MXPA98004466A - Carboxamidas and sulfonamidas de benzofur - Google Patents

Abstract

The benzofuran carbons and sulphonamides have therapeutic utility, for example, in the treatment of inflammation and asthma, by virtue of their ability to inhibit phosphodiesterase and tumor necrosis factor.

Description

CARBOXAMIDES AND SULFONE BENZOFURAN IDAS DESCRIPTION OF THE INVENTION The present invention relates to novel carboxamides and sulfonamides of benzofuran, and their formulation and use as pharmaceuticals. EP-A-0187387 describes benzofuransulfonamides having reductive aldose, platelet aggregation and inhibitory activity of arachidonic acid metabolism. US-A-4910193 discloses benzofuransulfonamides, in which the sulfonamide nitrogen is replaced by a variety of bridged saturated ring systems, as suitable drugs for the treatment of serotonin-induced gastrointestinal disorders. EP-A-0637586 describes benzofuran derivatives, including 4 -carboxamides, as inhibitors of acetylcholine esterases. O-A-408962 describes benzofuran analogs as fibrinogen receptor antagonists. O-A-9403427 describes benzofuran-2-carboxamides, with a substituent selected from hydroxy, acyloxy, alkoxy, optionally aminoalkoxy substituted with alkyl, alkylsulfonylamino, optionally aminoalkylsulfonyl substituted with alkyl or arylsulfonylamino, as a remedy for osteoporosis. EP-A0685475 describes benzofuran-2-carboxamides as anti-inflammatory agents. O-A-9603399 describes dihydrobenzofuran-4-carboxamides as inhibitors of phosphodiesterases. Phosphodiesterases (FDE) and tumor necrosis factor (TNF), their modes of action and the therapeutic utilities of inhibitors thereof are described in WO-A-9636595, WO-A-9636596 and WO-A-9636611 , the contents of which are incorporated herein for reference. The same documents describe sulfonamides which have utility as inhibitors of FDE and FDE. 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 mediate 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 Z is S02, CO or CS; R-L represents alkoxy optionally substituted with one or more halogens, OH or tialkyl; R2 and R3 are the same or different and are each H, Rβ, COR6, C (= NORu) R6, CN, C02H, CO2R10, CONH2, CONHRβ or CON (R6) 2; R 4 represents H, arylalkyl, heteroarylalkyl, S (O) mR 10 or alkyl optionally substituted with one or more substituents selected from hydroxy, alkoxy, C02R7, S02NR..R12, C0NRX1R12CN, carbonyl oxygen, NRBR9, COR10 and S (O) nR10; R5 represents aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl or heterocycloalkyl; In R4 and / or R5, the aryl / heteroaryl / heterocycle moiety is optionally substituted with one or more alkyl substituents -R13 or R13; R6 represents R10 optionally substituted at any position with (one or more) R14; R7 represents H, alkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl; R8 represents H, aryl, heteroaryl, heterocycle, alkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl, alkylcarbonyl, alkoxycarbonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclecarbonyl or alkylsulfonyl; R10 represents alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl or heterocycloalkyl; R9, R1X and R12 are the same or different, and are each H or R10; R 13 represents alkyl or alkoxy optionally substituted by halogen, aryl, heteroaryl, heterocycle, hydroxy, aryloxy, heteroaryloxy, heterocycloxy, arylalkyloxy, heteroarylalkyloxy, heterocycloalkyloxy, C02R7, CONRnR12, halogen, -CN, -NR8R9, COR10, S (O) nR10, Oxygen carbonyl; R14 represents OH, OR10, carbonyl oxygen, NRßR9, CN, C02H, CO2R10, CONR.xR12 or COR10; m represents 1-2; and n represents 0-2; and pharmaceutically acceptable salts. Combinations of substituents and / or variables are only permissible if such combinations result in stable compounds. Pharmaceutically suitable salts are pharmaceutically acceptable base salts and pharmaceutically acceptable acid addition salts. Certain of the compounds of the formula (i) which contain an acid group form base salts. Suitable pharmaceutically acceptable base salts include metal salts, salts such as alkali metal salts for example sodium salts, or salts of organic amines such as those provided with ethylenediamine. Certain of the compounds of the formula (i) which contain an amino group form the 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, metansulfate, 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 is extended 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) may give rise to stereoisomers, and in each case it is understood that the invention extends to all such stereoisomers, including enantiomers, and diastereomers and mixtures thereof. they include racemic mixtures thereof. When used herein the term "alkyl" whether used alone or when used as a part of another group includes straight or branched chain alkyl groups containing up to 6 atoms. "Alkoxy" means an alkyl-O-group in which the alky group is as previously described. Aryloxy means an aryl -O- group in which the aryl group is as defined below. Heteroaryloxy means a heteroaryl-O- group and heterocycloxy means a heterocycle-0- group in which the heteroaryl group and heterocycle are as previously defined. Arylalkyloxy means an aryl-alkyl-0- group. Heteroarylalkyloxy means a heteroaryl-alkyl-0 group and heterocycloalkyloxy means a heterocycle-alkyl-0- group. "Aryloxyalkyl" means an aryl-0-alkyl, heteroaryloxyalkyl group means a heteroaryl-O-alkyl and heterocyclooxyalkyl group means a heterocycle-O-alkyl 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 group are defined later). "Thioalkyl" means an alkyl-S group. Cycloalkyl includes a non-aromatic cyclic or multicyclic ring system of about 3 to 10 carbon atoms. The cyclic alkyl may optionally be partially unsaturated. Aryl indicates carbocyclic radicals containing about 6 to 10 carbon atoms. Arylalkyl means an aryl-alkyl group wherein the aryl and alkyl are as described herein. "Heteroarylalkyl" means a heteroaryl-alkyl 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- and heterocyclecarbonyl group 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 heterocycle-S02 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. Carbonyl oxygen means a group -CO-. It will be appreciated that an oxygen carbonyl can not be a substituent on the ring aryl or heteroaryl. The carbocyclic ring means a monocyclic or multicyclic ring system of about 5 to 10 which may be saturated or partially unsaturated. The 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 an element different from the carbon chosen from between atoms 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. "Heterocycle" means a saturated or partially saturated 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 different element to the carbon chosen from nitrogen, oxygen or sulfur. 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 or disease mediated by TNF" means any of the disease states in which the TNF plays a role, either by the production of TNF by itself, or because the TNF causes another cytokine to be released, such as but not limited to IL-1 or IL-6. A disease state in which II -1, for example, is a major component, and whose production or action is aggravated or secreted in response to TNF, can therefore be considered a disease state mediated by FNT. As FNT-ß (also known as lymphotoxin) has a close structural homology with TNF-a (also known as cachectin), and since each induces similar biological responses and links to the same cellular receptor, both TNF-a and FNT- β are inhibited by compounds of the present invention and thus are referred to herein to be collectively referred to as "FNT" unless otherwise specifically indicated. This invention relates to a method for mediating or inhibiting the enzymatic activity or catalytic activity of FDE IV in a mammal in need thereof and for inhibiting the production of TNF in a mammal in need thereof, which comprises administering to the mammal an amount effective of a compound of the 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, atopic dermatitis, atopic eczema, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eye inflammation, allergic responses in the eye, eosinophilic granuloma, psoriasis, Bechet's disease, erythematosis, anaphylactoid 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, reperfusion damage of the myocardium and brain, 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 (Alzheimer's disease), memory impairment associated with Parkinson's disease, depression and multi dementia. heart attack. FDE IV inhibitors are also useful under conditions improved by neuroprotective activity, such as cardiac arrest, infarction and intermittent claudication. Additionally, FED 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 group of viruses, such as, but are not limited to,, Herpes zoster and Herpes simplex. This invention relates more specifically to a method of treating a mammal, afflicted with a human immunodeficiency virus (HIV), which comprises administering to said mammal an effective TNF inhibitory amount of a compound of Formula (i) or a pharmaceutically acceptable salt thereof. 