JP2000505450A - Quinolones and their therapeutic use - Google Patents

Abstract

(57) Abstract: A compound represented by the following general formula (I) or a pharmaceutically acceptable salt, solvate or hydrate of the compound: R ¹ is a bicyclic structure in which a cycloalkyl ring or a heterocyclo ring is bonded to NH and is condensed with a second aryl group selected from aryl or heteroaryl, wherein one or each ring is optionally halogen Atoms, C _1-6 alkoxy, hydroxy, CN, CO ₂ H (or C _1-6 alkyl ester or C _1-6 alkyl amide), C _1-6 alkyl, NR ⁶ R ⁷ and SO ₂ NR ⁶ R ⁷ A bicyclic structure substituted by one or more substituents selected from the group consisting of: R ³ , R ⁴ and R ⁵ may be the same or different, and each has an H) halogen atom, C _{1- 6} alkoxy, hydroxy, CN, CO ₂ H (or its C _1-6 alkyl esters or C _1-6 alkyl ^{amide), NR 6 R 7, SO} 2 NR 6 R 7 or C _1-6 alkyl [wherein the alkyl Optionally halogen atom, C _1-6 alkoxy, hydroxy, CN, CO ₂ H (or its C _1-6 alkyl esters or C _1-6 alkyl amide), is substituted by NR ⁶ R ⁷ or SO ₂ NR ⁶ R ⁷ Or two of R ^{3 to} R ⁵ may form an optionally substituted carbocyclic, aromatic, heteroaromatic or saturated carbocyclic or heteroaromatic ring And R ⁶ and R ⁷ may be the same or different and are each H, C _1-6 alkyl, cycloalkyl, C _1-6 alkylcarbonyl, arylcarbonyl, C _1-6 alkoxycarbonyl, arylsulfonyl or C _{1 -6 represents} alkylsulfonyl, or NR ⁶ R ⁷ forms a 5- or 6-membered ring (eg, a pyrrolidine ring, a piperidine ring, a morpholine ring or a piperazine ring) X is-(CR ⁹ R ¹⁰ ) _2-3 , -Y- (CR ⁹ R ¹⁰ ) ₂ -,-(CR ⁹ R ¹⁰ ) ₂ -Y-, -CR ⁹ R ¹⁰ -Y-CR ⁹ R ¹⁰ - and -Y-CR ⁹ shows a linkage group selected from the group consisting of R ¹⁰ -Z- [Y and Z represents NR ^11, O or S (O) _0-2 independently of one another (although , Y and Z do not simultaneously represent S (O) _0-2 )], Q represents O or S, and R ⁹ , R ¹⁰ and R ¹¹ may be the same or different and each represents H or C _1-. Represents ₆ alkyl.

Description

DETAILED DESCRIPTION OF THE INVENTION                     Quinolones and their therapeutic use   Field of the invention   The present invention relates to novel quinolone derivatives and their pharmaceutically acceptable salts , Their preparation and their use as formulations and preparations.   Background of the Invention   Quinolone and quinolizine compounds are mainly antibacterial agents (JP-A-050251). 62; US-A-5037834; EP-A-0420069; JP-A-020 40379; EP-A-0343560; DE-A-3816119; EP-A- 0304158; FR-A-2644784; WO-A-940163; DE- A-3641312) or an antiviral agent (US-A-4959363). But inhibitors of 5-lipoxygenase (JP-A-021248). 71), cardiotonic and vasodilators (JP-A-0161461) and painful powders 5-HT for the treatment of peripheral diseases_ThreeAlso known as antagonists.   GB-A-2236751 discloses 5-HT used for treating neuropsychiatric diseases._ThreeAnn Quinolone-3-carboxamide as a agonist has been described. US-A -4001243 has benzoquinoline-2-carboxylic acid as an antibacterial agent and the same. Are described. GB-A-1433151 includes alleles including asthma -Tetrazolyl-benzoquinolidine-2-carboxy useful as an agent for treating ghee Samides are disclosed.   Phosphodiesterase (PDE) and tumor necrosis factor (TNF), their mode of action and And their therapeutic usefulness as inhibitors are described in WO-A-9704775 and And WO-A-9704779, and the contents of these publications are also described in this book. It forms part of the specification. These documents include PDE and TNF inhibitors Disclosed are quinolones having utility as a quinolone.   Summary of the Invention   The present invention relates to disease states, such as those associated with proteins that mediate cellular activity. The condition may be, for example, inhibition of tumor necrosis factor and / or phosphodiesterase IV. The present invention relates to compounds and their use for treating by suppression.   That is, the present invention provides a novel compound represented by the following formula (I) and a pharmaceutically acceptable For salts, solvates and hydrates of the compound:   R¹Is a cycloalkyl ring or a heterocyclo ring bonded to NH and A bicyclic structure fused to a second ring selected from aryl or heteroaryl. Thus, one or each ring may optionally have a halogen atom, C_1-6Alkoxy , Hydroxy, CN, CO_TwoH (or its C_1-6Alkyl ester or C_{1 -6} Alkylamide), C_1-6Alkyl, NR⁶R⁷And SO_TwoNR⁶R⁷Group consisting of A bicyclic structure substituted by one or more substituents selected from:   R^Three, R^FourAnd R^FiveMay be the same or different, and each represents H, a halogen atom , C_1-6Alkoxy, hydroxy, CN, CO_TwoH (or its C_1-6Alkyle Steal or C_1-6Alkylamide), NR⁶R⁷, SO_TwoNR⁶R⁷Or C_1-6A Alkyl wherein the alkyl is a halogen atom,_1-6Alkoxy, hydroxy, CN, CO_TwoH (or its C_1-6Alkyl ester or C_1-6Alkylam C), NR⁶R⁷Or SO_TwoNR⁶R⁷May be replaced by Or R^Three~ R^FiveAny two groups are optionally substituted carbocycles, aromatic Form an aromatic ring, a heteroaromatic ring or a saturated carbocyclic or heteroaromatic ring,   R⁶And R⁷May be the same or different, and each of H, C_1-6Alkyl, Cycloalkyl, C_1-6Alkylcarbonyl, arylcarbonyl, C_1-6Arco Xycarbonyl, arylsulfonyl or C_1-6Indicates alkylsulfonyl Or NR⁶R⁷Is a 5- or 6-membered ring (for example, a pyrrolidine ring, In Ring, morpholine ring or piperazine ring) to form   X is-(CR⁹R^Ten)_2-3-, Y- (CR⁹R^Ten)_Two-,-(CR⁹R^Ten)_Two-Y-, -C R⁹R^Ten-Y-CR⁹R^Ten-And -Y-CR⁹R^TenSelected from the group consisting of -Z- [Y and Z are independently of each other NR¹¹, O or S (O)_0-2Show (However, Y and Z are simultaneously S (O)_0-2)],   Q represents O or S,   R⁹, R^TenAnd R¹¹May be the same or different and are each H or C_1-6A Indicate the kill.   