Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • 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
• • 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 oxime derivatives and more particularly oxime 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 oxime derivatives and novel pharmaceutical compositions containing them.
• Also included in the invention is the use of said oxime 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.
• the oxime derivatives described hereinafter are inhibitors of 5- O, which enzyme is known to be involved in catalysing the oxidation of arachidonic acid to give rise via a cascade process to the physiologically active leukotrienes such as leukotriene B, ( TB.) and the peptido-lipid leukotrienes such as leukotriene C, ( TC.) and leukotriene D, (LTD, ) and various metabolites.
• 5- O which enzyme is known to be involved in catalysing the oxidation of arachidonic acid to give rise via a cascade process to the physiologically active leukotrienes such as leukotriene B, ( TB.) and the peptido-lipid leukotrienes such as leukotriene C, ( TC.) and leukotriene D, (LTD, ) and various metabolites.
• the biosynthetic relationship and physiological properties of the leukotrienes are summarised by G.U. Taylor and S.R. Clarke in Trends in Pharmacological Sciences, 1986, _ 1 , 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) 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, angina and peripheral vascular disease.
• 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 A2 and 0385662 A2 that certain heterocyclic derivatives possess inhibitory properties against 5-LO.
• European Patent Applications Nos. 0409413 and 0420511 are also concerned with heterocyclic derivatives which possess inhibitory properties against 5-LO.
• R 5 0-N C(R )-Ar 1 -A 1 -X 1 -Ar 2 -C-R 2 I
• R is hydrogen, carboxy, carba oyl, amino, cyano, trifluoromethyl, (l-4C)alkylamino, di-(l-4C)alkylamino, (l-4C)alkyl,
• R 5 is hydrogen, (l-4C)alkyl, (3-4C)alkenyl, (3-4C)alkynyl, (2-5C)alkanoyl, halogeno-(2-4C)alkyl, hydroxy-(2-4C)alkyl, (l-4C)alkoxy-(2-4C)alkyl, carbamoyl, N-(l-4C)alkylcarbamoyl, N,N-di-(l-4C)alkylcarbamoyl, cyano-(l-4C)alkyl, carboxy-(l-4C)alkyl, (l-4C)alkoxycarbonyl-(l-4C)alkyl, (2-5C)alkanoyl-(l-4C)alkyl, phenyl-(l-4C)alkyl or heteroaryl-(l-4C)alkyl and wherein each pheny
• Ar is phenylene or a heteroaryl diradical which may optionally bear one or two substituents selected from halogeno, cyano, trifluoromethyl, hydroxy, amino, (l-4C)alkyl, (l-4C)alkoxy, phenyl-(l-4C)alkoxy, (l-4C)alkylamino and di-(l-4C)alkylamino;
• n 1 or 2
• X is oxy, thio, sulphinyl, sulphonyl, imino or
• (l-4C)alkylimino and one of the -CH relie- groups may optionally be replaced by a -CH(Me)- or -C(He) shadow- group;
• A is a direct link to X , or A is (l-4C)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, (2-5C)alkanoyl or benzoyl, and wherein said benzoyl group may optionally bear one or two substituents selected from halogeno, (l-4C)alkyl and (l-4C)alkoxy; and
• R and R together form a group of the formula -A -X -A - which 2 3 together with the carbon atom to which A and A are attached define a
• 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.
• oxime derivatives may exist in different geometric isomeric forms, commonly designated as (E) - or ( ⁇ )-isomers
• the invention includes in its definition any such geometric isomeric form which possesses the property of inhibiting 5-L0.
• 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. Examples of such techniques are set out in the accompanying Examples which are set out hereinafter.
• 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.
• (2-5C)alkanoyl is, for example, acetyl, propionyl, butyryl or
• R or R when R or R is phenyl-(1-4C)alkyl is, for example, benzyl, phenethyl or 3-phenylpropyl.
• a suitable value for R when it is (l-4C)alkoxycarbonyl is, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or tert-butoxycarbonyl; when it is N-(l-4C)alkylcarbamoyl is, for example, N-methylcarbamoyl, N-ethylcarbamoyl or N-propylcarbamoyl; and when it is N_-,N-di-(l-4C)alkylcarbamoyl is, for example,
• R when it is (l-4C)alkylamino is, for example, methylamino, ethylamino, propylamino or isopropyla ino; when it is di-(l-4C)alkylamino is, for example, dimethylamino, diethylamino or N-ethyl-N-methylamino; when it is (l-4C)alkylthio is, for example, methylthio, ethylthio or propylthio; when it is (l-4C)alkylsulphinyl is, for example, methylsulphinyl, ethylsulphinyl or propylsulphinyl; when it is (l-4C)alkylsulphonyl is, for example, methylsulphonyl, ethylsulphonyl or propylsulphonyl; when it is hydroxy-(1-4C)alkyl is, for example,
• (1-4C)alkylthio-(1-4C)alkyl is, for example, methylthiomethyl, ethylthiomethyl, 1-methylthioethyl or 2-methylthioethyl.
