JP2002504925A - Quinoline derivatives as PDE IV and / or TNF inhibitors - Google Patents

Abstract

(57) Abstract: A compound of formula (i) wherein R ₁ represents C _1-6 alkoxy (alkyl moiety optionally substituted with one or more halogen) or thioalkyl; Represents an aryl or heteroaryl ring optionally bonded at any position with one or more substituents R ₅ through a suitable atom). The compounds can be used, for example, to treat diseases associated with proteins that mediate cellular activity, for example, by inhibiting tumor necrosis factor and / or by inhibiting phosphodiesterase IV.

Description

DETAILED DESCRIPTION OF THE INVENTION     Quinoline derivatives as PDE IV and / or TNF inhibitors Field of the invention   The present invention relates to novel quinolines and their preparation and use as medicaments.Background of the Invention   Japanese Patent Publication No. 2-184673 discloses quinoline sulfonamides.   U.S. Pat. No. 4,910,193 discloses that sulfonamide nitrogens are formed by various bridged saturated ring systems. Quinoline as a substituted drug suitable for the treatment of serotonin-induced gastrointestinal disorders A sulfonamide is disclosed.   U.S. Patent Application No. 4,857,301 and U.S. Patent Application No. 5,340,811 Quinoline in the treatment of asthma as a bronchodilator and antiallergic compound A sulfonamide is disclosed.   Trecourt et al., J. Het. Chem. (1995)32 1261 is a 5-arylquine as an intermediate for the synthesis of pyridocarbazole Disclosed is the preparation of Norin. Trekart et al., Syn.Commun. (199) 5)25  4011 is 5-Fe as an intermediate for the synthesis of indoloquinoline Disclosed is nilquinoline.   5-Heteroarylquinoline and 5-heterocycloquino having antimicrobial activity Phosphorus is described in Khalil et al., J. Indian Chem. Sok. Soc.) (1987)LXIV42, and ibid (1990)67  821. More disclosed.   A series of patents by Bayer (US Patent Application No. 5304563, European Patent Application 05 82908 and European Patent Application 0545170) include 5-arylquinolines. Disclosed are 2-substituted quinolines as lipoxygenase inhibitors.   Phosphodiesterase (PDE) and tumor necrosis factor (TNF), their mode of action and And its inhibitors have therapeutic efficacy in WO-A-9636595, WO-A-963 6596 and WO-A-9636611, the contents of which are incorporated by reference. It is built into the riko. As PDE and TNF inhibitors Potent sulfonamides are disclosed in the same document.   Some quinolines are known that have no associated therapeutic effect. This includes 5, 5′-bis (8-methoxyquinoline), 5,5′-bis (8-methoxyquinaldine), 1- ( 8-ethoxy-5-quinolyl) -3,4-dihydroisoquinoline, 1- (8-ethoxy-5- Quinolyl) isoquinoline, 2- (8-ethoxy-5-quinolyl) -1,2,3,4-tetrahi Droisoquinoline, 8-isopropoxy-5- (1-naphthyl) quinoline, 5-methoxy Ci-8-phenylquinoline, 5-methoxy-8- [2- (t-butylcarbonylamino) phenyl Enyl] quinoline and 5-methoxy-8- [2- (t-butylcarbonylamino) -5- [Methoxyphenyl] quinoline. Chem.Abs. (19 62) 57 (9): 11159e; Chem.ABS. (1963) 59 (6): 6364. e; Beugelmans & Bois-Chaussy ), J. Org. Chem. (1991) 56: 2518-2522; And Trecourt et al., J. Heterocyclic Chem. clic Chem.) (1995) 32: 1261.Summary of the Invention   The present invention provides, for example, by inhibiting tumor necrosis factor and / or By inhibiting sterase IV, disease states (e.g., (A disease state associated with protein). According to the present invention, The novel compounds are compounds of formula (i) and pharmaceutically acceptable salts thereof. :   R₁Is C_1-6Alkoxy (an alkyl optionally substituted with one or more halogens) Kill moiety), OH or thioalkyl;   R_Two, R_ThreeAnd R_FourMay be the same or different, and H, OR₁₁, CO R₇, CN, CO_TwoR₈, C (= NOR₇) R₇, Alkyl-C (= NOR₇) R₇, Haloge , CF_Three, CONR₁₂R₁₃, NR₉R_TenOr R₇Represents;   R_FiveIs halogen, arylalkyl, heteroarylalkyl, heterocyclo Alkyl, alkyl, hydroxyl, alkoxy, CO_TwoR₈, SO_TwoNR₁₂R₁₃, CO NR₁₂R₁₃, CN, NR₉R_Ten, COR₁₁Or S (O)_nR₁₁Represents;   R₇Is H, alkyl, cycloalkyl, aryl, heteroaryl, hetero Cyclo, arylalkyl, heteroarylalkyl or heterocycloalkyl Wherein R is R at any position.