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WO1997000243A1 - 5-aminoalkyl-2-(2-alkoxyphenyl)-pyrrole derivatives having affinity for dopamine d3 receptors and their use in the treatment of psychoses - Google Patents

5-aminoalkyl-2-(2-alkoxyphenyl)-pyrrole derivatives having affinity for dopamine d3 receptors and their use in the treatment of psychoses Download PDF

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Publication number
WO1997000243A1
WO1997000243A1 PCT/EP1996/002498 EP9602498W WO9700243A1 WO 1997000243 A1 WO1997000243 A1 WO 1997000243A1 EP 9602498 W EP9602498 W EP 9602498W WO 9700243 A1 WO9700243 A1 WO 9700243A1
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Prior art keywords
group
formula
optionally substituted
galkyl
compound
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French (fr)
Inventor
Eric Alfred Watts
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SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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Priority to EP96920811A priority Critical patent/EP0832064A1/en
Priority to JP9502608A priority patent/JPH11507657A/en
Publication of WO1997000243A1 publication Critical patent/WO1997000243A1/en
Anticipated expiration legal-status Critical
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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
    • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • 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.
  • Schizophrenia is a devastating neurological disease for which there is currently no cure, although advances are now being made in understanding its causes and controlhng its symptoms. In general the age of onset is in late adolescence and it is a lifelong illness with a very poor prognosis. Subjects suffering from schizophrenia may exhibit positive symptoms, for example delusions and hallucinations, and /or negative symptoms such as withdrawal, isolation and demotivation leading ultimately to social decline and suicide. Since the 1950's antipsychotic drugs (neuroleptics) have been available and are used with varying degrees of success to treat the positive symptoms of schizophrenia.
  • EPA241053 and EPA259930 describe a variety of 2-(substituted phenyl)-5- (substituted piperidinylalkyl, piperazinylalkyl or pyrrolidinyl)-pyrroles, which compounds are said to have antipsychotic properties.
  • WO94/03426, WO95/00508, WO94/24129, WO95/04037, WO95.04039 and WO95/10504 describe further classes of 2- (substituted aryl)-5-substituted-pyrrole derivatives, which are said to have activity at dopamine D3 receptors.
  • Rl represents C ⁇ _4alkyl
  • R3 represents an optionally substituted phenyl group or an optionally substituted 5- or 6- membered heterocyclic aromatic group
  • R2, R 4 and R ⁇ each independently represent hydrogen, halogen; Cj galkyl; C _4--lkoxy; C ⁇ _4alkoxyC ⁇ .4alkyl; C _4alkylsulphonyl; trifluoromethylsulphonyl; optionally substituted arylsulphonyl; optionally substituted heteroarylsulphonyl; optionally substituted aralkylsulphonyl; optionally substituted heteroaralkylsulphonyl; nitro; cyano; amino; mono- or di-C gall y lamino; trifluoromethyl; trifluoromethoxy; hydroxyl; hydroxyC galkyl; C ⁇ _4alkylthio; C ⁇ _4alkanoyl Ci ⁇ alkoxycarbonyl; a sulphonate group of formula R ⁇ OSO2 wherein R ⁇ is an optionally substituted aryl or optionally substituted heteroaryl group; or a group wherein R > and l each independently represent hydrogen
  • R represents a group (R a )n-( Ar)-(CH2)j- wherein Ar represents phenyl, naphthyl, a 5- or 6-membered heterocyclic aryl group, or a 5- or 6-membered heterocyclic aryl group fused to a phenyl ring; j represents zero or an integer from 1-4; R a represents a substituent selected from halogen, C galkyl, C ⁇ _4alkoxy, C ⁇ _4-dkoxyC galkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, hydroxyC 1.4-dkyl, C ⁇ _4alkanoyl, C ⁇ _4alkoxycarbonyl, amino, mono- or -di-C ⁇ .4--lkylamino, C ⁇ _4alkylthio, C ⁇ _4a-kylsulphinyl, C ⁇ _4alkylsulphonyl and phenylC .4a
  • Y represents a group selected from (a) - (e):
  • R9 and R*0 independently represent hydrogen, Ci.galkyl, optionally substituted arylCi. galkyl or optionally substituted heteroaiylCi. galkyl; RU represents Ci.galkyl, C3_galkenyl or C3_gcycloalkylC galkyl; and
  • Rl2 represents Ci.galkyl; C3_galkenyl; C3_gcycloalkylC galkyl, optionally substituted arylC ⁇ _4a-kyl or optionally substituted heteroarylC ⁇ _4alkyl; or jsjRl 1R12 forms a heterocyclic ring; in group (b) :
  • R*3 represents Ci.galkyl; C3_galkenyl; C3_gcycloalkylC galkyl , optionally substituted arylC ⁇ .4--lkyl or optionally substituted heteroarylC galkyl; and q is 1 to 4; in group (c): Rl 4 and R ⁇ independently represent hydrogen, Ci.galkyl, optionally substituted arylCi.
  • R1 S R20 a- ⁇ R21 eacn independently represent hydrogen, halogen, C ⁇ _4alkyl, C ⁇ _4alkoxy, C ⁇ .4alko yC ⁇ _4alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, hydroxyalkyi, C ⁇ _4alkanoyl, C 1 _4alkoxycarbonyl, amino or mono- or - dialkylamino;
  • X is CH2, S or O; t is zero, 1 or 2; and salts thereof.
  • 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.
  • heterocyclic aryl group may contain one or more, e.g. 1, 2, 3, or 4 heteroatoms selected from oxygen, sulphur or nitrogen. Suitable examples thus include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazyl, pyrimidyl and pyrazolyl.
  • a heterocyclic aryl group Ar contains from 1 to 3 heteroatoms.
  • aryl groups or moieties present in any of the other substituents R 2 , R 3 , R 4 , R5, R9, RIO, RI ⁇ R 13 ⁇ R 14 f R15 and R 16 in compounds of formula (I) include phenyl, naphthyl, and tetrahydronaphthyl.
  • 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 galkyl, C ⁇ _4alkoxy, C ⁇ _4alkoxyC galkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, hydroxyC galkyl, C ⁇ _4-tlkanoyl, C ⁇ _4alkoxycarbonyl, amino and mono- or di-C ⁇ _4alkylamino.
  • a nitrogen atom present in a heteroaryl ring as defined above may carry a hydrogen atom, or an appropriate substituent selected from those defined above e.g.C galkyl.
  • Rl preferably represents methyl, ethyl or isopropyl, most preferably methyl or ethyl.
  • R 3 preferably represents optionaUy substituted phenyl.
  • suitable substituents include halogen, C1.4a.kyl, C ⁇ _4alkoxy, C ⁇ _4alkoxyC ⁇ _4alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, hydroxyC ⁇ _4alkyl, C ⁇ _4alkanoyl, C ⁇ _4-Ukoxycarbonyl, amino and mono- or di-C ⁇ _4a_kylamino.
  • R 3 preferably represents unsubstituted phenyl.
  • no more than one of R 2 , R 4 and R ⁇ represents a sulphonamido group
  • R6R7NSO2- When such a sulphonamide group is present it is preferably represented by R 4 .
  • R6R7N- represents a 5- to 7-membered ring fused to or substituted by an optionally substituted phenyl ring or substituted by an optionally substituted 5- or 6- membered heterocyclic ring
  • the sulphonamide group may be represented by formula (f) or (g):
  • R a and p are as hereinbefore defined;
  • Ar' represents phenyl or a 5- or 6-membered heterocyclic ring
  • R 22 represents -(CH 2 ) m - or -(CH 2 )kW(CH 2 )2-;
  • m represents zero or an integer from 1-4;
  • k represents zero or 1;
  • W represents O, S, SO, or SO2, and
  • n represents zero or an integer from 1-4; provided that in the group (f) the sum of n+m is from 2-4 and the sum of n+k is zero or 1 and in the group (g) the sum of n+m is from 3-5 and the sum of n+k is 1 or 2.
