Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C255/00—Carboxylic acid nitriles
  • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
  • C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
• • 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
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/02—Nutrients, e.g. vitamins, minerals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • 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
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
  • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
  • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
  • C07C275/64—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups singly-bound to oxygen atoms

Definitions

• the present invention is concerned with novel hydroxamic acid derivatives having anti-inflammatory activity, with processes for their preparation, with pharmaceutical formulations containing said derivatives and with their use in medicine.
• European Patent Specification 0196184 describes hydroxamic acid derivatives having anti-inflammatory activity by virtue of their ability to inhibit the enzymes 5- lipoxygenase and cyclooxygenase in the mammalian arachidonic acid cascade.
• the compounds in question include those of formula
• Ar is phenyl
• Ar ' is phenylene
• Y is C2-10 alkenylene
• Rl is C]_4 alkyl, amino, C1- alkylamino, or di-C ⁇ -4 alkylamino;
• Ar and Ar' are optionally substituted by one or more substitutents independently selected from C ⁇ _4 alkyl (which may itself be optionally substituted by one or more halogen atoms), C1- alkoxy, halo, nitro, amino, carboxy, C ⁇ _4 alkoxycarbonyl and hydroxy.
• K ⁇ is phenyl substituted by carbocyclic aryloxy optionally substituted by one, two, or three groups independently selected from halo, nitro, cyano, alkyl, alkoxy, and halosubstituted alkyl;
• X is C2-6 alkenylene
• R2 and R3 are independently selected from hydrogen, C ⁇ . ⁇ alkyl, and carbocyclic aryl.
• B is aryl or aryl substituted with one or more substituents selected from a group including halo, cyano, aminocarbonyl, ⁇ . alkylaminocarbonyl, di C ⁇ .(_. alkylaminocarbonyl, and C ⁇ . alkylsulphonyl;
• A is alkynylene
• R ] is hydrogen, C ⁇ __ ⁇ alkyl, or -NR2R3 (wherein R2 and R3 are independently selected from hydrogen and C 1-4 alkyl).
• A is phenyl optionally substituted by phenoxy (optionally substituted by C ⁇ .(_, alkyl, C ⁇ _6 haloalkyl, C ⁇ . ⁇ alkoxy, hydroxy or halogen);
• B is a bond or a straight or branched divalent C _ 2 alkylene group;
• Rl is hydrogen, C1-. 2 alkyl, C3-.8 cycloalkyl, or -NR2R3 (wherein R2and R3 are independently selected from hydrogen and C ⁇ alkyl) .
• rings A and B is/are substituted by one or more groups independently selected from halo, cyano, -CO R ⁇ R ⁇ (wherein R* and ⁇ are independently selected from hydrogen and C ⁇ _4 alkyl), and -S(O) n R ⁇ (wherein n is an integer of from 0 to 2, and R- is Cj_4 alkyl, C ⁇ . ⁇ aryl, or Cg_i2 aralkyl);
• D is C ⁇ _4 alkyl or -NR ⁇ R ⁇ (wherein * and R ⁇ are independently selected from hydrogen and C1- alkyl);
• R is hydrogen or C ⁇ _4 alkyl
• halo is meant fluoro, chloro, bromo, or iodo; most preferably fluoro.
• Ring A may be unsubstituted or substituted by 1 to 5 groups independently selected from those listed in the definition of formula (I); preferably, ring A is unsubstituted or is substituted by one group selected from halo, cyano, and -SO 2 CH 3 .
• Ring B may be unsubstituted or substituted by 1 to 4 groups independently selected from those listed in the definition of formula (I); preferably, ring B is unsubstituted or is substituted by a cyano group.
• Group Y may be attached to ring B at the 2-, 3-, or 4- position; preferably, the 3- position; relative to the -O- bridging group.
• R is preferably methyl
• D is preferably methyl or amino; most preferably methyl.
