MXPA00007632A - Benzofuran-4-carboxamides and their therapeutic use - Google Patents

Abstract

A compound of formula (i), has therapeutic utility via inhibition of phosphodiesterases and TNF release.

Description

BENZOFURAN-4-CARBOXAMIDAS * ITS THERAPEUTIC USE FIELD OF THE INVENTION The present invention is concerned with new benzofuran compounds and their formulation and use as pharmaceutical compounds.

BACKGROUND OF THE INVENTION EP-A-0637586 discloses benzofuran derivatives of acetylcholinesterase inhibitors. US-A-4910193 describes benzofuran amides for the treatment of gastrointestinal disorders induced by serotonin. WO-A-9408962 discloses benzofuran derivatives as fibrinogen receptor antagonists. WO-A-9744337, O-A-9720883, EP-A-0771794 and WO-A-9807715 describe benzofuran derivatives as selective inhibitors of phosphodiesterase IV (PDE). The modes of action of phosphodiesterases and also of tumor necrosis factors (TNF) and the therapeutic utilities of the inhibitors thereof are described in OA-9636638 and U.S. Patent No. 5,821,366, the content of which is incorporated herein by reference.

BRIEF DESCRIPTION OF THE INVENTION This invention provides novel compounds having therapeutic utility, in particular for the treatment of pathological conditions associated with proteins that measure cellular activity, for example by inhibiting TNF and / or PDE IV. According to the invention, the compounds are of formula (i): Z is CO or CS; Ri is OH, alkoxy optionally substituted with one or more halogens or thioalkyl optionally substituted with one or more halogens; R3 is H, alkyl or halogen; R is H or alkyl; R5 is aryl or heteroaryl any of which may be substituted at any position with (one or more) R substituents? or alkyl-R?; R 4 is alkyl optionally substituted with one or more halogens, aryl, heteroaryl, heterocycle, C02R8, CONRgRio, S02NR9R, or, ORu, halogen, CN, NR8R2, COR3, S (0) pR3, or NHS02CF3; p is 0-2; R8 is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl; R g and Rio are the same or different and are H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl or NR 9 R 0 represent a heterocyclic ring; Rn is H, alkyl (optionally substituted with one or more halogens), cycloalkyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl; Ri2 is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, heroarylcarbonyl, heterocyclecarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl or heterocyclosulfonyl; R 13 is alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl; R 2 is alkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkyl, any of which is attached at any position on the alkyl portion to A and (through the same or a different position) to the benzofuran ring, wherein the aryl group or heteroaryl is optionally substituted at any position by (one or more) substituents R14 or alkyl-R14, and the cycloalkyl or heterocycloalkyl group is optionally substituted at any position with (one or more) substituents R7 or alkyl-R7, or R2 is absent; A is -0-, -0- (C (R15) 2) nC (= 0) - (C (R15) 2) m-, -0- (C (Ri5) 2) n) -S0q- (C ( R15) 2) m-, -NR6-, -NR6- (C (R15) 2) n- -NR6- (C (R? 5) 2) nC (= 0) - (C (R15) 2) n- , -NR6- (C (R15) 2) n-S0q- (C (R15) 2) m-, S0q-, SOq- (C (R? 5) 2) n- or SOqNR6-; R6 is H or alkyl; n is 1-4; m is 0-4; q is 1 or 2; Ri5 is H or alkyl; R7 is carbonyl oxygen (ie = 0 bonded to a C atom), C02R8, CONR9R10, SO2NR9R? 0, NR8R12, ORn, alkyl (optionally substituted with one or more halogens), halogen, CN, NHS02CF3, tetrazolyl or heterocycle; when A is -0-, -0- (C (R15) 2) n-, -0- (C (Ri5) 2) nC (= 0) - (C (R15) 2) m-, "NR6-, -NR6- (C (R15) 2) n- or -NR6- (C (R? 5) 2) n ~ C (= 0) - (C (R? 5) 2) m- / then B is a ring heterocyclic (substituted at any position with (one or more) substituents R or alkyl-R7), or alkyl, aryl or heteroaryl (any of which is substituted at any position with (one or more) substituents Ri or alkyl-R? ); when A is -0- (C (R15) 2) n-S0q- (C (R15) 2) m-, -NR6- (C (R? 5) 2) n-SOq- (C (R15) 2) m-, S0q-, SOq- (C (R15) 2) n-, or SOqNR6-; then B is a heterocyclic ring (optionally substituted at any position with (one or more) substituents R7 or alkyl-R7), or alkyl, aryl or heteroaryl (any of which is optionally substituted at any position with (one or more) substituents , Ri4 or alkyl-R14); when R2 is cycloalkylalkyl, then B is a heterocyclic ring (optionally substituted at any position with (one or more) R? or alkyl-R7 substituents), or alkyl, aryl or heteroaryl (any of which is optionally substituted at any position with (one or more) substituents Ri4 or alkyl-R?) for all A; and when R2 is cycloalkylalkyl and A is -0-, B can also be H; in which the N-oxides and pharmaceutically acceptable salts are included. This invention also provides a method for mediating or inhibiting the enzymatic activity or catalytic activity of PDE IV in a mammal in need thereof and for inhibiting the production of TNF in a mammal in need thereof, which comprises administering to the mammal an effective amount of the compound of formula (i) or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION Suitable pharmaceutically acceptable salts are pharmaceutically acceptable basic addition salts and pharmaceutically acceptable acid addition salts. Certain compounds of formula (i) which contain an acid group form basic salts. The pharmaceutically acceptable basic salts include metal salts, such as alkali metal salts, for example, sodium salts, or organic amine salts such as those provided with ethylenediamine. Certain compounds of formula (i) which contain a basic group form basic addition salts. Suitable basic addition salts include pharmaceutically acceptable inorganic salts such as the sulfate, nitrate, phosphate, borate, hydrochloride and hydrobromide 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 formula (i) are prepared using conventional procedures. It will be appreciated by those skilled in the art that some of the compounds of formula (i) may exist in one or more of a tautomeric or geometric 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 carbon atoms. The presence of one or more of these asymmetric centers in a compound of formula (i) can give rise to stereoisomers and in each case it will be understood that the invention extends to all of these stereoisomers, in which the enantiomers and diastereomers and mixtures are included. which include racemic mixtures thereof. When used herein, the term alkyl, either alone or when used as part of another group, includes straight and branched chain alkyl groups having up to 6 carbon atoms. Alkoxy means an alkyl-O- group in which the alkyl group is as previously described and thioalkyl means an alkyl-S- group. Cycloalkyl includes a non-aromatic cyclic or multicyclic ring system of 3 to 10 carbon atoms. The cyclic alkyl may optionally be partially unsaturated. Aryl denotes mono- or multicicly carbocyclic radicals containing 6 to 10 carbon atoms. "Alkyl" means an aryl-alkyl group wherein the aryl and alkyl are as described herein. "Heteroaryl" means a 5- to 10-membered aromatic monocyclic or multicyclic hydrocarbon ring system in which one or more of the atoms in the ring system is a non-carbon element, selected from nitrogen, oxygen and sulfur. "Heterocyclic" means a saturated or partially unsaturated monocyclic or multicyclic hydrocarbon ring system of 4 to 10 members in which one or more of the atoms in the ring system is a different carbon element, selected from nitrogen, oxygen or sulfur. "Heteroarylalkyl" means a heteroaryl-alkyl- and heterocycloalkyl group means a heterocycle-alkyl- group. Alkylcarbonyl means an alkyl-CO- group in which the alkyl group is as previously described. Arylcarbonyl means an aryl-CO- group in which the aryl group is as previously described. Heteroarylcarbonyl means a heteroaryl-CO- group, and heterocyclocarbonyl means a heterocycle-CO- group. arylsufonyl 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 alkoxy-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 a carbonyl oxygen can not be a constituent on an aryl ring. Heterocyclic ring means a monocyclic or multicyclic ring system of 4 to 10 members (which may be saturated or partially unsaturated) wherein one or more of the atoms in the ring system is a different carbon element, selected from among nitrogen, oxygen or sulfur atoms. Halogen means fluorine, chlorine, bromine or iodine. The invention further provides a process for the preparation of a compound of formula (i), wherein R1-R15, m, n, p, q, A and B are as defined above. It will be appreciated that functional groups such as amino, hydroxyl or carbonyl groups present in the various compounds described below and which are desired to be retained, may need to be in protected forms before any reaction is initiated. In such cases, the removal of the protecting group may be the final step in a particular reaction. Suitable protecting groups for such functionalities will be apparent to those skilled in the art. For specific details, see Protective Groups in Organic Synthesis, Wiley Interscience, TW Greene. Thus, a process for preparing compounds of formula (i) in which B contains an -OH group which comprises deprotecting (eg by hydrogenolysis or hydrolysis) a compound of formula (i) in which B contains an appropriate -OP where P represents a suitable protecting group (for example, benzyl or acetyl). A process for the preparation of a compound of formula (i) comprising in the reaction of an appropriate carboxylic acid of formula (ii) with a suitable amine of formula (iii) < i¡) < ia) where Ría represents Ri as defined in relation to formula (i) or a group that can be converted to Ri and R2a-R5a similarly represent R2-R5 or groups that can be converted to R2-R5 and Aa represents A or a group that can be converted to A and Ba represents B or a group that can be converted to B; and after this, it is required to convert any Ria group to Ri and / or R2a to R2 and / or R3a to R3 and / or R4a to R and / or Rsa to R5 and / or Aa to A and / or Ba to B The reaction of a carboxylic acid of formula (ii) with an amine of formula (iii) can be carried out under any suitable condition known to those skilled in the art. Advantageously, the carboxylic acid is converted to an acid chloride, mixed anhydride, p-nitrophenyl ester or other activated intermediate before reaction with an amine of formula (iii). Favorably the reaction with the amine of formula (iii) 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 will be required, such as sodium hydride and a polar solvent such as dimethylformamide. The carboxylic acids of 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 formula (ii) is conveniently prepared from an appropriate benzofuran of formula (v) The conversion of a benzofuran of formula (v) to a carboxylic acid of formula (ii) can be carried out using any standard procedure known to those skilled in the art. For example, a benzofuran of formula (v) can be formulated to provide an aldehyde of formula (iv) which can then be oxidized to provide the corresponding acid of formula (ii). Alternatively, a benzofuran of formula (v) can be formed to provide a bromide of formula (vi) which can then be converted to a carboxylic acid of formula (ii), for example by a carboxylation catalyzed by an organometallic compound, or by generation of a Grignard reagent followed by quenching with carbon dioxide.

