MXPA06007348A - 1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxamide derivatives having 5-ht4 - Google Patents

Abstract

wherein R1 represents an alkyl group having from 1 to 4 carbon atoms or a halogen atom, R2 represents an alkyl group having from 1 to 4 carbon atoms, R3 represents a hydrogen atom or a hydroxy group, and A represents an oxygen atom or a group of the formula -C(R4)(R5)- (in which R4 represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms and R5 represents a hydroxy group or an alkoxy group having from 1 to 4 carbon atoms) or a pharmaceutically acceptable salts thereof. These compounds have 5-HT4 receptor agonistic activity, and thus are useful for the treatment of gastroesophageal reflux disease, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome or the like in mammalian, especially humans.

Description

CARBOXAMIDA THAT HAVE AGONISTA ACTIVITY OF THE RECEIVER 5-HT4 FIELD OF THE INVENTION This invention relates to new derivatives of 1-isopropyl-2-oxo-1,2-d-hydropyridine-3-carbQxamide. These compounds have 5-HT4 receptor agonist activity. The present invention also relates to a pharmaceutical composition, to a method of treatment and to use, comprising the above derivatives for the treatment of disease states mediated by the activity of the 5-HT4 receptor.

BACKGROUND OF THE INVENTION In general, 5-HT4 receptor agonists are considered to be useful for the treatment of numerous diseases such as gastroesophageal reflux disease, digestive disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, colon syndrome. irritable (SCI), constipation, dyspepsia, esophagitis, gastroesophageal disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders such as heart failure and cardiac arrhythmia and apnea (see TiPs, 1992, 13, 141; Ford APDW et al., Med. Res. Ev., 1993, 13, 633; Gullikson GW et al., Drug Dev. Res., 1992, 26, 405; Richard M Eglen et al, TiPS, 1995, 16, 391, Bockaert J. et al., CNS Drugs, 1, 6, Romanelli MN et al., Alzheimer Forsch./Drug Res., 1993, 43, 913, Kaumann A. et al., Naunyrr-Schniiedeberg's 1991, 344, 1 50; and Romanelli M. N. et al., Alzheimer Forsch. / Drug Res., 1993, 43, 913). International patent WO 2003/57688 describes derivatives of 1-alkyl-2-oxo-1,2-dihydropyridine-3-carboxamide as modulators of the 5-HT4 receptor. Especially, the compound represented by the following formula is described in example 4: Compound A However, this compound shows a weak affinity for the 5-HT4 receptor and a low permeability through the membranes of the caco2 cells. Therefore, it was desired to find 5-HT4 receptor agonists showing stronger 5HT4 receptor agonist activities and better permeability through the membranes of caco2 cells to decrease side effects.

SUMMARY OF THE INVENTION In this invention, we found that 1) replacing the amino group with an alkyl group, especially methyl or ethyl group, in position 6 greatly improved the permeability through the membranes of caco2 cells while retaining the affinity for the 5-HT4 receptor and 2) replacing the methyl group with the isopropyl group at position 1 improved the agonist activity of the 5HT4 receptor. Therefore, it has now surprisingly been found that the compounds of this invention have a stronger selective 5-HT4 receptor agonist activity with an improvement in permeability in caco2 cells, compared to prior techniques and, thus, They are useful for the treatment of disease states mediated by 5-HT4 activity such as gastroesophageal reflux disease, digestive disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageal disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain and cardiovascular disorders such as heart failure and cardiac arrhythmia, diabetes and apnea syndrome (caused especially by an administration of opioids). The compounds of the present invention may show lower toxicity, better absorption, distribution, good solubility, low binding affinity to the protein, lower drug-drug interaction and good metabolic stability.

The present invention provides compounds of the following formula (I) or pharmaceutically acceptable salts thereof wherein R 1 represents an alkyl group having 1 to 4 carbon atoms or a halogen atom, R 2 represents an alkyl group having from 1 to 4 carbon atoms, R 3 represents a hydrogen atom or a hydroxy group, and A represents an oxygen atom or a group of formula -C (R 4) (R 5) - (in wherein R4 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms and R5 represents a hydroxy group or an alkoxy group having 1 to 4 carbon atoms). Also, the present invention provides the use of a compound of formula (I) or its pharmaceutically acceptable salt, for the manufacture of a medicament for the treatment of a disease mediated by the activity of the 5-HT4 receptor. Preferably, the present invention also provides the use of a compound of formula (I) or its pharmaceutically acceptable salt, for the manufacture of a medicament for the treatment of selected diseases of gastroesophageal reflux disease, digestive disease, gastric motility disorder, dyspepsia non-ulcerative, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageal disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain and cardiovascular diseases such as heart failure and cardiac arrhythmia, diabetes and apnea syndrome. Also, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier for said compound. In addition, the present invention provides a method for the treatment of a disease mediated by 5-HT4 receptor activity in a mammal, which comprises administering, to a mammal in need of such treatment, a therapeutically effective amount of a compound of formula (I). ) or its pharmaceutically acceptable salt. Preferably, the present invention provides a method for the treatment of selected diseases of gastroesophageal reflux disease, digestive disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, disease gastroesophageal, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders such as heart failure and cardiac arrhythmia, diabetes and apnea syndrome.

DETAILED DESCRIPTION OF THE INVENTION In the compounds of the present invention, where R 1 represents an alkyl group having from 1 to 4 carbon atoms, R 2 represents an alkyl group having from 1 to 4 carbon atoms and R 4 represents an alkyl group having has from 1 to 4 carbon atoms, this may be a straight or branched chain group and examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butylyl. Of these, we prefer alkyl groups having from 1 to 3 carbon atoms, preferably methyl, ethyl, propyl and isopropyl, and most preferably, the methyl and ethyl groups. Where R1 represents a halogen atom, this may be a fluorine, chlorine, bromine or iodine atom. Of these, we prefer fluorine or chlorine. Where R5 represents an alkoxy group having from 1 to 4 carbon atoms, this represents the oxy group which is substituted with an alkyl group having from 1 to 4 carbon atoms defined above and can be a straight or branched chain group, and examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and t-butoxy. Of these, we prefer alkoxy groups having from 1 to 3 carbon atoms, preferably methoxy, ethoxy, propoxy and isopropoxy, and most preferably, methoxy and ethoxy groups.

The term "treat", as used herein, refers to reversing, alleviating, inhibiting the advancement, or preventing the disorder or disease to which that term applies, or one or more symptoms of said disorder or disease. The term "treatment", as used herein, refers to the act of treating, as just defined "treat" above. The classes of preferred compounds of the present invention are the compounds of formula (I) and salts thereof in which: A) R 1 represents a halogen atom; B) R 2 represents an alkyl group having 1 to 2 carbon atoms, C) R 3 represents a hydroxy group; D) A represents an oxygen atom. Particularly preferred compounds of the present invention are the compounds of formula (I) and salts thereof in which: E) R 1 represents a halogen atom, R 2 represents an alkyl group having 1 to 4 carbon atoms, R 3 represents a hydrogen atom or a hydroxy group and A represents an oxygen atom or a group of the formula -C (R4) (R5) - (in which R4 represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms and R6 represents a hydroxy group or an alkoxy group having from 1 to 4 carbon atoms); F) R1 represents an alkyl group having 1 to 4 carbon atoms or a halogen atom, R2 represents an alkyl group having 1 to 2 carbon atoms, R3 represents a hydrogen atom or a hydroxy group and A represents an oxygen atom or a group of the formula -C (R4) (R5) - (in which R4 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms and R5 represents a hydroxy group or a alkoxy group having from 1 to 4 carbon atoms); G) R1 represents an alkyl group having 1 to 4 carbon atoms or a halogen atom, R2 represents an alkyl group having 1 to 4 carbon atoms, R3 represents a hydroxy group and A represents an oxygen atom or a group of the formula -C (R4) (R5) - (in which R4 represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms and R5 represents a hydroxy group or an alkoxy group having 1 to 4 carbon atoms); H) R 1 represents an alkyl group having 1 to 4 carbon atoms or a halogen atom, R 2 represents an alkyl group having 1 to 4 carbon atoms, R 3 represents a hydrogen atom or a hydroxy group and A represents an oxygen atom. The most preferred classes of compounds of the present invention are those in which: I) R 1 represents a halogen atom, R 2 represents an alkyl group having 1 to 2 carbon atoms, R 3 represents a hydrogen atom or a hydroxy group and A represents an oxygen atom or a group of the formula -C (R4) (R5) - (wherein R4 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms and R6 represents a group hydroxy or an alkoxy group having 1 to 4 carbon atoms); J) R1 represents an alkyl group having 1 to 4 carbon atoms or a halogen atom, R2 represents an alkyl group having 1 to 4 carbon atoms, R3 represents a hydroxy group, and A represents an oxygen atom . K) R1 represents a halogen atom, R2 represents an alkyl group having 1 to 2 carbon atoms, R3 represents a hydroxy group and A represents an oxygen atom or a group of the formula -C (R4) (R5) - (wherein R4 represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms and R5 represents a hydroxy group or an alkoxy group having from 1 to 4 carbon atoms); L) R1 represents a halogen atom, R2 represents an alkyl group having from 1 to 4 carbon atoms, R3 represents a hydroxy group and A represents an oxygen; M) R 1 represents a halogen atom, R 2 represents an alkyl group having 1 to 2 carbon atoms, R 3 represents a hydroxy group and A represents an oxygen; The most preferred individual compounds of the present invention are 5-chloro -? / - (. {1 - [(4-hydroxytetrahydro-2fy-pyran-4-yl) methyl] piperidin-4-yl} methyl. ) -1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-chloro-6-ethyl-? / - ( { 1 - [(4-hydroxytetrahydro-2A / -pyran-4-yl) methyl] piperidin-4-yl.} Methyl) -1-isopropyl-2 -oxo-1, 2-dihydropyridine-3-carboxamide; ? - ( { 1 - [(4-hydroxytetrahydro-2-pyrran-4-yl) methyl] pyridin-4-yl.} Met.l) -1-isopropyl-5,6-dimethyl- 2-oxo-1,2-dihydropyridine-3-carboxanzide; 5-bromo-? Y- ( { 1 - [(4-Hydroxytetrahydro-2-pyran-4-yl) methyl] piperidin-4-yl.} Methyl) -1-isopropyl-6- methyl-2-oxo-1,2-d-hydropyridine-3-carboxamide; 5-fluoro- / V- ( { 1 - [(4-hydroxytetrahydro-2H-pyran-4-yl) methyl] piperidin-4-yl.} Methyl) -1-isopropyl-6-methyl-2- oxo-1, 2-dihydropyridine-3-carboxamide; 5-chloro -? / -. { [1- (cyclohexylmethyl) piperidin-4-yl] methyl) -1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-chloro -? / - ( { 1 - [(1-Hydroxycyclohexyl) methyl] piperidin-4-yl} methyl) -1-isopropyl-6-methyl-2-oxo-1, 2-dihydropyridine-3-carboxamide; or a pharmaceutically acceptable salt thereof. The compounds of the present invention can exist in the form of several stereoisomers, R and S isomers, depending on the presence of asymmetric carbon atoms. The present invention covers both individual isomers and mixtures thereof, including racemic mixtures. The compounds of the invention can absorb water upon exposure to the atmosphere to absorb water or produce a hydrate. The present invention covers such hydrates. Additionally, the compounds of the present invention can absorb other solvents determined to produce solvates, which also form part of the present invention. The compounds of the present invention can form salts. Examples of such salts include: salts with an alkali metal, such as sodium, potassium or lithium; salts with an alkaline earth metal, such as barium or calcium; salts with another metal, such as magnesium or aluminum; ammonium salts; salts of organic bases, such as a salt with methylamine, dimethylamine, triethylamine, diisopropylamine, cyclohexylamine or dicyclohexylamine; and salts with a basic amino acid, such as lysine or arginine.

GENERAL SYNTHESIS The compounds of the present invention can be prepared by a series of well known procedures for the preparation of compounds of this type, for example, as shown in the following methods A to E. The following methods A, C and D illustrate the preparation of compounds of formula (I). Unless indicated otherwise, R1, R2, R3, R4, R5 and A in the following methods are defined as above. The term "protecting group", as used hereafter, means a hydroxy or amino protecting group that is selected from the typical hydroxy or amino protecting groups described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley &Sons, 1999). All starting substances in the following general syntheses may be commercially available or obtained by conventional methods known to those skilled in the art. METHOD A The preparation of compounds of formula (1a) wherein R 1 is a halogen atom is illustrated. Reaction scheme A (WB) In the above formulas, R 1a represents a halogen atom; X represents a chlorine or bromine atom; and each R6 and R7 represents an alkyl group having from 1 to 4 carbon atoms.

