EP0773931A1 - Quinoline derivatives as leukotriene antagonists - Google Patents

Quinoline derivatives as leukotriene antagonists

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Publication number
EP0773931A1
EP0773931A1 EP95921729A EP95921729A EP0773931A1 EP 0773931 A1 EP0773931 A1 EP 0773931A1 EP 95921729 A EP95921729 A EP 95921729A EP 95921729 A EP95921729 A EP 95921729A EP 0773931 A1 EP0773931 A1 EP 0773931A1
Authority
EP
European Patent Office
Prior art keywords
acid
ethenyl
hydrogen
compound
formula
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.)
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Application number
EP95921729A
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German (de)
English (en)
French (fr)
Inventor
Dorte Kirstein
Schneur Rachlin
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Leo Pharma AS
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Leo Pharmaceutical Products Ltd AS
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Publication of EP0773931A1 publication Critical patent/EP0773931A1/en
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals

Definitions

  • the present invention relates to hitherto unknown compounds useful in the human and veterinary therapy, to pharmaceutically acceptable salts thereof, to bioreversible derivatives thereof, to methods for producing said new compounds, to pharmaceutical compositions containing the new compounds, to dosage units of the compositions, and to methods of treating patients using said compositions and dosage units.
  • Leukotrienes which are formed via the 5-lipoxygenase pathway of arachidonic acid metabolism, are implicated in a variety of pathophysiologic functions, such as bronchoconstriction, plasma exudation, coronary artery
  • X 1 and X 2 independently of each other stand for hydrogen or halogen
  • X3 and X 4 independently of each other stand for hydrogen, halogen, nitro, cyano, trifluoromethyl, C- C ⁇ alkyl, C ⁇ -C ⁇ alkoxy, carboxy or C..-C_ ⁇ carbalkoxy;
  • Z is a bond, O, S, S(O), S(O) 2 , NH or CH 2 ;
  • R 1 is hydrogen or a straight or branched, saturated or unsaturated C ⁇ -Cg hydrocarbon chain;
  • R j is hydrogen, a straight or branched, saturated or unsaturated C
  • R 2 R.. as defined above or R 2 is a pharmaceutically acceptable cation.
  • X ⁇ and X 2 independently of each other stand for hydrogen, fluoro or chloro;
  • X3 stands for hydrogen;
  • X 4 stands for hydrogen, fluoro, chloro or bromo;
  • Z is O or S in ortho-position;
  • p is 1;
  • R 1 is hydrogen;
  • R 3 is hydrogen or a straight or branched, saturated or unsaturated C.-C 6 hydrocarbon chain, or phenyl; and
  • A is COOR 2 , where R 2 is hydrogen, C..-C3 alkyl, an alkali metal cation, or tetrazol-5-yl.
  • the compounds are selected from the group consisting of E-2-[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyl)- phenoxy]-2-methylpropanoic acid, E-2-[2-(3-(2-(7-chloroquinolin-2-yl)- ethenyl)phenylaminomethyl)phenoxy]-2-methylpentanoic acid, E-2-[2-(3-(2-(7- chloroquinolin-2-yl)ethenyl)phenylaminomethyl)phenoxy]hexanoic acid, E-2- -[2-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyl)-4-bromophenoxy]- hexanoic acid, E-2-[2-(3-2-(2-(7-fluoroquinolin-2-yl)ethenyl)phe ⁇ ylamino
  • Some of the compounds described herein contain one or more centres of asymmetry and may thus give rise to stereoisomers, e.g. enantiomers or diastereoisomers.
  • the present invention is meant to compre ⁇ hend all such possible stereoisomers.
  • a particularly preferred compound is (S)(+)-E-2-[2-(3-(2-(7- chloroquinolin-2-yl)-ethenyl)phenylaminomethyl)phenoxy]hexanoic acid.
  • the present salts of the compounds of formula I may be formed with pharmaceutically acceptable inorganic or organic acids, such as hydrochloric, hydrobromic and hydroiodic acid, phosphoric acid, sulphuric acid, nitric acid, p-toluenesulphonic acid, methanesulphonic acid, formic acid, acetic acid, propionic acid, citric acid, tartaric acid, and maleic acid, without these examples being considered limiting for the invention.
  • the present salts of the compounds of formula I may also be formed with pharmaceutically acceptable, inorganic or organic bases.
