WO1995021165A1 - Phenylpyrrole derivatives and their use as dopamine d3 antagonists - Google Patents

Abstract

Compounds of formula (I), wherein R1 represents C¿1-4?alkyl; one of R?2, R3, R4 and R5¿ represents a sulphonamido group -SO¿2NR?6R7, wherein R6 represents hydrogen, C¿1-4?alkyl or C1-4alkoxyC1-4alkyl and R?7¿ represents C¿1-4?alkoxyC1-4alkyl, or NR?6R7¿ forms a 4- to 8-membered fully saturated heterocyclic ring, a 5- to 8-membered partially saturated heterocyclic ring, or a 5- to 8-membered fully saturated heterocyclic ring which contains in addition to the nitrogen atom an oxygen or sulphur atom; and Y represents a group selected from (a) - (d), and salts thereof, have activity at dopamine receptors and are potentially useful in the treatment of psychoses such as schizophrenia.

Description

PHENYLPYRROLE DERIVATIVES AND THEIR USE AS DOPAMINE D3 ANTAGONISTS

The present invention relates to novel pyrrole derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, in particular as antipsychotic agents.

European Patent Application No. 241053, describes compounds of the formula :

wherein A is an unsaturated 5-membered heterocyclic ring, such as 2,5-pyrrolyl, or 3,5- or 1,4- pyrazolyl; X is a nitrogen or carbon atom; R₁,R₂, R₃ are each hydrogen or alkyl; R₄ is aryl, heteroaryl, arylcarbonyl or heteroaryl-carbonyl; R is selected from a variety of substituents and n is 0-4. The compounds are said to have antipsychotic properties.

European Patent Application No. 259930 describes compounds of the formula :

wherein A is an unsaturated 5-membered heterocyclic ring, such as 2,5-pyrrolyl, 1,4-pyrazolyl or 2,5-furyl; R is hydrogen, alkyl or optionally substituted phenyl; R¹ is alkyl, alkenyl or forms a ring with the phenyl group; R² is hydrogen, hydroxy or alkoxy; R³ is selected from a variety of substituents and n is 0-3. These compounds are also said to have antipsychotic properties.

European Patent Application No. 539281 describes compounds of the formula:

wherein Z is a residue derived from 2-aminomethyl-N-alkyl-pyrrolidine, 2-aminoethyl-N,N-diethylamine, 2-aminoethyl-morpholine, 2-aminoethyl-N,N-dibutylamine, 4-amino-N-butyl (or N-benzyl) piperidine or 2-aminoethyl-pyrrolidine; Y is alkyl or alkenyl; X is H, Cl, Br, amino, aminoalkyl, aminosulphamoyl, S-containing group (eg thiocyanato, alkylthio, alkylsulphinyl, alkylsulphonyl) methoxy, nitro, cyano, or an electron attracting group; and R is H or methoxy. The compounds are said to be dopamine antagonists, acting at the D₃ receptor and to be useful inter alia as antipsychotics.

We have now found novel pyrrole derivatives which have affinity for dopamine receptors and thus have potential as antipsychotic agents.

In a first aspect the present invention provides compounds of formula (I) :

wherein

R¹ represents C_{1- 4}alkyl;

one of R², R³, R⁴ and R ⁵ represents a sulphonamido group -SO₂NR⁶R⁷, wherein R⁶ represents hydrogen, C_{1- 4}alkyl or C_{1- 4}alkoxyC_{1- 4}alkyl and R? represents

C_{1- 4}alkoxyC_{1- 4}alkyl, or NR⁶R⁷ forms a 4- to 8- membered fully saturated heterocyclic ring, a 5- to 8-membered partially saturated heterocyclic ring, or a 5- to

8-membered fully saturated heterocyclic ring which contains in addition to the nitrogen atom an oxygen or sulphur atom;

and the remaining R², R³, R⁴ and R⁵ each independently represent hydrogen, halogen, C_{1- 4}alkyl, C_{1- 4}alkoxy, C_{1- 4}alkoxyC_{1- 4}alkyl, C_{1- 4}alkylsulphonyl,

trifluoromethylsulphonyl; optionally substituted arylsulphonyl, optionally substituted heteroarylsulphonyl, optionally substituted aralkylsulphonyl, optionally substituted heteroaralkylsulphonyl, nitro, cyano, amino, mono- or di-alkylamino,

trifluoromethyl, trifluoromethoxy, hydroxyl, hydroxyalkyl, C_{1- 4}alkylthio,

C_{1- 4}alkanoyl or C_{1- 4}alkoxycarbonyl; or

R¹ and R² together form a C_2-4alkyl chain, which chain may be optionally substituted by one or two C_{1- 4}alkyl groups, in which case one of R³, R⁴ and R⁵ is a sulphonamide group as defined above, and the other two substituents are as hereinbefore defined; or

R₂ and R³ together form a phenyl ring, in which case R⁴ represents a sulphonamido group as defined above and R⁵ represents hydrogen; and Y represents a group selected from (a) - (d):

or when R² and R³ together form a phenyl ring, Y may also represent a group (e):

wherein

in group (a) :

