WO1997044322A1 - Quinoline sulfonamides as tnf inhibitors and as pde-iv inhibitors - Google Patents
Quinoline sulfonamides as tnf inhibitors and as pde-iv inhibitors Download PDFInfo
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- WO1997044322A1 WO1997044322A1 PCT/GB1997/001360 GB9701360W WO9744322A1 WO 1997044322 A1 WO1997044322 A1 WO 1997044322A1 GB 9701360 W GB9701360 W GB 9701360W WO 9744322 A1 WO9744322 A1 WO 9744322A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
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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
- C07D215/36—Sulfur atoms
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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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to novel quinoiines, 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.
- PDE Phosphodiesterases
- TNF Tumour Necrosis Factor
- 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 G):
- R is H, halogen or alkyl;
- R represents OH, alkoxy optionally substituted with one or more halogens, or thioalkyl;
- R 2 , R 3 and R 4 are the same or different and are each H, R 7 , OR,,, COR 7 ,
- Rj represents H, arylalkyl, heteroarylalkyl, S(O) m R,, or alkyl optionally substituted with one or more substituents chosen from hydroxy, alkoxy, CO 2 R protagonist, SO 2 NR, 2 R 13 , CONR 12 R, 3> CN, carbonyl oxygen, NR 9 R 10 , COR,, and S(O) n R u ;
- R represents aryl, heteroaryl, arylalkyl or heteroarylalkyl; in R 5 and/or R ⁇ , the aryl/heteroaryl portion is optionally substituted with one or more substituents a!kyl-R, 4 or R, 4 ;
- R 7 represents R,, optionally substituted at any position with (one or more) R l6 ;
- R g represents H, alkyl, cycloalkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl;
- R represents H, aryl, heteroaryl, heterocyclo, alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl, alkylcarbonyl, alkoxycarbonyl, arylsulphonyl, heteroarylsulphonyl, heterocyclosulphonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclocarbonyl or alkylsulphonyl;
- R, 0 represents H, aryl, heteroaryl, heterocyclo, alkyl, cycloalkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl;
- R ⁇ represents alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl or heterocycloalkyl;
- R, 2 and R, 3 are the same or different and are each H or R,,, or NR, 2 R 13 represents a heterocyclic ring as defined above;
- R, 4 represents alkyl (optionally substituted by one or more halogens), cycloalkyl, aryl, heteroaryl, heterocyclo, hydroxy, alkoxy (optionally substituted by one or more halogens), thioalkyl, aryloxy, heteroaryloxy, heterocyclooxy, arylalkyloxy, heteroarylalkyloxy, heterocycloalkyloxy, CO 2 R 8 , CONR, 2 R, 3 , SO 2 NR I2 R 13 , halogen, -CN, COR,,, S(O) n R u , or (where appropriate) carbonyl oxygen;
- R,s represents alkyl, arylalkyl or heteroarylalkyl
- R, 6 represents alkyl, OH, OR,,, NR,R 10 , CN, CO 2 H, CO 2 R protagonist, CONR, 2 R, 3 or COR,,
- m represents 1-2
- n represents 0-2; and pharmaceutically-acceptable salts.
- 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 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 defined 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).
- Thioalkyl means an alkyl-S-group.
- 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.
- Arylsulphonyl 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 wich 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.
- Carbocyclic ring means about a 5 to about a 10 membered monocyclic or multicyclic ring system which may saturated or partially unsaturated.
- Heterocyclo ring means about a 5 to about a 10 membered monocyclic or multicyclic ring system (which may 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 mo ⁇ holine 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 pu ⁇ ura 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 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 (HIV), which comprises administering to such mammal an effective TNF inhibiting amount of a compound of Formula (i) or a pharmaceutically-acceptable salt thereof.
- HIV human immunodeficiency virus
- the compounds of this invention may 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) or other retroviral infection such as equine infectious anaemia virus, caprine arthritis virus, visna virus, maedi virus and other lentiviruses.
- FTV feline immunodeficiency virus
- retroviral infection such as 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 cAMP 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, m and n are as defined above.
