JPH111456A - Amide derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound useful as a vasopressin antagonist or agonist, an oxytocin antagonist, etc. SOLUTION: An amide derivative of the formula [R<1> is H, a lower alkyl, a lower alkenyl; R<2> is a five or six-membered unsaturated heterocyclic residue having one or two atoms selected from N, S, O, etc.; R<3> is (substituted) phenyl, a cycloalkyl, etc.]. For example, 4-(2-chloro-4-pyrrolidylbenzoyl)-5,6,7,8- tetrahydro-4H-furo[3,2-b]azepine. The compound of the formula is obtained by the usual amide bond-producing reaction of an amine of the formula: R<1> -NH-R<2> with a carboxylic acid of the formula: R<3> -COOH, such as a method for reacting the carboxylic acid with an alkylhalocarbonate ester and subsequently reacting the obtained acid anhydride with the amine, a method for converting the carboxylic acid into an active ester such as a p-nitrophenyl ester and subsequently reacting the product with the amine, or a method for condensing the carboxylic acid with the amine in the presence of an activator such as carbonylimidazole.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel amide derivative.

[0002]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel amide derivative useful as a pharmaceutical.

[0003]

The amide derivative of the present invention is represented by the following general formula (1).

[0004]

Embedded image

[Wherein, R ¹ represents a hydrogen atom, a lower alkyl group or a lower alkenyl group.

R ² is a 5- to 6-membered unsaturated heterocyclic residue having one or ^two nitrogen atoms, sulfur atoms or oxygen atoms (the heterocyclic residue has, as a substituent, a group —CONR ⁴ R ⁵ (R ⁴
And R ⁵ are the same or different and represent a hydrogen atom, a lower alkenyl group or a phenyl group which may have a halogen atom as a substituent on the phenyl ring. ) May be included. ) Or group

[0007]

Embedded image

(P represents 1 or 2. R ⁶ is the same or different and is a hydrogen atom, a halogen atom, a lower alkyl group, a carboxy group, a lower alkoxycarbonyl group, a carboxy group as a substituent on a phenyl ring, A phenyl lower alkoxy group, a carboxy lower alkoxy group, a lower alkoxycarbonyl lower alkoxy group, which may have a group selected from the group consisting of a lower alkoxycarbonyl group and an aminocarbonyl group which may have a lower alkyl group as a substituent, -OA ₁ CONR ¹¹ R ¹² (A ₁ represents a lower alkylene group. R ¹¹ and R ¹² may be the same or different and are a hydrogen atom, a lower alkyl group, an amino lower alkyl group which may have a lower alkyl group as a substituent, or pyridyl. a lower alkyl group. the R ¹¹ and R ^12, the nitrogen atom to which they are attached Both may form a 5- to 7-membered saturated heterocyclic ring with or without a nitrogen atom or an oxygen atom.A lower alkyl group may be substituted as a substituent on the heterocyclic ring.) Or a group —CONR ⁷ R ⁸ (R
⁷ and R ⁸ are the same or different and are a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a phenyl lower alkyl group, a lower alkyl group as a substituent on a phenyl ring, a halogen atom, a lower alkoxy group, phenyl A lower alkoxy group, a lower alkoxycarbonyl group, a cyano group, a halogen-substituted lower alkyl group, an amino group which may have a lower alkyl group as a substituent and an amino lower alkyl group which may have a lower alkyl group as a substituent A phenyl group, a phthalimide lower alkyl group, a tetrahydropyranyloxy lower alkyl group, a lower alkanoyloxy lower alkyl group, a hydroxyl-substituted lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a lower alkoxy group which may have 1 to 3 selected groups Lower alkyl group, A boxy lower alkyl group, a cyano lower alkyl group, a tetrahydroisoquinolyl group which may have a lower alkyl group as a substituent on a tetrahydroisoquinolyl ring, a pyridyl group, a thiazolyl group, a furyl lower alkyl group or a group -A (CO ) _L -NR ⁹ R ¹⁰ (l is 0
Or 1 is shown. A represents a lower alkylene group. R ⁹ and R ¹⁰ are the same or different and represent a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group or a phenyl group. ). ).