The benzofurans of formula (v) can be prepared by any standard procedure known to those skilled in the art, for example by the methods described in WO-A-9720833 or by treatment of a compound of formula (vii) with a strong base ( such as butyllithium) followed by reaction of a BaAaR2aW agent wherein W is a suitable leaving group such as a halogen or a Gi agent, where Gi contains for example a reactive carbonyl moiety, a nitrile or a sulfonyl moiety and after the reaction constitutes the BaAaR2a group. Alternatively, the benzofurans of formula (v) can be prepared from the compounds of formula (vii) by modification of the group Aa, for example by the formation of a sulfonyl chloride from a salt of sulfinic acid using N-chlorosuccimide and a subsequent treatment with a reactive Ba species, for example dimethylamine. The compounds of formula (viii) can be prepared by treatment of a compound of formula 8vii) with a strong base (such as butyllithium) followed by reaction of an agent AaR2aW wherein W is a suitable leaving group such as a halogen, or an agent G2, wherein G2 contains for example a reactive carbonyl portion, a nitrile or a sulfonyl portion and after reaction constitutes the group AaR2a. A compound of formula (vii) can be prepared by any standard procedure known to those skilled in the art, for example by procedures similar to those described in Organic Syntheses, Coll. Vol. V, 251-254.

The amines of formula (iii) are either commercially available, compounds previously described or are prepared using standard procedures known to those skilled in the art. A compound of formula (Ia) can also be prepared by reaction of a carboxylic acid of formula (ii) with an amine of formula (ix) to provide a compound of formula (a) in which R 4a is H, followed by reaction with an appropriate alkylating agent of formula (x) R 4aX (x) (ia) wherein Ria-Rsa, Aa and Ba are as defined above and X represents a suitable leaving group such as a halogen. The reaction of a carboxylic acid of formula (ii) with an amine of formula (ix) can be carried out under any suitable condition known to those skilled in the art. Advantageously, the carboxylic acid is converted to an acid chloride, mixed anhydride, p-nitrophenyl ester or other activated intermediate prior to reaction with an amine of formula (ix). Advantageously, the reaction with the amine of formula (ix) 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 reaction of a compound of formula (a) in which R 4 is H with an alkylating agent of formula (x) can be carried out under any suitable condition known to those skilled in the art. The reaction is favorably carried out using an appropriate base, such as sodium hydride, preferably in an appropriate solvent such as dimethylformamide. The amines of formula (ix) and alkylating agents of formula (x) are either commercially available or are prepared using standard procedures known to those skilled in the art. Some compounds of formula (i) can be prepared from other compounds of formula (i). For example, compounds in which A-B contains an alkoxy group can be prepared from compounds in which A-B contains a hydroxy group by alkylation using any suitable condition known to those skilled in the art. Suitable conditions include the use of an appropriate base such as sodium hydride, in an appropriate solvent such as DMF, followed by the addition of a suitable alkyl halide such as iodomethane. The compounds in which A-B contain an amino group can be prepared by reductive amination of an appropriate carbonyl-containing compound. The compounds of formula (i) in which R5 contains an N-oxide-pyridyl can be prepared from compounds of formula (i) in which R5 contains a pyridyl group using any standard condition known to those skilled in the art. Suitable conditions include the use of an oxidizing agent such as peracetic acid in an appropriate solvent such as chloroform. It will be appreciated by those skilled in the art that in some cases it may be more appropriate to carry out the transformations mentioned above on compounds of formula (ii), (vi) or (v) rather than on compounds of formula (i). It will be appreciated that when a particular stereoisomer of formula (i) is required this can be obtained by conventional resolution techniques such as high performance liquid chromatography or the synthetic processes described herein can be performed using the appropriate homochiral starting material. The invention includes the prevention and treatment of diseases or disease states mediated by TNF, by which is meant any and all disease states in which TNF plays a role, either by the production of TNF itself or because TNF causes another cytosine is released, such as but not limited to IL-1 or IL-6. A pathological state in which IL-1, for example, is a major component, and whose production or action is exacerbated or secreted in response to TNF, would therefore be considered as a disease state mediated by TNF. Since TNF-β (also known as lymphotoxin) has close structural homology to TNF-a (also known as cachetin), each post induces similar biological responses and binds to the same cell receptor, it is considered that both TNF-α and TNF-β are inhibited by compounds of the present invention and thus are collectively referred to herein as "TNF" unless specifically delineated in another manner. PDE IV inhibitors are useful in the treatment of a variety of allergic and inflammatory diseases, including: asthma, chronic bronchitis, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease, atopic dermatitis, atopic eczema, urticaria, allergic rhinitis, allergic conjunctivitis , vernal conjunctivitis, eye inflammation, allergic eye responses, eosinophilic granuloma, psoriasis, Bechet's disease, erythomatosis, anaphylactoid nephritis purpura, joint inflammation, arthritis, rheumatoid arthritis, and other arthritic conditions such as rheumatoid spondylitis and osteoarthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock and adult respiratory distress syndrome. In addition, PDE IV inhibitors are useful in the treatment of diabetes insipidus and conditions associated with cerebral metabolic inhibition, such as cerebral senility, senile dementia (Alzheimer's disease), memory deficiency associated with Parkinson's disease, depression and dementia due to multiple infarctions. PDE IV inhibitors are also useful under conditions enhanced by neuroprotective activity, such as for cardiac, apoplexy and intermittent claudication. PDE IV inhibitors may be useful in the treatment of tardive dyskinesia, ischemia and Huntington's disease. Additionally, PDE IV inhibitors may have utility as gastroprotectors. A special embodiment of the therapeutic methods of the present invention is the treatment of asthma. Inhibitors of TNF release are useful in the treatment of viral infections. Viruses contemplated for treatment herein are those that produce TNF as a result of infection or those that are sensitive to inhibition, such as by replication decreased, directly or indirectly, by inhibitors of TNF release of 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 Herpes simplex This invention relates more specifically to a method for treating a mammal, afflicted with the human immunodeficiency virus (HIV), which comprises administering to said mammal an effective amount that inhibits the release of TNF from 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, that need inhibition of TNF production. The TNF-mediated diseases for treatment, therapeutically or prophylactically, in animals include pathological states such as those noted above, but in particular viral infections. Examples of such viruses include, but are not limited to, feline immunodeficiency virus (FIV) or other retroviral infections such as equine infectious anemia virus, caprine arthritis virus, visna virus, maedi virus. and other lentiviruses.

