MXPA98009740A

MXPA98009740A - Quinoline carboxamides as fnt inhibitors and as fde inhibitors

Info

Publication number: MXPA98009740A
Application number: MXPA/A/1998/009740A
Authority: MX
Inventors: Gary Montana John; Joan Dyke Hazel; Margaret Sabin Verity; Jayne Kendall Hannah; Lowe Christopher
Original assignee: Chiroscience Limited; Joan Dyke Hazel; Jayne Kendall Hannah; Lowe Christopher; Gary Montana John; Margaret Sabin Verity
Priority date: 1996-05-20
Filing date: 1998-11-19
Publication date: 1999-09-20

Abstract

A compound of the general formula (i) is described, wherein X is CO or CS, R is H, halogen or alkyl, R1 represents OH, alkoxy optionally substituted with one or more halogens, or thioalkyl; R2, R3 and R4 are the same or different and each are H, R7, OR11, COR7, C (= NOR7) R7, alkyl-C (= NOR7) R7, halogen, CF3, alkyl-C (= NOH) R7, C (= NOH) R7, C (= NOH) R7, CN, CO2H, CO2R11, CONH2, CONHR7, CON (R7) 2 NR9R10 or CONR12R13 wherein NR12R13 is a heterocyclic ring optionally substituted with one or more R15; R5 represents H, arylalkyl, heteroarylalkyl, heterocycloalkyl, S (O) mR11 or alkyl optionally substituted with one or more substituents selected from hydroxy, alkoxy, CO2R8, SO2NR12R13, CONR12R13, CN, carboxyl, NR9R10, COR11 and S (O) nR11, R6 represents aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl or heterocycloalkyl; in R5 and / or R6, the aryl / heteroaryl / heterocycle moiety is optionally substituted with one or more alkyl substituents R14. The compounds can be used to treat disease, for example disease states associated with proteins that mediate cellular activity, for example, by inhibiting tumor necrosis factor, and / or by inhibiting phosphodiesterase.

Description

OUINOLINE CARBOXAMIDES AS FNT INHIBITORS AND AS FDE-IV INHIBITORS DESCRIPTION OF THE INVENTION The present invention relates to novel quinolines, and their formulation and use as pharmaceuticals. EP-A-0498722 describes the quinoline amides as inhibitors of angiotensin A2 and endothelin. Phosphodiesterases (FDE) and Necrosis Factor Tumor (FNT), its modes of action and the therapeutic utilities of inhibitors thereof, are described in WO-A-963595, WO-A-9636596 and WO-A-9636611, the contents of which are incorporated herein. for reference. The same documents describe amides which have utility as inhibitors of FDE and FNT. This invention is based on the discovery of novel compounds that can be used to treat disease states, for example, disease states associated with proteins that measure cellular activity, for example, by inhibiting tumor necrosis factor and / or by inhibiting phosphodiesterase IV. According to the invention, the novel compounds are of the formula (i): where X is CO or CS; R is H, halogen or alkyl; R x represents OH, alkoxy optionally substituted with one or more halogens, or thioalkyl; R2, R3 and R4 are the same or different and each one is H, R7, ORn, COR7, C (= NOR7) R7, alkyl -C (= NOR7) R7, halogen. CF3, alkyl-C (= NOH) R7, C (= N0H) R7, C (= NOH) R7, CN, C02H, C02Rn, CONH2, CONHR7, CON (R7) 2? NR9R10 or CONR12R13 where NR12R13 is a ring heterocyclic (such as morpholine or piperidine) optionally substituted with one or more R15; R5 represents H, arylalkyl, heteroarylalkyl, heterocycloalkyl, SiO ^ or alkyl optionally substituted with one or more substituents selected from hydroxy, alkoxy, C02RB, S02NR12R13, CONR12R13, CN, carbonyl acid, NR9R10, COR ^ and S (0) "Rp, R6 represents aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl or heterocycloalkyl; in R5 and / or R6, the aryl / heteroaryl / heterocycle moiety is optionally substituted with one or more substituents alkyl R14 or R14; R7 represents Ra? optionally substituted at any position with (one or more) R16; RB represents H, alkyl, cycloalkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl; R9 represents H, aryl, heteroaryl, heterocycle, cycloalkyl, alkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl, alkylcarbonyl, alkoxycarbonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclecarbonyl or alkylsulfonyl; R10 represents H, aryl, heteroaryl, heterocycle, alkyl, cycloalkyl, arylalkyl, heteroarylalkyl or hecycloalkyl; R1X represents alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl or heterocycloalkyl; Ri2 and Rn are the same or different and each are H or Rl ?; or NR12R13 represents a heterocyclic ring co or defined above; R 14 represents alkyl (optionally substituted by one or more halogens), cycloalkyl, aryl, heteroaryl, heterocycle, hydroxy, alkoxy (optionally substituted by one or more halogens), thioalkyl, aryloxy, heteroaryloxy, heterocycloxy, arylalkyloxy, heteroarylalkyloxy, heterocycloalkyloxy, C02R8, CONR12R13, S02NR12R13, halogen, -CN, -NR9R10, CORn, S (0) nRu, or (where appropriate) carbonyl acid; R 15 represents alkyl, arylalkyl or heteroarylalkyl; R16 represents alkyl, OH, 0Rn, NR9R10, CN, C02H, O -R ^, CONR12R13 or COR, m represents 1-2; and n represents 0-2; and their pharmaceutically acceptable salts. Substitute and / or variable combinations are only permitted if such combinations result in stable compounds. Suitable pharmaceutically acceptable salts are pharmaceutically acceptable base salts and pharmaceutically acceptable acid addition salts. Certain compounds of the formula (i) which contain an acid group form base salts. The pharmaceutically acceptable base salts include metal salts, such as alkali metal salts, for example, sodium salts, or salts of organic amines such as those provided with ethylenediamine. Certain compounds of the formula (i) which contain an amino group form acid addition salts. Suitable acid addition salts include pharmaceutically acceptable inorganic salts, such as sulfate, nitrate, phosphate, borate, hydrochloride and bromohydrate and pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methansulfate, α-ketoglutarate, α-glycerophosphate and glucose-1-phosphate. The pharmaceutically acceptable salts of the compounds of the formula (i) are prepared using conventional procedures. It will be appreciated by those skilled in the art that some of the compounds of the formula (i) may exist in more than one tautomeric form. This invention extends to all tautomeric forms. It will be appreciated that the compounds according to the invention may contain one or more asymmetrically substituted atoms. The presence of one or more of these asymmetric centers in a compound of the formula (i) can give rise to stereoisomers, and it is understood that in each case, the invention extends to all isomers, including enantiomers and diastereomers and mixtures that include racemic mixtures thereof. When used herein the term "alkyl" whether used alone or when used as a separate from another group, includes straight or 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-0 group in which the aryl group is as defined below. Heteroaryloxy means a heteroaryl-0 group and heterocycloxy means a heterocycle-0 group in which the heteroaryl group and heterocycle are as defined below. Arylalkyloxy means an aryl-alkyl-O group. Alkylamino means an alkyl-N group in which the alkyl group is as previously defined, arylamino means aryl-N and heteroarylamino means a heteroaryl-N (aryl and heteroaryl defined below) group. Tialkyl means an alkyl-S group. Cycloalkyl includes a cyclic or multicyclic non-aromatic ring system of about 3 to 10 carbon atoms. The cyclic alkyl may optionally be partially unsaturated. Aryl indicates carbocyclic radicals containing 6 to 10 carbon atoms. Arylalkyl means an aryl-alkyl group wherein aryl and alkyl are as described herein. "Heteroarylalkyl" means a heteroaryl-alkyl and heterocycloalkyl group means a heterocycloalkyl 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 heterocyclecarbonyl means a heterocycle-CO group. Arylsulfonyl means an aryl-S02 group in which the aryl group is as previously described. Heteroarylsulfonyl means a heteroaryl-S02- group and heterocyclosulfonyl means a heterocyclic group. "Alkoxycarbonyl" means an alkyloxy-CO group in which the alkoxy group is as previously described. Alkylsulfonyl means an alkyl-S02- group in which the alkyl group is as previously described. Oxygen carbonyl means a group -CO-. It will be appreciated that a carbonyl oxygen can not be a substituent on an aryl or heteroaryl ring. "Carbocyclic ring" means a monocyclic or multicyclic ring system of about 5 to about 10 members, which may be saturated or partially unsaturated. "Heterocyclic ring" means a monocyclic or multicyclic ring system of about 5 to about 10 members (which may be saturated or partially unsaturated) wherein one or more of the atoms in the ring system is a different element to the carbon chosen from among atoms of nitrogen, oxygen or sulfur. "Heteroaryl" means an aromatic monocyclic or multicyclic hydrocarbon ring system of about 5 to about 10 members in which one or more of the atoms in the ring system is a non-carbon element, chosen from nitrogen, oxygen or sulfur; if desired, an N atom may be in the form of an N-oxide. "Heterocycle" means a saturated or partially saturated monocyclic or multicyclic hydrocarbon ring system of about 5 to about 10 members (which may be saturated or partially unsaturated) in which one or more of the atoms in the ring system is a non-carbon element, chosen from nitrogen, oxygen or sulfur atoms. Examples include morpholine and piperidine. Halogen means fluorine, chlorine, bromine or iodine. The compounds of the invention are useful for the treatment of disease states mediated by TNF. "Disease states of disease or disease mediated by TNF" means any and all disease states in which the TNF plays a role, either by the production of the same TNF, or by the TNF that causes another cytokine to be released, such as but not limited to IL-1 or IL-6. A disease state in which IL-1, for example, is a major component, and whose production or action is increased or secreted in response to TNF, can therefore be considered a disease state mediated by TNF. As FNT-ß (also known as lymphotoxin) has closed structural homology with TNF-a (also known as cachectin), and since each induces similar biological responses and binds to the same cellular receptor, both TNF-a and TNF are considered -β to be inhibited by compounds of the present invention and d, e this form are collectively referred to herein as "μFNT" unless specifically indicated otherwise This invention relates to an effect for mediating or inhibiting enzymatic activity or activity. catalytic activity of FDE IV in a mammal with the need for it and to inhibit production of TNF in a mammal in need thereof, which comprises administering to the mammal an effective amount of a compound of Formula (i) or a pharmaceutically acceptable salt thereof. Inhibitors of FDE IV are useful in the treatment of a variety of allergic and inflammatory diseases including: asthma, chronic bronchitis, chronic obstructive airway 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, amphilactoid purple nephritis, joint inflammation, arthritis, rheumatoid arthritis, and other arthritic conditions such as rheumatoid spondylitis and osteoarthritis, septic shock, sepsis, ulcerative colitis, Crohn's disease, myocardial and brain reperfusion damage, chronic glomerulonephritis, endotoxic shock and respiratory failure syndrome in adults. In addition, FDE IV inhibitors are useful in the treatment of diabetes insipidus and conditions associated with cerebral metabolic inhibition, such as cerebral senility, senile dementia (Alzehimer's disease), memory impairment associated with Parkinson's disease, depression and dementia. multi-infarct Inhibitors of FDE IV are also useful under conditions improved by europrotective activity, such as cardiac detection, infarction and intermittent claudication. FDE IV inhibitors may also be useful in the treatment of tardive dyskinesia, ischemia and Huntingdon's disease. Additionally, FDE IV inhibitors may have utility as gastroprotectors. A special embodiment of the therapeutic methods of the present invention is the treatment of asthma. The 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 replication decreased, directly or indirectly, by the TNF inhibitors of the formula (i). Such viruses include, but are not limited to HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus and the Herpes virus group, such as, but not limited to, Herpes zoster and Rorpes simplex. This invention relates more specifically to a method for treating a mammal, afflicted with a human immunodeficiency virus (HIV), which comprises administering to said mammal an inhibitory amount of TNF and a compound of the formula (i) or a pharmaceutically salt acceptable of it. The compounds of this invention can also be used in association with the veterinary treatment of animals, other than humans, in need of inhibition of TNF production. The diseases mediated by FNT for Treatment, either therapeutically or prophylactically, in animals, includes disease states such as indicated above, but in particular viral infections. Examples of such viruses include but are not limited to feline immunodeficiency virus (FIV) or other retroviral infection such as equine infectious anemia virus, goat arthritis virus, visna virus, maedi virus and other lentiviruses. The compounds of this invention are useful for treating infections by parasites, yeasts and fungi, where such fungi and yeasts are sensitive to upregulation by TNF or will cause the production of TNF in vivo. A disease status for treatment is fungal meningitis. The compounds of the invention can also suppress neurogenic inflammation through the increase of cAMP in sensory neurons. They are therefore analgesic, anti-inflammatory and antihyperalgesic in inflammatory diseases associated with irritation and pain. The compounds of the formula (i) are preferably in the pharmaceutically acceptable form. By pharmaceutically acceptable form is meant inter alia a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and not including material considered toxic at normal dose levels. A pharmaceutically acceptable level of purity will be at least 50% excluding additives normal pharmaceuticals, preferably 75%, more preferably 90%, and still more preferably 95%. The invention further provides a process for the preparation of a compound of the formula (i) wherein Rj, etc., m and n are as defined above. It will be appreciated that functional groups such as amino, hydroxyl or carboxyl present in the various compounds described below may be required to be protected before any reaction is initiated. In such examples, the removal of the protecting group may be in the final step in a particular reaction sequence. Suitable protection 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. In this way, the process for preparing compounds of the formula (i) in which R3 contains -OH comprises deprotecting (eg, by hydrogenolysis or hydrolysis) a compound of the formula (i) in which R, contains a -OP suitable where P represents a suitable protecting group (e.g., benzyl or acetate). It will be appreciated that where a particular stereoisomer of formula (i) is required, it can be obtained by conventional resolution techniques, such as high performance liquid chromatography or the synthetic processes described herein can be performed using the material of appropriate homoquiral starting. A process for the preparation of a compound of the formula (i), wherein X is CO comprises the reaction of an appropriate carboxylic acid of the formula (ii) with a suitable amine of the formula (iii) (ü) (ia) where Rla represents R1 as defined in relation to formula (i) or a group convertible to R1 and R2a-R6a similarly represent R2-R6 or groups convertible to R2-R6 respectively; and after that, if it is required to convert any group Rla and Rx and / or R2a to R2 and / or R3a to R3 and / or R4a to R4 and / or R5a to R5 and / or Rea to Re • It can be carried out the reaction of a carboxylic acid of the formula (ii) with an amine of the formula (iii) under any suitable conditions known to those skilled in the art. Preferably, the carboxylic acid is converted to an acid chloride, mixed anhydride or other activated intermediate prior to the reaction with an amine of the formula (iii). Preferably, it is carried out with the amine of the formula (iii) in the presence of a suitable base for example, an amine such as triethylamine, preferably in an appropriate solvent such as dichloromethane. In some cases, a strong base, such as sodium hydride, and a polar solvent such as dimethylformamide will be required. The carboxylic acids of the formula (ii) are either commercially available, compounds previously described or are prepared using standard procedures known to those skilled in the art. For example, a carboxylic acid of the formula (ii) of an appropriately substituted aminobenzoic acid of the formula (iv) and a ketone (or aldehyde) of the formula (v) can be conveniently prepared using a Skraup reaction (ZH Skraup, Ber 12: 2086 (1880)). The reaction can be carried out using standard conditions known to those skilled in the art. flv) (ü) The acids of the formula (iv) and ketones (or aldehydes) of the formula (v) are either commercially available, compounds previously described or are prepared using standard procedures known to those skilled in the art.