  • Salts formed with pharmaceutically acceptable, non-toxic bases may be alkali metal salts and alkaline earth metal salts, such as lithium, sodium, potassium, magnesium, calcium salts, as well as salts with ammonia and suitable non- -toxic amines, such as C ⁇ -Cg-alkylamines, e.g. triethylamine, C j -Cg alkanolamines, e.g. diethanolamine or triethanolamine, procaine, cycloalkyl- amines, e.g. dicyclohexylamine, benzylamines, e.g.
  • suitable non- -toxic amines such as C ⁇ -Cg-alkylamines, e.g. triethylamine, C j -Cg alkanolamines, e.g. diethanolamine or triethanolamine, procaine, cycloalkyl- amines, e.g. dicyclohexylamine, benzyl
  • Such derivatives are for instance esters of N-hydroxymethyl deriva ⁇ tives of compounds of the invention, such compounds being prepared by reaction of a secondary amine function of compounds of the invention with formaldehyde followed by reaction with a suitable acidic compound or activated derivatives of such compounds, for instance with bi-
  • R 7 sulfite , N,N-dimethylglycine, N,N-diethyl- ?-alanine, or phosphoric acid ,
  • esters formed with the acidic function in the molecule such as simple esters, e.g. methyl or ethyl, acyloxyalkyl, alkoxycarb- onyloxyalkyl or aminoacyloxyalkyl esters, which are readily hydrolyzed in vivo or in vitro.
  • esters the following are preferred: alkanoyloxy- methyl with from 3 to 6 carbon atoms, 1-(alkanoyloxy)ethyl with from 4 to 6 carbon atoms, alkoxycarbonyloxymethyl with from 3 to 6 carbon atoms, l-(alk- oxycarbonyloxy)ethyl with from 4 to 6 carbon atoms, and ⁇ -aminoalkanoyloxy- methyl with from 2 to 6 carbon atoms.
  • lactonyl esters e.g. 3-phthalidyl, 4-croton- olactonyl or y-butyrolacton-4-yl esters.
  • methoxymethyl, cyano- methyl, or mono- or dialkyl substituted aminoalkyl esters e.g. 3-dimethyl- aminoethyl, 2-diethylaminoethyl, or 3-dimethylaminopropyl esters.
  • esters are preferred which are well absorbed upon enteral administration and during or after the absorption are hydrolysed to the compounds of formula I.
  • esters are not to be considered as limiting for the inven ⁇ tion, and other suitable methods to improve the physicochemical properties and solubility of the compounds concerned can be used as well.
  • 5-lipoxygenase inhibitors and leukotriene antagonists are of potential interest in the therapy of asthma, allergy, rheumatoid arthritis, spondylo- arthritis, gout, atherosclerosis, prolrferative and inflammatory skin disorders, such as psoriasis and atopic dermatitis, chronic inflammatory bowel disease, and other inflammatory conditions, vasospasm associated with angina pectoris, pulmonary hypertension, cystic fibrosis, the adult respiratory distress syn-
  • Inhibitors of arachidonic acid metabolism may be identified using rat peritoneal leukocytes labelled with [1- C]arachidonate and stimulated with the
  • the compounds of the present invention were observed to inhibit the metabolism at an assay concentration of 10 ⁇ M.
  • Leukotriene antagonists may be identified by observing the contrac ⁇ tions elicited in preparations of guinea-pig ileum strips suspended in a physio- logical buffer by addition of pure leukotriene D 4 (LTD 4 ) .
  • LTD 4 pure leukotriene D 4
  • a plC 50 value is deter ⁇ mined as the negative logarithm of the molar concentration of antagonist inhibiting [ H]LTD 4 binding by 50%.
  • the plCg 0 values for the compounds o the present invention are unaffected by the presence of 0.1% human serum
  • the leukotriene antagonistic effect was tested in vivo on LTD 4 - q induced bronchoconstriction in anaesthetized guinea-pigs . Intravenously the compounds were administered 10 minutes, orally 4, 8 and 24 hours before the bronchoconstriction.
  • the EDgQ values represent the dose inhibiting the leukotriene induced bronchoconstriction by 50%.
  • the ED Q values were calcu ⁇ lated by regression analysis of 2 - 3 doses. The following Table II shows the results.
  • the present invention also relates to a method for producing the present compounds.