The compounds of this invention are also useful for treating infections by parasites, yeasts and fungi, wherein such yeasts and fungi are sensitive to up-regulation by TNF or will initiate the production of TNF in vivo. A preferred disease state for treatment is fungal meningitis. The compounds of formula (i) are preferably in pharmaceutically acceptable form. By pharmaceutically acceptable form is understood, 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 dosage levels. A pharmaceutically acceptable level of purity will generally be at least 50% excluding normal pharmaceutical additives, preferably 75%, more preferably 90%, and still more preferably 95%. When the term "pharmaceutically acceptable" is used herein, it includes materials suitable for both veterinary and human uses. A compound of formula (i) or when appropriate a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof, may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.

Thus, the present invention provides a pharmaceutical composition comprising a compound of formula (i) or when appropriate a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof and a pharmaceutically acceptable carrier. 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 unit dosage form, or in a form that a human patient can administer to itself. same in a single dose. Advantageously, the composition is suitable for oral, rectal, topical or parenteral administration or through the respiratory system. Preparations can be designed to give a slow release of the active ingredient. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular injections, intrasternal injection or infusion techniques. In addition to the treatment of warm-blooded animals, such as mice, 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, flasks, powders, granules, diamond-shaped tablets, suppositories, reconstitutable powders or liquid preparations such as sterile, oral or parenteral solutions or suspensions. Topicals are also considered when 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: the unit dosage forms 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; lubricants for tableting, for example, magnesium stearate, disintegrants, example starch, polyvinyl pyrrolidone, sodium starch glycolate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate. The solid oral compositions can be prepared by conventional methods of mixing, filling, tabletting or the like. Repeated mixing operations can be used to distribute the active agent in all these compositions employing large amounts of fillers. Such operations are of course conventional in the art. The tablets can be coated according to well-known methods 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 presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as dispersing agents, sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible fats.; emulsifying agents such as for example lecithin, sorbitan monooleate, or acacia, non-aqueous vehicles (which may include edible oils (eg, almond oil, fractionated coconut oil, fatty 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 be suitably presented for administration to the respiratory system, such as a spray or an aerosol or solution for a or in a microfine powder for insulting, alone or in combination with an inert carrier such as lactose, in which case the particles of the active compound suitably have diameters of less than 50 microns, such as from 0.1 to 50 microns, preferably less than 50 microns. 10 microns, for example from 1 to 10 microns, from 1 to 5 microns or from 2 to 5 microns. do, small amounts of other antiasthmatics and bronchodilators such as for example sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine; Corticosteroids such as prednisolone and adrenal stimulants such as ACTH may be included. For parenteral administration, fluid unit dosage forms are prepared using the compound and a sterile vehicle, depending on the concentration used, can be either suspended or dissolved in the vehicle. When the solutions are being prepared, the compound can be dissolved in water for injection and sterilized by filtration before depositing it in a suitable vial or ampoule and sealing it. Advantageously, adjuvants such as a local anesthetic, a preservative and damping agents can be dissolved in the vehicle. To improve stability, the composition can be frozen after filling in the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved and sterilization can not be achieved by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending it in a 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 39% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. The compounds of formula (i) or if appropriate a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof, can be administered as a topical formulation in combination with conventional topical excipients. Topical formulations may be presented for example as ointments, creams or lotions, impregnated dressings, gels, gel sticks, sprays and aerosols and may contain appropriate conventional additives such as preservatives, solvents to aid penetration of the drug and emollients in ointments. and creams. The formulations may contain compatible conventional carriers, such as cream and ointment base and ethanol or oleyl alcohol for lotions.

Suitable cream, lotion, gel, stick, ointment, spray or aerosol formulations that can be used for the compounds of formula (i) or if a pharmaceutically acceptable salt thereof is appropriate, are conventional formulations well known in the art, example, such as those described in standard textbooks such as Harry's Cosmeticology published by Leonard Hill Books, Remington's Pharmaceutical Sciences and the British and North American pharmacopoeias. Suitably, the compounds of formula (i) or a suitable pharmaceutically acceptable salt thereof, will comprise from about 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 manner with the seriousness of the disorder, the weight of the patient and the relative efficacy of the compound. However, as a general guide, suitable unit doses may be from 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, so that the total daily dosage for a adult 70 kg 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 a 0.05 mg / kg / day, for example 0.01, 0.02, 0.04, 0.05, 0.06, 0.08, 0.1 or 0.02 mg / kg / day, and each therapy can be extended for a number of weeks or months The following examples illustrate the invention.