STAGE A1 In this step, the pyridone compound (IV) is prepared by the condensation of the eneamine compound (II) with the enol ether compound (III) in an inert solvent. Normally and preferably, the reaction is carried out in the presence of the solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no side effect on the reaction or substances involved and that it can dissolve the starting substances, at least to some extent. Examples of suitable solvents include: aromatic hydrocarbons, such as benzene, toluene and xylene; and ethers such as diisopropyl ether, diphenyl ether, tetrahydrofuran and dioxane. Of these solvents, we prefer aromatic hydrocarbons. The reaction can be carried out over a wide range of temperatures, and the exact temperature of the reaction is not critical to the invention. The preferred reaction temperature will depend on such factors as the nature of the solvent and the starting substances. However, in general, we coer it convenient to carry out the reaction at a temperature of 50 ° C to 250 ° C, more preferably 120 ° C to 200 ° C. The time required for the reaction can also vary widely, depending on many factors, especially the temperature of the reaction and the nature of the starting materials and the solvent employed. However, as long as the reaction is carried out under the preferred conditions detailed above, a period of 5 minutes to 24 hours, more preferably 60 minutes to 12 hours, is sufficient. STAGE A2 In this step, the compound of formula (V) is prepared by the halogenation of the pyridone compound (IV) prepared as described in step A1.

Examples of suitable halogenating agents include: fluorinating agents, such as xenon difluoride; chlorinating agents, such as chlorine, sulfuryl chloride or N-chlorosuccinimide; brominating agents, such as bromine or N-bromosuccinimide; and iodinating agents, such as iodine or N-iodosuccinimide. The reaction can be carried out according to the methods described in detail in "The Chemistry of Heterocyclic Compounds", Vol 48, Part.1, p 348-395, published by John Wiley & Sons. Normally and preferably, the reaction is carried out in the presence of the solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no side effect on the reaction or substances involved and that it can dissolve the starting substances, at least to some extent. Examples of suitable solvents include: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; amides, such as? and, / V-dimethylformamide and? /,? / - dimethylacetamide; and ethers such as diisopropyl ether, diphenyl ether, tetrahydrofuran and dioxane. Of these solvents, we prefer halogenated hydrocarbons. The reaction can be carried out over a wide range of temperatures, and the exact temperature of the reaction is not critical to the invention. The preferred reaction temperature will depend on such factors as the nature of the solvent and the starting substances. However, in general, we consider it convenient to carry out the reaction at a temperature of 0 ° C to 120 ° C, more preferably 20 ° C to 80 ° C. The time required for the reaction can also vary widely, depending on many factors, especially the temperature of the reaction and the nature of the starting materials and the solvent employed. However, as long as the reaction is carried out under the preferred conditions detailed above, it is normal that a period of 5 minutes to 24 hours, more preferably 12 hours to 24 hours, is sufficient.

STAGE A3 In this step, the compound of formula (V) is prepared by hydrolysis of the ester portion of the compound of formula (IV) prepared as described in step A2. Normally and preferably, the reaction is carried out in the presence of the solvent: There is no particular restriction on the nature of the solvent to be employed, provided that it has no side effect on the reaction or reagents involved and that it can dissolve the reactants, less to a certain extent. Examples of suitable solvents include alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol; Water; and ethers such as diisopropyl ether, diphenyl ether, tetrahydrofuran and dioxane. Of these solvents, we prefer alcohols. The reaction is carried out in the presence of a base.

Likewise, there is no particular restriction on the nature of the bases used and, equally, any base commonly used in a reaction of this type can be used here. Examples of such bases include: meta! Hydroxides! alkaline, such as lithium hydroxide, sodium hydroxide and potassium hydroxide. Of these, we prefer sodium hydroxide or potassium hydroxide. The amount of the base required for the reaction can also vary widely, depending on many factors, especially the temperature of the reaction and the nature of the starting materials and the solvent employed. However, provided that the reaction is carried out under the preferred conditions, it will be sufficient that the amount of the base as chemical equivalent per starting substance is from 2 to 5. The reaction can be carried out over a wide range of temperatures, and the exact temperature of the the reaction is not critical to the invention. The preferred reaction temperature will depend on such factors as the nature of the solvent and the starting substances. However, in general, we consider it convenient to carry out the reaction at a temperature of 0 ° C to 120 ° C, more preferably 20 ° C to 80 ° C. The time required for the reaction can also vary widely, depending on many factors, especially the temperature of the reaction and the nature of the starting materials and the solvent employed. However, as long as the reaction is carried out under the preferred conditions detailed above, a period of 5 minutes to 24 hours, more preferably 60 minutes to 12 hours, is sufficient.

STAGE A4 In this step, the compound of formula (VII) is prepared by forming the acyl halide from the carboxylic portion of the compound of formula (V) prepared as described in step A9. Normally and preferably, the reaction is carried out in the presence of the solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no side effect on the reaction or reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane. Of these solvents, we prefer 1,2-dichloroethane. Examples of suitable reagents include: chlorinating agents, such as oxyalyl chloride or thionyl chloride; and brominating agents, such as thionyl bromide. The amount of reagent required for the reaction can also vary widely, depending on many factors, especially the temperature of the reaction and the nature of the starting materials and the solvent employed. However, provided that the reaction is carried out under the preferred conditions, it is sufficient that the amount of the reagent as chemical equivalent per starting substance is 2 to 5. The reaction can be carried out over a wide range of temperatures, and the exact temperature of the reaction is not critical to the invention. The preferred reaction temperature will depend on such factors as the nature of the solvent and the starting substances. Nevertheless, in general, we consider it convenient to carry out the reaction at a temperature of 0 ° C to 100 ° C, more preferably 0 ° C to 40 ° C. The time required for the reaction can also vary widely, depending on many factors, especially the temperature of the reaction and the nature of the starting materials and the solvent employed. However, as long as the reaction is carried out under the preferred conditions detailed above, it is normal that a period of 5 minutes to 10 hours, more preferably 60 minutes to 5 hours, is sufficient.

STEP A5 In this step, the desired compound of formula (1a) of the present invention is prepared by forming the amide from the compound of formula (VI) prepared as described in step A4 and the ninth compound of formula (VIII). Normally and preferably, the reaction is carried out in the presence of the solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no side effect on the reaction or reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane. Of these solvents, we prefer dichloromethane or 1,2-dichloroethane. The reaction is carried out in the presence of a base. Likewise, there is no particular restriction on the nature of the bases used and, equally, any base commonly used in reactions of this type can be used here. Examples of such bases include: amines, such as triethylamine, diisopropylethylamine, tributylamine, pyridine, picoline and 4- (N,? / - dimethylamino) pyridine. Of these, we prefer triethylamine, diisopropylethylamine or pyridine. The amount of the base required for the reaction can also vary widely, depending on many factors, especially the temperature of the reaction and the nature of the starting materials and the solvent employed. However, provided that the reaction is carried out under the preferred conditions, it will suffice that the amount of the base as chemical equivalent per starting substance is 1 to 4, more preferably 1 to 1.4. The reaction can be carried out over a wide range of temperatures, and the exact temperature of the reaction is not critical to the invention. The preferred reaction temperature will depend on such factors as the nature of the solvent and the starting substances. However, in general, we consider it convenient to carry out the reaction at a temperature of 0 ° C to 100 ° C, more preferably 0 ° C to 50 ° C. The time required for the reaction can also vary widely, depending on many factors, especially the temperature of the reaction and the nature of the starting materials and the solvent employed. However, as long as the reaction is carried out under the preferred conditions detailed above, a period of 5 minutes to 24 hours, more preferably 3 hours to 18 hours, is sufficient.

METHOD B The alternative preparation of the compound of formula (V) wherein R 1 is a halogen atom is illustrated; and R2 is an alkyl group having 2 to 4 carbon atoms. Reaction scheme B íttfa) W O} In the above formulas, R1a and R7 are as defined above; R3 represents an alkyl group having from 1 to 3 carbon atoms, and Y represents a halogen atom.

STAGE B1 In this step, the compound of formula (Vlb) is prepared by the alkylation of the compound of formula (IVa) with the compound of formula (IX) in the presence of a base. Normally and preferably, the reaction is carried out in the presence of the solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no side effect on the reaction or reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane. Of these solvents, we prefer tetrahydrofuran. Likewise, there is no particular restriction on the nature of the bases used and, equally, any basis commonly used in reactions of this type can be used. Examples of such bases include: alkali metal amides, such as potassium diisopropylamide, sodium diisopropylamide, lithium bis (trimethylsilyl) amide and potassium bis (trimethylsilyl) amide. Of these, we prefer the lithium diisopropylamide or the lithium bis (trimethylsilyl) amide. The amount of the base required for the reaction can also vary widely, depending on many factors, especially the temperature of the reaction and the nature of the starting materials and the solvent employed. However, provided that the reaction is carried out under the preferred conditions, it will suffice that the amount of the base as chemical equivalent per starting substance is 1 to 4, more preferably 1 to 1.4. The reaction can be carried out over a wide range of temperatures, and the exact temperature of the reaction is not critical to the invention. The preferred reaction temperature will depend on such factors as the nature of the solvent and the starting substances. However, in general, we consider it convenient to carry out the reaction at a temperature of 0 ° C to 120 ° C, more preferably 20 ° C to 80 ° C. The time required for the reaction can also vary widely, depending on many factors, especially the temperature of the reaction and the nature of the starting materials and the solvent employed. However, as long as the reaction is carried out under the preferred conditions detailed above, a period of 5 minutes to 24 hours, more preferably 60 minutes to 12 hours, is sufficient.

STEP B2 In this step, the compound of formula (Va) is prepared by the halogenation of the compound of formula (IVa) prepared as described in step B1. The reaction can be carried out under the same conditions as described in step A2 of method A. Method C The preparation of the desired compound of formula (1b) wherein R 1 is an alkyl group having 1 to 4 carbon atoms is illustrated. carbon. Reaction scheme C Et In the formulas above, X is as defined above; R1b represents an alkyl group having from 1 to 4 carbon atoms, and W represents a hydrogen atom or an alkali metal atom, such as lithium, sodium or potassium.

Step C1 In this step, the compound of formula (XII) is prepared by condensation of the compound of formula (X) with the compound of formula (XI) in the presence of an acid in an inert solvent. Normally and preferably, the reaction is carried out in the presence of the solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no side effect on the reaction or reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include amides, such as? /,? / - dimethylformamide and? /,? / - dimethylacetamide and, of these solvents, we prefer? /,? / - dimethylformamide. Likewise, there is no particular restriction on the nature of the acids used and, equally, any base commonly used in reactions of this type can be used. Examples of such acids include: carboxylic acids, such as acetic acid, propionic acid or benzoic acid. Of these acids, we prefer acetic acid. The amount of acid required for the reaction can also vary widely, depending on many factors, especially the temperature of the reaction and the nature of the starting materials and the solvent employed. However, provided that the reaction is carried out under the preferred conditions, it will suffice that the amount of the acid as chemical equivalent per starting substance is 1 to 4, more preferably 1 to 1.6. The reaction is carried out in the presence of a base. Likewise, there is no particular restriction on the nature of the bases used and, equally, any basis commonly used in reactions of this type can be used. Examples of such bases include: amines, such as diethylamine, triethylamine, diisopropylethylamine, tributylamine, piperidine, pyridine, picoline and 4- (N, N-dimethylamino) pyridine. Of these, we prefer diethylamine or piperidine. The amount of the base required for the reaction can also vary widely, depending on many factors, especially the temperature of the reaction and the nature of the starting materials and the solvent employed. However, provided that the reaction is carried out under the preferred conditions, it will be sufficient that the amount of the base as chemical equivalent per starting substance is 0.01 to 1, more preferably 0.05 to 0.4. The reaction can be carried out over a wide range of temperatures, and the exact temperature of the reaction is not critical to the invention. The preferred reaction temperature will depend on such factors as the nature of the solvent and the starting substances. However, in general, we consider it convenient to carry out the reaction at a temperature of 0 ° C to 100 ° C, more preferably 0 ° C to 50 ° C. The time required for the reaction can also vary widely, depending on many factors, especially the temperature of the reaction and the nature of the starting materials and the solvent employed. However, as long as the reaction is carried out under the preferred conditions detailed above, a period of 5 minutes to 24 hours, more preferably 3 hours to 24 hours is sufficient. Step C2 In this step, the compound of formula (Via) is prepared by hydrolysis of the compound of formula (XII) in an inert solvent. Normal and preferably, the reaction is carried out in the presence of the solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no side effect on the reaction or reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; dioxal aromatic hydrocarbons, such as benzene, toluene and nitrobenzene; alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol; and water. Of these solvents, we prefer the mixture of water and alcohols. The reaction is carried out in the presence of a base. Likewise, there is no particular restriction on the nature of the bases used and, equally, any base commonly used in reactions of this type can be used here. Examples of such bases include: alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide and potassium hydroxide. Of these, we prefer sodium hydride or potassium hydroxide. The amount of the base required for the reaction can also vary widely, depending on many factors, especially the temperature of the reaction and the nature of the starting materials and the solvent employed. However, provided that the reaction is carried out under the preferred conditions, it suffices that the amount of the base as chemical equivalent per starting substance is from 1 to 5. The reaction can be carried out over a wide range of temperatures, and the exact temperature of the the reaction is not critical to the invention. The preferred reaction temperature will depend on such factors as the nature of the solvent and the starting substances. However, in general, we consider it convenient to carry out the reaction at a temperature of 0 ° C to 120 ° C, more preferably 20 ° C to 80 ° C. The time necessary for the reaction can also vary widely, depending on many factors, especially the temperature of the reaction and the nature of the starting materials and the solvent employed. However, as long as the reaction is carried out under the preferred conditions detailed above, a period of 5 minutes to 24 hours, more preferably 60 minutes to 12 hours, is sufficient. Step C3 In this step, the compound of formula (VI la) is prepared by forming the acyl halide from the carboxylic portion of the compound of formula (Via) prepared as described in step C2. The reaction can be carried out in the same conditions as described in step A4 of method A.

