WO2005092882A1

WO2005092882A1 - 4-amino-5-halogeno-benzamide derivatives as 5-ht4 receptor agonists for the treatment of gastrointestinal, cns, neurological and cardiovascular disorders

Info

Publication number: WO2005092882A1
Application number: PCT/IB2005/000389
Authority: WO
Inventors: Chikara Uchida; Kiyoshi Kawamura
Original assignee: Pfizer Japan, Inc.; Pfizer Inc.
Priority date: 2004-03-01
Filing date: 2005-02-16
Publication date: 2005-10-06

Abstract

This invention provides a compound of the formula (I): wherein Rl represents a halogen atom; R2 represents a hydrogen atom etc.; R3 represents an alkyl group having from 1 to 4 carbon atoms etc.;R4 represents a hydrogen atom, a hydroxy group, a carboxy group etc.; A represents an oxygen atom etc. 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

4-AMINO-5-HALOGENO-BENZAMIDE DERIVATIVES AS 5-HT4 RECEPTOR AGONISTS FOR THE TREATMENT OF GASTROINTESTINAL , CNS , NEUROLOGICAL AND CARDIOVASCULAR DISORDERS

Technical Field This invention relates to novel 4-amino-5-halogeno-beιιzamide derivatives. 5 These compounds have selective 5~HT receptor agonistic activity. The present invention also relates to a pharmaceutical composition, a method of treatment and a use, comprising the above derivatives for the treatment of disease conditions mediated by 5ΗT₄ receptor agonistic activity.

10 Background Art In general, 5ΗT₄ receptor agonists are found to be useful for the treatment of a variety of diseases such as gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral 15 disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders such as cardiac failure and heart arrhythmia, and apnea syndrome (See ΗPs, 1992, 13, 141; Ford A. P. D. W. et al., Med. Res. Rev., 1993, 13, 633; GulHkson G. W. et al., Drug Dev. ites.,1992, 26, 405; Richard M. Eglen et al, TiPS, 1995, 16, 391; Bockaert J. Et al., 20 CNS Drugs, 1, 6; Eomanelli M. N. et al., Arzheim Forsch./Drug Res., 1993, 43, 913; Kaumann A. et al., NaunynSchmiedeberg's. 1991, 344, 150; and Romanelli M. N. et al, Arzheim Forsch. /Drug Res., 1993, 43, 913). WO 99/02494 discloses 4-aminomethyl piperidine derivatives as gastrointestinal motility stimulators. Especially, the compound represented by the 25 following formula is disclosed as compound No. 41:

Compound A WO 9902156 discloses 4-aminomethyl piperidine derivatives as gastrointestinal motility stimulators. Especially, the compound represented by the following formula is disclosed as compound No. 25:

30

Compound B JP 11001472 discloses 4-amino-5-halo^_2-alkoxy-N(4-piperidinylalkyl or

4-piperidinylcarbonyl)benzamides as 5ΗT₄ receptor agonists. Especially, the compound represented by the following formula is disclosed as Reference Example '-

However, these compounds show weak affinity to 5ΗT₄ receptor and/or low permeability against caco2 membrane.

Therefore, it was desired to provide 5ΗT₄ receptor agonists which show stronger 5HT₄ receptor agonistic activities and better permeability against caco2 membrane in order to reduce side effects.

Brief Disclosure of the Invention In this invention, we found out that (l) replacing the hydroxy group with a hydrogen atom at the piperidine ring improves the affinity to 5ΗT₄ receptor, (2) introducing an oxygen containing group at beta-position of the nitrogen atom of the piperidine ring improves receptor the affinity to 5"HT₄ receptor and (3) replacing the nitrogen atom at the end piperidine ring with an oxygen atom or a carbon containing group improves permeability against caco2 membrane whilst retaining affinity to 5-HT₄. Therefore, it has now surprisingly been found that compounds of this invention have stronger selective 5ΗT₄ agonistic activity with improved caco2 permeability, compared with the prior art, and thus are useful for the treatment of disease conditions mediated by 5^_HT₄ activity such as gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, and cardiovascular disorders such as cardiac failure and heart arrhythmia, diabetes and apnea syndrome (especially caused by an opioid administration). The compounds of the present invention may show less toxicity, good absorption, distribution, good solubility, less protein binding affinity, less drug-drug interaction, and good metabolic stability. The present invention provides compounds of the following formula (I) or pharmaceutically acceptable salts thereof.

wherein R¹ represents a halogen atom,^"

R² represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms and R³ represents an alkyl group having from 1 to 4 carbon atoms; or R² and R³ may form an alkylene bridge having from 2 to 3 carbon atoms to yield a 5 or 6 membered ring; R⁴ represents a hydrogen atom, a hydroxy group, a carboxy group or a group of formula -(CH₂)n"R⁵ (in which n represents integer 1 to 4 and R⁵ represents a hydroxy group, a carboxy group or a group of formula -COOR⁶ (in which R⁶ represents an alkyl group having from 1 to4 carbon atoms which is unsubstituted or is substituted with one substituent selected from group α)),' A represents an oxygen atom or a group of the formula -C(R⁷)(R⁸)- (in which R⁷ represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms and R⁸ represents a hydroxy group, an alkoxy group having from 1 to 4 carbon atoms or a group of formula -(CH2)πrR⁹ (in which m represents integer 1 to 4 and R⁹ represents a hydroxy group, a carboxy group or a group of formula -COOR¹⁰ (in. which R¹⁰ represents an alkyl group having from 1 to4 carbon atoms which is unsubstituted or is substituted with one substituent selected from group )); said group α is consisting of a cycloalkyl, alkylated-cycloalkyl, lieterocyclyl, alkylated-heterocyclyl, aryl and alkylated-aryl. 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 condition mediated by 5ΗT₄ receptor activity. 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 diseases selected from gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, and cardiovascular disorders such as cardiac failure and heart 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.

Further, the present invention provides a method for the treatment of a condition mediated by 5"HT₄ receptor activity, in a mammalian subject, 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 diseases selected from gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, and cardiovascular disorders such as cardiac failure and heart arrhythmia, diabetes and apnea syndrome.

Detailed Description of the Invention In the compounds of the present invention, Where R² represents an alkyl group having from 1 to 4 carbon atoms, R³ represents an alkyl group having from 1 to 4 carbon atoms, R⁶ represents an alkyl group having from 1 to 4 carbon atoms, R⁷ represents an alkyl group having fr-om 1 to 4 carbon atoms and R¹⁰ represents an alkyl group having from 1 to 4 carbon, atoms. These may be a straight or branched chain group, and examples include a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and έert-butyi. Of these, we prefer those alkyl groups having from 1 to 3 carbon atoms, preferably a methyl, ethyl, propyl and isopropyl, and most preferably a methyl and ethyl. Where R¹ represents a halogen atom, this may be a fluorine, clilorine, bromine or iodine atom. Of these, we prefer a fluorine and chlorine atom. Where R² and R³ represent an alkylene bridge, this may be an ethylene or trimethylene. Of these, we prefer an ethylene. Where the group α represents a cycloalkyl, this preferably has from. 3 to 8 carbon atoms in a single carbocyclic ring. And examples include a cyclopropyl, cyclopentyl or cyclohexyl. Of these, we prefer a cyclopropyl and cyclohexyl. Where the group α represents an alkylated-cycloalkyl, this represents the cycloalkyl group which is substituted by an alkyl group having lto 4 carbon atoms defined above. And examples include a 2-methylcyclopropyl, 2-ethylcyclopropyl, 2-propylcylopropyl, 2-butylcyclopropyl, 2-methylcyclopentyl, 2-ethylcyclopentyl, 2-metylcyclohexyl, 3-metylcyclohexyl and 2-ethylcyclohexyl. Of these, we prefer 2-methylcyclopropyl and 3-methylcyclohexyl. Where group α represents a heterocyclyl, this preferably has 5 or 6 ring atoms, of which one is a nitrogen atom, 0 or 1 is an additional hetero-ato selected from the group consisting of a nitrogen, oxygen and sulfur atoms, and the remaining atoms are carbon atoms. And examples include 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 1-pyperidyl, 2-pyperidyl, 3-pyperidyl, 4-pyperidyl, 1-piperazinyl, 2-piperazinyl, 3-piperadinyl, 2-morpholinyl, 3-morpholinyl, 2-thiomorphonyl and 3-thiomorphonyl. Of these, we prefer 2-pyrrolidinyl and 3-pyrrolidinyl. Where group α represents an alkylated-heterocyclyl, this represents the heterocycle group which is substituted by an alkyl group having lto 4 carbon atoms defined above. And examples include l-methyl-pyrrolidin-2-yl, l-methyl-pyrrolidin-3-yl, 2-methyl-pyrrolidin-3-yl, l-ethyl-pyrrolidin-3-yl, l-propyl-pyrrohdin-3-yl, l-butyl-pyrrolidin-3-yl, l-methyl-pyrazolidin-2-yl, l-methyl-piperidin-2-yl and l-methyl-piperidin-3-yl. Of these, we prefer l-methyl-pyrrolidin-2-yl and l-methyl-pyrrolidin-3-yl. Where group α represents an aryl, this preferably has 6 to 10 carbon atoms. And examples include a phenyl, α-naphthyl and β-naphthyl. Of these, we prefer a phenyl. Where group α represents an alkylated-aryl, this represents the aryl group which is substituted by an alkyl group having lto 4 carbon atoms defined above. And examples include 2-metylphenyl, 3-metylphenyl, 4-ethylphenyl, 4-propylphenyl, 4-butylphenyl, 4-metylphenyl and l-metyl-napht-2-yl. Of these, we prefer 3-methylphenyl. Where R⁸ represents an alkoxy group having from 1 to 4 carbon atoms, this represents the oxy group which is substituted by an alkyl group having from 1 to 4 carbon atoms defined above and may be a straight or branched chain group. And examples include a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and t-butoxy. Of these, we prefer those alkoxy groups having from 1 to 3 carbon atoms, preferably a methoxy, ethoxy, propoxy and isopropoxy, and most preferably a methoxy and ethoxy groups. Where R⁴ represents a group of formula -(CH2)n"R⁵, preferred substituent includes a group of formula -(CH2)n-COOR⁶ such as a group of formula -(CH₂)2-COOCH₃, -(CH₂)2-COOCH₂CH3, -(CH₂)3-COOCH₃, -(CHsDβ-COOCEfeCHβ,

