JPH08225571A - 6-alkoxy-1h-benzotriazole-5-carboxamide derivative and its intermediate and medicinal composition containing the derivative - Google Patents

Abstract

PURPOSE: To provide a new compound having a combination a excelleht antiemetic and digestive tract function promoting action, low in central nerve- suppressive action, thus useful for preventing and treating various digestive organ function abnormalities. CONSTITUTION: This new compound, an alkoxybenzotriazole carboxamide derivative, is expressed by formula I [W is (CH2 )n , CO, CH(OH), etc., (v) is 1 to 3; R<1> is a l-4C alkyl, 3-4C alkenyl etc.; A is a 1-4C alkyl; R<2> is H, a 1-4C alkyl, 3-6C cycloalkyl, etc.], e.g. N-(1-ethyl-1H-hexahydroazopin-3-yl)-6-methoxy-1- propyl-1H-benzotriazole-5-carboxamide. The compound of formula 1 is obtained by reaction between a compound of formula II and a compound of formula III in the presence of a condensation agent such as N,N'- dicyclohexylcarbodiimide.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel 6-alkoxy-1H-benzotriazole-5-carboxamide derivative characterized by excellent antiemetic action and digestive tract hyperactivity action and weak central inhibitory action. , More specifically, when the nitrogen atom of the amide moiety (-CONH-) is 7, 8
Or a 1H-benzotriazol-5-carboxamide derivative substituted with a 9-membered 1-substituted-azacycloalkane-3-yl group, a pharmaceutical composition containing the same and a novel intermediate.

[0002]

2. Description of the Related Art Japanese Unexamined Patent Publication (Kokai) No. 2-104572 describes that a compound represented by the following chemical formula 4 has a gastrointestinal function-enhancing action and is useful as an antiemetic agent or a gastrointestinal function-enhancing agent. .

[0003]

[Chemical 4]

[Wherein R ₁ represents a lower alkyl group or an aryl (lower) alkyl group which is unsubstituted or has a substituent, and R ₂ is a hydroxy group, an alkoxy group, an alkenyloxy group, a cycloalkyloxy group or a substituted group. Means an alkoxy group having a group (the substituent is a halogen atom, a hydroxy group or an oxo group), R ₃ means an amino group, a disubstituted amino group or an acylamino group, and R ₄ means a halogen atom. Alternatively, R ₃ and R ₄ may combine to form —NH—N═N—, R ₅ represents a hydrogen atom or a lower alkyl group, and X represents a single bond or a lower alkylene group. Y is a single bond, —CH ₂ —, —O
-, - S -, - SO -, - SO 2 - or -NR ₆ - refers to a group represented by aryl (lower) alkyl having R ₆ wherein the lower alkyl group or an unsubstituted or substituted group Or optionally together with R ₁ to form an ethylene group, n means 0 or 1, and the broken line optionally represents when Y is —CH ₂ — and n is 0. Means a double bond present. However, (i) Y is −
When NR ₆ -or a single bond, n means 0, and (i
i) when Y is -O-, n means 1; (iii) Y
Is a single bond or —CH ₂ — and n is 0, R
₁ means an aryl (lower) alkyl group which is unsubstituted or has a substituent, and (iv) when n is 0, X means a lower alkylene group. ]

However, in the above-mentioned publication, a 1H-benzotriazole skeleton represented by the following formula (I) and a nitrogen-containing 7
There is no specific disclosure of the compounds of the present invention having a membered, 8-membered or 9-membered aliphatic ring and their pharmacological actions.

JP-A-52-83737 discloses that a compound represented by the following chemical formula 5 has a strong condition avoidance inhibitory action, apomorphine stereotyped behavior inhibitory action and methamphetamine stereotyped behavior inhibitory action, and is a central inhibitor. In particular, it is disclosed to be useful as an antipsychotic drug.

[0007]

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(In the formula, A-CO is a 4-amino-5-chloro-2-methoxybenzoyl group, a 5-ethylsulfonyl-2-methoxybenzoyl group or 2-methoxy-4,5.
An azidobenzoyl group, B is an allyl group or a benzyl group with or without a substituent, and n is 1 or 2
Means )

[0009] Further, in JP-A-52-100473, the same disclosure is made for the compound represented by the chemical formula 6 below.

[0010]

[Chemical 6]

(Wherein R ¹ is a lower alkoxy group, R ² is a benzyl group with or without a substituent, or m
Means 1 or 2. )

However, in the compounds represented by Chemical formulas 5 and 6, the ring bonded to the amide (-CONH-) is a 5-membered ring or a 6-membered ring, and the ring-constituting nitrogen atom is an allyl group or benzyl. In that it is substituted with a group, it has a structure different from that of the compound having the formula (I) of the present invention, and its pharmacological action is completely different from that of the compound of the present invention.

[0013]

4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-methoxybenzamide [generic name metoclopramide;
Merck Index, 11th edition, 6063 (1989)] has both antiemetic action and gastrointestinal function enhancing action. Therefore, it has long been used as a gastrointestinal function improving drug for various digestive system diseases or various digestive disorders associated with treatment. It is used for the treatment and prevention of functional disorders. However, since metoclopramide has a central inhibitory action based on a dopamine D ₂ receptor antagonistic action as a side effect, it is clinically difficult to use. The number of patients suffering from gastrointestinal indefinite complaints is increasing due to the complication of social life and the advent of an aging society, etc. Development is desired.

As a result of intensive studies, the present inventors have found that the nitrogen atom of the amide moiety (-CONH-) is a 7-, 8- or 9-membered 6-alkoxy-1-substituted-azacycloalkane-.
Although the 6-alkoxy-1H-benzotriazole-5-carboxamide derivative substituted with a 3-yl group has both excellent antiemetic action and gastrointestinal function enhancing action,
The inventors have found that the central inhibitory action is weak and completed the present invention.

[0015]

According to the present invention, a 6-alkoxy-1H-benzotriazole-5-carboxamide derivative represented by the following formula (I), a physiologically acceptable acid addition salt thereof, and a salt thereof are provided. A pharmaceutical composition containing is provided.

[0016]

[Chemical 7]

[Wherein W is-(CH ₂ ) n-, -CO-,
^{-CHR 4 -, - CH (OH} ) -, - C (OR 4)
₂ -, - C [O (CH ₂₎ m O] -, - C (= N- OH)
- or ^{-C (= N-OR 4)} - refers to (wherein the, n represents mean 1, 2 or 3, m denotes 1 or 2, R ⁴ is a C ₁ -C ₃ alkyl group Mean), A is C
_{1 to} C ₄ alkyl group, R ¹ is a C _{1 to} C ₄ alkyl group, (C _{3 to} C ₆ cycloalkyl) C _{1 to} C ₄ alkyl group, C _{3 to} C ₄ alkenyl group, C _{3 to} C ₄ means an alkynyl group or a halogeno (C ₁ -C ₃ ) alkyl group, R
² is a hydrogen atom, C ₁ -C ₄ alkyl group, C ₃ -C ₆ cycloalkyl group, (C ₃ ~C ₆ cycloalkyl) C ₁ -C ₄
Alkyl group, C ₃ -C ₄ alkenyl group, C ₃ -C ₄ alkynyl, hydroxy (C ₁ ~C ₃₎ alkyl group, C ₁
To C ₃ alkoxy (C _{1 to} C ₃ ) alkyl group or di-substituted amino (C _{1 to} C ₃ ) alkyl group, and a wavy line (to)
Means that the configuration of the carbon atom to which it is attached is RS, R or S.

However, when W is-(CH ₂ ) n-, A is a methyl group and R ² is a hydrogen atom, a methyl group or an ethyl group, R ¹ is a methyl group, a propyl group or an isopropyl group. , Butyl group, isobutyl group, sec-butyl group, C ₃ ~
C ₆ cycloalkyl group, cyclopropyl (C ₂ ~C ₄₎
Alkyl, (C ₄ ~C ₆ cycloalkyl) C ₁ -C ₄
Alkyl group, C ₃ -C ₄ alkenyl group, C ₃ -C ₄ alkynyl group or a halogeno (C ₁ ~C ₃₎ means an alkyl group. ]

The present invention also relates to formula (I) wherein W is-
_{(CH 2) n -, -} CO- or -CHR ⁴ - and is, R ²
The present invention provides a compound of the following formula (II) and an acid addition salt thereof, which are useful as intermediates for producing a compound in which is a hydrogen atom.

[0020]

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[In the formula, W ¹ is-(CH ₂ ) n-, -CO-
Or —CHR ⁴ — (where n is 1, 2
Or 3, R ⁴ represents a C ₁ -C ₃ alkyl group), A ¹ represents a C ₁ -C ₄ alkyl group, and R ¹¹ represents C 1.
₁ -C ₄ alkyl group, C ₃ -C ₆ cycloalkyl group,
(C ₃ -C ₆ cycloalkyl) means a C ₁ -C ₄ alkyl group or a halogeno (C ₁ -C ₃ ) alkyl group, R ³ means a protecting group for an amino group, and wavy line (~) means that It means that the configuration of the bonded carbon atom is RS, R or S.

However, W ¹ is-(CH ₂ ) n- and A ¹
Is a methyl group, R ¹¹ is a methyl group, a propyl group,
Isopropyl group, butyl group, isobutyl group, sec- butyl group, C ₃ -C ₆ cycloalkyl group, cyclopropyl (C
₂ -C ₄₎ alkyl, (C _{4 ~C 6} cycloalkyl)
C ₁ -C ₄ alkyl or halogeno (C ₁ ~C ₃₎ means an alkyl group. ]

Further, in the present invention, W in formula (I) is
(CH ₂₎ n -,, intermediate represented by the following formula wherein R ¹ can be used to produce the same group are compounds wherein R ¹ other than a methyl group (IV _A),

[0024]

[Chemical 9]

(Wherein R ¹² is a C ₂ -C ₄ alkyl group, C
₃ -C ₆ cycloalkyl group, (C ₃ -C ₆ cycloalkyl) C ₁ -C ₄ alkyl group, C ₃ -C ₄ alkenyl group,
C ₃ -C ₄ alkynyl group or a halogeno (C ₁ ~C ₃₎ refers to an alkyl group, n and the wavy line means the same thing supra. )

And an acid addition salt thereof, and a compound of formula (IVa) useful as an intermediate for producing a compound of the formula (I) wherein the configuration of the carbon atom adjacent to the amino group to which the amide bond is attached is R. The present invention provides the compound and the acid addition salt thereof.

[0027]

[Chemical 10] (In the formula, R ¹² and n have the same meanings as described above.)

Examples of physiologically acceptable acid addition salts of the compound of formula (I) include 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 and methanesulfonate. Since the compound of the formula (I) and its acid addition salt may exist as a hydrate or a solvate, these hydrates and solvates are also included in the present invention.

Formulas (II) and (IV) which are intermediates of the present invention
Examples of the acid addition salt of the compound _A ) include the physiologically acceptable acid addition salts described above. Formula (II) and formula (I
Since the compound of _VA ) and its acid addition salt may exist as a hydrate or a solvate, these hydrates and solvates are also included in the present invention.

The compound in which R ² is a hydrogen atom in the formula (I) may exist in the form of a tautomer represented by the formula (I ′) or the formula (I ″). Variants are also included in the compounds of the invention.

[0031]

[Chemical 11] [In the formula, Az means a group represented by Chemical formula 12, and A means the same as above.

[0032]

[Chemical 12] (In the formula, R ¹¹ , W ¹ and the wavy line have the same meanings as described above.)]

In the following description, the structures of the compounds of the present invention are represented by the formula (I), and chemical names will also be named based on them.

In the present specification, the "halogen atom" means fluorine, chlorine, bromine or iodine. Specific examples of the “alkyl group” include methyl, ethyl, propyl,
Isopropyl may be mentioned. Specific examples of the "alkoxy group" include methoxy, ethoxy, propoxy and isopropoxy. “Cycloalkyl group” means cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. As a specific example of the “alkenyl group”,
Allyl and butenyl are specific examples of the "alkynyl group" include propargyl. "(Cycloalkyl)
The "alkyl group" means an alkyl group having 1 to 4 carbon atoms substituted with the above cycloalkyl group, and specific examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl. , 3-cyclohexylpropyl. The “halogenoalkyl group” means an alkyl group in which a carbon atom other than the 1-position is substituted with one or more halogen atoms, 2-chloroethyl, 2-fluoroethyl, 2-difluoroethyl, 2-trifluoroethyl. , 3-fluoropropyl. The “hydroxyalkyl group” means an alkyl group in which a carbon atom other than the 1-position is substituted with hydroxy, and specific examples thereof include 2-hydroxyethyl and 3-hydroxypropyl. The "alkoxyalkyl group" means an alkyl group in which a carbon atom other than the 1-position is substituted with alkoxy, and specific examples include 2-
Methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, 3-ethoxypropyl may be mentioned. The “di-substituted aminoalkyl group” means an amino group substituted with C _{1 to} C ₃ alkyl or an alkyl group substituted with cyclic amines forming a 5- to 8-membered ring, for example, 2-dimethylaminoethyl. , 2-diethylaminoethyl, 2- (1-pyrrolidinyl) ethyl, 2- (1-piperidinyl) ethyl, 2-morpholinoethyl. Specific examples of the "lower alkanoyl group" include acetyl and propionyl. Specific examples of the "lower alkoxycarbonyl group" include methoxycarbonyl and ethoxycarbonyl. The “optionally substituted benzyl group” means that the phenyl moiety may be substituted with one or two of the above-mentioned halogen atom, C ₁ -C ₃ alkyl group and C ₁ -C ₃ alkoxy group. A good benzyl group is preferred, eg benzyl, 2-, 3- or 4-chlorobenzyl, 3-
Bromobenzyl, 4-fluorobenzyl, 2,4- or 3,4-dichlorobenzyl, 4-methylbenzyl, 2
-, 3- or 4-methoxybenzyl and the like can be mentioned.
"A benzyloxycarbonyl group which may be substituted"
Is a benzyloxycarbonyl group whose phenyl moiety may be substituted with one or two of the above-mentioned halogen atom, C ₁ -C ₃ alkyl group, C ₁ -C ₃ alkoxy group and nitro group. Is shown, for example, benzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 4-
Examples thereof include bromobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl and 4-methoxybenzyloxycarbonyl. “Amino group protecting group” means
It means a protective group that can be eliminated by hydrolysis or hydrogenolysis, and includes, for example, the above-mentioned lower alkanoyl group, trifluoroacetyl, lower alkoxycarbonyl group, optionally substituted benzyl group, and optionally substituted benzyloxycarbonyl group. And benzyl and acetyl are particularly preferable.