  • Ar' preferably represents phenyl.
  • m preferably represents zero or 1 and n preferably represents 2 or 3 such that the sum of n+m is 2 or 3.
  • W preferably represents O and k and n preferably each represent zero.
  • R ⁇ preferably represents hydrogen or C galkyl, e.g. methyl or ethyl.
  • R 7 is the group (R a ) p -(Ar)- (CH2)j wherein Ar preferably represents phenyl or a 5- or 6-membered heterocyclic aiyl group containing 1, 2 or 3 atoms selected from O, N and S.
  • R a preferably represents one or more substituents selected from halogen, C1.4a.koxy (e.g. methoxy), cyano, C ⁇ _4alkylthio (e.g. methylthio), C ⁇ _4- ⁇ kylsulphinyl (e.g.
  • methyl sulphinyl phenyl C ⁇ _4-tlkoxy (e.g. benzyloxy), hydroxy and C1.4a.kyl (e.g. methyl), p preferably represents zero, 1 or 2 and j preferably represents zero, 1 or 2.
  • R 4 represents an alkylsulphonyl group, eg an ethylsulphonyl group.
  • R 2 and R ⁇ preferably each represent hydrogen.
  • R ⁇ and R*0 is preferably hydrogen.
  • R ⁇ and R*0 is hydrogen and the other is selected from hydrogen, C .galkyl and optionally substituted arylC 1.galkyl.
  • - NR ⁇ R 2 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 -NR* 1R* 2 may also be bridged, for example by a C1.3alky.ene chain e.g. a methylene or ethylene group.
  • the heterocyclic ring may be substituted by one or more C galkyl groups, or fused to an aromatic ring, such as phenyl.
  • Y is a group (a) one of R" and R is hydrogen and the other represents hydrogen or Ci.galkyl; R ⁇ represents Ci.galkyl; and R 2 represents Ci.galkyl or phenyl C ⁇ _4alkyl or -NR* 1R 2 forms a 5- or 6- membered saturated heterocyclic ring.
  • q is preferably 1 or 2 and R 3 is preferably C .galkyl e.g. ethyl.
  • R 14 and R ⁇ preferably represents hydrogen.
  • R* 4 and R ⁇ is hydrogen and the other is selected from hydrogen, Ci.galkyl and optionally substituted arylCi. galkyl.
  • R* 0" preferably represents optionally substituted phenyl or optionally substituted furyl.
  • Z preferably represents (CH2) U wherein u is 3, 4 or 5.
  • R 4 and R ⁇ is hydrogen and the other is hydrogen or Ci.galkyl;
  • R*" represents phenyl or optionally substituted furyl and z represents (CH2) U where u is 3 or 5.
  • Y is a group (d) r and s preferably each independently represents 1 or 2.
  • Y is a group (a), (b) or (c), most preferably (a).
  • 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.
  • asymmetric centre 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.
  • all possible diastereomeric forms (individual diastereomers and mixtures thereof) of compounds of formula (I) are included within the scope of the invention.
  • a particular compounds according to the invention is: (R,S)-2-((5-ethylsulphonyl-2-methoxy-4-phenyl)phenyl)-5-(l-(l-piperidinyl)ethyl)-lH- pyrrole and salts thereof.
  • the present invention also provides a process for preparing compounds of formula (I) which process comprises:
  • R9 and R ⁇ is hydrogen, a group (c) wherein at least one of R ⁇ or R 15 is hydrogen, a group (e) or a group of formula (b) or (d) carrying out a Vilsmeier reaction with a compound of
  • R10 > R14 ⁇ d R15 ⁇ Q hydrogen or Y is a group (e) reductive amination of a compound of formula (IX) :
  • L is a halogen atom or trifluoromethanesulphonyloxy group
  • Rl, R 2 , R 4 , R ⁇ and Y are as hereinbefore defined, with an appropriate aryl or heteroaryl metallo derivative
  • conversion of one compound of formula ( ⁇ ) into a different compound of formula (I) e.g. oxidation of a thiol function to a sulphinyl or sulphonyl function, or hydrogenation of a benzyloxy group to hydroxy; and optionally thereafter removing any protecting groups present and/or forming a salt of formula (I).
  • the Mannich reaction according to process (a) may be effected according to conventional methods.
  • the amine of formula (III), (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.
  • the amide of formula (VI) (VII) or (VIII) or the oxo derivative of group (b) or (d) may first be reacted with phosphorus oxychloride
  • 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 reducing agent such as sodium borohydride or cyanoborohydride and in the presence of a reducing agent such as sodium borohydride or cyanoborohydride and in the presence of a reducing agent such as sodium borohydride or cyanoborohydride and in the presence of a reducing agent such as sodium borohydride or cyanoborohydride and in the presence of a reducing agent such as sodium borohydride or cyanoborohydride and in the presence of a reducing agent such as sodium borohydride or cyanoborohydride
  • Lewis acid such as titanium (TV) chloride.
  • Reaction of a compound (IX) with the amine may conveniently be effected in a solvent such as dichloromethane or dichloroethane.
  • Process (d) may be effected using an aryl or heteroaryl metallo derivative such as an arylboronic acid, arylzinc halide or aryl tr _.(alkyl)stannane in the presence of a catalyst such as tetr ⁇ / w-(triphenylphosphine)palladium (0) in a solvent such as xylene or aqueous dimethoxyethane.
  • Inter-conversions according to process (e) may be carried out using standard procedures; for example oxidation of a thiol may be effected using hydrogen peroxide.
  • Conversion of a benzyloxy group into a hydroxy group may be effected by hydrogenation eg using palladium on carbon.
  • a compound of formula (II) may be prepared by cyclisation of a dicarbonyl compound of formula (XI) :
  • the reaction may be effected using an ammonium salt, e.g. ammonium acetate, in a solvent such as ethanol.
  • an ammonium salt e.g. ammonium acetate
  • a solvent such as ethanol
  • a compound of formula (XI) may itself be prepared by reacting the appropriate substituted aroyl halide or methoxyamide of formula (XII):
  • R 23 represents a halogen atom e.g. chlorine, or a group -N(CH3)OCH3 and R*- R5 are as hereinbefore defined
  • a compound of formula (XII) wherein R 23 represents a halogen atom may be prepared from the corresponding benzoic acid using standard procedures.
  • R 23 represents -N(CH3)OCH3 such compounds may be prepared by reacting the corresponding aroyl halide or anhydride with N-(methoxy) methylamine in the presence of a base, such as triethylamine, and a solvent such as dichloromethane.
  • An anhydride may be prepared by reacting the appropriate benzoic or naphthoic acid derivative with an alkyl haloformate e.g. isobutyl chloroformate, and may conveniently be utilised in situ.
  • a compound of formula (IT) may also be prepared by reacting a halo-substituted aryl derivative of formula (XIII):
  • Hal is a halogen atom e.g. bromine
  • R 24 represents an N-protecting group, e.g. t-butoxycarbonyl
  • the reaction may be effected in a suitable solvent such as benzene, toluene, aqueous dimethoxyethane, aqueous tetrahydrofuran or dimethylformamide and in the presence of a base such as sodium carbonate, and a palladium catalyst such as Pd(PPh3)4 or palladium dibenzylidene acetone and triphenylphosphine.
  • a suitable solvent such as benzene, toluene, aqueous dimethoxyethane, aqueous tetrahydrofuran or dimethylformamide
  • a base such as sodium carbonate
  • a palladium catalyst such as Pd(PPh3)4 or palladium dibenzylidene acetone and triphenylphosphine.
  • the N-protecting group may be removed by methods well known in the art, for example a t-butoxycarbonyl group may be cleaved using sodium methoxide in tetrahydrofuran or trifluoroacetic acid in dichloromethane.
  • An amine (V) may be obtained by reductive amination of a ketone of formula (XV) :
  • a compound of formula (DC) 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 hydrolysis.
