MX2008008141A - 3- (4-{ [4-(4-{ [3-(3, 3-dimethyl-1-piperidinyl) propyl]0xy} phenyl) -1-piperidinyl]carbonyl }-1-naphthalenyl) propanoic or propenoic acid as h1 and h3 receptor antagonists for the treatment of inflammatory and/or allergic disorders - Google Patents

Abstract

The present invention relates to a compound of formula (I), or a salt thereof wherein the naphthalene ring can be substituted in the 2, 3, 4, 5, 6, 7 or 8 position by R1, and R1represents -CH2CH2COOH or -CH=C(CH3)COOH, and to processes for their preparation, to compositions containing them and to their use in the treatment of various diseases such as allergic rhinitis.

Description

ACID 3- (4- (r4- (4- (f3- (3,3-DIMETHYL-1-PIPERIDINYL) PROPYL) OXY) FENIÜ-1- PIPERIDINYLCARCARBONYL-NAFTALENIUPROPANOIC OR PROPENOIC LIKE ANTAGONISTS OF RECEPTOR H1 AND H3 FOR THE TREATMENT OF INFLAMMATORY AND / OR ALLERGIC DYSFUNCTIONS Description of the Invention The present invention relates to compounds, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of various diseases, in particular inflammatory and / or allergic diseases of the respiratory tract. Allergic rhinitis, pulmonary inflammation and congestion are medical conditions that are often related to other conditions, such as asthma, chronic obstructive pulmonary disease (COPD), seasonal allergic rhinitis and perennial allergic rhinitis. In general these conditions are mediated, at least in part, by inflammation related to the release of histamine from several cells, in particular mastoid cells. Allergic rhinitis, known as "hay fever," affects the population worldwide on a large scale. There are two types of allergic, seasonal and perennial rhinitis. Clinical symptoms of seasonal allergic rhinitis typically include nasal pruritus and irritation, sneezing and runny nose, which are often accompanied by nasal congestion. The clinical symptoms of perennial allergic rhinitis are similar except that the nasal blockage may be more pronounced. Any type of allergic rhinitis can also cause other symptoms such as itching in the throat and / or eyes, tearing and edema around the eyes. The symptoms of allergic rhinitis can vary in intensity from the level of discomfort or debilitation. Allergic rhinitis and other allergic conditions are related to the release of histamine from various cell types, but particularly mastoid cells. The physiological effects of histamine are mediated in a classical manner by three receptor subtypes, designated H1, H2 and H3. H1 receptors are widely distributed through CNS and peripheries, and are involved in insomnia and acute inflammation. The H2 receptors measured the secretion of gastric acid in response to histamine. The H3 receptors are present at the nerve terminals in both, CNS and periphery and mediated inhibition of neurotransmitter release [Hill et al., Pharmacol. Rev., 49: 253-278, (1997)]. Recently a fourth member of the histamine receptor family has been identified, termed the H4 receptor [Hough, Mol. Pharmacol., 59: 415-419, (2001)]. When the distribution of the H4 receptor appears to be restricted to the cells of the immune and inflammatory systems, a physiological role for this receptor must be clarified. The activation of receptors in blood vessels and nerve terminals is responsible for many of the symptoms of allergic rhinitis, which include pruritus, sneezing, and the production of watery runny nose. The antihistamine compounds, i.e. Drugs, which are H1 receptor antagonists such as chlorpheniramine and cetirizine, are effective in the treatment of pruritus, sneezing and rhinorrhea related to allergic rhinitis, but are not effective against the symptoms of nasal congestion [Aaranson, Ann. Allergy, 67: 541-547, (1991)]. Thus, H1 receptor antagonists have been administered in combination with sympathomimetic agents such as pseudoephedrine or oxymetazoline to treat symptoms of nasal congestion of allergic rhinitis. These drugs are thought to produce a decongestant action activating ß-adrenergic receptors and increasing the vascular tone of the blood vessels in the nasal mucosa. The use of sympathomimetic drugs for the treatment of nasal congestion is frequently limited by the properties of the CNS stimulant and its effects on blood pressure and heart rate. A treatment which decreases nasal congestion without having effects on the CNS and cardiovascular system can, in this way, offer advantages over existing therapies. The histamine H3 receptors are widely expressed in both the CNS and nerve terminals and measured the inhibition of neurotransmitter release. In vitro electrical stimulation of peripheral sympathetic nerves in isolated human saphenous vein results in an increase in noradrenaline release and smooth muscle contraction, which can be inhibited by histamine H3 receptor agonists (Molderings et al., Naunyn -Schmiedeberg's Arch. Pharmacol., 346: 46-50, (1992); Valentine et al., Eur. J. Pharmacol., 366: 73-78, (1999)]. The H3 receptor agonists also inhibit the sympathetic nerve activation effect in vascular tone of porcine nasal mucosa [Varty & Hey., Eur. J. Pharmacol., 452: 339-345, (2002)]. In vivo, the H3 receptor agonists inhibit the decrease in nasal airway resistance produced by sympathetic nerve activation [Hey et al., Arzneim-Forsch Drug Res., 48: 881-888, (1998)]. The activation of histamine H3 receptors in the human nasal mucosa inhibits sympathetic vasoconstriction [Varty et al., Eur. J. Pharmacol., 484: 83-89, (2004)]. In addition, H3 receptor antagonists, in combination with H1 receptor antagonists, showed that they reverse the effects of mastoid cell activation on nasal airway resistance and nasal cavity volume, an index of nasal congestion [Mcleod] et al., Am J. Rhinol., (13; 391-399, (1999)], and further evidence for the contribution of H3 receptors to histamine-induced nasal blockade, is provided by histamine nasal challenge studies carried out in human subjects [Taylor-Clark et al., BR, J. Pharmacol., 144, 867-874, (2005)], although the H3 mechanism in this aspect appeared to be novel and unpredictable.A novel class of compounds has been found which are antagonists of the dual histamine H1 and H3 receptor By "dual" histamine H1 and H3 receptor antagonists it is meant that the compound has activity of both receptor subtypes In particular, the activity of the H1 receptor can be between about 10 folds of activity and the H3 receptor and more particularly these compounds can be approximately equipotent in both receptor subtypes. In this way, the present invention provides, in a first aspect, a compound of the formula (I) wherein the naphthalene ring is substituted in the 2, 3, 4, 5, 6, 7 or 8 position by R 1 and R 1 represents -C H2CH 2 COOH or -CH = C (CH 3) COO H; or a salt thereof, such as a pharmaceutically acceptable salt. The compounds of the invention can be expected to be useful in the treatment of various dysfunctions, in particular inflamatory and / or allergic dysfunctions, such as inflammatory and / or allergic dysfunctions of the respiratory tract, for example allergic rhinitis, which are related to the histamine release from cells, such as mastoid cells. The compounds of the invention may show an improved profile on the agonists of the dual H 1 / H 3 receptor antagonists in that they may possess one or more of the following properties: (i) the activity of the H 3 receptor antagonist with a higher pKi of about 7; (ii) H 1 receptor antagonist agonist with a pKi greater than about 7; (iii) lower SN C penetration; (iv) improved bioavailability; and (v) lower compensation and / or longer half-life in blood. Compounds which have such a profile may be expected to be effective orally, and / or capable of daily administration, once a day and / or in addition may have an improved side effect profile compared to other existing therapies. In one embodiment of the invention, R1 represents -CH2CH2COOH. In another embodiment of the invention, the naphthalene ring is substituted in the 4-position by R1. The compounds of formula (I) include the compound of the Examples as described below and salts thereof, such as pharmaceutically acceptable salts. Thus, another aspect of the present invention provides a compound of 3- (4- {[[4- (4-. {3- (3,3-dimethyl-1-piperidinyl) propyl] oxy}. phenyl-1-piperidinyl] carbonyl, p-1-naphthalenyl) propanoic acid or salts thereof, such as pharmaceutically acceptable salt It should further be understood that references to a compound according to the present invention or to compounds of the invention include one or more compounds of the formula (I) and salts thereof, such as pharmaceutically acceptable salts The present invention includes geometric isomers of the compounds of the formula (I) which include cis and trans configurations, and regioisomers which include exo and endo double bonds (for example -CH = C (CH3) COOH and -CH-C (= CH2) COOH), as individual isomers isolated to be substantially free or other isomers (ie pure) or as mixtures thereof. In this way, for example, the present invention includes an isolated single isomer pair to be substantially free or other isomers (i.e. pure) such as less than 10%, for example less than 1% or less than 0.1% of other isomer is present. The separation of geometric isomers can be obtained by conventional techniques, for example by fractional crystallization, chromatography or HPLC. Some compounds of formula (I) can exist in various tautomeric forms. It should be understood that the present invention includes all tautomers of the compounds of the formula (I) as individual tautomers or mixtures thereof. The compounds of formula (I) can be in crystalline or amorphous form. In addition, a compound of formula (I) can exist in one or more polymorphic forms. Therefore, the present invention includes within its scope all polymorphic forms of the compound of formula (I). In general, the most thermodynamically stable polymorph form of a compound of formula (I) is of particular interest. The polymorphic forms of the compound of formula (I) can be characterized and differentiated using a number of conventional analytical techniques, including but not limited to X-ray powder diffraction patterns (XRPD), infrared spectrum ( IR, for its acronym in English), Raman spectrum, differential scanning calorimetry (DSC, for its acronym in English), thermogravimetric analysis (TGA, for its acronym in English) and solid state nuclear magnetic resonance (NMR, for its acronym in English). It will be appreciated that many organic compounds can form solvates with the solvents in which they are reacted or from which they are precipitated or crystallized. For example, a solvate with water is known as a "hydrate". Solvents with high boiling points and / or solvents with a high propensity to form hydrogen bonds such as water, xylene, α / - methyl, pyrrolidinone and methanol, can be used to form solvates. Methods for identifying solvates include, but are not limited to, NMR and microanalysis. In this way, the solvates of the compounds of the formula (I) are within the scope of the invention. The compounds of the present invention may be in the form of and / or may be administered as a pharmaceutically acceptable salt. For the review of appropriate salts see Berge and co! J. Pharm. Sci., 1977, 66, 1-19. Appropriate pharmaceutically acceptable salts include acid and base addition salts. Typically, a pharmaceutically acceptable salt can be prepared using a desired acid or an appropriate base. The salt can be precipitated from the solution and can be collected by filtration or can be recovered by evaporation of the solvent. A pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of the formula (I) with an appropriate inorganic or organic acid (such as hydrobromic, hydrochloric, formic, sulfuric, nitric, phosphoric, succinic, maleic, acetic acid , fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic), optionally in an appropriate solvent, such as organic solvent, to obtain the salt, which is usually isolated for example by crystallization and filtration. Therefore, a pharmaceutically acceptable acid addition salt of a compound of the formula (I) can be, for example, a hydrobromide, hydrochloride, formate, sulfate, nitrate, phosphate, succinate, maleate, acetate, fumarate, citrate salt. , tartrate, benzoate, p-toluenesulfonate, methanesulfonate or naphthalenesulfonate. In one embodiment, a hydrochloride salt of the 3- (4. {[[4- (4. {[[3- (3,3-dimethyl-1-piperidinyl) propyl] oxy} acid compound is provided. phenyl) -1-piperidinyl [carbonyl.] -1-naphthalenyl) propanoic acid. In another embodiment, a hydrobromide salt of a 3- (4. {[[4- (4. {[[3- (3,3-dimethyl-1-piperidinyl) propyl] oxy compound is provided} phenyl) -1-pi peridinyl [carbonyl.] -1-naphthalenyl) propanoic acid. A pharmaceutically acceptable base addition salt can be formed by reaction of a compound of the formula (I) with an appropriate inorganic or organic base (for example triethylamine, ethanolamine, triethanolamine, choline, arginine, usin or histidine), optionally in a solvent suitable such as an organic solvent, to obtain the base addition salt which is usually isolated, for example by crystallization or filtration. Other acceptable pharmaceutically acceptable salts include pharmaceutically acceptable metal salts, for example pharmaceutically acceptable alkali metal or alkaline earth metal salts such as sodium, potassium, calcium or magnesium salts; in particular pharmaceutically acceptable metal salts of one or more carboxylic acid moieties which may be present in the compound of the formula (I). Other non-pharmaceutically acceptable salts, for example oxalates or trifluoroacetates, can be used, for example, in the isolation of compounds of the invention, and are included within the scope of the invention. The invention includes within its scope all the stoichiometric and non-stoichiometric forms of salts of the compounds of the formula (I). Included within the scope of the invention are all solvates, for example hydrates and polymorphs of compounds and salts of the invention. The present invention also provides processes for the preparation of a compound of the formula (I) or a salt thereof. According to a first process (A), a compound of the formula (I) can be prepared by deprotection and optionally hydrogenating a compound of the formula (Ia) wherein; ^ _ represents a single or double bond, and the naphthalene ring is substituted at the 2, 3, 4, 5, 6, 7, 8 position by R and R, 1 a represents a protected derivative of R1 such as a ester of R1, for example CH2CH2COORx or -CH = C (CH3) COORx wherein each R independently represents a protective group of carboxylic acid such as C ^ Ce alkyl, for example, methyl ethyl or t-butyl, especially methyl or ethyl. Other suitable protecting groups include aralkyl such as benzyl. The deprotection can be carried out under standard conditions. Therefore, the hydrolysis of a carboxylic acid ester can be carried out in the presence of an appropriate base, for example, sodium hydroxide or potassium hydroxide, in an appropriate aqueous solvent system such with methanol / water or tetrahydrofuran, optionally at an elevated temperature such as reflux. Alternatively to a carboxylic acid ester, for example, the t-butyl ester can be carried out in the presence of an appropriate acid such as hydrogen chloride in dioxane under standard conditions for acid hydrolysis. Deprotection by hydrogenolysis under standard conditions, such as in the presence of metal catalyst, such as palladium in carbon can be used when a protecting group is aralkyl, such as benzyl. The hydrogenation can be carried out under standard conditions. Thus, the hydrogenation can be carried out in the presence of an appropriate hydrogenation agent such as palladium in carbon or platinum oxide in a suitable solvent such as ethanol, optionally at atmospheric pressure, and optionally at an elevated temperature such as 40 ° C. 60 ° C. In one embodiment of process A, R1a is as defined, and ^^ represents a simple union in which case a step of hydrogenation is not required. The compounds of the formula (I) can be prepared by reacting a compound of the formula (II) wherein R, 1a is as defined above for the formula (la), with a compound of the formula (III) (III) where represents a single or double bond, under conditions that form amide. The amide of the formula (la) can be prepared under standard conditions for amide bonding, for example in the presence of an appropriate binding agent such as hexafluorophosphate O- (benzotriazol-1-yl) -? /,? /,? / T-tetramethyluronium (HBTU) or O- (benzotriazol-1-yl) -? /,?,? / '.? /' - tetramethyluronium tetrafluoroborate (TBTU, for its acronym in English ), in the presence of an appropriate base such as NN-dimethylformamide.

