JPH111472A - Benzamide derivative and pharmaceutical composition containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound which strongly acts on a serotonin 4 (5-HT ₄ ) receptor and is useful as a gastrointestinal tract function improving agent. Its physiologically acceptable acid addition salts. Embedded image Wherein R ¹ is halogen, R ² and R ³ are hydrogen atoms, R ⁴ is a lower alkoxy group, a and i are 1 or 2, b
And j is 2 or 3, k is 0, 1 or 2, X is-(CH ₂ )
m represents 1 or 2, and A represents a group represented by the formula [a] or [b]. Embedded image (Wherein p is 1, 2 or 3, q is 0, 1, 2 or 3,
r is 0, 1 or 2, R ^5a is a hydrogen atom, a lower alkyl group, etc., R ^5b is a hydrogen atom or a lower alkyl group, R ⁶ is
⁷ represents a hydrogen atom, a lower alkyl group or the like. )]

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel benzamide derivative having a potent action on serotonin 4 receptor (hereinafter sometimes referred to as 5-HT ₄ receptor), more specifically, a 1-position at 1-position. 4-amino-5 having an amine moiety such as a piperidine ring substituted with substituted-4-piperidinylalkyl or 1-substituted-4-piperidinylcarbonyl
The present invention relates to a halogeno-2-alkoxybenzamide derivative.

[0002]

BACKGROUND OF THE INVENTION No. WO-95-26953 Publication, the compound represented by the selectively actuated acts on 5-HT ₄ receptor by the following formula 3, for the prevention and treatment of such gastrointestinal various diseases Are described as being useful as medicaments.

[0003]

Embedded image

Wherein R ¹ is halogen, R ² is lower alkoxy, substituted lower alkoxy, cycloalkyloxy or cycloalkylalkoxy, and m is 1 or 2
And A is a group represented by the following formula 4.

[0005]

Embedded image

Wherein R ³ is hydrogen, hydroxy, lower alkyl or lower alkoxy, p is an integer of 1-6,
B is the following:

[0007]

Embedded image ^{-N (R 4) -X 1 -R} 5, -N (R 4) -X 2 -N (R 6) (R 7), -X 1 -N- (R 8) (R 9 )

And a group represented by X ¹
Is CO, CS or SO ₂ , X ² is CO or CS
R ⁴ is hydrogen, lower alkyl, phenyl, substituted phenyl, aralkyl or substituted aralkyl, and R ⁵ is lower alkyl, cycloalkyl, bridged cycloalkyl,
R ⁶ and R ⁷ are the same or different and are hydrogen, lower alkyl, cycloalkyl, aryl, substituted aryl and the like, or R ⁶ and R ⁷ are combined with an adjacent nitrogen atom to form a ring May be. R
⁸ and R ⁹ are the same or different and are hydrogen, lower alkyl, cycloalkyl, aryl, substituted aryl and the like, or R ⁸ and R ⁹ may be combined with an adjacent nitrogen atom to form a ring. ). ]

The compound of the present invention represented by Chemical Formula 6 is clearly different in the B moiety in Chemical Formula 4.

[0010]

SUMMARY OF THE INVENTION 4-Amino-5-chloro-N- [2- (diethylamino) ethyl] -2-methoxybenzamide [generic name metoclopramide;
Merck Index, 11th edition, 6063 (1989)] has both an antiemetic effect and a gastrointestinal hyperactivity, and has been used as a gastrointestinal function improving drug for various digestive diseases or various digestive diseases associated with treatment since ancient times. It is used for treatment and prevention of organ dysfunction. More recently, cis-4-amino-5-chloro-
N- [1- [3- (4-Fluorophenoxy) propyl] -3-methoxy-4-piperidinyl] -2-methoxybenzamide [generic name cisapride; for example, Merck In
dex, 11th edition, 2318 (1989)] has been clinically applied as a gastrointestinal function improving agent. Recently, metoclopramide and cisapride gastrointestinal motility in 5-HT ₄ receptor from a study of the receptor such as involved is found, to promote gastrointestinal motility by these benzamide derivatives activating 5-HT ₄ receptor (J.
Pharmacol. Exp. Ther., 252 , 1378-1386 (1990);
Pharmacol. Exp. Ther., 257 , 781-787 (1991)].
Thus, compounds acting on 5-HT ₄ receptors are widely distributed in the digestive tract is expected to promote the movement of the digestive tract. However, the above-mentioned metoclopramide and cisapride have a central inhibitory action based on dopamine D ₂ receptor antagonism, and thus are clinically difficult to use. In addition, there is a tendency that the number of patients suffering from indefinite complaints of digestive system is increasing due to the complication of social life and the arrival of an aging society. I have.

The present inventors have conducted intensive studies on benzamide derivatives acting on the 5-HT ₄ receptor.
4-amino-5-halogeno-2 having a piperidine ring or the like substituted at the 1-position with 1-substituted-4-piperidinylalkyl or 1-substituted-4-piperidinylcarbonyl in the amine moiety
- have strong agonistic activity alkoxy benzamide derivative with respect to 5-HT ₄ receptor, they found to be useful as an excellent prokinetic agent, and completed the present invention.

[0012]

According to the present invention, there are provided a benzamide derivative represented by the following formula (I) and a physiologically acceptable acid addition salt thereof.

[0013]

Embedded image

[Wherein R ¹ represents a halogen atom;
² represents a hydrogen atom or a lower alkyl group; R ³ represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group; R ⁴ represents a lower alkoxy group; a represents 1 or 2; means 2 or 3, i denotes 1 or 2, j denotes 2 or 3, k denotes 0, 1 or 2, X is - (CH ₂₎ m-or -CO (CH ₂ ) means n-, wherein m means 1 or 2, n means 0 or 1, and A is a compound of the formula [a] or [b]
Means a group represented by

[0015]

Embedded image

Wherein p represents 1, 2 or 3, q represents 0, 1, 2 or 3, r represents 0, 1 or 2, R ^5a represents a hydrogen atom, lower alkyl. Group, hydroxy group,
Hydroxy (lower) alkyl group, lower alkoxy group, lower alkoxy (lower) alkyl group, amino group, mono- or di-substituted amino group, amino (lower) alkyl group, mono- or di-substituted amino (lower) alkyl group, unsubstituted or A substituted phenyl group, an unsubstituted or substituted phenyl (lower) alkyl group, a lower alkoxycarbonyl group, a carboxyl group, a carbamoyl group or a carbamoyl (lower) alkyl group, or R ^5a is taken together with R ⁶ described below. A pyrrolidine ring, piperidine ring, hexahydroazepine ring or morpholine ring may be formed, R ^5b represents a hydrogen atom or a lower alkyl group, R ⁶ represents a hydrogen atom,
A lower alkyl group or a lower alkylsulfonyl group; R ⁷ represents a hydrogen atom or a lower alkyl group;
Alternatively, R ⁶ and R ⁷ may together form a pyrrolidine ring, a piperidine ring, a hexahydroazepine ring, a morpholine ring, or a piperazine ring in which one nitrogen atom may be substituted with a lower alkyl group. . ]]

The physiologically acceptable acid addition salts of the compounds of the formula (I) include, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate and phosphate; And organic acid salts such as oxalate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, methanesulfonate and succinic acid. Formula (I)
And the physiologically acceptable acid addition salts thereof may exist as hydrates or solvates, and these hydrates and / or solvates are also included in the present invention.

The compounds of formula (I) optionally have one or more asymmetric carbon atoms and can give rise to geometric isomerism. Thus, the compounds of formula (I) may optionally exist in more than one stereoisomeric form. These stereoisomers,
The mixtures and racemates are included in the compounds of the present invention.

The terms used in this specification are described below.

The lower alkyl group and the lower alkyl moiety are
Unless otherwise specified, it means one having 1 to 6 carbon atoms, which may be linear or branched. "Halogen atom"
Means fluorine, chlorine, bromine or iodine, with chlorine being preferred. Specific examples of “lower alkyl group” include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl,
Hexyl. Specific examples of the “lower alkoxy group” include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,
t-butoxy, pentyloxy, hexyloxy. "Lower alkoxy (lower) alkyl group"
It means a lower alkyl group substituted by the lower alkoxy group, and examples include methoxymethyl, 2-methoxyethyl, and 3-methoxypropyl. “Hydroxy (lower) alkyl group” means an alkyl group having 1 to 4 carbon atoms substituted with a hydroxy group, and includes, for example, hydroxymethyl, 2-hydroxyethyl, and 3-hydroxypropyl.

The term "mono- or di-substituted amino group" means an amino group substituted with one or two lower alkyl groups, such as methylamino, ethylamino, dimethylamino and diethylamino. "Amino (lower) alkyl group" means a lower alkyl group substituted with an amino group, such as aminomethyl, 2-aminoethyl,
-Aminopropyl. The “mono- or di-substituted amino (lower) alkyl group” means a lower alkyl group substituted with the above-mentioned mono- or di-substituted amino group, such as methylaminomethyl, ethylaminomethyl, 2-methylaminoethyl, Methylaminopropyl is exemplified. “Carbamoyl (lower) alkyl group” means a lower alkyl group substituted with a carbamoyl group, and examples include carbamoylmethyl and 2-carbamoylethyl.

"Unsubstituted or substituted phenyl group"
Substituted by one or two selected from a halogen atom, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, trifluoromethyl, amino, mono- or di (C ₁ -C ₃ ) alkylamino, cyano and nitro Phenyl; 2-, 3- or 4-chlorophenyl; 2-, 3- or 4-bromophenyl;
2,4-dichlorophenyl; 2,4-dibromophenyl; 2,4-difluorophenyl; 2-, 3- or 4-methylphenyl; 2
-, 3- or 4-methoxyphenyl; 2-, 3- or 4
2-, 3- or 4-methylaminophenyl; 2-, 3- or 4-methylaminophenyl; 2-, 3- or 4-dimethylaminophenyl; 2
-, 3- or 4-cyanophenyl; 2-, 3- or 4-
Nitrophenyl. The “unsubstituted or substituted phenyl (lower) alkyl group” is a group having 1 to 1 carbon atoms substituted with the above “unsubstituted or substituted phenyl group”.
4 means an alkyl group, for example, benzyl;
Or 4-chlorobenzyl; 4- or 4-fluorobenzyl; 4-methylbenzyl; 4-methoxybenzyl; phenethyl;

Specific examples of the "lower alkanoyl group" include acetyl, propionyl and butyryl.
Specific examples of the “lower alkoxycarbonyl group” include methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl. "Lower alkylsulfonyl group"
Specific examples include methylsulfonyl and ethylsulfonyl.

In the compounds of the present invention, preferred are those of the formula (I) wherein R ² and R ³ are both hydrogen atoms and R ⁴ is a methoxy, ethoxy, propoxy or isopropoxy group. And compounds in which R ¹ , A, X and k are the same as described above, and physiologically acceptable acid addition salts thereof.

More preferably, in the formula (I), R ^5a is a hydrogen atom, a lower alkyl group or a hydroxy (lower) alkyl group, R ^5b is a hydrogen atom or a lower alkyl group, and R ⁶ is A hydrogen atom, a lower alkyl group or a lower alkylsulfonyl group, or R ^5a and R ⁶ together form a piperidine ring;
^{1, R 2, R 3,} R 4, R 7, X, a, b, i, j,
Compounds wherein k, m, n, p, q and r are the same as defined immediately above, and physiologically acceptable acid addition salts thereof.

As a more preferred compound, in formula (I), k is 0 or 1, a, b, i and j are all 2, and R ¹ , R ² , R ³ , R ⁴ , R ^5a , R ^5b , R
⁶ , R ⁷ , X, m, n, p, q and r are the same as defined immediately above, and physiologically acceptable acid addition salts thereof.

Still more preferred compounds are those of the formula (I) wherein R ^5a is hydrogen, methyl, ethyl or hydroxymethyl and R ⁶ is hydrogen or methyl, or R ^5a And R ⁶ together with an adjacent nitrogen atom form a piperidine ring, R ⁷ is a hydrogen atom or a methyl group, and R ¹ , R ² , R ³ , R
⁴ , compounds wherein X, a, b, i, j, k, m, n, p, q and r are the same as defined immediately above, and physiologically acceptable acid addition salts thereof.

Still more preferred compounds are those of formula (I) wherein R ⁴ is methoxy or ethoxy and R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , X, a ,
Compounds wherein b, i, j, k, m, n, p, q and r are the same as defined immediately above, and physiologically acceptable acid addition salts thereof.

Particularly preferred compounds include the following compounds and their physiologically acceptable acid addition salts.

4-Amino-N- [1- [1- (3-aminopropyl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2-methoxybenzamide

4-Amino-N- [1- [1- (4-aminobutyl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2-methoxybenzamide

4-Amino-N- [1- [1- (5-aminopentyl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2-methoxybenzamide

4-amino-5-chloro-N- [1- [1
-(3-Dimethylaminopropyl) -4-piperidinylmethyl] -4-piperidinyl] -2-methoxybenzamide

4-Amino-N- [1- [1- (4-aminobutyryl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2-methoxybenzamide

4-amino-5-chloro-N- [1- (1
-Aminoacetyl-4-piperidinylmethyl) -4-piperidinyl] -2-methoxybenzamide

4-Amino-N- [1- [1- (3-aminopropionyl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2-methoxybenzamide

4-Amino-N- [1- [1- (3-aminobutyryl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2-methoxybenzamide

4-Amino-N- [1- [1- (3-aminopropyl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2-ethoxybenzamide

4-Amino-N- [1- [1- (3-aminopropyl) -4-piperidinylcarbonyl] -4-piperidinylmethyl] -5-chloro-2-methoxybenzamide

4-Amino-N- [1- [1- (4-amino-5-hydroxypentyl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2-methoxybenzamide

(S) -4-amino-N- [1- [1-
(4-Amino-5-hydroxypentyl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2
-Methoxybenzamide

As specific examples of the compounds included in the present invention,
In addition to the compounds of the examples described below, the following compounds and their physiologically acceptable acid addition salts can be mentioned.