Suitable examples of the compound of the present invention represented by the above formula (I) include compounds in which W is — (CH ₂ ) n —.

Further preferred are compounds in which A is a methyl group.

Regarding the configuration, a compound in which the configuration of the carbon atom to which the wavy line is bonded in formula (I) is RS or R is preferable, and a compound in which R is particularly preferable.

Regarding the size of the azacycloalkane ring, any of a 7-membered ring, an 8-membered ring and a 9-membered ring is preferable, but especially a 7-membered ring, that is, n is 1 in the formula (I). Compounds are preferred.

Suitable compounds among the above compounds include the compounds shown below and physiologically acceptable acid addition salts thereof.

N- (1-Ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1-propyl-1
H-benzotriazole-5-carboxamide, N-
(1-Ethyl-1H-hexahydroazepin-3-yl) -1-isopropyl-6-methoxy-1H-benzotriazole-5-carboxamide, 1-cyclopropyl-N- (1-ethyl-1H-hexahydroazepine −
3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide, 1-cyclobutyl-N- (1-
Ethyl-1H-hexahydroazepin-3-yl) -6
-Methoxy-1H-benzotriazole-5-carboxamide, 1-cyclopropylmethyl-N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide, 1 -Allyl-N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazol-5-carboxamide, N- (1-ethyl-1H-hexahydroazepin-3-yl) ) -6-Methoxy-1-propargyl-1H-benzotriazole-
5-carboxamide, and 6-methoxy-N- (1-propyl-1H-heptahydroazocin-3-yl) -1
H-benzotriazole-5-carboxamide.

Specific examples of other suitable compounds included in the present invention in addition to the above compounds include, for example, the following compounds and physiologically acceptable acid addition salts thereof.

(R) -N- (1-Ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1-propyl-1H-benzotriazole-5-carboxamide, (R) -N- (1 -Ethyl-1H-hexahydroazepin-3-yl) -1-isopropyl-6-methoxy-1H-benzotriazole-5-carboxamide,
(R) -1-Cyclopropyl-N- (1-ethyl-1H
-Hexahydroazepin-3-yl) -6-methoxy-
1H-benzotriazole-5-carboxamide,
(R) -1-Cyclobutyl-N- (1-ethyl-1H-
Hexahydroazepin-3-yl) -6-methoxy-1
H-benzotriazole-5-carboxamide, (R)
-1-Cyclopropylmethyl-N- (1-ethyl-1H
-Hexahydroazepin-3-yl) -6-methoxy-
1H-benzotriazole-5-carboxamide,
(R) -1-allyl-N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide, (R) -N-
(1-Ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1-propargyl-1H-benzotriazole-5-carboxamide, (R) -6-methoxy-N- (1-propyl-1H- Heptahydroazocin-3-yl) -1H-benzotriazole-5-carboxamide, (R) -N- (1-cyclopropyl-1H
-Heptahydroazocin-3-yl) -6-methoxy-
1H-benzotriazole-5-carboxamide,

N- (1-Ethyl-1H-heptahydroazocin-3-yl) -6-methoxy-1-propyl-1
H-benzotriazole-5-carboxamide, N-
(1-Ethyl-1H-octahydroazonin-3-yl) -6-methoxy-1-propyl-1H-benzotriazole-5-carboxamide, N- (1-ethyl-1)
H-heptahydroazocin-3-yl) -1-isopropyl-6-methoxy-1H-benzotriazole-5-
Carboxamide, N- (1-ethyl-1H-octahydroazonin-3-yl) -1-isopropyl-6-methoxy-1H-benzotriazole-5-carboxamide, 1-cyclopropyl-N- (1-ethyl- 1H-heptahydroazocin-3-yl) -6-methoxy-1H
-Benzotriazole-5-carboxamide, 1-cyclopropyl-N- (1-ethyl-1H-octahydroazonin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide, 1-cyclopropylmethyl -N- (1-ethyl-1H-heptahydroazocin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide, 1-cyclopropylmethyl-
N- (1-ethyl-1H-octahydroazonin-3-
Yl) -6-methoxy-1H-benzotriazole-5
-Carboxamide, 1-allyl-N- (1-ethyl-1
H-heptahydroazocin-3-yl) -6-methoxy-1H-benzotriazol-5-carboxamide, 1
-Allyl-N- (1-ethyl-1H-octahydroazonin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide, N- (1-ethyl-1H
-Heptahydroazocin-3-yl) -6-methoxy-
1-propargyl-1H-benzotriazole-5-carboxamide, N- (1-ethyl-1H-octahydroazonin-3-yl) -6-methoxy-1-propargyl-1H-benzotriazole-5-carboxamide,

6-methoxy-N- (1-propyl-1H
-Heptahydroazocin-3-yl) -1H-benzotriazole-5-carboxamide, 6-methoxy-N-
(1-Propyl-1H-octahydroazonin-3-yl) -1H-benzotriazol-5-carboxamide, N- (1-cyclopropyl-1H-heptahydroazocin-3-yl) -6-methoxy- 1H-benzotriazole-5-carboxamide, N- (1-cyclopropyl-1H-octahydroazonin-3-yl) -6-
Methoxy-1H-benzotriazole-5-carboxamide,

(R) -N- (1-Ethyl-1H-heptahydroazocin-3-yl) -6-methoxy-1-propyl-1H-benzotriazole-5-carboxamide, (R) -N- ( 1-Ethyl-1H-octahydroazonin-3-yl) -6-methoxy-1-propyl-1
H-benzotriazole-5-carboxamide, (R)
-N- (1-ethyl-1H-heptahydroazocine-3
-Yl) -1-isopropyl-6-methoxy-1H-benzotriazole-5-carboxamide, (R) -N-
(1-Ethyl-1H-octahydroazonin-3-yl) -1-isopropyl-6-methoxy-1H-benzotriazole-5-carboxamide, (R) -1-cyclopropyl-N- (1-ethyl- 1H-heptahydroazocin-3-yl) -6-methoxy-1H-benzotriazol-5-carboxamide, (R) -1-cyclopropyl-N- (1-ethyl-1H-octahydroazonin-3- Yl) -6-Methoxy-1H-benzotriazole-5-carboxamide, (R) -1-cyclopropylmethyl-N- (1-ethyl-1H-heptahydroazocin-3-yl) -6-methoxy-1H -Benzotriazole-5-carboxamide, (R) -1-cyclopropylmethyl-N- (1-ethyl-1H-octahydroazonin-3-yl) 6-methoxy -1H- benzotriazole-5-carboxamide, (R) -1- allyl -
N- (1-ethyl-1H-heptahydroazocine-3-
Yl) -6-methoxy-1H-benzotriazole-5
-Carboxamide, (R) -1-allyl-N- (1-ethyl-1H-octahydroazonin-3-yl) -6-
Methoxy-1H-benzotriazole-5-carboxamide, (R) -N- (1-ethyl-1H-heptahydroazocin-3-yl) -6-methoxy-1-propargyl-1H-benzotriazole-5-carboxamide ,
(R) -N- (1-Ethyl-1H-octahydroazonin-3-yl) -6-methoxy-1-propargyl-1
H-benzotriazole-5-carboxamide,

(R) -6-Methoxy-N- (1-propyl-1H-heptahydroazocin-3-yl) -1H-
Benzotriazole-5-carboxamide, (R) -6
-Methoxy-N- (1-propyl-1H-octahydroazonin-3-yl) -1H-benzotriazole-5
-Carboxamide, (R) -N- (1-cyclopropyl-1H-heptahydroazocin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide, (R) -N- (1-cyclo Propyl-1H-octahydroazonin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide,

N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-propoxy-1H-benzotriazole-5-carboxamide, N- (1-ethyl-
1H-hexahydroazepin-3-yl) -6-isopropoxy-1H-benzotriazole-5-carboxamide, (R) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-propoxy -1H-benzotriazole-5-carboxamide, (R) -N- (1
-Ethyl-1H-hexahydroazepin-3-yl)-
6-isopropoxy-1H-benzotriazole-5-
Carboxamide,

6-ethoxy-N- (1-ethyl-1H-
Hexahydroazepin-3-yl) -1-methyl-1H
-Benzotriazole-5-carboxamide, (R)-
6-ethoxy-N- (1-ethyl-1H-hexahydroazepin-3-yl) -1-methyl-1H-benzotriazole-5-carboxamide,

N- (1-Ethyl-5-methyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H
-Benzotriazole-5-carboxamide, N- (1
-Ethyl-5-oxo-1H-hexahydroazepine-
3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide, N- (1-ethyl-5-hydroxy-1H-hexahydroazepin-3-yl) -6-
Methoxy-1H-benzotriazole-5-carboxamide, and N- (1-ethyl-5,5-dimethoxy-1)
H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazol-5-carboxamide.

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

Process (a) The compound of formula (I) has the following formula (III)

[0052]

[Chemical 13] (In the formula, R ² and A mean the same as above.)

A compound represented by the following formula (IV) or a reactive derivative thereof:

[0054]

Embedded image

It can be produced by reacting with a compound represented by the formula (wherein R ¹ , W and wavy line have the same meanings as described above).

As the reactive derivative of the compound of the formula (III), for example, lower alkyl ester (especially methyl ester), active ester, acid anhydride, acid halide (especially acid chloride) can be mentioned. In the case of using the compound in which R ^2a is a hydrogen atom in III), the acid anhydride and the acid halide are excluded]. Specific examples of the active ester include p-nitrophenyl ester, pentachlorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-
Examples thereof include hydroxybenzotriazole ester, 8-hydroxyquinoline ester, 2-hydroxyphenyl ester and 2-hydroxy-4,5-dichlorophenyl ester. As the acid anhydride, a symmetrical acid anhydride or a mixed acid anhydride is used, and specific examples of the mixed acid anhydride include a mixed acid anhydride with a chlorocarbonic acid alkyl ester such as ethyl chlorocarbonate and isobutyl chlorocarbonate, and chloric acid. Mixed acid anhydride with chlorocarbonic acid aralkyl ester such as benzyl carbonate, mixed acid anhydride with chlorocarbonic acid aryl ester such as phenylchlorocarbonate, mixed acid anhydride with alkanoic acid such as isovaleric acid and pivalic acid Is mentioned.

As the amino-protecting group for R ^2a , for example, a protecting group which can be eliminated by hydrolysis or hydrogenolysis can be used, and examples thereof include a lower alkanoyl group, a trifluoroacetyl group, a lower alkoxycarbonyl group and a substituted group. Examples thereof include an optionally substituted benzyl group and an optionally substituted benzyloxycarbonyl group, with acetyl being particularly preferred.

When the compound of formula (III) itself is used,
N, N'-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N, N'-carbonyldiimidazole, N,
The reaction can be performed in the presence of a condensing agent such as N'-carbonyldisuccinimide, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, diphenylphosphoryl azide, propanephosphonic acid anhydride. N, N'-dicyclohexylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) as a condensing agent
When using carbodiimide hydrochloride, N-hydroxysuccinimide, 1-hydroxybenzotriazole, 3-hydroxy-1,2,3-benzotriazine-
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 (III) or its reactive derivative with the compound of formula (IV) is carried out in a solvent or without solvent. The solvent to be used should be appropriately selected according to the type of raw material compound, but for example, aromatic hydrocarbons such as benzene, toluene, xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, methylene chloride, Halogenated hydrocarbons such as chloroform, alcohols such as ethanol and isopropyl alcohol, ethyl acetate, acetone, acetonitrile, dimethylformamide, dimethylsulfoxide,
Examples thereof include 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, and 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. Examples thereof include alkali bicarbonates such as potassium bicarbonate, and organic bases such as triethylamine, tributylamine, diisopropylethylamine and N-methylmorpholine, but an excess amount of the compound of the formula (IV) can also serve. The reaction temperature varies depending on the type of raw material compound used, etc., but is usually about
-30 ° C to about 200 ° C, preferably about -10 ° C to about 150 ° C.

