WO1994027999A1 - Bicyclic ether derivatives and their use as 5-lipoxygenase inhibitors - Google Patents

Bicyclic ether derivatives and their use as 5-lipoxygenase inhibitors Download PDF

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Publication number
WO1994027999A1
WO1994027999A1 PCT/EP1994/001805 EP9401805W WO9427999A1 WO 1994027999 A1 WO1994027999 A1 WO 1994027999A1 EP 9401805 W EP9401805 W EP 9401805W WO 9427999 A1 WO9427999 A1 WO 9427999A1
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formula
alkyl
group
compound
methyl
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PCT/EP1994/001805
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French (fr)
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Philip Neil Edwards
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Zeneca Limited
Zeneca-Pharma S.A.
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Priority to AU70704/94A priority Critical patent/AU7070494A/en
Priority to JP6525832A priority patent/JPH09504775A/en
Priority to EP94919601A priority patent/EP0701560A1/en
Publication of WO1994027999A1 publication Critical patent/WO1994027999A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention concerns bicyclic ether derivatives and more particularly bicyclic ether derivatives which are inhibitors of the enzyme 5-lipoxygenase (hereinafter referred to as 5-LO).
  • the invention also concerns processes for the manufacture of said bicyclic ether derivatives and novel pharmaceutical compositions containing them. Also included in the invention is the use of said bicyclic ether derivatives in the treatment of various diseases such as 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.
  • the bicyclic ether derivatives 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 ⁇ (LTB.) and the peptido-lipid leukotrienes such as leukotriene C ⁇ (LTC.) and leukotriene D, (LTD.) and various metabolites.
  • 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 ⁇ (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, _, 100-103.
  • the leukotrienes and their metabolites have been implicated in the production and development of various diseases, for example 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 diseases (especially psoriasis, eczema and dermatitis), ocular conditions (especially allergic conjunctivitis and uveitis) and respiratory disease (especially asthma, bronchitis and allergic rhinitis), for example in the production and development of various cardiovascular and cerebrovascular disorders such as myocardial infarction, the formation of atherosclerotic plaques, hypertension, platelet aggregation, angina, stroke
  • 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.
  • 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, and/or disorders of bone metabolism, mediated alone or in part by one or more leukotrienes.
  • a bicyclic ether derivative of the formula I wherein Ar is phenyl or naphthyl, or a 10-membered bicyclic heterocyclic moiety containing one or two nitrogen heteroatoms and optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur, and Ar may optionally bear up to four substituents selected from halogeno, hydroxy, amino, cyano, formyl, oxo, thioxo, (l-4C)alkyl, (l-4C)alkoxy, fluoro-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (2-4C)alkanoyl, (2-4C)alkanoylamino, N-(1-4C)alkyl-(2-4C)alkanoylamino, hydroxyimino-(l-4C)alkyl, (l-4C)alkoxyimino-(l-4C) lkyl, (2-5
  • X is oxy, thio, sulphinyl or sulphonyl
  • Ar is phenylene, pyridinediyl, pyrimidinediyl, thiophendiyl, furandiyl or thiazolediyl which may optionally bear one or two substituents selected from halogeno, cyano, trifluoromethyl, hydroxy, amino, (1-4C)alkyl, (l-4C)alkoxy, (l-4C)alkylamino and di-(l-4C)alkylamino; and
  • R 1 is (l-4C)alkyl, (3-4C)alkenyl or (3-4C)alkynyl; or a pharmaceutically-acceptable salt thereof.
  • alkyl includes both straight-chain and branched-chain alkyl groups.
  • 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.
  • 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- 0.
  • 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.
  • a suitable value for Ar when it is naphthyl is, for example 1-naphthyl or 2-naphthyl.
  • a suitable value for Ar when it is a 10-membered bicyclic heterocyclic moiety containing one or two nitrogen heteroatoms and optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur is, for example, a 10-membered benzo-fused heterocyclic moiety such as quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, 4H-l,4-benzoxazinyl or 4H-l,4-benzothiazinyl, or a hydrogenated derivative thereof such as 1,2-dihydroquinolyl, 1,2,3, -tetrahydroquinolyl, 1,2-dihydroisoquinolyl, 1,2,3, -tetrahydroquinazolinyl, 2,3-dihydro-4H-1,4-benzoxazinyl or 2,3-dihydro-4H-1, -benzothiazinyl; or, for example, a 10-membered
  • the heterocyclic moiety may be attached through any available position including from either of the two rings of the bicyclic heterocyclic moiety and including through an available nitrogen atom.
  • the heterocyclic moiety may bear a suitable substituent such as, for example, a (l-4C)alkyl, fluoro-(l-4C)alkyl, phenyl, benzoyl or benzyl substituent on an available nitrogen atom.
  • Ar oorr oonn aannyy ooff tthhee ssuubbsstt:ituents on Ar which contain a phenyl group include, for example:-
  • halogeno fluoro, chloro, bromo and iodo
  • (l-4C)alkyl methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-b ' utyl
  • (l-4C)alkoxy methoxy, ethoxy, propoxy, isopropoxy and butoxy
  • fluoro-(l-4C)alkyl fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2- trifluoroethyl and pentafluoroethyl
  • for hydroxy-(l-4C)alkyl hydroxymethyl, 2-hydroxyethyl and
  • a suitable value for Ar when it is phenylene is, for example, 1,3- or 1, -phenylene.
  • a suitable value for Ar when it is pyridinediyl, pyrimidinediyl, thiophenediyl, furandiyl or thiazolediyl is, for example, 2,4-, 2,5- or 3,5-pyridinediyl, 4,6-pyrimidinediyl, 2,4- or
  • a suitable value for R when it is (1-4C)alkyl is, for example methyl, ethyl, propyl or butyl; when it is (3-4C)alkenyl is, for example allyl, 2-butenyl or 3-butenyl; and when it is (3-4C)alkynyl is, for example, 2-propynyl or 2-butynyl.
  • 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.