• a suitable value for the heteroaryl group in R when R is heteroaryl-(1-4C)alkyl is, for example, a 5-membered or 6-membered heterocyclic moiety containing up to four nitrogen heteroatoms and optionally containing a further heteroatom selected from oxygen and sulphur such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl which may be attached through any available position including through any available nitrogen atom.
• a suitable value for the (1-4C)alkyl group when R is heteroaryl-(1-4C)alkyl is, for example, methyl, ethyl, propyl, isopropyl or butyl.
• a convenient value for the heteroaryl group in R when R is heteroaryl-(1-4C)alkyl is, for example, a 5-membered heterocyclic moiety containing up to four nitrogen heteroatoms and optionally containing a further heteroatom selected from oxygen and sulphur such as imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl or tetrazolyl.
• a further convenient value for the heteroaryl group in R when R is heteroaryl-(1-4C)alkyl is, for example, a 6-membered heterocyclic moiety containing 1 or 2 nitrogen heteroatoms such as pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl.
• R or R is phenyl, phenyl-(1-4C)alkyl or heteroaryl-(1-4C)alkyl, or
• substituents on Ar or Ar or for substituents on the phenyl group when R is benzoyl, include, for example:- for halogeno: fluoro, chloro and bromo; for (l-4C)alkyl: methyl, ethyl, propyl and isopropyl; for (l-4C)alkoxy: methoxy, ethoxy, propoxy and isopropoxy; for (l-4C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl; for (l-4C)alkylamino: methylamino, ethylamino and propylamino; for di-(l-4C)alkylamino: dimethylamino, diethylamino and
• a suitable value for R when it is (3-4C)alkenyl is, for example, allyl, 2-butenyl or 3-butenyl; when it is (3-4C)alkynyl is, for example, 2-propynyl or 2-butynyl; when it is halogeno-(2-4C)alkyl is, for example, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 3-fluoropropyl or 3-chloropropyl; when it is hydroxy-(2-4C)alkyl is, for example, 2-hydroxyethyl or 3-hydroxypropyl; when it is (l-4C)alkoxy-(2-4C)alkyl is, for example, 2-methoxyethyl, 2-ethoxyethyl or 3-methoxypropyl; when it is N-(l-4C)alkylcarbamoyl is, for example, N-methylcarbamoyl or N-ethylcarb
• a suitable value for Ar or Ar when it is phenylene is, for example, 1,3- or 1,4-phenylene.
• a suitable value for Ar when it is a heteroaryl diradical is, for example, a 5-membered or 6-membered heteroaryl diradical containing one or two nitrogen heteroatoms and optionally containing a further heteroatom selected from oxygen and sulphur such as 2,4-, 2,5- or 3,5-pyridinediyl, 2,5- or 4,6-pyrimidinediyl, 2,5- or 2,6-pyrazinediyl, 3,5- or 3,6-pyridazinediyl, 2,4- or 2,5-imidazolediyl, 2,4- or 2,5-oxazolediyl, 2,4- or 2,5-thiazolediyl, l,2,4-triazole-3,5-diyl, 2,5-oxadiazolediyl or 2,5-thiadiazolediyl.
• 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
• a suitable value for R when it is (2-5C)alkanoyl is, for example, acetyl, propionyl or butyryl.
• (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:- for (l-4C)alkyl: methyl, ethyl, propyl, isopropyl, butyl and isobutyl; for (l-4C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy.
• Said substituents may be located on any available position including, when the substituent is (l-4C)alkyl, on the nitrogen atom when -XXI i .s imino.