• the present invention provides compounds of formula (Ia)
• A' and B 1 are independently sele ⁇ ed from hydrogen, halo, cyano, -CONR* a R2a (where R ⁇ a and R ⁇ a are independently selected from hydrogen and C _4 alkyl), and -S(O) m R 3a (where m is an integer of from 0 to 2 and R 3a is C 1- alkyl, C5-.10 aryl, or C8-12 aralkyl); and
• D' is Cj-4 alkyl or -NR ⁇ a R ⁇ a (where R ⁇ a and R ⁇ a are independently selected from hydrogen and C 1-.4 alkyl);
• R' is C 1- alkyl
• the present invention provides compounds of formula (I) wherein D is C 1-4 alkyl
• the present invention provides compounds of formula (I) wherein Y is -CH ⁇ CH-, and at least one of the substituents on ring A is other than halogen;
• Preferred compounds of formula (I) include those wherein: One/both of rings A and B is/are substituted by one group selected from halo, cyano, and -SO2CH3;
• Y is attached to ring B at the 3-position relative to the -O- bridging group
• R is methyl
• D is methyl or amino
• Salts of compounds of formula (I) which are suitable for use in medicine are those wherein the counterion is pharmaceutically acceptable.
• salts having non- pharmaceutically acceptable counterions are within the ambit of the present invention, either for use in non-medical applications or as intermediates in the preparation of compounds of formula (I) and their pharmaceutically acceptable salts and physiologically functional derivatives.
• Salts according to the invention include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium, salts with organic bases such as dicyclohexylamine and N-methyl-D- glucamine, and salts with amino acids, such as arginine and lysine.
• Examples of pharmaceutically acceptable acid addition salts include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, and sulphuric acids, and organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, glycoUic, gluconic, succinic and methanesulphonic and arylsulphonic, for example j>-toluenesulphonic, acids.
• physiologically functional derivatives is meant chemical derivatives of compounds of formula (I) which have the same physiological function as the free compound of formula (I), for example, by being convertible in the body thereto.
• examples of physiologically functional derivatives include compounds of formula (I) in which the hydroxyl of the hydroxamic acid functional group has been converted to a pharmaceutically acceptable salt, a urethane or an ester.
• compounds of formula (I) and salts, solvates, and physiologically functional derivatives thereof have use in the prophylaxis and treatment of clinical conditions for which an inhibitor of the lipoxygenase or cyclooxygenase mediated arachadonic acid metabolic pathway is indicated, as demonstrated hereinafter in the 5-lipoxygenase and cyclooxygenase inhibition assays in which representative compounds of the present invention have been shown to be active.
• spasmogenic conditions are those involving smooth muscle tissue, especially airway smooth muscle constriction such as asthma (including idiopathic bronchial asthma), bronchitis and arterial smooth muscle constriction such as coronary spasm (including that associated with myocardial infarction, which may or may not lead to left ventricular failure resulting in cardiac asthma), ischemia-induced myocardial injury, and cerebral spasm or 'stroke' (which may lead to central nervous pathophysiology).
• Other examples include bowel disease caused by abnormal colonic muscular contraction such as the conditions known as 'irritable bowel syndrome', 'spastic colon 1 and 'mucous colitis'.
• allergic conditions are extrinsic asthma, allergic skin diseases having a total or partial allergic origin, such as eczema, allergic bowel diseases (including coeliac disease), allergic eye conditions, such as hayfever (which may additionally or alternatively affect the upper respiratory tract), allergic rhinitis, and allergic conjunctivitis.
• tumours are skin neoplasms, mastocytoma and other forms of cellular proliferation, both benign and malignant. It is to be noted that the effectiveness of the present compounds in the prophylaxis and treatment of tumours may arise from properties in addition to 5 -lipoxygenase inhibition which also inhibit cell proliferation.
• conditions involving blood plateiet aggregation are those resulting from thrombosis, including 'strokes' having a total or partial thrombotic origin, coronary thrombosis, phlebitis and phlebothrombosis (the latter two conditions also possibly being associated with inflammation).
• inflammatory conditions are those of the lungs, joints, eyes, bowel, skin, and heart; particularly those associated with the infiltration of leucocytes into inflamed tissue.
• Inflammatory lung conditions include asthma, adult respiratory distress syndrome, bronchitis and cystic fibrosis (which may additionally or alternatively involve the bowel or other tissue(s)).
• Inflammatory joint conditions include rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions.
• Inflammatory eye conditions include uveitis (including ulceris) and conjunctivitis.
• Inflammatory bowel conditions include Crohn's disease, ulcerative colitis and distal proctitis.
