MXPA00009980A - 1-[(1-substituted-4-piperidinyl)methyl]-4-piperidine derivatives, process for producing the same, medicinal compositions containing the same and intermediates of these compounds - Google Patents

Abstract

Compounds represented by general formula (I) or physiologically acceptable acid addition salts thereof and medicinal compositions containing these compounds as the active ingredient, wherein Ar represents (Ar-1) or (Ar-2);and A represents -Z-N(Q1)(Q2), -CO-R7 or -(CH2)p-CH(R8)-COR9. Because of exhibiting strong affinity for 5-HT4 receptor, these compounds are useful as drugs for accelerating the peristalsis or drugs for improving digestive tract functions.

Description

DERIVATIVE OF 1- [(1-SUBSTITUTE-4-PIPERIDINYL) METHYL] -4- PIPERIDINE, PROCESS FOR THE PREPARATION OF THE SAME, PHARMACEUTICAL COMPOSITION THAT CONTAINS IT AND THE INTERMEDIARY FOR THE SAME TECHNICAL FIELD The present invention describes a new derivative of the 1 [(1-substituted-4-piperidinyl) methyl] -4-piperidine exhibiting potent agonistic activity at the 4 serotonin receptors (hereinafter, occasionally referred to as the 5-HT 4 receptors). More particularly, the present invention describes a 1 [(1-substituted-4-piperidinyl) methyl] -4-piperidine derivative which forms an amide with 4-amino-5-halobenzoic acid or with 4-amino-5 acid. halogeno-2, 3- ^ dihydrobenzo [b] furan-7-carboxyl, a process for the preparation thereof, a pharmaceutical composition containing the same, and an intermediate for this.

BACKGROUND ART The publication WO-95-26953 discloses that the compounds of the following formula (P-1), et cetera, have effects Ref. 123424 selective antagonists of 5-HT4 receptors, and are useful for the prophylaxis or treatment of various gastrointestinal diseases, etc. wherein Ri is a halogen atom, R 2 is a lower alkoxy group, etc. m is 1 or 2, p is an integer from 1 to 6, B is a group of the formula: -N (R 4) -X? R5, -N (R4) -X2-N (R6) (R7), -X! -N (R8) (R9), or -Het (Xi is CO, CS, or S02, X2 is CO or CS, R is a hydrogen atom, a lower alkyl group, etc., Rβ and R7 are a lower alkyl group, etc., or R6 and R-7 can be combined together with the adjacent nitrogen atom to form a ring, R8 and R9 are a lower alkyl group, etc., or R8 and R9 can be combined together with the adjacent nitrogen atom to form a ring, Het is a heterocycle, mono or bicyclic group, provided with 5- or 6-membered, having an amide or urea in the ring and having 1-5 heteroatom (s) selected from the oxygen atom, the sulfur atom and the nitrogen atom, and the definitions for some substituents are omitted).

The compounds of the present invention of the formula (I) as mentioned below are distinguished from the compounds of the formula (Pl) having an amide bond and a piperidine radical attached to each other via an alkylene, and furthermore have different substituents on the position 1 of the piperidine ring.

In addition, Publication EP-A-445862 (= JP-A-04-211685) discloses that the N- (4-piperidinyl) (dihydrobenzofuran or dihydro-2H-benzopyran) carboxamide derivatives of the following formula (P-2) they exhibit gastrointestinal motility stimulation properties. wherein A is a group of the following formula: -CH2-CH2- (a-1); -CH2-CH2-CH2- (a-2); or -CH2-CH2-CH2-CH2- (a-3); • where Ri is a hydrogen atom or a halogen atom, R2 is a hydrogen atom, an amino group and so on, R3 is a hydrogen atom, a C? -6 alkyl group, etc., L is a cycloalkyl group C3_6, etc., L is a group of the formula: -Alk-R4 (b-1); 10 -Alk-X-R5 (b-2); -Alk-Y (C = 0) -R7 (b-3); or -Alk-Y (C = 0) -NR9R10 (b-4); (each Alk is an alkanediyl group C? _6, R4 is an atom hydrogen, a cyano group, an alkylsulfonylamino group ^ fc C? _6, a C3-6 cycloalkyl group, a C5-6 cycloalkanone group, an aryl group, a di (aryl) -methyl group, or Het (Het is a heterocyclic group having 5- to 6- membered has 1,2,3, or 4 heteroatom (s) selected from oxygen, sulfur And nitrogen and etc.), R5 is a hydrogen atom, a C1-6 alkyl group, and so on, X is O, S, S02 or NRβ (Re is a hydrogen atom, a C1-6 alkyl group or an aryl group) , R7 is a hydrogen atom, a C? -6 alkyl group, and so on, and is NR8 or a direct bond (R8 is a hydrogen atom, a ^ F C6_6 alkyl group or an aryl group), Rg and Rio are independently a hydrogen atom, an alkyl group C? _6 et cetera, or R9 and Rio can be combined together with the nitrogen atom to which Rg and Rio are linked to form a pyrrolidinyl or piperidinyl ring which is optionally substituted with an Ci-β alkyl group, an amino group, etc. or Rg and Rio can be combined together with the atom of The nitrogen at which R9 and Rio are linked to form a piperazinyl or 4-morpholinyl ring which is optionally substituted with a Ci-β alkyl group, and definitions for some substituents are omitted).

Among the compounds of the above formula (P-2), when R 4 is Het and said Het is a piperidine, the compound of the formula (P-2) can theoretically be superimposed with some of the compounds of the formula (I ) of the present invention, but said EP publication exemplifies as such compounds only one compound of the formula (P-2 ') (Compound 57): The compound of the above formula (P-2 ') has a substituted piperidine attached at the 1-position thereof, which is very different from the compounds (I) of the present invention, since the present compound (I) has a ring piperidine that has a specific substituent (ie, • A) at the 1-position of said piperidine ring, and said piperidine ring is attached at the 4-position thereof, as described below. In the present, cis-4-amino-5-chloro-N- [1- [3- (4-fluorophenoxy) -propyl] -3-methoxy-4-piperidinyl] -2-methoxybenzamide (general name; cisapride; cf, Merck • Index, 12 ed, 2377 (1996)) has been widely used in the clinical field as a gastrointestinal motility enhancer or as a gastrointestinal prokinetic agent. Recently, 5-HT4 receptors were found during studies on serotonin receptors involved in stimulation of the Gastrointestinal motility by metoclopramide or cisapride, and it has been confirmed that these benzamide derivatives intensify gastrointestinal motility by stimulating 5-HT receptors (see J. Pharmacol. Exp. Ther., 1990, 252, 1378; Pharmacol, Exp. Ther., 1991, 5 257, 781). In this way, a compound that stimulates 5-HT4 receptors is widely distributed by all gastrointestinal organs can be expected to intensify gastrointestinal motility for cisapride as mentioned above disadvantageously inhibitory effects on the central nervous system based on antagonist activity against D2 dopamine receptors, or side effects on the heart. Therefore, it is difficult to use cisapride in the clinical field. In addition, there is a growing trend of the number of patients suffering from symptoms associated with gastrointestinal motor disorders due to the complicated society and the mature society, and under these circumstances, it has been strongly desired to develop an excellent gastrointestinal prokinetic agent. DESCRIPTION OF THE INVENTION The present inventors have intensively studied the derivative of 1 [(1-substituted-4-piperidinyl) methyl] -4-piperidine which acts on 5-HT4 receptors, and have found that a derivative of 1 [ (1-substituted-4-piperidinyl) methyl] -4-piperidine which forms an amide with a 4-amino-5-halobenzoic acid or a 4-amino-5-halogeno-2,3-dihydrobenzo [b] -furan acid -7-carboxylic acid shows a potent agonistic activity at 5-HT4 receptors, and its usefulness as an excellent enhancer of gastrointestinal mobility or as an excellent gastrointestinal prokinetic agent, and finally the present invention has been carried out. An object of the present invention is to provide a novel 1 [(1-substituted-4-piperidinyl) methyl] -4-piperidine derivative having potent agonistic activity at 5-HT4 receptors, more particularly, to provide a derivative of 1 [(1-substituted-4-piperidin) methyl] -4-piperidine which forms an amide with a 4-amino-5-halogenobenzoic acid or a 4-amino-5-halogeno-2,3-dihydrobenzo [b] acid ] -furan-7-carboxylic. Especially, the present invention provides a compound that is useful as an enhancer of gastrointestinal motility or as a prokinetic A gastrointestinal agent. Another object of the present invention is to provide a process for the preparation of said compound. Still another object of the present invention is to provide a pharmaceutical composition containing said compound. These and other objects and advantages of the present invention are obvious to any person skilled in the art of the following description.

The present invention provides a 1 [(1-substituted-4-piperidine) methyl] -4-piperidine derivative of the following formula (I), a pharmaceutically acceptable acid addition salt thereof, a process for preparing the same , and a pharmaceutical composition containing the same: wherein Ar is a group of the following formula (Ar-1) or (Ar-2): (Ar-1) (Ar-2) (wherein R1 is a halogen atom, R2 is a hydrogen atom or a lower alkyl group, R3 is a hydrogen atom, a lower alkyl group, or a lower alkanoyl group, R4 is a hydrogen atom or an alkyl group lower, R5 and R6 are the same or different and each a hydrogen atom or a lower alkyl group, and n is 1, 2 or 3), A is a group having the following formula (Al), (A-2) or (A-3): (wherein Z is -CO-, -CS- or -S02-, Q1 and Q2 are the same or different and each a hydrogen atom a lower alkyl group, a lower cycloalkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted phenyl lower alkyl group, or Q1 and Q2 can be combined together wthe nitrogen atom to which they are linked to form a pyrrolidine ring, a piperidine ring, a hexahydroazepine ring, a ring morpholine, a thiomorpholine ring, or a piperazine ring optionally having a lower alkyl or a subs benzyl titer in the other nitrogen atom); 5 -CO-R7 (A-2) (wherein R7 is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower alkyl group which is substituted by a hydroxy, a lower alkoxy group or • lower alkoxycarbonyl, or a substituted or unsubstituted phenyl group); - (CH2) P-CH (R8) -COR9 (A-3) (wherein p is 0, 1, 2, 3, 4 or 5, R8 is a hydrogen atom or a lower alkyl group, and R9 is a lower alkyl group or an alkoxy group • lower), and also provides an intermediate of the following formula (II) (hereinafter, occasionally referred to simply as the intermediate (II)) or an acid addition salt thereof; • where Ar is the same as defined above, which is, when Ar is a group of the previous formula (Ar- 1), an intermediate of the formula (II-l): or when Ar is a group of the above formula (Ar-2), an intermediate of the formula (II-2): and further provides an intermediate of the following formula (VIII) (hereinafter occasionally referred to simply as the intermediate (VIII)) or an acid addition salt thereof: • where A is the same as defined above.

The pharmaceutically acceptable acid addition salt of the compound of the formula (I) includes a salt wan inorganic acid such as hydrochloric, hydrobromic, hydroiodic, sulfate, phosphate, etc., or a salt wan organic acid such as an oxalate, maleate, fumarate, lactate, maleate, citrate, tartrate, benzoate, methanesulfonate, succinate, etc. The compound of formula (I) and an acceptable acid addition salt may exist in the form of a hydrate and / or solvate, and the present invention also includes these hydrates and / or solvates.

The acid addition salt of the compound of formula (II) or formula (VIII) can be the aforementioned pharmaceutically acceptable acid addition salts. The compound of the formula (II) or the formula (VIII) and an acid addition salt of the same may exist in the form of a hydrate and / or a solvate, and the present invention also includes these hydrates and / or solvates.

The compounds of the formula (I) and the formula (VIII) can optionally have one or more asymmetric carbon atoms, and of which the stereoisomers thereof probably exist, and the compounds of the Formula (I) and formula (VIII) can exist in a mixture of two or more stereoisomers. The present invention also includes these stereoisomers, a mixture thereof and a racemic mixture thereof. The terms used in the present specification are • 10 explained below. The lower alkyl group and the lower alkyl radical include a branched chain or straight open chain alkyl group having 1 to 6 carbon atoms, unless otherwise defined. The "halogen atom" is a fluorine atom, a ^ fc atom of chlorine, a bromine atom, an iodine atom, and a chlorine atom and a bromine atom are preferred. The most preferable halogen atom is the chlorine atom. The "lower alkyl group" is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, and hexyl.

The "cycloalkyl group" includes atoms having from 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The "lower alkoxy group" includes an alkoxy group having from 1 to 6 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy, and hexyloxy. The "substituted or unsubstituted phenyl group" includes a phenyl group which can be substituted by one or three groups selected from the group consisting of a halogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a C4-C4 alkoxycarbonyl group, a trifluoromethyl group, an amino group, a mono- or dialkylamino group Ci- C4, a cyano group and a nitro group, for example, phenyl; 2-, 3- or 4-chlorophenyl; 2-, 3- or 4-bromophenyl; 2-, 3- or 4-fluorophenyl; 2,4-dichlorophenyl; 2,4-dibromophenyl; 2,4-difluorophenyl; 2-, 3- or 4-methylphenyl; 2-, 3- or 4-methoxyphenyl; 4-trifluoromethylphenyl; 2-, 3-, or 4-aminophenyl; 4-methylaminophenyl; 2-, 3- or 4-dimethylaminophenyl; 2-, 3-, or 4-cyanophenyl; 2-, 3- or 4-nitrophenyl; and 4-amino-5-chloro-2-methoxy-phenyl.

The "substituted or unsubstituted phenyl lower alkyl group" includes an alkyl group having from 1 to 4 (B carbon atoms which are substituted by the above-mentioned "substituted or unsubstituted phenyl group", for example, benzyl; -, 3- or 4-chlorobenzyl, 4-bromobenzyl, 3- or 4-fluorobenzyl, 4-methylbenzyl, 4-methoxybenzyl, 1-phenethyl, and 2-phenethyl The "lower alkanoyl group" includes ones having 2 to 6 carbon atoms, for example, acetyl, • 10 propionyl, and butyryl. The "lower alkoxycarbonyl group" includes ones having from 1 to 6 carbon atoms in the alkoxy radical, for example, methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl. The "lower alkyl group which is substituted by a hydroxy, lower alkoxy or a lower alkoxycarbonyl group" includes a lower alkyl group which is substituted by a hydroxy group, the "lower alkoxy group" mentioned above or the "alkoxycarbonyl group". lower "mentioned above, for example, methoxymethyl, 2-hydroxyethyl, 2-methoxyethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, 2-ethoxycarbonylethyl, 2-ethoxycarbonylpropyl, and 3-methoxycarbonylpropyl. Among the compounds of the present invention, a preferred one is a compound of the formula (I) wherein in the group of the formula (Ar-1), both R 2 and R 3 are hydrogen atoms, and R 4 is a methyl group, a ethyl group, a propyl group or an isopropyl group, or in the group of the formula (Ar-2), both R2 and R3 are hydrogen atoms, and R5 and Rd are both hydrogen atoms, or one of these is a group methyl, and the other is a hydrogen atom, and n is 1, and A is the same as defined above, and a pharmaceutically acceptable acid addition salt thereof. The most preferable compounds are the compounds of the formula (I) wherein: (a) in the formula (Al), Q 1 is a hydrogen atom, a C 1 -C 4 alkyl group, or a C 3 -C 7 cycloalkyl group, Q 2 is a hydrogen atom, a C 1 -C 4 alkyl group, a C 3 -C 7 cycloalkyl group, a phenyl group which is optionally substituted by a halogen, a C 1 -C 4 alkyl or C 1 -C 4 alkoxy, or a benzyl group which is optionally substituted by the same substituents as the above, or Q1 and Q2 can be combined together with the nitrogen atom to which they are linked to form a pyrrolidine ring, a piperidine ring, a hexahydroazepine ring, a morpholine B ring, or a piperazine ring optionally having a C? -C4 alkyl or a benzyl substituent on the other atom of nitrogen, or (b) in the formula (A-2), R7 is a hydrogen atom; a C? ~ C alkyl group; a C? -C4 alkyl group; which is substituted by a C 1 -C 4 alkoxy or C 1 -C 4 alkoxycarbonyl group; a C 1 -C 4 alkoxy group; a C 1 -C 4 alkoxycarbonyl group; or a • phenyl group which is optionally substituted by 1 to 3 groups selected from the group consisting of a halogen atom, a C?-C4 alkyl group, a C?-C4 alkoxy group, and an amino group, or (c) in the formula (A-3), R8 is a hydrogen atom or a C? -C4 alkyl group, R9 is a C? -C4 alkyl group or a ^ fc C 1 -C 4 alkoxy group, and p is 0, 1 or 2, and R 1, R 2, R 3, R 4, R 5 and R 6 in the Ar are the same as those defined for the above-mentioned preferred compounds, and a salt of pharmaceutically acceptable acid addition thereof.

