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WO1997030999A1 - Quinolones et leur utilisation therapeutique - Google Patents

Quinolones et leur utilisation therapeutique Download PDF

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Publication number
WO1997030999A1
WO1997030999A1 PCT/GB1997/000491 GB9700491W WO9730999A1 WO 1997030999 A1 WO1997030999 A1 WO 1997030999A1 GB 9700491 W GB9700491 W GB 9700491W WO 9730999 A1 WO9730999 A1 WO 9730999A1
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WIPO (PCT)
Prior art keywords
alkyl
compound
disease
disease state
ring
Prior art date
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PCT/GB1997/000491
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English (en)
Inventor
Alan Findlay Haughan
Steven Colin Beasley
John Gary Montana
Karen Ann Runcie
Robert John Watson
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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 GBGB9702933.4A external-priority patent/GB9702933D0/en
Application filed by Darwin Discovery Limited filed Critical Darwin Discovery Limited
Priority to JP9529904A priority Critical patent/JP2000505450A/ja
Priority to AU18860/97A priority patent/AU710825B2/en
Priority to EP97905237A priority patent/EP0882046A1/fr
Publication of WO1997030999A1 publication Critical patent/WO1997030999A1/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-acceptable 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 benzoquinoline-2-carboxylic acids and esters as anti-microbial agents.
  • GB-A- 1433151 discloses N-tetrazolyl-benzoquinolizine-2-carboxamides, 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):
  • R 1 represents a bicyclic structure (e.g. indanyl) in which a cycloalkyl or heterocyclo ring is bound to NH and is fused to a second ring selected from aryl or heteroaryl, in which either or each ring is optionally substituted by one or more substituents chosen from halo, C M alkoxy, hydroxy, CN, CO ⁇ (or C, ⁇ alkyl esters or
  • R 3 , R 4 and R 5 are the same or different and represent H, halo, C w alkoxy, hydroxy, CN, CO ⁇ (or C w alkyl esters or C M alkyl amides thereof), NR*R ⁇ SO 2 NR*R 7 or C w alkyl in which alkyl is optionally substituted with halo, C M alkoxy, hydroxy, CN, CO 2 H (or C w alkyl esters or C w alkyl amides thereof), NR 6 R 7 or SO 2 NR*R 7 , or any adjacent two substituents R 3 -R 5 are joined to form an optionally substituted carbocyclic aromatic, heteroaromatic, saturated carbocyclic or heterocyclic ring; R* and R 7 are the same or different and represent H, C, ⁇ alkyl, cycloalkyl, C w alkylcarbonyl, arylcarbonyl, C, ⁇ alkoxycarbonyl, arylsulphonyl or C
  • X represents a linking group selected from -(CR'R 10 ) ⁇ -, -Y-(CR*R l0 ) 2 - > - (CR 9 R 10 ) 2 -Y-, -CR 9 R l0 -Y-CR 9 R 10 - and -Y-CR'R ⁇ -Z-, Y and Z being independently NR 11 , O or 8(0) 0 . 2 , provided that Y and Z are not both S(O)o_ 2 ; Q represents O or S; each R 9 , each R 10 and R u are the same or different and are H or C w alkyl; and pharmaceutically-acceptable salts, solvates and hydrates thereof. Combinations of substituents and/or variables are only permissible if such combinations result in stable compounds. Description ofthe Invention
  • Suitable pharmaceutically-acceptable salts are pharmaceutically-acceptable base salts and pharmaceutically-acceptable acid addition salts. Certain ofthe 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 ofthe compounds of formula (1) are prepared using conventional procedures.
  • some ofthe 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.
  • 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.
  • Alkoxy means an alkyl-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.
  • Arylcarbonyl means an aryl-CO- group.
  • Arylsulphonyl means an aryI-SO 2 - group.
  • Alkylsulphonyl means an alkyl-SO 2 - group.
  • Alkoxycarbonyl means an alkoxy-CO- group. When any two of R 3 , R 4 and R 5 are joined together, an example is methylenedioxy (OCH 2 O).
  • Halo means fluorine, chlorine, bromine or iodine.
  • the compounds of formula (I) are preferably in pharmaceutically-acceptable form.
  • pharmaceutically-acceptable form is meant, inter alia, 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%.
  • 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 J -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, 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 purpura nephritis, joint inflammation, arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondyiitis and osteoarthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury ofthe 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. 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 HTV-1, HTV-2 and HTV-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 (HTV), which comprises administering to such mammal an effective TNF-inhibiting amount of a compound of Formula (I) or a pharmaceutically-acceptable 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 (FTV) and other retroviral infections such as equine infectious anaemia virus, caprine arthritis virus, visna virus, aedi virus and other lentiviruses.
