on a conventional cotton pellet induced granuloma test the results shown hereafter were obtained. In these tests hydrocortisone (HC) was used as a positive control .

Compound Dose Inhibition a. Comp. Example 3 HC 10mg/kg 1Omg/kg 42% 43% b. Comp. Example 4 HC 10mg/kg 10mg/kg 24% 43% c. Comp, Example 6 HC 50mg/kg 10mg/kg 34% 43% d. Comp. Example 7 HC 50mg/kg 10mg/kg 43% 43% The compounds of Examples 3. 4, 6 and 7 were not found to exhibit any overt toxic effects during testing, for example no drug-induced lethalities were observed, no reduction in body weight gain was observed and no change in thymus weight was observed.

Claims

1. CLAIMS :1. A compound of the formula (II): CH, wherein is a hydrogen atom or a methyl group; Ar is a phenyl 5 group or is a phenyl group substituted by one or two groups selected from fluorine, chlorine, bromine, methyl, methoxyl or trifluoromethyl or is a thienyl group; and X is a CO or CHOH group; or a pro-drug therefore.

2. A compound as claimed in claim 1 wherein R^ and X are as 10 defined in claim 1 and Ar is a phenyl or substituted phenyl group.

3. A compound as claimed in claim 1 or 2 wherein Ar is a phenyl or mono-substituted phenyl group.

4. A compound as claimed in claims 1 or 2 wherein Ar is a phenyl, methylphenyl, fluorophenyl, chlorophenyl, methoxy15 phenyl or a dichlorophenyl group.

5. A compound as claimed in claim 1 or 2 wherein Ar is a dichlorophenyl group.

6. A compound as claimed in claim 1 wherein Ar is a thienyl group. 20

7. A compound as claimed in any of claims 1-4 wherein Ar is a phenyl group. - 29

8. A compound as claimed in claim 1 wherein Ar is a methylphenyl group.

9. A compound as claimed in claim 1 wherein Ar is a methoxyphenyl group. 5 1Q A compound as claimed in claim 1 wherein Ar is a chlorophenyl group. 11 . A compound as claimed in claim 1 wherein Ar is a fluorophenyl group. 12 . A compound as claimed in claim 6 wherein Ar is a 2-thienyl

10. Group . 13· A compound as claimed in claim 6 wherein Ar is a 3-thienyl group.

11. 14 . A compound as claimed in claim 8 wherein Ar is a 4-methylphenyl group. 15 15 . A compound, as claimed in claim 9 wherein Ar is a 4-methoxyphenyl group. 16 . A compound as claimed in claim 10 wherein Ar is a 4-chlorophenyl group. 17 . A compound as claimed in claim 11 wherein Ar is a 20 4-fluorophenyl group. - 30 46825 18. A compound as claimed in any of claims 1-17 wherein R^ is a hydrogen atom. 19. A compound as claimed in any of claims 1-17 wherein is a methyl group. 5 20. A compound as claimed in any of claims 1-17 wherein X is a CO group. 21. A compound as claimed in any of claims 1-19 wherein X is a CHOH group. 22. A compound as claimed in any of claims 1-17 wherein 10 the CHR^-CH^-X-CH^ side chain is a group of the sub-formulae (a)-(d): wherein R 1 is a hydrogen atom or a methyl group; R 2 is a - 31 46825 group GO.Rg wherein Rg is th·.- residue of a pharmaceutically acceptable carboxylic acid of up to 9 carbon atoms of the formula RgCOOlI; R- is a C 1 _ Zj alkyl group or a CO.Rg group; R^ ic a methyl, ethyl or propyl group and R Z| is a methyl, 5 ethyl or propyl group or Rg is joined to R, ( so that ’they together represent a CH^CHg or CHgCHgCHg group. 2p. A compound as claimed in any of claims 1- 19 wherein the 2-position side chain is a CHg.CHp.CO.CIL· group. • 24. A compound as claimed in any of claims 1-19 wherein the l 0 2-position side chain is a CI^.CHg.CHOH.CHg group. 25. A compound as claimed in any of claims 1-19 wherein the 2-position side chain ic a CH.,.CHj.Cn(O.CO.Rg)CH 3 group wherein Rg is as defined in claim 21. 26. A compound is claimed in claims 22 or 25 wherein Rg is

12. 15 a phenyl group , an alkyl group of 1-4 carbon atoms, an alkyl group of 1-4 carbon atoms substituted by a phenyl group, or one of the aforementioned groups substituted by a hydroxyl, acetoxyl, rnethoxyl, acetamido, optionally salted amino or alkylamino or optionally salted carboxyl group.