  • R 2 ⁇ represents a carboxyl group or a halogen atom e.g. bromine and R 2 ° represents optional ring substituents selected from OR*, R 2 , R 3 , R 4 and R ⁇
  • the reaction may conveniently be effected in the presence of a solvent e.g. tetrahydrofuran or water and optionally in the presence of a base.
  • a solvent e.g. tetrahydrofuran or water
  • a base e.g. tetrahydrofuran
  • an excess of the amine R ⁇ R7NH may serve as the base.
  • Compounds of formula (XVI) are known (e.g. German OLS 2,721,643) or may be prepared by standard methods.
  • a compound of formula (XVI) may also be reacted with an amine R 7 NH2 using conditions analogous to those described above and the product reacted with an alkylating agent corresponding to R", for example a halide or a tosyl derivative, in the presence of a base such as sodium hydride in a suitable solvent such as tetrahydrofuran.
  • an amine R°R 7 NH may be prepared by reaction of a primary amine (R a )p-(Ar)-(CH2)j-NH2 with an acyl halide R ⁇ COCl corresponding to R ⁇ in the presence of a base such as triethylamine and a suitable solvent e.g. dichloromethane, followed by reduction using e.g. lithium aluminium hydride in tetrahydrofuran.
  • a base such as triethylamine and a suitable solvent e.g. dichloromethane
  • the substituent R may be introduced after formation of the aryl pyrrole moiety, by reaction of a compound (XVII):
  • L is a halogen or trifluoromethanesulphonyloxy group
  • R 1 , R2 R 4 and R 5 are as hereinbefore described, with an appropriate aryl or heteroaryl metallo derivative such as an arylboronic acid, arylzinc halide or aryl- t (alkyl)stannane, in the presence of a catalyst such as tetr--i s-(triphenylphosphine)palladium (0) in a solvent such as xylene or aqueous dimethoxyethane, as described for process (d) above.
  • a catalyst such as tetr--i s-(triphenylphosphine)palladium (0)
  • solvent such as xylene or aqueous dimethoxyethane
  • groups or moieties present in any of the substituents R ⁇ to R ⁇ or in the group Y which may be sensitive to any of the reactions used in preparation of compounds (I) may be protected during the reaction by methods well known in the art and the protecting groups removed at any convenient stage of the synthesis, for example at the final stage, by standard procedures.
  • a hydroxy group may be protected as a benzyloxy group and deprotection effected by hydrogenation, eg using palladium on carbon.
  • a compound of formula (I) 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.
  • 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), (IV) or (V) may be prepared by resolving an enantiomeric mixture of the appropriate amine for example by coupling to a chiral auxiliary such as (S)-(+)- ⁇ -methoxyphenylacetic acid and separating the resulting diastereoisomers by chromatography.
  • the auxiliary moiety may be removed by standard methods to give the desired chiral amine.
  • the (S)-(+)- ⁇ -methoxyphenylacetyl moiety may be cleaved under basic conditions, preferably using methyl lithium in hexane or tetrahydrofuran.
  • Compounds of formula (I) have been found to exhibit affinity for dopamine receptors, in particular the D3 receptor, 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 cunently available antipsychotic agents 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.
  • Prefened 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.
  • 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.
  • 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.
  • the compound of formula (I) is preferably a dopamine D3 antagonist. Said compound is preferably used in the treatment of schizophrenia.
  • 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 sohds, 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 ca ⁇ ier(s) for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
  • a suitable liquid ca ⁇ ier(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.
  • suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
  • suitable pharmaceutical carrier(s) include magnesium stearate, starch, lactose, sucrose and cellulose.
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures.
  • pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule;
  • 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 pynolidone, lecithin, arachis oil or sesame oil. Altematively, the solution can be lyophihsed and then reconstituted with a suitable solvent just prior to administration.
  • a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pynolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophihsed 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.
  • 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.
  • the dosage form comprises an aerosol dispenser
  • a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluoro- chlorohydrocarbon.
  • 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.
  • 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.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more.
  • 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 (Ki) of test compounds for displacement of [ ⁇ 2 ⁇ I] iodosulpride binding to human D3 dopamine receptors expressed in CHO cells were determined as follows. 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.
  • the membrane pellet was resuspended in ice-cold 50 mM Tris salts (pH 7.4 @ 37°C), using an Ultra-Tunax, 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).
  • the compound ofExample 1 had an IC50 value of 4 nM at the human D3 receptor.
  • 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
  • Diluent e.g. Microcrystalline cellulose, lactose, starch Binder : e.g. Polyvinylpyrrolidone, hydroxypropymethylcellulose
  • Disintegrant e.g. Sodium starch giycollate, crospovidone Lubricant : e.g. Magnesium stearate, sodium stearyl fumarate.
  • 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
  • the cooled Grignard reagent (14 mmol), [prepared by adding 2-(2-bromoethyl)-l,3- dioxane (2.7 g, 14 mmol) to magnesium (0.47 g) in dry tetrahydrofuran at reflux for lh] was added dropwise at such a rate that the internal temperature was kept below -70 °C Stirring was continued at this temperature for 0.5 h and the mixture was warmed to room temperature over lh. After addition of 10 % aqueous citric acid (4 ml) the mixture was evaporated in vacuo and the residue partitioned between dichloromethane and 10 % aqueous citric acid.

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Abstract

Compounds of Formula (I) wherein R1 represents C¿1-4?alkyl; R?3¿ represents an optionally substituted phenyl group or an optionally substituted 5- or 6-membered heterocyclic aromatic group; R?2, R4 and R5¿ each independently represent hydrogen, halogen; C¿1-4?alkyl; C1-4alkoxy; C1-4alkoxyC1-4alkyl; C1-4alkylsulphonyl; trifluoromethylsulphonyl; optionally substituted arylsulphonyl; optionally substituted heteroarylsulphonyl; optionally substituted aralkylsulphonyl; optionally substituted heteroaralkylsulphonyl; nitro; cyano; amino; mono- or di-C1-4alkylamino; trifluoromethyl; trifluoromethoxy; hydroxyl; hydroxyC1-4alkyl; C1-4alkylthio; C1-4alkanoyl C1-4alkoxycarbonyl; a sulphonate group of formula R?8OSO¿2 wherein R8 is an optionally substituted aryl or optionally substituted heteroaryl group; or a group -SO¿2NR?6R7 wherein R?6 and R7¿ each independently represent hydrogen, C¿1-4?alkyl or C1-4alkoxyC1-4alkyl, or R?6¿ represents hydrogen, C¿1-6?alkyl, or C1-4alkoxyC1-4alkyl; and R?7¿ represents a group (Ra)p-(Ar)-(CH2)j- wherein Ar represents phenyl, naphthyl, a 5- or 6-membered heterocyclic aryl group, or a 5- or 6- membered heterocyclic aryl group fused to a phenyl ring; j represents zero or an integer from 1-4; Ra represents a substituent selected from halogen, C¿1-4?alkyl, C1-4alkoxy, C1-4alkoxyC1-4alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, hydroxyC1-4alkyl, C1-4alkanoyl, C1-4alkoxycarbonyl, amino, mono- or di-C1-4alkylamino, C1-4alkylthio, C1-4alkylsulphinyl, C1-4alkylsulphonyl and phenylC1-4alkoxy; and p represents zero or an integer from 1-4; or NR?6R7¿ forms a 3- to 8- membered fully saturated heterocyclic ring, a 5- to 8- membered partially saturated heterocyclic ring, a 5- to 8- membered fully saturated heterocyclic ring which contains in addition to the nitrogen atom an oxygen or sulphur atom; or a 5-7 membered heterocyclic ring which is fused to or substituted by a phenyl group, orsubstituted by a 5- or 6-membered heterocyclic aryl group, said phenyl or heteroaryl group being optionally substitued by a group (Ra)p, wherein Ra and p are as defined hereinabove; or R?1 and R2¿ together form a C¿2-4?alkyl chain, which chain may be optionally substituted by one or two C1-4alkyl groups, and R?3, R4 and R5¿ are as hereinbefore defined; and Y represents a group selected from (a) - (e) and salts thereof, are dopamine D3 antagonists with potential for the treatment of schizophrenia.