• Inflammatory skin diseases include those associated with cell proliferation, such as psoriasis, eczema and dermatitis (whether or not of allergic origin). Inflammatory conditions of the heart include coronary infarct damage. Other inflammatory conditions include tissue necrosis in chronic inflammation, endotoxin shock, smooth muscle proliferation disorders (for example, restenosis following angioplasty), and tissue rejection following transplant surgery.
• the compounds of the invention may also be employed in the prophylaxis or treatment of bone disorders (for example, osteoporosis), bacterial and fungal infections, dysmenorrhoea, multiple sclerosis and clinical conditions for which an immunosuppressant, anti-convulsant, or analgesic is indicated.
• the compounds of the invention also exhibit hypocholesteroiaemic activity.
• the present invention provides a method for the prophylaxis or treatment of a clinical condition in a mammal, such as a human, for which an inhibitor of the lipoxygenase or cyclooxygenase mediated arachadonic acid metabolic pathway, for example, a 5-lipoxygenase or cyclooxygenase inhibitor, is indicated; which comprises administration of a therapeuticaily effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.
• the present invention further provides a method for the prophylaxis or treatment of a clinical condition in a mammal, such as a human, which clinicai condition is a spasmogenic condition, an allergic condition, tumour formation, a condition involving blood platelet aggregation, or an inflammatory condition; which comprises administration of a therapeuticaily effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.
• a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof for use in medical therapy; particularly, for use in the prophylaxis or treatment of a ciinical condition in a mammal, such as a human, for which an inhibitor of the lipoxygenase or cyclooxygenase mediated arachadonic acid metabolic pathway, for example, a 5 -lipoxygenase or cyclooxygenase inhibitor, is indicated; for example a spasmogenic condition, an allergic condition, tumour formation, a condition involving blood platelet aggregation, or an inflammatory condition.
• a suitable daily dose for a mammal suffering from, or likely to suffer from, any of the clinical conditions described hereinbefore is in the range 0.1 ⁇ g - 500mg of compound/kilogram bodyweight.
• the daily dose is typically in the range 0.05 - 500mg of compound/kilogram bodyweight, the most preferred dosage being from 0.05 to 50mg kg bodyweight, for example, from 0.1 to lOmg/kg, administered as two or three sub-doses daily.
• a suitable dose is in the range O.lng - lOO ⁇ g of base per kilogram, typically about O.l ⁇ g/kg.
• a suitable dose of the compound of the invention may be as specified in the preceding paragraph, but preferably is from 0.1 mg to lOmg of compound kilogram bodyweight, the most preferred dosage being from 0.1 mg to 5mg/kg bodyweight.
• the dose is typically in the range 2 ⁇ g - lOOmg/kg, preferably, from 5 ⁇ g to 5mg/kg, for example from 0.01 to 1 mg/kg.
• the present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof in the manufacture of a medicament for the prophylaxis or treatment of a clinical condition for which an inhibitor of the lipoxygenase or cyclooxygenase mediated arachadonic acid metabolic pathway, for example, a 5 -lipoxygenase or cyclooxygenase inhibitor, is indicated; for example a spasmogenic condition, an allergic condition, tumour formation, a condition involving blood platelet aggregation, or an inflammatory condition.
• a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof in the manufacture of a medicament for the prophylaxis or treatment of a clinical condition for which an inhibitor of the lipoxygenase or cyclooxygenase mediated arachadonic acid metabolic pathway, for example, a 5 -lipoxygenase or cyclooxygenas
• the present invention further provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, and a pharmaceutically acceptable carrier or excipient, and optionally one or more other therapeutic ingredients.
• active ingredient means a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.
• the carrier or excipient must, of course, be compatible with the other ingredients in the formulation and must not be detrimental to the recipient.
• the active ingredient may comprise from 0.1% to 99.9% by weight of the formulation.
• Typical unit doses of a formulation according to the invention contain from O.Olmg to lg of the active ingredient.
• the active ingredient preferably constitutes from 1% to 2% by weight of the formulation, but the active ingredient may constitute as much as 10% w/w.
• Formulations suitable for nasal or buccal administration typically contain from 0.1 to 20% w/w, for example, 2% w/w of the active ingredient.
