WO1995016674A1 - Aminosulphonyl-phenyl-1h-pyrrole derivatives, method of their preparation and their use - Google Patents

Aminosulphonyl-phenyl-1h-pyrrole derivatives, method of their preparation and their use Download PDF

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Publication number
WO1995016674A1
WO1995016674A1 PCT/EP1994/004175 EP9404175W WO9516674A1 WO 1995016674 A1 WO1995016674 A1 WO 1995016674A1 EP 9404175 W EP9404175 W EP 9404175W WO 9516674 A1 WO9516674 A1 WO 9516674A1
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methyl
phenyl
pyrrole
aminosulphonyl
methoxy
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PCT/EP1994/004175
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French (fr)
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Roger Edward Markwell
Geoffrey Stemp
Harry John Wadsworth
Eric Alfred Watts
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Smithkline Beecham Plc
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Priority to AU13149/95A priority Critical patent/AU1314995A/en
Priority to JP7516539A priority patent/JPH09507472A/en
Priority to EP95904482A priority patent/EP0734378A1/en
Publication of WO1995016674A1 publication Critical patent/WO1995016674A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms
    • 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
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

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.
  • A is an unsaturated 5-membered heterocyclic ring, such as 2,5-pyrrolyl, or 3,5- or 1,4- pyrazolyl;
  • X is a nitrogen or carbon atom;
  • R 1 ,R 2 , R 3 are each hydrogen or alkyl;
  • R 4 is aryl, heteroaryl, arylcarbonyl or heteroaryl-carbonyl;
  • R is selected from a variety of substituents and n is 0-4.
  • the compounds are said to have antipsychotic properties.
  • A is an unsaturated 5-membered heterocyclic ring, such as 2,5-pyrrolyl, 1,4-pyrazolyl or 2,5-furyl;
  • R is hydrogen, alkyl or optionally substituted phenyl;
  • R 1 is alkyl, alkenyl or forms a ring with the phenyl group;
  • R 2 is hydrogen, hydroxy or alkoxy;
  • R 3 is selected from a variety of substituents and n is 0-3.
  • Z is a residue derived from 2-aminomethyl-N-alkyl-pyrrolidine, 2-aminoethylN,N-diethylamine, 2-aminoethyl-morpholine, 2-aminoethyl-N,N-dibutylamine, 4-amino-N-butyl (or N-benzyl) piperidine or 2-aminoethyl-pyrrolidine;
  • Y is alkyl or alkenyl;
  • X is H, Cl, Br, amino, aminoalkyl, aminosulphamoyl, S-containing group (eg thiocyanato, alkylthio, alkylsulphinyl, alkylsulphonyl) methoxy, nitro, cyano, or an electron attracting group; and
  • R is H or methoxy.
  • the compounds are said to be dopamine antagonists, acting at the D 3 receptor and to be useful inter alia as antipsychotics.
  • R 1 represents C 1-4 alkyl
  • R 2 , R 3 , R 4 an d R 5 represents a sulphonamido group R 6 R 7 NSO 2 -, wherein either: R 6 represents hydrogen, C 1-6 alkyl, or C 1-6 alkoxyC 1- 4 alkyl; and
  • R 7 represents a group (R a )n-( Ar)-(CH 2 )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 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxyC 1-4 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, hydroxyC 1-4 alkyl, C 1-4 alkanoyl, C 1-4 alkoxycarbonyl, amino, mono- or -di-C 1-4 alkylamino,
  • R 6 R 7 N- represents 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 (R a ) p , wherein R a and p are as defined hereinabove; and the remaining R 2 , R 3 , R 4 and R 5 each independently represent hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxyC 1-4 alkyl, C 1-4 alkylsulphonyl,
  • R 1 and R 2 together form a C 2-4 alkyl chain, which chain may be optionally substituted by one or two C 1-4 alkyl groups, in which case one of R 3 , R 4 and R 5 is a sulphonamide group as defined above, and the other two substituents are as hereinbefore defined; or
  • R 2 and R 3 together form a phenyl ring, in which case R 4 represents a sulphonamido group as defined above and R 5 represents hydrogen; and Y represents a group selected from (a) - (e):
  • R 8 and R 9 independently represent hydrogen, C 1-6 alkyl, optionally substituted arylC 1-6 alkyl or optionally substituted heteroarylC 1-6 alkyl;
  • R 10 represents C 1-6 alkyl, C 3-6 alkenyl or C 3-6 cycloalkylC 1-4 alkyl;
  • R 11 represents C 1-6 alkyl; C 3-6 alkenyl; C 3-6 cycloalkylC 1-4 alkyl, optionally substituted arylC 1-4 alkyl or optionally substituted heteroarylC 1-4 alkyl; or
  • NR 10 R 1 1 forms a heterocyclic ring
  • R 12 represents C 1-6 alkyl; C 3-6 alkenyl; C 3-6 cycloalkylC 1-4 alkyl , optionally substituted arylC 1-4 alkyl or optionally substituted heteroarylC 1-4 alkyl; and
  • q 1 to 4.
  • R 13 and R 14 independently represent hydrogen, C 1-6 alkyl, optionally substituted
  • R 15 represents an optionally substituted aryl or optionally substituted heteroaryl group
  • each of r and s independently represents an integer from 1 to 3;
  • R 16 represents C 1-6 alkyl, C 3-6 alkenyl or C 3-6 cycloalkylC 1-4 alkyl; and R 17 , R 18 , R 19 and R 20 each independently represent hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxyC 1-4 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, hydroxyalkyl, C 1-4 alkanoyl, C 1-4 alkoxycarbonyl, amino or mono- or - dialkylamino;
  • X is CH 2 , S or O
  • t is zero, 1 or 2;
  • 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 , R 5 , R 8 , R 9 , R 1 1 , R 12 , R 13 , R 14 and R 15 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 1- 4 alkyl, C 1-4 alkoxy, C 1-4 alkoxyC 1-4 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, hydroxyC 1-4 alkyl, C 1-4 alkanoyl, C 1-4 alkoxycarbonyl, amino and mono- or -diC 1-4 alkylamino.
  • 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 1-4 alkyl.
  • R 6 R 7 N- represents a 5- to 7-membered ring fused to an optionally substituted phenyl ring or fused to 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 21 represents -(CH 2 ) m - or -(CH 2 ) k W(CH 2 ) 2 -;
  • n zero or an integer from 1-4;
  • k zero or 1
  • W represents O, S, SO, or SO 2 ,
  • n zero or an integer from 1-4;
  • 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 6 R 7 N- represents a 5-7 membered ring, fused sulphonamides containing the group (f) are generally preferred.
  • R 6 R 7 NSO 2 - represents an acyclic sulphonamide group
  • R 6 preferably represents hydrogen or C 1-4 alkyl, e.g.
  • R 7 is the group (R a ) p -(Ar)-(CH 2 )j wherein Ar preferably represents phenyl or a 5- or 6-membered heterocyclic aryl group containing 1, 2 or 3 atoms selected from O, N and S.
  • R a preferably represents one or more substituents selected from halogen, C 1-4 alkoxy (e.g. methoxy), cyano,
  • C 1-4 alkylthio e.g. methylthio
  • C 1- 4 alkylsulphinyl e.g. methyl sulphinyl
  • phenyl C 1-4 alkoxy e.g. benzyloxy
  • hydroxy and C 1 -4 alkyl e.g. methyl
  • p preferably represents zero, 1 or 2 and n preferably represents zero, 1 or 2.
  • R 6 R 7 NSO 2 - is represented by R 3 or R 4 , preferably R 4 .
  • the remaining substituents R 2 , R 3 , R 4 or R 5 preferably represent hydrogen or C 1-4 alkyl, e.g. methyl.
  • R 4 represents the group
  • R 6 R 7 NSO 2 -, R 3 represents hydrogen or methyl and R 2 and R 5 each represent hydrogen.
  • R 1 preferably represents methyl, ethyl or isopropyl.
  • R 8 and R 9 are preferably hydrogen.
  • R 8 and R 9 is hydrogen and the other is selected from hydrogen, C 1-6 alkyl and optionally substituted arylC 1-6 alkyl.
  • - NR 10 R 1 1 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 10 R 1 1 may also be bridged, for example by a C 1-3 alkylene chain e.g. a methylene or ethylene group.
  • the heterocyclic ring may be substituted by one or more C 1-4 alkyl groups, or fused to an aromatic ring, such as phenyl.
  • Y is a group (a) one of R 8 and R 9 is hydrogen and the other represents hydrogen or C 1-6 alkyl; R 10 represents C 1-6 alkyl; and R 1 1 represents C 1-6 alkyl or phenyl C 1-4 alkyl or -NR 10 R 11 forms a 5- or 6-membered saturated heterocyclic ring.
  • q is preferably 1 or 2 and R 12 is preferably C 1-6 alkyl e.g. ethyl.
  • R 13 and R 14 preferably represents hydrogen.
  • R 13 and R 14 is hydrogen and the other is selected from hydrogen, C 1-6 alkyl and optionally substituted arylC 1-6 alkyl.
  • R 15 preferably represents optionally substituted phenyl or optionally substituted furyl.
  • Z preferably represents (CH 2 ) u wherein u is 3, 4 or 5.
  • R 13 and R 14 is hydrogen and the other is hydrogen or C 1-6 alkyl;
  • R 15 represents phenyl or optionally substituted furyl and
  • z represents (CH 2 ) 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 (c).
  • 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.
  • R 2 , R 3 , R 4 and R 5 represents a sulphonamido group
  • the dotted line represents a hydrogen atom or substituent R 23 attached to the phenyl ring;
  • R 22 represents hydrogen, C 1-6 alky!, or C 1-4 alkoxyC 1-4 alkyl;
  • n zero or an integer from 1-4;
  • R 22 represents -(CH 2 ) m - ;
  • n and m each represent zero or an integer from 1-4, such that the sum of n+m is from 2-4; and in either case
  • R 23 represents a substituent selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxyC 1-4 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, hydroxyC 1-4 alkyl, C 1-4 alkanoyl, C 1-4 alkoxycarbonyl, amino and mono- or -diC 1-4 alkylamino; and
  • R 1 to R 5 and Y are as defined for formula (I).
  • Preferred values for the substituents R 1 to R 5 and Y are also as defined for formula (I).
  • Particular compounds according to the invention include :
  • the present invention also provides a process for preparing compounds of formula (I) which process comprises :
  • 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 (POCl 3 ) and the resulting product subsequently reacted with a compound of formula (II) conveniently in a solvent such as dichloromethane or dichloroethane.
  • the product of this reaction is then reduced with, for example, sodium borohydride or cyanoborohydride.
  • the reduction may be carried out in a suitable solvent, for example dichloroethane, dichloromethane, methanol, ethanol, water or mixtures thereof.
  • Reductive amination according to process (c) will generally be carried out using a reducing agent such as sodium borohydride or cyanoborohydride and in the presence of a Lewis acid such as titanium (IV) chloride.
  • a reducing agent such as sodium borohydride or cyanoborohydride
  • a Lewis acid such as titanium (IV) chloride.
  • Reaction of a compound (IX) with the amine may conveniently be effected in a solvent such as dichloromethane or dichloroethane.
  • Inter-conversions according to process (d) 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 (X) :
  • the reaction may be effected using an ammonium salt, e.g. ammonium acetate, in a solve nt such as ethanol.
  • a solve nt such as ethanol.
  • a compound of formula (X) may itself be prepared by reacting the appropriate substituted aroyl halide or methoxyamide of formula (XI):
  • R 24 represents a halogen atom e.g. chlorine, or a group -N(CH 3 )OCH 3 and R 1 -R 5 are as hereinbefore defined
  • R 24 represents a halogen atom e.g. chlorine, or a group -N(CH 3 )OCH 3 and R 1 -R 5 are as hereinbefore defined
  • R 24 represents a halogen atom e.g. chlorine, or a group -N(CH 3 )OCH 3 and R 1 -R 5 are as hereinbefore defined
  • a compound of formula (XI) wherein R 24 represents a halogen atom may be prepared from the corresponding benzoic acid using standard procedures.
  • R 24 represents -N(CH 3 )OCH 3
  • 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 (II) may also be prepared by reacting a halo-substituted aryl derivative of formula (XII):
  • R 25 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(PPh 3 ) 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(PPh 3 ) 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 (XIV) :
  • a compound of formula (IX) may be prepared by carrying out a Vilsmeier reaction in which dimethylformamide is reacted with phosphorus oxychloride and the product reacted with a compound of formula (II), in a solvent such as dichloroethane, followed by hydrolysis.
  • Substituents R 1 to R 5 may be introduced at any appropriate stage of the synthesis, preferably at an early stage prior to formation of or coupling with the pyrrole moiety, using methods known in the art.
  • the substituent R 6 R 7 NSO 2 - may be formed by reaction of a compound of formula (XV).
  • R 27 represents a carboxyl group or a halogen atom e.g. bromine and R 28 represents optional ring substituents selected from OR 1 , R 2 , R 3 , R 4 and R 5 ) with an amine R 6 R 7 NH
  • reaction may conveniently be effected in the presence of a solvent e.g.
  • a compound of formula (XV) may also be reacted with an amine R 7 NH 2 using conditions analogous to those described above and the product reacted with an alkylating agent corresponding to R 6 , 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 alkylating agent corresponding to R 6 for example a halide or a tosyl derivative
  • an amine R 6 R 7 NH may be prepared by reacting the corresponding primary amine (R a ) p -(Ar)-NH 2 with an orthoester of R 6 , R 6' C(OEt) 3 in the presence of an acid catalyst such as trifluoroacetic acid, and
  • an amine R 6 R 7 NH may be prepared by reaction of a primary amine (R a ) p -(Ar)-(CH 2 ) j -NH 2 with an acyl halide R 6' COCl corresponding to R 6 , in the presence of a base such as
  • groups or moieties present in any of the substituents R 1 to R 5 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.
  • Preferred compounds of the present invention are therefore those which have higher affinity for dopamine D 3 than dopamine D 2 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 D 3 receptors.
  • compounds of formula (I) are dopamine D 3 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 D 3 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 D 3 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 D 3 receptors for example psychoses such as 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 solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the compound or physiologically acceptable salt in a suitable liquid carrier(s) for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
  • a suitable liquid carrier(s) for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
  • the formulation may also contain a suspending agent, preservative, flavouring or colouring agent.
  • a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
  • 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
  • pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • suitable pharmaceutical carrier(s) for example aqueous gums, celluloses, silicates or oils
  • Typical parenteral compositions consist of a solution or suspension of the compound or physiologically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone,. lecithin, arachis oil or sesame oil.
  • a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone,. lecithin, arachis oil or sesame oil.
  • the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
  • compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders.
  • Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device.
  • 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 fluorochlorohydrocarbon.
  • the aerosol dosage forms can also take the form of a pump-atomiser.
  • compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
  • 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.
  • Chlorosulphonic acid 35 ml was added dropwise over 2 h to a mixture of 2-methoxy-4-methylbenzoic acid (M Julia and Mme. Chastrette Bull. Soc. Chim. Fr 1962, 2255) (16.6 g, 100 mmol) and sodium chloride (6 g), in dichloroethane (40 ml). The mixture was warmed to 40°C for 1 h, then heated to 65°C for 17 h. The cooled mixture was poured into ice/water (ca 500 ml) and the resulting solid filtered, washed with water and hexane and dried (ca 24 g).
  • the dried acid chloride (5.3 g, 15 mmol) was dissolved in freshly distilled tetrahydrofuran (50 ml) under argon and cooled to -75°C.
  • the cooled Grignard reagent (15 mmol) (prepared from adding 2-(2-bromoethyl)-1,3-dioxan (2.9 g, 5 mmol) to magnesium (0.5 g) at reflux for 1 h) was added at such a rate that the internal temperature did not rise above -70°C.
  • the reaction was held at this temperature for 0.5 h and then allowed to rise to room temperature over a period of 1 h.
  • the reaction mixture was concentrated in vacuo then partitioned between dichloromethane and 10% aqueous citric acid.
  • Trifluoroacetic acid (6ml) was added to a stirred solution of 1-(tert-butoxycarbonyl)-2-[2-Methoxy-5-((N-methyl-N-(5-methyl-2-(1,3,4-thiadiazolyl)))aminosulphonyl)phenyl]-1H-pyrrole (0.6g, 1.29mmol) in dichloromethane (12ml) at 0°C under argon. The mixture was stirred at room temperature for lh. before being poured onto ice/dilute aqueous potassium carbonate. Extraction with dichloromethane (2 ⁇ 35ml) drying of the organic extracts (Na 2 SO 4 ) and evaporation in vacuo afforded the crude title compound.
  • N-Formyl-4-methylthioaniline (25g, 0.148mol) in THF (100ml) was added to a solution of LiAlH 4 (5.5g, 150mmol) in ether (500ml) The reaction was heated under reflux for 2h, and quenched by the addition of excess 10% NaOH solution. The organic phase was then separated, dried (Na 2 SO 4 ) and evaporated in vacuo to afford the title compound (22.16g, 97%).
  • reaction mixture was stirred at 10° C for 30 min, then poured into water
  • the solution was cooled to 0°C and then was treated with 2-(2-methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl)-1H-pyrrole (1 g, 2.92 mmol), and the reaction was stirred at 0°C for 3 h, and then was allowed to warm to room temperature overnight.
  • the reaction mixture was cooled to 0°C and then was treated with sodium borohydride (1 g) and stirred at this temperature for 1h.
  • the reaction mixture was treated with methanol (5 ml) at such a rate that the temperature did not rise above 10°C, and excessive frothing was avoided.
  • Phosphoryl chloride (0.33 ml; 0.54 g; 3.5 mmol) was added dropwise to 1-formyl-2-(R,S)-phenylazacycloheptane (0.65 g; 3.2 mmol) at 0°C under argon, and then stirred at room temperature for 0.5 h.
  • 1,2-dichloroethane (20 ml) was added and the solution was cooled (ice/salt) before adding a solution of 2-(5-((N-benzyl-N-ethyl)aminosulphonyl)-2-methoxyphenyl)-1H-pyrrole (0.6 g; 1.6 mmol) in 1,2 -dichloroethane (20 ml), dropwise.
  • the mixture was stirred at room temperature for 18 h.
  • the reaction mixture was cooled to 0°C (ice) and sodium borohydride (0.66 g) was added portionwise.
  • the mixture was stirred at room temperature for 2 h.
  • the excess hydride was decomposed by dropwise addition of methanol (5 ml) and water (10 ml).
  • the mixture was partitioned between water and dichloromethane and the aqueous fraction was further extracted with dichloromethane.
  • the reaction was cooled to 0°C and then was treated with sodium borohydride (0.75 g) and stirred at this temperature for 1 h.
  • the reaction mixture was cooled to 0°C and treated with methanol (3 ml) with stirring. It was quenched by addition of water (10 ml) and partitioned between saturated aqueous potassium carbonate (20 ml) and dichloromethane (3 ⁇ 50 ml). The organic phase was separated, washed with brine, dried (Na 2 SO 4 ), and evaporated in vacuo.
  • the resulting oil was chromatographed on silica eluting with 3-5% methanol in dichloromethane to give the title compound ( 0.322 g; 34%) as a foam.
  • the acidic layer was basified with 2.5N NaOH and extracted into dichloromethane (3 ⁇ 50ml). Combined organic extracts were dried (Na 2 SO 4 ) and evaporated in vacuo. Chromatography on silica using 0-2% methanol in dichloromethane afforded the title compound as the free base. This was dissolved in diethyl ether and extracted into 0.5N HCl (2 ⁇ 50ml). Acid extracts were combined and extracted with dichloromethane (4 ⁇ 40ml). Combined organic extracts were dried and evaporated in vacuo. Trituration with diethyl ether afforded the title compound in 56% yield.
  • the ability of the compounds to bind selectively to human D 3 dopamine receptors can be demonstrated by measuring their binding to cloned receptors.
  • the inhibition constants (IC 50 ) of test compounds for displacement of [ 125 I] iodosulpride binding to D 3 dopamine receptors expressed in CHO cells have been determined.
  • the cell lines were shown to be free from bacterial, fungal and mycoplasmal contaminants, and stocks of each were stored frozen in liquid nitrogen. Cultures were grown as monolayers or in suspension in standard cell culture media. Cells were recovered by scraping (from monolayers) or by centrifugation (from suspension cultures), and were washed two or three times by suspension in phosphate buffered saline followed by collection by centrifugation. Cell pellets were stored frozen at -40°C. Crude cell membranes were prepared by
  • the membrane pellet was resuspended in ice-cold 50 mM Tris salts (pH 7.4 @ 37°C), using an Ultra-Turrax, and recentrifuged at 18,000 r.p.m for 15 min at 4°C in a Sorvall RC5C. The membranes were washed two more times with ice-cold 50 mM Tris salts (pH 7.4 @ 37°C). The final pellet was resuspended in 50 mM Tris salts (pH 7.4 @ 37°C), and the protein content determined using bovine serum albumin as a standard (Bradford, M. M. (1976) Anal. Biochem. 72, 248-254).