Acids of the formula (ii) can alternatively be prepared by carboxylation of bromides of the formula (vi). Such carboxylations can be carried out using any standard conditions known to those skilled in the art, for example under the catalysis of organometals (eg, palladium catalysis). The bromides of the formula (vi) can be prepared by bromination of quinolines of the formula (vii) under standard conditions known to those skilled in the art, for example using the bromide in methanol. The quinolines of the formula (vii) are either commercially available, previously described compounds or are prepared using standard procedures known to those skilled in the art. For example, the quinolines of the formula (vii) can be conveniently prepared by a Skraup reaction of an appropriate aniline of the formula (viii) with a ketone (or aldehyde) of the formula (v). An alternative method for the preparation of quinolines of the formula (vii) is the Combes reaction (A. Combes, Bull, Soc. Chim. France ___: 89 (1988)). (ffi) (ii) (0 w) A compound of the formula (Ia) can also be prepared by reaction of the carboxylic acid of the formula (ii) with an amine of the formula H2NR6a (ix), to provide a compound of the formula (Ia) in the which R5a, is H, followed by the reaction with an appropriate agent of the formula R5ay (x), wherein Rla-R6a are as defined above and Y represents a suitable leaving group, such as halogen.The reaction of a carboxylic acid of the formula (ii) with an amine of the formula (ix) can be carried out under any suitable conditions known to those skilled in the art Preferably, the carboxylic acid is converted to acid chloride, mixed anhydride or other activated intermediate before the reaction with an amine of the formula (ix). Preferably, the reaction is carried out in the presence of a suitable base, for example an amine such as triethylamine, preferably in a suitable solvent such as dichloromethane In some cases a base may be required stronger such as sodium hydride and a polar solvent such as dimethylformamide. The amines of formula (ii) and (ix) and agents of formula (x) are either commercially available, compounds previously described or are prepared using standard procedures known to those skilled in the art. The reaction of a compound of the formula (Ia) in which R 5 is H with an agent of the formula (x) can be carried out under any suitable conditions known to those skilled in the art. Preferably, the reaction is carried out using an appropriate base such as sodium hydride, preferably in an appropriate solvent such as dimethylformamide. An agent (x) can be an alkylating agent such as propyl bromide, an acylating agent such as benzoyl chloride or a sulfolating agent such as methanesulfonyl chloride. A compound of the formula (i) can also be prepared by interconversion of other compounds of the formula (i). For example, a compound in which R3 contains an alkoxy group can be prepared by appropriate alkylation of a compound in which R3 contains a hydroxy group. Compounds in which R2-R4 containing a CO-alkyl, CO-aryl, CO-heteroaryl, CO-alkylaryl, CO-alkylheteroaryl, CO-alkylheterocyc can be prepared from the compounds in which R2-R4 contains a CN group by addition of a suitable organometallic agent (such as a Grignard agent). For forms of the additional example, compounds in which R2-R4 contain an oxime can be prepared from compounds wherein R2 ~ R4 contain a carboxyl group. This transformation can be carried out using any standard conditions known to those skilled in the art. Compounds of the formula (i) in which R2-R4 contain a carbonyl group can 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 the which R2-R4, contain an alcohol group. Compounds in which R2-R4 is alkyl or reduction of compounds in which R2-R4 is a Co-alkyl using standard conditions known to those skilled in the art (for example, hydrazine hydrated in the presence of a adequate base in an appropriate solvent). Other transformations can be carried out in compounds of the formula (i) in which R2-R4 contain a carbonyl group. Such transformations include but are not limited to, reductive amination and alkylation. Any of the above transformations can be carried out either at the end of the synthesis or in an appropriate intermediary. The compounds of the formula (i) in which X is CS can be prepared from the compounds of the formula (i) in which X is CO using any appropriate conditions, known to those skilled in the art, for example using Lawesson's reagent. A compound of the formula (i) or wherein a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof, can be administered per se, or preferably, as a pharmaceutical composition which will also comprise a pharmaceutically acceptable carrier. Accordingly, the present invention provides a pharmaceutical composition comprising a compound of the formula (i) or wherein a pharmaceutically acceptable salt thereof and / or pharmaceutically acceptable solvate thereof and a pharmaceutically acceptable carrier thereof are appropriate. The active compound can be formulated by administration by any suitable route, the preferred route will depend on the transfection for which treatment is required and is preferably in the form of unit doses, or in a form that a human patient can administer in a similar manner. single dose. Advantageously, the composition is suitable for oral, rectal, topical, parental or respiratory tract administration. The preparations can be designed to give a slow release of the active ingredient. The term "parental" as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc., the compounds 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, lesions, suppositories, reconstitutable powders, or liquid preparations such as sterile oral or parenteral solutions or suspensions. It also covers topical formulations where appropriate. In order to obtain administration consistency it is preferred that a composition of the invention be in the form of a unit dose. The dosage unit dosage 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, corn starch, calcium phosphate, sorbitol or glycine; tableting lubricants, for example, magnesium stearate; disintegrants, for example, starch, polyvinyl pyrrolidone, sodium starch glycolate or microcrystalline cellulose; or agents of pharmaceutically acceptable moistening, such as sodium lauryl sulfate. Solid oral compositions can be prepared by conventional methods of mixing, filling, tableting or the like. The repeated mixing operations can be used to distribute the active agent in all those compositions that employ large amounts of fillers. Such operations are of course conventional in the art. The tablets can 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 they may be prepared as a dry product by reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles, (which may consist of edible agents), for example, almond oil, fractionated coconut oil, oil esters such as glycerin esters, propylene glycol or ethyl alcohol; preservatives, for example, methyl or propyl p-hydroxybenzoate or sorbic acid; and if conventional flavors or coloring agents are desired. The compositions may be suitably presented for administration to the respiratory tractor as an aspiration or an aerosol or solution by a nebulizer, or by a microfine powder for insulphlation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the active compound have suitable diameters of less than 50 μm, such as from 0.1 to 50 μm, preferably less than 10 μm, for example from 1 to 10 μm, 1 to 5 μm, or from 2 to 5. μm. When appropriate, small amounts of other anti-asthmatics and bronchodilators may be included, for example, sympathomimetic amines, such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine; corticosteroids, such as prednisolone and adrenal stimulants such as ACTH. For parenteral administration, the fluid dosage unit forms are prepared using the compound and a sterile vehicle, and, depending on the concentration used, they may be either suspended or dissolved in the vehicle. When preparing the solutions the compound can be dissolved in water or for injection and sterilized by filter before filling a suitable vial or ampoules and sealing. Advantageously, adjuvants can be dissolved as a local anesthetic, a preservative and deadening agents in the vehicle. To increase stability, the composition can be frozen after filling the vial and the water removed under vacuum. The parenteral suspensions are prepared in substantially the same form except that the compound is suspended in the vehicle instead of being dissolved, and the sterilization can not be carried out by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound. The compositions may contain from 0.1% to 99% by weight, preferably 10-60% by weight, of the active material, depending on the method of administration. The compounds of the formula (i), or if appropriate a pharmaceutically acceptable salt thereof and / or pharmaceutically acceptable solvate thereof, can be administered as a typical formulation in combination with conventional topical excipients. Topical formulations such as ointments, creams or lotions, impregnated bandages, gels, gel tapes, spray and aerosols may be presented and may contain appropriate additives such as preservatives, solvents to aid drug penetration and emollients in ointments and creams. The formulations may contain compatible conventional carriers, such as cream bases or ointments or ethanol or oleyl alcohol for lotions. Suitable cream formulations, lotions, gels, tapes, ointments, sprays or aerosols that can be used for compounds of the formula (i) or if a pharmaceutically acceptable salt thereof is suitable, are conventional formulations well known in the art, example as described in standard textbooks such as Harry Cosmeticology published by Leonard Hill Books, Re ington Pharmaceutical Sciences, and The British and United States Pharmacopoeias. Suitably, the compound of the formula (i), or if appropriate a pharmaceutically acceptable salt thereof, will comprise from 0.5 to 20% by weight of the formulation, favorably from about 1 to 10%, for example 2 to 5% . The dose of the compound used in the treatment of the invention will vary in the usual way with the seriousness of the condition, the weight of the patient, and the relative efficiency of the compound. However, as a general guideline, the appropriate unit doses may be 0.1 to 1000 mg, such as 0.5 to 200, 0.5 to 100 or 0.5 to 10 mg, for example 0.5, 1, 2, 3, 4 or 5 mg; and such unit doses may be administered more than once a day, for example, 2, 3, 4, 5 or 6 times a day, but preferably 1 or 2 times per day, such that the dose Total daily for a 70 kg adult is in the range of about 0.1 to 1000 mg, this 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 at 0.5 mg / kg / day, for example, 0.01, 0.02, 0.04, 0.05, 0.06, 0.08, 0.1 or 0.2 mg / kg / day, and such therapy may be prolonged for a number of weeks or months. When used herein the term "pharmaceutically acceptable" encompasses materials suitable for both human and veterinary use. The following examples illustrate the invention. Intermediate 1 8-methoxyquinoline-5-carboxylic acid A mixture of 3-amino-4-methoxybenzoic acid (5.0 g), glycerol (4.16 g), and iodine (135 mg), in concentrated sulfuric acid (5 ml) is heated to 180 ° C for 2 hours. The reaction is allowed to cool, diluted with water (170 ml), brought to basic pH pH8 / 9 with 0.88 ammonia and stirred with activated charcoal (2.0 g). The mixture is filtered through Celite and the filtrate acidified to pH4/5 with acetic acid. The precipitate is obtained by filtration and dried in a desiccator to produce the desired product (4.21 g) as a dark solid. TLC Rf 0.35 (1% acetic acid, 5% methanol in ethyl acetate). Intermediate 2 8-methoxy-2-methylquinoline Treat at room temperature a mixture of 8- hydroxyquinoline (5.0 g) and tetrabutylammonium iodide (1.1 g) in tetrahydrofuran (90 ml) with sodium hydroxide (4.5 g) in water (45 ml). Methyl iodide (3.7 ml) is added and the reaction is stirred overnight. The THF is removed in vacuo and the remaining solution is fractionated and partitioned between ethyl acetate (100 ml) and water (100 ml). The aqueous layer is re-extracted with ethyl acetate and the organic extracts are combined. The organic layer is washed with saturated aqueous sodium hydrogen carbonate (100 ml) and saturated aqueous sodium chloride (100 ml). The organic layer is dried, filtered and the filtrate evaporated in vacuo to yield the final product as an off-white solid (5.85 g). TLC Rf 0.46 (ethyl acetate). The following intermediaries are prepared in a similar manner. Intermediate 3 8-methoxyquinoline-2-carbonylate The title compound is isolated as a white solid (325 mg). TLC R £ 0.27 (50% ethyl acetate in hexane). Intermediate 4 2-Bromo-8-methoxyquinoline Purification by flash chromatography on silica, eluting with 50% ethyl acetate in hexane afforded the title compound (1.45 g) as a pale yellow crystalline solid. TLC R £ 0.55 (50% ethyl acetate in hexane).

