WO1995030669A1

WO1995030669A1 - Ether derivatives and pharmaceutical compositions containing them

Info

Publication number: WO1995030669A1
Application number: PCT/GB1995/001001
Authority: WO
Inventors: Philip Neil Edwards
Original assignee: Zeneca Limited; Zeneca-Pharma
Priority date: 1994-05-06
Filing date: 1995-05-02
Publication date: 1995-11-16

Abstract

The invention concerns an ether derivative of formula (I), wherein each of A?1 and A2¿ includes, independently, direct links; wherein X1 includes thio; wherein Ar1 includes phenylene, optionally substituted; wherein Ar2 includes phenylene, optionally substituted; wherein R?1 and R4¿ independently includes hydrogen and (1-6C)alkyl; wherein R?2 and R3¿ together, and R?5 and R6¿ together, form a group of the formula -A3-X2-A4-, which together with the carbon atom to which both A?3 and A4¿ are attached define 4- to 7-membered rings, optionally substituted, wherein A?3 and A4¿ are independently (1-4C)alkylene and X2 includes oxy; or wherein R?5 and R6¿ together with the carbon atom to which both R?5 and R6¿ are attached define cyclopentyl or cyclohexyl groups, optionally substituted; or a pharmaceutically-acceptable salt; and processes for their preparation, pharmaceutical compositions containing them and their use as 5-lipoxygenase inhibitors.

Description

- 1 -

ETHER DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.

This invention concerns ether derivatives which are inhibitors of the enzyme 5-lipoxygenase (hereinafter referred to as 5- 0). The invention also concerns processes for the manufacture of said ether derivatives and novel pharmaceutical compositions containing them. Also included in the invention is the use of said ether derivatives 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 ether derivatives described hereinafter are inhibitors of 5- O, 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, (LTB.) and the peptido-lipid leukotrienes such as leukotriene C, (LTC.) and leukotriene D, (LTD.) 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 inflammation of the joints (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), skin disease (especially psoriasis, eczema and dermatitis), ocular conditions (especially allergic conjunctivitis and uveitis) and respiratory disease (especially asthma, bronchitis and allergic rhinitis), and in the production and development of various cardiovascular and cerebrovascular disorders such as myocardial infarction, the formation of atherosclerotic plaques, hypertension, platelet aggregation, stroke, reperfusion injury, vascular injury including restenosis, angina and peripheral vascular disease for example in the formation of the conditions of shock or trauma such as can follow burn injuries, toxaemia or surgery, and for example various disorders of bone metabolism such as osteoporosis (including senile and postmenopausal osteoporosis), Paget's disease, bone metastases, hypercalcaemia, hyperparathyroidism, osteosclerosis, osteopetrosis and periodontitis, and the abnormal changes in bone metabolism which may accompany rheumatoid arthiritis and osteoarthritis. 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.

It is disclosed in European Patent Application Nos 0375404, 0375452, 0375457 and 0385662 that certain heterocyclic derivatives possess inhibitory properties against 5-L0. Furthermore European Patent Applications Nos. 0409413, 0462812 and 0488602 are also concerned with heterocyclic derivatives which possess inhibitory properties against 5-L0. We have now discovered that certain ether derivatives, which possess some structural features which are similar to those of the compounds disclosed in the above-mentioned applications but which possess other structural features not envisaged in those earlier applications, are effective 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 an ether derivative of the formula I (set out hereinafter) wherein each of A

2 and A is, independently, a direct link or (l-3C)alkylene; wherein X is oxy, thio, sulphinyl or sulphonyl; wherein Ar is phenylene, pyridinediyl or pyrimidinediyl, which may optionally bear one or two substituents independently selected from halogeno, cyano, trifluoromethyl, hydroxy, amino, (l-4C)alkyl,

(l-4C)alkoxy, (l-4C)alkylamino and di-(l-4C)alkylamino;

2 wherein Ar is phenylene, pyridinediyl, pyrimidinediyl, thiophenediyl, furandiyl, thiazolediyl, oxazolediyl, thiadiazolediyl or oxadiazolediyl which may optionally bear one or two substituents independently selected from halogeno, cyano, trifluoromethyl, hydroxy, amino, (l-4C)alkyl, (l-4C)alkoxy, (l-4C)alkylamino and di-(1-4C)alkylamino;

