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WO1997031000A1 - Quinolones et leur utilisation therapeutique - Google Patents

Quinolones et leur utilisation therapeutique Download PDF

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Publication number
WO1997031000A1
WO1997031000A1 PCT/GB1997/000492 GB9700492W WO9731000A1 WO 1997031000 A1 WO1997031000 A1 WO 1997031000A1 GB 9700492 W GB9700492 W GB 9700492W WO 9731000 A1 WO9731000 A1 WO 9731000A1
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WIPO (PCT)
Prior art keywords
alkyl
disease
compound
disease state
formula
Prior art date
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PCT/GB1997/000492
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English (en)
Inventor
Alan Findlay Haughan
Steven Colin Beasley
John Gary Montana
Robert John Watson
Original Assignee
Darwin Discovery Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from GBGB9603689.2A external-priority patent/GB9603689D0/en
Priority claimed from GBGB9603655.3A external-priority patent/GB9603655D0/en
Priority claimed from GBGB9603654.6A external-priority patent/GB9603654D0/en
Priority claimed from GBGB9702929.2A external-priority patent/GB9702929D0/en
Application filed by Darwin Discovery Limited filed Critical Darwin Discovery Limited
Priority to EP97905238A priority Critical patent/EP0882047A1/fr
Priority to AU18861/97A priority patent/AU710876B2/en
Priority to JP9529905A priority patent/JP2000505451A/ja
Publication of WO1997031000A1 publication Critical patent/WO1997031000A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
    • 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
    • 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