R⁸ and R⁹ independently represent hydrogen, C_{1- 6}alkyl, optionally substituted aryl C_{1- 6}alkyl or optionally substituted heteroarylC_{1- 6}alkyl;

R¹⁰ represents C_{1- 6}alkyl, C_3-6alkenyl or C_3-6cycloalkylC_{1- 4}alkyl; and R¹¹ represents C_{1- 4}alkyl; C_3-6alkenyl; C_3-6cycloalkylC_{1- 4}alkyl, optionally substituted arylC_{1- 4}alkyl or optionally substituted heteroarylC_{1- 4}alkyl; or

NR¹⁰R^{1 1} forms a heterocyclic ring;

in group (b) :

R¹² represents C_{1- 6}alkyl; C_3-6alkenyl; C_3-6cycloalkylC_{1- 4}alkyl , optionally substituted arylC_{1- 4}alkyl or optionally substituted heteroarylC_{1- 4}alkyl; and

q is 1 to 4;

in group (c): each of r and s independently represents an integer from 1 to 3;

in group (d) R¹³ represents C_{1- 6}alkyl, C_3-6alkenyl or C_3-6cycloalkylC_{1- 4}alkyl;

R¹⁴, R¹⁵, R¹⁶ and R¹⁷ each independently represent hydrogen, halogen, C_{1- 4}alkyl, C_{1- 4}alkoxy, C_{1- 4}alkoxyC_{1- 4}alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, hydroxyalkyl, C_{1- 4}alkanoyl, C_{1- 4}alkoxycarbonyl, amino or mono- or - dialkylamino;

X is CH₂, S or O;

t is zero, 1 or 2;

and in group (e) R¹⁸ and R¹⁹ independently represent hydrogen, C_{1- 6}alkyl, optionally substituted arylC_{1- 6}alkyl or optionally substituted heteroarylC_{1- 6}alkyl;

R²⁰ represents an optionally substituted aryl or optionally substituted heteroaryl group; and

Z represents -(CH₂)_u wherein u is 2 to 8 or -(CH₂)_vCH=CH(CH₂)_w where v and w

independently represent 1 to 3;

and salts thereof.

In the compounds of formula (I) an alkyl group or moiety may be straight or branched. Alkyl groups which may be employed include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and any branched isomers thereof such as isopropyl, t-butyl, sec-pentyl,and the like.

A halogen atom present in the compounds of formula (I) may be fluorine, chlorine, bromine or iodine.

Representative aryl groups or moieties present in any of the substituents R², R ³, R⁴, R⁵, R⁸, R⁹, R¹¹, R¹², R¹⁸, R¹⁹ and R²⁰, in compounds of formula (I) include phenyl, naphthyl, and tetrahydronaphthyl. Suitable examples of heteroaryl groups include both 5 and 6-membered heterocycles containing one or more oxygen, sulphur or nitrogen atoms, such as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazyl, pyrimidyl and pyrazolyl. Substituents for said aryl and heteroaryl groups include halogen, C_{1- 4}alkyl, C_{1- 4}alkoxy, C_{1- 4}alkoxy C_{1- 4}alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, hydroxyC_{1- 4}alkyl, C_{1- 4}alkanoyl, C_{1- 4}alkoxycarbonyl, amino and mono- or -di C_{1- 4}alkylamino. When - NR¹⁰R¹¹ forms a heterocyclic ring, this preferably has from 4 to 10, e.g. 5 to 8 ring members, and it may be fully or partially saturated. A heterocyclic ring - NR¹⁰R¹¹ may also be bridged, for example by a C_{1- 3}alkylene chain e.g. a methylene or ethylene group. Furthermore, the heterocyclic ring may be substituted by one or more C_{1- 4}alkyl groups, or fused to an aromatic ring, such as phenyl.

In the group -SO₂NR⁶R⁷, when NR⁶R⁷ forms a 4- to 8- membered fully saturated heterocyclic ring this may be for example an azetidinyl, pyrrolidinyl, piperidinyl or azacycloheptyl ring. Examples of a 5- to 8-membered partially saturated heterocyclic ring include 1,2,3,6-tetrahydropyridinyl, and examples of a 5- to 8-membered fully saturated heterocyclic ring which contains in addition to the nitrogen atom an oxygen or sulphur atom include morpholinyl or thiomorpholinyl.

R¹ preferably represents methyl, ethyl or isopropyl. R² preferably represents hydrogen. R³ preferably represents hydrogen or methyl. R₄ preferably represents a sulphonamido group -SO₂NR⁶R⁷. R₅ preferably represents hydrogen.

In the group -SO₂NR⁶R⁷, NR⁶R⁷ preferably forms a partially saturated heterocyclic ring, for example 1,2,3,6-tetrahydropyridinyl, or a fully saturated ring containing an additional heteroatom, such as morpholinyl.

When Y is a group (a) at least one of R⁸ and R⁹ is preferably hydrogen. Suitably one of R⁸ and R⁹ is hydrogen and the other is selected from hydrogen, C_{1- 6}alkyl and optionally substituted arylC_{1- 6}alkyl.

When Y is a group (b) q is preferably 1 or 2 and R¹² is preferably C_{1- 6}alkyl e.g. ethyl. When Y is a group (c) r and s preferably each independently represents 1 or 2.