Combinations of substituents and / or variables are used in combinations where the combination results in stable compounds. Only allowed if   Description of the invention   Pharmaceutically acceptable salts include pharmaceutically acceptable basic salts and acid addition salts It is. Among the compounds represented by the formula (I), those having an acidic group form a basic salt. You. Pharmaceutically acceptable basic salts include metal salts, such as sodium salts. Alkali metal salts or organic amine salts, such as ethylenediamine Salt and the like.   Among the compounds represented by the formula (I), those having an amino group form an acid addition salt. Suitable acid addition salts include pharmaceutically acceptable inorganic salts (e.g., sulfates, nitrates, Phosphates, borates, hydrochlorides and hydrobromides) and pharmaceutically acceptable Organic acid addition salts (e.g., acetate, tartrate, maleate, citrate, Citrate, benzoate, ascorbate, methanesulfonate, α-ketogluta Phosphoric acid, α-glycerophosphate and glucose-1-phosphate). formula( The pharmaceutically acceptable salts of the compounds represented by I) are prepared by conventional methods .   As will be apparent to those skilled in the art, some of the compounds of formula (I) may have 1 or Although there exist a plurality of tautomers, the present invention includes all tautomers.   The compounds according to the invention comprise one or more asymmetrically substituted carbons and / or Alternatively, it may contain a sulfur atom. One or more compounds of the formula (I) When several asymmetric centers are present, stereoisomers are obtained, but the present invention provides enantiomers. Includes all stereoisomers and racemic mixtures of this type, including diastereomers and diastereomers These mixtures are also included.   As used herein, "alkyl" used alone or as part of another group may be straight chain And branched or branched alkyl groups. "Cycloalkyl" has a number of carbon atoms About 3-10 non-aromatic ring systems and polycyclic systems are included. Cyclic alkyl is optionally part May be unsaturated. "Alkoxy" is an alkyl-O-group (alkyl is as described above) Having the meaning of). "Alkylamide" includes monoalkyl and dial In the latter case, the alkyl group (having the meaning described above) may be the same or different. It may be. "Alkylcarbonyl" refers to an alkyl-CO- group (Al The kill group has the meaning described above). "Aryl" is a carbocyclic ring having about 6 to 10 carbon atoms. "Heteroaryl" refers to an aromatic monocyclic ring system having about 5 to about 10 ring atoms. Is a polycyclic ring system in which one or more ring atoms of the ring system are nitrogen, oxygen and And a ring system that is an atom other than a carbon atom selected from sulfur atoms. "Hetero Cyclo "has about 5 to about 10 ring atoms, which may be saturated or partially saturated. Monocyclic or polycyclic, wherein one or more atoms of the ring system is a nitrogen atom, an oxygen A ring system is an atom other than a carbon atom selected from atoms and sulfur atoms. " "Arylcarbonyl" means an aryl-CO- group. "Arylsulfonyl" Is aryl-SO_Two-Means a group. “Alkylsulfonyl” is alkyl-SO_Two− Means a group. "Alkoxycarbonyl" means an alkoxy-CO- group. R_Three , R^FourAnd R^FiveIs linked to methylenedioxy (O CH_TwoO) is exemplified. "Halogen atom" means fluorine, chlorine, bromine or Represents an iodine atom.   The compound of the formula (I) according to the present invention has a pharmaceutically acceptable form. preferable. Pharmaceutically acceptable forms are particularly toxic at normal dosages. And the usual pharmaceutical additives that do not contain Purity excluding-) is at a pharmaceutically acceptable level. Pharmaceutical science The acceptable purity (without the usual pharmaceutical excipients) is at least 50%, preferably 75%, more preferably 90%, especially 95%.   A compound according to the present invention is referred to as a "TNF-mediated disease or condition", i. Production of NF itself or other cytokines by TNF, including but not limited to For example, TNF plays a role in the release of, for example, IL-1 and IL-6). It can be used for the prevention or treatment of some disease states. For example, IL-1 Becomes a major component and its production or action worsens in response to TNF, or Disease states in which the component is secreted are those disease states mediated by TNF. Rin TNF-β, also known as patoxin, is TNF-β, also known as cachectin. It has similar structural homology to NF-α, and both induce similar biological reactions. TNF-α and TNF-β are Deviation is also suppressed by the compounds according to the invention. Therefore, in this specification, These are collectively referred to as "TNF" unless otherwise noted.   