EP0702680A1 - Derives de 2-oxo-1,2,3,4-tetrahydroquinoline - Google Patents

Derives de 2-oxo-1,2,3,4-tetrahydroquinoline

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Publication number
EP0702680A1
EP0702680A1 EP94919602A EP94919602A EP0702680A1 EP 0702680 A1 EP0702680 A1 EP 0702680A1 EP 94919602 A EP94919602 A EP 94919602A EP 94919602 A EP94919602 A EP 94919602A EP 0702680 A1 EP0702680 A1 EP 0702680A1
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European Patent Office
Prior art keywords
formula
oxo
methyl
compound
group
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Application number
EP94919602A
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German (de)
English (en)
Inventor
Pierre Andre Raymond Zeneca-Pharma S.A. BRUNEAU
Philip Neil Edwards
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AstraZeneca SAS
Syngenta Ltd
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Zeneca Pharma SA
Zeneca Ltd
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Priority to EP94919602A priority Critical patent/EP0702680A1/fr
Publication of EP0702680A1 publication Critical patent/EP0702680A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention concerns 2-oxo-l,2,3,4-tetrahydroquinoline derivatives and more particularly 2-oxo-l,2,3,4-tetrahydroquinoline derivatives which are inhibitors of the enzyme 5-lipoxygenase (hereinafter referred to as 5- O).
  • the invention also concerns processes for the manufacture of said 2-oxo-1,2,3, -tetrahydro- quinoline derivatives and novel pharmaceutical compositions containing them.
  • Also included in the invention is the use of said 2-oxo-l,2,3,4-tetrahydroquinoline derivatives in the treatment of various diseases such as inflammatory and/or allergic diseases in which the direct or indirect products of 5- O catalysed oxidation of arachidonic acid are involved, and the production of new medicaments for such use.
  • 2-oxo-l,2,3,4-tetrahydroquinoline derivatives described hereinafter are inhibitors of 5-LO, which enzyme is known to be involved in catalysing the oxidation of arachidonic acid to give rise via a cascade process to the physiologically active leukotrienes such as leukotriene B, (LTB,) and the peptido-lipid leukotrienes such as leukotriene C, ( TC,) and leukotriene D, (LTD.) and various metabolites.
  • 5-LO which enzyme is known to be involved in catalysing the oxidation of arachidonic acid to give rise via a cascade process to the physiologically active leukotrienes such as leukotriene B, (LTB,) and the peptido-lipid leukotrienes such as leukotriene C, ( TC,) and leukotriene D, (LTD.) and various metabolites.
  • the biosynthetic relationship and physiological properties of the leukotrienes are summarised by G.W. Taylor and S.R. Clarke in Trends in Pharmacological Sciences, 1986, _, 100-103.
  • the leukotrienes and their metabolites have been implicated in the production and development of various diseases, for example various inflammatory and allergic diseases such as inflammation of the joints (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), skin diseases (especially psoriasis, eczema and dermatitis), ocular conditions (especially allergic conjunctivitis and uveitis) and respiratory disease (especially asthma, bronchitis and allergic rhinitis), for example in the production and development of various cardiovascular and cerebrovascular disorders such as myocardial infarction, the formation of atherosclerotic plaques, hypertension, platelet aggregation, angina, stroke
  • leukotrienes are mediators of inflammatory diseases by virtue of their ability to modulate lymphocyte and leukocyte function.
  • Other physiologically active metabolites of arachidonic acid such as the prostaglandins and thromboxanes, arise via the' action of the enzyme cyclooxygenase on arachidonic acid.
  • Such compounds are of value as therapeutic agents in the treatment of, for example, allergic conditions, psoriasis, asthma, cardiovascular and cerebrovascular disorders, and/or inflammatory and arthritic conditions, and/or disorders of bone metabolism, mediated alone or in part by one or more leukotrienes.
  • Q is 2-oxo-l,2,3,4-tetrahydroquinolin- ' 6-yl which bears on the nitrogen atom at the 1-position a (l-4C)alkyl substituent;
  • X is thio, sulphinyl or sulphonyl
  • Ar is 1,3-phenylene which may optionally bear one or two halogeno substituents
  • R 1 is (l-4C)alkyl, (3-4C)alkenyl or (3-4C)alkynyl;
  • R and R together form a group of the formula -A -X -A - which
  • each is (l-3C)alkylene and X is oxy, and which ring may bear one or two (l-4C)alkyl substituents; or a pharmaceutically-acceptable salt thereof.
  • alkyl includes both straight-chain and branched-chain alkyl groups.
  • references to individual alkyl groups such as “propyl” are specific for the straight-chain version only and references to individual branched-chain alkyl groups such as “isopropyl” are specific for the branched-chain version only.
  • An analogous convention applies to other generic terms.
  • optically active or racemic forms by virtue of one or more asymmetric carbon atoms
