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GB1601107A - Pyrrole derivatives - Google Patents

Pyrrole derivatives Download PDF

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Publication number
GB1601107A
GB1601107A GB19465/77A GB1946577A GB1601107A GB 1601107 A GB1601107 A GB 1601107A GB 19465/77 A GB19465/77 A GB 19465/77A GB 1946577 A GB1946577 A GB 1946577A GB 1601107 A GB1601107 A GB 1601107A
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Prior art keywords
group
compound
methyl
formula
phenyl
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GB19465/77A
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Beecham Group PLC
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Beecham Group PLC
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Priority to GB19465/77A priority Critical patent/GB1601107A/en
Priority to ZA00782506A priority patent/ZA782506B/en
Priority to DE19782819463 priority patent/DE2819463A1/en
Priority to IL54642A priority patent/IL54642A/en
Priority to US05/903,194 priority patent/US4200645A/en
Priority to FR7813338A priority patent/FR2390431A1/en
Priority to NL7804942A priority patent/NL7804942A/en
Priority to DK204078A priority patent/DK204078A/en
Priority to IE942/78A priority patent/IE46825B1/en
Priority to BE187521A priority patent/BE866857A/en
Priority to CH503078A priority patent/CH640225A5/en
Priority to SE7805282A priority patent/SE7805282L/en
Priority to CA302,893A priority patent/CA1100142A/en
Priority to ES469631A priority patent/ES469631A1/en
Priority to JP5539178A priority patent/JPS53141268A/en
Priority to AU35990/78A priority patent/AU526256B2/en
Publication of GB1601107A publication Critical patent/GB1601107A/en
Expired legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