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. Diseases mediated by TNF for treatment, therapeutically or prophylactically, in animals include disease states such as those 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 and other slow viruses. The compounds of this invention are also useful in the treatment of parasites, yeasts and fungal infections, where such yeasts and fungi are sensitive to up-regulation by TNF or will cause the production of TNF in vivo. A preferred disease state for treatment is fungal meningitis. The compounds of the invention can also suppress neurogenic inflammation through the elevation of cAMP in sensory neurons. They are, therefore, analgesic, anti-cough and anti hyperalgesic in inflammatory diseases associated with irritation and pain. The compounds of the formula (i) are preferably in a pharmaceutically acceptable form. By pharmaceutically acceptable form is intended, inter alia, a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including materials considered non-toxic at normal dose levels. A pharmaceutically acceptable level of purity will generally be at least 50% excluding normal pharmaceutical additives, preferably 75%, more preferably 90% and still more preferably 95%. The invention further provides a process for the preparation of a compound of the formula (i), wherein Rx etc, m and n are as defined above. It will be appreciated that functional groups such as the amino, hydroxyl or carboxyl groups present in the various compounds described below, and which it is desired to retain, may need to be in protected form before any reaction is initiated. In such cases, the removal of the protecting group may be in the final stage in a particular reaction. Protective 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 the compounds of the formula (i) in which R4 contains an -OH comprises deprotecting (eg by hydrogenolysis or hydrolysis) a compound of the formula (i) in which R4 contains -OP appropriate in where P represents a suitable protecting group (e.g., benzyl). 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 homochiral starting material appropriate. A process for the preparation of a compound of the formula (i) wherein Z is S02 comprises the reaction of an appropriate sulfonyl chloride of the formula (ii) with a suitable amine of the formula (iii) wherein R14 represents Rx as defined in relation to formula (i) or a group convertible to R? and R2a-R5a represent similarly R2-R5 or groups convertible to R2-R5 respectively; and after this, if required, convert any group Rla to Rx and / or R2a to R2 and / or R3a to R3 and / or R4a to R4 and / or R5a to Rs- The reaction of the sulfonyl chloride of the formula (ii) with an amine of the formula (iii) can be carried out under any suitable conditions known to those skilled in the art. Favorably, the reaction is carried out in the presence of a suitable base, for example an amine such as triethylamine, preferably in an appropriate solvent such as dichloromethane. In some cases a stronger base, such as sodium hydride, and a polar solvent such as dimethylformamide will be required. The sulfonyl chlorides of the formula (ii) and amines (iii) are either commercially available, previously mentioned compounds or are prepared using standard procedures known to those skilled in the art. Some of the amines of the formula (iii) are conveniently prepared by reductive amination of a suitable carbonyl compound with a suitable amine. This amination can be carried out under any suitable standard methods known to those skilled in the art. For example, a sulfonyl chloride of the formula (iii) is conveniently prepared from an appropriate sulfonic acid (iv) by treatment with a suitable agent such as thionyl chloride or oxalyl chloride. Alternatively, a sulfonyl chloride of the formula (ii) can be prepared by sulfonation of an appropriate benzofuran of the formula (v) with a suitable sulfonylating agent such as chlorosulfonic acid.

*? : The benzofurans of the formula (v) can be prepared by any standard procedure known to those skilled in the art, for example by the reaction between a suitable 2-hydroxybenzaldehyde or 2-hydroxyphenyl ketone (vi) and a suitable alkylating agent (vii) in the presence of an appropriate base (such as potassium carbonate or sodium hydroxide) in a suitable solvent (such as dimethylformamide or ethanol) at an appropriate temperature (e.g. reflux temperature of the solvent).

Examples of suitable alkylating agents include chloroacetone and chloroacetonitrile. The compounds (vi) and suitable alkylating agents (vii) are previously described, commercially available compounds or can be prepared by standard procedures known to those skilled in the art. A compound of the formula (Ia) can also be prepared by reacting a sulfonyl chloride of the formula (ii) with an amine of the formula H2NR5a (viii) to provide a compound of the formula (Ia) in which R4a is H, followed by reaction with an appropriate agent of the formula R 4aY (ix) in which Y is a suitable leaving group such as a halogen. The reaction of a sulfonyl chloride of the formula (ii) with an amine of the formula (viii) can be carried out under any conditions known to those skilled in the art. Favorably, the reaction is carried out in the presence of a suitable base, for example an amine such as triethylamine, preferably in an appropriate solvent such as dichloromethane. In some cases a stronger base such as sodium hydride, and a polar solvent such as dimethylformamide may be required. The amines of the formula (viii) and agents (ix) are either previously described, commercially available compounds 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 4 is H with an agent of the formula (ix) can be carried out under any suitable conditions known to those skilled in the art. Favorably, the reaction is carried out using an appropriate base, such as sodium hydride, preferably in an appropriate solvent such as dimethylformamide. The agent (ix) can be an alkylating agent such as propyl bromide, an acylating agent such as benzoyl chloride or a sulfonylating agent such as methanesulfonyl chloride. A process for the preparation of a compound of the formula (i) wherein Z is CO comprises the reaction of an appropriate carboxylic acid of the formula (x) with a suitable amine of the formula (iii). m Where Rla etc are as defined above; and after that, if required, convert any group Rla to Rl and / or R2a to R2 and / or R3a to R3 and / or R4a to R4 and / or R5a to R5. The reaction of a carboxylic acid of the formula (x) with an amine of the formula (iii) can be carried out under any conditions suitable for those skilled in the art, preferably those described above for (ii) - »(ia ). Favorably, 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). The carboxylic acids of the formula (x) are either compounds described above, commercially available or are prepared using standard procedures known to those skilled in the art. For example, a carboxylic acid of the formula (x) is conveniently prepared from an appropriate benzofuran of the formula (v), using standard procedures known to those skilled in the art. For example, a benzofuran of the formula (v) can be formylated to provide an aldehyde of the formula (xi), which can then be oxidized to provide the corresponding acid of the formula (x). Alternatively, a benzofuran of the formula (v) can be brominated to provide a bromide of the formula (xii), which can then be converted to a carboxylic acid of the formula (x), for example by carboxylation catalyzed by organometals brominated oxidized carboxylation JZ A compound of the formula (ib) can also be prepared by reacting a carboxylic acid (x) with an amine (viii) to provide a compound of the formula (ib) in which R 4a is H, followed by reaction with an agent (ix).