When Y is a group (e) at least one of R¹⁸ and R¹⁹ preferably represents hydrogen. Suitably one of R¹⁸ and R¹⁹ is hydrogen and the other is selected from hydrogen, C_{1- 6}alkyl and optionally substituted arylC_{1- 6}alkyl. R²⁰ preferably represents optionally substituted phenyl or optionally substituted furyl. Z preferably represents (CH₂)_u wherein u is 3, 4 or 5. Most preferably one of R¹⁸ and R¹⁹ is hydrogen and the other is hydrogen or C_{1- 6}alkyl; R²⁰ represents phenyl or optionally substituted furyl and z represents (CH₂)_u where u is 3 or 5.

It will be appreciated that for use in medicine the salts of formula (I) should be physiologically acceptable. Suitable physiologically acceptable salts will be apparent to those skilled in the art and include for example acid addition salts formed with inorganic acids eg. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid; and organic acids eg. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulphonic, methanesulphonic or naphthalenesulphonic acid. Other non-physiologically acceptable salts eg. oxalates, may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention. Also included within the scope of the invention are solvates and hydrates of compounds of formula (I). When an asymmetric centre is present in a compound of formula (I) the compound will exist in the form of optical isomers (enantiomers). The present invention includes within its scope all such enantiomers and mixtures, including racemic mixtures, thereof. In addition, all possible diastereomeric forms (individual diastereomers and mixtures thereof) of compounds of formula (I) are included within the scope of the invention.

Particular compounds according to the invention include :

2-[2-Methoxy-5-(1-(1,2,3,6-tetrahydropyridyl)sulphonyl)phenyl]-5-(2-(1-ethylpyrrolidinyl))-1H-pyrrole;

2-[2-Methoxy-5-(4-morpholinylsulphonyl)phenyl]-5-(2-(1-ethylpyrrolidinyl))-1H-pyrrole;

2-[2-Methoxy-4-methyl-5-(4-morpholinylsulphonyl)phenyl]-5-(2-(1-ethylpyrrolidinyl))- 1H-pyrrole;

and salts thereof.

The present invention also provides a process for preparing compounds of formula (I) which process comprises :

(a) to prepare a compound of formula (I) wherein Y is a group (a) or (e) in which R⁸, R⁹, R¹⁸ and R¹⁹ are hydrogen or wherein Y is a group (d) carrying out a Mannich reaction with a compound of formula (II) :

and an amine of formula (III), (V) or (IV) respectively:

HNR¹⁰R¹¹

Formula (III)

in the presence of formaldehyde;

(b) to prepare a compound wherein Y is a group (a) wherein at least one of R⁸ and R⁹ is hydrogen, a group (e) wherein at least one of R¹⁸ and R¹⁹ is hydrogen, or a group of formula (b), (c) or (d) carrying out a Nilsmeier reaction with a compound of formula (II) and an amide of formula (VI), (VIII) or (VII):

R⁸C(O)ΝR¹⁰R¹¹

Formula (VI)

or the appropriate oxo derivative of group (b) or (c) respectively, and reducing the intermediate product with, for example, sodium borohydride or cyanoborohydride;

(c) to prepare a compound wherein Y is a group (a) or (e) in which R⁸, R⁹, R¹⁸ and R¹⁹ are hydrogen or Y is a group (d) reductive animation of a compound of formula (IX) :

with an amine of formula (III), (V) or (IV) respectively;

and optionally thereafter forming a salt of formula (I).

The Mannich reaction according to process (a) may be effected according to conventional methods. Thus for example the amine of formula (IIl), (IV) or (V) may first be reacted with formaldehyde and the product subsequently reacted with a compound of formula (II). The reaction is preferably effected in a protic solvent, for example an alcohol such as ethanol. An organic or inorganic acid, e.g. acetic acid may be employed as a catalyst.

The Vilsmeier reaction according to process (b) may also be effected according to conventional methods. Thus, for example, the amide of formula (VI), (VII) or (VIII) or the oxo derivative of group (b) or (c) may first be treated with phosphorus oxychloride and the resulting product subsequently reacted with a compound of formula (II), conveniently in a solvent such as dichloromethane or dichloroethane. The product of this reaction is then reduced with, for example, sodium borohydride or cyanoborohydride. The reduction may be carried out in a suitable solvent, for example dichloroethane, dichloromethane, methanol, ethanol, water or mixtures thereof.

Reductive amination according to process (c) will generally be carried out using a reducing agent such as sodium borohydride or cyanoborohydride and in the presence of a Lewis acid such as titanium (IV) chloride. Reaction of a compound (IX) with the amine may conveniently be effected in a solvent such as dichloromethane or dichloroethane.

A compound of formula (II) may be prepared by cyclisation of a dicarbonyl compound of formula (X) :

The reaction may be effected using an ammonium salt, e.g. ammonium acetate, in a solvent such as ethanol. (See, for example, C.G. Kruse et al., Heterocycles, vol 26, P3141, 1987).

A compound of formula (X) may itself be prepared by reacting the appropriate substituted aroyl halide with a metallo derivative of a 2-(2-haloethyl)-1,3-dioxolane or 2-(2-haloethyl)-1,3-dioxane and subsequent acid hydrolysis.