Further preferred compounds are the compounds of the following formula (1-1) or the formula (1-1 '), and a pharmaceutically acceptable acid addition salt thereof. wherein R1 is a halogen atom, R41 is a methyl group, an ethyl group a propyl group, or an isopropyl group, A1 is a group of the following formula (A1-!), (Ax-2) or (A1-) ^): -ZN (QU) (Q21) (A'-l) (where Z is -CO-, -CS- or S02-, Qu and Q21 are the same or different and each a methyl group, a group ethyl, a propyl group, or an isopropyl group, or Q11 is a hydrogen atom, and Q21 is a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, or a substituted or unsubstituted phenyl group (said substituents may be a halogen, a C? -C alkyl group, or a C1-C4 alkoxy group), or Q11 and Q21 may be combined together with the nitrogen atom to which they are linked to form a pyrrolidine ring or a morpholine ring); f -CO-R71 (Ax-2) (wherein R71 is a hydrogen atom, a group Methyl, an ethyl group, a propyl group, a methoxy group, an ethoxy group, a C 1 -C 4 alkyl group which is substituted by a methoxy, ethoxy, methoxycarbonyl, or ethoxycarbonyl group, or an unsubstituted or substituted phenyl group ( said substituent fc may be from 1 to 3 groups selected from a halogen atom, a C? -C4 alkyl group, an alkoxy group C? ~ C4, and an amino group); - (CH2) p'-CH (R81) -COR91 (Ax-3) (where p 'is 0, lo 2, R81 is a hydrogen atom, a methyl group, or an ethyl group, R91 is a methyl group , An ethyl group, a methoxy group, or an ethoxy group).

Especially preferred compounds are compounds of the following formula (1-2), or a pharmaceutically acceptable acid addition salt thereof. wherein R11 is a chlorine atom or a bromine atom, R41 is a methyl group, an ethyl group, a propyl group, or an isopropyl group, R82 is a hydrogen atom, a methyl group, or an ethyl group, R92 is a methyl group, an ethyl group, or an ethoxy group, and p "is 0, it 2, the compounds • of the following formula (1-3), or a pharmaceutically acceptable acid addition salt thereof, Wherein R11 is a chlorine atom or a bromine atom, Z2 is -CO- or -CS-, Q12 is a hydrogen atom, a methyl group, an ethyl group, Q22 is a methyl group, an ethyl group, or a phenyl group, or Q12 and Q22 can be combined together with the nitrogen atom to which they are bound for Forming a pyrrolidine ring, or the compounds of the following formula (1-4), or a pharmaceutically acceptable acid addition salt thereof, wherein R11 is a chlorine atom or a bromine atom, R42 is a methyl group , an ethyl group, or an isopropyl group, Z2 is -CO- or -CS-, Q12 is a hydrogen atom, a methyl group, or an ethyl group, Q22 is a methyl group, an ethyl group, or a group phenyl, or Q12 and Q22 can be combined together with the nitrogen atom to which they are • they bind to form a pyrrolidine ring.

A preferred example of the compound of formula (1-2) is the following compound, and a pharmaceutically acceptable acid addition salt thereof. 4-amino-5-chloro-2-methoxy-N- [1- [1- (2-butanon-3-yl) -4- • 15 piperidinyl) methyl] -4-piperidinyl] benzamide (Compound of Example 84) Preferred examples of the compound of formula (1-3) are the following compounds, and a pharmaceutically acceptable acid addition salt thereof. 4-amino-5-chloro-N- [1- (1-dimethylcarbamoyl-4-piperidinyl-methyl) -4-piperidinyl-2, 3-dihydrobenzo [b] furan-7-carboxamide (Compound of Example 18); 4-amino-5-chloro-N- [1- (1-diethylcarbamoyl-4-piperidinyl-5-methyl) -4-piperidinyl] -2,3-dihydrobenzo [b] furan-7-carboxamide (Compound of Example 19); 4-amino-5-chloro-N- [1- (1-dimethylthiocarbamoyl-4-piperidinyl-methyl) -4-piperidinyl] -2,3-dihydrobenzo [b] furan-7-carboxamide (Compound of Example 20); 10 4-amino-5-chloro-N- [1- [1- (1-pyrrolidinocarbonyl) -4-piperidinyl-methyl) -4-piperidinyl] -2,3-dihydrobenzo [b] furan-7-carboxamide (Compound of Example 21); and 4-amino-5-chloro-N- [1- (1-phenylcarbamoyl-4-piperidinylmethyl) -4-piperidinyl] -2,3-dihydrobenzo [b] furan-7- 15 carboxamide (Compound of Example 52 ). Preferred examples of the compound of the formula (1-4) are the following compounds, and a pharmaceutically acceptable acid addition salt thereof. 4-amino-5-chloro-N- [1- (1-dimethylcarbamoyl-4-piperidinyl-methyl) -4-piperidinyl] -methoxybenzamide (Compound of Example 1); 4-amino-5-chloro-N- [1- [1- (N-ethyl-N-methylcarbomoyl) -4- piperidinyl-methyl) -4-piperidinyl] -methoxybenzamide fl) (Compound of Example 4); 4-amino-5-chloro-2-methoxy-N- [1- [1- (N-methyl-N-phenyl-5 carbamoyl) -4-piperidinyl-methyl) -4-piperidinyl] benzamide (Compound of Example 8 ); 4-amino-5-chloro-N- [1- (1-dimethylthiocarbamoyl-4-piperidinyl-methyl) -4-piperidinyl] -2-methoxybenzamide (Compound of Example 10); 10 4-amino-5-chloro-2-methoxy-N- [1- [1- (1-pyrrolidinecarbonyl) -4-piperidinyl-methyl) -4-piperidinyl] benzamide (Compound of Example 12); 4-amino-5-chloro-N- [1- (1-dimethylcarbamoyl-4-piperidinyl-methyl) -4-piperidinyl] -2-ethoxybenzamide 15 (Compound of Example 25); 4-amino-5-bromo-N- [1- (1-dimethylcarbamoyl-4-piperidinyl-methyl) -4-piperidinyl] -2-methoxybenzamide (Compound of Example 26); 4-amino-5-chloro-N- [1- (1-diethylcarbamoyl-4-piperidinyl-20-methyl) -4-piperidinyl] -2-ethoxybenzamide (Compound of Example 27); 4-amino-5-chloro-N- [1- (1-dimethylcarbamoyl-4-piperidinyl-methyl) -4-piperidinyl] -2-isopropoxybenzamide (Compound of Example 30); 4-amino-5-bromo-2-methoxy-N- [1- [1- (1-pyrrolidinocarbonyl) -4-piperidinyl-methyl] -4-piperidinyl] benzamide (Compound of Example 34); and 4-amino-5-chloro-2-methoxy-N- [1- (1-phenylcarbamoyl-4-piperidinyl-methyl) -4-piperidinyl] benzamide (Compound of fc Example 37). Both R41 and R42 in the above formulas (1-2) and (1-4) are the most preferred methyl groups. The preferred intermediate (II) and the preferred intermediate (VIII) are those corresponding to the preferred compounds of the desired final compounds (I). This Thus, the examples of the intermediary (II) especially preferable are the following compounds and an acid addition salt thereof. 4-amino-5-chloro-2-methoxy-N- [1- (4-piperidinyl) methyl) -4-piperidinyl] benzamide; 20 4-amino-5-bromo-2-methoxy-N- [1- (4-piperidinylmethyl) -4-piperidinyl] benzamide; 4-amino-5-chloro-2-ethoxy-N- [1- (4-piperidinylmethyl) -4-piperidinyl] benzamide; and ^ 4-amino-5-chloro-N- [1- (4-piperidinylmethyl) -4-piperidinyl] -2,3-dihydrobenzo [b] furan-7-carboxamide. In addition, the examples of the especially preferred intermediates (VIII) are the following compounds, and an acid addition salt thereof. 4-amino-1- (1-dimethylcarbamoyl-4-piperidinylmethyl) -3-piperidine; 4-amino-1- (1-dimethylthiocarbamoyl-4-piperidinylmethyl) -piperidine; and 4-amino-1- [1- (1-pyrrolidinecarbonyl) -4-piperidinylmethyl) -piperidine. The examples of the intermediate (VIII) which are included within the present invention are, in addition to the above-mentioned preferred compounds, the following compounds and an acid addition salt thereof, as well as the compounds described in the Examples above. ahead. 20 4-amino-1- (1-diethylcarbamoyl-4-piperidinylmethyl) piperidine; and 4-amino-1- (1-phenylcarbamoyl-4-piperidinylmethyl) piperidine.

• THE BEST MODE FOR CARRYING OUT INVENTION 5 The compounds of the present invention can be prepared, for example, by the following processes.

Process (a) The compound of the formula (I) wherein A is a group • 10 of the formula (A-1) can be prepared by reacting a compound of the formula (II): wherein Ar is as defined above with a compound of formula (III): wherein X is a halogen atom, Z, Q1 and Q2 are the same as defined above.

The halogen atom represented by X is a chlorine atom, a bromine atom or an iodine atom, but one more preferable is a chlorine atom.

The reaction of the compound (II) with the compound (III) is carried out in a solvent or without a solvent. The solvent should be selected according to the types of the starting compounds, etc., and include, for example, aromatic hydrocarbons (eg, benzene, toluene, xylene), ethers (eg, diethyl ether, tetrahydrofuran, dioxane), halogenated hydrocarbons (for example, methylene chloride, chloroform), ketones (for example, acetone, methyl ethyl ketone), ethyl acetate, acetonitrile, dimethylformamide and dimethyl sulfoxide. These solvents can be used alone or in the form of a mixture of two or more solvents.

The reaction can optionally be carried out in the presence of a base, if necessary. The base includes, for example, an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide), an alkali metal carbonate (e.g., sodium carbonate, potassium carbonate), an alkali metal acid carbonate (e.g. example, sodium acid carbonate, potassium hydrogen carbonate), and organic bases (e.g., triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine), but an excess amount of compound (II) can be used in place of a base. The reaction temperature • varies according to the types of starting compounds to be used, but is usually in the range of about 5 -20 ° C to about 150 ° C, preferably in the range of about -10 ° C to about of 80 ° C. The processes for preparing the intermediary of formula (II) are explained below. The compound of formula (II) can be prepared by processes as shown in the following Diagram 1 and Diagram 2. fifteen • Scheme 1 Ar-COOH Stage 5 Check out! Step 6 (") Where L1, L2 and L3 are protecting groups, but L1 and L2, and L1 and L3 are each a protective group to be removed under different conditions, M is an alcoholic reactive ester residue, and Ar is the same as defined above.

Scheme 2 • Stage 1 (G) (H) Deprotection Stage 5 (ii) Where Ar, L2, L3 and M are the same as defined above.

REMOVAL OF PROTECTIVE GROUPS: In Scheme 1 and Scheme 2, the protecting groups represented by L2 and L3 can be any protecting group that is capable of being easily removed by hydrolysis or hydrogenolysis. The protecting group which is capable of being removed by hydrolysis include, for example, the ethoxycarbonyl group, the t-butoxycarbonyl group, the acetyl group, the bezoyl group, the trifluoroacetyl group, the benzyloxycarbonyl group, the 3-o group. 4- chlorobenzyloxycarbonyl, the triphenylmethyl group, the methanesulfonyl group, the p-toluenesulfonyl group, etc. and the protecting group which may be capable of being removed by attholysis include, for example, the benzyloxycarbonyl group, the 3- or 4- group chlorobenzyloxycarbonyl, the benzylsulfonyl group, and the like. The removal of protective groups by hydrolysis is carried out by a conventional method, for example, by contacting it with water under acidic or basic conditions in a suitable solvent. The solvent includes, for example, alcohols (for example, methanol, ethanol, isopropanol), acetone, dioxane, water and a mixture of these solvents. The acids include, for example, inorganic acids (for example, hydrochloric acid, hydrobromic acid, iohydric acid, sulfuric acid) and organic acids (for example formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid). The bases include, for example, an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide), and an alkali metal carbonate (e.g., sodium carbonate, potassium carbonate). The reaction is usually carried out at a temperature of about 0 ° C to 150 ° C. The removal of the protecting groups by hydrogenolysis is carried out by a conventional method, for example, by reacting in the presence of a catalyst (for example, palladium on carbon, Raney-nickel, etc.), and hydrogen gas or a donor of hydrogen (for example the ammonium formate, cyclohexane, etc.) in a suitable solvent. The solvent includes for example alcohols (eg, ethanol, methanol), water, acetic acid, dioxane, tetrahydrofuran, ethyl acetate, and dimethylformamide. The reaction is usually carried out at a temperature of about 0 ° C to about 80 ° C, under atmospheric pressure or under pressure. On the other hand, the protective group represented by L1 may be the same as those exemplified as the protecting groups for L2 and L3, but L1 and L2 may be removed under different conditions, and L1 and L3 may be removed. under different conditions. 10 REDUCTION: The reduction reactions of Stage 3 in the Scheme 1, and from Step 4 of Scheme 2 are carried out by using an appropriate reducing agent. This is the \ It \ him The reducing agent used in the present invention includes ? example, diborane, lithium aluminum hydride, an alkoxy complex thereof, or a salt of a transition metal thereof and a sodium borohydride which is added thereto to aluminum chloride, boron trifluoride, phosphorus oxychloride or carboxylic acid (for example, acetic acid, trifluoroacetic acid). The reduction reaction is carried out in a solvent such as ethers (for example diethyl ether, tetrahydrofuran, dimethoxyethane, dioxane, diglyme), toluene, chloroform, and • Methylene chloride, which must be selected according to the types of reducing agent to be used. The reaction temperature may vary according to the types of reducing agents to be used, but is usually in the range of about 0 ° C to about 160 ° C, preferably in the range of about 10 ° C to 80 ° C. C.

