Diaryl ether heterocycles

Claim 2

A diaryl ether heterocycle of the formula I wherein Ar¹ is phenyl or naphthyl which may optionally bear one or more substituents selected from amino, halogeno, hydroxy, cyano, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-4C)alkoxy, (1-4C)alkylthio, (1-4C)alkysulphinyl, (1-4C)alkylsulphonyl, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, (1-4C)alkoxycarbonyl, (2-4C)alkanoyl, hydroxy-(1-6C)alkyl, fluoro(1-4C)alkyl, cyano-(1-6C)alkyl, fluoro-(1-4C)alkoxy, cyano-(1-4C)alkoxy, (1-4C)alkoxy-(1-4C)alkyl, (1-4C)alkylthio-(1-4C)alkyl, (1-4C)alkylsulphinyl-(1-4C)alkyl, (1-4C)alkylsulphonyl-(1-4C)alkyl, cyano-(4-6C)cycloalkyl, (2-4C)alkanoylamino, N-[(1-4C)alkyl]-­(2-4C)alkanoylamino, N-(2,2,2-trifluoroethyl)-(2-4C)alkanoylamino, N-[(1-4C)alkoxycarbonyl-(1-2C)alkyl]-(2-4C)alkanoylamino, trifluoroacetyl, trifluoroacetamido, N-[(1-4C)alkyl]­trifluoroacetamido, 2-oxopyrrolidinyl, thia-(3-8C)-alkylene, oxothia-(3-8C)alkylene, dioxothia-(3-8C)alkylene, tri-(1-4C)alkylsilyl, phenyl, benzoyl, benzamido and N-[(1-4C)alkyl]benzamido, and wherein said phenyl, benzoyl, benzamido or N-[(1-4C)alkyl]benzamido substituent may optionally bear a substituent selected from halogeno, (1-4C)alkyl and (1-4C)alkoxy; wherein X¹ is oxy, thio, sulphinyl or sulphonyl; wherein Ar² is phenylene which may optionally bear one or two substituents selected from halogeno, hydroxy, amino, nitro, cyano, carbamoyl, (1-4C)alkyl, (3-4C)alkenyloxy, (1-4C)alkoxy, (1-­4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkysulphonyl, (1-­4C)alkylamino, di-[(1-4C)alkyl]amino, fluoro-(1-4C)alkyl, cyano-(1-­ 4C)alkyl, (1-4C)alkoxycarbonyl, N-[(1-4C)alkyl]carbamoyl, N,N-di-[(1-­4C)alkyl]carbamoyl, (2-4C)alkanoylamino, fluoro-(1-4C)alkoxy, cyano-­(1-4C)alkoxy, carbamoyl-(1-4C)alkoxy, amino-(2-4C)alkoxy, (1-­4C)alkylamino-(2-4C)alkoxy, di-[(1-4C)alkyl]amino-(2-4C)alkoxy and (1-­4C)alkoxycarbonyl-(1-4C)alkoxy; or Ar² is a 6-membered heterocyclene moiety containing up to three nitrogen atoms which may optionally bear one or two substituents selected from halogeno, hydroxy, amino, cyano, (1-4C)alkyl, (1-­4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino; wherein R¹ is (1-6C)alkyl, (3-6C)alkenyl, (3-6C)alkynyl, cyano-(1-4C)alkyl or (2-4C)alkanoyl, or R¹ is benzoyl which may optionally bear a substituent selected from halogeno, (1-4C)alkyl and (1-4C)alkoxy; and wherein R² and R³ together form a group of the formula -A²-X²-A³- which, together with the carbon atom to which A² and A³ are attached, defines a ring having 4 to 7 ring atoms, wherein A² and A³, which may be the same or different, each is (1-4C)alkylene and X² is oxy, thio, sulphinyl, sulphonyl or imino, and which ring may bear one, two or three substituents, which may be the same or different, selected from halogeno, hydroxy, cyano, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl and fluoro-(1-4C)alkyl, or which ring may bear a (1-4C)alkylenedioxy substituent; or a pharmaceutically-acceptable salt thereof.