4-amino-5-chloro-2-methoxy-
N- [1- [1- (3-methylaminopropyl) -4-
Piperidinylmethyl] -4-piperidinyl] benzamide, 4-amino-5-chloro-2-methoxy-N- [1
-[1- (4-methylaminobutyl) -4-piperidinylmethyl] -4-piperidinyl] benzamide, 4-amino-5-chloro-N- [1- [1- (3-ethylaminopropyl)- 4-piperidinylmethyl] -4-piperidinyl] -2-methoxybenzamide, 4-amino-5
-Chloro-N- [1- [1- (4-ethylaminobutyl) -4-piperidinylmethyl] -4-piperidinyl]
-2-methoxybenzamide, 4-amino-5-chloro-N- [1- [1- [3- (N-ethyl-N-methylamino) propyl] -4-piperidinylmethyl] -4-piperidinyl] -2-methoxybenzamide, 4-amino-5-chloro-N- [1- [1- [4- (N-ethyl-
N-methylamino) butyl] -4-piperidinylmethyl] -4-piperidinyl] -2-methoxybenzamide;

4-amino-5-chloro-2-methoxy-
N- [1- [1- (4-methylaminobutyl) -4-piperidinylcarbonyl] -4-piperidinyl] benzamide, 4-amino-N- [1- [1- (4-aminobutyl) -4 -Piperidinylcarbonyl] -4-piperidinyl] -5-chloro-2-ethoxybenzamide, 4-amino-N- [1- [1- (3-aminopropyl) -4-
Piperidinylmethyl] -4-piperidinyl] -5-bromo-2-methoxybenzamide, 4-amino-N- [1
-[1- (4-aminobutyl) -4-piperidinylmethyl] -4-piperidinylmethyl] -5-chloro-2-propoxybenzamide and N- [1- [1- (3-aminopropyl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-4-dimethylamino-2-methoxybenzamide.

The compound of the present invention can be produced, for example, by the following method.

Production method (a) In the formula (I), a compound wherein A is a group represented by the formula [a] and R ^5a is a group other than a carboxyl group is represented by the following formula (II)

[0047]

Embedded image

(Wherein R ¹ , R ² , R ³ , R ⁴ , X,
a, b, i, j and k mean the same as described above. )

A compound represented by the following formula (IIIa):

[0050]

Embedded image

(Wherein, R ⁵¹ is the same as R ^5a above except for a carboxyl group, R ⁶¹ is a hydrogen atom or a lower alkyl group, and R ⁷¹ is an amino-protecting group or a lower alkyl group. Means, or R ⁶¹ and R ⁷¹ are taken together and the phthalimide, pyrrolidine ring, piperidine ring, hexahydroazepine ring, morpholine ring or one nitrogen atom is substituted with a lower alkyl group or an amino group protecting group R ⁶¹ may form a pyrrolidine ring, a piperidine ring, a hexahydroazepine ring or a morpholine ring together with R ⁵¹ ,
¹ represents a reactive ester residue of an alcohol, R ^5b ,
p and q mean the same as above. However, when R ⁷¹ is a lower alkyl group, R ⁶¹ is not a hydrogen atom. )

The compound can be produced by reacting with a compound represented by the formula (1) and, if necessary, further removing an amino-protecting group.

In the formula (I), R ^5a is a hydroxy group, R ^5b is a hydrogen atom, p is 1, q
Is a compound of the formula (II) and a compound of the following formula (IIIb)

[0054]

Embedded image

(Wherein q ′ represents 1, 2 or 3;
⁶¹ and R ⁷¹ mean the same as above. )

The compound can be produced by reacting with the compound represented by the formula (1) and, if necessary, further removing an amino-protecting group.

[0057] As the reactive ester residue of an alcohol of the formula Z ¹ is, for example chlorine, bromine, halogen atom such as iodine, lower alkylsulfonyloxy groups such as methanesulfonyloxy, benzenesulfonyloxy, p- And arylsulfonyloxy groups such as toluenesulfonyloxy.

The protecting group for an amino group means a protecting group which can be eliminated by hydrolysis or hydrogenolysis. Examples of the protecting group which can be eliminated by hydrolysis include an ethoxycarbonyl group, a t-butoxycarbonyl group and an acetyl group. Group, benzoyl group, trifluoroacetyl group, benzyloxycarbonyl group, 3- or 4-chlorobenzyloxycarbonyl group, triphenylmethyl group, methanesulfonyl group, p-toluenesulfonyl group and the like. Examples of the releasable protecting group include a benzyloxycarbonyl group and a 3- or 4-chlorobenzyloxycarbonyl group.

A compound of the formula (II) and a compound of the formula (IIIa) or (II
The reaction with the compound of Ib) is carried out in a solvent or without solvent. The solvent to be used should be appropriately selected according to the type of the raw material compound and the like. For example, benzene, toluene,
Aromatic hydrocarbons such as xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, halogenated hydrocarbons such as methylene chloride and chloroform, alcohols such as ethanol and isopropyl alcohol, and acetone and methyl ethyl ketone Ketones, ethyl acetate, acetonitrile, dimethylformamide, dimethylsulfoxide, ethylene glycol, and water. These solvents may be used alone or in combination of two or more.

This reaction is carried out in the presence of a base, if necessary. Specific examples of the base include alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate and potassium carbonate, and the like. Sodium bicarbonate,
Examples thereof include alkali bicarbonates such as potassium bicarbonate, and organic bases such as triethylamine, tributylamine, diisopropylethylamine, and N-methylmorpholine, but they can also serve as an excess amount of the compound of the formula (II). When Z ¹ is chlorine or bromine, the reaction proceeds smoothly when an alkali metal iodide such as sodium iodide or potassium iodide is added. The reaction temperature varies depending on the type of the starting compound used and the like, but is usually about 0 ° C to about 200 ° C.
° C, preferably from about 80 ° C to about 150 ° C.

In the formula (IIIa) or (IIIb), R ⁶¹
And R ⁷¹ together form a phthalimide to form a compound having a phthalimide group by the reaction of the compound of the formula (II) with the compound of the formula (II), the product is decomposed or hydrolyzed by hydrazine. In the formula (I), A is a group represented by the formula [a];
R ^5a is a group other than a carboxyl group and a lower alkoxycarbonyl group, and can be converted to a compound in which R ⁶ and R ⁷ are both hydrogen atoms.

The decomposition reaction with hydrazine is carried out in a solvent such as alcohols such as methanol, ethanol and isopropanol, tetrahydrofuran, acetonitrile and dimethylformamide at about 30 ° C. to about 100 ° C. in the presence of hydrazine.

When a compound having an amino-protecting group is obtained by reacting the compound of the formula (IIIa) or (IIIb) with the compound of the formula (II), the product is hydrolyzed or hydrogenolyzed. , R ⁷ is a hydrogen atom, or R ⁶ and R ⁷
Is a hydrogen atom, or a compound in which R ⁶ and R ⁷ are taken together to form unsubstituted piperazine at the nitrogen atom.

The hydrolysis can be carried out according to a conventional method.
For example, the reaction is carried out by contacting water in a suitable solvent under acidic or basic conditions. As the solvent, for example, alcohols such as methanol, ethanol, and isopropanol, dioxane, water, or a mixture thereof is used.
Specific examples of the acid include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, and sulfuric acid, and organic acids such as formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, and methanesulfonic acid. Can be Specific examples of the base include alkali hydroxides such as sodium hydroxide and potassium hydroxide,
And alkali carbonates such as sodium carbonate and potassium carbonate. The reaction temperature is usually about 0 ° C to 150 ° C.

The hydrogenolysis can be carried out according to a conventional method. For example, the reaction is carried out in a suitable solvent in the presence of a catalyst such as palladium carbon or Raney nickel in the presence of hydrogen or a hydrogen donor such as ammonium formate or cyclohexene. This is done by: Examples of the solvent include ethanol,
Alcohols such as methanol, water, acetic acid, dioxane, tetrahydrofuran, ethyl acetate, dimethylformamide and the like are used. The reaction temperature is usually about 0 ° C. to about 80
C. and performed under normal pressure or under pressure.

The method for producing the compound of the formula (II) will be described below.

The compound of the formula (II) can be produced, for example, by the method shown in the following formulas 11 and 12.

[0068]

Embedded image

(In the formula, Y, Z ² and Z ³ are amino-protecting groups, and Y and Z ² and Y and Z ³ are amino-protecting groups which are deprotected under different conditions. , R
^{1, R 2, R 3,} R 4, X, Z 1, a, b, i, j,
k, m and n mean the same as described above. )

[0070]

Embedded image

(Wherein R ¹ , R ² , R ³ , R ⁴ , Z ¹ ,
Z ² , Z ³ , a, b, i, j, k, m, and n mean the same as described above. )

Each of the above chemical formulas 11 and 12 can be carried out by using the method described in the production method (a) and the deprotection reaction, and the method described in the production methods (b) and (c) described below.

The compounds of the formulas (IIIa) and (IIIb) are commercially available or can be prepared by known methods, but the methods for preparing some compounds of the formula (IIIa) are described in Reference Example 9 below. To 11 specifically.

Production method (b) In the formula (I), A is a group represented by the formula [b],
The compound wherein R ^5a is a group other than a carboxyl group has the following formula:
(II)

[0075]

Embedded image

(Wherein R ¹ , R ² , R ³ , R ⁴ , X,
a, b, i, j and k mean the same as described above. )

A compound represented by the following formula (IV):

[0078]

Embedded image

(In the formula, R ⁵¹ , R ^5b , R ⁶¹ , R ⁷¹ , q and r mean the same as described above.)

The compound can be produced by reacting with a compound represented by the formula (1) and, if necessary, further removing an amino-protecting group.

Examples of the reactive derivative of the compound of the formula (IV) include lower alkyl esters (especially methyl esters), active esters, acid anhydrides, acid halides (especially acid chlorides). Specific examples of the active ester include p-nitrophenyl ester, pentachlorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester, 8-hydroxyquinoline ester, 2-hydroxyphenyl ester and the like. Is mentioned. As the acid anhydride, a symmetric acid anhydride or a mixed acid anhydride is used. Specific examples of the mixed acid anhydride include a mixed acid anhydride with an alkyl chlorocarbonate such as ethyl chlorocarbonate and isobutyl chlorocarbonate, and chlorinated acid anhydride. Mixed anhydrides with aralkyl chlorocarbonates such as benzyl carbonate, mixed anhydrides with aryl chlorocarbonates such as phenyl chlorocarbonate, mixed anhydrides with alkanoic acids such as isovaleric acid and pivalic acid Is mentioned.

When the compound of the formula (IV) itself is used,
1,3-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N, N'-carbonyldiimidazole, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophos Fate,
The reaction can be carried out in the presence of a condensing agent such as N, N'-carbonyldisuccinimide, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, diphenylphosphorylazide, propanephosphonic anhydride. . When 1,3-dicyclohexylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride is used as the condensing agent, N-hydroxysuccinimide, 1-hydroxybenzotriazole, 3-hydroxy-1 , 2,3-benzotriazin-4 (3H) -one, N-hydroxy-5-norbornene-2,3-dicarboximide and the like may be added and reacted.

The reaction of the compound of the formula (IV) or a reactive derivative thereof with the compound of the formula (II) is carried out in a solvent or without solvent. Examples of the solvent to be used include the solvents described in the above-mentioned production method (a), and should be appropriately selected according to the raw material compounds and the like. This reaction is carried out in the presence of a base, if necessary. Specific examples of the base include the bases described in the above-mentioned production method (a), and the compounds represented by the formula (II)
Can also serve as an excess amount of the compound. The reaction temperature varies depending on the type of the starting compound used, etc., but is usually about -30 ° C.
To about 200 ° C, preferably from about -10 ° C to about 150 ° C.

[0084 formula (IV), when the compound having a phthalimide group by reaction with a compound of R ⁶¹ and R ⁷¹ form a phthalimide together with a compound of formula (II) is obtained, which product The product is decomposed with hydrazine or hydrolyzed to obtain A in the formula (I).
There is a group represented by the formula [b], R ^5a is a group other than a carboxyl group and a lower alkoxycarbonyl group, R ⁶
And R ⁷ can both be hydrogen compounds.

When a compound having an amino-protecting group is obtained by the reaction of the compound of the formula (IV) with the compound of the formula (II),
By hydrolyzing or hydrolyzing the product, R
^The compound can be converted into a compound in which ⁷ is a hydrogen atom, R ⁶ and R ⁷ are both hydrogen atoms, or a compound in which R ⁶ and R ⁷ are combined to form an unsubstituted piperazine having a nitrogen atom.

The compound of the formula (IV) is commercially available or can be prepared by a known method.

Production method (c) In the formula (I), X is-(CH ₂ ) m-, A is a group represented by the formula [a], and R ^5a is a group other than a carboxyl group and a lower alkoxycarbonyl group. The compound that is the group is
The following formula (V)

[0088]

Embedded image

(Wherein, R ⁵² is the same as R ^{5a described} above except for a carboxy group and a lower alkoxycarbonyl group, and R ¹ , R ² , R ³ , R ⁴ , R ^5b , R ⁶ , R ⁷ X ,
a, b, i, j, k, q and r mean the same as described above. )

Can be produced by reducing the compound represented by the formula:

As the reducing agent used in this reaction, for example, diborane, lithium aluminum hydride and its alkoxy complex or transition metal salt, aluminum chloride, boron trifluoride, phosphorus oxychloride or carboxylic acid (for example, acetic acid, trifluoroacetic acid) ) To which sodium borohydride is added. This reduction reaction is diethyl ether,
Tetrahydrofuran, dimethoxyethane, dioxane,
It is performed in an ethereal solvent such as diglyme. The reaction temperature varies depending on the type of the reducing agent and the like, and is usually from about 0 ° C.
0 ° C, but preferably about 10 ° C to 30 ° C.

The compound of the formula (V) is condensed using the compound of the formula (II) and the compound of the formula (IV) according to the method described in the above-mentioned production method (b), and then the protecting group for the amino group is eliminated. It can be manufactured by the following.

Process (d) The compound of the formula (I) can be prepared by reacting the compound of the following formula (VI)

[0094]

Embedded image

(Wherein R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above), and a compound represented by the following formula (VII):

[0096]

Embedded image

(Wherein B is-(CH ₂ ) p- or -CO
(CH ₂ ) r— represents a group represented by R ⁵² , R ^5b ,
R ⁶¹ , R ⁷¹ , X, a, b, i, j, k, p, q and r have the same meanings as described above. )

The compound can be produced by reacting with a compound represented by the formula (1) and, if necessary, further removing an amino-protecting group.

