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EP0702678A1 - Derives d'aniline - Google Patents

Derives d'aniline

Info

Publication number
EP0702678A1
EP0702678A1 EP94919603A EP94919603A EP0702678A1 EP 0702678 A1 EP0702678 A1 EP 0702678A1 EP 94919603 A EP94919603 A EP 94919603A EP 94919603 A EP94919603 A EP 94919603A EP 0702678 A1 EP0702678 A1 EP 0702678A1
Authority
EP
European Patent Office
Prior art keywords
formula
group
alkyl
hydrogen
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP94919603A
Other languages
German (de)
English (en)
Inventor
Philip Neil Edwards
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca SAS
Syngenta Ltd
Original Assignee
Zeneca Pharma SA
Zeneca Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zeneca Pharma SA, Zeneca Ltd filed Critical Zeneca Pharma SA
Priority to EP94919603A priority Critical patent/EP0702678A1/fr
Publication of EP0702678A1 publication Critical patent/EP0702678A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D309/08—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms

Definitions

  • This invention concerns aniline derivatives and more particularly aniline 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 aniline derivatives and novel pharmaceutical compositions containing them.
  • Also included in the invention is the use of said aniline derivatives in the treatment of various diseases such as inflammatory and/or allergic diseases in which the direct or indirect products of 5-LO catalysed oxidation of arachidonic acid are involved, and the production of new medicaments for such use.
  • aniline derivatives described hereinafter are inhibitors of 5-LO, which enzyme is known to be involved in catalysing the oxidation of arachidonic acid to give rise via a cascade process to the physiologically active leukotrienes such as leukotriene B, (LTB.) and the peptido-lipid leukotrienes such as leukotriene C, (LTC,) and leukotriene D, (LTD.) and various metabolites.
  • 5-LO which enzyme is known to be involved in catalysing the oxidation of arachidonic acid to give rise via a cascade process to the physiologically active leukotrienes such as leukotriene B, (LTB.) and the peptido-lipid leukotrienes such as leukotriene C, (LTC,) and leukotriene D, (LTD.) and various metabolites.
  • the biosynthetic relationship and physiological properties of the leukotrienes are summarised by G.W. Taylor and S.R. Clarke in Trends in Pharmacological Sciences, 1986, _, 100-103.
  • the leukotrienes and their metabolites have been implicated in the production and development of various diseases, for example various inflammatory and allergic diseases such as inflammation of the joints (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), skin diseases (especially psoriasis, eczema and dermatitis), ocular conditions (especially allergic conjunctivitis and uveitis) and respiratory disease (especially asthma, bronchitis and allergic rhinitis), for example in the production and development of various cardiovascular and cerebrovascular disorders such as myocardial infarction, the formation of atherosclerotic plaques, hypertension, platelet aggregation, angina, stroke
  • leukotrienes are mediators of inflammatory diseases by virtue of their ability to modulate lymphocyte and leukocyte function.
  • Other physiologically active metabolites of arachidonic acid such as the prostaglandins and thromboxanes, arise via the action of the enzyme cyclooxygenase on arachidonic acid.
  • Such compounds are of value as therapeutic agents in the treatment of, for example, allergic conditions, psoriasis, asthma, cardiovascular and cerebrovascular disorders, and/or inflammatory and arthritic conditions, and/or disorders of bone metabolism, mediated alone or in part by one or more leukotrienes.