R ¹ and R ² represent a group together with the nitrogen atom to which they are bonded.

[0010]

Embedded image

(Where

[0012]

Embedded image

Represents a nitrogen atom, a sulfur atom or an oxygen atom
And represents a 5- to 6-membered unsaturated heterocyclic residue having up to 2 members. R ³⁰
Represents the same or different and represents a lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a carboxy lower alkyl group and an aminocarbonyl lower alkyl group which may have a lower alkyl group as a substituent. u shows the integer of 0-3. W is - shows the (in t represents an integer of 0 to 3) (CH ₂₎ s-group (s is an integer of 2-5) or -CH = (CH ₂₎ t-group. -(CH ₂ ) s-group and -CH =
The carbon atom in the (CH ₂ ) t- group may be replaced by an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group or a —NH— group, and the above R ³⁰ may be substituted on the —NH— group. Good. ) May be formed.

R ³ is a halogen atom, a lower alkyl group or a group NR ³¹ R ³² (R ³¹ and R ³² are the same or different and are a hydrogen atom, a lower alkyl group,
It represents a lower alkoxycarbonyl group or a phenyl lower alkoxycarbonyl group. R ³¹ and R ³² may form a 5- or 6-membered saturated heterocycle with or without a nitrogen atom or an oxygen atom together with the nitrogen atom to which they are bonded. The heterocyclic ring may be substituted by a lower alkyl group as a substituent. 1) a group selected from the group
Selected from the group consisting of a phenyl group, a cycloalkyl group or a lower alkyl group which may have a hydroxyl group as a substituent on the phenyl ring, and a lower alkyl group which may have a hydroxyl group as a substituent. A benzoylamino-substituted phenyl group which may have a substituted group. The amide derivative represented by the general formula (1) has excellent vasopressin antagonism, oxytocin antagonism, vasopressin agonism, and the like, and is useful as a vasopressin antagonist, an oxytocin antagonist, a vasopressin agonist, and the like.

The vasopressin antagonist containing the compound of the present invention as an active ingredient includes, for example, vasodilatory action, hypotensive action, hepatic glucose release inhibitory action, mesangial cell growth inhibitory action, aquaretic action, platelet aggregation inhibitory action, vomiting inhibitory action, Urea excretion promoting effect, factor VIII secretion suppressing effect, cardiac function enhancing effect, mesangial cell contraction suppressing effect, hepatic gluconeogenesis suppressing effect, aldosterone secretion suppressing effect, endothelin production suppressing effect,
Has a renin secretion regulating action, a memory regulating action, a body temperature regulating action, a prostaglandin production regulating action, etc., and a vasodilator,
It is useful as an antihypertensive, aquaretic agent, platelet aggregation inhibitor, urea excretion enhancer, anti-heart failure agent, anti-renal failure agent, etc., and has high blood pressure, edema, ascites, heart failure, renal dysfunction, abnormal vasopressin secretion syndrome (SIADH) It is effective for the prevention and treatment of cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory insufficiency, motion sickness, water metabolism disorder, renal failure, various ischemic diseases and the like. Furthermore, the compounds of the present invention are characterized by having few side effects and a long duration of drug effect.

Oxytocin antagonists containing the compound of the present invention as an active ingredient include, for example, an inhibitory action on uterine smooth muscle contraction, an inhibitory action on milk release, an inhibitory action on prostaglandin synthesis and release,
It has a vasodilator effect and is effective for preventing or treating oxytocin-related diseases, particularly premature labor, prevention of delivery before cesarean section, and dysmenorrhea.

The vasopressin agonist containing the compound of the present invention as an active ingredient is useful for various dysuria, massive urine or bleeding conditions, and frequently causes urinary frequency, diabetes insipidus, urinary incontinence, enuresis, especially enuresis,
Spontaneous bleeding, hemophilia, von Willebran
It is effective for diagnosis, prevention or treatment of d disease, uremic disease, congenital or acquired platelet dysfunction, traumatic and surgical bleeding, cirrhosis, and the like.

Of the amide derivatives of the above general formula (1),
The compound represented by the following general formula is a novel compound.