₁₆Can be optionally substituted;   R₈Is H, alkyl, arylalkyl, heteroarylalkyl or hetero Represents cycloalkyl;   R₉Is alkylcarbonyl, alkoxycarbonyl, arylsulfonyl, Teloarylsulfonyl, heterocyclosulfonyl, arylcarbonyl, hete Represents arylcarbonyl, heterocyclocarbonyl or alkylsulfonyl , R_TenIs H or R₁₁Or NR₉R_TenIs one or more R_FifteenIs arbitrarily Represents a substituted heterocyclic ring (such as morpholine or piperidine);   R₁₁Is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo Represents arylalkyl, heteroarylalkyl or heterocycloalkyl ;   R₁₂And R₁₃May be the same or different, and each R₇Represents Or NR₁₂R₁₃Is one or more R_FifteenIs an optionally substituted heterocyclic ring ( Morpholine or piperidine);   R_FifteenRepresents alkyl, arylalkyl or heteroarylalkyl;   R₁₆Is halogen, hydroxyl, OR₁₁, NR₉R_Ten, CN, CO_TwoH, CO_TwoR₁₁, CONR₁₂R₁₃Or COR₁₁Represents;   n represents 0-2; and   Q is attached via any suitable atom, and one or more substituents R_FiveBig Any of the positions represents an optionally substituted aryl or heteroaryl ring.   Combinations of substituents and / or variants may make such combinations more stable. Only allowed to produce compounds.Description of the invention   Suitable pharmaceutically acceptable salts are pharmaceutically acceptable basic salts and pharmaceutically acceptable Acid addition salt. Certain compounds of formula (i) containing an acid group form basic salts . Suitable pharmaceutically acceptable basic salts include, for example, alkali Includes metal salts such as metals and organic amine salts provided with ethylenediamine You.   Certain compounds of formula (i) that contain an amino group form acid addition salts. Appropriate acid addition Salts include sulfate, nitrate, phosphate, borate, hydrochlora Pharmaceutically acceptable non-organic salts such as amides and hydrobromides; Salt, tartrate, maleate, citrate, succinate, benzoate, Ascorbate, methane sulfate, α-ketoglutarate, α-glycerophos Addition of pharmaceutically acceptable organic acids such as phosphate and glucose-1-phosphate Contains salt. The pharmaceutically acceptable salts of the compounds of formula (i) are prepared using conventional techniques. Is done.   Some of the compounds of formula (i) may exist in one or more tautomeric forms. It will be clear to those skilled in the art. The invention extends to all tautomeric forms.   It is clear that the compounds according to the invention can contain one or more asymmetrically substituted atoms. Or maybe. The presence of one or more of these asymmetric centers in the compounds of formula (i) Can give rise to structural isomers, and in each case, the invention provides for enantiomers or All such structures, including diastereomers and their racemic mixtures It should be understood that it extends to isomers.   As used herein, the term alkyl is intended to be used alone. Whether used as part of another group, straight and branched chain containing up to 6 atoms. It contains an alkyl group. Alkoxy is an alkyl wherein the alkyl group is as described above. A kill-O- group is meant. Aryloxy is such that the aryl group is defined below. Means an aryl-O- group. Heteroaryloxy is a heteroaryl And heterocyclooxy means a heterocyclo-O- group (f The teloaryl and heterocyclo groups are as defined below. A) Alkylamino refers to an alkyl-N- group wherein the alkyl group is as described above. Taste, arylamino means aryl-N-, and heteroarylamino is Loaryl-N-group (aryl and heteroaryl as defined below) . Cycloalkyls include non-aromatic rings or polycyclic systems of about 3 to 10 carbon atoms . Cyclic alkyls may optionally be partially unsaturated. Aryl is about 6 to 1 1 shows a carbocyclic radical containing 0 carbon atoms. Arylalkyl is aryl And aryl-alkyl groups wherein alkyl is as described herein. means. Heteroarylalkyl means a heteroaryl-alkyl group, wherein Telocycloalkyl means a heterocyclo-alkyl group. Alkyl carboni ル means an alkyl-CO- group in which the alkyl group is as previously described. Arylcarbonyl is aryl-C wherein the aryl group is as described above. O-group. Heteroarylcarbonyl refers to a heteroaryl-CO- group. Taste, heterocyclocarbonyl means a heterocyclo-CO- group. Aryls Ruphonyl is an aryl-SO wherein the aryl group is as described above._Two-Means group I do. Heteroarylsulfonyl is heteroaryl-SO_Two-Means group, hetero Cyclosulfonyl is heterocyclo-SO_Two-Means group. Alkoxycarbonyl Represents an alkyloxy-CO- group in which the alkoxy group is as described above. You. Alkylsulfonyl is alkyl- wherein the alkyl group is as previously described. SO_Two-Means group. Carbonyl oxygen means a -CO- group. Carbonyl oxygen It will be clear that there can be no substituents on the aryl or heteroaryl ring. Duplicate An acyclic ring system is one in which one or more atoms in the ring system are nitrogen, oxygen or sulfur atoms. An element other than carbon selected from about 5 to about 10 membered monocyclic or polycyclic (saturated Or partially unsaturated). As an example, morpholine And piperidine. Heteroaryl is one or more of the The atom is nitrogen, oxygen or sulfur; the N atom may optionally be in the form of an N-oxide; About 5 to about 10 membered aromatic mono- or polycyclic carbon, which is an element other than carbon of choice Means a hydrogen ring system. Heterocyclo is a compound in which one or more atoms in a ring system is nitrogen. From about 5 to about 10 members, other than carbon selected from oxygen or sulfur Or a partially saturated mono- or polycyclic hydrocarbon ring system. Halogen is Means chlorine, bromine or iodine.   