The invention concerns a diaryl ether cycloalkane of the formula I, or a pharmaceutically-acceptable salt thereof, ##STR1## wherein Ar.sup.1 is optionally substituted phenyl or naphthyl; X.sup.1 is oxy, thio, sulphinyl or sulphonyl; PA0 Ar.sup.2 is optionally substituted phenylene, or a 6-membered heterocyclene moiety containing up to three nitrogen atoms; PA0 R.sup.1 is (1-6C)alkyl, (3-6C)alkenyl, (3-6C)alkynyl, cyano-(1-4C)alkyl or (2-4C)alkanoyl, or optionally substituted benzoyl; and PA0 R.sup.2 and R.sup.3 together form a (3-6C)alkylene group which defines an optionally substituted ring having 4 to 7 ring atoms. The invention also concerns processes for the manufacture of a diaryl ether cycloalkane of the formula I, or a pharmaceutically-acceptable salt thereof, and pharmaceutical compositions containing said cycloalkane. The compounds of the invention are inhibitors of the enzyme 5-lipoxygenase.

This invention concerns novel diaryl ether cycloalkanes and more 
particularly novel diaryl ether cycloalkanes which are inhibitors of the 
enzyme 5-lipoxygenase (hereinafter referred to as 5-LO). The invention 
also concerns processes for the manufacture of said diaryl ether 
cycloalkanes and novel pharmaceutical compositions containing them. Also 
included in the invention is the use of said diaryl ether cycloalkanes in 
the treatment of various inflammatory and/or allergic diseases in which 
the direct or indirect products of 5-LO catalysed oxidation of arachidonic 
acid are involved, and the production of new medicaments for such use. 
As stated above the diaryl ether cycloalkanes described hereinafter are 
inhibitors of 5-LO, which enzyme is known to be involved in catalysing the 
oxidation of arachidonic acid to give rise via a cascade process to the 
physiologically active leukotrienes such as leukotriene B.sub.4 
(LTB.sub.4) and the peptido-lipid leukotrienes such as leukotriene C.sub.4 
(LTC.sub.4) and leukotriene D.sub.4 (LTD.sub.4) and various metabolites. 
The biosynthetic relationship and physiological properties of the 
leukotrienes are summarised by G. W. Taylor and S. R. Clarke in Trends in 
Pharmacological Sciences, 1986, 7, 100-103. The leukotrienes and their 
metabolites have been implicated in the production and development of 
various inflammatory and allergic diseases such as arthritic diseases, 
asthma, allergic rhinitis, atopic dermatitis, psoriasis, cardiovascular 
and cerebrovascular disorders and inflammatory bowel disease. In addition 
the leukotrienes are mediators of inflammatory diseases by virtue of their 
ability to modulate lymphocyte and leukocyte function. Other 
physiologically active metabolites of arachidonic acid, such as the 
prostaglandins and thromboxanes, arise via the action of the enzyme 
cyclooxygenase on arachidonic acid. 
We have now discovered that certain diaryl ether cycloalkanes are effective 
as inhibitors of the enzyme 5-LO and thus of leukotriene biosyntheses. 
Thus, such compounds are of value as therapeutic agents in the treatment 
of, for example, allergic conditions, psoriasis, asthma, cardiovascular 
and cerebrovascular disorders, and/or inflammatory and arthritic 
conditions, mediated alone or in part by one or more leukotrienes. 
According to the invention there is provided a diaryl ether cycloalkane of 
the formula I (set out hereinafter) wherein Ar.sup.1 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 X.sup.1 is oxy, thio, sulphinyl or sulphonyl; 
wherein Ar.sup.2 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)alkylsulphonyl, (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 
Ar.sup.2 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 R.sup.1 is (1-6C)alkyl, (3-6C)alkenyl, (3-6C)alkynyl, 
cyano-(1-4C)alkyl or (2-4C)alkanoyl, or R.sup.1 is benzoyl which may 
optionally bear a substituent selected from halogeno, (1-4C)alkyl and 
(1-4C)alkoxy; and 
wherein R.sup.2 and R.sup.3 together form a (3-6C)alkylene group which, 
together with the carbon atom to which R.sup.2 and R.sup.3 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. 
The chemical formulae referred to herein by Roman numerals are set out for 
convenience on a separate sheet hereinafter. 
In this specification the generic term "alkyl" includes both straight-chain 
and branched-chain alkyl groups. However references to individual alkyl 
groups such as "propyl" are specific for the straight-chain version only 
and references to individual branched-chain alkyl groups such as 
"isopropyl" are specific for the branched-chain version only. An analogous 
convention applies to other generic terms. It is to be understood that, 
insofar as certain of the compounds of formula I defined above may exist 
in optically active or racemic forms by virtue of one or more substituents 
containing an asymmetric carbon atom, the invention includes in its 
definition of active ingredient any such optically active or racemic form 
which possesses the property of inhibiting 5-LO. The synthesis of 
optically active forms may be carried out by standard techniques of 
organic chemistry well known in the art, for example by synthesis from 
optically active starting materials or by resolution of a racemic form. 
Similarly, inhibitory properties against 5-LO may be evaluated using the 
standard laboratory techniques referred to hereinafter. 
Suitable values for the generic terms referred to above include those set 
out below. 
A suitable value for a halogeno substituent which may be present on 
Ar.sup.1, Ar.sup.2 or R.sup.1, or on a phenyl or benzoyl substituent on 
Ar.sup.1, is, for example, fluoro, chloro, bromo or iodo. 
A suitable value for a (1-4C)alkyl substituent which may be present on 
Ar.sup.1, Ar.sup.2 or R.sup.1, or on a phenyl or benzoyl substituent on 
Ar.sup.1, is, for example, methyl, ethyl, propyl, isopropyl, butyl, 
isobutyl, sec-butyl or tert-butyl. 
A suitable value for a (2-4C)alkenyl substituent on Ar.sup.1 is, for 
example, vinyl, allyl, 2-butenyl or 3-butenyl. 
A suitable value for a (2-4C)alkynyl substituent on Ar.sup.1 is, for 
example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl or 2-butynyl. 
A suitable value for a (1-4C)alkoxy substituent which may be present on 
Ar.sup.1, Ar.sup.2 or R.sup.1, or on a phenyl or benzoyl substituent on 
Ar.sup.1, is, for example, methoxy, ethoxy, propoxy, isopropoxy or butoxy. 
Suitable values for substituents which may be present on Ar.sup.1 or 
Ar.sup.2 include, for example 
______________________________________ 
for (1-4C)alkythio: 
methylthio, ethylthio, propylthio, 
isopropylthio and butylthio; 
for (1-4C)alkylsulphinyl: 
methylsulphinyl, ethylsulphinyl, 
propylsulphinyl, isopropyl- 
sulphinyl and butylsulphinyl; 
for (1-4C)alkylsulphonyl: 
methylsulphonyl, ethylsulphonyl, 
propylsulphonyl, isopropylsulphonyl 
and butylsulphonyl. 