• 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, oxime derivatives of the formula I, or pharmaceutically-acceptable salts thereof, wherein:- 4
• R is hydrogen, cyano, trifluoromethyl, di-(l-4C)alkylamino
• (l-4C)alkyl (2-5C)alkanoyl, (l-4C)alkoxycarbonyl, (l-4C)alkylthio, phenyl, hydroxy-(1-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl or (l-4C)alkylthio-(l-4C)alkyl; and R 5 , Ar 1 , A 1 , X 1 , Ar 2 , R 1 , R 2 and R 3 have any of the meanings defined hereinbefore or in this section defining particular compounds;
• R 5 is hydrogen, (l-4C)alkyl, (3-4C)alkenyl, (3-4C)alkynyl, (2-5C)alkanoyl, halogeno-(2-4C)alkyl, hydroxy-(2-4C)alkyl, (l-4C)alkoxy-(2-4C)alkyl, cyano-(1-4C)alkyl, carboxy-(l-4C)alkyl, (l-4C)alkoxycarbonyl-(l-4C)alkyl, phenyl-(1-4C)alkyl or (2-5C)alkanoyl-(l-4C)alkyl; and R 4 , Ar 1 , A 1 , X 1 , Ar 2 , R 1 , R 2 and R 3 have any of the meanings defined hereinbefore or in this section defining particular compounds;
• R is heteroaryl-(1-4C)alkyl (especially imidazolyl- or thiazolyl-(l-4C)alkyl) and wherein each heteroaryl group may optionally bear one or two substituents selected from halogeno,
• R is heteroaryl-(1-4C)alkyl (especially pyridyl-(l-4C)alkyl); and R 4 , Ar 1 , A 1 , X 1 , Ar 2 , R 1 , R 2 and R 3 have any of the meanings defined hereinbefore or in this section defining particular compounds;
• Ar is phenylene which may optionally bear one or two substituents selected from halogeno, (1-4C)alkyl and (l-4C)alkoxy;
• R , R , A , X , Ar , R , R and R have any of the meanings defined hereinbefore or in this section defining particular compounds;
• Ar is 1,3- or 1,4-phenylene which may optionally bear a substituent selected from halogeno, hydroxy, (l-4C)alkyl, (l-4C)alkoxy and phenyl-(l-4C)alkoxy; and R 4 , R 5 , A 1 , X 1 , Ar 2 , R 1 , R 2 and R 3 have any of the meanings defined hereinbefore or in this section defining particular compounds;
• Ar is 2,5-pyridinediyl, 2,5-pyrazinediyl or
• R , R , A , X , Ar , R , R and R have any of the meanings defined hereinbefore or in this section defining particular compounds;
• Ar is 1,4-phenylene and R is linked to Ar ortho to the
• -N C(R )- group and defines an ethylene or vinylene group, or a group of the formula
• n 2 and X 3 is oxy; and R5, A1, X1, Ar2, R1, R2 and R3 have any of the meanings defined hereinbefore or in this section defining particular compounds;
• a 1 is a direct link to X 1 ; and R 4 , R 5 , Ar 1 , X 1 , Ar 2 , R 1 , R 2
• a 1 is (l-4C)alkylene and X 1 is oxy; and R 4 , R 5 , Ar 1 , Ar 2 ,
• R , R and R have any of the meanings defined hereinbefore or in this section defining particular compounds
• A is a direct link to X and X is thio; and R , R , Ar ,
• Ar is phenylene which may optionally bear one or two substituents selected from halogeno, trifluoromethyl, amino,
• Ar is pyridinediyl or thiophenediyl
• R , R , Ar , A , X , R , R and R have any of the meanings defined hereinbefore or in this section defining particular compounds;
• Ar is 1,3-phenylene which may optionally bear one or two c 1 1 1 1 0 halogeno substituents; and
• R , R , Ar , A , X , R , R and R have any of the meanings defined hereinbefore or in this section defining particular compounds;
• Ar is pyrimidinediyl which may optionally bear one amino
• R is hydrogen; and R , R , Ar , A , X , Ar , R and R have any of the meanings defined hereinbefore or in this section defining particular compounds; or
• a further preferred compound of the invention comprises an oxime derivative of the formula I
• R is hydrogen, cyano, trifluoromethyl, dimethylamino, methyl, ethyl, propyl, isopropyl, acetyl, methoxycarbonyl, ethoxycarbonyl, methylthio, phenyl, hydroxymethyl, methoxymethyl or methylthiomethyl;
• R is hydrogen, methyl, ethyl, propyl, isopropyl, allyl, prop-2-ynyl, acetyl, propionyl, butyryl, pivaloyl, 2-fluoroethyl, 2-hydroxyethyl,
• A is a direct link to X and X is thio or sulphonyl, or A is methylene and X is oxy;
• R is hydrogen; and R 2 and R3 together form a group of the formula -A2-X2-A3- which
• a further preferred compound of the invention comprises an oxime derivative of the formula I
• R is hydrogen, cyano, trifluoromethyl, dimethylamino, methyl, ethyl, propyl, isopropyl, acetyl, methoxycarbonyl, ethoxycarbonyl, methylthio or phenyl;
