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WO1997000243A1 - Derives de 5-aminoalkyle-2-(2-alkoxyphenyl)-pyrrole comportant une affinite pour des recepteurs de dopamine d3 et leur utilisation pour le traitement des psychoses - Google Patents

Derives de 5-aminoalkyle-2-(2-alkoxyphenyl)-pyrrole comportant une affinite pour des recepteurs de dopamine d3 et leur utilisation pour le traitement des 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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group
formula
optionally substituted
galkyl
compound
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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/fr
Priority to JP9502608A priority patent/JPH11507657A/ja
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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

La présente invention se rapporte à des composés de formule (I), dans laquelle R1 représente alkyle C¿1-4; R?3 représente optionnellement un groupe phényle substitué ou un groupe aromatique hétérocyclique à 5 ou 6 membres optionnellement substitué; R?2, R4 et R5¿ représentent chacun indépendamment hydrogène, halogène; alkyle C¿1-4?; alkoxy C1-4; alkoxy C1-4alkyle C1-4; alkyle C1-4sulfonyle; trifluorométhylsulfonyle; arylsulfonyle optionnellement substitué; hétéroarylsulfonyle optionnellement substitué; aralkylsulfonyle optionnellement substitué; hétéroaralkylsulfonyle optionnellement substitué; nitro; cyano; amino; mono- ou bi-alkyle C1-4amino; trifluorométhyle; trifluorométhoxy; hydroxyle; hydroxyalkyle C1-4; alkyle C1-4thio; alcanoyle C1-4alkoxy C1-4carbonyle; un groupe sulfonate de formule R?8OSO¿2, dans lequel R8 est un aryle optionnellement substitué ou un groupe hétéroalkyle optionnellement substitué; ou un groupe -SO¿2NR?6R7 dans lequel R6 et R7 représentent chacun indépendamment hydrogène, alkyle C¿1-4? ou alkoxy C1-4alkyle 1-4, ou R?6¿ représente hydrogène, alkyle C¿1-4? ou alkoxy C1-4 ou alkoxy C1-4alkyle C1-4; et R?7¿ représente un groupe (Ra)p-(Ar)-(CH2)1-dans lequel Ar représente phényle, naphtyle, un groupe hétérocyclique à 5 ou 6 membres, ou un groupe hétérocyclique à 5 ou 6 membres condensé avec un noyau phényle; j représente zéro ou un nombre entier de 1 à 4; Ra représente un substituant choisi parmi halogène, alkyle C¿1-4?, alkoxy C1-4, alkoxy C1-4alkyle C1-4, nitro, cyano, trifluorométhyle, trifluorométhoxy, hydroxy, hydroxyalkyle C1-4, alcanoyle C1-4, alkoxy C1-4carbonyle, amino, mono ou bi-alkyle C1-4amino, alkyle C1-4thio, alkyle C1-4sulfinyle, alkyle C1-4sulfonyle et phénylalkoxy C1-4; et p vaut zéro ou un nombre entier entre 1 et 4; ou NR?6R7¿ forment un cycle hétérocyclique totalement saturé de 3 à 8 membres, un cycle hétérocyclique partiellement saturé de 5 à 8 membres, un cycle hétérocyclique totalement saturé de 5 à 8 membres contenant en plus de l'atome d'azote un atome d'oxygène ou de soufre; ou un cycle hétérocyclique de 5 à 7 membres qui est condensé ou substitué par un groupe phényle, ou substitué par un groupe aryle hétérocyclique de 5 ou 6 membres, ledit groupe phényle ou hétéroaryle étant substitué optionnellement par un groupe (Ra)p, dans lequel Ra et p sont tels que définis ci-dessus; ou R1 et R2 forment ensemble une chaîne alkyle C¿2-4?, laquelle chaîne pouvant être substituée optionnellement par un ou deux groupe alkyle C1-4, et R?3, R4 et R5¿ sont tels que définis ci-dessus; et Y représente un groupe choisi parmi (a) - (e) et leurs sels, lesdits composés de formule (I) étant des antagonistes de la dopamine D3 présentant un potentiel pour le traitement de la schizophrénie.
PCT/EP1996/002498 1995-06-15 1996-06-07 Derives de 5-aminoalkyle-2-(2-alkoxyphenyl)-pyrrole comportant une affinite pour des recepteurs de dopamine d3 et leur utilisation pour le traitement des psychoses Ceased WO1997000243A1 (fr)

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EP96920811A EP0832064A1 (fr) 1995-06-15 1996-06-07 Derives de 5-aminoalkyle-2-(2-alkoxyphenyl)-pyrrole comportant une affinite pour des recepteurs de dopamine d3 et leur utilisation pour le traitement des psychoses
JP9502608A JPH11507657A (ja) 1995-06-15 1996-06-07 ドーパミンｄ３レセプタに対する親和性を有する５−アミノアルキル−２−（２−アルコキシフェニル）−ピロール誘導体および精神病の治療におけるその使用

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Publication number Priority date Publication date Assignee Title
WO1999034801A1 (fr) * 1998-01-09 1999-07-15 Akzo Nobel N.V. Derives de diphenylmethylene piperidine pour le traitement de la depression
WO1999034799A1 (fr) * 1998-01-09 1999-07-15 Akzo Nobel N.V. Utilisation de derives de diphenylmethylene piperidine dans la fabrication d'un medicament pour le traitement des troubles de la mobilite
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 (fr) * 1998-01-09 1999-07-15 Akzo Nobel N.V. Derives de diphenylmethylene piperidine pour le traitement de la depression
WO1999034799A1 (fr) * 1998-01-09 1999-07-15 Akzo Nobel N.V. Utilisation de derives de diphenylmethylene piperidine dans la fabrication d'un medicament pour le traitement des troubles de la mobilite
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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