The present invention provides for the enzymatic or catalytic activity of PDE IV in mammals. Or TNF production in mammals as needed A method of inhibiting, comprising a compound of formula (I) or a pharmaceutically acceptable The method comprising administering to the mammal an effective amount of the salt.   PDE IV inhibitors have a variety of allergic and inflammation, including the following diseases: Useful for the treatment of symptomatic diseases: asthma, chronic bronchitis, atopic dermatitis, atopy -Eczema, urticaria, allergic rhinitis, allergic conjunctivitis, spring conjunctivitis, eyes Inflammation, eye allergic reactions, eosinophilic granuloma, psoriasis, Behcet's disease, erythemato Cis, anaphylactoid purpura nephritis, joint inflammation, arthritis, rheumatic Arthritis and other arthritic conditions (e.g., rheumatic spondylitis and osteoarthritis), Septic shock, sepsis, ulcerative colitis, Crohn's disease, myocardium and brain reperfusion injury , Chronic glomerulonephritis, endotoxin shock and adult respiratory distress syndrome. In addition, PDE IV inhibitors may be associated with diabetes insipidus and cerebral metabolic depression, such as brain senescence, Senile dementia (Alzheimer's disease), memory impairment related to Parkinson's disease, depression and It is also useful for treating multiple infarct dementias. PDE IV inhibitors are nerve Symptoms improved by protective activity, such as cardiac arrest, seizures and intermittent claudication It is also useful for the treatment of In addition, PDE IV inhibitors may also be used as gastroprotectors. Yes It is for. A particular embodiment of the therapy according to the invention is the treatment of asthma.   In this case, the virus to be treated will produce TNF as a result of infection. Direct or indirect by irs or a TNF inhibitor of formula (I) It is a virus that is susceptible to suppression due to poor replication. Not particularly limited However, this type of virus includes HIV-1, HIV-2 and HIV-3, Megalovirus (CMV), influenza virus, adenovirus and Pess viruses, such as, but not limited to, herpes zoster virus and simplex Pests and the like.   The invention is particularly directed to mammals infected with the human immunodeficiency virus (HIV) of formula (I) Or a pharmaceutically acceptable salt of the compound represented by the formula It also relates to a method of treating said mammal, comprising administering an inhibitory amount.   Compounds according to the present invention may be used in veterinary medicine in non-human animals in need of suppression of TNF production It may be used for objective treatment. TNF-mediated diseases in animals in need of treatment, treatment or prevention Diseases include the aforementioned diseases, especially viral infections. As this kind of virus But not limited to, feline immunodeficiency virus (FIV) or other infectious diseases Retroviruses such as equine glanders infectious anemia virus, goat arthritis virus, Examples include Snaui virus, Maedi virus and other lentiviruses.   The compounds according to the invention are also useful for the treatment of parasitic, yeast and fungal infections. In this case, yeast and fungi are susceptible to upregulation by TNF, In addition, it induces the production of TNF in vivo. Preferred disease states requiring treatment are Fungal meningitis.   The compounds according to the invention can be used in neurogenesis by increasing cAMP in sensory neurons It also suppresses sexual inflammation. Thus, the compound is an analgesic for inflammatory diseases with irritation and pain, Becomes an antitussive and antihyperalgesic.   Compounds of general formula (I) can be prepared by any suitable method known in the art and And / or may be prepared by the following method, which is included as part of the present invention.   In the following description and formula, R¹, R^Three, R^Four, R^Five, R⁶, R⁷, R⁹, R^Ten, R¹¹, Q, X and Z have the same meanings as described above unless otherwise specified. Explained below Functional groups present in various compounds that need to be retained, for example, Amino, hydroxyl, or carboxyl groups should be preserved before any reaction. It may exist in a protected form. In this case, removal of the protecting group may be at the end of a particular reaction. It may be performed at the final stage. Suitable protecting groups for such functional groups will be apparent to those skilled in the art. Yes, for details, see for example: Goki, "published by Willie Interscience, T.W. W. Green and P.I. G. FIG. M. By Utz. Accordingly, the formula (I) (where, for example, R_FourIs CO_TwoH) The process for producing the compound includes a compound represented by the formula (I):_FourIs CO_TwoR (R is a suitable protecting group, for example, A methyl group) is deprotected by, for example, hydrolysis. The step includes:   In a preferred embodiment of the compound represented by the formula (I), X is (CR⁹R^Ten)_ThreeA compound that is Is included.   The method for producing the compound represented by the general formula (I) includes an acid represented by the following formula (II) or an activity thereof. Coupling of the sexual derivative with an amine represented by the following formula (III) is included.   