• Formulations according to the invention include those in a form suitable for oral, pulmonary, ophthalmic, rectal, parenteral (including subcutaneous, intramuscular and intravenous), intra-articular, topical, or nasal/buccal administration.
• formulations of the invention may conveniently be presented in unit dosage form and may be prepared by any method well known in the art of pharmacy. All such methods include the step of bringing the active ingredient into association with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier, or both, and then, if desired, shaping the product into the required form.
• Formulations according to the present invention which are suitable for oral administration may be in the form of discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous or non-aqueous liquid; or in the form of an oil-in-water or water-in-oil emulsion.
• the active ingredient may also be in the form of a bolus, electuary, or paste.
• a tablet may be made by compressing or moulding the active ingredient, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, and/or surface active or dispersing agent.
• Moulded tablets may be made by moulding, in a suitable machine, a mixture of the powdered active ingredient and a suitable carrier moistened with an inert liquid diluent.
• Formulations for rectal administration may be in the form of a suppository incorporating the active ingredient and a carrier such as cocoa butter, or in the form of an enema.
• Formulations suitable for parenteral administration typically comprise a sterile aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient.
• Formulations suitable for intra-articular administration may be in the form of a sterile aqueous preparation of the active ingredient, which latter may be in microcrystalline form, for example, an aqueous microcrystalline suspension.
• Liposomal formulations and biodegradable polymer systems may also be used to present the active ingredient for both intra-articular and ophthalmic administration.
• Formulations suitable for topical administration include liquid and semi-liquid preparations such as liniments, lotions and applications; oil-in-water and water-in-oil emulsions such as creams, ointments and pastes; and solutions and suspensions such as drops.
• the active ingredient may be presented as aqueous eye drops, for example, in the form of a 0.1 - 1.0% w/v solution.
• Suitable formulations for administration by inhalation include fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulisers, or insufflators.
• the particle size of the powder or droplets is typically in the range 0.5 - lO ⁇ m, preferably 1 - 5 ⁇ m, to ensure delivery into the bronchial tree.
• a particle size in the range 10 - 500 ⁇ m is preferred to ensure retention in the nasal cavity.
• Metered dose inhalers are pressurised aerosol dispensers, typically containing a suspension or solution formulation of the active ingredient in a liquefied propellant. During use, these devices discharge the formulation through a valve adapted to deliver a metered volume, typically from 10 to 150 ⁇ l, to produce a fine particle spray containing the active ingredient.
• Suitable propellants include certain chlorofluorocarbon compounds, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane and mixtures thereof.
• the formulation may additionally contain one or more co-solvents, for example, ethanol, surfactants, such as oleic acid or sorbitan trioleate, anti-oxidants and suitable flavouring agents.
• Nebulisers are commercially available devices that transform solutions or suspensions of the active ingredient into a therapeutic aerosol mist either by means of acceleration of a compressed gas through a narrow venturi orifice, typically air or oxygen, or by means of ultrasonic agitation.
• Suitable formulations for use in nebulisers consist of the active ingredient in a liquid carrier and comprising up to 40% w/w of the formulation, preferably less than 20% w/w.
• the carrier is typically water or a dilute aqueous alcoholic solution, preferably made isotonic with body fluids by the addition of, for example, sodium chloride.
• Optional additives include preservatives if the formulation is not prepared sterile, for example, methyl hydroxy-benzoate, anti-oxidants, flavouring agents, volatile oils, buffering agents and surfactants.
• Suitable formulations for administration by insufflation include finely comminuted powders which may be delivered by means of an insufflator or taken into the nasal cavity in the manner of a snuff.
• the powder is contained in capsules or cartridges, typically made of gelatin or plastic, which are either pierced or opened in situ and the powder delivered by air drawn through the device upon inhalation or by means of a manually-operated pump.
• the powder employed in the insufflator consists either solely of the active ingredient or of a powder blend comprising the active ingredient, a suitable powder diluent, such as lactose, and an optional surfactant.
• the active ingredient typically comprises from 0.1 to 100 w/w of the formulation.
• formulations according to the invention may include one or more additional ingredients such as diluents, buffers, flavouring agents, binders, compression aids, disintegrants, surface active agents, thickeners, lubricants, preservatives, for example, methyl hydroxybenzoate, anti-oxidants and emulsifying agents.