(54) PYRROLE DERIVATIVES (71) We, BEECHAM GROUP LIMITED, of Beecham House, Great West Road, Brentford, Middlesex, England, a British Company, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: The present invention relates to pyrrole derivatives, to a process for their preparation and to compositions containing them.
Tolmetin, a clinically used anti-inflammatory and analgesic agent of the formula (I):
has been reported in J. Pharmacol. Exptl. Therap. 1973, 185, 127-138 to possess anti-flammatory 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 inflammatory or painful conditions such as rheumatism, arthritis or the like.
The present invention provides the compounds of the formula (II):
wherein R1 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 henyl 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 Rl in the preceeding compounds represents a hydrogen atom.
Suitably R1 in the preceding compounds represents a methyl group.
Suitably X in the preceeding compounds is a CO group.
Suitably X in the preceding compounds is a CHOH group.
When used herein the term'ro-drug' means a compound metabolised in-vivo to or via a compound of the formula (II).
The pro-drugs will be compounds containing derivatives of the group X, for example those wherein the CHR1-CH2-X-CH3 side chain hereinafter referred to as 'Q' is the sub-formulae (a) - (d):
wherein R1 is a hydrogen atom or a methyl group; R2 is a group CO.R6 wherein R6 is the residue of a pharmaceutically acceptable carboxylic acid of up to 9 carbon atoms of the formula R6COOH; R3 is a C1.4 alkyl group or a CO.R6 group; R4 is a methyl, ethyl or propyl group and R5 is a methyl, ethyl or propyl group or R5 is joined to R4 so that they together represent a CH2CH2 or CII2CH2CH2 group.
A favoured side chain Q in the preceeding compounds is the CH2.CH2.CO.CH3 group.
Another favoured side chain Q in the preceeding compounds is the CH2. CH2. CHOH. CH3 group.
Further favoured side chains Q are those of the formula CH2.CH2.CH(O.CO.R6)CH3 wherein R6 is as defined in relation to sub-formula (a).
Apt values for R6 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 R6 include the methyl, ethyl, n'-propy-, iso-propyl, t-butyl, phenyl, benzyl, phenylethyl acetoxymethyl, methoxymethyl, hydroxymethyl optionally salted aminoethyl, a-acetoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl and 3,4,5trimethoxyphenyl groups.
Particularly suitable values for R6 include the methyl, ethyl, benzyl, 2-methoxyphenyl, phenyl and 3,4,5-trimethoxyphenyl group.
A preferred group R6 is the methyl group.
From the foregoing it will be realised a further favoured 2- position side chain is the CH2.CH2.CH(O.CO.CH3)CHs group.
One group of favoured side chains Q is that of the formula CH2CH2X1CH3 where X1 is a CO, CHOH or CHOCOR7 group where R7 is an alkyl group of 1-4 carbon atoms. Most suitably R7 is a methyl group.
These compounds of the formula (II) wherein R1 is a methyl group may be in the form of an isolated optical isomer or may be presented as a mixture of isomers, for example the R, S or RS form.
These compounds of the formula (II) wherein X is a CHOH or CHOR2 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 include those of the formula (it):
wherein R1 is a hydrogen atom or methyl group and X is a CO, CHOH or CH.OCOCH3 group.
In the compounds of formula (IV) R1 is suitably a hydrogen atom. In the compounds of the formula (IV) R1 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 CHOR group. In the compounds of the formula (IV) X is suitably a CHOCOCH3 group.
Certain other particularly effective compounds of this invention include those of the formula (V):
wherein R1 is a hydrogen atom or a methyl group and Xis a CO, CHOH or CH.O.CO.CH3 group.
In the compounds of the formula (V) R1 is suitably a hydrogen atom. In the compounds of the formula (V) R1 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 CHOCOCH3 group.
Certain further particularly effective compounds of this invention include those of the formula (VI):
wherein R1 is a hydrogen atom or a methyl group and X is a CO, CHOH or CHOCOCH3 group.
In the compounds of the formula (VI) R1 is suitably a hydrogen atom. In the compounds of the formula (VI) R1 is suitably a methyl group.
In the compounds of the formula (VI) X is suitably a 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 CHOCOCH3 group.
Particularly suitable compounds of this invention include: 4-( 1-methyl-5-p-toluoyl-2-pyrryl)butan-2-one; 2-acetoxy-4-(1-methyl-5-p-toluoyl(-2-pyrryl)butane; 4-( 1-methyl-5.p-cblorobenzoyl-2-pyrryl)butan-2-one; 4-( 1-methyl-5-p-chlorobenzoyl-2-pyrryl)butan-2-ol; 2-acetoxy-4-( 1-methyl-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-acetoxy-4-(1-methyl-5-thien-2'-oyl-2-pyrryl)-butane.