The amine represented by the formula (III) can be obtained as a commercial product, or Can be easily prepared from the starting materials by methods known to those skilled in the art. formula Some amines represented by (III) are derived from a suitable amine of a suitable carbonyl compound It is convenient to prepare by reductive amination. This amination is known to those skilled in the art. It may be performed under appropriate standard conditions. Active derivatives of acids of formula (II) Include, for example, acid anhydrides and acid halides (eg, acid chlorides).   The coupling reaction can be carried out under the standard conditions for this type of amination reaction. Good. For example, the reaction may be carried out in a solvent, for example, an inert organic solvent (e.g., tetrahydrogen). Ethers such as cyclic ethers such as lofran, and dimethylformamide Amides, halogenated hydrocarbons such as dichloromethane, etc.) At -30 ° C to ambient temperature (eg, -20 ° C to 0 ° C), as desired Bases, for example, organic bases (e.g., cyclic amines such as N-methylmorpholine and Triamine or an amine such as triethylamine). This reaction is further reduced The presence of a mixture, for example, a diimide such as N, N'-dicyclohexylcarbodiimide. In the presence of a triazole, preferably 1-hydroxybenzotriazole, It may be performed in the presence. Alternatively, the above acid is reacted with the amine represented by the formula (III). React with a chloroformate, e.g., ethyl chloroformate, You may let it.   The acids of the general formula (II) may be prepared according to the methods described in the following documents: DE-A-0683169; Kaminsky and Mel Tour, J. Med. Chem., 11, 160-164 (1968). This Includes hydrolysis of the corresponding ester of general formula (IV) (wherein , R¹²Is an alkyl or aralkyl such as methyl, ethyl, benzyl or Represents t-butyl):   In the formula (IV), the compound in which Q represents S is obtained by starting from the corresponding compound in which Q represents O. As a starting material, it can be prepared under standard sulfurization conditions for such compounds. example For example, under appropriate conditions, an organic solvent such as pyridine may be used at an appropriate temperature (recovery of the solvent). Flow temperature is preferred) and phosphorous pentasulfide (P_FourS_Ten) Is included.   In the general formula (IV), X is -Y'-CR⁹R^Ten-Z '(Y' and Z 'are each NR " , O or S), for example, -O-CR⁹R^Ten-NR¹¹-Represents an ester, Cyclization reaction of an intermediate represented by the following general formula (V) by a method apparent to those skilled in the art, for example, For example, as a reaction reagent, tetrabutylammonium fluoride It may be prepared by a cyclization reaction using alkylammonium fluoride (S Y ′ or Z ′ is then SO or SO_TwoMay be converted to :):   The intermediate represented by the general formula (V) is a corresponding intermediate represented by the following general formula (VI). May be prepared, for example, by using a formylation using formaldehyde. No.   The compound represented by the general formula (VI) is a corresponding protected compound represented by the following general formula (VII) The compound (where P represents any suitable protecting group, for example, Boc) is known to those of skill in the art. It may be prepared by a deprotection reaction using a suitable method (e.g., reaction with a base). Yo No.  The quinoline nucleus in the above compound is an ester represented by the following general formula (VIII) It may be formed by reaction with an amine represented by the following general formula (IX):   The intermediate represented by the general formula (VIII) is a benzoic acid derivative represented by the following general formula (X). It may be prepared according to the methods described in the following literature as starting materials: Med. Ch em., 34, 1142 (1992).   X is -CR⁹R^Ten-Y'-CR⁹R^TenWhen-, the ester represented by the general formula (IV) is The corresponding intermediate represented by the following general formula (XI) and the corresponding intermediate represented by the following general formula (XII) It may be prepared by reaction with a mate derivative:  The compound represented by the general formula (XI) hydrolyzes an intermediate represented by the following general formula (VIII) Wherein R is¹³Is a group in the protected form of Y′H, for example, OAc, SAc or NR¹¹Boc):   The quinoline nucleus in compounds (IV) and (XIII) was determined by Kaminsky and Melzer Based on the method described in the above-mentioned literature, an escaping compound represented by the following general formula (XIV) or (XV) May be prepared by cyclization of a ter: Suitable conditions in this case include, for example, diphenyl ether or diphenyl ether. Heating the eutectic mixture of ter and biphenyl to reflux is included.   