This reaction can be carried out in the same manner as in the production method (b), and the deprotection reaction can be carried out by the method described in the production method (a).

The compound of the formula (VII) can be produced, for example, by the method shown in the following formula.

[0101]

Embedded image

[Wherein, X, Y, Z ³ , a, b, i, j, and k have the same meanings as described above, and A ¹ has the following formula:

[0103]

Embedded image

(B, R ⁵² , R ^5b , R ⁶¹ , R ⁷¹ and q have the same meanings as described above). However, when R ⁷¹ is a protecting group for an amino group, Y and R ⁷¹
Is a protecting group which is deprotected under different conditions. ]

In step 2 of the above formula 18, the method described in the above-mentioned production method (a) or (b) can be used, and in steps 1 and 3, the above-mentioned deprotection reaction can be carried out.

In the compound of the formula (O), the compound in which X is CO (CH ₂ ) n and B is CO (CH ₂ ) r is reduced, and if necessary, an amino group is further added. By removing the protecting group, X is (CH ₂ ) m and B
Is CO (CH ₂ ) r or (CH ₂ ) p, or a compound wherein X is CO (CH ₂ ) n and B is (CH ₂ ) p.

The above reduction can be carried out by the method described in the above production method (c).

Further, the compound of the present invention can also be produced by the following method.

The compound of the formula (I) wherein R ^5a is a carboxyl group can be produced by hydrolyzing the compound of the formula (I) wherein R ^5a is a lower alkyloxycarbonyl group. The corresponding starting compound can be produced by the above-mentioned production method (b).

The compounds R ^5a is hydroxy (lower) alkyl group in formula (I), R ^5a in formula (I)
Is reduced with a reducing agent such as a metal borohydride in water or an alcoholic solvent at about 5 ° C. to 50 ° C. using a reducing agent such as a metal borohydride salt.

The compound of the formula (I) wherein R ^5a is a carbamoyl group can be produced by reacting the compound of the formula (I) wherein R ^5a is a lower alkoxycarbonyl group with ammonia.

The compound produced by each of the above production methods is isolated by a conventional method such as chromatography, recrystallization and reprecipitation.
Purified.

The compound of the formula (I) can be obtained by selecting a starting compound,
It is obtained in the form of a free base or an acid addition salt depending on the reaction and treatment conditions. The acid addition salt can be converted to a free base by a conventional method, for example, by treating with a base such as alkali carbonate or alkali hydroxide. On the other hand, the free base can be converted to an acid addition salt by treating it with various acids according to a conventional method.

The test results on the pharmacological action of the representative compound of the present invention and commercially available cisapride (Compound A) are shown below.

Test Example 1 : Serotonin 4 (5-HT ₄ ) receptor binding test The 5-HT ₄ receptor binding test and the preparation of a receptor membrane preparation were performed as follows.
Grossman et al. [British J. Pharmacol., 109 , 618-
624 (1993)].

Std-Hartley guinea pigs (body weight 300 to 40)
After decapitation of 0 g), the brain was immediately taken out and the striatum was separated. Add 15 volumes of Hepes buffer (50
mM, pH 7.4, 4 ° C), homogenized with a Teflon homogenizer, and centrifuged at 48,000 xg (4 ° C) for 10 minutes. Hepes buffer was added to the resulting sediment and the tissue wet weight 30.
The mixture was added and suspended at a ratio of 1 ml to mg to obtain a receptor sample.

The assay tube contains 0.1 nM [ ³ H] -GR.
113808, Hepes buffer (50 mM, pH 7.4, 4 ° C.) containing receptor sample and test compound or 30 μM serotonin 1
ml was incubated at 37 ° C. for 30 minutes. The reaction was stopped by rapid filtration using a Brandel cell harvester on Whatman GF / B filters soaked in 0.1% polyethyleneimine for 1 hour, and ice-cooled 50 mM Tris-
This was performed by washing three times with 4 ml of HCl (pH 7.7).
Radioactivity on the filter was measured with a liquid scintillation counter with the addition of ASC II scintillator.
The 50% inhibitory concentration (IC ₅₀ ) was determined from the inhibition rate of the test compound with respect to the specific binding obtained by subtracting the non-specific binding from the total binding amount of [ ³ H] -GR113808. Table 1 shows the results.

[0118]

[Table 1] ^* Means the compound of Example 1 (hereinafter also means the compound of Example).

[0119]

[Table 2]

As is clear from the above test, the compound of the present invention and the physiologically acceptable acid addition salt thereof are 5-HT
Since it has strong affinity for ₄ receptors, it can be used as a gastrointestinal tract function improving drug for the treatment and prevention of various digestive dysfunction associated with various diseases and treatments. Specifically, acute / chronic gastritis, reflux esophagitis, gastric / duodenal ulcer,
Anorexia, nausea, vomiting, abdominal bloating, upper abdomen in diseases such as gastric neurosis, gastric ptosis, postoperative paralytic ileus, senile ileus, postgastrectomy syndrome, scleroderma, diabetes, esophageal and biliary tract diseases, etc. For the treatment and prevention of discomfort, abdominal pain, heartburn, ambiguity, etc., and for the treatment of irritable bowel syndrome, flaccid constipation, addictive constipation, constipation induced by drugs such as morphine and antipsychotics, dysuria, and infant diarrhea And prevention.

The administration route may be any of oral administration, parenteral administration and rectal administration. The dose varies depending on the type of compound, the administration method, the symptoms and age of the patient, etc., but is usually 0.1 to 50 mg / kg / day, preferably 0.5 to 10 m / kg.
g / kg / day.

When the compound of the formula (I) or a physiologically acceptable acid addition salt thereof is used for the above-mentioned medicinal purposes, it is usually administered in the form of a preparation prepared by mixing with a preparation carrier. As a pharmaceutical carrier, it is commonly used in the pharmaceutical field,
A substance that does not react with the compound of the present invention is used. Specifically, for example, lactose, inositol, glucose, mannitol, dextran, sorbitol, cyclodextrin, starch, partially pregelatinized starch, sucrose,
Magnesium aluminate metasilicate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl starch, carboxymethylcellulose calcium, ion exchange resin, methylcellulose, gelatin, gum arabic, pullulan, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, Hydroxypropyl methylcellulose,
Polyvinylpyrrolidone, polyvinyl alcohol, alginic acid, sodium alginate, light anhydrous silicic acid, magnesium stearate, talc, tragacanth, bentonite, veegum, carboxyvinyl polymer, titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin, fatty acid glycerin ester, purification Lanolin, glycerogelatin, polysorbate, macrogol, vegetable oil, wax, water, propylene glycol, ethanol, sodium chloride, sodium hydroxide, hydrochloric acid, citric acid, benzyl alcohol, glutamic acid, glycine,
Examples include methyl paraoxybenzoate, propyl paraoxybenzoate, and the like.

Examples of the dosage form include tablets, capsules, granules, powders, syrups, suspensions, injections, suppositories and the like. These preparations are prepared according to a conventional method. In the case of a liquid preparation, it may be in the form of being dissolved or suspended in water or another appropriate medium at the time of use. Tablets and granules may be coated by a known method.

These preparations can contain the compound of formula (I) or a physiologically acceptable acid addition salt thereof in a proportion of 0.01% or more, preferably 0.1 to 70%. These formulations may also contain other therapeutically valuable components.

[0125]

EXAMPLES The present invention will be described more specifically with reference to the following Reference Examples and Examples, but the present invention is not limited to these Examples. The compound was identified by elemental analysis, mass spectrum, IR spectrum, NMR spectrum and the like.

Further, in the following Reference Examples and Examples,
The following abbreviations may be used to simplify the description.

[Substituents] Me: methyl group, Et: ethyl group, Pr: propyl group, i-Pr: isopropyl group, Ph: phenyl group, Z: benzyloxycarbonyl group.

[Recrystallization solvent] E: ethanol, M: methanol.

[NMR] J: coupling constant, s: singlet, d: doublet, t: triplet, m: multiplet, br: broad, DMSO: dimethylsulfoxide, Ar: aryl group.

Reference Example A Production of 1-benzyl-3- (t-butoxycarbonylaminomethyl) piperidine:

(1) A mixture of 500 ml of methyl ethyl ketone, 34.6 g of nipecotic acid amide, 49.5 g of benzyl bromide and 40 g of potassium carbonate is heated under reflux for 16 hours. After allowing the reaction mixture to cool, ethyl acetate is added, and the mixture is washed with water and saturated saline. The solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and the precipitated crystals were collected by filtration and dried to obtain 35.2 g of 1-benzylnipecotinamide.

(2) 70% bis (2-methoxyethoxy) aluminum hydride sodium toluene solution 130 ml
The above product 32.7 was added to a 500 ml solution of
g under ice-cooling. After stirring at room temperature for 30 minutes, the mixture is refluxed for 5 hours. The reaction solution is cooled on ice, and a saturated aqueous solution of sodium potassium tartrate is added dropwise until no more foaming occurs. After stirring for 30 minutes, chloroform is added to the reaction solution, and the insoluble matter is filtered off through celite. 32.7 g of di-tert-butyl dicarbonate is added to the filtrate, and the mixture is stirred at room temperature for 13 hours.
The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography.
Elution and purification in 1) give 32.9 g of the desired product as an oil. This target product was used as a raw material in Reference Example 1a to be described later.

Reference Example B Production of 3- (t-butoxycarbonylamino) piperidine:

(1) 1-benzyloxycarbonyl-
3-piperidinecarboxylic acid 5.3 g t-butanol 100
After adding 2.7 ml of triethylamine and 4.3 ml of diphenylphosphoric acid azide in this order, the mixture is heated under reflux for 15 hours. The solvent was distilled off under reduced pressure, and diethyl ether was added to the residue.
Wash with water, aqueous potassium carbonate, water, 10% aqueous citric acid, and saturated saline in that order, and dry over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure to obtain 6.4 g of crude 1-benzyloxycarbonyl-3- (t-butoxycarbonylamino) piperidine as an oil.

(2) The above product 5.0 g of methanol 50
After adding 1.9 g of ammonium formate and 0.5 g of 10% palladium carbon to the ml solution, the mixture is stirred at 40 ° C for 40 minutes. After removing the catalyst by filtration, the filtrate is evaporated under reduced pressure to remove the solvent. The residue is dissolved in chloroform, washed with a saturated aqueous solution of sodium bicarbonate and brine in that order, and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure to obtain 2.7 g of a crude product as an oil. In Reference Example 1c described below, this was used as a raw material without purification.

Reference Example 1 Production of 1-[(1-benzyloxycarbonyl) -4-piperidinylmethyl] -4- (t-butoxycarbonylamino) piperidine:

(1) After dissolving 95 g of 4-amino-1-benzylpiperidine in 600 ml of chloroform, a solution of 109 g of di-t-butyl dicarbonate in 600 ml of chloroform is added dropwise under ice-cooling. After stirring at room temperature for 5 hours, the reaction solution was
After washing twice and saturated saline, the extract is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Petroleum ether was added to the residue, and the insoluble solid was collected by filtration and dried to give 136 g of 1-benzyl-4- (t-butoxycarbonylamino) piperidine as a solid.

(2) 70 g of the above product was added to ethanol 6
After dissolving in 100 ml, add 5 g of 10% palladium on carbon, and add
And debenzylation. After absorbing the theoretical amount of hydrogen, the catalyst is filtered off and the ethanol of the filtrate is distilled off under reduced pressure to give 48.6 g of 4- (t-butoxycarbonylamino) piperidine as a solid. 155-158 ℃

(3) 1-benzyloxycarbonyl-
26 g of 4-piperidinecarboxylic acid in methylene chloride 200 m
After dissolving in l, add 14.4 ml of thionyl chloride dropwise at room temperature. After heating at reflux for 1 hour, the solvent and excess thionyl chloride are distilled off under reduced pressure. After adding 400 ml of methylene chloride to the residue, 20 g of the above product 4- (t-butoxycarbonylamino) piperidine and triethylamine were added under ice cooling.
Add 27 ml of the mixture. After stirring at room temperature for 4 hours,
% Aqueous citric acid, water, saturated aqueous sodium bicarbonate, and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 1- (1-benzyloxycarbonyl-4-piperidinylcarbonyl) -4-.
39 g of (t-butoxycarbonylamino) piperidine are obtained as a solid. 150-152 ° C (recrystallized from ethyl acetate)

(4) A 1M borane-tetrahydrofuran complex-tetrahydrofuran solution (100 ml) was added dropwise to a suspension of 16.5 g of the above product in 170 ml of tetrahydrofuran under ice-cooling, followed by stirring at room temperature for 13 hours. Methanol 1
00 ml is added dropwise, and the mixture is heated under reflux for 1 hour. After evaporating the solvent under reduced pressure, the residue is dissolved in ethyl acetate, washed with water, an aqueous sodium hydroxide solution and saturated saline in this order, and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is subjected to silica gel flash column chromatography, eluted and purified with ethyl acetate to obtain 13 g of the desired product as a solid.
130-132 ° C (recrystallized from ethyl acetate)

Reference Example 1a Preparation of 1-[(1-benzyloxycarbonyl) -4-piperidinylmethyl] -3- (t-butoxycarbonylaminomethyl) piperidine:

1-benzyl-4 in Reference Example 1 (2)
Reference Example 1 (2) to (4) using 1-benzyl-3- (t-butoxycarbonylaminomethyl) piperidine instead of-(t-butoxycarbonylamino) piperidine.
Reaction and treatment in the same manner as described above to obtain the desired product as an oil.

Reference Example 1b Preparation of 1-[(1-benzyloxycarbonyl) -4-piperidinylmethyl] -3- (t-butoxycarbonylamino) pyrrolidine:

Instead of 4- (t-butoxycarbonylamino) piperidine in Reference Example 1 (3), 3- (t-
Using butoxycarbonylamino) pyrrolidine, the reaction and treatment are carried out in the same manner as in Reference Examples 1 (3) and (4) to obtain the desired product as an oil.

Reference Example 1c Preparation of 1-[(1-benzyloxycarbonyl) -4-piperidinylmethyl] -3- (t-butoxycarbonylamino) piperidine:

Instead of 4- (t-butoxycarbonylamino) piperidine in Reference Example 1 (3), 3- (t-
Using butoxycarbonylamino) piperidine, the reaction and treatment are carried out in the same manner as in Reference Examples 1 (3) and (4) to obtain the desired product as an oil.