Of these, we prefer a group of formula.

The term "treating", as used herein, refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment" as used herein refers to the act of treating, as "treating" is defined immediately above.

Preferred classes of compounds of tlie present invention are those compounds of formula (I) and salts thereof in which:

(A) R¹ represents a chlorine atom or a fluorine atom;

(B) R² represents a hydrogen atom,"

(C) R³ represents an alkyl group having from 1 to 2 carbon atoms,^" (D) R² and R³ form a group of formula -(CTb to yield 5 membered ring,^"

(E) R⁴ represents a hydroxy group or a- carboxy group,"

(F) A represents an oxygen atom or a group of formula -CH(OH)-.

Particularly preferred compounds of the present invention are those compounds of formula (I) and salts thereof in whicli

(G) R¹ represents a chlorine atom or a fluorine atom, R² represents a hydrogen atom, R³ represents an alkyl group having from 1 to 4 carbon atoms, R⁴ represents a hydrogen atom, a hydroxy group, a carboxy group or a group of formula -(CH2)n-R⁵ (in which n represents integer 1 to 4 and R⁵ represents a hydroxy group, a carboxy group or a group of formula -COOR⁶ Gn which R⁶ represents an alkyl group having from 1 to 4 carbon atoms which is unsubstituted or is substituted one substituent selected from group α)); and A represents an oxygen atom or a group of formula -CH(OH)-; (H) R¹ represents a halogen atom, R² and R³ form a group of formula -(CH2)2- to yield 5 membered ring, R⁴ represents a hydrogen atom, a hydroxy group, a carboxy group or a group of formula -(CH2)n-R⁵ Gn which n represents integer 1 to 4 and R⁵ represents a hydroxy group, a carboxy group or a group of formula -COOR⁶ (in which R⁶ represents an alkyl group having from 1 to4 carbon atoms which is unsubstituted or is substituted with one substituent selected from group α)); and A represents an oxygen atom, a group of formula -CH(OH)-; (I) R¹ represents a chlorine atom or a fluorine atom, R² represents a hydrogen atom, R³ represents an alkyl group having from 1 to 2 carbon atoms, R⁴ represents a hydrogen atom, a hydroxy group, a carboxy group or a group of formula -(CH2)n-R⁵ (in which n represents integer 1 to 4 and R⁵ represents a hydroxy group, a carboxy group or a group of formula -COOR⁶ (in which R⁶ represents an alkyl group having from 1 to4 carbon atoms which is unsubstituted or is substituted with one substituent selected from group α)); and A represents an oxygen atom or a group of formula -CH(OH)-,"

(J) R¹ represents a chlorine atom or a fluorine atom, R² and R³ form a group of formula -(CH2)2- to yield 5 membered ring, R⁴ represents a hydrogen atom, a hydroxy group, a carboxy group or a group of formula -(CH₂)n-R⁵ (in which n represents integer 1 to 4 and R⁵ represents a hydroxy group, a carboxy group or a group of formula -COOR⁶ (in which R⁶ represents an alkyl group having from 1 to4 carbon atoms which is unsubstituted or is substituted with one substituent selected from group α)); and A represents an oxygen atom or a group of formula -CH(OH). The more preferred classes of compounds of the present invention are those in which^: (K) R¹ represents a chlorine atom or a fluorine atom, R² represents a hydrogen atom,

R³ represents an alkyl group having from 1 to 4 carbon atoms, R⁴ represents a hydrogen atom, a hydroxy group or a carboxy group and A represents an oxygen atom or a group of formula -CH(OH)-,"

(L) R¹ represents a halogen atom, R² represents a hydrogen atom, R³ represents an alkyl group having from 1 to 2 carbon atoms, R⁴ represents a hydrogen atom, a hydroxy group or a carboxy group and A represents an oxygen atom or a group of formula -CH(OH)S

(M) R¹ represents a halogen atom, R² and R³ form a group of formula -(CH2)2- to yield 5 membered ring, R⁴ represents a hydrogen atom', a hydroxy group or a carboxy group and A represents an oxygen atom or a group of formula -CH(OH)-,'

(N) R¹ represents a chlorine atom or a fluorine atom, R² represents a hydrogen atom, R³ represents an alkyl group having from 1 to 2 carbon atoms, R⁴ represents a hydrogen atom, a hydroxy group or a carboxy group and A represents an oxygen atom or a group of formula -CH(OH)-; (O) R¹ represents a chlorine atom or a fluorine atom, R² and R³ form a group of formula -(CH₂)2- to yield 5 membered ring, R⁴ represents a hydrogen atom, a hydroxy group or a carboxy group and A represents an oxygen atom or a group of formula -CH(OH)-. The most preferred individual compounds of the present invention are

4-Ammo-5-chloro-N-({l-[(4-hydroxytetrahydro-2/ -pyran-4-yl)methyl]piperidin-4-yl}methyl)-2- methoxybenzamide;

4-[(4-{[(4-Amino-5-chloro-2-methoxybenzoyl)amino]methyl}piperidin-l-yl)methyl]tetrahydro-2

H-pyran-4-carboxylic acid; 4-Amino-5-chloro-N-({l-[(l,4-dihydroxycyclohexyl)methyl]piperidm-4-yl}methyl)-2-methoxybe nzamide;

4-Amino-5-chloro-N-({l-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidin-4-yl}methyl)-2- ethoxybenzamide;

4-[(4-{[(4-Amino-5-chloro-2-ethoxybenzoyl)amino]methyl}piperidin-l-yl)methyl]tetrahydro-2H- pyran-4-carboxylic acid;

4-Amino-5-chloro-N-({l-[(l,4-dihydroxycyclohexyl)methyl]piperidin-4-yl}methyl)-2-ethoxybenz amide;

4-amino-5-chloro-N-({l-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidin-4-yl}methyl)-2,3

-dihydro- 1 -benzo uran-7-carboxamide; 4-amino-5-chloro-N-({l-[(4-carboxytetrahydro-2i7-pyran-4-yl)methyl]piperidin-4-yl}methyl)-2,3

-dihydro-l-benzo uran-7-carboxamide;

4-amino-5-chloro-({l-[(l,4-dihydroxycyclohexane-l-yl)methyl]piperidin-4-yl}methyl)-2,3-dihy dro-1 -benzo uran-7-carboxamide.

General Synthesis The compounds of the present invention may be prepared by a variety of processes well known for the preparation of compounds of this type, for example as shown in the following Methods A to G. The following Methods A and B illustrate the preparation of compounds of formula (I). Unless otherwise indicated, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and A in the following Methods are defined as above. The term "protecting group", as used hereinafter, means a hydroxy, carboxy or amino-protecting group which is selected from typical hydroxy, carboxy or amino-protecting groups described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1999). All starting materials in the following general syntheses may be commercially available or obtained by conventional methods known to those skilled in the art.

Method A TThhiiss iilllluusi trates the preparation of compounds of formula (I).