• additional ingredients such as diluents, buffers, flavouring agents, binders, compression aids, disintegrants, surface active agents, thickeners, lubricants, preservatives, for example, methyl hydroxybenzoate, anti-oxidants and emulsifying agents.
• the compounds of the invention may advantageously be employed in combination with one or more other therapeutic ingredients selected from an antibiotic (for example, an anti-bacterial), anti-fungal, or anti-viral agent, an anti- histamine (particularly a peripherally-acting anti-histamine), or a non-steroidal anti- inflammatory drug (NSAID).
• an antibiotic for example, an anti-bacterial
• a formulation according to the invention may contain, in addition to a compound of the invention, the further ingredient(s).
• Y, R, and the substituents on rings A and B are as defined for the compound of formula (I), or a salt thereof, with a suitable agent or agents to effect conversion of the N-hydrogen to an N-COD group, where D is (a) C ⁇ _4 alkyl, or (b) NR 4 R5 (wherein R 4 and R ⁇ are as defined for formula (I));
• Conversion (a) is typically carried out by treating of the compound of formula (II) with an acylating agent, for example, an appropriate anhydride or activated acid, such as an acid halide, for example, acetyl chloride.
• an acylating agent for example, an appropriate anhydride or activated acid, such as an acid halide, for example, acetyl chloride.
• This reaction is suitably effected in an inert solvent, such as a halohydrocarbon, for example, dichloromethane, at a temperature in the range -10°C to 150°C, for example 0-25°C.
• Conversion (b) is typically carried out by treating the compound of formula (II), or a salt thereof,
• R 4 and R ⁇ are to be hydrogen with a Group I cyanate, for example, potassium cyanate, in a non-polar solvent, such as tetrahydrofuran (THF), in the presence of acid, such as a mineral acid, for example, dilute aqueous HC1, at a temperature in the range -10°C to 150°, for example 0-25°C;
• a Group I cyanate for example, potassium cyanate
• THF tetrahydrofuran
• R 4 is to be C .4 alkyl and R ⁇ is to be hydrogen, with the corresponding isocyanate R 4 NCO, in a suitable solvent, such as a halohydrocarbon, for example, dichloromethane, at a temperature in the range of -10°C to 150°, for example 20- 100°C;
• a suitable solvent such as a halohydrocarbon, for example, dichloromethane
• R 4 and R ⁇ are each to be C ⁇ ._ alkyl, with the corresponding carbamoyl halide, for example R 4 R ⁇ NCOCl, in an inert solvent, such as a halohydrocarbon, for example, dichloromethane, in the presence of base, such as an organic base, for example, pyridine, at a temperature in the range -10°C to 150°C, for example, 20-100°C.
• an inert solvent such as a halohydrocarbon, for example, dichloromethane
• base such as an organic base, for example, pyridine
• Compounds of formula (II), and salts thereof may be prepared by acid or base hydrolysis of the corresponding N,O- or O- blocked compound, for example, the -N(CO2Me)OCO2Me, or -N(Boc)OBoc or -N(Boc)OH compound where Boc is t- butoxycarbonyl.
• the compound of formula (II), or a salt thereof may be prepared by treatment with an acid, such as an arylsulphonic acid, for example, p_-toluenesulphonic acid; in a non-polar solvent for example, toluene; at a moderate temperature, suitably in the range 10°-100°C, for example, 50-60°C.
• the resulting salt of the compound of formula (II) may then optionally be treated to release the free base, for example, by chromatography on silica.
• the N,O- or O- blocked compound may be obtained by reaction of the corresponding compound of formula (HI)
• rings A and B are optionally substituted as described for formula (I) and L is a suitable leaving group, for example, a halogen, (typically bromo or iodo) or trifluoromethanesulfonate; typically at elevated temperature in the presence of a catalyst, such as palladium (II) acetate, tri(o-tolyl)phosphine, and a suitable base, for example, triethylamine.
• a suitable leaving group for example, a halogen, (typically bromo or iodo) or trifluoromethanesulfonate
• a catalyst such as palladium (II) acetate, tri(o-tolyl)phosphine, and a suitable base, for example, triethylamine.