  • R.. , R3, X3, X 4 , A, Z and p have the above meanings
  • Y is capable of forming a "good leaving group", Y thus standing for e.g. a halogen atom, such as chlorine, bromine or iodine, or an alkyl- or arylsulphonyloxy group, but other leaving groups can be used as well, such as an alkylsulphate group, a chlorosulphonyloxy group, an alkylsulphite group, a mono- or di- alkylphosphate group or a nitrate group, to form a compound of the formula I.
  • the reaction is performed in a suitable inert organic solvent, such as methanol, ethanol, dimethyl formamide or hexamethyl phosphoric triamide, but
  • EP 0206 751 A Merck Frosst Canada Inc. C.R. Edwards, M.J. Readhead and N.J. Tweedle, J. Heterocyclic Chem. 24 (1987) 495.
  • other solvents can be used as well; the reaction is performed at a temperature about or above room temperature, up to the boiling point of the solvent used. In some cases it can, however, be convenient to cool the reaction mixture below room temperature, depending on the nature of the compound of the formula III used.
  • the reaction is also conveniently performed in the presence of an organic base, such as pyridine, triethylamine, sodium methanolate or sodium ethanolate or in the presence of a suitable inorganic base, such as an alkalimetal hydroxide, an alkalimetal carbonate or an alkalimetal hydrogen carbonate, but other bases can be used as well.
  • an organic base such as pyridine, triethylamine, sodium methanolate or sodium ethanolate
  • a suitable inorganic base such as an alkalimetal hydroxide, an alkalimetal carbonate or an alkalimetal hydrogen carbonate, but other bases can be used as well.
  • the crude reaction products of the formula I are collected by filtration, if convenient after dilution with e.g. water, or are extracted from the reaction mixture with a suitable solvent, such as diethyl ether, ethyl acetate, dichloromethane or chloroform.
  • the products are purified e.g.
  • an amine of the formula II is converted to a compound of the formula I by reductive alkylation, e.g. by reaction with a carbonyl compound of the formula IV, which compounds are commercially available or are prepared as described in 3 ,
  • R ⁇ R3, X3, X 4 , A, Z and p have the above meanings, followed by hydrogenation in the presence of a suitable catalyst or by reduction e.g. with
  • the reaction is performed in a suitable inert organic solvent, such as methanol or ethanol, but other solvents can be used as well.
  • a suitable inert organic solvent such as methanol or ethanol, but other solvents can be used as well.
  • the reaction is preferably performed at ambient temperature, but in some cases it is convenient to cool the reaction mixture below room temperature, or to heat the reaction mixture above room temperature, up to the boiling point of the solvent used, depending on the nature of the reactants of the formulae II and IV used.
  • the isolation and purification of the products can be performed as described above.
  • 17 18 1Q may be prepared by methods as described ,
  • the present compounds are intended for use in pharmaceutical compositions which are useful in the treatment of the above mentioned dis ⁇ eases.
  • a suitable dose of a compound of formula (I) for systemic treatment is 0.1 to 20 mg per kilogram bodyweight, the most preferred dosage being 0.1 to 10 mg/kg of mammal bodyweight, for example 0.2 to 10 mg/kg; administered one or more times daily, typically corresponding to a daily dose for an adult human being of from 5 mg to 5 g.
  • a suitable anti-asthmatic dose of a compound of formula (I) is 1 ⁇ g to 5 mg of compound per kilogram bodyweight, the most preferred dosage being 1 ⁇ g to 1 mg/kg of mammal bodyweight, for example from 1 ⁇ g to 0.5 mg/kg.
  • the active ingredient comprises from 0.1% to 100% by weight of the formulation.
  • dosage units of a formulation contain between 0.07 mg and 1 g of the active ingredient.
  • the active ingredient preferably comprises from 1% to 2% by weight of the formulation but the active ingredient may comprise as much as 10% w/w.
  • Formulations suitable for nasal or buccal administration may comprise 0.1 to 20% w/w, for example about 2% w/w of active ingredient.
  • dosage unit a unitary, i.e. a single dose which is capable of being administered to a patient, and which may be readily handled and packed, remaining as a physically and chemically stable unit dose comprising either the active material as such or a mixture of it with solid or liquid pharmaceutical diluents or carriers.
  • the formulations, both for veterinary and for human medical use, of the present invention comprise an active ingredient in association with a phar ⁇ maceutically acceptable carrier therefor and optionally other therapeutic in- gredient(s).