  • FTV feline immunodeficiency virus
  • retroviral infections such as equine infectious anaemia virus, caprine arthritis virus, visna virus, aedi virus and other lentiviruses.
  • the compounds ofthis 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 ofthe invention may also suppress neurogenic inflammation through elevation of cAMP in sensory neurones. They are, therefore, analgesic, anti-tussive and anti-hyperalgesic in inflammatory diseases associated with irritation and pain.
  • Compounds ofthe general formula (I) may be prepared by any suitable method known in the art and/or by the following process, which itself forms part ofthe invention.
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , R ⁇ , 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 ofthe 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 4 is CO ⁇ 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 9 ⁇ .
  • a process for preparing compounds of general formula (I) comprises coupling an acid of formula (II)
  • Amines of formula (III) are commercially available or can be readily obtained from commercially-available starting materials using methods known to those skilled in the art. Some ofthe amines of formula (III) are conveniently prepared by reductive amination of an appropriate carbonyl compound with a suitable amine. 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 ofthis 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-methylmorpholine.
  • 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,
  • 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 (III).
  • Acids of general formula (II) 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 co ⁇ esponding ester of general formula (TV)
  • R 12 represents an (ar)alkyl group such as methyl, ethyl, benzyl or tert-butyl.
  • suitable conditions comprise reaction with phosphorus pentasulphide (P S 10 ) in an organic solvent such as pyridine at an appropriate temperature. The reflux temperature of the solvent is preferred.
  • Y and Z' each being NR U , O or S, e.g. -O-CR 9 R I0 -NR 11 -, may be prepared by cyclisation of intermediates of general formula (V)
  • 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 (Vm) O O
  • esters of general formula (IV) may be prepared from the corresponding intermediate of general formula (XI)
  • R 13 represents a protected form of Y ⁇ such as OAc, SAc or NR ⁇ Boc.
  • the quinoline nucleus in the compounds (IV) and (XIII) may be generated by cyclisation of an ester of formula (XIV) or (XV) FT
  • 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.
  • 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, ⁇ 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 ofthe physico-chemical differences ofthe 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. Where desired, however, appropriate homochiral starting materials may be used in the reaction sequence to yield a particular stereoisomer of formula (I).
  • a compound of formula (I) or where appropriate a pharmaceutically-acceptable salt thereof and/or a pharmaceutically-acceptable solvate thereof, may be administered per 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 ofthe active ingredient.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc, the compounds ofthe 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.
  • 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 giycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycolate 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 lactose, sugar, maize-starch, calcium phosphate, sorbitol or giycine
  • tabletting lubricants for example magnesium stearate
  • disintegrants for
  • 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.
  • 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, as 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 sympathornimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine; corticosteroids such as prednisolone and adrenal stimulants such as ACTH may be included.
  • 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. In preparing solutions 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 sterihsed 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 ofthe compound.
  • compositions may contain from 0.1% to 99% by weight, preferably from 10- 60% by weight, ofthe 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, 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
  • Trirsthylamine (0.27 ml) was then added dropwise, followed by isopropenyl chloroformate (0.21 ml) and the whole stirred for 60 minutes.
  • 1-Amino- 5,6-dimethoxyindane (0.37 g) (prepared by the procedure of EP-A-0051391) was then added and the reaction stirred for 20 h, concentrated onto silica and purified by flash column chromatography to give the title compound (0.22 g) as an off-white solid.
  • the ability ofthe compounds of formula (I) to inhibit TNF production in human monocytes is measured as follows. 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 . Supernatants are tested for TNF ⁇ by ELISA using commercially available kits. Skin Eosinophilia Model