Reference Example 1d Preparation of 1-[(1-benzyloxycarbonyl) -3-piperidinylmethyl] -4- (t-butoxycarbonylamino) piperidine:

In place of 1-benzyloxycarbonyl-4-piperidinecarboxylic acid in Reference Example 1 (3), 1
Using -benzyloxycarbonyl-3-piperidinecarboxylic acid, the reaction and treatment were carried out in the same manner as in Reference Examples 1 (3) and (4) to obtain the desired product. 123-125 ° C (recrystallized from acetone-water)

Reference Example 2 4-amino-5-chloro-2-methoxy-N- [1-
Preparation of (4-piperidinylmethyl) -4-piperidinyl] benzamide:

(1) 1-[(1-Benzyloxycarbonyl) -4-piperidinylmethyl] -4- (t-butoxycarbonylamino) piperidine was added to 12.1 g of the mixture under ice-cooling.
After adding 60 ml of an ethanol solution containing 10% hydrogen chloride, the mixture is stirred at room temperature for 1 hour, and the solvent is distilled off under reduced pressure. After adding 100 ml of methylene chloride to the residue, 4-amino-5 was added under ice cooling.
-Chloro-2-methoxybenzoic acid 5.3 g, 1-ethyl-
5.4 g of 3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 27 ml of triethylamine are added in this order, and the mixture is stirred at room temperature for 3 hours. The reaction solution is washed with water, a saturated aqueous solution of sodium hydrogen carbonate, water and saturated saline in this order, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel flash column chromatography, and eluted and purified with chloroform-methanol (20: 1) to give 4
-Amino-N- [1- (1-benzyloxycarbonyl-4-piperidinylmethyl) -4-piperidinyl] -5
10.2 g of -chloro-2-methoxybenzamide are obtained.

(2) The above product was treated with chloroform 150 m
l, dissolve in anisole 19 ml, methanesulfonic acid 11.
After adding 5 ml, the mixture is heated under reflux for 3 hours. After allowing the reaction solution to cool, chloroform is removed by decantation. The residue is dissolved in water and washed with chloroform. The aqueous layer is made basic by adding potassium carbonate and then extracted with chloroform. The extract is washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain a crude target product. The desired product can be obtained as crystals of difumarate by treating with fumaric acid in a conventional manner. 187-189 ° C
(Recrystallized from ethanol)

Reference Example 2a 4-amino-5-chloro-2-methoxy-N- [1-
(4-piperidinylcarbonyl) -4-piperidinyl]
Production of benzamide:

Reference Example 2 1-[(1-benzyloxycarbonyl) -4-piperidinylmethyl]-
Instead of 4- (t-butoxycarbonylamino) piperidine, 1- (1-benzyloxycarbonyl-4-piperidinylcarbonyl)-obtained in Reference Example 1 (3) above.
Using 4- (t-butoxycarbonylamino) piperidine, the reaction and treatment are carried out in the same manner as in Reference Example 2 to obtain the desired product as an oil.

¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 1.2
0-1.65 (5H, m), 1.66-2.26 (4H, m), 2.27-2.99 (4H, m),
3.11-3.50 (2H, m), 3.75-4.11 (3H, m), 3.82 (3H, s, OC
H ₃ ), 4.23 (1H, m), 5.94 (2H, s, NH ₂ ), 6.47 (1H, s, Ar-
H), 7.67 (1H, s, Ar-H), 7.74 (1H, d, J = 7.5Hz, CONH).

Reference Examples 2b to 2h --- Corresponding to Reference Example 2 (1) in place of 1-[(1-benzyloxycarbonyl) -4-piperidinylmethyl] -4- (t-butoxycarbonylamino) piperidine The compounds of the following Reference Examples 2b to 2h are obtained as an oil by reacting and treating in the same manner as in Reference Example 2 using the piperidine or pyrrolidine derivative shown below.

( Reference Example 2b )-4-amino-5-chloro-2-methoxy-N- [1-
(4-Piperidinylmethyl) -3-piperidinylmethyl] benzamide:

1-[(1-benzyloxycarbonyl)
-4-piperidinylmethyl] -3- (t-butoxycarbonylaminomethyl) piperidine to obtain the desired product.

( Reference Example 2c )-4-amino-5-chloro-2-methoxy-N- [1-
(4-Piperidinylmethyl) -3-pyrrolidinyl] benzamide:

1-[(1-benzyloxycarbonyl)
-4-piperidinylmethyl] -3- (t-butoxycarbonylamino) pyrrolidine to give the desired product.

( Reference Example 2d )-4-amino-5-chloro-2-methoxy-N- [1-
(4-Piperidinylmethyl) -3-piperidinyl] benzamide:

1-[(1-benzyloxycarbonyl)
-4-piperidinylmethyl] -3- (t-butoxycarbonylamino) piperidine is used to obtain the desired product.

Reference Example 2e 4-Amino-5-chloro-2-methoxy-N- [1-
(3-Piperidinylmethyl) -4-piperidinyl] benzamide:

1-[(1-benzyloxycarbonyl)
-3-Piperidinylmethyl] -4- (t-butoxycarbonylamino) piperidine is used to obtain the desired product.

Reference Example 2f 4-amino-5-chloro-2-methoxy-N- [1-
(4-Piperidinylcarbonyl) -3-piperidinylmethyl] benzamide:

1 obtained as an intermediate of Reference Example 1a
The target compound is obtained using-(1-benzyloxycarbonyl-4-piperidinylcarbonyl) -3- (t-butoxycarbonylaminomethyl) piperidine.

( Reference Example 2g )-4-amino-5-chloro-2-methoxy-N- [1-
(4-piperidinylcarbonyl) -3-pyrrolidinyl]
Benzamide:

1 obtained as an intermediate of Reference Example 1b
-(1-benzyloxycarbonyl-4-piperidinylcarbonyl) -3- (t-butoxycarbonylamino)
The desired product is obtained using pyrrolidine.

( Reference Example 2h )-4-amino-5-chloro-2-methoxy-N- [1-
(3-piperidinylcarbonyl) -4-piperidinyl]
Benzamide:

1 obtained as an intermediate of Reference Example 1d
-(1-benzyloxycarbonyl-3-piperidinylcarbonyl) -4- (t-butoxycarbonylamino)
The desired product is obtained using piperidine.

Reference Example 3 4-amino-5-chloro-2-methoxy-N- [1-
Production of (4-piperidinylcarbonyl) -4-piperidinylmethyl] benzamide:

(1) Synth. Commun., 22 , 2357 (199)
2-aminomethyl-1- produced by the method described in 2)
After condensing with 4-amino-5-chloro-2-methoxybenzoic acid using (t-butoxycarbonyl) piperidine in the same manner as in Reference Example 2, the reaction and treatment were performed in the same manner as in Example 10 (2) described below. To give 4-amino-5-chloro-2-methoxy-N- (4-piperidinylmethyl) benzamide. 131-133 ° C

(2) The above product and 1-benzyloxycarbonyl-4-piperidinecarboxylic acid were prepared in Example 1 described below.
Reaction and treatment in the same manner as in 0 (1) to give 4-amino-N- [1
-(1-Benzyloxycarbonyl-4-piperidinylcarbonyl) -4-piperidinylmethyl] -5-chloro-2-methoxybenzamide is obtained.

(3) The above product is reacted and treated in the same manner as in Reference Example 2 (2) to obtain the desired product.

¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 0.7
6-1.18 (2H, m), 1.29-1.89 (8H, m), 2.74-3.49 (9H, m),
3.90 (1H, m), 3.81 (3H, s, OCH ₃ ), 4.35 (1H, m), 5.92
(2H, s, NH ₂ ), 6.48 (1H, s, Ar-H), 7.67 (1H, s, Ar-H), 7.
90 (1H, t, J = 5.5Hz, CONH).

Reference Example 4 ---- 4-amino-5-chloro-2-methoxy-N- [1-
Preparation of (4-piperidinylmethyl) -4-piperidinylmethyl] benzamide:

(1) 4 obtained in Reference Example 3 (2)
-Amino-N- [1- (1-benzyloxycarbonyl-4-piperidinylcarbonyl) -4-piperidinylmethyl] -5-chloro-2-methoxybenzamide and Example 21 (1) described later. Reaction and treatment in the same manner
Amino-N- [1- (benzyloxycarbonyl-4-
Piperidinylmethyl) -4-piperidinylmethyl] -5
-Chloro-2-methoxybenzamide is obtained.

(2) The above product is reacted and treated in the same manner as in Reference Example 2 (2) to obtain the desired product.

¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 0.7
0-1.29 (5H, m), 1.30-1.89 (8H, m), 2.04 (2H, d, J = 7H
z), 2.38 (1H, m), 2.58-3.30 (7H, m), 3.81 (3H, s, OC
H ₃ ), 5.91 (2H, s, NH ₂ ), 6.48 (1H, s, Ar-H), 7.67 (1H, s,
(Ar-H), 7.87 (1H, t, J = 7Hz, CONH).

Reference Example 5-4-amino-N- [1- [1- [4- (t-butoxycarbonylamino) -4-methoxycarbonylbutyryl]
-4-piperidinylmethyl] -4-piperidinyl] -5
Preparation of -chloro-2-methoxybenzamide:

4-Amino-5-chloro-2-methoxy-
N- [1- (4-piperidinylmethyl) -4-piperidinyl] benzamide and N- (t-butoxycarbonyl)
Using glutamic acid 1-methyl ester, the reaction and treatment are carried out in the same manner as in Example 10 (1) described below to obtain the desired product.

¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 0.8
0-3.05 (30H, m), 3.50-4.21 (4H, m), 3.62 (3H, s, CO ₂ OCH
₃ ), 3.84 (3H, s, OCH ₃ ), 5.93 (2H, s, NH ₂ ), 6.49 (1H, s,
Ar-H), 7.24 (1H, d, J = 7.5Hz, NH) 7.68 (1H, s, Ar-H), 7.
72 (1H, d, J = 7.5Hz, CONH).

Reference Example 6-4-amino-N- [1- [1- [4- (t-butoxycarbonylamino) -4-methoxycarbonylbutyl]-
4-piperidinylmethyl] -4-piperidinyl] -5-
Preparation of chloro-2-methoxybenzamide:

The 4-amino-N- [1
-[1- (4- (t-butoxycarbonylamino) -4
-Methoxycarbonylbutyryl] -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2-methoxybenzamide is reacted and treated in the same manner as in Example 21 (1) to give the desired product. .

¹ H-NMR spectrum (DMSO-d ₆ , δppm): 1.0
0-2.36 (20H, m), 1.38 [9H, (CH ₃ ) ₃ ], 2.55-2.88 (4H, m),
3.50-4.03 (3H, m), 3.61 (3H, s, CO ₂ OCH ₃ ), 3.84 (3H,
s, OCH ₃ ), 5.93 (2H, s, NH ₂ ), 6.48 (1H, s, Ar-H), 7.59
(1H, d, J = 7.5Hz, NH), 7.67 (1H, s, Ar-H), 7.72 (1H, d, J =
7.5Hz, CONH).

Reference Example 7 4-amino-1- [1- (3-phthalimidopropyl)
Preparation of [-4-piperidinylmethyl] piperidine:

(1) 5.6 g of 1-[(1-benzyloxycarbonyl) -4-piperidinylmethyl] -4- (t-butoxycarbonylamino) piperidine was added to ethanol
After dissolving in 100 ml, add 0.6 g of 5% palladium carbon,
Perform catalytic reduction at 30 ° C. After absorbing the theoretical amount of hydrogen, the catalyst was filtered off, and the ethanol in the filtrate was distilled off under reduced pressure to obtain 4.13 g of crude 4- (t-butoxycarbonylamino) -1- (4-piperidinylmethyl) piperidine. Get.

(2) 4.1 g of the above product was dissolved in 100 ml of methyl ethyl ketone, 3.9 g of potassium carbonate and 3.8 g of 3-bromopropylphthalimide were added, and the mixture was heated under reflux for 16 hours. After allowing the reaction solution to cool and removing insolubles by filtration, ethyl acetate was added to the filtrate and the mixture was washed three times with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel flash column chromatography.
The mixture was eluted and purified with chloroform-methanol (15: 1) to give 4- (t-butoxycarbonylamino) -1- [1-
5.5 g of (3-phthalimidopropyl) -4-piperidinylmethyl] piperidine are obtained as a solid. Melting point 123-1
27 ° C (recrystallized from ethanol-diethyl ether)

(3) 10% of the above product was added to 5.6 g under ice cooling.
After adding 5 ml of an ethanol solution containing hydrogen chloride and stirring at room temperature for 1 hour, 3 ml of an ethanol solution containing 10% hydrogen chloride is added, and the mixture is further stirred at 50 ° C. for 0.5 hour. After allowing to cool, the precipitated crystals are collected by filtration to obtain 1 g of the desired trihydrochloride. Melting point 264-2
70 ° C (recrystallized from methanol-ethanol)

Reference Example 8 4-amino-1- [1- (4-phthalimidobutyl)-
Preparation of 4-piperidinylmethyl] piperidine:

(1) 1-[(1-
Benzyloxycarbonyl) -4-piperidinylmethyl] -4- (t-butoxycarbonylamino) piperidine De-Z form 4- (t-butoxycarbonylamino) -1
-(4-Piperidinylmethyl) piperidine and Reference Example 7
Reference Example 7 using 4-bromobutylphthalimide instead of 3-bromopropylphthalimide in (2)
The reaction and treatment are carried out in the same manner as in (2) to obtain 4- (t-butoxycarbonylamino) -1- [1- (4-phthalimidobutyl) -4-piperidinylmethyl] piperidine.

(2) 7.9 g of the above product was added to ethanol 24
Then, 12 ml of a 30% hydrogen chloride-containing ethanol solution is added under ice-cooling, and the mixture is stirred at room temperature for 4 hours. After evaporating the solvent under reduced pressure, the residue is dissolved in water, and potassium carbonate is added to make the mixture basic. This is extracted with chloroform, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure to obtain 6.5 g of a crude product as an oil.