Description

5-AMINOALKYL-2-(2-ALKOXYPHENY )-PYRROLE DERIVATIVES HAVING AFFINITY FOR DOPAMINE D3 RECEPTORS AND THEIR USE IN THE TREATMENT OF PSYCHOSES
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.
Schizophrenia is a devastating neurological disease for which there is currently no cure, although advances are now being made in understanding its causes and controlhng its symptoms. In general the age of onset is in late adolescence and it is a lifelong illness with a very poor prognosis. Subjects suffering from schizophrenia may exhibit positive symptoms, for example delusions and hallucinations, and /or negative symptoms such as withdrawal, isolation and demotivation leading ultimately to social decline and suicide. Since the 1950's antipsychotic drugs (neuroleptics) have been available and are used with varying degrees of success to treat the positive symptoms of schizophrenia. However, the majority of these agents ("typical" neuroleptics) do not alleviate the negative symptoms and furthermore have a number of side effects, the most distressing of which are movement disorders known as extrapyramidal side effects (eps). Examples of typical neuroleptics include haloperidol and sulpiride. More recently second generation antipsychotic agents, so-called "atypical" neuroleptics, having enhanced efficacy and fewer extrapyramidal side effects have been developed, for example, clozapine. However, use of this drug has been severely limited by controversy over its propensity to produce neutropenia and its expense; hence it is reserved for the treatment of schizophrenia in subjects who do not respond to other neuroleptics. In addition there remains a proportion of patients who are resistant to treatment even with clozapine. There is thus a continuing need for new and improved treatments for schizophrenia.
EPA241053 and EPA259930 describe a variety of 2-(substituted phenyl)-5- (substituted piperidinylalkyl, piperazinylalkyl or pyrrolidinyl)-pyrroles, which compounds are said to have antipsychotic properties.
WO94/03426, WO95/00508, WO94/24129, WO95/04037, WO95.04039 and WO95/10504 describe further classes of 2- (substituted aryl)-5-substituted-pyrrole derivatives, which are said to have activity at dopamine D3 receptors.
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) :
Figure imgf000004_0001
Formula (I) wherein
Rl represents Cι_4alkyl; R3 represents an optionally substituted phenyl group or an optionally substituted 5- or 6- membered heterocyclic aromatic group;
R2, R4 and R^ each independently represent hydrogen, halogen; Cj galkyl; C _4--lkoxy; Cι_4alkoxyCι.4alkyl; C _4alkylsulphonyl; trifluoromethylsulphonyl; optionally substituted arylsulphonyl; optionally substituted heteroarylsulphonyl; optionally substituted aralkylsulphonyl; optionally substituted heteroaralkylsulphonyl; nitro; cyano; amino; mono- or di-C gall y lamino; trifluoromethyl; trifluoromethoxy; hydroxyl; hydroxyC galkyl; Cι_4alkylthio; Cι_4alkanoyl Ci^alkoxycarbonyl; a sulphonate group of formula R^OSO2 wherein R^ is an optionally substituted aryl or optionally substituted heteroaryl group; or a group
Figure imgf000004_0002
wherein R > and l each independently represent hydrogen, Ci _4alkyl or Ci _4alkoxyCι _4alkyl, or R6 represents hydrogen, Ci.galkyl, or C1.4alkoxyC1.4a.kyl; and
R represents a group (Ra)n-( Ar)-(CH2)j- wherein Ar represents phenyl, naphthyl, a 5- or 6-membered heterocyclic aryl group, or a 5- or 6-membered heterocyclic aryl group fused to a phenyl ring; j represents zero or an integer from 1-4; Ra represents a substituent selected from halogen, C galkyl, Cι_4alkoxy, Cι_4-dkoxyC galkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, hydroxyC 1.4-dkyl, Cι_4alkanoyl, Cι_4alkoxycarbonyl, amino, mono- or -di-Cι.4--lkylamino, Cι_4alkylthio, Cι_4a-kylsulphinyl, Cι_4alkylsulphonyl and phenylC .4a.koxy; and p represents zero or an integer from 1-4; or NR6R7 forms a 3- to 8- membered fully saturated heterocyclic ring, a 5- to 8- membered partially saturated heterocyclic ring, a 5- to 8-membered fully saturated heterocyclic ring which contains in addition to the nitrogen atom an oxygen or sulphur atom; or a 5-7 membered heterocyclic ring which is fused to or substituted by a phenyl group, or substituted by a 5- or 6-membered heterocyclic aryl group, said phenyl or heteroaryl group being optionally substituted by a group (Ra)p, wherein Ra and p are as defined hereinabove; or Rl and R2 together form a C2_4alkyl chain, which chain may be optionally substituted by one or two C galkyl groups, and R^, R4 and R^ are as hereinbefore defined;
and Y represents a group selected from (a) - (e):
Figure imgf000005_0001
(a) (b)
Figure imgf000005_0002
(c)
Figure imgf000005_0003
(d)
Figure imgf000005_0004
(e) wherein in group (a) : R9 and R*0 independently represent hydrogen, Ci.galkyl, optionally substituted arylCi. galkyl or optionally substituted heteroaiylCi. galkyl; RU represents Ci.galkyl, C3_galkenyl or C3_gcycloalkylC galkyl; and
Rl2 represents Ci.galkyl; C3_galkenyl; C3_gcycloalkylC galkyl, optionally substituted arylCι_4a-kyl or optionally substituted heteroarylCι_4alkyl; or jsjRl 1R12 forms a heterocyclic ring; in group (b) :
R*3 represents Ci.galkyl; C3_galkenyl; C3_gcycloalkylC galkyl , optionally substituted arylCι.4--lkyl or optionally substituted heteroarylC galkyl; and q is 1 to 4; in group (c): Rl4 and R^ independently represent hydrogen, Ci.galkyl, optionally substituted arylCi. galkyl or optionally substituted heteroarylCi.galkyl; Rl" 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; in group (d) each of r and s independently represents an integer from 1 to 3; and in group (e) R1? represents Ci.galkyl, C3_galkenyl or C3.gcycl0a.kylC galkyl; and R!8, R1 S R20 a-^ R21 eacn independently represent hydrogen, halogen, Cι_4alkyl, Cι_4alkoxy, Cι.4alko yCι_4alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, hydroxyalkyi, C ι_4alkanoyl, C 1 _4alkoxycarbonyl, amino or mono- or - dialkylamino; X is CH2, S or O; t is zero, 1 or 2; 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.
When Ar represents a 5- or 6- membered heterocyclic aryl ring or such a ring fused to phenyl the heterocyclic ring or moiety may contain one or more, e.g. 1, 2, 3, or 4 heteroatoms selected from oxygen, sulphur or nitrogen. Suitable examples thus include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazyl, pyrimidyl and pyrazolyl. Preferably a heterocyclic aryl group Ar contains from 1 to 3 heteroatoms. Representative aryl groups or moieties present in any of the other substituents R2, R3, R4, R5, R9, RIO, RI^ R13} R14f R15 and R16 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 galkyl, Cι_4alkoxy, Cι_4alkoxyC galkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, hydroxyC galkyl, Cι_4-tlkanoyl, Cι_4alkoxycarbonyl, amino and mono- or di-Cι_4alkylamino. It will be appreciated that a nitrogen atom present in a heteroaryl ring as defined above may carry a hydrogen atom, or an appropriate substituent selected from those defined above e.g.C galkyl.