1 4 wherein R and R are independently selected from hydrogen,

(l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, cyano-(l-4C)alkyl,

(2-4C)alkanoyl and benzoyl, which said benzoyl may optionally bear a substituent selected from halogeno, (l-4C)alkyl and (l-4C)alkoxy; wherein R and R together form a group of the formula -A -X -A -, which together with the carbon atom to which both A 3 and A4 are A attached defines a ring having 4 to 7 ring atoms, wherein A and A ,

2 which may be the same or different, each is (l-4C)alkylene and X is selected from oxy, thio, sulphinyl, sulphonyl and imino and which ring may optionally bear one, two or three substituents independently selected from hydroxy, (l-4C)alkyl, (l-4C)alkoxy and fluoro-(l-4C)alkyl, or which ring may bear a (l-4C)alkylenedioxy substituent;

C (L A and wherein R and R together form a group of the formula -A -X -A -, which together with the carbon atom to which both A 3 and A4 are attached defines a ring having 4 to 7 ring atoms wherein A 3 and A4,

2 which may be the same or different, each is (l-4C)alkylene and X is selected from oxy, thio, sulphinyl, sulphonyl and imino, and which ring may optionally bear one, two or three substituents independently selected from hydroxy, (l-4C)alkyl, (l-4C)alkoxy and fluoro-(l-4C)alkyl, or which ring may bear a (l-4C)alkylenedioxy substituent; or wherein R and R together with the carbon atom to which both R and R are attached, form a cyclopentyl or cyclohexyl group, and which ring may optionally bear one, two or three substituents independently selected from hydroxy, (l-4C)alkyl, (l-4C)alkoxy and fluoro-(l-4C)alkyl, or which ring may bear a (l-4C)alkylenedioxy substituent; or wherein R and R together form a group of the formula -A -X -A -, which together with the oxygen atom to which A is attached and with the carbon atom to which A is attached define a ring having 5 or 6 ring atoms, wherein A and A , which may be the same or different, 3 each is (l-3C)alkylene and X is oxy, thio, sulphinyl, sulphonyl or imino, and which ring may optionally bear one, two or three

(l-4C)alkyl substituents, and R is hydrogen or (l-4C)alkyl; 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 further 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 asymmetric carbon atoms, the invention includes in its definition 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.

Suitable values for the generic terms referred to above include those set out below.

1 2 A suitable value for A and A when each is independently

(l-3C)alkylene is, for example, methylene, ethylene or trimethylene.

A suitable value for Ar when it is phenylene, pyridinediyl or pyrimidinediyl is, for example, 1,3- or 1,4-phenylene, 2,4-, 2,5- or 3,5-pyridinediyl or 4,6-pyrimidinediyl.

2 A suitable value for Ar when it is phenylene, pyridinediyl, pyrimidinediyl, thiophenediyl, furandiyl, thiazolediyl, oxazolediyl, thiadiazolediyl or oxadiazolediyl is, for example, 1,3- or

1,4-phenylene, 2,4-, 2,5- or 3,5-pyridinediyl, 4,6-pyrimidinediyl,

2,4- or 2,5-thiophenediyl, 2,4- or 2,5-furandiyl, 2,4- or

2,5-thiazolediyl, 2,4- or 2,5-oxazolediyl, 2,5-thiadiazolediyl or

2,5-oxadiazolediyl. Suitable values for substituents which may be present on Ar

2 or Ar include, for example:-

for halogeno: fluoro, chloro, bromo and iodo; for (l-4C)alkyl: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl; for (l-4C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for (l-4C)alkylamino: methylamino, ethylamino, propylamino and isopropylamino; and for di-(l-4C)alkylamino: dimethyla ino, N-ethyl-N-methylamino and diethylamino.

A suitable value for R when it is (1-6C)alkyl is, for example, methyl, ethyl, propyl, butyl, pentyl or hexyl; when it is

(2-6C)alkenyl is, for example, allyl, 2-butenyl, 3-butenyl,

2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl or

5-hexenyl; when it is (2-6C)alkynyl is, for example, 2-propynyl,

2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl,

3-hexynyl, 4-hexynyl or 5-hexynyl; when it is cyano-(1-4C)alkyl is, for example, cyanomethyl, 2-cyanoethyl, 3-cyanopropyl or

2-cyanoprop-2-yl; and when it is (2-4C)alkanoyl is, for example, acetyl, propionyl or butyryl. Suitable values for substituents which may be present on R when it is benzoyl are, for example, when the substituent is halogeno, fluoro, chloro, bromo and iodo; when it is

(l-4C)alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl; and when it is (l-4C)alkoxy, methoxy, ethoxy, propoxy, isopropoxy and butoxy.