Alternatively the compound (Ia) can be prepared by reacting an acid chloride of a compound of formula (II) with an amine (III) in the presence of an appropriate base, such as triethylamine or potassium carbonate, in a solvent such as dichloromethane at a temperature between 0 and 20 ° C. A compound of the formula (II) wherein R1a represents -CH2CH2COORx and Rx is as defined above, can be prepared by hydrogenation of a compound of the formula (IV) Where the naphthalene ring is substituted at the 2,3,4,5,6,7 or 8 position by R 1b, and R 1b represents -CH = CH-COORx and Rx is as defined above. The hydrogenation is carried out under standard conditions. In this manner, the hydrogenation can be carried out in the presence of an appropriate hydrogenation agent such as palladium in carbon or platinum oxide in a suitable solvent such with ethanol. Optionally at an atmospheric pressure, and optionally at an elevated temperature such as 40 to 60 ° C. A compound of the formula (IV), as defined above, can be prepared by a Heck reaction in which a compound of the formula (V) or a protected derivative thereof Where the naphthalene ring is substituted in the 2, 3, 4, 5, 6, 7 or 8 position by bromine or iodine, it is reacted with acrylate ester such as methylacrylate, ethylacrylate, t-butylacrylate and benzylacrylate. It will be appreciated by those skilled in the art that the Br / I substituent will be in the position at which it is desired to introduce the carboxylate group into the compound of the formula (IV). Usually, the Heck reaction can be carried out in the presence of an appropriate base such as triethylamine, a phosphine such as triphenylphosphine, an appropriate catalyst such as palladium (II) acetate, in an appropriate solvent, such as? /,? / - dimethylformamide, at an elevated temperature, for example about 100 ° C. In an alternative method, a compound of the formula (IV) described above can be prepared by an ittig reaction in which the compound of the formula (VI) corresponds wherein the naphthalene ring is substituted at the 2, 3, 4, 5, 6, 7, or 8 position by CHO, it is reacted with a phosphorus ylide containing a carboalkoxymethylene group (-CH-COORx) wherein Rx represents d.6 alkyl) such as carboethoxymethylene triphenylphosphorane, in a suitable solvent such as toluene, at an elevated temperature such as reflux.

The compounds of the formula (II), wherein -CH = C (CH3) COORx and Rx is as defined above, can be prepared by a Heck reaction in which the compound of the formula (V) or a protected derivative it is reacted with an acrylate ester such as methyl methacrylate, ethyl methacrylate or t-butyl methacrylate, under conditions similar to the Heck reaction described above. Alternatively, a compound of formula (II), wherein R1a represents -CH = C (CH3) COORx and Rx is as defined above, can be prepared by a Wittig reaction in which the compound or formula (VI ) as described above, is reacted with a phosphorus ylide containing a carboethoxymethylene group (-CH-COORx wherein Rx represents C 1-6 alkyl), such as carboxyethylene-triphenylphosphorane, under conditions similar to the Wittig reaction described above. The compounds of formulas (V) and (VI) are known, or can be prepared from commercially available materials (for example, 1,4-dibromonaphthalene is commercially available from Acros and / or Alpha) according to published methods or by methods described therein. 5-Bromo-1-naphthalenecarboxylic acid can be prepared by methods described in J. E. Baldwin et al., Tetrahedron 1990, 46, 3019-28, 4-bromo-1-naphthalene acid can be prepared by methods described in Can. J. Chem. 1981, 59, 2629-41; and 8-formyl-1-naphthalenecarboxylic acid can be prepared by the methods described in J. Am. Chem. Soc, 1949, 71, 1870.

The acrylate esters are known and / or commercially available. Methyl acrylate, methyl methacrylate and benzylacrylate is available from Aldrich and / or Acros, and / or ABCR, and / or Chemos. The compounds of the formula (II) can be prepared according to the following reaction scheme: wherein 1. potassium carbonate, 2-butanone; 2. sodium iodide, potassium carbonate, acetonitrile; 3. nBuli, THF. Alternatively, magnesium chloride isopropyl can be used instead of pBuli at room temperature; a) triethysilane, trifluoroacetic acid, dichloromethane; b) 2M HCl in ether, to obtain a mixture of the compounds of the formula (III); 5. optional hydrogenation step, 10% weight of coal-based ethanol palladium. 6. Hydrogen chloride, ethanol. It will be appreciated that the mixture of the compounds of the formula (III) shown above can be used in subsequent reactions without the need to carry out the hydrogenation step 5. 4-iodophenol, 1-bromochloropropane, 3,3-dimethyl piperidine, and N-Boc-piperidone are known and / or commercially available, for example from Aldrich, Alpha, Manchester Organics, Scientific Matrix, ASDI and / or Chem Service. According to a second process (B), a compound of the formula (I) can be prepared: (i) by reacting a compound of the formula (II) with a compound of the formula (III) to form a compound of the formula (the); and (ii) deprotecting or optionally dehydrogenating the compound of the formula (la) to form a compound of the formula (I). In process (B), the intermediate protected amine, for example the amide ester (la), is not isolated. The amide bond and deprotection, such as by hydrolysis of carboxylic acid ester, and optional hydrogenation can be carried out under standard conditions as described above.

According to a third process (C), a compound of the formula (I) wherein R 1 represents -CH 2 CH 2 COO H can be prepared by hydrogenation and deprotection of a compound of the formula (le): where it represents a simple or double union, and the naphthalene ring can be substituted in the 2, 3, 4, 5, 6, 7 or 8 position by R 1 c and R 1 c represents -CH = CH COOR x wherein R x represents an appropriate carboxylic acid group such as aralk or ilo for example benzyl. Hydrogenation and deprotection (by hydrogen lis) can be carried out under standard conditions such as those described herein, and can be combined in a single step. A compound of the formula (le) can be prepared by reacting a compound of the formula (IV) with a compound of the formula (I I I). According to a fourth process (D), a compound of the formula () can be prepared by interconversion of other compounds of the formula (I). Therefore, a compound of the formula (I) can also be prepared from other compounds of the formula (I) using conventional inter-conversion processes such as isomerization of geometric isomers for example inter conversion between cis and trans isomers and inter conversion between a double junction exo and endo, for example, inter conversion between -CH = C (CH3) COO H and -CH2-C (= CH2) COOH. It may also include processes to change the counterion and the salt form of the compound of the formula (I). Therefore, the interconversion of other compounds of the formula (I) (process D) forms another aspect of the present invention. In this way, the present invention provides a process for preparing a compound of formula (I) or a salt thereof, the process selected from (A), (B), (C) or (D) therein. , and optionally subsequently form a salt. Typically, a salt can be prepared using a desired acid or base as appropriate. The salt can be precipitated from the solution and can be collected by filtration or it can be recovered by evaporation of the solvent. It should be understood that the free base of a compound of formula (I) may or may not be isolated prior to salt formation, as desired. It should be appreciated by those skilled in the art that it may be desirable to use protected derivatives of intermediates used in the preparation of the compounds of formula (I). Therefore, the above processes may require deprotection as an intermediate step or final step to yield the desired compound. The protection and deprotection of functional groups can be carried out using conventional means. Thus, the carboxylic acid groups can be protected using conventional protecting groups, for example, as described in Protective Groups in Organic Chemistry, Ed. J.F.W. McOmie (Plenum Press, 1973) or Protective Groups in Organic Chemistry by Theodora W. Green (John Wiley and sons, 1991) or P.J. Kocienski in Protecting Groups, Georg Thieme Verlag, 1994. Examples of carboxylic acid protecting groups include groups selected from alkyl (for example methyl, ethyl or t-butyl), aralkyl (for example benzyl, diphenylmethyl or triphenylmethyl, and silyl groups such as trialkylsilyl (for example t-butyldimethylsilyl) The carboxylic acid protecting groups can be removed by conventional techniques.Therefore, for example, the alkyl and silyl groups can be removed by solvolysis, for example by hydrolysis under acidic or basic conditions. Aralkyl groups, such as triphenylmethyl can be similarly removed by solvolysis, for example by hydrolysis under acid conditions.Aralkyl groups, such as benzyl can be removed by hydrogenolysis in the presence of a metal catalyst such as palladium in Coal Examples of disease states in which a compound of the formula (I), or a salt Therapeutically acceptable thereof can be expected to have anti-inflammatory and / or allergic effects including respiratory tract diseases such as bronchitis (including chronic bronchitis), asthma (including induced asthmatic reactions), chronic obstructive pulmonary disease (COPD), cystic fibrosis, sinusitis, and allergic rhinitis (seasonal or perennial). Other conditions of the disease include diseases of the gastrointestinal tract including inflammatory bowel disease (eg, Crohn's disease or ulcerative colitis) and inflammatory bowel diseases upon exposure to radiation or exposure to allergens. In addition, the compounds of the invention can be used to treat nephritis, skin diseases, such as psoriasis, eczema, allergic dermatitis and hypersensitivity reactions. The compounds of the invention may also be of use in the treatment of nasal pollinosis, conjunctivitis or pruritus. Other diseases include inflammatory diseases of the gastrointestinal tract such as inflammatory bowel disease. A disease of particular interest is allergic rhinitis. Compounds which are antagonists of the H3 receptor may also be of use in other diseases such as allergic rhinitis. It will be appreciated by those skilled in the art that references to treatment or therapy extend to the prophylactic as well as to the treatment of established conditions. As mentioned above, the compounds of the formula (I) or pharmaceutically acceptable salts thereof are useful as therapeutic agents. A compound of the formula (I) or a pharmaceutically acceptable salt thereof for use in therapy is provided as another aspect of the invention. According to another aspect of the invention, there is provided the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of one of the above diseases. In another aspect there is provided a method for the treatment of any of the foregoing diseases, in a human or animal subject in need thereof, which method comprises administering an effective amount of a compound of the formula (I) or an acceptable salt. pharmaceutically thereof. When used in therapy, the compounds of formula (I) are usually formulated in an appropriate pharmaceutical composition. Such pharmaceutical compositions can be prepared using standard procedures. Therefore, the present invention further provides a composition which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, optionally with one or more pharmaceutically acceptable carriers and / or excipients. A composition of the invention, which can be prepared by mixing, suitably at ambient temperature and atmospheric pressure, can be adapted for oral, parenteral, rectal or intranasal administration and, as such, can be in the form of tablets, capsules, preparations For example, oral preparations, powders, granules, coated tablets, reconstituted powders or injectable or infusible solutions or suspensions, or suppositories. Appropriate compositions can be prepared according to methods well known in the art for each particular type of composition. Appropriate compositions for oral administration of particular interest.

Pharmaceutical compositions adapted for oral administration can be presented as discrete units such as capsules or tablets; powders or n granules; solutions or suspensions in aqueous and non-aqueous liquids; It's edible cougars or smoothies; or oil-in-water emulsions or liquid-oil emulsions. For example, for oral administration in the form of a tablet or capsule, the active drug component can be combined with a non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Appropriate powders for incorporation into tablets or capsules can be prepared by reducing the compound to an appropriate fine measure (for example by micronisation) and mixing with pharmaceutically prepared carrier such as an edible carbohydrate., such as, for example, starch or mannitol. Agents can also be used for flavor, dispersion and color, and preservatives. The capsules can be prepared by preparing a powder mixture, as described above, and the gelatin fascias formed. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture prior to the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can be added to improve the availability of the medicament when the capsule is ingested.

