EP0696272A1 - Cyclooxygenase and 5-lipoxygenase inhibiting n(3-biphenylyl-1(s)-methyl-2-propenyl) acetohydroxamic acid derivatives - Google Patents

Cyclooxygenase and 5-lipoxygenase inhibiting n(3-biphenylyl-1(s)-methyl-2-propenyl) acetohydroxamic acid derivatives

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Publication number
EP0696272A1
EP0696272A1 EP94913700A EP94913700A EP0696272A1 EP 0696272 A1 EP0696272 A1 EP 0696272A1 EP 94913700 A EP94913700 A EP 94913700A EP 94913700 A EP94913700 A EP 94913700A EP 0696272 A1 EP0696272 A1 EP 0696272A1
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EP
European Patent Office
Prior art keywords
compound
formula
biphenylyl
methyl
physiologically functional
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Withdrawn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
EP94913700A
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German (de)
English (en)
French (fr)
Inventor
Simon Teanby Hodgson
Peter John Wates
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.)
Wellcome Foundation Ltd
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Wellcome Foundation Ltd
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Filing date
Publication date
Priority claimed from GB939308652A external-priority patent/GB9308652D0/en
Priority claimed from GB939318432A external-priority patent/GB9318432D0/en
Application filed by Wellcome Foundation Ltd filed Critical Wellcome Foundation Ltd
Publication of EP0696272A1 publication Critical patent/EP0696272A1/en
Withdrawn legal-status Critical Current

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
    • C07C17/263—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions
    • 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
    • C07C255/53—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and hydroxy groups bound to the carbon skeleton
    • 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
    • C07C255/56—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and doubly-bound oxygen atoms bound to the carbon skeleton
    • 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
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/28—Alcohols containing only six-membered aromatic rings as cyclic part with unsaturation outside the aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/227—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing halogen
    • C07C49/233—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings
    • C07C49/235—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings having unsaturation outside the aromatic rings