______________________________________ 
A suitable value for a (2-4C)alkanoyl substituent which may be present on 
Ar.sup.1 or for R.sup.1 when it is (2-4C)alkanoyl is, for example, acetyl, 
propionyl or butyryl. 
Suitable values for substituents which may be present on Ar.sup.1 or 
Ar.sup.2 include, for example 
______________________________________ 
for (1-4C)alkylamino: 
methylamino, ethylamino, propyl- 
amino and butylamino; 
for di-[(1-4C)alkyl]amino: 
dimethylamino, diethylamino and 
dipropylamino; 
for (1-4C)alkoxycarbonyl: 
methoxycarbonyl, ethoxycarbonyl and 
tert-butoxycarbonyl; 
for fluoro-(1-4C)alkyl: 
fluoromethyl, difluoromethyl, 
trifluoromethyl, 2-fluoroethyl, 2,2,2- 
trifluoroethyl and pentafluoroethyl; 
for cyano-(1-4C)alkyl: 
cyanomethyl, 1-cyanoethyl, 2- 
cyanoethyl, 3-cyanopropyl and 2- 
cyanoprop-2-yl; 
for cyano-(1-4C)alkoxy: 
cyanomethoxy, 2-cyanoethoxy and 3- 
cyanopropoxy; 
for fluoro-(1-4C)alkoxy: 
trifluoromethoxy, 2,2,2-trifluoro- 
ethoxy and pentafluoroethoxy. 
______________________________________ 
A suitable value for a hydroxy-(1-4C)alkyl substituent which may be present 
on Ar.sup.1 is, for example, hydroxymethyl, 1-hydroxyethyl, 
2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl or 3-hydroxypropyl. 
A suitable value for the number of substituents which may be present on 
Ar.sup.1 is, for example, one, two or three. 
A suitable value for Ar.sup.2 when it is phenylene is, for example, 
1,3-phenylene or 1,4-phenylene. 
A suitable value for Ar.sup.2 when it is a 6-membered heterocyclene moiety 
containing up to three nitrogen atoms is, for example, pyridylene, 
pyrimidinylene, pyridazinylene, pyrazinylene or 1,3,5-triazinylene. 
Conveniently Ar.sup.2 when it is a 6-membered heterocyclene moiety 
containing up to three nitrogen atoms is, for example, 2,4-, 2,5-, 3,5- or 
2,6-pyridylene, 2,4-, 2,5- or 4,6-pyrimidinylene, 3,5- or 
3,6-pyridazinylene or 2,5- or 2,6-pyrazinylene. 
Suitable values for substituents which may be present on Ar.sup.2 include, 
for example 
______________________________________ 
for (3-4C)alkenyloxy: 
allyloxy, methylallyloxy, but-2- 
enyloxy and but-3-enyloxy; 
for N-[(1-4C)alkyl]- 
N-methylcarbamoyl, N-ethyl- 
carbamoyl: carbamoyl and N-propylcarbamoyl; 
for N,N-di-[(1-4C)alkyl]- 
N,N-dimethylcarbamoyl and N,N- 
carbamoyl: diethylcarbamoyl; 
for (2-4C)alkanoylamino: 
acetamido, propionamido and 
butyramido; 
for carbamoyl-(1-4C)alkoxy: 
carbamoylmethoxy, 2-carbamoyl- 
ethoxy and 3-carbamoylpropoxy; 
for amino-(2-4C)alkoxy: 
2-aminoethoxy, 3-aminopropoxy and 
4-aminobutoxy; 
for (1-4C)alkylamino- 
2-methylaminoethoxy, 3- 
(2-4C)alkoxy: methylaminopropoxy and 2- 
ethylaminoethoxy; 
for di-[(1-4C)alkyl]amino- 
2-dimethylaminoethoxy, 3- 
(2-4C)alkoxy: dimethylaminopropoxy and 2- 
diethylaminoethoxy; 
for (1-4C)alkoxycarbonyl- 
methoxycarbonylmethoxy, 2- 
(1-4C)alkoxy: methoxycarbonylethoxy, ethoxy- 
carbonylmethoxy and 2-ethoxy- 
carbonylethoxy. 
______________________________________ 
A suitable value for R.sup.1 when it is (1-6C)alkyl is, for example, 
methyl, ethyl, propyl, butyl, pentyl or hexyl. 
A suitable value for R.sup.1 when it is (3-6C)alkenyl is, for example, 
allyl, 2-butenyl or 3-butenyl; and when it is (3-6C)alkynyl is, for 
example 2-propynyl or 2-butynyl. 
A suitable value for R.sup.1 when it is cyano-(1-4C)alkyl is, for example, 
cyanomethyl, 2-cyanoethyl or 3-cyanopropyl. 
A suitable value for R.sup.2 and R.sup.3 when they together form a 
(3-6C)alkylene group which, together with the carbon atom to which R.sup.2 
and R.sup.3 are attached, defines a ring having 4 to 7 ring atoms is, for 
example, trimethylene, tetramethylene, pentamethylene or hexamethylene. 
Suitable values for the one or two substituents which may be present on 
said 4- to 7-membered ring include for example: 
______________________________________ 
for halogeno: fluoro, chloro and bromo; 
for (1-4C)alkyl: 
methyl, ethyl, propyl, isopropyl 
and butyl; 
for (1-4C)alkoxy: 
methoxy, ethoxy, propoxy, isopropoxy 
and butoxy; 
for (1-4C)alkythio: 
methylthio, ethylthio, propylthio, 
isopropylthio and butylthio; 
for (1-4C)alkylsulphinyl: 
methylsulphinyl, ethylsulphinyl, 
propylsulphinyl, isopropyl- 
sulphinyl and butylsulphinyl; 
for (1-4C)alkylsulphonyl: 
methylsulphonyl, ethylsulphonyl, 
propylsulphonyl, isopropylsulphonyl 
and butylsulphonyl; 
for fluoro-(1-4C)alkyl: 
fluoromethyl, difluoromethyl, 
trifluoromethyl, 2-fluoroethyl, 
2,2,2-trifluoroethyl and penta- 
fluoroethyl; 
for (1-4C)alkylenedioxy: 
methylenedioxy and ethylenedioxy. 
______________________________________ 
A suitable pharmaceutically-acceptable salt of a diaryl ether cycloalkane 
of the invention is, for example, an acid-addition salt of a diaryl ether 
cycloalkane of the invention which is sufficiently basic, for example, an 
acid-addition salt with, for example, an inorganic or organic acid, for 
example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, 
citric or maleic acid. In addition a suitable pharmaceutically-acceptable 
salt of a diaryl ether cycloalkane of the invention which is sufficiently 
acidic is an alkali metal salt, for example a sodium or potassium salt, an 
alkaline earth metal salt, for example a calcium or magnesium salt, an 
ammonium salt or a salt with an organic base which affords a 
physiologically-acceptable cation, for example a salt with methylamine, 
dimethylamine, trimethylamine, piperidine, morpholine or 
tris-(2-hydroxyethyl)amine. 
