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WO1995030668A1 - Cyclic ether derivatives and pharmaceutical composition containing them - Google Patents

Cyclic ether derivatives and pharmaceutical composition containing them Download PDF

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Publication number
WO1995030668A1
WO1995030668A1 PCT/GB1995/001000 GB9501000W WO9530668A1 WO 1995030668 A1 WO1995030668 A1 WO 1995030668A1 GB 9501000 W GB9501000 W GB 9501000W WO 9530668 A1 WO9530668 A1 WO 9530668A1
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WIPO (PCT)
Prior art keywords
formula
methyl
alkyl
fluoro
oxo
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PCT/GB1995/001000
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French (fr)
Inventor
Philip Neil Edwards
David Waterson
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Zeneca Limited
Zeneca-Pharma
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Publication of WO1995030668A1 publication Critical patent/WO1995030668A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D309/06—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention concerns cyclic 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 cyclic ether derivatives and novel pharmaceutical compositions containing them. Also included in the invention is the use of said cyclic ether derivatives in the treatment of various inflammatory and/or allergic diseases in which the direct or indirect products of 5-LO catalysed oxidation of arachidonic acid are involved, and the production of new medicaments for such use.
  • cyclic 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 physiologically active leukotrienes
  • LTC. leukotriene C
  • LTC. leukotriene D
  • the biosynthetic relationship and physiological properties of the leukotrienes are summarised by G.W. Taylor and S.R. Clarke in Trends in Pharmacological Sciences, 1986, 7_, 100-103.
  • the leukotrienes and their metabolites have been implicated in the production and development of various inflammatory and allergic diseases such as inflammation of the joints (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), skin disease (especially psoriasis, eczema and dermatitis), ocular conditions (especially allergic conjunctivitis and uveitis) and respiratory disease (especially asthma, bronchitis and allergic rhinitis), and in the production and development of various cardiovascular and cerebrovascular disorders such as myocardial infarction, the formation of atherosclerosis plaques, hypertension, platelet aggregation, stroke, reperfusion injury, vascular injury including reste
  • 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 cyclic ether derivative of the formula I wherein Ar is phenyl or naphthyl, or a 9- or 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-(l-4C)alkyl-(2-4C)- alkanoylamino, hydroxyimino-(l-4C)alkyl, (l-4C)alkoxyimino-(l-4C)- al
  • X is oxy, thio, sulphinyl or sulphonyl
  • Ar is phenylene, pyridinediyl, pyrimidinediyl, thiophendiyl, furandiyl, thiazolediyl, oxazolediyl, thiadiazolediyl or oxadiazolediyl which may optionally bear one or two substituents selected from halogeno, cyano, trifluoromethyl, hydroxy, amino,
  • R and R together form a group of the formula -A -X -A - which,
  • X is oxy, thio, sulphinyl or sulphonyl
  • a 3 is (l-3C)alkylene; and which ring may bear one, two or three substituents, which may be the same or different and may be optionally geminally disubstituted, selected from hydroxy, (1-4C)alkyl, (l-4C)alkoxy and fluoro-(l-4C)alkyl, or which ring may bear a (l-4C)alkylenedioxy substituent; and
  • Y is halogeno, vinyl, 2-cyanovinyl, 2-halogenovinyl, hydroxyimino-(l-4C)alkyl, (l-4C)alkoxyimino-(l-4C)alkyl or
  • (2-5C)alkanoyloxyimino-(l-4C)alkyl 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-LO.
  • the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Suitable values for the generic terms referred to above include those set out below.
  • a suitable value for Ar when it is naphthyl is, for example 1-naphth l 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, 1,2,3,4-tetrahydroquinolyl, 1,2-dihydroisoquinolyl, 2,3-dihydro-4H-l,4-benzoxazinyl or 2,3-dihydro-4H-l,4-benzothiazinyl; or, for example, a 10-membered pyrido-fused heterocyclic moiety such as
  • a suitable value for Ar when it is a 9-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 benzo-fused heterocyclic moiety or a hydrogenated derivative thereof such as indolyl, indolinyl, isoindolyl, isoindolinyl, indolizinyl, benzimidazolyl, 2,3-dihydrobenzimidazolyl, lH-indazolyl, 2,3-dihydro-lH-indazolyl, benzoxazolyl, 2,3-dihydrobenzoxazolyl, benzo[c]isoxazolyl, benzo[d]isoxazolyl, 2,3-dihydrobenzo[d]isoxazolyl, benzothiazolyl, 2,3-dihydrobenzothiazolyl, benzo[c]iso
  • 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 1, on Ar2 or on any of the substituents on Ar1 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-butyl
  • (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-(1-4C)alkyl hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl
  • for (2-4C)alkanoyl acetyl, propionyl and butyryl
  • (2-4C)alkanoylamino acetamido, propionamid
  • N-ethyl-N-phenylsulphamoyl for (l-4C)alkylamino: methylamino, ethylamino, propylamino and isopropylamino; and for di-(l-4C)alkylamino: dimethylamino, N-ethyl-N-methylamino and diethylamino.
  • a suitable value for Ar when it is phenylene is, for example, 1,3- or 1,4-phenylene.
  • a suitable value for A when it is (l-4C)alkylene is, for example, methylene, ethylene or trimethylene.
  • a suitable value for Ar when it is pyridinediyl, pyrimidinediyl, thiophenediyl, furandiyl, thiazolediyl, oxazolediyl, thiadiazolediyl or oxadiazolediyl is, for example, 2,4-, 2,5- or
  • Suitable values for the one, two or three substituents which may be present on said 5- or 6-membered ring include, for example:- for (1-4C)alkyl: methyl, ethyl, propyl, isopropyl and butyl; for (l-4C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for fluoro-(l-4C)alkyl: fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl,
  • a suitable value for Y when it is halogeno is fluoro, chloro, bromo or iodo.
  • a suitable value for Y when it is 2-halogenovinyl is, for example, 2-bromovinyl, 2-chlorovinyl or 2-fluorovinyl.
  • a suitable value for Y is, for example, hydroxyiminomethyl, 1-hydroxyiminoethyl or 2-hydroxyiminoethyl.
  • a suitable value for Y is, for example, methoxyiminomethyl, ethoxyiminomethyl, 1-methoxyiminoethyl and 2-methoxyiminoethyl.
  • a suitable value for Y when it is (2-5C)alkanoyloxyimino-(l-4C)alkyl is, for example, acetoxyiminomethyl, propionyloxyiminomethyl, 1-acetoxyiminoethyl or 2-acetoxyiminoethyl.
  • 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, cyclic ether derivatives of the formula I, or pharmaceutically-acceptable salts thereof, wherein:-
  • Ar is phenyl or naphthyl which may optionally bear one, two or three substituents selected from any of those substituents on Ar defined hereinbefore other than oxo and thioxo; and A 1, X1, Ar2, R1,
  • 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,
  • Ar is a 9- or 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, 2,3-dihydro-4H-l,4-benzoxazinyl, indolyl, indolinyl, benzimidazolyl, 2,3-dihydrobenzimidazolyl, benzoxazolyl, 2,3-dihydrobenzoxazolyl, benzothiazolyl or 2,3-dihydrobenzothiazolyl, 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,
  • Ar is 2-oxo-1,2-dihydroquinolinyl, 2-thioxo-1,2-dihydro- quinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, 2-thioxo-1,2,3,4- tetrahydroquinolinyl, 3-oxo-2,3-dihydro-4H-l,4-benzoxazinyl, 2-oxoindolinyl, 2-oxo-2,3-dihydrobenzimidazolyl,
  • 2-oxo-2,3-dihydrobenzoxazolyl or 2-oxo-2,3-dihydrobenzothiazolyl 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- 1,2,3,4-tetrahydroquinolin-6-yl, 3-oxo-2,3-dihydro-4H-1,4- benzoxazin-7-yl, 2-oxoindolin-5-yl or 2-oxoindolin-6-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 substitus, 2-oxo-l,2-dihydroquinolin-3-yl, 2-oxo-l,2-
  • a 1 is a direct link to X 1 ; and Ar 1 , X 1 , Ar 2 , R 1 , R 2 and Y 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 , R , R and
  • A is a direct link to X and X is thio; and Ar , Ar , R ,
  • Ar is phenylene which may optionally bear one or two substituents selected from halogeno, trifluoromethyl and (l-4C)alkoxy,
  • Ar is pyridinediyl, thiophenediyl or thiazolediyl; and Ar , A , X 1, R1, R2 and Y have any of the meanings defined hereinbefore or in this section defining particular compounds;
  • R 1 and R2 together form a group of the formula -A2-X2-A3-
  • 2 A is methylene or ethylene
  • 3 A is methylene or ethylene; and which ring may bear one, two or three substituents, which may be the same or different, and may be optionally geminally disubstituted where possible, selected from hydroxy, methyl, ethyl, methoxy or ethoxy; and Ar , A , X and Y have any of the meanings defined hereinbefore or in this section defining particular compounds;
  • Y is fluoro, chloro, bromo, iodo, vinyl, 2-cyanovinyl, 2-bromovinyl, 2-chlorovinyl, hydroxyiminomethyl, methoxyiminomethyl, ethoxyiminomethyl, acetoxyiminomethyl or propionyloxyiminomethyl; and Ar , A , X , R and R have any of the meanings defined hereinbefore or in this section defining particular compounds;
  • Y is fluoro, chloro, bromo or iodo
  • Y is vinyl, 2-cyanovinyl, 2-bromovinyl, 2-chlorovinyl, hydroxyiminomethyl, methoxyiminomethyl, ethoxyiminomethyl, acetoxyiminomethyl or propionyliminomethyl; and Ar , A , X , R and R have any of the meanings defined hereinbefore or in this section defining particular compounds.
  • a preferred compound of the invention comprises a cyclic 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,
  • A is a direct link to X and X is thio or sulphonyl, or A is methylene and X is oxy;
  • Ar is 1,3-phenylene, 5-fluoro-l,3-phenylene or 2,5-thiophenediyl, or
  • 2 Ar is 2,4-thiophenediyl or 2,5-thiazolediyl (each with the group of the formula -A -X - in the 2-position);
  • R and R together form a group of the formula -A -X -A - which,
  • X is oxy
  • A is ethylene; and which ring may bear one substituent selected from methyl or ethyl;
  • Y is fluoro, chloro, bromo, 2-cyanovinyl, 2-chlorovinyl, hydroxyiminomethyl or methoxyiminomethyl; or a pharmaceutically-acceptable salt thereof.
  • a further preferred compound of the invention comprises a cyclic 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,
  • 3-oxo-2,3-dihydro-4H-l,4-benzoxazin-7-yl which may optionally bear one or two substituents selected from fluoro, chloro, methyl and ethyl, or
  • Ar is 2-oxoindolin-5-yl which may optionally bear one or two substituents selected from fluoro, chloro, methyl and ethyl;
  • A is a direct link to X and X is thio or sulphonyl, or A is methylene and X is oxy;
  • Ar is 1,3-phenylene, 5-fluoro-1,3-phenylene or 2,5-thiophenediyl, or
  • 2 Ar is 2,4-thiophenediyl or 2,5-thiazolediyl (each with the group of the formula -A -X - in the 2-position); 1 2 2 2 3
  • R and R together form a group of the formula -A -X -A - which,
  • X is oxy
  • 3 A is ethylene; and which ring may bear one substituent selected from methyl or ethyl; and
  • Y is fluoro, chloro or bromo; or a pharmaceutically-acceptable salt thereof.
  • a further preferred compound of the invention comprises a cyclic 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,
  • 3-oxo-2,3-dihydro-4H-l,4-benzoxazin-7-yl which may optionally bear one or two substituents selected from fluoro, chloro, methyl and ethyl, or
  • Ar is 2-oxoindolin-5-yl which may optionally bear one or two substituents selected from fluoro, chloro, methyl and ethyl;
  • A is a direct link to X and X is thio or sulphonyl, or A is methylene and X is oxy;
  • Ar is 1,3-phenylene, 5-fluoro-l,3-phenylene or 2,5-thiophenediyl, or
  • 2 Ar is 2,4-thiophenediyl or 2,5-thiazolediyl (each with the group of the formula -A -X - in the 2-position);
  • R and R together form a group of the formula -A -X -A - which,
  • A is ethylene
  • X is oxy
  • 3 A is ethylene; and which ring may bear one substituent selected from methyl or ethyl; and
  • Y is 2-cyanovinyl, 2-chlorovinyl, hydroxyiminomethyl or methoxyiminomethyl; or a pharmaceutically-acceptable salt thereof.
  • a further preferred compound of the invention comprises a cyclic 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 which bears at the 1-position a methyl or ethyl substituent;
  • A is methylene and X is oxy
  • Ar is 1,3-phenylene or 5-fluoro-l,3-phenylene
  • R 1 and R2 together form a group of the formula -A2-X2-A3- which,
  • A is ethylene
  • 3 A is ethylene; and which ring may bear one substituent selected from methyl or ethyl; and
  • Y is 2-cyanovinyl, 2-chlorovinyl, hydroxyiminomethyl or methoxyiminomethyl; or a pharmaceutically-acceptable salt thereof.
  • a further preferred compound of the invention comprises a cyclic ether derivative of the formula I wherein Ar is 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl or
  • A is a direct link to X and X is thio or sulphonyl
  • Ar is 1,3-phenylene or 5-fluoro-1,3-phenylene
  • R and R together form a group of the formula -A -X -A - which,
  • 3 A is ethylene; and which ring may ' bear one substituent selected from methyl or ethyl; and
  • Y is fluoro, chloro or bromo; or a pharmaceutically-acceptable salt thereof.
  • a further preferred compound of the invention comprises a cyclic ether derivative of the formula I wherein Ar is 2-oxo-l,2,3,4-tetrahydroquinolin-6-yl which bears at the 1-position a methyl or ethyl substituent, or Ar is
  • 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 and R together form a group of the formula -A -X -A - which,
  • 3 A is ethylene; and which ring may bear one substituent selected from methyl or ethyl; and
  • Y is fluoro, chloro or bromo; 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 cyclic 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 , R , R and Y have any of the meanings defined hereinbefore provided that when there is an amino
  • any such group may optionally be protected by a conventional protecting group which may be removed when so desired by conventional means.
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group for example a (2-4C)alkanoyl group
  • 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.
  • 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 acid such as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid
  • an arylmethoxycarbonyl group such as a benzyloxycarbonyl group
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example a (2-4C)alkanoyl group (especially acetyl), an aroyl group (especially benzoyl) or an arylmethyl group (especially benzyl).