Intermediate 1 Cyclopropyl- (7-methoxybenzofuran-2-yl) -methanone To a stirred solution of 7-methoxybenzofuran (3.0 g) in tetrahydrofuran (60 ml) cooled to -78 ° C under a nitrogen atmosphere was added dropwise n -butillitio (1.6 M in hexanes, 15.2 ml). After stirring at -78 ° C for 30 minutes, magnesium bromide-diethyl etherate (6.3 g) was added in a single portion and the reaction mixture was allowed to warm to 0 ° C and stirred for 30 minutes. Cyclopropyl cyanide (1.8 ml) was then added dropwise and the mixture was allowed to warm slowly to room temperature and stirred for 18 hours. Aqueous hydrochloric acid (2 M, 50 ml) was added to the reaction mixture and stirring continued for 1 hour. The mixture was extracted with ethyl acetate (250 ml), then washed successively with water (50 ml) and saline (50 ml). The organic layer was separated and dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel eluting with 5-20% hexyl acetate in hexane gave the title compound as a yellowish oil (1.96 g). TLC Rf = 0.41 (20% ethyl acetate in hexane) Intermediate Cyclopropyl- (7-methoxybenzofuran-2-yl) -e year1 To a stirred solution of 7-methoxybenzofuran (2.0 g) in tetrahydrofuran (30 ml) cooled to -60 ° C under a nitrogen atmosphere was added dropwise n -butyllithium (1.6 M in hexanes, 8.9 ml). After stirring at -60 ° C for 10 minutes, magnesium bromide-diethyl stearate (3.8 g) was added in a single portion and the reaction mixture was stirred at 50 ° C for 10 minutes. After cooling to -78 ° C, cyclopropane carboxaldehyde (1.0 ml) was added in a single portion and the mixture allowed to warm slowly to room temperature and stirred for 1 hour. Water (2 ml) was added and the tetrahydrofuran was removed in vacuo. The residue was partitioned between ethyl acetate (50 ml) and water (50 ml); the aqueous layer was extracted with ethyl acetate (50 ml); the organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with 0-5% methanol in dichloromethane gave the title compound as a yellow gum (1.88 g). TLC Rf = 0.14 (dichloromethane) Intermediate 2- (cyclopropyl-methoxy-methyl) -7-methoxybenzofuran To a stirred suspension of sodium hydride (60% dispersion in mineral oil, 0.52 g) in tetrahydrofuran (60 ml) under a nitrogen atmosphere was slowly added a solution of cyclopropyl- (7-methoxybenzofuran-2-yl) -methanol (1.88 g) in tetrahydrofuran (15 ml). After stirring for 5 minutes, iodomethane (1.6 ml) was added and the reaction mixture was stirred at room temperature for 1 hour. Water (5 ml) was added and the mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate (100 ml) and water (100 ml), the organic layer was washed with water (100 ml), separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography on silica, eluting with dichloromethane gave the title compound as a yellow gum (1.62 g). CCF Rf = 0.79 (dichloromethane) Intermediate 4 Lithium salt of 7-methoxybenzofuran-2-sulfinic acid n-Butyllithium (1.6 M in hexanes, 4.6 ml) was added dropwise to a stirred solution of 7-methoxybenzofuran (1 g) in tetrahydrofurans (10 ml) at -78 ° C under an inert atmosphere. After stirring for an additional 15 minutes, sulfur oxide was bubbled through the mixture for 10 minutes, until the reaction showed an acid pH on wet indicator paper. Hexane (40 ml) was added and the reaction was warmed to room temperature. The precipitate was filtered and washed with hexane (50 ml) to give the title compound as a tan solid (1.2 g). Mass spectrum = 211 [M-l] free acid Intermediate 5 7-methoxy-2-methylsulfonylbenzofuran. N-Butyllithium (1.6 M in hexanes, 10.2 ml) was added dropwise to a cooled solution (-78 ° C) of 7-methoxybenzofuran (2.0 g) in tetrahydrofuran (40 ml). under an inert atmosphere. Methyl disulfide (1.46 ml) was added and the reaction mixture was stirred at -78 ° C for 30 minutes, and then at room temperature for 1 hour. Water was added and the tetrahydrofuran was removed in vacuo. The aqueous residue was extracted with ether (3 x 100 ml) and the combined organic phases were washed with water (100 ml) and dried over sodium sulfate. The solvent was removed in vacuo to give the title compound as a yellow oil (2.73 g). TLC Rf = 0.75 (20% ethyl acetate in hexane) Intermediate 6 2-methanesulfonyl-7-methoxybenzofuran A solution of Oxono® (7.37 g) in water (40 ml) was added to a solution of 7-methoxy-2-methylsulfanylbenzofuran (2.24 g) and the reaction mixture was stirred at room temperature. atmosphere all night. The methanol was removed in vacuo and the resulting paste was extracted with ethyl acetate (2 x 200 ml). The combined organic phases were washed with saline (200 ml) and then dried over sodium sulfate. The solvent was removed in vacuo to give the title compound as a yellow solid (2.24 g). TLC Rf 0.26 (20% ethyl acetate in hexane) Intermediate 7-methoxybenzofuran-2-sulfonic acid dimethyl amide N-chlorosuccinimide (1 g) was added in portions to the lithium salt of 7-methoxybenzofuran-2-sulfinic acid (1.47 g) in dichloromethane (15 ml) at 0-5 ° C under an inert atmosphere. The reaction was stirred at this temperature for 15 minutes, and then warmed to room temperature and stirred for an additional 15 minutes. The mixture was filtered through a celite bed, washing well with dichloromethane. The solvent was removed in vacuo to. Give a solid cinnamon color as the raw intermediary. This intermediate is added to a stirred solution of dimethylamine hydrochloride (0.67 g) and triethylamine (2.2 ml) in tetrahydrofuran (20 ml) at 0-5 ° C under an inert atmosphere. The reaction was stirred at this temperature for 1 hour and then warmed to room temperature and stirred for an additional 48 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (2 x 40 ml) and water (50 ml). The combined organic phases were washed with 1 M hydrochloric acid (2 x 20 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was washed with hexane (40 ml) to give the title compound as a tan solid (0.88 g). TLC Rf 0.52 (50% ethyl acetate in hexane) Intermediate 8 (4-bromo-7-methoxybenzofuran-2-yl) -cyclopropyl methanone N-bromosuccinimide (0.21 g) was added in a single portion to a stirred solution of cyclopropyl- (7-methoxybenzofuran-2-yl) -methanone ( 0.25 g) in acetonitrile (20 ml) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 24 hours, water (20 ml) was added, the mixture was extracted with ethyl acetate (100 ml), the organic layer was separated, dried over magnesium sulfate, filtered and it was concentrated in vacuo. Purification by flash chromatography on silica, eluting with 5-10% ethyl acetate in hexane gave the title compound as an off white solid (0.24 g). TLC Rf 0.48 (20% ethyl acetate in hexane) The following intermediates were prepared using the above method.

Intermediate 4-bromo-2- (cyclopropyl-methoxy-methyl) -7-methoxy-benzofuran Prepared from 2- (cyclopropyl-methoxy-methyl) -7-methoxybenzofuran (3.12 g) and N-bromosuccinimide (2.4 g) in acetonitrile (45 ml). The title compound was obtained as an orange gum (3.49 g) TLC Rf 0.31 (50% cyclochloromethane in hexane) Intermediate 10-dimethylamide 4-bromo-7-methoxybenzofuran-2-sulfonic acid Prepared from dimethylamine 7-methoxybenzofuran-2-sulfonic acid (0.82 g9 and N-bromosuccinimide (0.57 g) in acetonitrile (50 ml). by column chromatography eluting with 50% ethyl acetate in hexane gave the desired product as a pale yellow solid (1.0 g) TLC Rf 0.34 (50% ethyl acetate in hexane) Intermediate 11 4-bromo-2-methanesulfonyl-7-methoxybenzofuran Prepared from 2-methansphonyl-7-methoxybenzofuran (0.50 g) and N-bromosuccinimide (0.39 g) in acetonitrile (30 ml). Purification by flash chromatography on silica eluting with 50% ethyl acetate in hexane gave the title compound as a white solid (0.73 g).