The compound represented by the general formula (XIV) or (XV) is represented by the following general formula (XVI) or (XVII) ) And a dialkylalkoxyethylene represented by the general formula (XVIII) Gimmalonate (R¹⁴Represents lower alkyl, for example methyl or ethyl) May be prepared by:   (R¹²OOC)_TwoC = CH-OR¹⁴      (XVIII) The reaction is performed under appropriate standard conditions known to those skilled in the art, for example, Kaminsky and Melza. May be performed under the conditions described in the above-mentioned document. For example, this reaction (E.g., 80-150C), in an inert solvent (e.g., xylene) or preferably It may be carried out in the absence of a solvent.   Represented by the above general formulas (IX), (X), (XII), (XVI), (XVII) and (XVIII) Intermediates may be obtained as commercial products or those skilled in the art It can be easily prepared by known methods.   Compounds of formula (I) are prepared by interconversion of other compounds of formula (I). It may be made. For example, in formula (I), R_FourIs C_1-6Compounds that are alkoxy groups In the formula (I), R_FourBy the appropriate alkylation of compounds in which It may be made.   The resulting mixture of either intermediates or end products will be Based on differences in chemical properties, known methods (e.g., chromatography, distillation, Fractional crystallization or salt formation where appropriate or possible under the conditions) Thus, it can be separated into a pure intermediate or a final product.   Where a particular stereoisomer of formula (I) is required, said stereoisomer may be a conventional It may be obtained by a separation method (for example, high performance liquid chromatography). But However, if desired, use the appropriate homochiral starting material in the above series of reactions. To obtain a specific stereoisomer represented by the formula (I).   Compounds of the formula (I) or, where appropriate, pharmaceutically acceptable The resulting salt and / or a pharmaceutically acceptable solvate of the compound is A pharmaceutical set that may be administered or that also contains a pharmaceutically acceptable carrier It may be administered as an adult.   Accordingly, the present invention provides compounds of formula (I) or, where appropriate, the preparation of said compounds. Pharmaceutically acceptable salts and / or pharmaceutically acceptable solvents for said compounds Provide a pharmaceutical composition containing a Japanese pharmaceutically acceptable carrier and a pharmaceutically acceptable carrier .   The active compound can be formulated to be administered by any suitable route of administration. Often, the preferred route of administration will depend on the condition requiring treatment, and will be more preferred. Or in unit dosage form or in a single dosage form that can be administered by human patients on their own Prepare. The composition may be administered orally, rectally, topically, parenterally, or Or, it is advantageously administered through the respiratory tract.   As used herein, "parenteral administration" includes subcutaneous injection, intravenous injection, intramuscular injection, intrasternal injection Includes injection or infusion. Mouse, rat, horse, cow, sheep, a In addition to the treatment of warm-blooded animals such as dogs and cats, the compounds according to the invention are useful for the treatment of humans. Is also effective.   The compositions according to the invention can be used as tablets, capsules, sachets, vials. l), powder, granules, lozenge, suppository, reconstituting powder or liquid Preparations, for example, in the form of sterile solutions or suspensions for oral or parenteral use. You may. Where appropriate, topical formulations may be prepared.   In order to effect a constant administration, the compositions according to the invention are prepared in unit dosage form Is preferred. Unit dosage forms for oral administration may be tablets and capsules Often, these are excipients such as conventional binders (e.g., syrup, acacia, Latin, sorbitol, tragacanth and polyvinylpyrrolidone), filler ( For example, microcrystalline cellulose, lactose, sugar, corn starch, phosphoric acid Calcium, sorbitol and glycine), tableting lubricants (e.g. stearyl Disintegrants (e.g., starch, polyvinylpyrrolidone, starch) Sodium glycolate and microcrystalline cellulose), pharmaceutically acceptable Humectants (eg, sodium lauryl sulfate).   Solid compositions for oral administration are prepared by conventional mixing, filling and tabletting methods. It can be made. When using a large amount of filler, repeat the mixing operation. This may evenly distribute the active ingredient in the composition. Such operations Is commonly used in the art. Tablets are well-known in the field of normal formulation According to the method, it may be coated, in particular with an enteric coating.   Liquid preparations for oral administration include, for example, emulsions, syrups and elixirs. Form, or with water or other suitable vehicle before use. It may be in the form of a dried product to be reformed. Liquid preparations of this kind are customary additives, For example, suspending agents (e.g., sorbitol, syrup, methylcellulose, Tin, hydroxyethylcellulose, carboxymethylcellulose, stearin Aluminum gel and hydrogenated edible fat), emulsifiers (e.g., lecithin, Non-aqueous vehicles that may contain tan monooleate, acacia, edible oils, such as For example, almond oil, fractionated coconut oil and oily esters (e.g., Serine, propylene glycol or ethyl alcohol esters)], preservatives ( For example, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate and Sorbic acid), and if desired, flavoring or coloring agents.   