In addition, when desired or necessary, the binders, glidants, lubricants, sweeteners, flavors, disintegrating agents or coloring agents can be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. The lubricants used in the dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrants include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. The tablets are formulated, by preparing a powder mix, granulating or removing, adding a lubricant and disintegrating and pressing the tablets. A powder mixture is prepared by mixing the appropriately processed compound with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a retardant solution such as paraffin, a resorption accelerator such as quaternary salt and / or an absorption agent such as bentonite, caolin or dicalcium phosphate. The powder mixture can be granulated by humidifying with a binder such as syrup, starch paste, acadia mucilage or solutions of cell or polymeric materials that are forced through a screen. As a granulation alternative the powder mixture can run through a tablet machine and the result is formed imperfectly by forming broken blocks in granules. The glands can be lubricated to prevent sticking to the plate by forming glands by the addition of stearic acid, a stearate salt, talc or mineral oil. The brightening mixture is then compressed into tablets. The compounds of the present invention can also be combined with an inert carrier flowed and compressed into tablets directly without passing through the granulation or blocking steps. A clear or opaque protective cover consisting of an adhesive cover, a sugar cover or polymeric material, and a polished wax cover can be provided. The dyes can be added to the covers to extinguish different dosage units. Oral fluids such as solution, moisturizers and elixirs can be prepared in unit dosage form so that a certain amount contains a predetermined amount of the compound. The syrups can be prepared by dissolving the compound in an aqueous solution with appropriate flavor, while the elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers, such as ethoxylated isostearyl alcohols and ethoxylated polyoxy sorbitol ethers, preservatives, flavor additives such as mint or natural sweeteners or saccharins, or other artificial endives, and the like can be added. If appropriate, the dosage unit compositions for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release of, for example, covering or inserting particle material into polymers, wax or the like. For intranasal administration, appropriate compositions may optionally contain one or more suspending agents, one or more preservatives, one or more wetting agents and / or one or more isotonicity adjusting agents. Examples of suspending agents include carboxymethylcellulose, veegum, tragacanth gum, bentonite, methylcellulose or polyethylene glycols, for example microcrystalline cellulose or carboxy methylcellulose sodium. For stability purposes, the composition of the present invention can be protected from microbial contamination and growth by inclusion of a preservative. Examples of pharmaceutically acceptable anti-microbial agents or preservatives can include quaternary ammonium compounds (for example benzalkonium chloride, benzethonium chloride, cetirimide and cetylpyridine chloride), mercurial agents (for example phenylmercuric mitrate, phenylmercuric acetate and thimerosal), alcohol (for example chlorobutanol, phenylethyl alcohol, benzyl alcohol), anibacterial esters (for example, esters of para-hydroxybenzenic acid), chelating agents such with edetate disodium (EDTA) and other anti-microbial agents such such as chlorhexidine, chlorocresol, sorbic acid and its salts and polymyxin.

The compositions, for example nasal compositions which contain suspended medicament, can include an acceptable humidifying agent which functions by humidifying the medicament particles to facilitate the dispersion thereof in the aqueous phase of the composition. Typically, the amount of humidifying agent used does not cause dispersion foaming during mixing. Examples of wetting agents include fatty alcohols, esters and ethers, such as polyoxyethylene (20) sorbitan monooleate (Polysorbate 80). An isotonicity adjusting agent may be included to achieve isotonicity with bodily fluids for example fluids of the nasal cavity, resulting in reduced levels of irritability. Axis-mplos of isotonicity adjusting agents include sodium chloride, dextrose and calcium chloride. The intranasal compositions of the present invention can be administered to the nasal passages by use of a precompression pump, such as VP3, VP7 or modifications, model developed by Valois SA. Pumps of this type are believed to be beneficial, since they can ensure that the composition is not released or atomized before sufficient force has been applied, otherwise smaller doses can be applied. Typically, pre-compression pumps can be used with a bottle (glass or plastic) capable of holding 8-50 ml of composition and each spray will typically deliver 50-100 μL. For parenteral administration, the fluid unit dosage forms are prepared by using a compound of the invention or pharmaceutically acceptable form thereof and a sterile vehicle. The compound, depending on the vehicle and the concentration used, can be suspended or dissolved in the vehicle. In the preparation of solutions, the compound can be dissolved for injection and sterilized filtration prior to delivery in an appropriate container or ampoule and sealed. Advantageously, adjuvants such as a local anesthetic, preservatives or regulating agents are dissolved in a vehicle. To improve stability, the composition can be frozen after filling the containers and the water is moved under vacuum. The parental suspensions are prepared in substantially the same manner, except that the compound is suspended in the container instead of being dissolved, and sterilization can not be accomplished by filtration. The compound can be sterilized by exposure of ethylene oxide before suspension of a sterile vehicle. A surfactant or wetting agent may be included in the composition to facilitate uniform distribution of the compound. The composition may contain from 0.1% to about 99% by weight, such as from 10% to about 60% by weight of active material, depending on the method of administration. The dose of the compound used in the treatment of the aforementioned dysfunctions will vary in a usual manner depending on the severity of the disease, the weight of the patient and other similar factors. However, as an appropriate guide of appropriate dose of the unit can be from 0.05% up to approximately 1000 mg, more appropriately from 1.0 to approximately 200 mg, for example from 20 to 100 mg, and such dose of unit can be administered more than once a day, for example two or three times a day. Such therapy can be extended for a number of weeks or months. In one embodiment the compounds are pharmaceutical compositions according to the invention, are suitable for oral administration and / or are capable of administration more than once a day, for example in a dose in the range of 20 to 200 mg (for example 20 to approximately 100 mg). The compounds and pharmaceutical compositions according to the invention can also be used in combination with, or include one or more therapeutic agents, for example other antihistaminic agents, for example H 4 receptor antagonists, anticholinergic agents, anti-inflammatory agents such as corticosteroids ( for example fluticasone propionate, beclomethasone dipropionate, mometasone furoate, triamcinolone acetonite, budesonide and steroids shown in WO02 / 12265); or non-steroidal anti-inflammatory drugs (NSAD) (eg, sodium cromoglycate, sodium nedecromil), PDE-4 inhibitors, leukotriene antagonists, lipoxygenase inhibitors, chemokine antagonists (e.g CCR3, CCR1, CCR2, CCR4, CCR8, CXR1), IKK antagonists, NOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine 2A agonists or beta andrenergic agents (eg, salmeterol, salbutamol, formiterol, terbutaline, and beta agonists) described in WO 02/66422, WO 02/270490, WO 02/076933, WO 03 / and WO 03/072539, or anti-affective agents); or antiinfective agents, for example antibiotic agents and antiviral agents. It would be clear to one skilled in the art, when appropriate, the other therapeutic agents may be used nasally, (for example alkali metal or amine salts or as acid addition salts), pro drugs or with esters (e.g. low alkyl esters), or as solvates (e.g. hydrate), to optimize activity and / or stability and / or physical characteristics (e.g., solubility) or the therapeutic agent. It is clear that when appropriate, the therapeutic agents can be used in pure optical form. The invention further provides, in another aspect, a combination comprising a compound of the formula (I) or a pharmaceutically acceptable salt together with one or more (such as one or two for example a) therapeutically active agents, optionally with one or more pharmaceutically acceptable carriers and / or excipients. Other histamine receptor antagonists, which may be used alone, or in combination with an H1 / H3 receptor antagonist include antagonists (and / or inverse agonists) of the H4 receptor, for example the compounds set forth in Jablonowski et al., Med. .

Chem 46; 3957-3960 (2003). In one embodiment, the invention provides a combination comprising a compound of formula (I) and β2-adrenoreceptor agonist. Examples of β2-adrenoreceptor agonists include salmeterol (which may be a racemate or a single enantiomer, such as R-enantiomer), salbutamol (which may be a racemate or a single enantiomer such as R-enantiomer), formoterol (the which may be racemate or a diastereomer such as R, R-diastereomer), salmefamol, fenoterol, carmoterol, ethanterol, naminterol, clenbuterol, pirbuterol, ferbuterol, reproterol, bambuterol, indacaterol, terbutaline and salts thereof, for example xinafoate salt (1-hydroxy-2-naphthalenecarboxylate) or salmeterol, sulphate salt or free base of salbutamol or salt of fumarate of formoterol. In one embodiment, combinations of the invention may include long-acting β2-adrenoceptor agonists, for example, compounds which provide effective bronchodilation of approximately 12 hours or longer. Other ß2-adrenoreceptor agonists include those described in WO 02/066422, WO 02/070490, WO 03/024439, WO 03/072539, WO 03/091204, WO 04/016578, WO 2004/037807, WO 2004/037773, WO 2004/037768, WO 2004039762, WO 2004/039766, WO 01/42193 and WO 03/042160. Examples of β2-adrenoreceptor agonists include: 3- (4- {[[6- ( { (2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino ) hexyl] oxy} butyl) benzenesulfonamide; 3- (3- { [7- ( { (2R) -2-hydroxy-2- [4-hydroxy-3-hydroxymethyl) phenyl] ethyl} -amino) heptyl] oxy} propyl benzenesulfonamide; 4-. { (1R) -2 - [(6- { 2 - [(2,6-dichlorobenzyl) oxy] ethoxy} hexyl) amino] -1-hydroxyethyl} -2- (hydroxymethyl) phenol; 4-. { (1R) -2 - [(6- { 4- [3- (Cyclopentylsulfoni!) Phenyl] butoxy.} Hexyl) amino] -1-hydroxyethyl} -2- (hydroxymethyl) phenol; N- [2-hydroxy-5 - [(1R) -1-hydroxy-2 - [[2-4 - [[2R) -2-hydroxy-2-phenylethyl] amino] phenyl] ethyl] amino] ethyl] phenyl] formamide: N-2. { 2- [4- (3-phenyl-4-methoxyphenyl) aminophenyl] ethyl} -2-hydroxy-2- (8-hydroxy-2 (1H) -quinoline-5-yl) ethylamine; and 5 - [(R) -2- (2- {4- [4- (2-amino-2-methyl-propoxy) -phenylamino] -phenyl} -ethylamino) -1-hydroxy-ethyl] -8-hydroxy-1 H-quinoline-2-one. The β2-adrenoreceptor agonist can be in the form of a salt formed with a pharmaceutically acceptable acid selected from sulfuric, hydrochloric, fumaric, hydroxynaphthoic (eg 1- or 3-hydroxy-2-naphthoic), substituted cinnamic cinnamic, triphenylacetic acid, sulfamic, sulfanilic, naphthalene acrylic, benzoic, 4-methoxybenzoic, 2-or 4-hydroxybenzoic, 4-chloro benzoic and 4-phenylbenzoic. In another embodiment, the invention provides a combination comprising a compound of formula (I) and a 2a agonist of adenosine. A2a agonists include those described in the international patent application No. PCT / EP2005 / 005651, such as (2R, 3R, 4S, 5R, 2'R, 3'R, 4'S, 5'R) -2.2 ' -. { trans-1,4-cyclohexanediylbis [imino (2- {{2- (1-methyl-1 H-imidazol-4-yl) ethyl] amino} -9H-purine-6,9-dyl )]} bis [5- (2-ethyl-2H-tetrazol-5-yl) tetrahydro-3,4-furandiol]. In another embodiment, the invention provides a combination comprising a compound of formula (I) and an anti-inflammatory agent.

