JP2005104896A - 2-alkoxy-6-amino-5-halogenopyridine-3-carboxamide derivative and pharmaceutical composition containing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide compounds which exhibit a strong agonistic action on a 5-HT<SB>4</SB>receptor and are useful as drugs for accelerating the movement of digestive organs or improving functions. <P>SOLUTION: The compounds are represented by formula (I) [wherein R<SP>1</SP>is a halogen; R<SP>2</SP>is H, a lower alkyl or a lower alkanoyl; R<SP>3</SP>is a lower alkyl; X is the formula: (X-1) [wherein R<SP>4</SP>is a lower alkenyl, a lower alkynyl, -CH=CH-A (wherein A is phenyl, an unsaturated monocycle or bicyclic hereocycle or a saturated monocyclic heterocycle) or -(CH<SB>2</SB>)<SB>n</SB>-B (wherein B is a saturated monocyclic heterocycle; and n is an integer of 0-3); and in the above both definitions, when N is present in the saturated monocyclic heterocycle, the N may has a substituent of a lower alkyl, a lower alkanoyl or a lower alkoxyxcarbonyl] or the formula: (X-2) (wherein Z is -CO-, -CS- or -SO<SB>2</SB>-; Q<SP>1</SP>is a lower alkyl, a lower alkenyl or a lower alkynyl; and Q<SP>2</SP>is a lower alkenyl or a lower alkynyl)] and their salts are described. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

The present invention relates to a novel 2-alkoxy-6-amino-5-halogenopyridine having potent agonist (agonist) action on serotonin 4 receptor (hereinafter also referred to as “5-HT ₄ receptor”). The present invention relates to 3-carboxamide derivatives and pharmaceutical compositions containing the same. More specifically, a piperidine ring is bonded to the amine moiety, the piperidine ring has a (1-substituted-4-piperidinyl) methyl group at the 1-position, and 2-alkoxy-6-amino-5 at the 4-position of the piperidine ring. -It relates to a 3-substituted pyridine-3-carboxamide derivative having an amide bond with halogenopyridine-3-carboxylic acid.

Gastrointestinal motility of metoclopramide [4-amino-5-chloro-N- (2-diethylaminoethyl) -2-methoxybenzamide], which is a gastrointestinal motility promoter or a gastrointestinal function improving drug widely used in recent years From the study of serotonin receptors involved in promotion, the subtype 5-HT ₄ receptor was found. Then, such as metoclopramide or cisapride [cis-4-amino-5-chloro-N- [1- [3- (4-fluorophenoxy) propyl] -3-methoxy-4-piperidinyl] -2-methoxybenzamide] prokinetic action of benzamide derivatives, be due to the activation of 5-HT ₄ receptor was revealed (for example, see below non Patent literature 1 and 2).
Thus, compounds that activate 5-HT ₄ receptor widely distributed in the digestive tract is expected to promote the movement of the digestive tract.

In addition, as a compound having a piperidine ring, in Patent Document 1 below, a compound represented by the following formula, etc. selectively acts on a 5-HT ₄ receptor and is useful as a gastrointestinal function improving drug. Has been described.

[式中、Ｒ^１はハロゲン原子を意味し、Ｒ^２およびＲ^３は各々水素原子等であり、Ｒ^４は低級アルコキシ基であり、ａおよびｉは１または２であり、ｂおよびｊは２または３であり、ｋは０、１または２であり、Ｘは−（ＣＨ_２）_ｍ−等であり、ｍは１または２であり、Ａは下記式[ａ]または[ｂ]

[Wherein, R ¹ represents a halogen atom, R ² and R ³ are each a hydrogen atom, R ⁴ is a lower alkoxy group, a and i are 1 or 2, and b and j are 2 Or 3, k is 0, 1 or 2, X is — (CH ₂ ) _m — or the like, m is 1 or 2, and A is represented by the following formula [a] or [b]

(Wherein R ^5a and R ⁶ may be combined to form a pyrrolidine ring, piperidine ring, hexahydroazepine ring or morpholine ring, R ^5b is a hydrogen atom or the like, and R ⁶ is a hydrogen atom or the like. And R ⁷ means a hydrogen atom, etc. The definition of each substituent is omitted. ]

In addition, as a compound having a piperidine ring, in Patent Document 2 below, a compound represented by the following formula, etc. selectively acts on 5-HT ₄ receptor and is useful as a gastrointestinal function improving drug. Has been described.

[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 the like, and R ⁴ represents a hydrogen atom or a lower alkyl group. Means
X represents —NH— or —O—;
A means a group represented by the following formula (A-1), (A-2) or (A-3).

_{- (CH 2) p -C (} R 7) (R 8) -COR 9 (A-1)

(Wherein p represents 0, 1, 2, 3, 4 or 5, R ⁷ represents a hydrogen atom, a lower alkyl group or the like, R ⁸ represents a hydrogen atom or a lower alkyl group, and R ⁹ Means a lower alkoxy group or the like.)

-CO-R ¹⁰ (A-2)

Wherein R ¹⁰ is an optionally substituted phenyl (lower) alkyl group, an optionally substituted heteroaryl group, a saturated monocyclic or bicyclic heterocycle, a cycloalkyl group, a lower alkenyl group. , A trifluoromethyl group, a lower alkyl group substituted with a heteroaryl, etc.)

^{_{- (CH 2) q -Z-}} R 11 (A-3)

(Wherein q represents 0, 1, 2, 3 or 4; Z represents —CH ₂ — or —O—; R ¹¹ represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, or the like. However, (1) when q is 0, Z is —CH ₂ — etc.)]

DOUGLAS. A. CRAIG, 1 other, “J. Pharmacol. Exp. Ther”, USA, 1990, Vol. 252, p. 1378-1386 Y. YOSHIDA, 3 others, “J. Pharmacol. Exp. Ther”, USA, 1991, Vol. 257, p. 781-787 Japanese Patent Laid-Open No. 11-1472 Japanese Patent Laid-Open No. 2000-80081

Metoclopramide and cisapride described in the background art show dopamine D ₂ receptor antagonistic action that contributes to side effects in addition to the action of activating 5-HT ₄ receptor. Therefore, it is difficult to use clinically. Cisapride is particularly difficult to use clinically because serious side effects on the heart were observed. On the other hand, the development of excellent gastrointestinal motility promotors or gastrointestinal function improving drugs with few side effects has tended to increase due to the increasing number of patients suffering from indefinite digestive complaints due to the complexity of social life and the arrival of an aging society. This is strongly desired, and it can be said that this is a problem to be solved by the background art.

Accordingly, it is an object of the present invention to solve the above-mentioned problems of the background art and to provide a potent gastrointestinal motility promoting agent or gastrointestinal function improving agent which exhibits a strong agonist activity against the 5-HT ₄ receptor. And

In order to solve the above problems, the present inventors have developed a 4-amino-1-[(1-substituted-4-piperidinyl) methyl] piperidine derivative different from the structure of the compounds disclosed in Patent Documents 1 and 2. As a result of extensive research, 2-alkoxy-6-amino-5-halogenopyridine-3-, obtained by bonding a 4-aminopiperidine ring to a 2-, 5-, 6-substituted pyridine-3-carboxylic acid. The present inventors have found that a carboxamide derivative exhibits a strong agonist activity with respect to the 5-HT ₄ receptor and is useful as an excellent gastrointestinal motility promoting agent or gastrointestinal function improving agent.

  According to the present invention, a 2-alkoxy-6-amino-5-halogenopyridine-3-carboxamide derivative represented by the following formula (I):

〔式中、Ｒ^１はハロゲン原子を意味し、Ｒ^２は水素原子、低級アルキル基または低級アルカノイル基を意味し、Ｒ^３は低級アルキル基を意味し、Ｘは下記式（Ｘ−１）または（Ｘ−２）で表される基を意味する。

[Wherein R ¹ represents a halogen atom, R ² represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group, R ³ represents a lower alkyl group, and X represents the following formula (X-1) or This means a group represented by (X-2).