Claim 3

A diaryl ether heterocycle of the formula I as claimed in claim 1 wherein Ar¹ is phenyl, naphth-1-yl or naphth-2-yl which may optionally bear one or two substituents selected from amino, fluoro, chloro, cyano, methyl, tert -butyl, methoxy, methylthio, methylsulphinyl, methylsulphonyl and 2-cyanoprop-2-yl; X¹ is thio, sulphinyl or sulphonyl; Ar² is 1,3-phenylene or 1,4-phenylene which may optionally bear one substituent selected from fluoro, hydroxy, amino, nitro, methoxy, methylamino, cyanomethoxy and trifluoromethyl; or Ar² is 3,5-pyridylene; R¹ is methyl or ethyl; and R² and R³ together form a group of the formula -A²-X²-A³- which, together with the carbon atom to which A² and A³ are attached, defines a ring having 5 or 6 ring atoms, wherein A² is ethylene, A³ is methylene or ethylene, and X² is oxy or thio, and which ring may bear a substituent selected from fluoro, methyl, methoxy and trifluoromethyl; or a pharmaceutically-acceptable salt thereof.

Claim 4

A diaryl ether heterocycle of the formula I as claimed in claim 1 wherein Ar¹ is phenyl or naphth-2-yl which may optionally bear one or two substituents selected from fluoro, chloro, bromo, methyl, ethyl, isopropyl, tert -butyl, methoxy, ethoxy, isopropoxy, methylthio, methylsulphinyl, methylsulphonyl, acetyl, propionyl, isobutyryl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxyprop-2-yl, 3-hydroxypent-3-yl, difluoromethyl, trifluoromethyl, cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 2-cyanoprop-­2-yl, 3-cyanopent-3-yl, trifluoromethoxy, 2,2,2-trifluoroethoxy, methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-methoxyprop-2-yl, methylthiomethyl, 1-methylthioethyl, 2-methylthioethyl, 2-methylthioprop-2-yl, methylsulphinylmethyl, 1-methylsulphinylethyl, 2-methylsulphinylethyl, 2-methylsulphinylprop-2-yl, methylsulphonyl­methyl, 1-methylsulphonylethyl, 2-methylsulphonylethyl, 2-methyl­sulphonylprop-2-yl, 1-cyanocyclopentyl, 1-cyanocyclohexyl, acetamido, propionamido, N-methylacetamido, N-methylpropionamido, trifluoroacetyl, trifluoroacetamido, N-methyltrifluoroacetamido, 2-oxopyrrolidin-1-yl, 1,1,3,3-tetramethyl-2,2-dioxo-2-­thiatrimethylene, trimethylsilyl and phenyl; X¹ is oxy, thio, sulphinyl or sulphonyl; Ar² is 1,3-phenylene or 1,4-phenylene which may optionally bear one or two substituents selected from fluoro, chloro, bromo, amino, nitro, cyano, methyl, methoxy, methylamino, dimethylamino and trifluoromethyl, or Ar² is 3,5-pyridylene; R¹ is methyl, ethyl, allyl or 2-propynyl; and R² and R³ together form a group of the formula -A²-X²-A³- which, together with the carbon atom to which A² and A³ are attached, defines a ring having 4 to 7 ring atoms, wherein A² and A³, which may be the same or different, each is methylene or ethylene and X² is oxy, and which ring may bear one or two substituents selected from fluoro, hydroxy, methyl, ethyl, propyl, methoxy and trifluoromethyl; or a pharmaceutically-acceptable salt thereof.