General formula

[0020]

Embedded image

[In the formula, R ¹ represents a hydrogen atom, a lower alkyl group or a lower alkenyl group.

R ^2AA is a ^5- to 6-membered unsaturated heterocyclic residue having one or two nitrogen atoms, sulfur atoms or oxygen atoms (the heterocyclic residue has a substituent —CONR ^4AA R
^5AA (R ^4AA and R ^5AA are the same or different, a hydrogen atom, a lower alkenyl or. To a phenyl group having a halogen atom as a substituent on the phenyl ring) may have. ) Or group

[0023]

Embedded image

(P represents 1 or 2. R ^6AA is the same or different and is a hydrogen atom, a halogen atom, a lower alkyl group, a carboxy group, a lower alkoxycarbonyl group, a carboxy group as a substituent on a phenyl ring, A phenyl lower alkoxy group, a carboxy lower alkoxy group, a lower alkoxycarbonyl lower alkoxy group, which may have a group selected from the group consisting of a lower alkoxycarbonyl group and an aminocarbonyl group which may have a lower alkyl group as a substituent, -OA ₁ CONR ¹¹ R ¹² (A ₁ represents a lower alkylene group. R ¹¹ and R ¹² may be the same or different and are a hydrogen atom, a lower alkyl group, an amino lower alkyl group which may have a lower alkyl group as a substituent, or pyridyl. a lower alkyl group. the R ¹¹ and R ^12, the nitrogen source which they are attached Together with or without a nitrogen atom or oxygen atom to form a 5- to 7-membered saturated heterocyclic ring, on which a lower alkyl group may be substituted as a substituent), Or group -CONR ^7AA R ^8AA
(R ^7AA and R ^8AA are the same or different and are each a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group,
A phenyl lower alkyl group, a lower alkyl group as a substituent on the phenyl ring, a halogen atom, a lower alkoxy group, a phenyl lower alkoxy group, a lower alkoxycarbonyl group, a cyano group, a halogen-substituted lower alkyl group, and a lower alkyl group as a substituent A phenyl group, a phthalimide lower alkyl group, or a tetrahydropyranyloxy lower alkyl, which may have 1 to 3 groups selected from the group consisting of an amino group and an amino lower alkyl group which may have a lower alkyl group as a substituent. Group, lower alkanoyloxy lower alkyl group, hydroxyl-substituted lower alkyl group, lower alkoxycarbonyl lower alkyl group, lower alkoxy lower alkyl group, carboxy lower alkyl group,
Cyano lower alkyl group, furyl lower alkyl group or group-
A (CO) _l -NR ⁹ R ¹⁰ (1 represents 0 or 1. A represents a lower alkylene group. R ⁹ and R ¹⁰ may be the same or different and are a hydrogen atom, a lower alkyl group, a lower alkanoyl group. , A lower alkoxycarbonyl group or a phenyl group.). ).

R ¹ and R ^2AA represent a group together with the nitrogen atom to which they are bonded.

[0026]

Embedded image

(Where

[0028]

Embedded image

Represents a nitrogen atom, a sulfur atom or an oxygen atom
And represents a 5- to 6-membered unsaturated heterocyclic residue having up to 2 members. R ³⁰
Represents the same or different and represents a lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a carboxy lower alkyl group and an aminocarbonyl lower alkyl group which may have a lower alkyl group as a substituent. u shows the integer of 0-3. W is - shows the (in t represents an integer of 0 to 3) (CH ₂₎ s-group (s is an integer of 2-5) or -CH = (CH ₂₎ t-group. -(CH ₂ ) s-group and -CH =
The carbon atom in the (CH ₂ ) t- group may be replaced by an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group or a —NH— group, and the above R ³⁰ may be substituted on the —NH— group. Good. ) May be formed.