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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, R1 représente une structure bicyclique dans laquelle un groupe cycloalkyle ou hétérocyclo est lié à NH et fusionné avec un second cycle aryle ou hétéroaryle 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/GB1997/000491 1996-02-21 1997-02-21 Quinolones et leur utilisation therapeutique WO1997030999A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP9529904A JP2000505450A (ja) 1996-02-21 1997-02-21 キノロン類およびこれらの治療的使用
AU18860/97A AU710825B2 (en) 1996-02-21 1997-02-21 Quinolones and their therapeutic use
EP97905237A EP0882046A1 (fr) 1996-02-21 1997-02-21 Quinolones et leur utilisation therapeutique

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
GB9702933.4 1997-02-13
GBGB9702933.4A GB9702933D0 (en) 1997-02-13 1997-02-13 Quinolones and their therapeutic use

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JP (1) JP2000505450A (fr)
AU (1) AU710825B2 (fr)
CA (1) CA2242598A1 (fr)
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WO2002002558A1 (fr) * 2000-07-05 2002-01-10 Pharmacia & Upjohn Company Pyrroloquinolones en tant qu'agents antiviraux
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
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
WO2006002421A3 (fr) * 2004-06-24 2006-09-21 Vertex Pharma Modulateurs de transporteurs de cassette de liaison a l'atp
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
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
EP2502912A2 (fr) * 2004-06-24 2012-09-26 Vertex Pharmaceuticals Incorporated Modulateurs de transporteurs de cassette de liaison a l´ATP
US8354427B2 (en) 2004-06-24 2013-01-15 Vertex Pharmaceutical Incorporated Modulators of ATP-binding cassette transporters
US8410274B2 (en) 2005-12-28 2013-04-02 Vertex Pharmaceuticals Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US8802700B2 (en) 2010-12-10 2014-08-12 Vertex Pharmaceuticals Incorporated Modulators of ATP-Binding Cassette transporters
US9701639B2 (en) 2014-10-07 2017-07-11 Vertex Pharmaceuticals Incorporated Co-crystals of modulators of cystic fibrosis transmembrane conductance regulator
US9751839B2 (en) 2009-03-20 2017-09-05 Vertex Pharmaceuticals Incorporated Process for making modulators of cystic fibrosis transmembrane conductance regulator
US10272046B2 (en) 2012-02-27 2019-04-30 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
US10646481B2 (en) 2008-08-13 2020-05-12 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
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AU2003219913A1 (en) * 2002-02-27 2003-09-09 Teva Pharmaceutical Industries, Ltd. Propargylamino indan derivatives and propargylamino tetralin derivatives as brain-selective mao inhibitors
WO2015174511A1 (fr) 2014-05-16 2015-11-19 塩野義製薬株式会社 Dérivé hétérocyclique tricyclique présentant un effet d'inhibition de la réplication du vih

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GB1433151A (en) * 1973-04-05 1976-04-22 Allen & Hanburys Ltd Benzo-ij-quinolizines

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GB1433151A (en) * 1973-04-05 1976-04-22 Allen & Hanburys Ltd Benzo-ij-quinolizines

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EP2193808A1 (fr) 1999-08-21 2010-06-09 Nycomed GmbH Combinaision synergique
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
WO2002002558A1 (fr) * 2000-07-05 2002-01-10 Pharmacia & Upjohn Company Pyrroloquinolones en tant qu'agents antiviraux
US7271162B2 (en) 2000-11-03 2007-09-18 Wyeth Cycloocta[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
US7271164B2 (en) 2000-11-03 2007-09-18 Wyeth Cyclohepta[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
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
US7687620B2 (en) 2002-04-25 2010-03-30 Wyeth Llc [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
EP2502911A3 (fr) * 2004-06-24 2013-11-06 Vertex Pharmaceuticals Incorporated Modulateurs de transporteurs de cassette de liaison a l´ATP
US10662192B2 (en) 2004-06-24 2020-05-26 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US7495103B2 (en) 2004-06-24 2009-02-24 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US9090619B2 (en) 2004-06-24 2015-07-28 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US8101767B2 (en) 2004-06-24 2012-01-24 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
EP2489659A1 (fr) * 2004-06-24 2012-08-22 Vertex Pharmaceuticals Incorporated Modulateurs de transporteurs de cassette de liaison a l´ATP
EP2502912A2 (fr) * 2004-06-24 2012-09-26 Vertex Pharmaceuticals Incorporated Modulateurs de transporteurs de cassette de liaison a l´ATP
US8324242B2 (en) 2004-06-24 2012-12-04 Vertex Pharmaceutical Incorporated Modulators of ATP-binding cassette transporters
US8354427B2 (en) 2004-06-24 2013-01-15 Vertex Pharmaceutical Incorporated Modulators of ATP-binding cassette transporters
EP2530075A3 (fr) * 2004-06-24 2014-12-24 Vertex Pharmaceuticals Incorporated Modulateurs de transporteurs de cassette de liaison a l´ATP
WO2006002421A3 (fr) * 2004-06-24 2006-09-21 Vertex Pharma Modulateurs de transporteurs de cassette de liaison a l'atp
EP2502912A3 (fr) * 2004-06-24 2013-11-06 Vertex Pharmaceuticals Incorporated Modulateurs de transporteurs de cassette de liaison a l´ATP
EP2522659A3 (fr) * 2004-06-24 2013-11-27 Vertex Pharmaceuticals Incorporated Modulateurs de transporteurs de cassette de liaison a l´ATP
EP2502914A3 (fr) * 2004-06-24 2013-12-04 Vertex Pharmaceuticals Incorporated Modulateurs de transporteurs de cassette de liaison a l´ATP
US8614327B2 (en) 2004-06-24 2013-12-24 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US8629162B2 (en) 2004-06-24 2014-01-14 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US8741925B2 (en) 2004-06-24 2014-06-03 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
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
US8754224B2 (en) 2005-12-28 2014-06-17 Vertex Pharmaceuticals Incorporated Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
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US8410274B2 (en) 2005-12-28 2013-04-02 Vertex Pharmaceuticals Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
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US10646481B2 (en) 2008-08-13 2020-05-12 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
US11564916B2 (en) 2008-08-13 2023-01-31 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
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US8802700B2 (en) 2010-12-10 2014-08-12 Vertex Pharmaceuticals Incorporated Modulators of ATP-Binding Cassette transporters
US10272046B2 (en) 2012-02-27 2019-04-30 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
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AU710825B2 (en) 1999-09-30
AU1886097A (en) 1997-09-10
CA2242598A1 (fr) 1997-08-28
EP0882046A1 (fr) 1998-12-09
JP2000505450A (ja) 2000-05-09

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