  • the invention includes in its definition any such optically active or racemic form which possesses the property of inhibiting 5-LO.
  • the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • a suitable value for the (1-4C)alkyl substituent which is present on Q is, for example, methyl, ethyl or propyl.
  • a suitable value for a halogeno substituent which may be present on Ar is, for example, fluoro.
  • a suitable value for R when it is (l-4C)alkyl is, for example, methyl, ethyl or propyl; when it is (3-4C)alkenyl is, for example, allyl; and when it is (3-4C)alkynyl is, for example,
  • (l-3C)alkylene is, for example, methylene, ethylene or trimethylene.
  • Suitable values for the (1-4C)alkyl substituents which may be present on said 5- or 6-membered ring include, for example, methyl and ethyl.
  • 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, 2-oxo-l,2,3,4-tetrahydroquinoline derivatives of the formula I, or pharmaceutically-acceptable salts thereof, wherein the variable groups Q, X 1, Ar, R1, R2 and R3 have the values disclosed hereinbefore or hereinafter in this section concerning particular compounds of the invention:-
  • Q is l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6-yl
  • Ar is 1,3-phenylene or 5-fluoro-l,3-phenylene
  • Ar is 2,5-difluoro-l,3-phenylene
  • R is methyl
  • A is ethylene and X is oxy, and which ring may bear a
  • a preferred compound of the invention comprises a
  • X is thio or sulphonyl
  • Ar is 1,3-phenylene or 5-fluoro-l,3-phenylene
  • R is methyl
  • R and R together form a group of the formula -A -X -A - which
  • a further preferred compound of the invention comprises a
  • Q is l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6-yl
  • X is thio or sulphonyl
  • Ar is 1,3-phenylene, 5-fluoro-l,3-phenylene or
  • R is methyl
  • R and R together form a group of the formula -A -X -A - which
  • a further preferred compound of the invention comprises a 2-oxo-l,2,3,4-tetrahydroquinoline derivative of the formula I wherein Q is l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6-yl; X is thio or sulphonyl; Ar is 5-fluoro-l,3-phenylene;
  • R is methyl
  • R and R together form a group of the formula -CH 2 CH 2 OCH(CH 3 )CH 2 -; or a pharmaceutically-acceptable salt thereof.
  • a further preferred compound of the invention comprises a
  • Q is l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6-yl
  • X is thio or sulphonyl
  • Ar is 5-fluoro-l,3-phenylene or 2,5-difluoro-l,3-phenylene;
  • R is methyl
  • R and R together form a group of the formula -CH 2 CH 2 0CH(CH-.)CH 2 -; or a pharmaceutically-acceptable salt thereof.
  • a specific preferred compound of the invention is the following compound of the formula I:-
  • a specific especially preferred compound of the invention is the following compound of the formula I:-
  • a specific especially preferred compound of the invention is the following compound of the formula I:-
  • a compound of the invention comprising a 2-oxo-l,2,3,4-tetrahydroquinoline 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 representative examples in which, unless otherwise stated, Q, X , Ar,
  • R , R and R have any of the meanings defined hereinbefore.
  • a suitable displaceable group Z is, for example, a halogeno or sulphonyloxy group, for example a fluoro, chloro, bromo, iodo, methane- sulphonyloxy or toluene-4-sulphonyloxy group.
  • a suitable base for the coupling reaction is, for example, an alkali or alkaline earth metal carbonate, (l-4C)alkoxide, hydroxide or hydride, for example sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride, or an organometallic base such as (l-4C)alkyl-lithium, for example n-butyl-lithium.
  • the coupling reaction is conveniently performed in a suitable inert solvent or diluent, for example N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulphoxide, acetone, 1,2-dimethoxyethane or tetrahydrofuran, and at a temperature in the range, for example, 10 to 150°C, conveniently at or near 100°C.
  • a suitable inert solvent or diluent for example N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulphoxide, acetone, 1,2-dimethoxyethane or tetrahydrofuran, and at a temperature in the range, for example, 10 to 150°C, conveniently at or near 100°C.
  • reaction may be performed in the presence of a suitable catalyst, for example a metallic catalyst, for example palladium(O) or copper(I) such as tetrakis(triphenylphosphine)- palladiu , cuprous chloride or cuprous bromide.
  • a suitable catalyst for example a metallic catalyst, for example palladium(O) or copper(I) such as tetrakis(triphenylphosphine)- palladiu , cuprous chloride or cuprous bromide.
  • the starting materials of the formula Q-X -H and of the formula II may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described within the accompanying non-limiting Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist. The disclosure of European Patent Application No. 0420511 is particularly relevant to the preparation of suitable starting materials.
  • the coupling reaction is conveniently performed in a suitable inert solvent as defined hereinbefore and at a temperature in the range, for example, 10 to 150°C, conveniently at or near 100°C.