The compounds of the present invention are effective in treating TNF-mediated disease states. "TNF-mediated “Disease and disease state” refers to the production of TNF itself or to IL-1 or I TNF triggers the release of other cytokines such as, but not limited to, L-6 Means any and all disease states that TNF affects by causing You. Thus, for example, IL-1 is a major component and its production or reaction in response to TNF Disease states in which the action is intensified or secreted are those in which TNF is mediated. Will be considered. TNF-β (also known as lymphotoxin) is TNF-α (Also known as cachectins) with similar structural homology to each other TNF-α and TNF-β both induce biological responses and bind to the same cellular receptors. Is believed to be inhibited by the compounds of the invention, and is thus particularly otherwise herein When not shown, they are collectively referred to as "TNF".   The present invention requires the mediation or suppression of PDE IV enzymatic or catalytic activity. Mediates or inhibits the enzymatic or catalytic activity of PDE IV in mammals Suppresses TNF production in mammals that need to suppress TNF production An effective amount of a compound of formula (i) or a pharmaceutically acceptable salt thereof for the mammal. Providing a method.   PDE IV inhibitors are asthma, chronic asthmatic bronchitis, chronic obstructive tracheal disorders , Atopic dermatitis, atopic eczema, urticaria, allergic rhinitis, allergy Conjunctivitis, spring conjunctivitis, eye inflammation, eye allergic reaction, eosinophil granulomas, psoriasis , Behcet's disease, lupus erythematosus, anaphylactoid purpura nephritis, joints Inflammation, arthritis, rheumatoid arthritis and rheumatic spondylitis and osteoarthritis Other arthritis diseases, septic shock, sepsis, ulcerative colitis, Crohn's disease, myocardium Regurgitation disorder of the brain and brain, chronic glomerulonephritis, endotoxin shock and adult respiratory distress It is effective in treating a variety of allergic and inflammatory diseases, including symptomatic groups. In addition, P DE IV inhibitors include diabetes insipidus, cerebral senility, senile dementia (Alzheimer's disease), Cerebral metabolic depression such as Parkinson's disease with memory disorders, depression and multi-infarct dementia It is effective for treating diseases associated with the system. PDE IV inhibitors have neuroprotective effects It is also beneficial for conditions such as improved cardiac arrest, stroke, and intermittent paraplegia . PDE IV inhibitors are tardive dyskinesia, ischemia and Huntington's disease of It may be effective for treatment. In addition, PDE IV inhibitors are used as gastrointestinal Can also have the effect. A particular aspect of the treatment of the invention is the treatment of asthma.   Viruses that are expected to be addressed here produce TNF as a result of infection. That is directly or indirectly replicated by the TNF inhibitor of formula (i). It is susceptible to inhibitory effects such as being reduced. HI for such viruses V-1, HIV-2 and HIV-3, cytomegalovirus (CMV), flu Enza, adenovirus, but not limited to shingles and simple Herpesviruses such as, but not limited to, herpes.   The present invention provides a method for the effective inhibition of TNF of a compound of formula (i) or a pharmaceutically acceptable salt thereof. Administering an amount to a mammal afflicted with the human immunodeficiency virus (HIV). A method of treating a mammal afflicted with the human immunodeficiency virus (HIV). I do.   The compounds of the present invention may be used in veterinary medicine in non-human animals requiring suppression of TNF production. It can be used in connection with treatment. TN in need of therapeutic or prophylactic treatment in animals F-mediated diseases include the above-mentioned disease states, in particular, viral infection. I can do it. Examples of such viruses include feline immunodeficiency virus (FIV) Or horse infectious anemia virus, goat arthritis virus, visna virus, ma Includes other retroviral infections, such as Eddy virus and other lentiviruses But not limited to.   