RENT REACTION: The alkylation reactions using the compound of formula C2a of step 2b are Scheme 1, and from Step 3b in Scheme 2, they are carried out in a solvent or without a solvent. The solvent must be selected according to The types of the starting compounds to be used include, for example, aromatic hydrocarbons (for example, benzene, toluene, xylene), ethers (eg, diethyl ether, tetrahydrofuran, dioxane), halogenated hydrocarbons ( for example, chloride Methylene, chloroform), alcohols (e.g., ethanol, isopropanol), ketones (e.g., acetone, methyl ethyl ketone), ethyl acetate, acetonitrile, dimethylformamide, dimethylsulfoxide, ethylene glycol, and these solvents can be used alone or in the form of a mixture of two or more 19 solvents. The reaction is carried out in the presence of a base, if necessary. The base includes, for example, an alkali metal hydroxide (eg, sodium hydroxide, potassium hydroxide), < an alkali metal carbonate (e.g., sodium carbonate, potassium carbonate), an alkali metal acid carbonate (e.g. sodium hydrogen carbonate, potassium hydrogen carbonate), and some organic bases (for example, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine), but an excess amount of amine which is a substrate for the alkylation reaction can be used 15 the place of a base. The residue of the alcohol reactive ester represented by M can be a halogen atom (for example, chlorine, bromine, iodine), a lower alkylsulfonyloxy group (for example methanesulfonyloxy), and an arylsulfonyloxy group (for example, benzenesulfonyloxy, p-toluenesulfonyloxy) ), and a halogen atom, especially a chlorine or methanesulfonyloxy and p-toluenesulfonyloxy atom are more preferred. When M is a chlorine atom or a bromine atom, then the reaction may proceed smoothly by the addition of an alkali metal iodide such as sodium iodide, potassium iodide. The reaction temperature varies according to the types of starting compounds to be used, but is usually in the range of about 0 ° C to about 200 ° C, preferably in the range of about 20 ° C to about 150 ° C. In addition, the reductive alkylation reactions using the compound of formula C2b of step 2b in Scheme 1 and Step 3b in Scheme 2 are carried out by the catalytic reduction using platinum dioxide as a catalyst in the presence of a catalytic amount of an acid, or in the presence of a complex borane (eg, pyridine borane, triethyl borane) or sodium cyanoborohydride. The solvent is the same as those defined by the alkylation reaction mentioned above using the compound of the formula C2a. The acid can be p-toluenesulfonic acid, etc. The reaction is usually carried out at a temperature of about 0 ° C to about 100 ° C, preferably at a temperature of about 20 ° C to about 80 ° C.AMIDATION REACTION: The amidation reactions of Step 2a and Step 5 in Scheme 1, and of Step 1 and Step 3a in Scheme 2 are carried out by the method described in Process (d) as describe later. On the other hand, the compound of the formula (III) may be one of those commercially available or it may be prepared by a conventional method.

Process (b) The compound of the formula (I) wherein A is a group of the formula (Al), Q1 is a hydrogen atom, and Z is -CO- or -CS- can be prepared by reacting a compound of Formula (II): (II) Where Ar is the same as defined above, with a compound of the formula (IVa) or (IVb): wherein Q? 23 is of the same substituents as those defined by Q2 above, or a trimethylsilyl group). • The reaction of the compound (II) with the compound (IVa) or (IVb) is carried out in a solvent or without solvent. The solvent can be selected according to the types of the starting compounds to be used, but they can be the same as those defined by the previous Process (a).

When Q23 is a trimethylsilyl group, said group ^ fc trimethylsilyl is made free during the treatment after the reaction, and as a result a compound of the formula (I) is obtained wherein Q1 and Q2 are both hydrogen atoms. The compounds of the formulas (IVa) and (IVb) are commercially available, or can be prepared by a conventional method.

Process (c) The compound of formula (I) wherein A is a group of the formula (A-1), and Z is -CO- is prepared by reacting a compound of the formula (V): Ar-CONH- í-CH2- N-CO-L4 (V) wherein L4 is a residual group, and Ar is the same as defined above, with a compound of the formula (VI): HNIC / MQ2) (VI) wherein Q1 and Q2 are the same as defined above.

The reaction of the compound (V) with the compound (VI) is carried out in a solvent or without a solvent. The solvent must be selected according to the types of the starting compounds to be used, and can be the same solvents as those defined by the aforementioned Process (a). The reaction temperature varies according to the types of the starting compounds to be used, but is usually in the range of about 0 ° C to 250 ° C wax, preferably in the range of about 25 ° C to about of 200 ° C. The compound (V) can be prepared by reacting the compound (II) with NN '-carbonyldiimidazole, phosgene, diphosgene, triphosgene, di- (2-pyridyl) carbonate, NN'-disuccinimidyl carbonate, bis ( 4-nitro-phenyl), bis (trichloromethyl) carbonate, phenoxycarbonyl-tetrazole, phenyl chlorocarbonate, chloromethyl chlorocarbonate, 2,4,5- 10 trichlorophenyl chlorocarbonate, trichloromethyl chlorocarbonate, 1-chloroethyl chlorocarbonate, chlorocarbonate 1,2,2,2-tetrachloroethyl, norborun-5-ene-2, 3-dicarboxyimidyl chlorocarbonate, etc., in the presence of a base. The reaction is carried out in the same solvent under the same reaction conditions as those defined for process (a). The compound of the formula (I) wherein Z is -CO- can also be prepared by reacting a chloromethylcarbamate compound, which is obtained by reacting Chloromethyl chlorocarbonate with the compound of the formula (VI) according to the method described in Synth.

Commun, 1996 26, 4253, with the compound of the formula (II) in the same manner as in the preparation of the compound f (V) as mentioned above. In this reaction, an alcohol such as ethanol can be used as a solvent, and the detailed procedures thereof are explained in Example 37 as described below.

Process (d) The compound of the formula (I) is prepared by reacting a compound of the formula (VII): Ar-COOOH (VII) wherein Ar is the same as defined above or a reactive derivative thereof, with a compound of formula (VIII): where A is the same as defined above. The reactive derivative of the compound (VII) includes, for example, a lower alkyl ester (especially, a Methyl ester), an active ester, an acid anhydride, and an acid halide (especially, an acid chloride). The active ester includes, for example, p-nitrophenyl ester, pentachlorophenyl ester, pentafluroprophenyl ester, N-hydroxysuccimide ester, N-hydroxyphthalimide, 1-hydroxybenzotriazole ester, 8-hydroxy quinoline ester, and 2-hydroxyphenyl ester. The acid anhydride includes, for example, a symmetrical acid anhydride and a mixture of acid anhydride. The mixed acid anhydride includes for example, an acid anhydride mixed with an alkyl chlorocarbonate such as an ethyl chlorocarbonate and an isobutyl chlorocarbonate, an acid anhydride mixed with an aralkyl chlorocarbonate such as benzyl chlorocarbonate, an anhydride acid mixed with an aryl chlorocarbonate such as phenyl chlorocarbonate, and an acid anhydride mixed with an alkanoic acid such as isovaleric acid and pivalic acid. When the compound (VII) itself is used, the reaction can be carried out in the presence of a condensing agent such as 1,3-dicyclohexylcarbodiimide, the hydrochloride of l-ethyl-3- (3- dimethylaminopropyl) carbodiimide, NN 'carbonyldiimidazole, benzotriazol-1-yloxy-tris- (dimethylamino) phosphonium hexafluorophosphate, NN' -carbonyl-disuccinimide, 1-ethoxycarbonyl-2-ethoxy-l, 2-dihydroquinoline, diphenylphosphoryl azide, and propanophosphonic anhydride. When 1, 3-dicyclohexylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride is used as a condensing agent, N-hydroxy-succinimide, 1-hydroxybenzotriazole, 3-hydroxy-1 , 2, 3-benzotriazin-4 (3H) -one, or N-hydroxy-5-norbonen-2,3-dicarboxyimide can be added into the reaction system. The reaction of the compound (VII) or a reactive derivative thereof with the compound (VIII) is carried out in a solvent or without a solvent. The solvent varies according to the types of the starting compounds, etc., and includes, for example, aromatic hydrocarbons (for example, benzene, toluene, xylene), ethers (for example, diethyl ether, tetrahydrofuran, dioxane), hydrocarbons halogenated (for example methylene chloride, chloroform), ketones (for example, acetone, methyl ethyl ketone), ethyl acetate, acetonitrile, dimethylformamide, dimethisulfoxide, and these solvents can be used alone, or in the form of a mixture of two or more solvents.

The reaction may optionally be carried out in the presence of a base, if necessary. The base includes, • for example, an alkali metal hydroxide (for example sodium hydroxide, potassium hydroxide), an alkali metal carbonate (for example sodium carbonate, potassium carbonate), an acidic carbonate of an alkali metal (for example, sodium acid carbonate, potassium hydrogen carbonate) and organic bases (for example triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine), but an excess amount of the compound (VIII) can be used in place of a base. The reaction temperature varies according to the types of the starting components, but is usually in the range of about -30 ° C to about 200 ° C, preferably in the range of about -10 ° C to about 150 ° C. The compound (VIII) is prepared by the process as shown in Scheme 3 as described below.

Scheme 3 (D) wherein L1, L3 X and A are the same as defined above. Stage 2 in Scheme 3 is carried out in a similar manner as in Process (a), and Stage 1 and Stage 3 in Scheme 3 are carried out in the same way as in the group removal process protector as mentioned above. Process (e) The compound of the formula (I) wherein A is a group of the formula (A-2) is prepared by reacting a compound of the formula (II): wherein Ar is the same as defined above, with a compound of the formula (A-2 '): HO-CO-R72 (A-2') wherein R72 is the same as R7, or a reactive derivative thereof , provides that when (1) R72 is a lower alkyl group substituted by a hydroxy group, then a reactive derivative of the compound (A-2 ') is not used, and when (2) R72 in a lower alkoxy group, then a halide of the acid of the compound (A-2 ') is used. The reaction of the compound (A-2 ') or a reactive derivative thereof with the compound (II) is carried out in a solvent or without a solvent. The reactive derivative of the compound (A-2 ') can be some of the same as those defined for the process (d). In addition, when the compound (A-2 ') itself is used, the reaction can be carried out in the presence of the same condensation agents as mentioned in Process (d). The solvent can be the same solvents as those defined for Process (d). The solvent can be the same solvents as those defined for process (d), but it must be selected according to the types of the starting compounds to be used. The reaction can be carried out in the presence of a base, if necessary. The base may be the same as those defined for Process (d), but an excess amount of compound (II) may be used in place of a base. The reaction temperature varies according to the types of the starting compounds to be used, but is usually in the range of about -30 ° C to about 200 ° C, preferably in the range of about -10 ° C. at about 150 ° C. The compound (A-2 ') may be one of those commercially available, or may be prepared by a conventional method.

Process (f) The compound of the formula (I) wherein A is a group of the formula (A-3) is prepared by reacting a compound of the formula (II): wherein Ar is the same as defined above, with a compound of the formula (A-3 '): M- (CH2) p-CH (R8) -COR9 (A-3') wherein M is a residue of reactive ester as mentioned above. And R8, R9 and p are the same as defined above, or with a compound of the formula (A-3 '): 0 = CH- (CH2) p'-CH (R8) -COR9 (A-3") in where p 'is 1, 2, 3 or 4, and R8 and R9 are the same as defined above The reaction of the compound (II) with the compound (A-3') is carried out in a solvent or without solvent The solvent must be selected according to the types of the starting compounds to be used, and include, for example, aromatic hydrocarbons (for example benzene, toluene, xylene), ethers (for example diethyl ether, tetrahydrofuran, dioxane), halogenated hydrocarbons (e.g., methylene chloride, chloroform), alcohols (e.g., ethanol, isopropanol), ketones (e.g., acetone, methyl ethyl ketone), ethyl acetate, acetonitrile, dimethylformamide, dimethyl sulfoxide, and ethylene glycol, and These solvents can be used alone, or in the form of a mixture of two or more solvents.The reaction is also carried out in the presence of a base, if necessary. The base includes, for example, an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide), an alkali metal carbonate (e.g., sodium carbonate, . { B potassium), an alkali metal acid carbonate (by For example, sodium acid carbonate, potassium hydrogen carbonate) and organic bases (for example, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine), but an excess amount of compound (II) can be used in place of the base. When M is a chlorine atom or In the case of a bromine atom, the reaction can proceed smoothly f) by the addition of an alkali metal iodide such as sodium iodide, or potassium iodide. The reaction temperature varies according to the types of the starting compounds to be used, but is usually in the range of about 0 ° C to about 200 ° C, preferably in the range of about -80 ° C to about 150 ° C.

The reaction of the compound (II) with the compound (A-3 ') is carried out in a solvent or without a solvent. The solvent must be selected according to the types of the starting compounds to be used, and may be the same as those mentioned above. The reaction is carried out in the presence of a complex borane (eg, pyridine borane, triethylamine borane), or a sodium cyanoborohydride, or a catalyst such as a platinum oxide under a hydrogen atmosphere, if necessary , in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, etc. The reaction temperature varies according to the types of the starting compounds to be used, but is usually in the range of about 0 ° C to about 100 ° C, preferably in the range of about 20 ° C to about of 180 ° C. On the other hand, an iminium salt compound, which is produced during the reaction of the compound (II) with the compound (A-3 '), can be collected, and can be reduced by a previously known method.

The compound (A-3 ') and the compound (A-3") may be one of those commercially available, or may be • pred by a conventional method. In addition, the compounds of the present invention can be pred by the following processes as well. The compounds of the formula (I) wherein A is a formyl group is pred by a conventional formilization of the compound (II), and the detailed B procedures thereof are explained in Example 79 as described later. The desired compounds obtained in the above Processes can be isolated and purified by a conventional method such as chromatography, recrystallization, ecipitation, etc. The compound (I) can be obtained either in the form of a free base or in the form of an acid addition salt thereof, according to the types of starting compounds and the reaction conditions. The acid addition salt can be converted to a free base by a conventional method, for example, by treatment with a base such as an alkali metal carbonate, an alkali metal hydroxide. Otherwise, the compound (I) in the form of a free base can be converted to an acid addition salt by the treatment with various acids in a conventional manner. The pharmacological activities of the present compounds explained by the following pharmacological experiments in the esentative compounds of the present invention.