Particular novel compounds of the invention are, for example, diaryl ether 
cycloalkanes of the formula I wherein: 
(a) Ar.sup.1 is phenyl, naphth-1-yl or naphth-2-yl which may optionally 
bear one, two or three substituents selected from amino, fluoro, chloro, 
bromo, iodo, cyano, methyl, ethyl, isopropyl, tert-butyl, methoxy, 
methylthio, methylsulphinyl, methylsulphonyl, methoxycarbonyl, 
difluoromethyl, trifluoromethyl, 1-cyanoethyl, 2-cyanoethyl, 
2-cyanoprop-2-yl and cyanomethoxy; and X.sup.1, Ar.sup.2, R.sup.1, R.sup.2 
and R.sup.3 have any of the meanings defined hereinbefore; 
(b) Ar.sup.1 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; and X.sup.1, 
Ar.sup.2, R.sup.1, R.sup.2 and R.sup.3 have any of the meanings defined 
hereinbefore; 
(c) X.sup.1 is thio, sulphinyl or sulphonyl; and Ar.sup.1, Ar.sup.2, 
R.sup.1, R.sup.2 and R.sup.3 have any of the meanings defined 
hereinbefore; 
(d) Ar.sup.2 is 1,3-phenylene or 1,4-phenylene which may optionally bear 
one substituent selected from fluoro, chloro, hydroxy, amino, nitro, 
methyl, methoxy, methylthio, methylsulphinyl, methylsulphonyl, 
methylamino, dimethylamino, trifluoromethyl, acetamido, cyanomethoxy and 
carbamoylmethoxy; and Ar.sup.1, X.sup.1, R.sup.1, R.sup.2 and R.sup.3 have 
any of the meanings defined hereinbefore; 
(e) Ar.sup.2 is 1,3-phenylene which may optionally bear a substituent 
selected from fluoro, chloro, bromo and trifluoromethyl; and Ar.sup.1, 
X.sup.1, R.sup.1, R.sup.2 and R.sup.3 have any of the meanings defined 
hereinbefore; 
(f) Ar.sup.2 is 2,4-, 2,5-, 3,5- or 2,6-pyridylene or 4,6-pyrimidylene 
which may optionally bear one substituent selected from chloro, methyl and 
methoxy; and Ar.sup.1, X.sup.1, R.sup.1, R.sup.2 and R.sup.3 have any of 
the meanings defined hereinbefore; 
(g) Ar.sup.2 is 3,5-pyridylene; and Ar.sup.1, X.sup.1, R.sup.1, R.sup.2 and 
R.sup.3 have any of the meanings defined hereinbefore; 
(h) R.sup.1 is methyl, ethyl, allyl, 2-propynyl or cyanomethyl; and 
Ar.sup.1, X.sup.1, Ar.sup.2, R.sup.2 and R.sup.3 have any of the meanings 
defined hereinbefore; 
(i) R.sup.1 is methyl, ethyl, allyl or 2-propynyl; and Ar.sup.1, X.sup.1, 
Ar.sup.2, R.sup.2 and R.sup.3 have any of the meanings defined 
hereinbefore; 
(j) R.sup.2 and R.sup.3 together form a tetramethylene or pentamethylene 
group which, together with the carbon atom to which R.sup.2 and R.sup.3 
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, hydroxy, methyl, methoxy, ethoxy, methylthio, 
methylsulphinyl, methylsulphonyl, trifluoromethyl and methylenedioxy; and 
Ar.sup.1, X.sup.1, Ar.sup.2 and R.sup.1 have any of the meanings defined 
hereinbefore; 
(k) R.sup.2 and R.sup.3 together form a tetramethylene or pentamethylene 
group which, together with the carbon atom to which R.sup.2 and R.sup.3 
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; and 
Ar.sup.1, X.sup.1, Ar.sup.2 and R.sup.1 have any of the meanings defined 
hereinbefore; or a pharmaceutically-acceptable salt thereof. 
A preferred compound of the invention comprises a diaryl ether cycloalkane 
of the formula I wherein Ar.sup.1 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; 
X.sup.1 is thio, sulphinyl or sulphonyl; 
Ar.sup.2 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 
Ar.sup.2 is 3,5-pyridylene; 
R.sup.1 is methyl or ethyl; 
R.sup.2 and R.sup.3 together form a tetramethylene or pentamethylene group, 
which, together with the carbon atom to which R.sup.2 and R.sup.3 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. 
A further preferred compound of the invention comprises a diaryl ether 
cycloalkane of the formula I wherein 
Ar.sup.1 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; 
X.sup.1 is oxy, thio, sulphinyl or sulphonyl; 
Ar.sup.2 is 1,3-phenylene which may optionally bear a substituent from 
fluoro, chloro, bromo and trifluoromethyl; or 
Ar.sup.2 is 3,5-pyridylene; 
R.sup.1 is methyl, ethyl, allyl or 2-propynyl; 
R.sup.2 and R.sup.3 together form a tetramethylene or pentamethylene group 
which, together with the carbon atom to which R.sup.2 and R.sup.3 are 
attached, defines a ring having 5 or 6 rings atoms and which ring may bear 
one or two substituents selected from methyl, methoxy and ethoxy; or a 
pharmaceutically-acceptable salt thereof. 
A further preferred compound of the invention comprises a diaryl ether 
cycloalkane of the formula I wherein Ar.sup.1 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 
Ar.sup.1 is naphth-2-yl which may optionally bear a fluoro substituent; 
X.sup.1 is thio, sulphinyl or sulphonyl; 
Ar.sup.2 is 1,3-phenylene which may optionally bear one substituent 
selected from fluoro, amino, nitro, methoxy and trifluoromethyl; or 
Ar.sup.2 is 3,5-pyridylene; 
R.sup.1 is methyl or ethyl; 
R.sup.2 and R.sup.3 together form a tetramethylene or pentamethylene group, 
which, together with the carbon atom to which R.sup.2 and R.sup.3 are 
attached, defines a ring having 5 or 6 ring atoms and which ring bears a 
methoxy substituent; 
or a pharmaceutically-acceptable salt thereof. 
A further preferred compound of the invention comprises a diaryl ether 
cycloalkane of the formula I wherein 
Ar.sup.1 is phenyl which bears a substituent selected from tert-butyl and 
phenyl; or 
Ar.sup.1 is naphth-2-yl; 
X.sup.1 is thio, sulphinyl or sulphonyl; 
Ar.sup.2 is 1,3-phenylene wihch are moptonally bear a substituent selected 
from fluoro, chloro, bromo and trifluoromethyl; 
R.sup.1 is methyl, ethyl or allyl; 
R.sup.2 and R.sup.3 together from a tetramethylene group which, together 
with the carbon atom to which R.sup.2 and R.sup.3 are attached, defines a 
ring having 5 ring atoms and which ring bears a methoxy substituent; 
or a pharmaceutically-acceptable salt thereof. 