Compounds of formulae (III) and (V) are available commercially or may be prepared by standard methods.

An amine (IV) may be obtained by reductive amination of a ketone of formula (XI) :

with an amine R¹²NH₂ , in the presence of a titanium (IV) chloride followed by reduction with e.g. sodium cyanoborohydride, as described above for process (c).

Compounds of formula (VI) and (VIII) wherein R⁸ and R¹⁸ respectively are other than hydrogen may be prepared by acylation of the appropriate amine of formula (III) or (V) for example using the corresponding acyl halide.

Compounds of formula (VI) and (VIII) wherein R⁸ and R¹⁸ respectively represent hydrogen as well as compounds (VII) may be prepared by reacting the appropriate amine of formula (IIl), (V) or (IV) respectively with a formylating agent, such a acetic anhydride in formic acid.

A compound of formula (IX) may be prepared by carrying out a Vilsmeier reaction in which dimethylformamide is reacted with phosphorus oxychloride and the product reacted with a compound of formula (II) in a solvent such as dichloroethane, followed by acid hydrolysis.

When a compound of formula (I) is obtained as a mixture of enantiomers these may be separated by conventional methods such as crystallisation in the presence of a resolving agent, or chromatography, for example using a chiral HPLC column.

Alternatively a compound of formula (I) may be prepared as a single enantiomer by employing a chiral amine in the synthesis, for example directly in process (a) or (c) or in the preparation of an amide for use in process (b). A chiral amine of formula (III) or (IV) may be prepared by resolving an enantiomeric mixture of the appropriate amine for example by coupling to a chiral auxiliary such as (S)-(+)-α-methoxyphenylacetic acid and separating the resulting diastereoisomers by chromatography. The auxiliary moiety may be removed to give the desired chiral amine. Thus for example the (S)-(+)-α-methoxyphenylacetyl moiety may be cleaved under basic conditions.

Compounds of formula (I) have been found to exhibit affinity for dopamine receptors, in particular D₃ receptors, and are expected to be useful in the treatment of disease states which require modulation of such receptors, such as psychotic conditions. The therapeutic effect of currently available antipsychotic agents (neuroleptics) is generally believed to be exerted via blockade of D₂ receptors; however this mechanism is also thought to be responsible for undesirable extrapyramidal side effects (eps) associated with many neuroleptic agents. Without wishing to be bound by theory, it has been suggested that blockade of the recently characterised dopamine D₃ receptor may give rise to beneficial antipsychotic activity without significant eps. (see for example Sokoloff et al, Nature, 1990; 347: 146-151; and Schwartz et al, Clinical Neuropharmacology, Vol 16, No. 4, 295-314, 1993). Preferred compounds of the present invention are therefore those which have higher affinity for dopamine D₃ than dopamine D₂ receptors (such affinity can be measured using standard methodology for example using cloned dopamine receptors). Said compounds may advantageously be used as selective modulators of D₃ receptors. In particular compounds of formula (I) are dopamine D₃ receptor antagonists and as such are of potential use as antipsychotic agents for example in the treatment of schizophrenia, schizo-affective disorders, psychotic depression and mania. Other conditions which may be treated by modulation of dopamine D₃ receptors include dyskinetic disorders such as Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesias; depression; and drug (eg. cocaine) dependency.

In a further aspect therefore the present invention provides a method of treating conditions which require modulation of dopamine D₃ receptors, for example psychoses such as schizophrenia, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) or a physiologically acceptable salt thereof.

The invention also provides the use of a compound of formula (I) or a

physiologically acceptable salt thereof in the manufacture of a medicament for the treatment of conditions which require modulation of dopamine D₃ receptors, for example psychoses such as schizophrenia.

For use in medicine, the compounds of the present invention are usually administered as a standard pharmaceutical composition. The present invention therefore provides in a further aspect pharmaceutical compositions comprising a novel compound of formula (I) or a physiologically acceptable salt thereof and a physiologically acceptable carrier.

The compounds of formula (I) may be administered by any convenient method, for example by oral, parenteral, buccal, sublingual, nasal, rectal or transdermal

administration and the pharmaceutical compositions adapted accordingly.

The compounds of formula (I) and their physiologically acceptable salts which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.

A liquid formulation will generally consist of a suspension or solution of the compound or physiologically acceptable salt in a suitable liquid carrier(s) for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring or colouring agent. A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using routine

encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension of the compound or physiologically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.

Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device. Alternatively the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomiser.

Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.

Compositions for rectal administration are conveniently in the form of

suppositories containing a conventional suppository base such as cocoa butter.

Compositions suitable for transdermal administration include ointments, gels and patches.

Preferably the composition is in unit dose form such as a tablet, capsule or ampoule.

Each dosage unit for oral administration contains preferably from 1 to 250 mg

(and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the formula (I) or a physiologically acceptable salt thereof calculated as the free base. The physiologically acceptable compounds of the invention will normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose of between 1 mg and 500 mg, preferably between 10 mg and 400 mg,e.g. between 10 and 250 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 50 mg, e.g. between 1 and 25 mg of the compound of the formula (I) or a physiologically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more.