• R is hydrogen, methyl, ethyl, propyl, isopropyl, allyl, prop-2-ynyl, acetyl, propionyl, butyryl, pivaloyl, 2-fluoroethyl, 2-hydroxyethyl,
• Ar is 1,4-phenylene which may optionally bear one substituent selected from fluoro, chloro, hydroxy, methyl, methoxy and benzyloxy;
• A is a direct link to X and X is thio or sulphonyl, or A is methylene and X is oxy;
• Ar is 3,5-pyridinediyl, 2-amino-4,6-pyrimidinediyl,
• R is hydrogen
• a further preferred compound of the invention comprises an oxime derivative of the formula I
• R is methyl, ethyl, isopropyl, hydroxymethyl or methoxymethyl
• R is hydrogen, methyl, allyl, prop-2-ynyl, acetyl, pivaloyl,
• Ar is 1,4-phenylene or 2,5-pyridinediyl (with the X group in the
• A is a direct link to X and X is thio or sulphonyl
• 2 Ar is 1,3-phenylene, 5-fluoro-l,3-phenylene, 2,4-thiophenediyl (with the X group in the 2-position), 2,4-thiazolediyl (with the X group in the 2-position) or 2,5-thiazolediyl (with the X group in the
• R is hydrogen
• R and R together form a group of the formula -A -X -A - which
• a further preferred compound of the invention comprises an oxime derivative of the formula I wherein R is hydrogen, methyl, acetyl, pivaloyl, cyanomethyl,
• A is a direct link to X and X is thio, or A is methylene and X is oxy;
• Ar is 1 , 3-phenylene , 5-fluoro-l , 3-phenylene ,
• R is hydrogen
• R and R together form a group of the formula -A -X -A - which
• a further preferred compound of the invention comprises an oxime derivative of the formula I
• R is hydrogen, methyl, prop-2-ynyl, acetyl, pivaloyl or cyanomethyl
• Ar is 1,4-phenylene
• A is a direct link to X and X is thio or sulphonyl
• Ar is 1,3-phenylene, 5-fluoro-l,3-phenylene,
• R is hydrogen
• R and R together form a group of the formula -A -X -A - which
• a specific especially preferred compound of the invention is, for example, the following oxime derivative of the formula I:- (E)-4'- ⁇ 5-fluoro-3-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4- yl]phenylthio ⁇ acetophenone oxime; or a pharmaceutically-acceptable salt thereof.
• a further specific especially preferred compound of the invention is, for example, the following oxime derivative of the formula I:- ( , E) -4 / - ⁇ 5-fluoro-3- [ (2S , 4R) -4-hydroxy-2-methyltetrahydropyran-4-yl] - phenylsulphonylj acetophenone oxime ,
• a compound of the invention comprising an oxime 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. Such procedures are provided as a further feature of the invention and are illustrated by the following
• a suitable base for the reaction is, for example, an alkali or alkaline earth metal carbonate, (l-4C)alkoxide, (l-4C)alkanoate, hydroxide or hydride, for example sodium carbonate, potassium carbonate, barium carbonate, sodium ethoxide, potassium butoxide, sodium acetate, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride.
• a suitable base for the reaction is, for example, an organic amine base such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene.
• 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 starting materials of the formula II may be obtained by standard procedures of organic chemistry which are within the ordinary skill of an organic chemist.
• R is (1-4C)alkyl or substituted-alkyl, the alkylation, conveniently in the presence of a suitable base as defined hereinbefore, of an oxime of the formula III OR 1
• H0-N C(R 4 ) -Ar 1 -A 1 -X 1 -Ar 2 -C-R 2
• a suitable displaceable group Z is, for example, a halogeno or sulphonyloxy group, for example a chloro, bromo, iodo, methanesulphonyloxy or toluene-4-sulphonyloxy group.
• the reaction is conveniently performed in a suitable inert solvent or diluent, for example N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetone, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxan or methylene chloride, an ⁇ J at a temperature in the range, for example, -10 to 150°C, conveniently at or near ambient temperature.
• a suitable inert solvent or diluent for example N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetone, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxan or methylene chloride, an ⁇ J at a temperature in the range, for example, -10 to 150°C, conveniently at or near ambient temperature.
• the starting materials of the formula III may be obtained by the process of paragraph (a) hereinbefore utilising a hydroxylamine of the formula R 0-NH- wherein R is hydrogen.