  • the present invention relates to novel quinolone derivatives and pharmaceutically-acceptabie salts thereof, processes for their production, and their formulation and use as pharmaceuticals.
  • Quinolone and quinolizine compounds are known mainly as antibacterial agents (JP-A-05025162; US-A-5037834; EP-A-0420069; JP-A-02040379; EP-A-0343560; DE-A-3816119; EP-A-0304158; FR-A-2644784; WO-A-9410163; DE-A-3641312) or antiviral agents (US-A-4959363), but also as inhibitors of 5-lipoxygenase (JP-A- 02124871), cardiotonics and vasodilators (JP-A-01061461) and 5-HT 3 antagonists for the treatment of peripheral disorders associated with pain (WO-A-9501793, GB-A- 2236751).
  • GB-A-2236751 describes quinolone-3-carboxamides as 5-HT 3 antagonists, for use in the treatment of neuro-psychiatric disorders.
  • US-A-4001243 discloses be ⁇ zoquinoline-2-carboxylic acids and esters as anti-microbial agents.
  • GB-A-1433151 discloses N-tetrazolyl-benzoquinoiizine-2-carboxarnides, as agents that may be useful in the treatment of allergies including asthma.
  • PDE Phosphodiesterases
  • TNF Tumour Necrosis Factor
  • novel compounds are of formula (I): Q O
  • R 1 represents cycloalkyi, aryl, heteroaryl or heterocyclo, in which any ring may be fused to a second ring selected from aryl and heteroaryl, to give a bicyclic structure, and in which any group is optionally substituted by one or more substituents chosen from halo, C M alkoxy, hydroxy, CN, CO 2 H (or C, ⁇ alkyl esters or C alkyl amides thereof), Cs alkyl, NR S R 7 and SO 2 NR 6 R 7 ; R 3 , R* and R s are the same or different and represent H, halo, C 1-6 alkoxy, hydroxy, CN, COjH (or C M alkyl esters or C w alkyl amides thereof), NR 6 R 7 , SO 2 NR'R 7 or C w alkyl in which alkyl is optionally substituted with halo, C, ⁇ alkoxy, hydroxy, CN, CO
  • R 6 and R 7 are the same or different and represent H, C,_ 6 alkyl, cycloalkyi, C M alkylcarbonyl, arylcarbonyi, C l ⁇ ! alkoxycarbonyl, arylsulphonyi or C w alkylsulphonyl or NR 6 R 7 is a 5 or 6-membered ring such as pyrrolidine, piperidine, mo ⁇ holine or piperazine; X represents a linking group selected from -(CR'R 10 ) ⁇ -, -Y-(CR 9 R l0 ) 2 -,
  • Suitable pharmaceutically-acceptabie salts are pharmaceutically-acceptabie base salts and pharmaceutically-acceptabie acid addition salts. Certain of the compounds of formula (I) which contain an acidic group form base salts. Suitable pharmaceutically- acceptabie 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-acceptabie inorganic salts such as the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide and pharmaceutically-acceptabie organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methanesuiphate, -ketoglutarate, ⁇ - glycerophosphate and glucose- 1 -phosphate.
  • the pharmaceutically-acceptabie salts of the compounds of formula (1) are prepared using conventional procedures.
  • some of the compounds according to the invention can contain one or more asymmetrically-substituted carbon and/or sulphur 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 whether used alone or when used as part of another group includes straight and branched chain alkyl groups.
  • Cycloalkyi includes a non-aromatic cyclic or multicyclic ring system of about 3 to 10 carbon atoms.
  • the cyclic alkyl may optionally be partially unsaturated.
  • Alkoxy means an alkyi-O- group in which the alkyl group is as previously described.
  • Alkyl amide includes both monoalkyl and dialkyl amides, in which the alkyl groups (previously defined) may be the same or different.
  • Alkylcarbonyl means an alkyl-CO- group in which the alkyl group is as previously described.
  • Aryl indicates carbocyclic radicals containing about 6 to 10 carbon atoms.
  • Heteroaryl means an about 5 to about 10-membered aromatic monocyclic or multicyclic 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.
  • Heterocyclo means an about 5 to about 10-membered saturated or partially saturated monocyclic or multicyclic 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.
  • Arylcarbonyi means an aryl-CO- group.
  • Arylsulphonyi means an aryl-SO 2 - group.
  • Alkylsulphonyl means an alkyl-SO 2 - group.
  • Alkoxycarbonyl means an alkoxy-CO- group.
  • the compounds of formula (I) are preferably in pharmaceutically-acceptabie form.
  • pharmaceutically-acceptabie form is meant, inter alia, a pharmaceutically- acceptabie level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
  • a pharmaceutically-acceptabie level of purity will generally be at least 50% excluding normal pharmaceutical additives, preferably 75%, more preferably 90% and still more preferably 95%.
  • TNF- mediated disease or disease states i.e. 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- acceptabie salt thereof.
  • PDE IV inhibitors are useful in the treatment of a variety of allergic and inflammatory diseases, including: asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, inflammation of the eye, allergic responses in the eye, eosinophilic granuloma, psoriasis, Bechet's disease, erythematosis, anaphylactoid pu ⁇ ura nephritis, joint inflammation, arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis and osteoarthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock and adult respiratory distress syndrome.