The invention is further illustrated by the following non-limiting examples :

Description 1

2-Methoxy-5-(1-(1,2,3,6-tetrahydropyridyl)sulphonyl)benzoic acid

To a solution of 1,2,3,6-tetrahydropyridine (5ml, 0.055mol) in water (50ml) and triethylamine (5ml, 0.036mol) was added 5-chlorosulphonyl-2-methoxybenzoic acid (German OLS 2,721,643; 10g, 0.04mol,) portionwise. The resultant mixture was stirred overnight at room temperature, then acidified with 5N HCl and the resultant solid filtered, washed with water and dried to yield the title compound (5.6g, 47%).

NMR δ (CDCl₃) 2.20 (2H, bm), 3.20(2H, t, J=6Hz), 3.60(2H, m), 4.15(3H, s), 5.55-5.85(2H, m), 7.20(1H, d, J=9Hz), 8.00(1H, dd, J=1Hz, 9Hz), 8.55(1H, d, J=1H).

Similarly prepared were:

2-Methoxy-5-(4-morpholinylsulphonyI)benzoic acid

m.p. 181-183 °C.

2-Methoxy-4-methyI-5-(4-morpholinylsulphonyl)benzoic acid

m.p. 181-182 ºC Description 2

2-[2-Methoxy-5-(1-(1,2;3,6-tetrahydropyridyl)sulphonyI)phenyI]-1H pyrrole

To a stirred suspension of 5-(1,2,3,6-tetrahydropyridine-1-sulphonyl)-2-methoxybenzoic acid (5.47g, 0.0185mol) in dry toluene (200ml) was added oxalyl chloride (3.5ml, 0.037mol) followed by dry DMF (2 drops). The mixture was stirred at room temperature for lδhours, filtered and the filtrate evaporated in vacuo. The residue was dissolved in dry THF (50ml), cooled to -76°C and stirred in an argon atmosphere as a 0.51 molar solution of 2-(1,3-dioxan-2-yl)ethylmagnesium bromide (31ml) (prepared as in J. Org. Chem, 41, 3, 560-1, 1978) was added dropwise over 0.5hour. On complete addition the mixture was stirred at -76°C for lhour, allowed to warm to -40°C and stirred for a further 0.5hour and finally allowed to warm to room temperature and stir for a further 2hours. The mixture was evaporated in vacuo and the residue partitioned between 10% citric acid and CH₂CI₂. The aqueous layer was extracted with CH₂CI₂, the combined organics dried (Na₂SO₄) and evaporated in vacuo. The residue was dissolved in MeOH(1L) and p-toluenesulphonic acid (0.5g) added. The mixture was refluxed for lhour, allowed to cool and made basic with saturated NaHCO_3, then concentrated to approximately 200ml in vacuo, poured into water and extracted with CH₂CI₂. The organic extracts were dried (Na₂SO₄), evaporated in vacuo and the residue dissolved in THF (50ml) and 5N HCl (25ml) added. The mixture was stirred at room temperature for 18hours, evaporated in vacuo and the residue partitioned between water and CH₂CI₂. The organic layer was dried (Na₂SO₄) and evaporated in vacuo. The residue was dissolved in THF (20ml) and added dropwise to a warm solution of ammonium acetate (5g) in EtOH (50ml). The mixture was refluxed for 2hours, cooled and evaporated in vacuo. The residue was partitioned between CH₂CI₂ and saturated NaHCO₃. The organic layer was dried (Na₂SO₄), evaporated in vacuo and the residue purified by chromatography on silica gel using CH₂CI₂ as eluent to furnish the title compound (D2) as a colourless solid (0.7g, 12%).

NMR δ (CDCI₃) 2.20(2H, bm), 3.20(2H, t, J=6Hz), 3.60(2H, m), 4.05(3H, s), 5.55-5.85(2H, m), 6.30(1H, m), 6.70(1H, m), 6.90(1H, m), 7.05(1H, d, J=9Hz), 7.60(1H, dd, J=1Hz, 9Hz), 8.00(1H, d, J=1Hz), 9.75(1H, bs).

Similarly prepared were: 2-[2-Methoxy-5-(4-morpholinylsulphonyl)phenyI]-1H-pyrrole

Found: C, 55.57; H, 5.57; N, 8.64. C₁₅H₁₈N₂SO₄ requires C, 55.89; H, 5.63; N, 8.69%.

2-[2-Methoxy-4-methyl-5-(4-morpholinylsulphonyI)phenyl]-1H-pyrrole

m.p. 169-170 °C. ¹H NMR (CDCI₃) δ: 2.62 (3H, s), 3.13 (4H, m), 3.72 (4H, m), 4.02 (3H, s), 6.30 (1H, m), 6.68 (1H, m), 6.85-6.88 (2H, m), 8.14 (1H, s), 9.6-9.7 (1H, br s).