These reactions, with amine (viii) and agent (ix), can be carried out as described above. Preferably, the carboxylic acid is converted to an acid chloride, mixed anhydride or other activated intermediate prior to the reaction with the amine (viii). The compounds of the formula (i) can also be prepared by interconversion of other compounds of the formula (i). For example, a compound in which R4 contains an alkoxy group can be prepared by appropriate alkylation of a compound in which R4 contains a hydroxy group. For further exemplary form, the compounds in which R 2 and / or R 3 contain an oxyme can be prepared from compounds in which R 2 and / or R 3 contain a carbonyl group. This transformation can be carried out using appropriate standard conditions concocted by those skilled in the art. The compounds of the formula (i) in which R 2 and / or R 3 contain a carbonyl group can be reduced using standard conditions known to those skilled in the art (e.g. with sodium borohydride in an appropriate solvent) to provide compounds in which R2 and / or R3 contain an alcohol group. Compounds in which R2 and / or R3 is alkyl can be prepared by reduction of compounds in which R2 and / or R3 is CO-alkyl using standard conditions known to those of skill in the art (for example hydrazin hydrated in the presence of a suitable base in an appropriate solvent). Other transformations can be carried out in the compounds of the formula (i) in which R2 and / or R3 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 Z is CS can be prepared from compounds of the formula (i) in which Z is CO using any appropriate conditions known to those skilled in the art, for example using the reagent Lawesson. A compound of the formula (i) may be administered or, where appropriate, a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof., per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier. Accordingly, the present invention provides a pharmaceutical composition comprising a compound of the formula (i) or where appropriate a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier thereof. The active compound can be formulated for administration by any suitable route, the preferred route depends on the disorder for which the treatment is required, and is preferably in a dosage form or in the form in which the human patient can administer it by itself. same in a single dose. Advantageously, the composition is suitable for oral, rectal, topical or parental administration or through the respiratory tract. The preparations can be designed to give a slow release of the active ingredient. The term "parental" as used herein includes subcutaneous, intravenous, intramuscular, intramuscular 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, lotions, suppositories, reconstitutable powders, or liquid preparations such as orals, sterile parental solutions or suspensions. Topical formulations are also covered where appropriate. In order to obtain the consistency of administration it is preferred that a composition of the invention be in the form of a unit dose. Dosage forms of a dosage unit for oral administration can be tablets and capsules and can 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 pharmaceutically acceptable humectants such as sodium lauryl sulfate. The solid oral compositions can be prepared by conventional methods of mixing, filling, tableting or the like. Repeated mixing operations can be used to distribute the active agent fully in 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 pharmaceutical practice, in particular with an enteric coating. Oral liquid preparations may be in the form of, for example, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, stearate and aluminum gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia, non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerin esters, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavoring or coloring agents. The compositions may also suitably be presented for administration to the respiratory tract as a snuff or an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case the particles of the active compound suitably have diameters of less than 50 μm, such as 0.1 to 50 μm, preferably less than 10 μm, for example 1 to 10 μm, 1 to 5 μm or 2 to 5 μm. Where appropriate, small amounts of other anti-asthmatics or bronchodilators may be included eg sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine or ephedrine; corticosteroids such as prednisolone and adrenal stimulants such as ACTH. For parental administration, dosage unit forms are prepared using the compound and a sterile vehicle, and, depending on the concentration used, they can be either suspended or dissolved in the vehicle. When preparing the solutions the compound can be dissolved in water for injection and sterilized in a filter before filling the appropriate vial or ampoule and sealing. Advantageously, adjuvants such as local anesthetic, a preservative and buffering agents can be dissolved in the vehicle. To improve stability, the composition can be frozen after filling the vial and the water is removed under vacuum. The parental 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 a pharmaceutically acceptable solvate thereof, it can also be administered as a topical formulation in combination with conventional topical excipients. Topical formulations may be presented as, for example, ointments, creams or lotions, impregnated dressings, gels, gel tapes, aerosols and sprays, and may contain appropriate conventional additives such as preservatives, solvents for asister to drug penetration and emollients in ointments and creams. The formulations may contain compatible conventional carriers, such as cream bases or ointments and ethanol or oleyl alcohol for lotions. Suitable cream, lotion, gel, tape, spray or spray formulations that can be used for compounds of the formula (i) or if a pharmaceutically acceptable salt thereof is appropriate, are conventional formulations well known in the art, example, as described in standard textbooks such as Harry's Cosmetology published by Leonard Hill Books, Remington's Pharmaceutical Sciences, and the British and the pharmacopoeias of the United States. Suitably, the compound of the formula (i), or if appropriate a pharmaceutically salt thereof, will comprise from about 0.5 to 20% by weight of the formulation, advantageously 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 disorders, the weight of the patient, and the relative efficacy of the compound. However, as a general guide, suitable unit doses may be 0.1 to 1000 mg, such as 0.5 to 200, 0.5 to 100 or 0.5 to 10 mg, for example 0.5, 1, 2, 3, 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 daily dose for an adult of 70 kg is in the range of about 0.1 to 1000 mg, that is in the range of about 0.001 to 20 mg / kg / day, such as 0.007 to 3, 0.007 to 1.4, 0.007 to 0.14 or 0.01 to 0.5 mg / kg / day, for example 0.01, 0.02, 0.04, 0.05, 0.06, 0.08, 0.1 or 0.2 mg / kg / day, and such therapy may be prolonged for a number of weeks and months. When used herein the term "pharmaceutically acceptable" encompasses materials suitable for both human and veterinary use. The following examples illustrate the invention. Intermediary 1 N-furfurylpropylamine A solution of furfurylamine (1.0 g) in dry DMF (3 ml) is added to a stirred cold (0-5 ° C) suspension of sodium hydride (60% dispersion, 0.46 g) in DMF ( 5ml). After 15 minutes, a solution of 1-bromopropane (1.3 g) in dry DMF (2 ml) is added for 5 minutes. Stirring is continued for 1 hour and the reaction mixture is then allowed to warm to room temperature and stir overnight. The reaction is stopped by the addition of dilute hydrochloric acid. An aqueous solution of sodium