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • 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 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, (l-4C)alkanoate, (1-4C)alkyl, amide, hydroxide or hydride, for example sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium acetate, n-butyl-lithium, sodium amide, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride.
  • an alkali or alkaline earth metal carbonate for example, an alkali or alkaline earth metal carbonate, (l-4C)alkoxide, (l-4C)alkanoate, (1-4C)alkyl, amide, hydroxide or hydride, for example sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium acetate, n-butyl-lithium, sodium amide, lithium hydroxide, sodium hydroxide, potassium hydroxide,
  • a suitable base for the reaction is for example, an organic amine base such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene.
  • organic amine base such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene.
  • the reaction is conveniently performed in a suitable inert solvent or diluent, for example N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, N-methylpyrrolidin-2-one, dimethylsulphoxide, acetonitrile, acetone 1,2-dimethoxyethane or tetrahydrofuan, and at a temperature in the range, for example, 10°C to 100°C, conveniently at or near ambient temperature.
  • a suitable inert solvent or diluent for example N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, N-methylpyrrolidin-2-one, dimethylsulphoxide, acetonitrile, acetone 1,2-dimethoxyethane or tetrahydrofuan, and at a temperature in the range, for example, 10°C to 100°C, conveniently at or near ambient temperature.
  • the starting materials of the formula II and of the formula Ar -A -Z may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described within the accompanying non-limiting Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.
  • a suitable reagent for the reaction is, for example, a boron trihalide such as boron trichloride or boron tribromide or, for example, a di-(l-4C)alkylaminosulphur trihalide such as diethylaminosulphur trifluoride.
  • the reaction is conveniently performed in a suitable inert solvent as defined hereinbefore, at a temperature in the range -10°C to 60 C C, conveniently at or near 5°C.
  • the starting materials of the formula I wherein Y is a hydroxy or (l-4C)alkoxy group may be obtained by standard procedures of organic chemistry as illustrated by the procedures disclosed in the European Patent Applications which are mentioned by way of reference hereinbefore. The preparation of such starting materials is also described within the accompanying, non-limiting, Examples. Alternatively, necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.
  • a suitable hydrohalogenating agent for the reaction is, for example, an appropriate acid such as 45% hydrobromic acid in glacial acetic acid.
  • the hydrohalogenating agent may serve as a convenient suitable solvent or diluent for the reaction which is performed at a temperature in the range, for example, -10°C to 60°C, conveniently at or near ambient temperature.
  • the starting materials of the formula III may be obtained by standard procedures of organic chemistry using analogous procedures to those illustrated in the accompanying Examples.
  • a suitable hydroxylamine salt such as, for example hydroxylamine hydrochloride, hydroxylamine sulphate or hydroxylamine phosphate, or an appropriate 0-substituted hydroxylamine salt, such as methoxylamine hydrochloride or ethoxylamine hydrochloride, may be used.
  • the reaction is conveniently performed in a suitable inert solvent or diluent, for example, one or more of water, a (l-4C)alcohol such as methanol, ethanol and propanol, pyridine, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxan or a dipolar aprotic solvent such as N,N-dimethylformamide and dimethylsulphoxide.
  • a suitable inert solvent or diluent for example, one or more of water, a (l-4C)alcohol such as methanol, ethanol and propanol, pyridine, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxan or a dipolar aprotic solvent such as N,N-dimethylformamide and dimethylsulphoxide.
  • a suitable inert solvent or diluent for example, one or more of water, a (l-4C)alco
  • the reaction is conveniently performed in a suitable inert solvent as defined hereinbefore, and at a temperature in the range 10°C to 100°C, convenietly at or near ambient temperature.
  • a suitable Wittig or similar reagent is, for example, a triphenylphosphonium salt of the formula V or a phosphonate of the formula VI; wherein a suitable value for T is, for example, halogeno, such as, fluoro, chloro, bromo, or T is, for example, cyano; wherein Q in formula V is an anion, such as, for example, bromide ion or
  • R in formula VI is a (l-4C)alkyl group such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
  • the reaction is performed in a suitable inert solvent as defined hereinbefore, at a temperature in the range 10°C to 100 C C, conveniently at or near ambient temperature.
  • the starting materials of the formula V and VI may be obtained by standard procedures of organic chemisty.
  • a suitable oxidising agent is, for example, any agent known in the art for the oxidation of thio to sulphinyl and/or sulphonyl, for example hydrogen peroxide, a peracid (such as 3-chloroperoxybenzoic acid or peroxyacetic acid), an alkali metal peroxysulphate (such as potassium peroxymonosulphate) , a di-(l-4C)alkyldioxirane (such as dimethyldioxirane) , chromium trioxide or gaseous oxygen in the presence of platinum.
  • a peracid such as 3-chloroperoxybenzoic acid or peroxyacetic acid
  • an alkali metal peroxysulphate such as potassium peroxymonosulphate
  • a di-(l-4C)alkyldioxirane such as dimethyldioxirane
  • chromium trioxide or gaseous oxygen in the presence of platinum for example, any agent known in the art for the oxid
  • the oxidation is generally carried out under as mild conditions as possible and with the required stoichiometric amount of oxidizing 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 dichloromethane, chloroform, acetone, tetrahydrofuran, tert-butylmethyl ether, water or a water/(1-4C)alcohol mixture with (1-4C)alcohols such as methanol, ethanol and propanol.
  • the reaction is carried out at a temperature in the range 15°C to 35°C, conveniently at or near ambient temperature.
  • a milder oxidizing 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 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-LO.
  • the effects of this inhibition may be demonstrated using one or more of the standard procedures set out below:- a) An i ⁇ i vitro assay system involving incubating a test compound with heparinised human blood, prior to challenge with the calcium ionophore A23187 and then indirectly measuring the inhibitory effects on 5-LO by assaying the amount of LTB, using specific radioimmunoassays described by Carey and Forder (F. Carey and R.A. Forder, Prostaglandins, Leukotrienes Med. , 1986, 2_2, 57; Prostaglandins, 1984, 28, 666; Brit. J. Pharmacol.
  • the compound:- (2S,4R)-4-chloro-2-methyl-4-[3-(l-methyl-2-oxo-l,2,3,4- tetrahydroquinolin-6-ylthio)phenyl]tetrahydropyran has an IC-. n of approximately 0.02 ⁇ M against LTB, in test (a);
  • These compounds are examples of compounds of the invention which show selective inhibitory properties for 5-LO as opposed to cyclooxygenase, which selective properties are expected to impart improved therapeutic properties, for example, a reduction in or freedom from the gastrointestinal side-effects frequently associated with cyclooxygenase inhibitors such as indomethacin.
  • a pharmaceutical composition which comprises a cyclic 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
  • the amount of active ingredient (that is a cyclic 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 cyclic 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 allergic and inflammatory conditions which are due alone or in part to the effects of the metabolites of arachidonic acid arising by the linear (5-LO catalysed) pathway and in particular the leukotrienes, the production of which is mediated by 5-L0.
  • such conditions include, for example, asthmatic conditions, allergic reactions, allergic rhinitis, allergic shock, psoriasis, atopic dermatitis, cardiovascular and cerebrovascular disorders of an inflammatory nature, arthritic and inflammatory joint disease, inflammatory bowel diseases, conjunctivitis, the conditions of shock or trauma and various disorders of bone metabolism.
  • 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-LO inhibitor of the formula I with a NSAIA can result in a reduction in the quantity of the latter agent needed to produce a therapeutic effect, thereby reducing the likelihood of adverse side-effects.
  • a pharmaceutical composition which comprises a cyclic 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-hista ine, steroid such as beclomethasone dipropionate
  • sodium cromoglycate sodium cromoglycate
  • phosphodiesterase inhibitor or a beta-adrenergic stimulant
  • 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;
  • the 4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-1,4- benzoxazin-7-ylthio)phenyl]-4-methoxytetrahydropyran used as starting material was obtained as follows:- n-Butyl-lithium (1.6M in hexane, 1 ml) was added dropwise to a mixture of 7-mercapto-4-methyl-3-oxo-2,3-dihydro-4H-l,4-benzoxazine (0.292 g), 4-(3,5-difluorophenyl)-4-methoxytetrahydropyran (0.342 g) and NMP (3.75 ml) which had been cooled in an ice-bath.
  • the mixture was stirred and allowed to warm to ambient temperature. The mixture was heated to 145°C for 90 minutes, the hexane being distilled out of the reaction mixture. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic phase was washed with water and with N aqueous sodium hydroxide solution, dried (MgSO.) and evaporated. The residue was purified by column chromatography using a 15:1 mixture of dichloromethane and diethyl ether as eluent.
  • Trifluoroacetic acid (4.2 g) was added dropwise to a stirred suspension of a portion (1.5 g) of the benzoxazine so obtained in dichloromethane (45 ml) and the solution so obtained was stirred at ambient temperature for 30 minutes and then heated to reflux for 30 minutes. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water and with a saturated aqueous sodium bicarbonate solution, dried (MgSO.) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of dichloromethane and diethyl ether as eluent. There was thus obtained di-(4-methyl-3-oxo-2,3-dihydro-4H-l,4- benzoxazin-7-yl) disulphide (0.68 g, 60%), m.p. 133-135°C.
  • triphenylphosphine (0.576 g) was added to a suspension of the disulphide (0.776 g) in 1,4-dioxane (9 ml). Water (2.5 ml) and concentrated hydrochloric acid (1 drop) were added in turn and the mixture was heated to 50°C for 1 hour. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and 0.5 N aqueous sodium hydroxide solution. The organic phase was washed with water and with brine, dried (MgSO.) and evaporated. There was thus obtained the required starting material (0.425 g, 55%) m.p. 95-96°C. The 4-(3,5-difluorophenyl)-4-methoxytetrahydropyran used as a starting material was obtained as described in European Patent Application No. 0462813, Example 5 thereof.
  • Example 5 thereof 0.547 g) and NMP (6 ml) which had been cooled to 0°C.
  • the mixture was stirred at 0°C for 5 minutes and then heated to 145°C for 2.2 hours with the concomitant distillation of the hexane.
  • the mixture was cooled to ambient temperature and partitioned between ethyl acetate and water.
  • the organic phase was washed with water, with a 0.5N sodium hydroxide solution and with brine, dried (MgSO,) and evaporated.
  • the residue was purified by column chromatography using increasingly polar mixtures of dichloromethane and diethyl ether as eluent. The oil so obtained was triturated under diethyl ether.
  • 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-1-methyl-1,2,3,4-tetrahydro- quinolin-2-one as a solid (35.5 g, 92%) which was used without further purification.
  • the (2S,4R)-4-hydroxy-4-(3-iodophenyl)-2-methyltetrahydro- pyran used as a starting material was obtained as follows:- n-Butyl-lithium (1.5M in hexane, 40 ml) was added dropwise to a stirred solution of 1,3-diiodobenzene (19.8 g) in THF (200 ml) which had been cooled to -70°C. The mixture was stirred at -70°C for 12 minutes. (2S)-2-Methyltetrahydropyran-4-one (5.7 g) was added. The mixture was stirred, allowed to warm to ambient temperature and stirred at ambient temperature 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 brine, dried (Na ⁇ S0,) and evaporated.
  • a solution of the residue in diethyl ether (50 ml) was added to concentrated sulphuric acid (35%, 200 ml) which had been cooled to 0°C.
  • the mixture was stirred and allowed to warm to ambient temperature. The mixture was stirred at ambient temperature for 3 hours.
  • the mixture was poured onto crushed ice and extracted with diethyl ether.
  • the organic phase was washed with water, with a saturated aqueous sodium bicarbonate solution and with brine, dried (Na 2 S0.) and evaporated.
  • the mixture of dihydropyrans used as starting material may be obtained as follows:-
  • Example 11 n-Butyl-lithium (1.6 M in hexane, 2.7 ml) was added to a solution of chloromethyltriphenylphosphonium chloride (1.4 g) in THF (13 ml). After the addition the mixture was stirred for 15 minutes and then a solution of 4-formyl-4-[3-(2-naphthylmethoxy)phenyl]tetra ⁇ hydropyran (1 g) in THF (4 ml) was added. After 2 hours the mixture was purified by medium pressure liquid chromatography using increasingly polar mixtures of ethyl acetate and hexane as eluent. There were thus obtained in turn
  • 3-Chloroperbenzoic acid (0.242 g, 55%) was added to a solution of 4-chloro-4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-l,4- benzoxazin-7-ylthio)phenyl]tetrahydropyran (0.10 g) in dichloromethane (5 ml) and the mixture stirred overnight at ambient temperature. The reaction mixture was partitioned between water and dichloromethane and extracted with 3 aliquots of dichloromethane. The combined organic extracts were washed with water and brine, dried and evaporated.
  • Maize starch paste (5% w/v paste) 2.25
  • Citric acid 0.38% w/v
  • the above formulations may be obtained by conventional procedures well known in the pharmaceutical art.
  • the tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.
  • the aerosol formulations (h)-(k) may be used in conjunction with standard, metered dose aerosol dispensers, and the suspending agents sorbitan trioleate and soya lecithin may be replaced by an alternative suspending agent such as sorbitan monooleate, sorbitan sesquioleate, polysorbate 80, polyglycerol oleate or oleic acid.

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Abstract

The invention concerns a cyclic ether derivative of formula (I), wherein Ar1 is phenyl or naphthyl, or a 9- or 10-membered bicyclic heterocyclic moiety, and Ar1 may be optionally substituted; A1 includes (1-4C)alkylene; X1 includes oxy; Ar2 includes phenylene, pyridinediyl and pyrimidinediyl which may optionally bear one or two substituents; R?1 and R2¿ together form a group of the formula: -A2-X2-A3- which, together with the carbon atom to which both A?2 and A3¿ are attached, define a 5- or 6-membered ring wherein: A2 is (1-3C)alkylene; X2 includes oxy; and A3 is (1-3C)alkylene; and which ring may be optionally substituted; and Y includes halogeno, 2-cyanovinyl, 2-halogenovinyl, hydroxyimino-(1-4C)alkyl and (1-4C)alkoxyimino-(1-4C)alkyl; or a pharmaceutically-acceptable salt thereof; processes for their preparation; pharmaceutical compositions containing them and their use as 5-lipoxygenase inhibitors.