Intermediate 5 3-ethyl-8-methylquinoline Freshly distilled 2-ethyl acrolein (1.7 ml) is added in 20 minutes to a solution of o-anisidine (1.5 g) and iodine (20 mg) in 70% sulfuric acid (10 mg). ml) with stirring at 110 ° C. After 2 hours the reaction is cooled to 0 ° C and brought to basic pH with 25% aqueous sodium hydroxide (pH 13). The aqueous layer is extracted with ethyl acetate (2x100 ml) and the extracts are combined. The organic layer is extracted with 2M hydrochloric acid (2x100 ml) and the combined extracts are brought to basic pH again with 25% sodium hydroxide. The aqueous layer is extracted with ethyl acetate (2x100 ml), the extracts combined, dried over magnesium sulfate, filtered and the filtrate evaporated in vacuo. The residue is purified by column chromatography, eluting with 25% -50% ethyl acetate, to yield the title product as a dark oil (0.42 g). TLC R £ 0.17 (50% ethyl acetate in hexane). Intermediate 6 2-ethyl-8-methoxyquinoline N-butyllithium (1 ml, 1.6 M in hexanes) is added in drops to a stirred solution of 8-methoxy-2-methylquinoline (0.25 g) in tetrahydrofuran (4 ml) at -60 ° C under an inert atmosphere. The resulting red solution is stirred at -60 ° C for 15 minutes, and then heated to -40 ° C. The iodomethane (0.27 ml) is then added dropwise and the reaction is heated slowly to room temperature with continuous stirring. 12 hours. The reaction is stopped with brine (50 ml) and extracted with dichloromethane (2 × 50 ml). The organic phases are combined, dried in magnesium sulfate and pre-adsorbed on silica. Purification is accomplished by column chromatography eluting with ethyl acetate to yield the title compound as a light yellow solid (0.16 g). RLC Rf 0.53 (ethyl acetate). Intermediate 7 7-fluoro-8-methoxyquinoline A solution of 3-fluoro-2-methoxyaniline (5.0 g) in 1,2-dichlorobenzene (50 ml) at 170 ° C is heated and treated with p-toluenesulfonic acid (0.7 g). ). A solution of acrolein (4.0 g) in 1,2-dichlorobenzene (20 ml) is added dropwise over 20 minutes. The reaction is stirred for 1 hour at 170 ° C before it is allowed to cool. The mixture is extracted with 2N hydrochloric acid (3 x 200 ml) and the combined extracts are washed with dichloromethane (20 ml), basic pH is taken with 25% aqueous sodium hydroxide and extracted with ethyl acetate (3 x 200 ml). Dry the combined extracts in magnesium sulfate, filter and evaporate the filtrate in vacuo. The residue is purified by column chromatography on silica gel eluting with 50% ethyl acetate in hexane to yield the desired product (2.6 g) as a clear oil. TLC Rf 0.21 (50% ethyl acetate in hexane). Intermediate 8 5-bromo-8-methoxy-2-methylquinoline A solution of 8-methoxy-2-methylquinoline is treated (1.0 g) in methanol (30 ml) at room temperature with bromine (0.31 ml). The mixture is heated at 45 ° C for 2 hours and the reaction is stopped with 5% aqueous sodium metabisulfite (50 ml). The solution is brought to basic pH with 25% aqueous sodium hydroxide at pH 13 and the product is extracted with ethyl acetate (2 x 100 ml). The extracts are combined, dried over magnesium sulfate, filtered and evaporated in vacuo. The residue is dissolved in ethyl acetate and passed through a silica pad. The solution is evaporated in vacuo to yield the desired product as an off-white solid (0.43 g) • TLC R 0.57 (ethyl acetate). The following intermediaries are prepared in a similar manner. Intermediate 9 5-bromo-3-yl-8-methylquinoline The title compound is isolated as a dark solid (0.501 g). TLC R £ 0.125 (50% ethyl acetate in hexane) Intermediate 10 5 -bromo-2-ethyl-8-methoxyquinoline The title compound is isolated as a brown oily solid (3.3 g) TLC R £ 0.67 (ethyl acetate). 15% ethyl in dichloromethane) Intermediate 11 5-Bromo-8-methoxy -2 - (trifluoromethyl (quinoline) The title compound (4.15 g) is obtained as a solid white. p.f. 84-85 ° C Intermediate 12 5-bromo-7- fluoro-8-methoxyquinoline Bromine (0.48 ml) is added dropwise to a solution of 7-fluoro-8-methoxyquinoline (1.6 g) in glacial acetic acid (24 ml) ). The mixture is heated at 40 ° C for 4 hours and the reaction is stopped with 5% aqueous sodium metabisulfite (100 ml). The solution is brought to pH basic with 25% aqueous sodium hydroxide at pH 13 and the product is extracted with ethyl acetate (3 x 150 ml). The extracts are combined, dried over magnesium sulfate, filtered and the filtrate evaporated in vacuo. Purify the residue in column chromatography on silica gel eluting with 25% ethyl acetate in hexane to yield the desired product as a white solid (0.50 g). TLC R £ 0.46 (50% ethyl acetate in hexane). Intermediate 13 5-bromo-8-methoxyquinoline-2-carbonitrile Sodium acetate (690 mg) is added to a solution of Intermediate 3 (310 mg) in glacial acetic acid (10 ml). Bromine (0.1 ml) is added dropwise, and the mixture is stirred at room temperature for 17 hours. This is stopped with 5% aqueous sodium metabisulfite (20 ml), then brought to basic pH with 25% aqueous sodium hydroxide at pH 13 and extracted with ethyl acetate (3x 60 ml). The extracts are combined, dried over magnesium sulfate, filtered and evaporate the filtrate in vacuo. The residue is purified by column chromatography on silica gel eluting with 33% ethyl acetate in hexane to yield the desired product as a white solid (365 mg). TLC Rf 0.63 (50% ethyl acetate in hexane). Intermediate 14 Methyl 5-bromo-8-methoxyquinoline-2-carboxylate Purification by flash chromatography gives the title compound (0.48 g) as a white solid. TLC R £ 0.37 (ethyl acetate in hexane). Intermediate 15 5-bromo-8-difluoromethoxyquinoline Aqueous sodium hydroxide (47%, 15 ml) and benzyltriethylammonium chloride (0.25 g) are added to a suspension of 5-bromo-8-hydroxyquinoline (2.74 g) in dioxane (150 ml ). The vigorously stirred mixture is heated to 75 ° C and chlorodifluoromethane gas is bubbled through the reaction mixture with a diffuser for 50 minutes. The solution is allowed to cool to room temperature and the reaction mixture is poured into water (250 ml) and extracted with ethyl acetate (3 x 200 ml). The combined organic extracts are washed with water (2 x 150 ml), dried (magnesium sulfate) and evaporated in vacuo. Purify the residue by chromatography on silica eluting with 50% ethyl acetate in hexane to give the title compound (1.64 g) as a yellow solid. TLC R £ 0.70 (50% ethyl acetate in hexane).