The composition may be prepared in a form suitable for administration to the respiratory tract, and such forms include Odorants, aerosols, nebulizer solutions, alone or with inert carriers (e.g. And fine powder for aeration mixed with (tooth). In such cases, the active compound Particle size is 50 μm or less, for example, 0.1 to 50 μm, preferably 10 μm or less, for example, It is 1 to 10 μm, 1 to 5 μm or 2 to 5 μm. If appropriate, a small amount of other Antiasthmatics and bronchodilators such as sympathomimetic amines (e.g. isoprenaline (Phosphorus, isoethalin, salbutamol, phenylephrine and ephedrine) , Corticosteroids (eg, prednisolone) and adrenal stimulants (eg, A CTH).   For parenteral administration, fluid unit dosage forms use the active compound and a sterile vehicle. And suspending or dissolving the active compound in the vehicle depending on the concentration used. Therefore, it may be prepared. When preparing solutions, dissolve the active compound in water for injection. After the solution is subjected to a sterile filtration treatment, the solution is filled in an appropriate vial or ampoule. Can be sealed.   Adjuvants, such as local anesthetics, preservatives and buffers, are dissolved in the vehicle Advantageously. Fill the vial with the liquid composition for increased stability After that, the mixture may be frozen and water may be removed under reduced pressure. Suspension for parenteral administration is above In this case, the active compound is dissolved in the vehicle. Suspend without dissolving, and do not sterilize by filtration. Active compound is sterile It is sterilized by exposure to an appropriate bactericide before suspension in the vehicle. interface Uniform dispersion of the active compound by incorporating an activator or wetting agent into the composition It is advantageous to promote it.   The compositions may contain from 0.1 to 99% by weight, preferably 10% by weight of active compound, depending on the method of administration. -60% by weight.   Compounds of the formula (I) or, where appropriate, pharmaceutically acceptable The resulting salt and / or a pharmaceutically acceptable solvate of the compound can be prepared by conventional topical methods. It may be applied as a topical composition containing an excipient.   Topical compositions include, for example, ointments, creams or lotions, impregnated bandages, gels, , Gel sticks, sprays or aerosols, The compositions may contain suitable conventional additives such as preservatives, agents for enhancing drug penetration and the skin. Emollients (in the case of ointments and creams) may also be included. Further, the composition Soluble conventional carriers, such as cream or ointment bases and ethanol Or oleyl alcohol (in the case of lotions).   Compounds of the formula (I) or, where appropriate, pharmaceutically acceptable Suitable creams, lotions, gels, sticks, ointments for formulating the resulting salt , Sprays or aerosols are well known in the art and include, for example, -Cosmeticology of Leonardo Hill Books, Inc. Pharmaceutical Sciences of Pharmaceuticals, etc. and in the British Pharmacopoeia .   Compounds of the formula (I) or, where appropriate, pharmaceutically acceptable A suitable amount of the obtained salt is about 0.5 to 20% by weight of the composition, preferably about 1 to 1%. 0% by weight, for example 2 to 5% by weight.   The dose of the compound used in the treatment according to the present invention should be determined by those skilled in the art. Depending on the severity of the disease, the weight of the patient and the relative potency of the compound It should be done. However, a suitable unit dose as a general rule is 0.1. -1000 mg, for example, 0.5-200 mg, 0.5-100 mg or 0.5-10 mg For example, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg or 5 mg; Administration at lower doses may be performed at least once a day, for example, twice, three, four, or five times a day. Or 6 times, but preferably once or twice a day, So that the total dose per adult is about 0.1-1000 mg for an adult weighing 70 kg. To Such dosages may range from about 0.001 to 20 mg / kg / day, for example, 0.007. ~ 3mg / kg / day, 0.007 ~ 1.4mg / kg / day, 0.007 ~ 0.14mg / kg / day Or 0.01 to 0.5 mg / kg / day, for example, 0.01 mg / kg / day, 0.02 mg / kg / Day, 0.04 mg / kg / day, 0.05 mg / kg / day, 0.06 mg / kg / day, 0.08 mg / Kg / day, 0.1 mg / kg / day, or 0.2 mg / kg / day. Above dosage The treatment may take place over a period of weeks or months.   The phrase "pharmaceutically acceptable" applies to both humans and other animals Used for substances. When the compound represented by the formula (I) is used at the above dose, No toxic effect was confirmed.   The following examples are illustrative of the invention.   