Description

CYCLIC ETHER DERIVATIVES AND PHARMACEUTICAL COMPOSITION CONTAINING THEM
This invention concerns cyclic 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 cyclic ether derivatives and novel pharmaceutical compositions containing them. Also included in the invention is the use of said cyclic ether derivatives in the treatment of various inflammatory and/or allergic diseases in which the direct or indirect products of 5-LO catalysed oxidation of arachidonic acid are involved, and the production of new medicaments for such use.
As stated above the cyclic 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.
The biosynthetic relationship and physiological properties of the leukotrienes are summarised by G.W. Taylor and S.R. Clarke in Trends in Pharmacological Sciences, 1986, 7_, 100-103. The leukotrienes and their metabolites have been implicated in the production and development of various inflammatory and allergic diseases such as inflammation of the joints (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), skin disease (especially psoriasis, eczema and dermatitis), ocular conditions (especially allergic conjunctivitis and uveitis) and respiratory disease (especially asthma, bronchitis and allergic rhinitis), and in the production and development of various cardiovascular and cerebrovascular disorders such as myocardial infarction, the formation of atherosclerosis plaques, hypertension, platelet aggregation, stroke, reperfusion injury, vascular injury including restenosis, angina and peripheral vascular disease for example in the formation of the conditions of shock or trauma such as can follow from injuries, toxaemia or surgery, and for example various disorders of bone metabolism such as osteoporosis (including senile and postmenopausal osteoporosis), Paget's disease, bone metastases, hypercalcaemia, hyperparathyrodism, osteosclerosis, osteopetrosis and periodontitis, and the abnormal charges 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-L0. Furthermore European Patent Applications Nos. 0409413, 0420511, 0462812, 0462813, 0466452, 0488602, 0555068 and 04262830 are also concerned with heterocyclic derivatives which possess inhibitory properties against 5-LO. We have now discovered that certain cyclic 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 which were not envisaged in those earlier applications, are effective inhibitors of the enzyme 5-LO and thus of leukotriene biosyntheses. Thus such compounds are of value as therapeutic agents in the treatment of, for example, allergic conditions, psoriasis, asthma, cardiovascular and cerebrovascular disorders, and/or inflammatory and arthritic conditions, and/or disorders of bone metabolism, mediated alone or in part by one or more leukotrienes.
According to the invention there is provided a cyclic ether derivative of the formula I (set out hereinafter) wherein Ar is phenyl or naphthyl, or a 9- or 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-(l-4C)alkyl-(2-4C)- alkanoylamino, hydroxyimino-(l-4C)alkyl, (l-4C)alkoxyimino-(l-4C)- alkyl, (2-5C)alkanoyloxyimino-(l-4C)alkyl, cyano-l-4C)alkoxyimino- (1-4C)alkyl, hydroxyamino-(l-4C)alkyl, (l-4C)alkoxyamino-(l-4C)alkyl, N-hydroxyureido-(1-4C)alkyl, N-(l-4C)alkoxyureido-(1-4C)alkyl, N-hydroxy-(2-4C)alkanoylamino-(1-4C)alkyl, N-(l-4C)alkoxy-(2-4C)alkanoylamino-(1-4C)alkyl, (1-6C)alkylideneaminooxy-(1-4C)alkyl, (1-4C)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 one or two substituents selected from halogeno, (l-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, thiazolediyl, oxazolediyl, thiadiazolediyl or oxadiazolediyl 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;
1 2 2 2 3
R and R together form a group of the formula -A -X -A - which,
2 3 together with the carbon atom to which both A and A are attached, define a ring having 5 or 6 ring atoms wherein:
2 A is (l-3C)alkylene;
2 X is oxy, thio, sulphinyl or sulphonyl; and
A3 is (l-3C)alkylene; and which ring may bear one, two or three substituents, which may be the same or different and may be optionally geminally disubstituted, selected from hydroxy, (1-4C)alkyl, (l-4C)alkoxy and fluoro-(l-4C)alkyl, or which ring may bear a (l-4C)alkylenedioxy substituent; and
Y is halogeno, vinyl, 2-cyanovinyl, 2-halogenovinyl, hydroxyimino-(l-4C)alkyl, (l-4C)alkoxyimino-(l-4C)alkyl or
(2-5C)alkanoyloxyimino-(l-4C)alkyl; or a pharmaceutically-acceptable salt thereof.
• The chemical formulae referred to herein by Roman numerals are set out for convenience on a separate sheet hereinafter.
In this specification the generic term "alkyl" includes both straight-chain and branched-chain alkyl groups. However references to individual alkyl groups such as "propyl" are specific for the straight-chain version only and references to individual branched-chain alkyl groups such as "isopropyl" are specific for the branched-chain version only. An analogous convention applies to other generic terms.
It is 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 vinyl and oxime derivatives and it is well known that both vinyl and oxime derivatives may exist in different geometric iso eric 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-LO. 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-LO. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Suitable values for the generic terms referred to above include those set out below.
A suitable value for Ar when it is naphthyl is, for example 1-naphth l 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, 1,2,3,4-tetrahydroquinolyl, 1,2-dihydroisoquinolyl, 2,3-dihydro-4H-l,4-benzoxazinyl or 2,3-dihydro-4H-l,4-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.
A suitable value for Ar when it is a 9-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 benzo-fused heterocyclic moiety or a hydrogenated derivative thereof such as indolyl, indolinyl, isoindolyl, isoindolinyl, indolizinyl, benzimidazolyl, 2,3-dihydrobenzimidazolyl, lH-indazolyl, 2,3-dihydro-lH-indazolyl, benzoxazolyl, 2,3-dihydrobenzoxazolyl, benzo[c]isoxazolyl, benzo[d]isoxazolyl, 2,3-dihydrobenzo[d]isoxazolyl, benzothiazolyl, 2,3-dihydrobenzothiazolyl, benzo[c]isothiazolyl, benzo[d]isothiazolyl and 2,3-dihydrobenzo[d]isothiazolyl, or, for example, a pyrido-fused heterocyclic moiety or a hydrogenated derivative thereof such as lH-pyrrolo[2,3-b]pyridyl, 2,3-dihydro-lH-pyrrolo[2,3-b]pyridyl, lH-pyrrolo[2,3-c]pyridyl, 2,3-dihydro-lH-pyrrolo[2,3-c]pyridyl, lH-imidazo[ ,5-b]pyridyl, 2,3-dihydro-lH-imidazo[4,5-b]pyridyl, lH-imidazo[4,5-c]pyridyl and 2,3-dihydro-lH-imidazo[4,5-c]pyridyl.
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
Ar 1, on Ar2 or on any of the substituents on Ar1 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-butyl; 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-(1-4C)alkyl: hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl; for (2-4C)alkanoyl: acetyl, propionyl and butyryl; for (2-4C)alkanoylamino: 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-methox iminoethyl and 2-methoxyiminoethyl; for (2-5C)alkanoyloxyimino- (l-4C)alkyl: acetoxyiminomethyl, propionyloxy- iminomethyl, 1-acetoxyiminoethyl and 2-acetoxyiminoethyl; for cyano-(l-4C)alkoxyimino- (l-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-hydroxyureidomethy1, l-(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- a ino-(1-4C)alkyl: N-hydroxyacetamidomethyl, N-hydroxy- propionunidomethyl, 1-(N-hydroxy- acetamido)ethyl and 2-(N-hydroxy- acetamido)ethyl; for N-(l-4C)alkoxy-(2-4C)- alkanoylamino-(1-4C)alkyl: N-methoxyacetamidomethy1, N-ethoxy- acetamidomethyl, 1-(N-methoxy- acetamido)ethyl and 2-(N-methoxy- aceta ido)ethyl; for (l-6C)alkylideneaminooxy- (l-4C)alkyl: methyleneaminooxymethyl, ethylidene- curιinooxj*methyl, isopropylideneamino- oxy ethyl, l-(isopropylidene- aminooxy)ethyl and 2-(isopropylidene- aminooxy)ethyl; for (l-4C)alkanesulphonamido: methanesulphonamido and ethanesulphonamido; for N-(l-4C)alkyl-(l-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-(l-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)alkylamino: dimethylamino, N-ethyl-N-methylamino and diethylamino.
A suitable value for Ar when it is phenylene is, for example, 1,3- or 1,4-phenylene.
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 pyridinediyl, pyrimidinediyl, thiophenediyl, furandiyl, thiazolediyl, oxazolediyl, thiadiazolediyl or oxadiazolediyl 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, 2,4- or 2,5-thiazolediyl, 2,4- or 2,5-oxazolediyl,
2,5-thiadiazolediyl or 2,5-oxadiazolediyl.
1 2 When R and R together form a group of the formula
-A 2-X2-A3- which together with the carbon atom to which A2 and A3 are attached define a ring having 5 or 6 ring atoms, then suitable values
2 3 for A and A when each is (l-3C)alkylene are, independently, for example, methylene, ethylene and trimethylene.
Suitable values for the one, two or three substituents which may be present on said 5- or 6-membered ring include, for example:- for (1-4C)alkyl: methyl, ethyl, propyl, isopropyl and butyl; for (l-4C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for fluoro-(l-4C)alkyl: fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl,
2,2,2-trifluoromethyl and pentafluoroethyl; for (l-4C)alkylenedioxy: methylenedioxy and ethylenedioxy.
A suitable value for Y when it is halogeno is fluoro, chloro, bromo or iodo. A suitable value for Y when it is 2-halogenovinyl is, for example, 2-bromovinyl, 2-chlorovinyl or 2-fluorovinyl. When it is hydroxyimino-(l-4C)alkyl a suitable value for Y is, for example, hydroxyiminomethyl, 1-hydroxyiminoethyl or 2-hydroxyiminoethyl. When it is (l-4C)alkoxyimino-(l-4C)alkyl a suitable value for Y is, for example, methoxyiminomethyl, ethoxyiminomethyl, 1-methoxyiminoethyl and 2-methoxyiminoethyl. A suitable value for Y when it is (2-5C)alkanoyloxyimino-(l-4C)alkyl is, for example, acetoxyiminomethyl, propionyloxyiminomethyl, 1-acetoxyiminoethyl or 2-acetoxyiminoethyl.
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, cyclic ether derivatives of the formula I, or pharmaceutically-acceptable salts thereof, wherein:-
(a) Ar is phenyl or naphthyl which may optionally bear one, two or three substituents selected from any of those substituents on Ar defined hereinbefore other than oxo and thioxo; and A 1, X1, Ar2, R1,
2 R and Y 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
1 1 2 1 2 methoxy; and A , X , Ar , R , R and Y 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,
1 1 2 1 2 ethoxy and trifluoromethyl; and A , X , Ar , R , R , and Y have any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention; (d) Ar is a 9- or 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
1 1 2 1 2 thioxo; and A , X , Ar , R , R and Y 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, 2,3-dihydro-4H-l,4-benzoxazinyl, indolyl, indolinyl, benzimidazolyl, 2,3-dihydrobenzimidazolyl, benzoxazolyl, 2,3-dihydrobenzoxazolyl, benzothiazolyl or 2,3-dihydrobenzothiazolyl, 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
1 1 2 1 2 methoxy; and A , X , Ar , R , R and Y 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-1,2-dihydro- quinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, 2-thioxo-1,2,3,4- tetrahydroquinolinyl, 3-oxo-2,3-dihydro-4H-l,4-benzoxazinyl, 2-oxoindolinyl, 2-oxo-2,3-dihydrobenzimidazolyl,
2-oxo-2,3-dihydrobenzoxazolyl or 2-oxo-2,3-dihydrobenzothiazolyl 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
1 1 2 1 selected from fluoro, chloro, methyl and methoxy; and A , X , Ar , R ,
2 R , and Y 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- 1,2,3,4-tetrahydroquinolin-6-yl, 3-oxo-2,3-dihydro-4H-1,4- benzoxazin-7-yl, 2-oxoindolin-5-yl or 2-oxoindolin-6-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,
1 1 * 2 1 2 chloro, methyl and methoxy; and A , X , Ar , R , R and Y have any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention;
(h) A1 is a direct link to X1; and Ar1, X1, Ar2, R1, R2 and Y have any of the meanings defined hereinbefore or in this section concerning particular compounds;
1 1 1 2 1 2
(i) A is (l-4C)alkylene and X is oxy; and Ar , Ar , R , R and
Y 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; and Ar , Ar , R ,
2 R and Y 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 and (l-4C)alkoxy,
2 1 1 or Ar is pyridinediyl, thiophenediyl or thiazolediyl; and Ar , A , X 1, R1, R2 and Y have any of the meanings defined hereinbefore or in this section defining particular compounds;
(1) R 1 and R2 together form a group of the formula -A2-X2-A3-
2 3 which, together with the carbon atom to which both A and A are attached, define a ring having 5 or 6 ring atoms wherein:
2 A is methylene or ethylene;
2 X is oxy; and
3 A is methylene or ethylene; and which ring may bear one, two or three substituents, which may be the same or different, and may be optionally geminally disubstituted where possible, selected from hydroxy, methyl, ethyl, methoxy or ethoxy; and Ar , A , X and Y have any of the meanings defined hereinbefore or in this section defining particular compounds;
(m) Y is fluoro, chloro, bromo, iodo, vinyl, 2-cyanovinyl, 2-bromovinyl, 2-chlorovinyl, hydroxyiminomethyl, methoxyiminomethyl, ethoxyiminomethyl, acetoxyiminomethyl or propionyloxyiminomethyl; and Ar , A , X , R and R have any of the meanings defined hereinbefore or in this section defining particular compounds;
(n) Y is fluoro, chloro, bromo or iodo; and Ar , A , X , R and
2 R have any of the meanings defined hereinbefore or in this section defining particular compounds; or
(o) Y is vinyl, 2-cyanovinyl, 2-bromovinyl, 2-chlorovinyl, hydroxyiminomethyl, methoxyiminomethyl, ethoxyiminomethyl, acetoxyiminomethyl or propionyliminomethyl; and Ar , A , X , R and R have any of the meanings defined hereinbefore or in this section defining particular compounds.
A preferred compound of the invention comprises a cyclic 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 or two substituents selected from fluoro, chloro, methyl and ethyl, or Ar is 2-oxoindolin-5-yl which may optionally bear one or two substituents selected from fluoro, chloro, methyl and ethyl;
A is a direct link to X and X is thio or sulphonyl, or A is methylene and X is oxy;
2 Ar is 1,3-phenylene, 5-fluoro-l,3-phenylene or 2,5-thiophenediyl, or
2 Ar is 2,4-thiophenediyl or 2,5-thiazolediyl (each with the group of the formula -A -X - in the 2-position);
1 2 2 2 3
R and R together form a group of the formula -A -X -A - which,
2 3 together with the carbon atom to which both A and A are attached, define a ring having 6 ring atoms wherein:
2 A is ethylene;
X is oxy; and
A is ethylene; and which ring may bear one substituent selected from methyl or ethyl; and
Y is fluoro, chloro, bromo, 2-cyanovinyl, 2-chlorovinyl, hydroxyiminomethyl or methoxyiminomethyl; or a pharmaceutically-acceptable salt thereof.