In the formula (III), the compound in which R ² is a group other than a hydrogen atom is 4-chloro-2-methoxy-5-nitrobenzoic acid as a starting material, and propyl is prepared by the method of step 1 of the following chemical formula 22. After introducing the corresponding amide using a suitable amine such as amine, the corresponding product other than hydrogen atom is introduced into R ² by the method of Step 2 and Step 3 of the following 22. Reduction and further the corresponding 6-methoxy-1H by the method described in the following production method (b).
-A benzotriazole-5-carboxamide derivative can be produced and then hydrolyzed according to a conventional method.

The production method of the compound of formula (IV) is described below.

In the formula (IV), W is-(CH ₂ ) n-, n is 1 and R ¹ is other than a halogeno (C ₁ -C ₃ ) alkyl group and a C ₃ -C ₆ cycloalkyl group. The compound which is the group of can be produced, for example, by the method represented by the following Chemical formula 15.

[0063]

[Chemical 15]

[Wherein Tr represents a triphenylmethyl group, R ¹³ represents a halogeno (C ₁ -C ₃ ) alkyl group and C
_The same as the above-mentioned R ¹ other than a _3- C ₆ cycloalkyl group is meant, X means the reactive ester residue of alcohol, and the wavy line means the same as the above. ]

Step 1 : The reaction of the compound of formula (A) with chlorotriphenylmethane is usually carried out in a suitable solvent in the presence of a base. As the solvent and the base to be used, the specific examples described in the above production method (a) can be mentioned as they are. The reaction temperature is generally about -10 ° C to about 150 ° C, preferably about 0 ° C to about 100 ° C. In addition, as the R and S isomers of the formula (A), which are raw material compounds, commercially available racemates are used.
For example, optically resolving by the method described in J. Org. Chem., 44 , 4841-4847 (1979) or using optically active lysine, for example, according to the method described in Synthesis, 1978 , 614-616. You can

Step 2 : The compound of formula (C) has the formula (B)
The compound can be produced by reducing the compound with a metal hydride such as diisobutylaluminum hydride, lithium aluminum hydride or sodium bis (2-methoxyethoxy) aluminum hydride. Specific examples of the solvent used include ethers such as diethyl ether and tetrahydrofuran, aromatic hydrocarbons such as benzene and toluene, and halogenated hydrocarbons such as methylene chloride and chloroform. The reaction temperature varies depending on the type of metal hydride used, etc., but is usually about
-10 ° C to about 100 ° C, preferably about 0 ° C to about 50 ° C.

Step 3 : Compound of formula (C) and formula: R ^13-
The reaction with the R ¹³ introducing agent represented by X is usually carried out in a suitable solvent,
It is carried out in the presence of a base. Examples of the reactive ester residue of alcohol represented by X include a halogen atom such as chlorine, bromine and iodine, a lower alkylsulfonyloxy group such as methanesulfonyloxy, and an arylsulfonyloxy group such as benzenesulfonyloxy. Can be mentioned. Specific examples of the solvent include aromatic hydrocarbons such as benzene and toluene, ketones such as acetone and methyl ethyl ketone, ethers such as tetrahydrofuran and dioxane, alcohols such as ethanol and isopropyl alcohol, acetonitrile and chloroform. , Ethyl acetate, dimethylformamide, dimethylsulfoxide, or a mixture thereof. Specific examples of the base used include the specific examples described in the above production method (a) as they are. When X is chlorine or bromine in the R ¹³ introducing agent, the reaction proceeds smoothly by adding an alkali metal iodide such as sodium iodide or potassium iodide. The reaction temperature will differ depending on the kind of R ¹³ introducing agent used and the like, but is usually about 0 ° C. to about 200 ° C., preferably about 80 ° C. to about 150 ° C.

Step 4 : The reaction of this step is usually carried out using a mineral acid such as dilute hydrochloric acid or dilute sulfuric acid in a suitable solvent. Specific examples of the solvent used include alcohols such as methanol and ethanol, ethers such as diethyl ether and tetrahydrofuran, acetone, acetonitrile,
Examples thereof include ethylene glycol or a mixed solution thereof. The reaction temperature will differ depending on the types of starting compounds used, but it is usually about 0.degree. C. to about 100.degree.

In the formula (IV), n is 1 and R ¹ is a straight chain C ₁ -C ₃ alkyl group.
It can also be produced by replacing the reduction reaction of step 2 in step 5 with the R ¹³ introduction reaction (alkylation reaction) of step 3. That is, the compound of formula (B) can be converted to the compound of formula (D) by alkylating (step 2 ′) and then reducing (step 3 ′). In this case, it is preferable to use a strong base such as sodium hydride for the alkylation reaction in step 2 ′ instead of the base described in the above-mentioned production method (a), and hydrogen for the reduction reaction in step 3 ′. It is preferable to use sodium bis (2-methoxyethoxy) aluminum chloride.

In the formula (IV), W is — (CH ₂ ) n —, n is 1 and R ¹ is a halogeno (C ₁ -C ₃ ) alkyl group. It can be manufactured by the method shown.

[0071]

Embedded image

[In the formula, Ph means a phenyl group, and R ¹⁴
Means a halogeno (C ₁ -C ₃ ) alkyl group, and the wavy line means the same as above. ]

In the step 1 in the above chemical formula 16, the compound of the formula (A) and benzaldehyde are present in a suitable solvent in the presence of a reducing agent suitable for reducing an imine such as sodium cyanoborohydride and borane-triethylamine complex. It is carried out by reacting below. Methanol, ethanol or the like is used as the solvent. The preferred reaction temperature is about 0.
C to about 40 ° C. Step 2 can be performed in the same manner as Step 2 in Chemical formula 15 above. Process 3 is J. Org.
It can be performed according to the method described in Chem., 40 , 3453-3456 (1975), and step 4 can be performed in the same manner as in the production method (c) described below.

In formula (IV), W is-(CH ₂ ) n-, n is 2 or 3, and R ¹ is halogeno (C ₁ -C 2).
₃ ) The compound which is a group other than the alkyl group and the C ₃ -C ₆ cycloalkyl group can be produced, for example, by the method represented by the following Chemical formula 17.

[0075]

[Chemical 17]

(In the formula, Y means a halogen atom, and n '
Means 2 or 3, and R ¹ and X mean the same as above. )

The step 1 in the above chemical formula 17 is the same as the step 2'in the modification of the method shown in the chemical formula 15 above, for example, starting from commercially available 2-azacyclooctanone or 2-azacyclononanone. Can be done. The halogenation in step 2 can be carried out, for example, according to J. Am. Chem. Soc.
80 , 6233-6237 (1958), and the steps 3 and 4 can be performed, for example, by Helv. Chim. Ac.
ta, 41 , 181-188 (1958).

In the formula (IV), W is — (CH ₂ ) n — and R ¹ is a group other than a halogeno (C ₁ -C ₃ ) alkyl group. Can be manufactured by.

[0079]

Embedded image

(In the formula, R ¹⁵ means the same group as R ¹ other than a halogeno (C ₁ -C ₃ ) alkyl group, and Tr and n mean the same as above.)

Step 1 in the above Chemical Formula 18 can be carried out by generating an anion in the compound of formula (E) with a strong base in a suitable solvent and then reacting it with dry ice. The conversion of the carboxyl group to the amino group in step 2 is carried out by reacting the compound of formula (F) with ethyl chlorocarbonate and sodium azide in a suitable solvent, and then heating the resulting acyl azide body to form an isocyanate body, It can be carried out by reacting an acid. The triphenylmethylation in Step 3, the reduction in Step 4 and the deprotection of the triphenylmethyl group in Step 5 can be carried out in the same manner as in Step 1, Step 2 and Step 4 in Chemical Formula 15, respectively.

The starting compound of the formula (E) can be produced by the method of Chemical formula 16 step 1 using ε-caprolactam, 2-azacyclooctanone or 2-azacyclononanone as a starting material.

In the formula (IV), W is-(CH ₂ ) n-, n is 2 or 3, and R ¹ is halogeno (C ₁ -C).
₃ ) The compound which is an alkyl group is, for example, 2-azacyclooctanone or 2-azacyclononanone as a starting material and is described in the section of the method shown in Chemical formula 15, Chemical formula 16, Chemical formula 17 and Chemical formula 18. It can be produced by combining the described method and a conventional method.

In formula (IV), W is --CHR ⁴ -,-
C (OR ⁴⁾ ₂ - or -C [O (CH ₂₎ m O] - those compounds can be prepared by ring expansion reaction by the method described in JP-A-2-104572, also W is - CO-,-
CH (OH)-, -C (= N-OH)-or -C (= N
-OR ⁴⁾ - those compounds can be derived from the ketal or carbonyl derivative of the product.

According to the method represented by Chemical Formula 15 or Chemical Formula 16, the configuration of the starting compound (A) is retained in the final product represented by the formula (IV ′) or (IV ″). On the other hand, the final product of formula (IV ′ ″) or (IV ″ ″) produced by the method shown in Chemical formula 17 or Chemical formula 18 is racemic. The racemic compound of formula (IV) can be resolved into two optical isomers according to a conventional method. For example, by treating a compound of formula (IV) with an optically active acid to form a diastereomeric salt, followed by separation into two diastereomeric salts, which are then converted into free bases. .

The compound of the above formula (IV _A ) is a novel compound. The following formula (IVa) in which W is-(CH ₂ ) n-, R ¹ is the same group as R ^{1 described} above other than a methyl group, and the configuration is R.

[0087]

[Chemical 19]

In the compound represented by the formula (wherein R ¹² and n have the same meanings as described above), W in formula (I) is-.
(CH ₂ ) n-, R ¹ is the same group as R ^{1 described} above other than a methyl group, and is useful as a novel intermediate for a compound in which the configuration is R, particularly R ¹² is an ethyl group or cyclopropyl. The base one is preferable. Furthermore, the following formula (IVb),

[0089]

Embedded image

(In the formula, R ¹² represents the same as above.)
The compound represented by is preferable, and the compound in which R ¹² is an ethyl group is most preferable.

Process (b) The compound of formula (I) has the following formula (V)

[0092]

[Chemical 21]

[Wherein, W ² is — (CH ₂ ) n — or —CH
R ⁴ −, A, R ¹ , R ² , R ⁴ , n and the wavy line have the same meanings as described above. ]

It can be produced by diazotizing the compound represented by:

The ring-closing reaction from the compound of formula (V) to the compound of formula (I) by diazotization is carried out under the conditions usually used for diazotization of aromatic amines. Examples of the diazotizing agent include sodium nitrite, tert-butyl nitrite, and alkyl nitrite such as isoamyl nitrite. In the case of a ring-closing reaction with nitrous acid, sodium nitrite is usually added to an aqueous solution of a compound of formula (V) or an acid addition salt thereof after adding an excess of a mineral acid (eg hydrochloric acid) or an organic acid (eg acetic acid). Is performed by adding an aqueous solution of. The reaction temperature is generally about -20 ° C to about 60 ° C, preferably about 0 ° C to about 40 ° C. In the case of the ring-closing reaction with an alkyl nitrite, it is usually carried out by reacting a compound of the formula (V) or an acid addition salt thereof (for example, hydrochloride, acetate) with an alkyl nitrite in a suitable solvent. Done. Examples of the solvent include methanol, acetic acid, acetic acid-
Dioxane, 1,2-dimethoxyethane, tetrahydrofuran, acetone and methylene chloride are used, and the reaction temperature is usually about 0 ° C to about 100 ° C, preferably about 30 ° C to about 80 ° C.

The starting compound represented by the formula (V) can be produced, for example, by the method shown in the following Chemical formula 22.

[0097]

[Chemical formula 22]

(In the formula, Z means a halogen atom,
R ² , Az and wavy line have the same meanings as above. )

Step 1 : The reaction of the compound of formula (J) or its reactive derivative with the compound of formula (IV) can be carried out in the same manner as in the production method (a). The compound of formula (J), which is a starting material compound, is, for example, Helv. Chim. Acta, 40 ,
It can be produced according to the method described in 369-372 (1957).

Step 2 : Compound of formula (K) and formula: H ₂ N
The reaction with the compound represented by —R ² is carried out without solvent or in a suitable solvent. Examples of the solvent to be used include alcohols such as methanol and ethanol, dimethylformamide, dimethylsulfoxide, and water. The reaction temperature is usually about 0 ° C to about 150 ° C.