Anti-inflammatory agents include corticosteroids. Suitable corticosteroids which can be used in combination with the compounds of the invention are oral and inhaled corticosteroids and their pro-drugs having anti-inflammatory activity. Examples include methylprednisolone, prednisolone, dexamethasone, fluticasone propionate, 6a, 9a-difluoro-1β-hydroxy-16 a-methyl-17a - [(4-methyl-1,3-thiazole-5-carbonyl) oxy] -3-oxo-androsta-1, 4-diene-17β-carbothioic ester S-fluoromethyl, 6a, 9a-difluoro-17a - [(2-furanylcarbonyl) oxy] -11β-hydroxy-16a-methyl-3- oxo-androsta-1, 4-diene-17β-carbothioic S-fluoromethyl ester (flutizasone furoate), 6a, 9a-difluoro-11β-hydroxy-16a-methyl-3-oxo-17a-propionyloxy-androsta-1, 4-diene-17β-carbothioic S- (2-oxo-te tra h id cleavage non-3S-i I) ester, 6a, 9a-difluoro-11β-hydroxy-16a-methyl-3-oxo-17a- (2 , 2,3,3-tetramethylcyclopropylcarbonyl) oxy-androsta-1,4-diene-17β-carbothioic acid S-cyanomethyl ester and 6a, 9a-difluoro-11β-hydroxy-16a-methyl-17a- (1-methicyclopropylcarbonyl) ) oxy-3-oxo-androsta-1,4-diene-17β-carbothioic S-fluoromethyl ester, beclomethasone esters (for example the 17-propionate ester or the 17, 21-dipropionate ester), budesonide, flunisolide esters of mometasone (for example mometasone furoate), triamcinolone acetonide, rofleponide, ciclesonide (16a, 17 - [[(R) -cyclohexylmethylene] bis (oxy)] - 11β, 21-dihydroxy-preg na- 1 , 4-diene-3,20-dione), butixocort propionate, RPR-106541 and ST-126. Corticosteroids of particular interest may include fluticasone propionate, 6a, 9a-difluoro-11β-hydroxy-16a-methyl-17a - [(4-methyl-1,3-thiazole-5-carbonyl) oxy] -3- acid. oxo-androsta-1, 4-diene-17β-carbothioic ester S-fluoromethyl, 6a, 9a-difluoro-17a - [(2-furanylcarbonyl) oxy] -11β-hydroxy-16a-methyl-3-oxo-androstatic acid 1, 4-diene-17β-carbothioic S-fluoromethyl ester, 6a, 9a-difluoro-11β-h id roxy-16a-methyl-3-oxo-17a- (2, 2,3,3, - tetra me ti cycloprop i Icarbon il) oxy-and rosta-1,4-diene-17β-carbothioic ester S-fluoromethyl, 6a, 9a-difluoro-11β-hydroxy-16a-methyl-17a- (1-methyclopropi Ica rbonil ) oxy-3-oxo-and rosta-1,4-diene-17β-carbothioic ester S-fluoromethyl and mometasone furoate. In one embodiment the corticosteroid is 6a, 9a-difluoro-17a - [(2-furanylcarbonyl) oxy] -11β-hydroxy-16a-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid ester S -fluoromethyl or mometasone furoate. Non-steroidal compounds that have glucocorticoid agonism that may possess selectivity for transrepression and that may be useful in combination therapy include those covered in the following patent application and patents: WO 03/082827, WO 98/54159, WO 04/005229 , WO 04/009017, WO 04/018429, WO 03/104195, WO 03/082787, WO 03/082280, WO 03/059899, WO 03/101932, WO 02/02565, WO 01/16128, WO 00/66590 WO 03/086294, WO 04/026248, WO 03/06165.1, WO 03/08277, WO 06/000401, WO 06/000398 and WO 06/015870. Anti-inflammatory agents include nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE), inhibitors (eg, theophylline, PDE4 inhibitors or mixed PDE3 / PDE4 inhibitors), leukotriene antagonists, leukotriene synthesis inhibitors (eg Montelukast. ), inhibitors NOS (inducible nitric oxide synthase) (for example, oral NOS inhibitors), IKK antagonists, tryptase and elastase inhibitors, integrin beta-2 antagonists and adenosine receptor agonists or antagonists (for example 2a adenosine agonists) ), cytokine antagonists (chemokine antagonists, such as antagonists CCR1, CCR2, CCR3, CCR4 or CCR8) or inhibitors of cytokine synthesis, or 5-lipoxygenase inhibitors. The NOS inhibitors include those illustrated in WO 93/13055, WO 98/30537, WO 95/34534 and WO 99/62875. In one embodiment, the present invention provides the use of a compound of formula (I) in combination with a phosphodiesterase 4 (PDE4) inhibitor. The specific PDE4 inhibitor useful in this aspect of the invention may be a compound that is known to • inhibit the enzyme PFDE4 or which is discovered to act as a PDE4 inhibitor, and which are only PDE3 inhibitors, not compounds which inhibit the other members of the PDE5 family, as well as PDE4.

Compounds that may be of interest include cis-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenol) -cyclohexane-1-carboxylic acid, 2-vrbomethoxy-4-cyano-4-3-cyclopropylmethoxy-4- difluoromethoxyphenyl, cyclohexane-1-one and cis- [4-cyano-4-3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexane-1-ol]. Also, cis-4-cyano-4- [3- (cyclopentyloxy) -4-methoxife nor l] cyclohexane-1-carboxylic acid (also known as cilomilast) and its salts, esters, pro-drugs, which are described in U.S. Patent No. 5,552,438 issued September 3, 1996.

Other PDE 4 inhibitors include AWD-12-281 from Elbion (Hofgem et al., EMC 15 Int. Symp, Med. Chem-. (Sept. 6-10, Edinburgh) 1998, Abs .. p 98; CAS reference No. 247584020 -9); a 9-benzyl adenine derivative called NCS-613 (INSERM); D-4418 of Chiroscience and ScheringPlough; a PDE 4 inhibitor of nenziodisepina identified as CI-1018 (PD-168787) and attributed to Pfizer; a benzodioxolo derivative shown by Kyowa Hakka in WO 99/16766; K-34 of Kyowa Hakko; V-11294A Napp (Landells, LJ et al., Eur. Resp. J. [Ann. Cong. Eur. Resp. Soc (Sept. 19-23, Geneve) 1998] 1998, 12 (Suppl. 28); Abst P2393 ); roflumiast (No reference CAS 162401 -32-3) and a phthalazinone (WO 99/47505) from Byk-Gulden; Pumafentrine, (-) - p - [(4aR *, 10bS) -9-ethoxy1,2,3,4,4a, 10b-hexahydro-8-methoxy-2-methylbenzo [c] [1, 6] naphthyrifin-6 -il] -? /,? / - diisipropylbenzamide which is a mixed PDE3 / PDE4 inhibitor, which has been prepared and published by Byk-Gulden, now Altana; arophylline under the development of Almirall- Prodesfarma; VM554 / UM565 from Vernalis; or T-440 (Tanabe Seiyaku; Fuji, K. et al., J. Pharmacol. Exp. Ther., 284 (1); 162, (1998)), and T2585.

Other compounds which may be of interest are shown in published international patent applications WO 04/024728 (Glaxo Group Ltd), WO 04/056823 (Glaxo Group Ltd) and WO 04/103998 (Glaxo Group Ltd). In yet another embodiment, the invention provides a combination comprising a compound of formula (I) and an anticholinergic agent.

The anticholinergic agents are the compounds that act as antagonists as muscarinic receptors, in particular the compounds that are antagonists of M-0 M3 receptors, dual antagonists of M / M3 or M2 / M3, M2IM3 M receptors or pan-antagonists. Exemplary compounds for administration via inhalation include ipratropium (e.g., as bromide, CAS 22254-24-6, sold under the name of Atrovent), oxitropium (e.g., as bromide, CAS 30286-75-0) and tiotropium (for example, as bromide, CAS 136310-93-5, sold under the name of Spiriva). Also of interest is revatropathy (eg, as a hydrobromide, CAS 262586-79-8 which is shown in WO 01/04118) Exemplary compounds for oral administration include pirenzepine (eg, CAS 28797-61-7), darifenacin (for example, CAS 133099-04-4 or CAS 133099-07-7 for the hydrobromide sold under the name of Enablex), oxybutynin (for example, CAS 5633-20-5, sold under the name of Ditropan), terodiline (for example, CAS 15793-40-5), tolterodine (for example, CAS 124937-51-5, or CAS 124937-52-6 for tartrate, sold under the name of Detrol), otilonium (for example, as bromide, CAS 26095-59-0, sold under the name of Spasmomen), trospium chloride (for example, CAS 10405-02-4) and solifenacin (for example, CAS 242478-37-1, or CAS) 242478-38-2, or succinate also known as YM-905 and sold under the name of Vesicare). Other anthocholine agents include compounds of the formula (XXI), which are shown in the US patent application 60/487981: wherein a particular alkyl chain attachment attached to the propane ring is endo; R31 and R32 are, independently, selected from the group consisting of straight or modified straight lower alkyl groups preferably having from 1 to 6 carbon atoms, cycloalkyl groups having from 5 to 6 carbon atoms, cycloalkyl-alkyl has from 6 to 10 carbon atoms, 2-thienyl, 2-pyridyl, phenyl, phenyl substituted with an alkyl group having no excess of 4 carbon atoms and phenyl substituted with alkoxy group having no excess of 4 carbon atoms; carbon; X "represents an anion related to the positive charge of the atom N. X" may be, but is not limited to chloride, bromide, iodide sulfate, benzene sulfonate and toluene sulfonate, including, for example: Octane bromide (3) -endo) -3- (2,2-di-2-thienylethenyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1]; Octane bromide (3-endo) -3- (2,2-diphenylethenyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1]; Octane methylbenzenesulfonate 4 (3-endo) -3- (2,2-diphenylethenyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1]; Octane bromide (3-endo) -8,8-dimethyl-3- [2-phenyl-2- (2-thienyl) ethenyl] -8-azoniabicyclo [3.2.1.]; and / or octane Bromide (3-endo) -8,8-dimethyl-3- [2-phenyl-2- (2-pyridinol) ethenyl] -8-azoniabicyclo [3.2.1]. Other anticholinergic agents include compounds of the formula (XXII) or (XXIII), which are shown in the US patent application 60/511009: (XXIII) wherein the H atom is exo position; R41"represents an anion related to the positive charge of the N atom.R1- can be but is not limited to chloride, bromide, iodide, sulfate, benzene sulfonate and toluene sulfonate.R42 and R43 are independently selected from the group consisting of low straight-chain or branched alkyl groups (preferably having from 1 to 6 carbon atoms), cycloalkyl groups (having from 5 to 6 carbon atoms), cycloalkyl-alkyl (having from 6 to 10 carbon atoms), heterocycloalkyl (having from 5 to 6 carbon atoms) and N or O, as heteroatom, heterocycloalkyl-alkyl (having from 6 to 10 carbon atoms) and N or O as heteroatom, aryl, optionally substituted aryl, heteroaryl and optionally substituted heteroaryl; R44 is selected from the group consisting of (C1-C6) alkyl, (C3-C12) cycloalkyl, (C3-C7) heterocycloalkyl, (C? -C6) (C3-C12) alkyl, cycloalkyl, (C1-C6) alkyl ( C3-C7) heterocycloalkyl, aryl, heteroaryl, (C? -C6) alkyaryl, (C1-C6) alkyl-heteroaryl, -OR45, CH2OR45, -CH2OH, -CN, -CF3, CH2O (CO) R46, -CO2R47, -CH2NH2, - CH2N (R47) SO2R45, -SO2N (R47) (R48), -CON (R7) (R48), -CH2N (R48) CO (R46), -CH2N (R48) SO2 (R46), - CH2N (R48) CO2 (R45), -CH2N (R48) CONH (R47); R45 is selected from the group consisting of (d-C-alkyl, (Cr C6) (C3-C12) alkyl, cycloalkyl, (C-C6) alkyl (C3-C7) hetero cycloalkyl, (C1-C6) alkylaryl, (Ci-) Β-Alkyl-heteroaryl; R46 is selected from the group consisting of (C ^ CeCalkyl, (C3-C12> cycloalkyl, (C3-C7) heterocycloalkyl, (C1-C6) alkyl (C3-C2) cycloalkyl, (C1-6) C6) (C3-C7) alkyl heterocycloalkyl, aryl, heteroaryl, (C? -C) alkylaryl, (Ci-CeCalkyl-heteroaryl; R47 and R48 are, independently, selected from the group consisting of H, (C1-C6) alkyl , (C3-C? 2) cycloalkyl, (C3-C7) heterocycloalkyl, (C1-C6) alkyl (C3-C12) cycloalkyl, (C, -C6) (C3-C7) alkyl heterocycloalkyl, (C? -C6) alkylaryl, and (CT-CeJalkyl-heteroaryl, including, for example: Octane iodide (Endo) -3- (2-methoxy-2,2-di-thiophen-2-yl-ethyl) -8,8-dimethyl- 8-azonia-bicyclo [3.2.1]; 3 - ((Endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propionitrile; Octane (Endo ) -8-methyl-3- (2,2,2-triphenyl-ethyl) -8-aza-bicyclo [3.2.1]; ((Endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propionamide; 3 - ((Endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propionic acid; Octane iodide (Endo) -3- (2-cyano-2,2-diphenyl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1]; Octane bromide (Endo) -3- (2-cyano-2,2-diphenyl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1]; 3 - ((Endo) -8-methylo-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propoane-1-ol; N-benzyl-3 - ((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphexylpropionamide; Octane iodide (Endo) -3- (2-carbamoyl-2,2-diphenyl-etik) -8,8-dimethyl-8-azonia-bicyclo [3.2.1]; 1-Benzyl-3 [3- (endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl-urea; 1-Ethyl-3- [3 - ((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl-urea: N- [3- ((Endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -acetamide; N- [3 - ((Endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -benzamide; 3 - ((Endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-di-thiophen-2-yl-propionitrile; Octane (endo) -3- (2-cyano-2,2-di-thiophen-2-yl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] iodide; N- [3- (8Endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propylj-benzenesulfonamide; [3 - ((Endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl-urea; N- [3 - ((Endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl-2,2-diphenyl-propyl] -methanesulfonamide; and / or octane-bromide (Endo) -3- (2,2-diphenyl-3 - [(1-phenyl-methanoyl) -amino] -propyl.} - 8,8-dimethyl-8-azonia-bicyclo [3.2.1]; Particular anticholinergic compounds which can be Use include: Octane iodide (Endo) -3- (2-methoxy-2,2-di-thiophen-2-yl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1]; of octane (Endo) -3-2-cyano-2,2-diphenyl) -8,8-dimethyl-bicyclo [3.2.1]; Bromide iodide (Endo) -3-2-cyano-2,2-diphenyl) -8,8-dimethyl-bicyclo [3.2.1]; Iodide octane (Endo) -3- (2-carbamoyl-2,2-diphenyl ether) -8,8-dimethyl-8-azonia-bicyclo [3.2.1]; Iodide Octane (Endo-3- (2-cyano-2,2-di-thiophen-2-yl-ethyl) -8,8-dimethyl-bicyclo [3.2.1], and / or Octane Bromide (endo) -3- { 2,2-diphenyl-3 - [(phenylmethanoyl) amino] -propiol.] -8,8-dimethyl-azoni-bicyclo [3.2.1] The invention further provides, in a further aspect, a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with a PDE4 inhibitor.