Example 1

2-[2-Methoxy-5-(1-(1,2,3,6-tetrahydropyridyl)sulphonyl)phenyl]-5-(2-(1-ethylpyrrolidinyl))-1H-pyrrole, hydrochloride

Phosphorus oxychloride (0.1ml, 1mmol) was added dropwise to 1-ethyl-2-pyrrolidinone (0.12ml, lmmol) with stirring under an argon atmosphere. After 0.5hours, 1,2- dichloroethane (5ml) was added and the resultant solution cooled to 0°C. 2-[5-(1,2,3,6- tetrahydropyridine-1-sulphonyl)-2-methoxyphenyl]-1H-pyrrole (0.22g, 0.69mmol) in 1,2- dichloroethane (5ml) was added dropwise over 5 minutes and the resultant solution stirred at 0°C for 2hours and at room temperature for a further 18hours. The mixture was cooled to 0°C and sodium borohydride (0.4g, 10.6mmol) added. After stirring at room temperature for 2hours the mixture was cooled to 0°C and water (2ml) followed by MeOH (2ml) added dropwise. Further water (50ml) was added and the solution extracted with CH₂CI₂ (2×100ml). Combined extracts were dried (Na₂SO₄) and evaporated in vacuo. The residue was dissolved in MeOH (5ml) and concentrated HCl (2.5ml) added and the mixture stirred at room temperature for 2hours. Water (50ml) was added and the solution made basic with 10% NaOH and extracted with CH₂CI₂ (2×100ml). Combined extracts were dried (Na₂SO₄) and evaporated in vacuo. Purification by chromatography on alumina using 0-0.25% MeOH in CH₂CI₂ as eluent furnished a light green oil. This was dissolved in Et₂O, washed with water and extracted into 0.5N HCl(50ml). The acidic extract was washed with Et₂O, basified with 10% NaOH and extracted with CH₂CI₂ (3× 25ml). Combined organic extracts were dried (Na₂SO₄) and evaporated in vacuo to afford the title compound as a beige gum (0.147g, 51%).

NMR δ (CDCI₃) 1.10(3H, t, J=7Hz), 1.75-2.30(8H, m), 2.55-2.85(1H, m), 3.30(2H, t, J=6Hz), 3.25-3.55(2H, m), 3.60(2H, m), 4.05(3H, s), 5.50-5.85(2H, m), 6.10(1H, m), 6.60(1H, m), 7.05(1H, d, J=9Hz), 7.55(1H, dd, J=1Hz, 9Hz), 8.00(1H, d, J=1Hz), 9.75(1H, bs).

2-[2-Methoxy-5-(4-morpholinylsulphonyl)phenyI]-5-(2-(1-ethylpyrrolidinyI))-1H-pyrrole hydrochloride

m.p. 125-127 °C. Mass Spectrum: Found M+ 419.1864. C₂₁H₂₉N₃O₄S requires M⁺ 419.1829.

2-[2-Methoxy-4-methyI-5-(4-morpholinylsulphonyI)phenyl]-5-(2-(1-ethylpyιτolidinyl))-1H-pyrrole

Mass Spectrum: Found M⁺ 433. C₂₂H₃₁N₃O₄S requires M⁺ 433.

¹H NMR (CDCI₃) δ: 1.05-1.11 (3H, t), 1.8-2.5 (6H, m), 2.6 (3H, s), 2.7-2.9 (1H, m), 3.10 (4H, m), 3.3-3.8 (6H, m), 4.05 (3H, s), 6.1 (1H, m), 6.55 (1H, m), 6.85 (1H, s), 8.1 (1H, s), 10.0-10.3 (1H, br s). Biological Test Methods

The ability of the compounds to bind selectively to human D₃ dopamine receptors can be demonstrated by measuring their binding to cloned receptors. The inhibition constants (K_i) of test compounds for displacement of [¹²⁵I] iodosulpride binding to human D₂ and D₃ dopamine receptors expressed in CHO cells have been determined. The cell lines were shown to be free from bacterial, fungal and mycoplasmal contaminants, and stocks of each were stored frozen in liquid nitrogen. Cultures were grown as monolayers or in suspension in standard cell culture media. Cells were recovered by scraping (from monolayers) or by centrifugation (from suspension cultures), and were washed two or three times by suspension in phosphate buffered saline followed by collection by centrifugation. Cell pellets were stored frozen at -40°C. Crude cell membranes were prepared by homogenisation followed by high-speed centrifugation, and characterisation of cloned receptors achieved by radioligand binding.

Preparation of CHO cell membranes

Cell pellets were gently thawed at room temperature, and resuspended in about 20 volumes of ice-cold 50 mM Tris salts (pH 7.4 @ 37°C), 20mM EDTA, 0.2 M sucrose. The suspension was homogenised using an Ultra-Turrax at full speed for 15 sec. The homogenate was centrifuged at 18,000 r.p.m for 20 min at 4°C in a Sorvall RC5C centrifuge. The membrane pellet was resuspended in ice-cold 50 mM Tris salts (pH 7.4 @ 37°C), using an Ultra-Turrax, and recentrifuged at 18,000 r.p.m for 15 min at 4°C in a Sorvall RC5C. The membranes were washed two more times with ice-cold 50 mM Tris salts (pH 7.4 @ 37°C). The final pellet was resuspended in 50 mM Tris salts (pH 7.4 @ 37°C), and the protein content determined using bovine serum albumin as a standard (Bradford, M. M. (1976) Anal. Biochem. 72, 248-254).