• L' is a leaving group, such as a halogen, for example, fluorine, and ring A is substituted as defined for a compound of formula (I), or a suitably protected form thereof, with a compound of formula (VI)
• This coupling may be effected by reaction in the presence of an inorganic base, for example, potassium carbonate, in an aprotic solvent, for example DMF; at an elevated temperature, for example, 50-200°C.
• an inorganic base for example, potassium carbonate
• an aprotic solvent for example DMF
• compounds of formula (II) may be prepared by oximation of the corresponding ketone, for example, using hydroxylamine in a polar solvent, such as methanol, followed by reduction of the resulting oxime, for example, using sodium cyanoborohydride/oxalic acid.
• the individual enantiomers of the compound of the invention may be obtained by separation of the components of the racemic mixture, for example, by means of a chiral chromatography column or by preparing and separating suitable diastereoisomers, or by direct synthesis from the corresponding chiral compound of formula (II) by the method described above.
• Optional conversion of a compound of formula (I) to a corresponding salt may conveniently be effected by reaction with the appropriate acid or base.
• Optional conversion of a compound of formula (I) to a corresponding solvate or physiologically functional derivative may be effected by methods known to those skilled in the art.
• the present invention provides compounds of formula (II) as defined above, or a salt thereof; particularly a compound selected from:
• Triethylamine (12.7g, Aldrich) was added to a stirred solution of the product from Example 1(a) (17.2g), N,O-bis(t-butoxycarbonylVN-[but-3-en-2- yl]hydroxylamine (19.8g, obtained from but-3-yn-2-ol by the method described in EPS 0384594, Synthetic Examples 2 and 3) and bis(tri-o- tolylphos ⁇ hine) ⁇ alladium(II) chloride (2.5g, Aldrich) in DMF (200 ml).
• p-Toluenesulphonic acid monohydrate (9.1g, Aldrich) was added in one portion to a stirred solution of the product from Example 1(b) (16.5g) in toluene (100ml). The mixture was heated at 50-60°C for 2 hours, then stirred overnight at room temperature and the desired product (1 l.Og) filtered off.
• Potassium cyanate (14.4g, Aldrich) was added in one portion to a stirred solution of the product from Example 1(c) (26.8g) in THF (200ml)/water (10ml) at 0°C followed by the dropwise addition of IN aqu. HCl (118ml) over 30 minutes. The mixture was stirred at room temperature for 2 hours, then poured into a mixture of ethyl acetate (1000ml) and water (500ml). The organic phase was separated and washed with 0.5N aqu. HCl, water, saturated aqu. sodium bicarbonate and saturated brine, dried over anhydrous sodium sulphate and evaporated in vacuo to give a pale tan foam.
• p-Toluenesulphonic acid monohydrate (260mg) was added to a solution of the product from Example 2(a) in toluene (8ml). The mixture was heated at 50°C for 2-3 hours, then stirred at room temperature for 24 hours. The reaction was then dried in vacuo. the residue taken up in toluene and the title product was precipitated by addition of diethyl ether and collected.
• the title product was obtained from 4-(3-bromophenoxy)benzonitetrile and N,O-bis (t-butoxycarbonyl)-N-[but-3-en-2(S)-yl]hydroxylamine (obtained from but-3-yn-2(R)-ol by the method described in EP 0384594), by the method of Examples 1 and 2.
• Example 3(a) The title product was obtained by reaction of the product from Example 3(a) with potassium cyanate under the conditions described in Example 2(c). The product was isolated as a white solid, mp 58-60° C.
• Example 3(a) The title products were prepared by reaction of the product from Example 1(a) and N,O-bis(t-butoxycarbonyl)-N-[but-3-en-2(S)-yl]hydroxylamine (see Example 3(a)) by the method of Example 2(a).
• the products were purified by column chromatography on silica, eluting with ethyl acetate/hexane (1:9).
• Example 15(a) The products from Example 15(a) were deprotected by heating in dry toluene with p-toluenesulphonic acid (1.05eq), under N2, a * 50°C for 2 hours, and then stirring at room temperature overnight. The crude products were combined, and the solvent removed in vacuo. The residue was purified by flash chromatography on silica, eluting with methanol dichloromethane (2:98) to afford the title product. (c) O-Acetyl-(EVN-(3-r3-(4-cyanophenoxy phenyl]-USVmethyl-prop-2-enyl ⁇ acetohydroxamic acid
• Example 16(a) To a solution of the product from Example 16(a) in water, was added calcium chloride dihydrate (93 mg) in water and the reaction was stirred at room temperature until the crude product precipitated. The precipitate was collected by filtration then washed with water, then diethyl ether. The product was dried at 40°C under high vacuum, mp 135°C (shrinks 100°C).