hydrogen carbonate (100 ml) is then added and the mixture is extracted with ethyl acetate (3 x 50 ml). The combined organic extracts are washed with water, brine and then dried (magnesium sulfate) and evaporated in vacuo. The residue is distilled under reduced pressure to provide the title compound (0.21 g) as a colorless liquid. p. and. 85-90 ° C / l5 mm Hg Intermediate 2 2 -acetyl-4-bromo-7-methoxybenzofuran A solution of bromine (5.5 ml) in methanol (100 ml) is added dropwise to a suspension of 2-acetyl-7- Ethoxybenzofuran (20 g) in methanol (300 ml) at 0 ° C. The ice bath is removed immediately and the mixture is allowed to warm to room temperature. After one hour the conversion is incomplete, therefore additional bromine (0.75 ml) in methanol (25 ml) is added and the mixture is stirred overnight. The reaction is stopped using sodium metabisulfite solution (300 ml) producing a precipitate which is filtered off and dried in vacuo to yield a brown solid (17.4 g). TLC Rf 0.90 (ethyl acetate) Intermediate 3 2-acetyl-7-methoxybenzofuran-4-carboxylic acid Purge a mixture of intermediate 2 (5 g), triphenylphosphine (98 mg), bis (triphenylphosphine) aladine (II) chloride (261 mg), triethylamine (2.85 ml) and water (1 ml) in tetrahydrofuran (25 ml) with carbon monoxide gas in a Parr pressure reactor at 110 psi (758 kPa). This is heated to 110 ° C (the pressure is now 220 psi = 1517 kPa) and left for a week. Upon cooling and releasing the pressure the mixture is dissolved in 50% dichloromethane-water (200 ml) and brought to pH 12 using aqueous sodium hydroxide (1M). The separated aqueous phase is acidified to pH 1 using dilute hydrochloric acid (1M) and the resulting suspension is extracted with dichloromethane (3 x 100 ml) then ethyl acetate (100 ml). Dry these combined organic extracts over magnesium sulfate, filter and evaporate in vacuo to yield a yellow solid (2.58 g). TLC Rf 0.61 (ethyl acetate) Intermediate 4 2-acetyl-7-methoxybenzofuran-4-carbonyl chloride Intermediate 3 (0.12 g) is suspended in anhydrous dichloromethane (4 ml) at room temperature under nitrogen and oxalyl chloride is added (0.1 ml) followed by 3 drops of N, N-dimethylformamide. Evaporation in vacuo after 2 hours gives the title compound as a yellow solid. (-0.5 g). TLC Rf 0.60 (50% ethyl acetate in hexane) Intermediate 5 2-ethyl-7-methoxybenzofuran-4-carboxylic acid 2-Methyl-2-butene (9 g) is added to a solution of 2-ethyl-7-methoxybenzofurancarboxyaldehyde (5 g) in 2-methyl-2-propanol (125 ml). A solution of sodium dihydrogen phosphate monohydrate (20.7 g) in water is added, followed by sodium chlorite (11.05 g). The resulting heterogeneous mixture is stirred vigorously for 30 minutes and then diluted with water (125 ml). The mixture is adjusted to a pH of 4 by the addition of 2M hydrochloric acid. The mixture is extracted with ethyl acetate (3 x 200 ml) and the combined organic extracts are washed with water (2 x 200 ml). The organic solution is concentrated to approximately 100 ml and then cooled to 10 ° C. The resulting precipitate is collected by filtration and dried at 50 ° C in vacuo to yield a beige solid (4 g). p. F. 215-216 ° C Intermediate 6 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) % p / 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 white solid produced is obtained by filtration and dried in air to yield a white solid (4.9 g). Rf 0.36 (ethyl acetate) m.p. 65-67 ° C. Intermediate 7 4- (propylamino) pyridine 4-Aminopyridine (0.499 g) and propionaldehyde (0.5 g) are stirred in dichloromethane (50 ml) under an inert atmosphere at room temperature for 1.5 hours. Sodium triacetoxyborohydride (2.7 g) is added and left overnight. The reaction mixture is washed with aqueous sodium bicarbonate (2 x 40 ml) and extracted into dilute hydrochloric acid (2 x 40 ml). These acid extracts are brought to basic pH using potassium hydroxide granules and extracted in dichloromethane (2 x 80 ml). Dry the combined organic extracts in anhydrous magnesium sulfate, filter and evaporate in vacuo to yield an oily residue (0.11 g). TLC Rf 0.49 (10% methanol in ethyl acetate) Intermediate 2-ethyl-7-methoxy-4-N- (3-carboethoxyphenyl) benzofuran-carboxamide 2-Ethyl-7-methoxybenzofuran-4-carbonyl chloride (1.0 g) to a solution of ethyl 3-aminobenzoate (0.72 g) in dichloromethane (30 ml) at room temperature under an inert atmosphere and the reaction mixture is stirred at room temperature overnight. The mixture is poured into dilute aqueous hydrochloric acid and extracted with ethyl acetate (2 x 50 ml). The combined organic extracts are washed with water (50 ml), brine (50 ml), dried (magnesium sulfate) and evaporated in vacuo to yield the title compound (1.39 g) as a white solid. p.f. 159-161 ° C.

The following compound is prepared according to the above procedure. Intermediate £ 2-ethyl-7-methoxy-4-N- (4-carboethoxyphenyl) benzofuran-carboxamide. It is prepared from 2-ethyl-7-methoxybenzofuran-4-carbonyl chloride (1.3 g) and ethyl 4-aminobenzoate (1.0 g) to yield the title compound (0.76 g) as a white solid. TLC Rf 0.18 (25% ethyl acetate in hexane). Intermediate lü 2- [1- (2, 2-dimethylpropyl)] -7-methoxybenzofuran Sodium hydroxide (2.89 g) is added to a solution of o-vanillin (10 g) in ethanol (230 ml) at 40 ° C. After 10 minutes, 1-bromopinacolone (9.7 ml) is added and the resulting mixture is heated at 60 ° C for 4 h. then it is refluxed for 4 h. Additional The reaction mixture is cooled to room temperature and then concentrated in vacuo. The residue was partitioned between ethyl acetate (100 ml) and 0.2% aqueous sodium hydroxide solution (100 ml). Extract the aqueous layer with ethyl acetate (2 x 75 ml) and wash the combined organic extracts with water (100 ml) and brine. (100 ml). Dry the solution (magnesium sulfate) and concentrate in vacuo to give 2- [1- (2, 2-dimethyl-l-oxopropyl)] -7-methoxybenzofuran as a brown oil. Hydrated hydrazine (3.2 ml) is added to a stirred suspension of 2- [1- (2, 2-dimethyl-l-oxopropyl)] -7-methoxybenzofuran (3.0 g) in ethylene glycol (38 ml). After heating the reaction mixture at 65 ° C for 1 h, it is heated under reflux for 1.75 h to produce a yellow solution. After cooling to room temperature, water (50 ml) is added and the mixture is extracted with dichloromethane (3 x 50 ml). The combined organic extracts are washed with 2M aqueous hydrochloric acid (15 ml), water (3 x 20 ml) and brine (50 ml). The solution is dried (magnesium sulfate) and concentrated in vacuo. Purification by column chromatography on silica, eluting with 5% ethyl acetate in hexane afforded the title compound (1.92 g) as a colorless oil. TLC Rf 0.35 (5% ethyl acetate in hexane). Intermediate H 2- [1- (2, 2-dimethylpropyl)] - 7-methoxybenzofuran-4-carboxaldehyde Phosphorus oxychloride (1.64 ml) is added dropwise to DMF (1 ml) at 0 ° C under nitrogen and stirred For 10 minutes. A solution of 2- [1- (2, 2-dimethylpropyl)] - 7-methoxybenzofuran (1.92 g) in DMF (3.5 ml) is then added. A pale yellow solid forms and the reaction mixture is heated at 100 ° C for 2 h. The reaction mixture is allowed to cool to room temperature overnight. An aqueous solution of 50% sodium acetate trihydrate (20 ml) is added carefully and the resulting mixture is extracted with MTBE (3 x 25 ml). The combined organic phases are washed with water (2 x 20 ml), saturated aqueous sodium hydrogen carbonate solution (20 ml) and brine (30 ml). The solution is dried (magnesium sulfate) and concentrated in vacuo to give the title compound (2.14 g) as a light brown oil. TLC Rf (5% ethyl acetate in hexane) Intermediate 12 2- [i- (2,2-dimethylpropyl)] - 7-methoxybenzofuran-4-carboxylic acid Prepared from intermediate 11 (2.14 g), by the same procedure as for intermediate 5. The title compound (1.81 g) is obtained as a pale yellow solid. p. F. 173-174 ° C Example 1 2-Acetyl-7-methoxy-N- [3-pyridylmethyl] -4-benzofuransulfonamide Triethylamine (0.43 ml) is added to a solution of 2-acetyl-7-methoxy-4-benzofuransulfonyl chloride (600 mg) and 3- (aminomethyl) pyridine (0.25 ml) in dichloromethane at room temperature. The resulting mixture is stirred for 20 hours and then diluted with dichloromethane (20 ml). The solution is washed with water (20 ml) and brine (20 ml) and dried (MgSO 4). Concentration in vacuo gives a dark oil which is applied to a silica column and eluted with 2% methanol in dichloromethane. The title compound is obtained as a pale yellow solid (161 mg). p.f. 168-170 ° C. Example 2 2-Acetyl-N-benzyl-7-methoxy-4-benzofuransulfonamide It is prepared from; 2-acetyl-7-methoxy-4-benzofuransulfonyl chloride and benzylamine using the procedure of Example 1. TLC R £ 0.25 (30% ethyl acetate in hexane) m.p. 158-159 ° C Example 2. 