  • R is hydrogen, (l-4C)alkyl, halogeno-(l-4C)alkyl, cyano-(l-4C)alkyl, hydroxy-(2-4C)alkyl, amino-(2-4C)alkyl, (l-4C)alkylamino-(2-4C)alkyl, di-[(l-4C)alkyl]amino-(2-4C)alkyl or phenyl-(l-4C)alkyl, and wherein said phenyl-(l-4C)alkyl group may optionally bear one or two substituents selected from halogeno, trifluoromethyl, cyano, (l-4C)alkyl and (l-4C)alkoxy; R is hydrogen, hydroxy, (l-4C)alkyl or (l-4C)alkoxy;
  • R is hydrogen or (l-4C)alkyl
  • X is oxy, thio, sulphinyl, sulphonyl or a group of the formula CR R
  • R is hydrogen or (l-4C)alkyl and R is hydrogen or
  • X is a direct link to the 2-position of the anilino ring; the anilino ring may optionally bear a halogeno substituent;
  • A is a direct link to X or is (l-3C)alkylene
  • X is oxy, thio, sulphinyl or sulphonyl
  • Ar is phenylene, pyridinediyl, pyrimidinediyl, thiophenediyl, furandiyl, thiazolediyl, oxazolediyl, thiadiazolediyl or oxadiazolediyl which may optionally bear one or two substituents selected from halogeno, cyano, trifluoromethyl, hydroxy, amino,
  • R is hydrogen, (l-4C)alkyl, (3-4C)alkenyl or (3-4C)alkynyl;
  • R 2 and R3 together form a group of the formula -A2-X2-A3- which
  • each is (l-3C)alkylene and X is oxy, thio, sulphinyl, sulphonyl or imino, and which ring may bear one, two or three substituents, which may be the same or different, selected from hydroxy, (l-4C)alkyl, (l-4C)alkoxy, fluoro-(l-4C)alkyl, cyano-(l-4C)alkyl, (3-4C)alkenyl and (3-4C)alkynyl;
  • R is ( l-4C)alkyl, (2-4C)alkenyl or (2-4C)alkynyl; or a pharmaceutically-acceptable salt, ester or amide 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.
  • the invention includes in its definition any neutral or zwitterionic form, or a mixture thereof, of a compound of the formula I.
  • the invention is not to be limited merely to any one form utilised for convenience within the formulae drawings or for the purpose of naming particular compounds of the invention.
  • 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.
  • R when it is (l-4C)alkyl is, for example, methyl, ethyl, propyl, isopropyl or butyl; when it is halogeno-(1-4C)alkyl is, for example, 2-fluoroethyl, 2-chloroethyl,
  • 3-cyanopropyl when it is hydroxy-(2-4C)allyl is, for example,
  • 2-hydroxyethyl and 3-hydroxypropyl when it is amino-(2-4C)alkyl is, for example, 2-aminoethyl and 3-aminopropyl; when it is (l-4C)alkylamino-(2-4C)alkyl is, for example, 2-methylaminoethyl, 2-ethylaminoethyl or 3-methylaminopropyl; when it is di-[(l-4C)allcyl]amino-(2-4C)alkyl is, for example, 2-dimethylaminoethyl, 2-diethylaminoethyl,
  • NR and R , R or R is (1-4C)alkyl, is, for example, methyl or ethyl.
  • a suitable value for R when it is (l-4C)alkoxy is, for example, methoxy or ethoxy.
  • a suitable value for A when it is (l-3C)alkylene is, for e ⁇ .ample, methylene, ethylene or trimethylene.
  • a suitable value for Ar when it is phenylene is, for example, 1,3- or 1,4-phenylene.
  • 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
  • Ar include, for example:-
  • halogeno fluoro, chloro and bromo
  • (1-4C)alkyl methyl, ethyl, propyl and isopropyl
  • (l-4C)alkoxy methoxy, ethoxy, propoxy and isopropoxy
  • (l-4C)alkylamino methylamino, ethyla ino and propylamino
  • di-(l-4C)alkylamino dimethylamino, diethylamino and
  • R when it is (l-4C)alkyl is, for example, methyl, ethyl, propyl or butyl; when it (3-4C)alkenyl is, for example allyl, 2-butenyl or 3-butenyl; and when it is (3-4C)alkynyl is, for example, 2-propynyl or 2-butynyl.
  • (l-3C)alkylene is, for example, methylene, ethylene or trimethylene.
  • Suitable values for the substituents which may be present on said 5- or 6-membered ring include, for example:-
  • (l-4C)alkyl methyl, ethyl, propyl, isopropyl, butyl and isobutyl; for (l-4C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for fluoro-(l-4C)alkyl: trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl and 3,3,3-trifluoroethyl; for cyano-(1-4C)alkyl: cyanomethyl and 2-cyanoethyl; for (3-4C)alkenyl: allyl; and for (3-4C)alkynyl: 2-propynyl.
