WO1998057936A1 - Derives de quinoline utilises en tant qu'inhibiteurs de la pde iv et/ou du tnf - Google Patents

Derives de quinoline utilises en tant qu'inhibiteurs de la pde iv et/ou du tnf Download PDF

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WO1998057936A1
WO1998057936A1 PCT/GB1998/001770 GB9801770W WO9857936A1 WO 1998057936 A1 WO1998057936 A1 WO 1998057936A1 GB 9801770 W GB9801770 W GB 9801770W WO 9857936 A1 WO9857936 A1 WO 9857936A1
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compound
disease
alkyl
optionally substituted
compounds
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PCT/GB1998/001770
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Hazel Joan Dyke
John Gary Montana
Alan Findlay Haughan
Verity Margaret Sabin
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Darwin Discovery Limited
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Priority to AU82228/98A priority Critical patent/AU735573B2/en
Priority to JP50397799A priority patent/JP2002504925A/ja
Priority to CA002289100A priority patent/CA2289100A1/fr
Priority to EP98932276A priority patent/EP0993449A1/fr
Publication of WO1998057936A1 publication Critical patent/WO1998057936A1/fr

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    • 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
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to novel quinolines, and to their formulation and use as pharmaceuticals.
  • Japanese Patent Publication 2-184673 discloses quinolinesulphonamides.
  • US-A-4910193 discloses quinolinesulphonamides, in which the sulphonamide nitrogen is substituted by a variety of bridged saturated ring systems, as medicaments suitable for the treatment of serotonin-induced gastrointestinal disturbances.
  • US-A-4857301 and US-A-5340811 disclose quinolinesulphonamides in the treatment of asthma, respectively as bronchodilators and as anti-allergic compounds.
  • 5-Heteroarylquinolines and 5-heterocycloquinolines with anti-microbial activity are described by Khalil etal, J. Indian Chem. Soc. (1987) L IV 42, and ibid(1990) 67.821.
  • 0545170 discloses 2-substituted quinolines, including 5-arylquinolines, as lipoxygenase inhibitors.
  • PDE Phosphodiesterases
  • TNF Tumour Necrosis Factor
  • Certain quinolines are known, without associated therapeutic activity. These include 5,5'-bis(8-methoxyquinoline), 5,5'-bis(8-methoxyquinaldine), l-(8-ethoxy-5- quinolyl)-3,4-dihydroisoquinoline, 1 -(8-ethoxy-5-quinolyl)isoquinoline, 2-(8-ethoxy-5- quinolyl)- 1 ,2,3 ,4-tetrahydroisoquinoline, 8-isopropoxy-5-( 1 -naphthyl)quinoline, 5 - methoxy-8-phenylquinoline, 5-methoxy-8-[2-(t-butylcarbonylamino)phenyl]quinoline and 5-methoxy-8-[2-(t-butylcarbonylamino)-5-methoxyphenyl]quinoline.
  • novel compounds that can be used to treat disease states, for example disease states associated with proteins that mediate cellular activity, for example by inhibiting tumour necrosis factor and/or by inhibiting phosphodiesterase IV.
  • novel compounds are of formula 0):
  • R represents C M alkoxy (alkyl portion optionally substituted with one or more halogens), OH or thioalkyl;
  • Rj represents halogen, arylalkyl, heteroarylalkyl, heterocycloalkyl, alkyl, hydroxy, alkoxy, CO 2 R 8 , SO 2 NR, 2 R, 3 , CONR 12 R 13 , CN, NI ⁇ R.,,,, COR n or S(O) confrontR ⁇ ;
  • R 7 represents H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl or heterocycloalkyl, any of which may be optionally substituted at any position with R 16 ;
  • R g represents H, alkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl;
  • R ⁇ represents alkylcarbonyl, alkoxycarbonyl, arylsulphonyl, heteroarylsulphonyl, heterocyclosulphonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclocarbonyl or alkylsulphonyl and
  • R I0 represents H or R ⁇ , or NR ⁇ ,,, represents a heterocyclic ring (such as morpholine or piperidine) optionally substituted with one or more R, 5 ;
  • R n represents alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl or heterocycloalkyl;
  • R 12 and R 13 which may be the same or different, each represent R 7 , or NR, 2 R 13 represents a heterocyclic ring (such as morpholine or piperidine) optionally substituted with one or more R, 5 ;
  • R 15 represents alkyl, arylalkyl or heteroarylalkyl