Specific especially preferred compounds of the invention include, for 
example, the following diaryl ether cycloalkanes of the formula I, or 
pharmaceutically-acceptable salts thereof: (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-methoxycycl 
opentane. 
According to a further aspect the invention there is provided a diaryl 
ether cycloalkane of the formula I (set out hereinafter) wherein Ar.sup.1 
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 and 
cyano-(1-4C)alkoxy; 
wherein X.sup.1 is oxy, thio, sulphinyl or sulphonyl; 
wherein Ar.sup.2 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 
Ar.sup.2 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 R.sup.1 is 
(1-6C)alkyl, (3-6C)alkenyl, (3-6C)alkynyl, cyano-(1-4C)alkyl or 
(2-4C)alkanoyl, or R.sup.1 is benzoyl which may optionally bear a 
substituent selected from halogeno, (1-4C)alkyl and (1-4C)alkoxy; and 
wherein R.sup.2 and R.sup.3 together form a (3-6C)alkylene group which, 
together with the carbon atom to which R.sup.2 and R.sup.3 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. 
A compound of the invention comprising a diaryl ether cycloalkane of the 
formula I, or a pharmaceutically-acceptable salt thereof, may be prepared 
by any process known to be applicable to the preparation of 
structurally-related compounds. Such procedures are provided as a further 
feature of the invention and are illustrated by the following 
representative examples in which, unless otherwise stated, Ar.sup.1, 
X.sup.1, Ar.sup.2, R.sup.1, R.sup.2 and R.sup.3 have any of the meanings 
defined hereinbefore. 
(a) The coupling, in the presence of a suitable base, of a compound of the 
formula Ar.sup.1 --X.sup.1 --H with a compound of the formula II wherein Z 
is a displaceable group; provided that, when there is an amino, alkylamino 
or hydroxy group in Ar.sup.1, Ar.sup.2, R.sup.2 or R.sup.3 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 Ar.sup.1, Ar.sup.2, R.sup.2 or 
R.sup.3 is removed by conventional means. 
A suitable displaceable group Z is, for example, a halogeno or sulphonyloxy 
group, for example a chloro, bromo, iodo, methanesulphonyloxy or 
toluene-p-sulphonyloxy group. 
A suitable base for the coupling reaction is, for example, an alkali or 
alkaline earth metal carbonate, (1-4C)alkoxide, hydroxide or hydride, for 
example sodium carbonate, potassium carbonate, sodium ethoxide, sodium 
butoxide, sodium hydroxide, potassium hydroxide, sodium hydride or 
potassium hydride. The alkylation reaction is preferably performed in a 
suitable inert solvent or diluent, for example N,N-dimethylformamide, 
N,N-dimethylacetamide, dimethylsulphoxide, acetone, 1,2-dimethoxyethane or 
tetrahydrofuran, and at a temperature in the range, for example, 
10.degree. to 150.degree. C., conveniently at or near 100.degree. C. 
Conveniently the reaction may be performed in the presence of a suitable 
catalyst, for example a metallic catalyst, for example palladium(O) or 
copper(I) such as tetrakis(triphenylphosphine)-palladium, cuprous chloride 
or cuprous bromide. 
A suitable protecting group for an amino or alkylamino group is, for 
example, an acyl group for example a (1-4C)alkanoyl group (especially 
acetyl), a (1-4C)alkoxycarbonyl group (especially methoxycarbonyl, 
ethoxycarbonyl or tert-butoxycarbonyl), an arylmethoxycarbonyl group 
(especially benzyloxycarbonyl) or an aroyl group (especially benzoly). The 
deprotection conditions for the above protecting groups necessarily vary 
with the choice of protecting group. Thus, for example, an acyl group such 
as an alkanoyl or alkoxycarbonyl or an aroyl group may be removed for 
example, by hydrolysis with a suitable base such as an alkali metal 
hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl 
group such as a tert-butoxycarbonyl group may be removed, for example, by 
treatment with a suitable acid such as hydrochloric, sulphuric or 
phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group 
such as a benzyloxycarbonyl group may be removed, for example, by 
hydrogenation over a catalyst such as palladium-on-charcoal. 
A suitable protecting group for a hydroxy group is, for example, an acyl 
group, for example a (1-4C)alkanoyl group (especially acetyl), an aroyl 
group (especially benzoyl) or an arylmethyl group (especially benzyl). The 
deprotection conditions for the above protecting groups will necessarily 
vary with the choice of protecting group. Thus, for example, an acyl group 
such as an alkanoyl or an aroyl group may be removed, for example, by 
hydrolysis with a suitable base such as an alkali metal hydroxide, for 
example lithium or sodium hydroxide. Alternatively an arylmethyl group 
such as a benzyl group may be removed, for example, by hydrogenation over 
a catalyst such as palladium-on-charcoal. 
The starting materials of the formula Ar.sup.1 --X.sup.1 --H and of the 
formula II may be obtained by standard procedures of organic chemistry. 
Conveniently intermediates of the formula II wherein Z, Ar.sup.2, R.sup.1, 
R.sup.2 and R.sup.3 have the meanings defined hereinbefore, may be 
obtained by way of compounds of the formula Z--Ar.sup.2 --Y, wherein Z and 
Ar.sup.2 have the meanings defined hereinbefore and Y is, for example, a 
halogeno, formyl, alkanoyl, nitrile or alkoxycarbonyl group, as 
illustrated in accompanying Scheme I (set out hereinafter). 
It will also be appreciated that the intermediate of the formula II may 
conveniently be obtained from the compound of the formula Z--Ar.sup.2 --Y, 
as defined hereinbefore, by reversing the order of introduction of the 
groups R.sup.2 and R.sup.3 which is used in Scheme I. 
(b) The coupling, in the presence of a suitable base as defined 
hereinbefore, of a compound of the formula III with a compound of the 
formula Ar.sup.1 --Z wherein Z is a displaceable group as defined 
hereinbefore; provided that, when there is an amino, alkylamino or hydroxy 
group in Ar.sup.1, Ar.sup.2, R.sup.1, R.sup.2 or R.sup.3, any amino, 
alkylamino or hydroxy group may be protected by a conventional protecting 
group as defined hereinbefore or alternatively any such group need not be 
protected; 
whereafter any desired protecting group in Ar.sup.1, Ar.sup.2, R.sup.1, 
R.sup.2 or R.sup.3 is removed by conventional means. 
The coupling reaction is conveniently performed in a suitable inert solvent 
as defined hereinbefore and at a temperature in the range, for example, 
10.degree. to 200.degree. C., conveniently in the range 70.degree. to 
150.degree. C. The reaction may conveniently be performed in the presence 
of a suitable catalyst as defined hereinbefore. 