R ^3AA represents a halogen atom, a lower alkyl group or a group NR ³¹ R ³² as a substituent on the phenyl ring (R ³¹ and R ³² may be the same or different and are a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or R ³¹ and R ³² may form a 5- or 6-membered saturated heterocyclic ring with or without a nitrogen atom or an oxygen atom together with the nitrogen atom to which they are bonded. A lower alkyl group may be substituted as a substituent on the heterocyclic ring.) A phenyl group, a cycloalkyl group or a phenyl ring which may have 1 to 3 groups selected from the group Having a group selected from the group consisting of a lower alkyl group and an amino-lower alkoxy group which may have a lower alkyl group which may have a hydroxyl group as a substituent Shows a benzoylamino-substituted phenyl group.

However, R ¹ represents a hydrogen atom, R ^7AA represents a lower alkyl group or phenyl which may have a lower alkyl group as a substituent on the phenyl ring, and R ^8AA represents a hydrogen atom, a lower alkyl group, or phenyl. A lower alkyl group, a hydroxyl-substituted lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a carboxy lower alkyl group or a group -A (C
O) _l- NR ⁹ R ¹⁰ (A is the same as above; l is 1, R ⁹ and R ¹⁰ are the same or different and each represent a hydrogen atom or a lower alkyl group), and R ¹ and R ^2AA together with the nitrogen atom to which they are attached

[0032]

Embedded image

(Where

[0034]

Embedded image

U and W are the same as above. R ³⁰ represents a lower alkyl group. )), R ^3AA is a halogen atom, a lower alkyl group or a group NR ³¹ R ³² (R ³¹ and R ³² are the same or different and are a hydrogen atom, a lower alkyl group, a lower alkyl group) An alkoxycarbonyl group or a phenyl-lower-alkoxycarbonyl group.) It should not be a phenyl group which may have 1 to 3 groups selected from the group consisting of: Or a salt thereof.

[0036]

BEST MODE FOR CARRYING OUT THE INVENTION The amide derivative of the general formula (1) of the present invention includes the compounds of the following various embodiments.

(1) R ¹ represents a hydrogen atom, and R ² represents a 5- to 6-membered unsaturated heterocyclic residue having one or ^two nitrogen, sulfur or oxygen atoms (the heterocyclic residue includes: Group as a substituent-
CONR ⁴ R ⁵ (R ⁴ and R ⁵ may be the same or different and each represent a hydrogen atom, a lower alkenyl group, or a phenyl group having a halogen atom as a substituent on a phenyl ring). Wherein R ³ is a halogen atom, a lower alkyl group or a group NR ³¹ R as a substituent on the phenyl ring.
³² (R ³¹ and R ³² are the same as defined in the general formula (1).) An amide derivative of the general formula (1) which is a phenyl group which may have 1 to 3 groups selected from the group or a salt thereof.

(2) R ¹ represents a hydrogen atom, and R ² represents a 5- to 6-membered unsaturated heterocyclic residue having one or ^two nitrogen, sulfur or oxygen atoms. Group as a substituent-
CONR ⁴ R ⁵ (R ⁴ and R ⁵ may be the same or different and each represent a hydrogen atom, a lower alkenyl group, or a phenyl group having a halogen atom as a substituent on a phenyl ring). The amide derivative of the general formula (1) or a salt thereof, wherein R ³ is a cycloalkyl group.

(3) R ¹ represents a hydrogen atom, and R ² represents a 5- to 6-membered unsaturated heterocyclic residue having one or ^two nitrogen, sulfur or oxygen atoms (heterocyclic residues include: Group as a substituent-
CONR ⁴ R ⁵ (R ⁴ and R ⁵ may be the same or different and each represent a hydrogen atom, a lower alkenyl group, or a phenyl group having a halogen atom as a substituent on a phenyl ring). Wherein R ³ is a benzoylamino having a group selected from the group consisting of a lower alkyl group as a substituent and an amino-lower alkoxy group which may have a hydroxyl group as a substituent on the phenyl ring; An amide derivative of the general formula (1), which is a substituted phenyl group, or a salt thereof.

(4) R ¹ represents a hydrogen atom, and R ² represents a group

[0041]

Embedded image

(R ⁶ and p are the same as defined in the general formula (1)), and R ³ is a halogen atom, a lower alkyl group or a group NR ³¹ R ³² (R ³¹
And R ³² are the same as defined in the general formula (1). ) An amide derivative of the general formula (1) or a salt thereof, which is a phenyl group which may have 1 to 3 groups selected from the group consisting of:

(5) R ¹ represents a hydrogen atom, and R ² represents a group

[0044]

Embedded image

An amide derivative of the general formula (1) or a salt thereof, wherein R ⁶ and p are the same as defined in the general formula (1), wherein R ³ is a cycloalkyl group.