2-Acetyl-N-furfuryl-7-methoxy-4-benzofuransulfonamide Prepared using the procedure of Example 1. Titration with diethyl ether yields the title compound (0.33 g) as a white solid. TLC R £ 0.42 (50% ethyl acetate in hexane) p. F. 182-184 ° C Example 4 2-Acetyl-N-furfuryl-N-propyl-7-methoxy-4-benzofuransulfonamide Prepared from 2-acetyl-7-methoxy-4-benzofuransulfonyl chloride and intermediate 1 using the procedure of Example 1. Purification by column chromatography on silica eluting with 5% ethyl acetate in dichloromethane gives the title compound (100 mg) as an off-white solid. TLC Rf 0.6 (5% ethyl acetate in dichloromethane) m.p. 109-111 ° C Example 5_ N-benzyl-2-ethyl-7-methoxy-4-benzofuransulfonamide Hydrazine (6.96 g) is added to a suspension of Example 2 (10 g) in ethylene glycol (120 ml) at 38 ° C. The mixture is heated and potassium carbonate (7.7 g) is added at 65 ° C. Heating is continued until a temperature of 170 ° C is reached. The mixture is cooled to room temperature and poured into a mixture of brine (300 ml), water (300 ml) and ethyl acetate (300 ml). Extract the aqueous layer with ethyl acetate (2 x 300 ml) and dry the combined organic extracts (MgSO4) and concentrate in vacuo. The residue is applied to a silica column and eluted with 30% ethyl acetate in heptane to give the title compound as an off-white solid (5.1 g). TLC R £ 0.13 (30% ethyl acetate in hexane). p.f. 105-107 ° C the following compound is prepared using the above procedure: Example £ 2-ethyl-7-methoxy-N- (3-pyridylmethyl) -4-benzofuransulfonamide Purification by column chromatography on silica eluting with 1% triethylamine 10% methanol in ethyl acetate affords the title compound as a pale yellow solid (0.36 g). TLC Rf 0.51 (10% methanol in ethyl acetate) m.p. 115-117 ° C Example 7 2-Acetyl-7-methoxy-N- (methanesulfonyl) -N- (3-pyridylmethyl) -4-benzofuransulfonamide A solution of Example 1 (126 mg) in dry DMF (2 ml) is cooled at 0 ° C under nitrogen. Sodium hydride is added (60% dispersion in oil, 17 mg) and the mixture is stirred by minutes. Methanesulfonyl chloride (54 μl) is added and the resulting mixture is stirred at 0 ° C for 1 hour and then at room temperature for 16 hours. Water (1 ml) is added and the mixture is concentrated in vacuo. The residue is partitioned between water (10 ml) and dichloromethane (15 ml) and the phases are separated. The aqueous phase is extracted with dichloromethane (2 x 15 ml) and the combined organic extracts are washed with brine (15 ml), dried (MgSO 4) and concentrated in vacuo. The residue is applied to a silica column and eluted with 2% methanol in dichloromethane. The title compound is obtained as a pale yellow solid (48 mg). TLC Rf0 0.15 (2% methanol in dichloromethane) m.p. 171-172 ° C The following compounds are prepared using the above procedure. Example 8 N-benzyl-2-ethyl-N- (methanesulfonyl) -7-methoxy-4-benzofuran-sulfonamide This is prepared from Example 5. TLC Rf 0.75 (50% ethyl acetate in hexane). IR (thin film) nraax 1620, 1594, 1366, 1323, 1164, 1098 cm "1 Example 9_ N-benzyl-2-ethyl-7-methoxy-N- (2-pyridylmethyl) -4-benzofuran-sulfonamide This is prepared as above using 2- (chloromethyl) pyridine TLC Rf 0.38 (50% ethyl acetate in hexane) IR (thin film) nmax 1618, 1592, 1332, 1161, 1095 cm "1 Example 10 2-Ethyl-7-methoxy-N- (methanesulfonyl) -N- (3-pyridylmethyl) -4-benzofuransulfonamide This is prepared from Example 6. Purification by column chromatography eluting with 10% methanol in ethyl acetate yield the title compound as a white foam (87 mg) TLC Rf 0.65 (10% methanol in ethyl acetate) IR (thin film) nmax 1575, 1405, 1290, 1164, 1095 cm "1 Example 11 2-ethyl-7-methoxy-N- (methanesulfonyl) -N- (3-pyridylmethyl) -4-benzofuransulfonamide hydrochloride A solution of acid chloride in ether (1M solution, 1.5 ml) is added to a solution of Example 10 (0.1 g) in dry dichloromethane (4 ml) under nitrogen. The resulting solution is stirred at room temperature for 90 minutes. Ether (10 ml) is added and the resulting precipitate is collected by filtration to provide the title compound as a cream colored solid (0.09 g). Similarly, Example 12 is prepared 2-Acetyl-7-methoxy-N- (methanesulfonyl) -N- (3-pyridylmethyl) -4-benzofuransulfonamide hydrochloride From Example 7 (0.08 g) as a pale yellow solid (0.06 g) . Example 13 2-Acetyl-7-methoxy-4-N- (3,5-dichloropyrid-4-yl) benzofurancarboxamide Sodium hydride (0.03 g) is added to a solution of 4-amino-3,5-dichloropyridine (0.08 g) in anhydrous N, N-dimethylformamide (1 ml) at room temperature under nitrogen. This stirred mixture is heated at 60 ° C for 1 h before the addition of the intermediate 4 washed in anhydrous N, N-dimethylformamide (2 ml). The brown mixture is heated at 60 ° C for 4 hours, allowed to cool, poured into water (100 ml) and extracted into ethyl acetate (2 x 50 ml). These organic extracts are washed with water (50 ml) and saturated brine (50 ml) then dried in anhydrous magnesium sulfate., filter, evaporate in vacuo to give the residue without purification (0.17 g). Purification by column chromatography on silica eluting with 20-80% ethyl acetate in hexane gradient yields a white solid (0.04 g). TLC Rf 0.20 (50% ethyl acetate in hexane) p. F. 252-254 ° C Example 14 2-Ethyl-7-methoxy-4-N- (3,5-dichloropyrid-4-yl) benzofurancarboxamide A suspension of intermediate 5 (300 mg) in dry toluene (50 ml) is treated under an inert atmosphere with thionyl chloride (2 ml) and heating under reflux for 2 hours. The cold reaction mixture is evaporated in vacuo and an azeotropic mixture of the residue is formed with dry toluene (2 x 10 ml) to yield the acid chloride as a white solid (325 mg). The 4-amino-3,5-dichloropyridine (230 mg) is treated in dry N, N-dimethylformamide (20 ml) under an inert atmosphere with bis (trimethylsilyl) amine (1.5 ml.; 1.0 M in tetrahydrofuran) at room temperature for 30 minutes. The solid acid chloride (325 mg) is added in this mixture and heated at 50 ° C for 3 hours then allowed to cool overnight. This is evaporated in vacuo, saturated aqueous sodium bicarbonate (50 ml) is added and it is extracted into dichloromethane (2 x 50 ml). Dry these extracts in magnesium sulfate, filter and evaporate in vacuo to give an unpurified residue. Purification by column chromatography on silica eluting with 50% ethyl acetate in hexane yields a white solid (210 mg). TLC Rf 0.15 (25% ethyl acetate in hexane) m.p. 199-200 ° C Example 15. 