Reference Example 9 Production of (S) -1-bromo-4- (t-butoxycarbonylamino) -5- (t-butyldimethylsilyloxy) pentane:

(1) N- (t-butoxycarbonyl)
-(L) -Glutamic acid 5-benzyl ester, prepared according to the method described in Tetrahedron Lett., 25 , 5267 (1984), using (S) -4- (t-butoxycarbonylamino) -5-hydroxypropyl. Benzoic acid benzyl ester
970 mg was dissolved in dimethylformamide (5 ml), t-butyldimethylsilyl chloride (900 mg) and imidazole (510) were dissolved.
mg and stir at room temperature for 3.5 hours. Toluene-ethyl acetate (1: 1) is added to the reaction solution, and the mixture is washed with 10% citric acid, water, a saturated aqueous solution of sodium hydrogen carbonate, water, and saturated saline in this order. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, the residue was subjected to silica gel flash column chromatography, and eluted and purified with hexane and then with ethyl acetate to give (S) -4- (t-butoxycarbonylamino).
1.3 g of benzyl -5- (t-butyldimethylsilyloxy) valerate are obtained as a white solid.

(2) 1.3 g of the above product was dissolved in 10 ml of tetrahydrofuran, 50 mg of sodium borohydride and 60 mg of lithium chloride were added under ice-cooling, and 10 ml of ethanol was added dropwise. After stirring for 2 hours under ice cooling, the mixture is stirred at room temperature overnight. After distilling off the solvent under reduced pressure, water was added,
Extract with chloroform. The extract is washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel flash column chromatography, and eluted with hexane-ethyl acetate (1: 1).
Purification gives 600 mg of (S) -4- (t-butoxycarbonylamino) -5- (t-butyldimethylsilyloxy) pentanol as an oil.

(3) 600 mg of the above product was methylene chloride
Dissolve in 20 ml, and cool on ice with triphenylphosphine 470
mg and 900 mg of carbon tetrabromide are added and stirred at room temperature for 4 hours.
Chloroform is added to the reaction solution, and the mixture is washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel flash column chromatography.
Then, elution and purification are performed with chloroform-methanol (15: 1) to obtain 560 mg of the desired product as an oil.

¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 0.0
0 [6H, s, Si (CH ₃ ) ₂ ], 0.89 [9H, s, Si (CH ₃ ) ₃ ], 1.40 [9H,
s, (CH ₃ ) ₃ ], 1.20-2.00 (4H, m), 3.18-3.70 (5H, m), 6.3
9-6.73 (1H, m, NH)

Reference Example 10-1-bromo-4- (t-butoxycarbonylamino)-
Preparation of 5-methoxypentane:

(1) 9.8 g of N-triphenylmethylglutamic acid 5-methyl ester was added to tetrahydrofuran
Dissolve in 100 ml, and cool with ice-cooled sodium bis (2-methoxyethoxy) aluminum 70% toluene solution 36 m
After l was added dropwise, the mixture was refluxed for 6 hours. After cooling, a saturated aqueous solution of sodium potassium tartrate is added, and the insoluble matter is removed by filtration using celite. After evaporating the solvent under reduced pressure, ethyl acetate is added, and the mixture is washed with water and saturated saline in this order. After drying over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure to obtain 7.6 g of 2-triphenylmethylamino-1,5-pentanediol as a yellow solid.

(2) The above compound (3.0 g) was reacted and treated in the same manner as in Reference Example 9 (1) to give 2.2 g of 5- (t-butyldimethylsilyloxy) -2-triphenylmethylaminopentanol as an oil. Get as things.

(3) Dissolve 1.0 g of the above compound in 40 ml of tetrahydrofuran, and add 100 mg of about 60% sodium hydride (oil-based) under ice-cooling. Further 360 mg methyl iodide
After dropwise addition, the mixture is stirred at room temperature for 5 hours. Add 170 mg of sodium hydride and stir for an additional 18 hours. After dropwise addition of water, the solvent is distilled off under reduced pressure. Chloroform is added to the reaction solution, and washed with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, the residue was subjected to silica gel flash column chromatography, and eluted and purified with chloroform to give 1- (t-butyldimethylsilyloxy).
890 mg of -5-methoxy-4-triphenylmethylaminopentane are obtained as an oil.

(4) Using 4.9 g of the above compound, a reaction and treatment were carried out in the same manner as in Example 36 (2) described below to give 5-methoxy-
3.3 g of 4-triphenylmethylaminopentanol are obtained as an oil.

(5) Using 2.6 g of the above compound, a reaction and treatment were conducted in the same manner as in Example 36 (3) described below to give 4-amino-5-.
660 mg of methoxypentanol are obtained as an oil.

(6) Using 660 mg of the above compound, the reaction and treatment were carried out in the same manner as in Reference Example 1 (1) to give crude 4- (t-butoxycarbonylamino) -5-methoxypentanol 1.
1 g is obtained as an oil.

¹ H-NMR spectrum (CDCl ₃ , δppm): 1.45
[9H, s, (CH ₃ ) ₃ ], 1.50-2.00 (4H, m), 3.34 (3H, s, OCH ₃ ),
3.49 (2H, d, J = 6.0Hz, -OCH _2- ), 3.55-3.83 (3H, m), 4.7
8 (br, 1H)

(7) Using 1.1 g of the above compound, the reaction and treatment were conducted in the same manner as in Reference Example 9 (3) to obtain 1.2 g of the desired product as an oil.

Reference Example 11 Production of 3- (3-bromopropyl) -4- (t-butoxycarbonyl) morpholine:

(1) A 70% toluene solution of sodium bis (2-methoxyethoxy) aluminum hydride was prepared using 2.5 g of N-benzoylglutamic acid instead of the 5-methyl ester of N-triphenylmethylglutamic acid in Reference Example 10 (1). Was used and reacted and treated in the same manner as in Reference Example 10 (1) using about 7 molar equivalents to obtain 610 mg of 2-benzylamino-1,5-pentanediol as an oil.

(2) 1.0 g of the above compound was treated with methylene chloride.
Dissolve in 35 ml and add 2 ml of 2N aqueous sodium hydroxide solution. Under ice cooling, 540 mg of chloroacetyl chloride was added dropwise, and the mixture was stirred at room temperature for 3 hours. The reaction solution is washed successively with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel flash column chromatography, and eluted and purified with chloroform, then chloroform-methanol (30: 1) to give 2-
[(N-benzyl-N-chloroacetyl) amino]-
750 mg of 1,5-pentanediol are obtained as an oil.

(3) 740 mg of the above compound was dissolved in 15 ml of t-butanol, 580 mg of potassium t-butoxide was added, and the mixture was heated under reflux for 3 hours. After the solvent was distilled off under reduced pressure, chloroform was added, and the mixture was washed with 2N hydrochloric acid and saturated saline in this order. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel flash column chromatography, and eluted and purified with chloroform, then chloroform-methanol (15: 1) to give 3- (4-benzyl- 530 mg of 5-oxo-3-morpholinyl) propanol
As an oil.

(4) Using 70 g of bis (2-methoxyethoxy) aluminum sodium hydride in a 70% toluene solution instead of 1.7 g of the above compound in place of N-triphenylmethylglutamic acid 5-methyl ester in Reference Example 10 (1), The reaction and treatment were carried out in the same manner as in Reference Example 10 (1) using three times the molar equivalent to obtain 1.4 g of 3- (4-benzyl-3-morpholinyl) propanol as an oil.

¹ H-NMR spectrum (CDCl ₃ , δppm): 1.48-
2.00 (3H, m), 2.22 (1H, m), 2.49 (1H, m), 2.68 (1H,
m), 3.16 (1H, d, J = 16.0Hz, PhCH ₂ ), 3.50-3.82 (7H, m),
4.19 (1H, d, J = 16.0Hz, PhCH ₂ ), 7.21-7.39 (5H, m, Ph)

(5) Using 1.3 g of the above compound, the reaction and treatment were carried out in the same manner as in Reference Example 1 (2) to obtain 790 mg of 3- (3-morpholinyl) propanol as an oil.

(6) The above compound (800 mg) was reacted and treated in the same manner as in Reference Example 1 (1) to give 3- [4- (t-butoxycarbonyl) -3-morpholinyl] propanol 1.
2 g are obtained as an oil.

(7) Using 1.2 g of the above compound, a reaction and treatment were conducted in the same manner as in Reference Example 9 (3) to obtain 1.5 g of the desired product as an oil.

Example 1 4-amino-N- [1- [1- (3- (3-aminopropyl)
-4-piperidinylmethyl] -4-piperidinyl] -5
Preparation of -chloro-2-methoxybenzamide:

(1) 4-amino-5-chloro-2-methoxy-N- [1- (4-piperidinylmethyl) -4-
Piperidinyl] benzamide (4.8 g) was dissolved in methyl ethyl ketone (60 ml).
3.5 g of bromopropylphthalimide is added and the mixture is heated under reflux for 16 hours. After allowing the reaction mixture to cool, ethyl acetate was added, and the mixture was added
After washing with saturated saline twice and drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The residue was subjected to silica gel flash column chromatography, and eluted and purified with chloroform-methanol (10: 1) to give 4-amino-5-.
5.5 g of chloro-2-methoxy-N- [1- [1- (3-phthalimidopropyl) -4-piperidinylmethyl] -4-piperidinyl] benzamide are obtained as an oil.

(2) 4.95 g of the above product was added to ethanol
After dissolving in 20 ml, 650 mg of hydrazine monohydrate is added thereto, and the mixture is refluxed for 30 minutes. Ethanol is distilled off under reduced pressure, chloroform is added, and insoluble matter is removed by filtration. The filtrate is washed with a small amount of water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain 3.5 g of the desired product as an oil.

(3) After dissolving the target substance in ethanol, 2.0 g of fumaric acid was added, and the precipitated crystals were collected by filtration and dried to obtain 4.2 g of the target substance, 3 fumarate.

Melting point 195-198 ° C. (recrystallized from ethanol) ¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 1.12-1.40 (2H,
m), 1.45-1.96 (9H, m), 2.08-2.43 (6H, m), 2.58-2.94
(6H, m), 3.07 (2H, d, J = 11Hz), 3.78 (1H, m), 3.83 (3H,
s, OCH ₃ ), 5.95 (disappears in 2H, s, D ₂ O, NH ₂ ), 6.48 (1H, s, A
rH), 6.56 (2H disappearance in 8H, s, D ₂ O, NH ₂ + CHCO ₂ H), 7.6
7 (1H, s, Ar-H), 7.72 (1H, d, J = 7Hz, disappeared at D ₂ O, CONH),
11.10 (6H, br, disappears with _{D 2 O, CO 2 H)} .

Examples 2 to 5 The corresponding halogenophthalimides were used in place of 3-bromopropylphthalimide in Example 1 (1).
The following compounds are obtained by reacting and treating in the same manner as in Example 1.
In Example 4, N- (2,3-epoxypropyl)
Phthalimide was used.

Example 2 4-amino-N- [1- [1- (4-aminobutyl)-
4-piperidinylmethyl] -4-piperidinyl] -5-
Chloro-2-methoxybenzamide / 3 fumarate / 1
/ 2 ethanol solvate: melting point 228-230 ° C (recrystallized from ethanol)

Example 3 4-Amino-N- [1- [1- [5- (5-aminopentyl)]
-4-piperidinylmethyl] -4-piperidinyl] -5
-Chloro-2-methoxybenzamide / 3 fumarate /
3/4 hydrate / 1/2 ethanol solvate: melting point 102-104
° C (recrystallized from methanol-ethanol)

Example 4 4-Amino-N- [1- [1- (3-amino-2-hydroxypropyl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro- 2-methoxybenzamide difumarate: melting point 213-215 ° C (recrystallized from ethanol)

Example 5 (a) 4-Amino-N- [1- [1- (3-aminopropyl) -4-piperidinylcarbonyl] -4-piperidinyl] -5-chloro-2 -Methoxybenzamide · 2
Hydrochloride hemihydrate: mp 177-180 ° C (recrystallized from methanol-ethanol)

(B) 4-amino-N- [1- [1-
(3-Aminopropyl) -4-piperidinylcarbonyl] -4-piperidinyl] -5-chloro-2-methoxybenzamide / 2 fumarate / 1 ethanol solvate: melting point
117-120 ° C (recrystallized from methanol-ethanol)

Examples 6 to 9 Example 3 was repeated using the corresponding halogen compound instead of 3-bromopropylphthalimide in Example 1 (1).
The following compounds are obtained by reacting and treating in the same manner as in (1) and (3). In Examples 7 and 8, oxalic acid was used instead of fumaric acid as the acid.

Example 6 4-amino-5-chloro-N- [1- [1- (3-dimethylaminopropyl) -4-piperidinylmethyl] -4
-Piperidinyl] -2-methoxybenzamide / 3 fumarate / 1/4 hydrate: melting point 205-207 ° C (recrystallized from methanol-ethanol)

Example 7 4-Amino-5-chloro-2-methoxy-N- [1-
[1- [3- (1-Piperidinyl) propyl] -4-piperidinylmethyl] -4-piperidinyl] benzamide / 3-oxalate / 1-hydrate / 1 / 2-ethanol solvate: melting point 118-120 ° C (Recrystallized from methanol-ethanol)

Example 8 4-Amino-5-chloro-N- [1- [1- (3-methanesulfonylaminopropyl) -4-piperidinylmethyl] -4-piperidinyl] -2- Methoxybenzamide, 5/2 oxalate, 1/2 hydrate, 1/2 ethanol solvate: melting point 92-94 ° C (recrystallized from methanol-ethanol)

Example 9 4-Amino-5-chloro-N- [1- [1- (4-dimethylamino-3-methylbutyl) -4-piperidinylmethyl] -4-piperidinyl]- 2-methoxybenzamide / 3 fumarate / 1/4 hydrate: mp 198-200 ° C
(Recrystallized from methanol-ethanol)

Example 10-4-amino-N- [1- [1- (4-aminobutyryl)
-4-piperidinylmethyl] -4-piperidinyl] -5
Preparation of -chloro-2-methoxybenzamide:

(1) 4-amino-5-chloro-2-methoxy-N- [1- (4-piperidinylmethyl) -4-
2.1 g of piperidinyl] benzamide, 1.1 g of 4- (t-butoxycarbonylamino) butyric acid, 2.4 g of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent)
Was dissolved in 30 ml of methylene chloride and triethylamine was added.
After dropwise addition of 1.1 ml, the mixture is stirred at room temperature overnight. The reaction solution is washed with water, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted and purified with chloroform-methanol (30: 1) to give 4-amino-N- [1- [1- [4- (t-butoxycarbonylamino) butyryl] -4. 1.3 g of -piperidinylmethyl] -4-piperidinyl] -5-chloro-2-methoxybenzamide are obtained as amorphous.