Reaction Scheme A

<»') In the above formulae, R^4a represents R⁴ defined as above, a group of formula -(CH2)kCOORⁿ, wherein k represents integer 0 to 4 and R¹¹ represents R⁶ defined as above or a carboxy-protecting group, or a group of formula -(CH2)ιOR¹², wherein 1 represents integer 0 to 4 and R¹² represents a hydroxy-protecting group; A^a represents A defined as above or a group of formula -CH((CH2)qCOOR¹³)-, wherein q represents integer 1 to 4 and R¹³ represents R¹⁰ defined as above or a carboxy-protecting group or a group of formula -CH((CH2)rOR¹⁴)-, wherein r represents integer 0 to 4 and R¹⁴ represents a hydroxy-protecting group. The term "carboxy-protecting group", as used herein, signifies a protecting group capable of being cleaved by chemical means, such as hydrogenolysis, hydrolysis, electrolysis or photolysis.and such carboxy-protecting groups are described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1999). Typical carboxy-protecting groups include methyl, ethyl, t-butyl, methoxymethyl, 2,2,2-trichloroethyl, benzyl, diphenylmethyl, trimethylsilyl, t-butyldimethylsilyl and allyl. Of these groups, we prefer t-butyl or ethyl. The term "hydroxy-protecting group", as used herein, signifies a protecting group capable of being cleaved by chemical means, such as hydrogenolysis, hydrolysis, electrolysis or photolysis.and such hydroxy-protecting groups are described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1999). Typical hydroxy-protecting groups include methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, t-butyl, allyl, benzyl, triphenylmethyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, C₂H₅O(C=0)-, CH₃(C=0)-, and benzyloxycarbonyl. Of these groups, we prefer t-butyldiphenylsilyl.

In this step, the desired compound of formula (I) of the present invention is prepared by amide coupling (Al-a) with the compound of formula (III) or forming amide(Al-b) via acyl halide. (Al-a) Amide coupling In this reaction, carboxyl group of the compound of formula (II) is coupled with the compound of formula (III) under the presence of the condensing agent and base. The reaction is normally and preferably effected in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve 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, tetrahydrofuran and dioxane,^'and amides, such as A N-dimethylformamide and iV-N-dimethylacetamide. Of these solvents, we prefer -ΛζNdimethylformamide. There is likewise no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type may equally be used here. Examples of such bases include: amines, such as triethylamine, A N-diisopropylethylamine, tributylamine, pyridine, picoline and 4-(ΛζN-dimethylamino)pyridine. Of these, we prefer iV_.N-diisopropylethylamine. There is likewise no particular restriction on the nature of the condensing agents used, and any condensing agent commonly used in reactions of this type may equally be used here. Examples of such condensing agents include: an azodiearboxylic acid di-lower alkyl ester- triphenylphosphine such as diethyl azodicarboxylate-triphenylphosphine," an AζN^dicycloalkylcarbodiimide such as N,N ieyclohexylcarbodiimide (DCC),^' a 2-halo-l-lower alkyl pyridinium halide such as 2-chloro-l-methy pyridinium iodide,^" a diarylphosphorylazide such as diphenylphosphorylazide (DPPA); a chloroformate such as ethyl chloroformate and isobutyl chloroformate," a phosphoryl chloride such as diethyl phosphorryl chloride," a phosphorocyanidate such as diethyl phosphorocyanidate (DEPC);. an imidazole derivative such as N,N^L carbodiimidazole (CDI); a carbodiimide derivative such as l-ethyl-3-(3" diethylaminopropyl)carbodiimide hydrochloride (EDAJPC); and a sulfonyl chloride derivative such as 2,4,6-triisopropylbenzenesulfonyl chloride. Of these, we prefer DEPC. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the sobvent, and the starting materials. However, in general, we find it convenient to carry out the reaction at a temperature of from 0°C to 80°C, more preferably from 10°C to 40°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under "the preferred conditions outlined above, a period of from 5 minutes to 24 hours, more preferably from 60 minutes to 12 hours, will usually suffice.

(Al-b) Forming amide via acyl halide In this reaction, carboxyl group of the compound of formula (ID is converted into acyl halide and then coupled with the compound of formula (III). (Acyl halide formation) The reaction is normally and preferably effected in the preserxce of solvent. There is no particular restriction on the nature of the solvent to ^"be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve 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. Examples of suitable reagents include: chlorinating agents, su-ch as oxyalyl chloride or thionyl chloride,^" and brominating agents, such as thionyl.^~bromide. The quantity of the reagent required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, that the reaction is effected under the preferred conditions, the quantity of the reagent as chemical equivalent to the starting material from 2 to 5, will usually suffice. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, we find it convenient to carry out the reaction at a temperature of from 0°C to 100°C, more preferably from 0°C to 40°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 5 minutes to 10 hours, more preferably from 60 minutes to 5 hours, will usually suffice. (Coupling with the compound (III)) The reaction is normally and preferably effected in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve 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. There is likewise no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type may equally be used here. Examples of such bases include: amines, such as triethylamine, diisopropylethylamine, tributylamine, pyridine, picoline and 4-(A N-dimethylamino)pyridine. Of these, we prefer triethylamine, diisopropylethylamine or pyridine. The quantity of the base required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, that the reaction is effected under the preferred conditions, the quantity of the base as chemical equivalent to the starting material from 1 to 4, more preferably from 1 to 1.4, will usually suffice. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, we find it convenient to carry out the reaction at a temperature of from 0°C to 100°C, more preferably from 0°C to 50°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 5 minutes to 24 hours, more preferably from 3 hours to 18 hours, will usually suffice. In the case R^4a represents a group of formula -(CH2)kCOOR¹¹ and/or A^a represents -CH((CH2)qCOOR¹³), the deprotection reaction will follow to yield a carboxy group. This reaction is described in detail by T. W. Greene et al. [Protective Groups in Organic Synthesis, 369-453, (1999)], the disclosures of which are incorporated herein by reference. The following is a typical one, provided the protecting group is t-butyl. The reaction is normally and preferably effected in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent. Examples of suitable solvents include: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane," and aromatic hydrocarbons, such as benzene, toluene and nitrobenzene. Of these solvents, we prefer halogenated hydrocarbons. The reaction is carried out in the presence of an acid. There is likewise no particular restriction on the nature of the acids used, and any acid commonly used in reactions of this type may equally be used here. Examples of such acids include: acids, such as hydrochloric acid, acetic acid p-toluenesulfonic acid or trifluoroacetic acid. Of these, we prefer trifluoroacetic acid. The reaction may be carried out in the presence of a radical scavenger. There is likewise no particular restriction on the nature of the radical scavenger used, and any radical scavenger commonly used in reactions of this type may equally be used here. Examples of such radical scavengers include ΗBr, dimethylsulfoxide or (CH₃CH2)₃SiH. Of these, we prefer (CH₃CH2)₃SiH. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, we find it convenient to carry out the reaction at a temperature of from 0°C to 100°C, more preferably from 0°C to 50°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 5 minutes to 24 hours, more preferably from 1 hours to 24 hours, will usually suffice.

In the case R^4a represents a group of formula -(CH₂)ιCH(OR¹²) and/or A^a represents a group of formula -CH((CH2)rCH(OR¹⁴)), the deprotection reaction will follow to yield a hydroxy group. This reaction is described in detail by T. W Greene et al. [Protective Groups in Organic Synthesis, 17-245, (1999)], the disclosures of which are incorporated herein by reference. The following is a typical one, provided the protecting group is t-butyldiphenylsilyl. The reaction is normally and preferably effected in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent. Examples of suitable solvents include: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; and ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane. Of these, we prefer ethers. The reaction is carried out in the presence of a catalyst. There is likewise no particular restriction on the nature of the catalyst used, and any catalyst commonly used in reactions of this type may equally be used here. Examples of such catalysts include-" acids, such as HCL' bases such as sodium hydroxide or potassium hydroxide," fluorine reagents such as HF, HF -pyridine or tetrabuthylammonium fluoride (TBAF). Of these, we prefer TBAF. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, we find it convenient to carry out the reaction at a temperature of from 0°C to 100°C, more preferably from 0°C to 50°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 5 minutes to 24 hours, more preferably from 1 hours to 24 hours, will usually suffice.

Method B This illustrates the alternative preparation of the desired compound of formula (la) or (lb) whrerein R⁴ is a hydroxy group or a hydrogen atom. Reaction Scheme B

(la) (lb) In the above formulae, A^a is defined as above," R¹⁵ represents an amino-protecting group. The term "amino-protecting group", as used herein, signifies 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,

CH3(C=0)-, t-butyldimethylsilyl, t-butyldiphenylsilyl, benzyloxycarbonyl and t-buthoxycarbonyl. Of these groups, we prefer t-buthoxycarbonyl.