  • allergic and inflammatory diseases including: asthma, chronic bronchitis, atopic dermatitis,
  • 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 multiple sclerosis, tardive dyskinesia, ischaemia and Huntingdon's disease.
  • 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 HTV-1, HJV-2 and HTV-3, cytomegalovirus (CMV), influenza, adenovirus and the He ⁇ es 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 (HTV), which comprises administering to such mammal an effective TNF-inhibiting amount of a compound of Formula (I) or a pharmaceutically-acceptabie salt thereof.
  • HTV human immunodeficiency virus
  • the compounds of this invention may be also be used in association with the veterinary treatment of animals, other than humans, in need of inhibition of TNF production.
  • TNF mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted above, but in particular viral infections.
  • viruses include, but are not limited to, feline immunodeficiency virus (FIV) and other retroviral infections such as equine infectious anaemia virus, caprine arthritis virus, visna virus, aedi virus and other lentiviruses.
  • FV feline immunodeficiency virus
  • retroviral infections such as equine infectious anaemia virus, caprine arthritis virus, visna virus, aedi 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 fiingal meningitis.
  • Compounds of the invention may also suppress neurogenic inflammation through elevation of cAMP in sensory neurones. They are, therefore, analgesic, anti-tussive and anti-hyperaigesic in inflammatory diseases associated with irritation and pain.
  • Compounds of the general formula (I) may be prepared by any suitable method known in the art and/or by the following process, which itself forms part of the invention.
  • R 11 , Q, X and Z are as defined above, except where otherwise indicated.
  • 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 form before any reaction is initiated. In such instances, removal of the protecting group may be the final step in a particular reaction. Suitable protecting groups for such functionalities will be apparent to those skilled in the art. For specific details see “Protective Groups in Organic Synthesis", Wiley Interscience, T W Greene, PGM Wuts.
  • a process for preparing compounds of formula (I) in which, say, R* is CO j H comprises deprotecting (for example by hydrolysis) a compound of formula (I) in which R 4 is CO 2 R wherein R represents a suitable protecting group (e.g. methyl).
  • a preferred embodiment of formula (I) comprises those compounds wherein X is (CR'R 10 ⁇
  • a process for preparing compounds of general formula (I) comprises coupling an acid of formula (II)
  • Amines of formula (HI) are commercially available or can be readily obtained from commercially-available starting materials using methods known to those skilled in the art. Some of the amines of formula (HI) are conveniently prepared by reductive amination of an appropriate carbonyl compound with a suitable arnine. This amination may be carried out under any suitable standard conditions known to those skilled in the art. Active derivatives of acids of formula (II) include, for example, acid anhydrides and acid halides, such as acid chlorides.
  • the coupling reaction may be performed using standard conditions for amination reactions of this type.
  • the reaction may be achieved in a solvent, for example an inert organic solvent such as an ether, e.g. a cyclic ether such as tetrahydrofuran, an amide, e.g. a substituted amide such as dimethylformamide, or a halogenated hydrocarbon such as dichloromethane, at a low temperature, e.g. -30°C to ambient temperature, such as -20°C to 0°C, optionally in the presence of a base, e.g. an organic base such as an amine, e.g. triethylamine or a cyclic amine such as N-methylmo ⁇ holine.
  • a solvent for example an inert organic solvent such as an ether, e.g. a cyclic ether such as tetrahydrofuran, an amide, e.g. a substituted amide such as dimethylform
  • the reaction may additionally be performed in the presence of a condensing agent, for example a diimide such as N,N-dicyclohexylcarbodiimide, advantageously in the presence of a triazole such as 1-hydroxybenzotriazole.
  • a condensing agent for example a diimide such as N,N-dicyclohexylcarbodiimide, advantageously in the presence of a triazole such as 1-hydroxybenzotriazole.
  • the acid may be reacted with a chloroformate, for example ethyl chloroformate, prior to reaction with the amine of formula (HI).
  • Acids of general formula (H) may be prepared according to the procedure described in EP-A-0373531, DE-A-0683169 or by Kaminsky and Meltzer, J. Med. Chem., 11: 160-164 (1968). This procedure includes hydrolysis of the corresponding ester of general formula (TV)
  • R 12 represents an (ar)alkyl group such as methyl, ethyl, benzyl or /er/-butyl.
  • suitable conditions comprise reaction with phosphorus pentasulphide (P 4 S, 0 ) in an organic solvent such as pyridine at an appropriate temperature. The reflux temperature of the solvent is preferred.
  • Esters of general formula IV wherein X is -Y'-CR 9 R ,0 -Z', Y* and Z' each being NR", O or S, e.g. -O-CR 9 R 10 -NR 11 -, may be prepared by cyclisation of intermediates of general formula (V)
  • cyclisation may utilise a tetraalkylammonium fluoride such as tetrabutylammonium fluoride as reagent.