The invention further provides, in another aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with a β2-adrenoreceptor agonist. The invention provides, in another aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with an anticholinergic. The invention further provides, in another aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with an anti-inflammatory agent (such as the classes of the agent formulations used herein). The invention further provides, in another aspect, a combination, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with a corticosteroid such as fluticasone propionate or S-fluoromethyl acid 6a, 9a-difluoro- ester. 17a - [(2-furanylcarbonyl) oxy] -11β-hydroxy-16a-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid or mometasone furoate. Such combinations may be of particular interest for intranasal administration. The invention further provides, in another aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with an A2a receptor agonist, such as the compounds described in PCT / EP2005 / 005651, such as (2R, 3R, 4S, 5R, 2'R, 3'R, 4'S, 5'R) -2,2-. { TRANS-1, 4-cyclohexanediylbis [imino (2- { [2- (1-methyl-1 H-imidazol-4-yl) ethyl] amino.}. -9 H-purine-6, 9-di il)]} bis [5- (2-ethyl-2H-tetrazol-5-yl) tetrahydro-3,4-furandiol]. The combinations referred to above may be presented for use in the form of a pharmaceutical composition and thus the pharmaceutical compositions comprise a combination as defined above together with a pharmaceutically acceptable diluent or carrier represent another aspect of the invention. . The individual compounds of these combinations can be administered either sequentially or simultaneously in separate or combined pharmaceutical compositions. In a proper manner, the individual compounds will be administered simultaneously in a combined pharmaceutical composition. The proper doses of known therapeutic agents will be fully appreciated by those skilled in the art. It is clear to one skilled in the art, when appropriate, that the other ingredients can be used in the form of salts, for example alkali metal or amine salts or as acid addition salts, or pro drugs, or as esters, for example low alkyl esters, or as solvates, for example hydrates, to optimize the activity and / or stability and / or physical characteristics, such as solubility, or therapeutic ingredient, It will also be clear, that, when appropriate, the Therapeutic ingredients can be used in pure form optically.

The compounds of the invention can be prepared by methods described above or by similar methods. In this manner, the following intermediates and Examples serve to illustrate the preparation of compounds of the invention, and are not considered as limiting the scope of the invention in any way. GENERAL EXPERIMENT Through the examples and intermediaries, the following abbreviations can be used: DCM: dichloromethane DIPEA:, N-diisopropylethylamine DMF: N, N-dimethylformamide EtO.Ac: ethyl acetate EtOH: ethanol h: hours HBTU: O- benzotriazol-1-yl) -? /,? /,? / ',? /' - tetramethyluronium hexafluorophosphate HCl: hydrochloric acid HPLC: High Performance Liquid Chromatography L: liters LCMS: Mass Spectrometry of Liquid Chromatography MDAP: mass Purified self-purifying HPLC MeOH: methanol min: minutes ml: milliliters NaCl: sodium chloride Na HCO3: sodium hydrogencarbonate NaOH: sodium hydroxide NMP: 1-methyl-2-pyrrolidinone RT: retention time TBTU: O-benzotriazole - 1 -il) -? /,? /,? / ',? /' - tetramethyluronium hexafluoroborate THF: tetrahydrofuran The silica gel regulator refers to Marck Art No. 9385: silica gel refers to Merck Art No. 7734. SCX cartridges are SP E columns ion exchange where the stationary phase is polymeric benzene sulfonic acid. These can be used to isolate amines. The SCX2 cartridges are ion exchange SPE columns where the stationary phase is polymeric propyl sulphonic acid. These can be used to isolate mines. The organic solutions can be dried, for example by means of magnesium sulfate or sodium sulfate. The reactions can be carried out under nitrogen, if desired. LCMS was carried out on a Supelcosil LCABZ + PLUS column (3.3 cmX4.6 min ID) eluting with 0.1% HCO2H and 0.01 M ammonium acetate in water (solvent A) and 0.05% HCO2H, 5% water in acetonitrile (solvent B), using the following elution g radient 0.0-7min% Bm 0.7-4.2min 100% B, 4.2-5.3 min% B, 5.3-5.5 min 0% B at a flow rate of 3ml / min. The mass spectrum was recorded in a Fisons VG platform electrometer using positive electrospray and negative mode (ES-ve and ES-ve). Flashmaster II is an automated multi-user regulatory chromatography system, available from Agonaut Technologies Ltd., which uses normal phase, disposable, SPE cartridges (2g to 100g). Solvent mixture is obtained in quaternary line to enable gradient methods to carry them out. The samples are queued using a multifunctional open access software, which handles solvents, flow ranges, gradient profile and collection conditions. The system is equipped with a Knauer variable wavelength UV-detector and two Gilson FC204 harvesters enabling automated peak cutting, collection and monitoring. The XRPD method, which was used to analyze crystalline forms of compounds, is as follows: The XRPD analysis was carried out in a XAPert X-Pro X-ray powder diffractometer, model X'Pert Pro PW3040 / 60, serial number DY1850 using an X'Celerator detector. The acquisition conditions were: radiation; CuKa, generator voltage; 40kV, generator current; 45 mA, beginning angle; 2. 0 ° 2p, final angula 40.0 ° 2p, step measurement; 0.0167 ° 2 p, time per step: 190.5 seconds. The sample was prepared by mounting a few milligrams of sample on a Silicon wafer plate (zero background), resulting in a thin layer of powder. The highest positions were measured using Highscore software. The DSC thermograms were obtained using TA Q1000 calorimeter, serial number 1000-0126. The sample was weighed on an aluminum tray, the lid of the tray is placed on top and slightly undulated without closing the tray. The experiment was carried out in a heat range of 10 ° C min "1. Intermediate 1 1 - [(3-chloropropyl) oxy] -4-iodo benzene or A mixture of p-iodophenol (20g, 91 mmol), Potassium carbonate (25.2 g, 182 mmol) and 1-bromo-3-chloropropane (commercially available, for example from Aldrich) (18 g, 114 mmol) in anhydrous 2-butanone (300 mL) was heated to a reflux of 72 g. h, cooled to room temperature, filtered and evaporated to dryness The resulting residue was purified by SPE filtration (70 g silica cartridge, eluting with 20: 1 cyclohexane-ethyl acetate) to obtain the base compound (24.9 g); NMR (CDCl 3) d 7.5 (2H, d), 6.7 (2H, d), 4.1 (2H, t), 3.8 (2H, t), 2.2 (2H, q).

Intermediary 2 1-. { 3 - [(4-iodophenyl) oxy] propiol-3,3-dimethylpiperidine A mixture of 1 - [(3-chloropropyl) oxy-4-iodobenzene (for example, as prepared by intermediate 1) (6.5 g, 20 mmol ), 3,3-dimethyl-piperidine (commercially available, for example from Alfa) (3.39 g, 30 mmol), sodium iodide (2.99, 20 mmol) and potassium carbonate (3.3 g, 20 mml) in anhydrous acetonitrile (100 ml) was heated at reflux overnight. The mixture was allowed to cool to room temperature, evaporated to dryness and quenched with water and extracted with dichloromethane, dried, filtered and concentrated to obtain the base compound (8 g). CMS RT-2.37 min, ES + ve m / z 374 (M + H) + Intermediate 3 Carboxylate 1,1-Dimethylethyl 4- (4- { [3- (3,3-dimethyl-1-piperidinyl) propyl ] oxy phenyl i I) -4-hydroxy-1-piperidine. A solution of 1-. { 3 - [(4-iodophenyl) oxypropyl} -3,3-dimethylpiperidine (for example as prepared by intermediate 2) (3 g, 8.02 mmol) in anhydrous THF (30 ml) was cooled to -78 ° C under nitrogen and treated with nBuLi (1.6 m solution in benches, 6.02 ml, 9.63 mml), after 0.5 hours, a solution of N-Boc-4-oxopiperidine (commercially available, for example from Aldrih) (1.88, 10 g mmol) in THF (10 ml) was added dropwise. The mixture was cooled to room temperature and stirred overnight. The mixture was annealed and deactivated with ammonium chloride solution and extracted with EtOAc., dried with magnesium sulfate, filtered and concentrated. The resulting residue was purified or FlasMaster II chromatography using a 100 cartridge, eluting with 100% cyclohexane for 5 minutes, 100% cyclohexane at 100% EtOAc for 15 minutes, 100% EtOAc at 100% DCM in 5 minutes and 100% DCM a 30% MeOH (containing 1% triethylimine) in DCM for 40 minutes then was kept constant for 5 min., Monitoring at 254 nm to obtain the base compound (1.25 g). LCMS RT = 2.48 min, ES + ve m / z 447 (M + H) +. Intermediate 4 Dihydrochloride 3-Dimethyl-1- (3 { [4- (4-piperidinyl) phenyl] oxy} propyl) piperidine A solution of 1,1-dimethylethyl 4- (4- { [3 , 3-dimethyl-1-pi perid inio) prop il] oxy} phenyl) -4-h id roxy-1-piperidine carboxylate (for example as prepared for Intermediate 3) (1.25 g, 2.8 mmol) in anhydrous DCM (10 ml) was treated with triethylsilane (2.2 mg, 13.7 mmol) and stirred at room temperature under nitrogen for 0.5 h. The solution was cooled to 078 ° C and trifluoroacetic acid (3 ml) was added. The reaction was warmed to room temperature and stirred overnight. The mixture was evaporated to dryness, and co-evaporated with toluene twice. The resulting residue was purified on an SCX-2 cartridge (20g) eluted with MeOH, followed by 2M ammonium solution in MeOH to obtain a yellow thin oil which was treated with 2M hydrogen chloride in ether, evaporated to obtain the base compound (886 mg), which contains some 4- (4- { [3- (3,3-dimethyl-1-piperidinyl) propyl] oxy} {phenyl} -1,2,3,6-dichloride tetrahydropyridine, so that an aliquot (0.54 g) was hydrogenated in EtOH) 15 ml) at room temperature using 10% weight of palladium in carbon (0.5 tg) at atmospheric pressure for 2 h. The catalyst was removed by filtration through Celite, washed with ethanol or the filtrate was evaporated to dry to obtain the base compound (448 mg). LCMS RT = 1.77 min, ES + ve m / z 331 (M + H) +. Intermediate 5 4 - [(1E) -3- (Methyloxy) -3-oxo-1-propen-1-yl] -1-naphthalenecarboxylic acid a) A mixture of 4-bromo-1-naphthalenecarboxylic acid (which may be prepared by methods described in Can. J. Chem. 1981, 59, 2629-41) (100 mg, 0.4 mmol), triethylamine (0.42 mL, 3 mmol), palladium acetate (12 mg, 0.04 mmol), triphenylphosphine (13 mg, 0.04 mmol) and methylacrylate (1.19 ml, 0.11 mmol) in anhydrous DMF (8 ml) was heated at 100 ° C for 4 hours under nitrogen. The mixture was allowed to cool to room temperature, evaporated to dryness under reduced pressure and purified by aminopropyl cartridge, eluted with MeOH, followed by 4M HCl in dioxane and then 2M ammonium in MeOH. The ammonia in methanol fractions was combined to obtain a residue that was divided between DCM and water, the DCM layers were combined, dried under magnesium sulfate, filtered and evaporated to obtain a base compound (99 mg, 97%). LCMS RT = 3.25 min, ES + ve m / z 255 (M + H) +. b) A mixture of 4-bromo-1-naphthalenecarboxylic acid (9.42 g), triethylamine (25 ml), palladium acetate (0.85 g), triphenylphosphine (0.98%) and methylacrylate (9.68 g) in anhydrous DMF (95%). ml) were heated at 100 ° C for 1 hour under nitrogen. The mixture was allowed to cool to room temperature, filtered through Celite and washed with diethyl ether / water. The filtrate was extracted with ether, then with EtOAC. The aqueous phase was acidified to approximately pH 1 with 2M aqueous hydrogen chloride. The solid was filtered, washed with water and dried at 40 ° C under vacuum, to obtain the base compound (8.2 g). Intermediate 6 4- [3- (Methyloxy) -3-oxopropyl] -1-naphthalenecarboxylic acid a) 4 - [(1E) -3- (Methyloxy) -3-oxo-1-propen-1-yl] -1 acid -carboxylic naphthalene (for example as it was prepared for the intermediary ) (1.73 g, 5.09 mmol) is hydrogenated with palladium on carbon (10% weight, 350 mg) in ethanol (50 ml) for 4 hours. The catalyst is removed by filtration through Celite, and the mixture is hydrogenated again with fresh catalyst (350 mg) overnight. The mixture is filtered through Celite and concentrated to obtain the base compound. b) 4 - [(1 E) -3- (Methyloxy) -3-oxo-1-propen-1-yl] -1-naphthalenecarboxylic acid (for example as prepared for intermediate 5) (4 g, 5.09 mmol) in 500 mL of ethanol was hydrogenated with palladium on carbon (10% weight, 1 g) for about 2 hours. The catalyst was removed by filtration of Celite, the solvent evaporated and the resulting solid left overnight under vacuum to obtain the base compound (3.8 g) ES + ve m / z 258 (M + H) +.