  • Said substituents may be located on any available position including, when the substituent is, for example, (1-4C)alkyl,
  • a suitable value for A and A which may be the same or different, when each is (l-3C)alkylene is, for example, methylene, ethylene or trimethylene. Suitable values for the
  • (1-4C)alkyl substituents which may be present on said 5- or 6-membered ring include, for example, methyl, ethyl, propyl, isopropyl and butyl.
  • R when it is (1-4C)alkyl is, for example, methyl, ethyl, propyl or butyl; when it is (2-4C)alkenyl is, for example, vinyl, allyl, 2-butenyl or 3-butenyl; and when it is (2-4C)alkynyl is, for example, ethynyl, 2-propynyl or 2-butynyl.
  • a suitable pharmaceutically-acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid.
  • a suitable pharmaceutically-acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt such as ammonium or tetramethylammonium or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with ethylamine, diethylamine, triethylamine or piperidine.
  • a suitable pharmaceutically-acceptable ester of a compound of the invention is, for example, an ester formed by the esterification of the carboxy group of the compound of the formula I with an alcohol, for example a (l-6C)alcohol such as methanol, ethanol, ethylene glycol, propanol or tert-butanol, or with a phenol or phenyl-(l-4C)alcohol such as phenol or benzyl alcohol or a substituted phenol or phenyl-(l-4C)alcohol wherein each substituent is selected from, for example, a halogeno (such as fluoro or chloro), (l-4C)alkyl (such as methyl) or (l-4C)alkoxy (such as methoxy) group.
  • an alcohol for example a (l-6C)alcohol such as methanol, ethanol, ethylene glycol, propanol or tert-butanol, or with a phenol or phenyl-(
  • a further suitable pharmaceutically-acceptable ester of a compound of the invention is, for example, an ester formed by the reaction of a hydroxy group within a compound of the formula I, for example, the hydroxy group formed when R is hydrogen, with, for example, a carboxylic acid, for example a (2-5C)alkanoic acid such as acetic acid or propionic acid, or, for example a benzoic acid or a substituted benzoic acid wherein each substituent is selected from, for example, a halogeno (such as fluoro or chloro), (l-4C)alkyl (such as methyl) or (l-4C)alkoxy (such as methoxy) group.
  • a halogeno such as fluoro or chloro
  • (l-4C)alkyl such as methyl
  • (l-4C)alkoxy such as methoxy
  • a suitable pharmaceutically-acceptable amide of a compound of the invention is, for example, an amide formed by the amidification of the carboxy group of the compound of the formula I with an amine, for example, a (l-6C)alkylamine such as methylamine, ethylamine or propyla ine or a di-(l-6C)alkylamine such as dimethylamine, diethylamine or N-ethyl-N-methylamine.
  • an amine for example, a (l-6C)alkylamine such as methylamine, ethylamine or propyla ine
  • a di-(l-6C)alkylamine such as dimethylamine, diethylamine or N-ethyl-N-methylamine.
  • novel compounds of the invention are, for example, aniline derivatives of the formula I, or pharmaceutically-acceptable salts, esters or amides thereof, wherein the variable groups R 4 , R 5 , R 6 , X 3 , A 1 , X 1 , Ar, R 1 , R 2 and R 3 have the values disclosed hereinbefore or hereinafter in this section defining particular compounds of the invention:-
  • R 4 is (l-4C)alkyl
  • R is hydrogen or (l-4C)alkyl
  • R is hydrogen or (1-4C)alkyl
  • X is oxy or thio or a group of the formula CR R wherein
  • each of R and R is hydrogen, or X is a direct link to the
  • X is a group of the formula CR R wherein each of R and R
  • A is (l-3C)alkylene and X is oxy;
  • A is a direct link to X and X is oxy, thio, sulphinyl or sulphonyl;
  • Ar is phenylene which may optionally bear one or two substituents selected from halogeno, trifluoromethyl, (1-4C)alkyl and
  • Ar is pyridinediyl or pyrimidinediyl which may optionally bear one amino substituent
  • Ar is thiophenediyl or thiazolediyl
  • R 1 is (l-4C)alkyl or (3-4C)alkenyl
  • R and R together form a group of the formula -A -X -A - 2 which together with the oxygen atom to which A is attached and with
  • 3 ring may bear one or two methyl substituents, and R is methyl or ethyl.