13. 20 27. A compound as claimed in claims 22 or 25 wherein Rg ic a methyl, ethyl, n-propyl, iso-propyl, t-butyl, phenyl, benzyl, phenylethyl, acetoxymethyl, methoxymethyl, hydroxymethyl optionally salted aminoethyl, α-acetoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl or 3)4,5-trimethoxyphenyl group. - 32 46825 28. A compound as claimed ;n claims 22 or --5 wherein is a methyj, ethyl, benzyl, 2-methoxyphenyl, phenyl or 3,4,5-trime thoxypheny l, gj oup. 29. A compound as claimed in claims 22 or 2 5 wherein Rg is 5 a methyl group. 30. A compound as claimed in any of claims 1-19 wherein the 2-position side chain is a CH 0 .CHp.CH(O.CO.CH 3 ).CH- group. 31. A compound as claimed in any of claims 1-19 wherein the 2-position side chain is a CH^CHg.X CIU group wherein X' is a 10 CO, CHOH or CHOCOR? group R? is an alkyl group of 1-4 carbon atoms. 32. A compound as claimed in claim 1 of the formula (IV): (IV) wherein Rj is a hydrogen atom or methyl group and X is a CO, 15 CHOH or CH.OCOCH^ group. 33. A compound as claimed in claim 32 wherein is a hydrogen a tom. - 33 46828 34. A compound as claimed in claim 33 wherein R^ is a methyl group. 35. A compound, as claimed in claims 32-34 wherein X is a CO group. '26. A compound as claimed in claims 32-34 wherein X is a CHOH group. 37. A compound as claimed in claims 32-34 wherein X is a CH.OCOCH^ group. 38. A compound as claimed in claim 1 of the formula (V): Cl CO wherein R^ is a hydrogen atom or a methyl group and X is a CO, CHOH or CH.O.CO.CHj group. 39. A compound as claimed in claim 38 wherein R^ is a hydrogen atom. 40. A compound as claimed in claim 38 wherein is a methyl group. 4682S 41. Λ compound as c1uirncd any oi c1 aims 38-40 wherein X ic a CO group). 42. A compound as claimed in any of cluj ms 38-40 wherein X is a CHOH group. 43. A compound as claimed in any of claims 38-40 wherein X is a CHOCOSH, group. 44. A compound as claimed in claim 1 of the formula (VI): wherein R^ is a hydrogen atom or a methyl group and X is a 10 CO, CHOH or CHOCOCH- group. 45. A compound as claimed in claim 44 wherein R 1 is a hydrogen atom. 46. A compound as claimed in claim 44 wherein R^ is a methyl group 47. A compound as claimed in any of claims 44-46 wherein X 15 is a CO group;. 48. A compound as claimed in any of claims 44-46 wherein X is a CHOH group. - 35 46825 49. Λ compound as claimed m any of cJaims 44-46 whoroin X a CHOCOCH-j group. . 50. 4-(1-Met.hyl-5-p- fcoluoyl-2-pyrryl) butan-2-one. 51. ' 4-(1-Methyl-5-p-toluoyl-2-pryyrl)butan-2-ol. 5 52. 2-Acetoxy-4-,(1-B.ethyl-5-p-toluoyl-2-pyrryl)butane I 5 3. 4-(1 -Methyl-5-p- chlorcbenzcyl -2-pyrryl )butan-2-one. 54. 4-(1-Methyl-5-p- chlorcbenzcyl -2-pyrryl)butan-2-ol. 5 5. 2-Acetoxy-4- (1 -methyl-5-p- chlorcbenzcyl -2-pyrryl )butane. 5 6. 4-(1-Methyl-5-thien-2’-oyl-2-pyrryl)butan-2-one. 10 57. 4-(1*-Methyl-5-'thien-2 , -oyl-2-pyrryl)butan-2-ol. ( Γ 58. 2-Acetoxy-4-(1-B,ethyl-5-thien-2 , -oyl-2-pyrryl)butane. - 56 4682S 59. A compound as claimed in any of claims 1, 16-30 wherein Ar is a di-halogenated phenyl group. 60. A compound as claimed in claim 59 wherein Ar is a dichlorophenyl group. 5 61. A compound as claimed in claim 60 wherein Ar is a 2,4-dichlorophenyl group. 62. A pharmaceutical composition which comprises a compound as claimed in any of claims 1-61 and a pharmaceutically acceptable carrier. 10 63. A composition as claimed in claim 62 adapted, for oral administration. 