4 A suitable value for R when it is (1-6C)alkyl is, for example, methyl, ethyl, propyl, butyl, pentyl or hexyl; when it is

(2-6C)alkenyl is, for example, allyl, 2-butenyl, 3-butenyl,

2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl or

5-hexenyl; when it is (2-6C)alkynyl is, for example, 2-propynyl,

2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl,

3-hexynyl, 4-hexynyl or 5-hexynyl; when it is cyano-(l-4C)alkyl is, for example, cyanomethyl, 2-cyanoethyl, 3-cyanopropyl or 2-cyanoprop-2-yl; and when it is (2-4C)alkanoyl is, for example, acetyl, propionyl or butyryl. Suitable values for substituents which may be present on R when it is benzoyl are, for example, when the substituent is halogeno: fluoro, chloro, bromo and iodo; when the substituent is (1-4C)alkyl: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl; and when the substituent is

(l-4C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy. 2 o fi

When R and R together or R and R together form a group

3 2 4 3 4 of the formula -A -X -A -, suitable values for A and A , which may be the same or different, when each is (1-4C))alkylene are, for example, methylene, ethylene, trimethylene and tetramethylene. When R 4 and R5 together form a group of the formula

-A -X -A -, suitable values for A and A , which may be the same or different, when each is (l-3C)alkylene are, for example, methylene, ethylene and trimethylene; and a suitable value for R when it is

(1-4C)alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and ter -butyl.

Suitable values for substituents which may be present on the rings invollvviinngg

aanndd

together include, for example:

for (l-4C)alkyl: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl;

for (l-4C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy;

for fluoro-(l-4C)alkyl: fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoromethyl, 2,2,2-trifluoroethyl and pentafluoroethyl;

for (l-4C)alkylenedioxy: methylenedioxy, ethylenedioxy, trimethylenedioxy and tetra ethylenedioxy. It is to be understood that, insofar as certain of the rings involving R and R together, R and R together or R and R together may be disubstituted, the invention includes in its definition any compounds of the formula I which contain geminally disubstituted rings.

A suitable pharmaceutically-acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound 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 compound 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 compounds of the invention include, for example, ether derivatives of the formula I, or pharmaceutically-acceptable salts thereof, as defined in paragraphs (a) to (i) below.

(a) Each of A 1 and A2 are direct links; and X1, Ar1, Ar2, R1, R2,

R , R , R and R have any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention.

(b) Ar is phenylene or pyridinediyl which may optionally bear one or two substituents selected from halogeno, cyano, trifluoromethyl,

1 2 1 2 1 hydroxy, amino, (l-4C)alkyl and (l-4C)alkoxy; and A , A , X , Ar , R ,

R , R

have any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention.

2

(c) Ar is phenylene or pyridinediyl which may optionally bear one or two substituents selected from halogeno, cyano, trifluoromethyl,

2 hydroxy, amino, (1-4C)alkyl and (l-4C)alkoxy; or Ar is thiophenediyl or

1 0 1 1 1 ^*3 / *_ _t_ thiazolediyl; and A , A , X , Ar , R , R , R , R , R and R have any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention. (d) Ar is phenylene which may optionally bear one substituent

1 2 1 2 1 2 3 selected from halogeno and (1-4C)alkyl; and A , A , X , Ar , R , R , R ,

R , R and R have any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention.

2

(e) Ar is phenylene which may optionally bear one substituent selected from halogeno, cyano, trifluoromethyl, hydroxy, amino,

2 (l-4C)alkyl and (l-4C)alkoxy; or Ar is thiophenediyl or thiazolediyl;

1 0 1 1 1 0 . / ζ _E_ and A , A , X , Ar , R , R , R , R , R and R have any of the meanings defined hereinbefore or in this section covering particular compounds of the invention.