  • Y* or Z' as S may subsequently be converted to SO or SO 2 .
  • P is any suitable protecting group, e.g. Boc, by deprotection using methods evident to those skilled in the art, such as reaction with base.
  • the quinoline nucleus in the above compounds may be generated by reaction of an ester of formula (VTH) O
  • esters of general formula (IV) may be prepared from the corresponding intermediate of general formula (XT)
  • R 13 represents a protected form of Y ⁇ such as OAc, SAc or NR n Boc.
  • the quinoline nucleus in the compounds (IV) and (XHI) may be generated by cyclisation of an ester of formula (XTV) or (XV)
  • Suitable conditions include, for example, heating to reflux in diphenyl ether or a eutectic mixture of diphenyl ether and biphenyl.
  • Compounds of formula (XTV) or (XV) may be prepared by the reaction of an aniline of general formula (XVI) or (XVH)
  • R 14 is a lower alkyl group such as methyl or ethyl.
  • This reaction may be carried out under suitable standard conditions known to those skilled in the art, for example those described by Kaminsky and Meltzer, supra.
  • the reaction may be carried out at elevated temperature, for example 80-150°C, in an inert solvent (such as xylene) or, preferably, in the absence of solvent.
  • inert solvent such as xylene
  • Compounds of formula (I) may also be prepared by interconversion of other compounds of formula (I).
  • a compound of formula (I) wherein R 4 is C,. 6 alkoxy may be prepared by appropriate alkylation of a compound of formula (I) wherein R 4 is a hydroxy group.
  • Any mixtures of final products or intermediates obtained can be separated on the basis of the physico-chemical differences of the constituents, in known manner, into the pure final products or intermediates, for example by chromatography, distillation, fractional crystallization, or by formation of a salt if appropriate or possible under the circumstances. It will be appreciated that where a particular stereoisomer of formula (I) is required, this may be obtained by conventional resolution techniques such as high performance liquid chromatography.
  • a compound of formula (I) or where appropriate a pharmaceutically-acceptabie salt thereof and/or a pharmaceutically-acceptabie solvate thereof, may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically-acceptabie carrier.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or where appropriate a pharmaceutically- acceptabie salt thereof and/or a pharmaceutically-acceptabie solvate thereof, and a pharmaceutically-acceptabie carrier.
  • the active compound may be formulated for adrriinistration 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, intrastemal 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 lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or pharmaceutically-acceptabie wetting agents such as sodium lauryl sulphate.
  • Solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers.
  • 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, as desired, conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats
  • emulsifying agents for example lecithin, sorbitan monooleate,
  • compositions may also suitably be presented for adrriinistration 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 a suitable sterilising agent, 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-acceptabie salt thereof and/or a pharmaceutically-acceptabie 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- acceptabie salt thereof will comprise from about 0.5 to 20% by weight of the formulation, preferably from about 1 to 10%, for example 2 to 5%.
  • suitable unit doses may be 0.1 to 1000 mg, such as 0.5 to 200, 0.5 to 100 or 0.5 to 10 mg, for example 0.5, 1, 2, 3, 4 or 5 mg; 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 70 kg adult is in the range of about 0.1 to 1000 mg, 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 0.5 mg/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 a number of
  • Example 1 9-fluoro-6.7-dihvdro-5-methyl-N-f2-t4-pyridvnethvn-l-oxo-lH.5H- benzo-[i.i1quinolizine-2-carboxamide Flumequine (0.46 g) and dichloromethane (16.3 ml) were combined under nitrogen and cooled to 0°C. Triethylamine (0.27 ml) was then added dropwise, followed by isopropenyl chloroformate (0.21 ml) and the whole stirred for 60 minutes.
  • Triethylamine (0.27 ml) was then added dropwise, followed by isopropenylchloroformate (0.21 ml) and the whole stirred for 60 minutes.
  • 4-(Aminomethyl)pyridine (0.2 ml) was then added and the reaction stirred for 20 h, after which time it was diluted with dichloromethane, washed with water (3 times), dried (MgSO 4 ), concentrated in vacuo and triturated with acetone to give the title compound (0.49 g) as a yellow solid.
  • Example 4 9-fluoro-6.7-dihvdro-5-methyl-N-[(4-pyridv0methyl1-l-oxo-lH.5H- benzo-fi.j "
  • Peripheral blood mononuclear cells are prepared from freshly taken blood or "Buffy coats" by standard procedures. Cells are plated out in RPMI + 1% foetal calf serum in the presence and absence of inhibitors. LPS (100 ng/ml) is added and cultures are incubated for 22 h at 37° C in an atmosphere of 95% air/5% CO 2 . Supematants are tested for TNF ⁇ by ELISA using commercially available kits. Skin EosinophHia Model
  • TNF tumour necrosis factor LPS lipopolysaccharide endotoxin