Intermediate 7 Methyl 3- (4- { [4- (4- { [3- (3,3-Dimethyl-1-piperidinyl) propyl] oxy}. Phenyl] -1-pi pe ridinil carbonyl.} -1-naphthale or I) propanoate A solution of 4- [3- (methyloxy) -3-oxopropyl] -1-naphthalenecarboxylic acid (eg as prepared for Intermediate 6) (0.197 g, 0.76 mmol) in anhydrous DMF (2 ml) was treated with HBTU (0.29 g, 0.77 mmol), diisopropylethylamine (0.6 ml, 3.82 mmol), the mixture was stirred at room temperature for 20 minutes, 3,3-dimethyl-1 dihydrochloride -/3-. { [4- (4-piperidinyl) phenyl [oxy]} propyl) piperidine (for example as prepared for Intermediate 4) (250 mg, 0.63 mmol) was added and the mixture stirred at room temperature for 4 hours. The mixture was evaporated to dryness and purified in a SCX-2 cartridge (5 g) eluted with MeOH, followed by ammonium solution in methanol to obtain the base compound (238 mg). LCMS RT = 2.79 min, ES + ve m / z 571. Example 1 Acid 3- (4- { [4- (4- { [3- (3,3-dimethyl-1-piperidinyl) propyl] oxy} .phenyl) -1-piperidinyl] carbonyl.} -1-naphthalenyl) propanoic, formic acid (1: 1) A mixture of methyl 3- (4- { [4- (4. {[[3- (3,3-dimethyl-1-piperidinyl) propyl] oxy} phenyl-1-piperidinyl] carbonyl. .1-naphthalenyl) propanoate (eg, as prepared in Intermediate 7 (238 mg, 0.42 mmol) and potassium hydroxide (117 mg, 2.08 mmol), in methane! (15 ml) - water. (1 ml. ) was heated to reflux for about 2 hours, cooled to room temperature, evaporated and the residue was purified by preparative auto-HPLC with mass direction to obtain a base compound (60 mg) LCMS RT = 2.73 min, ES + ve m / z 557 (M + H) 1H NMR d (250 MHz: DMSO-d6, 120 ° C) 8.19 (1H, s), 8.18-8.12 (1H, m), 7.89-7.82 (1H, m), 7.64- 7.54 (2H.M), 7.44 (1H, d, J = 7.5 Hz), 7.37 (1H, d, J = 7.5 Hz), 7.18-7.12 (2H, m), 6.89-6.82 (2H, m), 4.02 (2H, t, J = 6.5 Hz), 3.38 (2H, t, J = 7.5 Hz), 310-2.97 (2H, m), 2.84-2.73 (1H, m), 2.69 (2h, t, J = 7.5) Hz), 2.38 (2H, t, J = 7.0 Hz), 2.34-2.27 (2H, m), 2.03 (2H, s), 1.90-1.74 (4H, m), 1.66-1, 48 (4H, m) , 1.23-1.17 (2H, m), 0.92 (6H, s). or 2 Acid 3-4-. { [4-. { [3- (3,3-dimethyl-1-piperidinyl) propyl] oxy} phenyl) -1-piperidinyl] carbonyl} -1-naphthalenyl) propanoic The compound can be prepared according to the following reaction schemes: Stage 1 Stage 2 Stage 5 which Bn represents benzyl BOC represents t-butoxycarbonyl Intermediate 8 (Stage 0) 1, 4-D i bromine naphtha le not A solution of bromine (120.9 ml, 3 equiv) in chloroform (400 ml) is added for 6 hours in a solution Naphthalene (100 g) in chloroform (200 ml) and DMF (19 ml) at 0-10 ° C. The reaction is stirred at 0-30 ° C (for example 20-30 ° C) until about 25 hours and then the chloroform (100 ml) is added. The reaction mixture is washed with sodium bisulfite (1x600 ml), then washed with 5% aqueous sodium bicarbonate (1x300 ml), then washed with water (300 ml), then evaporated. The residue is crystallized from methanol (2600 ml), by heating to 65-70 ° C, and cooling to 20-30 ° C for 3-4 hours. The product is filtered, and dried under vacuum at 50-55 ° C (dry weight 117 g) - Intermediary 9 (Stage 1) Acid 4-b ro mo -1- carboxylic naphtha A solution of 1,4-dibromonaphthalene (100 g) in THF (500 ml) is added to magnesium (8.49 g) and iodide (trace) in THF (200 ml) for about 2 hours and heated to 65-75 ° C for up to 7 hours (typically 3-4 hours) to prepare a Grignard reagent solution. The solution is cooled to 0-10 ° C and the carbon dioxide gas is passed through the solution for 10-16 hours. The water (100 ml) is added slowly, and after stirring for about 30 min at 0-10 ° C, it is acidified (typically pH 2-3) with hydrochloric acid. The THF layer is separated, and concentrated. The residue is added to the aqueous sodium carbonate (20%, 500 ml) and washed with toluene (2 × 200 ml). The aqueous solution is treated with hydrochloric acid (typically pH 2-3). The product is filtered, washed with water and dried under vacuum to about 90-100% by about 12 hours (dry weight 60 g). Intermediary 10 (Stage 2) Acid 4-. { [1E) -3-Oxo-3 - [(phenylmethyl) oxy] -1-propen-1-yl} -1-naphthalecarboxylic acid A mixture of 4-bromo-1-naphthalenecarboxylic acid (100 g), benzylacrylate (96.8 g), triphenylphosphine (10.2 g), palladium (II) acetate (2 g), triethylamine (258) ml) and DMF (600 ml) are heated at 90-100 ° C for 4-12 hours (typically 10-12 hours). Two additional portions of palladium (II) acetate (20 g) were added at four hour intervals during the period of agitation. The mixture is treated with charcoal (3x15 g) at 50-80 ° C (typically 70-80 ° C) then filtering each charge at 40-45 ° C. The DMF is then distilled at 80-90 ° C under vacuum and the residue is cooled to 25-35 ° C. Dichloromethane (100 ml) and water (100 ml) are added to the residue and the mixture is acidified with concentrated hydrochloric acid and stirred at 20-35 ° C for about 30 minutes. The mixture is filtered, and the solid product dried. The residue is dissolved in a mixture of DMF (600 ml) then in water (400 ml) at 90-100 ° C and stirred for 1-1.5 hours. The solution is filtered at 80-85 ° C, cooled to 20-35 ° C and stirred for about 2 hours. The product is filtered and dried (dry weight 43 g). Intermediate 11 (Stage 3) 3,3-dimethyl-1- (phenylmethyl) -2,6-piperidinedione A solution of glutaric acid (250 g) in xylene (1.87 L) is treated with p-toluene sulfonic acid (5.9 g) and heated to reflux. A solution of benzylamine (165.5 g) in xylene (6 ml) is added over about 2 h, and the reflux is continued for about 24 hours, removing the water azeotropically. The mixture is cooled, and the solvent is removed by distillation under reduced pressure to leave the desired product (dry weight 321 g).

Intermediate 12 (step 4) 3,3-dimethyl-1- (phenylmethyl) piperidine A solution of 3,3-dimethyl-1- (phenylmethyl) -2,6-piperidinedione (200 g) in THF (400 ml) is added over 1-4 hours (for example 1-2 hours) at -5 to + 5 ° C to a lithium aluminum hybrid solution (68 g) in THF (2 L). The mixture is then heated at 20-35 ° C for about 1-2 hours, and then refluxing for 24-30 hours. The mixture is then cooled to -5 to + 5 ° C and the ethyl acetate (280 ml) is slowly added, followed by aqueous sodium sulfate (257 g in water 1.4 L) and then ethyl acetate (1L). The mixture is stirred at 25-35 ° C for about 1 hour. The organic layer is filtered through a Hyflow bed, washed with ethyl acetate (2x2 L). The filtered layers are combined, then washed with brine (1L) and evaporated to obtain the product. The product can be further purified by column chromatography, eluted with petroleum ether and ethyl acetate mixtures or by fractional distillation (dry weight 105 g). Intermediary 13 (Stage 5) 3,3-Dimethylpiperidine To a solution of 1-chloroethylchloroformate (94.5 g) in dichloromethane (560 ml) cooled to 0-15 ° C (typically 0-5 ° C, is added to 3,3, -dimethyl-1- (phenylmethyl) piperidine (112 g) over 15 minutes and the reaction mixture is stirred for 1 hour, allowing it to warm to 20-30 ° C. The reaction is heated to reflux for 2-20 hours (for example for about 2 hours), then the solvent is removed in vacuo. Methanol (560 ml) is added to the residue at 5-30 ° C (typically 20-30 ° C) then the mixture is heated to reflux for 3-20 hours (for example 3-4 hours) then cooled to 5-30 ° C and concentrated. Diethyl ether (400 ml) and isopropanol (20 ml) were added, then the mixture was stirred at 25-35 ° C for 30 min-2 hours. The solid material is filtered and washed with diethyl ether (200 ml). The solid is dissolved in water (336 ml) and diethyl ether (560 ml), and then 10 M sodium hydroxide (200 ml) is added at 20-30 ° C. The layers are separated and the aqueous layer is extracted with diethyl ether (560 ml). The combined ether solutions are concentrated and the product is purified by fractional distillation (dry weight 41 g). Intermediate 1 (Step 6) 1 - [(3-Chloropropyl) oxy] -4-iodobenzene A mixture of 4-iodophenol (250 g), potassium carbonate (313.6 g) and 2-butanone (1500 ml) is stirred for 15 hours. -20 minutes. 1-Bromochloropropane (357.71 g) is added over about 10 minutes, the reaction mass is heated to reflux (about 80-85 ° C) for 22-24 hours. After cooling to 25-30 ° C, the mixture is filtered, washing the cake with 2-butanone (750 ml). The filtrate is concentrated under reduced pressure to 50-60 ° C. Ethyl acetate (3750 ml) is added and stirred for 10-20 min to obtain a clear solution. It has been washed with 2N sodium hydroxide solution (1250 ml), water (2500 ml) and aqueous sodium chloride (2500 ml) and then dried with sodium sulfate. The solvent is concentrated under reduced pressure at 50-60 ° C. N-heptane (250 ml) is added and stirred for about 20 min at 25-30 ° C. The solution is then cooled to -5 to 10 ° C and stirred for about 30 min. The solid is filtered, washed with chilled n-heptane (125 ml, 0-5 ° C) and the solid is left to dry. Isolation of second cut The combined filtrate and washings are concentrated and n-heptane (70 ml) is added and the mixture stirred for approximately 20 minutes at 25-30 ° C. The solution is cooled to -5 to 10 ° C, stirred for about 35 minutes and then the solid is filtered and washed with n-heptane (30 ml, 0-5 ° C). The products of both cuttings were dried at 35-40 ° C under vacuum for 6-10 hours, to obtain the base compound (285 g). intermediary 2 (Stage 7) 1-. { 3 - [(4-iodophenol) oxy] propyl} -3,3-dimethylpiperidine A mixture of 1 - [(3-chloropropyl) oxy] -4-iodobenzene (100 g) and acetonitrile (600 ml) is stirred for about 5 min at 25-35 ° C, then the carbonate potassium (93.07 g) followed by 3,3-dimethylpiperidine (49.53 g) is added thereto for about 10 minutes. Potassium iodide (2.24 g) is added, then the mixture is stirred for approximately 15 minutes, before it has been heated at 78-82 ° C for 22-24 hours. The reaction mixture is cooled to 25-35 ° C, and the solid residue is filtered and washed with acetonitrile (200 ml). The filtrate and the washings are concentrated under reduced pressure at 50-60 ° C to obtain a thin liquid, which is stirred with n-heptane (100 ml) for about 30 min at 25-30 ° C. The solution is then cooled to -5 to 10 ° C and stirred for about 30 minutes. The solid is filtered, washed with chilled n-heptane (50 ml, 0-5 ° C), then dried at 35-40 ° C under vacuum for 6-10 hours to obtain the base compound (97 g).