Step 3 : Reduction of the compound of formula (L) is carried out according to a conventional method. For example, it is carried out by treating the compound of formula (L) with a reducing agent in a suitable solvent. Specific examples of the reducing agent include a combination of a metal (for example, tin, zinc, iron) or a metal salt (for example, stannous chloride) and an acid (for example, hydrochloric acid, acetic acid). Itin can be used alone as a reducing agent. Alternatively, it is also carried out by hydrogenating the compound of formula (L) in the presence of a catalyst in a suitable solvent. Specific examples of the catalyst include palladium carbon, Raney nickel,
Platinum oxide can be used. The solvent to be used should be appropriately selected depending on the reducing agent or the reducing means, and examples thereof include alcohols such as methanol and ethanol, ethyl acetate, acetone, acetic acid, dioxane, water, or a mixed solution thereof. The reaction temperature will differ depending on the reducing agent or reducing means, but is usually about 10 ° C to about 100 ° C, and in the case of catalytic reduction, it is preferably about 10 ° C to about 50 ° C. In the case of a compound in which R ² is a C ₃ -C ₄ alkenyl group or a C ₃ -C ₄ alkynyl group in the formula (L), reduction with a metal or a metal salt and an acid, or iron or stannous chloride Preferably.

The resulting compound of formula (V) can be used as a starting compound for the production method (b) without isolation and purification.

Production method (c) In formula (I), R ² is a hydrogen atom, (i) W is — (CH ₂ ) n —, A is a methyl group, R ¹ is a methyl group, propyl group, an isopropyl group, butyl group, isobutyl group, sec- butyl group, C ₃ -C ₆ cycloalkyl group, cyclopropyl (C ₂ ~C ₄₎ alkyl group, (C ₄
-C ₆ cycloalkyl) C ₁ -C ₄ alkyl or halogeno (C ₁ ~C ₃₎ compound is an alkyl group, _{(ii) W - (CH 2} ) n - and is, A is C ₂ -C ₄ An alkyl group in which R ¹ is a C ₁ -C ₄ alkyl group, a C ₃ -C ₆ cycloalkyl group, a (C ₃ -C ₆ cycloalkyl) C ₁ -C ₄ alkyl group or a halogeno (C ₁ -C ₃ ). A compound which is an alkyl group, and (iii) W is —CHR ⁴ — and A is C ₁
To C ₄ alkyl group, R ¹ is a C _{1 to} C ₄ alkyl group, a C _{3 to} C ₆ cycloalkyl group, a (C _{3 to} C ₆ cycloalkyl) C _{1 to} C ₄ alkyl group or a halogeno (C ₁ to
The compound which is a C ₃ ) alkyl group has the following formula (IIa)

[0104]

[Chemical formula 23]

[Wherein, R ^3a represents a protecting group for an amino group (for example, an optionally substituted benzyl group or an optionally substituted benzyloxycarbonyl group), and W ² is-.
(CH ₂ ) n − or —CHR ⁴ — means A ^1a and R
^11a is the A described in (i), (ii) and (iii) above, respectively.
And R ¹ mean the same, and R ⁴ , n and the wavy line mean the same as above. ]

It can also be produced by hydrogenolysis of the compound represented by:

This hydrogenolysis can be carried out according to a conventional method, for example, by reacting with hydrogen in the presence of a catalyst such as palladium carbon or Raney nickel in a suitable solvent, or by reacting with hydrogen in the presence of a catalyst such as palladium carbon. A donor (eg,
It is carried out by reacting with ammonium formate, cyclohexene). Examples of the solvent include alcohols such as ethanol and methanol, water, acetic acid, dioxane, and tetrahydrofuran. The reaction temperature is usually about 0 ° C to about 80 ° C, and the reaction is carried out under normal pressure or increased pressure.

In the formula (IIa), the compound in which R ^3a is an ^optionally substituted benzyl group is represented by the formula (V).
It can be produced by the above production method (b) using a compound in which ² is an optionally substituted benzyl group as a starting compound. On the other hand, the starting compound (V) can be produced according to the method shown in Chemical formula 22 above. In this case, the reduction reaction in step 3 is preferably reduction with a combination of a metal or a metal salt and an acid, or iron or stannous chloride.

The compound in which R ^3a in the formula (IIa) is an ^optionally substituted benzyloxycarbonyl group is prepared from the compound in which R ² in the above formula (III) is an optionally substituted benzyloxycarbonyl group. It can be used as a compound and can be produced by the above production method (a). Specifically, it can be produced by the same method as in Reference Example 39 described later. The compound in which R ² in the formula (III) is an optionally substituted benzyloxycarbonyl group is described in, for example, JP-A-51-80858 (US Pat.
4,039,672 specification) or a method similar thereto.

[0110]Manufacturing method (d) In formula (I), R²Is a hydrogen atom, and (i) W is
-(CH₂) n-, A is a methyl group, R¹ The
Cyl group, propyl group, isopropyl group, butyl group, iso
Butyl group, sec-butyl group, C₃ ~ C₆ Cycloalkyl
Group, cyclopropyl (C₂~ C_Four) Alkyl group, (C_Four
~ C₆ Cycloalkyl) C₁~ C_FourAlkyl group, C₃ ~
C_FourAlkenyl group, C₃ ~ C_FourAlkynyl group or halogen
No (C₁ ~ C₃ ) A compound which is an alkyl group, (ii) W is-
(CH₂) n- and A is C₂~ C_FourIs an alkyl group
R¹ Is C₁ ~ C_FourAlkyl group, C₃ ~ C₆ Cycloa
Rukiru group, (C₃~ C₆ Cycloalkyl) C₁ ~ C_FourA
Rukiru group, C₃ ~ C_FourAlkenyl group, C₃ ~ C_FourArchi
Nyl group or halogeno (C₁ ~ C₃ ) Alkyl group
Compound, and (iii) W is -CO- or -CHR^Four−
And A is C₁~ C_FourAn alkyl group, R¹ Is C₁ ~ C
_FourAlkyl group, C₃ ~ C₆ Cycloalkyl group, (C ₃~
C₆ Cycloalkyl) C₁ ~ C_FourAlkyl group, C₃ ~ C
_FourAlkenyl group, C₃ ~ C_FourAlkynyl group or halogeno
(C₁ ~ C₃ ) A compound which is an alkyl group is represented by the following formula (II
b),

[0111]

[Chemical formula 24]

[Wherein R ^3b represents a protecting group for an amino group (eg, lower alkanoyl group, trifluoroacetyl group, lower alkoxycarbonyl group or optionally substituted benzyloxycarbonyl group), and W ³ represents - (CH ₂₎
n -, - CO- or -CHR ⁴ - means, A ^1b and R
^11b is the A described in (i), (ii) and (iii) above.
And R ¹ mean the same, and R ⁴ , n and the wavy line mean the same as above. ]

It can also be produced by hydrolyzing the compound represented by:

This hydrolysis reaction can be carried out according to a conventional method, for example, by bringing it into contact with water under acidic or basic conditions in a suitable solvent. As the solvent, for example, alcohols such as methanol, ethanol, isopropyl alcohol, dioxane, water or a mixed solution thereof is used. Specific examples of the acid include mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid, organic acids such as formic acid, acetic acid, propionic acid and oxalic acid, and silica gel. When a compound in which R ^3b is an acetyl group in the formula (IIb) is used, it can be easily converted to a compound in which R ² is a hydrogen atom in the formula (I) by eliminating the acetyl group by using silica gel. it can. 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 20 ° C to about 10
It is 0 ° C.

The compound of formula (IIb), which is an intermediate of the present invention, has the following formula (III) in which R ² is a lower alkanoyl group:
Using the compound which is a trifluoroacetyl group, a lower alkoxycarbonyl group or an optionally substituted benzyloxycarbonyl group as a starting compound, the above production method (a)
Can be manufactured by. Specifically, it can be produced by the same method as in Reference Example 40 described later. The compound in which R ² in the above formula (III) is, for example, a lower alkanoyl group, a trifluoroacetyl group, a lower alkoxycarbonyl group or an optionally substituted benzyloxycarbonyl group is described in, for example, JP-A-51-80858 (US Pat. It can be produced by the method described in Japanese Patent No. 4,039,672) or a method similar thereto.

According to the production methods (a), (b), (c) and (d), the compound of the formula (IV) which is the starting compound, the compound of the formula (V)
The configurations of the compound of formula (IIa) and the compound of formula (IIa) and formula (IIb) are retained in the product of formula (I). Therefore, formula (I) having the desired configuration
The compound of formula (I) is produced by using a starting compound having a corresponding configuration or by using a starting compound which is a racemic compound,
It can be produced by optical resolution according to a conventional method.

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

The compound of the formula (I) and the compound of the formula (II) can be obtained in the form of a free base or an acid addition salt depending on the selection of the starting compound, reaction and treatment conditions and the like. Acid addition salts are
For example, it can be converted into a free base by treating 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 it with various acids according to a conventional method.

In the following, representative compounds of the present invention, reference compounds (Reference Examples 24 to 38) in which the compound of formula (IV _A ) can be used as an intermediate, and commercially available gastrointestinal function improving agents The pharmacological action of a certain metoclopramide hydrochloride monohydrate (Compound A) is shown below.

Test Example 1 : Inhibitory effect on apomorphine-induced vomiting--A group of 3 to 4 beagle dogs (weight 8 to 15 kg) was used, and Ch
The method of en and Ensor [J.Pharmacol. Exp. Ther., 98 , 245
-250 (1950)], the inhibitory effect of the test compound on apomorphine-induced vomiting was examined.
A predetermined dose of the test compound dissolved or suspended in a 0.5% tragacanth solution was orally administered, 2 hours later, apomorphine hydrochloride (0.3 mg / kg) was subcutaneously injected into the back, and the number of vomiting was counted over 1 hour thereafter. The suppression rate was calculated by comparing the vomiting frequency of the test compound administration group with that of the control group. The results are shown in Table 1.
Shown in

[0121]

[Table 1] ^* ) Means the compound of Example 1 (the same applies hereinafter). ^** ) means the compound of Reference Example 24 (the same applies hereinafter).

Test Example 2 : Gastric emptying enhancing action--This test was conducted by the method of Scarpignato et al. [Arch. Int. Pharmac.
odyn., 246 , 286-294 (1980)]. After Wistar male rats (body weight 130-150 g) were fasted for 18 hours, they contained phenol red in a ratio of 0.05%
1.5 ml of 1.5% methylcellulose solution was orally administered. 15 minutes after the administration, the stomach was removed and the amount of phenol red remaining in the stomach was measured. The test compound was dissolved or suspended in a 0.5% tragacanth solution and orally administered 60 minutes before the administration of phenol red. The gastric emptying rate was calculated based on the amount of residual phenol red in the stomach, and further compared with the gastric emptying rate of the control group to obtain the enhancement rate. The number of animals used was 5 for the control group and the metoclopramide hydrochloride monohydrate (Compound A) administration group, and 4 for the other animals. Table 2 shows the results.

[0123]

[Table 2] ^* ) Means the compound of Example 1 (the same applies hereinafter). ^** ) means the compound of Reference Example 25 (the same applies hereinafter).

Test Example 3 : Exploratory behavior inhibitory action—Five male Std-ddY mice (body weight: 20 to 25 g) in each group were used. Test compound dissolved or suspended in 0.5% tragacanth solution was orally administered, and 2 hours later, one mouse was animated.
ex Momentum measuring device (Farad) upper measurement cage (23 × 35
× 30 cm) and the amount of exploratory activity for 3 minutes was measured. The average value of the exploratory activity amount (count / 3 minutes) of the test compound administration group was calculated, and the inhibition rate was calculated by comparing with that of the control group, and the 50% inhibition dose (ID ₅₀ ) was determined by the probit method.
The results are shown in Table 3.

[0125]

[Table 3] ^* ) Means the compound of Example 1 (the same applies hereinafter). ^** ) means the compound of Reference Example 24 (the same applies hereinafter).

As is clear from the above test results, the compound of formula (I) and its physiologically acceptable acid addition salt have both excellent anti-emetic action and gastrointestinal function-promoting action, and central inhibition. Since it has a weak action, it can be used as a gastrointestinal function improving drug for the treatment and prevention of various gastrointestinal dysfunction associated with various diseases and treatments. Specifically, acute / chronic gastritis, reflux esophagitis, gastric / duodenal ulcer, gastric neuropathy, gastroptosis, postgastrectomy syndrome, scleroderma, diabetes, esophageal / biliary tract disease, periodic vomiting in children, For the treatment and prevention of anorexia, nausea, vomiting, abdominal distention, upper abdominal discomfort, abdominal pain, heartburn, vomiting, etc. in diseases such as upper respiratory tract infections, and treatment of irritable bowel syndrome, constipation, infant diarrhea And can be used for prevention. Furthermore, it can be used for the treatment and prevention of nausea or vomiting during administration of various anticancer agents or levodopa preparations or during irradiation of radiation.

The route of administration may be oral, parenteral or rectal administration. The dose varies depending on the kind of compound, administration method, patient's symptoms and age, etc., but usually 0.01 to 50 mg / kg / day, preferably 0.1 to 10 m
The range is g / kg / day.

When the compound of formula (I) or a physiologically acceptable acid addition salt thereof is used for the above-mentioned pharmaceutical use, it is usually administered in the form of a preparation prepared by mixing with a carrier for preparation. The pharmaceutical carrier 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 aluminometasilicate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethyl cellulose, hydroxypropyl starch, calcium carboxymethyl cellulose, ion exchange resin, methyl cellulose, gelatin, gum arabic, pullulan, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, 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 and suppositories. These preparations are prepared according to a conventional method. The liquid preparation may be dissolved or suspended in water or another suitable medium before use. The tablets and granules may be coated by a known method.