(6) R ¹ represents a hydrogen atom, and R ² represents a group

[0047]

Embedded image

(R ⁶ and p are the same as defined in the general formula (1)), wherein R ³ represents a lower alkyl group as a substituent on a phenyl ring and a lower alkyl group which may have a hydroxyl group as a substituent. An amide derivative of the general formula (1) or a salt thereof, which is a benzoylamino-substituted phenyl group having a group selected from the group consisting of an amino lower alkoxy group which may have.

(7) R ¹ represents a lower alkyl group, and R ² represents a 5-alkyl group having one or ^two nitrogen, sulfur or oxygen atoms.
A 6-membered unsaturated heterocyclic residue (for a heterocyclic residue, a group -CONR ⁴ R ⁵ (R ⁴ and R ⁵ may be the same or different and are each a hydrogen atom, a lower alkenyl group or a phenyl ring) A phenyl group having a halogen atom is shown as a substituent.)
May be provided. Wherein R ³ is a halogen atom, a lower alkyl group or a group NR on the phenyl ring as a substituent.
³¹ R ³² (R ³¹ and R ³² are the same as defined in the general formula (1).) An amide derivative of the general formula (1) which is a phenyl group which may have 1 to 3 groups selected from the group or a phenyl derivative thereof. salt.

(8) R ¹ represents a lower alkyl group, and R ² represents a 5-alkyl group having ¹ or ² nitrogen, sulfur or oxygen atoms.
A 6-membered unsaturated heterocyclic residue (for a heterocyclic residue, a group -CONR ⁴ R ⁵ (R ⁴ and R ⁵ may be the same or different and are each a hydrogen atom, a lower alkenyl group or a phenyl ring) A phenyl group having a halogen atom is shown as a substituent.)
May be provided. The amide derivative of the general formula (1) or a salt thereof, wherein R ³ is a cycloalkyl group.

(9) R ¹ represents a lower alkyl group, and R ² represents a 5-alkyl group having ¹ or ² nitrogen, sulfur or oxygen atoms.
A 6-membered unsaturated heterocyclic residue (for a heterocyclic residue, a group -CONR ⁴ R ⁵ (R ⁴ and R ⁵ may be the same or different and are each a hydrogen atom, a lower alkenyl group or a phenyl ring) A phenyl group having a halogen atom is shown as a substituent.)
May be provided. Wherein R ³ is a benzoylamino having a group selected from the group consisting of a lower alkyl group as a substituent and an amino-lower alkoxy group which may have a hydroxyl group as a substituent on the phenyl ring; An amide derivative of the general formula (1), which is a substituted phenyl group, or a salt thereof.

[0052] (10) R ¹ is a lower alkyl group, R ²
Is based

[0053]

Embedded image

Wherein R ⁶ and p are the same as defined in formula (1), and R ³ is a halogen atom, a lower alkyl group or a group NR ³¹ R ³² (R ³¹
And R ³² are the same as defined in the general formula (1). ) An amide derivative of the general formula (1) or a salt thereof, which is a phenyl group which may have 1 to 3 groups selected from the group consisting of:

[0055] (11) R ¹ is a lower alkyl group, R ²
Is based

[0056]

Embedded image

An amide derivative of the general formula (1) or a salt thereof, wherein R ⁶ and p are the same as defined in the general formula (1), wherein R ³ is a cycloalkyl group.

[0058] (12) R ¹ is a lower alkyl group, R ²
Is based

[0059]

Embedded image

(R ⁶ and p are the same as defined in the general formula (1)), and R ³ represents a lower alkyl group as a substituent on a phenyl ring and a lower alkyl group which may have a hydroxyl group as a substituent. An amide derivative of the general formula (1) or a salt thereof, which is a benzoylamino-substituted phenyl group having a group selected from the group consisting of an amino lower alkoxy group which may have.