Intermediate 16 5-bromo-8-difluoromethoxy-quinidine Purification by recrystallization from aqueous methanol yields the title compound as an off-white solid (4.8 g). TLC R £ 0.86 (50% ethyl acetate in hexane). Intermediary 17 8-methoxy-2-methylquinoline-5-carboxylic acid A mixture of 5-bromo-8-methoxy-2-ethylquinoline (2.0 g), triethylamine (11 ml), triphenylphosphine is stirred. (0.79 g), and bis (triphenylphosphine) palladium (II) chloride (1.56 g) in tetrahydrofuran (200 ml) and water (90 ml) in a pressurized reaction vessel and charged with carbon monoxide at a pressure of 160 psi. The vessel is heated to 80 ° C and stirred for 72 hours. It is allowed to cool and depressurize the reaction. The mixture is filtered and the organic solvent is removed in vacuo. The aqueous residue is brought to basic pH with 1M sodium hydroxide and washed with ethyl acetate (300 ml).

The aqueous solution is acidified to pH 5 with glacial acetic acid and extracted with ethyl acetate (2 x 400 ml). The organic extracts are combined, dried over magnesium sulfate, filtered and the filtrate evaporated in vacuo to yield the title compound (1.0 g) as an off-white solid. TLC R £ 0.17 (ethyl acetate). The following intermediaries are prepared in a similar way: Intermediate 18 3-ethyl-8-methoxyquinoline-5-carboxylic acid The title compound of 5-bromo-3-ethyl-8-methoxyquinoline is obtained and isolated as a bone-colored solid (0.6 g) - TLC Rf 0.7 (methanol at 10% in ethyl acetate). Intermediate 19 2 [(t-Butyloxycarbonyl) - (methyl) amino] -8-methoxy-quinoline-5-carboxylic acid The title compound (0.311 g) of 5-bromo-2- [(t-butyloxycarbonyl) (methyl) is prepared amino] -8-methoxyquinoline (1.18 g). Mass Spectrum (El) 233 [M-Boc + H] + The following intermediates are prepared in a similar manner, but in acidification of the aqueous phase at pH 4-5 with glacial acetic acid, the title compounds are precipitated. They are separated by filtration and dried in vacuo. Intermediate 20 8-difluoromethoxyquinoline-5-carboxylic acid The title compound is isolated as a beige solid (0.85 g). p.f. 280 ° C (decomposition). Intermediate 21 8-difluoromethoxyquinoline-5-carboxylic acid The title compound is isolated as a beige solid (2.9 g). TLC R £ 0.6 (10% methanol in dichloromethane). Intermediate 22 7-Fluoro-8-methoxyquinoline-5-carboxylic acid The title compound is isolated as a bone-colored solid (0.58 g), TLC Rf 0.1 (ethyl acetate).

Intermediate 23 8-methoxy-2- (pyrid-3-yl) -quinoline-4-carboxylic acid A title compound is obtained as a beige powder (366 mg). p.f. 264 ° C (decomposition). The following intermediates are prepared in a similar manner, but using dimethylformamide as the solvent in place of tetrahydrofuran: Intermediate 24 2-cyano-8-methoxy-4-quinoline-5-carboxylic acid The title compound is isolated as an off-white solid (0.304 g). TLC Rf 0.1 (ethyl acetate). Intermediate 25 8-methoxy-2- (trifluoromethyl) quinoline-5-carboxylic acid The title compound (3.10 g) is obtained as a white solid. p.f. 248-249 ° C. Intermediate 26 2-ethyl-8-methoxyquinoline-5-carboxylic acid A mixture of 5-bromo-2-ethyl-8-methoxyquinoline (3.3 g), sodium hydroxide (3.1 g, 46% solution in water) is stirred, triphenylphosphine (0.22 g) and bis (triphenylphosphine) palladium (II) chloride (0.14 g) in tetrahydrofuran (14 ml) and water (7 ml) in a pressurized reaction vessel and charged with carbon monoxide at a pressure of 160 psi.

The vessel is heated to 105 ° C and stirred for 24 hours. The reaction is allowed to cool and depressurized. HE filter the mixture and collect the washed solid with tetrahydrofuran (2x 10 ml). The solid is dissolved in hot methanol (10 ml) and water (10 ml), and the solution is filtered to remove any remaining solid. The hot solution is treated with glacial acid (2 ml) and cooled in ice. The resulting precipitate is filtered off and dried on silica gel under vacuum to yield the title compound as a white solid (0.44 g). TLC R £ 0.2 (ethyl acetate). Intermediate 27 8-methoxyquinoline-5-carbonyl chloride, hydrochloride A suspension of 8-methoxyquinoline-5-carboxylic acid (1.5 g) in dichloromethane (12 ml) is cooled to 0 ° C and treated with oxalyl chloride (1.3 ml). ) followed by DMF (8 drops). The reaction is allowed to warm to room temperature and is stirred overnight. The solvent is removed in vacuo and the residue is formed in azeotropic mixture with toluene (2 x 10 ml) to yield the desired product (1.61 g) as an off-white powder. The following acid chlorides are prepared in a similar manner from the carboxylic acid: Intermediate 28 8-methoxy-2-methyl-quinoline-5-carbonyl chloride, hydrochloride The title compound is isolated as an off-white solid (0.5 g) .

Intermediate 29 3-ethyl-8-methoxyquinoline-5-carbonyl chloride, hydrochloride The title compound is isolated as a bone-colored solid (0.68 g). P.f. 185-186 ° C (decomposition). Intermediate 30 7-Fluoro-8-methoxyquinoline-5-carbonyl chloride, hydrochloride The title compound is isolated as a brown solid (0.64 g). Intermediary 31 2-cyano-8-methoxyquinoline-5-carbonyl chloride, Hydrochloride The title compound is isolated as a brown solid (0.32 g). Intermediate 32 8-difluoromethoxyquinoline-5-carbonyl chloride, hydrochloride The title compound is isolated as a beige solid (0.853 mg). Intermediate 33 2-ethyl-8-methoxyquinoline-5-carbonyl chloride, hydrochloride The title compound is isolated as a deep red (dark) oily solid (0.48 g). Intermediate 34 8-methoxy-2- (3-pyridyl) -quinoline-5-carbonyl chloride, hydrochloride The title compound is obtained as a beige solid (0.39 g).