  • 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.
  • Diluent e.g. Microcrystalline cellulose, lactose, starch
  • Binder e.g. Polyvinylpyrrolidone, hydroxypropymethylcellulose
  • Disintegrant e.g. Sodium starch glycollate, crospovidone
  • Lubricant e.g. Magnesium stearate, sodium stearyl fumarate. Oral Suspension
  • 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

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Abstract

Compounds of formula (I) wherein R1 represents C¿1-4?alkyl; one of R?2, R3, R4 and R5¿ represents a sulphonamido group R6R7NSO2-, wherein either: R6 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 R?6R7¿N- represents 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; and Y represents a group selected from (a) - (e); and salts thereof, have activity at dopamine receptors and are potentially useful in the treatment of psychoses such as schizophrenia.

Description

Aminosulphonyl -phenyl -1 H pyrrole derivatives method of
their preparation and their use
The present invention relates to novel pyrrole derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, in particular as antipsychotic agents.
European Patent Application No. 241053, describes compounds of the formula
Figure imgf000003_0001
wherein A is an unsaturated 5-membered heterocyclic ring, such as 2,5-pyrrolyl, or 3,5- or 1,4- pyrazolyl; X is a nitrogen or carbon atom; R1,R2, R3 are each hydrogen or alkyl; R4 is aryl, heteroaryl, arylcarbonyl or heteroaryl-carbonyl; R is selected from a variety of substituents and n is 0-4. The compounds are said to have antipsychotic properties.
European Patent Application No. 259930 describes compounds of the formula :
Figure imgf000003_0002
wherein A is an unsaturated 5-membered heterocyclic ring, such as 2,5-pyrrolyl, 1,4-pyrazolyl or 2,5-furyl; R is hydrogen, alkyl or optionally substituted phenyl; R1 is alkyl, alkenyl or forms a ring with the phenyl group; R2 is hydrogen, hydroxy or alkoxy; R3 is selected from a variety of substituents and n is 0-3. These compounds are also said to have antipsychotic properties.
European Patent Application No. 539281 describes compounds of the formula:
Figure imgf000003_0003
wherein Z is a residue derived from 2-aminomethyl-N-alkyl-pyrrolidine, 2-aminoethylN,N-diethylamine, 2-aminoethyl-morpholine, 2-aminoethyl-N,N-dibutylamine, 4-amino-N-butyl (or N-benzyl) piperidine or 2-aminoethyl-pyrrolidine; Y is alkyl or alkenyl; X is H, Cl, Br, amino, aminoalkyl, aminosulphamoyl, S-containing group (eg thiocyanato, alkylthio, alkylsulphinyl, alkylsulphonyl) methoxy, nitro, cyano, or an electron attracting group; and R is H or methoxy. The compounds are said to be dopamine antagonists, acting at the D3 receptor and to be useful inter alia as antipsychotics.
We have now found novel pyrrole derivatives which have affinity for dopamine receptors and thus have potential as antipsychotic agents.
In a first aspect the present invention provides compounds of formula (I) :
Figure imgf000004_0001
wherein
R1 represents C1-4alkyl;
one of R2, R3, R4 an d R5 represents a sulphonamido group R6R7NSO2-, wherein either: R6 represents hydrogen, C1-6alkyl, or C1-6alkoxyC 1- 4alkyl; and
R7 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, C1-4alkyl, 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
R6R7N- represents 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; and the remaining R2, R3, R4 and R5 each independently represent hydrogen, halogen, C1-4alkyl, 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-alkylamino,
trifluoromethyl, trifluoromethoxy, hydroxyl, hydroxyalkyl, C1-4alkylthio,
C1-4alkanoyl or C1 -4alkoxycarbonyl; or R1 and R2 together form a C2-4alkyl chain, which chain may be optionally substituted by one or two C1-4alkyl groups, in which case one of R3, R4 and R5 is a sulphonamide group as defined above, and the other two substituents are as hereinbefore defined; or
R2 and R3 together form a phenyl ring, in which case R4 represents a sulphonamido group as defined above and R5 represents hydrogen; and Y represents a group selected from (a) - (e):
Figure imgf000005_0001
Figure imgf000005_0002
Figure imgf000005_0003
Figure imgf000005_0004
or
Figure imgf000005_0005
wherein
in group (a) : R8 and R9 independently represent hydrogen, C1-6alkyl, optionally substituted arylC1-6alkyl or optionally substituted heteroarylC1-6alkyl;
R10 represents C1-6alkyl, C3-6alkenyl or C3-6cycloalkylC1-4alkyl; and
R11 represents C1-6alkyl; C3-6alkenyl; C3-6cycloalkylC1-4alkyl, optionally substituted arylC1-4alkyl or optionally substituted heteroarylC1-4alkyl; or
NR10R1 1 forms a heterocyclic ring;
in group (b) :
R12 represents C1-6alkyl; C3-6alkenyl; C3-6cycloalkylC1-4alkyl , optionally substituted arylC1-4alkyl or optionally substituted heteroarylC1-4alkyl; and
q is 1 to 4;
in group (c):
R13 and R14 independently represent hydrogen, C1-6alkyl, optionally substituted
arylC1-6alkyl or optionally substituted heteroarylC1-6alkyl;
R15 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) R16 represents C1-6alkyl, C3-6alkenyl or C3-6cycloalkylC1-4alkyl; and R17, R18, R19 and R20 each independently represent hydrogen, halogen, C1-4alkyl, C1-4alkoxy, C1-4alkoxyC1-4alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, hydroxyalkyl, C1-4alkanoyl, C1-4alkoxycarbonyl, 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, R8, R9, R 1 1, R12, R13, R14 and R15 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, C1- 4alkyl, C1-4alkoxy, C1-4alkoxyC1-4alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, hydroxyC1-4alkyl, C1-4alkanoyl, C1-4alkoxycarbonyl, amino and mono- or -diC1-4alkylamino.
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.C1-4alkyl.
When R6R7N- represents a 5- to 7-membered ring fused to an optionally substituted phenyl ring or fused to or substituted by an optionally substituted 5- or 6- membered heterocyclic ring the sulphonamide group may be represented by formula (f) or (g):
Figure imgf000007_0001
Figure imgf000007_0002
wherein Ra and p are as hereinbefore defined;
Ar' represents phenyl or a 5- or 6-membered heterocyclic ring;
R21 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 R21 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 R21 represents -(CH2)kW(CH2)2-, W preferably represents O and k and n preferably each represent zero. When R6R7N- represents a 5-7 membered ring, fused sulphonamides containing the group (f) are generally preferred. When R6R7NSO2- represents an acyclic sulphonamide group, R6 preferably represents hydrogen or C1-4alkyl, 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 aryl group containing 1, 2 or 3 atoms selected from O, N and S. Ra preferably represents one or more substituents selected from halogen, C1-4alkoxy (e.g. methoxy), cyano,
C1-4alkylthio (e.g. methylthio), C1- 4alkylsulphinyl (e.g. methyl sulphinyl), phenyl C1-4alkoxy (e.g. benzyloxy), hydroxy and C1 -4alkyl (e.g. methyl), p preferably represents zero, 1 or 2 and n preferably represents zero, 1 or 2.
Suitably the sulphonamido group R6R7NSO2- is represented by R3 or R4, preferably R4. The remaining substituents R2, R3, R4 or R5 preferably represent hydrogen or C1-4alkyl, e.g. methyl. Advantageously, R4 represents the group
R6R7NSO2-, R3 represents hydrogen or methyl and R2 and R5 each represent hydrogen.
R1 preferably represents methyl, ethyl or isopropyl.
When Y is a group (a) at least one of R8 and R9 is preferably hydrogen. Suitably one of R8 and R9 is hydrogen and the other is selected from hydrogen, C1-6alkyl and optionally substituted arylC1-6alkyl. When - NR10R1 1 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 -NR10R1 1 may also be bridged, for example by a C1-3alkylene chain e.g. a methylene or ethylene group. Furthermore, the heterocyclic ring may be substituted by one or more C1-4alkyl groups, or fused to an aromatic ring, such as phenyl. Most preferably, when Y is a group (a) one of R8 and R9 is hydrogen and the other represents hydrogen or C1-6alkyl; R10 represents C1-6alkyl; and R1 1 represents C1-6alkyl or phenyl C1-4alkyl or -NR10R11 forms a 5- or 6-membered saturated heterocyclic ring.
When Y is a group (b) q is preferably 1 or 2 and R12 is preferably C1-6alkyl e.g. ethyl. When Y is a group (c) at least one of R13 and R14 preferably represents hydrogen.
Suitably one of R13 and R14 is hydrogen and the other is selected from hydrogen, C1-6alkyl and optionally substituted arylC1-6alkyl. R15 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 R13 and R14 is hydrogen and the other is hydrogen or C1-6alkyl; R15 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 (c).
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.
In a futher aspect the invention also provides compounds of formula (IA):
Figure imgf000009_0001
wherein
one of R2, R3, R4 and R5 represents a sulphonamido group
Figure imgf000009_0002
wherein either
the dotted line represents a hydrogen atom or substituent R23 attached to the phenyl ring; R22 represents hydrogen, C 1-6alky!, or C1-4alkoxyC1-4alkyl; and
n represents zero or an integer from 1-4;
or
the dotted line represents a single bond;
R22 represents -(CH2)m- ; and
n and m each represent zero or an integer from 1-4, such that the sum of n+m is from 2-4; and in either case
R23 represents a substituent selected from halogen, C1-4alkyl, C1-4alkoxy, C1-4alkoxyC1-4alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, hydroxyC1-4alkyl, C1-4alkanoyl, C1-4alkoxycarbonyl, amino and mono- or -diC1-4alkylamino; and
p represents zero or an integer from 1-4; and the remaining R2, R3, R4 and R5, as well as R1 and Y are as defined for formula (I). Preferred values for the substituents R1 to R5 and Y are also as defined for formula (I).
Particular compounds according to the invention include :
2-(2-Methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl)-5-(1-(2-(R,S)phenylazacycloheptyl)-methyl)-1H-pyrrole;
2-[5-((N-Benzyl-N-methyl)aminosulphonyl)-2-methoxyphenyl]-5-[1-(2-(R,S)-phenylazacycloheptyl)methyl]-1H-pyrrole;
2-[2-Methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-5-(1-(R,S)-(2-phenylpyrrolidinyl)methyl)-1H-pyrrole;
(-)-2-[2-Methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-5-(1-(2-phenylpyrrolidinyl methyl)-1H-pyrrole;
(+)-2-[2-Methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-5-(1-(2-phenylpyrrolidinyl)methyl)-1H-pyrrole;
(-)-2-[2-Methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-5-(1-(2-phenylpiperidinylmethyl)-1H-pyrrole;
(+)-2-[2-Methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-5-(1-(2-phenylpiperidinyl)methyl)-1H-pyrrole;
2-(5-((N-(4-Bromophenyl)-N-methyl)aminosulphonyl)-2-methoxyphenyl)-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole;
2-(2-Methoxy-5-((N-(4-methoxyphenyl)-N-methyl)amino-sulphonyl)phenyl)-5-(1-(2- (R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole;
2-(5-((N-(4-Cyanophenyl)-N-methyl)aminosulphonyl)-2-methoxyphenyl)-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole;
2-(5-(4-(3,4-Dihydro-1,4-benzoxazinyl)sulphonyl)-2-methoxy-phenyl)-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole;
2-(5-((N-(3,4-Dimethoxybenzyl)-N-ethyl)aminosulphonyl)-2-methoxyphenyl)-5-(1-(2- (R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole;
2-(2-Methoxy-5-((N-methyl-N-(4-methylthio)phenyl)aminosulphonyl)phenyl)-5-(1-(2- (R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole;
2-(2-Methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl)-5-(1-(2-(R)-phenylazacycloheptyl)methyl)-1H-pyrrole;
2-(2-Methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl)-5-(1-(2-(S)-phenylazacycloheptyl)methyl)-1H-pyrrole; 2-[5-((N-Benzyl-N-ethyl)aminosulphonyl)-2-methoxyphenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole;
2-[5-((N-(2,4-Difluorophenyl)-N-methyl)aminosulphonyl-2-methoxyphenyl]-5-(1-(2- (R,S) phenylazacycloheptyl)methyl)-1H-pyrrole;
2-[2-Methoxy-5-((1-(2-phenylpyrrolidinyl))sulphonyl)phenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole;
2-[2-Methoxy-5-((N-ethyl-N-(2-phenyl)ethyl)aminosulphonyl)-phenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole;
2-[2-Methoxy-5-((N-methyl-N-(5-methyl-3-isoxazolyl))amino-sulphonyl)phenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole;
2-[2-Methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-5-(1-(R,S)-(1-piperidinyl)ethyl)-1H-pyrrole;
2-[5-((N-Ethyl-N-(2-pyridyl)methyl)aminosulphonyl)-2-methoxy-phenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole;
2-[5-((N-Ethyl-N-(2-furyl)methyl)aminosulphonyl)-2-methoxy-phenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl-1H-pyrrole;
2-[5-((N-(4-Fluorophenyl)-N-methyl)aminosulphonyl)-2-methoxyphenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole;
2-[2-Methoxy-4-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-5-[1-(2-(R,S)-phenylazacycloheptyl)methyl]-1H-pyrrole;
2-[5-((N-Benzyl-N-ethyl)aminosulphonyl)-2-methoxyphenyl]-5-[1-(2-(R)-phenylazacycloheptyl)methyl]-1H-pyrrole;
2-[5-((N-Benzyl-N-ethyl)aminosulphonyl)-2-methoxyphenyl]-5-[1-(2-(S)-phenylazacycloheptyl)methyl]-1H-pyrrole;
2-[2-Methoxy-5-((2-(1,2,3,4-tetrahydroisoquinolinyl))sulphonyl)phenyl]-5-[1-(2-(R,S)-phenylazacycloheptyl)methyl]-1H-pyrrole;
2-[2-Methoxy-5-((1-(1,2,3,4-Tetrahydroquinolinyl))sulphonyl)
phenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl-1H-pyrrole;
2-[5-((N-Ethyl-N-phenyl)aminosulphonyl)-2-methoxyphenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole;
2-[2-(R,S)-(1-Ethylpyrrolidinyl)]-5-[(2-methoxy-4-methyl-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-1H- pyrrole;
2-[2-(R,S)-(1-Ethylpyrrolidinyl))-5-(2-methoxy-5-((N-methyl-N-phenyl]aminosulphonyl)phenyl)-1H-pyrrole;
2-(2-(R,S)-(1-Ethylpyrrolidinyl))-5-[2-methoxy-5-((1-(1,2,3,4-tetrahydroquinolinyl))aminosulphonyl)phenyl]-1H-pyrrole;
2-(2-(R,S)-(1-Ethylpyrrolidinyl))-5-(1-methoxy-4-((N-methyl-N-phenyl)aminosulphonyl)- 2-naphthyl)-1H-pyrrole; 2-(2-(R,S)-(1-n-Butylpyrrolidinyl))-5-[2-methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-1H-pyrrole;
2-[2-(R,S)-(1-Ethylpyrrolidinyl)]-5-[2-methoxy-4-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-1H-pyrrole;
2-[2-Methoxy-4-methyl-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl)-5-(1-(2-(R)-phenylazacycloheptyl)methyk)-1H-pyrrole;
2-[5-((N-(4-Hydroxyphenyl)-N-methyl)aminosulphonyl)-2-methoxyphenyl]-5-[1-(2- (R,S)-phenylazacycloheptyl)methyl]-1H-pyrrole;
2-(5-((N-(4-Iodophenyl)-N-methyl)aminosulphonyl)-2-methoxyphenyl)-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole;
2-(N-Benzyl-N-ethyl)aminomethyl-5-(2-methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl)-1H-pyrrole;
2-(N-Benzyl-N-ethyl)aminomethyl-5-[2-methoxy-4-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-1H-pyrrole;
2-[2-Methoxy-4-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-5-[1-(R,S)-(1-piperidinyl)ethyl]-1H-pyrrole;
2-(2-Methoxy-5-((N-methyl-N-(4-methylsulphinyl)phenyl)
aminosulphonyl)phenyl)-5-(1-(2-(R,S)-phenylazacycloheptyl)
methyl)-1H-pyrrole;
and salts thereof.
The present invention also provides a process for preparing compounds of formula (I) which process comprises :
(a) to prepare a compound of formula (I) wherein Y is a group (a) or (c) in which R8, R9 , R13 and R14are hydrogen or wherein Y is a group (e) carrying out a Mannich reaction with a compound of formula (II) :
Figure imgf000012_0001
and an amine of formula (III) (IV) or (V): HNR10R11
Formula (III)
Figure imgf000013_0002
in the presence of formaldehyde;
Figure imgf000013_0001
(b) to prepare a compound wherein Y is a group (a) wherein at least one of R8 and R9 is hydrogen, a group (c) wherein at least one of R13 or R14 is 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):
R8C(O)NR10R11
Formula (VI)
Figure imgf000013_0003
Figure imgf000013_0004
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 R8, R9, R13 and R14 are hydrogen or Y is a group (e) reductive amination of a compound of formula (IX) : Formula IX
with an amine of formula (III) (IV) or (V);
(d) conversion of one compound of formula (I) 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 (POCl3) and the resulting product subsequently reacted with a compound of formula (II) conveniently in a solvent such as dichloromethane or dichloroethane. The product of this reaction is then reduced with, for example, sodium borohydride or cyanoborohydride. The reduction may be carried out in a suitable solvent, for example dichloroethane, dichloromethane, methanol, ethanol, water or mixtures thereof.
Reductive amination according to process (c) will generally be carried out using a reducing agent such as sodium borohydride or cyanoborohydride and in the presence of a Lewis acid such as titanium (IV) chloride. Reaction of a compound (IX) with the amine may conveniently be effected in a solvent such as dichloromethane or dichloroethane.
Inter-conversions according to process (d) 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 (X) :
Figure imgf000015_0001
The reaction may be effected using an ammonium salt, e.g. ammonium acetate, in a solve
Figure imgf000015_0003
nt such as ethanol. (See, for example, C.G. Kruse et al., Heterocycles, vol 26, P3141, 1987).
A compound of formula (X) may itself be prepared by reacting the appropriate substituted aroyl halide or methoxyamide of formula (XI):
Figure imgf000015_0002
(wherein R24 represents a halogen atom e.g. chlorine, or a group -N(CH3)OCH3 and R1-R5 are as hereinbefore defined) with a metallo derivative of a 2-(2-haloethyl)-1,3-dioxolane or 2-(2-haloethyl)-1,3-dioxane and subsequent acid hydrolysis.
A compound of formula (XI) wherein R24 represents a halogen atom may be prepared from the corresponding benzoic acid using standard procedures. When R24 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 (II) may also be prepared by reacting a halo-substituted aryl derivative of formula (XII):
Figure imgf000016_0001
(wherein Hal is a halogen atom e.g. bromine) with an N-protected pyrrole derivative of formula (XIII):
Figure imgf000016_0002
(wherein R25 represents an N-protecting group, e.g. t-butoxycarbonyl), followed by removal of the protecting group R25.
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 (III) and (IV) are available commercially or may be prepared by standard methods.
An amine (V) may be obtained by reductive amination of a ketone of formula (XIV) :
Figure imgf000016_0003
with an amine R16NH2, in the presence of a titanium (IV) chloride followed by reduction with e.g. sodium cyanoborohydride, as described above for process (c).
Compounds of formula (VI) and (VII) wherein R8 and R13 respectively are other than hydrogen may be prepared by acylation of the appropriate amine of formula (III) or (IV) for example using the corresponding acyl halide.
Compounds of formula (VI), and (VII) wherein R8 and R13 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 (IX) may be prepared by carrying out a Vilsmeier reaction in which dimethylformamide is reacted with phosphorus oxychloride and the product reacted with a compound of formula (II), in a solvent such as dichloroethane, followed by hydrolysis.
Substituents R1 to R5 may be introduced at any appropriate stage of the synthesis, preferably at an early stage prior to formation of or coupling with the pyrrole moiety, using methods known in the art. Thus, for example the substituent R6R7NSO2- may be formed by reaction of a compound of formula (XV).