The compounds of the present invention include parasites, yeasts and fungi (yeasts and fungi are TNF That are sensitive to up-regulation by (If it triggers the production of NF). Treat A suitable disease state to treat is fungal meningitis.   The compounds of the present invention increase neuronal inflammation by increasing cAMP in sensory nerves. It can also be suppressed. Therefore, disease states suitable for treatment include inflammation and painful inflammation. Analgesic, anti-cough and anti-hyperalgesic in sexual diseases.   The compound of formula (i) is preferably a pharmaceutically acceptable formulation. Pharmaceutically acceptable Pharmaceutical preparations are especially pharmaceutically acceptable ingredients that exclude the usual pharmaceutical additives such as diluents and carriers. Does not contain substances of bell purity and that are considered toxic at normal dosage levels , A formulation of a pharmaceutically acceptable level of purity is meant. Pharmaceutically acceptable levels of net The degree is generally at least 50% excluding the usual excipients, or preferably 7%. 5%, more preferably 90%, and even more preferably 95%.   The invention further relates to R₁Preparation of compounds of formula (i) as otherwise defined above Provide a way for Functionality such as amino, hydroxy or carboxyl groups The group is present in the various compounds described below, and is desired to be retained. It is necessary to be in a protected state before the entire reaction can begin. It will be clear. In such instances, removal of the protecting group is a special sequence of reactions. Can be the final stage. Suitable protecting groups for such functions will be apparent to those skilled in the art. Or maybe. For more information, see Protecting Groups in Organic Synthesis, See Jens, TW Greene. R_ThreeA method for preparing compounds of formula (i) wherein_ThreeIs suitable -OP (P Represents a suitable protecting group (such as benzyl or acetyl)) Deprotecting the compound (eg, by hydrogenolysis or hydrolysis).   If a special structural isomer of formula (i) is required, this may be a high performance liquid chromatograph. Can be obtained by conventional splitting techniques, such as fee, or synthesized as described herein. The procedure is followed by using the appropriate homochiral starting material.   Methods for preparing compounds of formula (i) include, for example, aryl or heteroaryl of formula (iii) Formulas with suitably substituted aryl or heteroaryl moieties, such as ruboric acid (ii) The reaction of bromine is included.Where R_1aIs R defined in relation to formula (i)₁Or R₁And a group convertible,_2a -R_5aIs similarly R_Two-R_FiveOr R_Two-R_FiveEach represents a convertible group; and then , Optionally any R_1aThe group R₁And / or R_2aTo R_TwoTo And / or R_3aTo R_ThreeAnd / or R_4aTo R_FourAnd / or R_5aAny of That group is R_FiveIs converted to Separately, the bromine of formula (ii) is replaced with the corresponding bromic acid (art (Using conventional conditions known to the artisan), which may be an aryl or It may be combined with a heteroaryl halide, preferably bromide.   This coupling reaction is described, for example, by Trekort et al., J. Het. 5) Articles described by 32 1261 and the references cited therein. Conditions can be performed under any of the conventional conditions well known to those skilled in the art. formula( The preparation of ii) bromine is described in WO-A-9744036. Of the formula (iii) Bromic acid is a compound described above which may be generally utilized, or conventional methods known to those skilled in the art. It is prepared using   Compounds of formula (i) may also be prepared by interconversion of other compounds of formula (i). For example, R_FiveIs a compound containing a carboxylic acid,_FiveIs an alkoxycarbonyl group (for example, (Methoxycarbonyl group).   R_Two-R_FourIs, for example, CO-alkyl, CO-aryl, CO-heteroaryl, CO -Alkylaryl, CO-alkylheteroaryl or CO-alkylheterocy Compounds containing a CO group such as black are represented by R_Two-R_FourIs a suitable compound from a compound containing a CN group. It can be prepared by the addition of organic metal reagents (such as Grignard reagents).   