Step C4 In this step, the desired compound of formula (Ib) of the present invention is prepared by forming the amide of the compound of formula (VI la) prepared as described in step C3. The reaction can be carried out under the same conditions as described in step A5 of method A. Method D The alternative preparation of the desired compound of formula (le) and (Id) is illustrated. Diagram of reaction D In the above formulas, R9 represents an amino protecting group. The term "amino protecting group", as used herein, means a protecting group capable of being cleaved by chemical means, such as hydrogenolysis, hydrolysis, electrolysis or photolysis, and such amino protecting groups are described in Protective Groups in Organic Synthesis edited by T. W Greene et al. (John Wiley &Sons, 1999). Typical amino protecting groups include benzyl, C2H5 (C = O) -, CH3 (C = O) -, t-butyldimethylsilyl, t-butyldiphenylsilyl, benzyloxycarbonyl and t-butoxycarbonyl. Of these groups, we prefer t-butoxycarbonyl. Step D1 In this step, the piperidine compound (XIV) is prepared by deprotection of the compound of formula (XIII) which may have been prepared, for example, with the same method as described in both method A and method C This method is described in detail in T. W. Greene et al. [Protective Groups in Organic Synthesis, 494-653, (1999)], the descriptions of which are incorporated herein by reference. What follows is a typical method, provided that the protective group is io-butoxycarbonyl. Normally and preferably, the reaction is carried out in the presence of the solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no side effect on the reaction or reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; and alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol. Of these solvents, we prefer alcohols. The reaction is carried out in the presence of an excess amount of an acid. Likewise, there is no particular restriction on the nature of the acids used and, likewise, any acid commonly used in reactions of this type can be used here. Examples of such acids include acids, such as hydrochloric acid or trifluoroacetic acid. Of these acids, we prefer hydrochloric acid. The reaction can be carried out over a wide range of temperatures, and the exact temperature of the reaction is not critical to the invention. The preferred reaction temperature will depend on such factors as the nature of the solvent and the starting substances. However, in general, we consider it convenient to carry out the reaction at a temperature of 0 ° C to 100 ° C, more preferably 0 ° C to 50 ° C. The time required for the reaction can also vary widely, depending on many factors, especially the temperature of the reaction and the nature of the starting materials and the solvent employed. However, as long as the reaction is carried out under the preferred conditions detailed above, a period of 5 minutes to 24 hours, more preferably 3 hours to 24 hours is sufficient. Stage D2. In this step, the compound of formula (le) is prepared by the epoxy-opening substitution of the compound of formula (XIV) prepared as described in step D1. Normally and preferably, the reaction is carried out in the presence of the solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no side effect on the reaction or reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane, and alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol. Of these solvents, we prefer alcohols. The reaction can be carried out over a wide range of temperatures, and the exact temperature of the reaction is not critical to the invention. The preferred reaction temperature will depend on such factors as the nature of the solvent and the starting substances. However, in general, we consider it convenient to carry out the reaction at a temperature of 0 ° C to 120 ° C, more preferably 20 ° C to 80 ° C. The time required for the reaction can also vary widely, depending on many factors, especially the temperature of the reaction and the nature of the starting materials and the solvent employed. However, as long as the reaction is carried out under the preferred conditions detailed above, a period of 5 minutes to 24 hours, more preferably 3 hours to 24 hours is sufficient. Step D3 In this step, the compound of formula (Id) is prepared by reductive amination of the compound of formula (XIV) prepared as described in step D1. Normally and preferably, the reaction is carried out in the presence of the solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no side effect on the reaction or reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; ethers such as diethyl ether, diisopropyl ether, dimethoxyethane, tetrahydrofuran and dioxane; alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol; acetic acid; and water. Of these solvents, we prefer halogenated hydrocarbons. The reaction is carried out in the presence of a reducing reagent.

Likewise, there is no particular restriction on the nature of the reducing reagents used and, equally, any reducing reagent commonly used in reactions of this type can be used here. Examples of such reducing reagents include: sodium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride. Of these, we prefer sodium triacetoxyborohydride. The amount of the reducing reagent required for the reaction can also vary widely, depending on many factors, especially the temperature of the reaction and the nature of the starting materials and the solvent employed. However, provided that the reaction is carried out under the preferred conditions, it suffices that the amount of the reducing reagent as chemical equivalent per starting substance is from 1 to 3. The reaction can be carried out over a wide range of temperatures, and the exact temperature of the the reaction is not critical to the invention. The preferred reaction temperature will depend on such factors as the nature of the solvent and the starting substances. However, in general, we consider it convenient to carry out the reaction at a temperature of -20 ° C to 60 ° C, more preferably from 0 ° C to 50 ° C. The time required for the reaction can also vary widely, depending on many factors, especially the temperature of the reaction and the nature of the starting materials and the solvent employed. However, as long as the reaction is carried out under the preferred conditions detailed above, it is usual for a period of 5 minutes to 24 hours, more preferably 1 hour to 12 hours, to suffice. Method E The preparation of the compound of formula (VIII) is illustrated. Reaction scheme E IX) In the formulas above, R j10 represents an ammo protecting group.

Step E1 In this step, the compound of formula (XVIII) is prepared by substitution that opens the epoxy of the compound of formula (XVII). The reaction can be carried out under the same conditions as described in step D2 of method D. Step E2 In this step, the compound of formula (XIX) is prepared by reductive amination of the compound of formula (XVII). The reaction can be carried out under the same conditions as described in step D3 of method D. Step E3 In this step, the compound of formula (VIII) is prepared by deprotection of the compound of formula (XVIII) or (XIX) prepared as described in step E1 or E2. The reaction can be carried out under the same conditions as described in step D1 of method D. The compounds of formula (I), and the methods of preparation of the above-mentioned intermediates, can be isolated and purified by conventional procedures, such as distillation , retrocrystallization or chromatographic purification. The optically active compounds of this invention can be prepared by various methods. For example, the optically active compounds of this invention can be obtained by chromatographic separation, enzymatic resolution or fractional crystallization from the final compounds. Several compounds of this invention possess an asymmetric center. Therefore, the compounds can exist in the separated optically active forms (+) and (-), as well as in the racemic form thereof. The present invention includes all these forms within its scope. Individual isomers can be obtained by known methods, such as optically selective reaction or chromatographic separation, in the preparation of the final product or its intermediate. The present invention also includes isotopically-labeled compounds, which are identical to those cited in formula (I), except for the fact that one or more atoms are replaced by an atom having an atomic mass or a mass number other than the atomic mass or the atomic number that is normally found in nature. Examples of isotopes that can be included in the compounds of the invention include hydrogen isotopes, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36CI, respectively. The compounds of the present invention, prodrugs thereof, pharmaceutically acceptable esters of said compounds and pharmaceutically acceptable salts of said compounds, said esters or said prodrugs which contain the isotopes mentioned above and / or are within the scope of this invention. other isotopes of other atoms. Certain isotopically-labeled compounds of the present invention, for example, those in which radioactive isotopes such as 3H and 14C are incorporated, are useful in the tissue distribution analysis of the drug and / or substrate. Particularly preferred are the tritiated isotopes, namely 3H, and carbon 14, namely 14C, for their ease of presentation and detectability. In addition, replacement by heavier isotopes such as deuterium, namely 2H, may provide a therapeutic advantage as a result of increased metabolic stability, for example, an increase in half-life in vivo or a decrease in the dose required and, therefore, it may be preferred in some circumstances. The isotopically-labeled compounds of the formula (I) of this invention and the prodrugs thereof can generally be prepared by carrying out the process described in the schemes described above and / or the examples and the preparations below, by presenting a reagent marked isotopically easy to achieve by a non-isotopically labeled reagent. The present invention includes salt forms of the compounds (I) as obtained. Some compounds of the present invention may be capable of forming a non-toxic pharmaceutically acceptable cation. The non-toxic pharmaceutically acceptable cations of the compounds of formula (I) can be prepared by conventional techniques, for example, by contacting said compound with a stoichiometric amount of a suitable alkali metal or alkaline earth metal hydroxide or alkoxide (sodium, potassium, calcium and magnesium) in water or a suitable organic solvent such as ethanol, isopropanol, mixtures thereof, or the like. The bases which are used to prepare pharmaceutically acceptable base addition salts of the acidic compounds of this invention of formula (I) are those which form basic non-toxic addition salts, namely salts containing pharmaceutically acceptable cations, such as adenine, arginine, cytosine, lysine, benetamine (namely, N-benzyl-2-phenylethylamine), benzathine (namely, / V,? / - dibenzylethylenediamine), choline, diolamine (namely, diethanolamine), ethylenediamine, glucosamine, glycine, guanidine, guanine, meglumine (ie, N-methylglucamine), nicotinamide, olamine (ie, ethanolamine), ornithine, procaine, proline, pyridoxine, serine, tyrosine, valine and tromethamine [namely, tris or tris (hydroxymethyl) aminomethane ] The base addition salts can be prepared by conventional methods. To the extent that certain compounds of this invention are basic compounds, they are capable of forming a wide variety of different salts with various organic and inorganic acids. Acids which are used to prepare pharmaceutically acceptable acid addition salts of the basic compounds of this invention of formula (I) are those which form non-toxic acid addition salts, namely, salts containing pharmaceutically acceptable anions, such as chloride , bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or citrate acid, tartrate or bitartrate, succinate, malate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate ', p- toluenesulfonate, adipate, camsilated aspartate, edisilate (namely 1,2-ethanedisulfonate), estolate (viz. lauryl sulfate), gluceptate (viz. gluscoheptonate), gluconate, 3-hydroxy-2-naphthoate, xionofoate (viz., 1-hydroxy-2-naphthoate), isethionate, (namely 2-hydroxyethanesulfonate), mucate (viz., Galactarate), 2-naphsylate (viz., Naphthalene sulfonate), stearate, cholate, glucuronate, glutamate, hippurate, lactobionate , lysinate, maleate, mandelato, napadisilato, nicatinato, polygalacturonate, salicylate; sulfosalicylate, tannate, tryptophanate, borate, carbonate, oleate, phthalate and pamoate (ie, 1,1'-methylene-bis- (2-hydroxy-3-naphthoate) .The acid addition salts can be prepared by conventional methods For a review of suitable salts, see Berge et al., J. Pharm. Sci., 66, 1-19, 1977. Also included within the scope of this invention are the bioprecursors (also called prodrugs) of the compounds of the invention. The formula (I) A bioprecursor of a compound of the formula (I) is a chemical derivative thereof which is easily converted to the parent compound of the formula (I) in biological systems, in particular a bioprecursor of a compound of formula (I) is converted into the parent compound of formula (I) after the bioprecursor has been administered to a mammal, and has been absorbed by it, eg, a human being. possible to manufacture a bioprecursor of the compounds of formula (I) and n that one, or both, L and W include hydroxy groups by making an ester of the hydroxy group. When only one L and W includes the hydroxy group, only one monoester is possible. When both L and W include hydroxy, monoesters and diesters (which may be the same or different) can be manufactured. Typical esters are simple alkanoate esters, such as acetate, propionate, butyrate, etc. In addition, when L or W includes a hydroxy group, bioprecursors can be manufactured by converting the hydroxy group to an acyloxymethyl derivative (ie, a pivaloxymethyl derivative) by reaction with an acyloxymethyl halide (eg, pivaloxymethyl chloride). When the compounds of the formula (I) of this invention can form solvates such as hydrates, such solvates are included within the scope of this invention. Method for evaluating biological activity: The binding affinities of the compounds of this invention for the 5-HT receptor are determined by the following methods. Binding to human 5-HT4 HEK293 cells transfected with human 5-HT4 (d) were prepared and cultured in incubators. The collected cells were suspended in 50 mM HEPES (pH 7.4 at 4 ° C) supplemented with a cocktail of protease inhibitors (Boehringer, dilution 1: 1000) and homogenized with a hand-held Polytron PT 1200 homogenizer fixed to its maximum total power for 30 s on ice. The homogenates were centrifuged at 40,000 x g at 4 ° C for 30 min. Then, the pellets were resuspended in 50 mM HEPES (pH 7.4 at 4 ° C) and centrifuged once more in the same way. The final pellets were resuspended in an appropriate volume of 50 mM HEPES (pH 7.4 at 25 ° C), homogenized, aliquoted and stored at -80 ° C until used. An aliquot of the membrane fractions was used for the determination of protein concentration with a BCA protein analysis kit (PIERCE) and an ARVOsx plate reader (Wallac). For the binding experiments, 25 μl of the compounds to be tested were incubated with 25 μl of [3 H] -GR113808 (Amersham, 0.2 nM final) and 150 μl of membrane homogenates and WGA suspension of beads. SPA (Amersham) (10 μg of protein and 1 mg of SPA beads per well) for 60 minutes at room temperature. Non-specific binding was determined by GR113808 at 1 μM (Tocris) at the final concentration. The incubation was terminated by centrifugation at 1000 rpm. The radioactivity bound to the receptor was quantified by counting with a MicroBeta plate counter (Wallac). The results are shown in Table 1. Table 1 Compound A is the following compound which is described in the international patent W02003 / 57688, mentioned above. In this test, the compound of the present invention showed excellent selective binding activity of human 5-HT4. Increase of cAMP induced by agonists in cells HEK293 cells transfected with human 5-HT4 (d) were placed in incubators. Cells were cultured at 37 ° C and in 5% CO 2 in DMEM supplemented with 10% FCS, 20 mM HEPES (pH 7.4), 200 μg / ml hygromycin B (Gibco), 100 units / ml penicillin and 100 μg / ml streptomycin. The cells were cultured at a 60 to 80% confluence. The day before the treatment with the compounds, the normal FCS was replaced by dialyzed FCS (Gibco) and the cells were incubated overnight. The compounds were prepared in 96-well plates (12.5 μl / well). The cells were cultured with PBS / 1 mM EDTA, centrifuged and washed with PBS. At the beginning of the analysis, the cell pellet was resuspended in DMEM supplemented with 20 mM HEPES, 10 μM pargyline (Sigma) and 3-isobutyl-1-methylxanthine (Sigma) at 1 mM at the concentration of 1.6 x 105 cells / ml and left for 15 minutes at room temperature.