These preparations may contain the compound of 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.

[0131]

The present invention will be described in more detail below with reference to Reference Examples and Examples, but the present invention is not limited to these Examples. Compounds are identified by elemental analysis value, mass spectrum, UV spectrum, IR spectrum, N
It was performed by MR spectrum and the like.

In the following Reference Examples and Examples,
The following abbreviations may be used for simplification of description.

[Recrystallization Solvent] A: ethanol, AT: acetone, E: diethyl ether, HX: n-hexane, T: toluene.

[Substituent] Me: methyl group, Et: ethyl group, Pr: n-propyl group, i-Pr: isopropyl group, Bu: n-butyl group, i-Bu: isobutyl group, sec-Bu: sec -Butyl group,
△: cyclopropyl group, □: cyclobutyl group,
Ph: Phenyl group.

[NMR] J: binding constant, s: singlet, d: doublet,
dd: double doublet, t: triplet, q: quartet, m: multiplet, br-s: broad singlet.

[Others] ee: Enantiomeric excess rate

Example 1 N- (1-ethyl-1H-hexahydroazepine-3-
Preparation of (yl) -6-methoxy-1-propyl-1H-benzotriazole-5-carboxamide:

5-amino-N- (1 obtained in Reference Example 9
-Ethyl-1H-hexahydroazepin-3-yl)-
After adding 5 ml of acetic acid to an aqueous solution containing 2-methoxy-4-propylaminobenzamide, sodium nitrite 0.3
4 g of an aqueous solution was added at an internal temperature of 5 ° C, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was made alkaline with an aqueous sodium hydroxide solution and then extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give an oily substance. This oily substance was subjected to silica gel column chromatography, eluted and purified with chloroform-methanol (9: 1), and the obtained solid was recrystallized from toluene-diethyl ether to obtain 1.22 g of the desired product. Melting point
88 ~ 89 ℃

Examples 2 to 8 — Performed using the corresponding 5-amino-4-substituted amino-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxybenzamide in aqueous acetic acid. Reaction and treatment were carried out in the same manner as in Example 1 to obtain the compounds of Table 4 represented by Chemical formula 25.

[0140]

[Chemical 25]

[0141]

[Table 4] ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Example R ² Q Melting point (° C.) Recrystallization solvent ━━━ ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 2 i-Pr 1 / 4H ₂ O 61-63 E-HX 3 Bu 1 / 2H ₂ O 118-119 TE 4 i-Bu 129-130 TE 5 sec-Bu Amorphous 6 △ 1 / 10H ₂ O 94-95 E 7 □ Amorphous 8 CH ₂ △ 105-107 E 9 CH ₂ CH ₂ OH 1 / 4H ₂ O 132-134 EA-E 10 CH ₂ CH ₂ OCH ₃ 78-80 EA-HX ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

Example 11 N- (1-ethyl-1H-hexahydroazepine-3-
Preparation of (yl) -6-methoxy-1- [2- (1-pyrrolidinyl) ethyl] -1H-benzotriazole-5-carboxamide:

5-Amino-N-obtained in Reference Example 19
Reaction was carried out in the same manner as in Example 1 using an aqueous hydrochloric acid solution containing (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-4-[[2- (1-pyrrolidinyl) ethyl] amino] benzamide. -Treatment and recrystallization of the product from diethyl ether-n-hexane gave the desired product. Melting point 58-60 ° C

Example 12 Preparation of 1-allyl-N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide:

4-allylamino-obtained in Reference Example 21
Using an aqueous hydrochloric acid solution containing 5-amino-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxybenzamide, the reaction and treatment were carried out in the same manner as in Reference 39 described below, and the product was converted from diethyl ether. Recrystallization gave the target hemihydrate. Melting point 73-74 ℃

Example 13 N- (1-ethyl-1H-hexahydroazepine-3-
Preparation of yl) -6-methoxy-1-propargyl-1H-benzotriazole-5-carboxamide:

5-Amino-N-obtained in Reference Example 22
Using an aqueous hydrochloric acid solution containing (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-4-propargylaminobenzamide, the reaction and treatment were carried out in the same manner as in Reference 39 described later to obtain the target product as an amorphous substance. .

Example 14 N- (1-methyl-1H-hexahydroazepine-3-
Yl) -6-methoxy-1H-benzotriazole-5
-Production of carboxamide:

6-Methoxy-1H-benzotriazole-5-carboxylic acid 0.73 g of dimethylformamide 10
0.62 g of N, N'-carbonyldiimidazole in ml solution
Was added, and the mixture was stirred at room temperature for 6 hours. 3-amino-in the reaction solution
0.49 g of 1-methyl-1H-hexahydroazepine was added, and the mixture was further stirred at room temperature for 14 hours. The solvent was distilled off under reduced pressure,
The residue was subjected to silica gel column chromatography, eluted and purified with chloroform-methanol (10: 1), and recrystallized from acetone-diethyl ether to give the desired product 0.56 g.
I got Melting point 178-182 ° C

Examples 15 to 22 -Instead of 3-amino-1-methyl-1H-hexahydroazepine in Example 14, the corresponding 3-amino-
Using 1-substituted-1H-hexahydroazepines, reaction and treatment were carried out in the same manner as in Example 14 to obtain the compound of Table 5 represented by Chemical formula 26.

[0151]

[Chemical formula 26]

[0152]

[Table 5]

Example 23 Preparation of N- (1-cyclohexylmethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide:

Instead of 3-amino-1-methyl-1H-hexahydroazepine in Example 14, 3-amino-1-cyclohexylmethyl-1H-hexahydroazepine was used, and the reaction and treatment were carried out in the same manner as in Example 14. The desired product was obtained as an amorphous product.

Example 24 6-Ethoxy-N- (1-ethyl-1H-hexahydroazepin-3-yl) -1H-benzotriazole-5
-Production of carboxamide:

3-Amino-1-methyl-1H-hexahydroazepine and 6-methoxy-1 in Example 14
Instead of H-benzotriazole-5-carboxylic acid,
Using 3-amino-1-ethyl-1H-hexahydroazepine and 6-ethoxy-1H-benzotriazole-5-carboxylic acid, the reaction and treatment were carried out in the same manner as in Example 15, and the product was regenerated from methanol-diethyl ether. Crystallization gave the desired product. Melting point 174-175 ° C

Example 25 N- (1-ethyl-5,5-ethylenedioxy-1H-
Hexahydroazepin-3-yl) -6-methoxy-1
Preparation of H-benzotriazole-5-carboxamide:

Instead of 3-amino-1-methyl-1H-hexahydroazepine in Example 14, 3-amino-1-ethyl-5,5-ethylenedioxy-1H-hexahydroazepine was used. Reaction similar to 14
The product was treated to obtain the desired product as an amorphous substance.

Example 26 Preparation of 3-amino-1-ethyl-1H-hexahydroazepine:

(1) α-Amino-ε-caprolactam
125 g and triethylamine 118 g chloroform 600 m
To the suspension, 288 g of chlorotriphenylmethane was added with stirring under ice cooling. The mixture was further stirred under the same conditions for 1 hour and then at room temperature for 2 hours. The precipitate was collected by filtration, washed thoroughly with acetone, and dried to obtain α-
330 g of triphenylmethylamino-ε-caprolactam
I got Melting point 240-241 ° C

(2) 100 g of the above product and iodoethane
To a solution of 65 g of dimethylformamide in 500 ml, 12 g of 60% sodium hydride was gradually added with stirring at room temperature, and the mixture was stirred under the same conditions for 4 hours and then poured into ice water. The reaction solution was extracted with diethyl ether, the extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crystals are collected by filtration, dried, and 1-ethyl-3.
88 g of triphenylmethylamino-1H-hexahydroazepin-2-one were obtained. Melting point 120-121 ° C

(3) 180 g of 70% sodium bis (2-methoxyethoxy) aluminum hydride solution in toluene
Toluene (800 ml) was added to the above, and the above product (83 g) was added thereto with stirring under ice cooling, and the mixture was stirred for 1 hour under the same conditions.
It was stirred at room temperature for another 2 hours. 48 hours with water under ice-cooling
After adding a% sodium hydroxide aqueous solution, the organic layer was separated. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained oily residue was crystallized with ethanol, the crystals were collected by filtration, dried and 1-
65 g of ethyl-3-triphenylmethylamino-1H-hexahydroazepine was obtained. Melting point 85-86 ℃

(4) To a solution of 134 g of the above product in 30 ml of tetrahydrofuran was added 500 ml of 10% hydrochloric acid, and the mixture was allowed to stand at room temperature for 2 hours.
Stir for hours. The reaction solution was washed with diethyl ether, and then excess potassium carbonate was added to the aqueous layer, followed by extraction with chloroform. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the desired product (48 g) as an oil.

¹ H-NMR spectrum (CDCl ₃ , δppm): 1.0
4 (3H, t, J = 7.5Hz), 1.3-1.9 (8H, m), 2.42 (1H, dd,
J = 13.5Hz, J = 6.9Hz), 2.5-2.6 (4H, m), 2.70 (1H, d
d, J = 13.5, J = 3.5Hz), 2.98 (1H, m).

Example 27 Preparation of (R) -3-amino-1-ethyl-1H-hexahydroazepine:

(1) A suspension of 173 g of (R) -α-amino-ε-caprolactam hydrochloride and 266 g of triethylamine in 1700 ml of chloroform was added to chlorotriphenylmethane.
293 g was added with stirring under ice cooling. The mixture was stirred under the same conditions for 1 hour and then at room temperature for 2 hours.
The reaction solution was washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and 600 ml of a mixed solution of n-hexane-ethyl acetate (2: 1) was heated and stirred to the oily residue. added. The precipitated crystals were collected by filtration, washed with 1000 ml of a mixed solution of n-hexane-ethyl acetate (10: 1) and dried to obtain 290 g of (R) -α-triphenylmethylamino-ε-caprolactam. It was Melting point 189 ℃

(2) 300 g of the above product and iodoethane
To a solution of 193 g of tetrahydrofuran in 1500 ml, 60 g of sodium hydride (42 g) was gradually added with stirring at room temperature.
After stirring for 1.5 hours under the same conditions, cool the container with ice water,
Water was added slowly until the insoluble material dissolved. The reaction solution was concentrated under reduced pressure, 1000 ml of ethyl acetate was added to the residue, washed with water, the organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. To the oily residue was added 350 ml of a mixture of hexane: ethyl acetate (50: 1), and the precipitated crystals were collected by filtration and dried (R) -1-ethyl-3-triphenylmethylamino-1H-hexa. 287 g of hydroazepin-2-one were obtained. Melting point 127 ℃

(3) 70% toluene solution of sodium bis (2-methoxyethoxy) aluminum hydride 615 g
Toluene (1400 ml) was added to the above, and the above product (280 g) was added thereto while stirring under ice cooling. After stirring for 1.5 hours under the same conditions, the reaction solution was cooled with ice under ice-cooling with a 15% sodium hydroxide solution 100
After adding 0 ml, the organic layer was separated, and the aqueous layer was further extracted with 1500 ml of toluene. The combined organic layers were washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
The obtained oily residue was crystallized with ethanol, the crystals were collected by filtration, and dried (R) -1-ethyl-3-triphenylmethylamino-1H-hexahydroazepine 247
got g. Melting point 83 ~ 84 ℃

(4) To a solution of 177 g of the above product in 50 ml of tetrahydrofuran was added 700 ml of 10% hydrochloric acid, and the mixture was allowed to stand at room temperature for 2 hours.
Stir for hours. The reaction solution was washed with diethyl ether, and then excess potassium carbonate was added to the aqueous layer, followed by extraction with chloroform. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the desired product (65 g) as an oil.

¹ H-NMR spectrum (CDCl ₃ , δppm): 1.
04 (3H, t, J = 7.5Hz), 1.3-1.9 (8H, m), 2.42 (1H, dd,
J = 13.5Hz, 6.9Hz), 2.5-2.6 (4H, m), 2.70 (1H, dd, J
= 13.5, J = 3.5Hz), 2.98 (1H, m).

Example 28 Preparation of (S) -3-amino-1-ethyl-1H-hexahydroazepine:

Α-Amino-ε in Example 26 (1)
-(S) -α-amino-ε-instead of caprolactam
Using caprolactam, the reaction and treatment were carried out in the same manner as in Example 26 to obtain the desired product as an oil.

Example 29 Preparation of 3-amino-1-propyl-1H-hexahydroazepine:

Using 1-iodopropane instead of iodoethane in Example 26 (2), Example 26 (2)
The reaction and treatment were carried out in the same manner as in (4) to obtain the desired product as an oil.

Example 30 Preparation of 3-amino-1-isopropyl-1H-hexahydroazepine:

(1) α-triphenylmethylamino-
ε-caprolactam 19 g tetrahydrofuran 200 m
l solution of diisobutylaluminium hydride at room temperature
500 ml of M toluene solution was added dropwise, and the mixture was stirred at the same temperature for 16 hours. Saturated Rochelle salt (potassium sodium tartrate-4
(Hydrate) aqueous solution was added dropwise to decompose excess diisobutylaluminum hydride, and then the precipitated salt was filtered off. The filtrate was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
19.6 g of -triphenylmethylamino-1H-hexahydroazepine were obtained as an oil.