1 1 2

(f) X is thio or sulphonyl and each of A and A is a direct link;

1 1 '_{) '}3 / ^_ _ and Ar , Ar , R , R , R , R , R and R have any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention. Q 0. 0 /

(g) R and R together form a group of the formula -A -X -A -, which together with the carbon atom to which both A 3 and A4 are attached

3 4 defines a ring having 5 or 6 ring atoms, wherein A and A , which may be

2 the same or different, each is (l-4C)alkylene and X is oxy; and which ring may optionally bear one substituent selected from hydroxy,

(1-4C)alkyl and (l-4C)alkoxy; and A¹, A², X¹, Ar¹, Ar², R¹, R⁴, R⁵ and R⁶ have any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention.

C _£_ 0 0 /

(h) R and R together form a group of the formula -A -X -A -,

3 4 which together with the carbon atom to which both A and A are attached

3 4 defines a ring having 5 or 6 ring atoms wherein A and A , which may be

(1-4C)alkyl and (l-4C)alkoxy; and A¹, A², X¹, Ar¹, Ar², R¹, R², R³ and R⁴ have any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention. (i) R and R are independently selected from hydrogen, (1-6C)alkyl and (2-4C)alkanoyl; and A¹, A², X¹, Ar¹, Ar², R², R³, R⁵ and R⁶ have any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention.

A preferred compound of the invention comprises an ether derivative of the formula I wherein;

1 2 each of A and A is a direct link;

Ar is phenylene which may optionally bear one substituent selected from halogeno;

2 Ar is phenylene which may optionally bear one substituent selected from

2 halogeno, or Ar is thiophenediyl or thiazolediyl;

X is thio;

O 0 0 0 /

R and R together form a group of the formula -A -X -A -, which together with the carbon atom to which both A 3 and A4 are attached defines a ring having 5 or 6 ring atoms, wherein A 3 and A4, which may be the same or

2 different, each is (l-4C)alkylene and X is oxy, and which ring may optionally bear one substituent selected from hydroxy, (l-4C)alkyl and

(l-4C)alkoxy;

*_ _c_ 0 0 /

R and R together form a group of the formula -A -X -A -, which together with the carbon atom to which both A 3 and A4 are attached defines a ring

3 4 having 5 or 6 ring atoms wherein A and A , which may be the same or

(l-4C)alkoxy; and

R and R each are independently hydrogen or (1-6C)alkyl; or a pharmacologically-acceptable salt thereof.

A further preferred compound of the invention comprises an ether derivative of the formula I wherein;

1 2 each of A and A is a direct link;

Ar is 1,4-phenylene which may optionally bear one substituent selected from fluoro, chloro, bromo and iodo;

Ar is 1,3-phenylene, 2,4- or 2,5-thiophenediyl or 2,5-thiazolediyl which may optionally bear one substituent selected from fluoro, chloro, bromo and iodo;

X is thio; O 0 0 /

R and R together form a group of the formula -A -X -A -, which together

3 4 with the carbon atom to which both A and A are attached defines a ring

3 4 2 having 6 ring atoms, wherein A and A are each ethylene and X is oxy, and which ring may optionally bear one substituent selected from hydroxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,

-, which together

w t t e car on atom to w c ot A an A are attac ed defines a ring

3 4 2 having 6 ring atoms wherein A and A are each ethylene and X is oxy, and which ring may optionally bear one substituent selected from hydroxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,

1 4 methoxy, ethoxy, propoxy, isopropoxy and butoxy; and R and R each are independently hydrogen or (l-6C)alkyl; or a pharmaceutically-acceptable salt thereof.

A specifically especially preferred compound of the invention is the following compound of the formula I:-

4-{5-fluoro-3-[4-(4-hydroxytetrahydropyran-4-yl)phenylthio]phenyl}-4- methoxytetrahydropyran or (2S,4R)-4-{3-[4-(4-hydroxytetrahydropyran-4- yl)phenylthio]phenyl}-4-methoxytetrahydropyran; or a pharmaceutically-acceptable salt thereof.

A compound of the invention comprising an ether derivative 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. Suitable procedures are provided hereinafter as a further feature of the invention and are illustrated by the following representative examples in which, unless otherwise stated,

1 0 1 1 O l O / ζ _(_

A , A , X , Ar , Ar , R , R , R , R , R and R have any of the meanings defined hereinbefore provided that when there is an amino, alkylamino, or

1 2 2 hydroxy group in Ar , Ar , or, as substituents, in the rings involving R

3 5 6 and R together or the rings involving R and R together, then any such group may optionally be protected by a conventional protecting group which may be removed when so desired by conventional means.