(2) 1.3 g of the above product was added to ethanol 8
After dissolving in ethanol, 4 ml of an ethanol solution containing 30% hydrogen chloride was added under ice cooling, and the mixture was stirred for 5 minutes.
Stir for hours. After evaporating the solvent under reduced pressure, the residue is dissolved in a small amount of water, made basic by adding potassium carbonate, and extracted with chloroform. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
Is obtained as amorphous.

(3) After dissolving 950 mg of the above-mentioned target product in ethanol, 370 mg of oxalic acid and methanol were added thereto, and the precipitated crystals were collected by filtration, dried and dried to obtain the target 2-oxalate / 1.
1.2 g of / 2 hydrate / 1/2 ethanol solvate is obtained. 105-107 ° C

[0235] Example 11 to 20 - reacted with a carboxylic acid with a protected amino group corresponding to the place of 4-(t-butoxycarbonylamino) butyric acid in Example 10 (1), and the protective group elimination Thereafter, using the corresponding acid, the reaction and treatment were carried out in the same manner as in Example 10 (3) to obtain the compounds shown in Table 3.

[0236]

Embedded image

[0237]

[Table 3] Example A Q Melting point (° C) recrystallization Solvent ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 11 -COCH_Two-NH_Two 2 fumarate, 3 / 4H_TwoO 173-175 M-E 12 -CO (CH_Two)_Two-NH_Two 2 fumarate, 1 / 4H_TwoO 174-176 M-E 13 -CO (CH_Two)_Four-NH_Two 2-Fumarate 138-140 M-E 14 -COCH (Me) CH_Two-NH_Two 5/2 hydrochloride, 5 / 4H_TwoO 195-197 E 15 -COCH_TwoCH (Me) -NH_Two 2 fumarate, 1 / 4H_TwoO 165-167 M-E 16 -COCH (Me) -NH_Two 2 fumarate 167-169 M-E 17 -COCH (Et) -NH_Two 2 Fumarate 180-182 M-E 18 -COCH (CH_TwoPh) -NH_Two 2-oxalate, 1 / 2EtOH 149-152 M-E19-COCH (Ph) -NH_Two 2 Oxalate 194-196 M-E 20 -CO (CH_Two)_TwoCH (COOMe) -NH_Two Oil^* --━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ ^* : M / z of mass spectrum (MH⁺= 524)

Example 21 4-amino-N- [1- [1- (2-aminoethyl)-
4-piperidinylmethyl] -4-piperidinyl] -5-
Preparation of chloro-2-methoxybenzamide:

(1) Instead of 4- (t-butoxycarbonylamino) butyric acid, N- (t-butoxycarbonyl)
4-Amino-N- [1- [1- [1- (t-butoxycarbonylaminoacetyl) -4-piperidinylmethyl]-] produced in the same manner as in Example 10 (1) using glycine.
4-Piperidinyl] -5-chloro-2-methoxybenzamide (1.9 g) was dissolved in tetrahydrofuran (30 ml), and the mixture was cooled with ice to give a 1M borane-tetrahydrofuran solution.
ml is added dropwise and stirred at room temperature overnight. 12 ml of methanol is added dropwise to the reaction solution, and the mixture is heated under reflux for 1 hour while stirring, and then the solvent is distilled off under reduced pressure. Chloroform is added to the residue, washed with water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with chloroform-methanol [(20: 1) → (10: 1)] to give 4-amino-N- [1- [1- [2- (t- Butoxycarbonylamino) ethyl] -4-piperidinylmethyl] -4-
1.1 g of piperidinyl] -5-chloro-2-methoxybenzamide are obtained as amorphous.

(2) The above product was reacted and treated in the same manner as in Example 10 (2) to obtain 960 mg of the desired product.

(3) After dissolving 800 mg of the above-mentioned target substance in ethanol, 660 mg of fumaric acid and methanol were added, and the precipitated crystals were collected by filtration, dried and dried to obtain the desired 3-fumarate / 1/2 hydrate.
1.1 g are obtained. Melting point 193-195 ℃

Examples 22 to 24 Using the corresponding t-butoxycarbonyl amino acid, the reaction and treatment were carried out in the same manner as in Example 21 to obtain the following compounds.

Example 22 4-Amino-N- [1- [1- (3-aminobutyl)-
4-piperidinylmethyl] -4-piperidinyl] -5-
Chloro-2-methoxybenzamide / 3 fumarate / 3
/ 4-hydrate: melting point 94-96 ° C (recrystallized from methanol-ethanol)

Example 23 4-Amino-N- [1- [1- (3-amino-2-methylpropyl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro- 2-methoxybenzamide-3
Fumarate monohydrate: melting point 98-103 ° C (methanol-
Recrystallized from ethanol)

Example 24 4-Amino-N- [1- [1- (4-amino-4-methoxycarbonylbutyl) -4-piperidinylmethyl]-
4-piperidinyl] -5-chloro-2-methoxybenzamide: oil ¹ H-NMR spectrum _{(DMSO-d 6, δppm)} : 1.27-2.35 (19H,
m), 2.55-2.88 (4H, m), 3.15-3.54 (5H, m), 3.62 (3H, s,
CO ₂ OCH ₃ ), 3.85 (3H, s, OCH ₃ ), 4.36 (1H, m), 5.93 (2H,
s, NH ₂ ), 6.49 (1H, s, Ar-H), 7.67 (1H, s, Ar-H), 7.71
(1H, d, J = 7.5Hz, CONH).

Example 25 4-amino-5-chloro-2-methoxy-N- [1-
Production of [1- (4-piperidinylmethyl) -4-piperidinylmethyl] -4-piperidinyl] benzamide:

(1) 4-amino-5-chloro-2-methoxy-N- [1- (4-piperidinylmethyl) -4-
Example 10 using [piperidinyl] benzamide and 1-benzyloxycarbonyl-4-piperidinecarboxylic acid.
Reaction and treatment in the same manner as in (1),
[1- (1-Benzyloxycarbonyl-4-piperidinylcarbonyl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2-methoxybenzamide is obtained.

(2) Using 6.3 g of the above product, a reaction and treatment were conducted in the same manner as in Example 21 (1) to give 4-amino-N-
[1- [1- (1-benzyloxycarbonyl-4-piperidinylmethyl) -4-piperidinylmethyl] -4-
Piperidinyl] -5-chloro-2-methoxybenzamide (2.0 g) is obtained.

(3) The above product (2.0 g) was added to chloroform.
After dissolving in 30 ml, add 3.5 ml of anisole and 2 ml of methanesulfonic acid, and heat to reflux for 3 hours while stirring. After allowing the reaction solution to cool, chloroform is removed by decantation. The residue is dissolved in water, washed with chloroform, the aqueous layer is made basic by adding potassium carbonate, and extracted with chloroform. The extract is washed with brine, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is subjected to silica gel column chromatography, and eluted and purified with chloroform-methanol (10: 1) to obtain 1.6 g of a crude product.

(4) After dissolving 440 mg of the above product in ethanol, 250 mg of oxalic acid and methanol are added. The precipitated crystals were collected by filtration, dried and dried to obtain the target product, 3 oxalate.
Obtain 580 mg of tetrahydrate / 3/4 ethanol solvate. Melting point
113-115 ° C

Example 26 : 4-amino-5-chloro-2-methoxy-N- [1-
Production of [1- (3-piperidinylmethyl) -4-piperidinylmethyl] -4-piperidinyl] benzamide:

(1) 4-amino-5-chloro-2-methoxy-N- [1- (4-piperidinylmethyl) -4-
Using piperidinyl] benzamide and N-benzyloxycarbonyl nipecotic acid, the reaction and treatment were carried out in the same manner as in Example 10 (1) to give 4-amino-N- [1- [1- (N-benzyloxycarbonyl nipecotic). Nyl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2-
Obtain methoxybenzamide.

(2) Example 21 using the above product
Reaction and treatment in the same manner as in (1),
[1- (1-Benzyloxycarbonyl-3-piperidinylmethyl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2-methoxybenzamide is obtained.

(3) Example 25 using the above product
The desired product is obtained by reacting and treating in the same manner as in (3). Melting point 19
5-197 ° C (recrystallized from chloroform-ethyl acetate)

Example 27 4-Amino-N- [1- [1- (4-amino-4-carbamoylbutyl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2- Preparation of methoxybenzamide:

(1) 4-amino- obtained in Reference Example 6
N- [1- [1- [4- (t-butoxycarbonylamino) -4-methoxycarbonylbutyl] -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2-
After dissolving 1.4 g of methoxybenzamide in 10 ml of ethanol, 10 ml of 28% aqueous ammonia is added dropwise, and the mixture is stirred at room temperature for 20 hours. After evaporating the solvent under reduced pressure, chloroform is added, washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with chloroform-methanol (10: 1) to give 4-amino-N- [1-
[1- [4- (t-butoxycarbonylamino) -4-
Carbamoylbutyl] -4-piperidinylmethyl] -4
-Piperidinyl] -5-chloro-2-methoxybenzamide 1.2 g are obtained.

(2) The above product was reacted and treated in the same manner as in Example 10 (2), and then treated with ethanol containing hydrogen chloride to give the desired product, 13/4 hydrochloride / 3/2 hydrate / 1 770 mg of / 4 ethanol solvate is obtained. 203-205 ° C (recrystallized from methanol-ethanol)

Example 28 4-Amino-N- [1- [1- (4-amino-4-carbamoylbutyryl) -4-piperidinylmethyl] -4-
Preparation of piperidinyl] -5-chloro-2-methoxybenzamide:

The 4-amino-N- [1] obtained in Reference Example 5
-[1- [4- (t-butoxycarbonylamino) -4
-Methoxycarbonylbutyryl] -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2-methoxybenzamide was reacted and treated in the same manner as in Example 27 to obtain the desired dihydrochloride.5 Obtain / 4 hydrate / 3/4 ethanol solvate. 185-187 ° C (recrystallized from ethanol)

Example 29 : 4-Amino-N- [1- [1- (4-amino-5-hydroxypentyl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2- Preparation of methoxybenzamide:

(1) 4-amino- obtained in Reference Example 6
N- [1- [1- [4- (t-butoxycarbonylamino) -4-methoxycarbonylbutyl] -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2-
1.4 g of methoxybenzamide in 10 m of tetrahydrofuran
After adding 180 mg of sodium borohydride and 200 mg of lithium chloride under ice-cooling, 20 ml of ethanol is added dropwise. After stirring for 1 hour under ice cooling, the mixture is stirred at room temperature overnight. After evaporating the solvent under reduced pressure, water is added and the mixture is extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to remove 4-amino-N- [1- [1- [4- (t-butoxycarbonylamino) -5- 1.3 g of hydroxypentyl] -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2-methoxybenzamide are obtained as amorphous.

(2) The above product was reacted and treated in the same manner as in Example 27 (2) to give the desired product, trihydrochloride dihydrate 790.
get mg. 185-187 ° C (recrystallized from methanol-ethanol)

Example 30 4-Amino-N- [1- [1- (4-amino-5-hydroxyvaleryl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2 Preparation of methoxybenzamide:

(1) The 4-amino- obtained in Reference Example 5
N- [1- [1- [4- (t-butoxycarbonylamino) -4-methoxycarbonylbutyryl] -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2
Using -methoxybenzamide, the reaction and treatment were carried out in the same manner as in Example 29 to give 4-amino-N- [1- [1- [4- (t
-Butoxycarbonylamino) -5-hydroxyvaleryl] -4-piperidinylmethyl] -4-piperidinyl]
This gives -5-chloro-2-methoxybenzamide.

(2) The above product was reacted and treated in the same manner as in Example 27 (2) to obtain the desired dihydrochloride / 5/4 hydrate. 144-146 ° C (recrystallized from ethanol)

Example 31 4-amino-N- [1- [1- (1-amino-4-carboxybutyl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2- Preparation of methoxybenzamide:

The 4-amino-N- obtained in Example 24
2.2 g of [1- [1- (4-amino-4-methoxycarbonylbutyl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2-methoxybenzamide was dissolved in 35 ml of methanol and 1N Add 8.6 ml of aqueous sodium hydroxide solution and stir at room temperature for 3.5 hours. After the methanol was distilled off under reduced pressure, 25.8 ml of 2N hydrochloric acid was added in an ice bath. The solvent was distilled off under reduced pressure, the residue was subjected to CHP-20P medium pressure column chromatography, purified with 30% acetonitrile, and recrystallized from methanol-ethanol to give 9/9 of the desired product.
4 Obtain 890 mg of hydrochloride, 1/2 hydrate, 3/4 ethanol solvate. 208-210 ° C

Example 32 4-Amino-N- [1- [1- (3-aminopropyl)
Preparation of -4-piperidinylmethyl] -4-piperidinylmethyl] -5-chloro-2-methoxybenzamide:

Using 4-amino-5-chloro-2-methoxy-N- [1- (4-piperidinylmethyl) -4-piperidinylmethyl] benzamide obtained in Reference Example 4,
The reaction and treatment were carried out in the same manner as in Example 1 to obtain the desired trifumarate / 1/4 hydrate. 113-115 ° C (methanol-
Recrystallized from ethanol)

Example 33 4-Amino-N- [1- [1- (3-aminopropyl)
Preparation of -4-piperidinylcarbonyl] -4-piperidinylmethyl] -5-chloro-2-methoxybenzamide:

Example 1 was repeated using 4-amino-5-chloro-2-methoxy-N- [1- (4-piperidinylcarbonyl) -4-piperidinylmethyl] benzamide obtained in Reference Example 3. Reaction and treatment in the same manner as in (1) to obtain the desired difumarate salt / 1/2 hydrate. 139-142 ° C (recrystallized from methanol-ethanol)

Example 34 4-amino-N- [1- [1- (3-aminopropyl)
-4-piperidinylmethyl] -4-piperidinyl] -5
Preparation of -chloro-2-ethoxybenzamide:

4-Amino-5-chloro-2-ethoxybenzoic acid and 4-amino-1- [1-
(3-phthalimidopropyl) -4-piperidinylmethyl] piperidine was reacted and treated in the same manner as in the condensation reaction in Reference Example 2 (1), and then reacted in the same manner as in Examples 1 (2) and (3).・ Three fumarate of target substance after treatment
1/4 hydrate is obtained. 158-160 ° C (recrystallized from methanol-ethanol)

Example 35 N- [1- [1- (3-aminopropyl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2
Preparation of -methoxy-4-methylaminobenzamide:

5-chloro-2-methoxy-4-methylaminobenzoic acid and 4-amino-1- obtained in Reference Example 7
After reaction and treatment in the same manner as in the condensation reaction in Reference Example 2 (1) using [1- (3-phthalimidopropyl) -4-piperidinylmethyl] piperidine, the same as in Examples 1 (2) and (3) 3 fumarate salt of the target product
3/4 hydrate is obtained. 172-174 ° C (recrystallized from methanol-ethanol)

Example 36-(S) -4-amino-N- [1- [1- (4-amino-
5-hydroxypentyl) -4-piperidinylmethyl]
Preparation of -4-piperidinyl] -5-chloro-2-methoxybenzamide:

(1) 4-amino- obtained in Reference Example 2
1.5 g of 5-chloro-2-methoxy-N- [1- (4-piperidinylmethyl) -4-piperidinyl] benzamide
Was dissolved in 40 ml of methyl ethyl ketone, to which 0.5 g of potassium carbonate and 1.5 g of (S) -1-bromo-4- (t-butoxycarbonylamino) -5- (t-butyldimethylsilyloxy) pentane were added overnight. Heat to reflux. After allowing the reaction solution to cool, the solvent is distilled off under reduced pressure, chloroform is added, and the mixture is washed with water and saturated saline. After the chloroform layer is dried over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure.
The residue was subjected to basic silica gel flash column chromatography, and chloroform-methanol (15: 1)
And purified by (S) -4-amino-N- [1- [1
-[4- (t-butoxycarbonylamino) -5- (t
-Butyldimethylsilyloxypentyl)]-4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2
1.2 g of methoxybenzamide are obtained as amorphous.