  • the reaction may conveniently be performed in the presence of a suitable catalyst as defined hereinbefore.
  • the starting materials of the formula Q-Z and of the formula III may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described within the accompanying non-limiting Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist. The disclosure of European Patent Application No. 0420511 is particularly relevant to the preparation of suitable starting materials.
  • H is an alkali metal or alkaline earth metal such as lithium or calcium or H represents the magnesium halide portion of a conventional Grignard reagent.
  • the coupling reaction is conveniently performed in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, -80 to +50°C, conveniently in the range -80°C to ambient temperature.
  • the alkylation reaction is conveniently performed in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, -20 to +70°C, conveniently at or near ambient temperature.
  • a suitable alkylating agent is, for example, any agent known in the art for the alkylation of an available nitrogen atom, for example an alkyl halide, for example a (1-4C)alkyl chloride, bromide or iodide, in the presence of a suitable base as defined hereinbefore.
  • the alkylation reaction is preferably performed in a suitable inert solvent or diluent, for example N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetone, 1,2-dimethoxyethane or tetrahydrofuran, and at a temperature in the range, for example, 10 to 150°C, conveniently at or near 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 peroxy onosulphate) , chromium trioxide or gaseous oxygen in the presence of platinum.
  • the oxidation is generally carried out under as mild conditions as possible and with the required stoichiometric amount of oxidising agent in order to reduce the risk of over oxidation and damage to other functional groups.
  • the reaction is carried out in a suitable solvent or diluent such as methylene chloride, chloroform, acetone, tetrahydrofuran or tert-butyl methyl ether and at a temperature, for example, at or near ambient temperature, that is in the range 15 to 35°C.
  • a milder oxidising agent may also be used, for example ' sodium or potassium metaperiodate, conveniently in a polar solvent such as acetic acid or ethanol.
  • a compound of the formula I containing a sulphonyl group it may be obtained by oxidation of the corresponding sulphinyl compound as well as of the corresponding thio compound.
  • a pharmaceutically-acceptable salt of a novel compound of the formula I When a pharmaceutically-acceptable salt of a novel 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 ij 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 (F. Carey and R.A. Forder, Prostaglandins, Leukotrienes Med. , 1986, 22_, 57; Prostaglandins, 1984, 28, 666; Brit. J. Pharmacol.
  • test b) An ex vivo assay system, which is a variation of test a) above, involving administration to a group of rats of a test compound (usually orally as the suspension produced when a solution of the test compound in dimethylsulphoxide is added to carboxymethylcellulose) , blood collection, heparinisation, challenge with A23187 and radioimmunoassay of LTB, and TxB ? .
  • This test provides an indication of the bioavailability of a test compound as an inhibitor of 5-L0 or cyclooxygenase.
  • Test a IC 50 (LTB 4 ) in the range, for example, 0.01-40 ⁇ M IC c0 (TxB 2 ) in the range, for example, 40-200 ⁇ M;
  • Test b) oral ED,- 0 (LTB,) in the range, for example, 0.1-lOOmg/kg;
  • Test c oral ED (LTB,) in the range, for example, 0.1-lOOmg/kg.
  • the compound (2S,4R)-4-[5-fluoro-3- (l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6-ylsulphonyl)phenyl]-4- methoxy-2-methyltetrahydropyran has an IC of 0.07 ⁇ M against LTB, in test a), and an ED,- 0 of approximately 0.25 mg/kg against LTB, in test c).
  • These compounds are examples of compounds of the invention which show selective inhibitory properties for 5-L0 as opposed to cyclooxygenase, which selective properties are expected to impart improved therapeutic properties, for example, a reduction in or freedom from the gastrointestinal side-effects frequently associated with cyclooxygenase inhibitors such as indomethacin.
  • a pharmaceutical composition which comprises a 2-oxo-l,2,3,4- tetrahydroquinoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, in association with a pharmaceutically-acceptable diluent or carrier.
  • the composition may be in a form suitable for oral use, for example a tablet, capsule, aqueous or oily solution, suspension or emulsion; for topical use, for example a cream, ointment, gel or aqueous or oily solution or suspension; for nasal use, for example a snuff, nasal spray or nasal drops; for vaginal or rectal use, for example a suppository; for administration by inhalation, for example as a finely divided powder such as a dry powder, a microcrystalline form or a liquid aerosol; for sub-lingual or buccal use, for example a tablet or capsule; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example a sterile aqueous or oily solution or suspension.