• the preparation of such starting materials is described within the accompanying non-limiting Examples.
• H0-N C(R 4 )-Ar 1 -A 1 -X 1 -Ar 2 -C-R 2
• R3 with an acylating agent of the formula R -Z, wherein Z is a displaceable group as defined hereinbefore.
• reaction is conveniently performed in a suitable inert solvent or diluent as defined in paragraph (b) hereinbefore, and at a temperature in the range, for example, -10 to 150°C, conveniently at or near ambient temperature.
• a suitable alkylnitrite is, for example, isopentylnitrite.
• the reaction is conveniently performed in a suitable inert solvent or diluent as defined in paragraph (b) hereinbefore, and at a temperature in the range, for example, 10 to 100°C, conveniently at or near 50°C.
• the starting materials of the formula IV may be obtained by standard procedures of organic chemistry.
• R is amino, (1-4C)alkylamino, di-(l-4C)alkylamino or
• (l-4C)alkylthio the alkylation of ammonia, a (l-4C)alkylamine, a di-(l-4C)alkylamine or a (l-4C)alkanethiol with an alkylating agent of the formula V
• reaction is conveniently performed in a suitable inert solvent or diluent as defined in paragraph (b) hereinbefore, and at a temperature in the range, for example, 10 to 100°C, conveniently at or near ambient temperature.
• the starting material of the formula V may be obtained by standard procedures of organic chemistry, (f) The coupling of a compound of the formula VI
• R 5 0-N C(R )-Ar 1 -A 1 -X 1 -Z VI
• Z is a displaceable group as defined hereinbefore, or alternatively, when X is a thio group, Z may be a group of the formula
• R 5 0-N C(R 4 )-Ar 1 -A 1 -X 1 -
• 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.
• a suitable oxidising agent is, for example, any agent known in the art for the oxidation of thio to sulphinyl and/or sulphonyl, for example, hydrogen peroxide, a peracid (such as 3-chloroperoxybenzoic or peroxyacetic acid) , an alkali metal peroxysulphate (such as potassium peroxymonosulphate) , chromium trioxide or gaseous oxygen in the presence of platinum.
• the oxidation is generally carried out under as mild conditions as possible and with the required stoichiometric amount of oxidising agent in order to reduce the risk of over oxidation and damage to other functional groups.
• 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.
• the hydrolysis is conveniently performed in the presence of a suitable base as defined hereinbefore.
• a suitable base as defined hereinbefore.
• the hydrolysis may be performed in the presence of a suitable acid as defined hereinbefore.
• the reaction is conveniently performed in a suitable solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 10 to 150°C, conveniently at or near 50°C.
• R , Ar , Ar or the ring defined by R and R are set out hereinafter.
• 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 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 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; or, for example, a tert-butyl group which may be removed, for example, by treatment with a suitable acid such as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid.
• a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide
• a tert-butyl group which may be removed, for example, by treatment with a suitable acid such as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid.
• 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 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-L0.
• the effects of this inhibition may be demonstrated using one or more of the standard procedures set out below:- a) An in vitro assay system involving incubating a test compound with heparinised human blood, prior to challenge with the calcium ionophore A23187 and then indirectly measuring the inhibitory effects on 5-L0 by assaying the amount of LTB, using specific radioimmunoassays described by Carey and Forder (Prostaglandins, Leukotrienes Med. , 1986, 22 ⁇ , 57; Prostaglandins, 1984, 28, 666; Brit. J.
• Test b oral ED 5Q (LTB.) in the range, for example, 0.1-lOOmg/kg;
• Test c oral EDc 0 (LTB.) in the range, for example, 0.1-50mg/kg.
• the compound (E)-4'- ⁇ 5-fluoro-3- [(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl]phenylthioJacetophenone oxime has an IC,- 0 of 0.07 ⁇ M against LTB, in test a) and an oral ED of approximately 0.05 mg/kg versus LTB, in test c).
• those compounds of the formula I which are particularly preferred have an IC 50 of ⁇ l ⁇ tf against LTB, in test a) and an oral ED 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-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 an oxime derivative of the formula I, or a pharmaceutically- acceptable salt thereof, in association with a pharmaceutically- acceptable diluent or carrier.
• a pharmaceutical composition which comprises a compound of the formula II, or a pharmaceutically-acceptable salt thereof, in association with a pharmaceutically-acceptable diluent or carrier.