Step Bl In this step, the piperidine compound (V) is prepared by the deprotection of the compound of fomula (IV) which may have been prepared, for example, as the same method as described in Method A. This method is described in detail by T. W. Greene et al. [Protective Groups in Organic Synthesis, 494-653, (1999)], the disclosures of which are incorporated herein by reference. The following is a typical method, provided the protecting group is t-buthoxycarbonyl. The reaction is normally and preferably effected in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve 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 excess amount of an acid. There is likewise no particular restriction on the nature of the acids used, and any base commonly used in reactions of this type may equally be used here. Examples of such acids include: acids, such as hydrochloric acid, or trifluoroacetic acid. Of these, we prefer hydrochloric acid. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, we find it convenient to carry out the reaction at a temperature of from 0°C to 100°C, more preferably from 0°C to 50°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 5 minutes to 24 hours, more preferably from 3 hours to 24 hours, will usually suffice.

In this step, the desired compound of formula (la) is prepared by the epoxy-opening substitution of the compound of formula (V) prepared as described in

Step Bl. The reaction is normally and preferably effected in the presence of solvent.

There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent. Examples of suitable solvents include: ethers, such as diethyl ether, dhsopropyl ether, tetrahydrofuran and dioxane; and alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol. Of these solvents, we prefer alcohols. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, we find it convenient to carry out the reaction at a temperature of from 0°C to 120°C, more preferably from 20°C to 80°C.

The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 5 minutes to 24 hours, more preferably from 3 hours to 24 hours, will usually suffice. In the case A^a represents a group of formula -CH((CH2)qCOOR¹³) and/or a group of formula -CH((CH2)rCH(OR¹⁴)), the deprotection reaction will follow to yield a carboxy group and/or a hydroxy group. The reaction may be carried out under the same conditions as described in Step Al of Method A.

In this step, the desired compound of formula (lb) is prepared by the reductive amination of the compound of formula (V) prepared as described in Step Bl. The reaction is normally and preferably effected in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve 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. There is likewise no particular restriction on the nature of the reducing reagents used, and any reducing reagent commonly used in reactions of this type may equally be used here. Examples of such reducing reagent include: sodium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride. Of these, we prefer sodium triacetoxyborohydride. The quantity of the reducing reagent required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, that the reaction is effected under the preferred conditions, the quantity of the reducing reagent as chemical equivalent to the starting material from 1 to 3, will usually suffice. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, we find it convenient to carry out the reaction at a temperature of from -20°C to 60°C, more preferably from 0°C to 50°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outhned above, a period of from 5 minutes to 24 hours, more preferably from 1 hour to 12 hours, will usually suffice. In the case A^a represents a group of formula -CH((CH2)qCOOR¹³) and/or a group of formula -CH((CH2)rCH(OR¹⁴)), the deprotection reaction will follow to yield a carboxy group and/or a hydroxy group. The reaction may be carried out under the same conditions as described in Step Al of Method A.

Method C This illustrates the preparation of the compound of formula (III) wherein R⁴ is a hydroxy group or a hydrogen atom.

Reaction Scheme C

(X)

In the above formulae, A^a is defined as above," R^4b represents a hydroxy group or a hydrogen atom,^" and R¹⁶ represents an amino-protecting group.

In this step, the compound of formula (IX) is prepared by the epoxy-opening substitution of the compound of formula (VIII). The reaction may be carried out under the same conditions as described in Step B2 of Method B, provided the deporotection process is unnecessary.

In this step, the compound of formula (X) is prepared by the reductive amination of the compound of formula (VIII). The reaction may be carried out under the same conditions as described in Step B3 of Method B, provided the deporotection process is unnecessary.

In this step, the compound of formula (Ilia) is prepared by the deprotection of the compound of formula (IX) or (X) prepared as described in Step Bl or B2. The reaction may be carried out under the same conditions as described in Step Bl of Method B.

Method D This illustrates the preparation of the compound of formula (III) wherein R^4a is a group of formula -COOR¹¹.

Reaction Scheme D

("lb) In the above formulae, A^a and R¹¹ are defined as above," each of R and R' represents an alkyl group having 1 to 4 carbon atoms, preferably a methyl group, or an aralkyl group such as a benzyl or phenethyl group preferably a benzyl group; and X represents a halogen atom such as a iodine atom, a chlorine atom or a bromine atom. In this step, the compound of formula (XIII) is prepared by annulation with the compound of formula (XII). The reaction is normally and preferably effected in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve 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, tetrahydrofiiran and dioxane; and amides, such as A Ndimethylformamide and A N-dimethylacetamide. Of these, we prefer N_.N-dimethylformamide. The reaction is carried out in the presence of a base. There is likewise no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type may equally be used here. Examples of such bases include: alkali metal hydrides, such as lithium hydride, sodium hydride and potassium hydride; and alkali metal alkoxides, such as sodium methoxide, sodium ethoxide, potassium t-butoxide. Of these, we prefer sodium hydride. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, we find it convenient to carry out the reaction at a temperature of from 0°C to 120°C, more preferably from 20°C to 80°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outhned above, a period of from 5 minutes to 48 hours, more preferably from 60 minutes to 24 hours, will usually suffice.

In this step, the compound of formula (XIV) is prepared by reduction of the cyano group of the compound of formula (XIII). The reaction is normally and preferably effected in the presence of solvent.

There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent. Examples of suitable solvents include: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofiiran and dioxane," aromatic hydrocarbons, such as benzene, toluene and nitrobenzene; and alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol. Of these, we prefer methanol. The reaction is carried out in the presence of a reducing agent. There is likewise no particular restriction on the nature of the reducing agents used, and any reducing agent commonly used in reactions of this type may equally be used here. Examples of such reducing agents include: metal borohydrides such as sodium borohydride and sodium cyanoborohydride; combinations of hydrogen gas and a catalyst such as palladium-carbon, platinum and Raney nickel," and hydride compounds such as lithium aluminum hydride, sodium borohydride and diisobutyl aluminum hydride. Of these, we prefer Raney nickel. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, we find it convenient to carry out the reaction at a temperature of from 0°C to 100°C, more preferably from 10°C to 40°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outhned above, a period of from 5 minutes to 24 hours, more preferably from 60 minutes to 12 hours, will usually suffice.

In this step, the compound of formula (XVI) is prepared by forming piperidinone ring from the compound of formula (XIV). The reaction is normally and preferably effected in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent. Examples of suitable solvents include: water,^" and alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol. Of these, we prefer the mixture of water and methanol. The reaction is carried out in the presence of a base. There is likewise no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type may equally be used here. Examples of such bases include: alkali metal hydroxides, alkah metal alkoxides, such as sodium methoxide, sodium ethoxide, potassium t-butoxide! and alkah metal carbonates, such as lithium carbonate, sodium carbonate and potassium carbonate. Of these, we prefer potassium carbonate. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, we find it convenient to carry out the reaction at a temperature of from 0°C to 120°C, more preferably from 50°C to 100°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 5 minutes to 24 hours, more preferably from 60 minutes to 12 hours, will usually suffice.

In this step, the compound of formula (XVII) is prepared by converting the carbonyl group of the compound of formula (XVI) to a cyano group under the presence of jrtoluenesulfonylmethyl isocyanide. The reaction is normally and preferably effected in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent. Examples of suitable solvents include: ethers, such as diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofiiran and dioxane," and alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol. Of these, we prefer the mixture of ethylene glycol dimethyl ether and ethanol. The reaction is carried out in the presence of a base. There is likewise no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type may equally be used here. Examples of such bases include: alkali metal alkoxides, such as sodium methoxide, sodium ethoxide and potassium t-butoxide. Of these, we prefer potassium t-butoxide. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, we find it convenient to carry out the reaction at a temperature of from 0°C to 100°C, more preferably from 20°C to 80°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outhned above, a period of from 5 minutes to 24 hours, more preferably from 60 minutes to 12 hours, will usually suffice.

In this step, the compound of formula (Illb) is prepared by reduction of the cyano group of the compound of formula (XVII). The reaction may be carried out under the same conditions as described in Step D2 of Method D.

Method E This illustrates the preparation of the compound of formula (IV).

Reaction Scheme E

(XVIII) (IV) In the above formula, A^a is defined as above. Step El In this step, the compound of formula (IV) is prepared by conveting the carbonyl group of the compound of formula (XVIII) into the epoxide group. The reaction is normally and preferably effected in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent. Examples of suitable solvents include: amides, such as formamide, ΛζNdimethylformamide, A iV-dimethylacetamide and hexamethylphosphoric triamide," sulfoxide such as • dimethyl sulfoxide or sulfolane. Of these solvents, we prefer dimethyl sulfoxide. The reaction is carried out in the presence of a base. There is likewise no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type may equally be used here. Examples of such bases include-" alkah metal alkoxides, such as sodium methoxide, sodium ethoxide and potassium t-butoxide; and alkali metal carbonates, such as lithium carbonate, sodium carbonate and potassium carbonate. Of these, we prefer potassium t-butoxide. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, we find it convenient to carry out the reaction at a temperature of from 0°C to 100°C, more preferably from 10°C to 50°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outhned above, a period of from 5 minutes to 24 hours, more preferably from 60 minutes to 12 hours, will usually suffice. In the case the resulting compound of formula (IV) has the diastereomer, such diastereomer may be separated by chromatographic separation.