  • R 16 represents halogen, hydroxy, OR n , N sR,,,, CN, CO 2 H, COjR,,, CONR 12 R 13 or COR n ; n represents 0-2; and Q represents an aryl or heteroaryl ring, attached through any appropriate atom and optionally substituted at any position(s) with one or more substituents R ⁇ ; and pharmaceutically-acceptable salts thereof.
  • Suitable pharmaceutically-acceptable salts are pharmaceutically-acceptable base salts and pharmaceutically-acceptable acid addition salts. Certain of the compounds of formula (i) which contain an acidic group form base salts. Suitable pharmaceutically- acceptable base salts include metal salts, such as alkali metal salts for example sodium salts, or organic amine salts such as that provided with ethylenediamine.
  • acid addition salts include pharmaceutically-acceptable inorganic salts such as the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide and pharmaceutically-acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methanesulphate, ⁇ -ketoglutarate, ⁇ - glycerophosphate and glucose- 1 -phosphate.
  • the pharmaceutically-acceptable salts of the compounds of formula (i) are prepared using conventional procedures.
  • the compounds according to the invention can contain one or more asymmetrically substituted atoms.
  • the presence of one or more of these asymmetric centers in a compound of formula (i) can give rise to stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, including enantiomers and diastereoisomers, and mixtures including racemic mixtures thereof.
  • alkyl when used herein the term alkyl whether used alone or when used as a part of another group includes straight and branched chain alkyl groups containing up to 6 atoms.
  • Alkoxy means an alkyl-O- group in which the alkyl group is as previously described.
  • Aryloxy means an aryl-O- group in which the aryl group is as defined below.
  • Heteroaryloxy means a heteroaryl-O- group and heterocyclooxy means a heterocyclo-O- group in which the heteroaryl and heterocyclo group are as de ined below.
  • Alkylamino means an alkyl-N- group in which the alkyl group is as previously defined, arylamino means aryl-N- and heteroarylamino means an heteroaryl-N- group (aryl and heteroaryl defined below).
  • Cycloalkyl includes a non-aromatic cyclic or multicyclic ring system of about 3 to 10 carbon atoms. The cyclic alkyl may optionally be partially unsaturated.
  • Aryl indicates carbocyclic radicals containing about 6 to 10 carbon atoms.
  • Arylalkyl means an aryl-alkyl- group wherein the aryl and alkyl are as described herein.
  • Heteroarylalkyl means a heteroaryl-alkyl group and heterocycloalkyl means a heterocyclo-alkyl group.
  • Alkylcarbonyl means an alkyl-CO- group in which the alkyl group is as previously described.
  • Arylcarbonyl means an aryl-CO- group in which the aryl group is as previously described.
  • Heteroarylcarbonyl means a heteroaryl-CO- group and heterocyclocarbonyl means a heterocyclo-CO- group.
  • Aiylsulphonyl means an aryl-SO 2 - group in which the aryl group is as previously described.
  • Heteroarylsulphonyl means a heteroaryl-SO 2 - group and heterocyclosulphonyl means a heterocyclo-SO 2 - group.
  • Alkoxycarbonyl means an alkyloxy-CO- group in which the alkoxy group is as previously desribed.
  • Alkylsulphonyl means an alkyl-SO 2 - group in which the alkyl group is as previously described.
  • Carbonyl oxygen means a -CO- group. It will be appreciated that a carbonyl oxygen cannot be a substituent on an aryl or heteroaryl ring.
  • Heterocyclic ring means about a 5 to about a 10 membered monocyclic or multicyclic ring system (which may be saturated or partially unsaturated) wherein one or more of the atoms in the ring system is an element other than carbon chosen from amongst nitrogen, oxygen or sulphur atoms. Examples include morpholine and piperidine. Heteroaryl means about a 5 to about a 10 membered aromatic monocyclic or multicyclic hydrocarbon ring system in which one or more of the atoms in the ring system is an element other than carbon, chosen from amongst nitrogen, oxygen or sulphur; if desired, a N atom may be in the form of an N-oxide.
  • Heterocyclo means about a 5 to about a 10 membered saturated or partially saturated monocyclic or multicyclic hydrocarbon ring system in which one or more of the atoms in the ring system is an element other than carbon, chosen from amongst nitrogen, oxygen or sulphur.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • TNF mediated disease or disease states means any and all disease states in which TNF plays a role, either by production of TNF itself, or by TNF causing another cytokine to be released, such as but not limited to IL-1 or IL-6.