The reaction was started by adding the cells to the plates (12.5 μl / well). After incubating for 15 minutes at room temperature, 1% Triton X-100 was added to stop the reaction (25 μl / well) and the plates were left for 30 minutes at room temperature. The detection of cAMP based on homogeneous fluorescence over time (HTRF) (Schering) was carried out according to the manufacturer's instructions. The ARVOsx multi-rate counter (Wallac) was used to measure the HTRF (excitation at 320 nm, emission at 665 nm / 620 nm, delay time 50 μs, time interval 400 μs). The data were analyzed according to the proportion of the fluorescence intensity of each well at 620 nm and 665 nm followed by the quantification of cAMP with an AMPc standard curve. The increase in cAMP production triggered by each compound was normalized by the amount of cAMP produced with serotonin at 1000 nM (Sigma). All the compounds of the examples showed an agonist activity by the 5-HT4 receptor. Binding of human dofetilide HEK293S cells transfected with human HERG were prepared and cultured in incubators. The collected cells were suspended in Tris-HCI at 50 MM (pH 7.4 at 4 ° C) and homogenized with a hand-held Polytron PT 1200 homogenizer set at its maximum power for 20 s on ice. The homogenates were centrifuged at 48,000 x g at 4 ° C for 20 min. Then, the pellets were resuspended, homogenized and centrifuged once more in the same manner. The final pellets were resuspended in an appropriate volume of 50 mM Tris-HCl, 10 mM KCl, 1 mM MgCfe (pH 7.4 at 4 ° C), homogenized, aliquoted and stored at -80. ° C until they are used. An aliquot of the membrane fractions was used to determine the protein concentration with BCA protein analysis kit (PIERCE) and ARVOsx plate reader (Wallac). Binding analyzes were performed in a total volume of 200 μl in 96-well plates. Twenty μl of the test compounds were incubated with 20 μl of [3 H] -dofetilide (Amersham, 5 nM final) and 160 μl of membrane homogenate (25 μg of protein) for 60 minutes at room temperature. Non-specific binding was determined by dofetilide at the final concentration of 10 μM. Incubation was terminated by rapid filtration in vacuo over a GF / B Betaplate filter pre-packed at 0.5% with a Skatron cell harvester with Tris-HCI at 50 mM, 10 mM KCl, 1 mM MgCfe, pH 7.4 at 4 ° C. The filters were dried, placed in sample bags and filled with Betaplate Scint. The radioactivity bound to the filter was counted with a Wallac Betaplate counter. Permeability in Caco-2 cells Permeability in caco-2 cells was measured according to the method described in Shiyin Yee, Pharmaceutical Research, 763 (1997). Caco-2 cells were grown on filter holders (Falcon HTS multi-well insert system) for 14 days. The culture medium was removed from the apical and basolateral compartments and the monolayers were pre-incubated with 0.3 ml of preheated apical buffer and 1.0 ml basolateral buffer for 0.5 hours at 37 ° C in a shaking water bath at 50 cycles / min. The apical buffer consisted of a balanced salt solution of Hanks, D-glucose monohydrate at 25 mM, a biological buffer MES at 20 mM, CaCI2 at 1.25 mM and MgCl2 at 0.5 mM (pH 6.5). The basolateral buffer consisted of balanced salt solution of Hanks, D-glucose monohydrate at 25 mM, biological buffer HEPES at 20 mM, CaCl2 at 1.25 mM and MgCl2 at 0.5 mM (pH 7.4). At the end of preincubation the medium was removed and the solution of the test compound (10 μM) in the buffer was added to the apical compartment. The inserts were transferred to wells containing a new basolateral buffer after 1 h. The concentration of drug in the buffer was measured by LC / MS analysis. The flow velocity (F, mass / time) was calculated from the slope of the cumulative occurrence of substrate on the receptor side, and the apparent permeability coefficient (Pap) was calculated from the following equation. Pap (cm / s) = (F * VD) / (SA * MD) where SA is the surface area for transport (0.3 cm2), RV is donor volume (0.3 ml), MD is the quantity total of the drug on the donor side at = 0. All data represent the average of 2 inserts.

The integrity of the monolayer was determined by the transport of yellow Lucifer.

Results are shown in table 2.