- 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. Suitable protecting groups for such functionality will be apparent to those skilled in the art. For specific details, see Protective Groups in Organic Synthesis, Wiley Interscience, TW Greene.
- the process for preparing compounds of formula (i) in which R 3 contains an -OH comprises of deprotecting (for example by hydrogenolysis or hydrolysis) a compound of formula (i) in which R 3 contains an appropriate -OP wherein P represents a suitable protecting group (e.g. benzyl or acetate).
- P represents a suitable protecting group
- this may be obtained by conventional resolution techniques such as high performance liquid chromatography or the synthetic processes herein described may by performed using the appropriate homochiral starting material.
- a process for the preparation of a compound of formula (i) comprises reaction of an appropriate sulphonyl chloride of formula (ii) with a suitable amine of formula (iii)
- R u represents R, as defined in relation to formula (i) or a group convertible to R
- R ⁇ -R f c similarly represent R 2 -R 6 or groups convertible to R 2 -R ⁇ ; respectively; and thereafter, if required, converting any group R u to R, and/or R ⁇ to R, and/or R 3l to R 3 and/or R u to R 4 and/or Rj, to R, and/or converting any group R ⁇ to R ⁇ .
- the reaction of a sulphonyl chloride of formula (ii) with an amine of formula (iii) may be carried out under any suitable conditions known to those skilled in the art.
- the reaction is carried out in the presence of a suitable base, for example an amine such as triethylamine, preferably in an appropriate solvent such as dichloromethane.
- a suitable base for example an amine such as triethylamine, preferably in an appropriate solvent such as dichloromethane.
- a stronger base such as sodium hydride, and a polar solvent such as dimethylformamide, will be required.
- Sulphonyl chlorides of formula (ii) are either commercially available, previously described compounds or are prepared using standard procedures known to those skilled in the art.
- a sulphonyl chloride of formula (ii) is conveniently prepared from the appropriate sulphonic acid (iv)
- a sulphonyl chloride of formula (ii) may be prepared by sulphonylation of an appropriate quinoline of formula (v)
- a compound of formula (ia) may also be prepared by reaction of a sulphonyl chloride of formula (ii) with an amine of the formula (vi), to provide a compound of formula (ia) in which Rj, is H, followed by reaction with an appropriate agent of formula R j ,Y (vii), wherein R -R ⁇ are as defined above and Y represents a suitable leaning group such as halogen.
- the reaction of a sulphonyl chloride of formula (ii) with an amine of formula (vi) may be carried out under any suitable conditions known to those skilled in the art.
- the reaction is carried out in the presence of a suitable base, for example an amine such as triethylamine, preferably in an appropriate solvent such as dichloromethane.
- a suitable base for example an amine such as triethylamine, preferably in an appropriate solvent such as dichloromethane.
- a stronger base such as sodium hydride, and a polar solvent such as dimethylformamide, may be required.
- agent of formula (vii) may be carried out under any suitable conditions known to those skilled in the art.
- the reaction is carried out using an appropriate base, such as sodium hydride, preferably in an appropriate solvent such as dimethylformamide.
- Agents of formula (vii) are either commercially available or are prepared using standard procedures known to those skilled in the art.
- Agent (vii) can be an alkylating agent such as propyl bromide, an acylating agent such as benzoyl chloride or a sulphonylating agent such as methanesuiphonyl chloride.
- Amines of formulae (iii) and (vi) are commercially available, previously described compounds or are prepared using standard procedures 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 R 3 contains an alkoxy group may be prepared by appropriate alkylation of a compound in which R 3 contains a hydroxy group.
- R 2 -R 4 contain a CO-alkyl, CO-aryl, CO-heteroaryl, CO- alkylaryl, CO-alkylheteroaryl or CO-aikylheterocyclo group 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 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 of the active ingredient.
- parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrastemal injection or infusion tecniques.
- the compounds of the invention are effective in the treatment of humans.
- the 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 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 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. Such operations are of course conventional in the art.
- 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.
- 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 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 oieyl 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.