  • 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, bicyclic ether derivatives of the formula I, or pharmaceutically-acceptable salts thereof, wherein:-
  • Ar is phenyl or naphthyl which may optionaallllyy bbeeaarr oonnee,, two or three substituents selected from any of those substituents on Ar
  • Ar 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, phenyl, benzoyl and benzyl, and wherein said phenyl, benzoyl or benzyl substituents may optionally bear a substituent selected from fluoro, chloro, methyl and
  • Ar is phenyl which bears one substituent selected from formyl, acetyl, propionyl, acetamido, propionamido, N-methylacetamido, N-ethylacetamido, hydroxyiminomethyl, 1-hydroxyiminoethyl, methoxyiminomethyl, ethoxyiminomethyl, 1-methoxyiminoethyl, 1-ethoxyiminoethyl, acetoxyiminomethyl, propionyloxyiminomethyl, 1-acetoxyiminoethyl, cyanomethoxyiminomethyl, 1-cyanomethoxyiminoethyl, methanesulphonamido, ethanesulphonamido, N-methylmethanesulphonamido, N-ethylmethanesulphonamido, N-methylsulphamoyl, N,N-dimethylsulphamoyl, phenyl
  • Ar is a 10-membered benzo-fused heterocyclic moiety containing one or two nitrogen heteroatoms and optionally containing a further heteroatom selected from oxygen and sulphur, which heterocyclic moiety may optionally bear one or two oxo or thioxo substituents and up to two further substituents selected from any of those substituents on Ar defined hereinbefore other than oxo or
  • Ar- is quinolyl, 1,2-dihydroquinolyl, 1,2,3,4- tetrahydroquinolyl or 2,3-dihydro-4H-l,4-benzoxazinyl which may optionally bear one oxo or thioxo substituent and up to two further substituents selected from fluoro, chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, acetyl, propionyl, phenyl, benzoyl and benzyl, and wherein each phenyl, benzoyl or benzyl substituent may optionally bear a substituent selected from fluoro, chloro, methyl and
  • Ar is 2-oxo-1,2-dihydroquinolinyl, 2-thioxo-l,2-dihydro- quinolinyl, 2-oxo-1,2,3, -tetrahydroquinolinyl, 2-thioxo-1,2,3,4- tetrahydroquinolinyl or 3-oxo-2,3-dihydro-4H-l,4-benzoxazinyl which may optionally bear up to three substituents selected from fluoro, chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, acetyl, propionyl, phenyl, benzoyl and benzyl, and wherein each phenyl, benzoyl or benzyl substituent may optionally bear a substituent
  • Ar is 2-oxo-l,2-dihydroquinolin-3-yl, 2-oxo-l,2- dihydroquinolin-6-yl, 2-oxo-l,2-dihydroquinolin-7-yl, 2-oxo-
  • 1,2,3, -tetrahydroquinolin-6-yl or 3-oxo-2,3-dihydro-4H-l,4- benzoxazin-7-yl which may optionally bear up to three substituents selected from fluoro, chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, acetyl, propionyl, phenyl, benzoyl and benzyl, and wherein each phenyl, benzoyl or benzyl substituent may optionally bear a substituent selected from fluoro, chloro, methyl and methoxy; and
  • A is a direct link to X; and Ar , X, Ar and R have any of the meanings defined hereinbefore or in this section concerning particular compounds;
  • A is (l-4C)alkylene and X is oxy; and Ar , Ar and R have any of the meanings defined hereinbefore or in this section concerning particular compounds;
  • A is a direct link to X and X is thio, sulphinyl or
  • Ar is phenylene which may optionally bear one or two substituents selected from halogeno, trifluoromethyl, amino
  • Ar is pyridinediyl, pyrimidinediyl, thiophenediyl or thiazolediyl; and Ar , A, X and R have any of the meanings defined hereinbefore or in this section defining particular compounds; and
  • R is hydrogen or (l-4C)alkyl; and Ar , A, X and Ar have any of the meanings defined hereinbefore or in this section defining particular compounds.
  • a preferred compound of the invention comprises a bicyclic ether derivative of the formula I wherein Ar is phenyl which may optionally bear one substituent selected from tert-butyl, acetyl, acetamido, N-methylacetamido, 1-hydroxyiminoethyl, 1-methoxyiminoethyl, 1-cyanomethoxyiminoethyl, benzoyl and benzyl and wherein said benzoyl or benzyl substituents may optionally bear a fluoro group, or Ar is naphth-2-yl which may optionally bear one substituent selected from fluoro, chloro, methyl, methoxy and trifluoromethyl, or
  • Ar is 2-oxo-l,2-dihydroquinolin-6-yl, 2-oxo-l,2,3,4-tetra- hydroquinolin-6-yl or 3-oxo-2,3-dihydro-4H-l,4-benzoxazin-7-yl which may optionally bear one substituent selected from methyl and ethyl;
  • A is a direct link to X and X is thio, sulphinyl or sulphonyl, or A is methylene and X is oxy;
  • Ar is 1,3-phenylene, 5-fluoro-l,3-phenylene, 2,5-thiophenediyl,
  • R is hydrogen, methyl, ethyl or allyl; or a pharmaceutically-acceptable salt thereof.
  • a further preferred compound of the invention comprises a bicyclic ether derivative of the formula I wherein Ar is naphth-2-yl which may optionally bear one substituent selected from fluoro, methyl and trifluoromethyl, or Ar is 2-oxo-l,2-dihydroquinolin-6-yl or
  • A is methylene and X is oxy, or A is a direct link to X and X is thio, sulphinyl or sulphonyl;
  • Ar is 1,3-phenylene or 5-fluoro-l,3-phenylene
  • R is hydrogen, methyl, ethyl or allyl; or a pharmaceutically-acceptable salt thereof.
  • a further preferred compound of the invention comprises a bicyclic ether derivative of the formula I wherein Ar 1 is naphth-2-yl or Ar1 is l-methyl-2-oxo-l,2,3,4- tetrahydroquinolin-6-yl;
  • A is methylene and X is oxy, or A is a direct link to X and X is thio or sulphonyl;
  • Ar is 1,3-phenylene or 5-fluoro-l,3-phenylene
  • R is methyl; or a pharmaceutically-acceptable salt thereof.
  • a specific especially preferred compound of the invention is the following compound of the formula I:-
  • a compound of the invention comprising a bicyclic 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
  • Ar , A, X, Ar and R have any of the meanings defined hereinbefore provided that when there is an amino, alkylamino
  • any such group may optionally be protected by a conventional protecting group which may be removed when so desired by conventional means.
  • a suitable displaceable group Z is, for example, a halogeno or sulphonyloxy group, for example a fluoro, 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, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride.
  • an alkali or alkaline earth metal carbonate for example sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, lithium hydroxide, 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, N-methylpyrrolidin-2-one, di ethylsulphoxide, acetonitrile, acetone, 1,2-dimethoxyethane or tetrahydrofuran, and at a temperature in the range, for example, 10 to 150°C, conveniently at or near ambient temperature.
  • a suitable inert solvent or diluent for example N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one, di ethylsulphoxide, acetonitrile, acetone, 1,2-dimethoxyethane or tetrahydrofuran, and at a temperature in the range, for example, 10 to 150°C, conveniently at or near ambient temperature.
  • the starting materials of the formula II may be obtained by standard procedures of organic chemistry. Necessary starting materials are obtainable by analogous procedures to those illustrated in the accompanying non-limiting Examples.
  • 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.
  • 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.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • 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 (2- C)alkanoyl group (especially acetyl), an aroyl group (especially benzoyl), an arylmethyl group (especially benzyl), a tri-(l-4C)alkylsilyl group (especially trimethylsilyl or tert-butyldimethylsilyl) or an aryldi-(l-4C)alkylsilyl group (especially dimethylphenylsilyl).
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • 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.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-charcoal.
  • a trialkylsilyl or an aryldialkylsilyl group such as a tert-butyldimethylsilyl or a dimethylphenylsilyl group may be removed, for example, by treatment with a suitable acid such as hydrochloric, sulphuric, phosphoric or trifluoroacetic acid or with an alkali metal or ammonium fluoride such as sodium fluoride or, preferably, tetrabutylammonium fluoride.
  • a suitable acid such as hydrochloric, sulphuric, phosphoric or trifluoroacetic acid
  • an alkali metal or ammonium fluoride such as sodium fluoride or, preferably, tetrabutylammonium fluoride.
  • the reaction is conveniently performed in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 10 to 150°C, conveniently at or near ambient temperature.
  • the starting materials of the formula III may be obtained by standard procedures of organic chemistry as illustrated in the accompanying Examples.
  • reaction is conveniently performed in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 20 to 200°C, conveniently at or near 150°C.
  • the starting materials of the formula Ar -A-X-H and of the formula IV may be obtained by standard procedures of organic chemistry as illustrated in the accompanying Examples.
  • the coupling reaction is conveniently performed in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example -80 to +50°C, conveniently in the range -80°C to ambient temperature.
  • H is an alkali metal or alkaline earth metal such as lithium or calcium or M represents the magnesium halide portion of a conventional Grignard reagent, with the ketone 3-oxo-6,8-dioxa[3,2,1]octane.
  • reaction is conveniently performed in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example -80 to +50 C C, conveniently in the range -80°C to ambient temperature.
  • the starting materials may be obtained by standard procedures of organic chemistry as illustrated in the accompanying Examples.
  • a suitable oxidising group 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.
  • 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 to 35 C C.
  • 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.