Method F This illustrates the preparation of compounds of formula (III) wherein R^4a is neither a hydroxy group nor a group of formula —COOR¹¹.

Reaction Scheme F

(XX') (XXII) In the above formula, s represents integer 0 to 3, A^a is defined as above; R^4c represents R^4a defined as above with proviso a hydroxy group and a group of formula

—COOR¹¹ are excluded," R¹¹ is defined as above or R¹⁷ represents an amino-protecting group.

In this step, the compound of formula (XIX) is prepared by reducing the ester group and the cyano group of the compound of formula (XIII). The reaction is normally and preferably effected in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent. Examples of suitable solvents include: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofiiran and dioxane," and amides, such as formamide, iV-N-dimethylformamide, A Ndimethylacetamide and hexamethylphosphoric triamide. Of these solvents, we prefer tetrahydrofiiran. The reaction is carried out in the presence of a reducing agent. There is likewise no particular restriction on the nature of the reducing agents used, and any reducing agent commonly used in reactions of this type may equally be used here. Examples of such reducing agents include: hydride compounds such as lithium aluminum hydride, sodium borohydride and diisobutyl aluminum hydride. Of these, we prefer lithium aluminium hydride. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, we find it convenient to carry out the reaction at a temperature of from -78°C to 25°C, more preferably from -78°C to 0°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outhned above, a period of from 5 minutes to 24 hours, more preferably from 60 minutes to 12 hours, will usually suffice.

In this step, the compound of formula (IIIc) is prepared by forming the piperidine methyl amino group from the compound of formula (XIX). The reaction may be carried out under the same conditions as described in Steps D3 to D5 of

Method D.

Step F3 In this step, the compound of formula (XX) is prepared by oxidizing the hydroxy group of the compound of formula (XIX). In this reaction, an introduction of the amino-protecting group (F3-a) is carried out before the oxidization (F3-b) (F3-a) Introduction of the amino-protecting group.

This reaction is described in detail by T. W. Greene et al. [Protective Groups in Organic Synthesis, 494-653, (1999)], the disclosures of which are incorporated herein by reference. The following is a typical one, provided the protecting group is t-buthoxycarbonyl. The reaction is normally and preferably effected in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent. Examples of suitable solvents include: water; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofiiran and dioxane; and sulfoxide such as dimethyl sulfoxide and sulfolane. Of these solvents, we prefer tetrahydrofiiran. The reaction is carried out in the presence of reagent. There is likewise no particular restriction on the nature of the reagents used, and any reagent commonly used in reactions of this type may equally be used here. Examples of such reagents include: di- tert-butyl carbonate and l-(tert-butoxycarbonyl)benztriazole. Of these, we prefer di- tert-butyl carbonate. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, we find it convenient to carry out the reaction at a temperature of from 0°C to 120°C, more preferably from 20°C to 80°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outhned above, a period of from 5 minutes to 24 hours, more preferably from 60 minutes to 12 hours, will usually suffice.

(F3-b) Oxidization The reaction is normally and preferably effected in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent. Examples of suitable solvents include: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane," and ethers, such as diethyl ether, diisopropyl ether, tetrahydrofiiran and dioxane. Of these solvents, we prefer tetrahydorfuran. The reaction is carried out in the presence of an oxidizing agent. There is likewise no particular restriction on the nature of the oxidizing agents used, and any oxidizing agent commonly used in reactions of this type may equally be used here. Examples of such condensing agents include: a manganese oxide such as manganese dioxide; a chromic acid compound such as chromic anhydride -pyridine complex," a reagent used for Swern oxidation (a combination of dimethyl sulfoxide and an activating agent (dicyclohexylcarbodiimide, dicyclohexylcarbodiimide and pyridine-trifluoroacetic acid, oxalyl chloride, acetic anhydride, phosphorus pentoxide, pyridine-sulfuric anhydride, sulfur trioxide- pyridine, mercury acetate, chlorine or N-chlorosuccinimide)); a transition metal oxidizing agent such as tetrapropylammonium perruthenate; or a high valence iodine oxidizing agent such as l,l,l-triacetoxy-l,l- dihydro-l,2-benziodoxol"3(lH)-one. Of these, we prefer manganese dioxide. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, we find it convenient to carry out the reaction at a temperature of from O°C to 120°C, more preferably from 20°C to 80°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outhned above, a period of from 5 minutes to 24 hours, more preferably from 60 minutes to 12 hours, will usually suffice.

Step F4 In this step, the compound of formula (XXI) is prepared by converting the carbonyl group of the compound of formula (XX) to a cyano group under the presence of /rtoluenesulfonylmethyl isocyanide. The reaction may be carried out under the same conditions as described in Step D4 of Method D.

Step F5 In this step, the compound of formula (XXII) is prepared by converting the cyano group of the compound of formula (XXI) to a ester group. This reaction is accomphshed (F5-a) hydrolyzing the cyano group of the compound of formula (XXI) to result a carboxy group and (F5-b) condensing the carboxy group and the compound of formula R"-OH. (F5-a) Hydrolyzing the cyano group The reaction is normally and preferably effected in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent. Examples of suitable solvents include: water,^" amides, such as formamide, AζNdimethylformamide, ΛζiV-dimethylacetamide and hexamethylphosphoric triamide; and alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol. Of these solvents, we prefer the mixture of water and methanol. The reaction is carried out in the presence of a base. There is likewise no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type may equally be used here. Examples of such bases include: alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide and potassium hydroxide,^" and alkah metal alkoxides, such as sodium methoxide, sodium ethoxide and potassium t-butoxide. Of these, we prefer sodium hydroxide. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, we find it convenient to carry out the reaction at a temperature of from 0°C to 120°C, more preferably from 20°C to 80°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outhned above, a period of from 5 minutes to 24 hours, more preferably from 60 minutes to 12 hours, will usually suffice. (F5"b) Condensing the carboxy group The reaction may be carried out under the same conditions as described in

(Al-a) of Step Al of Method A.

Step F6 In this step, the compound of formula (XXIII) is prepared by reducing the ester group of the compound of formula (XXII). The reaction may be carried out under the same conditions as described in Step FI of Method F.

In this step, the compound of formula (XX) is prepared by oxidizing the hydroxy group of the compound of formula (XXIII). The reaction may be carried out under the same conditions as described in (F3"b) of Step FI of Method F. Step F8 In this step, the compound of formula (Hie) is prepared by forming the piperidine methyl amino group from the compound of formula (XXIII). The reaction may be carried out under the same conditions as described in Step F2 of Method F.

In this step, the compound of formula (IIIc) is prepared by forming the piperidine methyl amino group from the compound of formula (XXII). The reaction may be carried out under the same conditions as described in Step F2 of Method F.

Method G This illustrates the preparation of compounds of formula (III) wherein A^a is neither an oxygen atom nor a group of formula -CH(OR¹⁴)-. Reaction Scheme G

In the above formula, t represents integer 0 to 4, A^b represents A^a defined as above with proviso an oxygen atom and a group of formula -CH(OR¹⁴)- are excluded," R^4a is defined as above,^" R^u is defined as above or R¹⁸ represents an amino-protecting group. Step Gl In this step, the compound of formula (XXV) is prepared by converting the carbonyl group of the compound of formula (XXTV) to a cyano group under the presence of jrtoluenesulfonylmethyl isocyanide. The reaction may be carried out under the same conditions as described in Step D4 of Method D.

Step G2 In this step, the compound of formula (XXVI) is prepared by converting the cyano group of the compound of formula (XXV) to a ester group. The reaction may be carried out under the same conditions as described in Step F5 of Method F.

In this step, the compound of formula (XXVII) is prepared by reducing the ester group the compound of formula (XXVI). The reaction may be carried out under the same conditions as described in Step FI of Method F.

Step G4 In this step, the compound of formula (XXVIII) is prepared by oxidizing the hydroxy group the compound of formula (XXVII). The reaction may be carried out under the same conditions as described in Step F7 of Method F.

In this step, the compound of formula (XXIX) is prepared by converting the carbonyl group of the compound of formula (XXVIII) to a cyano group under the presence of -toluenesulfonylmethyl isocyanide. The reaction may be carried out under the same conditions as described in Step D4 of Method D.

In this step, the compound of formula (XXVI) is prepared by converting the cyano group of the compound of formula (XXIX) to a ester group. The reaction may be carried out under the same conditions as described in Step F5 of Method F.