(2) The above product (1.2 g) was dissolved in tetrahydrofuran (15 ml), and thereto was added a 1 M tetrabutylammonium fluoride-tetrahydrofuran solution (2.3 ml) under ice-cooling, followed by stirring at room temperature overnight. After the solvent was distilled off under reduced pressure, chloroform was added, and the mixture was washed with water and saturated saline. After the chloroform layer is dried over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure. The residue was subjected to basic silica gel flash column chromatography, and eluted and purified with chloroform-methanol (50: 1) to give (S) -4-amino-
0.2 g of N- [1- [1- [4- (t-butoxycarbonylamino) -5-hydroxypentyl] -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2-methoxybenzamide was obtained in an amorphous state. Get as.

(3) 0.2 g of the above product was added to ethanol 6
After dissolving in ethanol, 3 ml of a 30% hydrogen chloride-containing ethanol solution was added under ice-cooling, and the mixture was stirred for 5 minutes and further stirred at room temperature for 4 hours. After evaporating the solvent under reduced pressure, the residue was subjected to basic silica gel flash column chromatography, and eluted and purified with chloroform-methanol (20: 1) to obtain 130 mg of the desired product as an oil.

(4) After dissolving the desired product in ethanol, 90 mg of fumaric acid was added, and the precipitated crystals were collected by filtration and dried to obtain 120 mg of the desired product 3-fumarate. Melting point 218-
220 ° C

Examples 37-39 (S) -1-bromo-4-in Example 36 (1)
The corresponding halogen compound was used in place of (t-butoxycarbonylamino) -5- (t-butyldimethyl) silyloxypentane. In the case of the compound of Example 37, Examples 36 (1), (3) and (4) ), Example 38 (1) and (3) in Example 38, and the compound of Example 39 in the same manner as in Example 36 (1) and (4) to obtain the following compound. .

Example 37 4-Amino-N- [1- [1- (4-amino-5-methoxypentyl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro- 2-methoxybenzamide
9/4 fumarate salt, 1/4 hydrate: melting point 155-158 ° C
(Recrystallized from ethanol)

Example 38 4-Amino-5-chloro-2-methoxy-N- [1-
[1- [3- (3-morpholino) propyl] -4-piperidinylmethyl] -4-piperidinyl] benzamide:
159-161 ° C (recrystallized from chloroform-ethyl acetate)

Example 39 4-Amino-5-chloro-2-methoxy-N- [1-
[1- [2- (1-Pyrrolidinyl) ethyl] -4-piperidinylmethyl] -4-piperidinyl] benzamide
Trifumarate: melting point 220-222 ° C (recrystallized from methanol-ethanol)

Example 40 : 4-amino-5-chloro-N- [1- [1- (2,4-
Diaminobutyryl) -4-piperidinylmethyl] -4-
Preparation of piperidinyl] -2-methoxybenzamide:

(1) 4-amino-5-chloro-2-methoxy-N- [1- (4-piperidinylmethyl) -4-
Piperidinyl] benzamide (1.9 g) and 2,4-di (t-
1.6 g of butoxycarbonylamino) butyric acid and 2.2 g of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent) are dissolved in 30 ml of methylene chloride, and 1.0 ml of triethylamine is added dropwise. Under stirring overnight.
The reaction solution is washed with water, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted and purified with chloroform-methanol (30: 1) to give 4-amino-5-chloro-N- [1- [1-
[2,4-di (t-butoxycarbonylamino) butyryl] -4-piperidinylmethyl] -4-piperidinyl]
3.7 g of 2-methoxybenzamide are obtained as amorphous.

(2) 1.0 g of the above product was added to ethanol 1
After dissolving the mixture in 0 ml, 5 ml of an ethanol solution containing 30% hydrogen chloride was added under ice-cooling, and the mixture was stirred for 5 minutes.
Stir for hours. After evaporating the solvent under reduced pressure, the residue is dissolved in a small amount of water, made basic by adding potassium carbonate, and extracted with chloroform. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
Is obtained as amorphous.

(3) After dissolving 140 mg of the above-mentioned target substance in ethanol, a methanol solution of 100 mg of fumaric acid was added, and the precipitated crystals were collected by filtration and dried. 200 mg of hydrate / 1/4 ethanol solvate is obtained.
112-116 ° C

Examples 41 to 48 --After reaction and purification using carboxylic acids having a corresponding protected amino group in place of 2,4-di (t-butoxycarbonylamino) butyric acid in Example 40 (1) Example 4
The compound of Table 4 is obtained by reacting and treating in the same manner as in 0 (3).

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Table 4 Example A Q Melting point (° C) Recrystallization solvent ４１ 41 -COCH (NH ₂ ) CH ₂ -NH ₂ 7/2 Fumarate, 126-130 E 1/4 EtOH 42 -COCH (Pr) -NH ₂ 2 fumarate 174-176 E 43 -COCH ₂ CH (i-Pr) -NH ₂ 2 fumarate 181-183 ME 44 -COCH ₂ CH (Ph) -NH ₂ 2 fumarate, 1 / 4H ₂ O 158-160 ME 45 -COCH ₂ C (Me ₂ ) -NH ₂ 2 fumarate 220-222 ME 46 -COCH ₂ CH (OH) CH ₂ -NH ₂ 2 fumarate, 1 / 4H ₂ O 168-170 ME 47 -COCH [CH (Me) OH] -NH ₂ 2 hydrochloride, H ₂ O 203-206 E 48 -COCH ( CH ₂ CONH ₂ ) -NH ₂ 9/4 hydrochloride, 3/4 EtOH 214-217 E ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ ━━━━━━

Example 49 : 4-amino-5-chloro-2-methoxy-N- [1-
Preparation of (1-Nipecotyl-4-piperidinylmethyl) -4-piperidinyl] benzamide:

(1) 4-amino-5-chloro-2-methoxy-N- [1- (4-piperidinylmethyl) -4-
Using piperidinyl] benzamide and N-benzyloxycarbonyl nipecotic acid, the reaction and treatment were carried out in the same manner as in Example 40 (1) to give 4-amino-N- [1- [1- (N-benzyloxycarbonylnipeco acid). Tyl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2-methoxybenzamide.

(2) 620 mg of the above product was added to chloroform
After dissolving in 10 ml, 1.1 ml of anisole and 0.6 ml of methanesulfonic acid are added, and the mixture is refluxed for 3 hours while stirring. After allowing the reaction solution to cool, chloroform is removed by decantation. The residue is dissolved in water, washed with chloroform, the aqueous layer is made basic by adding potassium carbonate, and extracted with chloroform. The extract is washed with brine, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is subjected to basic silica gel column chromatography, and eluted and purified with chloroform-methanol (50: 1) to obtain 120 mg of a crude target compound.

(3) After dissolving 120 mg of the above-mentioned target product in ethanol, a methanol solution of 60 mg of fumaric acid was added, and the precipitated crystals were collected by filtration and dried to obtain the desired 2-fumarate salt of the target product.
Obtain 0 mg. Melting point 171-173 ° C

Example 50 Preparation of 4-amino-5-chloro-N- [1- (1-dimethylaminoacetyl-4-piperidinylmethyl) -4-piperidinyl] -2-methoxybenzamide

4-Amino-5-chloro-2-methoxy-
Using N- [1- (4-piperidinylmethyl) -4-piperidinyl] benzamide and N, N-dimethylglycine, the reaction and treatment were carried out in the same manner as in Examples 49 (1) and (3) to give the desired product. This gives the difumarate salt hemihydrate. Melting point
136-138 ° C (recrystallized from methanol-ethanol)

Example 51 : 4-Amino-N- [1- [1- (4-amino-3-hydroxybutyl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2- Preparation of methoxybenzamide:

(1) Example 40 using 4- (t-butoxycarbonylamino) -3-hydroxybutyric acid instead of 2,4-di (t-butoxycarbonylamino) butyric acid
4-Amino-N- [1-- produced by the same method as (1)
[1- [4- (t-butoxycarbonylamino) -3-
Hydroxybutyryl] -4-piperidinylmethyl] -4
-Piperidinyl] -5-chloro-2-methoxybenzamide (1.6 g) was dissolved in tetrahydrofuran (30 ml), 9.6 ml of a 1M borane-tetrahydrofuran complex-tetrahydrofuran solution was added dropwise under ice cooling, and the mixture was stirred at room temperature overnight. 10 ml of methanol is added dropwise to the reaction solution, and the mixture is heated under reflux for 1 hour while stirring, and then the solvent is distilled off under reduced pressure. Chloroform is added to the residue, washed with water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue was subjected to basic silica gel column chromatography, and chloroform-methanol (50: 1) was used.
And purified by elution with 4-amino-N- [1- [1- [4-
740 mg of (t-butoxycarbonylamino) -3-hydroxybutyl] -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2-methoxybenzamide are obtained as an amorphous.

(2) The above product was reacted and treated in the same manner as in Example 40 (2) to obtain 430 mg of the desired product as amorphous.

(3) After dissolving 430 mg of the desired product in ethanol, a methanol solution of 320 mg of fumaric acid was added, and the precipitated crystals were collected by filtration, dried and dried to obtain 440 mg of the fumaric acid salt of the desired product.
Get. Melting point 182-184 ℃

Example 52 : 4-amino-5-chloro-N- [1- [1- (2,4-
Preparation of diaminobutyl) -4-piperidinylmethyl] -4-piperidinyl] -2-methoxybenzamide:

The amino 4-amino obtained in Example 40 (1)
N- [1- [1- [2,4-di (t-butoxycarbonylamino) butyryl] -4-piperidinylmethyl] -4
-Piperidinyl] -5-chloro-2-methoxybenzamide, and the reaction was carried out in the same manner as in Examples 51 (1) to (3).
Treatment gives the desired 4-fumarate. 156-158
° C (recrystallized from methanol-ethanol)

Example 53 : 4-Amino-N- [1- [1- (4-aminobutyl)-
Preparation of 4-piperidinylcarbonyl] -4-piperidinylmethyl] -5-chloro-2-methoxybenzamide:

(1) 4-amino- obtained in Reference Example 3
1.4 g of 5-chloro-2-methoxy-N- [1- (4-piperidinylcarbonyl) -4-piperidinylmethyl] benzamide was dissolved in 30 ml of methyl ethyl ketone, and 0.7 g of potassium carbonate and 4-bromo- Add 1.4 g of butylphthalimide and heat to reflux for 15 hours. The reaction solution is left to cool, the insolubles are removed by filtration, and the solvent is distilled off under reduced pressure. The residue is dissolved in chloroform, washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel flash column chromatography, and chloroform-methanol [(30: 1) → (20:
1)] and eluted and purified to give 4-amino-5-chloro-2-
1.4 g of methoxy-N- [1- [1- (4-phthalimidobutyl) -4-piperidinylcarbonyl] -4-piperidinylmethyl] benzamide are obtained as amorphous.

(2) 1.1 g of the above product was added to ethanol 8
After dissolving the mixture in 180 ml, add 180 mg of hydrazine and heat to reflux for 1 hour. Ethanol is distilled off under reduced pressure, chloroform is added, and insoluble matter is removed by filtration. The filtrate is washed with a small amount of water and saturated saline, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure to obtain 1.0 g of the desired product.

(3) After dissolving the target substance in ethanol, a methanol solution of 480 mg of fumaric acid was added, and the precipitated crystals were collected by filtration and dried to obtain 1.2 g of the 3/2 fumarate of the target substance. Melting point 202-204 ℃

Example 54 : 4-Amino-N- [1- [1- (2-aminoethyl)-
Preparation of 4-piperidinylcarbonyl] -4-piperidinylmethyl] -5-chloro-2-methoxybenzamide:

(1) Using chloroacetonitrile instead of 4-bromobutylphthalimide in Example 53 (1), the reaction and treatment were carried out in the same manner as in Example 53 (1).
-Amino-5-chloro-N- [1- (1-cyanomethyl-4-piperidinylcarbonyl) -4-piperidinylmethyl] -2-methoxybenzamide is obtained as amorphous.

(2) 920 mg of the above product was dissolved in methanol, and 980 mg of cobalt (II) chloride hexahydrate was added.
Add 780 mg of sodium borohydride under ice cooling, and add
Stir for 1.5 hours. 6 ml of 2M hydrochloric acid are added and the solvent is distilled off under reduced pressure. After adding water to the residue, concentrated aqueous ammonia is added dropwise. After extracting with chloroform and washing with saturated saline,
After drying over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure.
The residue was subjected to basic silica gel flash column chromatography, and chloroform-methanol [(50:
1) → (40: 1)] to elute and purify to obtain the target product as amorphous.