Claim 5

A diaryl ether heterocycle of the formula I as claimed in claim 1 wherein Ar¹ is phenyl or naphth-2-yl which may optionally bear one or two substituents selected from amino, fluoro, chloro, bromo, methyl, ethyl, isopropyl, tert -butyl, methoxy, ethoxy, isopropoxy, methylthio, methylsulphinyl, methylsulphonyl, methylamino, dimethylamino, acetyl, propionyl, isobutyryl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxyprop-2-yl, 3-hydroxypent-3-yl, difluoromethyl, trifluoromethyl, cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 2-cyanoprop-2-yl, 3cyanopent-3-yl, trifluoromethoxy, 2,2,2-trifluoroethoxy, methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-methoxyprop-2-yl, methylthiomethyl, 1-methylthioethyl, 2-methylthioethyl, 2-methylthioprop-2-yl, methylsulphinylmethyl, 1-methylsulphinylethyl, 2-methylsulphinylethyl, 2-methylsulphinyl­prop-2-yl, methylsulphonylmethyl, 1-methylsulphonylethyl, 2-methylsulphonylethyl, 2-methylsulphonylprop-2-yl, 1-cyanocyclopentyl, 1-cyanocyclohexyl, acetamido, propionamido, N-methylacetamido, N-methylpropionamido, N-(2,2,2-trifluoroethyl)­acetamido, N-(methoxycarbonylmethyl)acetamido, N-(ethoxycarbonyl­methyl)acetamido, trifluoroacetyl, trifluoroacetamido, N-methyltrifluoroacetamido, 2-oxopyrrolidin-1-yl, 1,1,3,3-tetramethyl-­2,2-dioxo-2-thiatrimethylene, trimethylsilyl, phenyl, benzoyl, benzamido and N-methylbenzamido, and wherein said phenyl, benzoyl, benzamido or N-methylbenzamido substituent may optionally bear a substituent selected from fluoro, chloro, methyl and methoxy; X¹ is oxy, thio, sulphinyl or sulphonyl; Ar² is 1,3-phenylene or 1,4-phenylene which may optionally bear one or two substituents selected from fluoro, chloro, bromo, amino, nitro, cyano, methyl, methoxy, methylamino, dimethylamino and trifluoromethyl, or Ar² is 3,5-pyridylene; R¹ is methyl, ethyl, allyl or 2-propynyl; and R² and R³ together form a group of the formula -A²-X³-A³- which, together with the carbon atom to which A² and A³ are attached, defines a ring having 4 to 7 ring atoms, wherein A² and A³, which may be the same or different, each is methylene or ethylene and X² is oxy, and which ring may bear one or two substituents selected from fluoro, hydroxy, methyl, ethyl, propyl, methoxy and trifluoromethyl; or a pharmaceutically-acceptable salt thereof.

Claim 6

A diaryl ether heterocycle of the formula I as claimed in claim 1 wherein Ar¹ is phenyl which may optionally bear one or two substituents selected from chloro, isopropyl, tert -butyl, isopropoxy, dimethylamino, acetyl, isobutyryl, 2-hydroxyprop-2-yl, 2-cyanoprop-2-yl, 3-cyanopent-3-yl, 2,2,2-trifluoroethoxy, 2-methoxyprop-2-yl, 1-cyanocyclopentyl, acetamido, N-methylacetamido, propionamido, N-methylpropionamido, N-(methoxycarbonylmethyl)acetamido, trifluoroacetyl, N-methyltrifluoroacetamido, 2-oxopyrrolidin-1-yl, 1,1,3,3-tetramethyl-­2,2-dioxo-2-thiatrimethylene, trimethylsilyl, phenyl, benzoyl, 4-chlorobenzoyl and N-methylbenzamido; or Ar¹ is naphth-2-yl which may optionally bear a substituent selected from fluoro, methyl and trifluoromethyl; X¹ is oxy, thio, sulphinyl or sulphonyl; Ar² is 1,3-phenylene which may optionally bear one or two substituents selected from fluoro, chloro, bromo, amino, nitro, cyano, methoxy and trifluoromethyl; R¹ is methyl, ethyl or allyl; and R² and R³ together form a group of the formula -A²-X²-A³- which, together with the carbon atom to which A² and A³ are attached, defines a ring having 5 or 6 ring atoms, wherein A² is ethylene, A³ is methylene or ethylene, and X² is oxy, and which ring may bear one or two substituents selected from methyl, ethyl and methoxy; or a pharmaceutically-acceptable salt thereof.