Rl preferably represents methyl, ethyl or isopropyl, most preferably methyl or ethyl. R3 preferably represents optionaUy substituted phenyl. When R3 represents substituted phenyl suitable substituents include halogen, C1.4a.kyl, Cι_4alkoxy, Cι_4alkoxyCι_4alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, hydroxyC ι_4alkyl, Cι_4alkanoyl, Cι_4-Ukoxycarbonyl, amino and mono- or di-Cι_4a_kylamino. R3 preferably represents unsubstituted phenyl. Suitably, no more than one of R2, R4 and R^ represents a sulphonamido group
R6R7NSO2-. When such a sulphonamide group is present it is preferably represented by R4.
When R6R7N- represents a 5- to 7-membered ring fused to or substituted by an optionally substituted phenyl ring or substituted by an optionally substituted 5- or 6- membered heterocyclic ring the sulphonamide group may be represented by formula (f) or (g):
(R ). NS02- (R )p-(Ar')— ^ / NSO, (CH2)n
(f) (9)
wherein Ra and p are as hereinbefore defined;
Ar' represents phenyl or a 5- or 6-membered heterocyclic ring; R22 represents -(CH2)m- or -(CH2)kW(CH2)2-; m represents zero or an integer from 1-4; k represents zero or 1; W represents O, S, SO, or SO2, and n represents zero or an integer from 1-4; provided that in the group (f) the sum of n+m is from 2-4 and the sum of n+k is zero or 1 and in the group (g) the sum of n+m is from 3-5 and the sum of n+k is 1 or 2.
In the group (g) Ar' preferably represents phenyl. In the group (f) when R22 represents -(CH2)m-, m preferably represents zero or 1 and n preferably represents 2 or 3 such that the sum of n+m is 2 or 3. When R22 represents -(CH2)kW(CH2)2-, W preferably represents O and k and n preferably each represent zero. When R^R N- represents a 5-7 membered ring, fused sulphonamides containing the group (f) are generally preferred.
When R6R7NSO2- represents an acyclic sulphonamide group, R^ preferably represents hydrogen or C galkyl, e.g. methyl or ethyl. R7 is the group (Ra)p -(Ar)- (CH2)j wherein Ar preferably represents phenyl or a 5- or 6-membered heterocyclic aiyl group containing 1, 2 or 3 atoms selected from O, N and S. Ra preferably represents one or more substituents selected from halogen, C1.4a.koxy (e.g. methoxy), cyano, Cι_4alkylthio (e.g. methylthio), Cι_4-ϋkylsulphinyl (e.g. methyl sulphinyl), phenyl Cι_4-tlkoxy (e.g. benzyloxy), hydroxy and C1.4a.kyl (e.g. methyl), p preferably represents zero, 1 or 2 and j preferably represents zero, 1 or 2.
Suitably R4 represents an alkylsulphonyl group, eg an ethylsulphonyl group. R2 and R^ preferably each represent hydrogen.
When Y is a group (a) at least one of R^ and R*0 is preferably hydrogen. Suitably one of R^ and R*0 is hydrogen and the other is selected from hydrogen, C .galkyl and optionally substituted arylC 1.galkyl. When - NR ^ R 2 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 -NR* 1R*2 may also be bridged, for example by a C1.3alky.ene chain e.g. a methylene or ethylene group. Furthermore, the heterocyclic ring may be substituted by one or more C galkyl groups, or fused to an aromatic ring, such as phenyl. Most preferably, when Y is a group (a) one of R" and R is hydrogen and the other represents hydrogen or Ci.galkyl; R^ represents Ci.galkyl; and R 2 represents Ci.galkyl or phenyl Cι_4alkyl or -NR* 1R 2 forms a 5- or 6- membered saturated heterocyclic ring.
When Y is a group (b) q is preferably 1 or 2 and R 3 is preferably C .galkyl e.g. ethyl.
When Y is a group (c) at least one of R14 and R^ preferably represents hydrogen. Suitably one of R*4 and R^ is hydrogen and the other is selected from hydrogen, Ci.galkyl and optionally substituted arylCi. galkyl. R*0" 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 R 4 and R^ is hydrogen and the other is hydrogen or Ci.galkyl; R*" represents phenyl or optionally substituted furyl and z represents (CH2)U where u is 3 or 5.
When Y is a group (d) r and s preferably each independently represents 1 or 2. Advantageously Y is a group (a), (b) or (c), most preferably (a).
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.
A particular compounds according to the invention is: (R,S)-2-((5-ethylsulphonyl-2-methoxy-4-phenyl)phenyl)-5-(l-(l-piperidinyl)ethyl)-lH- 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 (c) in which R9, R10 , Rl4 and R^ are hydrogen or wherein Y is a group (e) carrying out a Mannich reaction with a compound of formula (II) :
Figure imgf000010_0001
Formula π
and an amine of formula (IH) (TV) or (V):
16
H R \ /
HN
HNR11R12
Formula (HI) Formula (IV)
Figure imgf000010_0002
Formula (V) in the presence of formaldehyde;
(b) to prepare a compound wherein Y is a group (a) wherein at least one of
R9 and R^ is hydrogen, a group (c) wherein at least one of R ^ or R 15 is hydrogen, a group (e) or a group of formula (b) or (d) carrying out a Vilsmeier reaction with a compound of
Figure imgf000010_0003
Formula (VI) Formula (VII)
Figure imgf000011_0001
Formula (Vm) or the appropriate oxo derivative of group (b) or (d) 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 (c) in which R^,
R10> R14 ^d R15 ^Q hydrogen or Y is a group (e) reductive amination of a compound of formula (IX) :
Figure imgf000011_0002
Formula IX with an amine of formula (HI) (IV) or (V);
(d) reacting a compound of formula (X) :
Figure imgf000011_0003
Formula (X)
wherein L is a halogen atom or trifluoromethanesulphonyloxy group, and Rl, R2, R4, R^ and Y are as hereinbefore defined, with an appropriate aryl or heteroaryl metallo derivative; (e) conversion of one compound of formula (ϊ) into a different compound of formula (I) e.g. oxidation of a thiol function to a sulphinyl or sulphonyl function, or hydrogenation of a benzyloxy group to hydroxy; and optionally thereafter removing any protecting groups present and/or 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 (III), (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 (d) may first be reacted with phosphorus oxychloride
(POCI3) 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 (TV) chloride. Reaction of a compound (IX) with the amine may conveniently be effected in a solvent such as dichloromethane or dichloroethane.
Process (d) may be effected using an aryl or heteroaryl metallo derivative such as an arylboronic acid, arylzinc halide or aryl tr _.(alkyl)stannane in the presence of a catalyst such as tetrα/ w-(triphenylphosphine)palladium (0) in a solvent such as xylene or aqueous dimethoxyethane. Inter-conversions according to process (e) may be carried out using standard procedures; for example oxidation of a thiol may be effected using hydrogen peroxide.
Conversion of a benzyloxy group into a hydroxy group may be effected by hydrogenation eg using palladium on carbon.
A compound of formula (II) may be prepared by cyclisation of a dicarbonyl compound of formula (XI) :
Figure imgf000013_0001
Formula XI
The reaction may be effected using an ammonium salt, e.g. ammonium acetate, in a solvent such as ethanol. (See, for example, CG. Kruse et al., Heterocycles, vol 26, P3141, 1987).
A compound of formula (XI) may itself be prepared by reacting the appropriate substituted aroyl halide or methoxyamide of formula (XII):
Figure imgf000013_0002
Formula (Xu)
(wherein R23 represents a halogen atom e.g. chlorine, or a group -N(CH3)OCH3 and R*- R5 are as hereinbefore defined)
with a metallo derivative of a 2-(2-haloethyl)-l,3-dioxolane or 2-(2-haloethyl)-l,3-dioxane and subsequent acid hydrolysis.
A compound of formula (XII) wherein R23 represents a halogen atom may be prepared from the corresponding benzoic acid using standard procedures. When R23 represents -N(CH3)OCH3 such compounds may be prepared by reacting the corresponding aroyl halide or anhydride with N-(methoxy) methylamine in the presence of a base, such as triethylamine, and a solvent such as dichloromethane. An anhydride may be prepared by reacting the appropriate benzoic or naphthoic acid derivative with an alkyl haloformate e.g. isobutyl chloroformate, and may conveniently be utilised in situ.