—CO—R ⁴ (X-1)
[Wherein R ⁴ represents a lower alkenyl group, a lower alkynyl group, —CH═CH—A (A represents a phenyl group, an unsaturated monocyclic or bicyclic heterocycle, or a saturated monocyclic heterocycle. Or — (CH ₂ ) _n —B (B means a saturated monocyclic heterocycle, n means 0, 1, 2 or 3) (in both definitions above) When a saturated monocyclic heterocycle contains a nitrogen atom, the nitrogen atom may have a substituent of a lower alkyl group, a lower alkanoyl group or a lower alkoxycarbonyl group. ]

^{-Z-N (Q 1) (} Q 2) (X-2)
(In the formula, Z represents —CO—, —CS— or —SO ₂ —, Q ¹ represents a lower alkyl group, a lower alkenyl group or a lower alkynyl group, and Q ² represents a lower alkenyl group or a lower alkynyl group. Means)))

And physiologically acceptable acid addition salts thereof (hereinafter sometimes referred to as “compounds of the present invention”), as well as pharmaceutical compositions containing the compounds of the present invention.

  Further provided are serotonin 4 receptor agonists comprising the compound represented by formula (I) and physiologically acceptable acid addition salts thereof as active ingredients.

  In addition, a gastrointestinal motility promoting agent or a gastrointestinal function improving agent comprising a compound represented by the formula (I) and a physiologically acceptable acid addition salt thereof as an active ingredient is provided.

  Examples of the physiologically acceptable acid addition salt of the compound represented by the formula (I) include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, and phosphate, And organic acid salts such as oxalate, maleate, fumarate, malonate, lactate, malate, citrate, tartrate, benzoate, methanesulfonate, succinate, etc. .

  Since the compounds represented by the formula (I) and physiologically acceptable acid addition salts thereof may exist as hydrates or solvates, these hydrates and / or solvates may also be present. Included in the compounds of the present invention.

  The compounds of the formula (I) optionally have one or more asymmetric carbon atoms and can therefore optionally exist in the form of two or more stereoisomers. These stereoisomers, mixtures thereof and racemates are included in the compounds of the present invention. In some cases, one or more geometric isomers exist, and these isomers are also included in the compound of the present invention.

  Terms used in this specification are explained below.

  The “lower alkyl group” means a saturated hydrocarbon group having 1 to 6 carbon atoms unless otherwise specified, and may be any of linear, branched or cyclic.

  Specific examples of the “lower alkyl group” include, for example, methyl, ethyl, propyl, cyclopropyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, cyclopropylmethyl, cyclobutyl, pentyl, cyclopentyl and hexyl.

  “Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a chlorine atom or a bromine atom.

  The “lower alkenyl group” means an alkenyl group having 2 to 6 carbon atoms in which at least one double bond is present, and may be any of linear, branched or cyclic. For example, vinyl, 1- or 2-methyl-vinyl, allyl, 1-propenyl, 2-methyl-2-propenyl, isopropenyl, 1-, 2- or 3-butenyl, 1- or 2-cyclopentenyl, 1- or Examples include 3-cyclohexenyl and 1,3-butadienyl.

  The “lower alkynyl group” means an alkynyl group having 2 to 6 carbon atoms in which at least one triple bond is present, and may be any of linear, branched or cyclic. Examples include ethynyl, 1- or 2-propynyl, 1-methyl-2-propynyl, 1-butynyl and 1-, 2-, 3- or 4-pentynyl.

  The “lower alkanoyl group” means a group in which a carbonyl group is bonded to an alkyl group having 1 to 6 carbon atoms, and specific examples thereof include acetyl, propionyl, and butyryl.

  The “lower alkoxycarbonyl group” means a group in which a carbonyl group is directly bonded to the lower alkoxy group, and the lower alkoxy group means a group in which an alkyl group having 1 to 6 carbon atoms is bonded to an oxygen atom. Specific examples thereof include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and t-butoxycarbonyl.

  “Unsaturated monocyclic or bicyclic heterocycle” means a 5- to 12-membered heterocycle containing at least one nitrogen atom, oxygen atom or sulfur atom. , Furan, thiophene, pyrazole, imidazole, pyridine, indole, benzisoxazole, quinoline and the like.

  “Saturated monocyclic heterocycle” means a 4-membered to 7-membered heterocycle containing at least one nitrogen atom, oxygen atom or sulfur atom. Specific examples thereof include azetidine, pyrrolidine, tetrahydrofuran , Tetrahydrothiophene, morpholine, piperidine, piperazine, tetrahydropyran, tetrahydrothiopyran, hexahydroazepine and the like. When the ring of the “saturated monocyclic heterocycle” contains at least one nitrogen atom, the nitrogen atom may have a substituent of a lower alkyl group, a lower alkanoyl group or a lower alkoxycarbonyl group. Good. When the ring contains at least one nitrogen atom, it preferably contains 1 to 2 nitrogen atoms in a saturated monocyclic heterocycle, and the nitrogen atom is a substituent of a lower alkoxycarbonyl group. It is preferable to have it. Specific examples include t-butoxycarbonylpyrrolidine and t-butoxycarbonylpiperidine.

In the definition of formula (X-1), when R ⁴ is —CH═CH—A or — (CH ₂ ) _n —B, and A or B is a saturated monocyclic heterocycle containing a nitrogen atom In addition to a carbon atom in the ring, a nitrogen atom may be directly bonded to —CH═CH— or — (CH ₂ ) _n —.

Among the compounds represented by formula (I), R ¹ is a chlorine atom or a bromine atom, R ² is a hydrogen atom, and R ³ is a methyl group, an ethyl group, a propyl group, or isopropyl. And compounds that are groups and physiologically acceptable acid addition salts thereof.

Further preferred compounds are those in the formula (I) wherein X is a group represented by the formula (X-1), wherein R ⁴ is a lower alkenyl group, lower alkynyl group, —CH═CH—A ( A represents a phenyl group, an unsaturated monocyclic or bicyclic heterocycle or a saturated monocyclic heterocycle.) Or — (CH ₂ ) _n —B (B is a saturated monocyclic heterocycle) A ring, and n is 0, 1, 2 or 3. (In both definitions above, when a saturated monocyclic heterocycle contains a nitrogen atom, the nitrogen atom May have a substituent of a lower alkyl group, a lower alkanoyl group or a lower alkoxycarbonyl group) and their physiologically acceptable acid addition salts.

  More preferred compounds include compounds represented by formula (I-1) or physiologically acceptable acid addition salts thereof.

[式中、Ｒ^１１は塩素原子または臭素原子を意味し、Ｒ^３１はメチル基、エチル基、プロピル基またはイソプロピル基を意味し、Ｒ^４１は低級アルケニル基、低級アルキニル基、−ＣＨ＝ＣＨ−Ａ^１（Ａ^１はフェニル基または不飽和もしくは飽和した単環性のヘテロ環を意味する。）または−（ＣＨ_２）_n−Ｂ（Ｂは飽和した単環性のヘテロ環を意味し、ｎは０，１，２または３を意味する。）を意味する（上記の両定義において、飽和した単環性のへテロ環内に窒素原子を含む場合には、当該窒素原子は低級アルキル基、低級アルカノイル基または低級アルコキシカルボニル基の置換基を有していてもよい。）。]

[Wherein R ¹¹ represents a chlorine atom or a bromine atom, R ³¹ represents a methyl group, an ethyl group, a propyl group or an isopropyl group, R ⁴¹ represents a lower alkenyl group, a lower alkynyl group, —CH═CH— A ¹ (A ¹ represents a phenyl group or an unsaturated or saturated monocyclic heterocycle) or — (CH ₂ ) _n —B (B represents a saturated monocyclic heterocycle, n Means 0, 1, 2 or 3) (in both definitions above, when a saturated monocyclic heterocycle contains a nitrogen atom, the nitrogen atom is a lower alkyl group, It may have a substituent of a lower alkanoyl group or a lower alkoxycarbonyl group. ]

  Particularly preferred compounds represented by the formula (I-1) include the following compounds or physiologically acceptable acid addition salts thereof.