- the title compound was obtained as a colourless gum (250mg) from 8- methoxyquinoline-5-(N-benzyl)sulphonamide and bromopropane using a similar procedure to that described in Example 1.
- 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
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Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP09541789A JP2000510866A (en) | 1996-05-20 | 1997-05-20 | Quinoline sulfonamides as inhibitors of TNF and PDE-IV |
BR9709105A BR9709105A (en) | 1996-05-20 | 1997-05-20 | Quinoline sulfonamides as tnf inhibitors and as pde-iv inhibitors |
EP97923192A EP0912519A1 (en) | 1996-05-20 | 1997-05-20 | Quinoline sulfonamides as tnf inhibitors and as pde-iv inhibitors |
CA002252501A CA2252501A1 (en) | 1996-05-20 | 1997-05-20 | Quinoline sulfonamides as tnf inhibitors and as pde-iv inhibitors |
AU29059/97A AU722662B2 (en) | 1996-05-20 | 1997-05-20 | Quinoline sulfonamides as TNF inhibitors and as PDE-IV inhibitors |
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GBGB9623234.3A GB9623234D0 (en) | 1996-11-07 | 1996-11-07 | Novel compounds |
GBGB9626883.4A GB9626883D0 (en) | 1996-12-24 | 1996-12-24 | Compounds |
GB9626883.4 | 1996-12-24 | ||
GB9708071.7 | 1997-04-22 | ||
GBGB9708071.7A GB9708071D0 (en) | 1997-04-22 | 1997-04-22 | Compounds |
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EP (1) | EP0912519A1 (en) |
JP (1) | JP2000510866A (en) |
CN (1) | CN1219168A (en) |
AU (1) | AU722662B2 (en) |
BR (1) | BR9709105A (en) |
CA (1) | CA2252501A1 (en) |
WO (1) | WO1997044322A1 (en) |
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS61169845A (en) * | 1985-01-23 | 1986-07-31 | Fuji Photo Film Co Ltd | Silver halide color photographic sensitive material |
JPH02184673A (en) * | 1989-01-11 | 1990-07-19 | Yoshitomi Pharmaceut Ind Ltd | Sulfonamide compound |
JPH03258763A (en) * | 1990-03-09 | 1991-11-19 | Asahi Chem Ind Co Ltd | Sulfonamide derivative and drug composition containing the same |
WO1994022852A1 (en) * | 1993-03-31 | 1994-10-13 | Syntex (U.S.A.) Inc. | Quinolines as type iv phosphodiesterase inhibitors |
WO1995003051A1 (en) * | 1993-07-26 | 1995-02-02 | Pharmacia Ab | Use of quinoline-3-carboxamide compounds for inhibiting the production of tumour necrosis factor (tnf) and/or for the treatment of septic shock |
WO1996036611A1 (en) * | 1995-05-19 | 1996-11-21 | Chiroscience Limited | 3,4-disubstituted-phenylsulphonamides and their therapeutic use |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5571821A (en) * | 1993-05-20 | 1996-11-05 | Texas Biotechnology Corporation | Sulfonamides and derivatives thereof that modulate the activity of endothelin |
US5340811A (en) * | 1990-03-08 | 1994-08-23 | Asahi Kasei Kogyo Kabushiki Kaisha | Isoquinoline-or quinoline-sulfonamide derivative and a pharmaceutical composition comprising the same |
US5646677A (en) * | 1995-02-23 | 1997-07-08 | Motorola, Inc. | Method and apparatus for interactively viewing wide-angle images from terrestrial, space, and underwater viewpoints |
-
1997
- 1997-05-20 CN CN97194734A patent/CN1219168A/en active Pending
- 1997-05-20 AU AU29059/97A patent/AU722662B2/en not_active Ceased
- 1997-05-20 EP EP97923192A patent/EP0912519A1/en not_active Withdrawn