4-( 1-methyl-5-p-toluoyl-2-pyrryl)butan-2-ol.
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 100mg 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 daily dose for a 70Kg 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 preceding 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, or granulate and may advantageously be in intimate mixture with a lubricant 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 stearate, a filler such as microcrystalline cellulose and a disintegrant such as sodium starch glycollate.
The present invention also provides a method of treating inflammatory 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 mammals which may be thus treated include domestic animals such as dogs, cats or horses.
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 (II) 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 aromatic nuclei wherein Ar is as defined in relation to formula (II), with a compound of the formula (IX):
wherein Q' i a group of the sub-formulae (a) - (d) as hereinbefore defined or a group of the sul-formula (e): -CHR,-(1I-CO-CH3 (e) wherein Rl is I hydrogen atom or a methyl group; and thereafter if desired reducing the carboxyl present in oil group of the sub-formula (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 for the acylation of nucleophilic aromatic nuclei wherein Ar is as defined in relation to formula (II), with a compound of the formula (X):
wherein R1 is as defined in relation to formula (II) and 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):
wherein Q2 is a group of the sub-formulae (a) - (d) as hereinbefore defined.
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 (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 non-extreme temperature for example from 5"C to 50"C and more usually from 10 C to 300C if a Lewis acid is used. If no catalyst is used the acylation reaction is normally carried out at a higher temperature than 50"C e.g.
100"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 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 amine 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 by diluting with an aqueous acid, extracting into an organic solvent, washing and drying the organic phase and thereafter evaporating the solvent. The resulting ketone may then be purified by chromatography and/or recrystallisa tion.
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 by 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.
The compounds wherein X is a CHOH group may be acylated in conventional manner, for example, by reaction with the acid R2CO2H in the presence of a condensation promoting agent such as dicyclohexylcarbodiimide 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 (e):
Suitable methods of acylation include those described in 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):
Suitable methods of enol acylation or enol etherification include those described in West German Application P2647966.3.
DESCRIPTION 1 4- (I -Methyl-2-pyrryl) -butan-2-one 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-2one (2.46g).
EXAMPLE 1 4- (1-Methyl.5-p-toluoyl-2-pyrryl) butan-2-one
To a solution of 4-(1-Methyl-2-pyrryl)-butan-2-one (2.46g) in 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 (2.52g:0.016 mole). After a further 20 minutes the mixture was treated with dilute hydrochloric acid (SN, 10 ml) and extracted with dichloromethane (50ml). The organic layer was washed with water (20ml), aqueous unsymmetrical-dimethylethylenediamine (20% 20ml), dilute hydrochloric acid (SN, 10ml) and extracted with dichloromethane (SOml). The organic layer was washed with water (20ml), aqueous unsymmetrical-dimethylethylenediamine (20% 20ml), dilute hydrochloric acid (1N.20ml) and finally brine (20ml). After drying (Na2SO4) 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-topluoyl-2-pyrryl)-butan-2-one, m.p. 103-4 .
N.m.r. (CDCl3) 5 = 7.65 (2H, d, J = 8Hz), 7.17 (2H, d, J = 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).
EXAMPLE 2 4- (1 -Methyl-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 60-800C petrol (4 x 250ml) and the solution cooled (-30"C) causing a solid to precipitate. This solid was purified by 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)-butan-2-one (40% yield) as a white solid, m.p. 103-104"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).
EXAMPLE 3 4- (1-Methyl.5-p.chlorobenzoyl-2-pyrtyl) butan-2-one