  6-amino-5-chloro-N- [1- (1-methacryloyl-4-piperidinylmethyl) -4-piperidinyl] -2-methoxypyridine-3-carboxamide;

  6-amino-5-bromo-N- [1- (1-methacryloyl-4-piperidinylmethyl) -4-piperidinyl] -2-methoxypyridine-3-carboxamide;

  6-amino-5-chloro-2-methoxy-N- [1- (1-vinylacetyl-4-piperidinylmethyl) -4-piperidinyl] pyridine-3-carboxamide;

  6-amino-5-bromo-2-methoxy-N- [1- (1-vinylacetyl-4-piperidinylmethyl) -4-piperidinyl] pyridine-3-carboxamide;

  6-amino-N- [1- [1- (2-butinoyl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2-methoxypyridine-3-carboxamide;

  6-amino-5-bromo-N- [1- [1- (2-butinoyl) -4-piperidinylmethyl] -4-piperidinyl] -2-methoxypyridine-3-carboxamide;

  6-amino-5-chloro-2-methoxy-N- [1- [1- (2-tetrahydrofurancarbonyl) -4-piperidinylmethyl] -4-piperidinyl] pyridine-3-carboxamide;

  (R) -6-amino-5-chloro-2-methoxy-N- [1- [1- (2-tetrahydrofurancarbonyl) -4-piperidinylmethyl] -4-piperidinyl] pyridine-3-carboxamide;

  (S) -6-amino-5-chloro-2-methoxy-N- [1- [1- (2-tetrahydrofurancarbonyl) -4-piperidinylmethyl] -4-piperidinyl] pyridine-3-carboxamide;

  6-amino-5-bromo-2-methoxy-N- [1- [1- (2-tetrahydrofurancarbonyl) -4-piperidinylmethyl] -4-piperidinyl] pyridine-3-carboxamide,

  (R) -6-amino-5-bromo-2-methoxy-N- [1- [1- (2-tetrahydrofurancarbonyl) -4-piperidinylmethyl] -4-piperidinyl] pyridine-3-carboxamide;

  (S) -6-amino-5-bromo-2-methoxy-N- [1- [1- (2-tetrahydrofurancarbonyl) -4-piperidinylmethyl] -4-piperidinyl] pyridine-3-carboxamide;

  6-amino-5-chloro-2-methoxy-N- [1- [1- [3- [1- (t-butoxycarbonyl) -4-piperidinyl] acryloyl] -4-piperidinylmethyl] -4- Piperidinyl] pyridine-3-carboxamide,

  6-amino-5-bromo-2-methoxy-N- [1- [1- [3- [1- (t-butoxycarbonyl) -4-piperidinyl] acryloyl] -4-piperidinylmethyl] -4- Piperidinyl] pyridine-3-carboxamide,

  6-amino-5-chloro-2-methoxy-N- [1- [1- [3- [1- (t-butoxycarbonyl) -4-piperidinyl] propionyl] -4-piperidinylmethyl] -4- Piperidinyl] pyridine-3-carboxamide,

  6-amino-5-bromo-2-methoxy-N- [1- [1- [3- [1- (t-butoxycarbonyl) -4-piperidinyl] propionyl] -4-piperidinylmethyl] -4- Piperidinyl] pyridine-3-carboxamide,

  6-amino-5-bromo-2-methoxy-N- [1- [1- [3- (4-piperidinyl) propionyl] -4-piperidinylmethyl] -4-piperidinyl] pyridine-3-carboxamide;

  6-amino-5-chloro-2-methoxy-N- [1- [1- [3- (4-piperidinyl) propionyl] -4-piperidinylmethyl] -4-piperidinyl] pyridine-3-carboxamide;

  6-amino-5-bromo-2-methoxy-N- [1- [1- [trans-3- (4-piperidinyl) acryloyl] -4-piperidinylmethyl] -4-piperidinyl] pyridine-3-carboxamide ,and

  6-amino-5-chloro-2-methoxy-N- [1- [1- [trans-3- (4-piperidinyl) acryloyl] -4-piperidinylmethyl] -4-piperidinyl] pyridine-3-carboxamide .

As will be apparent from the test examples described below, the compounds of the present invention exhibit potent agonist activity at the 5-HT ₄ receptor, and therefore the compounds of the present invention and their physiologically acceptable compounds are achieved by the completion of the present invention. An excellent gastrointestinal motility promoting agent or gastrointestinal tract function improving agent comprising a salt as an active ingredient can be provided.

  The compound represented by the formula (I) can be produced, for example, by the following production methods (a) to (c).

Manufacturing method (a)
The compound in which X is a group represented by the formula (X-1) in the formula (I) is represented by the following formula (II):

(In the formula, the definitions of R ¹ , R ² and R ³ mean the same as above.)
In the compound represented by the following formula (III):

R ⁴ —COOH (III)

(In the formula, the definition of R ⁴ means the same as described above.)
It can manufacture by making the compound represented by these react.

  Examples of reactive derivatives of the compound of formula (III) include lower alkyl esters (particularly methyl esters), active esters, acid anhydrides, and acid halides (particularly acid chlorides). Specific examples of the active ester include p-nitrophenyl ester, pentachlorophenyl ester, pentafluorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester, 8-hydroxyquinoline. And esters of 2-hydroxyphenyl. As the acid anhydride, a symmetric acid anhydride or a mixed acid anhydride is used. Specific examples of the mixed acid anhydride include mixed acid anhydrides such as ethyl chlorocarbonate and chlorocarbonic acid alkyl esters such as isobutyl chlorocarbonate, chloro Mixed anhydrides with chlorocarbonic aralkyl esters such as benzyl carbonate, mixed anhydrides with chlorocarbonic arylesters such as phenyl chlorocarbonate, mixed anhydrides with alkanoic acids such as isovaleric acid and pivalic acid Is mentioned.

  When using the compound of formula (III) itself, 1,3-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N, N′-carbonyldiimidazole, benzotriazole-1 -Iloxytris (dimethylamino) phosphonium hexafluorophosphate, N, N'-carbonyldisuccinic acid imide, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, diphenylphosphoryl azide, propanephosphonic anhydride Can be reacted in the presence of a condensing agent. 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 or the like may be added and reacted.

  The reaction of the compound of formula (II) with the compound of formula (III) or a reactive derivative thereof is carried out in a solvent or without solvent. The solvent to be used should be appropriately selected according to the kind of the raw material compound. For example, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran and dioxane, methylene chloride, Examples include halogenated hydrocarbons such as chloroform, ketones such as acetone and methyl ethyl ketone, ethyl acetate, acetonitrile, dimethylformamide, and dimethyl sulfoxide. These solvents are used alone or in combination of two or more. .

  This reaction is performed in the presence of a base as 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, sodium bicarbonate. In addition, an alkali bicarbonate such as potassium bicarbonate, or an organic base such as triethylamine, tributylamine, diisopropylethylamine, and N-methylmorpholine can be used, but an excess amount of the compound of the formula (II) can also be used.

  While the reaction temperature varies depending on the type of raw material compound used, it is generally about −30 ° C. to about 200 ° C., preferably about −10 ° C. to about 150 ° C.

  Below, the manufacturing method of the compound of Formula (II) which is an intermediate body is demonstrated.

  The compound of the formula (II) can be produced, for example, by the methods shown in the following chemical formulas 7 and 9.

[Wherein L ¹ , L ² and L ³ represent protecting groups, but L ¹ and L ² and L ¹ and L ³ are protecting groups which are deprotected under different conditions, respectively, and M is a reaction of an alcohol An Ar represents a substituent represented by the following formula:

(In the formula, the definitions of R ¹ , R ² and R ³ are the same as those described above.) ]

(In the formula, the definitions of Ar, L ² , L ³ and M are the same as described above.)

Deprotection reaction : ( Deprotection reaction in Chemical Formulas 7 and 9)
In Chemical Formula 7 and Chemical Formula 9, the protecting group represented by L ² and L ³ means a protecting group that can be eliminated by hydrolysis or hydrogenolysis, and examples of the protecting group that can be eliminated by hydrolysis include ethoxy Carbonyl group, t-butoxycarbonyl group, acetyl group, benzoyl group, trifluoroacetyl group, benzyloxycarbonyl group, 3- or 4-chlorobenzyloxycarbonyl group, triphenylmethyl group, methanesulfonyl group, p-toluenesulfonyl group Etc. Examples of the protecting group that can be eliminated by hydrogenolysis include a benzyloxycarbonyl group, a 3- or 4-chlorobenzyloxycarbonyl group, and a benzylsulfonyl group.

  Deprotection by hydrolysis can be performed according to a conventional method, for example, by contacting with water in an appropriate solvent under acidic or basic conditions. As the solvent, for example, alcohols such as methanol, ethanol, isopropanol, acetonitrile, dioxane, water, or a mixture thereof can be used. Specific examples of the acid include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid and sulfuric acid, organic acids such as formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid and methanesulfonic acid. It is done. 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.

  Further, deprotection by hydrogenolysis can be carried out according to a conventional method. For example, the reaction is carried out in an appropriate 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. Is done. Examples of the solvent include alcohols such as ethanol and methanol, water, acetic acid, dioxane, tetrahydrofuran, ethyl acetate, dimethylformamide, and the like. The reaction temperature is usually about 0 ° C. to about 80 ° C., and the reaction is carried out at normal pressure or under pressure.