Intermediate 35 8-methoxy-2- (trifluoromethyl) quinoline-5-carbonyl chloride, hydrochloride The title compound is obtained as a light yellow solid. Intermediate 36 4-amino-3-chloropyridine Treat a solution of 4-aminopyridine (4.0 g) in concentrated hydrochloric acid (50 ml) at 80-85 ° C with an aqueous solution of hydrogen peroxide (13.5% w / v) . The solution is cooled to 0 ° C. After 30 minutes the solution is carefully treated with an aqueous solution of sodium hydroxide (50% w / v) keeping the temperature below 15 ° C. The precipitate is filtered off and air is dried to yield the title compound or a white solid (4.9 g). TLC R £ 0.36 (ethyl acetate). P.f. 65-67 ° C. Intermediate 37 8-methoxy-2- (3-pyridyl) quinoline Powdered potassium hydroxide (675 mg) is added to a stirred mixture of 2-bromo-8-methoxyquinoline (956 mg), diethyl (3-pyridyl) borane ( 590 mg), tetrakis (triphenylphosphine) -palladium (0) (250 mg) and tetra-n-butylammonium iodide (740 mg) in anhydrous tetrahydrofuran (60 ml). The stirred mixture is brought to reflux under an inert atmosphere for 1.25 hours. The solvent is removed in vacuo and the residue is partitioned between dichloromethane (100 ml) and water (80 ml). The aqueous phase is re-extracted with dichloromethane (2 x 50 ml) and the phases are dried organic combined (magnesium sulfate), filtered through a small pad of Celite and evaporated in vacuo. Purify the product without purification by flash chromatography on silica, eluting with ethyl acetate to yield the title compound (780 mg) as a clear oil. TLC R £ 0.25 (ethyl acetate). Intermediate 38 5-bromo-8-methoxy-2- (3-pyridyl) quinoline Bromine (200 μl) is added in a dropwise form to a cold, stirred solution (0.5 ° C) of 8-methoxy-2- ( 3-pyridyl) quinoline (780 mg) in methanol (30 ml) under a nitrogen atmosphere. The reaction mixture is stirred for 15 minutes then stopped by the addition of 5% aqueous sodium metabisulfite solution (7 ml). The reaction mixture is evaporated in vacuo and the residue is partitioned in 0.5N hydroxide solution (65 ml) and dichloromethane (75 ml). The aqueous phase is re-extracted with dichloromethane (2 x 75 ml) and the combined organic phases are dried (magnesium sulfate), filtered and evaporated in vacuo. Trituration with diethyl ether affords the title compound (570 mg) as a light brown solid. TLC R £ 0.2 (ethyl acetate). Intermediate 39 5- [8-methoxy-5- [N- (3,5-dichloropyridin-4-yl) J-aminocarbonylquinolin-2-yl] -2-trimethylstannyl-2H-tetrazole. Heat refluxing for 16 hours 2-cyano-8-methoxyquinoline-5- [N- (3,5-dichloropyridin-4-yl] - carboxamide (390 mg) and trimethyltin azide (580 mg) in toluene (20 ml) and tetrahydrofuran (20 ml). The reaction is cooled to room temperature and the resulting precipitate is filtered off, washed with toluene (2 x 5 ml) and dried in vacuo at 40 ° C to yield the title compound as a light yellow solid (299 mg). . P.f. 229-231 ° C. Intermediate 40 Methyl 8-hydroxyquinoline-2-carboxylate Combine 8-hydroxyquinoline-2-carboxylic acid (2.08 g) and tetrahydrofuran (200 ml) and stir with ice-bath cooling. Then add diazo ethane (approximately 16.6 mmol in solution in diethyl ether) and stir completely for 1.5 hours while heating slowly to room temperature. Nitrogen is passed through the reaction mixture to purge any excess diazomethane and the vacuo solution is evaporated to yield the title compound (1.6 g) TLC R £ 0.12 (50% ethyl acetate in hexane). Intermediate 41 8-methyl methoxyquinoline-2-carboxylate Methyl 8-hydroxyquinoline-2-carboxylate (1.6 g), acetone (15 ml), potassium carbonate (1.3 g) and iodomethane (0.6 ml) are combined and stirred at room temperature for 48 hours. The solvents are removed in vacuo and the resulting white residue is resuspended in water (25 ml), which is extracted with ethyl acetate (3 x 25 ml). The organic layers are dried Compounds (magnesium sulfate) and the solvents are removed in vacuo to give the title compound as a white solid (1.72 g). TLC R £ 0.22 (50% ethyl acetate in hexane). Intermediate 42 5-bromo-8-methoxyquinoline-2-carboxylic acid Combined methyl 5-bromo-8-methoxyquinoline-2-carboxylate (1.54 g), tetrahydrofuran (40 ml), water (40 ml) and lithium hydroxide monohydrate (0.436 g) and stirred at room temperature for 1.5 hours. The tetrahydrofuran is removed in vacuo and the resulting aqueous mixture is acidified with hydrochloric acid. The resulting white precipitate is collected and collected by filtration and dried in vacuo to give the title compound (1.33 g) as a white solid. Mass spectrum (El (296 and 298 [M + H] + Intermediate 43 5-bromo-2-t-butyloxycarbonylamino-8-methoxyquinoline) Combine 5-bromo-8-methoxyquinoline-2-carboxylic acid (2 g), t-butanol (25 ml) and triethylamine (1.48 ml) under a nitrogen atmosphere and heated to 80 ° C. Diphenylphosphorylazide (2.29 ml) is added to the solution and heating is continued for 60 hours, at which time the shows a white precipitate. The reaction mixture is evaporated in vacuo on silica and purified by flash chromatography to give the title compound (1.21 g) as a color solid. bone. TLC R £ 0.50 (50% ethyl acetate in hexane) Intermediate 44 5-bromo-2 [(t-butyloxycarbonyl) (methyl) amino] -8-methoxyquinoline Combine 5-bromo-2-t-butyloxycarbonylamino-8- methoxyquinoline (1.21 g) and tetrahydrofuran (20 ml) at room temperature under nitrogen atmosphere. Sodium hydride (60% dispersion in oil) is added (164 mg) and the reaction mixture is stirred for 2 hours while effervescence occurs and a yellow color appears. Iodomethane (0.43 ml) is then added and stirring is continued for 2 hours, after which time the reaction is diluted with ethyl acetate (100 ml), washed successively with water, saturated aqueous sodium bicarbonate, then dried ( magnesium sulfate) and evaporated in vacuo to give the title compound (1.18 g) as a yellow solid. TLC R £ 0.60 (50% ethyl acetate in hexane). Intermediate 45 2- [(t-Butyloxycarbonyl) (methyl) amino] 8-methoxyquinoline-5-carboxylic acid 4-nitrophenyl Combine 2 - [(t-butyloxycarbonyl) (methyl) amino] -8-methoxyquinoline-5- carboxylic (0.311 g), ethyldimethylaminopropylcarbodiimide hydrochloride (0.269 g), 4-nitrophenol (0.195 g), N, N-dimethylaminopyridine (20 mg) and dichloromethane (20 ml) and then stirred at room temperature for 17 hours. The reaction mixture is evaporated in Vortex on silica and purify by flash chromatography to give the title compound (0.384 g) as a light yellow solid. TLC R £ 0.50 (50% ethyl acetate in hexane). The following intermediates are prepared in a similar manner using the appropriate starting materials. Intermediate 46 8-difluoromethoxyquinoline-5-carboxylate 4-nitrophenyl Purification by column chromatography eluting with 50% ethyl acetate in hexane affords the title compound as a cream solid (0.63 g). TLC R £ 0.76 (10% methanol in dichloromethane). Intermediate 47 8- t-butyldimethylsilyloxyquinoline. 8-hydroxyquinoline (10 g), t-butyldimethylsilyl chloride (10 g) is dissolved in imidazole (8.6 g) in N, N-dimethylformamide (150 ml) and stirred at room temperature overnight. Additional t-butyldimethylsilyl chloride (4.7 g) is added and the reaction is stirred for another 30 minutes. The reaction is diluted with water (600 ml) and extracted with dichloromethane (3 x 300 ml). Dry the combined organic phases in magnesium sulfate and concentrate in vacuo to yield the title compound as an orange oil (17). g). TLC R £0.9 (10% methanol in ethyl acetate). Intermediate 48 5-bromo-8-t-butyldimethylsilyloxyquinoline N-bromosuccinimide (14 g) is added in one portion to a stirred solution of 8-t-butyldimethylsilyloxyquinoline (15 g) in chloroform at -40 ° C under a nitrogen atmosphere. The reaction is warmed to room temperature and then heated to reflux for 6 hours. Additional N-bro-osuccinimide (6 g) is added to the reaction at room temperature and stirring is continued for 3 days. The reaction mixture is poured into 5% aqueous sodium metabisulfite solution (300 ml) and extracted with chloroform (3 x 300 ml). The combined organic phases are dried over magnesium sulfate and concentrated in vacuo to yield the title compound as an orange oil (16.4 g). TLC R £ 0.8 (dichloromethane). Intermediate 49 5-bromo-8-hydroxyquinoline Tetrabutylammonium fluoride is added dropwise (54 ml, 1 M in tetrahydrofuran) was added to a stirred solution of 5-bromo-8-t-butyldimethylsilyloxyquinoline (16.3 g) in tetrahydrofuran (500 ml). After stirring for 10 minutes, the reaction is diluted with dichloromethane (500 ml) and extracted with water (3 x 200 ml). The organic phase is dried over magnesium sulfate and concentrated in vacuo. Purification by recrystallization from aqueous methanol yields the title compound as an off-white solid (7.7 g). TLC R £ 0.58 (10% methanol in dichloromethane). Example 1 8-Methoxyquinoline-5- [N- (pyridin-4-yl) J -carboxamide A suspension of 8-methoxyquinoline-5-carbonyl chloride hydrochloride (0.5 g) in dichloromethane (3 ml) is added to a solution of 4-aminopyridine (94 mg) and triethylamine (140 μl) in dichloromethane (3 ml) at 0 ° C under nitrogen. The reaction is stirred at room temperature during 16 hours and then diluted with dichloromethane. The organic solution is washed with saturated aqueous sodium hydrogen carbonate (20 ml), water (5 ml) and extract the aqueous layer with dichloromethane (25 ml). The organic extracts are combined and dried over magnesium sulfate, filtered and the filtrate evaporated in vacuo. The residue is purified by column chromatography on silica gel eluting with 15% methanol in dichloromethane to give the title compound as an off-white solid (130 mg). TLC R £ 0.4 (15% methanol in dichloromethane). P.f. 257-258 ° C The following examples are prepared from the 8-methoxyquinoline-5-carbonyl chloride, hydrochloride and the appropriate amine using a procedure similar to one described above. Example 2 8-methoxyquinoline-5- [N- (thiazol-2-yl) J -carboxamide The title compound is obtained as an off-white solid (80 mg). TLC R 0. 0.32 (10% methanol in ethyl acetate). P-f. 249-251 ° C.

Example 3 8-methoxyquinoline-5- [N-2- (trifluoromethoxy-phenyl) -carboxamide The title compound is obtained as an off-white solid (125 mg). TLC Rf 0.54 (10% methanol in ethyl acetate). P.f. 206-208 ° C. Example 4 8-methoxyquinoline-5- [N-2- (piperidin-1-yl) phenyl] carboxamide The title compound is obtained as an off-white solid (100 mg). TLC R £ 0.50 (10% methanol in dichloromethane). P.f. 214-216 ° C. Example 5 8-methoxyquinoline-5- [N- (2-fluoro-phenyl) -carboxamide The title compound is obtained as an off-white solid (90 mg). TLC R £ 0.41 (10% methanol in ethyl acetate). P.f. 190-192 ° C. Example 6 8-methoxyquinoline-5- [N- (2-methylphenyl)] carboxamide The title compound is obtained as an off-white solid (630 mg). TLC R £ 0.46 (10% methanol in dichloromethane). P.f. 215-216 ° C. Example 7 8-methoxyquinolin-5- [N- (2,6-dimethylphenyl) Jcarboxamide The title compound is obtained as an off-white solid (550 mg).