64. A composition as claimed in claims 61 or 62 which is in the form of a unit dose containing from 20 to 1000mg of a compound as claimed in any of claims 1-61. 15 65. A composition as claimed in claim 64 which comprises from 30 to 500 mg of a compound as claimed in any of claims 1-61. 66. A caiposition as claimed in claim 65 which comprises fran 50 to 25Qrg of a caipound as claimed in any of claims 1-61, 67. A process for the preparation of a composition according to any me of 2q claims 62-66 which process ccnpriseg hringing together the caipound and the carrier. 68. A method cf treating inflammatory and/or painful conditions in non-human manmals which canprises the administration per day of fran 200 to 4000 ng of a canpcund of any of claims 1-61 said caipound being present in a composition as claimed in any of claims 62-66- 37 468 2S 69. A method as claimed in claim 67 which utilizes 300 to 3000 mg of a compound of any of claims 1-61. 70. A method as claimed in claim 68 which utilizes 500 to 2000 mg of a compound of any of claims 1-61. 5 71. A process for the preparation of a qompound of the formula (II) as' claimed in claim 1 or a pro-drug thereof which process comprises the reaction of a compound of the formula (VII): Ar.CO.Cl (VII) or an equivalent agent for the acylation of nucleophilic 10 aromatic nuclei wherein Ar is as defined in relation to formula (II), with a compound of the formula (IX): ch 3 wherein Q is a group of the sub-formulae (a) - (d) as hereinbefore defined or a group of the sub-formula (e): -CH^-CHg-CO-CHj (e) wherein R 1 is a hydrogen atom or a methyl group; and thereafter if desired reducing the carbonyl present in a group of the subformula (e) to a CHOH group. - 38 72. A process as claimed in claim 70 which comprises the reaction of a compound of the formula (VII): Ar.CO.Cl (VII) or an equivalent agent for the acylaticn of nucleophilic aranatic nuclei 5 wherein Ar is as defined in relation to formula, (ii) , with a canpound of the formula (X): wherein R^ is as defined in relation to formula (II) and thereafter if desired reducing the carbonyl group X to a CHOH 10 group X and/or thereafter converting the CO or CHOH group X to a pro-drug thereof. 73. A process as claimed in claim 70 for the present invention also provides a process for the preparation of the pro-drugs of the compounds of the formula (II) which process comprises the 15 reaction of a compound of the formula (VII) as hereinbefore defined or an equivalent agent for the acylation of nucleophilic aromatic nuclei with a compound of the formula (XI): (XI) CH, wherein q' is a group of the sub-formulae (a) - (d) as hereinbefore defined. - 39 46825 74. . A process as claimed in any of claims 70-72 wherein the condensation is effected at a temperature of 5°to 50°C in the presence of a Lewis acid. 75. A process as claimed in any of claims 70-72 in the absence of a Lewis acid at a temperature above 50°C. 76. A process as claimed in any of claims 70-72 or 74 carried out in a solvent comprising an inert organic solvent and a tertiary amine. 77. A process as claimed in claim 75 wherein the amine is 10 pyridine. 78. A compound as claimed in any of claims 1-61 when prepared by a process as claimed in any of claims 70-76. 79. ' A compound substantially as described with reference to any of Examples 1-7 herein. 80. A composition substantially as described with reference to either of Examples 8 or 9 herein. 81 A process according to any one of claims 71 to 77 substantially as described with reference to any of Examples 1-7 herein.