  • TNF- ⁇ also known as lymphotoxin
  • TNF- ⁇ also known as cachectin
  • This invention relates to a method for mediating or inhibiting the enzymatic activity or catalytic activity of PDE IV in a mammal in need thereof and for inhibiting the production of TNF in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (i) or a pharmaceutically- acceptable salt thereof.
  • PDE IV inhibitors are useful in the treatment of a variety of allergic and inflammatory diseases, including: asthma, chronic bronchitis, chronic obstructive airways disease, atopic dermatitis, atopic eczema, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, inflammation of the eye, allergic responses in the eye, eosinophilic granuloma, psoriasis, Bechet's disease, erythematosis, anaphylactoid purpura nephritis, joint inflammation, arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis and osteoarthritis, septic shock, sepsis, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock and adult respiratory distress syndrome.
  • PDE IV inhibitors are useful in the treatment of diabetes insipidus and conditions associated with cerebral metabolic inhibition, such as cerebral senility, senile dementia (Alzheimer's disease), memory impairment associated with Parkinson's disease, depression and multi-infarct dementia.
  • PDE IV inhibitors are also useful in conditions ameliorated by neuroprotectant activity, such as cardiac arrest, stroke and intermittent claudication.
  • PDE IV inhibitors may be useful in the treatment of tardive dyskinesia, ischaemia and Huntingdon's disease. Additionally, PDE IV inhibitors could have utility as gastroprotectants.
  • a special embodiment of the therapeutic methods of the present invention is the treatment of asthma.
  • viruses contemplated for treatment herein are those that produce TNF as a result of infection, or those which are sensitive to inhibition, such as by decreased replication, directly or indirectly, by the TNF inhibitors of Formula (i).
  • viruses include, but are not limited to HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus and the Herpes group of viruses, such as, but not limited to, Herpes zoster and Herpes simplex.
  • This invention more specifically relates to a method of treating a mammal, afflicted with a human immunodeficiency virus (HIV), which comprises administering to such mammal an effective TNF inhibiting amount of a compound of Formula (i) or a pharmaceutically-acceptable salt thereof.
  • HAV human immunodeficiency virus
  • TNF mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted above, but in particular viral infections.
  • viruses examples include, but are not limited to feline immunodeficiency virus
  • FTV retroviral infection
  • equine infectious anaemia virus caprine arthritis virus, visna virus, maedi virus and other lentiviruses.
  • the compounds of this invention are also useful in treating parasite, yeast and fungal infections, where such yeast and fungi are sensitive to upregulation by TNF or will elicit TNF production in vivo.
  • a preferred disease state for treatment is fungal meningitis.
  • Compounds of the invention may also suppress neurogenic inflammation through elevation of c AMP in sensory neurones. They are, therefore, analgesic, anti-tussive and anti-hyperalgesic in inflammatory diseases associated with irritation and pain.
  • the compounds of formula (i) are preferably in pharmaceutically-acceptable form.
  • pharmaceutically-acceptable form is meant, inter alia, of a pharmaceutically-acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
  • a pharmaceutically- acceptable level of purity will generally be at least 50% excluding normal pharmaceutical additives, preferably 75%, more preferably 90% and still more preferably 95%.
  • the invention further provides a process for the preparation of a compound of formula (i), in which R, etc. are as defined above. It will be appreciated that functional groups such as amino, hydroxyl or carboxyl groups present in the various compounds described below, and which it is desired to retain, may need to be in protected forms before any reaction is initiated. In such instances, removal of the protecting group may be the final step in a particular reaction sequence.