In this step, the compound of formula (Hid) is prepared by forming the piperidine methyl amino group from the compound of formula (XXVT). The reaction may be carried out under the same conditions as described in Step F2 of Method F. Step G8 In this step, the compound of formula (Hid) is prepared by forming the piperidine methyl amino group from the compound of formula (XXVII). The reaction may be carried out under the same conditions as described in Step F2 of Method F.

The compounds of formula (I), and the intermediates above-mentioned preparation methods can be isolated and purified by conventional procedures, such as distillation, recrystalhzation or chromatographic purification. The optically active compounds of this invention can be prepared by several methods. For example, the optically active compounds of this invention may be obtained by chromatographic separation, enzymatic resolution or fractional crystallization from the final compounds. Several compounds of this invention possess an asymmetric center. Hence, the compounds can exist in separated (+)- and (-)-optically active forms, as well as in racemic one thereof. The present invention includes all such 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 subject invention also includes isotopically-labelled compounds, which are identical to those recited in formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷0, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶C1, respectively. Compounds of the present invention, prodrugs thereof, pharmaceutically acceptable esters of said compounds and pharmaceutically acceptable salts of said compounds, of said esters or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as ^H and l^C are incorporated, are useful in drug and/or substrate tissue distribution assay. Tritiated, i.e., ³H, and carbon- 14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of presentation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., ²H, can afford therapeutic advantage resulting from greater metabohc stabihty, for example increased in vivo half-life or reduced dosage requirement and, hence, may be preferred in some circumstances. Isotopically labeled compounds of formula (I) of this invention and prodrugs thereof can generally be prepared by carrying out the procedure disclosed in above-disclosed Schemes and/or Examples and Preparations below, by submitting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. The compounds of the invention may take up water upon exposure to the atmosphere to absorb water or to produce a hydrate. The present invention covers such hydrates. Additionally, certain other solvents may be taken up by the compounds of the present invention to produce solvates, which also form pa t of the present invention. The present invention includes salt forms of the compounds (I) as obtained. Certain compounds of the present invention may be capable of forming pharmaceutically acceptable non-toxic cations. Pharmaceutically acceptable non-toxic cations of compounds of formula (I) may be prepared by conventional techniques by, for example, contacting said compound with a stoichiometric amount of an appropriate alkah or alkaline earth metal (sodium, potassium, calcium and magnesium) hydroxide or alkoxide in water or an appropriate organic solvent such as ethanol, isopropanol, mixtures thereof, or the like. The bases which are used to prepare the pharmaceuticaUy acceptable base addition salts of the acidic compounds of this invention of formula (I) are those which form non-toxic base addition salts, i.e., salts containing pharmaceutically acceptable cations, such as adenine, arginine, cytosine, lysine, benethamine (i.e., Nbenzyl-2-phenyletylamine), benzathine (i.e., A^N-dibenzylethylenediamine), choline, diolamine (i.e., diet anolamine), ethylenediamine, glucosamine, glycine, guanidine, guanine, meglumineG.e., N-methylglucamine), nicotinamide, olamineG.e., ethanolamine), ornithine, procaine, prohne, pyridoxine, serine, tyrosine, valine and tromethamineG.e., tris or tris(hydroxymethyl)aminomethane). The base addition salts can be prepared by conventional procedures. Insofar as the certain compounds of this invention are basic compounds, they are capable of forming a wide variety of different salts with various inorganic and organic acids. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the basic compounds of this invention of formula (I) are those which form non-toxic acid addition salts, i.e., salts containing pharmaceuticaUy acceptable anions, such as the chloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bi^_tartrate, succinate, malate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, adipate, aspartate camsylate, edisylate (i.e., 1,2-ethanedisulfonate), estolate(i.e., laurylsulfate), gluceptateCi.e., gluscoheptonate), gluconate, 3-hydroxy-2-naphthoate, xionofoate(i.e., l-hydrroxy-2-naphthoate), isethionate,(i.e., 2-hydroxyethanesulfonate), mucated.e., galactarate), 2-naphsylate(i.e., naphthalenesulphonate, stearate, cholate, glucuronate, glutamate, hippurate, lactobionate, lysinate, maleate, mandelate, napadisylate, nicatinate, polygalacturonate, sahcylate, sulphosalicylate, tannate, tryptophanate, borate, carbonate, oleate, phthalate and pamoate (i.e., l.l'-methylene-bis-(2-hydroxy-3-naphthoate). The acid addition salts can be prepared by conventional procedures. For a review of on suitable salts see Berge et a , J. Pharm. Sci., 66, 1-19, 1977. Also included within the scope of this invention are bioprecursors (also called pro-drugs) of the compounds of the formula (I). A bioprecursor of a compound of the formula (I) is a chemical derivative thereof which is readily converted back into the parent compound of the formula (I) in biological systems. In particular, a bioprecursor of a compound of the formula (I) is converted back to the parent compound of the formula (I) after the bioprecursor has been administered to, and absorbed by, a mammalian subject, e.g., a human subject. For example, it is possible to make a bioprecursor of the compounds of formula G) in which one or both of R⁴ and A include hydroxy groups by making an ester of the hydroxy group. When only one of R⁴ and A includes hydroxy group, only mono-ester is possible. When both R⁴ and A include hydroxy, mono- and di-esters (which can be the same or different) can be made. Typical esters are simple alkanoate esters, such as acetate, propionate, butyrate, etc. In addition, when R⁴ or A includes a hydroxy group, bioprecursors can be made by converting the hydroxy group to an acyloxymethyl derivative (e.g., a pivaloyloxymethyl derivative) by reaction with an acyloxymethyl halide (e.g., pivaloyloxymethyl chloride). When the compounds of the formula (I) of this invention may form solvates such as hydrates, such solvates are included within the scope of this invention.

Method for assessing biological activities- The 5-HT4 receptor binding affinities of the compounds of this invention are determined by the following procedures.

Human 5-HT4 binding Human 5"HT₄(d) transfected HEK293 cells were prepared and grown in-house. The collected cells were suspended in 50 mM HEPES (pH 7.4 at 4°C) supplemented with protease inhibitor cocktail (Boehringer, 1:1000 dilution) and homogenized using a hand held Polytron PT 1200 disruptor set at full power for 30 sec on ice. The homogenates were centrifuged at 40,000 x g at 4 °C for 30 min. The pellets were then resuspended in 50 mM HEPES (pH 7.4 at 4 °C) and centrifuged once more in the same manner. The final peUets were resuspended in an appropriate volume of 50 mM HEPES (pH 7.4 at 25 °C), homogenized, aliquoted and stored at -80°C until use. An aliquot of membrane fractions was used for protein concentration determination using BCA protein assay kit (PIERCE) and ARVOsx plate reader (Wallac). For the binding experiments, 25 μl of test compounds were incubated with 25 μl of [³H]-GR113808 (Amersham, final 0.2 nM) and 150 μl of membrane homogenate and WGA-SPA beads (Amersham) suspension solutions (10 μg protein and lmg SPA beads/well) for 60 minutes at room temperature. Nonspecific binding was determined by 1 μM GR113808 (Tocris) at the final concentration. Incubation was terminated by centrifugation at 1000 rpm. Receptor-bound radioactivity was quantified by counting with MicroBeta plate counter (Wallac).

Agonist-induced cAMP elevation in human 5-HT₄(d) transfected HEK293 cells Human 5"HT (d) transfected HEK293 cells were established in-house. The cells were grown at 37°C and 5% C0₂ 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 grown to 60-80% confluence. On the previous day before treatment with compounds dialyzed FCS (Gibco) was substituted for normal and the cells were incubated overnight.

Compounds were prepared in 96-well plates (12.5 μl/well). The cells were harvested with PBS/1 mM EDTA, centrifuged and washed with PBS. At the beginning of the assay, cell pellet was resuspended in DMEM supplemented with 20 mM HEPES, 10 μM pargyline (Sigma) and 1 mM 3-isobutyM-methylxanthine (Sigma) at the concentration of 1.6 x 10⁵ cells/ml and left for 15 minutes at room temperature. The reaction was initiated by addition of the cells into plates (12.5 μl/well). After incubation 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. Homogenous time-resolved fluorescence-based cAMP (Schering) detection was made according to the manufacturer's instruction. ARVOsx multilabel counter (Wallac) was used to measure HTRF (excitation 320 nm, emission 665 nm/620 nm, delay time 50 μs, window time 400 μs).

Data was analyzed based on the ratio of fluorescence intensity of each well at 620 nm and 665 nm followed by cAMP quantification using cAMP standard curve. Enhancement of cAMP production elicited by each compound was normahzed to the amount of cAMP produced by 1000 nM serotonin (Sigma). All compounds of Examples showed 5HT₄ receptor agonistic activity.