Isolation of second cut The combined filtrate and washings are concentrated to a thin syrup and n-heptane (50 ml) is added and stirred for about 20 min at 25-30 ° C. The solution is cooled to -5 to -10 ° C, stirred for 40 minutes, then the solid is filtered and washed with chilled n-heptane (40 ml, 0-5 ° C). The solid is dried at 35-40 ° C under vacuum for 6-10 hours to obtain the base compound. The total dry weight of the base compound (from the first to the second cut) is 92.1 g.

Intermediate 3 (Stage 8) 1,1-dimethylethyl-4- (4- { [3- (3,3-dimethyl-2-piperidinyl) propyl] xi.} Phenyl) -4-hydroxy-1-piperidinecarboxylate . A solution of 1- (3 - [(4-iodophenyl) oxy] propyl] -3,3-dimethylpiperidine (25 g) in THF (125 ml) is stirred for about 15 minutes, then cooled for approximately 15 min. , then cooled 0-5 ° C. The magnesium chloride solution of isopropyl (70.5 ml, 1.9 M) is added at 0-5 ° C for 40 minutes, then the mixture is stirred at 0-5 ° C for 2- 3 hours, The mixture is then cooled to -78 to -80 ° C and a pre-cooled solution (-29 to -30 ° C) of N-Boc- • piperidinone (16 g) in THF (125 ml) is added. over about 1-2 hours and the reaction mixture is stirred for about 1.5 hours at -78 to -80 ° C. The reaction mixture is allowed to warm to 25-30 ° C, then stirred for 23-24 hours. of saturated ammonium chloride (375 ml) is added at 25-30 ° C, followed by ethyl acetate (500 ml) and the mixture stirred for about 50 min.The aqueous layer is extracted with ethyl acetate (250 ml). The layer The combined organics are washed with water (375 ml), dried with sodium sulfate and concentrated under reduced pressure to obtain the base product (30.3 g). Intermediary 14 (Stage 9) 4- (4- { [3- (3, 3-dimethyl-1-piperidinyl) propyl [oxy]} phenol) -1, 2,3,6-tetrahydropyridine A mixture of crude 1, 1-dimethiethyl-4- (4- { [3- (3,3, -dimethyl-1-piperidinyl) propyl] oxy .}. phenyl) -4-hydroxy-1-piperidinecarboxylate (100 g) in 95% ethanol (500 ml) is cooled to 5-10 ° C and concentrated hydrogen chloride (300 ml) is added at 5-10 ° C over about 45 min, then stir about 15 minutes. The mixture is then heated to reflux (approximately 80-85 ° C) for 6 hours. The mixture is concentrated under vacuum at 50-60 ° C, then the water (500 ml) is added. The mixture is then cooled to 5-10 ° C and the pH adjusted to pH 10-12 with 2N sodium hydroxide solution at 5-10 ° C. The mixture is heated to 25-35 ° C, and extracted with ethyl acetate (500 ml, then 2x200 ml). The combined ethyl acetate layers are washed with water (200 ml), then the 10% aqueous sodium chloride solution. The solvent is removed under vacuum and the product is purified by column chromatography (100-200 mixed silica gels) using a linear gradient of 0-70% MeOH / DCM to obtain the base compound (21.7 g). Intermediate 15 (Stage 10) Phenylmethyl (2E) -3- (4- { [4- (4- { [3- / 3,3-dimethyl-1-piperidinyl) propyl] oxy} phenyl) -3,6-dihydro-1 (2H) -pyridinyl] carbonyl} -1-naphthalenyl) -2-propeonate A mixture of 4- acid. { (1E) -3-oxo-3 - [(phenylmethyl) oxy] -1-propen-1-yl} -1-naphthalene carboxylic acid ethyl acetate (570 ml) is stirred at 25-35 ° C for 10-15 minutes. Triethylamine (73.6 g) is added over about 10 min at 25-25 ° C, followed by TBTU (61.2 g) over about 5 min at 25-35 ° C. The mixture is stirred for about 35 min and then cooled to 0-10 ° C. A solution of 4- (4- { [3- (3,3-dimethyl-1-piperidinyl) propyl] oxy} phenyl-1,2,36-tetrahydrate pyridine (57 g) in acetate of ethyl (570 ml) is added over about 15 minutes at 0-10 ° C, and stirred for about 15 min.The temperature is slowly raised to 25-35 ° C and stirred for 2.5-3.5 hours.The ethyl acetate ( 570 ml) and sodium hydrogen carbonate solution captured (570 ml) are added and stirred for about 70 minutes at 25-35 ° C. The aqueous layer is separated and the ethyl acetate is washed with water (570 ml) and the aqueous sodium chloride solution (570 ml) The organic layer is concentrated under reduced pressure below about 55 ° C to obtain a thin liquid Acetone (114 ml) is added and the solution is cooled to 25-35 ° C and stirred for about 20 minutes n-Heptane (114 ml) is added slowly and the mixture is then cooled to 0-5 ° C, stirred for about 60 minutes and the The residue is filtered and washed with cooled n-heptane (57 ml). The solid is dried under vacuum at 35-40 ° C to obtain the base compound (47 g). Example 2 (step 11) 3- (4- {[[4- (4. {[[3- (3,3-dimethyl-1-piperidinyl) propyl] oxy} phenyl) -1-piperidinyl acid [carbonyl.} -1-naphthalenyl) propanoic, free base A solution of phenylmethyl- (2E) -3- (4- { [4- (4- { [3- (3,3-dimethyl- 1-p iperidinyl) propyl] oxy} phenyl) -3,6-dihydro-1 (2H) -pyridinyl} - 1 -naphthalen-2-propionate (47 g) in methanol (705 ml) is added to a hydrogenation flask.10% Pd / C (11.75 g, 50% wetting) is added and the mixture heated to 40-45 ° C under 60-70 psi hydrogen pressure and stirred for approximately 2-3 The reaction mixture is cooled to 25-30 ° C and filtered through Celite, washed with MeOH (235 ml) .The filtrate is concentrated under vacuum at a temperature of about 60 ° C to obtain the base compound (37.2 g). g) NMR analysis confirms the compound to be a base compound Example 3 3- (4- { [4- (4- { [3- (3,3-di methyl-1-piperidi ni ) propyl.} phenyl) -1-piperidinyl] carbonyl.} -1-naphtha lenil) propanoic, hydrochloride salt Acid 3- (4-. { [4- (4- { [3- (3, 3-d-methyl-1-piperidinyl) propyl] oxy} fyl) -1-piperidinyl] carbonyl} -1-naphthalenyl) propanoic (321.2 g) was added over 5-10 minutes to isopropanol (1.93 L) at 30-30 ° C under nitrogen and diluted at about 300-400 rpm. More isopropanol (1.61 L) was added and the mixture heated to 65-70 ° C to obtain a solution, which was then cooled to 40-45 ° C and stirred at about 300 rpm. Concentrated hydrochloric acid (50 ml) was added over approximately 1 hour and then for 40 minutes, a seed of 3- (4-. {[4- (4-. {[3- (3,3- dimethyl-1-piperidinyl) propyl] oxy.} phenyl) -1-piperidinyl] carbonyl.] -1-naphthalenyl) propanoic acid, hydrochloride salt was added as suspension in isopropanol (approximately 10-12 ml). The mixture was then cooled to about 15 ° C for about 4 hours. The mixture was then stirred at this temperature overnight. The suspension was filtered, washing the solid with isopropanol (1.2 L and 0.6 L), then the solid was dried for about 4 hours, then drying under vacuum for 21 hours at 50-60 ° C to obtain the base compound (dry weight 236 g). The seed was prepared as follows: the free base (300 mg) was dissolved in isopropanol (3.3 ml) with heating. Hydrogen chloride (37%, 0465 ml, 1.05 equivalents) was added to the free base solution at room temperature. The reaction was left to the temperature cycle (0-40 ° C) during the weekend. The white solid was isolated, washed with isopropanol and air dried for about 2 hours after drying under vacuum overnight at 40 ° C (weight 1 37 mg). A representative XRPD standard for the salt of 3- (4. {[[4- (4. {[[3- (3,3-dimethyl-1-piperidinyl) propyl] oxy] hydrochloride. phenyl) -1-piperidinyl] carbonyl.] -1-naphthalenyl) propanoic (Example 3) as shown in Figure 1. The highest angles are presented below.

A representative DSC thermogram for the salt of 3- (4-. {[[4- (4- { [3- (3,3-dimethyl-1-piperidinyl) propyl] oxy} phenyl) hydrochloride. -1-piperidinyl] carbonyl.] -1-naphthalenyl) propanoic (example 3) is shown in Figure 2 with a mixture of about 164 ° C. Biological Information The compounds of the invention can be tested for biological activity in vitro and / or in vivo, for example according to the following or similar assays: Generation of H1 receptor cell line and FLIPR assay protocol 1. Generation of cell line Histamine h1 The human H1 receptor can be cloned using known procedures described in the literature [Biochem. Biophys. Common Res., 201 (2): 894 (1994)]. Chinese hamster ovary (CHO) cells stably expressing the human H1 receptor can be generated, according to the known procedures described in the literature [Br. J. Pharmacol., 117 (6): 1071 (1996)]. Functional histamine H1 antagonist assay: determination of functional pKi values Histamine H1 cell line is seeded in tissue culture dishes of 384 clear bottom wells with black walls not covered in minimal essential medium (Gibco / Invitrogen, cat. 22561-021), supplemented with 10% fetal bovine serum (Gibco / Invitrogen, cat No.12480-021) and 2 mM L-glutamine (Gibco / Invitrogen, cat.