The starting materials of the formula Ar.sup.1 --Z and of the formula III 
may be obtained by standard procedures of organic chemistry. Such starting 
materials are obtainable by analogous procedures to those illustrated in 
accompanying Scheme II (set out hereinafter) or by modifications thereto 
which are within the ordinary skill of an organic chemist. 
A suitable protecting group R.sup.4, as employed in Scheme II, is any one 
of the many such groups known in the art and includes any appropriate 
protecting group as defined hereinbefore. Examples of such groups are 
given in Scheme II. The conditions for the introduction and removal of 
such protecting groups are described in standard textbooks of organic 
chemistry such as, for example, "Protective Groups in Organic Synthesis" 
by T W Green (J Wiley and Sons, 1981). 
(c) The alkylation, in the presence of a suitable base as defined 
hereinbefore, of a compound of the formula IV with a compound of the 
formula R.sup.1 --Z, wherein R.sup.1 and Z have the meanings defined 
hereinbefore, provided that, when there is an amino, alkylamino or hydroxy 
group in Ar.sup.1, Ar.sup.2, R.sup.2 or R.sup.3 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 Ar.sup.1, Ar.sup.2, R.sup.2 or R.sup.3 is 
removed by conventional means. 
The tertiary alcohol starting material of the formula IV may be obtained by 
standard procedures of organic chemistry. The preparation of examples of 
such tertiary alcohols is described within the accompanying non-limiting 
Examples which are provided for the purpose of illustration only. Further 
required tertiary alcohol starting materials are obtainable by analogous 
procedures to those described or by modification thereto which are within 
the ordinary skill of an organic chemist. Conveniently, and as illustrated 
in accompanying Scheme III (set out hereinafter), intermediates of the 
formulae Ar.sup.1 --X.sup.1 --Ar.sup.2 --Y, wherein Ar.sup.1, X.sup.1 and 
Ar.sup.2 have the meanings defined hereinbefore and Y is, for example, a 
halogeno, formyl, alkanoyl, nitrile or alkoxycarbonyl group may be 
utilised in the preparation of the tertiary alcohol starting material of 
the formula IV. 
(d) For the production of those compounds of the formula I wherein Ar.sup.1 
or Ar.sup.2 bears an alkylsulphinyl or alkylsulphonyl substituent; wherein 
X.sup.1 is a sulphinyl or sulphonyl group; or wherein R.sup.2 and R.sup.3 
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 Ar.sup.1 or Ar.sup.2 bears an alkylthio substituent; wherein 
X.sup.1 is a thio group; or wherein R.sup.2 and R.sup.3 together form a 
(3-6C)alkylene group which bears one or two alkylthio groups. 
A suitable oxidising agent is, for example, any agent known in the art for 
the oxidation of thio to sulphinyl and/or sulphonyl, for example, hydrogen 
peroxide, a peracid (such as 3-chloroperoxybenzoic or peroxyacetic acid), 
an alkali metal peroxysulphate (such as potassium peroxymonosulphate), 
chromium trioxide or gaseous oxygen in the presence of platinum. The 
oxidation is generally carried out under as mild conditions as possible 
and with the required stoichiometric amount of oxidising agent in order to 
reduce the risk of over oxidation and damage to other functional groups. 
In general the reaction is carried out in a suitable solvent or diluent 
such as methylene chloride, chloroform, acetone, tetrahydrofuran or 
tert-butyl methyl ether and at a temperature, for example, at or near 
ambient temperature, that is in the range 15.degree. to 35.degree. C. When 
a compound carrying a sulphinyl group is required a milder oxidising agent 
may also be used, for example sodium or potassium metaperiodate, 
conveniently in a polar solvent such as acetic acid or ethanol. It will be 
appreciated that when a compound of the formula I containing a sulphonyl 
group is required, it may be obtained by oxidation of the corresponding 
sulphinyl compound as well as of the corresponding thio compound. 
(e) For the production of those compounds of the formula I wherein Ar.sup.2 
bears an alkanoylamino substituent, the acylation of a compound of the 
formula I wherein Ar.sup.2 bears an amino substituent. 
A suitable acylating agent is, for example, any agent known in the art for 
the acylation of amino to acylamino, for example an acyl halide, for 
example a (2-6C)alkanoyl chloride or bromide, in the presence of a 
suitable base, an alkanoic acid anhydride, for example a (2-6C)alkanoic 
acid anhydride, or an alkanoic acid mixed anhydride, for example the mixed 
anhydride formed by the reaction of an alkanoic acid and a 
(1-4C)alkoxycarbonyl halide, for example a (1-4C)alkoxycarbonyl chloride, 
in the presence of a suitable base. In general the reaction is carried out 
in a suitable solvent or diluent such as methylene chloride, acetone, 
tetrahydrofuran or tert-butyl methyl ether and at a temperature, for 
example, at or near ambient temperature, that is in range 15.degree. to 
35.degree. C. A suitable base when it is required is, for example, 
pyridine, 4-dimethylaminopyridine, triethylamine, ethyldiisopropylamine, 
N-methylmorpholine, an alkali metal carbonate, for example potassium 
carbonate, or an alkali metal carboxylate, for example sodium acetate. 
(f) For the production of those compounds of the formula I wherein R.sup.1 
is alkanoyl or benzoyl optionally bearing a substituent as defined 
hereinbefore, the acylation of a compound of the formula I wherein R.sup.1 
is hydrogen. For the production of those compounds of the formula I 
wherein R.sup.1 is alkanoyl the acylation reaction may be carried out 
using, for example, a suitable acylating agent as defined hereinbefore. 
For the production of those compounds of the formula I wherein R.sup.1 is 
benzoyl optionally bearing a substituent the acylation may be carried out 
using, for example, a benzoyl halide, for example a benzoyl chloride or 
bromide, in the presence of a suitable base as defined hereinbefore. 
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. When 
an optically active form of a compound of the formula I is required, it 
may be obtained by carrying out one of the aforesaid procedures using an 
optically active starting material, or by resolution of a racemic form of 
said compound using a conventional procedure. 
Many of the intermediates defined herein are novel, for example those of 
the formulae III and IV and these are provided as a further feature of the 
invention. 
As stated previously, the compounds of the formula I are inhibitors of the 
enzyme 5-LO. The effects of this inhibition may be demonstrated using one 
or more of the standard procedures set out below: 
a) An in vitro spectrophotometric enzyme assay system, which assesses the 
inhibitory properties of a test compound in a cell free system using 5-LO 
isolated from guinea pig neutrophils and as described by D. Aharony and R. 