  • a compound of the formula I containing a sulphonyl group it may be obtained by oxidation of the corresponding sulphinyl compound as well as of the corresponding thio compound.
  • a pharmaceutically-acceptable salt of a compound of the formula I 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.
  • an optically active form of a compound of the formula I 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.
  • the compounds of the formula I are inhibitors of the enzyme 5- 0.
  • 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- O 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, 28, 666; Brit. J. Pharmacol.
  • test b) An ex 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 carboxymethylcellulose) , 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-LO or cyclooxygenase.
  • Test a IC (LTB,) in the range, for example, 0.01-40 ⁇ M IC 5Q (TxB 2 ) in the range, for example, 40-200 ⁇ M;
  • Test c oral ED (LTB.) in the range, for example, 0.1-lOOmg/kg.
  • the compound:- (lS,3S,5R)-3-[5-fluoro-3-(l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6- ylthio)phenyl]-3-methoxy-6,8-dioxabicyclo[3,2,l]octane has an IC of 0.06 ⁇ M against LTB, in test a) and an ED of approximately 1.5 mg/kg versus 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.
  • a pharmaceutical composition which comprises a bicyclic 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.
  • the above compositions may be prepared in a conventional manner using conventional excipients.
  • the amount of active ingredient (that is a bicyclic 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.
  • 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.
  • a bicyclic 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.
  • compounds of the formula I are useful in treating those diseases such as allergic and inflammatory conditions and disorders of bone metabolism which are due alone or in part to the effects of the metabolites of arachidonic acid arising by the linear (5-L0 catalysed) pathway and in particular the leukotrienes, the production of which is mediated by 5-LO.
  • such conditions include, for example, asthmatic conditions, allergic reactions, allergic rhinitis, allergic shock, psoriasis, atopic dermatitis, cardiovascular and cerebrovascular disorders, arthritic and inflammatory joint disease, inflammatory bowel diseases, conjunctivitis, the conditions of shock or trauma and various disorders of bone metabolism.
  • 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.
  • lower doses will be administered when a parenteral route is employed.
  • a dose in the range for example, 0.5 mg to 30 mg per kg body weight will generally be used.
  • a dose in the range for example, 0.5 mg to 25 mg per kg body weight will be used.
  • 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-L0. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
  • 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.
  • NSAIA cyclooxygenase inhibitory non- steroidal anti-inflammatory agents
  • 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.
  • a pharmaceutical composition which comprises a bicyclic 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.
  • 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.
  • 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.
  • 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.
  • an anti-histamine, steroid such as beclomethasone dipropionate
  • sodium cromoglycate 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.
  • 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: -
  • Example 1 n-Butyl-lithium (1.5M in hexane, 1 ml) was added dropwise to a stirred solution of 3-(naphth-2-ylmethoxy)bromobenzene (0.47 g) in THF (10 ml) which had been cooled to -70°C. The mixture was stirred at -70°C for 30 minutes. A solution of (lS,5R)-3-oxo-6,8-dioxabicyclo- [3,2,l]octane (Carbohydrate Research, 1979, 77, 231; 0.13 g) in THF (1 ml) was added. The mixture was stirred and allowed to warm to ambient temperature. The mixture was stirred at ambient temperature for 2 hours.
  • the aqueous phase was washed with diethyl ether and then acidified to pH2 by the addition of dilute aqueous hydrochloric acid.
  • the acidic mixture was extracted with ethyl acetate.
  • the organic phase was dried (MgSO.) and evaporated.
  • the residual oil was dissolved in diethyl ether and hexane was added. There was thus obtained 6-mercapto-l-methyl-l,2,3,4-tetrahydro- quinolin-2-one as a solid (35.5 g, 92%) which was used without further purification.

Abstract

The invention concerns a bicyclic ether derivative of formula (I), wherein Ar1 is phenyl or naphthyl, or a 10-membered bicyclic heterocyclic moiety containing one or two nitrogen heteroatoms and optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur; A is a direct link to the group X or A is (1-4C)alkylene; X is oxy, thio, sulphinyl or sulphonyl; Ar2 is phenylene, pyridinediyl, pyrimidinediyl, thiophendiyl, furandiyl or thiazolediyl; and R1 is (1-4C)alkyl, (3-4C)alkenyl or (3-4C)alkynyl; or a pharmaceutically-acceptable salt thereof; processes for their preparation; pharmaceutical compositions containing them and their use as 5-lipoxygenase inhibitors.

Description

BICYCLIC ETHER DERIVATIVES AND THEIR USE AS 5-LIPOXYGENASE INHIBITORS
This invention concerns bicyclic ether derivatives and more particularly bicyclic ether derivatives which are inhibitors of the enzyme 5-lipoxygenase (hereinafter referred to as 5-LO). The invention also concerns processes for the manufacture of said bicyclic ether derivatives and novel pharmaceutical compositions containing them. Also included in the invention is the use of said bicyclic ether derivatives in the treatment of various diseases such as 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 bicyclic ether derivatives 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 Bή (LTB.) and the peptido-lipid leukotrienes such as leukotriene Cή (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, _, 100-103. The leukotrienes and their metabolites have been implicated in the production and development of various diseases, for example 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 diseases (especially psoriasis, eczema and dermatitis), ocular conditions (especially allergic conjunctivitis and uveitis) and respiratory disease (especially asthma, bronchitis and allergic rhinitis), for example in the production and development of various cardiovascular and cerebrovascular disorders such as myocardial infarction, the formation of atherosclerotic plaques, hypertension, platelet aggregation, angina, stroke, reperfusion injury, vascular injury including restenosis 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), Faget's disease, bone metastases, hypercalcaemia, hyperparathyroidism, osteosclerosis, osteopetrosis and periodontitis, and the abnormal changes in bone metabolism which may accompany rheumatoid arthritis 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 and 0385662 that certain heterocyclic derivatives possess inhibitory properties against 5- 0. Furthermore European Patent Applications Nos. 0409413, 0420511, 0462812, 0462813, 0466452 and 0488602 are also concerned with heterocyclic derivatives which possess inhibitory properties against 5-L0. We have now discovered that certain bicyclic 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 in particular a 6,8-dioxabicyclo[3,2,l]octane group which was not envisaged in those earlier applications, are effective inhibitors of the enzyme 5-L0 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, and/or disorders of bone metabolism, mediated alone or in part by one or more leukotrienes.
According to the invention there is provided a bicyclic ether derivative of the formula I (set out hereinafter) wherein Ar is phenyl or naphthyl, or a 10-membered bicyclic heterocyclic moiety containing one or two nitrogen heteroatoms and optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur, and Ar may optionally bear up to four substituents selected from halogeno, hydroxy, amino, cyano, formyl, oxo, thioxo, (l-4C)alkyl, (l-4C)alkoxy, fluoro-(l-4C)alkyl, hydroxy-(l-4C)alkyl, (2-4C)alkanoyl, (2-4C)alkanoylamino, N-(1-4C)alkyl-(2-4C)alkanoylamino, hydroxyimino-(l-4C)alkyl, (l-4C)alkoxyimino-(l-4C) lkyl, (2-5C)alkanoyloxyimino-(l-4C)alkyl, cyano-(1-4C)alkoxyimino-(1-4C)alkyl, hydroxyamino(1-4C)alkyl, (l-4C)alkoxyamino-(l-4C)alkyl, N-hydroxyureido-(l-4C)alkyl, N-(l-4C)alkoxyureido-(l-4C)alkyl, N-hydroxy-(2-4C)alkanoylamino- (l-4C)alkyl, N-(l-4C)alkoxy-(2-4C)alkanoylamino-(l-4C)alkyl, (l-6C)alkylideneaminooxy-(l-4C)alkyl, (l-4C)alkanesulphonamido, N-(1-4C)alkyl-(l-4C)alkanesulphonamido, N-(l-4C)alkylsulphamoyl, N,N-di-(l-4C)alkylsulphamoyl, phenyl, benzoyl, benzyl, N-phenylsulphamoyl and N-(l-4C)alkyl-N-phenylsulphamoyl, and wherein said phenyl substituent or any of said substituents which contains a phenyl group may optionally bear a substituent selected from halogeno, (l-4C)alkyl and (l-4C)alkoxy; A is a direct link to the group X or A is (l-4C)alkylenej
X is oxy, thio, sulphinyl or sulphonyl;
2 Ar is phenylene, pyridinediyl, pyrimidinediyl, thiophendiyl, furandiyl or thiazolediyl which may optionally bear one or two substituents selected from halogeno, cyano, trifluoromethyl, hydroxy, amino, (1-4C)alkyl, (l-4C)alkoxy, (l-4C)alkylamino and di-(l-4C)alkylamino; and
R1 is (l-4C)alkyl, (3-4C)alkenyl or (3-4C)alkynyl; 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 the formula I defined above may exhibit the phenomenon of tautomerism and any formula drawing presented herein may represent only one of the possible tautomeric forms, the invention includes in its definition any tautomeric form of a compound of the formula I which possesses the property of inhibiting 5-LO and is not to be limited merely to any one tautomeric form utilised within the formulae drawings.