(2) A mixture of 2.0 g of the above product, 50 ml of methyl ethyl ketone, 2.3 g of potassium carbonate and 1.4 g of 2-iodopropane was heated under reflux for 5 hours. After cooling to room temperature, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted and purified with chloroform-methanol (10: 1) to give 1-isopropyl-3-triphenylmethylamino-1H-hexahydroazepine (2.1 g) as an oil.

(3) A mixture of 2.1 g of the above product, 7 ml of tetrahydrofuran and 40 ml of 10% hydrochloric acid was stirred at room temperature for 5 hours. The reaction solution was washed with diethyl ether, the aqueous layer was made alkaline with concentrated potassium carbonate, and then extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the desired product (1.0 g) as an oil.

Example 31 Preparation of 3-amino-1-butyl-1H-hexahydroazepine:

Using 1-iodobutyl in place of iodoethane in Example 26 (2),
The reaction and treatment were carried out in the same manner as in (4) to obtain the desired product as an oil.

Example 32 : Preparation of 3-amino-1-sec-butyl-1H-hexahydroazepine:

Using 2-iodobutyl instead of iodoethane in Example 26 (2),
The reaction and treatment were carried out in the same manner as in (4) to obtain the desired product as an oil.

Example 33-(R) -3-Amino-1-cyclopropylmethyl-1H
-Production of hexahydroazepine:

(1) (R) -α-Triphenylmethylamino-ε-caprolactam 37 g of toluene 370 ml
1M of diisobutylaluminium hydride in solution at room temperature
1000 ml of a toluene solution was added dropwise and stirred for 16 hours. After completion of the reaction, water was added dropwise to decompose excess diisobutylaluminum hydride. The precipitated salt was filtered off, the filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give (R) -3-triphenylmethylamino-1.
34 g of H-hexahydroazepine were obtained as an oil.

(2) To a solution of 10 g of the above product in 100 ml of methyl ethyl ketone was added 10.5 g of potassium carbonate and 5.1 g of cyclopropylmethyl bromide, and the mixture was heated under reflux for 5 hours. After the reaction was completed, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (10: 1) and purified to give (R) -1-cyclopropylmethyl-3-triphenylmethylamino-1H-hexahydroazepine (10 g) as an oil. Obtained as a thing.

(3) To a solution of 9.0 g of the above product in 10 ml of tetrahydrofuran was added 100 ml of 10% hydrochloric acid, and the mixture was stirred at room temperature for 5 hours. The reaction solution was washed with diethyl ether,
The aqueous layer was saturated with potassium carbonate and then extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the desired product (4.0 g) as an oil.

Example 34 Preparation of 3-amino-1-cyclopropylmethyl-1H-hexahydroazepine:

Example 33 (R) -α-triphenylmethylamino-ε-caprolactam in place of (R) -α-triphenylmethylamino-ε-caprolactam was used and reacted and treated in the same manner as in Example 33. The desired product was obtained as an oil.

Example 35 Preparation of 3-amino-1-cyclohexylmethyl-1H-hexahydroazepine:

Using cyclohexyl bromide in place of iodoethane in Example 26 (2), Examples 26 (2)-
The reaction and treatment were carried out in the same manner as in (4) to obtain the desired product as an oil.

Example 36 Preparation of 3-amino-1- (2-fluoroethyl) -1H-hexahydroazepine:

Example 26 Using 2-fluoroethane bromide instead of iodoethane in Example 26 (2),
The reaction and treatment were carried out in the same manner as (2) to (4) to obtain the desired product as an oil.

Example 37 Preparation of 1-allyl-3-amino-1H-hexahydroazepine:

Allyl bromide was used in place of 2-iodopropane in Example 30 (2) to give Example 30 (2) and
The reaction and treatment were carried out in the same manner as in (3) to obtain the desired product as an oil.

Example 38 --3-amino-1- (2,2,2-trifluoroethyl)
Preparation of -1H-hexahydroazepine:

(1) α-Amino-ε-caprolactam
12.8 g was melt | dissolved in 100 ml of methanol, and 23.3 g of benzaldehyde was added to this. Then, 13.2 g of sodium cyanoborohydride was added little by little, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, methanol was distilled off under reduced pressure, water was added to the residue for dilution, and the mixture was extracted with chloroform. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted and purified with chloroflum-methanol (12: 1) to obtain 18.3 g of α-benzylamino-ε-caprolactam as an oil.

(2) To a solution of 14.5 g of the above product in 150 ml of tetrahydrofuran was added 500 ml of a 1M solution of diisobutylaluminum hydride in toluene over 1.5 hours at room temperature, and the mixture was stirred at the same temperature for 16 hours. Excessive diisobutylaluminum hydride was decomposed with water, a 48% sodium hydroxide aqueous solution was added until the liquid layer became two layers, and then extracted with toluene. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 3-benzylamino-1H-.
Hexahydroazepine (15.8 g) was obtained as an oil.

(3) To a mixed solution of 6.2 ml of trifluoroacetic acid and 10 ml of toluene, 0.93 g of sodium borohydride was added little by little so that the internal temperature did not exceed 20 ° C. A solution of 1.0 g of the above product in 10 ml of toluene was added dropwise to this mixture at room temperature, and the mixture was heated under reflux for 3 hours. After adding a 2N sodium hydroxide aqueous solution under ice cooling, the mixture was extracted with toluene. The extract was dried over anhydrous sodium sulfate, toluene was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (15: 1) and purified to give 3-benzylamino-1- ( 2, 2, 2
-Trifluoroethyl) -1H-hexahydroazepine
1.1 g was obtained as an oil.

(4) 1.1 g of ethanol 3 of the above product
0.15 g of 10% palladium carbon was added to the 0 ml solution, and catalytic reduction was carried out at normal pressure and room temperature. After the theoretical amount of hydrogen had been absorbed, the palladium on carbon was filtered off. The filtrate was distilled off under reduced pressure to obtain 0.8 g of the desired product as an oily substance.

Example 39 Preparation of 3-amino-1-ethyl-1H-heptahydroazocine:

(1) 2-azacyclooctanone 27 g
To a solution of 50 g of iodoethane and 50 g of iodoethane in 250 ml of tetrahydrofuran, 10 g of 60% sodium hydride was gradually added while stirring under ice cooling. The reaction mixture was stirred at room temperature for 4 hours, poured into ice water, and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (100: 1) and purified to give 1-ethyl-1H-heptahydro. Azocin-2-one
36 g was obtained as an oil.

¹ H-NMR spectrum (CDCl ₃ , δppm): 1.1
5 (3H, t, J = 7Hz), 1.4-1.7 (6H, m), 1.82 (2H, m), 2.
48 (2H, m), 3.38 (2H, q, J = 7Hz), 3.47 (2H, m).

(2) Chloroform of 25 g of the above product
34 g of phosphorus pentachloride was gradually added to a 200 ml solution while stirring under ice cooling, and the mixture was stirred for 30 minutes under the same conditions. 0.4 g of iodine was added to this mixed solution with stirring under ice cooling, then 25 g of bromine was slowly added dropwise under the same conditions, and the mixture was heated under reflux for 2 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate and then washed successively with water and an aqueous sodium thiosulfate solution.
The ethyl acetate solution was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, n-hexane-ethyl acetate (4: 1).
Elution and purification were carried out with and the obtained crystals were recrystallized from n-hexane to give 3-bromo-1-ethyl-1H-heptahydroazocin-2-one and 3-chloro-1-ethyl-1H-heptahydro. 10 g of a mixture of azocin-2-ones was obtained.

(3) A solution of 10 g of the above mixture, 12 g of sodium azide and 2.0 g of sodium iodide in 100 ml of dimethylformamide was stirred overnight at 80 ° C., poured into ice water and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with n-hexane-ethyl acetate (4: 1) to give 3-azido-1-ethyl-1H-heptahydroazocin-2-one.
4.8 g was obtained as an oil.

¹ H-NMR spectrum (CDCl ₃ , δppm): 1.1
8 (3H, t, J = 7Hz), 1.5-1.8 (6H, m), 2.2 (2H, m), 3.0
8 (1H, m), 3.28 (1H, m), 3.53 (1H, m), 3.76 (1H, m
m), 4.0 (1H, dd, J = 10.5Hz, J = 5.6Hz).

(4) 70% toluene solution of sodium bis (2-methoxyethoxy) aluminum hydride 36.
To 4 g, add 100 ml of toluene, and add the above product 4.8
g was slowly added with stirring under ice cooling, and the mixture was stirred at room temperature for 2 hours. Water and 48% aqueous sodium hydroxide solution were slowly added to the reaction solution while stirring under ice cooling, and the mixture was extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the desired product (3.8 g) as an oil.

Example 40 Preparation of 3-amino-1-ethyl-1H-octahydroazonin:

(1) 200 g of 1,2-dimethoxyethane of 17 g of 2-azacyclononanone and 29 g of iodoethane
To the 1 solution, 6.0 g of 60% sodium hydride was gradually added with stirring at room temperature, the mixture was stirred for 4 hours under the same conditions, water was added, and the mixture was extracted with chloroform. Wash the extract with water,
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure,
1-ethyl-1H-octahydroazonin-2-one 2
0 g was obtained as an oil.

(2) To a solution of 20 g of the above product in 200 ml of tetrahydrofuran was added dropwise a solution of 2M lithium diisopropylamide in 78 ml of tetrahydrofuran under ice-cooling.
Stir for hours. The reaction solution was poured into dry ice, the resulting mixed solution was diluted with water, and this was washed with ethyl acetate.
The aqueous layer was acidified with concentrated hydrochloric acid, extracted with chloroform,
After washing with saturated saline and drying over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure to give 3-carboxy-1-ethyl-1.
14 g of H-octahydroazonin-2-one was obtained.
Melting point 109-110 ° C (recrystallized from diethyl ether-n-hexane)

(3) 100 g of the above product 12 g of acetone
12 ml of water and 7.0 ml of triethylamine were added to the ml solution. To this mixed solution, under ice-cooling, 30 ml of an acetone solution of 8.0 g of ethyl chlorocarbonate was added dropwise, and after stirring for 30 minutes, about 30 ml of an aqueous solution of 6.1 g of sodium azide was added dropwise.
Stir for hours. The reaction mixture was poured into ice water and extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added 200 ml of toluene, and the mixture was heated with stirring at 70 ° C, and when foaming stopped, the temperature was raised to 100 ° C and the mixture was stirred for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was treated with 20% hydrochloric acid.
120 ml was added with stirring under ice cooling, and the mixture was refluxed for 1.5 hours. The reaction mixture was washed with ethyl acetate, the aqueous layer was made alkaline with excess potassium carbonate, and then extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 3-amino-1-
Ethyl-1H-octahydroazonin-2-one 8.5 g
Was obtained as an oil.

(4) Chloroform of 8.5 g of the above product
7.0 ml of triethylamine was added to 100 ml solution, and 14 g of chlorotriphenylmethane was added little by little under ice cooling.
Stir at room temperature for 3 hours. The reaction mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate-n-hexane (1:10) and purified to give 3-triphenylmethylamino-1-ethyl-1H.
14 g of -octahydroazonin-2-one were obtained as a solid. Melting point 160-162 ° C (recrystallized from n-hexane-ethyl acetate)

(5) 70% toluene solution of sodium bis (2-methoxyethoxy) aluminum hydride 30
Toluene 100 ml was added to g, and the above product 14 g
Was slowly added with stirring under ice-cooling, and the mixture was stirred at room temperature for 24 hours. After cooling, 2N aqueous sodium hydroxide solution was added dropwise to the reaction solution, 48% aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted and purified with ethyl acetate-n-hexane (1:10) to give 3-triphenylmethylamino-1-ethyl-1H-octahydroazonin (13 g).

(6) To a solution of 13 g of the above product in 3 ml of tetrahydrofuran was added 45 ml of 10% hydrochloric acid, and the mixture was stirred at room temperature for 5 hours. The reaction solution was washed with diethyl ether, the aqueous layer was made alkaline with excess potassium carbonate, and then extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the desired product (5.0 g) as an oil.

Reference Example 1 Preparation of 4-chloro-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-5-nitrobenzamide:

22.7 g of thionyl chloride was added to a suspension of 14.7 g of 4-chloro-2-methoxy-5-nitrobenzoic acid, 300 ml of chloroform and 1 ml of dimethylformamide, and the mixture was heated under reflux for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was dissolved in 200 ml of methylene chloride. 12.9 g of triethylamine and 3-amino-1-ethyl-
After adding 9.0 g of 1H-hexahydroazepine at room temperature
Stir for 15 hours. The reaction mixture was washed with water, 10% hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with chloroform-methanol (9: 1) to obtain 9.8 g of the desired product as a solid.