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  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

L'invention concerne un composé de la formule (I), ses hydrates, ses solvates et ses sels acceptables sur le plan pharmaceutique. Dans cette formule, n est un nombre entier pouvant aller jusqu'à 3; R1 représente un groupe cycloalkyle, aryle, hétéroaryle ou hétérocyclo éventuellement fusionné avec un second cycle aryle ou hétéroaryle pour donner une structure bicyclique et chacun des deux cycles peut porter, indépendamment, un ou plusieurs substituants choisis parmi halo, C¿1-6? alcoxy, hydroxy, CN, CO2H (ou un C1-6 alkyle ester ou un C1-6 alkyle amide dérivé de CO2H), C1-6 alkyle, NR?6R7¿ et SO¿2?NR?6R7; R3, R4 et R5¿ sont identiques ou différents et ils représentent H, halo, C¿1-6? alcoxy, hydroxy, CN, CO2H (ou un C1-6 alkyle ester ou un C1-6 alkyle amide dérivé de CO2H), NR?6R7, SO¿2NR6R7, ou C¿1-6? alkyle dans lequel le groupe alkyle peut être substitué par halo, C1-6 alcoxy, hydroxy, CN, CO2H (ou un C1-6 alkyle ester ou un C1-6 alkyle amide dérivé de CO2H), NR?6R7¿ ou SO¿2NR?6R7 ou deux substituants adjacents quelconques R3-R5 peuvent être joints pour former un groupe carbocyclique, aromatique, hétéroaromatique, carbocyclique saturé ou hétérocyclique; R6 et R7 sont les mêmes ou différents et ils représentent H, C¿1-6? alkyle, cycloalkyle, C1-6 alkylcarbonyle, arylcarbonyle, C1-6 alcoxycarbonyle, arylsulphonyle ou C1-6 alkylsulfonyle ou NR?6R7¿ est un cycle à 5 ou 6 éléments tel que pyrrolidine, pipéridine, morpholine ou pipérazine; X représente un groupe de liaison choisi parmi -(CR9R10)2-3-, -Y-(CR9R10)2-, -(CR9R10)2-Y-, -CR?9R10-Y-CR9R10¿- et -Y-CR9R10-Z-, Y et Z étant, d'une manière indépendante, NR11, O ou S(O)¿0-2?, à condition que Y et Z ne soient pas tous deux S(O)0-2; Q représente O ou S; et R?9, R10 et R11¿ sont identiques ou différents et ils représentent H ou C¿1-6? alkyle.
PCT/GB1997/000492 1996-02-21 1997-02-21 Quinolones et leur utilisation therapeutique WO1997031000A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP97905238A EP0882047A1 (fr) 1996-02-21 1997-02-21 Quinolones et leur utilisation therapeutique
AU18861/97A AU710876B2 (en) 1996-02-21 1997-02-21 Quinolones and their therapeutic use
JP9529905A JP2000505451A (ja) 1996-02-21 1997-02-21 キノロン類およびこれらの治療的使用