Experiment 1: Receptor (5-HT4) serotonin binding assay 4. The binding assays of the 5-HT4 receptor and the pration of receptor membrane fractions are therefore carried out according to a modified method of the invention. Grossman et al. British J. Pharmacol., 1993, 109, 618-624. Std Hartley guinea pigs weighing 300 to 400 g are decapitated and their brains are immediately taken and the striatum is dissected. The tissue thus obtained is added a 15-fold volume of Hepes buffer (50 mM, pH 7.4, 4 ° C), homogenized in a Teflon homogenizer, and centrifuged at 48,000 X g at 4 ° C for 15 minutes. The paste is suspended in the same Hepes buffer in a volume of 1 ml per 30 mg of the wet tissue to give the fractions of the membrane of the • receiver. In the test tubes, the Hepes buffer (50 mM, pH 7.4, 4 ° C, 1 ml) containing [3H] -GR113808 0.1 nM (chemical name; [1- [2- (methyl-sulfonylamino) ethyl] -4-piperidinyl] l-methylindolo-3-carboxylate] methyl), and the fraction of the receptor membrane, either the test compound or (30 μM serotonin, incubated at 37 ° C for 30 minutes.

The reaction is terminated by rapid vacuum filtration and washing (3 X 4 ml) with a 50 mM buffer ice-bath tris-HCl (pH 7.7) through the Whatman GF / B filter paper using a Brandel cell harvester. . Before filtering, the filter to be used is tanned in a solution of 0.1% polyethylamine for one hour. The radioactivity in the filter is determined with an ACS-II scintillation cocktail by means of a liquid scintillation counter. The concentration of the test compounds causes a % inhibition of the specific linkage of [3 H] -GR113808 (IC50 value) is determined by an inhibitory proportion of the test compounds against specific ligation which is obtained by subtracting the nonspecific linkage from the total linkage [3H] ] - ^ GR113808. The results are shown in Table 1.

• • TABLE Studies of the linkage of the receptors (5-HT4) serotonin 4 • *: The compound of Example 1 (fumarate) (hereinafter, the numbers of the compounds of 1 approves mean fumarates of the compounds of the corresponding Examples except for the numbers marked by **) **: Free bases of the compound of the Examples corresponding. 10 comp. A: Cisapride Experiment 2: Evacuation test in mice. Male Std-ddY mice weighing 25-30 g are used. With free access to food and water that is allowed 5 at the beginning of the procedure. The mice (each group of five mice) are placed in a box with a mesh bottom to secure, and are left for feeding to a new environment for about one hour before the start of the experiment. A test compound, the • 10 which is previously suspended in a 0.5% tragacanth solution, is orally administered to the mice in a dose of 1 mg / kg. Faecal pellets are counted and collected at 30, 60 and 120 minutes after the treatment of a test compound, and weighed. 15 The statistical criterion of efficacy is carried out between the control group and the treated group, and is determined • by Dunnett's test. -: inactive +: moderately stimulated (P <0.05) 20 ++: markedly stimulated (p <0.01).

Table 2 Evacuation test in mice *: The compound of Example 1 (fumarate) (hereinafter, the numbers of test compounds mean a fumarate of the corresponding Example compound except for the numbers marked with **) **: the free base of the compound of the corresponding Examples.

Experiment 3: Acute toxicity Male Std-ddY mice weighing 25-30 g are used in a group of 5 animals. A test compound is suspended in a physiological saline solution or a 1% lactose solution and administered intravenously to the mice. Then, the lethality of the mice is observed for 7 days after the treatment, and a 50% lethal dose (LD5o) is determined. The LD50 dose of the compounds of the • 10 Examples 1, 10, 12, 18, 20, 21, 25 and 26 were all greater than 100 mg / Kg. As shown in the results of the above pharmacological experiments, the compounds of the present invention and an acceptable pharmaceutically acceptable acid addition salt thereof show a potent affinity to 5-HT4 receptors, therefore, they are useful as agonists of the • 5-HT4 receptor in the prophylaxis or treatment of diseases or disorders, which are caused by the lack of stimulation of 5-HT4 receptors. For example, the compounds of the present invention and a pharmaceutically acceptable acid addition salt thereof can be used in the prophylaxis or treatment of gastrointestinal diseases, such as irritable bowel syndrome, flaccid constipation, habitual constipation, induced constipation. by medication • (eg, constipation induced by morphine, a psychotropic), chronic diarrhea, infantile diarrhea. The compounds of the present invention and a pharmaceutically acceptable addition salt thereof are also useful in the prophylaxis or treatment of gastrointestinal diseases such as chronic or acute gastritis, reflux esophagitis, gastric neurosis, paralytic ileus after surgical intervention, ileus. senile, post-gastroctomy syndrome and intestinal pseudo-obstruction, as well as in the prophylaxis or treatment of anorexia, nausea, vomiting, abdominal abundance, upper abdominal discomfort, visceral pain, heartburn and belching that are accompanied by previous gastrointestinal diseases, gastric or duodenal ulcer, scleroderma, diabetes, bile duct disorder , etc. The compounds of the present invention and a pharmaceutically acceptable acid addition salt thereof are further useful in the prophylaxis or treatment of diseases of the central nervous system such as schizophrenia, depression, memory disturbance, anxiety etc., urinary diseases such co or dysuria accompanied by urinary obstruction or prostatomegaly. Therefore, the compounds of the present invention and a pharmaceutically acceptable acid addition salt thereof can be used in the prophylaxis or treatment of the various aforementioned diseases, especially gastrointestinal diseases, or various gastrointestinal dysfunctions accompanied by the treatment of several diseases mentioned above, and therefore are? ^^ especially useful as a mobility enhancer gastrointestinal or as a gastrointestinal prokinetic agent. The compounds of the present invention can be administered either orally, parenterally or rectally. The dose of the compounds of the present invention varies from according to the types of compounds, the routes of administration, the conditions, age of the patients, • etc., but they are usually in the range of 0.01-30 mg / Kg / day, preferably in the range of 0.05-10 mg / Kg / day. The compounds (I) of the present invention and a salt of The pharmaceutically acceptable acid addition thereof is usually administered in the form of a pharmaceutical preparation, which is prepared by mixing them with a pharmaceutically acceptable carrier or diluent. The pharmaceutically acceptable carrier or diluent can be any conventionally that are usually used in the pharmaceutical field and do not react with the compounds of the present invention. Suitable examples of pharmaceutically acceptable carriers or diluents are, for example, lactose, inositol, glucose, mannitol, dextran, sorbitol, cyclodextrin, starch, partly pregelatinized starch, white sugar, magnesium metasilicate aluminate, synthetic aluminum silicate, cellulose crystalline, sodium carboxymethylcellulose, hydroxypropyl starch, calcium carboxymethylcellulose, ion exchange resin, methylcellulose, gelatin, gum arabic, swarm, hydroxypropylcellulose, substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, alginic acid, sodium alginate, silicic acid light anhydrous, magnesium stearate, talc, tragacanth, bentonite, veegum, carboxyvinyl polymer, titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin, glycerin fatty acid ester, purified lanolin, glycerogelatine, polysorbate, macrogol, vegetable oil, wax, a gua, propylene glycol, ethanol, sodium chloride, sodium hydroxide, hydrochloric acid, citric acid, benzyl alcohol, glutamic acid, glycerin, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, etc. The pharmaceutical preparation is for example, in tablets, capsules, granules, powders, syrups, suspensions, injection preparations, suppositories, nasal drops, sublingual preparations, etc. These preparations can be prepared by a conventional method. In the preparation of liquids, the compound of the present invention can be dissolved or suspended in water or other suitable solvent, when administered. The tablets and granules can be coated by a conventional method. In injectable preparations, it is preferable to dissolve the compound of the present invention in water, but if necessary, it can be dissolved by using an isotonic agent or a solubilizer, and in addition, a pH adjuster, a buffering agent or a preservative can be added to this. These preparations may contain the compound (I) of the present invention or a pharmaceutically acceptable acid addition salt thereof in a proportion of at least 0.01%, preferably in a proportion of 0.1-70%. These preparations may also contain other therapeutically effective compounds.

The present invention is illustrated in more detail by the following Reference Examples and Examples, but not P should be construed as limiting this. The identification of the compounds is carried out 5 by Elemental Analysis, Mass Spectrum, IR Spectrum, NMR Spectrum, etc. The following abbreviations may be used in the following Reference Examples and Examples in addition to ^ k to simplify the description. 10 [Substituents] Me: methyl group Et: ethyl group Pr: propyl group iPr: isopropyl group 15 Bu: butyl group ^ k iBu: isobutyl group tBu: t-butyl group Fe: phenyl group [solvents for recrystallization] 20 CF: chloroform E: Ethanol AE: ethyl acetate HX: n-Hexane M: methanol MEC: methyl ethyl ketone T: Toluene [NMR] s: single d: doublet t: triplet m: multiplet brs; simplete wide J: constant coupling Reference example 1: Preparation of 1- [(1-benzyloxycarbonyl) -4-piperidinylmethyl] -4- (t-butoxycarbonylamino) piperidine: (1) To a solution of 4-amino-1-benzylpiperidine (95 g) in chloroform (600 ml) is added dropwise a solution of di-t-butyl bicarbonate (109 g) in chloroform (600 ml) under cooling with ice. The mixture is stirred at room temperature for 5 hours, and washed twice with water, and washed with a saturated solution of aqueous sodium chloride. The solution is dried with anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. To the residue thus obtained is added petroleum ether, and the insoluble solid is collected by filtration, and dried to give l-benzyl-4- (t-butoxycarbonylamino) piperidine (136 g) as a solid. (2) To a solution of the above product (70 g) and ethanol (600 ml) is added 10% palladium on carbon (5 g), and the mixture is hydrogenated at 40 ° C under atmospheric pressure. Then a theoretical amount of hydrogen is consumed, the catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure to remove the ethanol to give 4- (t-butoxycarbonylamino) piperidine (48.6 g) as a solid. P. f. 155-158 ° C (3) To a solution of l-benzyloxycarbonyl-4-piperidinecarboxylic acid (26 g) in methylene chloride (200 ml) is added thionyl chloride (14.4 ml) dropwise at room temperature. The mixture is heated at reflux for one hour, and the solvent and the excess amount of thionyl chloride are removed under reduced pressure. To the residue is added methylene chloride (400 ml), to which a mixture of the above is added to obtain 4- (t-butoxycarbonylamino) piperidine (20 g) and triethylamine (27 ml) under ice-cooling. The mixture is stirred at room temperature for 4 hours, and washed successively with water, a solution of aqueous citric acid, water, a saturated solution of aqueous sodium hydrogen carbonate and a saturated solution of aqueous sodium chloride, and dried with sulfate. of anhydrous magnesium. The solvent is evaporated under reduced pressure to provide 1- (1-benzyloxycarbonyl-4-piperidinylcarbonyl) -4- (t-butoxycarbonylamino) piperidine (39 g) as a solid. P. f. 150-152 ° C (recrystallized from ethyl acetate). (4) To a suspension of the above product (16.5 g) in tetrahydrofuran (170 ml) is added dropwise to a bora · M tetrahydrofuran complex solution in tetrahydrofuran (100 ml) under ice-cooling, and the mixture is stirred at room temperature for 13 hours. Methanol (100 ml) is added dropwise to the reaction mixture, and the mixture is heated to reflux for one hour. The solvent is evaporated under reduced pressure, and the resulting residue is dissolved in ethyl acetate. The solution is washed successively with water, a solution of aqueous sodium hydroxide, and a saturated solution of aqueous sodium chloride, and dried with anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, and the residue is purified by equilibrium column chromatography with silica gel (eluent, ethyl acetate) to give the desired compound (13 g) as a solid. P. f. 130-132 ° C (recrystallized from ethyl acetate).

Reference Example 2 Preparation of 4-amino-1- (1-benzyloxycarbonyl-4-piperidinylmethyl) -piperidine: To a solution of 1- (1-benzyloxycarbonyl-4-piperidinylmethyl) -4- (t-butoxycarbonylamino) piperidine (7.77 g) in ethanol (30 ml) a 30% solution of hydrochloric acid in ethanol (15 ml) is added under cooling with ice, and the mixture is stirred at room temperature for 5 hours. The solvent is evaporated under reduced pressure, and the residue is dissolved in water. The solution is basified with potassium carbonate and extracted with chloroform. The extract is washed with a saturated solution of aqueous sodium chloride, dried with anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure to provide the desired compound (6.04 g) as an oily product.

Examples for preparing intermediate (II) and intermediate (VIII) are shown in the following Examples A-D.

Example A Preparation of 4-amino-1- (1-dimethylcarbamoyl-4-piperidinylmethyl) -piperidine: (1), To a solution of 1- (1-benzyloxycarbonyl-4-piperidinylmethyl) -4- (t-butoxycarbonylamino) piperidine (5.6 g) in ethanol (100 ml) is added 5% palladium on carbon (0.6 g), and the mixture is hydrogenated at 30 ° C under atmospheric pressure. Then a theoretical amount of hydrogen is consumed, the catalyst is removed by filtration, and the ethanol in the filtrate is evaporated under reduced pressure to give crude 4- (t-butoxycarbonylamino) -1- (4-piperidinylmethyl) piperidine (4.13 g) . (2) The above product and dimethylcarbamoyl chloride are treated in a similar manner as Example 1 as described above to provide 4- (t-butoxycarbonylamino) -1- (1-dimethylcarbamoyl-4-piperidinylmethyl) -piperidine.

Spectrum XH-NMR (CDC13, d ppm): 1.12-2.18 (13H, m), 1.46 [9H, s, (CH3) 3], 2.63-2.82 (4H, m), 2.80 [6H, s, (CH3) 2], 3.42 (HH, m), 3.59-3.70 (2H, m), 4.42 (HH, d, J = 8.2 Hz, NH). 5 (3) The above product is treated in a similar manner as Reference Example 2 to provide the desired compound.

Examples Al and A2 The following compounds are prepared in a similar manner as Example A- (2) and (3) except that the corresponding carbomoyl or thiocarbamoyl chlorides are used in place of the dimethylcarbamoyl chloride in Example A- (2 ). 15 fl (Example Al) 4-amino-1- (1-dimethylthiocarbamoyl-4-piperidinylmethyl) piperidine.

(Example A2) 4-amino-1- (1-pyrrolidinecarbonyl-4-piperidinylmethyl) piperidine.

Example A3 Preparation of 4-amino-1- (1-methylcarbamoyl-4-piperidinylmethyl) -piperidine: (1) To a solution of diphosgene (160 mg) in methylene chloride (20 ml) is added dropwise a solution of pentafluorophenol (290 mg) in methylene chloride (10 ml) under cooling with ice, and the mixture is stirred at room temperature for one hour. A solution of 4- (t-10-butoxycarbonylamino) -1- (4-piperidinyl-methyl) piperidine (480 mg) and triethylamine (160 mg) in methylene chloride (10 mg) are added dropwise to the reaction solution. ml) under cooling with ice, and the mixture is stirred at room temperature for 4 hours. The reaction mixture is washed with water and a saturated solution of sodium chloride Water is added, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by column chromatography with silica gel (eluent: chloroform: methanol = 30: 1) to give 4- (t-butoxycarbonylamino) -1- (1-pentaflurophenoxycarbonyl-4-piperidinyl-methyl) piperidine (740 mg). (2) To a solution of the above product (740 mg) in ethanol (10 ml) is added a 30% solution of methylamine in ethanol (1.51 g), and the mixture is stirred at room temperature for 8 hours, and the solvent It is evaporated under reduced pressure. The residue is dissolved in chloroform, and the solution is washed with water and a saturated solution of aqueous sodium chloride, dried with anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform: methanol = 10: 1) to give 4- (t-butoxycarbonylamino) -1- (1-methylcarbamoyl-4-piperidinylmethyl) piperidine (460 mg). (3) The above product is treated in a similar manner as in Reference Example 2 to provide the desired compound. Example A4 Preparation of 4-amino-1- (1-carbamoyl-4-piperidin methyl) piperidine: (1) To a solution of 4- (t-butoxycarbonylamino) -1- (4-piperidinyl-methyl) piperidine (590 mg) in methylene chloride (30 ml) is added trimethylsilyl isocyanate (220 mg) under cooling with ice, and the mixture is stirred at room temperature for 8 hours. The reaction mixture is washed with water and a saturated solution of aqueous sodium chloride, dried with anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform: methanol = 10: 1) to give 4- (t- • butoxycarbonylamino) -1- (l-carbamoyl-4-piperidinylmethyl) piperidine (540 mg) . (2) The above product is treated in a similar manner as in Reference Example 2 to provide the desired compound.