Figure imgf000017_0001
(wherein R27 represents a carboxyl group or a halogen atom e.g. bromine and R28 represents optional ring substituents selected from OR1, R2, R3, R4 and R5) 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 R6R7NH may serve as the base. Compounds of formula (XV) are known (e.g. German OLS 2,721,643) or may be prepared by standard methods.
To prepare compounds where R6 is other than hydrogen, a compound of formula (XV) 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 R6, 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 C1-6alkyl or C1-6alkoxyC1 -4alkyl, an amine R6R7NH may be prepared by reacting the corresponding primary amine (Ra)p-(Ar)-NH2 with an orthoester of R6, R6'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 R6R7NH may be prepared by reaction of a primary amine (Ra)p-(Ar)-(CH2)j-NH2 with an acyl halide R6'COCl corresponding to R6, 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.
If necessary, groups or moieties present in any of the substituents R1 to R5 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.
Alternatively a compound of formula (I) may be prepared as a single enantiomer by employing a chiral amine in the synthesis, for example directly in process (a) or (c) or in the preparation of an amide for use in process (b). A chiral amine of formula (III), (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 D3 receptors, and are expected to be useful in the treatment of disease states which require modulation of such receptors, such as psychotic conditions. The therapeutic effect of currently available antipsychotic agents (neuroleptics) is generally believed to be exerted via blockade of D2 receptors; however this mechanism is also thought to be responsible for undesirable extrapyramidal side effects (eps) associated with many neuroleptic agents. Without wishing to be bound by theory, it has been suggested that blockade of the recently characterised dopamine D3 receptor may give rise to beneficial antipsychotic activity without significant eps. (see for example Sokoloff et al, Nature, 1990; 347: 146-151; and Schwartz et al, Clinical Neuropharmacology, Vol 16, No. 4, 295-314, 1993). Preferred compounds of the present invention are therefore those which have higher affinity for dopamine D3 than dopamine D2 receptors (such affinity can be measured using standard methodology for example using cloned dopamine receptors). Said compounds may advantageously be used as selective modulators of D3 receptors. In particular compounds of formula (I) are dopamine D3 receptor antagonists and as such are of potential use as antipsychotic agents for example in the treatment of schizophrenia, schizo-affective disorders, psychotic depression and mania. Other conditions which may be treated by modulation of dopamine D3 receptors include dyskinetic disorders such as Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesias; depression; and drug (eg. cocaine) dependency.
In a further aspect therefore the present invention provides a method of treating conditions which require modulation of dopamine D3 receptors, for example psychoses such as schizophrenia, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) or a physiologically acceptable salt thereof.
The invention also provides the use of a compound of formula (I) or a
physiologically acceptable salt thereof in the manufacture of a medicament for the treatment of conditions which require modulation of dopamine D3 receptors, for example psychoses such as schizophrenia.
For use in medicine, the compounds of the present invention are usually administered as a standard pharmaceutical composition. The present invention therefore provides in a further aspect pharmaceutical compositions comprising a novel compound of formula (I) or a physiologically acceptable salt thereof and a physiologically acceptable carrier.
The compounds of formula (I) may be administered by any convenient method, for example by oral, parenteral, buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.
The compounds of formula (I) and their physiologically acceptable salts which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
A liquid formulation will generally consist of a suspension or solution of the compound or physiologically acceptable salt in a suitable liquid carrier(s) for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring or colouring agent.
A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose. A composition in the form of a capsule can be prepared using routine
encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
Typical parenteral compositions consist of a solution or suspension of the compound or physiologically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone,. lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device. Alternatively the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomiser.
Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
Compositions suitable for transdermal administration include ointments, gels and patches.
Preferably the composition is in unit dose form such as a tablet, capsule or ampoule.
Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the formula (I) or a physiologically acceptable salt thereof calculated as the free base.
The physiologically acceptable compounds of the invention will normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose of between 1 mg and 500 mg, preferably between 10 mg and 400 mg,e.g. between 10 and 250 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 50 mg, e.g. between 1 and 25 mg of the compound of the formula (I) or a physiologically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more.
The invention is further illustrated by the following non-limiting examples :
Description 1
2-(R,S)-Phenylazacycloheptane
To a solution of 1-aza-2-methoxy-1-cycloheptene (50.9 g) in benzene (600 ml) under argon was added phenyl magnesium bromide (300 ml of a 3M solution in ether) and the mixture was heated at reflux for 4 h. The reaction mixture was cooled (ice/water) and LiAlH4 (16.9 g) was added portion-wise. The mixture was then heated at reflux for a further 5 h before being cooled to room temperature. The mixture was poured onto crushed ice with vigorous effervescence. The resultant slurry was basified with aqueous 10% sodium hydroxide and filtered through kieselguhr, which was then washed with ether. The layers were separated and the aqueous fraction was further extracted with ether. The combined ether layers were dried (Na2SO4) and evaporated to dryness in vacuo to give an orange-gold liquid, which on distillation (0.5 mm Hg) gave the title compound as a colourless liquid (46.43 g, 66%), bp 82-9°C.
1H NMR (CDCl3) δ: 1.50 - 2.09 (8H, br m), 2.75 - 2.95 (1H, m), 3.06 - 3.24 (1H, m), 3.65 - 3.81 (1H, dd, J=4,10 Hz), and 7.13 - 7.45 (5H, m).
Descriptions (2a) and (2b)
1-[(S)-2-Methoxy-2-phenyl]acetyl-2-(R)-phenylazacycloheptane (D2a) and 1-[(S)-2-methoxy-2-phenyl]acetyl-2-(S)-phenylazacycloheptane (D2b)
To a solution of (S)-(+)-2-methoxy-2-phenylacetic acid (3.65 g, 22 mmol) in
dichloromethane (35 ml) and dimethylformamide (1 drop) was added oxalyl chloride (2.8 ml, 33 mmol), dropwise, under argon at room temperature. After 2 h the volatiles were removed in vacuo and the residue was dissolved in dichloromethane (90 ml). The solution was added at room temperature, with vigorous mechanical stirring, to a solution of 2-(R,S)-phenylazacycloheptane (3.88 g, 22 mmol) in dichloromethane (90 ml) and 5% aqueous NaOH (190 ml). After 0.25 h the layers were separated and the organic layer was washed with water, dried, and evaporated in vacuo to give a colourless oil.
Chromatography on silica gel eluting with 20-30% ethyl acetate/pentane afforded the title compounds [total yield 88%] as two diastereoisomers:
the faster eluting isomer (D2a) (3.18g, 45%) 1H NMR (CDCl3) exists as a mixture of E/Z isomers, δ: 0.80 - 1.06 (broad m) and 1.14 -1.47 (br m) (together 1H), 1.55 - 1.90 (6H, br m), 2.17 - 2.40 (1H, br m), 2.80 - 2.97 (1H, br m), 3.14 (s) and 3.47 (s) (together 3H), 3.90 - 4.05 (br d, J=13 Hz) and 4.29 - 4.45 (br d, J=13 Hz) (together 1H), 4.98 (s) and 5.08 (s) (together 1H), 5.12 (q, J=5 Hz) and 5.42 (q, J=5 Hz) (together 1H), and 7.02 - 7.48 (10H, m).
and the slower eluting isomer (D2b) (3.04 g, 43%)
1H NMR (CDCl3) exists as a mixture of E/Z isomers, δ: 0.54 - 0.79 (br m) and 1.10 - 1.45 (br m) (together 1H), 1.50 - 1.98 (6H, br m), 2.13 - 2.49 (br m) and 2.76 - 3.10 (br m) (together 2H), 3.18 (s) and 3.40 (s) (together 3H), 3.78 and 4.58 (br d, J=16 Hz) (together 1H), 4.64 (s) and 5.03 (s) (together 1H), 4.72 (q, J=5 Hz) and 5.64 (q, J=5 Hz) (together 1H), and 6.94 - 7.50 (10H, m).
Description 3
2-(R)-Phenylazacycloheptane
To a solution of the faster eluting amide diastereoisomer (D2a) (3.18 g, 9.8 mmol) in dry tetrahydrofuran (32 ml), under argon at room temperature, was added methyllithium (25.4 ml, 4 eqiv. of a 1.5 M solution in ether). After 40 min. the reaction was basified with saturated aqueous potassium carbonate and extracted into ether. The ether fraction was extracted into aqueous 5N hydrochloric acid, rebasified, and extracted into ether. It was dried (Na2SO4) and evaporated to dryness in vacuo to give the crude product as a yellow oil, which was distilled using a Kugelrohr to give the title compound as a colourless oil (0.67g, 39%), bp 100°C (0.3 mm Hg), [α]D 20 + 35° (c, 0.89%, MeOH), ee > 92.6% by
HPLC on a Chiralcel OJ column using hexane/ethanol as the eluant.
1H NMR (CDCl3) δ: 1.54 - 2.04 (8H, br m), 2.78 - 2.96 (1H, m), 3.07 - 3.23 (1H, m), 3.68 - 3.84 (1H, m), and 7.18 - 7.47 (5H, m).
Description 4
2-(S)-Phenylazacycloheptane
The slower eluting diastereoisomer (D2b) (3.04 g, 9.4 mmol) was employed in a procedure similar to Description 3, to give the title compound in 33% yield [α]D 20 -30.1° (c, 0.9 %,
MeOH), ee > 98.8% by HPLC on a Chiralcel OJ column using hexane/ethanol as the eluant
1H NMR (CDCl3) δ: 1.49 - 2.10 (8H, br m), 2.76 - 2.97 (1H, m), 3.05 - 3.23 (1H, m), 3.68 - 3.84 (1H, m), and 7.12 - 7.50 (5H, m). Description 5
1-Formyl-2-(R,S)-phenylazacycloheptane
To a mixture of 98-100% formic acid (30 ml) and acetic anhydride (100 ml) was added 2-(R,S)-phenylazacycloheptane (10 g, 57.1 mmol) and the mixture warmed to 70°C for 2 h. The reaction mixture was then cooled and evaporated to dryness in vacuo and the residue was partitioned between ether and saturated aqueous potassium carbonate. The ether layer was separated and evaporated to dryness in vacuo to afford the title compound (11.24 g; 97%) as a mixture of E/Z isomers.
1H NMR (CDCl3) δ 1.2-2.1 (5H, m), 2.3-2.6 (1.5 H, m), 2.7-2.95 (0.5 H, m), 2.8 (t, J=12 Hz) and 2.95 (t, J=12 Hz) (together 1H), 3.15 (m) and 3.77 (m) (together 1H), 3.65 (br d, J=12 Hz) and 4.24 (br d, J=12 Hz) (together 1H), 4.67 (dd, J=12,4 Hz) and 5.3, (dd, J=12,4 Hz) (together 1H), 7.13-7.45, (5H, m), 8.15 (s) and 8.3 (s) (together 1H).
Description 6
1-Formyl-2-(R)-phenylazacycloheptane
A mixture of 98-100% formic acid (8.3 ml) and acetic anhydride (2.7 ml) was added dropwise to 2-(R)-phenylazacycloheptane (0.92 g) under argon, and the solution was stirred at 70°C for 2 h. The reaction mixture was allowed to cool and the volatiles were removed in vacuo. The residual oil was taken up in water and extracted into
dichloromethane. The combined organic extracts were washed with saturated aqueous sodium bicarbonate, water, brine, dried (Na2SO4), and evaporated in vacuo to give the title compound as a straw coloured oil (0.75 g, 71%).
1H NMR (CDCl3) exists as a mixture of E/Z isomers, δ: 1.19 - 2.09 (7H, m), 2.39 (m) and 2.57 (m) (together 1H), 2.81 (t, J=13 Hz) and 3.34 (t, J=13 Hz) (together 1H), 3.68 (br d, J=13 Hz) and 4.24 (br d, J=13 Hz) (together 1H), 4.68 (q, J=7 Hz) and 5.31 (q, J=7 Hz) (together 1H), 7.13 - 7.50 (5H, m), 8.15 (s) and 8.29 (s) (together 1H).
Description 7
1-Formyl-2-(S)-phenylazacycloheptane
The title compound was prepared in 85% yield from 2-(S)-phenylazacycloheptane using a procedure similar to that of Description 6
1H NMR (CDCl3) exists as a mixture of E/Z isomers, δ: 1.26 - 2.12 (7H, m), 2.36 (m) and 2.57 (m) (together 1H), 2.81 (dt, J=13,l Hz) and 3.34 (dt, J=13,1 Hz) (together 1H), 3.70 (br d, J=13 Hz) and 4.25 (br d, J=13 Hz) (together 1H), 4.69 (q, J=5 Hz) and 5.32 (q, J=5 Hz) (together 1H), 7.13 - 7.45 (5H, m), 8.16 (s) and 8.29 (s) (together 1H). Description 8
2-Methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)benzoic acid
A suspension of 5-chlorosulphonyl-2-methoxybenzoic acid [W. Liebenow et al. Ger. Offen. 2,721,643 (CA 90 103673j)] (10 g, 43 mmol) in water (70 ml) at 0°C was stirred with N-methylaniline (18.2 g, 172 mmol) for 10 min. and the mixture was allowed to warm to room temperature over a period of 1h. The reaction mixture was then adjusted to pH 1 with 5N hydrochloric acid. The product was recovered by extraction into dichloromethane, and the extract dried (Na2SO4) and concentrated in vacuo to a gum which crystallized from ether to give the title compound (8.3g; 60%) as needles, mp160-161°C,
1H NMR (CDCl3) δ: 3.2 (3H, s), 4.1 (3H, s), 7.08 (1H, d, J=8.5 Hz), 7.1 (2H, m), 7.3 (3H, m), 7.6 (1H, dd J=8.5,2.5 Hz), and 8.35 (1H, d, J=2.5 Hz).
The following compounds were prepared in a similar manner to Description 8:
(a) 5-[(N-Benzyl-N-Methyl)aminosulphonyl]-2-methoxybenzoic acid
mp 142-144° C (ether). Found: C, 55.28; H, 4.96, N, 4.27. C16H17NO5S. 0.75 H2O requires C, 55.08; H, 5.34; N, 4.05%. (b) 5-[(N-(4-Benzyloxyphenyl)-N-methyl)aminosulphonyl]-2-methoxybenzoic acid mp 155-157° C (ether). Found: C, 61.88; H, 4.93; N, 3.45. C22H21NO6S requires C, 61.81; H, 4.95; N, 3.28%.
(c) 5-[(N-(2,4-Difluorophenyl)-N-methyl)aminosulphonyl]-2-methoxybenzoic acid 1H NMR (CDCl3) δ: 3.22 (3H, s), 4.15 (3H, s), 6.73-6.95 (2H, m), 7.15 (1H, d), 7.35 (1H, m), 7.85 (1H, m), 8.48 (1H, d)
(d) 5-[(N-(4-Bromophenyl)-N-methyl)aminosulphonyl]-2-methoxybenzoic acid mp 178-180° C. Found: C, 44.77; H, 3.59; N, 3.52. C15H14BrNO5S requires C, 45.01; H, 3.53; N, 3.50%.
(e) 2-Methoxy-5-[(N-(4-methoxyphenyl)-N-methyl)amino-sulphonyl]benzoic acid
Mass Spectrum: found M+ 351.0787. C16H17NO6S requires 351.0776 (f) 5-[(N-(4-Cyanophenyl)-N-methyl)aminosulphonyl]-2-methoxybenzoic acid
Mass Spectrum: found M+ 346.0609. C16H14N2O5S requires 346.0623 (g) 5-[4-(3,4-Dihydro-2H-1,4-benzoxazinyl)]sulphonyl-2-methoxybenzoic acid
Found: C, 54.83; H, 4.44; N, 4.16. C16H15NO6S requires C, 55.01: H, 4.33; N, 4.01%. (h) 2-Methoxy-5-(1-(2-phenyl)pyrrolidinyl)sulphonylbenzoic acid
1H NMR (CDCl3) δ: 1.70-2.0 (3H, m), 2.10 (1H, m), 3.52 (1H, m), 3.65 (1H, m), 4.13 (3H, s), 4.80 (1H, m), 7.06 (1H, d, J = 9 Hz), 7.25 (5H, m), 7.88 (1H, dd, J = 9, 3 Hz) and 8.50 (1H, d, J = 3 Hz). (i) 2-Methoxy-5-(N-ethyl-N-((2-phenyl)ethyl)aminosulphonyl)benzoic acid
Mass spectrum: found M+ 363.1149. C18H21NO5S requires 363.1158
(j) 5-((N-Ethyl-N-(3-pyridyl)methyl)aminosulphonyl)-2-methoxy -benzoic acid 1H NMR (CDCl3) δ: 1.00 (3H, t, J = 7 Hz), 3.15 (2H, q, J = 7 Hz), 4.00 (3H, s), 4.35 (2H, s), 7.05 (1H, d, J = 8 Hz), 7.30 (1H, m), 7.70 (2H, m), 8.25 (1H, d, J = 2 Hz), 8.55 (2H, m)
(k) 2-Methoxy-5-((N-methyl-N-(5-methyl-3-isoxazolyl))amino-sulphonyl)benzoic acid
1H NMR (CDCl3) δ: 2.40 (3H, s), 3.29 (3H, s), 4.15 (3H, s), 6.50 (1H, s), 7.16 (1H, d, J = 9 Hz), 7.92 (1H, dd, J = 9,3 Hz), 8.53 (1H, d, J = 3 Hz). (l) 5-[(N-(4-Fluorophenyl)-N-methyl)aminosulphonyl]-2-methoxybenzoic acid 1H NMR (CDCl3) δ: 3.15 (3H, s), 4.00 (3H, s), 7.00 (5H, m), 7.55 (1H, dd, J=9Hz), 8.08 (1H, d, J=2Hz)
(m) 2-Methoxy-5-[(N-methyl-N-(3-pyridyl))aminosulphonyl]benzoic acid
1H NMR (d6-DMSO) δ: 3.15 (3H, s), 3.91 (3H, s), 7.33 (1H, d, J=9Hz), 7.40 (1H, dd, J=9, 6Hz), 7.56 (1H, m), 7.63 (1H, dd, J=9, 3Hz), 7.71 (1H, d, J=3Hz), 8.40 (1H, d, J=3Hz), 8.48 (1H, d, J=6Hz).
(n) 5-[(N-Ethyl-N-(4-pyridyl)methyl)aminosulphonyl]-2-methoxybenzoic acid 1H NMR (CDCl3) δ: 1.00 (3H, t, J=8Hz), 3.26 (2H, q, J=8Hz), 4.09 (3H, s), 4.41 (2H, s), 7.15 (1H, d, J=9Hz), 7.39 (2H, d, J=6Hz), 7.60-8.50 (1H, br s), 7.99 (1H, dd, J=9, 3Hz), 8.45 (1H, d, J=3Hz), 8.65 (2H, d, J=6Hz) (o) 5(1-Indolinesulphonyl)-2-methoxybenzoic acid
1H NMR (CDCl3) δ: 2.9 (2H, t J=8Hz), 3.95 (2H, t, J=8Hz), 4.10 (3H, s), 7.0 (1H, t, J=8Hz), 7.1 (2H, t, J=8Hz), 7.2 (1H, t, J=8Hz), 7.6 (1H, d, J=8Hz), 7.95 (1H, d, J=8Hz), 8.55 (1H, d, J=2Hz), 8.5-9.5(1H, br s).
(p) 5-[(N-Ethyl-N-(2-furyl)methyl)aminosulphonyl]-2-methoxybenzoic acid
1H NMR (d6-DMSO) δ: 0.95 (3H, t, J = 7Hz), 3.10 (2H, q, J = 7Hz), 3.90 (3H, s), 4.40 (2H, s), 6.40 (2H, m), 7.30 (1H, d, 8Hz), 7.50 (2H, m), 7.90 (1H, dd, J = 8,2Hz), 8.00 (1H, d, J = 2Hz).
Description 9
3-[3-(2-(1,3-Dioxanyl))propionyl]4-methoxy-(N-methyl-N-phenyl)benzensulphonamide
2-Methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)benzoic acid (7g, 21.8 mmol) in dichloromethane (50 ml) was treated with oxalyl chloride (8.2g, 65 mmol) and one drop of dimethylformamide at room temperature under an atmosphere of argon, with continuous stirring for 2 h, when the evolution of gas had ceased. The reaction mixture was then evaporated to dryness in vacuo to a gum which was repeatedly azeotroped with toluene to remove the last traces of oxalyl chloride and hydrochloric acid, to give the acid chloride, which was used directly in the next step.