A suitable protecting group for an amino or alkylamino group is, for example, an acyl group for example a (2-4C)alkanoyl group

(especially acetyl), a (l-4C)alkoxycarbonyl group (especially methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl) , an arylmethoxycarbonyl group (especially benzyloxycarbonyl) or an aroyl group (especially benzoyl). 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 group 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-butoxycarbony1 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 (2-4C)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.

(a) The alkylation, conveniently in the presence of a suitable base, of a compound of the formula II with a compound of the formula III wherein Z is a displaceable group.

A suitable displaceable group Z is, for example, a halogeno or sulphonyloxy group, for example a chloro, bromo, iodo, methanesulphonyloxy or toluene-4-sulphonyloxy group.

A suitable base for the reaction is, for example, an alkali or alkaline earth metal carbonate, (l-4C)alkoxide, hydroxide or hydride, for example sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride. The reaction is conveniently performed in a suitable inert solvent or diluent, for example N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile, acetone, dichloromethane, 1,2-dimethoxyethane or tetrahydrofuran, and at a temperature in the range, for example, 10° to 180°C, conveniently at or near 120°C. The reaction is conveniently catalysed by a copper(I) salt, for example copper(I) chloride.

The starting materials of the formula II and of the formula III may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described within the accompanying non-limiting Examples. Alternatively, necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.

(b) The alkylation, conveniently in the presence of a suitable base as defined hereinbefore, of a compound of the formula IV with a compound of the formula V wherein Z is a displaceable group as defined hereinbefore.

The reaction is conveniently performed in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range of, for example, 10° to 180^CC, conveniently at or near 120°C. The reaction is conveniently catalysed by a copper(I) salt, for example copper(I) chloride.

The starting materials of the formula IV and of the formula V may be obtained by standard procedures of organic chemistry using analogous procedures to those illustrated in the accompanying Examples.

When a pharmaceutically-acceptable salt of a 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.

As stated previously, the compounds of the formula I are inhibitors of the enzyme 5-L0. The effects of this inhibition may be demonstrated using one or more of the standard procedures set out below:- a) 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-L0 by assaying the amount of LTB, using specific radioimmunoassays described by Carey and Forder (F. Carey and R.A. Forder, Prostaglandins, Leukotrienes Med., 1986, 22_, 57; Prostaglandins, 1984, 2£, 666; Brit. J. Pharmacol. 1985, 84, 34P) which involve the use of a protein-LTB, conjugate produced using the procedure of Young et alia (Prostaglandins, 1983, 2e>(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„(TxB₂) 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-L0 or cyclooxygenase to be assessed. b) An ec vivo assay system, which is a variation of test a) above, involving administration to a group of rats of a test compound (usually orally as the suspension produced when a solution of the test compound in dimethylsulphoxide is added to carboxy ethylcellulose), blood collection, heparinisation, challenge with A23187 and radioimmunoassay of LTB, and TxB_. This test provides an indication of the bioavailability of a test compound as an inhibitor of 5-L0 or cyclooxygenase. c) An iji vivo system involving measuring the effects of a test compound administered orally against the liberation of LTB, 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, in the washings. This test provides an indication of inhibitory effects against 5-L0 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-L0 inhibitory effects at the following concentrations or doses in at least one of the above tests a)-c):-

Test a): IC₅₀ (LTB.) in the range, for example, 0.01-40μM IC₅₀ (TxB„) in the range, for example, 40-200μM;

Test b): oral ED,.-.(LTB, ) in the range, for example, O.l-lOOmg/kg;

Test c): oral ED-.-(LTB.) in the range, for example, 0.1-lOOmg/kg.

No overt toxicity or other untoward effects are present in tests b) and/or c) 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:- 4-{5-fluoro-3-[4-(4-hydroxytetrahydropyran-4-yl)phenylthio]phenyl}-4- methoxytetrahydropyran has an IC--₀ of 0.11 μM against LTB, in test (a); and

(2S, R)-4-{3-[4-(4-hydroxytetrahydropyran-4-yl)phenylthio]phenyl}-4- methoxy-2-methyltetrahydropyran has an ED of <0.5 mg/kg against LTB, in test (c).