A further preferred compound of the invention comprises a cyclic 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-tetrahydroquinolin-6-yl or
3-oxo-2,3-dihydro-4H-l,4-benzoxazin-7-yl which may optionally bear one or two substituents selected from fluoro, chloro, methyl and ethyl, or
Ar is 2-oxoindolin-5-yl which may optionally bear one or two substituents selected from fluoro, chloro, methyl and ethyl;
A is a direct link to X and X is thio or sulphonyl, or A is methylene and X is oxy;
2 Ar is 1,3-phenylene, 5-fluoro-1,3-phenylene or 2,5-thiophenediyl, or
2 Ar is 2,4-thiophenediyl or 2,5-thiazolediyl (each with the group of the formula -A -X - in the 2-position); 1 2 2 2 3
R and R together form a group of the formula -A -X -A - which,
2 3 together with the carbon atom to which both A and A are attached, define a ring having 6 ring atoms wherein:
2 A is ethylene;
X is oxy; and
3 A is ethylene; and which ring may bear one substituent selected from methyl or ethyl; and
Y is fluoro, chloro or bromo; or a pharmaceutically-acceptable salt thereof.
A further preferred compound of the invention comprises a cyclic 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-1,2,3,4-tetrahydroquinolin-6-yl or
3-oxo-2,3-dihydro-4H-l,4-benzoxazin-7-yl which may optionally bear one or two substituents selected from fluoro, chloro, methyl and ethyl, or
Ar is 2-oxoindolin-5-yl which may optionally bear one or two substituents selected from fluoro, chloro, methyl and ethyl;
A is a direct link to X and X is thio or sulphonyl, or A is methylene and X is oxy;
2 Ar is 1,3-phenylene, 5-fluoro-l,3-phenylene or 2,5-thiophenediyl, or
2 Ar is 2,4-thiophenediyl or 2,5-thiazolediyl (each with the group of the formula -A -X - in the 2-position);
1 2 2 2 3
R and R together form a group of the formula -A -X -A - which,
2 3 together with the carbon atom to which both A and A are attached, define a ring having 6 ring atoms wherein:
A is ethylene;
X is oxy; and
3 A is ethylene; and which ring may bear one substituent selected from methyl or ethyl; and
Y is 2-cyanovinyl, 2-chlorovinyl, hydroxyiminomethyl or methoxyiminomethyl; or a pharmaceutically-acceptable salt thereof.
A further preferred compound of the invention comprises a cyclic 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 which bears at the 1-position a methyl or ethyl substituent;
A is methylene and X is oxy;
2 Ar is 1,3-phenylene or 5-fluoro-l,3-phenylene;
R 1 and R2 together form a group of the formula -A2-X2-A3- which,
2 3 together with the carbon atom to which both A and A are attached, define a ring having 6 ring atoms wherein:
A is ethylene;
2 X is oxy; and
3 A is ethylene; and which ring may bear one substituent selected from methyl or ethyl; and
Y is 2-cyanovinyl, 2-chlorovinyl, hydroxyiminomethyl or methoxyiminomethyl; or a pharmaceutically-acceptable salt thereof.
A further preferred compound of the invention comprises a cyclic ether derivative of the formula I wherein Ar is 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl or
3-oxo-2,3-dihydro-4H-l,4-benzoxazin-7-yl which bears one substituent selected from methyl and ethyl;
A is a direct link to X and X is thio or sulphonyl;
2 Ar is 1,3-phenylene or 5-fluoro-1,3-phenylene;
1 2 2 2 3
R and R together form a group of the formula -A -X -A - which,
2 3 together with the carbon atom to which both A and A are attached, define a ring having 6 ring atoms wherein:
2 A is ethylene;
2 X is oxy; and
3 A is ethylene; and which ring may' bear one substituent selected from methyl or ethyl; and
Y is fluoro, chloro or bromo; or a pharmaceutically-acceptable salt thereof.
A further preferred compound of the invention comprises a cyclic ether derivative of the formula I wherein Ar is 2-oxo-l,2,3,4-tetrahydroquinolin-6-yl which bears at the 1-position a methyl or ethyl substituent, or Ar is
3-oxo-2,3-dihydro-4H-l,4-benzoxazin-7-yl which bears at the 4-position a methyl or ethyl substituent;
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;
1 2 2 2 3
R and R together form a group of the formula -A -X -A - which,
'2 3 together with the carbon atom to which both A and A are attached, define a ring having 6 ring atoms wherein;
2 A is ethylene;
2 X is oxy; and
3 A is ethylene; and which ring may bear one substituent selected from methyl or ethyl; and
Y is fluoro, chloro or bromo; or a pharmaceutically-acceptable salt thereof.
A specific especially preferred compound of the invention is the following compound of the formula I:-
4-bromo-4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7- ylthio)phenyl]tetrahydropyran,
4-chloro-4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin- 7-ylthio)phenyl]tetrahydropyran,
4-bromo-4-[5-fluoro-3-(l-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6- ylthio)phenyl]tetrahydropyran,
(2S,4R)-4-chloro-2-methyl-4-[3-(l-methyl-2-oxo-l,2,3,4- tetrahydroquinolin-6-ylthio)phenyl]tetrahydropyran, (2S,4R)-4-fluoro-2-methyl-4-[3-(l-methyl-2-oxo-l,2,3,4- tetrahydroquinolin-6-ylthio)phenyl]tetrahydropyran, (2S,4R)-4-bromo-2-methyl-4-[5-fluoro-3-(l-methyl-2-oxo-l,2,3,4- tetrahydroquinolin-6-ylthio)phenyl]tetrahydropyran, 4-(hydroxyiminomethyl)-4-[3-(2-naphthylmethoxy)phenyl]tetrahydropyran, 4-(methoxyiminomethyl)-4-[3-(2-naphthylmethoxy)phenyl]tetrahydropyran,
(E)-4-(2-cyanovinyl)-4-[3-(2-naphthylmethoxy)phenyl]tetrahydropyran,
(E)-4-(2-cyanovinyl)-4-[3-(l-methyl-2-oxo-l,2-dihydroquinolin-6- ylmethoxy)phenyl]tetrahydropyran,
(E)- and (Z)-4-(2-chlorovinyl)-4-[3-(2-naphthylmethoxy)phenyl]- tetrahydropyran,
4-bromo-4-[5-fluoro-3-( -methyl-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-7- ylsulphonyl)phenyl]tetrahydropyran,
4-chloro-4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-
7-ylsulphonyl)phenyl]tetrahydropyran,
4-bromo-4-[5-fluoro-3-(l-methyl-2-oxo-1,2,3, -tetrahydroquinolin-6- ylsulphonyl)phenyl]tetrahydropyran, or
(2S, R)-4-chloro-2-methyl-4-[3-(l-methyl-2-oxo-1,2,3,4-tetrahydro- quinolin-6-ylsulphonyl)phenyl]tetrahydropyran; or a pharmaceutically-acceptable salt thereof.
A compound of the invention comprising a cyclic 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 1 1 2 1 2 otherwise stated, Ar , A , X , Ar , R , R and Y have any of the meanings defined hereinbefore provided that when there is an amino,
1 2 1 2 alkylamino or hydroxy group in Ar , Ar , R or R then any such group may optionally be protected by a conventional protecting group which may be removed when so desired by conventional means.
A suitable protecting group for an amino or alkylamino group is, for example, an acyl group for example a (2-4C)alkanoyl group
(especially acetyl), a (l-4C)alkoxycarbonyl group (especially methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl), an arylmethoxycarbonyl group (especially benzyloxycarbonyl) or an aroyl group (especially benzoyl). The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tert-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 (2-4C)alkanoyl group (especially acetyl), an aroyl group (especially benzoyl) or an arylmethyl group (especially benzyl). The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-charcoal.
(a) The alkylation, conveniently in the presence of a suitable base, of a compound of the formula II with a compound of the formula Ar -A -Z wherein Z is a suitable 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, (l-4C)alkanoate, (1-4C)alkyl, amide, hydroxide or hydride, for example sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium acetate, n-butyl-lithium, sodium amide, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride. Alternatively a suitable base for the reaction, is for example, an organic amine base such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene. The reaction is conveniently performed in a suitable inert solvent or diluent, for example N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, N-methylpyrrolidin-2-one, dimethylsulphoxide, acetonitrile, acetone 1,2-dimethoxyethane or tetrahydrofuan, and at a temperature in the range, for example, 10°C to 100°C, conveniently at or near ambient temperature.
The starting materials of the formula II and of the formula Ar -A -Z may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described within the accompanying non-limiting Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.
(b) The conversion of a compound of the formula I wherein Y is a hydroxy or (l-4C)alkoxy group such as methoxy or ethoxy to a compound of the formula I wherein Y is halogeno.
A suitable reagent for the reaction is, for example, a boron trihalide such as boron trichloride or boron tribromide or, for example, a di-(l-4C)alkylaminosulphur trihalide such as diethylaminosulphur trifluoride. The reaction is conveniently performed in a suitable inert solvent as defined hereinbefore, at a temperature in the range -10°C to 60CC, conveniently at or near 5°C.
The starting materials of the formula I wherein Y is a hydroxy or (l-4C)alkoxy group may be obtained by standard procedures of organic chemistry as illustrated by the procedures disclosed in the European Patent Applications which are mentioned by way of reference hereinbefore. The preparation of such starting materials is also described within the accompanying, non-limiting, Examples. Alternatively, necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.
(c) The hydrohalogenation of an olefin of the formula III, or of an admixture of isomers of the olefin of the formula III.
A suitable hydrohalogenating agent for the reaction is, for example, an appropriate acid such as 45% hydrobromic acid in glacial acetic acid. The hydrohalogenating agent may serve as a convenient suitable solvent or diluent for the reaction which is performed at a temperature in the range, for example, -10°C to 60°C, conveniently at or near ambient temperature.
The starting materials of the formula III may be obtained by standard procedures of organic chemistry using analogous procedures to those illustrated in the accompanying Examples.
(d) For the production of compounds of the formula I wherein Y is a hydroxyimino-(l-4C)alkyl group or an 0-substituted hydroxyimino-(l-4C)alkyl group, the reaction, conveniently in the presence of a suitable base as defined hereinbefore, of a compound of the formula I wherein Y is a formyl or (2-4C)alkanoyl group with hydroxylamine or an appropriate 0-substituted hydroxylamine.
A suitable hydroxylamine salt, such as, for example hydroxylamine hydrochloride, hydroxylamine sulphate or hydroxylamine phosphate, or an appropriate 0-substituted hydroxylamine salt, such as methoxylamine hydrochloride or ethoxylamine hydrochloride, may be used.
The reaction is conveniently performed in a suitable inert solvent or diluent, for example, one or more of water, a (l-4C)alcohol such as methanol, ethanol and propanol, pyridine, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxan or a dipolar aprotic solvent such as N,N-dimethylformamide and dimethylsulphoxide. The reaction is conveniently performed at a temperature in the range 10°C to 60°C, conveniently at or near ambient temperature.
The preparation of starting materials of the formula I wherein Y is a formyl or (l-4C)alkanoyl group is described within the accompanying, non-limiting, Examples. Alternatively, necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skills of an organic chemist.
(e) For the production of those compounds of the formula I wherein Y is a (l-4C)alkoxyimino-(l-4C)alkyl or (2-5C)alkanoyloxyimino- (l-4C)alkyl group, the alkylation or acylation, conveniently in the presence of a suitable base as defined hereinbefore, of a compound of the formula I wherein Y is a hydroxyimino-(l-4C)alkyl group with an appropriate alkylating agent of the formula R -Z wherein R is a (1-4C)alkyl group or with an
__L 3. appropriate acylating agent of the formula R -Z wherein R is a (2-5C)alkanoyl group and Z is a displaceable group as defined hereinbefore.
The reaction is conveniently performed in a suitable inert solvent as defined hereinbefore, and at a temperature in the range 10°C to 100°C, convenietly at or near ambient temperature.
(f) For the production of those compounds of the formula I wherein Y is a vinyl or substituted vinyl group, the reaction of an aldehyde of the formula IV with an appropriate Wittig or similar reagent, using a suitable base as defined hereinbefore.
A suitable Wittig or similar reagent is, for example, a triphenylphosphonium salt of the formula V or a phosphonate of the formula VI; wherein a suitable value for T is, for example, halogeno, such as, fluoro, chloro, bromo, or T is, for example, cyano; wherein Q in formula V is an anion, such as, for example, bromide ion or
3 chloride ion; and wherein R in formula VI is a (l-4C)alkyl group such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
The reaction is performed in a suitable inert solvent as defined hereinbefore, at a temperature in the range 10°C to 100CC, conveniently at or near ambient temperature.
The starting materials of the formula V and VI may be obtained by standard procedures of organic chemisty.