Binding experiments on cloned dopamine receptors

Crude cell membranes were incubated with 0.1 nM [¹²⁵I] iodosulpride (-2000 Ci/mmol; Amersham, U. K.), and the test compound in a buffer containing 50 mM Tris salts (pH 7.4 @ 37°C), 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 1 mM MgCl₂, 0.1% (w/v) bovine serum albumin, in a total volume of 1 ml for 30 min at 37°C. Following incubation, samples were filtered using a Brandel Cell Harvester, and washed three times with ice-cold 50 mM Tris salts (pH 7.4 @ 37°C), 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 1 mM MgCl₂. The radioactivity on the filters was measured using a Cobra gamma counter (Canberra Packard). Non-specific binding was defined as the radioligand binding remaining after incubation in the presence of 100 μM iodosulpride. For competition curves, 14 concentrations (half-log dilutions) of competing cold drug were used. Competition curves were analysed simultaneously whenever possible using non-linear least-squares fitting procedures, capable of fitting one, two or three site models. Compounds of Example 1 had IC₅₀ values of between 5 and 15 nM at the human D₃ receptor.

Pharmaceutical Formulations

The following represent typical pharmaceutical formulations according to the present invention, which may be prepared using standard methods.

IV Infusion

Compound of formula (I) 1-40 mg

Buffer to pH ca 7

Solvent/complexing agent to 100 ml

Bolus Injection

Compound of formula (I) 1-40 mg

Buffer to pH ca 7

Co-Solvent to 5 ml

Buffer : Suitable buffers include citrate, phosphate, sodium hydroxide/hydrochloric acid.

Solvent : Typically water but may also include cyclodextrins (1-100 mg) and co-solvents such as propylene glycol, polyethylene glycol and alcohol.

Tablet

Compound 1 - 40 mg

Diluent/Filler * 50 - 250 mg

Binder 5 - 25 mg

Disentegrant * 5 - 50 mg

Lubricant 1 - 5 mg

Cyclodextrin 1 - 100 mg

* may also include cyclodextrins

Diluent : e.g. Microcrystalline cellulose, lactose, starch

Binder : e.g. Polyvinylpyrrolidone, hydroxypropymethylcellulose

Disintegrant : e.g. Sodium starch glycollate, crospovidone

Lubricant : e.g. Magnesium stearate, sodium stearyl fumarate. Oral Suspension

Compound 1 - 40 mg

Suspending Agent 0.1 - 10 mg

Diluent 20 - 60 mg

Preservative 0.01 - 1.0 mg

Buffer to pH ca 5 - 8

Co-solvent 0 - 40 mg

Flavour 0.01 - 1.0 mg

Colourant 0.001 - 0.1 mg

Suspending agent : e.g. Xanthan gum, microcrystalline cellulose

Diluent : e.g. sorbitol solution, typically water

Preservative : e.g. sodium benzoate

Buffer : e.g. citrate

Co-solvent : e.g. alcohol, propylene glycol, polyethylene glycol, cyclodextrin

Claims

Claims :

A compound of formula (I) :

wherein

R¹ represents C_1-4alkyl;

one of R², R³, R⁴ and R⁵ represents a sulphonamido group -SO₂NR⁶R⁷, wherein R⁶ represents hydrogen, C_{1- 4}alkyl or C_{1- 4}alkoxyC_{1- 4}alkyl and R⁷ represents

C_{1- 4}alkoxyC_{1- 4}alkyl, or NR⁶R⁷ forms a 4- to 8- membered fully saturated heterocyclic ring, a 5- to 8-membered partially saturated heterocyclic ring, or a 5- to 8-membered fully saturated heterocyclic ring which contains in addition to the nitrogen atom an oxygen or sulphur atom;

and the remaining R², R³, R⁴ and R⁵ each independently represent hydrogen, halogen, C_{1- 4}alkyl, C_{1- 4}alkoxy, C_{1- 4}alkoxyC_{1- 4}alkyl, C_{1- 4}alkylsulphonyl,

trifluoromethylsulphonyl; optionally substituted arylsulphonyl, optionally substituted heteroarylsulphonyl, optionally substituted aralkylsulphonyl, optionally substituted heteroaralkylsulphonyl, nitro, cyano, amino, mono- or di-alkylamino,

trifluoromethyl, trifluoromethoxy, hydroxyl, hydroxyalkyl, C_{1- 4}alkylthio,

C_1-4alkanoyl or C_{1- 4}alkoxycarbonyl; or

R¹ and R² together form a C_2-4alkyl chain, which chain may be optionally substituted by one or two C_{1- 4}alkyl groups, in which case one of R³, R⁴ and R⁵ is a sulphonamide group as defined above, and the other two substituents are as hereinbefore defined; or

R² and R³ together form a phenyl ring, in which case R⁴ represents a sulphonamido group as defined above and R⁵ represents hydrogen; and Y represents a group selected from (a) - (d):

or when R² and R³ together form a phenyl ring, Y may also represent a group (e):

wherein

in group (a) :