On the other hand, as the protecting group represented by L ¹ , the protecting groups mentioned in the above L ² and L ³ can be used, but L ¹ and L ² are protecting groups that are deprotected under different conditions. Similarly, L ¹ and L ³ are protecting groups that are similarly deprotected under different conditions.

Reduction reaction : (Step 3 of Chemical Formula 7 and Step 4 of Chemical Formula 9)
This reduction reaction is carried out in a solvent using an appropriate reducing agent. That is, 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) And sodium borohydride to which is added. This reduction reaction is carried out in an ether such as diethyl ether, tetrahydrofuran, dimethoxyethane, dioxane and diglyme, and in a solvent such as toluene, chloroform and methylene chloride, and is appropriately selected depending on the type of reducing agent used. While the reaction temperature varies depending on the type of reducing agent, etc., it is generally about 0 ° C. to about 160 ° C., preferably about 10 ° C. to 80 ° C.

Alkylation reaction : (Step 2b of Chemical Formula 7 and Step 3b of Chemical Formula 9)
The alkylation using the compound of the formula (C _2a ) in Step 2b of Chemical Formula 7 and Step 3b of Chemical Formula 9 is carried out in a solvent or without solvent. The solvent to be used should be appropriately selected according to the kind of the raw material compound. For example, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran and dioxane, methylene chloride, Examples include halogenated hydrocarbons such as chloroform, alcohols such as ethanol and isopropanol, ketones such as acetone and methyl ethyl ketone, ethyl acetate, acetonitrile, dimethylformamide, dimethyl sulfoxide, and ethylene glycol. It is used alone or in combination of two or more.

  This reaction is performed in the presence of a base as 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, sodium bicarbonate. , Alkali bicarbonates such as potassium bicarbonate, or organic bases such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, but can also be combined with an excess of amine as a substrate for alkylation. is there.

  Examples of the alcohol reactive ester residue represented by the symbol M include halogen atoms such as chlorine, bromine and iodine, lower alkylsulfonyloxy groups such as methanesulfonyloxy, benzenesulfonyloxy and p-toluenesulfonyloxy. Examples of such arylsulfonyloxy groups include halogen atoms, particularly chlorine and bromine, or methanesulfonyloxy and p-toluenesulfonyloxy.

  When M is chlorine or bromine, the reaction proceeds smoothly when an alkali metal iodide such as sodium iodide or potassium iodide is added. While the reaction temperature varies depending on the type of raw material compound used, it is generally about 0 ° C to about 200 ° C, preferably about 20 ° C to about 150 ° C.

The reductive alkylation using the compound of the formula (C _2b ) in Step 2b of Chemical Formula 7 and Step 3b of Chemical Formula 9 is catalytic reduction using platinum dioxide as a catalyst in the presence of a catalytic amount of acid, or pyridine borane. In the presence of a borane complex such as triethylborane or sodium cyanoborohydride. As the solvent to be used, the solvent used in the alkylation using the compound of the above formula (C _2a ) is used. As the acid used, p-toluenesulfonic acid or the like is used. The reaction temperature is generally about 0 ° C to about 100 ° C, preferably about 20 ° C to about 80 ° C.

Amidation reaction : (Step 2a and Step 5 in Chemical Formula 7 and Step 1 and Step 3a in Chemical Formula 9)
This amidation reaction can be carried out using the method described in the production method (c) described later. The compound represented by Ar—COOH used in the above steps can be produced by the methods shown in Reference Examples 1 to 3 described below or known methods.

  On the other hand, the compound of the formula (III) is commercially available or can be produced by a known method.

Manufacturing method (b)
In the formula (I), a compound in which X is a group represented by the formula (X-2) is represented by the following formula (II):

(Wherein R ¹ , R ² and R ³ are the same as described above)
In the compound represented by the following formula (IV):

MZN (Q ¹ ) (Q ² ) (IV)

(Wherein M represents a leaving group, and Z, Q ¹ and Q ² represent the same as described above)
It can manufacture by making the compound represented by these react.

  Examples of the leaving group represented by the symbol M include a chlorine atom, a bromine atom, and an iodine atom, and a chlorine atom is preferable.

  The reaction between the compound of formula (II) and the compound of formula (IV) is carried out in a solvent or without a solvent. The solvent to be used should be appropriately selected according to the type of raw material compound, etc., for example, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran and dioxane, methylene chloride, Examples include halogenated hydrocarbons such as chloroform, ketones such as acetone and methyl ethyl ketone, ethyl acetate, acetonitrile, dimethylformamide, and dimethyl sulfoxide. These solvents are used alone or in combination of two or more. .

  This reaction is performed in the presence of a base as 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, sodium bicarbonate. , Alkali bicarbonates such as potassium bicarbonate, or organic bases such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, but can be combined with an excess of the compound of formula (II). . While the reaction temperature varies depending on the type of raw material compound used, it is generally about −20 ° C. to about 150 ° C., preferably about −10 ° C. to about 80 ° C.

The compound of the formula (IV) is prepared from the corresponding HN (Q ¹ ) (Q ² ) compound, which is commercially available, in the presence of the base described in the above production method (a), N, N′-carbonyldiimidazole, Phosgene, diphosgene, triphosgene, thiophosgene, sulfuryl chloride, di (2-pyridyl) carbonate, N, N′-disuccinimidyl carbonate, bis (4-nitrophenyl) carbonate, bis (trichloromethyl) carbonate, phenoxycarbonyltetrazole, Phenyl chlorocarbonate, chloromethyl chlorocarbonate, 2,4,5-trichlorophenyl chlorocarbonate, trichloromethyl chlorocarbonate, 1-chloroethyl chlorocarbonate, 1,2,2,2-tetrachloroethyl chlorocarbonate, norborn-5-chlorocarbonate It can be produced by reacting ene-2,3-dicarboxyimidyl and the like. This reaction can be carried out in the solvent and reaction conditions described in the above production method (a).

  For example, the following compounds can be produced by the above production method.

N- [1- [1- (N-allyl-N-methylaminocarbonyl) -4-piperidinylmethyl] -4-piperidinyl] -6-amino-5-chloro-2-methoxypyridine-3-carboxamide;

  6-amino-5-chloro-2-methoxy-N- [1- [1- (N-methyl-N-2-propynylaminocarbonyl) -4-piperidinylmethyl] -4-piperidinyl] pyridine-3- Carboxamide,

  6-amino-5-chloro-N- [1- [1- [N-ethyl-N- (2-methyl-allyl) aminocarbonyl] -4-piperidinylmethyl] -4-piperidinyl] -2-methoxy Pyridine-3-carboxamide,

  6-amino-5-chloro-N- [1- [1- (N, N-diallylaminocarbonyl) -4-piperidinylmethyl] -4-piperidinyl] -2-methoxypyridine-3-carboxamide;

  N- [1- [1- (N-allyl-N-methylaminocarbonyl) -4-piperidinylmethyl] -4-piperidinyl] -6-amino-5-bromo-2-methoxypyridine-3-carboxamide;

  6-amino-5-bromo-2-methoxy-N- [1- [1- (N-methyl-N-2-propynylaminocarbonyl) -4-piperidinylmethyl] -4-piperidinyl] pyridine-3- Carboxamide,

  6-amino-5-bromo-N- [1- [1- [N-ethyl-N- (2-methyl-allyl) aminocarbonyl] -4-piperidinylmethyl] -4-piperidinyl] -2-methoxy Pyridine-3-carboxamide, and

  6-Amino-5-bromo-N- [1- [1- (N, N-diallylaminocarbonyl) -4-piperidinylmethyl] -4-piperidinyl] -2-methoxypyridine-3-carboxamide.

Manufacturing method (c)
The compound of formula (I) is represented by the following formula (V):

(In the formula, the definitions of R ¹ , R ² and R ³ mean the same as above.)
Or a reactive derivative thereof, and the following formula (VI):

(In the formula, X means a group represented by the formula (X-1) or the formula (X-2)).
It can manufacture by making the compound represented by these react.

  Examples of reactive derivatives of the compound of formula (V) include lower alkyl esters (particularly methyl esters), active esters, acid anhydrides, and acid halides (particularly acid chlorides). Specific examples of the active ester include p-nitrophenyl ester, pentachlorophenyl ester, pentafluorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester, 8-hydroxyquinoline. And esters of 2-hydroxyphenyl. As the acid anhydride, a symmetric acid anhydride or a mixed acid anhydride is used. Specific examples of the mixed acid anhydride include mixed acid anhydrides such as ethyl chlorocarbonate and chlorocarbonic acid alkyl esters such as isobutyl chlorocarbonate, chloro Mixed anhydrides with chlorocarbonic aralkyl esters such as benzyl carbonate, mixed anhydrides with chlorocarbonic arylesters such as phenyl chlorocarbonate, mixed anhydrides with alkanoic acids such as isovaleric acid and pivalic acid Is mentioned.