TLC Rf 0.43 (10% methanol in dichloromethane). P.f. 273-275 ° C. Example 8 8-methoxyquinoline-5- [N- (2-chlorophenyl)] carboxamide The title compound is obtained as an off-white solid (490 mg). TLC R £ 0.47 (5% methanol in dichloromethane). P.f. 196-197 ° C. Example 9 8-methoxyquinoline-5- [N- (2-methoxyphenyl) Jcarboxamide The title compound is obtained as an off-white solid (150 mg). TLC R £ 0.60 (10% methanol in dichloromethane). EXAMPLE 10 8-Methoxyquinoline-5- [N- (4-methoxyphenyl) J -carboxa-ida The title compound is obtained as an off-white solid (780 mg). Mass spectrum (El) 309 [M + H] + Example 11 8-methoxyquinoline-5- [N- (2-chloro-6-methylphenyl) Jcarboxamide The title compound is obtained as an off-white solid (700 mg). Mass Spectrum (El) 327 [M + H] + The following example of 8-methoxy-2-methylquinoline-5-carbonyl chloride hydrochloride and 2-chloroaniline is prepared using a similar procedure to that described above. Example 12 8-methoxy-2-methylquinoline-5- [N- (2 - chlorophenyl) Jcarboxamide Purification by flash chromatography on silica eluting with 50% ethyl acetate in dichloromethane afforded the title compound (50 mg) as a light brown solid. TLC R £ 0.4 (50% ethyl acetate in dichloromethane). p.f. 225-226 ° C. Example 13 8-methoxyquinoline-5- [N- (2, 5-dichloropyridin-3-yl) J -carboxamide A solution of 3-amino-2,5-dichloropyridine (504 mg) in anhydrous DMF (5 ml) is carefully added to a suspension of sodium hydride (272 mg, 60% dispersion in oil) in DMF anhydrous (5 ml) at room temperature under nitrogen. The resulting mixture is stirred for 10 minutes and then treated with drops of a solution of 8-methoxyquinoline-5-carbonyl chloride hydrochloride (800 mg) in anhydrous DMF. (10 ml). The reaction is stirred for two hours at 50 ° C and 18 hours at room temperature. The solvent is evaporated in vacuo and the residue is partitioned in dichloromethane (50 ml) and saturated aqueous sodium hydrogen carbonate solution (50 ml). The aqueous layer is extracted with dichloromethane (30 ml). The organic extracts are combined and washed with saturated aqueous sodium chloride (10 ml), dried over magnesium sulfate, filtered and the filtrate evaporated in vacuo. The waste is purified by column chromatography on silica gel eluting with 10% methanol in ethyl acetate to yield the title compound as an off-white solid (230 mg). TLC Rf 0.30 (10% methanol in ethyl acetate). P.f. 251-252 ° C. The following examples are prepared from 8-methoxyquinoline-5-carbonyl chloride hydrochloride and the appropriate amine using a procedure similar to one described above. Example 14 8-methoxyquinoline-5- [N- (pyridim-4-yl) J -carboxamide The title compound is obtained as an off-white solid (130 mg). TLC R £ 0.39 (15% methanol in ethyl acetate). P.f. 225-226 ° C. Example 15 8-methoxyquinoline-5- [N- (3,5-disloropyridin-2-yl)) Jcarboxamide The title compound is obtained as an off-white solid (89 mg). Example 16 8-methoxyquinoline-5- [N- (3,5-dichloropyridin-4-yl) J -carboxamide The title compound is obtained as an off-white solid (452 mg). TLC R £ 0.45 (10% methanol in dichloromethane). P.f. 258-260 ° C. Example 17 8-methoxyquinoline-5- [N- (4,6-dichloropyridimidin-5-) il) Jcarboxamide The title compound is obtained as a bone-colored solid (264 mg). TLC R £ 0.39 (10% methanol in ethyl acetate). P.f. 249-251 ° C. Example 18 8-methoxyquinoline-5- [N- (4-chloropyridin-4-yl) J -carboxamide The title compound is obtained as an off-white solid (40 mg). TLC R £ 0.35 (10% methanol in dichloromethane). P.f. 232-234 ° C. Example 19 8-methoxyquinoline-5- [N- (2-trifluoromethylphenyl) Jcarboxamide The title compound is obtained as an off-white solid (470 mg). TLC R 0. 0.50 (15% methanol in ethyl acetate). P.f. 247-248 ° C. Example 20 8-methoxyquinoline-5- [N- (3-bromo-5-methylpyridin-2-yl) J -carboxamide The title compound is obtained as an off-white solid (250 mg). TLC R £ 0.15 (3% methanol in dichloromethane). Example 21 8-methoxyquinoline-5- [N- (2-chloropyridin-3-yl) J -carboxamide The title compound is obtained as a solid bone color (60 mg). TLC R £ 0.15 (3% methanol in ethyl acetate). The following examples are prepared from 8-methoxy-2-methylquinoline-5-carbonyl chloride hydrochloride and the appropriate amine using a procedure similar to that described above. Example 22 8-methoxy-2-methylquinoline-5- [N- (3-chloropyridin-4-yl) J -carboxamide Purification by flash chromatography on silica eluting with 10% methanol in ethyl acetate yields the title compound (190 mg ) as a light yellow solid. TLC R 0. 0.35 (10% methanol in ethyl acetate). p.f. 222-223.5 ° C. Example 23 8-methoxy-2-methylquinoline-5- [N- (5-chloropyridimin-4-yl)] -carboxamide Purification by flash chromatography on silica eluting with 10% methanol in ethyl acetate and trituration with diethyl ether yield the title compound (110 mg) as a light yellow solid. TLC R £ 0.38 (10% methanol in ethyl acetate). p.f. 192-193.5 ° C. Example 23 8-methoxy-2-methylquinoline-5- [N- (3,4-dichloropyridin-4-yl) J -carboxamide The title compound is obtained as a pale yellow solid (20 mg).

TLC R £ 0.58 (5% methanol in ethyl acetate). P.f. 273-275 ° C (decomposition). The following examples are prepared from the appropriate quinolincarbonyl chloride hydrochloride and 4-amino-3, 5-dichloropyridine using a procedure similar to that described in Example 13. EXAMPLE 25 3-Ethyl-8-methoxyquinolin-5- (N- (3,5-dichloropyridin-4-yl) J-carboxamide The compound of title as a bone-colored solid (50 mg) TLC R £ 0.34 (5% methanol in dichloromethane) Mass spectrum (El) 376 [M + H] + Example 26 7-fluoro-8-methoxyquinoline-5- [N - (3,5-dichloropyridin-4-yl)] carboxamide The title compound is obtained as an off-white solid (210 mg) TLC R 0.48 (ethyl acetate) Mass spectrum (El) 366 [M + H ] EXAMPLE 27 2-Cyano-8-methoxyquinoline-5- [N- (3,5-dichloropyridin-4-yl) J -carboxamide The title compound is obtained as an off-white solid (72 mg) TLC R £ 0.48 ( ethyl acetate) Mass spectrum (El) 373 [M + H] + Example 28 2-ethyl-8-methoxyquinoline-5- [N- (3,5-dichloropyridin-4-) il) carboxamide Purification is carried out through chromatography eluting with ethyl acetate to yield the title compound as a peach-colored solid (0.14 g). TLC R £ 0.35 (ethyl acetate) m.p. 256-257.5 ° C Example 29 8-difluoromethoxyquinoline-5- [N- (3,5-dichloropyridin-4-ylcarboxamide) The title compound is obtained as a white solid (530 mg) TLC R £ 0.25 (ethyl acetate 50% in hexane) mp 200-202 ° C Example 30 8-methoxy-2- (3-pyridyl) quinoline-5- [N- (3,5-dichloropyridin-4-yl) J -carboxamide Purification by flash chromatography on silica, eluting with 10% methanol in ethyl acetate afforded the title compound (175 mg) as a white powder, TLC R £ 0.4 (10% methanol in ethyl acetate), mp 258-259 ° C. 8-methoxy-2- (trifluoromethyl) quinoline-5- [N- (3,5-dichloropyridin-4-yl) J -carboxamide The title compound (0.94 g) is obtained as a white solid, mp 254-255 ° C. TLC Rf 0.24 (50% ethyl acetate in hexane).