Reference Example 2 — Preparation of (R) -4-chloro-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-5-nitrobenzamide:

(R) -3-Amino-1-ethyl-1H-
Reaction using hexahydroazepine in the same manner as in Reference Example 1
The desired product was obtained as a solid by processing.

Reference Example 3 Preparation of (S) -4-chloro-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-5-nitrobenzamide:

(S) -3-Amino-1-ethyl-1H-
Reaction using hexahydroazepine in the same manner as in Reference Example 1
The desired product was obtained as a solid by processing.

Reference Example 4 Preparation of 5-amino-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-4-methylaminobenzamide:

(1) 4-chloro-N- (1-ethyl-
1H-hexahydroazepin-3-yl) -2-methoxy-5-nitrobenzamide 4.9 g ethanol 100 m
50 ml of a 30% methylamine ethanol solution was added to the l solution, and the mixture was heated under reflux for 1.5 hours. After the solvent was distilled off under reduced pressure, water was added to the residue and the crystals were collected by filtration. The crystals are washed with water, dried and N- (1-ethyl-1H-hexahydroazepine-
3-yl) -2-methoxy-4-methylamino-5-nitrobenzamide (3.6 g) was obtained.

(2) 3.3 g of the above product was dissolved in 200 ml of 20% hydrous methanol, 10% palladium carbon was added, and catalytic reduction was carried out at normal pressure and room temperature. After the theoretical amount of hydrogen was absorbed, the palladium carbon was filtered off, and the methanol in the filtrate was distilled off under reduced pressure to obtain an aqueous solution of the desired product.

Reference Examples 5 to 18 : 5-amino-4-substituted amino-N- (1-ethyl-1H
-Hexahydroazepin-3-yl) -2-methoxy-
Production of benzamide or its optical isomer:

(R)-having the same configuration as the target product,
(S)-or (RS) -4-chloro-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-
Methoxy-5-nitrobenzamide and the corresponding amines were reacted and treated in the same manner as in Reference Example 4 to obtain an aqueous solution of the compound of Table 6 represented by Chemical formula 27.

[0225]

[Chemical 27]

[0226]

[Table 6]

Reference Example 19 --5-amino-4-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-[[2- (1
Preparation of -pyrrolidinyl) ethyl] amino] benzamide:

1- (2-Aminoethyl) pyrrolidine was used in place of the 30% methylamine ethanol solution of Reference Example 4 (1), and the reaction and treatment were carried out in the same manner as in Reference Example 4 to obtain the desired product. Reference Example 20 --5-amino-4-benzylamino-N- (1-ethyl-
Preparation of 1H-hexahydroazepin-3-yl) -2-methoxybenzamide:

(1) 4-chloro-N- (1-ethyl-
1H-hexahydroazepin-3-yl) -2-methoxy-5-nitrobenzamide 2.0 g ethanol 50 ml
6.0 g of benzylamine was added to the solution, and the mixture was heated under reflux for 22 hours. The solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (12: 1) and purified to give 4-benzylamino-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy. 2.4 g of -5-nitrobenzamide was obtained as a solid.

(2) 6 g of concentrated hydrochloric acid was added to 1.6 g of the above product.
And ethanol (3 ml) were added, and a solution of 2.6 g of stannous chloride dihydrate in ethanol (3 ml) was added, and the mixture was stirred at 80 ° C for 1 hr. After completion of the reaction, ethanol was distilled off under reduced pressure to obtain a hydrochloric acid aqueous solution containing the target substance.

Reference Example 21 --Preparation of 1-allyl-N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide:

Allylamine was used in place of benzylamine in Reference Example 20 (1), and the reaction and treatment were carried out in the same manner as in Reference Example 20 to obtain a hydrochloric acid aqueous solution containing the desired product.

Reference Example 22 Preparation of 5-amino-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-4-propargylaminobenzamide:

Propargylamine was used instead of benzylamine in Reference Example 20 (1), and the reaction and treatment were carried out in the same manner as in Reference Example 20 to obtain an aqueous hydrochloric acid solution containing the desired product.

Reference Example 23 : Preparation of 6-methoxy-1-methyl-1H-benzotriazole-5-carboxylic acid:

(1) 3-Amino-1 in Reference Example 1
-Ethyl-1H-hexahydroazepine was replaced with propylamine, reacted and treated in the same manner as in Reference Example 1, and 4
-Chloro-2-methoxy-5-nitro-N-propylbenzamide was obtained as a solid.

(2) 4-chloro-N- (1-ethyl-1H-hexahydroazepine-in Reference Example 4 (1)
3-yl) -2-methoxy-5-nitrobenzamide The above product was used in place of the above product, reacted and treated in the same manner as in Reference Example 4, to give 5-amino-2-methoxy-4-methylamino-.
N- (1-propyl) benzamide was obtained as a solid.

(3) 5-Amino-N- (1-methyl-1H-hexahydroazepine-3 in Example 1)
-Yl) -2-methoxy-4-propylaminobenzamide was used in place of the above product, reacted and treated in the same manner as in Example 1 to give 6-methoxy-1-methyl-N- (1.
-Propyl) -1H-benzotriazole-5-carboxamide was obtained as a solid.

(4) The mixture of the above product and concentrated hydrochloric acid was added to 5.
The mixture was heated under reflux for 5 hours. After cooling the reaction solution, it was concentrated under reduced pressure,
The precipitated crystals were collected by filtration, washed with water, and dried to obtain the desired product as a solid.

Reference Example 24 --N- (1-ethyl-1H-hexahydroazepine-3-
Preparation of yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide:

5-amino-N- (1 obtained in Reference Example 4
-Ethyl-1H-hexahydroazepin-3-yl)-
After adding 5 ml of acetic acid to an aqueous solution of 2-methoxy-4-methylaminobenzamide, the mixture was cooled to 5 ° C., an aqueous solution of 0.8 g of sodium nitrite was added, and the mixture was stirred at the same temperature for 1 hour.
The reaction solution was made alkaline with an aqueous sodium hydroxide solution and then extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give an oily substance. This oil was subjected to silica gel column chromatography, eluted and purified with chloroform-methanol (9: 1), and the obtained solid was recrystallized from toluene-n-hexane to obtain 2.3 g of the desired product. Melting point 103-10
4 ° C

Reference Example 25 Preparation of (R) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide:

(R) -5-amino-obtained in Reference Example 5
N- (1-ethyl-1H-hexahydroazepine-3-
Iyl) -2-methoxy-4-methylaminobenzamide was used in the same reaction and treatment as in Reference Example 24, and the product was recrystallized from toluene-n-hexane to obtain the desired product. Melting point 118-120 ° C [α] _D ²⁷ -70.6 ° (c = 1.0, ethanol)

Reference Example 26 : Preparation of (S) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide:

(S) -5-amino-obtained in Reference Example 6
N- (1-ethyl-1H-hexahydroazepine-3-
Iyl) -2-methoxy-4-methylaminobenzamide was used in the same reaction and treatment as in Reference Example 24, and the product was recrystallized from toluene-n-hexane to obtain the desired product. Melting point 119-120 ° C

Reference Example 27 : Preparation of 1-ethyl-N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide:

5-Amino-N- (1 obtained in Reference Example 7
-Ethyl-1H-hexahydroazepin-3-yl)-
Using an aqueous solution of 4-ethylamino-2-methoxybenzamide, the reaction and treatment were carried out in the same manner as in Reference Example 24, and the product was recrystallized from toluene-n-hexane to obtain the desired product.
Melting point 84-85 ℃

Reference Example 28 Preparation of (R) -1-ethyl-N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide:

(R) -5-amino-obtained in Reference Example 8
N- (1-ethyl-1H-hexahydroazepine-3-
And an aqueous solution of (yl) -4-ethylamino-2-methoxybenzamide were reacted and treated in the same manner as in Reference Example 24 to obtain the desired product as an oil.

Reference Example 29 --N- (1-ethyl-1H-hexahydroazepine-3-
Yl) -6-methoxy-1H-benzotriazole-5
-Production of carboxamide:

6-Methoxy-1H-benzotriazole-5-carboxylic acid 0.85 g of dimethylformamide 10
0.78 g of N, N'-carbonyldiimidazole was added to the ml solution, and the mixture was stirred at room temperature for 6 hours. 3-amino-1 in the reaction solution
0.75 g of -ethyl-1H-hexahydroazepine was added, and the mixture was stirred at room temperature for 14 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, eluted and purified with chloroform-methanol (10: 1), and recrystallized from ethanol-diethyl ether to obtain 1.3 g of the desired product. Obtained.

Melting point 156-158 ° C. ¹ H-NMR spectrum (CDCl ₃ , δppm): 1.09 (3H, t, J =
7Hz), 1.5-2.1 (6H, m), 2.5-3.1 (6H, m), 3.83 (3H,
s), 4.4 (1H, m), 6.4 (1H, br-s), 7.07 (1H, s), 8.05
(1H, d, J = 8Hz), 8.78 (1H, s).

Reference Example 30 Preparation of (R) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide:

(A) 3-Amino-in Reference Example 29
Instead of 1-ethyl-1H-hexahydroazepine,
Using (R) -3-amino-1-ethyl-1H-hexahydroazepine, the reaction and treatment were carried out in the same manner as in Reference Example 29, and the product was recrystallized from diethyl ether-n-hexane to obtain the desired product. . Melting point 127-128 ° C

(A ') The above target compound was again added with ethyl acetate-
Recrystallization from n-hexane gave the desired product. Melting point 142
~ 144 ° C [α] _D ²⁵ -71.9 ° (c = 1.0, methanol)

The compound showed a retention time of 37.2 minutes by high performance liquid chromatography (HPLC) under the following conditions:
The optical purity was 99% ee or higher. [HPLC conditions] HPLC column: SUMICHIRAL OA-4 manufactured by Sumika Chemical Analysis Service
900; 4.6 mm x 250 mm, mobile phase: n-hexane-methylene chloride-ethanol-trifluoroacetic acid (400: 100: 100: 0.6), flow rate: 1.0 ml / min, temperature: 25 ° C, detection: UV 230 nm .

(B) The product obtained in (a) above was treated with fumaric acid to give a fumarate, which was recrystallized from isopropyl alcohol-methanol to obtain the target 3/2 fumarate. Melting point 131-133 ° C

(B ') The product obtained in (a) above was treated with fumaric acid to give a fumarate, which was recrystallized from isopropyl alcohol to obtain the desired 3/2 fumarate. Melting point 162-163 ° C

(C) 1-Acetyl-6-methoxy-1
To 31.5 g of H-benzotriazole-5-carboxylic acid were added 20.3 g of triethylamine and 400 ml of ethyl acetate, and 17.5 g of ethyl chlorocarbonate was added dropwise at -7 to -10 ° C. After stirring at -5 ° C to -7 ° C for 2 hours, (R) -3-
Amino-1-ethyl-1H-hexahydroazepine 22.
8g of ethyl acetate 80ml solution was added dropwise and after stirring for 1 hour,
The mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. 1000 ml of a mixed solution of chloroform-methanol (8: 1) was added to the residue, 180 g of silica gel was added, and the mixture was stirred at room temperature for 16 hours. The silica gel was filtered off, washed with 1000 ml of a mixed solution of chloroform-methanol (5: 1), and the solvent was distilled off under reduced pressure to obtain 32 g of a crude product of the desired product.

To 24 g of the above crude product, 2.5 g of fumaric acid was added.
~ 3 times the amount (22.5 g) used, and recrystallized from methanol-isopropyl alcohol to obtain the desired 3/2 fumarate salt 2
Got 5 g. Melting point 131-133 ° C

(D) (R) obtained in Reference Example 40 described later
-1-Acetyl-N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide 1.85 g mixed solution of chloroform-methanol (8: 1) 55 After adding ml, silica gel 18.5 g was added and stirred at room temperature for 16 hours.
The silica gel was filtered off, washed with chloroform-methanol (9: 1) containing 1% aqueous ammonia, and the solvent was distilled off under reduced pressure to obtain 1.78 g of a crude product of the desired product.

Reference Example 31 --Preparation of (S) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide:

Instead of 3-amino-1-ethyl-1H-hexahydroazepine in Reference Example 29, (S) -3
-Amino-1-ethyl-1H-hexahydroazepine was reacted and treated in the same manner as in Reference Example 29, and then the product was treated with fumaric acid to give a fumarate, which was then recrystallized from isopropyl alcohol to give the desired product. 3/2 fumarate was obtained. Melting point 156-158 ° C

The title compound was converted into H under the same conditions as in Reference Example 29.
The PLC showed a retention time of 44.0 minutes and had an optical purity of 99% ee or higher.

Reference Examples 32 to 35 --Compared with 3-amino-1-ethyl-1H-hexahydroazepine in Reference Example 29, corresponding amines were used in the same reaction and treatment as in Reference Example 29. The compound of Table 7 represented by 28 was obtained.