  • a preferred compound of the invention comprises an aniline derivative of the formula I
  • R is methyl, ethyl or propyl
  • R is hydrogen or methyl
  • R is hydrogen or methyl
  • X is oxy or thio or a group of the formula CR R wherein each of R o and R is hydrogen;
  • A is methylene and X is oxy, or A is a direct link to X and X is oxy, thio, sulphinyl or sulphonyl;
  • Ar is 1,3- or 1,4-phenylene which may optionally bear one or two substituents selected from fluoro, chloro, trifluoromethyl, methyl and methoxy, or Ar is 3,5-pyridinediyl, 4,6-pyrimidinediyl,
  • R is hydrogen, methyl, ethyl or allyl
  • R 2 and R3 together form a group of the formula -A2-X2-A3- which
  • 2 is ethylene and X is oxy, and which ring may bear one or two substituents selected from methyl and ethyl; or a pharmaceutically-acceptable salt thereof.
  • a further preferred compound of the invention comprises an aniline derivative of the formula I
  • R is methyl, ethyl or propyl
  • R is hydrogen or methyl
  • R is hydrogen or methyl
  • X is a group of the formula CR R wherein each of R and R is hydrogen;
  • A is methylene and X is oxy, or A is a direct link to X and X is oxy, thio, sulphinyl or sulphonyl;
  • Ar is 1,3- or 1,4-phenylene which may optionally bear one or two substituents selected from fluoro, chloro, trifluoromethyl, methyl and methoxy, or Ar is 3,5-pyridinediyl, 4,6-pyrimidinediyl, 2-amino-4,6-pyrimidinediyl, 2,4- or 2,5-thiophenediyl or 2,4- or 2,5-thiazolediyl;
  • R is hydrogen, methyl, ethyl or allyl
  • R and R together form a group of the formula -A -X -A - which
  • 2 is ethylene and X is oxy, and which ring may bear one or two substituents selected from methyl and ethyl; or a pharmaceutically-acceptable salt thereof.
  • a further preferred compound of the invention comprises an aniline derivative of the formula I
  • R is methyl or ethyl
  • R is hydrogen
  • X is oxy or CH
  • A is a direct link to X and X is thio or sulphonyl
  • Ar is 1,3-phenylene, 5-fluoro-l,3-phenylene, 2,4-thiophenediyl (with the X group in the 2-position), 2,5-thiophenediyl, 2,4-thiazolediyl
  • R is hydrogen or methyl
  • R and R together form a group of the formula -A -X -A - which
  • a further preferred compound of the invention comprises an aniline derivative of the formula I
  • R is methyl or ethyl
  • R is hydrogen
  • R is hydrogen
  • X 3 is CH
  • a 1 is a direct link to X1 and X1 is thio or sulphonyl;
  • Ar is 1,3-phenylene, 5-fluoro-l,3-phenylene, 2,4-thiophenediyl (with the X group in the 2-position), 2,5-thiophenediyl, 2,4-thiazolediyl (with the X group in the 2-position) or 2,5-thiazolediyl (with the X group in the 2-position) ;
  • R is hydrogen or methyl
  • R and R together form a group of the formula -A -X -A - which
  • a further preferred compound of the invention comprises an aniline derivative of the formula I
  • R is hydrogen
  • R is hydrogen
  • X 3 is CH_
  • A is a direct link to X and X is thio or sulphonyl
  • Ar is 1,3-phenylene or 5-fluoro-l,3-phenylene
  • R is methyl
  • R and R together form a group of the formula -A -X -A - which together with the carbon atom to which A 2 and A3 are attached define a
  • a specific especially preferred compound of the invention is, for example, the following aniline derivative of the formula I, or a pharmaceutically-acceptable salt thereof:-
  • a compound of the invention comprising an aniline derivative of the formula I, or a pharmaceutically-acceptable salt, ester or amide thereof, may be prepared by any process known to be applicable to the preparation of structurally-related compounds.