TLC Rf 0.27 (20% ethyl acetate in hexane).

Intermediate 12 2-cyclopropanecarbonyl-7-methoxybenzofuran-4-carboxylic acid To a solution of (4-boron-7-methoxybenzofuran-2-yl) -cyclopropyl-methanone (1.0 g) in tetrahydrofuran / water (40 ml / 20 ml) palladium acetate (76 mg), 1,3-bis (diphenylphosphino) propane (280 mg) and triethylamine (4.7 ml) were added. The reaction mixture was heated to 90 ° C under one. atmosphere of 10.5 kg / cm2 (150 pounds / square inch) of carbon monoxide for 3 days. The reaction mixture was allowed to cool to room temperature and the carbon monoxide pressure was released. The tetrahydrofuran was removed in vacuo and the aqueous residue was washed with ethyl acetate (2 x 75 ml) and acidified to pH 3 with 2M hydrochloric acid. Extracted with ethyl acetate (2 x 200 ml), the organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to provide the title compound as a light yellow solid (0.76 g). TLC Rf 0.35 (50% ethyl acetate in hexane) The following intermediates were prepared using the above method.

Intermediate 13 2- (Cyclopropyl-methoxy-methyl) -7-methoxybenzofuran-7-carboxylic acid Prepared from 4-bromo-2- (cyclopropyl-methoxy-methyl) -7-methoxy-benzofuran (350 mg), palladium (25 mg), 1,3-bis (diphenylphosphino) propane (93 mg) and triethylamine (1.6 ml) in tetrahydrofuran (20 ml / 10 ml). The title of the compound was obtained as a cream solid (250 mg). TLC Rf 0.10 (20% ethyl acetate in hexane) Intermediary 14 2-dimethylsulfamyl-7-methoxybenzofuran-4-carboxylic acid Prepared from 4-bromo-7-methoxybenzofuran-2-sulfonic acid dimethylamide (1.0 g), triphenylphosphine (0.28 g), bis (triphenylphosphine) palladium (II) chloride (0.15 g) and triethylamine (4.2 ml) in tetrahydrofuran / water (40 ml / 20 ml). The title compound was obtained as a white solid (0.79 g). TLC Rf 0.57 (10% methanol in dichloromethane) Intermediate 15 2-methanesulfonyl-7-methoxybenzofuran-4-carboxylic acid Prepared from 4-bromo-2-methanesulfonyl-7-methoxybenzofuran (1.64 g), triphenylphosphine (0.49 g), bis ((triphenylphosphine) palladium chloride (II ) (0.25 g) and triethylamine (7.2 ml) in tetrahydrofuran / water (68 ml / 35 ml) The title compound was obtained as a white solid (1.23 g) TLC Rf 0.21 (ethyl acetate) Intermediate 16 4-Nitrophenyl ester of 2-cyclopropanecarbonyl-7-methoxybenzofuran-4-carboxylic acid To a stirred suspension of 2-cyclopropanecarbonyl-7-methoxybenzofuran-4-carboxylic acid (0.50 g) in dichloromethane (30 ml) under an atmosphere of nitrogen was added 4-nitrophenol (0.29 g), 4-dimethylaminopyridine (20 mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.41 g). The reaction mixture was stirred at room temperature for 18 hours, water (30 ml) was added, and the mixture was extracted with dichloromethane (150 ml). The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with 40% ethyl acetate in hexane gave the title compound as a pale yellow solid (0.59 g). TLC Rf 0.31 (40% ethyl acetate in hexane) The following intermediates were prepared using the above method.

Intermediary 17 2-Cyclopropyl-methoxy-methyl-7-methoxybenzofuran-4-carboxylic acid 4-nitrophenyl ester Prepared from 2- (cyclopropyl-methoxy-methyl) -7-methoxybenzofuran-4-carboxylic acid (250 mg) , 4-nitrophenol (140 mg), 4-dimethylaminopyridine (11 mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (190 mg) in dichloromethane (20 ml). The title compound was obtained as a pale yellow oil (230 mg). TLC Rf 0.24 (20% ethyl acetate in hexane) Intermediate 18 4-nitrophenyl ester of 2-diemthylsulfamyl-7-methoxybenzofuran-4-carboxylic acid Prepared from 2-dimethylsulfamyl-7-methoxybenzofuran-4-carboxylic acid (0.5 g), 4-nitrophenol (270 mg), 4- dimethylaminopyridine (11 mg) and l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (370 mg) in dichloromethane (30 ml). Trituration from ethyl acetate and hexane gave the desired product as a cream solid (0.61 g). TLC Rf 0.79 (ethyl acetate).

Intermediary 19 7-Methoxy-2- (1-methyl-piperidin-4-yloxymethyl) -benzofuran-4-carboxylic acid 4-nitrophenyl ester Prepared from 7-methoxy-2- (1-methyl-piperidin-4) acid -iloxymethyl) -benzofuran-4-carboxylic acid (1.9 g), 4-nitrophenol (835 mg), 1- (3-dimethiaminopropyl) -3-ethylcarbodiimide hydrochloride (1.15 g) and 4-dimethylaminopyridine (catalytic amount) in dichloromethane ( 40 ml). Purification by column chromatography eluting with 10% ethanol in dichloromethane gave the desired product as a pale yellow solid (720 mg). TLC Rf 0.30 (10% methanol in dichloromethane).

Intermediate 2-cyclopropanecarbonyl-7-methoxybenzofuran-4-carboxylic acid 20 (3-methylpyridin-4-yl) amide To a stirred solution of 4-amino-3-methylpyridine (160 mg) in dimethylformamide (10 ml) under one. hexamethyldisilazide (1.0 M solution in tetrahydrofuran, 1.5 ml) was added to the nitrogen atmosphere. The reaction mixture was stirred at room temperature for 10 minutes. 2-Cyclopropanecarbonyl-7-methoxy-benzofuran-4-carboxylic acid 4-nitrophenyl ester (280 mg) was then added and stirring was continued for 18 hours. Water (10 ml) was added and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (150 ml), washed with water (3 x 50 ml) and washed with saline (50 ml). The combined aqueous layers were extracted with dichloromethane (2 x 50 ml), the organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with 5% methanol in dichloromethane, followed by trituration with diethyl ether gave the title compound as an off white solid (130 mg).