  • the carrier(s) must be "acceptable” in the sense of being compat ⁇ ible with the other ingredients of the formulations and not deleterious to the recipient thereof.
  • the formulations include those in a form suitable for oral, ophthalmic, rectal, parenteral (including subcutaneous, intramuscular and intravenous), transdermal, intra-articular, topical, nasal, or buccal administration.
  • the formulations may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
  • 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 necessary, shaping the product into the desired formula ⁇ tion.
  • Formulations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, 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 aque ⁇ ous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion.
  • the active ingredient may also be administered in the form of a bolus, electuary or paste.
  • Formulations for rectal administration may be in the form of a sup ⁇ pository incorporating the active ingredient and a carrier, or in the form of an enema.
  • Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient.
  • Formulations suitable for intra-articular or ophthalmic administration may be in the form of a sterile aqueous preparation of the active ingredient which may be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension.
  • Liposomal formulations or biodegradable polymer systems may also be used to present the active ingredient for both intra-articu ⁇ lar and ophthalmic administration.
  • Formulations suitable for topical or ophthalmic administration include liquid or semi-liquid preparations, such as oil-in-water or water-in-oil emulsions, ointments or pastes; or solutions or suspensions, such as drops.
  • Formulations suitable for administration to the nose or buccal cavity include powder, self-propelling and spray formulations, such as aerosols and atomizers.
  • formulations suitable for nasal administration include a fine powder which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • compositions of this invention may include one or more additional ingredients.
  • the compositions may further contain other therapeutically active compounds usually applied in the treatment of the above mentioned pathologi ⁇ cal conditions, for instance glucocorticoids, anti-histamines, platelet activating factor (PAF) antagonists, anticholinergic agents, methyl xanthines, ?-adre- nergic agents, salicylates, indomethacin, flufenamate, naproxen, timegadine, gold salts, penicillamine, serum cholesterol-reducing agents, retinoids, zinc salts, and salicylazosulfapyridin (Salazopyrin).
  • PAF platelet activating factor
  • Step 1 E-3-f 2-Quinolin-2-v0ethenyll-N-(2-carboxymethoxybenzylidene - aniline
  • step 2 To a suspension of the Schiff base obtained from step 1 (0.41 g, 1 mmol) in ethanol (10 ml) is added sodium borohydride (0.1 g). This is stirred for 2 hours at room temperature. To this reaction mixture is then added H 2 O (5 ml) and evaporated in vacuo. The residue is treated with water (10 ml) and the resulting solution is neutralized to pH 7 with diluted acetic acid (0.5 ml).
  • the precipitate that forms is filtered off, triturated with MeOH, fil ⁇ tered off, washed with methanol and diethyl ether.
  • the title compound is obtained with a melting point of 108-111 °C.
  • Example 2 E-2-r3-(2-(7-Chloroguinolin-2-yl)ethenv ⁇ phenylaminomethvnphenoxyacetic acid
  • Step 1 E-3-r2-(7-Chloroguinolin-2-vhethenvnnitrobenzene
  • a solution of 7-chloroquinaldine (3.6 g, 20 mmol) and 3-nitrobenz- aldehyde (3.0 g, 20 mmol) in acetic anhydride (20 ml) is stirred for 414 hours at 130°C. The mixture is cooled to room temperature and the precipitate filtered off, washed with water and diethyl ether. The title compound obtained, with a melting point of 181-183°C, is used directly in the next step.
  • Step 2 E-3-r2-(7-Chloroouinolin-2-vhethenyl1aniline
  • Example 3 E-Ethyl 2-r2-(3- ( 2- ( 7-Chloro g uinolin-2-v ⁇ ethenyl ) phenylaminomethv ⁇ phenoxyl- hexanoate Step 1 E-2-f3- ( 2- ( 7-Chloroouinolin-2-vhethenvhphenylaminomethyllphenol
  • step 3 but replacing 2-formylphenoxyacetic acid with salicylaldehyde, E-3-[2-(7-chloroquinolin-2- yl)ethenyl]-N-(2-hydroxybenzylidene)aniline is obtained as an intermediate, which without isolation by following the procedure of Example 2, step 4, is reacted to give the title compound, which is obtained with a melting point of 151-152°C.
  • the obtained hydrochloride is filtrated and treated with 1 N sodium hydrogen- carbonate (200 ml) and diethyl ether.