2-Acetyl-7-methoxy-4-N- (pyrid-4-yl) benzofurancarboxamide A solution of intermediate 4 (164 mg) in anhydrous dichloromethane (10 ml) under nitrogen at 0 is treated. ° C, with 4-aminopyridine (0.07 g), triethylamine (0.12 g) and dimethylaminopyridine (2 mg). This solution is allowed to warm to room temperature and is stirred overnight. The reaction mixture is washed with saturated aqueous sodium bicarbonate (10 ml), water (10 ml) and saturated brine (10 ml) then dried in mangesium sulfate, filtered and evaporated in vacuo to give an unpurified residue. . Purification by column chromatography on silica eluting with 5% methanol in dichloromethane yields a pale yellow solid (85 mg). TLC Rf 0.27 (5% methanol in dichloromethane). p. f. 247-248 ° C (dec). Example 16 2-Acetyl-7-methoxy-4- [N- (pyrid-4-yl) -N-propyl] benzofurancarboxamide Intermediate 7 (0.08 g) is treated with intermediate 4 (0.15 g) as in Example 15 to produce a pale yellow foam (129 mg). TLC R £ 0.57 (5% methanol in dichloromethane). IR (film); 1292, 1587, 1647, 1685 cm "1. EXAMPLE 1 2-Acetyl-7-methoxy-4-N- (2-chlorophenyl) benzofarcarboxamide The 2-chloroaniline (0.42 ml) is treated with intermediate 4 (1 g) as in Example 15. Purification by column chromatography on silica eluting with 50% ethyl acetate in hexane yields a solid (137 mg), mp 179-181 ° C Example ifi 2-acetyl-7-methoxy-4 - N- (2,6-dimethylphenyl) benzofurancarboxamide The 2,6-dimethylaniline (0.49 ml) is treated with intermediate 4 (1 g) as in Example 15. Purification by column chromatography on silica eluting with ethyl acetate 50% in hexane yields a solid (255 mg) TLC R £ 0.23 (50% ethyl acetate in hexane) mp 225-226 ° C Example 19_ 2-Acetyl-7-methoxy-4-N- (4-methoxyphenyl) ) benzofurancarboxamide 4-methoxyaniline (567 mg) is treated with intermediate 4 (1.19 g) as in Example 15. Purification by column chromatography on silica eluting with 50% ethyl acetate in heptane produces a yellow solid (103 mg). TLC Rf0.26 (50% ethyl acetate in heptane) Example Q_ 2-acetyl-7-methoxy-4-N- (3-bromo-5-methylpyrid-2-yl) benzofurancarboxamide 2-amino-3 is treated -bromo-5-methylpyridine (0.64 g) in dry tetrahydrofuran (20 ml) with sodium hydride (0.15 g, 60% dispersion in oil) under inert atmosphere at room temperature for 15 minutes. A solution of intermediate 4 (0.86 g) in dry tetrahydrofuran (10 ml) is added and stirred overnight before evaporation in vacuo. Aqueous sodium bicarbonate (50 ml) is added and the mixture is extracted with ethyl acetate (2 x 50 ml). Dry these extracts with magnesium sulfate, filter and evaporate in vacuo. Purify the residue without purification by column chromatography on silica eluting with 50% ethyl acetate in hexane to yield a pale yellow powder (95 mg). TLC R £ (50% ethyl acetate in hexane) EXAMPLE 21 2-Acetyl-7-methoxy-4-N- (3-methylphenyl) benzofcarboxamide M-toluidine (0.42 ml) is treated with intermediate 4 (1 g) as in Example 15. Purification by column chromatography on silica eluting with 50% ethyl acetate in hexane yields a yellow solid (200 mg). TLC R 0.5 (50% ethyl acetate in hexane). p.f. 193-195 ° C Example 22 2-Acetyl-7-methoxy-4-N- (3,5-dichloropyrid-3-yl) benzofurancarboxamide 2-Amino-3,5-dichloropyridine (0.758 g) is treated with the intermediate 4 (1.17 g) as in Example 13 using N, N-dimethylformamide as a solvent. Purification by column chromatography on silica eluting with methanol to 3% in dichloromethane produces a yellow solid (13 mg). TLC Rf 0.05 (50% ethyl acetate in hexane). Example 21 2-Acetyl-7-methoxy-4-N- (2-methylphenyl) benzofurancarboxamide 2-Methylaniline (0.21 g) is treated with intermediate 4 (0.5 g) as in Example 15. Purification by column chromatography on silica eluting with 50% ethyl acetate in hexane yields a yellow solid (128 mg).

TLC R £ 0.24 (50% ethyl acetate in hexane) m.p. 174-175 ° C. Example 2 2-Acetyl-7-methoxy-4-N- (4-methoxy-2-methylphenyl) benzofurancarboxamide 2-Methoxy-2-methylaniline (0.56 g) is treated with intermediate 4 (1.0 g) as in Example 15. Purification by column chromatography on silica eluting with 50% ethyl acetate in hexane yields a yellow solid (235 mg). TLC Rf 0.25 (50% ethyl acetate in hexane) m.p. 217-218 ° C. Example 25. 2-Acetyl-7-methoxy-4-N- (pyrimidin-4-yl) benzofurancarboxamide The 4-aminopyrimidine (0.376 g) is treated with intermediate 4 (1.0 g) as in Example 15. The purification by column chromatography on silica eluting with 0-10% methanol in ethyl acetate yields a yellow solid (0.14 g) • TLC Rf 0.49 (10% methanol in ethyl acetate) mp 212-214 ° C. Example 26. 2-Acetyl-7-methoxy-4-N- (2-trifluoromethylphenyl) benzofurancarboxamide The 2-aminobenzotrifluoride (0.5 ml) is treated with intermediate 4 (1.0 g) as in Example 15. Purification by chromatography of column on silica eluting with 50% ethyl acetate in hexane yields a yellow solid (0.12 mg). p.f. 164-166 ° C. Example 27 2-Acetyl-7-methoxy-4-N- [2 - (piperidin-1-yl) phenyl] benzofurancarboxamide N- (2-aminophenyl) piperidine (700 mg) is treated with intermediate 4 (1.0 g) as in Example 15. Purification by column chromatography on silica eluting with 40% ethyl acetate in hexane yields a yellow solid (300 mg). TLC Rf 0.5 (50% ethyl acetate in hexane) m.p. 170-171 ° C. Example 28 2-Acetyl-7-methoxy-4-N- (3-chloropyrid-4-yl) benzofurancarboxamide Intermediate 6 (0.26 g) is treated with intermediate 4 (0.5 g) as in Example 13, except that performs initial anion generation at room temperature and using 15-crown-5 (0.90 g). Purification by column chromatography on silica eluting with 5% methanol in dichloromethane yields a tan solid (0.08 g). TLC Rf 0.65 (5% methanol in dichloromethane) m.p. 197-200 ° C Example 22. 2-Acetyl-7-methoxy-4-N- (2-trifluoromethoxyphenyl) benzofurancarboxamide 2-trifluoromethoxyaniline (0.49 g) is treated with intermediate 4 (0.7 g) as in Example 15. Purification by column chromatography on silica eluting with 50% ethyl acetate in hexane yields a yellow solid (0.065 g). TLC R £ 0.49 (50% ethyl acetate in hexane) m.p. 170-171 ° C. EXAMPLE 2 2-Acetyl-7-methoxy-4-N- (2-ethylphenyl) benzofurancarboxamide 2-ethylaniline (0.48 g) is treated with intermediate 4 (1.0 g) as in Example 15. Purification by column chromatography on silica eluting with 25% ethyl acetate in hexane yields a tan solid (310 mg). TLC Rf 0.13 (25% ethyl acetate in hexane) m.p. 174-175 ° C. Example 3_1 2-Acetyl-7-methoxy-4-N- (2-biphenyl) benzofurancarboxamide The 2-aminobiphenyl (0.5 g) is treated with intermediate 4 (0.73 g) as in Example 15. Purification by column chromatography on silica eluting with 5% methanol in dichloromethane and then trituration with diethyl ether yields a cream-colored solid (0.17 g). TLC R 0.5 (50% ethyl acetate in hexane) m.p. 131-133 ° C. EXAMPLE 32 2-Acetyl-7-methoxy-4-N- (3-methylpyrid-2-yl) benzofurancarboxamide The 2-amino-3-picoline (0.32 g) is treated with intermediate 4 (0.73 g) as in Example 15. Purification by column chromatography on silica eluting with 5% methanol in dichloromethane yields a yellow solid (0.12 g). TLC Rf 0.40 (5% methanol in dichloromethane) Example 3_3_ 2-ethyl-7-methoxy-4-N- (2-chloropyrid-3-yl) benzofurancarboxamide 3-Amino-2-chloropyridine (0.88 g) is treated with intermediary 4 (1.8 g) as in Example 13, except that the initial anion generation is carried out at room temperature for 1.5 hours. Purification by flash chromatography on silica eluting with hot ethyl acetate and then trituration with diethyl ether yields a beige solid (0.53 g). TLC R 0. 0.35 (50% ethyl acetate in hexane) m.p. 124-125 ° C Example 3_4_ 2-Acetyl-7-methoxy-4-N- (3-methoxyphenyl) benzofurancarboxamide The o-anisidine (0.49 g) is treated with intermediate 4 (1 g) as in Example 15. The purification by column chromatography on silica eluting with 30% ethyl acetate in hexane yields a yellow solid (160 mg). Example 35 2-Acetyl-7-methoxy-4-N- (2-chloropyrid-3-yl) benzofurancarboxamide 3-Amino-2-chloropyridine (509 mg) is treated with intermediate 4 (1.0 g) as in Example 13. Purification by column chromatography on silica eluting with 25% ethyl acetate in hexane yields a yellow solid (205 mg).