  • a suitable displaceable group Z is, for example, a halogeno or sulphonyloxy group, for example a fluoro, chloro, bromo, iodo, methane- sulphonyloxy or toluene-£-sulphonyloxy group.
  • a suitable base for the coupling reaction is, for example, an alkali or alkaline earth metal carbonate, (l-4C)alkoxide, hydroxide or hydride, for example sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride, or an organometallic base such as (l-4C)alkyl-lithium, for example n-butyl-lithium.
  • the coupling reaction is conveniently performed in a suitable inert solvent or diluent, for example N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulphoxide, acetone, 1,2-dimethoxyethane or tetrahydrofuran, and at a temperature in the range, for example, 10 to 150 C, conveniently at or near 100°C.
  • a suitable inert solvent or diluent for example N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulphoxide, acetone, 1,2-dimethoxyethane or tetrahydrofuran, and at a temperature in the range, for example, 10 to 150 C, conveniently at or near 100°C.
  • reaction may be performed in the presence of a suitable catalyst, for example a metallic catalyst, for example palladium(O) or copper(I) such as tetrakis(triphenylphosphine)- palladium, cuprous chloride or cuprous bromide.
  • a suitable catalyst for example a metallic catalyst, for example palladium(O) or copper(I) such as tetrakis(triphenylphosphine)- palladium, cuprous chloride or cuprous bromide.
  • a suitable protecting group for an amino, imino or alkylamino group is, for example, an acyl group for example a (2-4C)alkanoyl group (especially acetyl), a (l-4C)alkoxycarbonyl group (especially methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl) , an arylmethoxycarbonyl group (especially benzyloxycarbonyl) or an aroyl group (especially benzoyl).
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl 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 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 carboxy group is, for example, an esterifying group, for example a (l-4C)alkyl group (especially methyl or ethyl) which 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.
  • 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 14
  • 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.
  • the starting materials of the formulae II and III may be obtained by standard procedures of organic chemistry.
  • the preparation of such starting materials may be achieved by analogous procedures to those illustrated within the accompanying non-limiting Examples.
  • the disclosures of European Patent Applications Nos. 0375404, 0385662, 0409413, 0420511, 0462812 and 0462813 are particularly relevant to the preparation of suitable starting materials.
  • the coupling reaction is conveniently performed in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 10 to 150 C, conveniently at or near 100°C.
  • the reaction may conveniently be performed in the presence of a suitable catalyst as defined hereinbefore.
  • the starting materials of the formulae IV and V may be obtained by standard procedures of organic chemistry.
  • the preparation of such starting materials may be achieved by analogous procedures to those illustrated within the accompanying non-limiting Examples.
  • 0409413, 0420511, 0462812 and 0462813 are particularly relevant to the preparation of suitable starting materials.
  • M is an alkali metal or alkaline earth metal such as lithium or calcium or M represents the magnesium halide portion of a conventional Grignard reagent.
  • the coupling reaction is conveniently performed in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, -80 to +50°C, conveniently in the range -80°C to ambient temperature.
  • the hydrolysis reaction is conveniently performed in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 10 to 180°C, conveniently in the range 100 to 150°C.
  • X is a thio group or wherein R and R together form a
  • a suitable oxidising agent is, for example, any agent known in the art for the oxidation of thio to sulphinyl and/or sulphonyl, for example, hydrogen peroxide, a peracid (such as
  • 3-chloroperoxybenzoic or peroxyacetic acid an alkali metal peroxysulphate (such as potassium peroxymonosulphate) , a di-(l-4C)alkyldioxiran (such as dimethyldioxiran) , chromium trioxide or gaseous oxygen in the presence of platinum.
  • the oxidation is generally carried out under as mild conditions as possible and with the required stoichiometric amount of oxidising agent in order to reduce the risk of over oxidation and damage to other functional groups.
  • the reaction is carried out in a suitable solvent or diluent such as methylene chloride, chloroform, acetone, tetrahydrofuran or tert-butyl methyl ether and at a temperature, for example, at or near ambient temperature, that is in the range 15 to 35°C.
  • a milder oxidising agent may also be used, for example sodium or potassium metaperiodate, conveniently in a polar solvent such as acetic acid or ethanol.