Table 2 In this test, the compound of the present invention showed excellent permeability in caco2 cells. The compounds of formula (1) of this invention can be administered orally, parenterally or topically to mammals. In general, these compounds are most desirably administered to humans in doses ranging from 0.3 mg to 750 mg per day, preferably from 0.3 mg to 500 mg per day, although variations according to weight and disease will necessarily result. of the subject to be treated, the state of the disease to be treated and the particular route of administration chosen. However, for example, a dose level in the range of 0.004 mg to 7 mg per kg of body weight per day is more desirably employed for the treatment of gastroesophageal reflux disease. The compounds of the present invention can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the aforementioned prior routes, and such administration can be carried out in a single dose or in multiple doses. More particularly, the novel therapeutic agents of the invention can be administered in a wide variety of different dosage forms, namely, they can be combined with several inert pharmaceutically acceptable carriers in the form of tablets, capsules, lozenges, troches, soluble candies, powders, sprays, creams, ointments, suppositories, gelatins, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Such carriers include diluents or solid fillers, sterile aqueous media and various non-toxic organic solvents, etc. In addition, oral pharmaceutical compositions can be sweetened and / or flavored appropriately. In general, the therapeutically effective compounds of this invention are present in such dosage forms at concentration levels ranging from 5% to 70% by weight, preferably from 10% to 50% or by weight. For oral administration, tablets that. They contain various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dipotassium phosphate and glycine can be used together with various disintegrators such as starch and preferably corn, potato or cassava starch, alginic acid and certain complex silicates, together with granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often very useful in helping to form tablets. Solid compositions of a similar type can also be employed as fillers in gelatin capsules; preferred materials in this regard also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient may be combined with various sweeteners or flavors, coloring substances or dyes and, if desired, also emulsifiers and / or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and various similar combinations thereof. For parenteral administration, solutions of a compound of the present invention or in sesame or peanut oil or in aqueous propylene glycol can be employed. Aqueous solutions should be suitably buffered (preferably pH> 8) if necessary and the liquid diluent should be made isotonic first. These aqueous solutions are suitable for intravenous injection purposes. Oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is easily accomplished by standard pharmaceutical methods well known to those skilled in the art. Additionally, topical administration of the compounds of the present invention is also possible when inflammatory diseases of the skin are treated and this can be done, preferably, by means of creams, gelatins, gels, pastes, ointments and the like, in accordance with pharmaceutical practice standard. EXAMPLES The invention is illustrated in the following non-limiting examples, in which, unless stated otherwise, all operations were carried out at room temperature, i.e. in the range of 18 to 25 ° C.; the evaporation of the solvent was carried out with a rotary evaporator at low pressure with the bath at a temperature of up to 60 ° C; the reactions were controlled by thin-layer chromatography (tic) and the reaction times are given only for polishing; the melting points (p.f.) are given uncorrected (the polymorphism can give rise to different melting points); the structure and purity of all isolated compounds was ensured by at least one of the following techniques: tic (TLC plates precoated with Merck 60 F254 silica gel or HPTLC plates precoated with Merck's F250 NH2), spectrometry mass, nuclear magnetic resonance (NMR), infrared absorption (IR) spectra or microanalysis. The returns are given for illustrative purposes only. Flash column chromatography was performed with Merk silica gel 60 (230 mesh 400 ASTM) or Fuji Silysia Chromatorex (TM) DU3050 (Amino Type, 3050 mesh) The data of the low resolution mass spectra (El) were obtained in an Integrity mass spectrometer (Waters) or in an Automass 120 mass spectrometer (JEOL) .The data of low resolution mass spectra (ESI) were obtained in a mass spectrometer ZMD2 (Waters) or in a spectrometer of Quattro II masses (Micromass) The NMR data were determined at 270 MHz (JEOL JNM-LA 270 spectrometer) or at 300 MHz (JEOL JNM-LA300) with deuterated chloroform (99.8% D) or dimethyl sulfoxide (99.9% D) as solvent unless otherwise indicated, with respect to tetramethylsilane (TMS) as the internal standard in parts per million (ppm); The conventional abbreviations used are: s = singlet, d = doublet, t = triplet, q = quadruplet, m = multiplet, br. = width, etc. The IR spectra were measured with a Shizamu infrared spectrometer (IR-470). Optical rotations were measured with a JASCO digital polarimeter DIP-370 (Japan Spectroscopic CO, Ltd.). Chemical symbols have their usual meanings; p. and. (boiling point), p. F. (melting point), I (Liter (s)), mi (milliliter (s)), g (gram (s)), mg (milligram (s)), mol (moles), mmol (millimoles), eq. (equivalent (s)). EXAMPLE 1 5-CHLORINE -? / - ((1-r (4-HYDROXYETHRAHDRO-2ry-PIRAN-4-IL) METHYUPIPERIDIN-4-IL) METHYL) -1-ISOPROPIL-6-METHYL-2-OXY-1.2- DIHYDROPIRLDIN-3-CARBOXAMIDE AND CHLORHYDRATE OF THE SAME 1 (1) Benzyl ({1-((4-hydroxytetrahydro-2H-pyran-4-yl) metinpiperidin-4-yl.} Methyl) -carbamate A mixture of benzyl (piperidin-4-yl-methyl) carbamate (7.77 g, 1.3 mmol, prepared according to Bose, D. Subhas et al., Tetrahedron Lett, 1990, 31, 6903) and 1.6 -dioxaspiro [2.S] octane (4.29 g, 37.6 mmol, prepared according to Satyamurthy, Nagichettiar et al., Phosphorus Sulfur, 1984, 19, 113) in methanol (93 ml) was stirred at room temperature for 20 minutes. h. Then, the mixture was refluxed for 8 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was chromatographed on a column of silica gel eluting with dichloromethane / methanol (v / v = 20/1) to give 5.60 g (49%) of the title compound as a colorless oil. 1 H-NMR (CDCl 3) d ppm: 7.40 to 7.30 (5 H, m), 5.09 (2 H, s), 4.85 (1 H, br.), 3.85 to 3, 72 (4 H, m), 3.08 (2 H, t, J = 6.4 Hz), 2.88 to 2.83 (2 H, m), 2.61 (1 H, s), 2 , 36 to 2.30 (4 H, m), 1.77 to 1.19 (9 H, m). 1 (2) 4-. { f4- (amnomethyl) pyridin-1-inmethyl} tetrahydro-2H-pyran-4-ol A mixture of benzyl (. {- 1 - [(4-hydroxytetrahydro-2 - / - pyran-4-yl) methyl] piperidin-4-yl} methyl) carbamate as prepared in 1 ( 1) (5.60 g, 15.5 mmol) and palladium on activated carbon (10% by weight, 1.20 g) in methanol (250 ml) was hydrogenated at room temperature for 20 h. Then, the mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to give 3.30 g (94%) of the title compound as a slightly yellow oil. MS (ESI) m / z: 229 (M + H) +. 1 H-NMR (CDCl 3) d ppm: 3.70 to 3.81 (4 H, m), 2.85 to 2.90 (2 H, m), 2.57 (2 H, d, J = 5, 7 Hz), 2.35 (2 H, t, J = 11.0 Hz), 2.32 (2 H, s), 1.65 to 1.71 (2 H, m), 1.44 to 1 , 63 (8 H, m), 1, 19 to 1, 28 (2 H, m). 1 (3) ( { 1-r (4-hydroxytetrahydro-2H-pyran-4-yl) methyl] piperidin-4-yl.} Erc-butyl me-tipcarbamate To a stirred solution of tere-butyl (piperidin-4-ylmethyl) carbamate (22.3 g, 104 mmol) in methanol (120 ml) was added 1,6-dioxaspiro [2.5] octane (14.2 g). g, 124 mmol, prepared according to Satyamurthy, Nagichettiar et al., Phosphorus Sulfur, 1984, 19, 113) at room temperature. Then, the mixture was heated at 60 ° C for 4 hours. The volatile components were removed by evaporation and the resulting viscous oil was precipitated with a mixture of hexane and diethyl ether. The precipitate was collected by filtration and backcrystallized from a mixture of n-hexane and 2-propanol to give the title compound [14.2 g (42%)] as a colorless powder. MS (ESI) m / z: 329 (M + H) +. p. f .: 104 ° C. 1 H-NMR (CDCl 3) d ppm: 3.85 to 3.70 (4 H, m), 3.00 (2 H, t, J = 6.2 Hz), 2.88 to 2.83 (2 H) , m), 2.38 to 2.27 (4 H, m), 1.69 to 1.51 (8 H, m), 1.44 (9 H, s), 1.31 to 1.23 ( 2 H, m). No signal due OH was observed. Anal, caled, for C? 7H32N2O4: C, 62.17; H, 9.82; N, 8.53. Experimental: C, 62.07; H, 9.92; N, 8.58. 1 (4) 4-. { f4- (amomethyl) pyridin-1-ylmethyl} tetrahydro-2H-pyran-4-ol To a solution of tere-butyl (. {1 - [(4-hydroxytetrahydro-2 / - / - pyran-4-yl) methyl] piperidin-4-yl} methyl) carbamate as prepared in 1 (3) (50, 28 g, 153 mmol) in methanol (100 mL) was added a solution of 4 N hydrochloric acid in dioxane (200 mL, 800 mmol) at room temperature. After 4 hours, the volatiles were removed by evaporation. The resulting amorphous was precipitated with diethyl ether / methanol (v / v = 5/1). The precipitate was collected and gradually added to a 6 N aqueous sodium hydroxide solution cooled in ice (200 ml). The mixture was extracted with dichloromethane / methanol (v / v = 10/1, 500 ml x 4). The combined organic layers were washed with saline, dried over magnesium sulfate and concentrated in vacuo to give 24.90 g (99%) of the title compound as a pale brown amorphous solid. MS (ESI) m / z: 229 (M + H) +. 1 H-NMR (CDCl 3) d ppm: 3.70 to 3.81 (4 H, m), 2.85 to 2.90 (2 H, m), 2.57 (2 H, d, J = 5, 7 Hz), 2.35 (2 H, t, J = 11.0 Hz), 2.32 (2 H, s), 1.65 to 1.71 (2 H, m), 1.44 to 1 , 63 (8 H, m), 1.19 to 1.28 (2 H, m). 1 (5) 1-ethylpropyl-6-methyl-2-oxo-1,2-dihydro-aridine-3-carboxylate ethyl A mixture of isopropyl (1-methylethylidene) amine (7.94 g, 80.0 mmol, prepared according to Newcomb, Martin et al., J. Amer. Chem. Soc, 1990, 112, 5186) and (ethoxymethylene) malonate of diethyl (17.31 g, 80.0 mmol) in diphenyl ether (48 ml) was stirred in a sealed tube at 180-190 ° C for 18 h. After cooling, the mixture was chromatographed on a column of silica gel eluting with n-hexane / ethyl acetate (v / v = 1/1 ~ 1/2) to give 12.5 g (70%) of the title as a brown oil. MS (ESI) m / z: 224 (M + H) +, 222 (MH) \ 1 H-NMR (CDCl 3) d ppm: 7.93 (1 H, d, J = 7.4 Hz), 5.99 (1 H, d, J = 7.4 Hz), 4.48 (1 H, br.), 4.33 (2 H, q, J = 7.1 Hz), 2.41 (3 H, s) , 1.63 (6 H, d, J = 6.8 Hz), 1.34 (3 H, t, J = 7.1 Hz). 1 (6) ethyl 5-chloro-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carbo-xylate - ** MQ A mixture of ethyl 1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate as prepared in 1 (5) (3.0 g, 13.44 mmol ) and N-chlorosuccinimide (1.79 g, 13.44 mmol) in A /,? / - dimethylformamide (27 ml) was stirred at room temperature for 16 hours, and the solvent was removed in vacuo. The residue was chromatographed on a ge! Column. of silica eluting with n-hexane / ethyl acetate (v / v = 2 / 1-1 / 1) to give 3.19 g (92%) of the title compound as a brown oil. MS (ESI) m / z: 258 (M + H) +, 256 (M-H) ~. 1 H-NMR (CDCl 3) d ppm: 8.02 (1 H, s), 4.72 (1 H, br.), 4.34 (2 H, q, J = 7.2 Hz), 2.56 (3 H, s), 1, 62 (6 H, d, J = 6.8 Hz), 1, 36 (3 H, t, J = 7.2 Hz). 1 (7) 5-chloro-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid To a stirred solution of ethyl 5-chloro-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate as prepared in 1 (6) (203 mg, 0, 79 mmol) in tetrahydrofuran (2 mL) and methanol (2 mL) was added a 2N sodium hydroxide aqueous solution (2 mL) at room temperature, and the mixture was stirred at room temperature for 16 hours. Then, the solvent was removed in vacuo. The residue was diluted with water (30 ml), acidified with an aqueous 2 N hydrochloric acid solution (pH ~ 2) and extracted with dichloromethane (50 ml x 3). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give 171 mg (94%) of the title compound as a white solid. MS (ESI) m / z: 230 (M + H) +, 228 (M-H) '. 1 H-NMR (CDCl 3) d ppm: 14.16 (1 H, s), 8.42 (1 H, s), 4.74 (1 H, br.), 2.67 (3 H, s), 1.68 (6 H, d, J = 6.8 Hz). 1 (8) 5-chloro -? / - ( { 1-r (4-hydroxytetrahydro-2-pyran-4-yl) metinpiperi-din-4-ylmethyl) -1-isopropyl-6-met L-2-oxo-1,2-d-hydropyridine-3-carboxamide and the hydrochloride thereof To a solution of 5-chloro-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid as prepared in 1 (7) (171 mg, 0.745 mmol) in dichloromethane (3 ml) was added oxalyl chloride (284 mg, 2.24 mmol) and a drop of?, / V-dimethylformamide at room temperature and the mixture was stirred at room temperature for 2 hours. The solvent and the excess amounts of the oxalyl chloride were removed in vacuo. The residue was dissolved in dichloromethane (2 ml). To the resulting solution was added 4-. { [4- (aminomethyl) piperidin-1-yl] methyl} tetrahydro-2rV-pyran-4-ol as prepared in 1 (2) and 1 (4) (255 mg, 1.12 mmol),? /, / V-diisopropylethylamine (144 mg, 1.12 mmol) at room temperature, and the mixture was stirred at room temperature for 18 hours. Then, the mixture was quenched with a saturated aqueous solution of sodium hydrogencarbonate (50 ml) and extracted with dichloromethane (50 ml x 3). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified on a TLC plate eluting with dichloromethane / methanol (v / v = 20 / 1-15 / 1) to give the title compound as a salt-free form. This was treated with 10% hydrochloric acid in methanol, and the solvent was removed in vacuo. The residue was crystallized from 2-propanol to give 187 mg (53%) of the title compound as a white solid. MS (ESI) m / z: 440 (M + H) +. p. f .: 283 ° C (decomposition). IR (KBr) v: 3321, 2858, 2529, 1674, 1618, 1533, 1439, 1533, 1439, 1350, 1304, 1254, 1105, 1022, 991, 945, 899, 856, 799, 698, 606, 548 cm "1 1 H-NMR (DMSO-de) d ppm: 9.67 (1 H, br. ), 8.15 (1 H, s), 4.77 (1 H, br.), 3.60 to 3.55 (5 H, m), 3.33 (3 H, s), 3.30 at 2.93 (9 H, m), 1.74 to 1.52 (13 H, m) No signal due to OH was observed Anal, caled, for C22H34N3O4CI-HCl 0.1H2O: C, 55, 25; H, 7.42; N, 8.79 Experimental: C, 54.96; H, 7.49; N, 8.79.

Example 2 5-CHLORO-6-ETlL -? / - ((1-r (4-HlDROXITETRAHIDRO-2ry-PIRAN-4-IL) METIUPIPERLDIN-4-IL) METHYL) -1-ISOPROPYL-2-OXO-1.2- DIHYDROPIRI-DINA-3-CARBOXAMIDE AND THE ETANODIOATE OF THE SAME 2 (1) ethyl 6-ethyl-1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxylate To a stirred solution of ethyl 1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate as prepared in Example 1 (5) (515 mg, 2.0 mmol) in tetrahydrofuran (3 mL) was added a solution of lithium diisopropylamide (2.0 M, 1.0 mL, 1.0 mmol) dropwise at -30 ° C for 40 min. After the addition, the mixture was stirred at 0 ° C for 3 h. Then, methyl iodide (426 mg, 3.0 mmol) was added at 0 ° C, and the mixture was stirred at room temperature for 16 hours. The mixture was quenched with water (5.0 ml) and extracted with dichloromethane (30 ml x 3). Then, the combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified on a TLC plate eluting with n-hexane / ethyl acetate (v / v = 2/1) to give 110 mg (23%) of the title compound as a yellow oil. 1 H-NMR (CDCl 3) d ppm: 7.95 (1 H, d, J = 7.6 Hz), 6.00 (1 H, d, J = 7.4 Hz), 4.45 (1 H, br.), 4.32 (2 H, q, J = 7.1 Hz), 2.67 (2 H, q, J = 7.4 Hz), 1, 64 (6 H, d, J = 6 , 8 Hz), 1, 33 (3 H, t, J = 7.1 Hz), 1, 26 (3 H, t, J = 7.4 Hz). 2 (2) ethyl 5-chloro-6-ethyl-1-isopropyl-2-oxo-1,2-dihydropyridine-3-carbo-xylate The title compound was prepared according to the procedure of Example 1 (6), but using ethyl 6-ethyl-1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxylate as prepared in Example 2. (1) in place of ethyl 1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate. 1 H-NMR (CDCl 3) d ppm: 7.97 (1 H, s), 4.44 (1 H, br.), 4.31 (2 H, q, J = 7.1 Hz), 2.88 (2 H, q, J = 7.4 Hz), 1.63 (6 H, d, J = 6.6 Hz), 1.32 (3 H, t, J = 7.1 Hz), 1, 22 (3 H, t, J = 7.4 Hz). 2 (3) 5-Chloro-6-ethyl-1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid The title compound was prepared according to the procedure of Example 1 (7), but using ethyl 5-chloro-6-ethyl-1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxylate as was prepared in 2 (2) in place of ethyl 5-chloro-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate.