No.25030-024) and is kept overnight at 5% CO2, 37 ° C. The excess medium is removed from each well to leave 10 μl-30 μl of charged ink (250 μM Brilliant Black, 2 μM Fluo-4 diluted in Tyrodes + probenecid solution (145 mM NaCl, 2.5 mM KCl, 10 mM HEPE, 10 mM D-glucose, 1.2 mM MgCl2, 1.5 CaCl2, 2.5 mM probenecid, pH adjusted to 7.40 with 1.0 M NaOH) is added to each well and the plates are incubated for 60 min at 5% CO2, 37 ° C. 10 μl of the test compound, diluted to the required concentration in Tyrodes + probenecid solution (or 10 μl Tyrodes-probenecid solution as a control) is added to each well and the plate incubated for 30 min at 37 ° C, 5% CO2. The dishes are then placed in a FLIPR ™ (Molecular Devices, UK) to monitor cell fluorescence (? Ex = 488 nm,? Ex = 540 nm) in the manner described in Sullivan et al., (En: Lambert DG ( ed.) Calcium Signaling Protocols, New Jersey: Humana Press, 1999, 125-136) before and after the addition of 10 μM histamine in a concentration resulting in the final histamine test concentration being EC80. Functional antagonism is indicated by an induced histamine suspension that increases in fluorescence, as measured by the FLIPR ™ system (Molecular Devices). By means of concentration effect curves, functional affinities are determined using standard pharmacological mathematical analysis. Histamine H1 Functional Antagonist Assay: Determination of pA2 Antagonist Histamine H1 receptor expressing CHO cells is cultured in 96 well clear tissue well culture dishes with uncovered blackish walls as described above. The next culture overnight, the growth medium is removed from each well, washed with 200 μl of phosphate-based saline (PBS) and replaced with 50 μl of ink loading (250 μM Black). Bright, 1 μ; Fluo-4 diluted in Tyrodes + probenecid solution (145 mM NaCl, 2.5 mM KCl, 1.0 mM EPES, 1.0mM D-glucose, 1.2mM MgCl2, 1.5mM CaCl2, 2.5mM probenecid pH adjusted to 7.4 with 1.0 M NaOH)). Cells without incubated for 45 minutes at 37 ° C. The loaded solution is removed and the cells washed as above, and 90 μl of Tyrodes + probenecid solution is added to each well. 10 μl of test compound ', diluted to the required concentration in Tyrodes + probenecid solution as a control) is added to each well and the plate incubated for 30 min at 37 ° C, 5% CO2. The dishes are then placed in a FLI PR ™ (Molecular Devices, UK) to monitor cell fluorescence ((? Ex = 488 nm,? Ex = 540 nm) in the manner described in Sullivan et al., (En: Lambert DG (ed.) Calcium Signaling Protocols, New Jersey; Humana Press, 1999, 1 25-1 36) before and after the addition of 50 μl of histamine over a concentration range of 1 μM-0. 1 nM. The resulting concentration response curves are analyzed by a non-linear regression using the four-parameter equation to determine the histamine EC50, the histamine concentration required to produce a 50% response to the amino acid response of histamine. The antagonist pA2 is calculated using the following standard equation: pA2 = log (DR-1) -log [B] where DR = dose range, defined as EC50 antagonist-treated / EC50 control and [B] = antagonist concentration. 2. Generation of H3 receptor cell line, membrane preparation and protocoles of functional GTPyS assay. Generation of histamine H3 cell line Histamine H3 cADB is isolated from its vector holder, pcDNA3.1TOPO (I nVitrogen), by restricted digestion of DNA plasmid with BamH 1 and Not-1 enzymes and ligated into the induced expression vector pGene (InVitrogen) digested with the same enzyme. The system GeneSwitch ™ (a system in which the expression of trans is disconnected in the absence of an inductor and connected in the presence of an inductor) is carried out as described in the North American patents; 5, 364,791; 5, 874, 534 and 5,935, 934. Ligated DNA is transformed into E. coli competent bacterial DH5a host cells or placed on Luria Broth (LB) agar containing Zeocin ™ (an antibiotic which allows the selection of cells expressing the sh gene). which is present in pGene and pSwitch) at 50 μgml "1. Colonies containing re-linked plasmids are identified by restriction analysis DNA for transfection in mammary cells is prepared from 250 ml of host bacterial culture containing plasmid pGeneH3 and isolated using a DNA preparation kit (Qiagen Midi Prep) according to the manufacturer's guideline (Qiagen). CHO K1 cells previously transfected with the pSwitch regulating asmid (InVitrogen) are seeded at 2 × 10 6 cells per T75 flask. in Complete Medium containing Hams F12 (GIBCOBRL, Life Technologies) medium supplemented with 10% v / v of dialyzed fetal bovine serum, L-glutamine and hygromycin (100 μgml "1), 24 before use. Plasmid DNA is transfected into cells using Lipofectamine according to the manufacturer's guidelines InVitrogen). 48 hours after transfection, the cells are placed in complete medium supplemented with 500 μgml'1 Zeocin ™. 10-14 days after selection, 10 nM Mifepristone (InVitrogen) is added to the culture medium to induce receptor expression. 18 hours post induction, the cells are detached from the flask using ethylenediamine tetra-acetic acid 8EDTA, 1: 5000; InVitrogen), following some washes with pH 7.4 phosphate-mediated solution and then resuspended in a Classified Medium containing Medium Essential Medium (MEM), without red phenol, and supplemented with salts Earles and 3% Fetal Clone II (Hyclone). Approximately 1X107 cells are examined for receptor expression by staining with a rabbit polyclonal antibody, 4a, raised against the N-terminal domain of the histamine H3 receptor, incubated on ice for 6 min, followed by two washes in sorting medium. . The antibody combined with receptor is detected by incubation of cells for 60 minutes on ice with a goat anti-rabbit antibody, conjugated with fluorescent marker Alexa 488 (Molecular Tests). Following another two washes with Classification Medium, the cells are filtered through 50 μm Filcon ™ (BD Biosciences) and then analyzed in a SE Flor Vantage FACS cytometer fitted with an automatic deposition unit. The control cells are non-induced cells treated in a similar manner. The contaminated cells are classified as single cells in 96-well dishes containing Complete Medium containing 5 and allowed to expand before analysis for receptor expression through antibody and ligand binding studies. The clone, 3H3, is selected for membrane preparation. Preparation of membrane of cultured cells All steps of the protocol are carried out at 4 ° C and with pre-cooled reagents. The cell pellet is resuspended in 10 volumes of homogenization solution (50 nM N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (H EPES), 1 mM ethylenediamine tetraacetic acid (EDTA), pH 7.4 with KOH, supplemented with 1 0'6 M of leupeptin (acetyl-leucyl-leucyl-arginine, Sigma L2844), 25 μgml "1 bacitracin" (Sigma B0125), 1 mM of phenylmethylsulfonyl fluoride (PMSF) and 2x1-0- 6 M pepstatin A (Sigmal)) The cells are then homogenized for 2 x 15 seconds in a 1 liter Warlg glass blender, followed by centrifugation at 500 g for 20 min.The supernatant is then centrifuged at 48,000 g for 30 minutes The pallet is resuspended in homogenization solution (4x the volume of the cell palette) by homogenization for 5 seconds, followed by homogenization in a Dounce homogenizer (1 0-1 5 pulses). the polypropylene tubes and the storage at -80 ° C.

Histamine H3 Functional Antagonist Assay For each compound that is tested, in a 384 well plate of white solid, it is added: a) 0.5 μl of test compound diluted to the desired concentration in DMSO (or 0.5 μl DMSO as a control) ); b) 30 μl of microsphere / membrane / GDP mix is repaired by mixing in Centello Analysis by proximity for wheat germ agglutinin and polystyrene ® (WGA PS LS) (SPA) membrane microspheres (prepared according to the methodology described above) and diluting a test solution (20 mM N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (H EPES) + 1 00 mM NaCl + 1 0 mM MgCl 2, pH 7.4 NaOH) to obtain a volume end of 30 μl, which contains 5 μg of protein, 0.25 mg microsphere per well and 1 0 μM final assay concentration of guanosine 5'-diphosphate (GDP) (Sigma, diluted in test solution) incubating at room temperature for 60 minutes min on a roller. c) 1 5 μl 0.38 nM [35S] -GTP? S (Amersham, concentration of radioactivity = 37 MBqml "1; Specific activity = 1 1 60 Cimmol" 1); histamine (in a concentration that results in the final test concentration of histamine being EC8o) - After 2-6 hours, the dish is centrifuged for 5 minutes at 1500 rpm and counted with a Viewlux counter using a filter 61 3/55 for a 5 minplate "1. The information is analyzed using a logistic equation of 4 parameters, the basic activity used as a minimum, ie histamine not added to the well, model of papules and erythematous antiinflammatory reaction in vivo. Guinea Dunkin-Hartley 500-1 kg are dosed with test compound or vehicle using a 1 ml syringe in the oral cavity (0.5 ml (kg po) or through the marginal ear vein (0.33 ml / kg iv). The compounds are formulated in 5% DMSO / 45% PEG200 / 50% water. Whether it is 2 hours later or 15 minutes after the administration of the compound intravenously, guinea pigs are anesthetized with isufloran (5%, 2-31 min O2) and receive Evans blue solution (2% in saline solution). , 0.33 ml (kg i .v through the marginal vein of the ear.) Immediately from the Evans blue administration, and while under isoflurane, the animals are placed in an incline position, and the area of the back shaved. Histamine (10 μg / 1000 μl x 4) and the vehicle (1 x 1000 μl PBS) is injected intradermally into the shaved dorsal surface.As the histamine provocation, the animals are allowed to recover from anesthesia and 30 minutes later they are euthanatized with an overdose of pentobarbitone, the dorsal skin is carefully removed and the area with blotch (blue spotting) measured from the surface of the inner skin taking two perpendicular diameters using engineer clamps and calculating the rad The average value is used to calculate the area of each swelling, and the average value of bruises induced by hysterectomy is calculated by each animal. If Evans blue is seen in a bruise caused by a vehicle, then the animal is excluded from the set of information. Response curves are constructed for each test combo and I D50 values can be determined for each administration route (oral and intravenous).

CNS Penetration (i) CNS penetration by bolus administration Compounds are administered intravenously at a nominal dose level of 1 mk / kg to CD male Sprague Dawley rats.

The compounds are formulated in 5% DMSO / 45% PEG "00/50% water.The blood samples are taken under terminal anesthesia with isoflurane at 5 minutes after the dose and the brains are removed by evaluation or cerebral penetration. The blood samples are prepared for analysis using protein precipitation and brain samples are prepared using the extraction of drug from the brain by homogenization and precipitation of subsequent protein. and the brain extracts are determined by quantitative MS / MS analysis using compound-specific mass transitions (ii) CNS penetration following intravenous infusion to a permanent stage A loading dose of the compounds is administered to male CD Sprague Dawley rats at a nominal dose level 0.4 mg / kg.

The compounds are then administered infusion intravenously for four hours at a nominal dose level of 0.1 mg / 1 kg / h. Compounds are formulated in 2% DMSO / 30% PEG "00/68% water, Many blood samples were taken at 0.5, 1.5, 2.5, 3, 3.5 and 4 hours after the dose. The final sample is collected under final anesthesia with isoflurane and the brains are also removed by brain penetration evaluation.The blood samples are taken directly into the heparinized tubes.The blood samples are prepared for the analysis using protein precipitation and brain samples are Prepared using drug extraction by homogenization and subsequent protein precipitation The concentration of the matrix drug in blood and brain extracts is determined by quantitative LS-MS / MS analysis using com-specific mass transitions.

Rat Pharmacokinetics Compounds are dosed to CD Sprague Dawley rats by simple or oral administration at the nominal dose level of 1 mg / kg and 3 mg / kg. The compounds are formulated in 5% DMSO / 45% peg200 / 50% WATER. An intravenous profile is obtained by taking sera samples or blood terminals at 0.083, 0.25, 0.5, 1, 2.4 and 7 hours post dose (for some studies samples can be taken from 1 2 to 24 hours). An oral profile is obtained by taking serial or terminal samples of blood at 0.25, 0.5, 1, 2, 4, 7, and 12 hours post dose (for some studies 24 and 30 hours of sample can be taken). Blood samples are taken directly in heparinized tubes. The blood samples are prepared by protein precipitation and subjected to quantitative analysis by LC-MS / MS using specific mass transitions of the compound. The profiles of drug concentration are generated and the non-compartmental analysis used to generate estimates of half-life, liquidation, volume or distribution and oral biocapacity. Dog pharmacokinetics The compounds are dosed to male Beagle dogs by simple intravenous administration at a nominal dose level of 1 mg / kg and 2 mg / kg respectively. The study is carried out according to the cross design so that the same dog is used for the two dose events that occur at a distance of 1 week from each other. The compounds are formulated in 5% DMSO / 45% Peg200 / 50% water. An intravenous profile is obtained by taking serial blood samples at 0.083, 0.25, 0.5, 0.75, 1, 2.4, 6 and 1 2 hours post dose (for some studies samples can be taken for 24 hours). An oral profile is obtained by taking serial blood samples at 0.25, 0.5, 0.75, 1, 2.4, 6 and 12 and 24 hours after the dose. Blood samples are taken directly in the heparinized tubes. The blood samples are prepared by protein precipitation and subjected to quantitative analysis by LC-MS / MS using compound-specific mass transitions. The drug time concentration profiles are generated and the non-compartmental analysis used to generate estimates of half-life, liq uidation, volume or oral biocapacity distribution.

Results In these, or similar assays, the compound of Examples 1 and 3, have (i) an average pKi (pKb) to H3 of about 7.4 for example 1 and 7.3 during Example 3 (ii) an average of pKi (pKb) ) at H 1 of about 7.8 for Example 1 and 7.9 for Example 3, and pA2 of about 8.1 for Example 3 (iii) inflammatory activity in vivo (in the papules and erythematous reaction an I D50 of about 0.6 mg / Kg iv and approximately 2.8 mg / Kg oral (Example 3) (iv) oral biocapacity in the rat and dog (approximately 59% in the rat of Example 1, and combined information for Example 1 and 3 of approximately 60% in a dog. (v) Liquidation of low plasma in rat and dog (Example 1 of half-life according to 4-5 hours (Vta route) in the rat), and the combined information for example .1 and 3 of half-life of about 3 hours in the dog. (vi) Low CNS penetration, less than 50nm / gm (Example 1 and 3).

Claims (10)

2. A compound of the formula (I) wherein the naphthalene ring can be substituted at the 2,3,4,5,6,0 position by R 1, and R 1 represents -CH 2 CH 2 COOH or -CH = C (CH 3) COOH; or a salt of them. 2. A compound according to claim 1, wherein the naphthalene ring can be substituted at positions 2,3,4,6,7 or 8 by R1, and R1 represents -CH2CH2COOH, or a salt thereof.
3. 3. 3- (4- { [4- (4. {[[3- (3,3-Dimethyl-1-piperidinyl) propyl] oxy} phenyl) -1-pyridinyl] carbonyl acid .}. -1-naphthalenyl) propanoic, or a salt thereof.
4. 4. A compound according to any of claims 1 to 3, wherein the compound is in pharmaceutically acceptable salt form.
5. 5. A compound according to claim 3, wherein the compound is in the form of the hydrochloride salt.
6. 6. A compound or a pharmaceutically acceptable salt thereof according to any of claims 1 to 5, for use in therapy.
7. 7. A compound or a pharmaceutically acceptable salt thereof according to claim 6, for use in the treatment of inflammatory and / or allergic dysfunctions.
8. 8. A compound or a pharmaceutically acceptable salt thereof according to claim 7, for use in the treatment of allergic rhinitis.
9. 9. A composition which comprises a pharmaceutically acceptable salt compound thereof according to any of claims 1 to 5, optionally with one or more pharmaceutically acceptable carriers or excipients.
10. 10. A combination comprising a compound or a pharmaceutically acceptable salt thereof according to any of claims 1 to 5, and one or more other therapeutic compounds. eleven . The use of a pharmaceutically acceptable salt compound thereof according to any of claims 1 to 5 in the manufacture of a medicament for the treatment or prophylaxis of inflammatory and / or allergic dysfunctions. The use according to claim 1, wherein the dysfunction is allergic rhinitis. 1 3. A method for the treatment or prophylaxis of inflammatory and / or allergic dysfunctions, which comprises administering to a patient in need of an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 1 .