Definitions

  • the present invention is concerned with hydroxamic acid derivatives which are inhibitors of the lipoxygenase and cyclooxygenase mediated arachidonic acid metabolic pathway, 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 the ability to inhibit the enzymes 5-lipoxygenase and cyclooxygenase in the mammalian arachidonic acid cascade.
  • the compounds in question include those of formula
  • Y is C2-10 alkenylene
  • Rl is Cj_4 alkyl, amino, C]_4 alkylamino, or di-C ⁇ -4 alkylamino;
  • Ar is phenyi optionally substituted by one or more substituents independently selected from:
  • WO 90/12008, WO 92/10469, and WO 92/01682 also disclose compounds having lipoxygenase inhibitory activity.
  • X is cyano, fluoro, or chloro
  • the present invention provides a compound selected from:
  • 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 as intermediates in the preparation of compounds of formula (I) and their pharmaceutically acceptable salts, solvates, 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.
  • 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 urethane, an alkyl ether, or an ester.
  • the definition of the compounds of the invention provides compounds of formula (I) in the (S) form.
  • the present invention also provides compounds of formula (I) as mixtures of the (R) and (S) forms, provided that the (R) form constitutes less than 50% of the mixture.
  • 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 arachidonic 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' 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 platelet 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 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 arachidonic acid metabolic pathway, for example, a 5- lipoxygenase or cyclooxygenase inhibitor, is indicated; which comprises administration of a therapeutically 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 clinical 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 therapeutically 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 clinical condition in a mammal, such as a human, for which an inhibitor of the lipoxygenase or cyclooxygenase mediated arachidonic 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 - 50mg of compound/kilogram bodyweight.
  • the daily dose is typically in the range 0.05 - 50mg of compound/kilogram bodyweight, the most preferred dosage being from 0.05 to 20mg/kg bodyweight, for example, from 0.1 to lOmg/kg, administered as two or three sub-doses daily.
  • topical administration e.g. to the skin or eye
  • a suitable dose is in the range 0.1 ⁇ g - lOO ⁇ g of base per kilogram, typically about 0. l ⁇ g/kg.
  • a suitable dose of the compound of the invention may be as specified in the preceding paragraph, but preferably is from O.lmg to lOmg of compound/kilogram bodyweight, the most preferred dosage being from O.lmg 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 arachidonic 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 arachidonic acid metabolic pathway, for example, a 5-lipoxygenase or cyclooxygenase inhibitor, is indicated;
  • 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.
  • the 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.
  • the particle size of the active ingredient may be reduced before formulation, for example, by micronisation.
  • 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, suspension, or a microfine 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 disintegrant, compression aid, 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 or non-aqueous preparation such as an emulsion, suspension, or colloid of the active ingredient which is preferably isotonic with the blood of the recipient. Such formulations may also be freeze-dried and then reconstituted by addition of a sterile fluid shortly before administration.
  • a sterile aqueous or non-aqueous preparation such as an emulsion, suspension, or colloid of the active ingredient which is preferably isotonic with the blood of the recipient.
  • Such formulations may also be freeze-dried and then reconstituted by addition of a sterile fluid shortly before administration.
  • 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, for example to present the active ingredient for parenteral, 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 ⁇ , 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 shu 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).
  • Conversion of the N-hydrogen to an N-C(O)CH3 group is typically carried out by treating a 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, or an alkylbenzene, for example, toluene, at a temperature in the range -10°C to 150°C, for example 0-25°C in the presence of an organic base, such as a trialkylamine, for example, triethylamine.
  • Any N,O-diacylated product of this reaction may be mono-O-deacylated, suitably by treatment with an inorgan
  • the compound of formula (II) may be obtained as the (S) enantiomer.
  • the compound of formula (II) may be obtained as the (S) enantiomer by : (i) separating the enantiomers obtained from the acylation reaction by any suitable method; (ii) effecting the mono-O-deacylation reaction by treatment with an enzyme capable of selectively reacting with the (S) enantiomer, for example a lipase, to produce a mixture of the compound of formula (I) as the (S) enantiomer and the N,O-diacylated (R) enantiomer which can then be separated, for example by chromatography; (iii) effecting the mono-O-deacylation reaction by treatment with an enzyme capable of selectively reacting with the (R) enanti
  • X is as defined for a compound of formula (I)
  • P' is a protecting group, such as an alkoxycarbonyl group, for example, -CO2CH3, a cyclic ether, for example, tetrahydropyran, or t-butoxycarbonyl (Boc) and P" is a protecting group as described for P' or is hydrogen.
  • the conversion to a compound of formula (II) is suitably effected by acid or base hydrolysis as would be understood by the person skilled in the art.