  • a process for the preparation of a compound of formula (i) comprises reaction of a bromide of formula (ii) with a suitably substituted aryl or heteroaryl portion, for example an aryl or heteroarylboronic acid of formula (iii)
  • R la represents R, as defined in relation to formula (i) or a group convertable to R
  • R ⁇ -Rs a similarly represent R 2 -Rs or groups convertable to R 2 -Rs respectively; and thereafter, if required, converting any group R l!t to Rj and/or R ⁇ to R 2 and/or R 3a to R 3 and/or R ⁇ to R, and/or converting any group R S ⁇ to R 5 .
  • a bromide of formula (ii) may be converted into the corresponding boronic acid (using standard conditions known to those skilled in the art) and this may be coupled with an aryl or heteroaryl halide, preferably a bromide.
  • This coupling reaction may be carried out under any standard conditions known to those skilled in the art, for example conditions described by Trecourt et al, J. Het. Chem. (1995) 32 1261, and references cited therein.
  • the preparation of bromides of formula (ii) is described in WO-A-9744036.
  • Boronic acids of formula (iii) are commercially available, previously described compounds, or are prepared using standard conditions known to those skilled in the art.
  • a compound of formula (i) may also be prepared by interconversion of other compounds of formula (i).
  • a compound in which Rj contains a carboxylic acid may be prepared by appropriate hydrolysis of a compound in which R., contains an alkoxycarbonyl group (for example a methoxycarbonyl group).
  • R 2 -R 4 may be prepared from compounds in which R 2 -R 4 contain a CN group, by addition of a suitable organometallic agent (such as a Grignard reagent).
  • a suitable organometallic agent such as a Grignard reagent
  • compounds in which R 2 -R 4 contain an oxime may be prepared from compounds in which R 2 -R 4 contain a carbonyl group. This transformation may be carried out using any appropriate standard conditions known to those skilled in the art. Compounds of formula (i) in which R 2 -R 4 contain a carbonyl group may be reduced using standard conditions known to those skilled in the art (for example with sodium borohydride in an appropriate solvent) to provide compounds in which R 2 -R 4 contains an alcohol group.
  • R 2 -R 4 is alkyl
  • R 2 -R 4 is CO-alkyl
  • standard conditions for example hydrazine hydrate in the presence of a suitable base in an appropriate solvent.
  • Other transformations may be carried out on compounds of formula (i) in which R 2 -R 4 contains a carbonyl group.
  • Such transformations include, but are not limited to, reductive amination and alkylation. Any of the above transformations may be carried out either at the end of the synthesis or on an appropriate intermediate.
  • a compound of formula (i) or where appropriate a pharmaceutically-acceptable salt thereof and/or a pharmaceutically-acceptable solvate thereof, may be administeredper se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically- acceptable carrier.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (i) or where appropriate a pharmaceutically-acceptable salt thereof and/or a pharmaceutically-acceptable solvate thereof, and a pharmaceutically- acceptable carrier.
  • the active compound may be formulated for administration by any suitable route, the preferred route depending upon the disorder for which treatment is required, and is preferably in unit dosage form or in a form that a human patient may administer to himself in a single dosage.
  • the composition is suitable for oral, rectal, topical, parenteral administration or through the respiratory tract. Preparations may be designed to give slow release of the active ingredient.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc.
  • the compounds of the invention are effective in the treatment of humans.
  • compositions of the invention may be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations such as oral or sterile parenteral solutions or suspensions. Topical formulations are also envisaged where appropriate.
  • a composition of the invention is in the form of a unit dose.
  • Unit dose presentation forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers for example microcrystalline cellulose, lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically-acceptable wetting agents such as sodium lauryl sulphate.
  • binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone
  • fillers for example microcrystalline cellulose, lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine
  • tabletting lubricants for example magnesium
  • the solid oral compositions may be prepared by conventional methods ofblending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • Oral liquid preparations may be in the form of, for example, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia, non- aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose,
  • compositions may also suitably be presented for administration to the respiratory tract as a snuff or an aerosol or solution for a nebuliser, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
  • the particles of active compound suitably have diameters of less than 50 ⁇ m, such as from 0.1 to 50 ⁇ m, preferably less than 10 ⁇ m, for example from 1 to 10 ⁇ m, 1 to 5 ⁇ m or from 2 to 5 ⁇ m.
  • small amounts of other anti-asthmatics and bronchodilators for example sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine; corticosteroids such as prednisolone and adrenal stimulants such as ACTH may be included.
  • sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine
  • corticosteroids such as prednisolone
  • adrenal stimulants such as ACTH
  • fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • compositions may contain from 0.1% to 99% by weight, preferably from 10- 60% by weight, of the active material, depending on the method of administration.
  • Compounds of formula (i), or if appropriate a pharmaceutically-acceptable salt thereof and/or a pharmaceutically-acceptable solvate thereof, may also be administered as a topical formulation in combination with conventional topical excipients.
  • Topical formulations may be presented as, for instance, ointments, creams or lotions, impregnated dressings, gels, gel sticks, spray and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the formulations may contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • Suitable cream, lotion, gel, stick, ointment, spray or aerosol formulations that may be used for compounds of formula (i) or if appropriate a pharmaceutically-acceptable salt thereof, are conventional formulations well known in the art, for example, as described in standard text books such as Harry's Cosmeticology published by Leonard Hill Books, Remington's Pharmaceutical Sciences, and the British and US Pharmacopoeias.
  • the compound of formula (i), or if appropriate a pharmaceutically- acceptable salt thereof will comprise from about 0.5 to 20% by weight of the formulation, favourably from about 1 to 10%, for example 2 to 5%.
  • suitable unit doses may be 0.1 to lOOOmg, such as 0.5 to 200, 0.5 to 100 or 0.5 to lOmg, for example 0.5, 1, 2, 3, 4 or 5mg; and such unit doses may be administered more than once a day, for example 2, 3, 4, 5 or 6 times a day, but preferably 1 or 2 times per day, so that the total daily dosage for a 70kg adult is in the range of about 0.1 to lOOOmg, that is in the range of about 0.001 to 20 mg/kg/day, such as 0.007 to 3, 0.007 to 1.4, 0.007 to 0.14 or 0.01 to 0.5mg/kg/day, for example 0.01, 0.02, 0.04, 0.05, 0.06, 0.08, 0.1 or 0.2 mg/kg/day, and such therapy may extend for example 0.01, 0.02, 0.04, 0.05, 0.06, 0.08, 0.1 or 0.2 mg/kg/day, and such therapy may extend for example 0.01, 0.02, 0.04, 0.05,
  • pharmaceutically-acceptable encompasses materials suitable for both human and veterinary use.
  • Example 8-Methoxy-2-methyl-5-phenylquinoline 5-Bromo-8-methoxy-2-methylquinoline (509 mg) and benzene boronic acid (323 mg) were added to a mixture of 2 M aqueous potassium carbonate (2 ml), toluene (10 ml) and ethanol (1 ml) and refluxed for 30 minutes under a nitrogen atmosphere.
  • the mixture was cooled, triphenylphosphine (75 mg) and dichlorobis(triphenylphosphine)palladium chloride (66 mg) were added and the mixture was heated at 60°C overnight. After cooling, the reaction mixture was diluted with ethyl acetate (30 ml).
  • the assays used to confirm the phosphodiesterase IV inhibitory activity of compounds of formula (i) are standard assay procedures as disclosed by Schilling et al, Anal. Biochem. 216:154 (1994), Thompson and Strada, Adv. Cycl. Nucl. Res. 8:119 (1979) and Gristwood and Owen, Br. J. Pharmacol. 87:91P (1986).
  • PMBC's peripheral blood mononuclear cells