  • the above compositions may be prepared in a conventional manner using conventional excipients.
  • the amount of active ingredient (that is a 2-oxo-l,2,3,4- tetrahydroquinoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof) that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.
  • the invention also includes a method of treating a disease or medical condition mediated alone or in part by one or more leukotrienes which comprises administering to a warm-blooded animal requiring such treatment an effective amount of an active ingredient as defined above.
  • the invention also provides the use of such an active ingredient in the production of a new medicament for use in a leukotriene mediated disease or medical condition.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of the formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
  • compounds of the formula I are useful in treating those diseases such as allergic and inflammatory conditions and disorders of bone metabolism which are due alone or in part to the effects of the metabolites of arachidonic acid arising by the linear (5-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, arthritic and inflammatory joint disease, inflammatory bowel diseases, conjunctivitis, the conditions of shock or trauma and various disorders of bone metabolism.
  • a daily dose in the range for example, 0.5 mg to 75 mg per kg body weight is received, given if required in divided doses.
  • lower doses will be administered when a parenteral route is employed.
  • a dose in the range for example, 0.5 mg to 30 mg per kg body weight will generally be used.
  • a dose in the range for example, 0.5 mg to 25 mg per kg body weight will be used.
  • the compounds of the formula I are primarily of value as therapeutic agents for use in warm-blooded animals (including man) , they are also useful whenever it is required to inhibit the enzyme 5-L0. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
  • the compounds of the formula I have certain cytoprotective effects, for example they are useful in reducing or suppressing certain of the adverse gastrointestinal effects of the cyclooxygenase inhibitory non- steroidal anti-inflammatory agents (NSAIA), such as indomethacin, acetylsalicylic acid, ibuprofen, sulindac, tolmetin and piroxicam.
  • NSAIA cyclooxygenase inhibitory non- steroidal anti-inflammatory agents
  • co-administration of a 5-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 a 2-oxo-l,2,3,4-tetrahydroquinoline 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 crystallisation from a conventional organic solvent such as ethanol, methanol, acetone, ether or hiexane, alone or in admixture; and
  • Example 1 n-Butyl-lithium (1.4M in hexane, 1.5 ml) was added dropwise to a stirred mixture of 6-mercapto-l-methyl-l,2,3,4-tetrahydro- quinolin-2-one (0.386 g), 4-(3,5-difluorophenyl)-4-methoxytetrahydro- pyran (European Patent Application No. 0462813, Example 5 thereof; 0.547 g) and NMP (6 ml) which had been cooled to 0°C. The mixture was stirred at 0°C for 5 minutes and then heated to 145°C for 2.2 hours with the concomitant distillation of the hexane.
  • the aqueous phase was washed with diethyl ether and then acidified to pH2 by the addition of dilute aqueous hydrochloric acid.
  • the acidic mixture was extracted with ethyl acetate.
  • the organic phase was dried (MgSO.) and evaporated.
  • the residual oil was dissolved in diethyl ether and hexane was added. There was thus obtained 6-mercapto-l-methyl-l,2,3,4-tetrahydro- quinolin-2-one as a solid (35.5 g, 92%) which was used without further purification.
  • Potassium peroxymonosulphate (4.4 g) was added to a mixture of (2S,4R)-4-[5-fluoro-3-(l-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6- ylthio)phenyl]-4-methoxy-2-methyltetrahydropyran (2 g), ethanol (20 ml) and water (10 ml). The mixture was stirred at ambient temperature for 18 hours. The mixture was partitioned between methylene chloride and water. The organic phase was washed with an aqueous sodium bisulphite solution, dried (MgSO.) and evaporated.
  • (2S,4R)-4-methoxy-4-[3-(l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6- ylthio)phenyl]-2-methyltetrahydropyran was oxidised to give (2S,4R)-4- methoxy-4-[3-(l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6- ylsulphonyl)phenyl]-2-methyltetrahydropyran in 57% yield, m.p. 144-147°C;
  • the 4-methoxy-4-(2,3,5-trifluorophenyl)tetrahydropyran used as a starting material was obtained as follows:- l-Bromo-2,3,5-trifluorobenzene (0.15 ml) and 1,2-dibromoethane (0.03 ml) were added in turn to a stirred mixture of magnesium (0.075 g) and THF (3 ml). The mixture was warmed to initiate the formation of a Grignard reagent. A second portion (0.15 ml) of l-bromo-2,3,5-trifluorobenzene was added and the mixture was stirred at ambient temperature for 30 minutes.
  • (2S,4R)-4-[2,5-difluoro-3-(l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin- 6-ylthio)phenyl]-4-methoxy-2-methyltetrahydropyran was oxidised to give (2S,4R)-4-[2,5-difluoro-3-(l-methyl-2-oxo-1,2,3,4-tetrahydro- quinolin-6-ylsulphonyl)phenyl]-4-methoxy-2-methyltetrahydropyran in 20% yield, m.p. 141-143°C;