  • the compound of formula (II), or a salt thereof may be prepared by treatment with an acid, such as an arylsulphonic acid, for example, para-toluenesulphonic acid; in a non-polar solvent, for example, toluene; at a moderate temperature, suitably in the range 10-100°, for example, 50-60°C.
  • the resulting salt of the compound of formula (II) may then optionally be hydrolysed to release the free base, for example, by chromatography on silica or by treatment with an inorganic base, such as a carbonate, for example, sodium carbonate.
  • X is as defined for the compound of formula (I) and L is a suitable leaving group, for example, a halogen, (typically bromo or iodo) or a substituted sulphonate, for example, trifluoromethanesulfonate; typically at elevated temperature, for example, 50-150°C, in a polar solvent, for example, N,N-dimethylformamide, in the presence of a catalyst, such as palladium (II) acetate with tri(o-tolyl)phosphine, and a suitable base, such as a trialkylamine, for example, triethylamine; or
  • X is as defined for formula (I), with a compound of formula HN(P')OP' wherein P' is as defined for the compound of formula (III).
  • This reaction may be effected under Mitsunobu conditions, for example in the presence of diethyl azodicarboxylate (DEAD) or diwopropyl azodicarboxylate (DIAD) and triphenylphosphine (PP1-3); in a non-polar solvent, such as toluene; at low temperature, ie -20° to 50°C, for example in the region of 0°C.
  • DEAD diethyl azodicarboxylate
  • DIAD diwopropyl azodicarboxylate
  • PP1-3 triphenylphosphine
  • this reaction may be effected by activation of the compound of formula (VI), for example by esterification of the hydroxyl group, typically using an acid anhydride (eg. acetic anhydride) or an acid halide (e.g. chloroacetyl chloride); in the presence of a base (eg. 4-dimethylaminopyridine, DMAP); and a catalyst, for example, tetrakis(triphenylphosphine) palladium (O); in a non-polar solvent, such as tetrahydrofuran (THF); at elevated temperature, for example, 40-120°C.
  • an acid anhydride eg. acetic anhydride
  • an acid halide e.g. chloroacetyl chloride
  • a base eg. 4-dimethylaminopyridine, DMAP
  • a catalyst for example, tetrakis(triphenylphosphine) palladium (O); in a non-polar solvent,
  • X is as defined for the compound of formula (I).
  • the reduction may be done in such a way that a chiral alcohol of formula (VI) is obtained, for example, (a) by using a chiral inducing catalyst, suitably an oxazaborolidine CBS catalyst (E.J. Corey et al Tet Letters 31(5), 611 (1990)) with the reducing agent, suitably catechol borane in an inert solvent, such as a cyclic ether (eg. THF) or an alkylbenzene (eg. toluene) at low temperature, for example in the range -100°C to 50°C, or (b) by an enzymic reduction process.
  • a chiral inducing catalyst suitably an oxazaborolidine CBS catalyst (E.J. Corey et al Tet Letters 31(5), 611 (1990)
  • the reducing agent suitably catechol borane in an inert solvent, such as a cyclic
  • the reduction may be carried out to give the racemic alcohol of formula (VI) using conventional reducing agents of organic chemistry for example, treatment with sodium borohydride in a polar solvent, such as an alcoholic solvent, at low temperature, for example in the range -50°C to 30°C.
  • a polar solvent such as an alcoholic solvent
  • the enantiomeric mixture of compounds of formula (VI) so obtained may be separated into the individual enantiomers by any suitable method, for example, by an enzymic resolution process, typically an enzyme catalysed acyl-transfer or hydrolysis reaction effected by treating the racemic compound of formula (VI) with an acyl donor, such as an enol ester (eg. vinyl acetate), an activated ester (eg.
  • an acid anhydride eg. succinic anhydride
  • a suitable enzyme capable of acylating only one enantiomer, such as a lipase
  • an inert solvent such as an aromatic solvent (eg. toluene)
  • a suitable enzyme capable of selectively hydrolising one acylated enantiomer, such as a lipase.
  • the resulting enantiomers may then be separated because one of them is present in acylated form, by any appropriate method, for example, by chromatography. If desired, the unwanted enantiomer may be "recycled", for example by racemic deacylation, suitably by hydrolysis; or
  • This reaction may be carried out in the presence of a suitable catalyst system, for example, palladium (II) acetate/tri-(o- tolyl)phosphine, and a base, such as a trialkylamine, for example, triethylamine.
  • a suitable catalyst system for example, palladium (II) acetate/tri-(o- tolyl)phosphine
  • a base such as a trialkylamine, for example, triethylamine.
  • Subsequent removal of the hydroxyl protecting group P' may be effected by any suitable method, such as hydrolysis, for example, acid hydrolysis; or
  • the compound of formula (VII) may be prepared by reaction of the corresponding aldehyde of formula (IX)
  • R' is C ] _4 alkyl or, alternatively with acetone; in the presence of a base, such as sodium carbonate; in a polar solvent, such as THF, at a non-extreme temperature, for example -50° to 30°C.
  • a base such as sodium carbonate
  • a polar solvent such as THF
  • Compounds of formula (IX) may be prepared from compounds of formula (V) as defined above, typically by lithiation (for example with n-butyl lithium at low temperature, i ⁇ -100° to -20°C) followed by reaction with N,N-dimethylformamide (DMF).
  • lithiation for example with n-butyl lithium at low temperature, i ⁇ -100° to -20°C
  • DMF N,N-dimethylformamide
  • L is as defined above for formula (V) and L' is either the same as L or is a different leaving group as understood by a skilled person.
  • This coupling may suitably be effected in the presence of a suitable catalyst, for example, tetrakis (triphenylphosphine) palladium (0) and an inorganic base, for example, sodium carbonate.
  • a suitable catalyst for example, tetrakis (triphenylphosphine) palladium (0) and an inorganic base, for example, sodium carbonate.