L. Stein (J. Biol. Chem., 1986, 261(25), 11512-11519). This test provides 
a measure of the intrinsic inhibitory properties against soluble 5-LO in 
an extracellular environment. 
b) An in vitro assay system involving incubating a test compound with 
heparinised human blood, prior to challenge with the calcium ionophore 
A23187 and then indirectly measuring the inhibitory effects on 5-LO by 
assaying the amount of LTB.sub.4 using the specific radioimmunoassay 
described by Carey and Forder (F. Carey and R. A. Forder, Brit. J. 
Pharmacol. 1985, 84, 34P) which involves the use of a protein-LTB.sub.4 
conjugate produced using the procedure of Young et alia (Prostaglandins, 
1983, 26(4), 605-613). The effects of a test compound on the enzyme 
cyclooxygenase (which is involved in the alternative metabolic pathway for 
arachidonic acid and gives rise to prostaglandins, thromboxanes and 
related metabolites) may be measured at the same time using the specific 
radioimmunoassay for thromboxane B.sub.2 (TxB.sub.2) described by Carey 
and Forder (see above). This test provides an indication of the effects of 
a test compound against 5-LO and also cyclooxygenase in the presence of 
blood cells and proteins. It permits the selectivity of the inhibitory 
effect on 5-LO or cyclooxygenase to be assessed. 
c) An ex vivo assay system, which is a variation of test b) above, 
involving administration of a test compound (usually orally as the 
suspension produced when a solution of the test compound in 
dimethylsulphoxide is added to carboxymethylcellulose), blood collection, 
heparinisation, challenge with A23187 and radioimmunoassay of LTB.sub.4 
and TxB.sub.2. This test provides an indication of the bioavailability of 
a test compound as an inhibitor of 5-LO or cyclooxygenase. 
d) An in vitro assay system involving the measurement of the inhibitory 
properties of a test compound against the liberation of LTC.sub.4 and 
PGE.sub.2 induced by zymosan on mouse resident peritoneal macrophages, 
using the procedure of Humes (J. L. Humes et alia, Biochem. Pharmacol., 
1983, 32, 2319-2322) and conventional radioimmunoassay systems to measure 
LTC.sub.4 and PGE.sub.2. This test provides an indication of inhibitory 
effects against 5-LO and cyclooxygenase in a non-proteinaceous system. 
e) An in vivo system involving the measurement of the effects of a test 
compound in inhibiting the inflammatory response to arachidonic acid in 
the rabbit skin model developed by D. Aked et alia (Brit. J. Pharmacol., 
1986, 89, 431-438). This test provides an in vivo model for 5-LO 
inhibitors administered topically or orally. 
f) An in vivo system involving measuring the effects of a test compound 
administered orally or intravenously on a leukotriene dependent 
bronchoconstriction induced by an antigen challenge in guinea pigs 
pre-dosed with an antihistamine (mepyramine), a .beta.-adrenergic blocking 
agent (propranolol) and a cyclooxygenase inhibitor (indomethacin), using 
the procedure of W. H. Anderson et alia (British J. Pharmacology, 1983, 
78(1), 67-574). This test provides a further in vivo test for detecting 
5-LO inhibitors. 
g) An in vivo system involving measuring the effects of a test compound 
administered orally against the liberation of LTB.sub.4 induced by zymosan 
within an air pouch generated within the subcutaneous tissue of the back 
of male rats. The rats are anaesthetised and air pouches are formed by the 
injection of sterile air (20 ml). A further injection of air (10 ml) is 
similarly given after 3 days). At 6 days after the initial air injection 
the test compound is administered (usually orally as the suspension 
produced when a solution of the test compound in dimethylsulphoxide is 
added to hydroxypropylmethylcellulose), followed by the intrapouch 
injection of zymosan (1 ml of a 1% suspension in physiological saline). 
After 3 hours the rats are killed, the air pouches are lavaged with 
physiological saline, and the specific radioimmunoassay described above is 
used to assay LTB.sub.4 in the washings. This test provides an indication 
of inhibitory effects against 5-LO in an inflammatory milieu. 
Although the pharmacological properties of the compounds of the formula I 
vary with structural changes as expected, in general compounds of the 
formula I possess 5-LO inhibitory effects at the following concentrations 
or doses in one or more of the above tests a)-f): 
Test a): IC.sub.50 in the range, for example, 0.01-30 .mu.M; 
Test b): IC.sub.50 (LTB.sub.4) in the range, for example, 0.01-40 .mu.M 
IC.sub.50 (TxB.sub.2) in the range, for example, 40-200 .mu.M; 
Test c): oral ED.sub.50 (LTB.sub.4) in the range, for example, 1-100 mg/kg; 
Test d): IC.sub.50 (LTC.sub.4) in the range, for example, 0.001-1 .mu.M, 
IC.sub.50 (PGE.sub.2) in the range, for example, 20-1000 .mu.M; 
Test e): inhibition of inflammation in the range, for example, 0.3-100 
.mu.g intradermally; 
Test f): ED.sub.50 in the range, for example, 0.5-10 mg/kg i.v.; 
Test g): oral ED.sub.50 (LTB.sub.4) in the range, for example, 0.5-50 
mg/kg. 
No overt toxicity or other untoward effects are present in tests c), e), f) 
and/or g) when compounds of the formula I are administered at several 
multiples of their minimum inhibitory dose or concentration. 
Thus, by way of example, the compound 
(1RS,2SR)-1-[5-fluoro-3-(naphth-2-ylthio)phenyl]-1,2-dimethoxycyclopentane 
has an IC.sub.50 of approx. 0.2 .mu.M against LTB.sub.4 in test b); and 
the compound 
(1RS,2SR)-1-allyloxy-1-[5-fluoro-3-(naphth-2-ylthio)phenyl]-2-methoxycyclo 
pentane also has an IC.sub.50 of approx. 0.2 .mu.M against LTB.sub.4 in 
test b). 
These compounds are examples of diaryl ether cycloalkanes of the invention 
which show selective inhibitory properties for 5-LO as opposed to 
cyclooxygenase, which selective properties are expected to impart improved 
therapeutic properties, for example, a reduction in or freedom from the 
gastrointestinal side-effects frequently associated with cyclooxygenase 
inhibitors such as indomethacin. 
According to a further feature of the invention there is provided a 
pharmaceutical composition which comprises a diaryl ether cycloalkane of 
the formula I, or a pharmaceutically-acceptable salt thereof, in 
association with a pharmaceutically-acceptable diluent or carrier. 
The composition may be in a form suitable for oral use, for example a 
tablet, capsule, aqueous or oily solution, suspension or emulsion; for 
topical use, for example a cream, ointment, gel or aqueous or oily 
solution or suspension; for nasal use, for example a snuff, nasal spray or 
nasal drops; for vaginal or rectal use, for example a suppository; for 
administration by inhalation, for example as a finely divided powder or a 
liquid aerosol; for sub-lingual or buccal use, for example a tablet or 
capsule; or for parenteral use (including intravenous, subcutaneous, 
intramuscular, intravascular or infusion), for example a sterile aqueous 
or oily solution or suspension. 