[0266]

[Chemical 28]

[0267]

[Table 7]

Reference Example 36 : Preparation of (R) -N- (1-cyclopropylmethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide :

Using the corresponding starting compounds, Example 33,
Obtained by reacting and treating in the same manner as in Reference Examples 1 and 4 (R)
-5-amino-N- (1-cyclopropylmethyl-1H
-Hexahydroazepin-3-yl) -2-methoxy-
Using an aqueous solution of 4-methylaminobenzamide, the reaction and treatment were carried out in the same manner as in Example 1, and the product was recrystallized from toluene to obtain the desired product. Melting point 127-128 ° C

Reference Example 37 --N- (1-ethyl-1H-heptahydroazocin-3-
Preparation of yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide:

6-Methoxy-1H- in Example 14
Benzotriazole-5-carboxylic acid and 3-amino-
6 instead of 1-methyl-1H-hexahydroazepine
-Methoxy-1-methyl-1H-benzotriazole-
Using 5-carboxylic acid and 3-amino-1-ethyl-1H-heptahydroazocine, the reaction and treatment were carried out in the same manner as in Example 14, and the product was recrystallized from a mixed solution of ethanol-diethyl ether to give the desired product. Got Melting point 116 ~
118 ° C

Reference Example 38 --N- (1-ethyl-1H-octahydroazonin-3-
Preparation of yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide:

6-Methoxy-1H- in Example 14
Benzotriazole-5-carboxylic acid and 3-amino-
6 instead of 1-methyl-1H-hexahydroazepine
-Methoxy-1-methyl-1H-benzotriazole-
Using 5-carboxylic acid and 3-amino-1-ethyl-1H-octahydroazonin, respectively, the reaction and treatment were carried out in the same manner as in Example 14, and the product was recrystallized from ethyl acetate to obtain the desired product. Melting point 155-156 ° C

In Reference Example 39 and Reference Example 40 below,
The method for producing the compound of formula (II), which is an intermediate of the present invention, is shown.

Reference Example 39 : Preparation of 1-benzyl-N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide:

5-Amino-4-benzylamino-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxybenzamide obtained in Reference Example 20 About 1.
30 ml of 5N hydrochloric acid and 70 ml of water were added to 6 ml of hydrochloric acid aqueous solution containing 5 and 1 ml of an aqueous solution of 0.29 g of sodium nitrite under ice cooling.
Was added, and the mixture was stirred under the same conditions for 30 minutes and further at room temperature for 1 hour. The reaction solution was made alkaline with 48% aqueous sodium hydroxide solution and then 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 an oil. The oil was subjected to silica gel column chromatography, eluted and purified with chloroform-methanol (20: 1), and the obtained solid was recrystallized from diethyl ether to obtain 1.1 g of the desired product.
Melting point 136-137 ° C

Reference Example 40- (R) -1-Acetyl-N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-
Preparation of benzotriazole-5-carboxamide:

To 11.5-acetyl-6-methoxy-1H-benzotriazole-5-carboxylic acid (31.5 g) was added triethylamine (20.3 g) and ethyl acetate (400 ml).
17.5 g of ethyl chlorocarbonate was added dropwise at -10 ° C. -5 ° C
After stirring at ~ -7 ° C for 2 hours, (R) -3-amino-1
A solution of 22.8 g of -ethyl-1H-hexahydroazepine in 80 ml of ethyl acetate was added dropwise, and the mixture was stirred at the same temperature for 1 hour and then at room temperature for 16 hours. The reaction solution was washed with water and saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and recrystallized from ethyl acetate to obtain 36 g of the desired product.
Melting point 134-135 ° C

¹ H-NMR spectrum (CDCl ₃ , δppm): 1.
04 (3H, t, J = 7.0Hz), 1.5-2.1 (6H, m), 2.45-2.95 (6
H, m), 3.00 (3H, s), 4.09 (3H, s), 4.35 (1H, m),
7.76 (1H, s), 8.60 (1H, d, J = 9.0Hz), 8.95 (1H, s)

Reference Example 41 : Preparation of 3-amino-1-methyl-1H-hexahydroazepine:

Iodomethane was used instead of iodoethane in Example 26 (2), and Example 26 (2)-
The reaction and treatment were carried out in the same manner as in (4) to obtain the desired product as an oil.

Formulation Example 1 : Preparation of tablets: N- (1-ethyl-1H-hexahydroazepine-3-
Yl) -6-methoxy-1-propyl-1H-benzotriazole-5-carboxamide (5 g), lactose (80
g), corn starch (30 g), crystalline cellulose (25 g), hydroxypropyl cellulose (3 g), light anhydrous silicic acid (0.7 g), and magnesium stearate (1.3 g).

After mixing and granulating the above components by a conventional method,
Each tablet is tableted at 145 mg to produce 1000 tablets.

Formulation Example 2 : Preparation of Capsule: 1-Cyclopropyl-N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide ( 10 g), lactose (160 g), corn starch (22 g), hydroxypropyl cellulose (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 to obtain 1000
Fill capsules.

Formulation Example 3 : Preparation of powder: N- (1-ethyl-1H-hexahydroazepine-3-
1-isopropyl-6-methoxy-1H-benzotriazole-5-carboxamide 1/4 hydrate (10 g), lactose (960 g), hydroxypropyl cellulose (25 g), and light anhydrous silicic acid (5 g).

After mixing the above components by a conventional method, a powder is prepared.

Formulation Example 4 : Preparation of injection (100
(Per 0 ampoule):

[0289]

[Table 8] ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 6-methoxy-N- (1-propyl -1H-hexahydroazepin-3-yl) -1H-benzotriazole-5-carboxamide (10 g) -sorbitol (100 g) -water for injection (appropriate amount) ━━━━━━━━━━━━━━━ ━━━━━━━━━━━━━━━━━━━━━ Total volume 2000 ml ━━━━━━━━━━━━━━━━━━━━━━━━━━━ ━━━━━━━━━

6-methoxy-N- (1-propyl-1H
-Hexahydroazepin-3-yl) -1H-benzotriazole-5-carboxamide and sorbitol are dissolved in a part of water for injection, and the remaining water for injection is added to prepare a total amount. Add this solution to a membrane filter (0.22μ
m)), the filtrate is filled into 2 ml ampoules, which are then sterilized at 121 ° C. for 20 minutes.

[0291]

INDUSTRIAL APPLICABILITY As described above, the compound of the present invention represented by the formula (I) and the physiologically acceptable acid addition salt thereof have both excellent antiemetic action and gastrointestinal function enhancing action. In addition, since it has a weak central inhibitory effect, it can be used as a gastrointestinal function improving drug for the treatment and prevention of various gastrointestinal dysfunction associated with various diseases and treatments. Intermediates of the present invention represented by the formula (II), in formula (I), W is - (CH ₂₎ n -
And R ¹ is a methyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, C _{1 to} C ₃
Alkyl group, cyclopropyl (C ₂ ~C ₄₎ alkyl group, (C ₄ -C ₆ cycloalkyl) C ₁ -C ₄ alkyl group, C ₃ -C ₄ alkenyl group ,, C ₃ -C ₄ alkynyl group or a halogeno A (C ₁ -C ₃ ) alkyl group, R ²
It is useful as a synthetic intermediate for a compound in which is a hydrogen atom. Also, intermediates of the present invention represented by the formula (IV _A) is Oite of formula (I), W is - (CH ₂₎ n -, and the same group R ¹ is as R ¹ other than a methyl group Is useful as a synthetic intermediate for the compound.

Claims (14)

[Claims] 1. A 6-alkoxy-1 represented by the following chemical formula 1.
An H-benzotriazole-5-carboxamide derivative or a physiologically acceptable acid addition salt thereof. Embedded image Wherein, W is _{- (CH 2) n -,} - CO -, - CHR
^{4 -, - CH (OH)} -, - C (OR 4) 2 -, - C
[O (CH ₂₎ m O] -, - C (= N- OH) - or -C
Means (= N-OR ⁴ )-(where n is 1,
2 or 3, m means 1 or 2, R ⁴ is C ₁
To C ₃ alkyl group), A means a C _{1 to} C ₄ alkyl group, R ¹ is a C _{1 to} C ₄ alkyl group, (C ₃ to
C ₆ cycloalkyl) C ₁ -C ₄ alkyl group, C ₃ -C
₄ alkenyl group, C ₃ -C ₄ alkynyl group or halogeno (C ₁ -C ₃ ) alkyl group, R ² is hydrogen atom,
A C ₁ -C ₄ alkyl group, a C ₃ -C ₆ cycloalkyl group,
(C ₃ -C ₆ cycloalkyl) C ₁ -C ₄ alkyl group,
C ₃ -C ₄ alkenyl group, C ₃ -C ₄ alkynyl, hydroxy (C ₁ -C ₃₎ alkyl group, C ₁ -C ₃ alkoxy (C ₁ -C ₃₎ alkyl group or a di-substituted amino (C ₁
-C ₃₎ refers to an alkyl group, the wavy line (~) means that the configuration of the carbon atom to which it is attached is RS, R or S. However, W is - (CH ₂₎ n -, and, A is a methyl group, when R ² is hydrogen atom, methyl group or ethyl group, R ¹ is a methyl group, propyl group, isopropyl group, butyl group , Isobutyl group, sec-butyl group, C ₃
~ C ₆ cycloalkyl group, cyclopropyl (C ₂ ~
C ₄₎ alkyl group, (C ₄ ~C ₆ cycloalkyl) C ₁
-C ₄ alkyl group, C ₃ -C ₄ alkenyl group, C ₃ -C
_{4 It} means an alkynyl group or a halogeno (C ₁ -C ₃ ) alkyl group. ] 2. The compound according to claim 1, wherein W is-(CH ₂ ) n-. 3. The compound according to claim 2, wherein A is a methyl group. 4. The compound according to any one of claims 1 to 3, wherein the steric configuration of the carbon atom adjacent to the amide-bonded amino group is RS. 5. The compound according to any one of claims 1 to 3, wherein the steric configuration of the carbon atom adjacent to the amide-bonded amino group is R. 6. N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1-propyl-
1H-benzotriazole-5-carboxamide, N- (1-ethyl-1H-hexahydroazepine-3-
Yl) -1-isopropyl-6-methoxy-1H-benzotriazole-5-carboxamide, 1-cyclopropyl-N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzo Triazole-5-carboxamide, 1-cyclobutyl-N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide, 1-cyclopropylmethyl-N- ( 1-ethyl-1H-
Hexahydroazepin-3-yl) -6-methoxy-1
H-benzotriazole-5-carboxamide, 1-allyl-N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide, N- (1-ethyl -1H-hexahydroazepine-3-
Yl) -6-Methoxy-1-propargyl-1H-benzotriazole-5-carboxamide, and 6-methoxy-N- (1-propyl-1H-heptahydroazocin-3-yl) -1H-benzotriazole-5. -A compound selected from carboxamide or a physiologically acceptable acid addition salt thereof. 7. A 6-alkoxy-1 represented by the following chemical formula 2.
H-benzotriazole-5-carboxamide derivative or its acid addition salt. Embedded image Wherein, W ¹ is _{- (CH 2) n -,} - CO- or -CHR
⁴ - refers to a (wherein, n represents mean 1, 2 or 3, R ⁴ means C ₁ -C ₃ alkyl group), A ¹ denotes a C ₁ -C ₄ alkyl radical, R ¹¹ C ₁ -C ₄ alkyl group, C ₃ -C ₆ cycloalkyl group, (C ₃ -C ₆ cycloalkyl) C ₁ -C ₄ alkyl or halogeno (C
₁ -C ₃₎ refers to an alkyl group, meaning that R ³ means a protecting group for the amino group, the wavy line (~) in the configuration of the carbon atom to which it is attached is RS, R or S To do. However, when W ¹ is — (CH ₂ ) n — and A ¹ is a methyl group, R ¹¹ is a methyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, or C _3- . C
₆ cycloalkyl group, cyclopropyl (C ₂ -C ₄ ) alkyl group, (C ₄ -C ₆ cycloalkyl) C ₁ -C ₄ alkyl group or halogeno (C ₁ -C ₃ ) alkyl group. ] 8. A 3-aminoazacycloalkane derivative represented by the following chemical formula 3 or an acid addition salt thereof. Embedded image Wherein, R ¹² is C ₂ -C ₄ alkyl group, C ₃ -C ₆ cycloalkyl group, (C ₃ ~C ₆ cycloalkyl) C ₁ -C
₄ alkyl group, C ₃ -C ₄ alkenyl group, C ₃ -C ₄ alkynyl group or halogeno (C ₁ -C ₃ ) alkyl group, n means 1, 2 or 3 and wavy line (~) means It means that the configuration of the carbon atom to which it is attached is RS, R or S. ] 9. The (R) -3-aminoazacycloalkane derivative or the acid addition salt thereof according to claim 8, wherein the configuration is R. 10. The compound according to claim 8, wherein R ¹² is an ethyl group or a cyclopropylmethyl group. 11. The compound according to claim 10, wherein the configuration is R. 12. The (R) -3-amino-1H-hexahydroazepine derivative or the acid addition salt thereof according to claim 8, wherein the configuration is R and n is 1. 13. The compound according to claim 12, wherein R ¹² is an ethyl group. 14. The 6 according to claim 1.
-Alkoxy-1H-benzotriazole-5-carboxamide derivative or a pharmaceutical composition containing a physiologically acceptable acid addition salt thereof.