MS (ESI) m / z: 244 (M + H) +, 242 (M-HV, 1 H-NMR (CDCl 3) d ppm: 14.52 (1 H, br.), 8.37 (1 H, s) ), 4.64 (1 H, br.), 3.00 (2 H, q, J = 7.5 Hz), 1.68 (6 H, d, J = 6.8 Hz), 1.28 (3 H, t, J = 7.5 Hz). 2 (4) 5-Chloro-6-ethyl- / V - ((1 - [(4-hydroxy-tetrahydro-2-yr-pyran-4-yl) methyl-1-piperid-4-yl) ) methyl) -1-isopropyl-2-oxo-1,2-dithiazide-3-carboxamide and the ethanedioate thereof To a solution of 5-chloro-6-ethyl-1-isopropyl-2-oxo-1,2-dihydropyridine-3-carbo-xylic acid as prepared in 2 (3) (75 mg, 0.308 mmol) in dichloromethane (2 ml) was added oxalyl chloride (117 mg, 0.923 mmol) and a drop of? /,? / - dimethylformamide at room temperature, and the mixture was stirred at room temperature for 2 hours. The solvent and excess amounts of oxalyl chloride were removed in vacuo. The residue was dissolved in dichloromethane (2 ml). To the resulting solution was added 4-. { [4- (aminomethyl) piperidin-1-yl] methyl} tetrahydro-2-yl-pyran-4-ol as prepared in example 1 (2) and 1 (4) (105 mg, 0.462 mmol),? /,? / - diisopropylethylamine (60 mg, 0.462 mmol) at room temperature environment, and the mixture was stirred at room temperature for 18 hours. Then, the mixture was quenched with a saturated aqueous solution of sodium hydrogencarbonate (30 ml) and extracted with dichloromethane (30 ml x 3). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified on a TLC plate eluting with dichloromethane / methanol / 25% ammonium hydroxide (v / v / v = 10/1/0, 2) to give 122 mg (87%) of the title compound as an unsalted form. This was treated with oxalic acid in 2-propanol, and retro-crystallized to give 87 mg (52%) of the title compound as a white solid. MS (ESI) m / z: 454 (M + H) +, 452 (MH) ".pf: 123 ° C (dec.). IR (KBr) v: 3254, 2939, 2860, 2415, 1767, 1668, 1616 , 1526, 1454, 1356, 1167, 1097, 1061, 1020, 982, 949, 845, 800, 718, 673, 613 cm "1. 1 H-NMR (DMSO-de) d ppm: 9.67 (1 H, br.), 8.16 (1 H, s), 4.68 (1 H, br.), 3.60 to 3.58 (4 H, m), 3.41 to 3.37 (2 H, m), 3.24 to 3.21 (2 H, m), 2.99 to 2.77 (6 H, m), 1 , 73 to 1.45 (9 H, m), 1.66 (6 H, d, J = 6.6 Hz), 1.16 (3 H, t, J = 7.1 Hz). No signal due to OH was observed. Anal. caled. for C23H36N3O4CI'C2H2O4'1, OC3H8O (2-propanol) + 1.0H2O: C, 54.05; H, 7.78; N, 6.75. Experimental: C, 54.11; H, 7.66; N, 6.80.

Example 3? / - (f1-f (4-Hydroxytetrahydro-2H-PIRAN-4-IL) METIUPIPERI-DlN-4-IL> METlL) -1-lSOPROPlL-5,6-DIMETHYL-2-OXO-1,2-DlHlDROPlRLDINE- 3-CARBOXAMIDE AND THE ETANODIOATE OF THE SAME 3 (1) 1-lsopropyl-5,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile To a stirred solution of the sodium salt of 2-methyl-3-oxobutanal (2.73 g, 22.4 mmol, prepared according to Paine, John B et al., J. Heterocycl. Chem., 1987, 24, 351) , 2-cyano -? / - isopropylacetamide (2.17 g, 17.2 mmol, prepared according to Wuerthner, Frank et al., J. Amer, Chem. Soc, 2002, 32, 9431) in? /,? / - Dimethylformamide (17.2 ml) was added piperidine (292 mg, 3.43 mmol) and acetic acid (1.34 g, 22.4 mmol) successively at room temperature, and the mixture was stirred at 135 ° C for 7 hours. h. After cooling, the mixture was quenched with water (100 ml), extracted with dichloromethane (50 ml x 4). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with n-hexane / ethyl acetate (v / v = 2 / 1-1 / 1) to give 840 mg (26%) of the title compound as a solid of color orange. MS (ESI) m / z: 191 (M + H) +, 189 (MH). "1 H-NMR (CDCl 3) d ppm: 7.48 (1 H, s), 4.71 (1 H, br. ), 2.36 (3 H, s), 2.06 (3 H, s), 1.54 (6 H, d, J = 6.8 Hz). 3 (2) 1-isopropyl-5,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid A mixture of 1-isopropyl-5,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile as prepared in 3 (1) (840 mg, 4.42 mmol), potassium hydroxide ( 1.84 g, 32.7 mmol), ethanol (12 mL) and water (3 mL) was refluxed for 16 hours. After cooling, the mixture was concentrated in vacuo. The aqueous residue was diluted with water (80 ml), washed with ethyl acetate (80 ml) and acidified with an aqueous 2N hydrochloric acid solution (pH ~ 5) at 0 ° C. The aqueous suspension was extracted with dichloromethane (50 ml x 3). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give 838 mg (91%) of the title compound as a white solid. MS (ESI) m / z: 210 (M + H) +, 208 (M-H) '. 1 H-NMR (CDCl 3) d ppm: 14.96 (11 H, s), 8.25 (1 H, s), 4.70 (1 H, br.), 2.46 (3 H, s), 2.20 (3 H, s), 1.65 (6 H, d, J = 6.8 Hz). 3 (3) A / - ( { 1-r (4-hydroxytetrahydro-2H-pyran-4-yl) methyl-4-piperidin-4-yl} methyl) -1-isopropyl-5,6-dimethyl-2-oxo- 1,2-dihydropyridine-3-carboxamide and the ethanedioate thereof The title compound was prepared according to the procedure of example 2 (4), but using 1-isopropyl-5,6-dimethyl-1 2-oxo-1,2-dihydropyridine-3-carboxylic acid as prepared in 3 (2) in place of 5-chloro-6-ethyl-1-isopropyl-2-oxo-1,2-dihydropyridine-3 acid -carboxylic MS (ESI) m / z: 420 (M + H) +, 418 (MH) ".pf: 178 ° C (dec.). IR (KBr) v: 3209, 2922, 2872, 2536, 1665, 1609, 1537 , 1450, 1362, 1306, 1221, 1186, 1099, 1018, 951, 851, 800, 719, 617 cm "1. 1 H-NMR (DMSO-d 6) d ppm: 9.92 (1 H, br.), 8.08 (1 H, s), 4.32 (1 H, br.), 3.60 to 3.58 (4 H, m), 3.41 to 3.37 (2 H, m), 3.23 to 3.19 (2 H, m), 2.94 to 2.84 (4 H, m), 2.40 (3 H, s), 2.12 (3 H, s), 1.74 to 1.45 (9 H, m), 1.62 (6 H, d, J = 6.8 Hz). No signal due to OH was observed. Anal, caled, for C23H37N3? 4-C2H2? 4-1.1H2O: C, 56.72; H, 7.84; N, 7.94. Experimental: C, 56.43; H, 8.09; N, 7.67.

EXAMPLE 4 5-BROMINE -? / - ((1-r (4-HYDROXYETHRAHLDRO-2H-PIRAN-4-IL) METlUPIPERIDIN-4-IL) METHYL) -1-ISOPROPYL-6-METHYL-2-OXY-1.2- DIHI-DROPYRIDINE-3-CARBOXAMIDE AND THE ETANODIOATE OF THE SAME 4 (1) 5-bromo-1-isopropyl-6-methylene-2-oxo-1,2-dihydropyridine-3-carboxylate of ethyl A mixture of 1-ethylpropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid ethyl ester as prepared in Example 1 (5) (1.12 g, 5.00 mmol) and? / -bromosuccinimide (890 g, 5.00 mmol) in? /,? / - dimethylformamide (10 mL) was stirred at room temperature for 16 hours, and then, the solvent was removed in vacuo. The residue was chromatographed on a column of silica gel eluting with n-hexane / ethyl acetate (v / v = 2 / 1-1 / 1) to give 1.34 g (91%) of the title compound as a solid yellow. MS (ESI) m / z: 302 (M + H) +, 300 (MH). "1 H-NMR (CDCl 3) d ppm: 8.14 (1 H, s), 4.72 (1 H, br. ), 4.35 (2 H, q, J = 7.2 Hz), 2.62 (3 H, s), 1.63 (6 H, d, J = 6.8 Hz), 1.37 ( 3 H, t, J = 7.2 Hz). 4 (2) 5-bromo-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid The title compound was prepared according to the procedure of Example 1 (7), but using ethyl 5-bromo-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate as was prepared in 4 (1) in place of ethyl 5-chloro-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate. MS (ESI) m / z: 274 (M + H) +, 272 (MH). "1 H-NMR (CDCl 3) d ppm: 14.43 (1 H, s), 8.54 (1 H, s) , 4.77 (1 H, br.), 2.72 (3 H, s), 1.67 (6 H, d, J = 6.9 Hz). 4 (3) 5-bromo- / V- (. {1-i (4-hydroxytetrahydro-2 - / - pyran-4-yl) met.ppiperi-din-4-yl.} Methyl ) -1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide and the ethanedioate thereof The title compound was prepared according to the procedure of Example 2 (4), but using 5-bromo-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid as prepared in 4 (2) in place of 5-chloro-6-ethyl-1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid. MS (ESI) m / z: 484 (M + H) +, 482 (MH) ".pf: 205 ° C (dec.). IR (KBr) v: 3271, 2936, 2864, 2353, 1767, 1614, 1529 , 1454, 1344, 1248, 1204, 1167, 1099, 1022, 982, 949, 847, 800, 689, 613 cm "1. 1 H-NMR (DMSO-d 6) d ppm: 9.68 (1 H, br.), 8.27 (1 H, s), 4.78 (1 H, br.), 3.65 to 3.57 (4 H, m), 3.46 to 3.37 (2 H, m), 3.27 to 3.21 (2 H, m), 3.00 to 2.83 (4 H, m), 2 , 67 (3 H, s), 1.75 to 1.48 (9 H, m), 1.65 (6 H, d, J - 3.3 Hz). No signal due to OH was observed. Anal, caled, for C22H34N3? 4Br-C2H2O4O.5H2O: C, 49.40; H, 6.39; N, 7.20. Experimental: C, 49.06; H, 6.33; N, 6.91.