(g) 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 agent is, for example, any agent known in the art for the oxidation of thio to sulphinyl and/or sulphonyl, for example hydrogen peroxide, a peracid (such as 3-chloroperoxybenzoic acid or peroxyacetic acid), an alkali metal peroxysulphate (such as potassium peroxymonosulphate) , a di-(l-4C)alkyldioxirane (such as dimethyldioxirane) , 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 oxidizing 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 dichloromethane, chloroform, acetone, tetrahydrofuran, tert-butylmethyl ether, water or a water/(1-4C)alcohol mixture with (1-4C)alcohols such as methanol, ethanol and propanol. The reaction is carried out at a temperature in the range 15°C to 35°C, conveniently at or near ambient temperature. When a compound carrying a sulphinyl group is required a milder oxidizing 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 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-LO. The effects of this inhibition may be demonstrated using one or more of the standard procedures set out below:- a) An iτi vitro assay system involving incubating a test compound with heparinised human blood, prior to challenge with the calcium ionophore A23187 and then indirectly measuring the inhibitory effects on 5-LO by assaying the amount of LTB, using specific radioimmunoassays described by Carey and Forder (F. Carey and R.A. Forder, Prostaglandins, Leukotrienes Med. , 1986, 2_2, 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, ^(4), 605-613). The effects of a test compound on the enzyme cyclooxygenase (which is involved in the alternative metabolic pathway for arachidonic acid and gives rise to prostaglandins, thromboxanes and related metabolites) may be measured at the same time using the specific radioimmunoassay for thromboxane B„(TxB2) described by Carey and Forder (see above). This test provides an indication of the effects of a test compound against 5-LO and also cyclooxygenase in the presence of blood cells and proteins. It permits the selectivity of the inhibitory effect on 5-LO or cyclooxygenase to be assessed. b) An ej 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 ij vivo system involving measuring the effects of a test compound administered orally against the liberation of LTB, induced by zymosan within an air pouch generated within the subcutaneous tissue of the back of male rats. The rats are anaesthetised and air pouches are formed by the injection of sterile air (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 I'i 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-LO in an inflammatory milieu. Although the pharmacological properties of the compounds of the formula I vary with structural changes as expected, in general compounds of the formula I possess 5-LO inhibitory effects at the following concentrations or doses in at least one of the above tests a)-c):-
Test a): IC5Q (LTB^) in the range, for example, 0.01-40μM IC50 (TxB„) in the range, for example, 40-200μM; Test b): oral ED5Q(LTB.) in the range, for example,
O.l-lOOmg/kg; Test c): oral ED,-,-(LTB,) in the range, for example, 0.1-100mg/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:- (2S,4R)-4-chloro-2-methyl-4-[3-(l-methyl-2-oxo-l,2,3,4- tetrahydroquinolin-6-ylthio)phenyl]tetrahydropyran has an IC-.n of approximately 0.02μM against LTB, in test (a);
4-bromo-4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-1, -benzoxazin-7- ylsulphonyl)phenyl]tetrahydropyran has an IC_-0 of approximately 0.04 μM against LTB, in test (a); and
4-bromo-4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-7- ylthio)phenyl]tetrahydropyran has an EDC of approximately 1 mg/kg in test (c).
These compounds are examples of compounds of the invention which show selective inhibitory properties for 5-LO as opposed to cyclooxygenase, which selective properties are expected to impart improved therapeutic properties, for example, a reduction in or freedom from the gastrointestinal side-effects frequently associated with cyclooxygenase inhibitors such as indomethacin.
According to a further feature of the invention there is provided a pharmaceutical composition which comprises a cyclic 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 cyclic 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 cyclic ether derivative of the formula I, or a pharmaceutically-acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy.
The invention also includes a method of treating a disease or medical condition mediated alone or in part by one or more leukotrienes which comprises administering to a warm-blooded animal requiring such treatment an effective amount of an active ingredient as defined above. The invention also provides the use of such an active ingredient in the production of a new medicament for use in a leukotriene mediated disease or medical condition.
The size of the dose for therapeutic or prophylactic purposes of a compound of the formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine. As mentioned above, compounds of the formula I are useful in treating those allergic and inflammatory conditions which are due alone or in part to the effects of the metabolites of arachidonic acid arising by the linear (5-LO catalysed) pathway and in particular the leukotrienes, the production of which is mediated by 5-L0. As previously mentioned, such conditions include, for example, asthmatic conditions, allergic reactions, allergic rhinitis, allergic shock, psoriasis, atopic dermatitis, cardiovascular and cerebrovascular disorders of an inflammatory nature, arthritic and inflammatory joint disease, inflammatory bowel diseases, conjunctivitis, the conditions of shock or trauma and various disorders of bone metabolism.
In using a compound of the formula I for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.5 mg to 75 mg per kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, 0.5 mg to 30 mg per kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.5 mg to 25 mg per kg body weight will be used.
Although the compounds of the formula I are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to inhibit the enzyme 5-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-LO inhibitor of the formula I with a NSAIA can result in a reduction in the quantity of the latter agent needed to produce a therapeutic effect, thereby reducing the likelihood of adverse side-effects. According to a further feature of the invention there is provided a pharmaceutical composition which comprises a cyclic 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-hista ine, 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 Kieselgel silica (Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silica obtained from E. Merck, Darmstadt, Germany;
(iv) yields are given for illustration only and are not necessarily the maximum attainable;
(v) the end-products of the formula I in general 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;
(viii) the following abbreviations have been used:-
THF tetrahydrofuran;
DMF N,N-dimethylformamide.
DMSO dimethylsulphoxide
NMP N-methylpyrrolidin-2-one
(ix) sodium hydride was generally used as a 60% dispersion in mineral oil. Example 1
Boron tribro ide (1M in dichloromethane, 1.85 ml) was added dropwise to a stirred, ice-cooled solution of 4-[5-fluoro-3-(4-methyl-3- oxo-2,3-dihydro-4H-l,4-benzoxazin-7-ylthio)phenyl]-4-methoxytetra- hydropyran (0.25 g) in dichloromethane (10 ml). The temperature of the mixture was maintained at 5-10°C during the addition of the boron tribromide and was then allowed to rise to ambient temperature. The mixture was stirred for 2 hours at ambient temperature, and then partitioned between dichloromethane and water. The mixture was extracted into dichloromethane and the combined organic extracts washed with water and brine, dried and evaporated. The residue was purified by column chromatography using a 1:1 mixture of ethyl acetate and hexane as eluent and then triturated with diethyl ether. There was thus obtained
4-bromo-4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-l, -benzoxazin-7- ylthio)phenyl]tetrahydropyran (0.23 g, 82%), m.p. 131-133°C. NMR Spectrum 2.05-2.20 (m, 2H); 2.30-2.43 (m, 2H) ; 3.38 (s, 3H) ; 4.0 (m, 4H); 6.78 (m, IH) ; 6.95-7.28 (m, 5H).
The 4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-1,4- benzoxazin-7-ylthio)phenyl]-4-methoxytetrahydropyran used as starting material was obtained as follows:- n-Butyl-lithium (1.6M in hexane, 1 ml) was added dropwise to a mixture of 7-mercapto-4-methyl-3-oxo-2,3-dihydro-4H-l,4-benzoxazine (0.292 g), 4-(3,5-difluorophenyl)-4-methoxytetrahydropyran (0.342 g) and NMP (3.75 ml) which had been cooled in an ice-bath. The mixture was stirred and allowed to warm to ambient temperature. The mixture was heated to 145°C for 90 minutes, the hexane being distilled out of the reaction mixture. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic phase was washed with water and with N aqueous sodium hydroxide solution, dried (MgSO.) and evaporated. The residue was purified by column chromatography using a 15:1 mixture of dichloromethane and diethyl ether as eluent. There was thus obtained 4-[5-fluoro-3-(4-methyl-3-oxo- 2,3-dihydro-4H-l,4-benzoxazin-7-ylthio)phenyl]-4-methoxytetrahydro- pyran (0.202 g, 33%), m.p. 131-133°C.
NMR Spectrum 1.8-2.1 (m, 4H); 2.98 (s, 3H); 3.37 (s, 3H); 3.75-3.95
(m, 4H); 4.63 (s, 2H); 6.76-7.25 (m, 6H).
The 7-mercapto-4-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazine used as a starting material was obtained as follows:-
A mixture of 5-fluoro-2-nitrophenol (10.05 g) , potassium carbonate (10.6 g) and acetone (125 ml) was heated to reflux for 10 minutes. The mixture was cooled to ambient temperature and a solution of ethyl bromoacetate 7.8 ml) in acetone (10 ml) was added dropwise. The mixture was heated to reflux for 2.5 hours. The mixture was evaporated and the residue was partitioned between diethyl ether and water. The organic phase was washed with water, dried (MgSO.) and evaporated. There was thus obtained ethyl 2-(5-fluoro-2-nitrophenoxy)acetate (14.28 g, 92%), m.p. 44-46°C.
A mixture of ethyl 2-(5-fluoro-2-nitrophenoxy)acetate (11 g), benzylmercaptan (5.2 g), triethylamine (5.08 g) and DMF (50 ml) was stirred an heated to 80°C for 7 hours. The mixture was cooled, poured into water and acidified by the addition of dilute aqueous hydrochloric acid. The mixture was extracted with diethyl ether. The organic phase was washed with water and with brine, dried (MgSO,) and evaporated to give ethyl 2-(5-benzylthio-2-nitrophenoxy)acetate (10.6 g, 68%) as a solid.
A mixture of a portion (8.68 g) of the product so obtained, stannous chloride dihydrate (Tet. Let., 1984, 839; 28.1 g), ethyl acetate (5 ml) and ethanol (50 ml) was heated to reflux for 30 minutes. The mixture was poured onto ice and a saturated aqueous sodium bicarbonate solution was added. The resultant precipitate was removed by filtration and the filtrate was extracted with ethyl acetate. The organic phase was washed with water and with brine, dried (MgSO,) and evaporated to give
7-benzylthio-3-oxo-2,3-dihydro-4H-l,4-benzoxazine (3.32 g, 49%), m.p. 153-154°C.
A portion (2.7 g) of the product so obtained was added to a stirred suspension of sodium hydride (60% dispersion in mineral oil, 0.52 g; the oil was removed by washing the solid dispersion with petroleum ether) in DMF (10 ml) and the mixture was stirred at ambient temperature for 30 minutes. Methyl iodide (2.13 g) was added and the mixture was stirred at ambient temperature for 30 minutes. The mixture was partitioned between diethyl ether and water. The organic phase was washed with water and with brine, dried (MgSO.) and evaporated to give 7-benzylthio-4-methyl-3-oxo-2,3-dihydro-4H-l,4- benzoxazine (2.6 g, 91%) as a solid.
A solution of 3-chloroperbenzoic acid (1.72 g) in chloroform (10 ml) was added dropwise to a solution of a portion (2 g) of the benzoxazine so obtained in chloroform (15 ml) which had been cooled to 0°C and the mixture was stirred at 0°C for 4 hours. Calcium hyroxide (0.74 g) was added and the mixture was stirred at ambient temperature for 15 minutes. The mixture was filtered and the filtrate was evaporated to give 7-benzylsulphinyl-4-methyl-3-oxo-2,3-dihydro-4H- 1,4-benzoxazine (2.1 g) as a solid which was used without further purification.
Trifluoroacetic acid (4.2 g) was added dropwise to a stirred suspension of a portion (1.5 g) of the benzoxazine so obtained in dichloromethane (45 ml) and the solution so obtained was stirred at ambient temperature for 30 minutes and then heated to reflux for 30 minutes. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water and with a saturated aqueous sodium bicarbonate solution, dried (MgSO.) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of dichloromethane and diethyl ether as eluent. There was thus obtained di-(4-methyl-3-oxo-2,3-dihydro-4H-l,4- benzoxazin-7-yl) disulphide (0.68 g, 60%), m.p. 133-135°C.
After repetition of the preceding step, triphenylphosphine (0.576 g) was added to a suspension of the disulphide (0.776 g) in 1,4-dioxane (9 ml). Water (2.5 ml) and concentrated hydrochloric acid (1 drop) were added in turn and the mixture was heated to 50°C for 1 hour. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and 0.5 N aqueous sodium hydroxide solution. The organic phase was washed with water and with brine, dried (MgSO.) and evaporated. There was thus obtained the required starting material (0.425 g, 55%) m.p. 95-96°C. The 4-(3,5-difluorophenyl)-4-methoxytetrahydropyran used as a starting material was obtained as described in European Patent Application No. 0462813, Example 5 thereof.
Example 2
Boron trichloride (1M in dichloromethane, 1.85 ml) was added dropwise to a stirred, ice-cooled solution of 4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-7- ylthio)phenyl]-4-methoxytetrahydropyran (0.25 g) in dichloromethane (10 ml). The temperature of the mixture was maintained at 0-5°C during the addition of the boron trichloride and was then allowed to rise to ambient temperature. The mixture was stirred for 2 hours at ambient temperature, and then quenched with water. The mixture was extracted into dichloromethane and the combined organic extracts washed with water and brine, dried and evaporated. The residue was purified by column chromatography using a 1:1 mixture of ethyl acetate and hexane as eluent and then triturated with diethyl ether. There was thus obtained 4-chloro-4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro- 4H-l,4-benzoxazin-7-ylthio)phenyl]tetrahydropyran (0.24 g, 95%), m.p. 114-115°C.
NMR Spectrum 2.1-2.3 (m, 4H); 3.38 (s, 3H) ; 3.85-4.08 (m, 4H); 4.65 (s, 2H); 6.8 (m, IH); 6.96 (d, IH); 7.03-7.20 (m, 3H); 7.26 (m, IH).
Example 3
Boron tribromide (1M in dichloromethane, 3.75 ml) was added dropwise to a stirred, ice-cooled solution of 4-[5-fluoro-3-(1-methyl- 2-oxo-l,2,3,4-tetrahydroquinolin-6-ylthio)phenyl]-4- methoxytetrahydropyran (0.5 g) in dichloromethane (10 ml). The temperature of the mixture was maintained at 5-10°C during the addition of the boron tribromide and was then allowed to rise to ambient temperature. The mixture was stirred for 2 hours at ambient temperature, and then partitioned between dichloromethane and water. The mixture was extracted into dichloromethane and the combined organic extracts washed with water and brine, dried and evaporated. The residue was purified by column chromatography using a 1:1 mixture of ethyl acetate and hexane as eluent. There was thus obtained 4-bromo-4-[5-fluoro-3-(l-methyl-2-oxo-l,2,3, -tetrahydroquinolin-6- ylthio)phenyl]tetrahydropyran (0.49 g, 87%), m.p. 124-126°C. NMR Spectrum (in D6-DMS0) 2.1 (m, 2H); 2.35-2.60 (m, 4H); 2.9 (m, 2H) ; 3.27 (s, 3H); 3.8 (m, 4H); 6.78 (m, IH); 7.15-7.50 (m, 5H).
The 4-[5-fluoro-3-(l-methyl-2-oxo-l,2,3,4-tetrahydro- quinolin-6-ylthio)phenyl]-4-methoxytetrahydropyran used as starting material was obtained as follows:- n-Butyl-lithium (1.4M in hexane, 1.5 ml) was added dropwise to a stirred mixture of 6-mercapto-1-methyl-1,2,3,4-tetrahydro- quinolin-2-one (0.386 g), 4-(3,5-difluorophenyl)-4-methoxytetrahydro- pyran (European Patent Application No. 0462813, Example 5 thereof; 0.547 g) and NMP (6 ml) which had been cooled to 0°C. The mixture was stirred at 0°C for 5 minutes and then heated to 145°C for 2.2 hours with the concomitant distillation of the hexane. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic phase was washed with water, with a 0.5N sodium hydroxide solution and with brine, dried (MgSO,) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of dichloromethane and diethyl ether as eluent. The oil so obtained was triturated under diethyl ether. There was thus obtained
4-[5-fluoro-3-(l-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6- ylthio)phenyl]-4-methoxytetrahydropyran (0.404 g, 50%), m.p. 124-125°C;
NMR Spectrum 1.8-2.1 (m, 4H); 2.55-3.0 (m, 4H); 2.99 (s, 3H); 3.38 (s, 3H); 3.7-4.0 (m, 4H); 6.7-7.15 (m, 4H); 7.2-7.5 (m, 2H).