Example A5 Preparation of 4-amino-1- (1-methoxycarbonyl-4-piperidinylmethyl) -piperidine: The desired compound is obtained in a similar manner as in Example 1 as described below and the Reference example 2 except that the chloroformate of methyl (= methyl chlorocarbonate) is used instead of (f) dimethylcarbamoyl chloride in Example A- (2).

Example A6 Preparation of 4-amino-1- (1-piperidinecarbonyl-4-piperidinylmethyl) -piperidine: (1) Similar procedures as in Example 1 are repeated except that phenyl chloroformate is used in place of dimethylcarbamoyl chloride in Example A- (2) to provide 4- (t-butoxycarbonylamino) -1- (1-phenoxycarbonyl-4-piperidinylmethyl) piperidine. (2) Similar procedures as in Example 55 are repeated except that the above product and the piperidine are used in place of 4-amino-5-chloro-2-methoxy-N- [1- (1-phenoxycarbonyl-4-piperidinylmethyl) -4-piperidinyl] -benzamide and pyrrolidine in Example 55 as described subsequently, respectively, to provide 4- (t-butoxycarbonylamino) -1- (1-piperidinecarbonyl-4- (piperidinylmethyl) piperidine. (3) The above product is treated in a similar manner as in Reference Example 2 to provide the desired compound.

Example A7 fl Preparation of 4-amino-1- [1- (3-methoxypropionyl) -4-piperidinylmethyl) -piperidine: (1) Similar procedures as in Example 60 are repeated except that 4- (t-butoxycarbonylamino) -1- (4- 20 piperidinylmethyl) piperidine, and 3-methoxypropionic acid are used in place of 4-methoxybenzoic acid in Example 60 as described below to provide 4- (t-butoxycarbonylamino) -1- [1- (3-methoxypropionyl) -4-piperidinylmethyl] piperidine. • (2) The above product is treated in a similar manner as in Reference Example 2 to provide the desired compound.

Examples A8-A10 The following compounds are obtained in a similar manner as in Example 1 or 72 as described and Reference Example 2 except that the corresponding starting compounds are used in place of dimethylcarbamoyl chloride in Example A- (2).

(Example A8) 15 4-amino-1- [1- (1-morpholinecarbonyl) -4-fl piperidinylmethyl) piperidine (Example A9) 4-Amino-l- (l-acetyl-4-piperidinylmethyl) piperidine 20 (Example A10) 4-amino-1- (1-dimethylsulphamoi-1-4-piperidinylmethyl) piperidine Example B Preparation of 4-amino- 5-Chloro-2-methoxy-N- [1- (4-piperidinylmethyl) -4-piperidinyl] benzamide: (1) A 1- (1-benzyloxycarbonyl-4-piperidinylmethyl) -4- (t-5-butoxy) carbonylamino) piperidine (12.1 g) a 10% solution of hydrochloric acid in ethanol (60 ml) is added under ice-cooling, and the mixture is stirred at room temperature for one hour, and the solvent is evaporated under reduced pressure. . The residue is added Methylene chloride (100 ml), and then to this are further added successively 4-amino-5-chloro-2-methoxybenzoic acid (5.3 g), l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride ( 5.4 g), and triethylamine (27 ml) under cooling with ice, and the mixture is stirred at room temperature for 3 hours. The reaction mixture is washed successively with water, a saturated solution of aqueous sodium hydrogen carbonate, water, and a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, and the solvent is evaporated under pressure. reduced. The residue is purified by equilibrium column chromatography with silica gel (eluent: chloroform: methanol = 20: 1) to give 4-amino-N- [1- (1-benzyloxycarbonyl-4-piperidinylmethyl) -4-piperidinyl] -5- chloro-2-methoxybenzamide (10.2 g). (2) The above product is dissolved in chloroform (150 ml), and to this are added anisole (19 ml), and acid methanesulfonic acid (11.5 ml), and the mixture is heated under reflux for 3 hours. The reaction mixture is left to cool, and more of the chloroform is removed by decantation. The residue is dissolved in water and washed with chloroform. The ^ k aqueous layer is basified with potassium carbonate and extracted with chloroform. The extract is washed with a saturated solution of aqueous sodium chloride, dried with anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure to provide the desired crude compound, which is further treated with fumaric acid by a The conventional method for providing the difumarate of the desired compound. • P.f. 187-189 ° C (recrystallization from ethanol) Spectrum * H-NMR (CDCL3, d ppm): 1.00-1.17 (2H, m), 1.43-2.20 (12H, m), 2.53-2.67 (2H, m) , 2.68-2.80 (2H, m), 3.02- 20 3.10 (2H, m), 3.88 (3H, s, OCH3), 3.99 (HI, m), 4.39 (2H, s, NH2), 6.29 (HH, s, Ph-H), 7.64 (HH, d, J = 7.7 Hz, CONH), 8.10 (ÍH, s, Ph-H).

Example C Preparation of 4-amino-5-chloro-N- [1- (4-piperidinylmethyl) -4-piperidinyl] -2,3-dihydrobenzo [b] furan-7-carboxamide: 5 (1) 4-acetylamino- Methyl 5-chloro-2,3-dihydrobenzo [b] furan-7-carboxylate (11.3 g), which is prepared by the method described in Synlett, 1993, 269, is suspended in a mixture of methanol: water (1 1) (200 ml), and an aqueous sodium hydroxide solution is added dropwise thereto (23). • 10 ml) under cooling with ice. The mixture is heated under reflux for 3 hours, and concentrated under reduced pressure to remove the methanol. A solution of 2N aqueous hydrochloric acid is added to an aqueous solution of the residue, and the precipitated solid is collected by Filtration, and dried to provide 4-acetylamino-5-chloro-2,3-dihydrobenzo [b] furan-7-carboxylic acid (10.5 g). • (2) To a solution of the above product (4.6 g) in dimethylformamide (60 ml) is added N-N '-carbonyldiimidazole (2.9 g), and the mixture is stirred at room temperature by 30 minutes. To the mixture is further added dropwise a solution of 4-amino-1- (1-benzyloxycarbonyl-4-piperidinylmethyl) piperidine (6.0 g) in dimethylformamide (30 ml), and the mixture is stirred overnight at room temperature . The mixture is concentrated to dryness under reduced pressure, and the residue is dissolved in chloroform, washed successively with water and a saturated solution of aqueous sodium chloride, and dried with anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to provide 4-acetylamino-N- [1- (1-benzyloxycarbonyl-4-piperidinyl-methyl) -4-piperidinyl] -5-chloro-2,3-dihydrobenzo [b] furan-7 -carboxamide crude (11.3 g) as an oily product. (3) To a solution of the above product (11.3 g) in methanol (52 ml) is added dropwise a solution of IN aqueous sodium hydroxide (54 ml) under ice-cooling, and the mixture is heated under reflux by 5 hours. The reaction mixture is concentrated to dryness under reduced pressure, and the residue is dissolved in chloroform, washed successively with water and a saturated solution of aqueous sodium chloride, and dried with anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to provide 4-amino-N- [1- (1-benzyloxycarbonyl-4-piperidinylmethyl) -4-piperidinyl] -5-chloro-2,3-dihydrobenzo [b] furan-7-carboxamide raw (7.59 g) as an oily product. (4) The above product is treated in a similar manner as in Example B- (2) to provide the desired compound. Spectrum 1H-NMR (CDCL3, d ppm): 0.95-1.20 (2H, m), 1.42- 5 2.20 (12H, m), 2.50-2.65 (2H, m), 2.68-2.82 (2H, m), 3.00- 3.12 (4H, m), 3.97 (HH, m), 4.26 (2H, brs, NH2), 4.77 (2H, t, J = 8.1 Hz), 7.25 (HH, d, J = 7.8 Hz CONH), 7.86 ( ÍH, s, Ph-H). ^ fl Example D 10 Preparation of 4-amino-5-chloro-N- [1- (4-piperidinylmethyl) -4-piperidinyl] -2,2-dimethyl-2, 3-dihydrobenzo [b] furan-7-carboxamide : (1) Similar procedures as Example C- (2) are repeated except that 4-amino-5-chloro-2,2-dimethyl-2, 3-dihydrobenzo [b] furan-7-carboxylic acid is used instead of fl-4-acetylamino-5-chloro-2,3-dihydrobenzo [b] -furan-7-carboxylic acid in Example C- (2) to provide 4-amino-5-chloro-N- [1- (L-benzyloxycarbonyl-4-piperidinylmethyl) -4-piperidinyl] -2,2-dimethyl-2,3-dihydrobenzo [b] furan-7-carboxamide. (2) The above product is treated in a similar manner as in Example B- (2) to provide the desired compound.

Example 1 Preparation of 4-amino-5-chloro-N- [1- (1-dimethylcarbamoyl-4-piperidinylmethyl) -4-piperidinyl] -2-methoxybenzamide: To a solution of 4-amino-5-chloro-2- methoxy-N- [1- (4-piperidinylmethyl) -4-piperidinyl] benzamide (610 mg) in methylene chloride (30 ml) is added triethylamine (0.22 ml), and furthermore dimethylcarbamoyl chloride (0.15 ml) is added thereto. ) under cooling with ice. The mixture is stirred at room temperature for 5 hours. The reaction mixture is washed with water and a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by a basic column chromatography with silica gel (eluent, chloroform) to give the desired compound (720 mg) as a white amorphous. P.f. 124-126 ° C (recrystallized from ethyl acetate-toluene). The desired compound obtained above (free base) is dissolved in ethanol, and to this is added fumaric acid, and the precipitated white crystals are collected by filtration, and dried to provide fumarate of the desired compound. P. f. 223-225 ° C (recrystallized from ethanol).

Examples 2-17 Using various carbamoyl chlorides, chlorides of • Thiocarbamoyl or sulfamoyl chlorides in place of dimethylcarbamoyl chloride in Example 1, the following compounds as listed in Table 3 are obtained in a similar manner as in Example 1.

Table 3 Ahem. To Solv. for No. Q P. f (ßC) recrist. 2 -CO-N (Et) to Fumarate 164-166 E 3 -CO-N (iPr) to 1/2 Fumarate 1/2 EtOH 192-194 E 4 -CO-N (e) Et Fumarate 1/4 H20 205 -207 E 5 -CO-N (Me) Pr Fumarate 1/4 ^ 0 191-193 E • 6 -CO-N (Me) iPr Fumarate? / 4 H20 206-208 E 10 7 -CO-N (Me) CH 2 CH (Me) 2 Fumarate 1/4 H20 190-192 E 8 -CO-N (e) Ph Fumarate 171-173 E 9 -CO-N (Ph) 2 Fumarate 1/4 H20 163-165 E 10 -CS-N (e) 2 Fumarate 212-214 E 10a -CS-N (Me) 2 - 136- 138 MEK-T 11 -CS-N (Et) 2 Fumarate 1/2 H ^ O 171-173 E Fumarate 223-225 E 1/4 HjO 156-158 EA-T / - v, • 13 -CO-N O Fumarate 227-229 E 14 -co-r ^ G? S Fumarate, 1/4 HaO, 1/4 EtOH 236-238 E fifteen - . 15 -CO-N N-Me 2 FumaratQ 1/4 H2 ?, 1/4 EtOH 204-206 E 16 -S02N (Me) 2 Fumarate 215-217 EQ 20 17 -co-r Fumarate 225-227 E Examples 18- The following compounds as listed in Table 4 are obtained in a similar manner as in Example 1 except that 4-amino-5-chloro-N- [1- (4-piperidinylmethyl) -4,5-piperidinyl] -2 , 3-dihydrobenzo [b] furan-7-carboxamide and the various corresponding carbamoyl chlorides or thiocarbamoyl chlorides are used in place of 4-amino-5-chloro-2-methoxy-N- [1- (4-piperidinylmethyl ) -4-piperidinyl] benzamide and dimethylcarbamoyl chloride in Example 1, 10 respectively. However, the compounds of Examples 22 to 23 are obtained in a similar manner as in Example C- (2) by using the corresponding starting compounds. fifteen • Table 4 18 -. 18 -C0-N (Me) 2 Fumarate 222-225 E 19 -CO-N (Et) - Fumarate 172-174 E 20 -CS-N (Me) 3 1/2 Fumarate, MeOH 165-168 M 20a -CS -N (Me) 2 _ 179-180 CF-EA • 21 Fumarofco 229-231 M-E 22 -C0-NH2 1/2 Fumarate 205-207 M-E 23 -CO-NH (Me) Furarate, 1/4 H20 212-214 M-E Example 24 5 Preparation of 4-amino-5-chloro-N- [1- (1-dimethylthiocarbamoyl-4-piperidinylmethyl) -4-piperidinyl] -2, 2-dimethyl-2,3-dihydrobenzo [b] -furan- 7-carboxamide. • The desired compound is obtained in a similar manner as in Example 1 except that 4-amino-5-chloro-N- [1- (4- (piperidinylmethyl) -4-piperidinyl] -2,2-dimethyl-2 , 3- dihydrobenzo [b] furan-7-carboxamide and dimethylthiocarbamoyl chloride are used in place of 4-amino-5-chloro-2-methoxy-N- [1- (4-piperidinylmethyl) -4-piperidinyl] benzamide and dimethylcarbamoyl chloride in Example 1, respectively. The desired compound (free base) thus obtained is dissolved in ethanol, and acid is added to this. fumaric, and the precipitated crystals are collected by filtration, and dried to provide the fumarate of the desired compound. P. f. 193-195 ° C (recrystallized from ethanol).

• Example 25 Preparation of 4-amino-5-chloro-N- [1- (1-dimethylcarbamoyl-4-piperinylmethyl) -4-piperidinyl] -2-ethoxybenzamide: Similar procedures of Example C- (2) are repeated except that 4-amino-5-chloro-2-ethoxybenzoic acid and 15-amino-1- (1-dimethyl-carbamoyl-4-piperidinylmethyl) piperidine are used in place of 4-acetyl-amino-5-chloro-2 acid , 3- dihydrobenzo [b] furan-7-carboxylic acid and 4-amino-1- (1-benzyloxycarbonyl-4-piperidinylmethyl) piperidine in Example C- (2), respectively, and the obtained compound is recrystallized from the ethanol to provide 1/2 ethanolate of the desired compound. P. f. 207-209 ° C (recrystallized from ethanol).