Example 5 5-FLUORO -? / - ((1-r (4-HYDROXlTETRAHYDRO-2H-PlRAN-4-lL) METIUPIPERIDIN-4-lL) METlL) -1-ISOPROPIL-6-METHYL-2-OXO-1.2 DIHlDROPIRIDINE -3-CARBOXAMlDA (1) ethyl 5-fluoro-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carbo-xylate A mixture of ethyl 1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate as prepared in Example 1 (5) (2.23 g, 10.0 mmol) and bis (tetrafluoroborate) of 1- (c! oromethyl) -4-fluoro-1,4-diazoniab-cyclo [2.2.2] octane (3.76 g, 10.6 mmol) in acetonitrile (80 ml) was stirred at room temperature for 16 hours. The mixture was quenched with water (300 ml) and extracted with ethyl acetate (100 ml x 4). The combined organic layers were washed with water (100 ml x 6), saline (100 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with n-hexane / ethyl acetate (v / v = 2 / 1-1 / 1) to give 572 mg (24%) of the title compound as a yellow solid. MS (ESI) m / z: 242 (M + H) +. 1 H-NMR (CDCl 3) d ppm: 7.91 (1 H, d, J = 8.8 Hz), 4.50 (1 H, br.), 4.29 (2 H, q, J = 7, 2 Hz), 2.36 (3 H, d, J = 3.1 Hz), 1.58 (6 H, d, J = 6.8 Hz), 1.31 (3 H, t, J = 7 , 0 Hz). (2) 5-Fluoro-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid The title compound was prepared according to the procedure of Example 1 (7), but using ethyl 5-fluoro-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate as was prepared in 5 (1) in place of ethyl 5-chloro-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate. MS (ESI) m / z: 214 (M + H) +, 212 (MH). "1 H-NMR (CDCl 3) d ppm: 14.77 (1 H, s), 8.30 (1 H, d, J = 8.1 Hz), 4.65 (1 H, br.), 2.52 (3 H, d, J = 3.1 Hz), 1.68 (6 H, d, J = 6.9 Hz). (3) 5-fluoro-? / - ((1-f (4-hydroxytetrahydro-2 / - / - pyran-4-yl) methynpipe-ridin-4-yl> methyl) -1 -isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide To a solution of 5-fluoro-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid as prepared in 5 (2) (213 mg, 1.0 mmol) in dichloromethane (10 mL) was added oxalyl chloride (381 mg, 3.0 mmol) and a drop of? /,? / - dimethylformamide at room temperature. The mixture was stirred at room temperature for 2 hours. The solvent and excess amounts of oxalyl chloride were removed in vacuo. The residue was dissolved in dichloromethane (7 ml). To the resulting solution was added 4-. { [4- (aminomethyl) piperidin-1-yl] methyl} tetrahydro-2yr-pyran-4-ol as prepared in example 1 (2) and 1 (4) (342 mg, 1.50 mmol), N, N-diisopropylethylamine (194 mg, 1.50 mmol) at room temperature, and the mixture was stirred at room temperature for 18 hours. Then, the mixture was quenched with a saturated aqueous solution of sodium hydrogencarbonate (30 ml) and extracted with dichloromethane (50 ml x 4). Then, the combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified on a TLC plate eluting with dichloromethane / methanol (20/1) to give 275 mg (65%) of the title compound as a white solid. MS (ESI) m / z: 424 (M + H) +, 422 (M-H). " p. f .: 133 ° C (decomposition). IR (KBr) v: 2870, 1676, 1624, 1551, 1448, 1371, 1348, 1225, 1200, 1155, 1107, 1065, 1011, 935, 889, 841, 797, 710 cm "1 H-NMR (CDCl 3 ) d ppm: 9.91 (1 H, br.), 8.32 (1 H, d, J = 9.2 Hz), 4.55 (1 H, br.), 3.81 to 3.68 (4 H, m), 3.29 (2 H, t, J = 6.2 Hz), 2.86 to 2.83 (2 H, m), 2.41 to 2.32 (4 H, m ), 2.28 (3 H, s), 1.72 to 1.23 (9 H, m), 1.62 (6 H, d, J = 6.8 Hz) No signal was observed due to the OH Anal, caled, for C22H34N3O4 F-0.03H2O: C, 62.31; H, 8.10; N, 9.91 Experimental: C, 61.91; H, 8.13; N, 9 98 EXAMPLE 6 5-CHLORINE -? / - IG1 - (CYCLOHEXYLMETHYL) P1PER1P1N-4-1ÜMET1L) -1-1SOPROPYL-6-METHYL-2-OXO-1,2-DIHYDROPYRIDINE-3-CARBQXAMIDE 6 (1) 4 ((r (5-Chloro-1-ylpropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) carbonylamino} methyl) piperidine-1-carboxylate fer -butyl To a solution of 5-chloro-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid as prepared in Example 1 (7) (2.66 mg, 11%). 6 mmol) in dichloromethane (30 ml) was added oxalyl chloride (4.41 mg, 34.8 mmol) and a drop of? /,? / - dimethylformamide at room temperature, and the mixture was stirred at room temperature for 2 hours. The solvent and excess amounts of oxalyl chloride were removed in vacuo. The residue was dissolved in dichloromethane (80 ml). To the resulting solution was added 4- (aminomethyl) piperidine-1-tert-butylcarboxylate (3.72 g, 17.4 mmol, prepared according to Carceller, Elena et al., J. Med. Chem., 1996, 39, 487), N, N-diisopropylethylamine (2.25 mg, 17.4 mmol) at room temperature, and the mixture was stirred at room temperature for 18 hours. Then, the mixture was quenched with a saturated aqueous solution of sodium hydrogencarbonate (100 ml) and extracted with dichloromethane (100 ml × 4). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with n-hexane / ethyl acetate (v / v = 1/1) to give 5.27 mg (99% of the title compound as a white solid.) m / z: 426 (M + H) +, 424 (MH) "1 H-NMR (CDCl 3) d ppm: 9.81 (1 H, br.), 8.41 (1 H, s), 4.73 (1 H, br), 4.13 to 4.06 (2 H, m), 3.33 to 3.29 (2 H, m), 2.72 to 2.64 (2 H, m), 2 , 59 (3 H, s), 1.75 to 1.71 (3 H, m), 1.63 (6 H, d, J = 6.8 Hz), 1.44 (9 H, s), 1.25 to 1.11 (2 H, m). 6 (2) 5-chloro-1-isopropyl-6-methyl-2-oxo -? / - (piperidin-4-yl-methyl) -1,2-dihydro-pyridine-3-carboxamide A mixture of 4- ( { [(5-Chloro-1-ylpropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) carbo-nyl] amino.} Methyl) piperidine- 1-tert-butyl carboxylate as prepared in 6 (1) (4.77 g, 11.2 mmol) in a solution of hydrochloric acid in 10% methanol) (30 mL) was stirred at room temperature for 18 hours. The mixture was concentrated in vacuo. The residue was dissolved in methanol (15 ml) and tetrahydrofuran (15 ml). To the resulting solution was added potassium carbonate (3.0 g, 21.7 mmol) at room temperature and the mixture was stirred at room temperature for 18 hours. Then, the mixture was filtered through a pad of Celite, and washed with methanol / tetrahydrofuran (v / v = 1/1, 200 ml). The filtrate was concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with dichloromethane / methanol / 25% ammonium hydroxide (v / v / v = 10/1 / 0.2) to give 3.43 mg (94%) of the compound of the title as a white solid. MS (ESI) m / z: 326 (M + H) +, 324 (MH). "1 H-NMR (CDCl 3) d ppm: 9.98 (1 H, br.), 8.41 (1 H, s). ), 4.67 (1 H, br.), 3.30 (2 H, t, J = 6.0 Hz), 3.10 to 3.06 (2 H, m), 2.62 to 2, 54 (5 H, m), 1.77 to 1.12 (5 H, m), 1.62 (6 H, d, J = 6.8 Hz) No signal due to NH was observed. 6 (3) 5-chloro- / V- (ri - (cyclohexylmethyl) piperidin-4-yl] methyl.} -1- isopropyl-6-methyl-2-oxo-1.2-dih drop-iron-3-carboxamide To a stirred solution of 5-chloro-1-isopropyl-6-methyl-2-oxo -? / - (piperidin-4-ylmethyl) -1,2-dihydropyridine-3-carboxamide as prepared in 6 (2) (228 mg, 0.70 mmol), cyclohexanecarboxaldehyde (94 mg, 0.84 mmol) in dichloromethane (11 mL) was added sodium triacetoxyborohydride (312 mg, 1.40 mmol) at room temperature, and the mixture was stirred at room temperature for 4 hours. Then, the mixture was quenched with a saturated aqueous solution of sodium hydrogencarbonate (80 ml) and extracted with dichloromethane (50 ml x 4). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with dichloromethane / methanol (v / v = 20/1) to give 213 mg (72%) of the title compound as a white solid. MS (ESI) m / z: 422 (M + H) +, 420 (MH) ".pf: 168 ° C (decomposition) IR (KBr) v: 3215, 2922, 2847, 1672, 1618, 1535, 1443, 1348, 1298, 1263, 1151, 1136, 1105, 1053, 1036, 988, 972, 945, 799, 694, 606, 536 cm "1. 1 H-NMR (CDCl 3) d ppm: 9.77 (1 H, br.), 8.41 (1 H, s), 4.72 (1 H, br.), 3.81 (2 H, t, J = 6.3 Hz), 2.89 to 2.85 (2 H, m), 2.58 (3 H, s), 2.11 to 2.08 (2 H, m), 1.91 a 1.11 (16 H, m), 1.63 (6 H, d, J = 6.9 Hz), 0.91 to 0.79 (2 H, m). Anal, caled, for C23H36N3O2CI: C, 65.46; H, 8.60; N, 9.96. Experimental: C, 65.10; H, 8.67; N, 9.79.

Example 7 5-CHLORINE -? / - ((1-r (1-HYDROXICICLOHEXIL) METIUPlPERlDIN-4-IL > METHYL) -1-ISOPROPYL-6-METHYL-2-OXO-1,2-DIHYDROPYRIDINE-3-CARBO-XAMIDE A mixture of 5-chloro-1-isopropyl-6-methyl-2-oxo -? / - (piperidin-4-yl-methyl) -1,2-dihydropyridine-3-carboxamide as prepared in Example 6 (2) (484 mg, 1.49 mmol) and 1-oxaspiro [2.5] octane (200 mg, 1.78 mmol, prepared according to Blake, Alexander J et al., J. Chem. Soc. Dalton Trans., 1998 , 14, 2335) in methanol (5 ml) was stirred at 50 ° C for 16 h. Then, the solvent was removed in vacuo. The residue was chromatographed on a column of silica gel eluting with dichloromethane / methanol (v / v = 20/1) to give 751 mg (99%) of the title compound as a white solid. MS (ESI) m / z: 438 (M + H) +, 436 (MH) "mp: 187 ° C (decomposition) IR (KBr) v: 3215, 2922, 2853, 2758, 1672, 1620, 1537, 1439 , 1350, 1300, 1275, 1169, 1140, 1115, 1082, 1053, 1036, 972, 945, 878, 799, 702 cm "1. 1 H-NMR (CDCl 3) d ppm: 9., 78 (1 H, br.), 8.41 (1 H, s), 4.70 (1 H, br.), 3.30 (2 H, t , J = 6.2 Hz), 2.89 to 2.85 (2 H, m), 2.58 (3 H, s), 2.34 to 2.28 (4 H, m), 1.72. at 1.22 (15 H, m), 1.62 (6 H, d, J = 6.8 Hz). No signal due to OH was observed. Anal, caled, for C23H36N3O3CI-0.3H2O: C, 62.30; H, 8.32; N, 9.48. Experimental: C, 62.39; H, 8.27; N, 9.35.