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 produce was purified by passage through alumina using methylene chloride as solvent, followed by recrystallisation from carbon tetrachloride to give pure 4-(1-methyl-5p-chlorobenzoyl-2-pyrryl)-butan-2-one as colourless needles, m.p. 108-109"C.
N.m.r. (CDCl3) 6 = 7.7 (2H, d, J=9Hz), 7.35 (2H, d, J=9Hz), 6.53 (1H, d, J=4Hz), 5.85 (1H, d, J=4Hz), 3.93 (3H, s), 3.0-2.7 (4H, m), 2.15 (3H, s).
EXAMPLE 4 4-(1-Methyl-S-thien-2 '-oyl-2-pyrryl) butan-2-one
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-(1-methyl-5-thien-2'-oyl-2-pyrryl)butan-2-one as rhombic crystals, m.p. 78-79"C.
N.m.r. (CDCl3) 6 = 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).
EXAMPLE 5 4- (1 -Methyl-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 (Na2SO4) and concentrated to afford somewhat crude 4-(1-methyl-5-p-toluoyl-2-pyrryl)butan-2-ol as a pale purple oil (2.06g).
EXAMPLE 6 2-Acetoxy-4-(1-methyl-5-p-toluoyl-2-pyrryl)butane
The product of Example 5 was taken up in toluene (tOOml) 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 (2x 50ml) and dried (Na2SO4) 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-( 1-methyl-5-p-toluoyl-2-pyrryl)butane as colourless needles, m.p. 88-89 .
N.m.r. (CDCl3) 5 = 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).
EXAMPLE 7 2-Methyl-2-[2- (1 -methyl-5-p-toluoyl-2-pyrryl)ethy0-1,3-dioxolane
A mixture of 4-(1-Methyl-5-p-toluoyl-2-pyrryl)butan-2-one (1.0g), ethylene glycol (6ml), p-toluene-sulphonic acid (40 mg) and benzene (100ml) was refluxed for 5 hours with constant separation of H20 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 (Na2SO4) and concentrated to give a purple oil. This was chromatographed on alumina using ether as eluant to give pure 2-methyl-2-[2-(1-methyl-5-p-toluoyl-2-pyrryl)ethyljl,3 dioxolane as a colourless oil.
N.m.r.
(CDCl3), 5 = 7.69 (2H, d, J = 8Hz), 7.20 (2H, d, J=8Hz), 6.64 (1H, d, J=4Hz), 5.95 (1H, d, ZJ = 4Hz), 3.99 (4H, s), 3.95 (3H, s) 3.0-1.8 (4H, m), 2.40 (3H, s), 1.39 (3H, s).
EXAMPLE 8 Compositions (a) Tablets of the following composition may be prepared: 4-( 1-Methyl-5-p-toluoyl- 2-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-p-toluoyl- 2-pyrryl)butan-2-one 50 mg Lactose 75 mg Sodium lauryl sulphate 5 mg EXAMPLE 9 Compositions (a) Tablets of the following composition may be prepared: 4-( 1-Methyl-5-p-chlorobenzoyl- 2-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'-oyl 2-pyrryl)butan-2-one 50 mg Lactose 75 mg Sodium lauryl sulphate 5 mg (c) Hard gelatin capsules may be prepared containing the following: 4-(t-Methyl-5-p-chlorobenzoyl- 2-pyrryl)butan-2-one 100 mg Lactose 25 mg Sodium lauryl sulphate 5 mg 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 ED50 values when administered orally to mice: Compound ED50 (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 10 30 6 10 2 Compound of Example 1 270 1 90 1 30 0 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 foranti-inflammatory activity, the compound of Example 1 was classed as active at 10mg/kg per oral in rats (as compared to about Smg/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.
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 10mg/kg 42% HC 10mg/kg 43% b. Comp. Example 4 10mg/kg 24% HC 10mg/kg 43% c. Comp. Example 6 50mg/kg 34% HC 10mg/kg 43% d. Comp. Example 7 50/mg/kg 43% HC 10mg/kg 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.
WHAT WE CLAIM IS: 1. A compound of the formula (II):
wherein R1 is a hydrogen atom or a methyl group; Ar is a phenyl 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 thereof.
2. A compound as claimed in claim 1 wherein R1 and X are as 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, methoxyphenyl 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.
7. A compound as claimed in any of claims 1-4 wherein Ar is a phenyl group.
8. A compound as claimed in claim 1 wherein Ar is a methyl-phenyl group.
9. A compound as claimed in claim 1 wherein Ar is a methoxyphenyl group.
10. 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 group.
13. A compound as claimed in claim 6 wherein Ar is a 3-thienyl group.
14. A compound as claimed in claim 8 wherein Ar is a 4-methylphenyl group.
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 4-fluorophenyl group.
18. A compound as claimed in any of claims 1-17 wherein R1 is a hydrogen atom.
19. A compound as claimed in any of claims 1-17 wherein R1 is a methyl group.
20. A compound as claimed in any of claims 1-17 wherein X is a CO group.
**WARNING** end of DESC field may overlap start of CLMS **.