Human dofetilide binding Human HERG transfected HEK293S cells were prepared and grown in-house. The collected cells were suspended in 50 mM Tris-HCl (pH 7.4 at 4°C) and homogenized using a hand held Polytron PT 1200 disruptor set at full power for 20 sec on ice. The homogenates were centrifuged at 48,000 x g at 4 °C for 20 min. The pellets were then resuspended, homogenized, and centrifuged once more in the same manner. The final peUets were resuspended in an appropriate volume of 50 mM Tris-HCl, 10 mM KCl, 1 mM MgCl₂ (pH 7.4 at 4°C), homogenized, aliquoted and stored at -80°C until use. An aliquot of membrane fractions was used for protein concentration determination using BCA protein assay kit (PIERCE) and ARVOsx plate reader (Wallac). Binding assays were conducted in a total volume of 200 μl in 96-well plates. Twenty μl of test compounds were incubated with 20 μl of [³H]- dofetilide (Amersham, final 5 nM) and 160 μl of membrane homogenate (25 μg protein) for 60 minutes at room temperature. Nonspecific binding was determined by 10 μM dofetilide at the final concentration. Incubation was terminated by rapid vacuum filtration over 0.5% presoaked GF/B Betaplate filter using Skatron cell harvester with 50 mM Tris-HCl, 10 mM KCl, 1 mM MgCb, pH 7.4 at 4°C. The filters were dried, put into sample bags and filled with Betaplate Scint. Radioactivity bound to filter was counted with Wallac Betaplate counter.

Caco-2 permeability Caco-2 permeability was measured according to the method described in

Shiyin Yee, Pharmaceutical Research, 763 (1997). Caco-2 cells were grown on filter supports (Falcon HTS multiwell insert system) for 14 days. Culture medium was removed from both the apical and basolateral compartments and the monolayers were preincubated with pre-warmed 0.3 ml apical buffer and 1.0 ml basolateral buffer for 0.5 hour at 37°C in a shaker water bath at 50 cycles/min. The apical buffer consisted of Hanks Balanced Salt Solution, 25 mM D-glucose monohydrate, 20 M MES Biological Buffer, 1.25 mM CaCb and 0.5 mM MgC (pH 6.5). The basolateral buffer consisted of Hanks Balanced Salt Solution, 25 mM D-glucose monohydrate, 20 mM HEPES Biological Buffer, 1.25 mM CaCb and 0.5 mM MgCl₂ (pH 7.4). At the end of the preincubation, the media was removed and test compound solution (lOμM) in buffer was added to the apical compartment. The inserts were moved to wells containing fresh basolateral buffer at 1 hr. Drug concentration in the buffer was measured by LC MS analysis. Flux rate (F, mass/time) was calculated from the slope of cumulative appearance of substrate on the receiver side and apparent permeability coefficient (Papp) was calculated from the following equation. Papp (cm/sec) = (F * ND) / (SA * MD) where SA is surface area for transport (0.3 cm²), VD is the donor volume (0.3ml),

MD is the total amount of drug on the donor side at t = 0. All data represent the mean of 2 inserts. Monolayer integrity was determined by Lucifer Yellow transport.

The compounds of formula (I) of this invention can be administered via either the oral, parenteral or topical routes 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 will necessarily occur depending upon the weight and condition of the subject being treated, the disease state being treated and the particular route of administration chosen. However, for example, a dosage level that is in the range of from 0.004 mg to 7 mg per kg of body weight per day is most desirably employed for treatment of gastroesophageal reflux disease. The compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the above routes previously indicated, and such administration can be carried out in single or multiple doses. More particularly, the novel therapeutic agents of the invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the hke. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, oralpharmaceutical compositions can be suitably sweetened and/or flavored. In general, the therapeutically-effective compounds of this invention are present in such dosage forms at concentration levels ranging 5% to 70% by weigiit, preferably 10% to 50% by weight. For oral administration, tablets containing various excipients such as microcrystalhne cellulose, sodium citrate, calcium carbonate, dijpotassium phosphate and glycine may be employed along with various disintegr antes such as starch and preferably corn, potato or tapioca starch, alginic acid and certa_in complex silicates, together with granulation binders like polyvinylpyrrohdone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules^ preferred materials in this connection 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 sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various hke combinations thereof. For parenteral administration, solutions of a compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered (preferably pH>8) if necessary and the hquid diluent first rendered isotonic. These a_queous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intra-articular, intra-muscular and subcutaneous injection* purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art. Additionally, it is also possible to administer the compounds of tlie present invention topically when treating inflammatory conditions of the skin and this may preferably be done by way of creams, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.

Examples The invention is illustrated in the following non-limiting examples in which, unless stated otherwise: all operations were carried out at room or ambient temperature, that is, in the range of 18-25 °C," evaporation of sobvent was carried out using a rotary evaporator under reduced pressure with a bath temperature of up to 60 °C," reactions were monitored by thin layer chromatograplvy (tic) and reaction times are given for illustration only," melting points (m.p.) given are uncorrected (polymorphism may result in different melting points)," the structure and purity of all isolated compounds were assured by at least one of the following techniques: tic (Merck silica gel 60 F254 precoated TLC plates or Merck NH2 F254S precoated HPTLC plates), mass spectrometry, nuclear magnetic resonance (NMR), infrared red absorption spectra GR) or microanalysis. Yields are given for illustrative purposes only. Flash column chromatography was carried out using Merck silica gel 60 (230-400 mesh ASTM) or Fuji Silysia Chromatorex® DU3050 (Amino Type, 30-50 μm). Low-resolution mass spectral data (El) were obtained on a Integrity (Waters) mass spectrometer or a Automass 120 (JEOL) mass spectrometer. Low-resolution mass spectral data (ESI) were obtained on a ZMD2 (Waters) mass spectrometer or a Quattro II (Micromass) mass spectrometer. NMR data was determined at 270 MHz (JEOL JNM-LA 270 spectrometer) or 300 MHz (JEOL JNM-LA300) using deuterated chloroform (99.8% D) or dimethylsulfoxide (99.9% D) as solvent unless indicated otherwise, relative to tetramethylsilane (TMS) as internal standard in parts per million (ppm); conventional abbreviations used are: _s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br. = broad, etc. IR spectra were measured by a Shimazu infrared spectrometer GR'47θ). Optical rotations were measured using a JASCO DIP- 370 Digital Polarimeter (Japan Spectroscopic CO, Ltd.). Chemical symbols have their usual meanings,^" b.p. (boiling point), m.p. (melting point), 1 (liter(s)), mL (milhhter(s)), g (gram(s)), mgGnilligram(s)), mol (moles), mmol (millimoles), eq. (equivalent(s)). Example 1

4-AMINO-5-CHLORO- N -({l-[(4-HYDROXYTETRAHYDRO-2H^:PYRA -4-YL)METHYL]PIPERIDIN-4-Y L}METHYL)-2-METHOXYBENZAMIDE 1(1) Benzyl ({l-[(4-hvdroxytetrahvdro-2H-pyran-4-yl)methyl]piperidin-4-yl}methyl)-carbamat

A mixture of benzyl (piperidin-4-ylmethyl)carbamate (7.77 g, 31.3 mmol, prepared according to Bose, D. Subhas et a , Tetrahedron Lett, 1990, 31, 6903) and l,6"dioxaspiro[2.5]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 h. Then, the mixture was refluxed- for 8 h. After coohng to room temperature, the solvent was removed in vacuo. Ttie residue was chromatographed on a column of silica gel eluting with dichlorometliane/methanol (v/v=20/l) to give 5.60 g (49%) of the title compound as colorless oil.

1H-NMR (CDCls, 300MHz) δ ppm: 7.40-7.30 (5 H, m), 5.09 (2 H, s), 4.85 (l H, br.), 3.85-3.72 (4 H, m), 3.08 (2 H, t, J=6.4 Hz), 2.88-2.83 (2 H, m), 2.61 (l HZ, s), 2.36-2.30 (4 H, m), 1.77-1.19 (9 H, m). 1 (2) 4- {[4- (Aminomethyl)piperidin- 1 - yl] methyljtetr ahydro- 2H-p yraπ.- 4-ol

A mixture of benzyl ({l- [(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidin-4-yl}methyDcarbamate as prepared in l(l) (5.60 g, 15.5 mmol) and palladium on activated carbon. (10 wt.%, 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 slightly yellow oil. MS (ESI) m/z: 229 (M+Η)⁺.

1H-NMR (CDCls, 300MHz) δ ppm: 3.70-3.81 (4 H, m), 2.85-2.90 (2 H, ML), 2.57 (2 H, d, J .l Hz), 2.35 (2 H, t, ^=11.0 Hz), 2.32 (2 H, s), 1.65-1.71 (2 H, m), 1.44-1.63 (8 H, m), 1.19-1.28 (2 H, m).