According to a further embodiment method, R_Two-R_FourIs a compound containing oxime,_Two-R_FourMosquito It can be prepared from compounds containing a rubonyl group. This component replacement is well known to those skilled in the art. And may be performed using any of the appropriate conventional conditions. R_Two-R_FourIs a carbonyl group Compounds of formula (i) containing are prepared using conventional conditions known to those skilled in the art (e.g., (Eg, using sodium borohydride in a medium)_Two-R_FourIs an alcohol group Are provided. R_Two-R_FourIs an alkyl,_Two-R_FourIs CO Reduction of compounds that are -alkyl, using conventional conditions well known to those skilled in the art. (E.g., hydrazine hydration in the presence of a suitable base in a suitable solvent) Things). R_Two-R_FourFor compounds of formula (i) containing a carbonyl group, Can be performed. Such component substitutions include reductive amination and alkylation, However, it is not limited to this. Any of the above component substitutions may be at the end of the synthesis or a suitable intermediate Can be performed in   A compound of formula (i) or, where appropriate, a pharmaceutically acceptable salt thereof and / or The solvates that are acceptable can be administered per se, and are preferably pharmaceutically acceptable Administered as a pharmaceutical composition comprising the carrier.   Accordingly, the present invention provides a compound of formula (i) or a pharmaceutically acceptable salt thereof, where appropriate. And / or a pharmaceutically acceptable solvate thereof and a pharmaceutically acceptable carrier. And a pharmaceutical composition comprising:   The active compound can be formulated for administration by any suitable route, but is preferably The preferred route will depend on the condition for which treatment is required, and is preferably single dose It is a dosage form or a dosage form that a human patient can take in a single dose. Fortunately, The composition is suitable for oral, rectal, topical, parenteral administration or administration via the respiratory tract Also suitable for. The formulation may be designed to give a slow release of the active ingredient.   The term parenteral as used herein refers to subcutaneous injections, intravenous injections, intramuscular injections, Includes bone injection or infusion. Mouse, rat, horse, cow, sheep, dog, cat, etc. In addition to the treatment of homeothermic animals such as, the compounds of the present invention are effective in treating humans.   The compositions of the present invention include tablets, capsules, sachets, vials, powders, condyles. Granules, troches, suppositories, reconstitutable powders, or oral or sterile parenteral solutions or It can be a liquid formulation such as a suspension. Topical formulations, where appropriate, are also conceivable.   In order to achieve consistency of administration, the compositions of the present invention may be in unit dosage form preferable.   Unit dosage presentation formulations for oral administration can be tablets and capsules, e.g. Syrup, acacia, gelatin, sorbitol, tragacanth gum or polyvinyl chloride Binders such as nilpyrrolidone; e.g., microcrystalline cellulose, lactose Sucrose, corn starch, calcium phosphate, sorbitol or Fillers such as syn; tablet lubricants such as magnesium stearate; e.g. Starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystal Disintegrants such as phosphocellulose; or pharmaceutically acceptable such as sodium lauryl sulfate Conventional excipients such as wetting agents;   Solid oral compositions can be prepared by conventional methods, such as mixing, filling, tableting and the like. If the composition contains a large amount of filler, iterative mixing operation may be carried out with the active ingredient throughout the composition. Can be used to spread.   Such operations are, of course, conventional in the art. Tablets, usually Coatings, especially with enteric coatings, I can do it.   Oral liquid preparations can be, for example, in the form of emulsions, syrups or elixirs, It may also be provided as a dry product for reconstitution before use with other suitable media. Such liquid preparations include, for example, sorbitol, syrup, methylcellulose, Latin, hydroxyethylcellulose, carboxymethylcellulose, aluminum Suspending agents such as umstearic acid gel, hydrogenated edible fats; for example, lectin, sorbitan Emulsifiers such as monooleate or acacia; e.g., almond oil, fractionated Non-aqueous media such as coconut oil (which may include edible oils); Oily esters such as pyrene glycol or ethyl alcohol esters; for example Preservatives such as methyl or propyl p-hydroxybenzoate or sorbic acid; And, if desired, conventional additives such as commercially available fragrances or colorants.   