The desired compound (free base) thus obtained is dissolved in ethanol, and to this acid is added. (fumárico, and the precipitated crystals are collected by filtration, and dried to provide the fumarate • 1/2 hydrate of the desired compound. P. f. 203-205 ° C (recrystallized from ethanol).

Example 26 Preparation of 4-amino-5-bromo-N- [1- (1-dimethylcarbamoyl-4-piperidinylmethyl) -4-piperidinyl] -2-methoxybenzamide: The desired compound is obtained in a similar manner as in Example C- (2) except that 4-amino-5-bromo-2-methoxybenzoic acid and 4-amino-1- (1-dimethylcarbamoyl-4-piperidinylmethyl) piperidine are used in place of 4-acetylamino-5-acid 2-chloro-2-dihydrobenzo [b] furan-7-carboxylic acid and 4-amino-1- (1-benzyloxycarbonyl-4-piperidinylmethyl) piperidine in Example C- (2), respectively. The desired compound thus obtained is dissolved in ethanol, and to this is added fumaric acid, and the precipitated crystals are collected by filtration, and dried to provide the fumarate of the desired compound as white crystals. P. f. 226-230 ° C (recrystallized from ethanol).

Examples 27-36 Compounds as listed in Table 5 are obtained in a similar manner as in Example C- (2) except that the corresponding starting compounds are used in place of 4-acetylamino-5-chloro-2 acid. , 3-dihydrobenzo [b] furan-7-carboxylic acid and 4-amino-1- (1-benzyloxycarbonyl-4-piperidinylmethyl) piperidine in Example C- (2). Table 5 Example R «QI na Q P.f () Solv- for No, recrist 27 Et Et Et 1 l /, ^ a? ° '1 / 2Ha °' 154-157 E 27a Et Et Et - 164-165 E 28 Pr Me Me Fumarate 178-180 E 29 Pr Et Et FumarateOi EtOH 115-118 E 30 I Pr Me Me 1/2 Fumarate, 1/4 HaO, 202_205 R 31 iPr Et Et Fumarat®, EtOH 114-117 E 32 Et - (CHJ - Fumarate 211-213 E (Example 33) 4-amino-5-chloro-N- [1- (1-dimethylthiocarbamoyl-4 • piperidinylmethyl) -4-piperidinyl] -2-ethoxybenzamide • fumarate • 1/2 hydrate: p. F. 210-212 ° C (recrystallized from 5 ethanol).

(Example 34) 4-amino-5-bromo-2-methoxy-N- [1- [1- (1- (pyrrolidinecarbonyl) -4-piperidinylmethyl] -4- (10) piperidinyl] benzamide • fumarate: p. F. 221-225 ° C (recrystallized from ethanol).

(Example 35) 4-amino-5-bromo-N- [1- (l-carbamoyl-4-piperidinylmethyl) -4- 15 piperidinyl] -2-methoxybenzamide • H fumarate •% ethanolate: • p. f. 228-230 ° C (recrystallized from ethanol).

(Example 36) 4-amino-5-bromo-2-methoxy-N- [1- (1-methylcarbamoyl-4-piperidinyl-methyl) -4-piperidinyl] benzamide • fumarate: m.p. 206-208 ° C (recrystallized from ethanol).

Example 37 Preparation of 4-amino-5-chloro-2-methoxy-N- [1- (1-phenylcarbamoyl-4-piperidinylmethyl) -4-piperidinyl] benzamide: To a solution of chloromethyl-N-phenylcarbamate (220 mg), which is prepared by the method described in Synth. Commun., 1996, 26, 4253, in ethanol (20 ml) a solution of 4-amino-5-chloro-2-methoxy-N- [1- (4-piperidinylmethyl) -4-piperidinyl] is added dropwise. Benzamide (910 mg) in ethanol (10 ml) at room temperature, and the mixture is stirred at room temperature for 7 hours. The mixture is concentrated to dryness under reduced pressure, and the residue is dissolved in chloroform, washed with water and a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure.

The residue is purified by column chromatography with silica gel flk (eluent: chloroform: methanol = 30: 1) to give the desired compound (480 mg) as a white amorphous. The desired compound (free base) (470 mg) of this The obtained form is dissolved in ethanol, and to this is added fumaric acid (110 mg), and the precipitated white crystals are collected by filtration, and dried to provide the fumarate • 1/4 hydrate (530 mg) of the desired compound. P. f. 212-214 ° C (recrystallized from ethanol).

Examples 38-51 Compounds as listed in Table 6 are obtained in a similar manner as in Example 37 except that the corresponding chloromethyl carbamates (N-substituted) are used in place of the N-phenyl carbamate Chloromethyl in Example 37. fifteen • Table 6 • Axis P.f (ßC) Solv. for No. Qa Q recrist. 38 Ph-4-Cl * Fumarate, 1/4 ^ 0 213-215 E 39 Ph-4-OMe Fumarate, 3 / 4HaO 188-190 ME 10 40 Ph-4-Me Fumarate, 1/21 ^ 0 197-199 E 41 Ph-4-COOEt Fumaratot 1/4 ^ 0 214-216 E 42 Pr Fumarate 215-217 E 43 iPr Fumarate 209-211 E 44 Bu Fumarate 211-213 E 45 iBu Fumarate 220-222 E 46 tBu Fumarate 203-205 E 47 CHaPh Fumarate, 1 / 4H20 197-199 E 48 Cyclopropyl Fumarate 213-215 E 49 Cyclopentyl Fumarate 214-216 E 50 Cyclohexyl Fumarate 211-213 E 51 Cycloheptyl Fumarate 193-195 E Ph-4CI means a 4-chlorophenyl group. Example 52 Preparation of 4-amino-5-chloro-N- [1- (1-phenylcarbamoyl-4-piperidinylmethyl) -4-piperidinyl] -2,3-dihydrobenzo [b] furan-7 carboxamide: The fumarate of the desired compound is obtained in a similar manner as in Example 37 except that 4-amino-5-chloro-N- [1- (4-piperidinylmethyl) -4-piperidinyl] -2, 3 - dihydrobenzo [b] furan-7-carboxamide is used in place of 4-amino-5-chloro-2-methoxy-N- [1- (4-piperidinylmethyl) -4- 10 piperidinyl] benzamide in Example 37. P. f. 213-215 ° C (recrystallized from ethanol) Example 53 Preparation of 4-amino-N- [1- (1-carbamoyl-4-piperidinylmethyl) -4-piperidinyl] 5-chloro-2-methoxybenzamide: A solution of 4-amino-5-chloro-2-methoxy-N- [1- (4-piperidinylmethyl) -4-piperidinyl] benzamide (610 mg) in methylene chloride (30 ml) is added trimethylsilyl isocyanate. (180 mg) under cooling with ice, and the The mixture is stirred at room temperature for 15 hours. The reaction mixture is washed with water and a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by basic column chromatography with silica gel (eluent: chloroform: • methanol = 40: 1) to provide 4-amino-5-chloro-N- [1- (1-carbamoyl-4-piperidinylmethyl) -4-piperidinyl] -2- 5-methoxybenzamide (440 mg) as a white amorphous. The desired compound (free base) thus obtained is dissolved in ethanol, and to this is added fumaric acid, and the precipitated white crystals are collected by filtration, and dried to provide the 1/2 fumarate • 1/2 ethanolate of the desired compound. P. f. 222-224 ° C (recrystallized from ethanol).

Example 54 Preparation of 4-amino-5-chloro-N- [1- (1-ethylcarbamoyl-4-piperidinylmethyl) -4-piperidinyl] -2-methoxybenzamide: The fumarate of the desired compound is obtained in a similar manner as in Example 53 except that the ethyl isocyanate is used in place of the trimethylsilyl isocyanate in Example 53. P. P. f. 215-217 ° C (recrystallized from ethanol).

Example 55 Preparation of 4-amino-5-chloro-2-methoxy-N- [1- [1- (1- (pyrrolidinecarbonyl) -4-piperidinylmethyl] -4- piperidinyl] benzamide (the same as the compound of Example 5) ): To 4-amino-5-chloro-2-methoxy-N- [1- (1-phenoxycarbonyl-4-piperidinylmethyl) -4-piperidinyl-J-benzamide (1 g), which is prepared in the same manner as in Example 1 except that flfc the phenyl chloroformate is used in place of the chloride dimethylcarbamoyl, pyrrolidine (3 ml) is added, and the mixture is heated under reflux for 10 hours. The mixture is concentrated to dryness under reduced pressure, and chloroform is added to the residue. The solution is washed with water and a saturated solution of aqueous sodium chloride, dried with Anhydrous magnesium sulfate is added, and the solvent is evaporated under reduced pressure. The residue is purified by column chromatography with silica gel (eluent; chloroform: methanol = 40: 1) to give the desired compound (790 mg) as a white amorphous. The desired compound (free base) thus obtained is dissolved in ethanol, and to this is added fumaric acid, and the precipitated white crystals are collected by filtration, and dried to provide the fumarate of the desired compound as white crystals. P. f. 223-225 ° C (recrystallized from ethanol).

Example 56 Preparation of 4-amino-5-chloro-2-methoxy-N- [1- (1-methylcarbamoyl-4-piperidinylmethyl) -4-piperidinyl] benzamide: A 4-amino-5-chloro-2- methoxy-N- [1- (l-phenoxycarbonyl-4-α-piperidinyl] benzamide (880 mg), which is prepared from a In a similar manner as in Example 1 except that the phenyl chloroformate is used in place of dimethylcarbamoyl chloride, a 30% solution of methylamine in ethanol (20 ml) is added, and the mixture is heated to 110 ° C for 8 hours in an electronic closing tube hermetic. The mixture is concentrated to dryness under pressure The solution is washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. by column chromatography with silica gel (eluent, chloroform: methanol = 20: 1 → 10: 1) to give the desired compound (200 mg) as amorphous.

The desired compound thus obtained is dissolved in ethanol, and to this is added fumaric acid, and the • precipitated crystals are collected by filtration, and dried to provide the fumarate • 1/2 hydrate of the desired compound. P. f. 202 - 204 ° C (recrystallized from ethanol) Example 57 Preparation of 4-amino-5-chloro-2-hydroxy-N- [1- [1- (1- (piperidine-carbonyl) -4-piperidinylmethyl] -4-piperidinyl] benzamide: The fumarate of the desired compound is obtained in a similar manner as in Example 55 except that the piperidine is used in place of pyrrolidine in Example 15 55. (mp 210-212 ° C (recrystallized from ethanol).

Example 58 Preparation of 4-amino-5-chloro-N- [1- (1-dimethylcarbamoyl-4-piperidinylmethyl) -4-piperidinyl] -2-hydroxybenzamide: The fumarate of the desired compound is obtained in a similar manner as in Example C- (2) except that 4-amino-5-chloro-2-hydroxy-benzoic acid and 4-amino-1- (1-dimethylcarbamoyl-4-piperidinylmethyl) -piperidine are used in place of the acid. -acetylamino-5-chloro-2, 3-dihydrobenzo [b] furan-7-carboxylic acid and 4-amino-1- (1-benzyloxycarbonyl-4-piperidinylmethyl) piperidine in Example C- (2), respectively. P. f. 211-213 ° C (recrystallized from ethanol) Example 59 ^ k Preparation of 4-amino-5-chloro-2-hydroxy-N- [1- [1- (1- 10-pyrrolidine-carbonyl) -4-piperidinylmethyl] -4-piperidinyl] benzamide: fumarate • 1 The hydrate of the desired compound is obtained in a similar manner as in Example C- (2) except that 4-amino-5-chloro-2-hydroxybenzoic acid and 4-amino-1- [1- (1 -pyrrolidine-carbonyl) -4- ^ piperidinylmethyl] piperidine are used in place of 4-acetyl-amino-5-chloro-2,3-dihydrobenzo [b] furan-7-carboxylic acid and 4-amino-1- (1-benzyloxycarbonyl-4-piperidinylmethyl) piperidine in Example C- (2), respectively. P. f. 209-211 ° C (recrystallized from ethanol-isopropanol) Example 60 Preparation of 4-amino-5-chloro-2-methoxy-N- [1- [1- (4- ^ p-methoxybenzoyl) -4-piperidinylmethyl] -4-piperidinyl] benzamide: To a solution of 4-amino-5-chloro-2-methoxy-N- [1- (4- (5-piperidinylmethyl) -4-piperidinyl] benzamide (610 mg), 4-methoxybenzoic acid ( 220 mg), and benzotriazole-1-yloxytris (dimethylamino) -phosphonium • hexafluorophosphate (BOB reagent) (710 mg) in methylene chloride (30 ml) was (B adds triethylamine (0.33 ml) at room temperature, and the The mixture is stirred for 5 hours. The reaction mixture is washed with water, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by column chromatography with silica gel (eluent; • chloroform: methanol = 40: 1 - > 20: 1) to provide the desired compound (650 mg) as a yellow amorphous. The desired compound (free base) thus obtained is dissolved in ethanol, and to this is added solution of fumaric acid in ethanol, and the precipitated white crystals are collected by filtration, and dried to provide the fumarate • monohydrate of the desired compound. • P.f. 187-189 ° C (recrystallized from ethanol).

Examples 61-71 Compounds as listed in Table 7 are obtained in a similar manner as in Example 60 except that the various carboxylic acids are used in (J) 4-methoxycarboxylic acid in Example 60. fifteen Table 7 Example R Solv. for Q P.f (ßC): recrist. 61 Ph-4-Me * Fumarate 207-209 E 62 Ph-2-OMe-4-NHa-5-CI 1 / 4H, 0 259-261 ME 63 -CH2OMe Fiunarate 209-211 E 64 - (CH ^ -OMc Smoking ato 184-186 E 65 - { CHJ ^ OH Fumarate 213-215 E 66 - (CH2) 2-OEt Fumarate 194-196 E 67 - (CHa) 3-0Et Fumarate 190-192 E 68 - { CH2) 3-0Pr Fmnarate 182-184 E 69 - (CH ^ -COOMe Fumarate 201-203 E 70 Et Fumarate 230-232 E 71 Pr Fumarate 222-224 E Ph-4-Mc means a methylphenyl group Example 72 Preparation of 4-amino-N- [1- (l-benzoyl-4-piperidinylmethyl) -4-piperidinyl] -5-chloro-2-methoxybenzamide: To a solution of 4-amino-5-chloro-2- Methoxy-N- [1- (4-piperidinylmethyl) -4-piperidinyl] benzamide (610 mg) and triethylamine (0.22 ml) in methylene chloride (30 ml) were added. adds benzoyl chloride (0.19 ml) at room temperature, and the mixture is stirred for 5 hours. The reaction mixture is washed with water, and a saturated solution of sodium chloride • aqueous, dried with anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform: methanol = 20: 1) to give the desired compound (610 mg). P. f. 114-116 ° C (recrystallized from ethanol).

Examples 73-78 Compounds as listed in Table 8 are obtained in a similar manner as in Example 72 except that several acid chlorides or alkyl chloroformates are used in place of benzoyl chloride in the Example 72.