  When the compound of formula (V) itself is used, 1,3-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N, N′-carbonyldiimidazole, benzotriazole-1 -Iloxytris (dimethylamino) phosphonium hexafluorophosphate, N, N'-carbonyldisuccinic acid imide, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, diphenylphosphoryl azide, propanephosphonic anhydride Can be reacted in the presence of a condensing agent. 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 or the like may be added and reacted.

  The reaction of the compound of formula (V) or a reactive derivative thereof and the compound of formula (VI) is carried out in a solvent or without solvent. The solvent to be used should be appropriately selected according to the kind of the raw material compound. For example, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran and dioxane, methylene chloride, Examples include halogenated hydrocarbons such as chloroform, ketones such as acetone and methyl ethyl ketone, ethyl acetate, acetonitrile, dimethylformamide, and dimethyl sulfoxide. These solvents are used alone or in combination of two or more. .

  This reaction is performed in the presence of a base as 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, sodium bicarbonate. , Alkali bicarbonates such as potassium bicarbonate, or organic bases such as triethylamine, tributylamine, diisopropylethylamine, and N-methylmorpholine, but may be combined with an excess of the compound of formula (V).

  While the reaction temperature varies depending on the type of raw material compound used, it is generally about −30 ° C. to about 200 ° C., preferably about −10 ° C. to about 150 ° C.

  The compound of Formula (V) can be manufactured by the method shown to the postscript reference examples 1-3, or a well-known method.

  Moreover, the compound of Formula (VI) can be manufactured, for example by the method shown by following Chemical formula 13.

(In the formula, the definitions of L ¹ , L ³ , M, Z and X are the same as described above.)
Step 2 of Chemical Formula 13 can be carried out using the methods described in the above production methods (a) and (b), and Steps 1 and 3 can be carried out using the aforementioned deprotection reaction.

  The compounds produced by the above production methods are isolated and purified by conventional methods such as chromatography, recrystallization and reprecipitation.

  The compound represented by the formula (I) can be obtained in the form of a free base or an acid addition salt depending on the selection of raw material compounds, reaction / treatment conditions, and the like. The acid addition salt can be converted to the free base by a conventional method, for example, treatment with a base such as alkali carbonate or alkali hydroxide. On the other hand, the free base can be converted into an acid addition salt by treating with various acids according to a conventional method.

As apparent from the test shown below, the compounds of the present invention show a potent agonist activity relative to 5-HT ₄ receptors, 5-HT ₄ receptor as 5-HT ₄ receptor agonist stimulation It can be used for the treatment and prevention of diseases or disorders resulting from deficiency. Specifically, gastrointestinal irritable bowel syndrome, flaccid constipation, habitual constipation, constipation induced by drugs such as morphine and antipsychotics, acute / chronic gastritis, reflux esophagitis, gastric neuropathy , Postoperative paralytic ileus, senile ileus, post-gastrectomy syndrome, treatment and prevention of digestive system diseases such as pseudo-intestinal obstruction, and these digestive system diseases and gastroduodenal ulcers, scleroderma, diabetes, It can be used for the treatment and prevention of anorexia, nausea, vomiting, abdominal discomfort, upper abdominal discomfort, abdominal pain, heartburn, ambiguity, etc. in diseases such as esophageal and biliary tract diseases. Furthermore, it can also be used for the treatment and prevention of central nervous system diseases (schizophrenia, depression, memory impairment, anxiety, etc.) and urinary system diseases (urinary tract obstruction, dysuria due to prostatic hypertrophy, etc.). As described above, the compound of the present invention can be used for the treatment and prevention of various gastrointestinal dysfunctions associated with the above-mentioned various diseases, particularly digestive system diseases and the above-mentioned various diseases. It is particularly useful as a promoter or a gastrointestinal function improving drug.

  The administration route may be oral administration, parenteral administration, or rectal administration. The dose varies depending on the type of compound, administration method, patient symptom / age, etc., but is usually in the range of 0.01 to 30 mg / kg / day, preferably 0.05 to 10 mg / kg / day.

  When the compound represented by the formula (I) or a physiologically acceptable acid addition salt thereof is used for pharmaceutical use as described above, it is usually administered in the form of a preparation prepared by mixing with a pharmaceutical carrier. As a pharmaceutical carrier, a substance which is commonly used in the pharmaceutical field and does not react with the compound represented by the formula (I) or a physiologically acceptable acid addition salt thereof 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, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, alginic acid, sodium alginate, light anhydrous silicic acid, Magnesium stearate, talc, tragacanth, bentonite, beegum, Ruboxyvinyl polymer, titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin, fatty acid glycerin ester, purified lanolin, glycerogelatin, polysorbate, macrogol, vegetable oil, wax, water, propylene glycol, ethanol, sodium chloride, sodium hydroxide Hydrochloric acid, citric acid, benzyl alcohol, glutamic acid, glycine, methyl paraoxybenzoate, propyl paraoxybenzoate and the like.

  Examples of the dosage form include tablets, capsules, granules, powders, syrups, suspensions, injections, suppositories, nasal agents, and sublingual agents. These preparations are prepared according to a conventional method. The liquid preparation may be dissolved or suspended in water or other suitable medium at the time of use. Tablets and granules may be coated by a known method. In the case of an injection, it is prepared by dissolving the compound represented by formula (I) in water, but it may be dissolved using a tonicity agent or a solubilizing agent as necessary, and pH Regulators, buffers and preservatives may be added.

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

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

  In the following reference examples and examples, the following abbreviations may be used for the sake of simplicity.

[Recrystallization solvent]
E: ethanol,
AC: acetone,
IP: isopropanol,
T: Toluene,
DE: diethyl ether,
AN: acetonitrile.

[NMR]
s: single line,
d: double line,
t: Triple line,
m: multiple line,
br.s: Wide single line,
J: coupling constant.

Reference example 1:
Preparation of 6-benzylamino-2-methoxypyridine-3-carboxylic acid methyl ester:

Method 1 : (1) A mixture of 6.1 g of 2-methoxy-6- (p-toluenesulfinyl) pyridine-3-carboxylic acid methyl ester, 3.6 g of benzylamine and 60 ml of dimethylformamide was heated at 100 ° C. for 23 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography to obtain two fractions eluted with ethyl acetate / hexane = 10/1 to 5/1. The low polar part was obtained as a solid with 2.4 g of 6-dimethylamino-2-methoxypyridine-3-carboxylic acid methyl ester, and the high polar part was the target product (6-benzylamino-2-methoxypyridine-3-carboxylic acid). 1.6 g of a methyl ester as a solid.

Method 2: (2-1) 34.9 g of di-t-butyl dicarbonate dicarbonate was added dropwise to a solution of 17.1 g of benzylamine in 300 ml of chloroform under ice cooling. After stirring at room temperature for 15.5 hours, the reaction solution was washed with water and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 34.5 g of N-benzyl-N- (t-butoxycarbonyl) amine as an oil.

(2-2) 7.0 g of about 60% sodium hydride was added little by little to a solution of 34.5 g of the above product in 400 ml of dimethylformamide under ice cooling. After the internal temperature was raised from 40 ° C. to 50 ° C., 34.6 g of 2,6-dichloro-3-trifluoromethylpyridine was slowly added. After stirring at the same temperature for 2.5 hours, 100 ml of saturated aqueous sodium hydrogen carbonate and 500 ml of water were added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 6- [N-benzyl-N- (t-butoxycarbonyl) amino] -2-chloro-3. 62.7 g of a residue containing trifluoromethylpyridine was obtained.

(2-3) A mixture of 62.7 g of the above crude product, 123.4 g of 28% sodium methoxide in methanol, and 800 ml of tetrahydrofuran was refluxed for 18.5 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, water was added to the resulting residue, and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 6-benzylamino-2-chloro-3-trimethoxymethylpyridine and 6-benzylamino-2- 50.8 g of a mixture of methoxy-3-trimethoxymethylpyridine was obtained.