Example 16. 2-Acetyl-7-methoxy-4-N- (2-chloro-6-methylphenyl) benzofurancarboxamide 2-Chloro-6-methylaniline (0.56 g) is treated with intermediate 4 (1.0 g) as in Example 15. Purification by crystallization from dichloromethane to yield a brown solid (160 mg). TLC R £ 0.4 (5% methanol in dichloromethane). EXAMPLE 37 2- (1-Hydroxyethyl) -7-methoxy-4-N- (3,5-dichloropyrid-4-yl) benzofurancarboxamide. Example 13 (0.50 g) is suspended in dry methanol. (20 ml) and treated with sodium borohydrate (196 mg) at room temperature. Some cooling of external ice is required and then it is stirred during the night. The reaction mixture is poured into water and extracted with ethyl acetate. Evaporation in vacuo yields a solid which is purified by column chromatography using 5% methanol in dichloromethane to yield a white solid (400 mg). TLC Rf 0.52 (80% ethyl acetate in heptane) m.p. 229-231 ° C. EXAMPLE 38 2- (3-Pyrid-3-yl-l-oxopropyl) -7-methoxy-4-N- (3,5-dichloropyrid-4-yl) benzofurancarboxamide A solution of Example 13 (0.40 g) is cooled in Dry N, N-dimethylformamide (5 ml) under an inert atmosphere at -10 ° C and add sodium hydride (60% dispersion in oil, 0.11 g) for 30 minutes. After 1 hour at -10 ° C, 3-picolyl chloride hydrochloride (0.20 g) is added and the mixture is stirred for an additional 2 hours before being allowed to warm to room temperature overnight. It is poured into water and extracted into ethyl acetate. The extracts are washed with water and saturated brine and then dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The resulting residue is purified by column chromatography using 3-10% methanol in dichloromethane gradient then triturated with diethyl ether to yield a beige powder (15.5 mg). TLC RE 0.27 (10% methanol in dichloromethane). Example 39 2- (1-benzyloximino) ethyl-7-methoxy-4-N- (3,5-dichloropyrid-4-yl) benzofurancarboxamine Example 13 (100 mg) is brought to reflux under Dean-Stark conditions in dry toluene (40 ml) with dry pyridine (64 μl) and O-benzylhydroxylamine hydrochloride (126 mg) under an inert atmosphere. After 2 hours the mixture is allowed to cool and is left stirring overnight. The addition of methanol and acetone forms a precipitate. This is filtered off to yield a solid (26 mg). TLC R £ 0.45 (50% ethyl acetate in hexane). Example á-Q. 2-ethyl-7-methoxy-4-N- (3-carboxyphenyl) benzofurancarboxamide A solution of intermediate 8 (0.78 g) in THF (25 ml) is treated with a solution of lithium hydroxide monohydrate (0.18 g) in water ( 25 ml) and the reaction mixture is stirred at room temperature overnight. The reaction mixture is concentrated in vacuo, diluted with water (100 ml) and acidified with dilute aqueous hydrochloric acid. The resulting white precipitate is collected, washed with water and dried in vacuo to yield the title compound (0.68 g) as a white solid. TLC Rf 0.35 (5% methanol in dichloromethane) m.p. 265-267 ° C the following compound is prepared according to the above procedure. EXAMPLE il 2-ethyl-7-methoxy-4-N- (4-carboxyphenyl) benzofurancarboxamide Prepared from intermediate 9 (0.67 g) to yield the title compound (0.59 g) as a white solid. TLC R £ 0.4 (5% methanol in dichloromethane) m.p. 279-280 ° C. Example 42 2- [1- (2, 2-dimethylpropyl)] -7-methoxy-4-N- (3,5-dichloropyrid-4-yl) benzofurancarboxamide Thionyl chloride (1.65 ml) is added to a suspension of the intermediate 12 (0.59 g) in toluene (10 ml) and the mixture is heated to reflux for 3 hours. The mixture is stirred at room temperature overnight and concentrated in vacuo. An azeotropic mixture of the residue is formed several times with toluene to give 2- [1- (2, 2-dimethylpropyl)] -7-methoxybenzofuran-4-carbonyl chloride (0.63 g).

Sodium hexamethyldisilazide (1M solution in THF, 4.5 ml) is added to a solution of 4-amino-3, 5-dichloroaminopyridine (0.74 g) in dry DMF (2 ml) at room temperature under nitrogen. The mixture is stirred at room temperature for 0.5 hours, then heated to 50 ° C. A solution of 2- [1- (2, 2-dimethylpropyl)] -7-methoxybenzofuran-4-carbonyl chloride (0.63 g) in DMF is added and the reaction mixture is stirred for an additional 3 hours, then at room temperature for 16 h. Water (20 ml) is added and the resulting precipitate is collected and dried in vacuo. Purification by column chromatography on silica, eluting with 25% ethyl acetate in TLC R £ 0.4 (50% ethyl acetate in hexane) affords the title compound (0.29 g) as a pale yellow solid. TLC R £ 0.4 (50% ethyl acetate in hexane) m.p. 164-165 ° C Test Methods The assays used to confirm the inhibitory activity of phosphodiesterase IV of the compounds of the formula (i) are standard assay procedures as described by Schilling et al, Anal. Biochem. 216: 154 (1994), Thompson and Strada, Adv. Cycl. Nucí Res. 8: 119 (1979) and Gristwood and Owen, Br. J. Pharmacol. 87: 91P (1986). The compounds of the formula (i) have the inhibitory activity 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 production in human monocytes is measured as follows. Peripheral blood mononuclear cells are prepared from freshly taken blood by standard procedures. The cells are laminated in RPMI1640 + 1% fetal calf serum in the presence and absence of inhibitors. LPS (100 ng / ml) is added and the cultures are incubated for 22 h at 37 ° C in a 95% air atmosphere / 5% C02. Supernatants for TNFα are tested by ELISA using commercially available equipment. In vivo activity is determined in a model of skin eosinophilia using the methods described by Hellewell et al, Br. J. Pharmacol. 111: 811 (1994) and Br. J. Pharmacol. 110: 416 (1993). Activity is measured in a lung model using the procedures described by Kallos and Rallos, Int. Archs. Allergy Appl. Immunol. 73:77 (1984), and Sanjar et al, Br. J. Pharmacol. 99: 679 (1990). An additional lung model is described, which allows the measurement of inhibition of early and late phase asthmatic responses and also the inhibition of airway hyper-activity, in Broadley et al, Pulmonary Pharmacol. 7: 311 (1994), J. Immunological Methods 190: 51 (1996) and British J. Pharmacol. 116: 2351 (1995). The compounds of the invention show activity in this model.