A compound of formula (IT) may also be prepared by reacting a halo-substituted aryl derivative of formula (XIII):
Figure imgf000014_0001
Formula (XIII)
(wherein Hal is a halogen atom e.g. bromine)
with an N-protected pyrrole derivative of formula (XIV):
Figure imgf000014_0002
Formula (XIV)
(wherein R24 represents an N-protecting group, e.g. t-butoxycarbonyl), followed by removal of the protecting group R24. The reaction may be effected in a suitable solvent such as benzene, toluene, aqueous dimethoxyethane, aqueous tetrahydrofuran or dimethylformamide and in the presence of a base such as sodium carbonate, and a palladium catalyst such as Pd(PPh3)4 or palladium dibenzylidene acetone and triphenylphosphine.
The N-protecting group may be removed by methods well known in the art, for example a t-butoxycarbonyl group may be cleaved using sodium methoxide in tetrahydrofuran or trifluoroacetic acid in dichloromethane.
Compounds of formulae OHI) and (TV) are available commercially or may be prepared by standard methods.
An amine (V) may be obtained by reductive amination of a ketone of formula (XV) :
Figure imgf000015_0001
Formula (XV) with an amine R17NH2, tne 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 (VII) wherein R^ and R 14 respectively are other than hydrogen may be prepared by acylation ofthe appropriate amine of formula (III) or (IV) for example using the corresponding acyl halide.
Compounds of formula (VI), and (VII) wherein and R14 respectively represent hydrogen, as well as compounds of formula (VΙII)may be prepared by reacting the appropriate amine of formula (III), (IV) or (V) with a formylating agent, for example acetic anhydride in formic acid.
A compound of formula (DC) 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 hydrolysis.
Substituents ORl to R^ may be introduced at any appropriate stage of the synthesis, using methods known in the art. Thus, for example the substituent R6R7 SO2- may be formed by reaction of a compound of formula (XVI):
Figure imgf000015_0002
Formula (XVI)
(wherein R2^ represents a carboxyl group or a halogen atom e.g. bromine and R2° represents optional ring substituents selected from OR*, R2, R3, R4 and R^)
with an amine R6R7NH
The reaction may conveniently be effected in the presence of a solvent e.g. tetrahydrofuran or water and optionally in the presence of a base. Advantageously an excess of the amine R^R7NH may serve as the base. Compounds of formula (XVI) are known (e.g. German OLS 2,721,643) or may be prepared by standard methods.
To prepare compounds where R" is other than hydrogen, a compound of formula (XVI) may also be reacted with an amine R7NH2 using conditions analogous to those described above and the product reacted with an alkylating agent corresponding to R", for example a halide or a tosyl derivative, in the presence of a base such as sodium hydride in a suitable solvent such as tetrahydrofuran.
When R7 represents a group (Ra)p-(Ar)-(CH2)j- wherein j represents zero and R6 represents Ci.galkyl or C .4alkoxyC1.4a.kyl, an amine R6R7NH may be prepared by reacting the corresponding primary amine (Ra)p-(Ar)-NH2 with an orthoester of R^, R^C(OEt)3 in the presence of an acid catalyst such as trifluoroacetic acid, and subsequently reducing the resulting imidate ester derivative (Ra)p-(Ar)N=C(R)OEt with sodium borohydride in ethanol. Alternatively, when n represents zero or 1 to 4 an amine R°R7NH may be prepared by reaction of a primary amine (Ra)p-(Ar)-(CH2)j-NH2 with an acyl halide R^COCl corresponding to R \ in the presence of a base such as triethylamine and a suitable solvent e.g. dichloromethane, followed by reduction using e.g. lithium aluminium hydride in tetrahydrofuran.
3 The substituent R may be introduced after formation of the aryl pyrrole moiety, by reaction of a compound (XVII):
Figure imgf000016_0001
Formula (XVII)
wherein L is a halogen or trifluoromethanesulphonyloxy group, and R 1 , R2 R 4 and R 5 are as hereinbefore described, with an appropriate aryl or heteroaryl metallo derivative such as an arylboronic acid, arylzinc halide or aryl- t (alkyl)stannane, in the presence of a catalyst such as tetr--i s-(triphenylphosphine)palladium (0) in a solvent such as xylene or aqueous dimethoxyethane, as described for process (d) above.
If necessary, groups or moieties present in any of the substituents R^ to R^ or in the group Y which may be sensitive to any of the reactions used in preparation of compounds (I) may be protected during the reaction by methods well known in the art and the protecting groups removed at any convenient stage of the synthesis, for example at the final stage, by standard procedures. Thus for example a hydroxy group may be protected as a benzyloxy group and deprotection effected by hydrogenation, eg using palladium on carbon.
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.
Altematively 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), (IV) or (V) 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 by standard methods to give the desired chiral amine. Thus for example the (S)-(+)-α-methoxyphenylacetyl moiety may be cleaved under basic conditions, preferably using methyl lithium in hexane or tetrahydrofuran. Compounds of formula (I) have been found to exhibit affinity for dopamine receptors, in particular the D3 receptor, 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 cunently 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). Prefened 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 the above embodiments the compound of formula (I) is preferably a dopamine D3 antagonist. Said compound is preferably used in the treatment of 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 sohds, 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 caπier(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; altematively, 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 pynolidone, lecithin, arachis oil or sesame oil. Altematively, the solution can be lyophihsed 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. Altematively 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 fluoro- chlorohydrocarbon. 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. 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 (Ki) of test compounds for displacement of [^2^I] iodosulpride binding to human D3 dopamine receptors expressed in CHO cells were determined as follows. 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-Tunax 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-Tunax, 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 [l^I] 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 (Canbena 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.
The compound ofExample 1 had an IC50 value of 4 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 giycollate, 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 - O 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
The invention is further illustrated by the following non-limiting examples :
Description 1
4-Bromo-5-ethyIsulphonyl-2-methoxybenzoic acid (Dl)
(a) Chlorosulphonic acid (14 ml) was added dropwise at room temperature over 2h to a stined suspension of sodium chloride (5 g) and 4-bromo-2-methoxybenzoic acid (10.0 g,
0.043 mol) (prepared as described by F.C. Chen and CT. Chang in J. Chem. Soc. 1958, 146). The reaction mixture was stined at 40 °C for lh, then heated to 65 °C overnight. The cooled mixture was poured into ice/water and allowed to stand for lh. The resultant suspension was filtered and the solid washed with pentane and dried in vacuo to give 4- bromo-5-chlorosulphonyl-2-methoxybenzoic acid (11.4 g, 80 %).
(b) 4-Bromo-5-chlorosulphonyl-2-methoxybenzoic acid (8.5 g, 0.026 mol) was added to a mixture of sodium sulphite (4.5 g, 0.036 mol) and sodium bicarbonate (6.6 g, 0.078 mol) in water (40 ml) at 75 °C The mixture was maintained at 70 - 80 °C for 3h, allowed to cool to 50 °C then treated with methanol (16 ml) and iodoethane (6 ml). The mixture was heated to 65 °C for 18 h, cooled and concentrated in vacuo. The oily aqueous mixture was extracted with chloroform (3 100ml). The combined organic extracts were dried over sodium sulphate, filtered and evaporated in vacuo to give the ethyl ester of the title compound (0.9 g, 10 %) as a low melting solid and the aqueous layer was acidified with dilute hydrochloric acid to give the titie compound (4.6 g; 55 %) as colourless microcrystals.
1H NMR (de-DMSO) 6: 1.13 (3H, t, J=7Hz), 3.48 (2H, q, J=7Hz), 3.95 (3H, s), 7.65 (IH, s), 8.29 (IH, s).