TLC Rf 0.21 (5% methanol in dichloromethane) Intermediate 2-cyclopropanecarbonyl-7-methoxybenzofuran-4-carboxylic acid 21 (3-methyl-1-oxy-pyridin-4-yl) amide To a stirred solution of 2- (3-methylpyridin-4-yl) amine of 2-acid Cyclopropancarbonyl-7-methoxybenzofuran-4-carboxylic acid (120 mg) in chloroform (10 ml) was added peracetic acid (36-40% solution in acetic acid, 0.13 ml). The reaction mixture was stirred at room temperature for 72 hours. The solvent was removed in vacuo and the residue was washed with water (5 ml) and diethyl ether (5 ml) to give the title compound as a pale yellow solid (106 mg). TLC Rf 0.24 (10% methanol in dichloromethane) Intermediate 22 Dimethyl acetal of 2- (2-foprtyl-6-methoxyphenoxy) acetaldehyde O-vanillin (20 g) and potassium carbonate (18 g) were stirred in N, N-dimethylformamide (80 ml) at room temperature for 30 minutes . Bromoacetaldehyde dimethyl acetal (24 g) was added dropwise, making sure that the temperature did not rise above 50 ° C. The mixture was then heated to reflux for 4 hours, then cooled to room temperature. Diethyl ether (30 ml) was added and the mixture was filtered. The solid was washed with ether (2 x 20 ml) and the combined organic phases were concentrated in vacuo to give the title compound (33 g) as a green oil. TLC Rf 0.66 (50% ethyl acetate in hexane).

Intermediate 23 2-formyl-7-methoxybenzofuran The dimethyl acetal of 2- (2-formyl-6-methoxyphenoxy) acetaldehyde (31 g) was heated under reflux in glacial acetic acid (120 ml) overnight. The mixture was then cooled, and solvent was removed in vacuo to give a red oil. Purification by distillation in Kugelrohr gave the title compound (17 g) as a pale yellow oil which solidified with time. CCF Rf 0.71 (dichloromethane) Intermediate 24 2-formyl-4-bromo-7-methoxybenzofuran. 2-Formyl-7-methoxybenzofuran (1.0 g) in dichloromethane (10 ml) was stirred under nitrogen at 0 ° C. Sodium acetate (1.4 g) was added, followed by the dropwise addition of bromine (0.29 ml). Additional dichloromethane (20 ml) was added to the mixture to facilitate stirring, and the mixture was stirred overnight. The reaction mixture was diluted with dichloromethane (40 ml) and washed with water (30 ml). Drying over magnesium sulfate was followed by removal of the solvent in vacuo, gave a pale orange solid. Purification by flash chromatography on silica eluting with 10% ethyl acetate in hexane gave the title compound (0.50 g) as a beige solid. TLC Rf 0.30 (10% ethyl acetate in hexane) Intermediate 25 (4-bromo-7-methoxybenzofuran-2-yl) -methanol Sodium borohydride (1.12 g) was added in portions to a stirred solution of 2-formyl-4-bromo-7-methoxybenzofuran (30 g) in 1 portion. -butanol (150 ml) at room temperature. After stirring for 1 hour, the reaction was quenched by the addition of 2M hydrochloric acid (100 ml) was stirred overnight. The mixture was separated and the organic phase was washed with water (200 ml). The combined aqueous phases were extracted with tert-butyl methyl ether (100 ml). The organic phases were combined and concentrated in vacuo followed by drying in vacuo at 60 ° C to give the title compound as a brown solid (26 g). TLC Rf 0.15 (25% ethyl acetate in hexane).

Intermediate 26 4-bromo-2-bromomethyl-7-methoxy-benzo-rano Carbon tetrabromide (1.52 g) was added to a stirred solution of (4-bromo-7-methoxybenzofuran-2-yl) -methanol (1 g) in dichloromethane (10 ml) at 0 ° C under an inert atmosphere. Then triphenylphosphine (1.53 g) was added, and the reaction was stirred for 1 hour. The reaction mixture was preabsorbed onto silica and purified by column chromatography eluting with 25% ethyl acetate in hexane to give the title compound as a yellow solid (0.78 g). TLC Rf 0.45 (25% ethyl acetate in hexane).

Intermediate 27 4- (4-Bromo-7-methoxybenzofuran-2-ylmethoxy) -piperidine-1-carboxylic acid tert-butyl ester Sodium hydride (72 mg of a 60% dispersion in oil) is added to a stirred solution tert-butyl ester of 4-hydroxy-piperidine-l-carboxylic acid (363 mg) in N ', N-dimethylformamide (10 ml) under an inert atmosphere at room temperature. After stirring for 30 minutes, 4-bromo-2-bromomethyl-7-methoxybenzofuran (526 mg) was added and the reaction was stirred overnight. The reaction mixture was preadsorbed onto silica and purified by column chromatography with 25% ethyl acetate in hexane to provide the desired product as a yellow oily solid (269 mg). TLC Rf 0.33 (25% ethyl acetate in hexane).

Intermediate 28 4- (4-bromo-7-methoxybenzofuran-2-ylmethoxy) -piperidine Trifluoroacetic acid (5 ml) was added to a stirred solution of 4- (4-bromo-7-methoxybenzofuran-2) -butyl ester. -ylmethoxy) -piperidine-1-carboxylic acid (1.3 g) in dichloromethane (50 ml). After stirring at room temperature overnight the reaction was diluted with dichloromethane (150 ml), washed with 1 M sodium hydroxide (100 ml) and dried over magnesium sulfate. The organic phase was concentrated in vacuo to give the title compound as a pale yellow gum (0.98 g). Mass spectrum 340 [M + H] +.

Intermediate 29 4- (4-boro-7-methoxybenzofuran-2-ylmethoxy) -1-methyl-piperidine The mixture was combined and heated at 95 ° C overnight (4- (4-bromo-7-methoxybenzofuran-2-ylmethoxy) - piperidine (0.98 g), formic acid (0.65 ml) and formaldehyde (0.56 g of a 37% w / w solution in water). After cooling to room temperature the mixture was diluted with water (70 ml) and a concentrated aqueous solution of sodium hydroxide was added until the solution was basic (pH = 14). This was extracted with ethyl acetate (2 x 100 ml). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to give the title compound as a pale yellow oil (1.03 g). Mass spectrum 355 [M + H] +.

Intermediate 30 7-Methoxy-2- (1-methyl-piperidin-4-yloxymethyl) -benzofuran-4-carboxylic acid. 4- (4-Bromo-7-methoxy-benzofuran-2-ylmethoxy) -1-methyl- piperidine (1 g), bis (triphenylphosphine) palladium chloride (142 mg), triphenylphosphine (300 mg), triethylamine (5 ml), tetrahydrofuran (12 ml) and water (4 ml) in a Parr pressure reactor and heated at 90 ° C under 9.84 kg / cm2 (140 pounds / square inch) of carbon monoxide for 3 days. After cooling to room temperature and releasing the pressure, the mixture was diluted with water (100 ml) and washed with ethyl acetate (2 x 100 ml). The aqueous layer was acidified with concentrated hydrochloric acid to .pH5. The water was evaporated in vacuo to give a yellow solid (1.91 g), which comprised the title compound and triethylamine hydrochloride. Mass spectrum 320 [M + H] +.

Example 1: 2-dimethylsulfamyl-7-methoxybenzofuran-4-carboxylic acid 1-3-methyl-pyridin-4-ylide To a stirred solution of 4-amino-3-methylpyridin (200 mg) in dimethylformamide (8 ml) under a nitrogen atmosphere at 0 ° C was added sodium hexamethyldisilazide (1.0 M solution in tetrahydrofuran, 1.9 ml). The reaction mixture was stirred at this temperature for 5 minutes, then 4-nitrophenyl ester of 2-dimethylsulfamil-7-methoxy-benzofuran-4-carboxylic acid (400 mg) was added and stirring continued for 30 minutes. Water (10 ml) was added and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (150 ml), washed with water (3 x 50 ml) and washed with saline (50 ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by column chromatography, eluting with 10% methanol in ethyl acetate gave the title compound as a white solid (0.3 g). TLC Rf 0.47 (10% methanol in ethyl acetate). Melting point 216-217 ° C.