It is further to be understood that, insofar as certain of the compounds of the formula I defined above are oxime derivatives and it is well known that oxime derivatives may exist in different geometric isomeric forms, commonly designated as (E)- or (Z)-isomers, the invention includes in its definition any such geometric isomeric form which possesses the property of inhibiting 5- 0. The separation of such geometric isomeric forms may be possible by the standard laboratory techniques of organic chemistry such as by chromatographic separation of a mixture of said isomeric forms or by crystallisation of one such isomeric form from a mixture thereof.
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- 0. 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.
A suitable value for Ar when it is naphthyl is, for example 1-naphthyl or 2-naphthyl.
A suitable value for Ar when it is a 10-membered bicyclic heterocyclic moiety containing one or two nitrogen heteroatoms and optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur is, for example, a 10-membered benzo-fused heterocyclic moiety such as quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, 4H-l,4-benzoxazinyl or 4H-l,4-benzothiazinyl, or a hydrogenated derivative thereof such as 1,2-dihydroquinolyl, 1,2,3, -tetrahydroquinolyl, 1,2-dihydroisoquinolyl, 1,2,3, -tetrahydroquinazolinyl, 2,3-dihydro-4H-1,4-benzoxazinyl or 2,3-dihydro-4H-1, -benzothiazinyl; or, for example, a 10-membered pyrido-fused heterocyclic moiety such as 1,7-naphthyridinyl, 1,8-naphthyridinyl, pyrido[2,3-d]pyrimidinyl, pyrido[2,3-b]pyrazinyl, 4H-pyrido[3,2-b] [l,4]oxazinyl and 4H-pyrido[3,2-b] [l,4]thiazinyl, or a hydrogenated derivative thereof.
The heterocyclic moiety may be attached through any available position including from either of the two rings of the bicyclic heterocyclic moiety and including through an available nitrogen atom. The heterocyclic moiety may bear a suitable substituent such as, for example, a (l-4C)alkyl, fluoro-(l-4C)alkyl, phenyl, benzoyl or benzyl substituent on an available nitrogen atom.
Suitable values for substituents which may be present on
1 22 1
Ar , on Ar oorr oonn aannyy ooff tthhee ssuubbsstt:ituents on Ar which contain a phenyl group include, for example:-
for halogeno: fluoro, chloro, bromo and iodo; for (l-4C)alkyl: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-b'utyl; for (l-4C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for fluoro-(l-4C)alkyl: fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2- trifluoroethyl and pentafluoroethyl; for hydroxy-(l-4C)alkyl: hydroxymethyl, 2-hydroxyethyl and
3-hydroxypropyl; for (2-4C)alkanoyl: acetyl, propionyl and butyryl; for (2-4C)alkanoyamino: acetamido, propionamido and butyramido; for N-(l-4C)alkyl-(2-4C)- alkanoylamino: N-methylacetamido, N-ethylacetamido and N-methylpropionamido; for hydroxyimino-(l-4C)alkyl: hydroxyiminomethyl, 1-hydroxyiminoethyl and 2-hydroxyiminoethyl; for ( l-4C)alkoxyimino- ( l-4C)alkyl: methoxyiminomethyl, ethoxyiminomethyl, 1-methoxyiminoethyl and 2-methoxyiminoethyl; for (2-5C)alkanoyloxyimino- (l-4C)alkyl: acetoxyiminomethyl, propionyloxy- iminomethyl, 1-acetoxyiminoethyl and 2-acetoxyiminoethyl; for cyano-(l-4C)alkoxyimino- (1-4C)alkyl: cyanomethoxyiminomethyl, 2-cyanoethoxy- iminomethyl, 1-cyanomethoxyiminoethyl and 2-cyanomethoxyiminoethyl; for hydroxyamino-(l-4C)alkyl: hydroxyaminomethyl, 1-hydroxyaminoethyl and 2-hydroxyaminoethyl; for (l-4C)alkoxyamino- (l-4C)alkyl: methoxyaminomethyl, ethoxyaminomethyl, 1-methoxyaminoethyl and 2-methoxy- aminoethyl; for N-hydroxyureido-(l-4C)- alkyl: N-hydroxyureidomethyl, 1-(N-hydroxy- ureido)ethyl and 2-(N-hydroxy- ureido)ethyl; for N-(l-4C)alkoxyureido- (l-4C)alkyl: N-methoxyureidomethyl, N-ethoxyureido- methyl, l-(N-methoxyureido)ethyl and 2-(N-methoxyureido)ethyl; for N-hydroxy-(2-4C)alkanoyl- amino-(1-4C)alkyl: N-hydroxyacetamidomethyl, N-hydroxy- propionamidomethyl, l-(N-hydroxy- acetamido)ethyl and 2-(N-hydroxy- acetamido)ethyl; for N-(l-4C)alkoxy-(2-4C)- alkanoylamino-(1- C)alkyl: N-methoxyacetamidomethyl, N-ethoxy- acetamidomethyl, l-(N-methoxy- acetamido)ethyl and 2-(N-methoxy- acetamido)ethyl; for (l-6C)alkylideneaminooxy- (1-4C)alkyl: methyleneaminooxymethyl, ethylidene- aminooxymethyl, isopropylideneamino- oxymethyl, l-(isopropylidene- aminooxy)ethyl and 2-(isopropylidene- aminooxy)ethyl; for (l-4C)alkanesulphonamido: methanesulphonamido and ethanesulphonamido; for N-(1-4C)alkyl-(1-4C)- alkanesulphonamido: N-methylmethanesulphonamido, N-ethylmethanesulphonamido and N-methylethanesulphonamido; for N-(l-4C)alkylsulphamoyl: N-methylsulphamoyl, N-ethylsulphamoyl and N-propylsulphamoyl; for N,N-di-(l-4C)alkyl- sulphamoyl: N,N-dimethylsulphamoyl, N-ethyl-N-methylsulphamoyl and N,N-diethylsulphamoyl; for N-(1-4C)alkyl-N-phenyl- sulphamoyl: N-methyl-N-phenylsulphamoyl and N-ethyl-N-phenylsulphamoyl; for (l-4C)alkylamino: methylamino, ethylamino, propylamino and isopropylamino; and for di-(l-4C)alkyamino: dimethylamino, N-ethyl-N-methylamino and diethylamino. A suitable value for A when it is (l-4C)alkylene is, for example, methylene, ethylene or trimethylene.