  • the organic layer is separated, dried (MgSO 4 ) and evaporated in vacuo to give the title compound, which after crystallisation from ethanol is obtained with a melting point of 84-86°C.
  • step 2 A mixture of the ethyl ester from Example 3, step 2 (6.3 g, 12 mmol), lithium hydroxide hydrate (10 g, 250 mmol), water (100 ml), methanol (200 ml), and tetrahydrofuran (140 ml) is stirred at ambient temperature for 4 hours. After filtration, the mixture is evaporated in vacuo to give the crude title compound. After recrystallization from ethanol, it is obtained with a melting point of 181-182°C.
  • Example 22 E-Ethyl 2-r3-t2-(7-Chloroguinolin-2-v ⁇ ethenv ⁇ phenylaminomethvnphenylthio acetate A mixture of the aniline obtained as in Example 2, step 2 (0.85 g, 3 mmol), potassium hydrogencarbonate (2.0 g) and ethyl 2-chloromethylphenyl- thio acetate (1.07 g, 4.4 mmol) in dimethyl sulfoxide (25.0 ml) is stirred at ambient temperature for 96 hours.
  • the resulting mixture is diluted with water (25.0 ml) and extracted twice with ethylacetate (2 x 25.0 ml).
  • the ester from Example 22 (0.5 g, 1 mmol) is hydrolyzed with 2N NaOH (1.0 ml) in ethanol (10.0 ml). The solution is refluxed for 2 hours and diluted with water (10.0 ml). After acidifying the solution with 3N acetic acid (0.5 ml) the precipitate is filtered off and washed with water and ethyl acetate.
  • Example 24 E-2-[3-(2-(Quinolin-2-yl)ethenyl)phenylaminomethvnphenylthioacetic acid
  • Step 1 E-Ethyl 2-r3-f2-fQuinolin-2-v ⁇ ethenv ⁇ p henylaminomethvnphenylthio acetate
  • E-3-[2-(7- chloroquinolin-2-yl)ethenyl]aniline with E-3-[2-(quinolin-2-yl)ethenyl]aniline (see Example 1 , step 1)
  • the title compound is obtained after flash chromatography using ethyl acetate/hexane (3:7) and used as such for the next step.
  • Step 2 E-2-r3-(2-(Quinolin-2-yl)ethenyl)phenylaminomethvnphenylthioacetic acid
  • Step 1 E-Ethyl 2-f2-(3-(2-( , 7-(Chloroguinolin-2-yl)ethenyl)phefiylaminometh- vDphenylthiolhexanoate
  • Step 2 E-2-r3-(2-f7-Chloroguinolin-2-v ⁇ ethenv ⁇ phenylaminomethvnaniline
  • stannous chloride dihydrate (13.7 g, 60 mmol) is added in portions, whereafter the reaction mixture is stirred at ambient temperature overnight.
  • Step 4 E-2-f2-(3-(2-(7-Chloroouinolin-2-yl ⁇ ethenvhphenylaminomethyl;- phenylamino ⁇ hexanoic acid
  • Example 28 E-2-f4- ( 3- ( 2- ( 7-Chloroouinolin-2-yl)ethenvflphenylamino ) phenoxy1hexanoic acid Step 1 E-4-,3- ( 2- ( 7-Chloroguinolin-2-yl ) ethenvhphenylaminomethyllphenol By following the procedure of Example 2, steps 3 and 4, but replac ⁇ ing 2-formylphenoxyacetic acid with 4-hydroxybenzaldehyde, the title compound is obtained with a melting point of 194-195°C. Step 2 E-Ethyl 2-f4-(3-t2-(7-Chloroouinolin-2-yltethenvnphenylaminometh- yhphenoxylhexanoate
  • Example 29 E-Ethyl 2-r2-f3-(2-(7-Chloroguinolin-2-vhethenv ⁇ phenylaminomethvn-6-meth- oxyphenoxylhexanoate
  • Step 1 E-2-f3-f2-f7-Chloroguinolin-2-v ⁇ ethenv ⁇ phenylaminomethvn-6-meth- oxyphenol
  • Step 2 E-Ethyl 2-r2-(3-(2-(7-chloroouinolin-2-vnethenyl,phenylaminometh- vD-6-metho ⁇ yphenoxylhexanoate
  • step 2 By following the procedure of Example 3, step 2, but replacing E-2-[3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyl]phenol with the phenol from step 1 , the title compound is obtained with a melting point of 101-102.5°C.