R⁸ and R⁹ independently represent hydrogen, C_{1- 6}alkyl, optionally substituted

aryl C_{1- 6}alkyl or optionally substituted heteroarylC_{1- 6}alkyl;

R¹⁰ represents C_{1- 6}alkyl, C_3-6alkenyl or C_3-6cycloalkylC_{1- 4}alkyl; and

R¹¹ represents C_{1- 6}alkyl; C_3-6alkenyl; C_3-6cycloalkylC_{1- 4}alkyl, optionally substituted arylC_{1- 4}alkyl or optionally substituted heteroarylC_{1- 4}alkyl; or

NR¹⁰R^{1 1} forms a heterocyclic ring;

in group (b) :

R¹² represents C_{1- 6}alkyl; C_3-6alkenyl; C_3-6cycloalkylC_{1- 4}alkyl , optionally substituted arylC_{1- 4}alkyl or optionally substituted heteroarylC_{1- 4}alkyl; and

q is 1 to 4; in group (c): each of r and s independently represents an integer from 1 to 3;

in group (d) R¹³ represents C_{1- 6}alkyl, C_3-6alkenyl or C_3-6cycloalkylC_1-4alkyl;

R¹⁴, R¹⁵, R¹⁶ and R¹⁷ each independently represent hydrogen, halogen, C_{1- 4}alkyl, C_{1- 4}alkoxy, C_{1- 4}alkoxyC_{1- 4}alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, hydroxyalkyl, C_{1- 4}alkanoyl, C_{1- 4}alkoxycarbonyl, amino or mono- or - dialkylamino;

X is CH₂, S or O;

t is zero, 1 or 2;

X is CH₂, S or O;

t is zero, 1 or 2;

and in group (e) R¹⁸ and R¹⁹ independently represent hydrogen, C_{1- 6}alkyl, optionally substituted arylC_{1- 6}alkyl or optionally substituted heteroarylC_{1- 6}alkyl;

R²⁰ represents an optionally substituted aryl or optionally substituted heteroaryl group; and

Z represents -(CH₂)_u wherein u is 2 to 8 or -(CH₂)_vCH=CH(CH₂)_w where v and w

independently represent 1 to 3;

or a salt thereof.

2. A compound according to claim 1 wherein R¹ represents methyl, ethyl, or isopropyl.

3. A compound according to claim 1 or claim 2 wherein R³ represents hydrogen or methyl.

4. A compound according to any of claims 1 to 3 wherein R⁴ represents a sulphonamido group -SO₂NR⁶R⁷.

5. A compound according to claim 1 selected from :

2-[2-Methoxy-5-(1-(1,2,3,6-tetrahydropyridyl)sulphonyl)phenyl]-5-(2-(1-ethylpyrrolidinyl))-1H-pyrrole;

2-[2-Methoxy-5-(4-morpholinylsulphonyl)phenyl]-5-(2-(1-ethylpyrrolidinyl))-1H-pyrrole; 2-[2-Methoxy-4-methyl-5-(4-morpholinylsulphonyl)phenyl]-5-(2-(1-ethylpyrrolidinyl))-1H-pyrrole;

or a salt thereof.

6. A process for preparing a compound of formula (I) which process comprises : The present invention also provides a process for preparing compounds of formula (I) which process comprises :

(a) to prepare a compound of formula (I) wherein Y is a group (a) or (e) in which R⁸, R⁹, R¹⁸ and R¹⁹ are hydrogen or wherein Y is a group (d) carrying out a Mannich reaction with a compound of formula (II) :

and an amine of formula (III), (V) or (IV) respectively:

HNR¹⁰R¹¹

Formula (III)

in the presence of formaldehyde;

(b) to prepare a compound wherein Y is a group (a) wherein at least one of R⁸ and R⁹ is hydrogen, a group (e) wherein at least one of R¹⁸ and R¹⁹ is hydrogen, or a group of formula (b), (c) or (d) carrying out a Vilsmeier reaction with a compound of formula (II) and an amide of formula (VI), (VIII) or (VII):

R⁸C(O)NR¹⁰R¹¹

Formula (VI)

or the appropriate oxo derivative of group (b) or (c) respectively, and reducing the intermediate product with, for example, sodium borohydride or cyanoborohydride;

(c) to prepare a compound wherein Y is a group (a) or (e) in which R⁸, R⁹, R¹⁸ and R¹⁹ are hydrogen or Y is a group (d) reductive amination of a compound of formula (IX) :

with an amine of formula (IIl), (V) or (IV) respectively;

and optionally thereafter forming a salt of formula (I).

7. A method of treating a condition which requires modulation of a dopamine receptor which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) or a physiologically acceptable salt thereof.

8. A method wherein the dopamine receptor is a dopamine D₃ receptor.

9. A method according to claim 7 or claim 8 wherein a dopamine antagonist is required.

10. A method according to any of claims 7 to 9 wherein the condition is a psychotic condition.

11. The use of a compound of formula (I) or a physiologically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition which requires modulation of a dopamine receptor.

12. A pharmaceutical composition comprising a compound of formula (I) or a physiologically acceptable salt thereof and a physiologically acceptable carrier.

13. A novel intermediate selected from formula (II), (IX) and (X).