The 6-mercapto-1-methyl-1,2,3,4-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-1-methyl-1,2,3,4-tetrahydro- quinolin-2-one as a solid (35.5 g, 92%) which was used without further purification.
Example 4
Boron trichloride (1M in dichloromethane, 1.2 ml) was added dropwise to a stirred, ice-cooled solution of (2S,4R)-4-hydroxy-2-methyl-4-[3-(l-methyl-2-oxo-l,2,3,4- tetrahydroquinolin-6-ylthio)phenyl]tetrahydropyran (0.15 g) in dichloromethane (1 ml). The temperature of the mixture was allowed to rise to ambient temperature and stirred for 2 hours at ambient temperature. The reaction was quenched with water (20 ml) and extracted with dichloromethane. The organic extract was dried, evaporated and the residue purified by column chromatography using increasingly polar mixtures of ethyl acetate and hexane as eluent. There was thus obtained
(2S,4R)-4-chloro-2-methyl-4-[3-(l-methyl-2-oxo-1,2,3,4-tetrahydro- quinolin-6-ylthio)phenyl]tetrahydropyran (0.13 g, 83%) as a colourless gum.
NMR Spectrum 1.25 (d, 3H); 1.80 (m, IH); 2.16 (m, 2H); 2.27 (m, IH); 2.66 (m, 2H); 2.88 (m, 2H); 3.36 (s, 3H); 4.0-4.15 (m, 3H); 6.95 (d, IH); 7.13 (m, IH); 7.2-7.4 (m, 4H); 7.50 (m, IH) .
The (2S,4R)-4-hydroxy-2-methyl-4-[3-(l-methyl-2-oxo-1,2,3,4- tetrahydroquinolin-6-ylthio)phenyl]tetrahydropyran used as starting material was obtained as follows:-
A mixture of 6-mercapto-1-methyl-1,2,3,4-tetrahydroquinolin- 2-one (0.23 g), (2S,4R)-4-hydroxy-4-(3-iodophenyl)-2-methyltetrahydro- pyran (0.35 g), potassium carbonate (0.2 g), cuprous chloride (0.05 g) and DMF (3 ml) was stirred and heated to 120°C for 2 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic phase was 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 (2S,4R)-4-hydroxy-2-methyl-4-[3-(l-methyl-2- oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)phenyl]tetrahydropyran (0.33 g), m.p. 135-137°C (recrystallised from a mixture of hexane and ethyl acetate) .
NMR Spectrum: 1.21 (d, 3H); 1.55-1.8 (m, 4H); 2.1 (m, IH); 2.66 (m, 2H); 2.86 (m, 2H); 3.35 (s, 3H); 3.85-4.05 (m, 3H); 6.93 (d, IH) ; 7.13 (m, IH); 7.2-7.4 (m, 4H); 7.47 (m, IH).
The (2S,4R)-4-hydroxy-4-(3-iodophenyl)-2-methyltetrahydro- pyran used as a starting material was obtained as follows:- n-Butyl-lithium (1.5M in hexane, 40 ml) was added dropwise to a stirred solution of 1,3-diiodobenzene (19.8 g) in THF (200 ml) which had been cooled to -70°C. The mixture was stirred at -70°C for 12 minutes. (2S)-2-Methyltetrahydropyran-4-one (5.7 g) was added. The mixture was stirred, allowed to warm to ambient temperature and stirred at ambient temperature 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 brine, dried (Na~S0,) and evaporated. A solution of the residue in diethyl ether (50 ml) was added to concentrated sulphuric acid (35%, 200 ml) which had been cooled to 0°C. The mixture was stirred and allowed to warm to ambient temperature. The mixture was stirred at ambient temperature for 3 hours. The mixture was poured onto crushed ice and extracted with diethyl ether. The organic phase was washed with water, with a saturated aqueous sodium bicarbonate solution 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 (2S,4R)-4-hydroxy-4-(3-iodophenyl)-2-methyltetrahydropyran (12 g, 75%).
Example 5
Diethylaminosulphur trifluoride (0.07 ml) was added dropwise to a stirred, ice-cooled solution of (2S,4R)-4-hydroxy-2-methyl-4-[3-(l-methyl-2-oxo-1,2,3,4-tetrahydro- quinolin-6-ylthio)phenyl]tetrahydropyran (0.1 g) in dichloromethane (1 ml). The mixture was stirred at 0°C for 1 hour then quenched with water (20 ml) and extracted with dichloromethane. The organic extract was dried, evaporated and the residue purified by column chromatography using increasingly polar mixtures of ethyl acetate and dichloromethane as eluent. There was thus obtained (2S,4RS)-4-fluoro-2-methyl-4-[3-(l-methyl-2-oxo-1,2,3,4-tetrahydro- quinolin-6-ylthio)phenyl]tetrahydropyran (0.07 g, 70%) as a yellow gum.
NMR Spectrum 1.2 (d, 1.5H); 1.25 (d, 1.5H); 1.6-2.15 (m, 3H) ; 2.3 (m, IH); 2.65 (m, 2H); 2.88 (m, 2H); 3.35 (s, 3H); 3.4 (m, 0.5H); 3.55 (m, 0.5H); 3.85-4.1 (m, 2H) ; 6.95 (m, IH); 7.1-7.4 (m, 6H).
Example 6
A solution of a mixture of (2S)-2-methyl-4-[5-fluoro-3-(l-methyl-2-oxo-1,2,3, -tetrahydro- quinolin-6-ylthio)phenyl]-2H-5,6-dihydropyran and (2S)-2-methyl-4-[5-fluoro-3-(l-methyl-2-oxo-l,2,3, -tetrahydro- quinolin-6-ylthio)phenyl]-6H-2,3-dihydropyran (0.2 g) in 45% hydrogen bromide in glacial acetic acid (3 ml) was stirred at ambient temperature for 1 hour. The solution was diluted with water and the mixture extracted with ethyl acetate. The extract was washed successively with aqueous sodium bicarbonate and brine, dried and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of ethyl acetate and hexane. There was thus obtained (2S,4R)-4-bromo-2-methyl-4-[5-fluoro-3-(l-methyl-2- oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)phenyl]tetrahydropyran (0.13 g, 54%) as a colourless gum.
NMR Spectrum 1.26 (d, 3H) ; 1.64 (m, IH); 1.98 (m, IH); 2.32 (m, IH); 2.42 (m, IH); 2.66 (m, 2H); 2.88 (m, 2H) ; 3.35 (s, 3H) ; 4.0-4.15 (m, 3H), 6.7 (m, IH); 6.98-7.03 (m, 2H); 7.22 (m, IH); 7.29 (m, IH); 7.38 (m, IH).
The mixture of dihydropyrans used as starting material may be obtained as follows:-
A mixture of (2S,4R)-4-methoxy-2-methyl-4-[5-fluoro-3-(1- methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)phenyl]tetrahydro- pyran (3.2 g), diethyl ether (40 ml) and a 1:1 mixture of concentrated sulphuric acid and water (200 ml) was stirred at ambient temperature for 24 hours and then poured onto ice. The mixture was extracted with ethyl acetate and the extract washed successively with water, aqueous sodium bicarbonate and brine. The extract was dried, evaporated and the residue recrystallised from methanol to give a mixture of (2S)-2-methyl-4-[5-fluoro-3-(l-methyl-2-oxo-l,2,3, -tetrahydro- quinolin-6-ylthio)phenyl]-2H-5,6-dihydropyran and (2S)-2-methyl-4-[5-fluoro-3-(l-methyl-2-oxo-l,2,3,4-tetrahydro- quinolin-6-ylthio)phenyl]-6H-2,3-dihydropyran (1.6 g, 54%) as a fawn solid which was used without further purification.
The (2S,4R)-4-[5-fluoro-3-(l-methyl-2-oxo-l,2,3,4- tetrahydroquinolin-6-ylthio)phenyl]-4-methoxy-2-methyltetrahydropyran used as starting material was obtained as follows:-
A mixture of 6-mercapto-l-methyl-l,2,3,4-tetrahydroquinolin- 2-one (0.247 g) , (2S,4R)-4-(3,5-difluorophenyl)-4-methoxy-2-methyl- tetrahydropyran (European Patent Application No. 0462813, Example 10 thereof; 0.31 g), lithium hydroxide monohydrate (0.056 g), di-(2-methoxyethyl) ether (1 ml) and NMP (4 ml) was stirred and heated to 140°C for 2 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic phase was washed with water, with IN aqueous hydrochloric acid and with brine, dried (MgSO.) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of dichloromethane and diethyl ether as eluent. The oil so obtained was triturated under diethyl ether. There was thus obtained (2S,4R)-4-[5-fluoro-3-(l-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6- ylthio)phenyl]-4-methoxy-2-methyltetrahydropyran (0.135 g, 25%), m.p. 137-139°C;
NMR Spectrum 1.8 (d, 3H); 1.4-2.2 (m, 4H); 2.50-2.96 (m, 4H); 2.98 (s, 3H); 3.37 (s, 3H); 3.65-4.15 (m, 3H); 6.65-7.50 (m, 6H).
Example 7
A solution of hydroxylamine hydrochloride (0.2 g) in water (0.5 ml) was added to a solution of 4-formyl-4-[3-(2-naphthylmethoxy)phenyl]tetrahydropyran (0.5 g) in a mixture of ethanol (5 ml) and THF (3 ml). Aqueous sodium acetate was added to give a pH of approximately 4, and the mixture stirred for 2 hours. The reaction mixture was quenched with water (20 ml) and extracted with diethyl ether (2 x 20 ml). The combined organic extracts were dried, evaporated and the residue recrystallised from ethanol to give 4-(hydoxyiminomethyl)-4-[3-(2-naphthylmethoxy)- phenyl]tetrahydropyran (0.3 g) , m.p. 159-161°C.
NMR Spectrum (in D6-DMS0) 2.05 (m, 4H) ; 3.7 (m, 4H) ; 5.25 (s, 2H); 7.0 (m, 3H); 7.3 (m, 2H); 7.6 (m, 3H); 8.0 (m, 4H) ; 10.7 (s, IH).
The 4-formyl-4-[3-(2-naphthylmethoxy)phenyl]tetrahydropyran used as starting material was obtained as follows:-
To a solution of 4-hydroxymethyl-4-[3-(2-naphthylmethoxy)- phenyl]tetrahydropyran (1.2 g) in dichloromethane (15 ml) was added pyridinium chlorochromate (1.1 g) and silica (2 g) . The mixture was stirred for 1 hour and then diethyl ether (60 ml) added. The solution was filtered through a silica pad and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of ethyl acetate and hexane as eluent to give 4-formyl-4-[3-(2-naphthyl¬ methoxy)phenyl]tetrahydropyran (0.9 g) as a white solid. NMR Spectrum 2.0 (m, 3H); 2.3 (m, 2H) ; 3.55 (m, 2H) ; 5.2 (s, 2H); 6.9 (m, 3H); 7.3 (m, IH); 7.5 (m, 3H); 7.8 (m, 4H) ; 9.4 (s, IH).
The 4-hydroxymethyl-4-[3-(2-naphthylmethoxy)phenyl]- tetrahydropyran used as starting material was obtained as follows:-
To a solution of 4-ethoxycarbonyl-4-[3-(2-naphthylmethoxy)- phenyl]tetrahydropyran (1.6 g) in THF (15 ml) was added a solution of lithium aluminium hydride (1 M in THF, 2.5 ml). After 2 hours the mixture was treated with a saturated aqueous solution of ammonium chloride. The THF solution was decanted, dried and evaporated to give 4-hydroxymethyl-4-[3-(2-naphthylmethoxy)phenyl]tetrahydropyran (1.3 g) as a white solid.
NMR Spectrum 1.9 (m, 2H), 2.1 (m, 2H); 3.55 (m, 4H); 3.8 (m, 2H); 5.2 (s, 2H); 7.0 (m, 3H); 7.3 (t, IH); 7.5 (m, 3H); 7.85 (m, 4H).
The 4-ethoxycarbonyl-4-[3-(2-naphthylmethoxy)phenyl]- tetrahydropyran used as starting material was obtained as follows:-
To a solution of ethyl 3-(2-naphthylmethoxy)phenylacetate (3.2 g) in NMP (30 ml) was added 2,2'-dibromodiethyl ether (2.35 g) and then, in portions, sodium hydride (0.95 g, 60% dispersion). The reaction mixture was stirred for 2 hours and then quenched with water (120 ml). The reaction mixture was extracted with diethyl ether (2 x 50 ml) and the combined extracts washed with water, dried and evaporated. The residue was purified by column chromatography using an increasingly polar mixture of ethyl acetate and hexane as the eluent to give 4-ethoxycarbonyl-4-[3-(2-naphthylmethoxy)phenyl]- tetrahydropyran as a white solid (1.7 g).
NMR Spectrum 1.2 (t, 3H); 2.0 (m, 2H) ; 2.5 (m, 2H); 3.55 ( , 2H); 3.9 (m, 2H); 4.1 (q, 2H) ; 5.2 (s, 2H); 7.0 (m, 3H) ; 7.25 (t, IH); 7.5 (m, 3H); 7.9 (m, 4H).
The ethyl 3-(2-naphthylmethoxy)phenylacetate used as starting material was obtained as follows:-
To a solution of ethyl 3-hydroxyphenylacetate (30 g) in DMF (150 ml) was added 2-bromomethylnaphthalene (35 g) and potassium carbonate (25 g). The mixture was stirred at ambient temperature for 18 hours. The reaction mixture was quenched with water (600 ml) and extracted with diethyl ether (2 x 200 ml). The combined organic extracts were washed with water, dried and evaporated to give ethyl 3-(2-naphthylmethoxy)phenylacetate as a white solid (42 g). NMR Spectrum in (D6-DMS0) 1.2 (t, 3H); 3.6 (s, 2H); 4.05 (q, 2H); 5.25 (s, 2H); 6.9 (m, 3H) ; 7.25 (t, IH); 7.55 (m, 3H); 7.9 (m, 4H).