To a stirred suspension of magnesium (10 g, 0.41 mol) in dry tetrahydrofuran (250 ml) under argon, was added 2-(2-bromoethyl)-1,3-dioxan (50g, 256 mmol) at such a rate to maintain moderate reflux (1/2 h), and the reaction was then heated under reflux for a further 0.5 h. The solution was then cooled and separated from the unreacted magnesium by syringe, and stored under an atmosphere of argon at 0°C to give 1-(2-(2-(1,3-dioxanyl))ethyl)magnesium bromide in tetrahydrofuran (278 ml of a 0.893 M solution). The solution of 1-(2-(2-(1,3-dioxanyl))ethyl)magnesium bromide (27ml, 24mmol) was added to a solution of 2-methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)benzoyl chloride (above), in dry tetrahydrofuran (150 ml) at -78°C under argon, at such a rate that the internal temperature did not rise above -70°C. The reaction was held at this temperature for 0.5 h and then allowed to rise to room temperature over a period of 1 h. The reaction mixture was then evaporated in vacuo and partitioned between
dichloromethane and 10% aqueous citric acid. The organic phase was separated and dried (Na2SO4), and evaporated to dryness in vacuo to a gum which was chromatographed on silica, eluting with 5%-10% ethyl acetate in dichloromethane to afford the title compound as a gum (4.03 g; 46%). 1H NMR (CDCl3) δ: 1.33 (1H, m), 2.0 (3H, m), 3.03 (2H t, J=7 Hz), 3.2 (3H, s), 3.75 (2H, t, J=12 Hz) 3.98 (3H, s) 4.08 (2H, m), 4.62 (1H, t, J=5 Hz), 6.95 (1H, d, J= 9 Hz), 7.1 (2H, m), 7.3 (3H, m), 7.53 (1H, dd, J= 9,2 Hz), and 7.85(1H d, J=2 Hz). Description 10
4-Methoxy-3-(4-oxobutanoyl)-(N-methyl-N-phenyl)benzenesulphonamide
3-[3-(2-(1,3-Dioxanyl))propionyl]4-methoxy-(N-methyl-N-phenyl)benzensulphonamide (4.0 g 10 mmol), in methanol (200 ml), was treated with 4-toluenesulphonic acid (0.5 g) and the solution was heated under reflux for 1 h, and then cooled. An excess of aqueous potassium carbonate solution was added and the mixture was evaporated in vacuo and the residue was partitioned between aqueous potassuim carbonate solution and
dichloromethane. The organic phase was separated and washed with water and evapoated to dryness in vacuo to a gum. The gum was dissolved in tetrahydrofuran (25 ml) and 5N HCl (25 ml) and then heated under reflux for 1 h. The reaction mixture was cooled and evaporated in vacuo. The product was recovered by extraction into dichloromethane, which was evaporated to dryness in vacuo to afford the title compound as a gum (3.43 g; 95%), which was used without further purification.
1H NMR (CDCl3) δ: 2.88 (2H, t, J=6 Hz), 3.18 (3H, s), 3.3 (2H, t, J=6 Hz), 4.0 (3H, s), 7.1(2H, m), 7.3 (4H, m), 7.57 (1H, d,d, J=9,2.5 Hz), 8.0 (1H, d, J=2.5 Hz,), and 9.88 (1H, s).
Description 11
2-(2-Methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl)-1H-pyrrole
4-Methoxy-3-(4-oxobutanoyl)-(N-methyl-N-phenyl)benzenesulphonamide, in
tetrahydrofuran (20 ml), was added to a solution of ammonium acetate (7 g) in ethanol (100 ml) and the reaction was heated under reflux for 2 h under argon. The reaction mixture was cooled to room temperature and the ethanol removed in vacuo to afford a gum, which was partitioned between saturated aqueous potassium carbonate solution and ether. The ether solution was dried over Na2SO4 and evaporated to in vacuo to a gum, which crystallized from ether to give the title compound (2.07 g, 53% ) as a slightly yellow solid, mp 136-138°C. Found: C, 62.44;H, 5.41; N, 7.81. C18H18N2O3S. 0.25 H2O requires, C, 62.32; H, 5.38; N, 8.07%. Description 12
2-(5-((N-Benzyl-N-ethyl)aminosulphonyl)-2-methoxyphenyl)-1H-pyrrole
5-Chlorosulphonyl-2-methoxybenzoic acid was reacted with N-benzylethylamine using the method of Description 8 to give 5-((N-benzyl-N-ethyl)aminosulphonyl)-2-methoxybenzoic acid (mp 94-96°C) and this product was further reacted by the route described in
Descriptions 9-11 to give the title compound mp 115-117°C (ether). Found: C, 64.61; H, 6.09; N, 7.59. C20H22N2O3S requires C, 64.84; H, 5.99; 7.5%.
Description 13
2-[2-Methoxy-5-(2-(1,2,3,4-tetrahydroisoquinolinyl))sulphonyl]phenyl-1H-pyrrole
5-Chlorosulphonyl-2-methoxybenzoic acid was reacted with 2-( 1,2,3,4-tetrahydroisoquinoline using the method of Description 8 to give 2-[2-methoxy-5-[2-(1,2,3,4-tetrahydroisoquinolinyl)sulphonyl]benzoic acid, (mp 158-160°C, ethyl acetate) and this product was further reacted by the route described in Descriptions 9-11 to give the titie compound mp 169-172°C (ether). Found: C, 65.01; H, 5.47; N, 7.54.
C20H20N2O3S requires C, 65.20; H, 5.47; 7.60%.
Description 14
2-Methoxy-5-(1-(1,2,3,4-tetrahydroquinolinyl)sulphonyl)-2-methoxybenzoic acid 5-Chlorosulphonyl-2-methoxybenzoic acid was treated with 1,2,3,4-tetrahydroquinoline following the method described in Description 8, to give the title compound, in 77% yield, m.p. 135-137 °C. Found: C, 59.05; H, 5.08; N, 3.97; C17H17NO5S requires C, 58.78; H, 4.93; N, 4.03%. Description 15.
2-(2-Methoxy-5-(1-(1,2,3,4-tetrahydroquinolinyl)sulphonyl)phenyl)-1H-pyrroIe
2-Methoxy-5-(1-(1,2,3,4-tetrahydroquinolinyl)sulphonyl)-2-methoxybenzoic acid was reacted according to the method of Descriptions 9-11 to give the title compound in 31% yield, m.p. 162.5-163.5°C (ether). Found: C, 64.9; H, 5.52; N, 7.55; C20H20N2O3S requires.C, 65.2; H, 5.47; N, 7.60%.
Description 16
5-((N-Ethyl-N-phenyl)aminosulphonyl)-2-methoxybenzoic acid
5-Chlorosulphonyl-2-methoxybenzoic acid was treated with N-ethylaniline following the method described in Description 8, to give the title compound, 1H NMR (CDCl3) δ: 1.1 (3H, t, J=7Hz), 3.64 (2H, q, J=7Hz), 4.13 (3H, s), 7.05 (1H, m), 7.1 (2H, m), 7.33 (3H, m), 7.71 (1H, dd J=9,2 Hz), and 8.49 (1H, d, J=2 Hz)
Description 17
2-[5-((N-Ethyl-N-phenyl)aminosulphonyl)-2-methoxyphenyl]-1H-pyrrole
5-((N-Ethyl-N-phenyl)aminosulphonyl)-2-methoxybenzoic acid was reacted according to the method of Descriptions 9-11 to give the title compound.
1H NMR (CDCl3) δ: 1.08 (3H, t, J=7 Hz), 3.60 (2H, q, J=7 Hz), 4.04 (3H, s), 6.27 (1H, m), 6.54 (1H, m), 6.89 (1H, m), 6.97 (1H, d, J=9 Hz), 7.08 (2H, m), 7.34 (4H, m), 7.81 (1H, d, J=2 Hz), and 9.70 (1H, br s).
The following compounds were also prepared from the corresponding substituted benzoic acids according to the method of Descriptions 9-11: (a) 2-[5-((N-Benzyl-N-methyl)aminosulphonyl)-2-methoxyphenyl]-1H-pyrrole mp 113-115° C (ether). Found: C.63.27; H, 5.66; N, 7.86. C19H2ON2O3S. 0.25 H2O requires C, 63.4; H, 5.85; N, 7.75%.
(b) 2-[5-((N-(4-Benzyloxy)-N-methyl)aminosulphonyl)-2-methoxyphenyl]-1H-pyrrole mp 123-124° C (ether). Found: C, 66.77; H, 5.52; N, 6.49. C25H24N2O4S requires C, 66.95; H, 5.39; N, 6.25%.
(c) 2-[5-((N-(2,4-Difluorophenyl)-N-methyl)aminosulphonyl)-2-methoxyphenyl]-1H-pyrrole
Found: C, 56.21; H, 4.26; N, 7.32%. C18H16F2N2O3S. 0.5 H2O requires, C, 55.81; H, 4.42; N, 7.23%.
(d) 2-[5-((N-(4-Bromophenyl)-N-methyl)aminosulphonyl)-2-methoxyphenyl]-1H-pyrrole
m.p. 158-159° C. Found: C, 51.23; H, 4.19; N, 6.53. C18H17BrN2O3S requires C, 51.31; H, 4.07; N, 6.65%.
(e) 2-[2-Methoxy-5-((N-(4-methoxyphenyl)-N-methyl)aminosulphonyl)phenyl]-1H-pyrrole
Found: C, 61.18; H, 5.37; N, 7.61. C19H20N2O4S requires C, 61.27; H, 5.41; N, 7.52%. (f) 2-[5-((N-(4-Cyanophenyl)-N-methyl)aminosulphonyl)-2-methoxyphenyl]-1H-pyrrole
Found: C, 62.00; H, 4.81; N, 11.35. C19H17N3O3S requires C, 62.11; H, 4.66; N, 11.44%.
(g) 2-[5-((4-(3,4-Dihydro-1,4-benzoxazinyl))sulphonyl)-2-methoxyphenyl]-1H-pyrrole
mp 115-117° C. Found: C, 61.63; H, 4.98; N, 7.54. C19H18N2O4S requires C, 61.61; H, 4.90; 7.56%.
(h) 2-[5-((N-(3,4-Dimethoxybenzyl)-N-ethyl)aminosulphonyl)-2-methoxyphenyl]-1H-pyrrole
Found: C, 61.17; H, 6.02; N, 6.67. C22H26N2O5S requires C, 61.38; H, 6.09; N, 6.51%. (i) 2-[2-Methoxy-5-((N-methyl-N-(2-methylphenyl))aminosulphonyl)phenyl]-1H-pyrrole
1H NMR (CDCl3) δ: 2.44 (3H, s), 3.14 (3H, s), 4.06 (3H, s), 6.27 (1H, m), 6.58 (1H, m), 6.66 (1H, d, J = 8 Hz), 6.91 (1H, m), 7.04 (2H, m), 7.25 (2H, m), 7.47 (1H, dd, J = 8, 3 Hz), 7.93 (1H, d, J = 3 Hz) and 9.74 (1H, br s).
(j) 2-[2-Methoxy-5-((2-(7-methylthio-1,2,3,4-tetrahydroisoquinolinyl))
sulphonyl)phenyl]-1H-pyrrole
(contaminated with 15-20% regioisomer - see Description 21 )
1H NMR (CDCl3) : 2.44 (3H, s), 2.88 (2H, t, J = 6Hz), 3.36 (2H, t, J = 6Hz), 4.04 (3H, s), 4.24 (2H, s), 6.32 (1H, m), 6.70 (1H, m), 7.00 (5H, m), 7.60 (1H, dd, J = 8,3Hz), 8.06 (1H, d, J = 3Hz), 9.74 (1H, br s).
(k) 2-[1-Methoxy-4-((N-methyl-N-phenyl)aminosulphonyl)]-2-naphthyl-1H-pyrrole m.p. 113-115° C.
(l) 2-[2-Methoxy-5-((1-(2-phenylpyrrolidinyl))sulphonyl)phenyl]-1H-pyrrole
Mass spectrum: Found M+ 382.1372. C21H22N2O3S requires 382.1393. (m) 2-[2-Methoxy-5-((N-ethyl-N-(2-phenyl)ethyl)aminosulphonyl)
phenyl]-1H-pyrrole
1H NMR (CDCl3) δ: 1.12 (3H, t, J = 7 Hz), 2.85 (2H, m), 3.25 (2H, q, J = 7 Hz), 3.38 (2H, m), 4.04 (3H, s), 6.32 (1H, m), 6.72 (1H, m), 6.90 (1H, m), 7.02 (1H, d, J = 9 Hz), 7.25 (5H, m), 7.59 (1H, dd, J = 9,3 Hz), 8.08 (1H, d, J = 3 Hz) and 9.72 (1H, br s).
(n) 2-[2-Methoxy-5-((N-methyl-N-(5-methyl-3-isoxazolyl))amino-ulfonyl)phenyl]-1H-pyrrole
1NMR (CDCl3) δ: 2.41 (3H, s), 3.29 (3H, s), 4.04 (3H, s), 6.31 (1H, m), 6.53 (1H, s), 6.63 (1H, m), 6.91 (1H, m), 7.02 (1H, d, J = 9 Hz), 7.49 (1H, dd, J = 9, 3 Hz), 7.99 (1H, d, J = 3 Hz), 9.69 (1H, br s).
(o) 2-[5-((N-(4-Fluorophenyl)-N-methyl)aminosulphonyl)-2-methoxyphenyl]-1H-pyrrole
1H NMR (CDCl3) δ: 3.15 (3H, s), 4.05 (3H, s), 6.29 (1H, m), 6.53 (1H, m), 6.90 (1H, m), 6.92 - 7.18 (5H, m), 7.30 (1H, dd, J=9, 3Hz), 7.78 (1H, d, J=3Hz), 9.53 (1H, br s).
(p) 2-(5-(1-IndoIinesulphonyl)-2-methoxyphenyl)-1H-pyrrole
Found: C, 64.37; H, 5.27; N, 7.85. C19H18N2O3S requires C, 64.39; H, 5.12; N, 7.80%.
(q) 2-(2-Methoxy-5-((N-methyl-N-(4-methylthio)phenyl)
aminosulphonyl)phenyl)-1H-pyrrole
m.p. 125-127 °C (ether).
1H NMR (CDCl3) δ: 2.5 (3H, s), 3.15 (3H, s), 4.0 (3H, s), 6.3 (1H, m,), 6.5 (1H, m), 6.8-7.4 (7H, m), 7.75 (1H, m), 9.7 (1H, s).
(r) 2-[2-Methoxy-4-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-1H-pyrrole
1H NMR (CDCl3) δ: 3.16 (3H, s); 3.74 (3H, s); 6.29 (1H, m); 6.72 (1H, m); 6.90 (2H, m); 7.2 (6H, m); 7.70 (1H, d, J = 9Hz); 9.90 (1H, br s)
(s) 2-[5-((N-Ethyl-N-(2-furyl)methyl)aminosulphonyl)-2-methoxy-phenyl]-1H-pyrrole
1H NMR (CDCl3) δ: 1.05 (3H, t, J = 7Hz), 3.20 (2H, q, J = 7Hz), 4.00 (3H, s), 4.45 (2H, s), 6.25 (3H, m), 6.70 (1H, m), 6.90 (1H, m), 7.00 (1H, d, J = 8Hz), 7.25 (1H, m), 7.55 (1H, dd, J = 8,2Hz), 8.05 (1H, d, J = 2Hz), 9.75 (1H, br s). Description 18
2-Methoxy-4-methyl-5-((N-methyl-N-phenyl)aminosulphonyl) benzoic acid
Chlorosulphonic acid (35 ml) was added dropwise over 2 h to a mixture of 2-methoxy-4-methylbenzoic acid (M Julia and Mme. Chastrette Bull. Soc. Chim. Fr 1962, 2255) (16.6 g, 100 mmol) and sodium chloride (6 g), in dichloroethane (40 ml). The mixture was warmed to 40°C for 1 h, then heated to 65°C for 17 h. The cooled mixture was poured into ice/water (ca 500 ml) and the resulting solid filtered, washed with water and hexane and dried (ca 24 g). This solid (11.5 g, 43 mmol) was added to a stirred mixture of N-methylaniline (14 g, 130 mmol) in water (100 ml). The mixture was stirred for 24 h. at ambient temperature. The resultant oily mixture was partioned between dichloromethane (100 ml) and water (100 ml). The organic layer was washed with water, extracted with 2.5 M sodium hydroxide and separated. The aqueous alkaline extract was washed with dichloromethane (50 ml), acidified with 5 M HCl and re-extracted with dichloromethane (2× 100 ml). The combined extracts were dried over Na2SO4 filtered and evaporated in vacuo. The resultant oil was triturated with dry ether to yield the title compound (8.0 g; 57%) as a colourless crystalline solid, mp 147-148°C.
1H NMR (CDCl3) δ: 2.23 (3H, s), 3.23 (3H, s), 4.07 (3H, s), 6.85 (1H, s), 7.15-7.32 (5H, m ), 8.57 (1H, s).
Description 19
5-[3-(2-(1,3-Dioxanyl))propionyl]-4-methoxy-2-methyl-(N-methyl-N-phenyl)benzenesulphonamide
2-Methoxy-4-methyl-5-((N-methyl-N-phenyl)aminosulphonyl)benzoic acid (5.0 g, 14.9 mmol) in dichloromethane (50 ml) was treated with oxalyl chloride (2.4 g, 19.5 mmol) and two drops of dimethylformamide at room temperature under an atmosphere of argon, with continuous stirring for 2 h, when the evolution of gas had ceased. The reaction mixture was repeatedly azeotroped with toluene to remove last traces of oxalyl chloride and hydrochloric acid, then triturated with hexane to give the acid chloride (5.3 g). The dried acid chloride (5.3 g, 15 mmol) was dissolved in freshly distilled tetrahydrofuran (50 ml) under argon and cooled to -75°C. The cooled Grignard reagent (15 mmol) (prepared from adding 2-(2-bromoethyl)-1,3-dioxan (2.9 g, 5 mmol) to magnesium (0.5 g) at reflux for 1 h) was added at such a rate that the internal temperature did not rise above -70°C. The reaction was held at this temperature for 0.5 h and then allowed to rise to room temperature over a period of 1 h. The reaction mixture was concentrated in vacuo then partitioned between dichloromethane and 10% aqueous citric acid. The organic phase was separated, dried over Na2SO4, filtered and evaporated in vacuo to an oil which was chromatographed on silica, eluting with 20-30% ethyl acetate in pentane to give the title compound (2.3 g; 35%) as colourless crystalline solid, mp 90-91°C
1H NMR (CDCl3) δ: 1.22-1.36 (1H, m), 1.71-2.04 (3H, m), 2.20 (3H, s), 2.99-3.06 (2H, t, J=7.2 Hz), 3.21 (3H, s), 3.69-3.81 (2H, m), 3.94 (3H, s), 4.04-4.17 (2H, m), 4.59-4.65 (1H, t, J=5 Hz), 6.76 (1H, s), 7.15-7.32 (5H, m), 8.18 (1H, s).
Description 20
2-[2-Methoxy-4-methyl-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-1H- pyrrole
5-[3-(2-(1,3-Dioxanyl))propionyl]-4-methoxy-2-methyl-(N-methyl-N-phenyl)benzenesulphonamide (2.0 g, 4.6 mmol) was dissolved in warm acetic acid (30 ml) under argon and treated with ammonium acetate (5.0 g) in water (5.0 ml). The mixture was heated under reflux for 1.5 h. The mixture was cooled, evaporated in vacuo and partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over Na2SO4, filtered and evaporated in vacuo. The resulting oil was chromatographed on silica eluting with 20-30% ethyl acetate in pentane to give the title compound (1.5 g; 91%) as a colourless crystalline solid, mp 146-147°C. Found: C, 63.23; H, 5.69; N, 7.63. C19H20N2O3S.(0.25H2O) requires C, 63.25; H, 5.68; N, 7.77%.
Description 21
1-Formyl-2-(R,S)-(2-(5-methylfuryl))-azacycloheptane
See M. Malmberg and K. Nyberg Acta Chemica Scandinavia 1981, B35, 411-417.