Claim 7

A diaryl ether heterocycle of the formula I as claimed in claim 1 wherein Ar¹ is 4- t -butylphenyl, 3-(2-cyanoprop-2-yl)phenyl, 4-(2-cyanoprop-2-­yl)phenyl, 3-chloro-4-(2-cyanoprop-2-yl)phenyl, 4-(1-cyanocyclopentyl)phenyl, 1,1,3,3-tetramethyl-1,3-dihydro­ benzo[c]thien-5-yl, 4-trimethylsilylphenyl, 3-biphenylyl, 4-biphenylyl, 4-benzoylphenyl or naphth-2-yl; X¹ is oxy, thio or sulphonyl; Ar² is 1,3-phenylene, 5-fluoro-1,3-phenylene, 2,5-difluoro-1,3-­phenylene, 5-bromo-1,3-phenylene or 5-trifluoromethyl-1,3-phenylene; R¹ is methyl or allyl; and R² and R³ together form a group of the formula -A²-X²-A³- which, together with the carbon atom to which A² and A³ are attached, defines a ring having 6 ring atoms, wherein each of A² and A³ is ethylene and X² is oxy and which ring may bear a methyl substituent alpha to X²; or a pharmaceutically-acceptable salt thereof.

Claim 8

A diaryl ether derivative of the formula I, or a pharmaceutically-acceptable salt thereof, selected from the group consisting of:- 4-methoxy-4-[3-(naphth-2-ylthio)phenyl]tetrahydropyran, 4-[3-(4- t -butylphenylthio)phenyl]-4-methoxytetrahydropyran, 4-methoxy-4-[3-(naphth-2-ylthio)-5-trifluoromethylphenyl]­tetrahydropyran and 4-[3-(4-(2-cyanoprop-2-yl)phenylthio)-5-trifluoromethylphenyl]-4-­methoxytetrahydropyran.

Claim 9

A diaryl ether derivative of the formula I, or a pharmaceutically-acceptable salt thereof, selected from the group consisting of:- 4-methoxy-4-[3-(naphth-2-ylthio)phenyl]tetrahydropyran, 4-[3-(4- t -butylphenylthio)phenyl]-4-methoxytetrahydropyran, 4-methoxy-4-[3-(naphth-2-ylthio)-5-trifluoromethylphenyl]­tetrahydropyran and 4-[3-(4-(2-cyanoprop-2-yl)phenylthio)-5-trifluoromethylphenyl]-4-­methoxytetrahydropyran.

Claim 10

A diaryl ether derivative of the formula I, or a pharmaceutically-acceptable salt thereof, selected from the group consisting of :- 4-allyloxy-4-[2,5-difluoro-3-(naphth-2-ylthio)phenyl]tetrahydropyran, (2RS, 4SR)-4-[3-(4- tert -butylphenylthio)phenyl]-4-methoxy-2-methyl­tetrahydropyran, (2RS,4SR)-4-allyloxy-4-[5-fluoro-3-(4- tert -butylphenoxy)phenyl]-2-­methyltetrahydropyran, 4-[3-(3-chloro-4-(2-cyanoprop-2-yl)phenylthio)phenyl]-4-methoxy tetrahydropyran, (2S,4R)-4-[3-(4- tert -butylphenylthio)phenyl]-4-methoxy-2-methyl­tetrahydropyran and (2S,4R)-4-[5-fluoro-3-(4- tert -butylphenylthio)phenyl]-4-methoxy-2-­ methyltetrahydropyran.

Claim 11

A diaryl ether derivative of the formula I, or a pharmaceutically-acceptable salt thereof, selected from the group consisting of :- 4-allyloxy-4-[2,5-difluoro-3-(naphth-2-ylthio)phenyl]tetrahydropyran, (2RS, 4SR)-4-[3-(4- tert -butylphenylthio)phenyl]-4-methoxy-2-methyl­tetrahydropyran, (2RS,4SR)-4-allyloxy-4-[5-fluoro-3-(4- tert -butylphenoxy)phenyl]-2-­methyltetrahydropyran, 4-[3-(3-chloro-4-(2-cyanoprop-2-yl)phenylthio)phenyl]-4-methoxy tetrahydropyran, (2S,4R)-4-[3-(4- tert -butylphenylthio)phenyl]-4-methoxy-2-methyl­tetrahydropyran and (2S,4R)-4-[5-fluoro-3-(4- tert -butylphenylthio)phenyl]-4-methoxy-2-­ methyltetrahydropyran.