These compounds are examples of compounds of the invention which show selective inhibitory properties for 5-L0 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 an ether derivative 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 such as a dry powder, a microcrystalline form 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 an ether derivative 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 an ether derivative of the formula I, or a pharmaceutically-acceptable 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 compound 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, compounds 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-L0. 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, inflammatory bowel diseases, conjunctivitis, the conditions of shock or trauma and various disorders of bone metabolism.

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 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-L0 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 an ether derivative 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 those 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 ambient temperature, that is in the range 18-25°C and under an atmosphere of an inert gas such as argon;

(iii) column chromatography (by the flash procedure) was performed on Merck Kieselgel silica (Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silica obtained from E. Merck, Darmstadt, 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 microanalyses and their structures were confirmed by nuclear magnetic resonance (NMR) and mass spectral techniques; unless otherwise stated, CDCl, solutions of the end-products of the formula I were used for the determination of NMR spectral data, chemical shift values were measured on the delta scale; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; m, multiplet;

(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 crystallisation 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;

DMF N,N-dimethylformamide.

Example 1

Potassium carbonate (0.4 g), copper(I) chloride (0.05 g) and 4-hydroxy-4-(iodophenyl)tetrahydropyran (0.4 g) were added to a solution of 4-(5-fluoro-3-mercaptophenyl)-4-methoxytetrahydropyran (European Patent Application No. 0420511, Example 4 thereof; 0.3 g) in DMF (1 ml). The reaction mixture was stirred under argon at 120°C for 1 hour, quenched with water (10 ml) and extracted with diethyl ether (2 x 20 ml). The combined organic extracts were washed with water, dried and evaporated. The residue was purified by gradient column chromatography using an increasingly polar mixture of hexane and ethyl acetate as eluent. The appropriate fractions were evaporated to give 4-{5-fluoro-3-[4-( -hydroxytetrahydropyran-4-yl)phenylthio]phenyl}-4- methoxytetrahydropyran (0.35 g, 52%) as a gum which crystallised on standing, m.p. 101-103°C.

NMR Spectrum 1.6-2.2 (m, 8H) ; 3.0 (s, 3H); 3.9 (m, 8H); 6.8 (m, IH); 6.95 (m, IH); 7.15 (t, IH); 7.45 (d, 2H); 7.5 (d, 2H) .

The 4-hydroxy-4-(iodophenyl)tetrahydropyran used as starting material was obtained as follows:- n-Butyl-lithium (1.6M, 6.25 ml) was added slowly to 1,4-diiodobenzene (3.3 g) in THF (30 ml) at -80°C. After 30 minutes, tetrahydropyran-4-one (1 g) was added and after a further 30 minutes the reaction mixture was warmed to ambient temperature. The reaction mixture was quenched with water (30 ml) and ether (50 ml) and the organic layer separated, dried and evaporated. The residue was purified by column chromatography using an increasingly polar mixture of hexane and ethyl acetate as eluent. The appropriate fractions were evaporated to give, after recrystallisation from hexane and ethyl acetate, 4-hydroxy-4-(iodophenyl)tetrahydropyran (1 g, 33%).

NMR Spectrum 1.6 (m, 3H); 2.1 (m, 2H); 3.9 (m, 4H); 7.25 (d, 2H) ; 7.7 (d, 2H). Example 2

Using a similar procedure to that described in Example 1, potassium carbonate, copper(I) chloride and 4-hydroxy-4-(iodophenyl)- tetrahydropyran were added to (2S,4R)-4-(3-mercaptophenyl)-4-methoxy-2- methyltetrahydropyran (European Patent Application No. 0420511, Example 6 thereof), in DMF. The reaction mixture was quenched with water and extracted with diethyl ether. The combined organic extracts were washed with water, dried and evaporated. The residue was purified by gradient column chromatography using an increasingly polar mixture of hexane and ethyl acetate as eluent. The appropriate fractions were evaporated to give (2S,4R)-4-{3-[4-(4-hydroxytetrahydropyran-4-yl)phenylthio]phenyl}-4- methoxy-2-methyltetrahydropyran in 60% yield as a gum. NMR Spectrum 1.2 (d, IH); 1.5-2.2 (m, 8H) ; 3.0 (s, 3H); 3.9 (m, 7H) ; 7.2-7.4 (m, 6H); 7.7 (d, 2H).