Example 32 8-hydroxyquinoline-5- [N- (3,5-dichloropyridin-4-yl) J -carboxamide Sodium hydride (1.6 g, 60% dispersion in oil) is washed with diethyl ether under nitrogen and dried in vacuo. The anhydrous N, -dimethylformamide (20 ml) is added, followed by careful addition of a solution of ethanethiol (3 ml) in PMF (3 ml). A solution of 8-methoxyquinoline-5- [N- (3,4-dichloropyridin-4-yl)] carboxamide (100 mg) in DMF (5 ml) is added to the mixture and the reaction is refluxed for 1.5 hours . The solvent is removed in vacuo and the residue is partitioned between saturated aqueous ammonium chloride solution (50 ml) and dichloromethane (50 ml). The aqueous phase is re-extracted with dichloromethane (75 m) and the organic extracts are combined. The organic phase is dried over magnesium sulfate, filtered and the filtrate is evaporated in vacuo. The residue is partitioned between dichloromethane (20 ml) and 0.5 M aqueous sodium hydroxide solution. The aqueous phase is separated and pH 4/5 is acidified with glacial acetic acid. The precipitate is collected by filtration and dried in vacuo to yield the title compound as an off-white solid (20 mg). Mass Spectrum (El) 334 [M] + Example 33 8-methoxyquinoline-5- [N- (3,5-dichloropyridin-4-yl) Jcarboxamide dihydrochloride, A solution of 8-methoxyquinoline-5- [N] - (3,4-dichloropyridin-4-yl)] - carboxamide (114 mg) in methanol (50 ml) with acid chloride gas for 5 minutes at 25 ° C. The solution is evaporated in vacuo to yield the title compound as an off-white solid (138 mg). Calculated Elemental Analysis 45.64% C 3.11% H 9.98% N Observed 44.51% C 3.09% H 9.67% N Example 4 8-Methoxyquinoline-5- [N- (3,5-dichloropyridin-4-yl) Jcarboxamide, dibromohydrate Carefully treated Cool methanol (50 ml) with acetyl bromide (0.25 ml) and stir the mixture below 5 ° C for 30 minutes. The solution is allowed to warm to room temperature and 8-methoxyquinoline-5- [N- (3,4-dichloropyridin-4-yl)] carboxamide (105 mg) is added. After 30 minutes the solution is evaporated in vacuo to yield the title compound as an off-white solid (148 mg). EXAMPLE 35 5- [8-Methoxy-5- [N- (3,5-dichloropyridin-4-yl) J-aminocarbonylquinolin-2-yl] -2H-tetrazole dichlorohydrate salt Acid chloride (0.6 ml, 1M in diethyl ether) to a stirred suspension of 5- [8-methoxy-5- [N- (3,5-dichloroiridin-4-yl)] aminocarbonylquinolin-2-yl] -2 -trimethyltin-2H-tetrazole (150 mg) in tetrahydrofuran (10 ml) at room temperature under an inert atmosphere with immediate dissolution observed. The reaction is stirred at room temperature for 90 minutes and the resulting precipitate is filtered off, washed with diethyl ether and dried in vacuo at 40 ° C. to produce the title compound as a white solid (92 mg). P.f. 242-244 ° C. Mass spectrum (El) 416 [M + H] + free base Example 36 5- [8-methoxy-5- [N- (3,5-dichloropyridin-4-yl)] aminocarbonylquinolin-2-yl] -2- methyltetrazole and 5- [8-methoxy-5- [N- (3,5-dichloropyridin-4-yl)] - aminocarbonylquinolin-2-yl] -l-methyltetrazole Dissolves 5- [8-methoxy-5- [N - (3,5-dichloropyridin-4-yl)] aminocarbonylquinolin-2-yl] -2-trimethylstannyl-2H-tetrazole (153 mg) and iodomethane (1.0 ml) in methanol (2.5 ml) and stirred under an inert atmosphere at room temperature for 5 days. The solvent is removed in vacuo and the resulting solid is suspended in diethyl ether, filtered and washed with diethyl ether (3 x 0 ml). Purification by column chromatography eluting with 5% methanol produces a 7: 1 mixture of the title compounds respectively as a white solid (55 mg). TLC R £ 0.71 (10% methanol in dichloromethane). P.f. 273-275 ° C. EXAMPLE 37 2-Acetyl-8-methoxy-quinoline-5- [N- (3,5-dichloropyridin-4-yl) J -carboxamide Methylmagnesium bromide (0.6 ml, 3.0 M in diethyl ether) is added dropwise to a stirred solution of 2 ml. -cyano-8-methoxyquinoline-5- [N- (3,5-dichloropyridin-4-yl) J -carboxamide (300 mg) in tetrahydrofuran 820 ml) at room temperature under a inert atmosphere. The reaction is stirred at room temperature for 1 hour then it is poured into brine (25 ml) and extracted with ethyl acetate (4 x 25 ml). The combined organic phases are dried over magnesium sulfate and concentrated in vacuo. Purification of column chromatography eluting with 5% methanol in dichloromethane affords the title compound as a light yellow solid (180 mg). TLC R £ 0.42 (ethyl acetate). P.f. 257-259 ° C. EXAMPLE 38 2- (1-Methoxyiminoethyl) -8-methoxyquinoline-5- [N- (3,5-dichloropyridin-4-yl) J -carboxamide: It is refluxed with 2-acetyl-8-methoxyquinoline-5- [N- (3 , 5-dichloropyridin-4-yl) Jcarboxamide (100 mg), ethoxylamine hydrochloride (75 mg) and pyridine (0.12 ml) in toluene (50 ml) under Dean Stark conditions for 3 days. The cold reaction mixture is evaporated to dryness in vacuo and passed through a silica column, eluting with 66% ethyl acetate in hexane to yield the title compound as a white solid (820 mg). TLC R £ 0.29 (66% ethyl acetate in hexane). P.f. 273-275 ° C. Example 39 2- (1-hydroxyethyl) -8-methoxyquinoline-5- [N- (3,5-dichloropyridin-4-yl) J -carboxamide Sodium borohydride (50 mg) is added to a stirred solution of 2-acetyl-8 -methoxyquinoline-5- [N- (3, 5-dichloropyridin- 4-yl) J -carboxamide (180 mg) in methanol (10 ml) at room temperature. The reaction is stirred for 90 minutes, stopped with water (drops) and the methanol is removed in vacuo. The residue was partitioned between ethyl acetate (4 x 20 ml) and water (10 ml). The combined organic phases are dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography eluting with 4% methanol in dichloromethane afforded the title compound as an orange solid (68 mg). TLC R £ 0.28 (10% methanol in dichloromethane). P.f. 252-254 ° C. Example 40 2 - [(t-Butyloxycarbonyl) - (methyl) amino] -8-methoxyquinoline-5- [N- (3,5-dichloropyrid-4-yl) J -carboxamide 4-amino-3,5-dichloropyridine is combined (138 mg) and dimethylformamide (10 ml) under an atmosphere of nitrogen at room temperature. Sodium hydride (60% dispersion in oil) is added (51 mg) and stirring is continued for 3 hours. Then 2 - [(t-butyloxycarbonyl) (methyl) amino] -8-methoxyquinoline-5-nitrophenylcarboxylate (384 mg) is added as a solution in dimethylformamide (10 ml) and stirring is continued for 16 hours . The reaction mixture is evaporated in vacuo on silica and purified by flash chromatography to give the title compound (217 mg) as a white solid. TLC Rf 0.20 (50% ethyl acetate in hexane) P.f. 184-186 ° C The following example is prepared in a similar manner using the appropriate starting materials. Example 41 8-difluoromethoxyquinoline-5- [N- (3,5-dichloropyridin-4-yl) J -carboxamide Purification by column chromatography eluting with 5% methanol in dichloromethane and trituration with ethyl acetate affords the title compound as a white solid (0.3 g). TLC R £ 0.24 (5% methanol in dichloromethane) M.p. 210-212 ° C. Example 42 2- (N-methyl) amino-8-methoxyquinoline-5- [N- (3, 5-dichloropyrid-4-yl) Jcarboxamide Combine 2- [(t-butyloxycarbonyl) (methyl) aminoj-8-methoxyquinoline-5- tN- (3,5-dichloropyrid-4-yl) J -carboxamide (195 mg) , dichloromethane (10 ml) and trifluoroacetic acid (6 ml) and stirred at room temperature for 5 hours. The solvents are removed in vacuo and the residue is partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. Extraction is carried out with dichloromethane (3 x 20 ml) which is then evaporated in vacuo on silica and purified by flash chromatography to give the title compound (108 mg) as a white solid. TLC R £ 0.30 (2% ammonium hydroxide in ethyl acetate) P.f. 271-272 ° C Example 43 2- [(pyridin-2-yl) carbonyl] -8-methoxyquinoline-5- [N- (3,5-dichloropyridin-4-yl) J -carboxamide n-Butyllithium is added in drops (0.87 ml, 1.6 M in hexanes), to a stirred solution of 2-bromopyridine (0.11 ml) in tetrahydrofuran (2 ml) at -78 ° C under an inert atmosphere.

After stirring at this temperature for 45 minutes, 2-cyano-8-methoxyquinoline-5- [N- (3,5-dichloropyridin-4-yl) J -carboxamide (0.2 g) in tetrahydrofuran (10 ml) is added dropwise. the reaction is allowed to warm to room temperature. After stirring at room temperature for 1 hour, the reaction is concentrated in vacuo. The residue is partitioned in water (45 ml) and dichloromethane (3 x 45 ml). The combined organic phases are dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography eluting with 0.5% triethylamine and 4.5% methanol in dichloromethane yield the title compound as a light orange solid (0.54 mg). TLC R £ 0.23 (0.5% triethylamine / 4.5% methanol in dichloromethane) m.p. 185-187 ° C. Test Methods The assays used to confirm the phosphodiesterase IV inhibitory activity of the compounds of the formula (i) are standard assay procedures as described by Schilling et al., Anal. Biochm. 2_JL * 154 (1994), Thompson and Strada, Adv. Cycl. Nucí Res. £. 119 (1979) and Grist Ood and Owen, Br., J. Pharmacol. £ 7: 91P (1986). The compounds of the formula (i) have activity exhibited at levels consistent with those believed to be useful in the treatment of disease states related to phosphodiesterase IV in those assays. The ability of the compounds of the formula (i) to inhibit the production of TNF in human peripheral blood mononuclear cells (PBMC) is measured as follows. PBMCs from freshly taken blood or "Buffy coatings" are prepared by standard procedures. The cells are plated in 1% fetal calf serum + RPMI1640 in the presence and absence of inhibitors. LPS (100 ng / ml) is added and the cultures are incubated for 22 hours at 37 ° C in a 95% air / 5% C02 atmosphere. The supernatants for TNFa are tested by ELISA using commercially available equipment. In vivo activity is determined in a model of skin eosinophilia using the methods described in Helle ell et al., Br. J. Pharmacol 111: 811 (1994) and Br. J. Pharmacol. JL Q.416 (1993). The activity of a lung model is measured using the procedures described by Rallos and Rallos, Int. Archs. Allergy Appl: Immunol. 71:77 (1984), and Sanjar et al., Br. J. Pharmacol 12: 679 (1990). An additional lung model is described, which allows the measurement of the inhibition of the early and late phase asthmatic response and also the inhibition of airway hyperreactivity, by Broadley et al., Pulmonary Pharmacol. UL_: 2351 (1995). The compounds of the invention show activity in this model. LPS abbreviations Lipopolysaccharide (endotoxin) ELISA Enzyme-linked immunosorbent assay

Claims

1. A compound of the general formula (i) characterized in that X is CO or CS; R is H, halogen or alkyl; R-L represents OH, alkoxy optionally substituted with one or more halogens, or thioalkyl; R2, R3 and R4 are the same or different and each are H, R7, 0RU, COR7 / C (= NOR7) R7, alkyl-C (= NOR7) R7, halogen, CF3, alkyl-C (= NOH) R7 , C (= NOH) R7, C (= NOH) R7 / CN, C02H, C02R11, CONH2, CONHR7, CON (R7) 2lNR9R10 or CONR12R13 wherein NR12R13 is a heterocyclic ring (such as morpholine or piperidine) optionally substituted with one or more R15; R. represents H, arylalkyl, heteroarylalkyl, heterocycloalkyl, SiO) ^^ or alkyl optionally substituted with one or more substituents selected from hydroxy, alkoxy, C02Rβ, S02NR12R13, CONR12R13, CN, carbonyl acid, NR9R10, CORn and S (0) nRu , R6 represents aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl or heterocycloalkyl; in R5 and / or R6, the aryl / heteroaryl / heterocycle moiety is optionally substituted with one or more alkyl substituents R14 or R14; R7 represents R optionally substituted at any position with (one or more) R16; R8 represents H, alkyl, cycloalkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl; R9 represents H, aryl, heteroaryl, heterocycle, cycloalkyl, alkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl, alkylcarbonyl, alkoxycarbonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclecarbonyl or alkylsulfonyl; R 10 represents H, aryl, heteroaryl, heterocycle, alkyl, cycloalkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl; R1L represents alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl or heterocycloalkyl; R12 and R13 are the same or different and each are H or Rllf or NR12R13 represents a heterocyclic ring as defined above; R 14 represents alkyl (optionally substituted by one or more halogens), cycloalkyl, aryl, heteroaryl, heterocycle, hydroxy, alkoxy (optionally substituted by one or more halogens), thioalkyl, aryloxy, heteroaryloxy, heterocycloyoxy, aryalkyloxy, heteroarylalkyloxy, heterocycloalkyloxy, C02R8, CONR12R13, S02NR12R13, halogen, -CN, -NR9R10, CORu, S (0) nR, or (where appropriate) carboxyl; R 15 represents alkyl, arylalkyl or heteroarylalkyl; R16 represents alkyl, OH, 0R, NR9R10, CN, C02H, C02R, CONR12R13 or C0R1X, m represents 1-2; and n represents 0-2; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, characterized in that R is H or halogen.

3. The compound according to claim 1 or 2, characterized in that Rx is alkoxy optionally substituted with one or more halogens.

4. The compound according to any of the preceding claims, characterized in that R2, R3, R4 are the same or different and each represents H, CF3, COR7, C (= NOR7) R7, C (= N0H) R7, CN , R7, C-alkyl (= NOH) R7 or C-alkyl (= NOR7) R7.

5. The compound according to any preceding claim, characterized in that R5 is H or alkyl.

6. The compound in accordance with any claim 6, characterized in that R6 is aryl or heteroaryl in which the aryl and heteroaryl portions may be optionally substituted with one or more alkyl substituents -R14 or R14.