1-Formyl-2-methoxy-azacycloheptane (2.24g) and 2-methylfuran (15g) were stirred at room temperature and 4-toluenesulphonic acid (2.0g) was added in one portion under argon. After stirring at room temperature for 1.5 hrs, saturated sodium hydrogen carbonate (40 ml) was added, followed by diethyl ether (100 ml). The organic layer was separated and the aqueous layer was reextracted with diethyl ether (2×40 ml). The combined organic layers were washed with water (30 ml), dried (Na2SO4) and the solvent was removed in vacuo. This gave an oil (2.5g) that was chromatographed (silica gel) using 1:1 ethyl acetate : pentane as eluant. This gave the title compound in 100% yield. 1H NMR (CDCl3) exists as a mixture of E/Z isomers δ: 1.2-2.0 (6H, m), 2.25 (3H, s), 2.3-2.5, 2.65-2.75 and 3.2-3.35 (together 3H, 3 × m), 3.45-3.55 and 3.92-4.05 together (1H, 2×m), 4.5-4.6 and 5.32- 5.45 (together 1H, 2xm), 5.87 (1H, m), 6.05 (1H, m) and 8.20 (1H, s). Description 22
2-Methoxy-5-((N-methyl-N-(4-methythio)phenyl)aminosulphonyl)benzoic acid
5-Chlorosulphonyl-2-methoxybenzoic acid (10g, 40mmol) was suspended in water (70ml) and cooled to 0°C. To this was added, with stirring, N-methyl-4-methylthioaniline (6.12g 40mmol), followed by potassium carbonate (16.56g, 120mmol) in water (50ml) over 1h. The reaction was then acidified to pH 0 with 5N HCl and extracted into dichloromethane. The organic phase was dried (Na2SO4) and evaporated in vacuo to a gum which was triturated with ether to give the title compound (11.65g, 85.9%) which crystallised as needles m.p. 153-157 °C. Found: C, 52.21; H, 4.65, N, 3.91, C16H17NO5S2 requires C, 52.30; H, 4.66; N, 3.81%.
The following compounds were prepared using a procedure similar to that of Description 22: (a) 2-Methoxy-5-((N-methyl-N-(2-methylphenyl))aminosulphonyl)
benzoic acid
Found: C, 57.02; H, 5.07; N, 4.20. C16H17NO5S requires C, 57.30; H, 5.11; N, 4.18%.
(b) 2-Methoxy-5-[(2-(7-methylthio)-1,2,3,4-tetrahydroisoquinolinyl)
sulphonyl]benzoic acid
The required starting 7-methylthio-1,2,3,4-tetrahydroisoquinoline was prepared according to U.S. patent 4,228,170 and was used with a 15-20% impurity (-SMe regioisomer) to give the title compound with a similar regioisomer impurity level. Mass Spectrum: found M+ 393.0715. C18H19NO5S2 requires 393.0704.
(c) 1-Methoxy-4-((N-methyl-N-phenyl)aminosulphonyl)-2-naphthoic acid
Mass Spectrum: found M+ 371.0831. C19H17NO5S requires 371.0827
(d) 5-[(N-(3,4-Dimethoxybenzyl)-N-ethyl)aminosulphonyl]-2-methoxybenzoic acid mp 126-127 °C. Found: C, 55.43; H, 5.50; N, 3.46. C19H23NO7S requires C, 55.75; H, 5.62; N, 3.42%. Description 23
N-(3-pyridyl)methyl-ethylamine
To a stirred solution of 3-pyridylmethylamine (100g, 0.924 mol) and triethylamine (135 ml; 0.971 mol) in tetrahydrofuran (0.5 1) was added acetyl chloride (69 ml; 0.971 mol) dropwise with ice-methanol cooling. Resulting mixture was stirred at room temperature for 18 h, filtered, and the filtrate evaporated in vacuo to give an oil. The latter was distilled at 1.5 mm Hg with argon entrainment to give a fraction boiling at 158-168° C (98g). A solution of this material in dry tetrahydrofuran (100 ml) was added dropwise to an ice-cooled suspension of lithium aluminium hydride (27.25g, 0.718 mol) in dry
tetrahydrofuran (400 ml) so as to maintain an internal temperature of <20° C. The resulting solution was heated at reflux for 3 h, then was cooled to room temperature. A 1% solution of water in tetrahydrofuran (200 ml) was then added dropwise with ice cooling, followed by a saturated solution of sodium potassium tartrate in water (120 ml). The resulting mixture was stirred at room temperature for 18h, then filtered through kieselguhr. The filtrate was evaporated in vacuo and the residue purified by distillation at 1.0 mmHg with argon entrainment. The title compound was obtained as an oil (23.6g, 26%) bp 186-190° C (1.0 mmHg).
1H NMR (CDCl3) δ: 1.15 (3H, t, J = 7 Hz), 2.70 (2H, q, J = 7 Hz), 3.80 (2H, s), 7.28 (1H, m), 7.70 (1H, d, J = 6 Hz), 8.45-8.60 (2H, m).
The following compounds were prepared in a similar manner to Description 23: (a) N-Ethyl-(2-phenyl)ethylamine
1H NMR (CDCl3) δ: 1.10 (3H, t, J = 7 Hz), 2.66 (2H, q, J =7 Hz), 2.88 (4H, m) and 7.25 (5H, m).
(b) N-(4-pyridyl)methyl-ethylamine
1H NMR (CDCl3) δ: 1.16 (3H, t, J=8Hz), 2.68 (2H, q, J=8Hz), 3.83 (2H, s), 7.28 (2H, d, J=6Hz), 8.55 (2H, d, J=6Hz).
Description 24
3-Bromo-4-methoxybenzenesulphonyl chloride
2-Bromoanisole (93.5g, 0.5mol) was added dropwise to chlorosulphonic acid (165ml) with stirring and ice cooling with an internal temperature below 10°C. The mixture was warmed to room temperature and stirred for 23h. Resulting solution was carefully poured onto crushed ice (1kg) with vigorous stirring and the precipiated solid filtered off to give the title compound (126g, 99%).
1H NMR (CDCl3) δ: 4.04 (3H, s), 7.05 (1H, d, J=9Hz), 7.99 (1H, dd, J=9, 3, Hz), 8.23 (1H, d, J=3Hz).
Description 25
3-Bromo-4-methoxy-N-(2-pyridyl)methylbenzenesulphonamide
To a stirred solution of 3-bromo-4-methoxybenzenesulphonyl chloride (23g, 0.09mol) in tetrahydrofuran (100ml) at room temperature was added 2-pyridylmethylamine (20g,
0.186mol) in tetrahydrofuan (20ml). The reaction mixture was stirred at room temperature for 1.5h, then partitioned between water (300ml) and 1:1 ethyl acetate-ether (200ml). The organic phase was dried (Na2SO4) and evaporated in vacuo to give a solid.
Chromatography on silica with ethyl acetate elution gave the title compound (18.5g, 57%).
1H NMR (CDCl3) δ: 3.93 (3H, s), 4.26 (2H, d, J=6Hz), 6.09 (1H, br t, J=6Hz), 6.89 (1H, d, J=9Hz), 7.17 (2H, m), 7.62 (1H, dt, J=8, 2Hz), 7.78 (1H, dd, J=9, 3Hz), 7.99 (1H, d, J=3Hz), 8.45 (1H, m). Prepared by an analogous method to Description 25:
(a) (3-Bromo-4-methoxy-N-phenyl)benzenesulphonamide
1H NMR (CDCl3) δ: 3.93 (3H, s), 6.35 - 7.00 (1H br s), 6.86 (1H, d, J = 9Hz), 7.09 (2H, m), 7.16 (1H, m), 7.27 (2H, m), 7.65 (1H, dd, J = 9,3Hz), 7.97 (1H, d, J = 3Hz).
Description 26
3-Bromo-(N-ethyl-N-(2-pyridyl)methyl)-4-methoxybenzene-sulphonamide
To a stirred suspension of sodium hydride (80%; 0.66g, 22 mmol) in dry tetrahydrofuran (100ml) at room temperature under argon was added, portionwise over 0.1h, 3-bromo-4-methoxy-N-(2-pyridyl)methylbenzene-sulphonamide (7.14g, 20mmol). The mixture was stirred for 0.75h, then diethyl sulfate (2.9ml; 22mmol) was added in one portion and stirring was continued for 2h, followed by reflux for 2 h. The resulting mixture was cooled then partitioned between water (400ml) and ethyl acetate (3×200ml). The organic extracts were combined and washed with 1% aqueous sodium hydroxide, dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography on silica eluting with 1:1 ethyl acetate-hexane gave the title compound as an oil (6.24g, 81%). 1H NMR (CDCl3) δ: 1.01 (3H, t, J=8Hz), 3.30 (2H, q, J=8Hz), 3.97 (3H, s), 4.48 (2H, s), 6.97 (1H, d, J=9Hz), 7.21 (1H, m), 7.55 (1H, d, J=8Hz), 7.70 (1H, dt, J=8, 2Hz), 7.78 (1H, dd, J=9, 3Hz), 8.03 (1H, d, J=3Hz), 8.50 (1H, m). Description 27
l-(tert-Butoxycarbonyl)pyrrole-2-boronic acid
Prepared (80%) by an analogous method to that described in WO 93/10127.
1H NMR (CDCl3) δ: 1.62 (9H, s), 6.29 (1H, t, J = 3 Hz), 7.12 (1H, m), 7.22 (2H, s) and 7.46 (1H, m).
Description 28
1-(tert-Butoxycarbonyl)-2-(2-methoxy-5-(N-phenylaminosulphonyl)phenyl)-1H-pyrrole To a mixture of 1-(tert-butoxycarbonyl)pyrrole-2-boronic acid (1.74g, 8.2 mmol) and (3-bromo-4-methoxy-N-phenyl)benzenesulphonamide (2.12g, 6.2 mmol) in 1,2-dimethoxyethane (130 ml) under argon at room temperature was added 2M aqueous sodium carbonate (9.4 ml, 18.8 mmol) followed by tetrakistriphenylphosphine palladium (0) (0.36g, 0.3 mmol, 5 mol%). The resulting mixture was heated under reflux for three hours. On cooling, water (100 ml) was added and the mixture was extracted with dichloromethane (2 × 100 ml). The combined organic extracts were dried (Na2SO4), evaporated to dryness in vacuo and chromatographed on silica gel, eluting with
hexane/ethyl acetate (9:1) followed by hexane/ethyl acetate (7:3). The title compound (1.66g, 63%) was obtained as a white solid.
1H NMR (CDCl3) δ: 1.25 (9H, s), 3.80 (3H, s), 6.04 (1H, m), 6.22 (1H, t, J = 3
Hz), 6.60 (1H, s), 6.85 (1H, d, J = 9 Hz), 7.08-7.40 (5H, m), 7.66 (1H, d, J = 2 Hz) and 7.76 (1H, dd, J = 9,2 Hz).
Also prepared by a method analogous to that of Description 28:
(a) 1-(tert-Butoxycarbonyl)-2-(2-methoxy-5-((N-(5-(1-ethyl)pyrazolyl)-N-methyl)aminosulphonyl)phenyl)-1H-pyrrole
1H NMR (CDCl3) δ: 1.40 (9H, s), 1.52 (3H, t, J = 7 Hz), 3.10 (3H, s), 3.88 (3H, s), 4.28 (2H, q, J = 7 Hz), 5.65 (1H, d, J = 2 Hz), 6.18 (1H, m), 6.28 (1H, t, J = 3 Hz), 6.96 (1H, d, J = 9 Hz), 7.38 (1H, m), 7.42 (1H, d, J = 2 Hz), 7.62 (1H, d, J = 2 Hz) and 7.69 (1H, dd, J = 9, 2 Hz). (b) 1-(tert-Butoxycarbonyl)-2-(5-(N-methyl-N-(5-methyl-2-(1,3,4-thiadiazolyl))aminosulphonyl)-2-methoxyphenyl)-1H-pyrrole
1H NMR (CDCl3) δ: 1.30 (9H, s), 2.70 (3H, s), 3.47 (3H, s), 3.80 (3H, s), 6.15 (1H, m), 6.25 (1H, m), 6.90 (1H, d, J=9Hz), 7.38 (1H, m), 7.68 (1H, d, J=Hz), 7.75 (1H, dd, J=9.2.Hz).
Description 29
2-(2-Methoxy-5-(N-phenylaminosulphonyl)phenyl)-1H-pyrrole
To a solution of 1-(tert-butoxycarbonyl)-2-(2-methoxy-5-(N-phenylaminosulphonyl)phenyl)-1H-pyrrole (0.60g, 1.40 mmol) in anhydrous
tetrahydrofuran (1.4 ml) under argon was added a 1M solution of sodium methoxide in methanol (8.4 ml, 8.4 mmol) at room temperature. The mixture was stirred at room temperature for 1 h and then at 50° C for 2h to complete the reaction. After cooling to room temperature, water (20 ml) was added and the mixture was brought to pH 7, and extracted with ether (2× 20 ml). The combined organic extracts were washed with brine (20 ml), dried (Na2SO4) and evaporated in vacuo. The crude product was
chromatographed on silica eluting with hexane/ethyl acetate (9:1) followed by
hexane/ethyl acetate (7:3) to give the title compound (0.37g, 80%) as a white solid. Mass spectrum: found M+ 328.0870 C17H16N2O3S requires 328.0859.
Also prepared by a method similar to that of Description 29 was:
(a) 2-[5-((N-(5-(1-Ethyl)pyrazolyl)-N-methyl)aminosulphonyl)phenyl]-1H-pyrrole
Mass spectrum: found M+ 360.1260. C17H20N4O3S requires 360.1265
Description 30
2-[2-Methoxy-5-(N-methyl-N-(5-methyl-2-(1,3,4-thiadiazolyl))aminosulphonyl)-2-methoxyphenyl]-1H-pyrrole
Trifluoroacetic acid (6ml) was added to a stirred solution of 1-(tert-butoxycarbonyl)-2-[2-Methoxy-5-((N-methyl-N-(5-methyl-2-(1,3,4-thiadiazolyl)))aminosulphonyl)phenyl]-1H-pyrrole (0.6g, 1.29mmol) in dichloromethane (12ml) at 0°C under argon. The mixture was stirred at room temperature for lh. before being poured onto ice/dilute aqueous potassium carbonate. Extraction with dichloromethane (2×35ml) drying of the organic extracts (Na2SO4) and evaporation in vacuo afforded the crude title compound.
Chromatography on silica using 10-50% ethyl acetate in hexane afforded the title compound in 80% yield. 1H NMR (CDCl3) δ: 2.68 (3H,s), 3.48 (3H, s), 4.00 (3H, s), 6.30 (1H, m), 6.65 (1H, m), 6.90 (1H, m), 7.00 (1H, d, J=9Hz), 7.50 (1H, dd, J=9,2Hz), 8.05 (1H, d, H=2Hz), 9.70 (1H, br s). Description 31
5-Methyl-3-methylaminoisoxazole
A mixture of 3-amino-5-methylisoxazole (26 g, 0.27 mol) and triethyl orthoformate (130 ml) was warmed to effect solution. Trifluoroacetic acid (1 ml) was added and the resultant heated at vigorous reflux under argon with distillation of ethanol of 2 h. Excess triethyl orthoformate was evaporated in vacuo and the resulting oil dissolved in ethanol (1 1). Sodium borohydride (11.8g, 0.31 mol) was added portionwise with ice cooling. The resulting mixture was stirred at room temperature for 18 h, then was evaporated in vacuo to give a residue which was partitioned between water (500 ml) and dichloromethane (3 × 200 ml). The combined extracts were dried (N2SO4) and evaporated in vacuo to give the title compound (27g, 91%).
1H NMR (CDCl3) δ: 2.29 (3H, s), 2.88 (3H, d, J = 7 Hz), 3.89 (1H, br s), 5.48
(1H, s).
The following compounds were prepared by a similar method to that of Description 31:
(a) N-methyl-4-fluoroaniline
1H NMR (CDCl3) δ: 2.80 (3H, s), 3.60 (1H, br s), 6.50 (2H, m), 6.90 (2H, m).
(b) (3-methylamino)pyridine
1H NMR (CDCl3) δ: 2.86 (3H, d, J=7Hz), 3.84 (1H, br s), 6.86 (1H, m), 7.10 (1H, m), 7.95 (1H, m), 8.02 (1H, d, J=3Hz).
Description 32
3-Bromo-(N-(1-ethyl-(5-pyrazolyl))-N-methyl)-4-methoxybenzene
sulphonamide
Prepared from 5-amino-1-ethyl-1H-pyrazole by the method of Descriptions 25 and 31 in 39% yield.
1H NMR (CDCl3) δ: 1.50 (3H, t, J = 9 Hz), 3.09 (3H, s), 4.00 (3H, s), 4.28 (2H, q, J = 8 Hz), 5.59 (1H, d, J = 2 Hz), 6.98 (1H, d, J = 9 Hz), 7.44 (1H, d, J = 2 Hz), 7.63 (1H, dd, J = 9, 3 Hz), 7.93 (1H, d, J = 3 Hz). Description 33
2-[5-((N-Ethyl-N-(3-pyridyl)methyl)aminosulphonyl)-2-methoxy)-phenyl]-1H-pyrrole
To a stirred solution of 5-((N-ethyl-N-(3-pyridyl)methyl)aminosulphonyl)-2-methoxybenzoic acid (10.8g, 30.9 mmol) in dichloromethane (250 ml) at 0° C under argon was added triethylamine (4.8 ml, 33.9 mmol) followed, dropwise by isobutyl
chloroformate (4.2g, 33.9 mmol). Reaction mixture was stirred at 0° C for 2 h, then N,O-dimethylhydroxyammonium chloride was added, followed by triethylamine (9.54 ml; 67.8 mmol). The resulting mixture was stirred at room temperature for 18 h, then was washed with saturated aqueous sodium bicarbonate (0.5 1). The aqueous phase was extracted with dichloromethane (2 × 200 ml) and the combined organic phases were dried (Na2SO4) and evaporated in vacuo to give an oil, which was purified by chromatography on silica, eluting with 50-100% ethyl acetate - hexane. The methoxyamide thus obtained (4.42g, 11.2 mmol) was dissolved in dry tetrahydrofuran (100 ml) and treated with a solution of 1-(2-(2-(1,3-dioxanyl))ethyl)magnesium bromide in tetrahydrofuran (0.99M; 25.6 ml, 25.3 mmol). The resulting mixture was stirred at room temperature for 18 h, then was quenched with 10% aqueous citric acid (100 ml). The mixture was partitioned between water (200 ml) and dichloromethane (3 × 100 ml). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil (5.34 g). The latter was dissolved in glacial acid (100 ml) and treated with a solution of ammonium acetate (7.34g, 95.4 mmol). This solution was heated at reflux under argon for 2 h, then evaporated in vacuo. The residue was partitioned between saturated aqueous sodium hydrogen carbonate (0.5 L) and dichloromethane (3 × 100 ml). Combined extracts were dried (Na2SO4) and evaporated in vacuo to give an oil which was purified by chromatography on neutral alumina with ethyl acetate elution to give the title compound as an oil (0.35g, 8%).
Mass spectrum: found M+ 371.1312. C19H21N3O3S requires 371.1302
Also prepared by a method similar to that described in Description 33 were:
(a) 2-[2-Methoxy-5-((N-methyl-N-(3-pyridyl))aminosulphonyl)phenyl]-1H-pyrrole 1NMR (CDCl3) δ: 3.22 (3H, s), 4.03 (3H, s), 6.28 (1H, m), 6.54 (1H, m), 6.89 (1H, m), 6.98 (1H, d, J=9Hz), 7.25 (2H, m), 7.56 (1H, m), 7.82 (1H, d, J=3Hz), 8.35 (1H, d), 8.53 (1H, m), 9.71 (1H, br s). (b) 2-[5-((N-Ethyl-N-(4-pyridyl)methyl)aminosulphonyl)-2-methoxy-phenyl]-1H-pyrrole
1H NMR (CDCl3) δ: 0.98 (3H, t, J=8Hz), 3.25 (2H, q, J=8Hz), 4.05 (3H, s), 4.35 (2H, s), 6.32 (1H, m), 6.72 (1H, m), 6.93 (1H, m), 7.05 (1H, d, J=9Hz), 7.27 (2H, d, J=6Hz), 7.62 (1H, dd, J=9, 3Hz), 8.10 (1H, d, J=3Hz), 8.58 (2H, d, J=6Hz), 9.78 (1H, br s).
Description 34
2-[5-((N-Ethyl-N-(2-pyridyl)methyl)aminosulphonyl)-2-methoxyphenyl]-1H-pyrrole Prepared by methods similar to those of Descriptions 28 and 30.
1H NMR (CDCl3) δ: 1.00 (3H, t, J=8Hz), 3.29 (2H, q, J=8Hz), 4.04 (3H, s), 4.49 (2H, s), 6.32 (1H, m), 6.71 (1H, m), 6.93 (1H, m), 7.05 (1H, d, J=9Hz), 7.20 (1H, m), 7.55 - 7.77 (3H, m), 8.12 (1H, d, J=3Hz), 8.50 (1H, m), 9.75 (1H, br s). Description 35
3-Bromo-4-methoxy-N-methyl-N-(5-methyl-2-(1,3,4-thiadiazolyl))benzenesulphonamide
Prepared from 2-amino-5-methyl-l,3,4-thiadiazole by the method of Descriptions 25 and 31 in 21% yield.