(2-4) 50.8 g of the above mixture was dissolved in 600 ml of methanol and 5.7 g of water, 3 ml of 5% sulfuric acid aqueous solution was added, and the mixture was stirred at 60 to 70 ° C. for 4.5 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the resulting residue, and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 6-benzylamino-2-chloropyridine-3-carboxylic acid methyl ester and 6-benzylamino-2. 43.6 g of a mixture with -methoxypyridine-3-carboxylic acid methyl ester were obtained.

(2-5) A mixture of 17.5 g of the above mixture, 36.5 g of 28% sodium methoxide in methanol and 350 ml of tetrahydrofuran was refluxed for 16 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, water was added to the resulting residue, and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain crude 6-benzylamino-2-methoxypyridine-3-carboxylic acid methyl ester solid, This solid was subjected to silica gel flash column chromatography, eluted and purified with ethyl acetate / hexane (10/1), and the obtained solid was recrystallized from ethyl acetate / hexane to obtain 2.8 g of the desired product as crystals. It was.

Reference example 2:
Preparation of 6-amino-5-chloro-2-methoxypyridine-3-carboxylic acid:

(1) A mixture of 2.3 g of 6-benzylamino-2-methoxypyridine-3-carboxylic acid methyl ester, 0.7 g of 10% palladium carbon, 60 ml of ethanol and 6 ml of acetic acid was subjected to catalytic reduction at room temperature and normal pressure. After confirming the absorption of a theoretical amount of hydrogen gas, the catalyst was removed by filtration under reduced pressure, and the residue obtained by distilling off the filtrate under reduced pressure was dissolved in chloroform. The organic layer was washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 6-amino-2-methoxypyridine-3-carboxylic acid methyl ester as a solid. 1.5 g was obtained.

(2) A mixture of 1.5 g of the above product, 1.1 g of N-chlorosuccinimide and 15 ml of dimethylformamide was heated at 80 ° C. for 2 hours. After cooling to room temperature, water was added to the reaction solution, and the precipitated crystals were collected by filtration, washed with water, and dried to obtain 1.6 g of 6-amino-5-chloro-2-methoxypyridine-3-carboxylic acid methyl ester. .

(3) A mixture of 1.55 g of the above product, 7.5 ml of 2 mol / l sodium hydroxide aqueous solution and 20 ml of methanol was refluxed for 4 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the residual solid was dissolved in water. The aqueous solution was acidified with 2 mol / l hydrochloric acid (added about 7.5 ml), and the precipitated solid was collected by filtration, washed with water and dried to obtain 1.4 g of the desired product.

Reference Example 3:
Preparation of 6-amino-5-bromo-2-methoxypyridine-3-carboxylic acid:

  Using N-bromosuccinimide in place of N-chlorosuccinimide in (2) of Reference Example 2, reaction and treatment were performed in the same manner as in Reference Examples 2 (2) and (3) to obtain the desired product.

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

(1) To a 600 ml chloroform solution of 95 g of 4-amino-1-benzylpiperidine, a 60 ml chloroform solution of 109 g of di-t-butyl dicarbonate was added dropwise under ice cooling. After stirring at room temperature for 5 hours, the reaction mixture was washed twice with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, petroleum ether was added to the resulting residue, the insoluble solid was collected by filtration and dried to give 136 g of 1-benzyl-4- (t-butoxycarbonylamino) piperidine. Was obtained as a solid.

(2) 5 g of 10% palladium carbon was added to a solution of 70 g of the product and 600 ml of ethanol, and catalytic reduction was performed at 40 ° C. under normal pressure. After absorbing the theoretical amount of hydrogen, the catalyst was removed by filtration, and ethanol in the filtrate was distilled off under reduced pressure to obtain 48.6 g of 4- (t-butoxycarbonylamino) piperidine as a solid. Melting point: 155-158 ° C

(3) To a solution of 26 g of 1-benzyloxycarbonyl-4-piperidinecarboxylic acid in 200 ml of methylene chloride, 14.4 ml of thionyl chloride was added dropwise at room temperature. After heating under reflux for 1 hour, the solvent and excess thionyl chloride were distilled off under reduced pressure. After adding 400 ml of methylene chloride to the residue, a mixture of 20 g of the above product 4- (t-butoxycarbonylamino) piperidine and 27 ml of triethylamine was added under ice cooling. After stirring at room temperature for 4 hours, the reaction solution was washed with water, 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 39 g of 1- (1-benzyloxycarbonyl-4-piperidinylcarbonyl) -4- (t-butoxycarbonylamino) piperidine as a solid. 150-152 ° C (recrystallized from ethyl acetate)

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

Reference example 5:
Preparation of 4-amino-1- (1-benzyloxycarbonyl-4-piperidinylmethyl) piperidine:

  1- (1-benzyloxycarbonyl-4-piperidinylmethyl) -4- (t-butoxycarbonylamino) piperidine (7.8 g) in ethanol (30 ml) was added with 30% hydrochloric acid ethanol solution (15 ml) under ice cooling. And stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in water, made alkaline with potassium carbonate, and extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 6.0 g of the desired product as an oil.

Reference Example 6:
Preparation of 4-amino-1- [1- (3-cyclohexene-1-carbonyl) -4-piperidinylmethyl] piperidine:

(1) 3.0 g of 10% palladium carbon in a solution of 35 g of 1-[(1-benzyloxycarbonyl) -4-piperidinylmethyl] -4- (t-butoxycarbonylamino) piperidine in 300 ml of ethanol and 15 ml of water. In addition, catalytic reduction was carried out for 4 hours under medium pressure (2.5 to 3.0 kgf / cm ² ). The catalyst was removed by filtration, and the solvent of the filtrate was distilled off under reduced pressure. The solid residue was triturated with diethyl ether, filtered and dried to give 24 g of 1- (4-piperidinylmethyl) -4- (t-butoxycarbonylamino) piperidine as a white solid.

(2) A mixture of 1.0 g of the above product, 0.47 g of 3-cyclohexene-1-carboxylic acid, 0.71 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 15 ml of methylene chloride at room temperature. Stir for 4 hours. The reaction solution was washed with water, a saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the solid residue was recrystallized with ethyl acetate to give 1-[(3-cyclohexene-1-carbonyl) -4-piperidinylmethyl] -4- (t-butoxycarbonylamino). ) 0.68 g of piperidine was obtained as white crystals.

¹ H-NMR spectrum (CDCl ₃ , δ ppm): 0.95-1.20 (2H, m), 1.25-1.53 (2H, m), 1.44 (9H, s), 1. 6-2.2 (13H, m), 2.33 (1H, m), 2.54 (1H, t, J = 12.0 Hz), 2.61-2.82 (3H, m), 3 .00 (1H, t, J = 12.0 Hz), 3.44 (1H, m), 3.92 (1H, d, J = 12.8 Hz), 4.41 (1H, m), 4 .63 (1H, d, J = 13.5 Hz), 5.60-5.80 (2H, m).

(3) To a solution of 0.68 g of the above product in 15 ml of methylene chloride was added 15 ml of trifluoroacetic acid at room temperature, and the mixture was stirred for 30 minutes. The solvent and the like were distilled off under reduced pressure, toluene was added to the residue, and the solvent was distilled off under reduced pressure again. The residue was dissolved in water, the liquidity was adjusted to alkaline with 2 mol / l sodium hydroxide solution, and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.5 g of the desired product.

  Reference Example A shown below is a reference example of Intermediate (II).

Reference example A:
Preparation of 6-amino-5-chloro-2-methoxy-N- [1- (4-piperidinylmethyl) -4-piperidinyl] pyridine-3-carboxamide:

(1) 390 mg of N, N′-carbonyldiimidazole was added to a solution of 490 ml of 6-amino-5-chloro-2-methoxypyridine-3-carboxylic acid in 10 ml of dimethylformamide at room temperature and stirred for 1 hour. A solution of 790 mg of amino-1- (1-benzyloxycarbonyl) -4-piperidinylmethyl) piperidine in 5 ml of dimethylformamide was added. After the mixture was stirred at room temperature for 24 hours, the solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform. The chloroform solution was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, eluted and purified from chloroform to chloroform / methanol (40/1) to give 6-amino-N-[[1- (1-benzyloxycarbonyl) -4-pi. Periginylmethyl] -4-piperidinyl] -5-chloro-2-methoxypyridine-3-carboxamide 1.0 g was obtained as an oil.