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
GBGB9603689.2A GB9603689D0 (en) 1996-02-21 1996-02-21 Novel compounds
GB9603655.3 1996-02-21
GB9603689.2 1996-02-21
GBGB9603655.3A GB9603655D0 (en) 1996-02-21 1996-02-21 Novel compounds
GB9603654.6 1996-02-21
GBGB9603654.6A GB9603654D0 (en) 1996-02-21 1996-02-21 Novel compounds
GBGB9702929.2A GB9702929D0 (en) 1997-02-13 1997-02-13 Quinolones and their therapeutic use
GB9702929.2 1997-02-13

Publications (1)

Publication Number Publication Date
WO1997031000A1 true WO1997031000A1 (fr) 1997-08-28

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PCT/GB1997/000492 WO1997031000A1 (fr) 1996-02-21 1997-02-21 Quinolones et leur utilisation therapeutique

Country Status (5)

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EP (1) EP0882047A1 (fr)
JP (1) JP2000505451A (fr)
AU (1) AU710876B2 (fr)
CA (1) CA2241891A1 (fr)
WO (1) WO1997031000A1 (fr)

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001519328A (ja) * 1997-10-07 2001-10-23 ベーリンガー インゲルハイム （カナダ） リミテッド Ｈｃｍｖ感染症治療のためのアゼチジノン誘導体
WO2002002558A1 (fr) * 2000-07-05 2002-01-10 Pharmacia & Upjohn Company Pyrroloquinolones en tant qu'agents antiviraux
WO2002064145A1 (fr) * 2001-02-13 2002-08-22 Pharmacia & Upjohn Company Thioxazinoquinolones utiles dans le traitement de maladies virales
US6518231B2 (en) 2000-12-18 2003-02-11 Unilever Home & Personal Care Usa, Division Of Conopco, Inc. Enhancement of air bleaching catalysts
WO2002085886A3 (fr) * 2001-04-25 2003-05-22 Souza Noel J De Nouvelle generation de derives chiraux d'acide piperidino-quinolone carboxylique substitue en 7, a triple cible et a large spectre antimicrobien, leur preparation, leurs compositions et leur utilisation comme medicaments
WO2003050107A1 (fr) * 2001-12-13 2003-06-19 Wockhardt Limited Nouveaux derives d'acide piperidino-quinolone carboxylique substitue en position 7, chiraux, a action antimicrobienne a large spectre et ciblage triple, preparation, compositions contenant ces derives et leur utilisation en tant que medicaments
US6608078B2 (en) 2000-05-08 2003-08-19 Wockhardt Limited Antibacterial chiral 8-(substituted piperidino)-benzo [i,j] quinolizines, processes, compositions and methods of treatment
US6664267B1 (en) 2002-05-28 2003-12-16 Wockhardt Limited Crystalline fluoroquinolone arginine salt form
US6759405B2 (en) 2000-11-03 2004-07-06 Wyeth Cycloocta[b][1,4]diazepino[6,7,1-hi]indoles and derivatives
US6777407B2 (en) 2000-11-03 2004-08-17 Wyeth Cyclopenta[b][1,4]diazepino[6,7,1-hi]indoles and derivatives
US6858604B2 (en) 2000-11-03 2005-02-22 Wyeth Cyclohepta[b][1,4]diazepino[6,7,1-hi]indoles and derivatives
US6878713B2 (en) 2001-04-25 2005-04-12 Wockhardt Limited Generation triple-targeting, chiral, broad-spectrum antimicrobial 7-substituted piperidino-quinolone carboxylic acid derivatives, their preparation, compositions and use as medicaments
US7012089B2 (en) 2002-04-25 2006-03-14 Wyeth [1,4]Diazocino[7,8,1-hi]indole derivatives as antipsychotic and antiobesity agents
US7071185B2 (en) 2002-04-25 2006-07-04 Wyeth 1,2,3,4,7,8-hexahydro-6H-[1,4]diazepino[6,7,1-ij]quinoline derivatives as antipsychotic and antiobesity agents
US7098219B2 (en) 2000-08-01 2006-08-29 Wockhart Limited Inhibitors of cellular efflux pumps of microbes
US7129237B2 (en) 2002-04-25 2006-10-31 Wyeth [1,4]Diazepino[6,7,1-ij]quinoline derivatives as antipsychotic and antiobesity agents
US7153824B2 (en) 2003-04-01 2006-12-26 Applied Research Systems Ars Holding N.V. Inhibitors of phosphodiesterases in infertility
US7164023B2 (en) 2003-09-04 2007-01-16 Wockhardt Limited Benzoquinolizine-2-carboxylic acid arginine salt tetrahydrate
WO2008002621A3 (fr) * 2006-06-28 2008-02-21 Merck & Co Inc Effecteurs allostériques positifs du récepteur m1 à base de quinolone à substitution benzyle
US7671196B2 (en) 2005-07-26 2010-03-02 Wyeth Llc Diazepinoquinolines, synthesis thereof, and intermediates thereto
EP2193808A1 (fr) 1999-08-21 2010-06-09 Nycomed GmbH Combinaision synergique
US7781427B2 (en) 2004-11-05 2010-08-24 Wyeth Llc Process for preparing quinoline compounds and products obtained therefrom
US9975906B2 (en) 2014-05-16 2018-05-22 Shionogi & Co., Ltd. Tricyclic heterocycle derivatives having HIV replication inhibitory effect
US10494380B2 (en) 2015-05-29 2019-12-03 Shionogi & Co., Ltd. Nitrogen-containing tricyclic derivatives having HIV replication inhibitory activity