  • the resulting precipitate is collected by filtration, washed with water and giving the title compound with a melting point of 223-226°C.
  • Example 36 E-2-r3-f2-f7-Chloroguinolin-2-yl)ethenv ⁇ phenylaminomethvnphenylacetic acid
  • E-ethyl 2-[3-(2-(quinolin-2-yl)ethenyl)phenylaminomethyl]phenyl acetate By following the procedure of Example 34, but replacing E-ethyl 2-[3-(2-(quinolin-2-yl)ethenyl)phenylaminomethyl]phenyl acetate with E-ethyl 2-[3-(2-(7-chloroquinolin-2-yl)ethenyl)phenylaminomethyl]phenyl acetate, the title compound is obtained with a melting point of 174-176°C.
  • Example 38 E-3-r2-(3-2-f7-Chloro g uinolin-2-yl ) ethenyl ) phenylaminomethvh p henvnpropionic acid
  • Example 39 E-Sodium 2-f2-(3-(2- ( 7-Chloro g uinolin-2-yl ) ethenv ⁇ phenylaminomethv ⁇ phen- oxy
  • E-2-[2-(3-(2-(7-Chloroquinolin-2-yl)ethenyl)phenylaminomethyl)phen- oxy]hexanoic acid (2.5 g, 5 mmol; prepared as described in Example 12) is dissolved in a mixture of 1 N aqueous sodium hydroxide (5.5 ml, 10% excess) and water (50 ml). The resulting solution is clarified by filtration, and left to precipitate the title compound, which is obtained crystallizing with 0.75 mol of water and with a melting point of 120°C.
  • Example 41 E-2-r3-(2-(7-fluoroguinolin-2-v ⁇ ethenvhphenylaminomethyl1phenoxyacetic acid
  • steps 3 and 4 but re ⁇ placing E-3-[2-(7-(chloroquinolin-2-yl)ethenyl)aniline with E-3-[2-(7-fluoroquinol- in-2-yl)ethenyl) aniline, the title compound is obtained with a melting point of 199-201 °C.
  • Step 1 E-2-f3-(2-(7-fluoroquinolin-2-yl)ethenyl)phenylaminomethvnphenol
  • step 1 E-2-f3-(2-(7-fluoroquinolin-2-yl)ethenyl)phenylaminomethvnphenol
  • N,N-dimethylformamide (25 ml) is stirred at ambient temperatre for 3 hours.
  • Step 1 E-2-f3-(2-(-6.7-difluoroouinolin-2-yl)ethenyl)phenylaminomethyl1- phenol
  • Step 3 E-2-f2-(3-(2-(6.7-difluoroguinolin-2-v ⁇ ethenyl)phenylaminomethyl ⁇ - phenoxyl-hexanoic acid, sodium salt
  • step 2 The ester from step 2 (0.85 g, 1.5 mmol) is refluxed for 3V_ hours in a solution of ethanol (20 ml) and 2 N aqueous sodium hydroxide (2 ml).
  • step 4 By following the procedure of Example 2, step 4, but replacing the Schiff base from Example 2, step 3, with the Schiff base from step 1 , and after recrystallization from n-propanol, the title compound is obtained with a melting point of 199-201 °C.
  • the resulting precipitate is collected by filtration, washed with water giving the title compound with a melting point of 153-155°C.
  • the mixture is filtered, and the resulting solution is evaporated in vacuo.
  • the residue is triturated with water and the precipitate is collected by filtration, washed with water.
  • the resulting solid is dissolved in ethyl acetate and filtered.
  • the filtrate is concentrated by colomn chromatography on silica gel (ethyl acet- ate:hexane, 7:3) and yielded a brown oil.
  • the resulting solid is dissolved in ethyl acetate and filtered.
  • the filtrate is concentrated by colomn chromatography on silica gel (ethyl acet- ate:hexane, 7:3) and yielded a brown oil.
  • the oil is triturated with a solution of HCI/Et 2 O.
  • the title compound is obtained as hydrochloride with a melting point of 99°C dec.