In general the above compositions may be prepared in a conventional manner 
using conventional excipients. 
The amount of active ingredient (that is a diaryl ether cycloalkane of the 
formula I or a pharmaceutically-acceptable salt thereof) that is combined 
with one or more excipients to produce a single dosage form will 
necessarily vary depending upon the host treated and the particular route 
of administration. For example, a formulation intended for oral 
administration to humans will generally contain, for example, from 0.5 mg 
to 2 g of active agent compounded with an appropriate and convenient 
amount of excipients which may vary from about 5 to about 98 percent by 
weight of the total composition. Dosage unit forms will generally contain 
about 1 mg to about 500 mg of an active ingredient. 
According to a further feature of the invention there is provided a diaryl 
ether cycloalkane of the formula I, or a pharmaceutically-accetable salt 
thereof, for use in a method of treatment of the human or animal body by 
therapy. 
The invention also includes a method of treating a disease or medical 
condition mediated alone or in part by one or more leukotrienes which 
comprises administering to a warm-blooded animal requiring such treatment 
an effective amount of an active ingredient as defined above. The 
invention also provides the use of such an active ingredient in the 
production of a new medicament for use in a leukotriene mediated disease 
or medical condition. 
The size of the dose for therapeutic or prophylactic purposes of a diaryl 
ether derivative of the formula I will naturally vary according to the 
nature and severity of the conditions, the age and sex of the animal or 
patient and the route of administration, according to well known 
principles of medicine. As mentioned above, diaryl ether cycloalkanes of 
the formula I are useful in treating those allergic and inflammatory 
conditions which are due alone or in part to the effects of the 
metabolites of arachidonic acid arising by the linear (5-LO catalysed) 
pathway and in particular the leukotrienes, the production of which is 
mediated by 5-LO. As previously mentioned, such conditions include, for 
example, asthmatic conditions, allergic reactions, allergic rhinitis, 
allergic shock, psoriasis, atopic dermatitis, cardiovascular and 
cerebrovascular disorders of an inflammatory nature, arthritic and 
inflammatory joint disease, and inflammatory bowel diseases. 
In using a compound of the formula I for therapeutic or prophylactic 
purposes it will generally be administered so that a daily dose in the 
range, for example, 0.5 mg to 75 mg per kg body weight is received, given 
if required in divided doses. In general lower doses will be administered 
when a parenteral route is employed. Thus, for example, for intravenous 
administration, a dose in the range, for example, 0.5 mg to 30 mg per kg 
body weight will generally be used. Similarly, for administration by 
inhalation, a dose in the range, for example, 0.5 mg to 25 mg per kg body 
weight will be used. 
Although the compounds of the formula I are primarily of value as 
therapeutic agents for use in warm-blooded animals (including man), they 
are also useful whenever it is required to inhibit the enzyme 5-LO. Thus, 
they are useful as pharmacological standards for use in the development of 
new biological tests and in the search for new pharmacological agents. 
By virtue of their effects on leukotriene production, the compounds of the 
formula I have certain cytoprotective effects, for example they are useful 
in reducing or suppressing certain of the example they are useful in 
reducing or suppressing certain of the adverse gastrointestinal effects of 
the cyclooxygenase inhibitory non-steroidal anti-inflammatory agents 
(NSAIA), such as indomethacin, acetylsalicylic acid, ibuprofen, sulindac, 
tolmetin and piroxicam. Furthermore, co-administration of a 5-LO inhibitor 
of the formula I with a NSAIA can result in a reduction in the quantity of 
the latter agent needed to produce a therapeutic effect, thereby reducing 
the likelihood of adverse side-effects. According to a further feature of 
the invention there is provided a pharmaceutical composition which 
comprises a diaryl ether cycloalkane of the formula I, or a 
pharmaceutically-acceptable salt thereof as defined hereinbefore, in 
conjunction or admixture with a cyclooxygenase inhibitory non-steroidal 
anti-inflammatory agent (such as mentioned above), and a 
pharmaceutically-acceptable diluent or carrier. 
The cytoprotective effects of the compounds of the formula I may be 
demonstrated, for example in a standard laboratory model which assesses 
protection against indomethacin-induced or ethanol-induced ulceration in 
the gastrointestinal tract of rats. 
The compositions of the invention may in addition contain one or more 
therapeutic or prophylactic agents known to be of value for the disease 
under treatment. Thus, for example a known platelet aggregation inhibitor, 
hypolipidemic agent, anti-hypertensive agent, beta-adrenergic blocker or a 
vasodilator may usefully also be present in a pharmaceutical composition 
of the invention for use in treating a heart or vascular disease or 
condition. Similarly, by way of example, an anti-histamine, steroid (such 
as beclomethasone dipropionate), sodium cromoglycate, phosphodiesterase 
inhibitor or a beta-adrenergic stimulant may usefully also be present in a 
pharmaceutical composition of the invention for use in treating a 
pulmonary disease or condition. 
The invention will now be illustrated in the following non-limiting 
Examples in which, unless otherwise stated: 
(i) evaporations were carried out by rotary evaporation in vacuo and 
work-up procedures were carried out after removal of residual solids by 
filtration; 
(ii) operations were carried out at room temperature, that is in the range 
18.degree.-25.degree. and under an atmosphere of an inert gas such as 
argon; 
(iii) column chromatography (by the flash procedure) and medium pressure 
liquid chromatography (MPLC) were performed on Merck Kieselgel silica 
(Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silica 
obtained from E. Meck, Darmstadt, W. Germany; 
(iv) yields are given for illustration only and are not necessarily the 
maximum attainable; 
(v) the end-products of the formula I have satisfactory microanalysis and 
their structures were confirmed by NMR and mass spectral techniques; 
(vi) intermediates were not generally fully characterised and purity was 
assessed by thin layer chromatographic, infra-red (IR) or NMR analysis; 
(vii) melting points are uncorrected and were determined using a Mettler 
SP62 automatic melting point apparatus or an oil-bath apparatus; melting 
points for the end-products of the formula I were determined after 
recrystallisation from a conventional organic solvent such as ethanol, 
methanol, acetone, ether or hexane, alone or in admixture; and 
(viii) the following abbreviations have been used: 
______________________________________ 
THF tetrahydrofuran; 
DMSO dimethylsulphoxide; 
DMF N,N-dimethylformamide; 
DMA N,N-dimethylacetamide. 
______________________________________

EXAMPLE 1 
A mixture of 
(1RS,2SR)-1-[5-fluoro-3-(naphth-2-ylthio)phenyl]-2-methoxycyclopentanol 
(0.12 g), sodium hydride (60% w/w dispersion in mineral oil; 0.026 g), 
1,4,7,10,13-pentaoxacyclopentadecane (hereinafter 15-crown-5, 0.005 g) and 
DMF (1.5 ml) was stirred at ambient temperature for 5 minutes. Methyl 
iodide (0.14 g) was added and the mixture was stirred at ambient 
temperature for 4 hours. The mixture was partitioned between diethyl ether 
and water. The organic phase was washed with water and with brine, dried 
(MgSO.sub.4) and evaporated. The residue was purified by column 
chromatography using initially petroleum ether (b.p. 40.degree.-60.degree. 