1H NMR (CDCl3) δ: 2.70 (3H, s), 3.48 (3H, s), 3.97 (3H, s), 6.97 (1H, d, J=9Hz), 7.71 (1H, dd, J=9, 3Hz), 7.97 (1H, d, J=3Hz).
Description 36
N-Formyl-4-methylthioaniline
4-Methylthioaniline (25g, 0.18mol) was added to a mixture of acetic anhydride (300ml) and formic acid (11) and the reaction warmed to 70°C for a period of 2h. The reaction was then evaporated in vacuo, then partitioned between 5N HCl and dichloromethane. The organic phase was separated, washed with saturated aqueous K2CO3 and evaporated in vacuo to a gum which crystallised from ether to give the title compound as needles (28.5g, 93%) m.p. 83-84 °C. Found: C, 57.32; H, 5.43; N, 8.22; C8H9NOS requires C, 57.46; H, 5.42; N, 8.38%. Description 37
N-methyl-4-methylthioaniline.
N-Formyl-4-methylthioaniline (25g, 0.148mol) in THF (100ml) was added to a solution of LiAlH4 (5.5g, 150mmol) in ether (500ml) The reaction was heated under reflux for 2h, and quenched by the addition of excess 10% NaOH solution. The organic phase was then separated, dried (Na2SO4) and evaporated in vacuo to afford the title compound (22.16g, 97%).
1H NMR (CDCl3 ) δ: 2.4 (3H, s), 2.85 (3H, s), 3.75 (1H, s), 6.5 (2H, d, J=8Hz), 7.25 (2H, d, J=8Hz).
Description 38
2-Methoxy-4-chlorosulphonylbenzoic acid, ethyl ester
4-Amino-2-methoxybenzoic acid, ethyl ester (30.0g 0.154 mol) was stirred with a mixture of concentrated hydrochloric acid (150 ml) and acetic acid (36 ml) until dissolved. The mixture was cooled to -10° C. A solution of sodium nitrite
(10.80g 0.154 mol) in water (15 ml) was added over 45 min, the reaction temperature being maintained at -10° C. The reaction was stirred at this temperature for a further 3 hr.
A suspension of cuprous chloride (3.84g 0.04 mol) in acetic acid (154.5 ml) was saturated with sulphur dioxide at room temperature. The mixture was cooled to 10° C and the solution of the diazonium salt prepared above was added over
45 min. The reaction temperature was kept below 30° C.
The reaction mixture was stirred at 10° C for 30 min, then poured into water
(11) and extracted with dichloromethane. The organic phase was washed with water, dried (Na2SO4) and evaporated to give an oil (38.08g).
Chromatography (Si gel) using dichloromethane as elutant gave an oil (26.51g
73%).
1H NMR (CDCl3) δ: 1.40 (3H, t, J = 7Hz); 4.01 (3H, s); 4.39 (2H, q, J = 7Hz);
7.56 (1H, d, J = 3Hz); 7.64 (1H, dd, J = 9,3Hz); 7.90 (1H, d, J = 9Hz).
Description 39
2-Methoxy-4-((N-methyl-N-phenyl)aminosulphonyl)benzoic acid, ethyl ester
2-Methoxy-4-chlorosulphonylbenzoic acid, ethyl ester (15.00g, 0.064 mol) was dissolved in dichloromethane (130 ml) under argon. N-Methylaniline (20.80 ml 0.19 mol) was added and the mixture stirred at room temperature for 4 hr. The reaction mixture was extracted with 5N hydrochloric acid and then with water. The organic phase was dried (Na2SO4) and evaporated to give an oil (19.45g 77% yield).
1H NMR (CDCl3) δ: 1.38 (3H, t, J = 7Hz); 3.19 (3H, s); 3.72 (3H, s); 4.36 (2H, q, J = 7Hz); 6.93 (1H, d, J = 3Hz); 7.21 (6H, m); 7.80 (1H, d, J = 9Hz).
Description 40
2-Methoxy-4-((N-methyl-N-phenyl)aminosulphonyl)benzoic acid
2-Methoxy-4-((N-methyl-N-phenyl)aminosulphonyl)benzoic acid, ethyl ester (19.45g, 0.049 mol) was dissolved in methanol (400 ml). A 40% w/v solution of sodium hydroxide in water (51 ml) was added and the mixture stirred at room temperature for 1 hr. The methanol was evaporated in vacuo and the residue dissolved in water. The mixture was acidified with concentrated hydrochloric acid and the resulting solid filtered, washed with water and dried over phosphorus pentoxide in vacuo to give the title compound as a white solid (16.11g 83%).
1H NMR (CDCl3) δ: 3.22 (3H, s); 3.89 (3H, s); 7.02 (1H, d, J = 3Hz); 7.09 (2H, m), 7.27 (4H, m); 8.21 (1H, d, J = 9Hz).
Description 41
4-Chlorosulfonyl-1-methoxy-2-naphthoic acid
1-Methoxy-2-naphthoic acid (25 g, 0.124 mol) was added portionwise, with stirring, to chlorosulfonic acid (125 mL), cooled with an ice-methanol bath. The reaction mixture was then stirred at room temperature for 4h, and added dropwise to crushed ice (50 g). Filtration gave the title compound (8.3 g) as an off-white solid.
NMR (CDCl3) δ 4.27 (3H, s), 7.81 (1H, t, J = 7Hz), 7.95 (1H, dt, J = 7, 1 Hz), 8.50 (1H, d, J = 7 Hz), 8.81 (1H, d, J = 7 Hz), 8.95 (1H, s).
Example 1
2-(2-Methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl)-5-(1-(2-(R,S)phenylazacycloheptyl)-methyl)-1H-pyrrole Oxalate
1-Formyl-2-(R,S)-phenylazacycloheptane (1.185 g, 5.84 mmol) was treated with phosphorus oxychloride (0.887 g, 5.84 mmol) at 0°C, under argon, with continuous stirring. The reaction was allowed to warm up to room temperature over a period of 1h and was diluted with 1,2-dichloroethane (10 ml). The solution was cooled to 0°C and then was treated with 2-(2-methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl)-1H-pyrrole (1 g, 2.92 mmol), and the reaction was stirred at 0°C for 3 h, and then was allowed to warm to room temperature overnight. The reaction mixture was cooled to 0°C and then was treated with sodium borohydride (1 g) and stirred at this temperature for 1h. The reaction mixture was treated with methanol (5 ml) at such a rate that the temperature did not rise above 10°C, and excessive frothing was avoided. It was then quenched by the addition of water (10 ml) and the reaction mixture was partitioned between water and saturated aqueous potassium carbonate. The organic phase was separated, dried over Na2SO4, and concentrated in vacuo to a gum. Chromatography on silica, eluting with 10% ethyl acetate in dichloromethane, gave the free base of the title compound, as a gum. The gum was dissolved in ether and treated with excess oxalic acid in ether to give the title compound as a powder (1.16g; 65%), m.p. 86-89°C (sinters). Found: C, 62.36; H, 5.91; N, 6.5; C31H35N3O3S·C2H 2O4·H2O requires, C, 62.15; H, 6.02; N, 6.78%.
The following compounds were also prepared from the corresponding pyrrole according to the procedure of Example 1:
(a) 2-[5-((N-Benzyl-N-methyl)aminosulphonyl)-2-methoxyphenyl]-5-[1-(2-(R,S)-phenylazacycloheptyl)methyl]-1H-pyrrole oxalate
m.p. 92-96° C (ether). Found: C, 62.96; H, 6.04; N, 6.51. C32H37N3O3S. C2H2O4. H2O requires C, 62.66; H, 6.34; N, 6.45%.
(b) 2-[2-Methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-5-(1-(R,S)-(2-phenylpyrrolidinyl)methyl)-1H-pyrrole oxalate
m.p. 133-135° C. 1H NMR (d6-DMSO) δ: 1.89-2.10 (3H, br m); 2.23-2.41 (1H, br m); 2.93-3.09 (1H, br m); 3.11 (3H, s); 3.31- 3.46 (1H, br s); 3.92 (3H, s); 3.95-4.27 (3H, br m); 6.18 (1H, br s); 6.43 (1H, m); 7.08- 7.42 (10H, m); 7.49 (2H, d, J = 7Hz); 7.62 (1H, S); 11.20 (1H, br s).
(c) (-)-2-[2-Methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-5-(1-(2-phenylpyrrolidinyl methyl)-1H-pyrrole oxalate
m.p. 86-88° C. 1H NMR (d6-DMSO) δ: 1.90-2.11 (3H, br m); 2.28-2.43 (1H, br m);
2.97-3.10 (1H, br m); 3.15 (3H, s); 3.35- 3.49 (1H, br s); 3.92 (3H, s); 3.95-4.28 (3H, br m); 6.19 (1H, m); 6.45 (1H, m); 7.08-7.52 (12H, m); 7.61 (1H, d, J = 2Hz); 11.20 (1H, br s). (d) (+)-2-[2-Methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-5-(1-(2-phenylpyrrolidinyl)methyl)-1H-pyrrole oxalate
m.p. 88-90° C. 1H NMR (d6-DMSO) δ: 1.90-2.10 (3H, br m); 2.24-2.41 (1H, br m); 2.93-3.09 (1H, br m); 3.14 (3H, s); 3.33- 3.48 (1H, br m); 3.92 (3H, s); 3.96-4.29 (3H, br m); 6.18 (1H, br s); 6.45 (1H, br s); 7.08-7.54 (12H, m); 7.63 (1H, s); 11.20 (1H, br s).
(e) (-)-2-[2-Methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-5-(1-(2-phenylpiperidinylmethyl)-1H-pyrrole oxalate
m.p. 111-113° C. 1H NMR (d6-DMSO) δ: 1.39-1.61 (1H, br m); 1.73-2.01 (6H, br m); 2.55-2.72 (1H, br m); 3.14 (3H, s); 3.24 (1H, br d, J = 11Hz); 3.75 (1H, br d, J = 15Hz); 3.91 (1H, br d, J = 15Hz); 3.95 (3H, s); 6.11 (1H, m); 6.47 (1H, m); 7.10-7.68 (13H, m); 11.28 (1H, br s).
(f) (+)-2-[2-Methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-5-(1-(2-phenylpiperidinyl)methyl)-1H-pyrrole oxalate
m.p. 112-114° C. 1H NMR (d6-DMSO) δ: 1.39-1.61 (1H, br m); 1.71-2.02 (6H, br m); 2.53-2.71 (1H, br m); 3.14 (3H, s); 3.25 (1H, br d, J = 11Hz); 3.74 (1H, br d, J = 14Hz); 3.90 (1H, br d, J = 14Hz); 3.95 (3H, s); 6.11 (1H, m); 6.48 (1H, m); 7.09-7.69 (13H, m); 11.26 (1H, br s).
(g) 2-(5-((N-(4-Bromophenyl)-N-methyl)aminosulphonyl)-2-methoxyphenyl)-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole, oxalate
m.p. 100-102° C. Found: C, 55.51; H, 5.04; N, 5.78. C31H34Br N3O3S. C2H2O4. H2O requires C, 55.31; H, 5.34; N, 5.86%.
(h) 2-(2-Methoxy-5-((N-(4-methoxyphenyl)-N-methyl)amino-sulphonyl)phenyl)-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole, oxalate
m.p.91-92° C. Found: C, 61.85; H, 5.89; N, 6.38. C32H37N3O4S. C2H2O4. 0.5H2O requires C, 61.99; H, 6.12; N, 6.38%.
(i) 2-(5-((N-(4-Cyanophenyl)-N-methyl)aminosulphonyl)-2-methoxyphenyl)-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole oxalate
m.p. 101-102° C. Mass Spectrum: Found MH+ 555. C32H34N4O3S requires MH+ 555. (j) 2-(5-(4-(3,4-Dihydro-1,4-benzoxazinyl)sulphonyl)-2-methoxy-phenyl)-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole
m.p. 123-124° C. Found: C, 68.81; H, 6.34; N, 7.68. C32H35N3O4S requires C, 68.92; H, 6.33; N, 7.53%.
A small sample of the title compound was converted to the oxalate, mp 103-105° C.
(k) 2-(5-((N-(3,4-Dimethoxybenzyl)-N-ethyl)aminosulphonyl)-2-methoxyphenyl)-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole oxalate
m.p. 90-94° C. Mass Spectrum: found M+ 617.2934 C35H43N3O5S requires M+ 617.2923 (l) 2-(2-Methoxy-5-(2-(7-methylthio-1,2,3,4-tetrahydroisoquinolin-2-yl)sulphonyl)phenyl)-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl-1H-pyrrole
(contaminated with 15 - 20% regioisomer).
m.p. 70-71 °C. Found: C, 67.20; H, 6.44; N, 6.85. C34H39N3S2O3. 0.5 H2O requires C, 66.85; H, 6.60; N, 6.88%.
(m) 2-(5-(1-Indolinesulphonyl)-2-methoxyphenyl)-5-(1-(2-(R,S)-phenyl
azacycloheptyl)methyl)-1H-pyrrole Oxalate
m.p. 106-109 °C (ether). Found:C, 63.54; H, 5.91; N, 6.53. C32H35N3O3S. C2H2O4 0.5H2O requires C, 63.73; H, 5.98; N, 6.56%.
(n) 2-(2-Methoxy-5-((N-methyl-N-(4-methylthio)phenyl)aminosulphonyl)phenyl)-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole oxalate
m.p. 104-107 °C. Found: C, 60.63; H, 5.73, N; 6.47. C32H37N3O3S2.C2H2O4.O.5 H2O requires C, 60.52; H, 5.97; N, 6.23%.
Example 2
2-(2-Methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl)-5-(1-(2-(R)-phenylazacycloheptyl)methyl)-1H-pyrrole, Oxalate
1-Formyl-2-(R)-phenylazacycloheptane (0.21 g) and 2-(2-methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl)-1H-pyrrole (0.31 g) were reacted using a procedure similar to that of Example 1 to give the title compound (0.26 g, 42%) mp 95-97°C.
1H NMR (d6-DMSO) δ: 1.45 - 2.14 (8H, br m), 2.93 - 3.31 (2H, br m), 3.12 (3H, s), 3.79 (2H, br s), 3.95 (3H, s), 4.12 (1H, br s), 6.10 (1H, br s), 6.45 (1H, br s), 7.08 - 7.46 (10H, m), 7.52 (2H, d, J=7 Hz), 7.62 (1H, br s), and 10.86 - 11.02 (1H, br s). [α]D 20 + 19.3° (c, 0.86%, MeOH)
Example 3
2-(2-Methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl)-5-(1-(2-(S)-phenylazacycloheptyl)methyl)-1H-pyrrole, Oxalate
1-Formyl-2-(S)-phenylazacycloheptane (0.21 g) and 2-(2-methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl)-1H-pyrrole (0.31 g) were reacted using-a procedure similar to that of Example 1 to give the title compound (0.244 g, 39%) mp 96-98°C 1H NMR (d6-DMSO) δ: 1.46 - 2.18 (8H, br m), 2.96 - 3.34 (2H, br m), 3.12 (3H, s), 3.81 (2H, br s;, 3.95 (3H, s), 4.16 (1H, br s), 6.12 (1H, br s), 6.45 (1H, br m), 7.10 - 7.48 (10H, m), 7.53 (2H, d, J=7 Hz), 7.63 (1H, s), and 10.90 - 11.10 (1H, br s). [α]D 20 -20.1° (c,
0.72% MeOH). Example 4
2-[5-((N-Benzyl-N-ethyl)aminosulphonyl)-2-methoxyphenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole Hydrochloride
Phosphoryl chloride (0.33 ml; 0.54 g; 3.5 mmol) was added dropwise to 1-formyl-2-(R,S)-phenylazacycloheptane (0.65 g; 3.2 mmol) at 0°C under argon, and then stirred at room temperature for 0.5 h. 1,2-dichloroethane (20 ml) was added and the solution was cooled (ice/salt) before adding a solution of 2-(5-((N-benzyl-N-ethyl)aminosulphonyl)-2-methoxyphenyl)-1H-pyrrole (0.6 g; 1.6 mmol) in 1,2 -dichloroethane (20 ml), dropwise. The mixture was stirred at room temperature for 18 h. The reaction mixture was cooled to 0°C (ice) and sodium borohydride (0.66 g) was added portionwise. The mixture was stirred at room temperature for 2 h. The excess hydride was decomposed by dropwise addition of methanol (5 ml) and water (10 ml). The mixture was partitioned between water and dichloromethane and the aqueous fraction was further extracted with dichloromethane. The combined organic fractions were dried (Na2SO4), evaporated in vacuo, and chromatographed on silica gel, eluting with hexane, followed by hexane/ether (1:1) to afford the free base of the title compound (0.5 g) (55%) as an oil. A portion (0.35 g) of the product was dissolved in chloroform and then shaken with 0.5 N hydrochloric acid. The organic phase was dried (Na2SO4) and evaporated to dryness in vacuo to afford a semi-solid which was triturated with ether to afford the title compound (0.32 g), mp 82-85°C. Found: C, 66.55; H, 6.53; N, 7.01. C33H39N3O3S.HCl requires C, 66.70; H, 6.79; 7.07 %. The following compounds were also prepared from the corresponding pyrroles according to the procedure of Example 4:
(a) 2-[5-((N-(4-Benzyloxyphenyl)-N-methyl)aminosulphonyl)-2-methoxyphenyl]-5-[1-(2-(R,S)-phenylazacycloheptyl)methyl]-1H-pyrrole
m.p. 137-139 °C (CHCl3-Et2O). Found: C, 71.38; H, 6.48; N, 6.61. C38H41N3O4S requires C, 71.78; H, 6.50; N, 6.61%.
(b) 2-[5-((N-(2,4-Difluorophenyl)-N-methyl)aminosulphonyl-2-meihoxyphenyl]-5-(1-(2-(R,S) phenylazacycloheptyl)methyl)-1H-pyrrole hydrochloride
Found: C, 61.22; H, 5.91; N, 6.65% C31H33F2N3O3S. HCl. 0.5 H2O requires C, 60.92; H, 5.77; N, 6.88%.
(c) 2-[2-Methoxy-5-(N-methyl-N-phenyl)aminosulphonyl)phenyl]-5-(1-(2-(R)-phenylazacycloheptyl)methyl)-1H-pyrrole hydrochloride
m.p. 106-108 °C.
1H NMR (d6-DMSO) as protomers δ: 1.60 - 2.12 (7H, br m); 2.23-2.46 (1H, br m); 3.15 (3H, s); 3.21-3.32 (1H, br m); 3.45- 3.59 (1H, br m); 3.96 and 4.00 together (3H, s); 4.01-4.17 (2H, m); 4.41 (1H, t, J = 8Hz); 6.21 and 6.26 together (1H, t, J = 2Hz); 6.37 and 6.44 together (1H, t, J = 2Hz); 7.16 (2H, d, J = 8Hz); 7.20-7.52 (9H, m); 7.63 (1H, s); 7.74 (1H, d, J = 7Hz); 11.02 (1H, br s); 11.47 and 11.86 together (1H, br s).
(d) 2-[2-Methoxy-5-((1-(2-phenylpyrrolidinyl))sulphonyl)phenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole hydrochloride
Found: C, 66.87; H, 6.66; N, 6.85. C34H39N3O3S. HCl. 0.25 H2O requires C, 66.87; H, 6.68; N, 6.88%.
(e) 2-[2-Methoxy-5-((N-ethyl-N-(2-phenyl)ethyl)aminosulphonyl)-phenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole hydrochloride
Found: C, 66.14; H, 6.82; N, 6.62. C34H41N3O3S. HCl. 0.5 H2O requires C, 66.16; H, 7.02; N, 6.81%.
(f) 2-[2-Methoxy-5-(N-phenylaminosulphonyl)phenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole hydrochloride
Found: C, 64.44; H, 6.32; N, 7.26. C30H33N3O3S requires C, 64.21; H, 6.29; N, 7.49%. (g) 2-[5-((N-(5-(1-Ethyl)pyrazolyl)-N-methyl)aminosulphonyl)-2-methoxyphenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole hydrochloride
Found: C, 60.60; H, 6.55; N, 11.63. C30H37N5O3S HCl. 0.5 H2O requires C, 60.74; H, 6.63; N, 11.81%.