Claims (14)

1. CLAIMS 1. A compound characterized by the general formula (i)
2. Wherein Rx represents alkoxy optionally substituted with one or more halogens, OH or thialkyl; R2 and R3 are the same or different and are each H, R6, COR6, C (= NOR11) R6, CN, C02H, CO2R10, CONH2, CONHR6 or CON (R6) 2; R 4 represents H, arylalkyl, heteroarylalkyl, S (O) mR 10 or alkyl optionally substituted with one or more substituents selected from hydroxy, alkoxy, C02R7, S02NR11R12, CONR ^ R.jCN, carbonyl oxygen, NR8R9, COR10 and S (O) nR10; R5 represents aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl or heterocycloalkyl; In R4 and / or R5, the aryl / heteroaryl / heterocycle moiety is optionally substituted with one or more alkyl substituents -R13 or R13; R6 represents R10 optionally substituted at any position with (one or more) R14; R7 represents H, alkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl;
3. R8 represents H, aryl, heteroaryl, heterocycle, alkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl, alkylcarbonyl, alkoxycarbonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclecarbonyl or alkylsulfonyl; R10 represents alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl or heterocycloalkyl; - '^ 11 Y ^ 12 are the same or different, and are each H or R10; R 13 represents alkyl or alkoxy optionally substituted by halogen, aryl, heteroaryl, heterocycle, hydroxy, aryloxy, heteroaryloxy, heterocycleoxy, arylalkyloxy, heteroarylalkyl, heterocycloalkyloxy, C02R7, CONR-.R ^, SOjNR ^ R ^, halogen, -CN, -NRaR9 , COR10, S (0) nR10, or carbonyl oxygen; R14 represents OH, OR10, carbonyl oxygen, NR8R9, CN, C02H, CO2R10, CONR- ^ 2 or COR10; m represents 1 to 2; and • n represents 0-2; or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, characterized in that: R is C1-3 alkoxy optionally substituted by one or more halogens;
4. R2 and R3 are each independently selected from H, CN, C02H (or C-.6 alkyl esters thereof or C1.6 alkyl amides thereof), and alkyl optionally substituted with one or more substituents chosen of the carbonyl oxygen, hydroxy, alkoxy, aryloxy, arylalkoxy, alkylamino, arylalkylamino or arylamino, and cycloalkyl optionally substituted with one or more substituents chosen from the carbonyl oxygen, hydroxy, C1_6 alkoxy, aryloxy, arylalkyloxy, C1.6 alkylamino, arylalkylamino or arylamino; R 4 represents H, arylalkyl, heteroarylalkyl,
5. S (O) mR10 or alkyl optionally substituted with oxygen carbonyl, NR8R9, S (O) nR10, COR10, hydroxy, Cl_6 alkoxycarbonyl, or CN alkylaminocarbonyl. R5 represents arylalkyl, heteroarylalkyl; R8 represents H, alkyl, alkylcarbonyl, alkoxycarbonyl, arylsulfonyl, arylcarbonyl, or alkylsulfonyl; R9 represents H or alkyl; and R10 represents alkyl, arylalkyl, heteroarylalkyl; 3. The compound according to claim 1, characterized in that: R2 and R3 are each independently selected from H, R6 and COR6; and R6 is alkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl or heterocycloalkyl. 4. The compound according to claim 1, characterized in that it is selected from 2-acetyl-N-benzyl-7-methoxy-4-benzofuransulfonamide N-benzyl-2-ethyl-7-methoxy-4-benzofuransulfonamide 2-acetyl- 7-methoxy-N- (methanesulfonyl) -N- (3-pyridylmethyl) -4-benzofransulphonamide N-benzyl-2-ethyl-N- (methanesulfonyl) -7-methoxy-4-benzofuransulfonamide and N-benzyl-2- ethyl-7-methoxy-N- (2-pyridylmethyl) -4-benzofuransulfonamide. The compound according to claim 1, characterized in that it is selected from 2-acetyl-N-furfuryl-7-methoxy-N- (2-pyridylmethyl) -4-benzofuransulfonamide 2 -acetyl-N-furfuryl-N-propyl -7-methoxy-4-benzofuransulfonamide 2-ethyl-7-methoxy-N- (3-pyridylmethyl) -4-benzofuransulfonamide, and 2-ethyl-7-methoxy-N- (methanesulfonyl) -N- (3-pyridylmethyl) -4-benzofuransulfonamide
6. 6. The compound according to claim 1, characterized in that it is selected from 2-ethyl-7-hydrochloride. -methoxy-N- (methanesulfonyl) -N- (3 -piridilmetil) -4 -benzofuransulfonamida Hydrochloride 2-acetyl-7-methoxy-N- (methanesulfonyl) -N- (3-pyridylmethyl) -4-benzofuransulfonamida
7. 7. compound according to any preceding claim, characterized in that it is in the form of an enantiomer thereof.
8. 8. A pharmaceutical composition for therapeutic use characterized in that it comprises a compound according to any preceding claim and a pharmaceutically acceptable carrier or excipient.
9. 9. The use of a compound according to claims 1 to 7, characterized by 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, or which is a pathological condition associated with a function of phosphodiesterase IV, eosinophil accumulation or an eosinophil function.
10. 10. The use according to claim 9, characterized in that the disease state is an inflammatory disease or autoimmune disease.
11. 11. The use according to claim 9, characterized in that the disease state is selected from asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, inflammation of the eye, allergic responses in the eye, granuloma. eosinophilic, psoriasis, rheumatoid arthritis, gouty arthritis and other arthritic conditions, ulcerative colitis, Crohn's disease, diabetes insipidus, keratosis, atopic eczema, atopic dermatitis, cerebral senility, multi-infarct dementia, senile dementia, memory impairment associated with the disease of Parkinson's, depression, cardiac arrest, infarction and intermittent claudication.
12. 12. The use according to claim 9, characterized in that the disease state is chronic bronchitis or allergic rhinitis.
13. 13. The use according to claim 9, characterized in that the disease state is selected from joint inflammation, arthritis, rheumatoid arthritis, rheumatoid spondylitis and osteoarthritis, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome. , acute respiratory insufficiency, cerebral malaria, chronic pulmonary inflammatory disease, pulmonary sarcoidosis, asthma, diseases of bone resorption, reperfusion injury, graft vs. host reaction, allograft rejection, malaria, myalgias, HIV, AIDS, ARC, cachexia, Crohn's disease, ulcerative colitis, pyresis, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes mellitus, psoriasis, Bechet's disease, anaphylactoid purpura nephritis, chronic glomerulonephritis, inflammatory bowel disease, leukemia, gastroprotection and neurogenic inflammatory disease associated with irritation and pain.
14. 14. The use according to claim 9, characterized in that the disease state is asthma.