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Abstract

L'invention concerne un dérivé de 2-oxo-1,2,3,4-tétrahydroquinoline répondant à la formule (I) dans laquelle Q représente 2-oxo-1,2,3,4-tétrahydroquinolin-6-yle qui porte un substituant alkyle(1-4C) sur l'atome d'azote en position 1; X1 représente thio, sulfinyle ou sulfonyle; Ar représente 1,3-phénylène éventuellement substitué; R1 représente alkyle(1-4C), alcényle(3-4C) ou alcynyle(3-4C); et R2 et R3 constituent ensemble un groupe de la formule -A2-X2-A3-, qui définit, avec l'atome de carbone auquel A2 et A3 sont rattachés, un cycle contenant 5 à 6 atomes cycliques, A2 et A3 représentent chacun alkylène(1-3C) et X2 représentant oxy; ou un sel pharmaceutiquement acceptable de ce dérivé. L'invention se rapporte également à des procédés destinés à leur préparation, à des compositions pharmaceutiques les contenant, et à leur utilisation comme inhibiteurs de 5-lipoxygénase.
EP94919602A 1993-06-07 1994-06-03 Derives de 2-oxo-1,2,3,4-tetrahydroquinoline Withdrawn EP0702680A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP94919602A EP0702680A1 (fr) 1993-06-07 1994-06-03 Derives de 2-oxo-1,2,3,4-tetrahydroquinoline

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP93401443 1993-06-07
EP93401443 1993-06-07
PCT/EP1994/001807 WO1994029297A1 (fr) 1993-06-07 1994-06-03 Derives de 2-oxo-1,2,3,4-tetrahydroquinoline
EP94919602A EP0702680A1 (fr) 1993-06-07 1994-06-03 Derives de 2-oxo-1,2,3,4-tetrahydroquinoline

Publications (1)

Publication Number Publication Date
EP0702680A1 true EP0702680A1 (fr) 1996-03-27

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Family Applications (1)

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EP94919602A Withdrawn EP0702680A1 (fr) 1993-06-07 1994-06-03 Derives de 2-oxo-1,2,3,4-tetrahydroquinoline

Country Status (4)

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EP (1) EP0702680A1 (fr)
JP (1) JPH08511254A (fr)
AU (1) AU7070594A (fr)
WO (1) WO1994029297A1 (fr)

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Publication number Priority date Publication date Assignee Title
US5891460A (en) * 1995-06-07 1999-04-06 University Of Southern California University Park Campus Method for reducing or preventing post-surgical adhesion formation using ketotifen and analogs thereof

Family Cites Families (3)

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Publication number Priority date Publication date Assignee Title
GB9018134D0 (en) * 1989-09-29 1990-10-03 Ici Plc Heterocyclic derivatives
GB9113137D0 (en) * 1990-07-13 1991-08-07 Ici Plc Thioxo heterocycles
IE913655A1 (en) * 1990-11-06 1992-05-22 Zeneca Ltd Synergistic agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9429297A1 *

Also Published As

Publication number Publication date
JPH08511254A (ja) 1996-11-26
AU7070594A (en) 1995-01-03
WO1994029297A1 (fr) 1994-12-22

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