• the composition may be in a form suitable for oral use, for example a tablet, capsule, aqueous or oily solution, suspension or emulsion; for topical use, for example a cream, ointment, gel or aqueous or oily solution or suspension; for nasal use, for example a snuff, nasal spray or nasal drops; for vaginal or rectal use, for example a suppository; for administration by inhalation, for example as a finely divided powder such as a dry powder, a microcrystalline form or a liquid aerosol; for sub-lingual or buccal use, for example a tablet or capsule; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example a sterile aqueous or oily solution or suspension.
• the above compositions may be prepared in a conventional manner using conventional excipients.
• the amount of active ingredient (that is an oxime derivative of the formula I, or a pharmaceutically-acceptable salt thereof, or a compound of the formula II, 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 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-L0 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, and inflammatory bowel diseases.
• 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-L0 inhibitor of the formula I with a NSAIA can result in a reduction in the quantity of the latter agent needed to produce a therapeutic effect, thereby reducing the likelihood of adverse side-effects.
• a pharmaceutical composition which comprises an oxime derivative of the formula I, or a pharmaceutically- acceptable salt thereof as defined hereinbefore, in conjunction or admixture with a cyclooxygenase inhibitory non-steroidal anti- inflammatory agent (such as those mentioned above), and a pharmaceutically-acceptable diluent or carrier.
• cytoprotective effects of the compounds of the formula I may be demonstrated, for example in a standard laboratory model which assesses protection against indomethacin-induced or ethanol-induced ulceration in the gastrointestinal tract of rats.
• compositions of the invention may in addition contain one or more therapeutic or prophylactic agents known to be of value for the disease under treatment.
• a known platelet aggregation inhibitor, hypolipidemic agent, anti-hypertensive agent, beta-adrenergic blocker or a vasodilator may usefully also be present in a pharmaceutical composition of the invention for use in treating a heart or vascular disease or condition.
• an anti-histamine, steroid such as beclomethasone dipropionate
• sodium cromoglycate sodium cromoglycate
• phosphodiesterase inhibitor or a beta-adrenergic stimulant may usefully also be present in a pharmaceutical composition of the invention for use in treating a pulmonary disease or condition.
• melting points are uncorrected and were determined using a Mettler SP62 automatic melting point apparatus or an oil-bath apparatus; melting points for the end-products of the formula I were determined after recrystallisation from a conventional organic solvent such as ethanol, methanol, acetone, ether or hexane, alone or in admixture;
• O-Methylhydroxylamine hydrochloride (0.054 g) was added to a stirred mixture of 4'- ⁇ 3-[(2S,4R)-4-hydroxy-2-methyltetrahydropyran-4- yl]phenylthio ⁇ acetophenone (0.2 g) and pyridine (2 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with a 2N aqueous hydrochloric acid solution and with brine, dried (MgSO,) and evaporated. The residue was purified by column chromatography using a 4:1 mixture of petroleum ether (b.p.
• the mixture was allowed to warm to ambient temperature and was stirred at that temperature for 3 hours.
• the mixture was acidified by the addition of glacial acetic acid and was partitioned between ethyl acetate and water.
• the organic phase was washed with brine, dried (MgSO,) and evaporated.
• the residue was purified by column chromatography using a 4:1 mixture of petroleum ether (b.p. 40-60°C) and ethyl acetate as eluent.
• Potassium tert-butoxide (0.316 g) was added portionwise to a stirred solution of 4-(2-methyl-l,3-dioxolan-2-yl)benzenethiol (0.506 g) in DMSO (8 ml) and the mixture was stirred at ambient temperature for 5 minutes.
• (2S,4R)-4-hydroxy-4-(3-bromophenyl)-2-methyltetrahydro- pyran (0.7 g) and tetrakis(triphenylphosphine)palladium were added and the mixture was stirred and heated to 115°C for 10 minutes. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water.
• 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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• 1993
  • 1993-12-27 IL IL10818793A patent/IL108187A0/xx unknown
• 1994
  • 1994-01-07 ZA ZA94107A patent/ZA94107B/xx unknown
  • 1994-01-24 GB GB9401271A patent/GB9401271D0/en active Pending
  • 1994-01-25 AU AU59989/94A patent/AU5998994A/en not_active Abandoned
  • 1994-01-25 JP JP6516673A patent/JPH08505865A/ja active Pending
  • 1994-01-25 EP EP94906140A patent/EP0681576A1/en not_active Withdrawn
  • 1994-01-25 WO PCT/EP1994/000186 patent/WO1994017054A1/en not_active Application Discontinuation

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