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1433151A (en) * 1973-04-05 1976-04-22 Allen & Hanburys Ltd Benzo-ij-quinolizines

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1433151A (en) * 1973-04-05 1976-04-22 Allen & Hanburys Ltd Benzo-ij-quinolizines

Cited By (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001519328A (ja) * 1997-10-07 2001-10-23 ベーリンガー インゲルハイム （カナダ） リミテッド Ｈｃｍｖ感染症治療のためのアゼチジノン誘導体
EP2193808A1 (fr) 1999-08-21 2010-06-09 Nycomed GmbH Combinaision synergique
US6608078B2 (en) 2000-05-08 2003-08-19 Wockhardt Limited Antibacterial chiral 8-(substituted piperidino)-benzo [i,j] quinolizines, processes, compositions and methods of treatment
WO2002002558A1 (fr) * 2000-07-05 2002-01-10 Pharmacia & Upjohn Company Pyrroloquinolones en tant qu'agents antiviraux
US6525049B2 (en) 2000-07-05 2003-02-25 Pharmacia & Upjohn Company Pyrroloquinolones as antiviral agents
US6683181B2 (en) 2000-07-05 2004-01-27 Pharmacia And Upjohn Comapny Pyrroloquinolones as antiviral agents
US7098219B2 (en) 2000-08-01 2006-08-29 Wockhart Limited Inhibitors of cellular efflux pumps of microbes
US7271164B2 (en) 2000-11-03 2007-09-18 Wyeth Cyclohepta[b][1,4]diazepino[6,7,1,-hi]indoles and derivatives
US6759405B2 (en) 2000-11-03 2004-07-06 Wyeth Cycloocta[b][1,4]diazepino[6,7,1-hi]indoles and derivatives
US6777407B2 (en) 2000-11-03 2004-08-17 Wyeth Cyclopenta[b][1,4]diazepino[6,7,1-hi]indoles and derivatives
US6858604B2 (en) 2000-11-03 2005-02-22 Wyeth Cyclohepta[b][1,4]diazepino[6,7,1-hi]indoles and derivatives
US7271162B2 (en) 2000-11-03 2007-09-18 Wyeth Cycloocta[b][1,4]diazepino[6,7,1-hi]indoles and derivatives
US7271163B2 (en) 2000-11-03 2007-09-18 Wyeth Cyclopenta[b][1,4]diazepino[6,7,1-hi]indoles and derivatives
US6518231B2 (en) 2000-12-18 2003-02-11 Unilever Home & Personal Care Usa, Division Of Conopco, Inc. Enhancement of air bleaching catalysts
WO2002064145A1 (fr) * 2001-02-13 2002-08-22 Pharmacia & Upjohn Company Thioxazinoquinolones utiles dans le traitement de maladies virales
US6821969B2 (en) 2001-02-13 2004-11-23 Pharmacia & Upjohn Company Thioxazinoquinolones as antiviral agents
US7626032B2 (en) 2001-04-25 2009-12-01 Wockhardt Limited Generation triple-targeting, chiral, broad-spectrum antimicrobial 7-substituted piperidino-quinolone carboxylic acid derivatives, their preparation, compositions and use as medicaments
US6964966B2 (en) 2001-04-25 2005-11-15 Wockhardt Limited Generation triple-targeting, chiral, broad-spectrum antimicrobial 7-substituted piperidino-quinolone carboxylic acid derivatives, their preparation, compositions and use as medicaments
US6878713B2 (en) 2001-04-25 2005-04-12 Wockhardt Limited Generation triple-targeting, chiral, broad-spectrum antimicrobial 7-substituted piperidino-quinolone carboxylic acid derivatives, their preparation, compositions and use as medicaments
