Diaryl ether cycloalkanes

Claim 2

A diaryl ether cycloalkane of the formula 1 wherein Ar¹ is phenyl or naphthyl which may optionally bear one or more substituents selected from amino, halogeno, hydroxy, cyano, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)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-(1-4C)alkyl, fluoro-(1-4C)alkyl, cyano-(1-4C)alkyl, fluoro-(1-4C)alkoxy, cyano-(1-4C)alkoxy, phenyl and benzoyl, and wherein said phenyl or benzoyl 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 (3-6C)alkylene group which, together with the carbon atom to which R² and R³ are attached, defines a ring having 4 to 7 ring atoms, and which ring may bear one or two 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 cycloalkane 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; R² and R³ together form a tetramethylene or pentamethylene group, which, together with the carbon atom to which R² and R³ are attached, defines a ring having 5 or 6 ring atoms and which ring may bear one or two substituents, which may be the same or different, selected from fluoro, methyl, methoxy and trifluoromethyl; or a pharmaceutically-acceptable salt thereof.

Claim 4

A diaryl ether cycloalkane 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, methyl, ethyl, isopropyl, tert -butyl, methoxy, trifluoromethyl, 2-cyanoprop-2-yl, phenyl and benzoyl, and wherein said phenyl or benzoyl substituent may optionally bear a substituent selected from chloro, methyl and methoxy; X¹ is oxy, thio, sulphinyl or sulphonyl; Ar² is 1,3-phenylene which may optionally bear a substituent from fluoro, chloro, bromo and trifluoromethyl; or Ar² is 3,5-pyridylene; R¹ is methyl, ethyl, allyl or 2-propynyl; R² and R³ together form a tetramethylene or pentamethylene group which, together with the carbon atom to which R² and R³ are attached, defines a ring having 5 or 6 ring atoms and which ring may bear one or two substituents selected from methyl, methoxy and ethoxy; or a pharmaceutically-acceptable salt thereof.

Claim 5

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

Claim 6

A diaryl ether cycloalkane of the formula I as claimed in claim 1 wherein Ar¹ is phenyl which bears a substituent selected from tert -butyl and phenyl; or Ar¹ is naphth-2-yl; X¹ is thio, sulphinyl or sulphonyl; Ar² is 1,3-phenylene which may optionally bear a substituent selected from fluoro, chloro, bromo and trifluoromethyl; R¹ is methyl, ethyl or allyl; R² and R³ together from a tetramethylene group which, together with the carbon atom to which R² and R³ are attached, defines a ring having 5 ring atoms and which ring bears a methoxy substituent; or a pharmaceutically-acceptable salt thereof.

Claim 7

A diaryl ether cycloalkane of the formula I, or a pharmaceutically-acceptable salt thereof, selected from (1RS,2SR)-1-­[5-fluoro-3-(naphth-2-ylthio)phenyl]-1,2-dimethoxycyclopentane and (1RS,2SR)-1-allyloxy-1-[5-fluoro-3-(naphth-2-ylthio)phenyl]-2-­methoxycyclopentane.

Claim 8

A diaryl ether cycloalkane of the formula I, or a pharmaceutically-acceptable salt thereof, selected from (1RS,2SR)-1-­[5-fluoro-3-(naphth-2-ylthio)phenyl]-1,2-dimethoxycyclopentane and (1RS,2SR)-1-allyloxy-1-[5-fluoro-3-(naphth-2-ylthio)phenyl]-2-­methoxycyclopentane.

Claim 9

A process for the manufacture of a diaryl ether cycloalkane 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 and amino, alkylamino or hydroxy group in Ar¹, Ar², R² or R³ any amino, 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, alkylamino or hydroxy group in Ar¹, Ar², R¹, R² or R³, any amino, 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, alkylamino or hydroxy group in Ar¹, Ar², R² or R³ any amino, 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 an alkylsulphinyl or alkylsulphonyl substituent; wherein X¹ is a sulphinyl or sulphonyl group; or wherein R² and R³ together form a (3-6C)alkylene group which bears one or two alkylsulphinyl or alkylsulphonyl groups; the oxidation of a compound of the formula I wherein Ar¹ or Ar² bears an alkylthio substituent; wherein X¹ is a thio group; or wherein R² and R³ together form a (3-6C)alkylene group which bears one or two alkylthio groups; (e) for the production of those compounds of the formula I wherein Ar² bears an alkanoylamino substituent, the acylation of a compound of the formula I wherein Ar² bears an amino substituent; or (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; 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 10

A pharmaceutical composition which comprises a diaryl ether cycloalkane of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 6 in association with a pharmaceutically-acceptable diluent or carrier.

Claim 11

A diaryl ether cycloalkane of the formula I, or a pharmaceutically-accetable salt thereof, as claimed in any one of claims 1 to 6 for use in a method of treatment of the human or animal body by therapy.

Claim 12

The use of a diaryl ether cycloalkane of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 6 in the production of a new medicament for use in a leukotriene mediated disease or medical condition.