Claim 12

A process for the manufacture of a diaryl ether heterocycle of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in claim 1 which comprises:- (a) the coupling, in the presence of a suitable base, of a compound of the formula Ar¹-X¹-H with a compound of the formula II wherein Z is a displaceable group; provided that, when there is an amino, imino, alkylamino or hydroxy group in Ar¹, Ar², R² or R³ any amino, imino, alkylamino or hydroxy group may be protected by a conventional protecting group or alternatively any such group need not be protected; whereafter any undesired protecting group in Ar¹, Ar², R² or R³ is removed by conventional means; (b) the coupling, in the presence of a suitable base, of a compound of the formula III with a compound of the formula Ar¹-Z wherein Z is a displaceable group; provided that, when there is an amino, imino, alkylamino or hydroxy group in Ar¹, Ar², R¹, R² or R³, any amino, imino, alkylamino or hydroxy group may be protected by a conventional protecting group or alternatively any such group need not be protected; whereafter any desired protecting group in Ar¹, Ar², R¹, R² or R³ is removed by conventional means; (c) the alkylation, in the presence of a suitable base, of a compound of the formula IV with a compound of the formula R¹-Z, wherein R¹ and Z have the meanings defined hereinbefore, provided that, when there is an amino, imino, alkylamino or hydroxy group in Ar¹, Ar², R² or R³ any amino, imino, alkylamino or hydroxy group may be protected by a conventional protecting group or alternatively any such group need not be protected; whereafter any undesired protecting group in Ar¹, Ar², R² or R³ is removed by conventional means; (d) for the production of those compounds of the formula I wherein Ar¹ or Ar² bears a sulphinyl or sulphonyl group; wherein X¹ is a sulphinyl or sulphonyl group; or wherein R² and R³ together form a group of the formula -A²-X²-A³- and X² is a sulphinyl or sulphonyl group, and which may bear one or two alkylsulphinyl or alkylsulphonyl groups; the oxidation of a compound of the formula I wherein Ar¹ or Ar² bears a thio group; wherein X¹ is a thio group; or wherein R² and R³ together form a group of the formula -A²-X²-A³-and X² is a thio group, and which may bear one or two alkylthio groups; (e) for the production of those compounds of the formula I wherein Ar¹ or Ar² bears an alkanoylamino substituent, the acylation of a compound of the formula I wherein Ar¹ or Ar² bears an amino substituent; (f) for the production of those compounds of the formula I wherein R¹ is alkanoyl or benzoyl optionally bearing a substituent as defined hereinbefore, the acylation of a compound of the formula I wherein R¹ is hydrogen; (g) for the production of those compounds of the formula I wherein Ar¹ or Ar² bears an alkyl or substituted alkyl substituent on an available nitrogen atom, or wherein Ar¹ or Ar² bears an alkoxy or substituted alkoxy substituent, the alkylation of a compound of the formula I wherein Ar¹ or Ar² bears a hydrogen atom on said available nitrogen atom, or wherein Ar¹ or Ar² bears a hydroxy substituent; or (h) for the production of those compounds of the formula I wherein Ar¹ or Ar² bears an amino substituent, the reduction of a compound of the formula I wherein Ar¹ or Ar² bears a nitro substituent; and when a pharmaceutically-acceptable salt of a novel compound of the formula I is required, it may be obtained, for example, by reaction of said compound with a suitable acid or base using a conventional procedure.

Claim 13

A pharmaceutical composition which comprises a diaryl ether heterocycle of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 8 in association with a pharmaceutically-acceptable diluent or carrier.

Claim 14

A heterocycle of the formula I, or a pharmaceutically-­acceptable salt thereof, as claimed in any one of claims 1 to 8 for use in a method of treatment of the human or animal body by therapy.

Claim 15

The use of a diaryl ether heterocycle of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 8 in the production of a new medicament for use in a leukotriene mediated disease or medical condition.