Example 3

The following illustrate representative pharmaceutical dosage forms containing the compound of formula I, or a pharmaceutically-acceptable salt thereof (hereafter compound X), for therapeutic or prophylactic use in humans:

(a) Tablet I mg/tablet

Compound 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

Lactose Ph.Eur 488.5

Magnesium stearate 1.5

(e) Injection I (50 mg/ml)

Compound X 5.0% w/v

IM 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%

(g) Injection III (lmg/ml,buffered to pH6)

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

Trichlorofluoro ethane 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.

CHEMICAL FORMULAE

OR OR

2 1 1 1 2 2 5

R -C-Ar -A -X -A -Ar -C-R^J

OR

2 1 1 1

R -C-Ar -A -X -H II

R-

OR

Z-A' -Ar' III

R⁶

4 OR

1 2 2 5

H-X -A -Ar -C-R IV

R⁶ CHEMICAL FORMULAE CONT'D

OR

2 1 1 R -C-Ar -A -Z

R-

Claims

CLAIHS

1. An ether derivative of the formula I

OR 0R^{^}

R²-C-Ar¹-A¹-X¹-A²-Ar²-C-R⁵

wherein each of A 1 and A2 is, independently, a direct link or

(l-3C)alkylene; wherein X is oxy, thio, sulphinyl or sulphonyl; wherein Ar is phenylene, pyridinediyl or pyrimidinediyl, which may optionally bear one or two substituents independently selected from halogeno, cyano, trifluoromethyl, hydroxy, amino, (1-4C)alkyl,

(l-4C)alkoxy, (1-4C)alkylamino and di-(l-4C)alkylamino;

2 wherein Ar is phenylene, pyridinediyl, pyrimidinediyl, thiophenediyl, furandiyl, thiazolediyl, oxazolediyl, thiadiazolediyl or oxadiazolediyl which may optionally bear one or two substituents independently selected from halogeno, cyano, trifluoromethyl, hydroxy, amino, (l-4C)alkyl, (l-4C)alkoxy, (1-4C)alkylamino and di-(l-4C)alkylamino;

1 4 wherein R and R are independently selected from hydrogen,

(l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, cyano-(1-4C)alkyl,

(2-4C)alkanoyl and benzoyl, which said benzoyl may optionally bear a substituent selected from halogeno, (l-4C)alkyl and (l-4C)alkoxy; 0 0 0 / wherein R and R together form a group of the formula -A -X -A -,

3 4 which together with the carbon atom to which both A and A are

0 / attached defines a ring having 4 to 7 ring atoms, wherein A and A ,

2 which may be the same or different, each is (l-4C)alkylene and X is selected from oxy, thio, sulphinyl, sulphonyl and imino and which ring may optionally bear one, two or three substituents independently selected from hydroxy, (l-4C)alkyl, (l-4C)alkoxy and fluoro-(1-4C)alkyl, or which ring may bear a (l-4C)alkylenedioxy substituent; c fi 0 0 / and wherein R and R together form a group of the formula -A -X -A -, which together with the carbon atom to which both A 3 and A4 are

0 / attached defines a ring having 4 to 7 ring atoms wherein A and A ,

2 which may be the same or different, each is (l-4C)alkylene and X is selected from oxy, thio, sulphinyl, sulphonyl and imino, and which ring may optionally bear one, two or three substituents independently selected from hydroxy, (1-4C)alkyl, (l-4C)alkoxy and fluoro-(1-4C)alkyl, or which ring may bear a (l-4C)alkylenedioxy substituent;

5 6 or wherein R and R together with the carbon atom to which both R and R are attached, form a cyclopentyl or cyclohexyl group, and which ring may optionally bear one, two or three substituents independently selected from hydroxy, (l-4C)alkyl, (l-4C)alkoxy and fluoro-(1-4C)alkyl, or which ring may bear a (l-4C)alkylenedioxy substituent; or wherein R and R together form a group of the formula -A -X -A -, which together with the oxygen atom to which A is attached and with the carbon atom to which A is attached define a ring having 5 or 6 ring atoms, wherein A and A , which may be the same or different,