The composition is preferably such as a solution for olfactory or aerosol or spraying, or alone. Or microphylls for inhalation in combination with an inert carrier such as lactose It may also be provided for administration to the respiratory tract, such as a powder. In such a case, The particles of active compound are preferably smaller than 50 μm (such as 0.1 to 50 μm), preferably Or less than 10 μm (eg 1 to 10 μm, 1 to 5 μm or 2 to 5 μm) Have a diameter. Where appropriate, e.g., isoprenaline, isoetalin, salbutarum Amines, such as phenylephrine and ephedrine, Anti-corticosteroids such as rednisolone and adrenal stimulants such as ACTH Small amounts of asthma and bronchodilators may be included.   For parenteral administration, liquid unit dosage formulations using the compound and a sterile vehicle Is prepared, but may be suspended or dissolved in a medium depending on the concentration used. solution When preparing a preparation, dissolve the compound in water for infusion and fill into an appropriate vial or ampoule. It can be filter sterilized before filling and sealing.   Advantageously, additives such as local anesthetics, preservatives and buffers are present in the vehicle. Can be dissolved. Frozen after filling the composition into vials for increased stability And the water can be removed under vacuum. Parenteral suspension instead of dissolving the compound In substantially the same manner, except that they cannot be suspended by filtration and sterilization cannot be achieved by filtration. Prepared. Exposing the compound to ethylene oxide before suspending it in a sterile medium Can be more sterile. Advantageously, surfactants and wetting agents are included in the composition to Promotes uniform dispersion of the compound.   The composition may be present in an amount of 0.1 to 99% by weight, preferably 10 to 60% by weight, depending on the method of administration. % Active substance.   A compound of formula (i) or, where appropriate, a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable solvates can be combined with conventional topical excipients to produce topical preparations. Can be administered.   Topical preparations include, for example, ointments, creams or lotions, impregnated dressings, gels, gels It can be offered as ticks, sprays and aerosols, smells ointments and creams Use appropriate conventional additives such as preservatives and solvents to assist May be included. The formulation may be ethanol or for the base or lotion of creams and ointments. A compatible conventional carrier such as oleic alcohol can be included.   Any suitable compound which can be used for the compound of formula (i) or optionally a pharmaceutically acceptable salt thereof Made of cream, lotion, gel, stick, ointment, spray or aerosol Agents include, for example, Harry's Cosmete, published by Leonard Hill Books. Harry's Cosmeticology, Remington's Pharmaceuticals Remington's Pharmaceutical Sciences and The British And the US Pharmacopoeias It is well known to those skilled in the art as described in any standard text.   Preferably, the compound of formula (i) or, optionally, a pharmaceutically acceptable salt thereof is About 0.5 to 20% by weight, preferably about 1 to 10%, for example 2 to 5% It is.   The dosage of the compound used for treatment is determined in the conventional manner and is based on the severity of the disease, the weight of the patient. And the relative potency of the compounds. However, in general, the preferred unit dosage Is 0.5 to 200, 0.5 to 100 or 0.5 to 10 mg, e.g. It can be from 0.1 to 1000 mg, such as 5, 1, 2, 3, 4 or 5 mg. Such unit dosage formulations can provide a total daily dosage of about 0.1 to 70 kg for an adult. Within the range of 1000 mg, ie 0.007 to 3, 0.007 1.4, 0.007 to 0.14, 0.01 to 0.5 mg / kg / day, for example For example, 0.01, 0.02, 0.04, 0.05, 0.06, 0.08, 0.1 or 0.2 mg / kg / day, etc., within the range of about 0.001 to 20 mg / kg / day At least once a day, for example 2, 3, 4, 5 or 6 times a day, preferably 1 It may be administered once or twice daily, and such treatment may extend for weeks or months.   The term "pharmaceutically acceptable" as used herein is used in humans and animals. Include materials suitable for use.   The following examples illustrate the invention.   