(h) 2-[2-Methoxy-5-((N-methyl-N-(5-methyl-3-isoxazolyl))amino-sulphonyl)phenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole, hydrochloride
FAB Mass spectrum: MH+ 535.2310. C29H35N4O4S requires 535.2379 (i) 2-[5-((N-Ethyl-N-(3-pyridyl)methyl)aminosulphonyl)-2-methoxyphenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole, hydrochloride
FAB Mass spectrum: M+ 558.2690. C32H38N4O3S requires 558.2664. (j) 2-[2-Methoxy-5-((N-methyl-N-(3-pyridyl))aminosulphonyl)phenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole, hydrochloride
Found: C, 61.35; H, 6.17; N, 9.42. C30H34N4O3S. HCl. H2O requires C, 61.58; H, 6.37; N, 9.57%.
(k) 2-[2-Methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-5-(1-(R,S)-(1-piperidinyl)ethyl)-1H-pyrrole, hydrochloride
m.p. 120-30 °C; Found: C, 59.47; H, 6.42; N, 8.45. C25H31N3O3S. HCl. H2O requires C, 59.10; H, 6.75; N, 8.27%.
(l) 2-[5-((N-Ethyl-N-(4-pyridyl)methyl)aminosulphonyl)-2-methoxy)
phenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole, hydrochloride m.p. 130-160 °C dec. Mass spectrum: found M+ 558.2708. C32H38N4O3S requires 558.2664.
(m) 2-[5-((N-Ethyl-N-(2-pyridyl)methyl)aminosulphonyl)-2-methoxy-phenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrroIe, hydrochloride
mp. 135-150°C dec. FAB mass spectrum: found M+ 558.2669. C32H38N4O3S requires 558.2664 (n) 2-[5-((N-Ethyl-N-(2-furyl)methyl)aminosulphonyl)-2-methoxy-phenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl-1H-pyrrole Hydrochloride
Found: C, 63.20; H, 6.33; N, 7.07; C31H37N3O4S. HCl, 0.25H2O requires C, 63.25; H, 6.59; N, 7.14%.
(o) 2-[5-((N-(4-Fluorophenyl)-N-methyl)aminosulphonyl)-2-methoxyphenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole Hydrochloride
m.p. 116-120 °C. Found: C, 61.79; H, 5.79; N, 6.97; C31H34FN3O3S. HCl. H2O requires. C, 61.83; H, 6.19; N, 6.98%.
(p) 2-[2-Methoxy-5-((N-methyl-N-(5-methyl-2-(1,3,4-thiadiazolyl))
aminosulphonyl)phenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)
methyl)-1H-pyrrole Hydrochloride
m.p. 123.5-126 °C. Mass spectrum: Found MH+ 552.2067; C28H33N5O3S2 requires MH+ 552.2103
(q) 2-[2-Methoxy-4-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-5-[1-(2-(R,S)-phenylazacycloheptyl)methyl]-1H-pyrrole hydrochloride
m.p. 122-132 °C (ether). Found: C, 64.73; H, 6.16; N, 7.29. C31H35N3O3S. HCl. 0.5H2O requires C, 64.73; H, 6.48; N, 7.36%.
(r) 2-[2-Methoxy-4-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-5-(1-(2-(R,S)-phenyl-1-pyrrolidinyl)methyl)-1H-pyrrole hydrochloride
m.p. 99-110 °C (ether). Found C, 62.28; H, 5.75; N, 7.52. C29H31N3O3S. HCl. H2O requires C, 62.63; H, 5.98; N, 7.56%.
(s) 2-(2-Methoxy-5-((N-methyl-N-(2-methylphenyl))aminosulphonyl)
phenyl)-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole hydrochloride m.p. 125-130 °C. Found: C, 64.96; H, 6.46; N, 7.22. C32H37N3O3S. HCl. 0.5 H2O requires C, 65.24; H, 6.66; N, 7.13%. Example 5
2-[5-((N-Benzyl-N-ethyl)aminosulphonyl)-2-methoxyphenyl]-5-[1-(2-(R)-phenylazacycloheptyl)methyl]-1H-pyrrole Oxalate
1-Formyl-2-(R)-phenylazacycloheptane and 2-[5-((N-benzyl-N-ethyl)aminosulphonyl)-2-methoxyphenyl]-1H-pyrrole were reacted using a procedure similar to that of Example 1 to give the title compound in 27% yield, mp 78-79°C.
1H NMR (d6-DMSO) δ: 0.83 (3H, t, J=7 Hz), 1.50 - 1.83 (6H, br m), 1.89 - 2.12 (2H, br m), 3.01 - 3.17 (1H, br m), 3.11 (2H, t, J=7 Hz), 3.22 - 3.34 (1H, br m), 3.82 (2H, br s), 3.98 (3H, s), 4.10 - 4.22 (1H, br m), 4.32 (2H, s), 6.14 (1H, br s), 6.67 (1H, t, J=3 Hz), 7.21 - 7.43 (9H, m), 7.52 (2H, d, J=7 Hz), 7.66 (1H, dd, J=8,2 Hz), 7.97 (1H, d, J=2 Hz), and 10.93 - 11.10 (1H, br s). [α]D 20 +22.7° (c, 0.48% MeOH).
Example 6
2-[5-((N-Benzyl-N-ethyl)aminosulphonyl)-2-methoxyphenyl]-5-[1-(2-(S)-phenylazacycloheptyl)methyl]-1H-pyrrole Oxalate
1-Formyl-2-(S)-phenylazacycloheptane and 2-[5-((N-benzyl-N-ethyl)aminosulphonyl)-2-methoxyphenyl]-1H-pyrrole were reacted using a procedure similar to that of Example 1 to give the title compound in 29% yield; mp 78-79°C.
1H NMR (d6-DMSO) δ: 0.83 (3H, t, J=8 Hz), 1.49 - 1.84 (6H, br m), 1.88 - 2.00 (1H, br m), 2.01 - 2.15 (1H, br m), 3.00 - 3.16 (1H, br m), 3.11 (2H, q, J=8 Hz), 3.20 - 3.33 (1H, br m), 3.82 (2H, br s), 3.98 (3H, s), 4.10 - 4.21 (1H, br m), 4.32 (2H, s), 6.14 (1H, br s), 6.68 (1H, t, J=3 Hz), 7.21 - 7.44 (9H, m), 7.53 (2H, d, J=7 Hz), 7.66 (1H, dd, J=7,2 Hz), 7.96 (1H, d, J=2 Hz), and 10.96 - 11.11 (1H, br s). [α]D 20 -19.1° (c, 1% MeOH). Example 7
2-[2-Methoxy-5-((2-(1,2,3,4-tetrahydroisoquinolinyl))sulphonyl)phenyl]-5-[1-(2-(R,S)-phenylazacycloheptyl)methyl]-1H-pyrrole Oxalate
1-Formyl-2-(R,S)-phenylazacycloheptane and 2-[2-methoxy-5-((2-(1,2,3,4-tetrahydroisoquinolinyl))sulphonyl)phenyl)-1H-pyrrole were reacted using a procedure similar to that of Example 1, to give the title compound in 50% yield; mp 116-118°C
(ether). Found: C, 64.12; H, 5.95; N, 6.46. C33H37N3O3S. C2H2O40.5 H2O requires C, 64.20; H, 6.15; 6.42 %. Example 8
2-[2-Methoxy-5-((1-(1,2,3,4-Tetrahydroquinolinyl))sulphonyl)
phenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl-1H-pyrrole Oxalate
1-Formyl-2-(R,S)-phenylazacycloheptane (0.77 g, 3.8 mmol) and 2-[2-methoxy-5-((1-(1,2,3,4-tetrahydroquinolinyl))sulphonyl)phenyl]-1H-pyrrole (1 g, 2.71 mmol) were
reacted by the method of Example 1 to give the title compound (1.45 g, 83%) as needles, mp 102-105 °C. Found: C; 63.68; H; 5.89, N; 6.38; C33H37N3O3S·C2H2O4·H2O
requires C, 63.33; H, 6.23; N, 6.33%. Example 9
2-[5-((N-Ethyl-N-phenyl)aminosulphonyl)-2-methoxyphenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole Hydrochloride
2-(5-((N-Ethyl-N-phenyl)aminosulphonyl)-2-methoxyphenyl)-1H-pyrrole and 1-formyl-2-(R,S)-phenylazacycloheptane were reacted by the method of Example 4 to give the title compound.
1H NMR (CDCl3) (mixture of protomers) δ: 1.07 (3H, t, J=7 Hz), 1.45 (m) and 1.70 (m) (together 1H), 1.8 - 2.18 (5H, m), 2.33 (m) and 2.47 (m) (together 1H), 2.55 (m) and 2.82 (m) (together 1H), 3.03 (m) and 3.25 (m) (together 1H), 3.15 (m) and 3.60 (m) (together 1H), 3.45 (m) and 4.27 (m) (together 1H), 3.60 (2H, m), 3.96 (m) and 5.03 (m) (together 1H), 4.13 (s) and 4.20 (s) (together 3H), 6.00 (m) and 6.33 (m) (together 1H), 6.14 (m) and 6.33 (m) (together 1H), 6.93 (d, J=9 Hz) and 6.96 (d, J=9 Hz) (together 1H), 7.08 (m) and 7.70 (m) (together 1H), 7.08 (1H, m), 7.27-7.54 (9H, m), 7.77 (1H, d, J=9 Hz), 11.39 (br s) and 11.95 (br s) (together 1H), 11.45 (br s) and 12.27 (br s) (together 1H).
Example 10
2-[2-(R,S)-(1-Ethylpyrrolidinyl)]-5-[(2-methoxy-4-methyl-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-1H- pyrrole
1-Ethyl-2-pyrrolidinone (0.31 g, 2.7 mmol) was treated with phosphorus oxychloride (0.55 g, 2.7 mmol) at 0°C, under argon, with continuous stirring. The reaction was allowed to warm to room temperature over a period of 1 h and was diluted with dichloroethane (10 ml). The solution was cooled to 0°C and was treated with 2-(2-methoxy-4-methyl-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl)-1H- pyrrole (0.75 g, 2.1 mmol), and the reaction stirred at 0°C for 3 h, and then allowed to warm to room temperature overnight. The reaction was cooled to 0°C and then was treated with sodium borohydride (0.75 g) and stirred at this temperature for 1 h. The reaction mixture was cooled to 0°C and treated with methanol (3 ml) with stirring. It was quenched by addition of water (10 ml) and partitioned between saturated aqueous potassium carbonate (20 ml) and dichloromethane (3 × 50 ml). The organic phase was separated, washed with brine, dried (Na2SO4), and evaporated in vacuo. The resulting oil was chromatographed on silica eluting with 3-5% methanol in dichloromethane to give the title compound ( 0.322 g; 34%) as a foam.
1H NMR (CDCl3) δ: 1.06-1.21 (3H, m), 1.80-2.60 (9H, m), 2.72-2.95 (1H, m), 3.20 (3H, s), 3.47-3.72 (2H, m), 4.03 (3H, s), 6.11 (1H, m ), 6.46 (1H, m), 6.73 (1H, s), 7.21-7.31 (5H, m), 8.00 (1H, s), 9.90-10.30 (1H, br s ).
The following compounds were prepared by a method similar to that of Example 10:
(a) 2-[5-((N-(4-Cyanophenyl)-N-methyl)aminosulphonyl)-2-methoxyphenyl]-5-(2-(R,S)-(1-ethylpyrroIidinyl))-1H-pyrrole hydrochloride
m.p. 108-110 °C. Mass Spectrum: found M+ 464.1894. C25H28O3N4S requires
464.1883.
(b) 2-[2-(R,S)-(1-Ethylpyrrolidinyl))-5-(2-methoxy-5-((N-methyl-N-phenyl]aminosulphonyl)phenyl)-1H-pyrrole
m.p. 55-57 °C. Mass Spectrum: found M+ 439.1947. C24H29N3O3S requires
439.1910.
(c) 2-(2-(R,S)-(1-Ethylpyrrolidinyl))-5-[2-methoxy-5-((N-methyl-N-(4-methylthio)phenyl)aminosulphonyl)phenyl]-1H-pyrroIe, hydrochloride
m.p. 106-108 °C. Found: C, 55.38; H, 6.05; N, 7.68. C25H31N3O3S2. HCl. H2O
requires C, 55.59; H, 6.34; N, 7.78%.
(d) 2-(2-(R,S)-(1-Ethylpyrrolidinyl))-5-[2-methoxy-5-((1-(1,2,3,4-tetrahydroquinolinyl))aminosulphonyl)phenyl]-1H-pyrrole
m.p. 51-53 °C. Mass Spectrum: found M+ 465.2087. C26H31N3O3S requires 465.2086. (e) 2-(2-(R,S)-(1-Ethylpyrrolidinyl))-5-(1-methoxy-4-((N-methyl-N-phenyl)aminosulphonyl)-2-naphthyl)-1H-pyrrole hydrochloride
m.p. 161-163 °C. Mass Spectrum: found M+ 489.2100. C28H31N3O3S requires
489.2087 (f) 2-(2-(R,S)-(1-n-Butylpyrrolidinyl))-5-[2-methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-1H-pyrrole hydrochloride
m.p. 97-99 °C. Mass Spectrum: found M+ 467.2240. C26H33N3O3S requires 467.2243. (g) 2-[2-(R,S)-(1-Ethylpyrrolidinyl)]-5-[2-methoxy-4-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-1H-pyrrole hydrochloride
m.p. 195-196 °C (ethyl acetate). Found: C, 60.30; H, 6.21; N, 8.75. C24H29N3O3S.
HCl requires C, 60.56; H, 6.35; N, 8.83%. Example 11
2-[2-Methoxy-4-methyl-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl)-5-(1-(2-(R)-phenylazacycloheptyl)methyl)-1H-pyrrole
1-Formyl-2-(R)-phenylazacycloheptane (0.365 g, 1.76 mmol) and 5-[2-methoxy-4-methyl-5-[(N-methyl-N-phenyl)aminosulphonyl)phenyl]-1H- pyrrole (0.492 g, 1.38 mmol) were reacted using a procedure similar to that of Example 4 to give the title compound (0.40 g; 53%) as a foam. 1H NMR ( CDCl3) δ: 1.45-2.05 (8H, m), 2.18 (3H, s), 2.72-3.12 (2H, m), 3.20 (3H, s),
3.47-3.72 (3H, m), 4.03 (3H, s), 5.99 (1H, m), 6.42 (1H, m), 6.74 (1H, s), 7.15-7.51 (10H, m), 8.00 (1H, s), 9.65-9.70 (1H, br s). Example 12
2-[5-((N-(4-Hydroxyphenyl)-N-methyl)aminosulphonyl)-2-methoxyphenyl]-5-[1-(2-(R,S)-phenylazacycloheptyl)methyl]-1H-pyrrole
A solution of 2-[5-((N-(4-benzyloxyphenyl)-N-methyl)aminosulphonyl)-2-methoxyphenyl]-5-[1-(2-(R,S)-phenzylazacycloheptyl)methyl]-1H-pyrrole (0.45g) in
ethanol (200 ml) containing 5N HCl (0.5 ml) was hydrogenated over 5% palladium on carbon for 18 h at atmospheric pressure. The mixture was filtered and the filtrate
evaporated to dryness in vacuo. The residue, in dichloromethane, was washed with
aqueous sodium bicarbonate, water and dried over Na2SO4. The product was
chromatographed on silica, eluting with 10-30% ethyl acetate - dichloromethane to afford the title compound (0.35g; mp 50-70° C (ether-pentane). Mass Spectrum: found M+
545.2365 C31H35N3O48 requires 545.2398. Example 13
2-(2-Methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl)-5-(1-(2-(R,S)-(2-(5-methylfuryl))azacycloheptyl)methyl)-1H-pyrrole hydrochloride
Prepared from 2-(2-methoxy-5-((N-methyl-N-phenyl)amino sulphonyl)phenyl)-1H-pyrrole and 1-formyl-2-(R,S)-(2-(5-methylfuryl))azacycloheptane following the method described in Example 4 in 9% yield.
FAB Mass Spectrum: found MH+ 534. C30H35N3O4S requires M+ 533.
Example 14
2-(5-((N-(4-Iodophenyl)-N-methyl)aminosulphonyl)-2-methoxyphenyl)-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole oxalate
Bis(tributyltin) (0.73 ml, 1.4 mmol) was added to a mixture of 2-(5-((N-(4-bromophenyl)-N-methyl)aminosulphonyl)-2-methoxyphenyl)-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole (0.730g, 1.2 mmol) and tetrakis
(triphenylphosphine) palladium (0) (0.140g, 0.12 mmol) in dry triethylamine (15 ml). The reaction was heated under reflux for 6h under argon. The resulting mixture was cooled to room temperature and the triethylamine was removed in vacuo to afford an oil which was chromatographed on silica, eluting with 0-20% ethyl acetate in pentane. The resulting stannane (0.356, 0.4 mmol, 29% yield) was dissolved in chloroform (20 ml) and was treated dropwise at -5° C with a solution of iodine (0.107g, 0.4 mmol) in chloroform (10 ml), with stirring. Aqueous saturated sodium thiosulphate (10 ml) was then immediately added. The organic phase was separated then washed successively with aqueous saturated sodium thiosulphate and brine. The organic phase was dried over Na2SO4 and the solvent was removed in vacuo to afford a yellow oil. This was chromatographed on silica, eluting with 0-30% ethyl acetate in pentane. The resulting oil was dissolved in acetonitrile (20 ml) and washed with hexane (3 × 10 ml) to remove any residual alkyltin impurities. The solvent was removed in vacuo to afford a colourless oil which was treated with oxalic acid to afford the title compound (0.110g, 42%, m.p. 107-109 °C. Found C, 52.35; H, 4.85; N.5.57. C31H34IN3O3S. C2H2O4. 0.5 H2O requires C, 52.52; H, 4.94; N, 5.57%.
Example 15
2-[2-Methoxy-5-((2-(7-methylsulphinyl)-1,2,3,4-tetrahydroisoquinolinyl)aminosulphony])phenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole
The title compound was prepared by the treatment of 2-(2-methoxy-5-((2-(7-methylthio)-1,2,3,4-tetrahydroisoquinolinyl)aminosulphonyl) phenyl)-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole with hydrogen peroxide according to Example 17, m.p. 87-89 °C. Mass Spectrum: found M+ 617.2376.
C34H39N3O4S2 requires 617.2376. Example 16
2-[5-((N-Ethyl-N-(2-furanyl)methyl)aminosulphonyl)-2-methoxyphenyl]-5-(1-piperidinylmethyl)-1H-pyrrole hydrochloride
37-40% Aqueous formaldehye (0.12ml; 1.39mmol) was added to stirred solution of piperidine (0.14ml; 1.39mmol) in ethanol (10ml) and the mixture stirred at room temperature for 0.5h. Glacial acetic acid (0.12ml; 1.94mmol) was added followed, after 0.16h, by 2-(5-((N-ethyl-N-(2-furanyl)methyl)aminosulphonyl)-2-methoxyphenyl)-1H-pyrrole (0,5g, 1.39mmol). After a further 20h the reaction mixture was evaporated in vacuo and the residue partitioned between diethyl ether and 0.5N HCl. The acidic layer was basified with 2.5N NaOH and extracted into dichloromethane (3×50ml). Combined organic extracts were dried (Na2SO4) and evaporated in vacuo. Chromatography on silica using 0-2% methanol in dichloromethane afforded the title compound as the free base. This was dissolved in diethyl ether and extracted into 0.5N HCl (2×50ml). Acid extracts were combined and extracted with dichloromethane (4×40ml). Combined organic extracts were dried and evaporated in vacuo. Trituration with diethyl ether afforded the title compound in 56% yield.
Found: C, 58.04; H, 6.39; N, 8.47. C24H31N3O4S.HCl requires, C, 58.35; H, 6.53; N, 8.51%.
Also prepared by a method similar to that of Example 16 were:
(a) 2-(N-Benzyl-N-ethyl)aminomethyl-5-(2-methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl)-1H-pyrrole, hydrochloride
m.p. 85-95 °C. Found: C, 62.96; H, 6.25; N, 7.79. C28H31N3O3S.HCl.0.4H2O requires C, 63.04; H, 6.20; N, 7.88%
(b) 2-(N-Benzyl-N-ethyl)aminomethyl-5-[2-methoxy-4-((N-methyl-N-phenyl)aminosulphony])phenyl]-1H-pyrrole hydrochloride
m.p. 110-114 °C. Found: C, 63.08; H, 6.08; N, 7.93. C28H31N3O3S. HCl. 0.5 H2O requires C, 62.85; H, 6.03; N, 7.85%. (c) 2-[2-Methoxy-4-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-5-(1-piperidinylmethyl)-1H-pyrrole hydrochloride
m.p. 165-167 °C (ether). Found: C, 60.34; H, 6.11; N, 8.89. C24H29N3O3S. HCl requires C, 60.56; H, 6.35; N, 8.83%.