  • compounds of formula (V) may be prepared by coupling a compound of formula (XII) as hereinbefore defined with the appropriate organometallic reagent (for example, the appropriately substituted PbMgY or PhZnY, where Y is a halogen) which may be prepared in situ from the corresponding halide by treatment with the metal (e.g. Mg or Zn).
  • organometallic reagent for example, the appropriately substituted PbMgY or PhZnY, where Y is a halogen
  • the coupling may be effected in an inert solvent, for example, THF, in the presence of a catalyst, for example, l,4-bis(diphenylphosphine)butane palladium (0) dichloride, palladium acetate, or tetrakistriphenyl phosphine palladium (0), at non-extreme temperature, for example 0-60°C.
  • a catalyst for example, l,4-bis(diphenylphosphine)butane palladium (0) dichloride, palladium acetate, or tetrakistriphenyl phosphine palladium (0), at non-extreme temperature, for example 0-60°C.
  • the enantiomeric compounds of the invention may be obtained (a) by separation of the components of the corresponding racemic mixture, for example, by means of a chiral chromatography column, enzymic resolution methods as described above, or preparing and separating suitable diastereoisomers, or (b) by direct synthesis from the appropriate chiral intermediates by the methods described above.
  • Optional conversion of a compound of formula (I) to a corresponding salt may conveniently be effected by reaction with the appropriate 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 novel intermediates for the preparation of compounds of formula (I), for example:
  • the reaction mixture was poured into water (250 ml) with stirring for 5 minutes, and then the mixture was extracted with ethyl acetate (3 x 100 ml). The extracts were combined, washed with water (3 x 150 ml), dried over anhydrous magnesium sulphate and filtered. The filtrate was evaporated under reduced pressure to give a tan, viscous oil (7.66g) which was used without further purification.
  • the reaction mixture was evaporated under reduced pressure and the residue treated with water (100ml) followed by acidification with citric acid.
  • the mixture was extracted with ethyl acetate (3 x 100ml) and the combined extracts were then washed with water (2 x 150ml) and dried over anhydrous magnesium sulphate.
  • the mixture was filtered and the filtrate evaporated under reduced pressure to give a pale orange gum from which the product (1.18g) was isolated as a pale yellow gum by silica gel column chromatography, eluting with diethyl ether.
  • reaction mixture was diluted with diethyl ether (125ml) and the resulting aqueous layer was separated and washed with diethyl ether (2x125ml).
  • diethyl ether 2x125ml
  • the combined ethereal solutions were washed with water and dried over MgSO4. Removal of the solvent gave the title compound as a cream solid (78.5g).
  • Example 2(e) The product from Example 2(e) (100 mg) was heated at 40OC and 0.05 mbar for 1 hour. The temperature was raised to 550C for a further 1 hour, then to 80OC for 3 hours. Heating was removed and the melt allowed to return to room temperature before the vacuum was released. The colourless, glassy residue was triturated with a 2: 1 mixture of diethyl ether and petroleum ether bp 40-60OC (5 ml) to yield a colourless, feathery, crystalline solid (70 mg); mp 115-1170C.
  • the first eluted compound (1.64g) was the N,O-bis(t-butoxycarbonyl) product and the slower-running component (1.74g) was the N-mono(t-butoxycarbonyl) compound. Both compounds were gums, containing impurities by NMR and were combined and used directly in the following step.
  • Example 2(b) To a solution of the product from Example 2(b) (5.0g) in THF (50ml), under nitrogen, was added n-butyl lithium (1.6M solution in hexane, 12.5ml), maintaining a temperature of around -70°C. DMF (1.55ml) was then added slowly keeping the temperature in the range -73° to -53°C.
  • reaction mixture was allowed to warm to room temperature and was diluted with water (50ml).
  • the resulting organic phase was washed with water (50ml) diluted with toluene (50ml) and solvent removed under reduced pressure to leave a colourless oil.
  • This oil was purified by column chromatography to give the product as a viscous colourless oil (0.49g).
  • the mixture was diluted with diethyl ether (50ml) and water (50ml) and the aqueous layer extracted with diethyl ether (50ml). The combined organic layers were washed with water (50ml), dried over magnesium sulphate, and concentrated to leave a yellow oil (5.6g). The oil was purified by column chromatography to give the product as a viscous colourless oil (2.86g).
  • Example 2(e) The product from Example 2(e) (0.299g, lmmol) was dissolved in dry THF (5ml) under nitrogen and N-methylmorpholine (0.202g, 0.220ml, 2mmol) was added in one portion, followed by ethyl isocyanatoacetate (0.129g, 0.112ml, lmmol). The mixture was stirred at room temperature overnight, then was partitioned between ethyl acetate and IN hydrochloric acid. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulphate, filtered and evaporated in vacuo. Chromatographic purification of the crude produce on silica, with 1 : 1 ethyl acetate: cyclohexane eluent gave the title compound (0.257g, 52%) as a waxy solid.
  • the "active ingredient" in the following formulations is as defined above; preferably one of the compounds of Synthetic Examples 1 to 4.
  • 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.
  • Example C Cream for topical use
  • Methyl hydroxybenzoate 0.1 g Distilled Water to 100.0 g Heat the Polawax, beeswax and lanolin together at 60°C. Add a solution of methyl hydroxybenzoate. Homogenise using high speed stirring. Allow the temperature to fall to 50°C. Add and disperse the active ingredient. Allow to cool with slow speed stirring.
  • 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
  • Example H Inhalation aerosol
  • Leukocytes were isolated from blood donated by normal aspirin-free volunteers by washing and centrifugation. A solution of the test compound in DMSO (10 ⁇ 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 A-23187 (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 minutes 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.