  • Step 1 m-E-Ethyl-2-r2- ⁇ 3- ⁇ 2- ⁇ 7-Chloroouinolin-2-yljethenyljPhenylamino- methvhphenoxylhexanoate
  • Step 1 E-2-r2-(3-f2-(7-chloroguinolin-2-yl)ethenyl)Phenylaminomethyl)phen- oxy
  • Step 2 E-2-r2-(3-(2-(7-chloroouinolin-2-v ethenvQ p henylaminomethvhphen- oxylpentyl nitrile
  • step 2 To the product from step 1 (2.1 g, 4.1 mmol) in benzene (50 ml) phosphortribromide (0.8 ml, 8.5 mmol) was added. After 5 hours reflux the mixture was cooled and then poured into ice water, and made basic with NaHCO ⁇ . Extraction with ethyl acetate, drying, and evaporation, followed by chromatography on silica gel yielded 1.6 g of the title compound used in the following step.
  • Step 3 E-5-2-r2-(3-f2-(7-chloroguinolin-2-yl)ethenvhphenylaminomethyl)- phenoxylpentyl-1 H-tetrazole
  • the active substance is micronized in a jet-mill.
  • the majority of the particles should be less than 5 ⁇ m in diameter.
  • a drug concentrate is prepared by dissolving sorbitan trioleate in a small amount of monofiuorotrichloromethane and adding the active substance. The concentrate is homogenized carefully. The concentrate is transferred to a sealed tank provided with a refrigeration system. The remaining propellents are added under stirring and cooling to -50°C.
  • Suitable aerosol container are filled with the calculated amount of formulation and sealed immediately with metering valves with suitable actuators. Each puff delivers 50 ⁇ g of the active substance.
  • the active substance, lactose and starch are mixed to a homogene- ous state in a suitable mixer and moistened with a 5 per cent aqueous solution of methylcellulose 15 cps. The mixing is continued until granules are formed. If necessary, the wet granulation is passed through a suitable screen and dried to a water content of less than 1% in a suitable dryer, e.g. fluid bed or drying oven. The dried granulaton is passed through a 1 mm screen and mixed to a homogeneous state with CMC-Na. Magnesium stearate is added, and the mixing is continued for a short period of time.
  • Tablets with a weight of 200 mg are produced from the granulation by means of a suitable tabletting machine.
  • Example 68 Formulation for injection
  • the active substance is dissolved in water for injection.
  • the solution is made isotonic with sodium chloride.
  • the solution is filled into ampoules and sterilized.

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EP95921729A 1994-07-20 1995-06-07 Quinoline derivatives as leukotriene antagonists Withdrawn EP0773931A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9414590A GB9414590D0 (en) 1994-07-20 1994-07-20 Chemical compounds
GB9414590 1994-07-20
PCT/DK1995/000223 WO1996002506A1 (en) 1994-07-20 1995-06-07 Quinoline derivatives as leukotriene antagonists

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JP (1) JPH10504026A (cs)
KR (1) KR970704691A (cs)
CN (1) CN1152915A (cs)
AU (1) AU686820B2 (cs)
CA (1) CA2192478A1 (cs)
CZ (1) CZ284799B6 (cs)
FI (1) FI970143A7 (cs)
GB (1) GB9414590D0 (cs)
HU (2) HUT76443A (cs)
NZ (1) NZ287850A (cs)
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WO (1) WO1996002506A1 (cs)

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FR2761687B1 (fr) * 1997-04-08 2000-09-15 Centre Nat Rech Scient Derives de quinoleines, possedant notamment des proprietes antivirales, leurs preparations et leurs applications biologiques

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GB8728051D0 (en) * 1987-12-01 1988-01-06 Leo Pharm Prod Ltd Chemical compounds
US4918081A (en) * 1988-06-20 1990-04-17 Rorer Pharmaceutical Corp. Quinoline derivatives and use thereof as antagonists of leukotriene d4
GB9216768D0 (en) * 1992-08-07 1992-09-23 Leo Pharm Prod Ltd Chemical compounds

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FI970143A0 (fi) 1997-01-14
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JPH10504026A (ja) 1998-04-14
AU2669695A (en) 1996-02-16
KR970704691A (ko) 1997-09-06
CA2192478A1 (en) 1996-02-01
GB9414590D0 (en) 1994-09-07
CN1152915A (zh) 1997-06-25
PL318106A1 (en) 1997-05-12
WO1996002506A1 (en) 1996-02-01
HUT76443A (en) 1997-09-29
CZ352996A3 (en) 1997-10-15
HU9603342D0 (en) 1997-01-28
FI970143A7 (fi) 1997-01-14
NZ287850A (en) 1998-05-27

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