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Abstract

L'invention concerne des composés de la formule (i) dans laquelle R1 représente un C1-6alcoxy (la partie alkyle étant éventuellement substituée par un ou plusieurs halogènes) ou un thioalkyle; Q représente une chaîne aryle ou hétéroaryle liée à n'importe quel atome approprié et éventuellement substituée au niveau de n'importe quelle(s) position(s) par un ou plusieurs substituants R5. Ces composés peuvent être utilisés pour traiter des états pathologiques, par exemple des états pathologiques associés à des protéines qui agissent sur l'activité cellulaire, par exemple, en inhibant le facteur de nécrose tumorale et/ou la phosphodiestérase IV.
PCT/GB1998/001770 1997-06-17 1998-06-17 Derives de quinoline utilises en tant qu'inhibiteurs de la pde iv et/ou du tnf WO1998057936A1 (fr)

Priority Applications (4)

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AU82228/98A AU735573B2 (en) 1997-06-17 1998-06-17 Quinoline derivatives as PDE IV and/or TNF inhibitors
JP50397799A JP2002504925A (ja) 1997-06-17 1998-06-17 Ｐｄｅ ｉｖおよび／又はｔｎｆインヒビターとしてのキノリン誘導体
CA002289100A CA2289100A1 (fr) 1997-06-17 1998-06-17 Derives de quinoline utilises en tant qu'inhibiteurs de la pde iv et/ou du tnf
EP98932276A EP0993449A1 (fr) 1997-06-17 1998-06-17 Derives de quinoline utilises en tant qu'inhibiteurs de la pde iv et/ou du tnf

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GB9712761.7 1997-06-17
GBGB9712761.7A GB9712761D0 (en) 1997-06-17 1997-06-17 Quinolines and their therapeutic use

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6521618B2 (en) 2000-03-28 2003-02-18 Wyeth 3-cyanoquinolines, 3-cyano-1,6-naphthyridines, and 3-cyano-1,7-naphthyridines as protein kinase inhibitors
WO2004103998A1 (fr) * 2003-05-21 2004-12-02 Glaxo Group Limited Derives de quinoleine utilises en tant qu'inhibiteurs de la phosphodiesterase
EP1992636A2 (fr) 1999-11-12 2008-11-19 Amgen Inc. Procédé pour la correction d'un mauvais repliement de bisulfure dans les molécules Fc
US7501516B2 (en) 2001-07-16 2009-03-10 Astrazeneca Ab Quinoline derivatives and their use as tyrosine kinase inhibitors
EP2087908A1 (fr) 2001-06-26 2009-08-12 Amgen, Inc. Anticorps opgl
US8367829B2 (en) 2010-05-10 2013-02-05 Gilead Sciences, Inc. Bi-functional pyrazolopyridine compounds
US8394829B2 (en) 2010-05-10 2013-03-12 Gilead Sciences, Inc. Bi-functional quinoline analogs
US9663486B2 (en) 2013-10-14 2017-05-30 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
US10087174B2 (en) 2013-10-14 2018-10-02 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
WO2022005494A1 (fr) * 2020-06-29 2022-01-06 Vtv Therapeutics Llc Dérivés de quinoléine, sels pharmaceutiquement acceptables et leurs procédés d'utilisation

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103980194B (zh) * 2014-05-15 2016-09-07 浙江省医学科学院 6,8-双取代喹啉化合物或其药学上可接受的盐及其制备方法和应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993007146A1 (fr) * 1991-10-09 1993-04-15 Syntex (U.S.A.) Inc. Composes benzo et pyrido pyridazinones et pyridazinthiones a activite inhibant la phosphodiesterase iv
WO1994022852A1 (fr) * 1993-03-31 1994-10-13 Syntex (U.S.A.) Inc. Quinoleines comme inhibiteurs de la phosphodiesterase type iv
WO1997044322A1 (fr) * 1996-05-20 1997-11-27 Darwin Discovery Limited Sulfonamides de quinoline en tant qu'inhibiteurs de tnf et inhibiteurs de photodiesterase-iv
WO1997044036A1 (fr) * 1996-05-20 1997-11-27 Darwin Discovery Limited Carboxamides de quinoline en tant qu'inhibiteurs de tnf et inhibiteurs de la photodiesterase-iv