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EP94913700A 1993-04-27 1994-04-26 Cyclooxygenase and 5-lipoxygenase inhibiting n(3-biphenylyl-1(s)-methyl-2-propenyl) acetohydroxamic acid derivatives Withdrawn EP0696272A1 (en)

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GB9308652 1993-04-27
GB939308652A GB9308652D0 (en) 1993-04-27 1993-04-27 Anti-inflammatory compounds
GB9318432 1993-09-06
GB939318432A GB9318432D0 (en) 1993-09-06 1993-09-06 Anti-inflammatory compounds
PCT/GB1994/000886 WO1994025431A1 (en) 1993-04-27 1994-04-26 Cyclooxygenase and 5-lipoxygenase inhibiting n(3-biphenylyl-1(s)-methyl-2-propenyl) acetohydroxamic acid derivatives

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US6136839A (en) * 1995-06-12 2000-10-24 G. D. Searle & Co. Treatment of inflammation and inflammation-related disorders with a combination of a cyclooxygenase-2 inhibitor and a 5-lipoxygenase inhibitor
CN1315858A (zh) * 1998-07-17 2001-10-03 富士药品工业株式会社 新型过敏性疾病的治疗剂
US6833373B1 (en) 1998-12-23 2004-12-21 G.D. Searle & Co. Method of using an integrin antagonist and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
US6858598B1 (en) 1998-12-23 2005-02-22 G. D. Searle & Co. Method of using a matrix metalloproteinase inhibitor and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
AR038957A1 (es) 2001-08-15 2005-02-02 Pharmacia Corp Terapia de combinacion para el tratamiento del cancer
EP1474127B1 (en) * 2002-02-15 2006-11-15 Endorecherche, Inc. Biphenyl derivatives and their use as antiandrogenic agents
CN112358416B (zh) * 2020-11-03 2021-10-15 北京科技大学 一种反式-3-氯-2-丙烯基羟胺的制备方法

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AU602485B2 (en) * 1985-03-16 1990-10-18 Wellcome Foundation Limited, The Lipoxygenase and/or cyclooxygenase inhibitory compounds
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