2 A suitable value for Ar when it is phenylene is, for example, 1,3- or 1, -phenylene.
2 A suitable value for Ar when it is pyridinediyl, pyrimidinediyl, thiophenediyl, furandiyl or thiazolediyl is, for example, 2,4-, 2,5- or 3,5-pyridinediyl, 4,6-pyrimidinediyl, 2,4- or
2,5-thiophenediyl, 2,4- or 2,5-furandiyl or 2,4- or 2,5-thiazolediyl.
A suitable value for R when it is (1-4C)alkyl is, for example methyl, ethyl, propyl or butyl; when it is (3-4C)alkenyl is, for example allyl, 2-butenyl or 3-butenyl; and when it is (3-4C)alkynyl is, for example, 2-propynyl or 2-butynyl.
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, bicyclic ether derivatives of the formula I, or pharmaceutically-acceptable salts thereof, wherein:-
(a) Ar is phenyl or naphthyl which may optionaallllyy bbeeaarr oonnee,, two or three substituents selected from any of those substituents on Ar
2 1 defined hereinbefore other than oxo and thioxo; and A, X, Ar and R have any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention;
(b) Ar 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, phenyl, benzoyl and benzyl, and wherein said phenyl, benzoyl or benzyl substituents may optionally bear a substituent selected from fluoro, chloro, methyl and
2 1 methoxy; and A, X, Ar and R have any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention;
(c) Ar is phenyl which bears one substituent selected from formyl, acetyl, propionyl, acetamido, propionamido, N-methylacetamido, N-ethylacetamido, hydroxyiminomethyl, 1-hydroxyiminoethyl, methoxyiminomethyl, ethoxyiminomethyl, 1-methoxyiminoethyl, 1-ethoxyiminoethyl, acetoxyiminomethyl, propionyloxyiminomethyl, 1-acetoxyiminoethyl, cyanomethoxyiminomethyl, 1-cyanomethoxyiminoethyl, methanesulphonamido, ethanesulphonamido, N-methylmethanesulphonamido, N-ethylmethanesulphonamido, N-methylsulphamoyl, N,N-dimethylsulphamoyl, phenyl, benzoyl, benzyl, N-phenylsulphamoyl and N-methyl-N-phenylsulphamoyl, and wherein said phenyl substituent or any of said substituents which contain a phenyl group may optionally bear one substituent selected from fluoro, chloro, methyl and methoxy, and Ar may optionally bear a further substituent selected from fluoro, chloro, methyl, ethyl, methoxy,
2 1 ethoxy and trifluoromethyl; and A, X, Ar and R have any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention;
(d) Ar is a 10-membered benzo-fused heterocyclic moiety containing one or two nitrogen heteroatoms and optionally containing a further heteroatom selected from oxygen and sulphur, which heterocyclic moiety may optionally bear one or two oxo or thioxo substituents and up to two further substituents selected from any of those substituents on Ar defined hereinbefore other than oxo or
2 1 thioxo; and A, X, Ar and R have any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention;
(e) Ar- is quinolyl, 1,2-dihydroquinolyl, 1,2,3,4- tetrahydroquinolyl or 2,3-dihydro-4H-l,4-benzoxazinyl which may optionally bear one oxo or thioxo substituent and up to two further substituents selected from fluoro, chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, acetyl, propionyl, phenyl, benzoyl and benzyl, and wherein each phenyl, benzoyl or benzyl substituent may optionally bear a substituent selected from fluoro, chloro, methyl and
2 1 methoxy; and A, X, Ar and R have any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention;
(f) Ar is 2-oxo-1,2-dihydroquinolinyl, 2-thioxo-l,2-dihydro- quinolinyl, 2-oxo-1,2,3, -tetrahydroquinolinyl, 2-thioxo-1,2,3,4- tetrahydroquinolinyl or 3-oxo-2,3-dihydro-4H-l,4-benzoxazinyl which may optionally bear up to three substituents selected from fluoro, chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, acetyl, propionyl, phenyl, benzoyl and benzyl, and wherein each phenyl, benzoyl or benzyl substituent may optionally bear a substituent
2 selected from fluoro, chloro, methyl and methoxy; and A, X, Ar and
R have any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention;
(g) Ar is 2-oxo-l,2-dihydroquinolin-3-yl, 2-oxo-l,2- dihydroquinolin-6-yl, 2-oxo-l,2-dihydroquinolin-7-yl, 2-oxo-
1,2,3, -tetrahydroquinolin-6-yl or 3-oxo-2,3-dihydro-4H-l,4- benzoxazin-7-yl which may optionally bear up to three substituents selected from fluoro, chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, acetyl, propionyl, phenyl, benzoyl and benzyl, and wherein each phenyl, benzoyl or benzyl substituent may optionally bear a substituent selected from fluoro, chloro, methyl and methoxy; and
2 1 A, X, Ar and R have any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention;
1 2 1 (h) A is a direct link to X; and Ar , X, Ar and R have any of the meanings defined hereinbefore or in this section concerning particular compounds;
1 2 1 (i) A is (l-4C)alkylene and X is oxy; and Ar , Ar and R have any of the meanings defined hereinbefore or in this section concerning particular compounds;
(j) A is a direct link to X and X is thio, sulphinyl or
1 2 1 sulphonyl; and Ar , Ar and R have any of the meanings defined hereinbefore or in this section concerning particular compounds;
2 (k) Ar is phenylene which may optionally bear one or two substituents selected from halogeno, trifluoromethyl, amino
(l-4C)alkyl and (l-4C)alkoxy, or Ar is pyridinediyl, pyrimidinediyl, thiophenediyl or thiazolediyl; and Ar , A, X and R have any of the meanings defined hereinbefore or in this section defining particular compounds; and
1 1 2
(1) R is hydrogen or (l-4C)alkyl; and Ar , A, X and Ar have any of the meanings defined hereinbefore or in this section defining particular compounds.
A preferred compound of the invention comprises a bicyclic ether derivative of the formula I wherein Ar is phenyl which may optionally bear one substituent selected from tert-butyl, acetyl, acetamido, N-methylacetamido, 1-hydroxyiminoethyl, 1-methoxyiminoethyl, 1-cyanomethoxyiminoethyl, benzoyl and benzyl and wherein said benzoyl or benzyl substituents may optionally bear a fluoro group, or Ar is naphth-2-yl which may optionally bear one substituent selected from fluoro, chloro, methyl, methoxy and trifluoromethyl, or
Ar is 2-oxo-l,2-dihydroquinolin-6-yl, 2-oxo-l,2,3,4-tetra- hydroquinolin-6-yl or 3-oxo-2,3-dihydro-4H-l,4-benzoxazin-7-yl which may optionally bear one substituent selected from methyl and ethyl;
A is a direct link to X and X is thio, sulphinyl or sulphonyl, or A is methylene and X is oxy;
2 Ar is 1,3-phenylene, 5-fluoro-l,3-phenylene, 2,5-thiophenediyl,
2, -thiophenediyl (with the group of the formula -A-X- in the
2-position) 2,4-thiazolediyl (with the group of the formula -A-X- in the 2-position) or 2,5-thiazolediyl (with the group of the formula
-A-X- in the 2-position);
R is hydrogen, methyl, ethyl or allyl; or a pharmaceutically-acceptable salt thereof.
A further preferred compound of the invention comprises a bicyclic ether derivative of the formula I wherein Ar is naphth-2-yl which may optionally bear one substituent selected from fluoro, methyl and trifluoromethyl, or Ar is 2-oxo-l,2-dihydroquinolin-6-yl or
2-oxo-l,2,3,4-tetrahydroquinolin-6-yl which may optionally bear a methyl or ethyl substituent;
A is methylene and X is oxy, or A is a direct link to X and X is thio, sulphinyl or sulphonyl;
2 Ar is 1,3-phenylene or 5-fluoro-l,3-phenylene; and
R is hydrogen, methyl, ethyl or allyl; or a pharmaceutically-acceptable salt thereof.