- 1997-05-20 JP JP09541789A patent/JP2000510866A/en active Pending
- 1997-05-20 US US08/858,969 patent/US5834485A/en not_active Expired - Fee Related
- 1997-05-20 WO PCT/GB1997/001360 patent/WO1997044322A1/en not_active Application Discontinuation
- 1997-05-20 BR BR9709105A patent/BR9709105A/en unknown
- 1997-05-20 CA CA002252501A patent/CA2252501A1/en not_active Abandoned
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS61169845A (en) * | 1985-01-23 | 1986-07-31 | Fuji Photo Film Co Ltd | Silver halide color photographic sensitive material |
JPH02184673A (en) * | 1989-01-11 | 1990-07-19 | Yoshitomi Pharmaceut Ind Ltd | Sulfonamide compound |
JPH03258763A (en) * | 1990-03-09 | 1991-11-19 | Asahi Chem Ind Co Ltd | Sulfonamide derivative and drug composition containing the same |
WO1994022852A1 (en) * | 1993-03-31 | 1994-10-13 | Syntex (U.S.A.) Inc. | Quinolines as type iv phosphodiesterase inhibitors |
WO1995003051A1 (en) * | 1993-07-26 | 1995-02-02 | Pharmacia Ab | Use of quinoline-3-carboxamide compounds for inhibiting the production of tumour necrosis factor (tnf) and/or for the treatment of septic shock |
WO1996036611A1 (en) * | 1995-05-19 | 1996-11-21 | Chiroscience Limited | 3,4-disubstituted-phenylsulphonamides and their therapeutic use |
Non-Patent Citations (11)
Title |
---|
AM. J. TROP. MED. HYG., vol. 4, - 1955, pages 224 - 248 * |
BIOORG. KHIM., vol. 16, no. 7, - 1990, pages 956 - 962 * |
BULL. FAC. SCI.,ASSIUT UNIV..B, vol. 22, no. 2, - 1993, pages 101 - 108 * |
CHEMICAL ABSTRACTS, vol. 100, no. 8, 20 February 1984, Columbus, Ohio, US; abstract no. 60857c, TIWARI,G.D. ET AL: "Studies on the ..." XP002039762 * |
CHEMICAL ABSTRACTS, vol. 106, no. 16, 20 April 1987, Columbus, Ohio, US; abstract no. 129242s, OKI,NOBUTAKA: "Siver halide color ..." XP002039760 * |
CHEMICAL ABSTRACTS, vol. 113, no. 18, 29 October 1990, Columbus, Ohio, US; abstract no. 164723r, TOCHILKIN, A.I. ET AL: "8-Methoxy-5-quinolinesulfonyl chloride , a ..." XP002025492 * |
CHEMICAL ABSTRACTS, vol. 114, no. 1, 7 January 1991, Columbus, Ohio, US; abstract no. 6308a, AO, EIBOKU ET AL: "Preparation of (iso)quinolinesulfonamides as ..." XP002025491 * |
CHEMICAL ABSTRACTS, vol. 116, no. 12, 30 March 1992, Columbus, Ohio, US; abstract no. 128690f, KAJIWARA,AKIO ET AL: "Preparation of quinolinesulfonamide ..." XP002025490 * |
CHEMICAL ABSTRACTS, vol. 122, no. 8, 20 February 1995, Columbus, Ohio, US; abstract no. 95157f, IBRAHIM,S.A. ET AL: "Antimicrobial quinolinol-5-sulfonamide ..." XP002039761 * |
CHEMICAL ABSTRACTS, vol. 51, no. 3, 1957, Columbus, Ohio, US; abstract no. 15005a3, PAUL E. THOMPSON ET AL: "Antiamebic action of ..." XP002039759 * |
J. INDIAN CHEM. SOC., vol. 60, no. 7, - 1983, pages 698 - 699 * |
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Also Published As
Publication number | Publication date |
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JP2000510866A (en) | 2000-08-22 |
CA2252501A1 (en) | 1997-11-27 |
AU722662B2 (en) | 2000-08-10 |
EP0912519A1 (en) | 1999-05-06 |
AU2905997A (en) | 1997-12-09 |
BR9709105A (en) | 1999-08-03 |
CN1219168A (en) | 1999-06-09 |
US5834485A (en) | 1998-11-10 |
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