• Table 8 Example p7 n P f? T. Solv. for No. R Q L (C) recrist. 73 Ph-4-Cl Fumarate 1 / 4H20 222-224 E 74 Ph-3,4,5- (OMe) 3 * .1 / 41 ^ 0 198-200 ME 75 Me Fumarate 229-231 E 76 -Im Fumarate i / 2HaO 233-235 E 77 -OEt Fumarate 220-222 ME 78 -COOEt Fumarate 203-205 E *: Ph-3,4,5- (OMe) means a 3,4,5-trimethoxyphenyl group Example 79 Preparation of 4-amino-5-chloro-N- [1- (1-formyl-4-piperidinylmethyl) -4-piperidinyl] -2-methoxybenzamide: To a solution of imidazole (330 mg) in dimethylformamide (0.74 ml) was add trimethylsilyl chloride (0.61 ml) at room temperature, and the mixture is stirred for 20 minutes. To the solution is added 4-amino-5-chloro-2-methoxy-N- [1- (4- (piperidinylmethyl) -4-piperidinyl] -benzamide (610 mg), and the reaction mixture is stirred at room temperature for 24 hours. A small amount of water is added to the reaction mixture, and the mixture is concentrated to dryness under reduced pressure. Water is added to the residue, and the mixture is extracted with chloroform. The organic layer is washed with a saturated solution of aqueous sodium chloride, dried with • Anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by column chromatography with silica gel (eluent: chloroform: methanol = 30: 1 -> 20: 1) to give the desired compound (200 mg) as amorphous. The desired compound (free base) thus obtained is dissolved in ethanol, and to this a solution of fumaric acid in ethanol is added, and the precipitated crystals are collected by filtration, and dried to provide the fumarate of the desired compound as white crystals. P. f. 206-208 ° C (recrystallized from ethanol). Example 80 Preparation of 4-amino-5-chloro-2-methoxy-N- [1- [1- (4-methoxybutyryl) -4-piperidinylmethyl] -4-piperidinyl] benzamide: The desired compound is obtained in a manner Similary as in Example 60 except that 4-methoxybutyric acid, which is prepared by the method described in J. Org. Chem. 1994, 5_9, 2253, is used in place of 4-methoxybenzoic acid in Example 60.

The desired compound (free base) thus obtained is dissolved in ethanol, and to this is added a solution of fumaric acid in ethanol, and the precipitated crystals are collected by filtration, and dried for provide the fumarate of the desired compound. P. f. 200-202 ° C (recrystallized from ethanol).

Example 81 wk Preparation of 4-amino-5-chloro-2-ethoxy-N- [1- [1- (3-methoxypropionyl) -4-piperidinylmethyl] -4-piperidinyl] benzamide: The desired compound is obtained from a similarly as in Example C- (2) except that 4-amino-5-chloro-2-ethoxybenzoic acid and 4-amino-1- [1- (3-methoxypropionyl) -l4-piperidinylmethyl] piperidine are used in place of ffl 4-acetylamino-5-chloro-2,3-dihydrobenzo [b] furan-7-carboxylic acid and 4-amino-l- (l-benzyloxycarbonyl-4-piperidinylmethyl) piperidine in Example C- (2), respectively. The desired compound (free base) in this way The obtained one is dissolved in ethanol, and to this is added a solution of fumaric acid in ethanol, and the precipitated crystals are collected by filtration, and dried to provide the fumarate • 1/2 ethanolate of the desired compound. P. f. 175-177 ° C (recrystallized from ethanol) Example 82 Preparation of 4-amino-5-bromo-2-methoxy-N- [1- [1- (3-methoxy-propionyl) -4-piperidinylmethyl] -4-piperidinyl] benzamide: The desired compound is obtained from a similar manner as in Example 81 except that 4-amino-5-bromo-2-methoxybenzoic acid is used in place of 4-amino-5-chloro-2-ethoxybenzoic acid in Example 81. The desired compound (base free) in this way obtained is dissolved in ethanol, and to this a solution of fumaric acid in ethanol is added, and the precipitated crystals are collected by filtration, and dried to provide the fumarate of the desired compound. P. f. 207-209 ° C (recrystallized from ethanol).

Example 83 Preparation of 4-amino-5-bromo-2-methoxy-N- [1- (1-methoxycarbonyl-4-piperidinylmethyl) -4-piperidinyl] benzamide: The desired compound is obtained in the same manner as in Example C- (2) except that 4-amino-5-bromo-2- • methoxybenzoic acid and 4-amino-1- (1-methoxycarbonyl-4-piperidinylmethyl) ] piperidine are used in place of 4-5-acetylamino-5-chloro-2,3-dihydrobenzo [b] furan-7-carboxylic acid and 4-amino-1- (l-benzyloxycarbonyl-4-piperidinyl-methyl) piperidine in Example C- (2), respectively The desired compound (free base) in this way ^ fl obtained is dissolved in ethanol, and to this is added The solution of fumaric acid in ethanol, and the precipitated crystals are collected by filtration, and dried to provide the fumarate of the desired compound. P. f. 233-235 ° C (recrystallized from ethanol).

Example 84 fl Preparation of 4-amino-N- [1- [1- (2-butanon-3-yl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2-methoxybenzamide: To one solution of 4-amino-5-chloro-2-methoxy-N- [1- (4-piperidinylmethyl) -4-piperidinyl] benzamide (610 mg) in acetinitrile (30 ml) is added potassium carbonate (80 mg) and 3-Chloro-2-butanone (220 mg), and the mixture is heated under reflux for 16 hours, and concentrated to dryness under reduced pressure. The residue is dissolved in chloroform, and the mixture is washed with water and a saturated solution of aqueous sodium chloride, dried with anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by column chromatography with silica gel (eluent: chloroform: methanol = 15: 1) to give the desired compound (640 mg) as a yellow oily product. The desired compound (free base) thus obtained is dissolved in ethanol, and a solution of fumaric acid in methanol is added thereto, and the precipitated crystals are collected by filtration, and dried to give the difumarate • 1/4 hydrate. desired compound as white crystals. P. f. 268-270 ° C (recrystallized from methanol-ethanol).

Examples 85-98 Compounds as listed in Table 9 are obtained in a similar manner as in Example 84 except that various alkyl halide derivatives are used in place of 3-chloro-2-butanone in Example 84.

Table 9 Axis pf co Solv "For No. recrist 85 -CH2COMe 3/2 Fumarate» 3/4 EtOH 202-204 ME 86 -CH2COEt 3/2 Fumarate, 1/4 EtOH 185-187 E 86a -CHjCOEt 5/4 HjO 97- 100 EA-HX 87 -CHjCOCÍMeJj 2 Fumarate 202-204 E 88 - (CH2) 3-COMe 2 Fumarate l / 4H, 0 163-165 E 10 89 - (CH2) 2-COEt 2 Fumarate 195-197 E 90 -CH2COOEt Fumarate 193-195 E 91 - (CH2) 2-COOEt 2 Fumarate 203-205 E 92 - (CH ^ -COOEt 2 Fumarate 177-180 ME 93 - (CH2), - C00Et 2 Fumarate 184-186 E 94 - (CHjJs -COOEt 2 Fumarate, l / 4Hj? 177-179 E 95 - (CH2) 2-CH (Me) COOMe 2 Fumarate 191-193 15 ME 96 -CH (Me) COOEt 3/2 Fumarate 199-201 E 97 -CH (Et) -COOEt 3/2 Fumarate 1 / 2H20 190-192 E 98 -CH (Bu) COOEt 3/2 Fumarate 200-202 E Example 99 Preparation of 4-amino-N- [1- [1- (2-butanon-l-yl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2,3-dihydrobenzo [b] furan -7-carboxamide: The difumarate • 1/4-hydrate • 1/2 ethanolate of the desired compound is obtained in a similar manner as in Example 84 except that 4-amino-5-chloro-N- [1- (4-piperidinylmethyl) -4-piperidinyl -2, 3-dihydrobenzo [b] furan-7-carboxamide and 1-chloro-butanone are used in place of 4-amino-5-chloro-2-methoxy-N- [1- (4-piperidinylmethyl) - 4-piperidinyl] benzamide and 3-chloro-2-butanone in Example 84, respectively. P. f. 210-213 ° C (recrystallized from ethanol) Example 100 Preparation of 4-amino-5-chloro-N- [1- [1- (3-ethoxycarbonylpropyl) -4-piperidinylmethyl] -4-piperidinyl] -2,3-dihydrobenzo [b] furan-7-carboxamide The difumarate of the desired compound is obtained in a similar manner as in Example 84 except that 4-amino-5-chloro-N- [1- (4-piperidinylmethyl] -4-piperidinyl] -2,3-dihydrobenzo [ b) furan-7-carboxamide and ethyl chlorobutyrate are used in place of 4-amino-5-chloro-2-methoxy-N- [1- (4-piperidinylmethyl) -4-piperidinyl] benzamide and the 3-chloro -2-butanone in Example 84, respectively, P. 188-189 ° C (recrystallized from ethanol).

Examples 101-105 The following compounds are obtained in a similar manner as in Example C- (2) except that the corresponding starting compounds are used in place of 4-acetylamino-5-chloro-2,3-dihydrobenzo [b] furan-7-carboxylic acid and 4-amino-1- (1-benzyloxycarbonyl-4-piperidinyl-methyl) piperidine in Example C- (2).

(Example 101) 4-amino-N- [1- (1-dimethylcarbamoyl-4-piperidinylmethyl) -4-piperidinyl] -5-iodo-2-methoxybenzamide • fumarate: p. F. 232-234 ° C (recrystallized from methanol-ethanol) (Example 102) 4-amino-5-iodo-2-methoxy-N- [1- [1- (1-pyrrolidinecarbonyl) -4-piperidinylmethyl] -4-piperidinyl] benzamide • fumarate: p. F. 235-237 ° C (recrystallized from methanol-ethanol).

(Example 103) 4-amino-5-chloro-N- [1- [1- (1-morpholinecarbonyl) -4- • piperidinylmethyl] -4-piperidinyl] -2,3-dihydrobenzo [b] furan-7-carboxamide • fumarate • 1/4 ethanolate: p. F. 230-232 ° C 5 (recrystallized from ethanol).

(Example 104) N- [1- (L-Acetyl-4-piperidinylmethyl) -4-piperidinyl] -4- • amino-5-chloro-2,3-dihydrobenxo [b] furan-7-carboxamide • 10 fumarate: p. F. 235-237 ° C (recrystallized from ethanol).

(Example 105) 4-amino-5-chloro-N- [1- (1-dimethylsulfamoyl-4-piperidinylmethyl) -4-piperidinyl] -2,3-dihydrobenzo [b] furan-7-carboxamide • fumarate: p. F. 236-238 ° C (recrystallized from ethanol) Example 106 Preparation of 4-amino-5-chloro-N- [1- [1- (1-hexahydroazepinecarbonyl) -4-piperidinylmethyl] -4-piperidinyl] -2-methoxybenzamide: The fumarate of the desired compound is obtained in a similar manner as in Example 1 except that the hexahydroazepinecarbonyl chloride, which is prepared by a conventional method, is used in place of the dimethylcarbamoyl chloride in Example 1. P. f. 213-215 ° C (recrystallized from ethanol).

Preparation 1: Preparation of tablets: The above compounds are mixed and kneaded in a conventional manner, and the mixture is granulated. The mixture is further tableted to provide 1,000 tablets (each of 145 mg).

Preparation 2: Preparation of capsules The above components are mixed and kneaded in a conventional manner, and the mixture is granulated, and each 200 mg of the resultant is packaged in a capsule to provide 1,000 capsules.

Preparation 3: Preparation of powder The above components are mixed in a conventional manner to provide a powder preparation.

Preparation 4: Preparation of injection (amount for 1000 ampoules) • 5 The fumarate of 4-amino-5-chloro-N- [1- (1-dimethylcarbamoyl-4-piperidinyl-methyl) -4-piperidinyl] -2-methoxybenzamide and sorbitol are dissolved in a portion of distilled water to- injection, to this is added a remnant portion of distilled water for injection to adjust the total volume of the mixture. The solution obtained in this way is filtered through a membrane filter (0.22 μm), and every 2 ml of the • Filtrate is filled in ampoules, which are also sterilized at 121 ° C for 20 minutes.

INDUSTRIAL APPLICABILITY The compound (I) of the present invention and a pharmaceutically acceptable acid addition salt thereof exhibits a potent affinity for 5-HT4 receptors, and may be useful for the prophylaxis or treatment of various diseases such as gastrointestinal diseases. (for example irritable bowel syndrome, flaccid constipation, habitual constipation, drug-induced constipation (eg, morphine-induced constipation, psychotropic, chronic diarrhea, etc.), central nervous diseases (eg, schizophrenia, depression, impairment of memory, anxiety, etc.), unitary diseases such as dysuria accompanied by a urinary obstruction or prostatomegaly, or several diseases of gastrointestinal function (for example anorexia, nausea, vomiting, abdominal fullness, etc.) accompanied by the treatment of various diseases. this way, they are useful especially as an intensifier of gastrointestinal motility or a gastrointestinal prokinetic agent. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (19)