A further preferred compound of the invention comprises a bicyclic ether derivative of the formula I wherein Ar 1 is naphth-2-yl or Ar1 is l-methyl-2-oxo-l,2,3,4- tetrahydroquinolin-6-yl;
A is methylene and X is oxy, or A is a direct link to X and X is thio or sulphonyl;
2 Ar is 1,3-phenylene or 5-fluoro-l,3-phenylene; and
R is methyl; or a pharmaceutically-acceptable salt thereof.
A specific especially preferred compound of the invention is the following compound of the formula I:-
(IS,3S,5R)-3-methoxy-3-[3-naphth-2-ylmethoxy)phenyl]-6,8-dioxabicyclo- [3,2,1]octane,
(lS,3S,5R)-3-[5-fluoro-3-(l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6- ylthio)phenyl]-3-methoxy-6,8-dioxabicyclo[3,2,1]octane or (IS,3S,5R)-3-[5-fluoro-3-(l-methyl-2-oxo-l,2,3, -tetrahydroquinolin-6- ylsulphonyl)phenyl]-3-methoxy-6,8-dioxabicyclo[3,2,1]octane; or a pharmaceutically-acceptable salt thereof.
A compound of the invention comprising a bicyclic 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
1 2 1 otherwise stated, Ar , A, X, Ar and R have any of the meanings defined hereinbefore provided that when there is an amino, alkylamino
1 2 or hydroxy group in Ar or Ar then any such group may optionally be protected by a conventional protecting group which may be removed when so desired by conventional means.
(a) The alkylation, conveniently in the presence of a suitable base, of a compound of the formula II wwiitthh ia compound of the formula Ar -A-Z wherein Z is a displaceable group.
A suitable displaceable group Z is, for example, a halogeno or sulphonyloxy group, for example a fluoro, 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, lithium hydroxide, 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, N-methylpyrrolidin-2-one, di ethylsulphoxide, acetonitrile, acetone, 1,2-dimethoxyethane or tetrahydrofuran, and at a temperature in the range, for example, 10 to 150°C, conveniently at or near ambient temperature.
The starting materials of the formula II may be obtained by standard procedures of organic chemistry. Necessary starting materials are obtainable by analogous procedures to those illustrated in the accompanying non-limiting Examples.
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-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 (2- C)alkanoyl group (especially acetyl), an aroyl group (especially benzoyl), an arylmethyl group (especially benzyl), a tri-(l-4C)alkylsilyl group (especially trimethylsilyl or tert-butyldimethylsilyl) or an aryldi-(l-4C)alkylsilyl group (especially dimethylphenylsilyl). 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. Alternatively a trialkylsilyl or an aryldialkylsilyl group such as a tert-butyldimethylsilyl or a dimethylphenylsilyl group may be removed, for example, by treatment with a suitable acid such as hydrochloric, sulphuric, phosphoric or trifluoroacetic acid or with an alkali metal or ammonium fluoride such as sodium fluoride or, preferably, tetrabutylammonium fluoride.
(b) The alkylation, conveniently in the presence of a suitable base as defined hereinbefore, of a compound of the formula III with a compound of the formula R -Z 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, for example, 10 to 150°C, conveniently at or near ambient temperature.
The starting materials of the formula III may be obtained by standard procedures of organic chemistry as illustrated in the accompanying Examples.
(c) The coupling, conveniently in the presence of a suitable base as defined hereinbefore, of a compound of the formula Ar -A-X-H with a compound of the formula IV 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, for example, 20 to 200°C, conveniently at or near 150°C.
The starting materials of the formula Ar -A-X-H and of the formula IV may be obtained by standard procedures of organic chemistry as illustrated in the accompanying Examples.
(d) The coupling of a compound of the formula Ar -A-X-Z or alternatively, when X is a thio group, Z may be a group of the formula -X-A-Ar , with an organometallic reagent of the formula V wherein M is an alkali metal or alkaline earth metal such as lithium or calcium or H represents the magnesium halide portion of a conventional Grignard reagent.
The coupling reaction is conveniently performed in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example -80 to +50°C, conveniently in the range -80°C to ambient temperature.
The starting materials of the formula Ar -A-X-Z and of the formula V may be obtained by standard procedures of organic chemistry using analogous procedures to those illustrated in the accompanying Examples.
(e) For the production of those compounds of the formula I wherein R is hydrogen, the coupling of compound of the formula
1 2 Ar -A-X-Ar -H wherein H is an alkali metal or alkaline earth metal such as lithium or calcium or M represents the magnesium halide portion of a conventional Grignard reagent, with the ketone 3-oxo-6,8-dioxa[3,2,1]octane.
The reaction is conveniently performed in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example -80 to +50CC, conveniently in the range -80°C to ambient temperature.
The starting materials may be obtained by standard procedures of organic chemistry as illustrated in the accompanying Examples.
(f) For the production of those compounds of the formula I wherein X is a sulphinyl or sulphonyl group, the oxidation of a compound of the formula I wherein X is a thio group.
A suitable oxidising group 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 to 35CC. 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.
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- 0. 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- O 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, 28, 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, 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 B2(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 ex 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 carboxymethylcellulose) , 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-LO or cyclooxygenase. c) An ijα vivo system involving measuring the effects of a test compound administered orally to a group of male rats against the liberation of LTB, induced by zymosan within an air pouch generated within the subcutaneous tissue of the back of the rats. The rats are anaesthetised and air pouches are formed by the injection of sterile air (20ml). A further injection of air (10ml) 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 (1ml 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): IC (LTB,) in the range, for example, 0.01-40μM IC5Q (TxB2) in the range, for example, 40-200μM;
Test b): oral ED(-0(LTB,) in the range, for example, 0.1-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:- (lS,3S,5R)-3-[5-fluoro-3-(l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6- ylthio)phenyl]-3-methoxy-6,8-dioxabicyclo[3,2,l]octane has an IC of 0.06 μM against LTB, in test a) and an ED of approximately 1.5 mg/kg versus 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 a bicyclic 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 a bicyclic 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 a bicyclic 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 diseases such as allergic and inflammatory conditions and disorders of bone metabolism which are due alone or in part to the effects of the metabolites of arachidonic acid arising by the linear (5-L0 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, 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-L0. 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 a bicyclic 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) and medium pressure liquid chromatography (MPLC) were performed on Merck ieselgel 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, CDC1, 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;
NMP N-methylpyrrolidin-2-one.
Example 1 n-Butyl-lithium (1.5M in hexane, 1 ml) was added dropwise to a stirred solution of 3-(naphth-2-ylmethoxy)bromobenzene (0.47 g) in THF (10 ml) which had been cooled to -70°C. The mixture was stirred at -70°C for 30 minutes. A solution of (lS,5R)-3-oxo-6,8-dioxabicyclo- [3,2,l]octane (Carbohydrate Research, 1979, 77, 231; 0.13 g) in THF (1 ml) was added. The mixture was stirred and allowed to warm to ambient temperature. The mixture was stirred at ambient temperature for 2 hours. The mixture was acidified by the addition of glacial acetic acid and partitioned between diethyl ether and water. The organic phase was washed with water and with brine, dried (Na-SO,) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate as eluent. There was thus obtained (lS,3S,5R)-3-hydroxy-3-[3-(naphth-2-ylmethoxy)- phenyl]-6,8-dioxabicyclo[3,2,l]octane (0.19 g, 532), m.p. 119-120°C; NMR Spectrum 1.9-2.1 (m, 2H), 2.27 (m, IH), 2.45 (m, IH), 3.75-3.85 (m, 2H), 4.49 (d, IH); 4.7 (m, IH) , 5.24 (s, 2H), 5.76 (s, IH), 6.9 (m, IH), 7.05 (m, IH), 7.2-7.32 (m, 2H), 7.4-7.6 (m, 3H) , 7.78-7.95 (m, 4H).