Example  8-methoxy-2-methyl-5-phenylquinoline   5-bromo-8-methoxy-2-methylquinoline (509 mg) and benzeneborough An acid (323 mg) was added to a 2 M aqueous potassium carbonate solution (2 ml), toluene (10 ml), And a mixture of ethanol (1 ml) and refluxed under a nitrogen atmosphere for 30 minutes. . The mixture was cooled and triphenylphosphine (75 mg) and dichlorobis (Riphenylphosphine) palladium chloride (66 mg) was added and the mixture was brought to 60 ° C. And heated overnight. After cooling, the reaction mixture was diluted with ethyl acetate (30 ml). Was. The organic layer was washed with a 2M aqueous solution of potassium carbonate (2 × 30 ml), dried and dried. Gnesium sulfate), filtered and evaporated in vacuo to give the title compound (272 mg). ) Was obtained as an off-white solid. TLCRf 0.26 (dichloromethane) mp 133-134 ° C Assay method   Used to determine the phosphodiesterase IV inhibitory activity of the compound of formula (i) One such assay is described by Schilling et al., Anal. Biochem.2 16 : 154 (1994), Thompson and Strada Adv.Cycl.Nucl.Res.8: 119 (1 979) and Gristwood and Owen, -R.J.Pharmacol. (Br.J.Pharmacol.)87： 91P (1986).   In these assays, the compound of formula (i) is a phosphodiesterase IV Levels of activity consistent with those considered to be effective in treating Gender.   Inhibition of TNF production in human peripheral blood mononuclear cells (PMBC's) by compounds of formula (i) The performance is measured as follows. PMBC's are routinely collected from freshly drawn blood or "buffy coat" Prepared by conventional techniques. Cells were transformed with RPMI 1640 + 1% containing inhibitor RPMI 1640 + 1% fetal bovine blood in fetal bovine plasma and without inhibitor Incubate in the serum. LPS (100 ng / ml) was added and the culture was incubated for 22 hours at 37 ° C. At 95% air / 5% CO2. EL using commercial kit The supernatant is tested for TNFα by ISA.   In vivo activity in cutaneous eosinophilia model was determined by Hellewell et al. -R.J.Pharmacol.111: 811 (1994) and B.G. Y.Pharmacol.110: 416 (1993) To decide. The activity in the lung model was determined by Karos and Kall. os), Int.Archs. (Int.Archs.) Allergy Apple. (Allergy Appl.) Munol.73: 77 (1984) and Sanjar et al., Be. R.J.Pharmacol.99: 679 (1990) Measure using   Allows measurement of suppression of early and late asthmatic responses and suppression of tracheal hyperreactivity Additional lung models include Broadley et al., Palmonary Pharmacol. onary Pharmacol.)7: 311 (1994), J. Immunological Methods (J. Immunological Methods)190: 51 (1996) and British Jay. Pharmacol.116: 2351 (1995).Abbreviation   LPS lipopolysaccharide (endotoxin)   ELISA enzyme-linked immunosorbent assay                 (Enzyme Iinked immunosorbent assay)

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61P 11/00 A61P 11/00 11/02 11/02 11/06 11/06 13/12 13/12 17 / 00 17/00 17/06 17/06 19/02 19/02 19/08 19/08 25/00 25/00 25/16 25/16 25/24 25/24 25/28 25/28 27/02 27/02 29/00 29/00 101 101 31/04 31/04 31/10 31/10 31/18 31/18 35/02 35/02 37/02 37/02 37/04 37/04 37/08 37/08 43/00 111 43/00 111 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL , PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), A (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ , DE, DK, EE, ES, FI, GB, GE, GH, GM, GW, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT , UA, UG, UZ, VN, YU, ZW (72) Inventor, Montana, John Gary, UK, CB4.4, Cambridge, Milton Road, Cambridge Science Park, Darwin・ Discovery Limited (7 2) Inventor Hogan, Alan Findlay United Kingdom, CB 4.4-4, Cambridge, Milton Road, Cambridge Science Park, Darwin Discovery Limited (72) Inventor Sabin, Verity Margaret CB 4.4 UK, Cambridge, Milton Road, Cambridge Science Park, Darwin Discovery Limited

Claims (1)

[Claims] 1. A compound of general formula (i) or a pharmaceutically acceptable salt thereof, for use in therapy; Wherein R ₁ represents C _1-6 alkoxy (an alkyl group optionally substituted with one or more halogens) or thioalkyl; R ₂ , R ₃ and R ₄ may be the same or different; _{oR 11, COR 7, C N} , CO 2 R 8, C (= NOR 7) R 7, alkyl _{-C (= NOR 7) R 7} , _{halogen, C F 3, CONR 12 R} 13, NR 9 R 10 or represents R _7; R ₅ is H or halogen, arylalkyl, heteroarylalkyl, heterocycloalkyl, alkyl, hydroxy, _{alkoxy, CO 2 R 8, SO 2} NR 1 2 R 13, CONR 12 R 13, -CN , NR ₉ R ₁₀ , COR ₁₁ and S (O) _n R ₁₁ ; R ₇ is H, alkyl, cycloalkyl, aryl which can be optionally substituted at any position with R ₁₆ , Heteroaryl, heterocyclo, ant Ruarukiru represents a heteroarylalkyl or heterocycloalkyl; R ₈ represents H, alkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl; R ₉ is alkylcarbonyl, alkoxycarbonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclo Represents sulfonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclocarbonyl or arylsulfonyl, R ₁₀ represents H or R ₁₁ , or NR ₉ R ₁₀ is a heterocyclic ring optionally substituted with one or more R ₁₅ R ₁₁ represents alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl or heterocycloalkyl; R ₁₂ and R ₁₃ may be the same or different; Represents R _7, or N R ₁₂ R ₁₃ represents one or more heterocyclic ring optionally substituted with R _15; R ₁₅ represents alkyl, arylalkyl or heteroarylalkyl; R ₁₆ Represents halogen, hydroxyl, OR ₁₁ , NR ₉ R ₁₀ , CN, CO ₂ H, CO ₂ R ₁₁ , CONR ₁₂ R ₁₃ or COR ₁₁ ; n represents 0-2; and Q represents any suitable bonded via an atom, and an aryl or heteroaryl ring which is optionally substituted with one or more R ₅ in position, provided that Q is a 5-membered ring 2-position containing the N atom It is not a bicyclic system that binds to the quinoline ring and is fused to the 6-membered ring at the 4,5-position. 2. 5,5'-bis (8-methoxyquinoline), 5,5'-bis (8-methoxyquinaldine), 1- (8-ethoxy-5-quinolyl) -3,4-dihydroisoquinoline, 1- (8 -Ethoxy-5-quinolyl) isoquinoline, 2- (8-ethoxy-5-quinolyl) -1,2,3,4-tetrahydroisoquinoline, 8-isopropoxy-5- (1-naphthyl) quinoline, 5-methoxy- Excluding 8-phenylquinoline, 5-methoxy-8- [2- (t-butylcarbonylamino) phenyl] quinoline and 5-methoxy-8- [2- (t-butylcarbonylamino) -5-methoxyphenyl] quinoline , Independent of use, a compound of formula (i) as defined in claim 1. 3. R ₁ is alkoxy optionally substituted with one or more halogen, claim 1 or compound of Claim 2. 4. R ₂ is H, alkyl, CF ₃ or the compound of any of claims alkoxyalkyl. 5. R ₃ and / or R ₄ is H, any of the compounds of the claims. 6. R ₅ is H, CO ₂ R _8, or CONR ₁₂ R _13, The compound of any of the preceding claims. 7. A compound according to any of the preceding claims, wherein Q is monocyclic. 8. The compound of claim 7, wherein Q is phenyl or pyridyl. 9. The compound of claim 1 which is 8-methoxy-2-methyl-5-phenylquinoline. 10. A pharmaceutical composition for therapeutic use, comprising a compound of any of the preceding claims and a pharmaceutically acceptable carrier or excipient. 11. For the manufacture of a medicament for use in the treatment of a disease condition which can be ameliorated by suppression of phosphodiesterase IV or tumor necrosis factor, phosphodiesterase IV function, eosinophil accumulation or pathological conditions associated with eosinophil function. Use of a compound according to any of claims 1 to 9. 12. Use according to claim 11, wherein the disease state is an inflammatory disease or an autoimmune disease. 13. Disease states are asthma, chronic asthmatic bronchitis, chronic pulmonary inflammatory disorder, chronic obstructive bronchial disorder, atopic dermatitis, allergic rhinitis, psoriasis, arthritis, rheumatoid arthritis, joint inflammation, ulcerative colitis, clone The use according to claim 11, wherein the disease is selected from disease, atopic eczema, stroke, bone resorption disease, multiple sclerosis and inflammatory bowel disease. 14． Disease states include urticaria, allergic conjunctivitis, spring conjunctivitis, ophthalmitis, ocular allergic reactions, eosinophilic granuloma, gouty arthritis and other joint disorders, adult respiratory distress syndrome, diabetes insipidus, keratosis , Nose senility, polyinfarct dementia, senile dementia, memory impairment associated with Parkinson's disease, depression, cardiac arrest, intermittent claudication, rheumatic spondylitis, osteoarthritis, sepsis, septic shock, endotoxin shock, Gram negative Sepsis, toxic shock syndrome, acute respiratory depression syndrome, cerebral malaria, silicosis, pulmonary sarcoma, reperfusion injury, graft-versus-host reaction, allograft rejection, infection-related fever or myalgia, malaria, HIV, AIDS , ARC, cachexia, keloid formation, scar formation, pyresis, systemic lupus erythematosus, type 1 diabetes, Behcet's disease, anaphylactoid purpura nephritis, chronic Glomerulonephritis, leukemia, tardive dyskinesia, yeast or fungal infection, a disease that requires gastric protection, is selected from inflammatory disease with itching and pain, the use of claim 11. 15. 13. Use according to claim 12, wherein the disease condition is asthma. 16. The use according to claim 12, wherein the disease state is chronic obstructive bronchial disease or chronic bronchitis.