Example 9-fluoro-6,7-dihydro-5-methyl-N- [1-amino-5 , 6-dimethoxyindanyl] -1-oxo-1H, 5H-benzo- [i, j] Quinolizine-2-carboxamide   Flumequin (0.46 g) and dichloromethane (16.3 ml) were mixed under a nitrogen atmosphere. And cooled to 0 ° C. After dropwise addition of triethylamine (0.27 ml), isopropane was added. Nilchloroformate (0.21 ml) was added dropwise and the whole was stirred for 60 minutes. 1-A Mino-5,6-dimethoxyindane (described in EP-A-0051391) (Prepared by the method) (0.37 g) was added and the reaction was carried out under stirring for 20 hours. . After concentrating the reaction mixture on silica, flash column chromatography To afford the title compound as an off-white solid [Rf of TLC = 0.1 (EtOAc); mp = 226-227 ° C].   Assay method PDE IV suppression assay   The phosphodiesterase IV inhibitory activity of the compound represented by the formula (I) according to the present invention is The method used to confirm is a standard assay described in: : Schilling et al., Anal. Biochem. 216, 154 (1994); Pson and Strada, Adv. Cycl. Nucl. Res. 8, Vol. 119, p. 119 (197 9)); Gristwood and Owen, Br. J. Pharmacol. , 87, 9 Page 1 (1986).   TNF suppression assay   Compounds of formula (I) are used in these assays for phosphodiesterase It has demonstrated levels of suppressive activity deemed useful in the treatment of IV-related disease states.   The inhibitory activity of the compounds of formula (I) on TNF production in human monocytes is The measurement was performed as follows. Peripheral blood nucleated cells can be fresh blood or bafico Prepared by standard procedures. Cells in the presence or absence of inhibitor Plated below in RPMI 1640 + 1% fetal calf serum. LPS (10 0 ng / ml) and the cultures are 95% air / CO2_Two22 at 37 ° C under 5% atmosphere Incubated for hours. TNFα by ELISA using a commercially available kit The effect of the supernatant on the was examined.Cutaneous eosinophilia model   The in vivo activity in a model of cutaneous eosinophilia is described in the following literature By Helvel et al., Br. J. Pharmacol. , Vol. 111, No. 811 P. (1994); Br. J. Pharmaco1. 110, 416 (1993). Activity in lung models was measured by the method described in the following literature: Karos and Karos, Int. Archs. Allergy Appl. Immunol. 73, p. 77 (198 Sanger et al., Br. J. Pharmacol. 99, 679 (1990) .   The following abbreviations have been used in this specification:   TNF: Tumor necrosis factor   LPS: Lipopolysaccharide (endotoxin)   ELSA: Enzyme-labeled immunosorbent assay   Certain general instructions and instructions relating to the preparation of the intermediates are the same as In a co-pending international application.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 31/4375 A61K 31/435 606 31/5365 31/535 603 31/542 31/54 603 C07D 471/06 C07D 471/06 498/06 498/06 513/06 513/06 (31) Priority claim number 9603689.2 (32) Priority date February 21, 1996 (Feb. 21, 1996) (33) Priority Claiming country United Kingdom (GB) (31) Priority claim number 9702933.4 (32) Priority date February 13, 1997 (Feb. 13, 1997) (33) Priority claiming country United Kingdom (GB) (81) Designation Country EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI) , CM, GA, GN, ML, R, NE, SN, TD, TG), AP (KE, LS, MW, SD, SZ, UG), UA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AU, AZ, BA, BB, BG, BR, BY, CA, CN, CU, CZ, EE, GB, GE, HU, IL, IS, JP, KE, KG, KP, KR, KZ, LC , LK, LR, LS, LT, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, RO, RU, SD, SG, SI, SK, TJ, TM, TR, TT, UA, UG, UZ, VN, YU (72) Inventor Beasley, Stephen Collin United Kingdom, CB 4.4-Doubley, Cambridge, Milton Road, Cambridge Science Park, Cairo Science Limited (72) Inventor Montana, J John Gary UK, CB 4.4-W, Cambridge, Milton Road, Cambridge Science Park, Cairo Science Limited (72) Inventor Lancy, Karen Ann UK, CB 4.4-W A, Cambridge, Milton Road, Cambridge Science Park, Cairo Science Limited (72) Inventor Watson, Robert John United Kingdom, CB 4.4-4, Cambridge, Milton Road, Ken In Bridge Science Park, Cairo Science Limited [Continued from the abstract] represents a group [Y and Z independently represent NR ¹¹ , O or S (O) _0-2 (where Y and Z represent S (O) _0-2 is not shown at the same time)], Q represents O or S, and R ⁹ , R ¹⁰ and R ¹¹ are the same Or may be different and each represents H or C _1-6 alkyl.

Claims (1)

[Claims]   1. A compound represented by the following general formula (I) or a pharmaceutically acceptable compound of the compound: The resulting salt, solvate or hydrate:   R¹Is a cycloalkyl ring or a heterocyclo ring bonded to NH and A bicyclic structure fused to a second moiety selected from aryl or heteroaryl And one or each ring is optionally halogen, C_1-6Arco Xy, hydroxy, CN, CO_TwoH (or its C_1-6Alkyl ester or Is C_1-6Alkylamide), C_1-6Alkyl, NR⁶R⁷And SO_TwoNR⁶R⁷Consisting of A bicyclic structure substituted by one or more substituents selected from the group , R^Three, R^FourAnd R^FiveMay be the same or different and each represents H, a halogen atom Child, C_1-6Alkoxy, hydroxy, CN, CO_TwoH (or its C_1-6Alkyl Ester or C_1-6Alkylamide), NR⁶R⁷, SO^TwoNR⁶R⁷Or C_1-6 Alkyl [where the alkyl is a halogen atom,_1-6Alkoxy, hydroxy , CN, CO_TwoH (or its C_1-6Alkyl ester or C_1-6Alkyria Mid), NR⁶R⁷Or