  • a compound of the formula I containing a sulphonyl group it may be obtained by oxidation of the corresponding sulphinyl compound as well as of the corresponding thio compound.
  • a pharmaceutically-acceptable salt of a compound of the formula I When a pharmaceutically-acceptable salt of a compound of the formula I is required, it may be obtained, for example, by reaction of said compound with a suitable acid or base using a conventional procedure.
  • a pharmaceutically-acceptable ester of a compound of the formula I it may be obtained, for example, by reaction of a carboxy group within said compound with a suitable alcohol or phenol using a conventional procedure or by reaction of a hydroxy group within said compound with a suitable carboxylic acid using a conventional procedure.
  • a pharmaceutically-acceptable amide of a compound of the formula I When a pharmaceutically-acceptable amide of a compound of the formula I is required it may be obtained, for example, by reaction of a carboxy group within said compound with a suitable amine 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
  • the compounds of the formula I are inhibitors of the enzyme 5-LO.
  • the effects of this inhibition may be demonstrated using one or more of the standard procedures set out below:- a) An in vitro 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 (Prostaglandins, Leukotrienes Hed. , 1986, 22, 57; Prostaglandins, 1984, 28, 666; Brit. J.
  • Test a IC 50 (LTB ⁇ ) in the range, for example, 0.01-40 ⁇ M ICC Q (TxB 2 ) in the range, for example, 40-200 ⁇ M;
  • Test b oral ED 50 (LTB.) in the range, for example, O.l-lOOmg/kg;
  • the compound sodium 3- ⁇ 5-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-2- methylaminophenyljpropionate has an IC of 1.3 ⁇ M against LTB, in test a) and an oral ED,- n of ⁇ 1.5 mg/kg versus LTB, in test c).
  • those compounds of the formula I which are particularly preferred have an oral ED,_ n of ⁇ 10 mg/kg against LTB, in tests b) and/or c).
  • These compounds are examples of compounds of the invention which show selective inhibitory properties for 5-L0 as opposed to cyclooxygenase, which selective properties are expected to impart improved therapeutic properties, for example, a reduction in or freedom from the gastrointestinal side-effects frequently associated with cyclooxygenase inhibitors such as indomethacin.
  • a pharmaceutical composition which comprises an aniline 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.
  • compositions may be prepared in a conventional manner using conventional excipients.
  • the amount of active ingredient (that is an aniline 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.
  • the invention also includes a method of treating a disease or medical condition mediated alone or in part by one or more leukotrienes which comprises administering to a warm-blooded animal requiring such treatment an effective amount of an active ingredient as defined above.
  • the invention also provides the use of such an active ingredient in the production of a new medicament for use in a leukotriene mediated disease or medical condition.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of the formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
  • compounds of the formula I are useful in treating those diseases such as allergic and inflammatory conditions and disorders of bone metabolism which are due alone or in part to the effects of the metabolites of arachidonic acid arising by the linear (5-LO catalysed) pathway and in particular the leukotrienes, the production of which is mediated by 5-LO.
  • such conditions include, for example, various inflammatory and allergic diseases such as inflammation of the joints (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), skin diseases (especially psoriasis, eczema and dermatitis), ocular conditions (especially allergic conjunctivitis and uveitis) and respiratory disease (especially asthma, bronchitis and allergic rhinitis), for example in the production and development of various cardiovascular and cerebrovascular disorders such as myocardial infarction, the formation of atherosclerotic plaques, hypertension, platelet aggregation, angina, stroke, reperfusion injury, vascular injury including restenosis and peripheral vascular disease, for example in the formation of the conditions of shock or trauma such as can follow burn injuries, toxaemia or surgery, and for example various disorders of bone metabolism such as osteoporosis (including senile and postmenopaus
  • 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-LO. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
  • 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 an aniline derivative of the formula I, or a pharmaceutically-acceptable salt thereof as defined hereinbefore, in conjunction or admixture with a cyclooxygenase inhibitory non-steroidal antiinflammatory agent (such as those mentioned above), and a pharmaceutically-acceptable diluent or carrier.
  • cytoprotective effects of the compounds of the formula I may be demonstrated, for example in a standard laboratory model which assesses protection against indomethacin-induced or ethanol-induced ulceration in the gastrointestinal tract of rats.