C.) and then a 1:1 v/v mixture of petroleum ether and methylene chloride 
as eluent. There was thus obtained 
(1RS,2SR)-1-[5-fluoro-3-(naphth-2-ylthio)phenyl]-1,2-dimethoxycyclopentane 
(0.095 g, 76%). 
NMR Spectrum (CDCl.sub.3, .delta. values) 1.5-2.25 (m, 6H), 2.95 (s, 3H), 
3.0 (s, 3H), 3.4-3.6 (m, 1H), 6.75-8.0 (m, 10H). 
The (1RS,2SR)-1-[5-fluoro-3-(naphth-2-ylthio)phenyl]-2-methoxycyclopentanol 
used as a starting material was obtained as follows: 
Sodium hydride (50% w/w dispersion in mineral oil, 0.58 g) was added 
portionwise to a mixture of 2-naphthalenethiol (1.6 g) and DMA (15 ml) and 
the mixture was stirred at ambient temperature for 1.5 hours. 
1-Bromo-3,5-difluorobenzene (1.93 g) was added and the mixture was heated 
to 60.degree. C. for 3 hours. The mixture was allowed to cool to ambient 
temperature and partitioned between diethyl ether and water. The organic 
phase was washed with brine (50 ml), dried (MgSO.sub.4) and evaporated. 
The residue was purified by column chromatography using petroleum ether 
(b.p. 40.degree.-60.degree. C.) as eluent. There was thus obtained 
3-bromo-5-fluorophenyl 2-naphthyl sulphide (2.1 g, 63%) as an oil. 
A Grignard reagent was prepared by stirring a mixture of the product so 
obtained (0.782 g), magnesium powder (0.065 g), THF (1 ml) and a crystal 
of iodine at ambient temperature for 0.5 hours. A solution of 
2-methoxycyclopentanone (0.336 g; Bull. Soc. Chim. France, 1973, 1417) in 
THF (1 ml) was added and the mixture was stirred at ambient temperature 
for 15 hours. The mixture was partitioned between diethyl ether and water. 
The organic phase was washed with brine, dried (MgSO.sub.4) and 
evaporated. The residue was purified by column chromatography using 
methylene chloride as eluent. There was thus obtained and separated a 
mixture of diastereoisomers. The required starting material (0.272 g, 31%) 
was the more polar diastereoisomer, having the methoxy and hydroxy groups 
in a trans-relationship. 
EXAMPLE 2 
The procedure described in Example 1 was repeated except that allyl bromide 
was used in place of methyl iodide. There was thus obtained 
(1RS,2SR)-1-allyloxy-1-[5-fluoro-3-(naphth-2-ylthio)phenyl]-2-methoxycyclo 
pentane in 62% yield, as an oil. 
NMR Spectrum (CDCl.sub.3, .delta. values) 1.5-2.25 (m, 6H), 3.0 (s, 3H), 
1.25-1.75 (m, 3H), 4.8-5.25 (m, 2H), 5.5-6.0 (m, 1H), 6.75-8.0 (m, 10H). 
EXAMPLE 3 
The following illustrate representative pharmaceutical dosage forms 
containing the compound of formula I, or a pharmaceutically-acceptable 
salt salt thereof (hereafter compound X), for therapeutic or prophylactic 
use in humans: 
______________________________________ 
(a) Tablet I mg/tablet 
Copound X 100 
Lactose Ph. Eur 182.75 
Croscarmellose sodium 12.0 
Maize starch paste (5% w/v paste) 
2.25 
Magnesium stearate 3.0 
(b) Tablet II mg/tablet 
Compound X 50 
Lactose Ph. Eur 223.75 
Croscarmellose sodium 6.0 
Maize starch 15.0 
Polyvinylpyrrolidone (5% w/v paste) 
2.25 
Magnesium stearate 3.0 
(c) Tablet III mg/tablet 
Compound X 1.0 
Lactose Ph. Eur 93.25 
Croscarmellose sodium 4.0 
Maize starch paste (5% w/v paste) 
0.75 
Magnesium stearate 1.0 
(d) Capsule mg/capsule 
Compound X 10 mg 
Lactose Ph. Eur 488.5 
Magnesium stearate 1.5 
(e) Injection I (50 mg/ml) 
Compound X 5.0% w/v 
1M Sodium hydroxide solution 
15.0% v/v 
0.1M Hydrochloric acid 
(to adjust pH to 7.6) 
Polyethylene glycol 400 
4.5% w/v 
Water for injection to 100% 
(f) Injection II (10 mg/ml) 
Compound X 1.0% w/v 
Sodium phosphate BP 3.6% w/v 
0.1M Sodium hydroxide solution 
15.0% v/v 
Water for injection to 100% 
(1 mg/ml, 
(g) Injection III buffered to pH 6) 
Compound X 0.1% w/v 
Sodium phosphate BP 2.26% w/v 
Citric acid 0.38% w/v 
Polyethylene glycol 400 
3.5% w/v 
Water for injection to 100% 
(h) Aerosol I mg/ml 
Compound X 10.0 
Sorbitan trioleate 13.5 
Trichlorofluoromethane 910.0 
Dichlorodifluoromethane 
490.0 
(i) Aerosol II mg/ml 
Compound X 0.2 
Sorbitan trioleate 0.27 
Trichlorofluoromethane 70.0 
Dichlorodifluoromethane 
280.0 
Dichlorotetrafluoroethane 
1094.0 
(j) Aerosol III mg/ml 
Compound X 2.5 
Sorbitan trioleate 3.38 
Trichlorofluoromethane 67.5 
Dichlorodifluoromethane 
1086.0 
Dichlorotetrafluoroethane 
191.6 
(k) Aerosol IV mg/ml 
Compound X 2.5 
Soya lecithin 2.7 
Trichlorofluoromethane 67.5 
Dichlorodifluoromethane 
1086.0 
Dichlorotetrafluoroethane 
191.6 
______________________________________ 
Note 
The above formulations may be obtained by conventional procedures well 
known in the pharmaceutical art. The tablets (a)-(c) may be enteric coated 
by conventional means, for example to provide a coating of cellulose 
acetate phthalate. The aerosol formulations (h)-(k) may be used in 
conjunction with standard, metered dose aerosol dispensers, and the 
suspending agents sorbitan trioleate and soya lecithin may be replaced by 
an alternative suspending agent such as sorbitan monooleate, sorbitan 
sesquioleate, polysorbate 80, polyglycerol oleate or oleic acid. 
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