EXAMPLE 8 5-CHLORINE -? / - (1-r (C / S-1-HYDROXY-4-METOXICICLOHEXIL) ME-TlLPPERIDIDIN-4-IL) METHYL) -1-ISOPROPYL-6-METHYL-2-OXO-1.2 -DIHIDRO-PYRIDINE-3-CARBOXAMIDE 8 (1) 6-Methoxy-1-oxaspiroí2.51octane fefe) (irra) To a stirred suspension of sodium hydride (60% in mineral oil, 120 g, 30.0 mmol) in dimethylsulfoxide (19 ml) was added trimethylsulphoxonium iodide (6.89 g, 31.3 mmol). ) at room temperature, and the mixture was stirred at room temperature for 30 minutes. To this mixture was added a solution of 4-methoxycyclohexanone (3.53 g, 10.0 mmol, prepared according to Shvily, Ronit et al., J. Chem. Soc Perkin Trans.2, 1997, 6, 1221) in dimethylsulfoxide. (95 ml) dropwise at room temperature, and the mixture was stirred at room temperature for 20 hours. Then, the mixture was diluted with water (1.0 L) and extracted with diethyl ether (200 ml x 6). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with n-hexane / ethyl acetate (v / v = 15 / 1-10 / 1) to give 338 mg (9%, cis) and 204 mg (5%, trans) of the title compound as a colorless oil, respectively. (cis) 1 H NMR (CDCl 3) d: 3.37 (3 H, s), 3.36 to 3.28 (1 H, m), 2.65 (2 H, s), 1.95 to 1, 88 (2 H, m), 1.81 to 1.55 (6 H, m). (trans) 1 H NMR (CDCl 3) d: 3.46 to 3.40 (1 H, m), 3.36 (3 H, s), 2.64 (2 H, a), 1.99 to 1, 91 (2 H, m), 1.85 to 1.67 (4 H, m), 1.48 to 1.39 (2 H, m). 8 (2) 5-chloro- / V - ((1-r (e / s-1-hydroxy-4-methoxycyclohexyl) methyl] piperi-din-4-yl> metin-1-isopropyl-6-methyl- 2-oxo-1,2-dihydropyridine-3-carboxamide A mixture of 5-chloro-1-isopropyl-6-methyl-2-oxo-? / - (piperidin-4-yl-methyl) -1,2-dihydropyridine-3-carboxamide as prepared in Example 6 (2) (326 mg, 1.0 mmol) and (3S, 6S) -6-methoxy-1-oxaspiro [2.5] octane (cis) as prepared in example 8 (1) (204 mg , 1.43 mmol) in methanol (3 mL) were stirred at room temperature for 3 days and then, the solvent was removed in vacuo. The residue was chromatographed on a column of silica gel eluting with dichloromethane / methanol (v / v = 20 / 1-10 / 1) to give 435 mg (93%) of the title compound as a white solid. MS (ESI) m / z: 468 (M + H) +, 466 (MH) ". Mp: 165 ° C (decomposition). IR (KBr) v: 3481, 2912, 2804, 1670, 1537, 1448, 1375 , 1350, 1288, 1229, 1171, 1105, 1055, 968, 949, 932, 887, 800, 708 cm "1 H-NMR (CDCl 3) d: 9.79 (1 H, br.), 8.42 (1 H , s), 4.69 (1 H, br.), 3.35 (3 H, s), 3.31 (2 H, t, J = 6.2 Hz), 3.16 to 3.06 (1 H, m), 2.89 to 2.85 (2 H, m), 2.59 (3 H, s), 2.36 to 2.27 (2 H, m), 2.26 (2 H, s), 1.86 to 1.55 (9 H, m), 1.64 (6 H, d, J = 6.8 Hz), 1.40 to 1.17 (4 H, m). No signal due to OH was observed. Anal, caled, for C 24 H 38 N 3 O 4 Cl: C, 61.59; H, 8.18; N, 8.98. Experimental: C, 61.28; H, 8.15; N, 8.87.

EXAMPLE 9 5-CHLORINE-N- ((TRA? / S-1-HYDROXY-METOXIClCLOHE-XIL) METHYLP1-CYPIDID-4-ILGMETIL) -1-ISOPROPYL-6-METHYL-2-OXQ-1.2-DIHYDROPYRIDINE-3-CARBOXAMIDE One mixture of 5-chloro-1-isopropyl-6-methyl-2-oxo-γ / - (piperidin-4-yl-methyl) -1,2-dihydropyridine-3-carboxamide as prepared in Example 6 (2) (326 mg, 1.0 mmol) and (3?, 6f?) - 6-methoxy-1-oxaspiro [2.5] octane (trans) as prepared in Example 8 (1) (204 mg, 1.43 mmol) in methanol (3 ml) was stirred at room temperature for 3 days and then the solvent was removed in vacuo. The residue was chromatographed on a column of silica gel eluting with dichloromethane / methanol (v / v = 20 / 1-10 / 1) to give 425 mg (91%) of the title compound as a white solid. MS (ESI) m / z: 468 (M + H) +, 466 (MH) ".pf: 175 ° C (dec.). IR (KBr) v: 3217, 2924, 1672, 1618, 1541, 1439, 1375 , 1350, 1202, 1169, 1151, 1090, 1051, 982, 972, 945, 891, 799, 706 cm "1. 1 H-NMR (CDCl 3) d: 9.79 (1 H, br.), 8.42 (1 H, s), 4.68 (1 H, br.), 3.42 to 3.36 (1 H , m), 3.33 to 3.29 (5 H, m), 2.89 to 2.85 (2 H, m), 2.59 (3 H, s), 2.36 to 2.28 ( 4 H, m), 1.90 to 1.51 (9 H, m), 1.64 (6 H, d, J = 7.0 Hz), 1.42 to 1.26 (4 H, m) . No signal due to OH was observed. Anal, caled, for C 24 H 38 N 3 O 4 Cl-0.3 H 2 O: C, 60.89; H, 8.22; N, 8.88: Experimental: C, 60.57; H, 8.27; N, 8.80.

EXAMPLE 10 5-CHLORINE -? / - ( { 1 -HTRANS-. 4-DIHYDROXY-4-METOXICICLOHE-XIL) METIUPIPERIDIN-4-lL) METlL) -1-ISOPROPYL-6-METHYL-2-OXO-1.2 -DIHl- DROPYRIDINE-3-CARBOXAMIDE 10 (1) 1-ir (3 6R) -6-hydroxy-1-oxaspiror-2-fluo-6-ylmethyl > piperidine-na-4-carboxamide A mixture of isonipecotamide (128 mg, 1.0 mmol) and (3 6R) -1,7-dioxadispiro [2.2.2.2] decane (280 mg, 2.0 mmol, prepared according to Alfredo G. Causa et al. , J. Org. Chem., 1973, 7, 1385) in methanol (10 ml) was stirred at room temperature for 18 hours and, then, the solvent was removed in vacuo. The remainder was dispersed in dichloromethane (10 ml) and the resulting suspension was filtered by washing with dichloromethane (10 ml). The filtered solid was collected and dried in vacuo to give 196 mg (73%) of the title compound as a white solid. MS (ESI) m / z: 269 (M + H) +. 1 H-NMR (DMSO-d 6) d ppm: 7.19 (1 H, br.), 6.69 (1 H, br.), 2.93 a 2.88 (2 H, m), 2.56 (2 H, s), 2.22 (2 H, s), 2.16 to 1.93 (4 H, m), 1.61 to 1, 48 (8 H, m), 1.27 to 1.24 (1 H, m), 1.05 to 1.00 (2 H, m). No signal due to OH was observed. (2) trans- - (f4- (aminomethyl) piperdin-1-methyl) -4-methylcyclohexane-1,4-diol To a hectic suspension of 1-. { [(3R, 6R) -6-hydroxy-1-oxaspiro [2.5] oct-6-yl] methyl} piperidine-4-carboxamide as prepared in 10 (1) (196 mg, 0.73 mmol) in tetrahydrofuran (25 mL) was added lithium aluminum hydride (83 mg, 2.19 mmol) at 0 °. C, and the mixture was stirred at room temperature for 5 hours and then, refluxed for 20 hours. The mixture was quenched with water (0.1 ml) at 0 ° C, and stirred at room temperature for 20 min. Then, an aqueous solution of 15% sodium hydroxide (0.1 ml) was added, and it was stirred at room temperature for 20 min. Finally, water (0.3 ml) was added and stirred at room temperature for 20 minutes. The mixture was filtered through a pad of Celite washing with tetrahydrofuran (25 ml). The filtrate was concentrated to give 220 mg (99%) of the title compound as a colorless oil. MS (ESI) m / z: 257 (M + N) +. (3) 5-chloro -? / - ( { 1 - \ (trans - "\. 4-dihydroxy-methoxycyclohexyl) methyl] piperidin-4-yl> meth) -1-isopropyl l-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide A solution of 5-chloro-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid and as prepared in example 1 (7) (168 mg, 0.73 mmol) in dichloromethane (5 mmI) was added oxalyl chloride (278 mg, 2.19 mmol) and a drop of? /, / V-dimethylformamide at room temperature, and the mixture was stirred at room temperature during 2 hours. The solvent and excess amounts of oxalyl chloride were removed in vacuo. The residue was dissolved in dichloromethane (3 mL). To the resulting solution were added frans-1 -. { [4- (aminomethyl) piperidin-1-yl} methyl } -4-methylcyclohexane-1,4-diol as prepared in 10 (2) (187 mg, 0.73 mmol),? /,? / - diisopropylethylamine (94 mg, 0.73 mmol) at room temperature environment and the mixture was stirred at room temperature for 18 hours. Then, the mixture was quenched with a saturated aqueous solution of sodium hydrogencarbonate (50 ml) and extracted with dichloromethane (50 ml x 3). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified on a TLC plate eluting with dichloromethane / methanol / ammonium hydroxide % (v / v / v = 10/1 / 0.2) to give 69 mg (20%) of the title compound as a white solid. MS (ESI) m / z: 468 (M + H) +, 466 (MH) ".pf: 189 ° C (dec.). IR (KBr) v: 3431, 3211, 2918, 1666, 1537, 1448, 1308 , 1290, 1231, 1169, 1113, 1082, 1045, 997, 957, 903, 881, 800, 710 cm "1 1 H-NMR (CDCl 3) d: 9.80 (1 H, br.), 8.42 ( 1 H, s), 4.68 (1 H, br.), 3.31 (2 H, t, J = 6.4 Hz), 2.91 to 2.87 (2 H, m), 2.60 (3 H, s), 2.37 to 2.30 (4 H, m), 1.85 to 1.23 (16 H, m), 1.64 (6 H, d, J = 0.8 Hz). Two signals due to OH were not observed. Anal, caled, for C 24 H 38 N 3 O 4 Cl-0.2 H 2 O: C, 61, 12; H, 8.21; N, 8.91. Experimental: C, 61.06; H, 8.26; N, 8.53

Claims (11)

1. - A compound of the formula (I): wherein R1 represents an alkyl group having 1 to 4 carbon atoms or a halogen atom, R2 represents an alkyl group having 1 to 4 carbon atoms, R3 represents a hydrogen atom or a hydroxy group, and A represents an oxygen atom or a group of formula -C (R4) (R5) - (in which R4 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms and R5 represents a hydroxy group or an alkoxy group having 1 to 4 carbon atoms). or their pharmaceutically acceptable salts.

2. The compound according to claim 1, wherein R1 represents a halogen atom.

3. The compound according to claim 1 and claim 2, wherein R2 represents an alkyl group having 1 to 2 carbon atoms.

4. The compound according to any one of claims 1 to 3, wherein R 3 represents a hydroxy group.

5. The compound according to any one of claims 1 to 4, wherein A represents an oxygen atom.

6. The compound of claim 1 which is 5-chloro -? / - (. {1 - [(4-hydroxytetrahydro-2-piran-4-yl) methyl] p¡per¡d¡n- 4-yl.} Methyl) -1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-chloro-6-ethyl-N- ( { 1 - [(4-hydroxytetrahydro-2-r7-pyran-4-yl) methyl] piperidin-4-yl.} Methyl) -1-isopropyl-2- oxo-1, 2-dihydropyridine-3-carboxamide; ? / - ( { 1 - [(4-hydroxytetrahydro-2 H -pyran-4-yl) methyl] piperidin-4-yl.}. Methyl) -1-isopropyl-5,6-dimethyl-2-oxo- 1,2-dihydropyridine-3-carboxamide; 5-bromo-? / - ( { 1 - [(4-hydroxytetrahydro-2 / - / - pyran-4-yl) methyl] piperidin-4-yl.} Methyl) -1-isopropyl-6-methyl -2-oxo-1, 2-dihydropyridine-3-carboxamide; 5-fluoro- / V- ( { 1 - [(4-hydroxytetrahydro-2-piran-4-yl) methyl] piperidin-4-yl] methyl) -1-isopropyl-6-methyl -2-oxo-1,2-dihydropyridine-3-carboxamide; 5-chloro -? / -. { [1- (cyclohexylmethyl) piperidin-4-yl] methyl) -1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-chloro -? / - ( { 1 - [(1-hydroxycyclohexyl) methyl] piperdin-4-yl.} Methyl) -1-isopropyl-6-methyl-2-oxo-1,2- dihydropyridine-3-carboxamide; or one of its pharmaceutically acceptable salts.

7. The use of a compound according to any of claims 1 to 6 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease mediated by the activity of the 5-HT4 receptor.

8. The use according to claim 7, wherein a disease mediated by the activity of the 5-HT4 receptor represents a member selected from gastroesophageal reflux disease, digestive disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia , irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageal disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, and cardiovascular disorders such as heart failure and cardiac arrhythmia, diabetes and apnea syndrome.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier for said compound.

10. A method for the treatment of a disease mediated by the activity of the 5-HT4 receptor, in a mammal, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to any one of the claims 1 to 6 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined in claim 9.

11. A method according to claim 10, wherein said disease mediated by the activity of the 5-HT4 receptor is a member selected from gastroesophageal reflux disease, digestive disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageal disease, nausea, central nervous system disease, Alzheimer's, cognitive disorder, emesis, migraine, neurological disease, pain and cardiovascular disorders such as heart failure and cardiac arrhythmia, diabetes and apnea syndrome.