Example 2 2- (Cyclopropyl-methoxy-methyl) -7-methoxybenzofuran-4-carboxylic acid (2, 3-dichloro-l-oxy-pyridin-4-yl) amide To a stirred solution of 4-amino-3, 5-dichloro-1-oxy-pyridine (960 mg) in dimethylformamide (40 ml) under a nitrogen atmosphere was added sodium hydride (60% dispersion in mineral oil, 236 mg). The reaction mixture was stirred at room temperature for 10 minutes. Then 4-nitrophenyl ester of 2-cyclopropyl-methoxy-methyl) -7-methoxybenzofuran-4-carboxylic acid (710 mg) was added and stirring continued for 90 minutes. Water (5 ml) was added and the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, eluting with ethyl acetate, to afford the title compound as an orange solid (47 mg). TLC Rf 0.18 (ethyl acetate).

Melting point 162-164 ° C (decomposition). The following compound was prepared by a similar procedure.

Example 3 7-Methoxy-2- (1-methyl-pyridin-4-yloxymethyl) -benzofuran-4-carboxylic acid 3,5-dichloro-l-hydroxy-piperidin-4-yl) amide Prepared from hydride sodium (115 mg of a 60% dispersion in oil), N-oxide of 4-amino-3,5-dichloropyridine (474 mg), 4-nitrophenyl ester of 7-methoxy-2- (l-methyl) -piperidin-4-yloxymethyl) -benzofuran-4-carboxylic acid (389 mg) in N, -dimethylformamide. Purification by column chromatography eluting with u? 20% methanol in dichloromethane gave the desired product as a light brown solid (106 mg). TLC Rf 0.23 (20% methanol in dichloromethane). Mass spectrum 481 [M + H] +.

Example 2 (2-methanesulfonyl-7-methoxybenzofuran-4-carboxylic acid oxalyl chloride) (2-methanesulfonyl-7-methoxybenzofuran-4-carboxylic acid 0.27 ml) (0.40 g) ) in dichloromethane (15 ml) under an inert atmosphere. Dimethyl formamide (catalytic amount) was added, and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo to provide the corresponding acid chloride, as a yellow solid. 4-Amino-3-methylpyridine (0.32 g) was added to the acid chloride in dichloromethane (30 ml). The reaction mixture was stirred at room temperature overnight, and then the solvent was removed in vacuo. The product was first purified by flash chromatography on silica eluting with 10% methanol in ethyl acetate to give the title compound as an off-white solid (0.38 g). TLC Rf 0.2 (10% methanol in ethyl acetate). Melting point 191-193 ° C Example 5: 2-Dimethylsulfamyl-7-methoxybenzofuran-4-carboxylic acid (3-methyl-1-oxy-pyridin-4-yl) amide A stirred solution of (3-methyl-pyridin-4-yl) -amide of the acid 2-dimethylsulfamyl-7-methoxybenzofuran-4-carboxylic acid (0.16 g) in chloroform (15 ml) was added peracetic acid (36-40% solution in acetic acid, 0.08 ml). The reaction was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was purified by column chromatography, eluting with 10% methanol in dichloromethane to give the desired compound as a white solid (0.14 g). TLC Rf 0.36 (10% methanol in dichloromethane) Melting point 186-187 ° C The following examples were prepared by a similar procedure.

Example 6 2-methanesulfonyl-7-methoxybenzofuran-4-carboxylic acid 6-methyloxy-pyridin-4-yl) amide Prepared from 2-methanesulfonyl-7-methanesulfonyl-3-methyla-pyridin-4-ylide -methoxybenzofuran-4-carboxylic acid (0.20 g). The title compound was obtained as a white solid (0.17 g). TLC Rf 0.4 (50% methanol in ethyl acetate) Mp 171-173 ° C.

Example 7 2- (Cyclopropyl-hydroxy-methyl) -7-methoxybenzofuran-4-carboxylic acid 7 (3-methyl-l-oxy-pyridin-4-yl) amide To a stirred suspension of (3-methyl-1-oxy) 2-cyclopropanecarbonyl-7-methoxybenzofuran-4-carboxylic acid (-pyridin-4-yl) amide (50 mg) in ethanol (10 ml) cooled to 0 ° C was added in portions sodium borohydride (20 mg). The reaction mixture was allowed to warm to room temperature and stirred for 10 minutes. Water (5 ml) was added and the methanol removed in vacuo. The aqueous residue was extracted with dichloromethane (2 x 100 ml), the organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Trituration with diethyl ether gave the title compound as a white solid (28 mg).

TLC Rf 0.32 (15% methanol in dichloromethane) Melting point 207-209 ° C (decomposition) Methods of Analysis The assays used to confirm the phosphodiesterase IV inhibitory activity of the compounds of formula (I) are standard assay procedures 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 formula (i) have exhibited activity at levels consistent with those believed to be useful for treating pathological conditions related to phosphodiesterase IV in these assays. The ability of the compounds (i) to inhibit the production of TNF in human peripheral blood mononuclear cells (PMBC) is measured as follows. PMBCs are prepared from freshly taken blood or "cloud-like coatings" by standard procedures. The cells are seeded in RPMI1640 + 1% fetal calf wax 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 an atmosphere of 95% air / 5% C02. Supernatants are tested for TNFa by ELISA using commercially available kits.

The activity in the coballo lung model is measured using the procedures described by Mauser et al, Am. Rev. Respir. Dis. 148 1623 (1993) and Am. J. Respir. Crit. Care Med. 152 467 (1995). The pharmacokinetic profile of the compounds of the invention is determined in cannulated rats in the right carotid artery for blood collection. For intravenous dosing, the compound is prepared in a suitable formulation, for example 10% volume / volume 'of DMSO, 50% volume / volume of PEG 400 in water, and the dosage is carried out by cannulation of the left jugular vein . Samples are collected at 5 minutes, 0.5, 1, 2, 4, 6 and 8 hours post-dosing. For oral dosing, the compound is prepared in a suitable formulation such as 0.4% w / v methylcellulose in water. Samples are collected at 0.5, 1, 2, 4, 6 and 8 hours post-dosing. In some cases, samples are also collected at 12 hours post-dosing. The plasma is obtained by centrifugation of each blood sample and the drug concentration is determined using standard methods, such as liquid chromatography-mass spectrometry following protein precipitation.