7. The compound in accordance with the claim 1, characterized in that R is H; R x is optionally substituted alkoxy; R2, R3 and R4 are independently R17 or alkyl-R17; R7 is H, OH, alkoxy, aryloxy, heteroaryloxy, heterocycloyoxy, arylalkoxy, heteroarylalkoxy heterocycloalkoxy, alkylamino, CF3 or COR, R8 is H, alkyl, arialkyl, heteroarylalkyl or heterocycloalkyl; R9 is not cycloalkyl; R10 is not cycloalkyl; Rlx is not cycloalkyl; and R14 is not alkyl, thioalkyl or cycloalkyl.

8. The compound according to claim 1, characterized in that it is 8-methoxyquinoline-5- [N- (pyridin-4-yl) J -carboxamide.

9. The compound according to claim 1, characterized in that it is 8-methoxyquinoline-5 [N- (thiazol-2-yl) Jcarboxamide 8-methoxyquinoline-5 [N- (2- trifluoromethoxyphenyl) Jcarboxamide 8-methoxyquinoline-5 [N-2- (piperidin-1-yl) phenylj-carboxamide 8-methoxyquinoline-5 [N- (2-fluorophenyl) Jcarboxamide 8-methoxyquinoline-5 [N- (2-methylphenyl)] Jcarboxamide 8-methoxyquinoline-5 [N- (2,6-dimethylphenyl) Jcarboxamide 8-methoxyquinoline-5 [N- (2-chlorophenyl) Jcarboxamide 8-methoxyquinoline-5 [N- (2-methoxyphenyl) Jcarboxamide 8-methoxyquinoline-5 [N- (4-methoxyphenyl)] carboxamic | at 8-methoxyquinoline-5 [N- (2-chloro-6-methylphenyl) Jcarboxamide 8-methoxy-2-methylquinoline-5- [N- (2-chlorophenyl) Jcarboxamide 8-methoxyquinoline-5- [N- (2, 5-dichloropyridin-3- il) Jcarboxamide 8-methoxyquinoline-5- [N- (pyrimidin-4-yl) J -carboxamide 8-methoxyquinoline-5- [N- (3,5-dichloropyridin-2-yl) Jcarboxamide 8-methoxyquinoline-5- [N- (3,5-dichloropyridin-4-yl) Jcarboxamide 8-methoxyquinoline-5- [N - (4,6-dichloropyrimidin-5-yl) Jcarboxamide 8-methoxyquinoline-5- [N- (4-chloropyridin-4-yl) Jcarboxamide 8-methoxyquinoline-5- [N- (2- trifluoromethylphenyl) Jcarboxamide 8-methoxyquinoline-5- [N- (3-bromo-5-methylpyridin-2-yl) Jcarboxamide 8-methoxyquinoline-5- [N- (2-chloropyridin-3-yl) J -carboxamide 8-methoxy-2 -methylquinoline-5- [N- (3-chloropyridin- -i1) Jcarboxamide 8-methoxy-2-methylquinoline-5- [N- (5-chloropyrimidin-4-yl) Jcarboxamide 8-methoxy-2-methylquinoline-5- [N- (3,5-dichloropyridin-4-yl) J -carboxamide 3-ethyl-8-methoxy-quinoline-5- [N- (3,5-dichloropyridin-4-yl) J -carboxamide 7-fluoro-8-methoxy-quinoline-5- [N- (3,5-dichloropyridin-4-yl) J -carboxamide 2-cyano-8-methoxy-quinoline-5- [N- (3,5-dichloropyridin-4-yl) J -carboxamide 2-ethyl-8-methoxy-quinoline-5- [N- (3,5-dichloropyridin-4-yl) carboxamide 8-difluoromethoxyquinoline-5- [N- (3,5-dichloropyridin-4-ylcarboxamide 8-methoxy-2- (3-pyridyl) quinoline- 5- [ N- (3,5-dichloropyridin-4-yl) Jcarboxamide 8-methoxy-2- (trifluoromethyl) quinoline-5- [N- (3,5-dichloropyridin-4-yl) J -carboxamide 8-hydroxyquinoline-5- [N- (3,5-dichloropyridin-4-yl) Jcarboxamide 8-methoxyquinoline-5- [N- (3,5-dichloropyridin-4-yl) J -carboxamide, dihydrochloride 8-methoxyquinoline-5- [N- (3,5-dichloropyridin-4-yl) J -carboxamide, dibromhydrate 5- [8-methoxy-5- [N- (3,5-dichloropyridin-4-yl)] -aminocarbonylquinoline-2-i1J dihydrochloride -2H-tetrazole 5- [8-methoxy-5- [N- (3,5-dichloropyridin-4-yl) J-aminocarbonyl-quinolin-2-yl-2-methyltetrazole 5- [8-methoxy-5- [ N- (3,5-dichloropyridin-4-yl)] - aminocarbonylquinolin-2-yl-1-methyltetrazole 2 -acetyl-8-methoxyquinoline-5- [N- (3,5-dichloropyridin-4-yl) J- carboxamide 2- (1-methoxyiminomethyl) -8-methoxyquinoline-5- [N- (3,5-dichloropyridin-4-yl) Jcarboxamide 2- (1-hydroxyethyl) -8-methoxyquinoline-5- [N- (3, 5-dichloropyridin-4-yl) Jcarboxamide 2- [(t-butyloxycarbonyl) - (methyl) aminoJ-8-methoxyquinoline-5- [N- (3,5-dichloropyrid-4-yl) Jcarboxamide 8-difluoromethoxyquinoline-5- [N- (3, 5-dichloropyrid-4-yl) Jcarboxamide 2- (N-methyl) l) amino-8-methoxyquinoline-5- [N- (3,5-dichloropyrid-4-yl) Jcarboxamide 2- [(pyridin-2-yl) carbonyl] -8-methoxyquinoline-5- [N-] (3, 5-dichloropyridin-4-yl) Jcarboxamide

10. The compound according to any preceding claim, characterized in that it is in the form of an enantiomer or mixture of enantiomers.

11. A pharmaceutical composition for therapeutic use characterized in that it comprises a compound of any preceding claim and a pharmaceutically acceptable carrier or excipient. The use of a compound according to any preceding claim 1 to 10, for the manufacture of a medicament for use in the treatment of a disease state capable of being modulated by inhibition of phosphodiesterase IV or Tumor Necrosis Factor. 13. The use according to claim 12, characterized in that the disease state is a pathological condition associated with a phosphodiesterase IV function, eosinophil accumulation or an eosinophil function. 14. The use according to claim 13, characterized in that the pathological condition is selected from asthma, chronic bronchitis, chronic obstructive airway disease, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eye inflammation, responses allergic to the eye, eosinophilic granuloma, psoriasis, rheumatoid arthritis, arthritis due to gout and other arthritic conditions, ulcerative colitis, disease of Crohn, syndrome of respiratory insufficiency in adults, diabetes insipidus, keratosis, atopic eczema, atopic dermatitis, cerebral senility, multiinfarct dementia, senile dementia, memory damage associated with Parkinson's disease, depression, heart attack, infarction and intermittent claudication. 15. The use according to claim 13, characterized in that the pathological condition is selected from chronic bronchitis, allergic rhinitis, and adult respiratory distress syndrome. 16. The use according to claim 12, characterized in that the disease state is an inflammatory disease or autoimmune disease. 17. The use according to claim 16, characterized in that the disease state is an inflammatory disease or autoimmune disease. 18. The use according to claim 17, characterized in that the disease state is selected from joint inflammation, arthritis, rheumatoid arthritis, rheumatoid spondylitis and osteoarthritis, septic shock, sepsis, endotoxic shock, gram negative sepsis, toxic shock syndrome. , water respiratory insufficiency syndrome, cerebral malaria, chronic pulmonary inflammatory disease, pulmonary sarcoidosis, asthma, bone resorption diseases, reperfusion injury, graft versus host reaction, allograft rejection, malaria, myalgia, HIV, AIDS, ARC, cachexia, Crohn's disease, ulcerative colitis, pyresis, systemic lupus erythematosus, multiple sclerosis, diabetes mellitus type 1, psoriasis, Bechet's disease, anaphylactoid purple nephritis, chronic glomerulonephritis, Inflammatory disease of the large intestine and leukemia. 19. The use according to claim 14 or claim 18, characterized in that the pathological condition or disease state is asthma. 20. The use according to claim 18, characterized in that the disease state is acute respiratory distress syndrome, pulmonary inflammatory disease or pulmonary sarcoidosis. 21. The use according to claim 18, characterized in that the disease state is joint inflammation. 22. The use according to claim 13 or claim 17, characterized in that the disease state is a disease or condition of the brain, such as brain trauma, infarction, ischemia, Huntindgon's disease, or tardive dyskinesia. 23. The use according to claim 16, characterized in that the disease state is yeast or fungal infection. 24. Use in accordance with any of the claims 1 to 10, characterized by the manufacture of a medicament for use in gastric protection. 25. The use of a compound according to claims 1 to 10, characterized in that the manufacture of a medicament is for the use of an anti-pegy or anti-hyperalgesic analgesic in the treatment of neurogenic inflammatory disease, associated with irritation and pain. 26. The use of a compound according to any of claims 1 to 10, in co-administration with another drug such as bronchodilator, steroid or xanthine, for asthma therapy. SUMMARY OF THE INVENTION A compound of the general formula (i) is described, , where X is CO or CS; R is H, halogen or alkyl; R x represents OH, alkoxy optionally substituted with one or more halogens, or thioalkyl; R2, R3 and R4 are the same or different and each are H, R7, 0Rllf COR7, C (= NOR7) R7, alkyl-C (= NOR7) R7, halogen, CF3, alkyl-C (= NOH) R7, C (= NOH) R7, C (= NOH) R7, CN, C02H, C02R11, CONH2, CONHR7, CON (R7) 2, NR9R10 or CONR12R13 wherein NR12R13 is a heterocyclic ring optionally substituted with one or more R15; R5 represents H, arylalkyl, heteroarylalkyl, heterocycloalkyl, SIOOH, or alkyl optionally substituted with one or more substituents selected from hydroxy, alkoxy, C02R8, S02NR12R13, CONR12R13, CN, carboxyl, NR9R10, COR1x, and SIO3, R6 represents aryl , heteroaryl, heterocycle, arylalkyl, heteroarylalkyl or heterocycloalkyl; in R. and / or Rc the aryl / heteroaryl / heterocycle moiety is optionally substituted with one or more alkyl substituents R14 or R14. The compounds can be used to treat disease, for example disease states associated with proteins that mediate cellular activity, for example, by inhibiting tumor necrosis factor, and / or by inhibiting phosphodiesterase IV.