Description 2 2-(2-(4-Bromo-5-ethylsulphonyl-2-methoxybenzoyl)ethyl)-l,3-dioxane (D2)
To a solution of 4-bromo-5-ethylsulphonyl-2-methoxybenzoic acid (Dl, 4.6 g, 14 mmol) in dichloromethane (114 ml) was added oxalyl chloride (2.08 ml) followed by two drops of dimethylformamide. This mixture was stined at room temperature under argon for 18 h, then evaporated in vacuo and the residue azeotroped with toluene. The crude acid chloride was dissolved in dry tetrahydrofuran (94 ml) under argon and cooled to -78 °C. The cooled Grignard reagent (14 mmol), [prepared by adding 2-(2-bromoethyl)-l,3- dioxane (2.7 g, 14 mmol) to magnesium (0.47 g) in dry tetrahydrofuran at reflux for lh] was added dropwise at such a rate that the internal temperature was kept below -70 °C Stirring was continued at this temperature for 0.5 h and the mixture was warmed to room temperature over lh. After addition of 10 % aqueous citric acid (4 ml) the mixture was evaporated in vacuo and the residue partitioned between dichloromethane and 10 % aqueous citric acid. The organic layer was separated, washed with 2 % aqueous sodium hydroxide, then brine, dried (sodium sulphate) and evaporated in vacuo. Chromatography on silica with 20 - 50 % ethyl acetate in n-pentane as eluant gave the title compound as a colourless oil (2.44 g, 41%).
1H NMR (CDC13) δ: 1.20 - 1.39 (4H, m), 1.92 - 2.08 (3H, ), 3.04 (2H, t, J=8),
3.41 (2H, q, J=8), 3.75 (2H, dt, J=13, J=3), 4.00 (3H, s), 4.03 - 4.16 (2H, m), 4.63 (IH, t, J=5), 7.31 (IH, s), 8.39 (IH, s).
Description 3
2-(4-Bromo-5-ethylsulphonyI-2-methoxyphenyl)-lH-pyrrole (D3)
2-(2-(4-Bromo-5-ethylsulphonyl-2-methoxybenzoyl)ethyl)-l,3-dioxane (D2, 2.44 g, 5.8 mmol) was dissolved in warm glacial acetic acid (18 ml) under argon and a solution of ammonium acetate (3.91 g) in water (3.6 ml) added dropwise. The mixture was heated at reflux for 1.25 h. After cooling, further ammonium acetate (3.91 g) was added before heating at reflux for another 1.25 h. The reaction mixture was allowed to cool and evaporated in vacuo. The residue was partitioned between dichloromethane and saturated aqueous potassium carbonate, and the organic phase washed with further potassium carbonate, then brine and dried (sodium sulphate). Removal of solvent in vacuo and trituration of the residue with ether gave the title compound as a cream coloured solid (1.38 g, 69 %).
1H NMR (CDC13) 6: 1.27 (3H, t, J=7), 3.42 (2H, q, J=7), 4.04 (3H, s), 6.29 - 6.34 (IH, m), 6.74 - 6.79 (IH, m), 6.89 - 6.94 (IH, m), 7.26 (IH, s), 8.34 (IH, s), 9.57 - 9.71 (IH, broad s).
Description 4 2-((5-EthylsulphonyI-2-methoxy-4-phenyl)phenyl)-lH-pyrroIe (D4) To a solution of 2-(4-bromo-5-ethylsulphonyl-2-methoxyphenyl)- IH-pynole (D3, 0.34 g, 1 mmol) and phenylboronic acid (0.14 g, 1.21 mmol) in 1,2-dimethoxy ethane (5 ml) was added aqueous sodium carbonate (1.7 ml of 2M solution) followed by tetrfl/ w(triphenylphosphine) palladium (0) (0.05 g). This mixture was heated at reflux under argon for 3.75 h. After being allowed to cool the mixture was acidified with 5M HCl and extracted with ethyl acetate. The organic phase was washed with brine, dried (Na2SO4) and evaporated in vacuo. Chromatography on silica with 20 - 40 % ethyl acetate in n-pentane as eluant gave the title compound as a yellow solid (0.28 g, 82 %). 1H NMR (CDCI3) δ: 1.02 (3H, t, J=8), 2.61 (2H, q, J=8), 4.00 (3H, s), 6.28 - 6.36 (IH, m), 6.77 - 6.84 (IH, m), 6.84 - 6.94 (2H, m), 7.39 - 7.53 (5H, m), 8.42 (IH, s), 9.66 - 9.84 (IH, broad s).
Example 1
(R,S)-2-((5-Ethylsulphonyl-2-methoxy-4-phenyl)phenyl)-5-(l-(l-piperidinyl)ethyl)- lH-pyrrole (El) Phosphorous oxychloride (0.12 ml) was added to N-acetyl piperidine (0.11 g, 0.9 mmol) under argon at 0 °C The mixture was stined for lh at room temperature, then diluted with 1,2-dichloroethane (12 ml), cooled to 5 °C and a solution of the pynole (D4, 0.28 g, 0.8 mmol) in 1,2-dichloroe thane (6 ml) added. The reaction mixture was stined at room temperature for 60 h. Sodium borohydride (0.22 g) was added and the mixture stined for a futher lh, then cooled 5 °C and methanol (2.4 ml) added dropwise. After warming to room temperature the reaction mixture was partitioned between dichloromethane and saturated aqueous potassium carbonate. The organic layer was dried (Na2SO4) and evaporated in vacuo to give an oil. Clrnmatography on silica using 2 - 5 % methanol in dichloromethane as eluant gave an oil which was triturated with ether to afford the title compound as an off-white powder, (0.14 g, 38%). m.p. 132-4°C 1H NMR (CDCI3) δ: 1.03 (3H, t, J=8), 1.37 (3H, d, J=6), 1.4 - 1.68 (6H, broad m),
2.36 - 2.54 (4H, broad m), 2.63 (2H, q, J=8), 3.83 (IH, q, J=6), 4.00 (3H, s), 6.02 - 6.10 (IH, m), 6.68 - 6.77 (IH, m), 6.86 (IH, s), 7.35 - 7.52 (5H, m), 8.38 (IH, s), 9.92 - 10.08 (IH, broad s).