(2) A mixture of 1.0 g of the above product, 1.9 g of methanesulfonic acid, 2.2 g of anisole, and 20 ml of chloroform was refluxed for 4 hours. After cooling to room temperature and removing most of the organic layer by decantation, the residue was dissolved in water. The aqueous solution was washed with chloroform, solid potassium carbonate was added to the aqueous layer, and the mixture was extracted with chloroform. The chloroform solution was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to basic silica gel column chromatography, and eluted and purified from chloroform with chloroform / methanol (40/1) to obtain 0.3 g of the desired product as an amorphous product.

(3) The above free base was treated with fumaric acid according to a conventional method to obtain the desired difumarate salt ¼ hydrate. Melting point 175-177 ° C (recrystallization from ethanol)

¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 1.1-1.4 (2H, q, J = 12.0 Hz), 1.45-1.6 (2H, q, J = 10. 0 Hz), 1.8 (5H, d, J = 12.0 Hz), 2.0-2.25 (4H, m), 2.7-2.9 (4H, m), 3.3 ( 2H, d, J = 12.0 Hz), 3.8 (1H, br.s), 3.92 (3H, s), 6.53 (2H, s), 6.92 (2H, s), 7.65 (1H, d, J = 7 Hz), 7.91 (1H, s).

Example 1:
Preparation of 6-amino-5-chloro-N- [1- (1-methacryloyl-4-piperidinylmethyl) -4-piperidinyl] -2-methoxypyridine-3-carboxamide:

 In a 30 ml methylene chloride solution of 1.0 g of 6-amino-5-chloro-2-methoxy-N- [1- (4-piperidinylmethyl) -4-piperidinyl] pyridine-3-carboxamide and 0.3 g of triethylamine. 274 mg of methacryloyl chloride was added at room temperature and stirred for 2 hours. The reaction solution was washed with water, 10% aqueous sodium hydroxide solution, water and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted and purified from chloroform to chloroform / methanol (9/1) to obtain 1.0 g of the desired product as an amorphous substance. According to a conventional method, the free base was treated with fumaric acid to obtain the desired fumarate salt. Melting point: 224-225 ° C (recrystallized from ethanol)

¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 0.85-1.1 (2H, m), 1.47-1.95 (7H, m), 1.84 (3H, s), 2 1-2.3 (4H, m), 2.4-3.1 (4H, m), 3.7-4.05 (2H, m), 3.92 (3H, s), 4.29 (1H, m), 4.92 (1H, s), 5.12 (1H, s), 6.60 (2H, s), 6.91 (2H, s), 7.65 (1H, d, J = 7.7 Hz), 7.91 (1H, s).

Example 2:
Preparation of 6-amino-5-chloro-2-methoxy-N- [1- (1-vinylacetyl-4-piperidinylmethyl) -4-piperidinyl] pyridine-3-carboxamide:

(1) 1-[(1-benzyloxycarbonyl) -4-piperidinylmethyl] -4- (t-butoxycarbonylamino) piperidine 35 g in a mixed solution of ethanol 300 ml and water 15 ml 10% palladium carbon 3. 0 g was added, and catalytic reduction was performed for 4 hours under medium pressure (2.5 to 3.0 kg / cm ² ). The catalyst was removed by filtration, and the solvent of the filtrate was distilled off under reduced pressure. The solid residue was triturated with diethyl ether, filtered and dried to give 24 g of 4- (t-butoxycarbonylamino) -1- (4-piperidinylmethyl) piperidine as a white solid.

(2) A mixture of 2.0 g of the above product, 0.64 g of vinyl acetate, 1.42 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, and 20 ml of methylene chloride was stirred at room temperature for 4 hours. The reaction solution was washed with water, 20% aqueous potassium carbonate solution, and then with saturated brine, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by flash silica gel column chromatography (eluent: chloroform / methanol = 30/1) to give 1- (1-vinylacetyl-4-piperidinylmethyl) -4- ( 2.0 g of (t-butoxycarbonylamino) piperidine was obtained as a white solid.

¹ H-NMR spectrum (CDCl ₃ , δ ppm): 0.95-1.15 (2H, m), 1.3-1.55 (2H, m), 1.44 (9H, s), 1. 6-2.15 (7H, m), 2.14 (2H, d, J = 6.7 Hz), 2.55 (1H, m), 2.66-2.85 (2H, m), 2 .98 (1H, m), 3.14 (2H, d, J = 6.6 Hz), 3.45 (1H, m), 3.82 (1H, m), 4.41 (1H, m) , 4.59 (1H, m), 5.07-5.1 (2H, m), 5.95 (1H, m).

(3) To a solution of 1.5 g of the above product in 10 ml of methylene chloride was added 5 ml of trifluoroacetic acid at room temperature, and the mixture was further stirred for 30 minutes. The solvent and the like were distilled off under reduced pressure, toluene was added to the residue, and the solvent was distilled off under reduced pressure again. The residue was dissolved in water, adjusted to alkaline with 20% aqueous potassium carbonate solution, and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.0 g of 4-amino-1- (1-vinylacetyl-4-piperidinylmethyl) piperidine as a pale yellow oil.
(4) A solution of 0.4 g of 6-amino-5-chloro-2-methoxypyridine-3-carboxylic acid and 0.35 g of N, N′-carbonyldiimidazole in 10 ml of dimethylformamide was stirred at room temperature for 2 hours. The above product was added thereto and stirred at room temperature for 16 hours. The reaction solution was washed with water, a saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 40/1) to obtain 0.7 g of the desired product as a pale yellow oil. According to a conventional method, the free base was treated with fumaric acid to obtain the desired fumarate salt. Melting point 203-204 ° C. (recrystallization from ethanol)

¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 0.86-1.1 (2H, m), 1.44-1.9 (7H, m), 2.0-2.3 (4H, m), 2.49 (1H, m), 2.68-2.85 (2H, m), 2.96 (1H, m), 3.11 (2H, d, J = 6.2 Hz), 3.7-4.0 (2H, m), 3.91 (3H, s), 4.32 (1H, m), 4.95-5.2 (2H, m), 5.85 (1H, m), 6.59 (2H, s), 6.90 (2H, s), 7.64 (1H, d, J = 7.7 Hz), 7.90 (1H, s).

Examples 3-6:
Using the corresponding carboxylic acids instead of vinyl acetic acid in Example 2 (2), the reaction and treatment were carried out in the same manner as in Example 2 (2 to 4) to obtain the compounds shown in Table 1 below.

Examples 7-12:
Various carboxylic acids corresponding to vinyl acetate in Example 2 (2) and 6-amino-5 instead of 6-amino-5-chloro-2-methoxypyridine-3-carboxylic acid in Example 2 (4) Using -bromo-2-methoxypyridine-3-carboxylic acid, the reaction and treatment were carried out in the same manner as in Example 2 (2-4) to obtain the compounds shown in Table 2 below.

Example 13:
Preparation of 6-amino-5-bromo-2-methoxy-N- [1- [1- [3- (4-piperidinyl) propionyl] -4-piperidinylmethyl] -4-piperidinyl] pyridine-3-carboxamide :

  6-amino-5-bromo-2-methoxy-N- [1- [1- [3- [1- (t-butoxycarbonyl) -4-piperidinyl] propionyl] -4-piperidinylmethyl] -4- 1 mol / l hydrochloric acid (10 ml) was added to a solution of piperidinyl] pyridine-3-carboxamide in 0.7 g (8.3 mmol) in methanol (1 ml), and the mixture was stirred overnight at room temperature. Under ice-cooling, the solution was alkalified with solid sodium hydroxide and extracted with chloroform. The extract was washed with saturated brine and dried. The solvent was distilled off under reduced pressure to obtain 0.46 g of the desired product, pale yellow oil quantitatively. According to a conventional method, the desired product, 2.5 fumarate 1/4 hydrate, was obtained.

Examples 14-16:
The corresponding 4- (t-butoxycarbonyl) piperidine compound was used instead of the starting material in Example 13 and reacted and treated in the same manner as in Example 13 to obtain the compounds shown in Table 3 below.

  In addition to the compounds produced in the above examples, for example, the compounds shown below can also be produced.