Example 8
Sodium hydride (0.042 g, 60% dispersion) was added to a solution of 4-(hydroxyiminomethyl)-4-[3-(2-naphthylmethoxy)phenyl]- tetrahydropyran (0.18 g) in NMP. After 2 hours iodomethane (0.35 g) was added and the mixture stirred for 16 hours. The reaction mixture was quenched with water (10 ml) and extracted with diethyl ether (2 x 10 ml). The combined organic extracts were dried and evaporated and the residue purified by column chromatography using an increasingly polar mixture of ethyl acetate and hexane as the eluent to give 4-(methoxyiminomethyl)-4-[3-(2-naphthylmethoxy)phenyl]tetrahydropyran as a gum (0.08 g).
NMR Spectrum 2.1 (m, 4H); 3.8 (m, 4H); 3.85 (s, 3H); 5.2 (s, 2H); 6.95 (m, 3H); 7.25 (m, 2H); 7.5 (m, 3H); 7.85 (m, 4H). Example 9
Sodium hydride (0.09 g, 60% dispersion) was added to a solution of diethyl cyanomethylphosphonate (0.35 g) in THF (5 ml). After evolution of hydrogen had ceased
4-formyl-4-[3-(2-naphthylmethoxy)phenyl]tetrahydropyran (0.5 g) was added and the mixture stirred at ambient temperature for 3 hours. The reaction mixture was quenched with water and extracted with diethyl ether. The organic extracts were dried and evaporated and the residue purified by medium pressure liquid chromatography using an increasingly polar mixture of ethyl acetate in hexane as eluent. The appropriate fraction was evaporated and triturated with diethyl ether. There was thus obtained ( E)-4-(2-cyanovinyl)-4-[3-
(2-naphthylmethoxy)phenyl[tetrahydropyran as a white solid (0.16 g), m.p. 88-90°C.
NMR Spectrum 2.0 (m, 2H); 2.2 (m, 2H) ; 3.7 (m, 4H) ; 5.1 (d, IH); 5.2 (s, 2H); 6.7 (d, IH); 6.9 (m, 3H); 7.3 (t, IH); 7.5 (m, 3H) ; 7.85 ( , 4H).
Example 10
Potassium carbonate (0.132 g) and 6-bromomethyl-l-methyl- l,2-dihydroquinolin-2-one (0.25 g) were added to a solution of 4-(2-cyanovinyl)-4-[3-hydroxyphenyl]tetrahydropyran (0.22 g) in NMP (2 ml) and the mixture stirred at ambient temperature for 6 hours. The reaction mixture was quenched with water (10 ml) and extracted with ethyl acetate (2 x 7 ml). The combined organic extracts were dried, evaporated and the reaction purified by column chromatography using increasingly polar mixtures of ethyl acetate and hexane as eluent. The appropriate fractions were evaporated to give (E)-4-(2-cyanovinyl)-4-[3-(1-methyl-
2-oxo-l,2-dihydroquinolin-6-ylmethoxy)phenyl]tetrahydropyran as a gum (0.27 g).
NMR Spectrum 2.0 (m, 2H); 2.2 (m, 2H); 3.7 (m, 7H) ; 5.1 (d, IH) ; 5.15 (s, 2H); 6.75 (d, IH); 6.9 (m, 4H); 7.35 (m, 2H) ; 7.7 (m, 3H).
The 4-(2-cyanovinyl)-4-(3-hydroxyphenyl)tetrahydropyran used as starting material was obtained as follows:-
To a solution of diethyl cyanomethylphosphonate (1.3 g) in THF (10 ml) was added, in portions, sodium hydride (0.3 g, 60% dispersion). After evolution of hydrogen had ceased a solution of 4-formyl-4-(3-hydroxyphenyl)tetrahydropyran (0.6 g) in THF (5 ml) was added and the mixture stirred at ambient temperature for 2 hours. The reaction mixture was quenched with water (5 ml), the pH adjusted to approximately 7 and the organic extracts separated, dried and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of ethyl acetate and hexane as eluent. The appropriate fractions were evaporated to give (Jl)-4-(2-cyanovinyl)-4-(3-hydroxyphenyl)tetrahydropyran as a gum (0.4 g)*
NMR Spectrum 2.0 (m, 2H); 2.2 (m, 2H) ; 3.7 (m, 4H); 5.1 (d, IH); 6.1
(s, IH); 6.8 (m, 4H); 7.2 (m, IH).
The 4-formyl-4-(3-hydroxyphenyl)tetrahydropyran used as starting material was obtained as follows:-
To a solution of 4-hydroxymethyl-4-[3-(benzyloxy)phenyl]tetrahydropyran (2.5 g) in ethanol (30 ml) was added palladium/carbon catalyst (0.5 g, 10%) and concentrated hydrochloric acid (3 drops). The mixture was hydrogenated under atmospheric pressure until the appropriate quantity of hydrogen had been absorbed. The mixture was filtered and evaporated. The residue was dissolved in a mixture of dichloromethane (20 ml) and acetonitrile (20 ml) treated with silica (2.4 g) and pyridinium chlorochromate (3.6 g) . After stirring for 18 hours at ambient temperature diethyl ether (100 ml) was added and the total mixture filtered through silica. The filtrate was evaporated and the residue purified by column chromatography using increasingly polar mixtures of ethyl acetate and hexane as eluent. The appropriate fractions were evaporated to give 4-formyl-4-(3-hydroxyphenyl)tetra- , hydropyran as a white solid (0.6 g).
NMR Spectrum 2.1 (m, 2H); 2.4 (m, 2H) ; 3.6 (m, 2H); 3.9 (m, 2H) ; 5.6 (s, IH); 6.8 (m, 3H); 7.3 (m, IH); 9.4 (s, IH).
The 4-hydroxymethyl-4-[3-(benzyloxy)phenyl]- tetrahydropyran used as starting material was obtained as follows:-
To a solution of 4-ethoxycarbonyl-4-[3-(benzyloxy)phenyl] etrahydropyran (3.6 g) in THF (40 ml) was added a solution of lithium aluminium hydride (1 M in THF, 6.6 ml). After 2 hours the mixture was treated with a saturated aqueous solution of ammonium chloride. The THF solution was decanted, dried and evaporated to give 4-hydroxymethyl-4-[3-(benzyloxy)phenyl]- tetrahydropyran as a white solid (2.7 g).
NMR Spectrum (in D6-DMS0) 1.9 (m, 4H); 3.3 (m, 4H); 3.65 (m, 2H); 5.1 (s, 2H); 6.9 (m, 3H) ; 7.4 (m, 6H).
The 4-ethoxycarbonyl-4-[3-(benzyloxy)phenyl]tetrahydropyran used as starting material was obtained as follows:-
To a solution of ethyl 3-hydroxyphenylacetate (25 g) in DMF (100 ml) was added potassium carbonate (19 g) and benzyl bromide (24 g) and the mixture stirred at ambient temperature for 18 hours. The reaction mixture was quenched with water (400 ml) and extracted with diethyl ether (2 x 300 ml). The combined organic extracts were dried and evaporated to give a clear oil (35 g) which was used without further purification. To the oil (6.8 g) in DMF (90 ml) was added 2,2'-dibromodiethyl ether (7 g) and then, in portions, sodium hydride (3 g, 60% dispersion). After stirring for 4 hours the reaction mixture was quenched with water (400 ml) and extracted with diethyl ether. The organic extracts were dried, evaporated and the residue purified by column chromatography using increasingly polar mixtures of ethyl acetate and hexane as eluent. The appropriate fractions were evaporated to give 4-ethoxycarbonyl-4-[3-(benzyloxy)phenyl]tetrahydro¬ pyran as a white solid (3.7 g).
NMR Spectrum (in D6-DMS0) 1.2 (t, 3H); 1.9 (m, 2H); 2.4 (d, 2H); 3.4 (t, 2H); 3.7 (m, 2H); 4.1 (m, 2H) ; 5.1 (s, 2H); 6.95 (m, 3H); 7.4 (m, 6H).
Example 11 n-Butyl-lithium (1.6 M in hexane, 2.7 ml) was added to a solution of chloromethyltriphenylphosphonium chloride (1.4 g) in THF (13 ml). After the addition the mixture was stirred for 15 minutes and then a solution of 4-formyl-4-[3-(2-naphthylmethoxy)phenyl]tetra¬ hydropyran (1 g) in THF (4 ml) was added. After 2 hours the mixture was purified by medium pressure liquid chromatography using increasingly polar mixtures of ethyl acetate and hexane as eluent. There were thus obtained in turn
(E)-4-(2-chlorovinyl)-4-[3-(2-naphthylmethoxy)phenyl]tetrahydropyran
(0.09 g) as a gum and
(Z)-4-(2-chlorovinyl)-4-[3-(2-naphthylmethoxy)phenyl]tetrahydropyran
(0.09 g).
NMR Spectrum 1.95 (m, 2H); 2.15 (m, 2H); 3.75 (m, 4H); 5.2 (s, 2H);
5.75 (d, IH); 6.0 (d, IH); 6.9 (m, 3H); 7.3 (t, IH); 7.5 (m, 3H); 7.9
(m, 4H).
Example 12
To a solution of 4-bromo-4-[5-fluoro-3-(4-methyl-3-oxo-2,3- dihydro-4H-l,4-benzoxazin-7-ylthio)phenyl]tetrahydropyran (0.15 g) in dichloromethane (5 ml) was added 3-chloroperbenzoic acid (0.327 g, 55%) and the mixture stirred overnight at ambient temperature. The reaction mixture was partitioned between water and dichloromethane and extracted with 3 aliquots of dichloromethane. The combined organic extracts were washed with water and brine, dried and evaporated. The residue was purified by column chromatography using a 3:5 mixture of ethyl acetate and hexane as eluent. The appropriate fractions were evaporated to give
4-bromo-4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-7- ylsulphonyl)phenyl]tetrahydropyran as a white crystalline solid (0.138 g, 86%), m.p. 176-177°C.
NMR Spectrum 2.15 (m, 2H); 2.4 (m, 2H); 3.38 (s, 3H) ; 4.0 (m, 4H); 4.68 (s, 2H); 7.07 (d, IH); 7.45 (m, IH); 7.5 (m, 2H); 7.66 (m, IH) ; 7.9 (m, IH).
Example 13
3-Chloroperbenzoic acid (0.242 g, 55%) was added to a solution of 4-chloro-4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-l,4- benzoxazin-7-ylthio)phenyl]tetrahydropyran (0.10 g) in dichloromethane (5 ml) and the mixture stirred overnight at ambient temperature. The reaction mixture was partitioned between water and dichloromethane and extracted with 3 aliquots of dichloromethane. The combined organic extracts were washed with water and brine, dried and evaporated. The residue was purified by column chromatography using a 1:2 mixture of ethyl acetate and isohexane as eluent. The appropriate fractions were evaporated and triturated with diethyl ether to give 4-chloro-4-[5- fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-ylsulphonyl)- phenyl]tetrahydropyran as a white crystalline solid (0.10 g, 93%), m.p. 162-164°C.
NMR Spectrum 2.10-2.35 (m, 4H); 3.38 (s, 3H); 3.92-4.10 (m, 4H); 4.68 (s, 2H); 7.09 (d, IH); 7.42-7.58 (m, 3H); 7.66 (m, IH); 7.90 (m, IH) .
The 4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-1,4- benzoxazin-7-ylthio)phenyl]-4-chlorotetrahydropyran used as starting material was obtained as described in Example 2.
Example 14
Potassium peroxymonosulphate (0.290 g) was added to a solution of
4-bromo-4-[5-fluoro-3-(l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6- ylthio)phenyl]tetrahydropyran (0.145 g) in a mixture of ethanol (15 ml) and water (6 ml) and the mixture stirred at ambient temperature. The reaction mixture was quenched with water (50 ml) and extracted with dichloromethane (3 x 25 ml). The combined organic extracts were dried, evaporated and the residue purified by column chromatography using a 3:5 mixture of ethyl acetate and hexane as eluent. There was thus obtained 4-bromo-4-[5-fluoro-3-(l-methyl-2-oxo-l,2,3,4- tetrahydroquinolin-6-ylsulphonyl)phenyl]tetrahydropyran as a gum (0.05 g, 32%).
NMR Spectrum (in D6-DMS0) 2.05-2.25 (m, 2H); 2.45-2.65 (m, 4H) ; 2.90-3.05 (m, 2H) ; 3.25 (s, 3H); 3.70-3.95 (m, 4H); 7.30 (d, IH); 7.75-8.00 (m, 5H) .
Example 15
Potassium peroxymonosulphate (0.18 g) was added to a solution of (2S,4R)-4-chloro-2-methyl-4-[3-(l-methyl-2-oxo-l,2,3,4- tetrahydroquinolin-6-ylthio)phenyl]tetrahydropyran (0.06 g) in a mixture of ethanol (1 ml) and water (1 ml) and the mixture stirred at ambient temperature for 18 hours. The mixture was partitioned between ethyl acetate and water, and the organic phase dried and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of ethyl acetate and dichloromethane as eluent. There was thus obtained
(2S, R)-4-chloro-2-methyl-4-[3-(l-methyl-2-oxo-l,2,3,4-tetrahydro- quinolin-6-ylsulphonyl)phenyl]tetrahydropyran as a foam (0.02 g, 31%). NMR Spectrum 1.27 (d, 3H); 1.85 (m, IH); 2.15-2.4 (m, 3H); 2.67 (m, 2H); 2.98 (m, 2H); 3.36 (s, 3H); 4.0-4.15 (m, 3H); 7.05 (d, IH); 7.54 (m, IH); 7.7-7.9 (m, 4H); 8.12 (m, IH).