Claims (81)

**WARNING** start of CLMS field may overlap end of DESC **. activity, the compound of Example 1 was classed as active at 10mg/kg per oral in rats (as compared to about Smg/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. 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 10mg/kg 42% HC 10mg/kg 43% b. Comp. Example 4 10mg/kg 24% HC 10mg/kg 43% c. Comp. Example 6 50mg/kg 34% HC 10mg/kg 43% d. Comp. Example 7 50/mg/kg 43% HC 10mg/kg 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. WHAT WE CLAIM IS:
1. A compound of the formula (II):
wherein R1 is a hydrogen atom or a methyl group; Ar is a phenyl 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 thereof.
2. A compound as claimed in claim 1 wherein R1 and X are as 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, methoxyphenyl 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.
7. A compound as claimed in any of claims 1-4 wherein Ar is a phenyl group.
8. A compound as claimed in claim 1 wherein Ar is a methyl-phenyl group.
9. A compound as claimed in claim 1 wherein Ar is a methoxyphenyl group.
10. 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 group.
13. A compound as claimed in claim 6 wherein Ar is a 3-thienyl group.
14. A compound as claimed in claim 8 wherein Ar is a 4-methylphenyl group.
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 4-fluorophenyl group.
18. A compound as claimed in any of claims 1-17 wherein R1 is a hydrogen atom.
19. A compound as claimed in any of claims 1-17 wherein R1 is a methyl group.
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 CHOR group.
22. A compound as claimed in any of claims 1-17 wherein the CHR1-CH2-X-CH3 side chain is a group of the sub-formulae (a)-(d):
wherein R1 is a hydrogen atom or a methyl group; R2 is a group CO.R6 wherein R6 is the residue of a pharmaceutically acceptable carboxylic acid of up to 9 carbon atoms of the formula R6COOH; R3 is a C14 alkyl group or a CO.R6 group; R4 is a methyl, ethyl or propyl group and R4 is a methyl, ethyl or propyl group or R5 is joined to R4 so that they together represent a CH2CH2 or CH2CH2CH2 group.
23. A compound as claimed in any of claims 1-19 wherein the 2-position side chain is a CH2.CH2.CO.CH3 group.
24. A compound as claimed in any of claims 1-19 wherein the 2-position side chain is a CH2.CH2.CHOH.CH3 group.
25. A compound as claimed in any of claims 1-19 wherein the 2-position side chain is a CH2.CH2.CH(O.CO.R6)CHS group wherein R6 is as defined in claim 21.
26. A compound as claimed in claims 22 or 25 wherein R6 is 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, methoxyl, acetamido, optionally salted amino or alkylamino or optionally salted carboxyl group.
27. A compound as claimed in claims 22 or 25 wherein R6 is a methyl, ethyl, n-propyl, iso-propyl, t-butyl, phenyl, benzyl, phenylethyl, acetoxymethyl, methoxymethyl, hydroxymethyl optionally salted aminoethyl, a-acetoxyphenyl, 4-methoxyphenyl, 3,4dimethoxyphenyl or 3,4,5-trimethoxyphenyl group.
28. A compound as claimed in claims 22 or 25 wherein R6 is a methyl, ethyl, benzyl, 2-methoxyphenyl phenyl or 3,4,5-trimethoxyphenyl group.
29. A compound as claimed in claims 22 or 25 wherein R6 is a methyl group.
30. A compound as claimed in any of claims 1-19 wherein the 2-position side chain is a CH2. CH2.CH(O.CO.CH3). CH3 group.
31. A compound as claimed in any of claims 1-19 wherein the 2-position side chain is a CH2CH2.X'CH3 group wherein X' is a CO, CHOR or CHOCOR7 group R7 is an alkyl group of 1-4 carbon atoms.
32. A compound as claimed in claim 1 of the formula (IV):
wherein R1 is a hydrogen atom or methyl group and X is a CO, CHOH or CH.OCOCH3 group.
33. A compound as claimed in claim 32 wherein R1 is a hydrogen atom.
34. A compound as claimed in claim 33 wherein R1 is a methyl group.
35. A compound as claimed in claims 32-34 wherein X is a CO group.
36. 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.OCOCH3 group.
38. A compound as claimed in claim 1 of the formula (V):
wherein R1 is a hydrogen atom or a methyl group and X is a CO, CHOH or CH.O.CO.CH3 group.
39. A compound as claimed in claim 38 wherein R1 is a hydrogen atom.
40. A compound as claimed in claim 38 wherein R1 is a methyl group.
41. A compound as claimed in any of claims 38-40 wherein X is a CO group.
42. A compound as claimed in any of claims 38-40 wherein X is a CHOH group.
43. A compound as claimed in any of claims 38-40 wherein X is a CHOCOCH3 group.
44. A compound as claimed in claim 1 of the formula (VI):
wherein R1 is a hydrogen atom or a methyl group and X is a CO, CHOH or CHOCOCH3 group.
45. A compound as claimed in claim 44 wherein R1 is a hydrogen atom.
46. A compound as claimed in claim 44 wherein R1 is a methyl group.
47. A compound as claimed in any of claims 44-46 wherein X is a CO group.
48. A compound as claimed in any of claims 44-46 wherein X is a CHOH group.
49. A compound as claimed in any of claims 44-46 wherein X is a CHOCOCH3 group.
50. 4-(1-Methyl-5-p-toluoyl-2-pyrryl)butan-2-one.
51. 4-(1-MethylS-p-toluoyl-2-pryyrl)butan-2-ol.
52. 2-Acetoxy-4-(1-methyl-5-p-toluoyl-2-pyrryl)butane.
53. 4-(1-Methyl-5-p-chlorobenzoyl-2-pyrryl)butan-2-one.
54. 4- 1-Methyl-5-p-chlorobenzoyl-2-pyrrylbutan-2-ol.
55. 2-Acetoxy-4-( 1-methyl-5-p-chlorobenzyl-2-pyrryl)butane.
56. 4-( l-Methyl-5-thien-2'-oyl-2-pyrryl)butan-2
57. 4-( 1-Methyl-5-thien-2'-oyl-2-pyrryl)butan-2-ol.
58. 2-Acetoxy-4-(1-methyl-5-thien-2'-oyl-2-pyrryl)butane.
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.
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.
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.
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 composition as claimed in claim 65 which comprises from 50 to 250mg of a compound as claimed in any of claims 1-61.
67. A process for the preparation of a composition according to any one of claims 62-66 which process comprising bringing together the compound and the carrier.
68. A method of treating inflammatory and/or painful conditions in non-human mammals which comprises the administration per day of from 200 to 4000 mg of a compound of any of claims 1-61 said compound being present in a composition as claimed in any of claims 62-66.
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.
71. A process for the preparation of a compound of the formula (II) of 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 aromatic nuclei wherein Ar is as defined in relation to formula (II), with a compound of the formula (IX):
wherein Q is a group of the sub-formulae (a) - (d) as hereinbefore defined or a group of the sub-formula (e): -CHRI-CH2-CO-CH3 (e) wherein R1 is a hydrogen atom or a methyl group; and thereafter if desired reducing the carbonyl present in a group of the sub-formula (e) to a CHOH group.
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 acylation of nucleophilic aromatic nuclei wherein Ar is as defined in relation to formula (II), with a compound of the formula (X):
wherein R1 is as defined in relation to formula (II) and 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.
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 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):
wherein Q' is a group of the sub-formulae (a) - (d) as hereinbefore defined.
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 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.
GB19465/77A 1977-05-10 1977-05-10 Pyrrole derivatives Expired GB1601107A (en)