  6-amino-N- [1- [1- (2-butynoloyl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2-ethoxypyridine-3-carboxamide;

  6-amino-5-chloro-N- [1- [1- (2-hexynoloyl) -4-piperidinylmethyl] -4-piperidinyl] -2-methoxypyridine-3-carboxamide;

  6-amino-5-chloro-N- [1- [1- (2-propioloyl) -4-piperidinylmethyl] -4-piperidinyl] -2-methoxypyridine-3-carboxamide;

  6-amino-5-chloro-N- [1- [1- (trans-1-cinnamoyl) -4-piperidinylmethyl] -4-piperidinyl] -2-methoxypyridine-3-carboxamide;

  6-amino-5-chloro-N- [1- [1- [trans-3- (3-furoyl) acryloyl] -4-piperidinylmethyl] -4-piperidinyl] -2-methoxypyridine-3-carboxamide ,

  6-amino-5-chloro-N- [1- [1- [trans-3- (2-furoyl) acryloyl] -4-piperidinylmethyl] -4-piperidinyl] -2-methoxypyridine-3-carboxamide ,

  6-amino-5-chloro-2-methoxy-N- [1- [1- [trans-3- (3-thienyl) acryloyl] -4-piperidinylmethyl] -4-piperidinyl] pyridine-3-carboxamide ,

  6-amino-5-chloro-2-methoxy-N- [1- [1- [trans-3- (3-piperidinyl) acryloyl] -4-piperidinylmethyl] -4-piperidinyl] pyridine-3-carboxamide ,

  6-amino-5-chloro-2-methoxy-N- [1- [1- [trans-3- (3-tetrahydrofuryl) acryloyl] -4-piperidinylmethyl] -4-piperidinyl] pyridine-3- Carboxamide,

  6-amino-N- [1- [1- (trans, trans-2,4-pentadienoyl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2-ethoxypyridine-3-carboxamide;

  6-amino-N- [1- [1- (1-cyclopentene-1-carbonyl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2-ethoxypyridine-3-carboxamide;

  6-amino-5-chloro-2-methoxy-N- [1- [1- [3- (3-tetrahydrofuryl) propionyl] -4-piperidinylmethyl] -4-piperidinyl] pyridine-3-carboxamide; and

  6-Amino-N- [1- [1- (3-tetrahydrofurancarbonyl) -4-piperidinylmethyl] -4-piperidinyl] -5-chloro-2-ethoxypyridine-3-carboxamide.

Test Example 1 : Serotonin 4 (5-HT ₄ ) Receptor Binding Test The 5-HT ₄ receptor binding test and the preparation of the receptor membrane were prepared by the method of Grossman et al. [British J. Pharmacol., 1993, 109 , 618. Reference] was performed.

  After decapitation of a Std-Hartley guinea pig (body weight 300 to 400 g), the brain was immediately removed and the striatum was separated. 15 times the amount of Hepes buffer (50 mM, pH 7.4, 4 ° C.) is added to the resulting tissue, homogenized with a Teflon (registered trademark) homogenizer, and 48,000 Xg (4 ° C.) for 15 minutes. Centrifuged. A hepes buffer solution was added to the resulting sediment at a ratio of 1 ml to a wet weight of 30 mg of tissue to prepare a receptor sample.

The assay tube contained 0.1 nM [ ³ H] -GR113808 (chemical name: [1- [2- (methylsulfonylamino) ethyl] -4-piperidinyl] methyl 1-methylindole-3-carboxylate) , Receptor sample, and 1 ml of Hepes buffer (50 mM, pH 7.4, 4 ° C.) containing test compound or 30 μM serotonin were incubated at 37 ° C. for 30 minutes. The reaction was stopped by rapid filtration using a Brandel cell harvester on a Whatman GF / B filter soaked in 0.1% polyethyleneimine for 1 hour, and using 4 ml of ice-cooled 50 mM Tris-HCl (pH 7.7). This was done by washing 3 times. Radioactivity on the filter was measured with a liquid scintillation counter with ACSII scintillator added.

A 50% inhibitory concentration (IC ₅₀ ) was determined from the inhibition rate of the test compound for specific binding obtained by subtracting nonspecific binding from the total binding amount of [ ³ H] -GR113808. As a result, the IC ₅₀ of Examples 1, 3, 4 and 9 (respectively fumarate) was 24.78, 16.97, 23.52 and 15.95 nM, respectively.

In addition to the serotonin 4 (5-HT ₄ ) receptor binding test, the compound of the present invention also showed an excellent mouse defecation promoting action in a mouse defecation test.

  The following are examples relating to the formulation.

Formulation Example 1 : Production of tablets The following ingredients were mixed and granulated by a conventional method, and tableted at 145 mg per tablet to obtain the desired tablet.

Formulation Example 2 Production of Capsule According to a conventional method, the following components were mixed and granulated, and 200 mg of granules were filled into a capsule to obtain a desired capsule.

Formulation Example 3 : Production of powder After mixing the following components by a conventional method, a powder was produced to obtain a desired powder.

Formulation Example 4 Production of Injection 6-Amino-5-chloro-N- [1- (1-methacryloyl-4-piperidinylmethyl) -4-piperidinyl] -2-methoxypyridine-3-carboxamide fumaric acid Dissolve the salt and sorbitol in a portion of the water for injection, and then add the remaining water for injection to make a total amount. This solution was filtered through a membrane filter (0.22 μm), and the filtrate was filled in a 2 ml ampoule, which was then sterilized at 121 ° C. for 20 minutes to obtain the desired injection.

The compound represented by the general formula (I) of the present invention and a physiologically acceptable acid addition salt thereof exhibit a strong agonist activity with respect to the 5-HT ₄ receptor, and cause digestive system diseases (hypersensitivity). Bowel syndrome, flaccid constipation, addictive constipation, drug-induced constipation such as morphine and antipsychotics), central nervous system disorders (schizophrenia, depression, memory impairment, anxiety, etc.), urinary tract diseases (urinary tract) Use for the treatment and prevention of various diseases such as obstruction, dysuria due to prostatic hypertrophy, etc. and various gastrointestinal dysfunctions (eg, anorexia, nausea, vomiting, abdominal bloating) Can do. It is particularly useful as a gastrointestinal motility promoting agent or a gastrointestinal tract function improving agent, and these therapeutic agents can be provided.

Claims (7)

A compound represented by the following formula (I) or a physiologically acceptable acid addition salt thereof.

[Wherein R ¹ represents a halogen atom, R ² represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group, R ³ represents a lower alkyl group, and X represents the following formula (X-1) or This means a group represented by (X-2).

[Wherein R ⁴ represents a lower alkenyl group, a lower alkynyl group, —CH═CH—A (A represents a phenyl group, an unsaturated monocyclic or bicyclic heterocycle, or a saturated monocyclic heterocycle. Or — (CH ₂ ) _n —B (B means a saturated monocyclic heterocycle, n means 0, 1, 2 or 3) (in both definitions above) When a saturated monocyclic heterocycle contains a nitrogen atom, the nitrogen atom may have a substituent of a lower alkyl group, a lower alkanoyl group or a lower alkoxycarbonyl group). ]

(In the formula, Z represents —CO—, —CS— or —SO ₂ —, Q ¹ represents a lower alkyl group, a lower alkenyl group or a lower alkynyl group, and Q ² represents a lower alkenyl group or a lower alkynyl group. Means))) The compound or a physiologically acceptable acid thereof according to claim 1, wherein R ¹ is a chlorine atom or a bromine atom, R ² is a hydrogen atom, and R ³ is a methyl group, an ethyl group, a propyl group, or an isopropyl group. Addition salt.   The compound according to claim 2 or a physiologically acceptable acid addition salt thereof, wherein X means a group represented by the formula (X-1). A compound represented by the following formula (I-1) or a physiologically acceptable acid addition salt thereof.

[Wherein R ¹¹ represents a chlorine atom or a bromine atom, R ³¹ represents a methyl group, an ethyl group, a propyl group or an isopropyl group, R ⁴¹ represents a lower alkenyl group, a lower alkynyl group, —CH═CH— A ¹ (A ¹ represents a phenyl group or an unsaturated or saturated monocyclic heterocycle) or — (CH ₂ ) _n —B (B represents a saturated monocyclic heterocycle, n Means 0, 1, 2 or 3) (in both definitions above, when a saturated monocyclic heterocycle contains a nitrogen atom, the nitrogen atom is a lower alkyl group, It may have a substituent of a lower alkanoyl group or a lower alkoxycarbonyl group). ]   A pharmaceutical composition comprising the compound according to any one of claims 1 to 4 or a physiologically acceptable acid addition salt thereof.   A serotonin 4 receptor agonist comprising the compound according to any one of claims 1 to 4 or a physiologically acceptable acid addition salt thereof as an active ingredient.   A gastrointestinal motility promoting agent or a gastrointestinal tract function improving agent comprising the compound according to any one of claims 1 to 4 or a physiologically acceptable acid addition salt thereof as an active ingredient.