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993007146A1 (fr) * 1991-10-09 1993-04-15 Syntex (U.S.A.) Inc. Composes benzo et pyrido pyridazinones et pyridazinthiones a activite inhibant la phosphodiesterase iv
WO1994022852A1 (fr) * 1993-03-31 1994-10-13 Syntex (U.S.A.) Inc. Quinoleines comme inhibiteurs de la phosphodiesterase type iv
WO1997044322A1 (fr) * 1996-05-20 1997-11-27 Darwin Discovery Limited Sulfonamides de quinoline en tant qu'inhibiteurs de tnf et inhibiteurs de photodiesterase-iv
WO1997044036A1 (fr) * 1996-05-20 1997-11-27 Darwin Discovery Limited Carboxamides de quinoline en tant qu'inhibiteurs de tnf et inhibiteurs de la photodiesterase-iv

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEM. PAP., vol. 39, no. 5, - 1985, pages 667 - 686 *
CHEMICAL ABSTRACTS, vol. 105, no. 19, 10 November 1986, Columbus, Ohio, US; abstract no. 172254p, ASHAKS, J. ET AL: "8-Mercaptoquinoline(thiooxine) and its derivatives. ..." XP002057449 *

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1992636A2 (fr) 1999-11-12 2008-11-19 Amgen Inc. Procédé pour la correction d'un mauvais repliement de bisulfure dans les molécules Fc
US6689772B1 (en) 2000-03-28 2004-02-10 Wyeth 3-cyanoquinolines, 3-cyano-1,6-naphthyridines, and 3-cyano-1,7-naphthyridines as protein kinase inhibitors
US6521618B2 (en) 2000-03-28 2003-02-18 Wyeth 3-cyanoquinolines, 3-cyano-1,6-naphthyridines, and 3-cyano-1,7-naphthyridines as protein kinase inhibitors
EP2087908A1 (fr) 2001-06-26 2009-08-12 Amgen, Inc. Anticorps opgl
EP3492100A1 (fr) 2001-06-26 2019-06-05 Amgen Inc. Anticorps pour opgl
US7501516B2 (en) 2001-07-16 2009-03-10 Astrazeneca Ab Quinoline derivatives and their use as tyrosine kinase inhibitors
EP1944305A1 (fr) * 2003-05-21 2008-07-16 Glaxo Group Limited Dérivatifs de quinolinone en tant qu'inhibiteurs de phosphodiestérase
US7566786B2 (en) 2003-05-21 2009-07-28 Glaxo Group Limited Quinoline derivatives as phosphodiesterase inhibitors
US7572915B2 (en) 2003-05-21 2009-08-11 Glaxo Group Limited Quinoline derivatives as phosphodiesterase inhibitors
WO2004103998A1 (fr) * 2003-05-21 2004-12-02 Glaxo Group Limited Derives de quinoleine utilises en tant qu'inhibiteurs de la phosphodiesterase
US8394829B2 (en) 2010-05-10 2013-03-12 Gilead Sciences, Inc. Bi-functional quinoline analogs
US8450490B2 (en) 2010-05-10 2013-05-28 Gilead Sciences, Inc. Bi-functional pyrazolopyridine compounds
US8367829B2 (en) 2010-05-10 2013-02-05 Gilead Sciences, Inc. Bi-functional pyrazolopyridine compounds
US9663486B2 (en) 2013-10-14 2017-05-30 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
US10087174B2 (en) 2013-10-14 2018-10-02 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
USRE47193E1 (en) 2013-10-14 2019-01-08 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
WO2022005494A1 (fr) * 2020-06-29 2022-01-06 Vtv Therapeutics Llc Dérivés de quinoléine, sels pharmaceutiquement acceptables et leurs procédés d'utilisation

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EP0993449A1 (fr) 2000-04-19
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ZA985253B (en) 1999-06-17
AU8222898A (en) 1999-01-04
GB9712761D0 (en) 1997-08-20
JP2002504925A (ja) 2002-02-12
CA2289100A1 (fr) 1998-12-23

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