Priority Applications (16)

Application Number Priority Date Filing Date Title
GB19465/77A GB1601107A (en) 1977-05-10 1977-05-10 Pyrrole derivatives
ZA00782506A ZA782506B (en) 1977-05-10 1978-05-02 Pyrrole derivatives
DE19782819463 DE2819463A1 (en) 1977-05-10 1978-05-03 N-METHYL-PYRROL COMPOUNDS, THE PROCESS FOR THEIR MANUFACTURING AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS
IL54642A IL54642A (en) 1977-05-10 1978-05-04 4(5-(benzoyl or thenoyl)pyrrol 2-yl)butanol or butanone derivatives,their preparation and pharmaceutical compositions containing them
US05/903,194 US4200645A (en) 1977-05-10 1978-05-05 Pyrrole derivatives
FR7813338A FR2390431A1 (en) 1977-05-10 1978-05-05 NEW DERIVATIVES OF PYRROLE, USABLE AS A MEDICINAL PRODUCT
NL7804942A NL7804942A (en) 1977-05-10 1978-05-09 NEW N-METHYLPYRROOL DERIVATIVES WITH ANTI-INFLAMMATORY AND ANALGETIC ACTION, METHOD FOR PREPARING THESE COMPOUNDS AND PHARMACEUTICAL PREPARATIONS CONTAINING SUCH COMPOUND.
DK204078A DK204078A (en) 1977-05-10 1978-05-09 PROCEDURE FOR THE PREPARATION OF PYRROL DERIVATIVES
IE942/78A IE46825B1 (en) 1977-05-10 1978-05-09 Pyrrole derivatives
BE187521A BE866857A (en) 1977-05-10 1978-05-09 NEW DERIVATIVES OF PYRROLE, USABLE AS A MEDICINAL PRODUCT
CH503078A CH640225A5 (en) 1977-05-10 1978-05-09 Pyrrole derivatives and a process for their preparation
SE7805282A SE7805282L (en) 1977-05-10 1978-05-09 PYRROL DERIVATIVE
CA302,893A CA1100142A (en) 1977-05-10 1978-05-09 Pyrrole derivatives
ES469631A ES469631A1 (en) 1977-05-10 1978-05-09 Pyrole derivative process for preparing same and composition containing same
JP5539178A JPS53141268A (en) 1977-05-10 1978-05-10 Pyrole derivative process for preparing same and composition containing same
AU35990/78A AU526256B2 (en) 1977-05-10 1978-05-10 Pyrrole derivatives

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB19465/77A GB1601107A (en) 1977-05-10 1977-05-10 Pyrrole derivatives

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GB1601107A true GB1601107A (en) 1981-10-28

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BE866857A (en) 1978-11-09

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