SO_TwoNR⁶R⁷May be replaced by Or R^Three~ R^FiveAny two groups are optionally substituted carbocycles, aromatic Forming an aromatic ring, a heteroaromatic ring or a saturated carbocyclic or heteroaromatic ring,   R⁶And R⁷May be the same or different, and each of H, C_1-6Alkyl, Cycloalkyl, C_1-6Alkylcarbonyl, arylcarbonyl, C_1-6Arco Xycarbonyl, arylsulfonyl or C_1-6Indicates alkylsulfonyl Or NR⁶R⁷Is a 5- or 6-membered ring (for example, a pyrrolidine ring, In Ring, morpholine ring or piperazine ring) to form   X is-(CR⁹R^Ten)_2-3, -Y- (CR⁹R^Ten)_Two-,-(CR⁹R^Ten)_Two-Y-, -C R⁹R^Ten-Y-CR⁹R^Ten-And -Y-CR⁹R^TenSelected from the group consisting of -Z- [Y and Z are independently of each other NR¹¹, O or S (O)_0-2Shows (However, Y and Z are simultaneously S (O)_0-2)],   Q represents O or S,   R⁹, R^TenAnd R¹¹May be the same or different and are each H or C_1-6A Indicate the kill.   2. X is -Y-CR⁹R^TenThe compound according to claim 1, which is -Z-.   3. X is -CR⁹R^Ten-Y-CR⁹R^TenThe compound according to claim 1, which is-.   4. X is (CR⁹R^Ten) q, CR⁹R^TenCR⁹R^TenNR¹¹, NR¹¹CR⁹R^TenCR⁹R^Ten , CR⁹R^TenCR⁹R^TenO, OCR⁹R^TenCR⁹R^Ten, CR⁹R^TenCR⁹R^TenS (O) t or S (O) tR⁹R^TenCR⁹R^Ten(q represents a number of 2-3, t represents a number of 0-2) The compound according to claim 1, which is   5. X is (CR⁹R^Ten)_ThreeThe compound according to claim 4, which is   6. R¹Is an optionally substituted indanyl. A compound as described.   7. The compound according to any one of claims 1 to 6, wherein Q is O.   8.9-Fluoro-6,7-dihydro-5-methyl-N- [1-amino-5,6 -Dimethoxyindanyl] -1-oxo-1H, 5H-benzo- [i, j] quinolidine The compound according to claim 1, which is -2-carboxamide.   9. Enantiomeric or diastereomeric forms having one or more chiral centers The compound according to any one of claims 1 to 8, which is   10. 10. The compound according to claim 1 as an active ingredient together with a suitable excipient. A pharmaceutical composition containing the compound.   11. Treatment of disease states that can be modulated by suppression of phosphodiesterase IV Use of a compound according to any of claims 1 to 9 for the manufacture of a medicament.   12. If the disease state is the action of phosphodiesterase IV, eosinophil accumulation or eosinophilia 12. Use according to claim 11, wherein the condition is a condition associated with the action of a sphere.   13. The use according to claim 12, wherein the condition is selected from the following: Breath, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergy -Conjunctivitis, spring conjunctivitis, eye inflammation, eye allergic reaction, eosinophilic granuloma, psoriasis , Rheumatoid arthritis, gouty arthritis and other arthritic conditions, ulcerative colitis , Crohn's disease, multiple sclerosis, adult respiratory distress syndrome, diabetes insipidus, keratitis, atopy Notes related to eczema, cerebral senility, multiple infarct dementia, senile dementia, Parkinson's disease Memory impairment, depression, cardiac arrest, seizures and intermittent claudication.   14． If the condition is chronic bronchitis, allergic rhinitis or adult respiratory distress syndrome 13. Use according to claim 12, wherein   15. 12. The method of claim 11, wherein the disease state can be modulated by suppression of TNF. Use.   16. The use according to claim 15, wherein the disease state is an inflammatory disease or an autoimmune disease. for.   17． 17. Use according to claim 16, wherein the disease state is selected from the following diseases: : Joint inflammation, arthritis, rheumatoid arthritis, rheumatic spondylitis, osteoarthritis, Sepsis, septic shock, endotoxin shock, gram-negative sepsis, toxic shock Group, acute respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, pulmonary sarcoma, asthma Breath, bone resorbable disease, reperfusion injury, graft-host disease, primary graft rejection, malarial disease A, myalgia, HIV, AIDS, ARC, cachexia, Crohn's disease, ulcerative colon Inflammation, fever, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes mellitus, psoriasis, bechet Disease, anaphylactoid purpura nephritis, chronic glomerulonephritis, inflammatory bowel disease and white Blood disease.   18. The use according to claim 11 or 15, wherein the condition or disease state is asthma.   19. The disease condition is acute respiratory distress syndrome, pulmonary inflammatory disease or pulmonary sarcoma 18. Use according to claim 17.   20. The disease state is joint inflammation, arthritis, rheumatoid arthritis, rheumatic spine 18. Use according to claim 17, which is spondylitis or osteoarthritis.   21. The disease state is a brain disease or disorder, for example, brain injury, ischemia, han The use according to claim 15, which is for Tint disease or tardive dyskinesia.   22. 16. Use according to claim 15, wherein the disease state is a yeast infection or a fungal infection.   23. Use of a compound according to any of claims 1 to 9 for the manufacture of a gastroprotective agent. for.   24. Analgesic, antitussive or anti-inflammatory for the treatment of neurogenic inflammatory diseases with irritation and pain Use of a compound according to any of claims 1 to 9 for the manufacture of a hyperalgesic agent.