Example 2
Sodium hydride (50% dispersion in mineral oil, 0.05 g) was added to a stirred solution of (lS,3S,5R)-3-hydroxy-3-[3-(naphth-2- ylmethoxy)phenyl]-6,8-dioxabicyclo[3,2,1]octane (0.1 g) and methyl iodide (0.25 ml) in DMF (2 ml) which had been cooled in an ice-bath. The mixture was stirred and allowed to warm to ambient temperature. The mixture was stirred at ambient temperature for 16 hours. The mixture was acidified by the addition of glacial acetic acid and partitioned between diethyl ether and water. The organic phase was washed with water and with brine, dried (Na2S0,) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate as eluent. There was thus obtained (lS,3S,5R)-3-methoxy-3-[3-(naphth-2-ylmethoxy)phenyl]-6,8- dioxabicyclo[3,2,1]octane (0.09 g, 902), m.p. 70-72°C; NMR Spectrum 2.05 (m, IH), 2.1-2.3 (m, 2H), 2.37 (m, IH), 3.01 (s, 3H), 3.74 (t, IH), 4.42 (d, IH), 4.58 (m, IH), 5.23 (s, 2H) , 5.65 (s, IH) , 6.9-7.0 (m, 2H) , 7.03 (m, IH) , 7.27 (t, IH) , 7.4-7.6 (m, 3H) , 7.78-7.95 (m, 4H) .
Example 3
A mixture of 6-mercapto-l-methyl-l,2,3,4-tetrahydroquinolin- 2-one (0.24 g), (lS,3S,5R)-3-(3,5-difluorophenyl)-3-methoxy-6,8- dioxabicyclo[3,2,1]octane (0.32 g), lithium hydroxide monohydrate (0.06 g) and NMP (0.5 ml) was stirred and heated to 140°C for 4 hours. The mixture was cooled to ambient temperature and partitioned between diethyl ether and water. The organic phase was washed with water and with brine, dried (Na2S0,) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate as eluent. There was thus obtained (lS,3S,5R)-3-[5- fluoro-3-(l-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)phenyl]-3- methoxy-6,8-dioxabicyclo[3,2,1]octane (0.24 g, 44%), m.p. 136-137°C (recrystallised from methanol);
NMR Spectrum 1.97 (m, IH), 2.05-2.25 (m, 2H) , 2.32 (m, IH) , 2.67 (m, 2H), 2.90 (m, 2H), 3.03 (s, 3H), 3.37 (s, 3H), 3.74 (t, IH), 4.39 (d, IH), 4.55 (m, IH), 5.63 (m, IH) , 6.7 (m, IH) , 6.84 (m, IH), 6.95-7.05 (m, 2H), 7.26 (m, IH), 7.35 (m, IH).
The 6-mercapto-l-methyl-l,2,3,4-tetrahydroquinolin-2-one used as a starting material was obtained as follows:-
A mixture of concentrated hydrochloric acid (5 drops) and water (50 ml) was added to a stirred mixture of di-(l-methyl-2-oxo- l,2,3,4-tetrahydroquinolin-6-yl) disulphide (European Patent Application No. 0462812, Example 7 thereof; 38.4 g), triphenylphosphine (29 g) and 1,4-dioxan (300 ml). The mixture was stirred at ambient temperature for 30 minutes. The mixture was concentrated by evaporation to reduce the volume by approximately one half. The residue was partitioned between ethyl acetate and 0.5N aqueous sodium hydroxide solution. The aqueous phase was washed with diethyl ether and then acidified to pH2 by the addition of dilute aqueous hydrochloric acid. The acidic mixture was extracted with ethyl acetate. The organic phase was dried (MgSO.) and evaporated. The residual oil was dissolved in diethyl ether and hexane was added. There was thus obtained 6-mercapto-l-methyl-l,2,3,4-tetrahydro- quinolin-2-one as a solid (35.5 g, 92%) which was used without further purification.
The (lS,3S,5R)-3-(3,5-difluorophenyl)-3-methoxy-6,8- dioxabicyclo[3,2,1]octane used as a starting material was obtained as follows:-
A solution of (lS,5R)-3-oxo-6,8-dioxabicyclo[3,2,1]octane (0.35 g) in THF (10 ml) was added to a stirred solution of 3,5-difluorophenylmagnesium bromide (0.55M in THF, 10 ml) in THF. The mixture was stirred at ambient temperature for 2 hours. The mixture was acidified by the addition of glacial acetic acid and partitioned between diethyl ether and water. The organic phase was washed with water and with brine, dried (Na2S0,) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate as eluent. There was thus obtained (lS,3S,5R)-3-(3,5-difluorophenyl)-3-hydroxy-6,8-dioxabicyclo[3,2,1]- octane (0.41 g, 63%), m.p. 72-75°C.
Sodium hydride (50% dispersion in mineral oil, 0.12 g) was added to a stirred solution of the product so obtained and methyl iodide (0.5 ml) in DMF (5 ml) which had been cooled to an ice-bath. The mixture was allowed to warm to ambient temperature and was stirred for 1 hour. The mixture was acidified by the addition of glacial acetic acid and partitioned between diethyl ether and water. The organic phase was washed with water and with brine, dried (Na2S0,) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate as eluent. There was thus obtained (lS,3S,5R)-3-(3,5-difluorophenyl)-3-methoxy- 6,8-dioxabicyclo[3,2,l]octane as a gum (0.34 g, 83%).
Example 4
A mixture of (lS,3S,5R)-3-[5-fluoro-3-(l-methyl-2-oxo- 1,2,3, -tetrahydroquinolin-6-ylthio)phenyl]-3-methoxy-6,8-dioxabicyclo- [3,2,ljoctane (0.1 g), potassium peroxymonosulphate (0.3 g), ethanol (2 ml) and water (2 ml) was stirred at ambient temperature for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (Na-SO,) and evaporated. The residue was recrystallised from methanol. There was thus obtained (IS,3S,5R)-3-[5-fluoro-3-(l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6- ylsulphonyl)phenyl]-3-methoxy-6,8-dioxabicyclo[3,2,1]octane (0.08 g, 75%), m.p. 146-147°C;
NMR Spectrum 1.95-2.2 (m, 3H)', 2.36 (m, IH) , 2.67 (m, 2H), 2.95 (m, 2H), 3.05 (s, 3H), 3.36 (s, 3H) , 3.75 (m, IH), 4.4 (d, IH) , 4.6 (m, IH), 5.65 (m, IH) , 7.05 (m, IH), 7.25 (m, IH) , 7.5 (m, IH) , 7.7 (m, 2H), 7.85 (m, IH).