  • compositions of the invention may in addition contain one or more therapeutic or prophylactic agents known to be of value for the disease under treatment.
  • a known platelet aggregation inhibitor, hypolipidemic agent, anti-hypertensive agent, beta-adrenergic blocker or a vasodilator may usefully also be present in a pharmaceutical composition of the invention for use in treating a heart or vascular disease or condition.
  • an anti-histamine, steroid such as beclomethasone dipropionate
  • sodium cromoglycate sodium cromoglycate
  • phosphodiesterase inhibitor or a beta-adrenergic stimulant may usefully also be present in a pharmaceutical composition of the invention for use in treating a pulmonary disease or condition.
  • melting points are uncorrected and were determined using a Mettler SP62 automatic melting point apparatus or an oil-bath apparatus; melting points for the end-products of the formula I were determined after recrystallisation from a conventional organic solvent such as ethanol, methanol, acetone, ether or hexane, alone or in admixture; (viii ) the following abbreviations have been used: -
  • the aqueous phase was washed with diethyl ether and then acidified to pH2 by the addition of dilute aqueous hydrochloric acid.
  • the acidic mixture was extracted with ethyl acetate.
  • the organic phase was dried (MgSO.) and evaporated.
  • the residual oil was dissolved in diethyl ether and hexane was added. There was thus obtained 6-mercapto-l-methyl-1,2,3, -tetrahydro- quinolin-2-one as a solid (35.5 g, 92%) which was used without further purification.
  • n-Butyl-lithium (1.4M in hexane, 1.5 ml) was added dropwise to a stirred mixture of 6-mercapto-l-methyl-l,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 C for 2.2 hours with the concomitant distillation of the hexane.
  • Potassium peroxy onosulphate (4.4 g) was added to a mixture of (2S,4R)-4-[5-fluoro-3-(l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6- ylthio)phenyl]-4-methoxy-2-methyltetrahydropyran (2 g), ethanol (20 ml) and water (10 ml). The mixture was stirred at ambient temperature for 18 hours. The mixture was partitioned between methylene chloride and water. The organic phase was washed with an aqueous sodium bisulphite solution, dried (MgSO,) and evaporated.
  • 0385662 (Example 20 thereof); 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 2 S0,) and evaporated. A solution of the residue in diethyl ether (50 ml) was added to concentrated sulphuric acid (35% v/v, 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.

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Abstract

L'invention se rapporte à un dérivé d'aniline répondant à la formule (I), dans laquelle R4 peut représenter hydrogène ou (1-4C)alkyle; R5 peut représenter hydrogène ou (1-4C)alkyle; R6 représente hydrogène ou (1-4C)alkyle; X3 peut représenter un groupe de la formule CR7R8, dans laquelle R7 représente hydrogène ou (1-4C)alkyle et R8 représente hydrogène ou (1-4C)alkyle; A1 peut représenter une liaison directe avec X1; X1 peut représenter thio et sulfonyle; Ar peut représenter phénylène éventuellement substitué; R1 peut représenter hydrogène ou (1-4C)alkyle; et R2 et R3 constituent ensemble un cycle présentant 5 à 6 atomes cycliques contenant un atome d'oxygène, ce cycle pouvant porter un, deux ou trois substituants, y compris méthyle alpha sur l'atome d'oxygène; ou un sel pharmaceutiquement acceptable de ce dérivé. Des procédés destinés à leur préparation sont également décrits, ainsi que des compositions pharmaceutiques les contenant, et leur utilisation comme inhibiteurs de 5-lipoxygénase.
EP94919603A 1993-06-07 1994-06-03 Derives d'aniline Withdrawn EP0702678A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP94919603A EP0702678A1 (fr) 1993-06-07 1994-06-03 Derives d'aniline

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP93401442 1993-06-07
EP93401442 1993-06-07
EP94919603A EP0702678A1 (fr) 1993-06-07 1994-06-03 Derives d'aniline
PCT/EP1994/001808 WO1994029291A1 (fr) 1993-06-07 1994-06-03 Derives d'aniline

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EP0702678A1 true EP0702678A1 (fr) 1996-03-27

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