WO2002085886A3 (fr) * 2001-04-25 2003-05-22 Souza Noel J De Nouvelle generation de derives chiraux d'acide piperidino-quinolone carboxylique substitue en 7, a triple cible et a large spectre antimicrobien, leur preparation, leurs compositions et leur utilisation comme medicaments
US7393957B2 (en) 2001-04-25 2008-07-01 Wockhardt Limited Generation triple-targeting, chiral, broad-spectrum antimicrobial 7-substituted piperidino-quinolone carboxylic acid derivatives, their preparation, compositions and use as medicaments
WO2003050107A1 (fr) * 2001-12-13 2003-06-19 Wockhardt Limited Nouveaux derives d'acide piperidino-quinolone carboxylique substitue en position 7, chiraux, a action antimicrobienne a large spectre et ciblage triple, preparation, compositions contenant ces derives et leur utilisation en tant que medicaments
US7687620B2 (en) 2002-04-25 2010-03-30 Wyeth Llc [1,4]diazepino[6,7,1-IJ]quinoline derivatives as antipsychotic and antiobesity agents
US7012089B2 (en) 2002-04-25 2006-03-14 Wyeth [1,4]Diazocino[7,8,1-hi]indole derivatives as antipsychotic and antiobesity agents
US7129237B2 (en) 2002-04-25 2006-10-31 Wyeth [1,4]Diazepino[6,7,1-ij]quinoline derivatives as antipsychotic and antiobesity agents
US7071185B2 (en) 2002-04-25 2006-07-04 Wyeth 1,2,3,4,7,8-hexahydro-6H-[1,4]diazepino[6,7,1-ij]quinoline derivatives as antipsychotic and antiobesity agents
US7132541B2 (en) 2002-05-28 2006-11-07 Wockhardt Limited Crystalline fluoroquinolone arginine salt form
US6664267B1 (en) 2002-05-28 2003-12-16 Wockhardt Limited Crystalline fluoroquinolone arginine salt form
US7153824B2 (en) 2003-04-01 2006-12-26 Applied Research Systems Ars Holding N.V. Inhibitors of phosphodiesterases in infertility
US7164023B2 (en) 2003-09-04 2007-01-16 Wockhardt Limited Benzoquinolizine-2-carboxylic acid arginine salt tetrahydrate
US7781427B2 (en) 2004-11-05 2010-08-24 Wyeth Llc Process for preparing quinoline compounds and products obtained therefrom
US7671196B2 (en) 2005-07-26 2010-03-02 Wyeth Llc Diazepinoquinolines, synthesis thereof, and intermediates thereto
WO2008002621A3 (fr) * 2006-06-28 2008-02-21 Merck & Co Inc Effecteurs allostériques positifs du récepteur m1 à base de quinolone à substitution benzyle
US8178667B2 (en) 2006-06-28 2012-05-15 Merck Sharp & Dohme Corp. Benzyl-substituted quinolone M1 receptor positive allosteric modulators
US9975906B2 (en) 2014-05-16 2018-05-22 Shionogi & Co., Ltd. Tricyclic heterocycle derivatives having HIV replication inhibitory effect
US10494380B2 (en) 2015-05-29 2019-12-03 Shionogi & Co., Ltd. Nitrogen-containing tricyclic derivatives having HIV replication inhibitory activity
US10870661B2 (en) 2015-05-29 2020-12-22 Shionogi & Co., Ltd. Nitrogen-containing tricyclic derivatives having HIV replication inhibitory activity

Also Published As

Publication number Publication date
AU1886197A (en) 1997-09-10
JP2000505451A (ja) 2000-05-09
EP0882047A1 (fr) 1998-12-09
AU710876B2 (en) 1999-09-30
CA2241891A1 (fr) 1997-08-21

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