3 each is (l-3C)alkylene and X is oxy, thio, sulphinyl, sulphonyl or imino, and which ring may optionally bear one, two or three

2. An ether derivative of the formula I as claimed in claim 1 wherein; each of A 1 and A2 is a direct link;

2 Ar is phenylene which may optionally bear one substituent selected

2 from halogeno, or Ar is thiophenediyl or thiazolediyl;

X is thio;

0 0 0 0 /

R and R together form a group of the formula -A -X -A -, which

3 4 together with the carbon atom to which both A and A are attached

3 4 defines a ring having 5 or 6 ring atoms, wherein A and A , which may 2 be the same or different, each is (l-4C)alkylene and X is oxy, and which ring may optionally bear one substituent selected from hydroxy,

(l-4C)alkyl and (l-4C)alkoxy; c /" 0 0 /

R and R together form a group of the formula -A -X -A -, which together with the carbon atom to which both A 3 and A4 are attached defines a ring having 5 or 6 ring atoms wherein A 3 and A4, which may

2 be the same or different, each is (l-4C)alkylene and X is oxy, and which ring may optionally bear one substituent selected from hydroxy,

(l-4C)alkyl and (l-4C)alkoxy; and

1 4 R and R each are independently hydrogen or (l-6C)alkyl; or a pharmacologically-acceptable salt thereof.

3. An ether derivative of the formula I as claimed in claim 1 wherein;

1 2 each of A and A is a direct link;

2 Ar is 1,3-phenylene, 2,4- or 2,5-thiophenediyl or 2,5-thiazolediyl which may optionally bear one substituent selected from fluoro, chloro, bromo and iodo;

X is thio;

0 0 0 0 / ^"

R and R together form a group of the formula -A -X -A -, which together with the carbon atom to which both A 3 and A4 are attached defines a ring having 6 ring atoms, wherein A 3 and A4 are each

2 ethylene and X is oxy, and which ring may optionally bear one substituent selected from hydroxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy and butoxy; c * 0 0 /

R and R together form a group of the formula -A -X -A -, which together with the carbon atom to which both A 3 and A4 are attached defines a ring having 6 ring atoms wherein A 3 and A4 are each ethylene

2 and X is oxy, and which ring may optionally bear one substituent selected from hydroxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy

1 4 and butoxy; and R and R each are independently hydrogen or

(l-6C)alkyl; or a pharmaceutically-acceptable salt thereof. 4. An ether derivative of the formula I as claimed in claim 1 selected from:-

4-{5-fluoro-3-[4-(4-hydroxytetrahydropyran-4-yl)phenylthio]phenyl}-4- methoxytetrahydropyran and

(2S,4R)-4-{3-[4-(4-hydroxytetr__τydropyran-4-yl)phenylthio]phenyl}-4- methoxytetrahydropyran; or a pharmaceutically-acceptable salt thereof.

5. A process for the preparation of an ether derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 4 which comprises:-

(a) the alkylation of a compound of the formula II

OR¹

1 I 1 1 1

R -C-Ar -A -X -H II

I R³

with a compound of the formula III

OR⁴

2 2 Z-A -Ar -C- R" III

wherein Z is a displaceable group;

(b) the alkylation of a compound of the formula IV

OR

1 2 2 5 H-X -A -Ar -C-R IV

R⁶ with a compound of the formula V

OR¹

I

2 1 1

R -C-Ar -A -Z V

I R³

wherein Z is a displaceable group; and when a pharmaceutically-acceptable salt of a compound of the formula I is required, it may be obtained by reaction of said compound with a suitable avid or base using a conventional procedure; and 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.

6. A pharmaceutical composition which comprises an ether derivative of the formula I as claimed in any one of claims 1 to 4, or a pharmaceutically-acceptable salt thereof, in association with a pharmaceutically-acceptable diluent or carrier.

7. The use of an ether derivative of the formula I as claimed in any one of claims 1 to 4, or a pharmaceutically-acceptable salt thereof, in the production of a new medicament for use in a leukotriene mediated disease or medical condition.

8. A pharmaceutical composition which comprises an ether derivative of the formula I, as claimed in any one of claims 1 to 4 or a pharmaceutically-acceptable salt thereof, in conjunction or admixture with a cyclooxygenase inhibitory non-steroidal anti-inflammatory agent, and a pharmaceutically-acceptable diluent or carrier.