Abbreviations LPS Liposposaccharide (endotoxin) ELISA Analysis of enzyme-linked immunosorbent

Claims (18)

1. CLAIMS 1. A compound of formula (i) characterized in that Z is CO or CS; Ri is OH, alkoxy optionally substituted with one or more halogens or thioalkyl optionally substituted with one or more halogens; R3 is H, alkyl or halogen; R is H or alkyl; R5 is aryl or heteroaryl any of which may be substituted at any position with (one or more) R substituents? or alkyl-R?; Ri is alkyl (optionally substituted with one or more halogens), aryl, heteroaryl, heterocycle, C02Rs, CONR9R10, S02NR9R? Or, ORn, halogen, CN, NR8R? 2, COR? 3, S (0) pR? 3 or NHS02CF3; p is 0-2; R8 is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl; R9 and Rio are the same or different and are H, 4 alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl, or NR 9 R 10 represents a heterocyclic ring; Rn is H, alkyl (optionally substituted with one or more halogens), cycloalkyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl; R12 is H, alkyl, cycloalkyl, aryl, -heteroaryl, heterocycle, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, heroarylcarbonyl, heterocyclecarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl or heterocyclosulfonyl; R 13 is alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl; R 2 is alkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkyl, any of which is attached at any position on the alkyl portion to A and (through the same or a different position) to the benzofuran ring, wherein the aryl group or heteroaryl is optionally substituted at any position by (one or more) substituents Ri4 or alkyl-R? , and the cycloalkyl or heterocycloalkyl group is optionally substituted at any position with (one or more) substituents R7 or alkyl-R7, or R2 is absent; R7 is carbonyl oxygen, C02Rs, CONR9R10, SO2NR9R10, NR8R2, ORn, alkyl (optionally substituted by one or more halogens), halogen, CN, NHS02CF3, tetrazolyl or heterocycle; A is -0-, -0- (C (R15) 2) n, -0- (C (R15) 2) nC (= 0) - (C (R? 5) 2) m-, -0- ( C (R? 5) 2) n) -SOq- (C (R? 5) 2) m-, -NR6-, -NR6- (C (R15) 2) n- -NR6- (C (R15) 2 ) nC (= 0) - (C (R15) 2) m-, "NR6- (C (R15) 2) n-SOq- (C (R? 5) 2) m- / -SOq-, SOq- ( C (R? 5) 2) n- or SOqNR6-; R6 is H or alkyl, n is 1-4, m is 0-4, q is 1 or 2, RXs is H or alkyl and B is H, a ring heterocyclic (optionally substituted at any position with one or more substituents
2. R or alkyl-R7), or alkyl, aryl or heteroaryl (any of which may be optionally substituted at any position with one or more substituents R? 4 or alkyl-R? 4); provided that B is H only when R2 is cycloalkylalkyl and A is -0-, and that B is substituted when
3. R2 is not cycloalkyl, and A is -0-, -O- (C (Ri5) 2) nC (= 0) - (C (R? S) 2) nC (= 0) - (C (R15) 2) m, -NR6-, -NR6- (C (R? 5) 2) n- 0 -NR6- (C (R? 5) 2) nC (= 0) - (C (R15) 2) n-; or an N-oxide or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, characterized in that Z is CO. 3. A compound according to claim 1 or claim 2, characterized in that Ri is alkoxy optionally substituted with one or more halogens.
4. 4. A compound according to any preceding claim, characterized in that R3 is H.
5. 5. A compound according to any preceding claim, characterized in that R4 is H.
6. 6. A compound according to any preceding claim, characterized in that R5 is phenyl , pyrimidinyl, pyridyl or pyridyl-N-oxide, any of which may be substituted at any position with (one or more) substituents R? (in which Ri is alkyl optionally substituted with one or more halogens, halogen, ORn or CN).
7. 7. A compound according to any of the preceding claims, characterized in that R2 is not cycloalkylalkyl.
8. 8. A compound according to any of the preceding claims, characterized in that A is -NR6-, NR6- (C (R? 5) 2) n-, -O- or -O- (C (Ri5) 2) n "
9. 9. A compound according to any preceding claim, characterized in that R1 is alkyl (optionally substituted by one or more halogen), halogen or CN.
10. 10. A compound according to claim 1, characterized in that it is selected from: (2-dimethylsulfamyl) -1-7-methoxybenzofuran-4-carboxylic acid (3-methylpyridin-4-yl) amide, (3, 5-dichloro-l-) oxypyridin-4-yl) -amide of 2- (cyclopropyl-methoxy-methyl) -7-methoxybenzofuran-4-carboxylic acid, 7-Methoxy-2- (1-methyl-piperidin-4-yloxymethyl) -benzofuran-4-carboxylic acid (3, 5-dichloro-l-oxypyridin-4-yl) -amide, (3-methylpyridin-4-yl) 2-methanesulfonyl-7-methoxybenzofuran-4-carboxylic acid amide, 2-dimethylsulfamyl-1- methoxybenzofuran-4-carboxylic acid (3-methyl-1-oxy-pyridin-4-yl) amide, (3-methyl) 2-methanesulfonyl-1- methoxybenzofuran-4-carboxylic acid y-oxo-pyridin-4-yl) -2- (cyclopropyl-hydroxy) acid (3-methyl-1-oxy-pyridin-4-yl) amide -methyl) -7-methoxybenzofuran-4-carboxylic acid.
11. 11. A compound according to any of the preceding claims, characterized in that it is in the form of a single enantiomer thereof.
12. 12. A pharmaceutical composition for therapeutic use, characterized in that it comprises a compound according to any of the preceding claims and a pharmaceutically acceptable carrier or excipient. The compound according to any of claims 1 to 11, characterized in that it is used for the manufacture of a medicament that is used in the treatment of a pathological condition that is capable of being modulated by the inhibition of phosphodiesterase IV or the tumor necrosis factor or that is a pathological condition associated with a function of phosphodiesterase IV, eosinophil accumulation or a function of eosinophils. 14. The use according to claim 13, characterized in that the pathological condition is an inflammatory disease or an autoimmune disease. 15. The use according to claim 13, characterized in that the disease state is selected from asthma, chronic bronchitis, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease, atopic dermatitis, allergic rhinitis, psoriasis, arthritis, rheumatoid arthritis, inflammation of the joints, ulcerative colitis, Crhon's disease, atopic ezcema, apoplexy, bone resorption disease, multiple sclerosis and inflammatory bowel disease. 16. The use according to claim 13, characterized in that the pathological condition is selected from urticaria, allergic conjunctivitis, vernal conjunctivitis, inflammation of the eye, allergic responses in the eye, eosinophilic granuloma, gouty arthritis and other arthritic conditions, suffering syndrome adult respiratory disease, diabetes insipidus, keratosis, cerebral senility, dementia due to multiple infarctions, senile dementia, memory impairment associated with Parkinson's disease, depression, cardiac arrest, intermittent claudication, rheumatoid spondylitis, osteoarthritis, sepsis, septic shock, shock endotoxicity, sepsis due to gram-negative bacteria, toxic shock syndrome, acute respiratory distress syndrome, cerebral malaria, silicosis, pulmonary sarcoidosis, reperfusion injury, graft-versus-host reaction, allograft rejection, fever related to infection or myalgia, malaria , HIV, AIDS, ARC, cachexia, formation of keloids, scar tissue formation, pyresis, systemic lupus erythematosus, type I diabetes mellitus, Bechet's disease, purpura, anaphylactoid nephritis, gromerulonephritis, leukemia, tardive dyskinesia, yeast or fungal infection, conditions requiring gastroprotection, and neurogenic inflammatory disease associated with irritation and pain. 17. The use according to claim 14, characterized in that the pathological condition is asthma. 18. The use according to claim 14, characterized in that the pathological condition is chronic obstructive pulmonary disease or chronic bronchitis.