Example 16
The following illustrate representative pharmaceutical dosage forms containing the compound of formula I, or a pharmaceutically-acceptable salt thereof (hereafter compound X), for therapeutic or prophylactic use in humans:
(a) Tablet I mg/tablet
Compound X 100
Lactose Ph.Eur 182.75
Croscarmellose sodium 12.0
Maize starch paste (5% w/v paste) 2.25
Magnesium stearate 3.0
(b) Tablet II mg/tablet
Compound X 50
Lactose Ph.Eur 223.75
Croscarmellose sodium 6.0
Maize starch 15.0
Polyvinylpyrrolidone (5% w/v paste) 2.25
Magnesium stearate 3.0
(c) Tablet III mg/tablet
Compound X 1.0
Lactose Ph.Eur 93.25
Croscarmellose sodium 4.0
Maize starch paste (5% w/v paste) 0.75
Magnesium stearate 1.0 (d) Capsule mg/capsule
Compound X 10
Lactose Ph.Eur 488.5
Magnesium stearate 1.5
(e) Injection I (50 mg/ml)
Compound X 5.0% w/v
IM Sodium hydroxide solution 15.0% v/v
0.1M Hydrochloric acid
(to adjust pH to 7.6)
Polyethylene glycol 400 4.5% w/v
Water for injection to 100%
(f) Injection II (10 mg/ml)
Compound X 1.0% w/v
Sodium phosphate BP 3.6% w/v
0.IM Sodium hydroxide solution 15.0% v/v
Water for injection to 100%
(g) Injection III (lmg/ml,buffered to pH6)
Compound X 0.1% w/v
Sodium phosphate BP 2.26% w/v
Citric acid 0.38% w/v
Polyethylene glycol 400 3.5% w/v
Water for injection to 100%
(h) Aerosol I mg/ml
Compound X 10.0
Sorbitan trioleate 13.5
Trichlorofluoromethane 910.0
Dichlorodifluoromethane 490.0 (i) Aerosol II mg/ml
Compound X 0.2
Sorbitan trioleate 0.27
Trichlorofluoromethane 70.0
Dichlorodifluoromethane 280.0
Dichlorotetrafluoroethane 1094.0
(j) Aerosol III mg/ml
Compound X 2.5
Sorbitan trioleate 3.38
Trichlorofluoromethane 67.5
Dichlorodifluoromethane 1086.0
Dichlorotetrafluoroethane 191.6
(k) Aerosol IV mg/ml
Compound X 2.5
Soya lecithin 2.7
Trichlorofluoromethane 67.5
Dichlorodifluoromethane 1086.0
Dichlorotetrafluoroethane 191.6
Note
The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. The tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate. The aerosol formulations (h)-(k) may be used in conjunction with standard, metered dose aerosol dispensers, and the suspending agents sorbitan trioleate and soya lecithin may be replaced by an alternative suspending agent such as sorbitan monooleate, sorbitan sesquioleate, polysorbate 80, polyglycerol oleate or oleic acid. CHEMICAL FORMULAE
1 1 1 2 2
Ar -A -X -Ar -C-R
RJ
1 2 2
H-X -Ar -C-R II
R-
1 1 1 2 2
Ar -A -X -Ar -C=R III
R*
CHO
1 1 1 2 2
Ar -A -X -Ar -C-R^ IV
R1 CHEMICAL FORMULAE CONT'D
T-CH- -P+(Ph).
(R30)2- P -CH2-T VI

Claims

1. A cyclic ether derivative of the formula I
1 1 1 2 2 Ar -A -X -Ar -C-R
R-
wherein Ar is phenyl or naphthyl, or a 9- or 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-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (2-4C)alkanoyl, (2-4C)alkanoylamino, N-(1-4C)alkyl-(2-4C)alkanoylamino, hydroxyimino-(l-4C)alkyl, (l-4C)alkoxyimino-(l-4C)alkyl, (2-5C)alkanoyloxyimino-(l-4C)alkyl, cyano-(l-4C)alkoxyimino-(l-4C)alkyl, hydroxyamino-(l-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-(1-4C)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 one or two substituents selected from halogeno, (l-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;
Ar is phenylene, pyridinediyl, pyrimidinediyl, thiophendiyl, furandiyl, thiazolediyl, oxazolediyl, thiadiazolediyl or oxadiazolediyl which may optionally bear one or two substituents selected from halogeno, cyano, trifluoromethyl, hydroxy, amino,
(1-4C)alkyl, (l-4C)alkoxy, (1-4C)alkylamino and di-(l-4C)alkylamino;
1 2 2 2 3
R and R together form a group of the formula -A -X -A - which,
2 3 together with the carbon atom to which both A and A are attached, define a ring having 5 or 6 ring atoms wherein:
2 A is (l-3C)alkylene;
2 X is oxy, thio, sulphinyl or sulphonyl; and
3 A is (l-3C)alkylene; and which ring may bear one, two or three substituents, which may be the same or different and may be optionally geminally disubstituted, selected from hydroxy, (l-4C)alkyl, (l-4C)alkoxy and fluoro-(1-4C)alkyl, or which ring may bear a (l-4C)alkylenedioxy substituent; and
Y is halogeno, vinyl, 2-cyanovinyl, 2-halogenovinyl, hydroxyimino-(l-4C)alkyl, (l-4C)alkoxyimino-(l-4C)alkyl or
(2-5C)alkanoyloxyimino-(l-4C)alkyl; or a pharmaceutically-acceptable salt thereof.
2. A cyclic 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-1,2,3,4-tetrahydroquinolin-6-yl or
3-oxo-2,3-dihydro-4H-l,4-benzoxazin-7-yl which may optionally bear one or two substituents selected from fluoro, chloro, methyl and ethyl, or Ar is 2-oxoindolin-5-yl which may optionally bear one or two substituents selected from fluoro, chloro, methyl and ethyl;
A 1 is a direct link to X1 and X1 is thio or sulphonyl, or A1 is methylene and X is oxy;
Ar 2 is 1,3-phenylene, 5-fluoro-l,3-phenylene or 2,5-thiophenediyl, or Ar2 is 2,4-thiophenediyl or 2,5-thiazolediyl (each with the group of the formula -A -X - in the 2-position); 1 2 2 2 3
R and R together form a group of the formula -A -X -A - which, togethe
2 3 with the carbon atom to which both A and A are attached, define a ring having 6 ring atoms wherein:
2 A is ethylene;
Figure imgf000055_0001
; and which ring may bear one substituent selected from methyl or ethyl; and
Y is fluoro, chloro, bromo, 2-cyanovinyl, 2-chlorovinyl, hydroxyiminomethyl or methoxyiminomethyl; or a pharmaceutically-acceptable salt thereof.
3. A cyclic 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-1,2,3,4-tetrahydroquinolin-6-yl or
3-oxo-2,3-dihydro-4H-l,4-benzoxazin-7-yl which may optionally bear one or two substituents selected from fluoro, chloro, methyl and ethyl, or Ar is 2-oxoindolin-5-yl which may optionally bear one or two substituents selected from fluoro, chloro, methyl and ethyl;
A is a direct link to X and X is thio or sulphonyl, or A is methylene and X is oxy;
Ar 2 is 1,3-phenylene, 5-fluoro-1,3-phenylene or 2,5-thiophenediyl, or Ar2 is 2,4-thiophenediyl or 2,5-thiazolediyl (each with the group of the formula -A -X - in the 2-position);
1 2 2 2 3
R and R together form a group of the formula -A -X -A - which, together
2 3 with the carbon atom to which both A and A are attached, define a ring having 6 ring atoms wherein:
2 A is ethylene;
X is oxy; and
3 A is ethylene; and which ring may bear one substituent selected from methyl or ethyl; and
Y is 2-cyanovinyl, 2-chlorovinyl, hydroxyiminomethyl or methoxyiminomethyl; or a pharmaceutically-acceptable salt thereof.
4. A cyclic 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 which bears at the 1-position a methyl or ethyl substituent;
A is methylene and X is oxy;
2 Ar is 1,3-phenylene or 5-fluoro-l,3-phenylene;
1 2 2 2 3
R and R together form a group of the formula -A -X -A - which, together
2 3 with the carbon atom to which both A and A are attached, define a ring having 6 ring atoms wherein:
2 A is ethylene;
X is oxy; and
3 A is ethylene; and which ring may bear one substituent selected from methyl or ethyl; and
Y is 2-cyanovinyl, 2-chlorovinyl, hydroxyiminomethyl or methoxyiminomethyl; or a pharmaceutically-acceptable salt thereof.
5. A cyclic ether derivative of the formula I as claimed in claim 1 wherein Ar is
2-oxo-1,2,3, -tetrahydroquinolin-6-yl or
3-oxo-2,3-dihydro-4H-l,4-benzoxazin-7-yl which bears one substituent selected from methyl and ethyl;
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;
1 2 2 2 3
R and R together form a group of the formula -A -X -A - which, together
2 3 with the carbon atom to which both A and A are attached, define a ring having 6 ring atoms wherein:
2 A is ethylene;
X is oxy; and
3 A is ethylene; and which ring may bear one substituent selected from methyl or ethyl; and
Y is fluoro, chloro or bromo; or a pharmaceutically-acceptable salt thereof.
6. A cyclic ether derivative of the formula I as claimed in claim 1 wherein Ar is
2-oxo-l,2,3,4-tetrahydroquinolin-6-yl which bears at the 1-position a methyl or ethyl substituent, or Ar is
3-oxo-2,3-dihydro-4H-l,4-benzoxazin-7-yl which bears at the 4-position a methyl or ethyl substituent;
A is a direct link to X and X is thio or sulphonyl;
2 Ar is 1,3-phenylene or 5-fluoro-1,3-phenylene;
1 2 2 2 3
R and R together form a group of the formula -A -X -A - which, together with the carbon atom to which both A 2 and A3 are attached, define a ring having 6 ring atoms wherein;
2 A is ethylene;
X is oxy; and
3 A is ethylene; and which ring may bear one substituent selected from methyl or ethyl; and
Y is fluoro, chloro or bromo; or a pharmaceutically-acceptable salt thereof.
7. A cyclic ether derivative of the formula I, as claimed in claim 1, selected from:-
4-bromo-4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7- ylthio)phenyl]tetrahydropyran,
4-chloro-4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-7- ylthio)phenyl]tetrahydropyran,
4-bromo-4-[5-fluoro-3-(l-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6- ylthio)phenyl]tetrahydropyran,
(2S,4R)-4-chloro-2-methyl-4-[3-(l-methyl-2-oxo-l,2,3,4- tetrahydroquinolin-6-ylthio)phenyl]tetrahydropyran,
(2S,4R)-4-fluoro-2-methyl-4-[3-(l-methyl-2-oxo-1,2,3,4- tetrahydroquinolin-6-ylthio)phenyl]tetrahydropyran,
(2S,4R)-4-bromo-2-methyl-4-[5-fluoro-3-(l-methyl-2-oxo-l,2,3,4- tetrahydroquinolin-6-ylthio)phenyl]tetrahydropyran,
4-(hydroxyiminomethyl)-4-[3-(2-naphthylmethoxy)phenyl]tetrahydropyran, 4-(methoxyiminomethyl)-4-[3-(2-naphthylmethox )phenyl]tetrahydropyran,
(E)-4-(2-cyanovinyl)-4-[3-(2-naphthylmethoxy)phenyl]tetrahydropyran,
(E)-4-(2-cyanovinyl)-4-[3-(l-methyl-2-oxo-1,2-dihydroquinolin-6- ylmethoxy)phenyl]tetrahydropyran,
(E)- and (Z)-4-(2-chlorovinyl)-4-[3-(2-naphthylmethoxy)phenyl]- tetrahydropyran,
4-bromo-4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-7- ylsulphonyl)phenyl]tetrahydropyran,
4-chloro-4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-l,4-benzoxazin-7- ylsulphonyl)phenyl]tetrahydropyran,
4-bromo-4-[5-fluoro-3-(l-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6- ylsulphonyl)phenyl]tetrahydropyran, or
(2S,4R)-4-chloro-2-methyl-4-[3-(l-methyl-2-oxo-l,2,3,4-tetrahydro- quinolin-6-ylsulphonyl)phenyl]tetrahydropyran; or a pharmaceutically-acceptable salt thereof.
8. A process for the preparation of a cyclic ether derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 7 which comprises:-
(a) the alkylation of a compound of the formula II
1 2 2 H-X -Ar -C-R II
with a compound of the formula Ar -A -Z wherein Z is a displaceable group;
(b) the conversion of a compound of the formula I wherein Y is a hydroxy or (l-4C)alkoxy group to a compound of the formula I wherein Y is halogeno;
(c) the hydrohalogenation of an olefin of the formula III, or of an admixture of isomers of the olefin of the formula III 1 1 1 2 2
Ar -A -X -Ar -C=R
III
(d) for the production of compounds of the formula I wherein Y is a hydroxyimino-(l-4C)alkyl group or an 0-substituted hydroxyimino-(l-4C)alkyl group, the reaction of a compound of the formula I wherein Y is a formyl or (2-4C)alkanoyl group with hydroxylamine or an appropriate 0-substituted hydroxylamine;
(e) for the production of those compounds of the formula I wherein
Y is a (l-4C)alkoxyimino-(l-4C)alkyl or (2-5C)alkanoyloxyimino- (l-4C)alkyl group, the alkylation or acylation of a compound of the formula I wherein Y is a hydroxyimino-(l-4C)alkyl group with an appropriate alkylating agent of the formula Ra-Z wherein R is a (l-4C)alkyl group or with an appropriate acylating agent of the formula Ra-Z wherein Ra is a (2-5C)alkanoyl group and Z is a displaceable group;
(f) for the production of those compounds of the formula I wherein
Y is a vinyl or substituted vinyl group, the reaction of an aldehyde of the formula IV
CHO
ArJ 1 1 2 2 -A -X -Ar -C-R IV
with an appropriate Wittig reagent of the formula V
T-CH2-P+(Ph3)Q"
wherein T is halogeno or cyano, and wherein Q is an anion, or with a phosphonate of the formula VI (R30) 2-P-CH2-T VI
3 wherein T is halogeno or cyano and wherein R is (1-4C)alkyl;
(g) 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.
9. A pharmaceutical composition which comprises a cyclic ether derivative of the formula I or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 7, in association with a pharmaceutically-acceptable diluent or carrier.
10. The use of a cyclic ether derivative of the formula I or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 7, in the production of a new medicament for use in a leukotriene mediated disease or medical condition.
PCT/GB1995/001000 1994-05-06 1995-05-02 Cyclic ether derivatives and pharmaceutical composition containing them WO1995030668A1 (en)

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US6951855B2 (en) 2001-04-23 2005-10-04 Astrazeneca Ab Benzoxazinone derivatives for use in the treatment of angiogenesis
US7378415B2 (en) 2004-09-30 2008-05-27 Roche Palo Alto Llc Benzoxazine and quinoxaline derivatives and uses thereof
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* Cited by examiner, † Cited by third party
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US6951855B2 (en) 2001-04-23 2005-10-04 Astrazeneca Ab Benzoxazinone derivatives for use in the treatment of angiogenesis
US7456164B2 (en) * 2004-05-07 2008-11-25 Pfizer, Inc 3- or 4-monosubtituted phenol and thiophenol derivatives useful as H3 ligands
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