• the p-toluenesulphonate salt (2.2g) was stirred with a solution of potassium carbonate (2g) in water (50ml), then extracted 3 times with ethyl acetate. The combined organic phases were washed with water, then semi-saturated brine, before being dried over Na2SO4, filtered, and the solvent was removed in vacuo.
• the "active ingredient" in the following formulations is as defined above; preferably one of the compounds of Synthetic Examples 1 to 18.
• Disperse the active ingredient in a small volume of the vehicle Gradually incorporate this into the bulk to produce a smooth, homogeneous product. Fill into collapsible metal tubes.
• the methyl hydroxybenzoate and glycerin were dissolved in 70ml of the water at 75°C.
• the sorbitan monolaurate, Polysorbate 20 and cetostearyl alcohol were melted together at 75°C and added to the aqueous solution.
• the resulting emulsion was homogenised, allowed to cool with continuous stirring and the active ingredient added as a suspension in the remaining water. The whole was stirred until homogeneous.
• Example F Oral capsule
• Example G Powder capsules for inhalation
• the powders were mixed until homogeneous and filled into suitably sized hard gelatin capsules (50mg per capsule).
• LTB4 leukotriene B4
• test compound was administered both intravenously. (1/4 DMSO/3/4 PEG 200) and orally. (0.25% celacol).
• concentration of LTB4 in the plasma was measured periodically and expressed as a percentage of the mean control value.
• the procedure used is described in Br. J. Pharmacol. 94, 528 (1988) and may be summarised as follows.
• the compounds of Synthetic Examples 1 and 15 inhibited ex vivo LTB4 production by more than 80% for over 12 hours. Under the same conditions, the compounds of Synthetic Examples 2, 3, 11, and 18 gave 80% inhibition for at least one hour. Compounds of the other Synthetic Examples were either untested or gave less than 80% inhibition.
• Leukocytes were isolated from blood donated by normal aspirin-free volunteers by washing and centrifugation. A solution of the test compound in DMSO (lO ⁇ l, final concentration 0.01 - lOO ⁇ M) was added to the washed cell suspension (480 ⁇ l) and the mixture incubated at room temperature for 5 minutes. The tubes were placed on ice for 5 minutes and then stimulated with the calcium ionophore A23157 (lO ⁇ l, final concentration 2.0 ⁇ M) for 5 minutes at 37°C. The reaction was. terminated by boiling and the plasma concentration of LTB4 determined by Scintillation Proximity Assay (SPA).
• SPA Scintillation Proximity Assay
• Washed platelet suspensions from healthy human donors were prepared according to the method of Radomski et al (Thromb. Res., 30, 383-393, 1983). Tubes containing aliquots (0.5ml) of platelet suspension (10 ⁇ cells/ml) were incubated with test drug or vehicle for 5 minues at room temperature before being placed on an ice bath for a further 5 minutes. The calcium ionophore A-23187 was added (final concentration 2 ⁇ M) and the tubes were incubated for 5 minutes at 37°C. The reaction was terminated by boiling for 2 minutes and the cellular precipitate removed for centrifugation. The thromboxane B2 content of the supernatant was determined by radio-immunoassay .
• the animals were pre-sensitised to antigen (ovalbumin) 2 to 3 weeks prior to testing in the bronchospasm model. Compounds were given to the animals orally, 1-6 hours before antigen challenge at a dose of lOmg kg. Control animals were dosed only with vehicle. The time of dosing before challenge was noted. Indomethacin and mepyra ine were also given 10 minutes before challenge.
• a measured challenge of nebulised antigen was given to anaesthetised animals to promote an allergic asthma-like response, and the change in pulmonary inflation pressure (PIP) measured. PIP was measured continuously from before the challenge for 11 minutes.
• the compound of Synthetic Example 1, when given 1 hour before challenge gave 64% inhibition of response.
• the compound of Synthetic Example 15 gave 66% inhibition of response when given 6 hours before challenge.

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