Claims

Claims :
1. A compound of formula (I)
Figure imgf000026_0001
Formula (I) wherein
R1 represents C galkyl;
R3 represents an optionally substimted phenyl group or an optionally substituted 5- or 6- membered heterocyclic aromatic group; R2, R4 and R^ each independently represent hydrogen, halogen; C galkyl; C .4alkoxy; Cι_4alkoxyCι.4alkyl; Cι_4alkylsulphonyl; trifluoromethylsulphonyl; optionally substituted arylsulphonyl; optionally substituted heteroarylsulphonyl; optionally substituted aralkylsulphonyl; optionally substituted heteroaralkylsulphonyl; nitro; cyano; amino; mono- or di-Cι_4alky lamino; trifluoromethyl; trifluoromethoxy; hydroxyl; hydroxyC i _4alkyl; C i _4alkylthio; C i _4alkanoyl C .4alkoxycarbonyl; a sulphonate group of formula R^OSO2 wherein R is an optionally substituted aryl or optionally substituted heteroaryl group; or a group -SO2NR6R7 wherein R > and R7 each independently represent hydrogen, Cι_4alkyl or Cι_4alkoxyC galkyl, or R^ represents hydrogen, Ci.galkyl, or Cι.4alkoxyCι.4--lkyl; and
R7 represents a group (Ra)p-( Ar)-(CH2)j- wherein Ar represents phenyl, naphthyl, a 5- or 6-membered heterocyclic aryl group, or a 5- or 6-membered heterocyclic aryl group fused to a phenyl ring; j represents zero or an integer from 1-4; Ra represents a substituent selected from halogen, C galkyl, Cι_4alkoxy, Cι_4alkoxyC galkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, hydroxyC galkyl,
Cι_4alkanoyl, Cι_4alkoxycarbonyl, amino, mono- or -ch-Cι_4alkylamino, Cι_4alkylthio, Cι_4alkylsulphinyl, Cι_4alkylsulphonyl and phenylCι_4alkoxy; and p represents zero or an integer from 1-4; or NR6R7 forms a 3- to 8- membered fully saturated heterocyclic ring, a 5- to 8- membered partially saturated heterocyclic ring, a 5- to 8-membered fully saturated heterocyclic ring which contains in addition to the nitrogen atom an oxygen or sulphur atom; or a 5-7 membered heterocyclic ring which is fused to or substituted by a phenyl group, or substituted by a 5- or 6-membered heterocyclic aryl group, said phenyl or heteroaryl group being optionally substituted by a group (Ra)p, wherein Ra and p are as defined hereinabove; or Rl and R2 together form a C2_4alkyl chain, which chain may be optionally substituted by one or two C galkyl groups, and R3, R4 and R^ are as hereinbefore defined;
and Y represents a group selected from (a) - (e):
Figure imgf000027_0001
(a) (b)
Figure imgf000027_0002
(O (d)
Figure imgf000027_0003
(e) wherein in group (a) :
R9 and R*0 independently represent hydrogen, Ci.galkyl, optionally substituted arylCi .galkyl or optionally substituted heteroarylC . galkyl; Rl* represents Ci.galkyl, C3_galkenyl or C3_gcycloalkylC galkyl; and R*2 represents Ci.galkyl; C3_galkenyl; C3_gcycloalkylC galkyl, optionally substituted arylCι_4alkyl or optionally substituted heteroarylCi.4-dkyl; or NR 1R^ forms a heterocyclic ring; in group (b) :
R 3 represents Ci.galkyl; C3_galkenyl; C3_gcycloalkylC galkyl , optionally substituted arylCι_4alkyl or optionally substituted heteroarylCi.4alkyl; and q is 1 to 4; in group (c):
Rl4 and R^ independently represent hydrogen, Ci.galkyl, optionally substituted arylCi.galkyl or optionally substituted heteroarylCi. galkyl; Rl6 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; in group (d) each of r and s independently represents an integer from 1 to 3; and in group (e) R*7 represents Ci.galkyl, C3_galkenyl or C3_gcycloalkylCι.4alkyl; and R*8, R19? R20 ^^ R21 each independently represent hydrogen, halogen, Cι_4alkyl, Cι_4alkoxy, Cι_4alkoxyCι_4alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, hydroxyalkyi, C _4alkanoyl, Cι_4alkoxycarbonyl, amino or mono- or - dialkylamino; X is CH2, S or O; t is zero, 1 or 2; or a salt thereof.
2. A compound according to claim 1 wherein Rl represents methyl or ethyl.
3. A compound according to claim 1 or claim 2 wherein R3 is optionally substituted phenyl.
4. A compound according to any of claims 1 to 3 wherein Y is a group of formula (a).
5. A compound according to claim 1 which is :
(R,S)-2-((5-ethylsulphonyl-2-methoxy-4-phenyl)phenyl)-5-(l-(l-piperidinyl)ethyl)-lH- pyrrole or a salt thereof. A process for preparing a compound of formula (I) which process compnses
(a) to prepare a compound of formula (I) wherein Y is a group (a) or (c) in which R9, RlO ? R14 a^j R 15 are hydrogen or wherein Y is a group (e) carrying out a Mannich reaction with a compound of formula (II) :
Figure imgf000029_0001
Formula II
and an amine of formula (TH) (IV) or (V):
Figure imgf000029_0002
Formula (HE) Formula (IV)
Figure imgf000029_0003
Formula (V) in the presence of formaldehyde;
(b) to prepare a compound wherein Y is a group (a) wherein at least one of R and R*0 is hydrogen, a group (c) wherein at least one of R^4 or Rl5 1S hydrogen, a group (e) or a group of formula (b) or (d) carrying out a Vilsmeier reaction with a compound of formula (II) and an amide of formula (VI) (VII) or (VIII): 16
Figure imgf000030_0001
Formula (VI) Formula (VII)
Figure imgf000030_0002
Formula (VHD or the appropriate oxo derivative of group (b) or (d) 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 (c) in which R^,
R10} R14 ajyj R15 are hydrogen or Y is a group (e) reductive amination of a compound of formula (IX) :
Figure imgf000030_0003
Formula IX with an amine of formula (III) (IV) or (V);
(d) reacting a compound of formula (X) :
Figure imgf000030_0004
Formula (X) wherein L is a halogen atom or trifluoromethane-sulphonyloxy group, and R*. R2, R4, R^ and Y are as hereinbefore defined, with an appropriate aryl or heteroaryl metallo derivative;
(e) conversion of one compound of formula (I) into a different compound of formula (I); and optionally thereafter removing any protecting groups present and/or forming a salt of formula (I).
7. 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.
8. Use acording to claim 7 wherein the dopamine receptor is a dopamine D3 receptor.
9. Use according to claim 7 or claim 8 wherein a dopamine antagonist is required.
10. Use according to any of claims 7 to 9 wherein the condition is a psychotic condition.
11. 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.
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 formulae (II) and (IX).
PCT/EP1996/002498 1995-06-15 1996-06-07 5-aminoalkyl-2-(2-alkoxyphenyl)-pyrrole derivatives having affinity for dopamine d3 receptors and their use in the treatment of psychoses Ceased WO1997000243A1 (en)

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EP96920811A EP0832064A1 (en) 1995-06-15 1996-06-07 5-aminoalkyl-2-(2-alkoxyphenyl)-pyrrole derivatives having affinity for dopamine d3 receptors and their use in the treatment of psychoses
JP9502608A JPH11507657A (en) 1995-06-15 1996-06-07 5-Aminoalkyl-2- (2-alkoxyphenyl) -pyrrole derivatives having affinity for dopamine D3 receptors and their use in the treatment of psychosis

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WO1999034801A1 (en) * 1998-01-09 1999-07-15 Akzo Nobel N.V. Use of diphenylmethylene piperidine derivatives in the manufacture of a medicament for the treatment of depression
WO1999034799A1 (en) * 1998-01-09 1999-07-15 Akzo Nobel N.V. Use of diphenylmethylene piperidine derivatives in the manufacture of a medicament for the treatment of movement disorders
US6274593B1 (en) 1997-05-01 2001-08-14 Smithkline Beecham P.L.C. Substituted tetrahydro isoquinolines as modulators of dopamine D3 receptors
US6414154B1 (en) 1998-05-20 2002-07-02 Smithkline Beecham P.L.C. Tetraisoquinoline derivatives as modulators of dopamine D3 receptors
US6605607B1 (en) 1998-10-08 2003-08-12 Smithkline Beecham P.L.C. Tetrahydrobenzazepine derivatives useful as modulators of dopamine D3 receptors (antipsychotic agents)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6274593B1 (en) 1997-05-01 2001-08-14 Smithkline Beecham P.L.C. Substituted tetrahydro isoquinolines as modulators of dopamine D3 receptors
WO1999034801A1 (en) * 1998-01-09 1999-07-15 Akzo Nobel N.V. Use of diphenylmethylene piperidine derivatives in the manufacture of a medicament for the treatment of depression
WO1999034799A1 (en) * 1998-01-09 1999-07-15 Akzo Nobel N.V. Use of diphenylmethylene piperidine derivatives in the manufacture of a medicament for the treatment of movement disorders
US6414154B1 (en) 1998-05-20 2002-07-02 Smithkline Beecham P.L.C. Tetraisoquinoline derivatives as modulators of dopamine D3 receptors
US6605607B1 (en) 1998-10-08 2003-08-12 Smithkline Beecham P.L.C. Tetrahydrobenzazepine derivatives useful as modulators of dopamine D3 receptors (antipsychotic agents)

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JPH11507657A (en) 1999-07-06
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