(3) After dissolving 660 mg of the above-mentioned target product in ethanol, a methanol solution of 340 mg of fumaric acid was added, and the precipitated crystals were collected by filtration, dried and dried to obtain 430 m of fumaric acid salt of the target product.
Get g. 147-150 ℃

Example 55 4-amino-N- [1- [1- (4-aminobutyl)-
4-piperidinylmethyl] -4-piperidinyl] -5-
Preparation of chloro-2-ethoxybenzamide:

4-Amino-5-chloro-2-ethoxybenzoic acid and 4-amino-1- [1-
Using (4-phthalimidobutyl) -4-piperidinylmethyl] piperidine, amidation and purification were performed in the same manner as in Reference Example 2 (1), followed by reaction and treatment in the same manner as in Example 53 (2). To obtain the desired fumarate salt / 3/4 hydrate. 245-248 ° C (recrystallized from methanol-ethanol)

Examples 56 and 57 -The corresponding benzoic acids were used in place of 4-amino-5-chloro-2-ethoxybenzoic acid in Example 55, and the reaction and treatment were carried out in the same manner as in Example 55 to obtain the following compounds. Obtain the compound.

Example 56 : 4-Amino-N- [1- [1- (4-aminobutyl)-
4-piperidinylmethyl] -4-piperidinyl] -5-
Chloro-2-propoxybenzamide fumarate salt / 3
/ Dihydrate: amorphous; mass spectrum: m / z (MH ⁺ = 480)

Example 57 : 4-Amino-N- [1- [1- (4-aminobutyl)-
4-piperidinylmethyl] -4-piperidinyl] -5-
Chloro-2-isopropoxybenzamide 7/2 fumarate 5/4 hydrate: melting point 118-120 ° C (recrystallized from methanol-ethanol)

Example 58 : 4-Amino-N- [1- [1- (3-aminopropyl)
-3-piperidinylmethyl] -4-piperidinyl] -5
Preparation of -chloro-2-methoxybenzamide:

(1) 4-amino-5-chloro-2-methoxy-N- [1- (3-piperidinylmethyl) -4-piperidinyl] benzamide obtained in Reference Example 2e 2.2
was dissolved in 50 ml of methyl ethyl ketone, and 0.8 g of potassium carbonate and 1.6 g of 3-bromopropylphthalimide were added thereto.
Add g and heat to reflux for 15 hours. After allowing the reaction solution to cool, ethyl acetate is added, and the reaction solution is washed three times with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel flash column chromatography, eluted and purified with chloroform-methanol (10: 1) to give 4-amino-5-chloro-2-methoxy-N- [1- [1- (3-phthalimidopropyl). ) -3
-Piperidinylmethyl] -4-piperidinyl] benzamide is obtained as an oil.

(2) 1.8 g of the above product was added to ethanol 1
After dissolving in 0 ml, hydrazine monohydrate (240 mg) is added thereto, and the mixture is refluxed for 30 minutes. Ethanol is distilled off under reduced pressure, chloroform is added, and insoluble matter is removed by filtration. The filtrate is washed with a small amount of water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain 1.4 g of the desired product as an oil.

(3) After dissolving the above-mentioned target substance in ethanol, a methanol solution of fumaric acid (1.0 g) was added, and the precipitated crystal was collected by filtration and dried, and the target substance was obtained as a 3-fumarate / 1/4 hydrate
Obtain 0.8 g.

Melting point: 162-164 ° C. ¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 1.35-2.33 (18H,
m), 2.45-3.07 (7H, m), 3.78 (1H, m), 3.83 (3H, s, OC
H ₃ ), 5.94 (disappears in 2H, s, D ₂ O, NH ₂ ), 6.48 (1H, s, Ar-
H), 6.55 (2H disappearance in 8H, s, D ₂ O, NH ₂ + CHCO ₂ H), 7.66
(1H, s, Ar-H), 7.72 (1H, d, J = 7Hz, disappeared at D ₂ O, CONH), 1
0.0 (6H, br, disappears with _{D 2 O, CO 2 H)} .

Examples 59-69-3 -bromopropylphthalimide and 4-amino-5-chloro-2-methoxy-N- in Example 58 (1)
Using the corresponding halogenoalkylphthalimides and benzamide derivatives in place of [1- (3-piperidinylmethyl) -4-piperidinyl] benzamide, the reaction and treatment were conducted in the same manner as in Example 58 to obtain the compounds in Table 5.

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Table 5 ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Melting point recrystallization Example kab X ijt Q (° C ) Solvent ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 59 0 2 2 CH ₂ 1 3 4 3 Oxalate , 1 / 2EtOH 122-125 ME 60 0 1 2 CH ₂ 2 4 3 Fumarate 172-175 ME 61 0 1 2 CH ₂ 2 2 3 3 Fumarate 176-179 ME 62 0 1 3 CH ₂ 2 2 4 3 Oxalate, H ₂ O, 112-115 ME EtOH 63 0 2 2 CO 1 3 3 2 Oxalate, H ₂ O 160-163 ME 64 0 2 2 CO 1 3 4 2 Fumarate, H ₂ O 141-144 ME 65 0 1 2 CO 2 2 3 2 Fumarate 193-197 ME 66 0 1 2 CO 2 2 4 2 Oxalate, 1/2 EtOH 122-125 ME 67 1 1 3 CO 2 2 3 2 Fumarate 169-172 ME 68 1 1 3 CH ₂ 2 2 3 3 Fumarate 128-132 ME 69 1 1 3 CH ₂ 2 2 4 3 Oxalate, H ₂ O, 115-118 ME 1 / 2MeOH ━ ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

Example 70 N- [1- [1- (4-aminobutyl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2-
Preparation of isopropoxy-4-methylaminobenzamide:

Instead of 4-amino-5-chloro-2-ethoxybenzoic acid in Example 55, 5-chloro-2-
Using isopropoxy-4-methylaminobenzoic acid, the reaction and treatment were carried out in the same manner as in Example 55 to obtain the target product, 3-oxalate / 1/4 hydrate / 1/4 ethanol solvate. Melting point
139-141 ℃ (recrystallized from ethanol)

Formulation Example 1 : Preparation of tablet: 4-amino-N- [1- [1- (3-aminopropyl)
-4-piperidinylmethyl] -4-piperidinyl] -5
-Chloro-2-methoxybenzamide / 3 fumarate (5 g), lactose (80 g), corn starch (30 g)
g), microcrystalline cellulose (25 g), hydroxypropyl cellulose (3 g), light anhydrous silicic acid (0.7 g), and magnesium stearate (1.3 g).

The above ingredients are mixed and granulated in a conventional manner, and the mixture is tableted at 145 mg per tablet to produce 1,000 tablets.

Formulation Example 2 : Preparation of capsule: 4-amino-N- [1- [1- (3-aminopropyl)
-4-piperidinylmethyl] -4-piperidinyl] -5
-Chloro-2-methoxybenzamide / 3 fumarate (10 g), lactose (160 g), corn starch (22 g)
g), hydroxypropylcellulose (3.5 g), light anhydrous silicic acid (1.8 g), and magnesium stearate (2.7 g).

According to a conventional method, the above components are mixed and granulated, and 10
Fill into 00 capsules.

Formulation Example 3 : Preparation of powder: 4-amino-N- [1- [1- [3- (3-aminopropyl)
-4-piperidinylmethyl] -4-piperidinyl] -5
-Chloro-2-methoxybenzamide trifumarate (10 g), lactose (960 g), hydroxypropylcellulose (25 g), and light anhydrous silicic acid (5 g).

According to a conventional method, after mixing the above components, the mixture is made into a powder.

Formulation Example 4 : Production of injection (100
Per 0 ampule):

[0334]

[Table 6] 4-amino-N- [1- [ 1- (3-Aminopropyl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2-methoxybenzamide / 3 fumarate (10 g) Sorbitol (100 g) Water for injection (appropriate amount) ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Total volume 2000 ml ━━━━━━━━━━━━ ━━━━━━━━━━━━━━━━━━━━━━━

4-Amino-N- [1- [1- (3-aminopropyl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2-methoxybenzamide-3
After dissolving fumarate and sorbitol in a part of water for injection, the remaining amount of water for injection is added to prepare the whole amount. This solution was filtered through a membrane filter (0.22 μm), and the filtrate was filtered.
Fill into 2 ml ampules, then sterilize at 121 ° C for 20 minutes.

[0336]

As described above, according to the present invention, the compounds and their physiologically acceptable acid addition salts of the present invention represented by the formula (I) show a strong affinity for 5-HT ₄ receptor So
It can be used as a gastrointestinal tract function improving drug for the treatment and prevention of various digestive dysfunctions associated with various diseases and treatments.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07D 211/34 C07D 211/34 211/58 211/58 401/06 207 401/06 207 413/14 211 413/14 211 // A61K 31/40 A61K 31/40

Claims (9)

[Claims] 1. A benzamide derivative represented by the following formula 1 or a physiologically acceptable acid addition salt thereof. Embedded image [Wherein, R ¹ represents a halogen atom, R ² represents a hydrogen atom or a lower alkyl group, R ³ represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group, and R ⁴ represents a lower alkoxy group. A represents 1 or 2 and b represents 2
Or 3 means i is 1 or 2 and j is 2 or 3
And k represents 0, 1 or 2, and X represents-(CH ₂ )
m- or -CO (CH ₂₎ means n-, wherein
m represents 1 or 2, n represents 0 or 1, and A represents a group represented by the formula [a] or [b] in Chemical Formula 2 below. Embedded image [In the formula, p represents 1, 2 or 3, q represents 0, 1, 2 or 3, r represents 0, 1 or 2, R ^5a represents a hydrogen atom, a lower alkyl group, a hydroxy group. Group, hydroxy (lower) alkyl group, lower alkoxy group, lower alkoxy (lower) alkyl group, amino group, mono- or di-substituted amino group, amino (lower) alkyl group, mono- or di-substituted amino (lower) alkyl group, A substituted or substituted phenyl group, an unsubstituted or substituted phenyl (lower) alkyl group, a lower alkoxycarbonyl group, a carboxyl group, a carbamoyl group or a carbamoyl (lower) alkyl group, or R ^5a is the same as R ⁶ described below. is in a pyrrolidine ring, piperidine ring, may form a hexahydroazepine ring or morpholine ring, R ^5b is a hydrogen atom or a lower alkyl group , R ⁶ is a hydrogen atom, a lower alkyl group or a lower alkylsulfonyl group, or R ⁷ is a hydrogen atom or a lower alkyl group, or R ⁶ and R ⁷ together, pyrrolidine ring, piperidine ring , A hexahydroazepine ring, a morpholine ring, or a piperazine ring in which one nitrogen atom may be substituted with a lower alkyl group. ]] 2. R ² and R ³ are both hydrogen atoms;
^2. The benzamide derivative or the physiologically acceptable acid addition salt thereof according to claim 1, wherein ⁴ is a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group. 3. R ^5a is a hydrogen atom, a lower alkyl group or a hydroxy (lower) alkyl group, R ^5b is a hydrogen atom or a lower alkyl group, and R ⁶ is a hydrogen atom, a lower alkyl group or a lower alkylsulfonyl group. Or R
3. The benzamide derivative or the physiologically acceptable acid addition salt thereof according to claim 2, wherein ^5a and R ⁶ together form a piperidine ring. 4. k is 0 or 1, and a, b, i and j
Is 2, the benzamide derivative or a physiologically acceptable acid addition salt thereof according to claim 3. 5. R ^5a is a hydrogen atom, a methyl group, an ethyl group or a hydroxymethyl group, and R ⁶ is a hydrogen atom or a methyl group, or R ^5a and R ⁶ together form a piperidine ring. The benzamide derivative or a physiologically acceptable acid addition salt thereof according to claim 4, wherein R ⁷ is a hydrogen atom or a methyl group. 6. The benzamide derivative or the physiologically acceptable acid addition salt thereof according to claim 5, wherein R ⁴ is a methoxy group or an ethoxy group. 7. An amino compound comprising: 4-amino-N- [1- [1- (3-aminopropyl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2-methoxybenzamide; N- [1- [1- (4-aminobutyl)-
4-piperidinylmethyl] -4-piperidinyl] -5-
Chloro-2-methoxybenzamide, 4-amino-N- [1- [1- (5-aminopentyl)
-4-piperidinylmethyl] -4-piperidinyl] -5
-Chloro-2-methoxybenzamide, 4-amino-5-chloro-N- [1- [1- (3-dimethylaminopropyl) -4-piperidinylmethyl] -4
-Piperidinyl] -2-methoxybenzamide, 4-amino-N- [1- [1- (4-aminobutyryl)]
-4-piperidinylmethyl] -4-piperidinyl] -5
-Chloro-2-methoxybenzamide, 4-amino-5-chloro-N- [1- (1-aminoacetyl-4-piperidinylmethyl) -4-piperidinyl]
-2-methoxybenzamide, 4-amino-N- [1- [1- (3-aminopropionyl) -4-piperidinylmethyl] -4-piperidinyl]
-5-chloro-2-methoxybenzamide, 4-amino-N- [1- [1- (3-aminobutyryl)
-4-piperidinylmethyl] -4-piperidinyl] -5
-Chloro-2-methoxybenzamide, 4-amino-N- [1- [1- (3-aminopropyl)
-4-piperidinylmethyl] -4-piperidinyl] -5
-Chloro-2-ethoxybenzamide, 4-amino-N- [1- [1- (3-aminopropyl)
-4-piperidinylcarbonyl] -4-piperidinylmethyl] -5-chloro-2-methoxybenzamide, 4-amino-N- [1- [1- (4-amino-5-hydroxypentyl) -4] -Piperidinylmethyl] -4-piperidinyl] -5-chloro-2-methoxybenzamide and (S) -4-amino-N- [1- [1- (4-amino-
5-hydroxypentyl) -4-piperidinylmethyl]
-4-piperidinyl] -5-chloro-2-methoxybenzamide, or a physiologically acceptable acid addition salt thereof. 8. A pharmaceutical composition comprising the benzamide derivative according to claim 1 or a physiologically acceptable acid addition salt thereof. 9. A gastrointestinal tract function improving agent comprising the benzamide derivative according to any one of claims 1 to 7 or a physiologically acceptable acid addition salt thereof as an active ingredient.