1(3) tert-Butyl

({l-r(4-hvdroxytetrahvdro-2H-pyran-4-yl)methyl]piperidin-4-yl}metfcιyl)carbamat

To a stirred solution of tert-butyl (piperidin-4-ylmethyl)carbamate (22.3 g, 104 mmol) in methanol (120 mL) was added l,6"dioxaspiro[2.5]octane (14.2 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 h. The volatile components were removed by evaporation and the resulting viscous oil was precipitated with a mixture of hexane and diethyl ether. The parecipitate was collected by filtration and recrystallized from a mixture of irhexane and 2-propanol to give the title compound 14.2 g (42%) as a colorless powder. MS (ESI) m/z: 329 (M+H)⁺. m.p.: 104°C.

Η-NMR (CDCls, 300MHz) δ ppm: 3.85-3.70 (4 H, m), 3.00 (2 H, t, J=6.2 Hz), 2.88-2.83

(2 H, m), 2.38-2.27 (4 H, m), 1.69-1.51 (8 H, m), 1.44 (9 H, s), 1.31-1.23 (2 H, m). A signal due to OH was not observed.

Anal. Calcd. for Ci7H₃2N₂0₄: C, 62.17; H, 9.82," N, 8.53. Found: C, 62.07; H, 9.92; N,

8.58.

1(4) 4-{[4-(Aminomethyl)piperidin-l-yl]methyl}tetrahvdro-2H-pyran-4;-ol

To a solution of tert-butyl

({l-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidin-4-yl}methyi)ca_rbamate as prepared in 1(3) (50.28 g, 153 mmol) in methanol (100 mL) was added 4N hydrochloric acid dioxane solution (200 mL, 800 mmol) at room temperature. After 4 h, the volatile materials were removed by evaporation. The resulting^ amorphous was precipitated with diethyl ether/methanol (v/v=5/l). The precipitate was collected and added to the ice cooled 6N aqueous sodium hydroxide solution (200 mL) gradually. The mixture was extracted with dichloromethane/methanol (v/v=10/l, 500 mL x 4). The combined organic layers were washed with brine , 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+Η)+.

Η-NMR (CDCI3, 300MHz) δ ppm: 3.70-3.81 (4 H, m), 2.85-2.90 (2 H, m), 2.57 (2 H, d, J^5.7 Hz), 2.35 (2 H, t, J^ll.O Hz), 2.32 (2 H, s), 1.65-1.71 (2 H, m), 1.44-1 .63 (8 H, m), 1.19-1.28 (2 H, m).

1(5) 4-Amino-5-chloro-A^"

-({l-[(4-hvdroxytetrahvdro-2H-pyran-4-yl)methyl]piperidin-4-yl}methyl)-2-metho xybenzamide

To a solution of 4-amino-5-chloro-2-methoxybenzoic acid (200 mg, 0.99 mmol) in A N-dimethylformamide (10 mL) were added

4-{[4-(aminomethyl)piperidin-l-yl]methyl}tetrahydro-2H-pyran-4-ol as prepared in 1(2) and 1(4) (340 mg, 1.48 mmol), diethyl phosphorocyanidate (241 mg, 1.48 mmol) and A N-dhsopropylethylamine (191 mg, 1.48 mmol) at room temperature, and the mixture was stirred at room temperature for 18 h. Then, the mixture was concentrated in vacuo to give yellow oil. The residual yellow oil was chromatographed on a column of silica gel eluting with dichloromethane/methanol/25% ammonium hydroxide (v/v/v=30/l/0.l) to give 371 mg (91%) of the title compound as a white solid. The solid was washed with dichloromethane/diethyl ether (v/v=l/20, 20 mL) and collected by filtration to give 350 mg (86%) of the title compound as a white sohd. MS (ESI) m/z: 412 (M+Η)⁺, 410 (M-H)\ m.p.: 164.3°C

IR (KBr) v : 3456, 3402, 3315, 2943, 2927, 2858, 1629, 1596, 1541, 1498, 1309, 1263, 1180, 1105, 1089, 985, 842 em ¹.

1H-NMR (DMSO-de, 300MHz) δ ppm: 8.11 (l H, s), 7.74 (l H, br.), 6.30 (l H, br.), 4.37 (2 H, br.), 3.90 (3 H, s), 3.80-3.75 (5 H, m), 3.32 (2 H, t, J^6.4 Hz), 2.89-2.84 (2 H, m), 2.38-2.31 (4 H, m), 1.75-1.20 (8 H, m). A signal due to OH was not observed.

Anal. Calcd. for C20H30N3O4CI: C, 58.32,^" H, 7.34; N, 10.20. Found: C, 58.04; H, 7.47; N, 9.89.

Claims

1. A compound of the formula (I) :

wherein R¹ represents a halogen atom;

R² represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms and R³ represents an alkyl group having from 1 to 4 carbon atoms; or R² and R³ may form an alkylene bridge having from 2 to 3 carbon atoms to yield a 5 or 6 membered ring; R⁴ represents a hydrogen atom, a hydroxy group, a carboxy group or a group of formula -(CH₂)n-R⁵ (in which n represents integer 1 to 4 and R^s represents a hydroxy group, a carboxy group or a group of formula -COOR (in which R⁶ represents an alkyl group having from 1 to4 carbon atoms which is unsubstituted or is substituted with one substituent selected from group

«));

A represents an oxygen atom or a group of the formula -C(R⁷)(R⁸)- (in which R⁷ represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms and R⁸ represents a hydroxy group, an alkoxy group having from 1 to 4 carbon atoms or a group of formula -(CH₂)m-R⁹ (in which m represents integer 1 to 4 and R⁹ represents a hydroxy group, a carboxy group or a group of formula -COOR¹⁰ (in which R¹⁰ represents an alkyl group having from 1 to4 carbon atoms which is unsubstituted or is substituted with one substituent selected from group )); said group α is consisting of a cycloalkyl, alkylated-cycloalkyl, heterocyclyl, alkylated-heterocyclyl, aryl and alkylated-aryl; or a pharmaceutically acceptable salts thereof.

2. The compound according to claim 1, wherein R¹ represents a chlorine atom or a fluorine atom.

3. The compound according to claim 1 or claim 2, wherein R² represents a hydrogen atom.

4. The compound according to any one of claims 1 to 3, wherein R³ represents an alkyl group having from 1 to 2 carbon atoms.

5. The compound according to claim 1 or claim 2, wherein R and R³ form a group of formula -(CH₂)₂- to yield 5 membered ring.

6. The compound according to any one of claims 1 to 5, wherein R⁴ represents a hydroxy group or a carboxy group.

7. The compound according to any one of claims 1 to 6, wherein A represents an oxygen atom or a group of formula -CH(OH)-.

8. The compound of Claim 1 which is 4-Armno-5-chloro-N-({l-[(4-hydroxytetrahydro-2i7-pyran-4-yl)methyl]piperidin-4-yl}methyl)-2- methoxybenzamide;

H-pyran-4-carboxylic acid; 4-Amino-5-chloro-N-({l-[(l,4-dihydroxycyclohexyl)methyl]piperidin-4-yl}methyl)-2-methoxybe nzamide;

4-Amino-5-chloro-N-({l-[(4-hydroxytetrahydro-2fl^"-pyran-4-yl)methyl]piperidin-4-yl}methyl)-2- ethoxybenzamide;

4-[(4-{[(4-A)3iino-5-chloro-2-ethoxybenzoyl)amino]methyl}piperidin-l-yl)methyl]tetrahydro-2H-- pyran-4-carboxylic acid;

4-amino-5-chloro-N-({l-[(4 ydroxytetrahydro-2i7-pyran-4-yl)methyl]piperidin-4-yl}methyl)--2,3

-dihydro-l-benzofuran-7-carboxamide; 4-amino-5-chloro-N-({ 1 -[(4-carboxytetrahydro-2iϊ-pyran-4-yl)methyl]piperidin-4-yl}methyl)-2,3

-dihydro-l-benzofuran-7-carboxamide;

4-amino-5-chloro-( { 1 -[(1 ,4-dihydroxycyclohexane-l -yl)methyl]piperidin-4-yl}methyl)-2,3-dihyd ro- 1 -benzofuran-7-carboxamide; or a pharmaceutically acceptable salt thereof.

9. Use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a condition mediated by 5-HT4 receptor activity.

10. The use according to Claim 9, wherein a condition mediated by 5-HT4 receptor activity represents a member selected from gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, and cardiovascular disorders such as cardiac failure and heart arrhythmia, diabetes and apnea syndrome.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier for said compound.

12. A method for the treatment of a condition mediated by 5-HT₄ receptor activity, in a mammalian subject, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined in claim 11.

13. A method according to claim 12 wherein said condition mediated by 5-HT₄ receptor activity is a member selected from gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, and cardiovascular disorders such as cardiac failure and heart arrhythmia, diabetes and apnea syndrome.