CHEMICAL FORMULAE
Figure imgf000029_0001
Figure imgf000029_0002
Figure imgf000029_0003
Figure imgf000029_0004
V
Figure imgf000029_0005

Claims

1. A bicyclic ether derivative of the formula I
Figure imgf000030_0001
wherein Ar is phenyl or naphthyl, or a 10-membered bicyclic heterocyclic moiety containing one or two nitrogen heteroatoms and optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur, and Ar may optionally bear up to four substituents selected from halogeno, hydroxy, a ino, cyano, formyl, oxo, thioxo, (l-4C)alkyl, (l-4C)alkoxy, fluoro-(l-4C)alkyl, hydroxy-(1-4C)alkyl, (2-4C)alkanoyl, (2-4C)alkanoylamino, N-(l-4C)alkyl-(2-4C)alkanoylamino, hydroxyimino-(1-4C)alkyl, (1-4C)alkoxyimino-(1-4C)alkyl, (2-5C)alkanoyloxyimino-(l-4C)alkyl, cyano-1-4C)alkoxyimino-(1-4C)alkyl, hydroxyamino(1-4C)alkyl, (1-4C)alkoxyamino-(1-4C)alkyl, N-hydroxyureido-(l-4C)alkyl, N-(l-4C)alkoxyureido-(l-4C)alkyl, N-hydroxy-(2-4C)alkanoylamino-(l-4C)alkyl, N-(l-4C)alkoxy-(2-4C)alkanoylamino-(l-4C)alkyl, (l-6C)alkylideneaminooxy-(l-4C)alkyl, (l-4C)alkanesulphonamido, N-(l-4C)alkyl-(l-4C)alkanesulphonamido, N-(l-4C)alkylsulphamoyl, N,N-di-(l-4C)alkylsulphamoyl, phenyl, benzoyl, benzyl, N-phenylsulphamoyl and N-(l-4C)alkyl-N-phenylsulphamoyl, and wherein said phenyl substituent or any of said substituents which contains a phenyl group may optionally bear a substituent selected from halogeno, (1-4C)alkyl and (l-4C)alkoxy; A is a direct link to the group X or A is (l-4C)alkylene;
X is oxy, thio, sulphinyl or sulphonyl;
2 Ar is phenylene, pyridinediyl, pyrimidinediyl, thiophendiyl, furandiyl or thiazolediyl which may optionally bear one or two substituents selected from halogeno, cyano, trifluoromethyl, hydroxy, amino,
(l-4C)alkyl, (l-4C)alkoxy, (l-4C)alkylamino and di-(l-4C)alkylamino; and R1 is (l-4C)alkyl, (3-4C)alkenyl or (3-4C)alkynyl; or a pharmaceutically-acceptable salt thereof.
2. A bicyclic ether derivative of the formula I as claimed in claim 1 wherein Ar is phenyl which may optionally bear one substituent selected from tert-butyl, acetyl, acetamido, N-methylacetamido,
1-hydroxyiminoethyl, 1-methoxyiminoethyl, 1-cyanomethoxyiminoethyl, benzoyl and benzyl and wherein said benzoyl or benzyl substituents may optionally bear a fluoro group, or Ar is naphth-2-yl which may optionally bear one substituent selected from fluoro, chloro, methyl, methoxy and trifluoromethyl, or
Ar is 2-oxo-l,2-dihydroquinolin-6-yl, 2-oxo-1,2,3, -tetra- hydroquinolin-6-yl or 3-oxo-2,3-dihydro-4H-l,4-benzoxazin-7-yl which may optionally bear one substituent selected from methyl and ethyl;
A is a direct link to X and X is thio, sulphinyl or sulphonyl, or A is methylene and X is oxy;
2 Ar is 1,3-phenylene, 5-fluoro-l,3-phenylene, 2,5-thiophenediyl,
2,4-thiophenediyl (with the group of the formula -A-X- in the
2-position) 2,4-thiazolediyl (with the group of the formula -A-X- in the 2-position) or 2,5-thiazolediyl (with the group of the formula
-A-X- in the 2-position);
R is hydrogen, methyl, ethyl or allyl; or a pharmaceutically-acceptable salt thereof.
3. A bicyclic ether derivative of the formula I as claimed in claim 1 wherein Ar is naphth-2-yl which may optionally bear one substituent selected from fluoro, methyl and trifluoromethyl, or Ar is 2-oxo-l,2-dihydroquinolin-6-yl or 2-oxo-l,2,3,4-tetrahydroquinolin-6-yl which may optionally bear a methyl or ethyl substituent;
A is methylene and X is oxy, or A is a direct link to X and X is thio, sulphinyl or sulphonyl;
2 Ar is 1,3-phenylene or 5-fluoro-l,3-phenylene; and
R is hydrogen, methyl, ethyl or allyl; or a pharmaceutically-acceptable salt thereof.
4. A bicyclic ether derivative of the formula I as claimed in claim 1 wherein Ar 1 is naphth-2-yl or Ar1 is l-methyl-2-oxo-l,2,3,4- tetrahydroquinolin-6-yl;
A is methylene and X is oxy, or A is a direct link to X and X is thio or sulphonyl;
2 Ar is 1,3-phenylene or 5-fluoro-l,3-phenylene; and
R is methyl; or a pharmaceutically-acceptable salt thereof.
5. A bicyclic ether derivative of the formula I as claimed in claim 1 selected from:-
(IS,3S,5R)-3-methoxy-3-[3-naphth-2-ylmethoxy)phenyl]-6,8-dioxabicyclo- [3,2,ljoctane,
(lS,3S,5R)-3-[5-fluoro-3-(l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6- ylthio)phenyl]-3-methoxy-6,8-dioxabicyclo[3,2,1]octane and (lS,3S,5R)-3-[5-fluoro-3-(l-methyl-2-oxo-1,2,3, -tetrahydroquinolin-6- ylsulphonyl)phenyl]-3-methoxy-6,8-dioxabicyclo[3,2,1]octane; or a pharmaceutically-acceptable salt thereof.
6. A process for the preparation of a bicyclic ether derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 5 which comprises:-
(a) the alkylation of a compound of the formula II
Figure imgf000032_0001
with a compound of the formula Ar -A-Z wherein Z is a displaceable group;
(b) the alkylation of a compound of the formula III
Figure imgf000032_0002
with a compound of the formula R -Z wherein Z is a displaceable group; (c) the coupling of a compound of the formula Ar -A-X-H with a compound of the formula IV
Figure imgf000033_0001
wherein Z is a displaceable group;
(d) the coupling of a compound of the formula Ar -A-X-Z or alternatively, when X is a thio group, Z may be a group of the formula -X-A-Ar , with an organometallic reagent of the formula V
Figure imgf000033_0002
wherein M is an alkali metal or alkaline earth metal or M represents the magnesium halide portion of a conventional Grignard reagent; (e) for the production of those compounds of the formula I wherein R is hydrogen, the coupling of compound of the formula
1 2 Ar -A-X-Ar -M wherein M is an alkali metal or alkaline earth metal or M represents the magnesium halide portion of a conventional Grignard reagent, with the ketone 3-oxo-6,8-dioxa[3,2,1]octane; or
(f) for the production of those compounds of the formula I wherein X is a sulphinyl or sulphonyl group, the oxidation of a compound of the formula I wherein X is a thio 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 acid 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.
7. A pharmaceutical composition which comprises a bicyclic ether derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 5 in association with a pharmaceutically-acceptable diluent or carrier.
8. The use of a bicyclic ether derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 5 in the production of a new medicament for use in a leukotriene mediated disease or medical condition.
PCT/EP1994/001805 1993-06-02 1994-06-03 Bicyclic ether derivatives and their use as 5-lipoxygenase inhibitors WO1994027999A1 (en)

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US5252599A (en) * 1992-08-27 1993-10-12 Merck Frosst Canada, Inc. Heteroarylnaphthalene hydroxy acids as inhibitors of leukotriene biosynthesis
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US5252599A (en) * 1992-08-27 1993-10-12 Merck Frosst Canada, Inc. Heteroarylnaphthalene hydroxy acids as inhibitors of leukotriene biosynthesis
WO1994005653A1 (en) * 1992-08-27 1994-03-17 Merck Frosst Canada Inc. Phenylnaphthalene hydroxy acids as inhibitors of leukotriene biosynthesis

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Publication number Priority date Publication date Assignee Title
WO1997011079A1 (en) * 1995-09-18 1997-03-27 Pfizer Pharmaceuticals Inc. Novel imidazole lipoxygenase inhibitors
US6037355A (en) * 1995-09-18 2000-03-14 Pfizer Inc Imidazole lipoxygenase inhibitors

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