CLAIMS 1. A compound of formula (I): characterized in that Ar is a group of the following formula 5 (Ar-1) or (Ar-2): (wherein R1 is a halogen atom, R2 is a hydrogen atom or a lower alkyl group, R3 is a hydrogen atom, a lower alkyl group, or a lower alkanoyl group, R4 is a hydrogen atom or a group lower alkyl, R5 and R6 are the same or different and each an atom of • hydrogen or a lower alkyl group, and n is 1, 2 or 3), 15 A is a group having the following formula (Al), (A-2) or (A-3): -Z-NÍQ1) (Q2 ) (Al) (wherein Z is -CO-, -CS- or -S02-, Q1 and Q2 are the same or different and each a hydrogen atom a lower alkyl group, a lower cycloalkyl group, a substituted phenyl group or unsubstituted, a substituted or unsubstituted phenyl lower alkyl group, or Q1 and Q2 may be combined together with the nitrogen atom to which they are linked to form a pyrrolidine ring, a piperidine ring, a hexahydroazepine ring, a morpholine ring, a thiomorpholine ring, or a piperazine ring optionally having a lower alkyl or a benzyl substituent on the other nitrogen atom); -CO-R7 (A-2) (wherein R7 is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower alkyl group which is substituted by a hydroxy, lower alkoxy or a group lower alkoxycarbonyl, or a substituted or unsubstituted phenyl group); - (CH2) p-CH (R8) -COR9 (A-3) (wherein p is 0, 1, 2, 3, 4 or 5, R8 is a hydrogen atom or a lower alkyl group,
1. R9 is a lower alkyl group or a lower alkoxy group) or a pharmaceutically acceptable acid addition salt thereof. • The compound according to claim 1, characterized in that in the formula (Ar-1), both R 2 and R 3 are hydrogen atoms, and R 4 is a methyl group, an ethyl group, a propyl group or a group isopropyl, or in the formula (Ar-2), both R2 and R3 are hydrogen atoms, and R5 and R6 are both? k hydrogen atoms, or one of these is a methyl group, and the
2. The other is a hydrogen atom, and n is 1, or a pharmaceutically acceptable acid addition salt thereof.
3. 3. A compound of the formula (1-1): Wherein R1 is a halogen atom, R41 is a methyl group, an ethyl group a propyl group, or an isopropyl group, A1 is a group of the following formula (A1-!), (A1-2) or (Ax -3): -ZN (Qn) (Q21) (A'-l) 20 (where Z is -CO-, -CS- or S02-, Qn and Q21 are the same or different and each a methyl group, an ethyl group, a propyl group, or an isopropyl group, or Q11 is a hydrogen atom, and Q21 is a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, or a substituted or unsubstituted phenyl group (said substituents may be a halogen atom, a C? -C4 alkyl group, or a C? -C4 alkoxy group, or Q11 and Q21 can be combined together with the nitrogen atom to which they are linked to form a pyrrolidine ring or a morpholine ring); -CO-R71 (Ax-2) (wherein R71 is a hydrogen atom, a methyl group, an ethyl group, a propyl group, a methoxy group, an ethoxy group, a C? -C4 alkyl group which is substituted by a methoxy, ethoxy, methoxycarbonyl group, or ethoxycarbonyl, or an unsubstituted or substituted phenyl group (said substituent may be from 1 to 3 groups selected from a halogen atom, a C 1 -C alkyl group, a C 1 -C 4 alkoxy group, and an amino group); (CH2) p'-CH (R81) -COR91 (Ax-3) (wherein p 'is 0, lo 2, R81 is a hydrogen atom, a methyl group, or an ethyl group, R91 is a methyl group, an ethyl group, a methoxy group, or an ethoxy group), or a pharmaceutically acceptable acid addition salt thereof.
4. 4. A compound of [1-1]: characterized in that R1 is a halogen atom, R41 is a methyl group, an ethyl group a propyl group, or an isopropyl group, A1 is a group of the following formula (A1-!), (A1-2) or (Ax-) 3): -ZN (QU) (Q21) (A ^ l) (where Z is -CO-, -CS- or S02-, Q11 and Q21 are the same or different and each a methyl group, an ethyl group, a propyl group, or an isopropyl group, or Q11 is a hydrogen atom, and Q21 is a cyclopentyl group , a cyclohexyl group, a cycloheptyl group, or a substituted or unsubstituted phenyl group (said substituents may be a halogen atom, a C? -C4 alkyl group, or a C? -C4 alkoxy group), or Q11 and Q21 may combine together with the nitrogen atom to which they bind to form a pyrrolidine ring or a morpholine ring); -CO-R71 (A1-2) ^ P (wherein R71 is a hydrogen atom, a methyl group, an ethyl group, a propyl group, a methoxy group, a 5-ethoxy group, a C? -C4 alkyl group which is substituted by a methoxy, ethoxy group, methoxycarbonyl, or ethoxycarbonyl, or an unsubstituted or substituted phenyl group (said substituent may be from 1 to 3 groups selected from a halogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, and a 10 amino): - (CH2) p'-CH (R81) -COR91 (Ax-3) (where p 'is 0, lo 2, R81 is a hydrogen atom, a methyl group, or an ethyl group, R91 is a methyl group, an ethyl group, a methoxy group, or an ethoxy group), or a pharmaceutically acceptable acid addition salt thereof.
5. 5. a compound of the formula (1-2) characterized in that R11 is a chlorine atom or an atom Bromine, R41 is a methyl group, an ethyl group, a propyl group, or an isopropyl group, R82 is a hydrogen atom, a methyl group, or an ethyl group, R92 is a methyl group, an ethyl group, or an ethoxy group, and p "is 0, which is 2, or a pharmaceutically acceptable acid addition salt thereof.
6. 6. A compound of the formula (1-3): characterized in that R11 is a chlorine atom or a bromine atom, Z2 is -CO- or -CS-, Q12 is a hydrogen atom, a methyl group, an ethyl group, Q22 is a methyl group, an ethyl group, or a phenyl group, or Q12 and Q22 may be combined together with the nitrogen atom to which they are linked to form a pyrrolidine ring, or a pharmaceutically acceptable acid addition salt thereof.
7. 7. A compound of the formula (1-4): characterized in that R11 is a chlorine atom or a bromine atom, R42 is a methyl group, an ethyl group, or an isopropyl group, Z2 is -CO- or -CS-, Q12 is a hydrogen atom, a methyl group, or an ethyl group, Q22 is a methyl group, an ethyl group, or a phenyl group, or Q12 and Q22 may be combined together with the nitrogen atom to which they are linked to form a pyrrolidine ring, an acceptable acid addition salt pharmaceutically of the same.
8. 8. A compound that is selected from the following compounds: 4-amino-5-chloro-N- [1- (1-dimethylcarbamoyl-4-piperidinylmethyl) -4-piperidinyl] -2,3-dihydrobenzo [b ] furan-7- 15 carboxamide; 4-amino-5-chloro-N- [1- (1-diethylcarbamoyl-4-piperidinyl-methyl) -4-piperidinyl] -2,3-dihydrobenzo [b] furan-7-carboxamide; 4-amino-5-chloro-N- [1- (1-dimethylthiocarbamoyl-4-piperidinyl-methyl) -4-piperidinyl] -2,3-dihydrobenzo [b] furan-7-carboxamide; 4-amino-5-chloro-N- [1- [1- (l-pyrrolidinecarbonyl-4-piperidinyl-methyl) -4-piperidinyl] -2,3-dihydrobenzo [b] furan-> 7-carboxamide; and 4-amino-5-chloro-N- [1- (1-phenylcarbamoyl-4-piperidinyl-5-methyl) -4-piperidinyl] -2,3-dihydrobenzo [b] furan-7-carboxamide, or a salt of pharmaceutically acceptable acid addition thereof. ^ k
9. 9. A compound that is selected from the following Compounds: 4-amino-5-chloro-N- [1- (1-dimethylcarbamoyl-4-piperidinylmethyl) -4-piperidinyl] -methoxybenzamide; 4-amino-5-chloro-N- [1- [1- (N-ethyl-N-methylcarbomoyl) -4- piperidinyl-methyl) -4-piperidinyl] -methoxybenzamide; 15 4-amino-5-chloro-2-methoxy-N- [1- [1- (N-methyl-N-phenyl- < 4fc carbamoyl) -4-piperidinyl-methyl) -4-piperidinyl] benzamide; 4-amino-5-chloro-N- [1- (1-dimethylthiocarbamoyl-4-piperidinyl-methyl) -4-piperidinyl] -2-methoxybenzamide; 4-amino-5-chloro-2-methoxy-N- [1- [1- (1-pyrrolidinecarbonyl) -4-piperidinyl-methyl) -4-piperidinyl] benzamide; 4-amino-5-chloro-N- [1- (1-dimethylcarbamoyl-4-piperidinylmethyl) -4-piperidinyl] -2-ethoxybenzamide; 4-amino-5-bromo-N- [1- (1-dimethylcarbamoyl-4-piperidinylmethyl) -4-piperidinyl] -2-methoxybenzamide; • 4-amino-5-chloro-N- [1- (1-diethylcarbamoyl-4-piperidinylmethyl) -4-piperidinyl] -2-ethoxybenzamide; 5-amino-5-chloro-N- [1- (1-dimethylcarbamoyl-4-piperidinyl-methyl) -4-piperidinyl] -2-isopropoxybenzamide; 4-amino-5-bromo-2-methoxy-N- [1- (1-pyrrolidinocarbonyl) -4-piperidinyl-methyl] -4-piperidinyl] benzamide; ^ k 4-amino-5-chloro-2-methoxy-N- [1- (1-phenylcarbamoyl-4-piperidinyl-methyl) -4-piperidinyl] benzamide; and 4-amino-5-chloro-2-methoxy-N- [1- (2-butanon-3-yl) -4-piperidinyl-methyl) -4-piperidinyl] benzamide, or a pharmaceutically acceptable acid addition salt of the same. 15 ^ k
10. 10. A pharmaceutical composition, characterized in that it contains as an active ingredient the compound as claimed in any of claims 1-9, or a pharmaceutically acceptable acid addition salt thereof.
11. 11. A process for the preparation of a compound of formula (I): characterized in that Ar is a group of the following formula (Ar-1) or (Ar-2): (wherein R1 is a halogen atom, R2 is a hydrogen atom or a lower alkyl group, R3 is a hydrogen atom, a lower alkyl group, or a lower alkanoyl group, R4 is a hydrogen atom or a lower alkyl group, R5 and R6 are the same or different and each a hydrogen atom or a lower alkyl group , and n is 1, 2 or 3), A is a group having the following formula (Al), (A-2) or (A-3): -ZN (QX) (Q2) (Al) (where Z is -CO-, -CS- or -S02-, Q1 and 2 are the same or different and each a hydrogen atom a lower alkyl group, a lower cycloalkyl group, a substituted or unsubstituted phenyl group, an alkyl phenyl group substituted or unsubstituted lower, or Q1 and Q2 may be combined together with the nitrogen atom at Which they are linked to form a pyrrolidine ring, a piperidine ring, a hexahydroazepine ring, a morpholine ring, a thiomorpholine ring, or a piperazine ring optionally having a lower alkyl or a benzyl substituent on the other nitrogen atom); -CO-R7 (A-2) ^ k (wherein R7 is a hydrogen atom, an alkyl group Lower, a lower alkoxy group, a lower alkoxycarbonyl group, a lower alkyl group which is substituted by a hydroxy, lower alkoxy or a lower alkoxycarbonyl group, or a substituted or unsubstituted phenyl group); - (CH2) P-CH (R8) -COR9 (A-3) 15 (wherein p is 0, 1, 2, 3, 4 or 5, R8 is a hydrogen atom or a lower alkyl group, and R9 is a lower alkyl group or a lower alkoxy group), or a pharmaceutically acceptable acid addition salt thereof, characterized in that it comprises the following processes (a), (b), (c), (d), (e), or (f): (a) when the compound (I) is a compound of the formula (I) wherein A is a group of the formula (Al), which • a compound of the formula (II) reacts wherein Ar is as defined above with a compound of formula (III): X-Z-NÍQ1) (Q2) (III) • Wherein X is a halogen atom, Z, Q1 and Q2 are the same as defined above: (b) when the compound (I) is a compound of the formula (I) wherein A is a group of the formula (Al), Q1 is a hydrogen atom, and Z is -CO- or -CS-, which reacts with a compound of the formula (II): wherein Ar is the same as defined above, with a compound of the formula (IVa) or (IVb): 20 0 = C = N = OJJ (IVa) S = C = N = Q23 (IVb) wherein Q23 is of the same substituents as those defined by Q2 above, or a trimethylsilyl group); (c) when the compound of formula (I) is a compound of formula (I) wherein A is a group of the formula (Al), and Z is -CO-, which reacts a compound of the formula (V) : Ar-CONH- / N-CH2- / N-CO-L4 (V) • wherein L4 is a residual group, and Ar is the same as defined above, with a compound of the formula (VI): wherein Q1 and Q2 are the same as defined above. 15 (d) by reacting a compound of the formula (VII): Ar-COOOH (VII) wherein Ar is the same as defined above or a reactive derivative thereof, with a compound of the formula (VIII): where A is the same as defined above; 5 (e) when the compound (I) is a compound of the formula (I) wherein A is a group of the formula (A-2) which reacts with a compound of the formula (II): wherein Ar is the same as defined above, 10 with a compound of the formula (A-2 '): HO-CO-R72 (A-2 ') wherein R72 is the same as R7, or a reactive derivative thereof, provides that when (1) R72 is a lower alkyl group substituted by a hydroxy group, then a reactive derivative of the compound (A-2 ') is not used, and when (2) R72 in a lower alkoxy group, then a haloure of the acid of the compound (A-2') is used; or (f) when the compound (I) is a compound of the formula (wherein A is a group of the formula (A-3), which • reacts with a compound of the formula (II): 5 wherein Ar is the same as defined above, with a compound of the formula (A-3 '): M- (CH 2) p-CH (R 8) -COR 9 (A-3') 0 = CH- (CH 2 ) p'-CH (R8) -COR9 (A-3") wherein M is an alcoholic reactive ester residue, p 'is 1, 2, 3 or 4, and R8 and R9 is the same as defined above and, if necessary, followed by the conversion of the product to a pharmaceutically acceptable acid addition salt thereof
12. 12. A serotonin 4 receptor agonist, characterized in that it contains as an active ingredient the compound as claimed in any of the claims. 1-9, or a pharmaceutically acceptable acid addition salt of the 20 same.
13. 13. A method for the treatment of diseases caused by the lack of stimulation on the • serotonin 4 receptors in patients, characterized in that it comprises the administration of an effective amount of the compound as claimed in any one of claims 1-9, or a pharmaceutically acceptable acid addition salt thereof, for a patient who has suffered from said diseases.
14. 14. The use of a compound as claimed in any one of claims 1-9, or use pharmaceutically acceptable acid addition salt thereof, in the treatment of patients who have suffered from diseases caused by lack of stimulation. about the receivers 15 serotonin 4.
15. 15. A gastrointestinal prokinetic agent, characterized in that it contains as an active ingredient of the compound as claimed in any one of the 20 claims 1-9, or a pharmaceutically acceptable acid addition salt thereof.
16. 16. A method for the treatment of diseases of gastrointestinal mobility or gastrointestinal dysfunction, characterized in that it comprises the administration of an effective amount of the compound as claimed in any one of claims 1-9, or a pharmaceutically acceptable acid addition salt thereof, to a patient who has suffered from such diseases. fl) 17. The use of the compound as claimed in a
17. Any of claims 1-9, or a pharmaceutically acceptable acid addition salt thereof, in the treatment of a patient who has suffered from diseases of gastrointestinal motility or gastrointestinal dysfunction. 15 18. A computer; 2StC of the formula (H-2) characterized in that R1 is a halogen atom, R2 is a hydrogen atom or a lower alkyl group, R3 is a hydrogen atom, a lower alkyl group, or a group
18. Lower alkanoyl, R5 and R6 are the same or different and each a hydrogen atom or a lower alkyl group, and n is 1, 2 or 3, or an acid addition salt thereof.
19. 19. A compound of the formula (VIII): characterized in that A is a group having the following formula (Al), (A-2) or (A-3): (wherein Z is -CO-, -CS- or -S02-, Q1 and Q2 are the same or different and each a hydrogen atom a lower alkyl group, a lower cycloalkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted phenyl lower alkyl group, or Q1 and Q2 can be combined together with the nitrogen atom at which they link to form a pyrrolidine ring, a piperidine ring, a hexahydroazepine ring, a morpholine ring, a thiomorpholine ring, or a piperazine ring optionally having a lower alkyl or a benzyl substituent on the other nitrogen atom); -CO-R7 (A-2) (wherein R7 is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower alkyl group which is substituted by a hydroxy, a lower alkoxy group or lower alkoxycarbonyl, or a substituted or unsubstituted phenyl group); - (CH2) P-CH (R8) -COR9 (A-3) 5 (wherein p is O, 1, 2, 3, 4 or 5, R8 is a hydrogen atom or a lower alkyl group, R9 is a lower alkyl group or a lower alkoxy group (f), or a pharmaceutically acceptable acid addition salt thereof. fifteen twenty