(d) 2-(N,N-Diethylaminomethyl)-5-[2-methoxy-4-((N-methyl-N-phenyl)amino sulphonyl)phenyl]-1H-pyrrole hydrochloride
Found: C, 59.62; H, 5.93; N, 9.05. C23H29N3O3S. HCl requires C, 59.53; H, 6.52; N, 9.06%.
(e) 2-[2-Methoxy-4-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-5-[1-(R,S)-(1-piperidinyl)ethyl]-1H-pyrrole hydrochloride
m.p. 147-148 °C (ethyl acetate). Found C, 61.06; H, 6.40; N, 8.53. C25H31N3O3S. HCl. requires C, 61.27; H, 6.58; N, 8.57%.
Example 17
2-(2-Methoxy-5-((N-methyl-N-(4-methylsulphinyl)phenyl)
aminosulphonyl)phenyl)-5-(1-(2-(R,S)-phenylazacycloheptyl)
methyl)-1H-pyrrole
2-(2-Methoxy-5-((N-methyl-N(4-methylthio)phenyl)aminosulphonyl)
phenyl)-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole (500mg, 0.75mmol) in acetic acid (20ml) was treated with hydrogen peroxide (280mg 27% solution, 2.2mmol) at room temperature for 2h. The reaction was then poured into excess aqueous potassium carbonate solution and extracted with ether. The organic phase was separated, dried over Na2SO4and evaporated in vacuo to give the title compound as a foam.
m.p. 73-78 °C, sinters. Found: C, 64.57; H, 6.28; N, 6.96. C32H37N3O4S2 requires, C, 64.95; H, 6.30; N, 7.10%.
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 (IC50) of test compounds for displacement of [125I] iodosulpride binding to D3 dopamine receptors expressed in CHO cells have been determined. The cell lines were shown to be free from bacterial, fungal and mycoplasmal contaminants, and stocks of each were stored frozen in liquid nitrogen. Cultures were grown as monolayers or in suspension in standard cell culture media. Cells were recovered by scraping (from monolayers) or by centrifugation (from suspension cultures), and were washed two or three times by suspension in phosphate buffered saline followed by collection by centrifugation. Cell pellets were stored frozen at -40°C. Crude cell membranes were prepared by
homogenisation followed by high-speed centrifugation, and characterisation of cloned receptors achieved by radioligand binding.
Preparation of CHO cell membranes
Cell pellets were gently thawed at room temperature, and resuspended in about 20 volumes of ice-cold 50 mM Tris salts (pH 7.4 @ 37°C), 20mM EDTA, 0.2 M sucrose. The suspension was homogenised using an Ultra-Turrax at full speed for 15 sec. The homogenate was centrifuged at 18,000 r.p.m for 20 min at 4°C in a Sorvall RC5C centrifuge. The membrane pellet was resuspended in ice-cold 50 mM Tris salts (pH 7.4 @ 37°C), using an Ultra-Turrax, and recentrifuged at 18,000 r.p.m for 15 min at 4°C in a Sorvall RC5C. The membranes were washed two more times with ice-cold 50 mM Tris salts (pH 7.4 @ 37°C). The final pellet was resuspended in 50 mM Tris salts (pH 7.4 @ 37°C), and the protein content determined using bovine serum albumin as a standard (Bradford, M. M. (1976) Anal. Biochem. 72, 248-254).
Binding experiments on cloned dopamine receptors
Crude cell membranes were incubated with 0.1 nM [125I] iodosulpride (~2000 Ci/mmol; Amersham, U. K.), and the test compound in a buffer containing 50 mM Tris salts (pH 7.4 @ 37°C), 120 mM NaCl, 5 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 0.1% (w/v) bovine serum albumin, in a total volume of 1 ml for 30 min at 37°C. Following incubation, samples were filtered using a Brandel Cell Harvester, and washed three times with ice-cold 50 mM Tris salts (pH 7.4 @ 37°C), 120 mM NaCl, 5 mM KCl, 2 mM CaCl2, 1 mM MgCl2. The radioactivity on the filters was measured using a Cobra gamma counter (Canberra Packard). Non-specific binding was defined as the radioligand binding remaining after incubation in the presence of 100 μM iodosulpride. For competition curves, 14 concentrations (half-log dilutions) of competing cold drug were used.
Competition curves were analysed simultaneously whenever possible using non-linear least-squares fitting procedures, capable of fitting one, two or three site models.
The compounds of the Examples (excluding Examples 11, m; 4a, f, g, i, j, l, p, r, s; 10a, c; 13, 15, 16, 16c and d) had IC50 values of between 5 and 50 nm at the human D3 receptor. Pharmaceutical Formulations
The following represent typical pharmaceutical formulations according to the present invention, which may be prepared using standard methods.
IV Infusion
Compound of formula (I) 1-40 mg
Buffer to pH ca 7
Solvent/complexing agent to 100 ml Bolus Injection
Compound of formula (I) 1-40 mg
Buffer to pH ca 7
Co-Solvent to 5 ml Buffer : Suitable buffers include citrate, phosphate, sodium hydroxide/hydrochloric acid.
Solvent : Typically water but may also include cyclodextrins (1-100 mg) and co-solvents such as propylene glycol, polyethylene glycol and alcohol.
Tablet
Compound 1 - 40 mg
Diluent/Filler * 50 - 250 mg
Binder 5 - 25 mg
Disentegrant * 5 - 50 mg
Lubricant 1 - 5 mg
Cyclodextrin 1 - 100 mg
* may also include cyclodextrins
Diluent : e.g. Microcrystalline cellulose, lactose, starch
Binder : e.g. Polyvinylpyrrolidone, hydroxypropymethylcellulose
Disintegrant : e.g. Sodium starch glycollate, crospovidone
Lubricant : e.g. Magnesium stearate, sodium stearyl fumarate. Oral Suspension
Compound 1 - 40 mg
Suspending Agent 0.1 - 10 mg
Diluent 20 - 60 mg
Preservative 0.01 - 1.0 mg
Buffer to pH ca 5 - 8
Co-solvent 0 - 40 mg
Flavour 0.01 - 1.0 mg
Colourant 0.001 - 0.1 mg
Suspending agent : e.g. Xanthan gum, microcrystalline cellulose
Diluent : e.g. sorbitol solution, typically water
Preservative : e.g. sodium benzoate
Buffer : e.g. citrate
Co-solvent : e.g. alcohol, propylene glycol, polyethylene glycol, cyclodextrin

Claims

Claims : 1. A compound of formula (I) :
Figure imgf000061_0001
wherein
R1 represents C1-4alkyl;
one of R2, R3, R4 and R5 represents a sulphonamido group R6R7NSO2-, wherein either: R6 represents hydrogen, C1-6alkyl, or C1-4alkoxyC1-4alkyl; 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, C1-4alkyl, 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
R6R7N- represents a 5-7 membered heterocyclic ring which is fused to or substituted by α 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; and the remaining R2, R3, R4 and R5 each independently represent hydrogen, halogen, C1-4alkyl, 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-alkylamino,
trifluoromethyl, trifluoromethoxy, hydroxyl, hydroxyalkyl, C1-4alkylthio,
C1-4alkanoyl or C1-4alkoxycarbonyl; or
R1 and R2 together form a C2-4alkyl chain, which chain may be optionally substituted by one or two C1-4alkyl groups, in which case one of R3, R4 and R5 is a sulphonamide group as defined above, and the other two substituents are as hereinbefore defined; or
R2 and R3 together form a phenyl ring, in which case R4 represents a sulphonamido group as defined above and R5 represents hydrogen; and Y represents a group selected from (a) - (e):
Figure imgf000062_0001
Figure imgf000062_0002
Figure imgf000062_0003
Figure imgf000062_0004
Figure imgf000062_0005
wherein
in group (a) :
R8 and R9 independently represent hydrogen, C1-6alkyl, optionally substituted
arylC1-6alkyl or optionally substituted heteroarylC1-6alkyl;
R10 represents C1-6alkyl, C3-6alkenyl or C3-6cycloalkylC1-4alkyl; and
R11 represents C1-6alkyl; C3-6alkenyl; C3-6cycloalkylC1-4alkyl, optionally substituted arylC1-4alkyl or optionally substituted heteroarylC1-4alkyl; or
NR10R11 forms a heterocyclic ring; in group (b) :
R12 represents C1-6alkyl; C3-6alkenyl; C3-6cycloalkylC1-4alkyl , optionally substituted arylC1-4alkyl or optionally substituted heteroarylC1-4alkyl; and
q is 1 to 4;
and in group (c):
R13 and R14 independently represent hydrogen, C1- 6alky!, optionally substituted
arylC1-6alkyl or optionally substituted heteroarylC1-6alkyl;
R15 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;
in group (e) R16 represents C1-6alkyl, C3-6alkenyl or C3-6cycloalkylC1-4alkyl;
R17, R18, R19 and R20 each independently represent hydrogen, halogen, C1-4alkyl, C1-4alkoxy, C1-4alkoxyC1 -4alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, hydroxyalkyl, C1-4alkanoyl, C1-4alkoxycarbonyl, 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 R1 represents methyl, ethyl, or isopropyl.
3. A compound according to claim 1 or claim 2 wherein either R3 or R4 represents a group R6R7NSO2, as defined in claim 1.
4. A compound according to claim 3 wherein me remaining ring substituents selected from R2, R3, R4 and R4 represent hydrogen or C1-4 alkyl.
5. A compound according to any of claims 1 to 4 wherein R7 represents a group (Ra)p-(Ar)-(CH2); in which Ar represents phenyl or a 5- or 6-membered heterocyclic aryl group containing 1, 2 or 3 atoms selected from O, N or S, and Ra, p and j are as defined in claim 1.
6. A compound according to any of claims 1 to 4 wherein R6R7NSO2 represents a group of formula (f) or (g)
Figure imgf000064_0001
Figure imgf000064_0002
wherein Ra and p are as hereinbefore defined;
Ar1 represents phenyl or a 5- or 6-membered heterocyclic ring;
R21 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.
7. A compound of formula (IA):
Figure imgf000064_0003
wherein
one of R2, R3, R4 and R5 represents a sulphonamido group
Figure imgf000064_0004
wherein either
the dotted line represents a hydrogen atom or substituent R23 attached to the phenyl ring; R22 represents hydrogen, C1 -6alkyl, or C1-4alkoxyC1-4alkyl; and n represents zero or an integer from 1-4;
or
the dotted line represents a single bond;
R22 represents -(CH2)m- ; and
n and m each represent zero or an integer from 1-4, such that the sum of n+m is from 2-4; and in either case
R23 represents a substituent selected from
halogen, C1-4alkyl, C1-4alkoxy, C1-4alkoxyC1-4alkyl, nitro, cyano, triFLuoromethyl, trifLuoromethoxy, hydroxy, hydroxyC1-4alkyl, C1-4alkanoyl, C1-4alkoxycarbonyl, amino and mono- or -diC1-4alkylamino; and
p represents zero or an integer from 1-4;
and the remaining R2, R3, R4 and R5, as well as R1 and Y are as defined for formula (I).
8. A compound according to any of claims 1 to 7 wherein Y represents a group (c) in which at least one of R13 and R14 is hydrogen.
9. A compound according to claim 8 wherein one of R13 and R14 is hydrogen and die other is selected from hydrogen, C1-6alkyl and optionally substituted arylC1-6alkyl.
10. A compound according to any of claims 1 to 9 wherein R15 is optionally substituted phenyl.
11. A compound according to any of claims 1 to 10 wherein Z represents (CH2)u wherein u is 3, 4 or 5.
12. A compound according to claim 1 selected from :
2-(2-Methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl)-5-(1-(2-(R,S)phenylazacycloheptyl)-methyl)-1H-pyrrole;
2-[5-((N-Benzyl-N-methyl)aminosulphonyl)-2-methoxyphenyl]-5-[1-(2-(R,S)-phenylazacycloheptyl)methyl]-1H-pyrrole;
2-[2-Methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-5-(1-(R,S)-(2-phenylpyrrolidinyl)methyl)-1H-pyrrole;
(-)-2-[2-Methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-5-(1-(2-phenylpyrrolidinyl methyl)-1H-pyrrole;
(+)-2-[2-Methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-5-(1-(2-phenylpyrrolidinyl)methyl)-1H-pyrrole; (-)-2-[2-Methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-5-(1-(2-phenylpiperidinylmethyl)-1H-pyrrole;
(+)-2-[2-Methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-5-(1-(2-phenylpiperidinyl)methyl)-1H-pyrrole;
2-(5-((N-(4-Bromophenyl)-N-methyl)aminosulphonyl)-2-methoxyphenyl)-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole;
2-(2-Methoxy-5-((N-(4-methoxyphenyl)-N-methyl)amino-sulphonyl)phenyl)-5-(1-(2- (R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole;
2-(5-((N-(4-Cyanophenyl)-N-methyl)aminosulphonyl)-2-methoxyphenyl)-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole;
2-(5-(4-(3,4-Dihydro-1,4-benzoxazinyl)sulphonyl)-2-methoxy-phenyl)-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole;
2-(5-((N-(3,4-Dimethoxybenzyl)-N-ethyl)aminosulphonyl)-2-methoxyphenyl)-5-(1-(2- (R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole;
2-(2-Methoxy-5-((N-methyl-N-(4-methylthio)phenyl)aminosulphonyl)phenyl)-5-(1-(2- (R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole;
2-(2-Methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl)-5-(1-(2-(R)-phenylazacycloheptyl)methyl)-1H-pyrrole;
2-(2-Methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl)-5-(1-(2-(S)-phenylazacycloheptyl)methyl)-1H-pyrrole;
2-[5-((N-Benzyl-N-ethyl)aminosulphonyl)-2-methoxyphenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole;
2-[5-((N-(2,4-Difluorophenyl)-N-methyl)aminosulphonyl-2-methoxyphenyl]-5-(1-(2- (R,S) phenylazacycloheptyl)methyl)-1H-pyrrole;
2-[2-Methoxy-5-((1-(2-phenylpyrrolidinyl))sulphonyl)phenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole;
2-[2-Methoxy-5-((N-ethyl-N-(2-phenyl)ethyl)aminosulphonyl)-phenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole;
2-[2-Methoxy-5-((N-methyl-N-(5-methyl-3-isoxazolyl))amino-sulphonyl)phenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole;
2-[2-Methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-5-(1-(R,S)-(1-piperidinyl)ethyl)-1H-pyrrole;
2-[5-((N-Ethyl-N-(2-pyridyl)methyl)aminosulρhonyl)-2-methoxy-phenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole;
2-[5-((N-Ethyl-N-(2-furyl)methyl)aminosulphonyl)-2-methoxy-phenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl-1H-pyrrole;
2-[5-((N-(4-Fluorophenyl)-N-methyl)aminosulphonyl)-2-methoxyphenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole; 2-[2-Methoxy-4-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-5-[1-(2-(R,S)-phenylazacycloheptyl)methyl]-1H-pyrrole;
2-[5-((N-Benzyl-N-ethyl)aminosulphonyl)-2-methoxyphenyl]-5-[1-(2-(R)-phenylazacycloheptyl)methyl]-1H-pyrrole;
2-[5-((N-Benzyl-N-ethyl)aminosulphonyl)-2-methoxyphenyl]-5-[1-(2-(S)-phenylazacycloheptyl)methyl]-1H-pyrrole;
2-[2-Methoxy-5-((2-(1,2,3,4-tetrahydroisoquinolinyl))sulphonyl)phenyl]-5-[1-(2-(R,S)-phenylazacycloheptyl)methyl]-1H-pyrrole;
2-[2-Methoxy-5-((1-(l,2,3,4-Tetrahydroquinolinyl))sulphonyl)
phenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl-1H-pyrrole;
2-[5-((N-Ethyl-N-phenyl)aminosulphonyl)-2-methoxyphenyl]-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole;
2-[2-(R,S)-(1-Ethylpyrrolidinyl)]-5-[(2-methoxy-4-methyl-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-1H- pyrrole;
2-[2-(R,S)-(1-Ethylpyrrolidinyl))-5-(2-methoxy-5-((N-methyl-N-phenyl]aminosulphonyl)phenyl)-1H-pyrrole;
2-(2-(R,S)-(1-Ethylpyrrolidinyl))-5-[2-methoxy-5-((1-(1,2,3,4-tetrahydroquinolinyl))aminosulphonyl)phenyl]-1H-pyrrole;
2-(2-(R,S)-(1-Ethylpyrrolidinyl))-5-(1-methoxy-4-((N-methyl-N-phenyl)aminosulphonyl)-2-naphthyl)-1H-pyrrole;
2-(2-(R,S)-(1-n-Butylpyrrolidinyl))-5-[2-methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-1H-pyrrole;
2-[2-(R,S)-(1-Ethylpyrrolidinyl)]-5-[2-methoxy-4-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-1H-pyrrole;
2-[2-Methoxy-4-methyl-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl)-5-(1-(2-(R)-phenylazacycloheptyl)methyk)-1H-pyrrole;
2-[5-((N-(4-Hydroxyphenyl)-N-methyl)aminosulphonyl)-2-methoxyphenyl]-5-[1-(2- (R,S)-phenylazacycloheptyl)methyl]-1H-pyrrole;
2-(5-((N-(4-Iodophenyl)-N-methyl)aminosulphonyl)-2-methoxyphenyl)-5-(1-(2-(R,S)-phenylazacycloheptyl)methyl)-1H-pyrrole;
2-(N-Benzyl-N-ethyl)aminomethyl-5-(2-methoxy-5-((N-methyl-N-phenyl)aminosulphonyl)phenyl)-1H-pyrrole;
2-(N-Benzyl-N-ethyl)aminomethyl-5-[2-methoxy-4-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-1H-pyrrole;
2-[2-Methoxy-4-((N-methyl-N-phenyl)aminosulphonyl)phenyl]-5-[1-(R,S)-(1-piperidinyl)ethyl]-1H-pyrrole;
2-(2-Methoxy-5-((N-methyl-N-(4-methylsulphinyl)phenyl)
aminosulphonyl)phenyl)-5-(1-(2-(R,S)-phenylazacycloheptyl) methyl)-1H-pyrrole;
and salts thereof.
13. A process for preparing a compound of formula (I) which process comprises :
(a) to prepare a compound of formula (I) wherein Y is a group (a) or (c) in which R8, R9 , R13 and R1 4are hydrogen or wherein Y is a group (e) carrying out a Mannich reaction with a compound of formula (II) :
Figure imgf000068_0001
and an amine of formula (III) (IV) or (V):
HNR10R11
Formula (III)
Figure imgf000068_0002
Figure imgf000068_0003
in the presence of formaldehyde;
(d) to prepare a compound wherein Y is a group (a) wherein at least one of
R8 and R9 is hydrogen, a group (c) wherein at least one of R13 or R14 is 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): R8C(O)NR10R11
Formula (VI)
Figure imgf000069_0001
Figure imgf000069_0002
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 R8, R9, R13 and R14 are hydrogen or Y is a group (e) reductive amination of a compound of formula (IX) :
Figure imgf000069_0003
with an amine of formula (III) (IV) or (V);
(d) conversion of one compound of formula (I) 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).
14. 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.
15. Use according to claim 14 wherein the dopamine receptor is a dopamine D3 receptor.
16. Use according to claim 14 or claim 15 wherein a dopamine antagonist is required.
17. Use according to any of claims 14 to 16 wherein the condition is a psychotic condition.
18. 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.
19. A pharmaceutical composition comprising a compound of formula (I) or a physiologically acceptable salt thereof and a physiologically acceptable carrier.
20. A novel intermediate selected from formula (II), (IX), (X), (XI) and
(XII).
PCT/EP1994/004175 1993-12-17 1994-12-16 Aminosulphonyl-phenyl-1h-pyrrole derivatives, method of their preparation and their use WO1995016674A1 (en)

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DE19963174A1 (en) * 1999-12-27 2001-07-12 Gruenenthal Gmbh Substituted pyrrole Mannich bases
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WO1998006699A1 (en) * 1996-08-14 1998-02-19 Smithkline Beecham Plc Tetrahydroisoquinoline derivatives and their pharmaceutical use
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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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WO2007091140A1 (en) * 2006-02-06 2007-08-16 Pfizer Products Inc. Substituted phenylsulfamoyl compounds as ppar agonists
WO2009141274A1 (en) * 2008-05-21 2009-11-26 Basf Se Substituted pyridin-4 -yl-methyl sulfonamides as fungicides

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