(13) R ¹ represents a lower alkenyl group,
R ² is a 5- to 6-membered unsaturated heterocyclic residue having one or ^two nitrogen atoms, sulfur atoms or oxygen atoms (a heterocyclic residue includes a group —CONR ⁴ R ⁵ (R ⁴ and R ⁵ is the same or different and represents a hydrogen atom, a lower alkenyl group or a phenyl group having a halogen atom as a substituent on the phenyl ring.), And R ³ represents a phenyl ring. Phenyl which may have 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group and a group NR ³¹ R ³² (R ³¹ and R ³² are the same as defined in the general formula (1)). An amide derivative of the general formula (1) or a salt thereof.

(14) R ¹ represents a lower alkenyl group,
R ² is a 5- to 6-membered unsaturated heterocyclic residue having one or ^two nitrogen atoms, sulfur atoms or oxygen atoms (a heterocyclic residue includes a group —CONR ⁴ R ⁵ (R ⁴ and R ⁵ is the same or different and may be a hydrogen atom, a lower alkenyl group or a phenyl group having a halogen atom as a substituent on the phenyl ring.), And R ³ is a cycloalkyl group. An amide derivative of the general formula (1) or a salt thereof:

(15) R ¹ represents a lower alkenyl group,
R ² is a 5- to 6-membered unsaturated heterocyclic residue having one or ^two nitrogen atoms, sulfur atoms or oxygen atoms (a heterocyclic residue includes a group —CONR ⁴ R ⁵ (R ⁴ and R ⁵ is the same or different and represents a hydrogen atom, a lower alkenyl group or a phenyl group having a halogen atom as a substituent on the phenyl ring.), And R ³ represents a phenyl ring. A benzoylamino-substituted phenyl group having a group selected from the group consisting of a lower alkyl group as a substituent and an amino-lower alkoxy group which may have a lower alkyl group which may have a hydroxyl group as a substituent. An amide derivative or a salt thereof.

(16) R ¹ represents a lower alkenyl group,
R ² is based

[0065]

Embedded image

(R ⁶ and p are the same as defined in the general formula (1).) Wherein R ³ is a halogen atom, a lower alkyl group or a group NR ³¹ R ³² (R ³¹
And R ³² are the same as defined in the general formula (1). ) An amide derivative of the general formula (1) or a salt thereof, which is a phenyl group which may have 1 to 3 groups selected from the group consisting of:

(17) R ¹ represents a lower alkenyl group,
R ² is based

[0068]

Embedded image

An amide derivative of the general formula (1) wherein R ⁶ and p are the same as defined in the general formula (1), and R ³ is a cycloalkyl group, or a salt thereof.

(18) R ¹ represents a lower alkenyl group,
R ² is based

[0071]

Embedded image

(Wherein R ⁶ and p are the same as defined in formula (1)), wherein R ³ represents a lower alkyl group as a substituent on the phenyl ring and a lower alkyl group which may have a hydroxyl group as a substituent. An amide derivative of the general formula (1) or a salt thereof, which is a benzoylamino-substituted phenyl group having a group selected from the group consisting of an amino lower alkoxy group which may have.

(19) R ¹ and R ² represent a group together with a nitrogen atom to be bonded.

[0074]

Embedded image

(

[0076]

Embedded image

R ³⁰ , u and W are the same as defined in formula (1). Wherein R ³ is a halogen atom, a lower alkyl group or a group NR ³¹ R as a substituent on the phenyl ring.
³² (R ³¹ and R ³² are the same as defined in the general formula (1).) An amide derivative of the general formula (1) which is a phenyl group which may have 1 to 3 groups selected from the group or a salt thereof.

(20) R ¹ and R ² represent a group together with a nitrogen atom to be bonded.

[0079]

Embedded image

(

[0081]

Embedded image

R ³⁰ , u and W are the same as defined in the general formula (1). The amide derivative of the general formula (1) or a salt thereof, wherein R ³ is a cycloalkyl group.

(21) R ¹ and R ² represent a group together with a nitrogen atom to be bonded.

[0084]

Embedded image

(

[0086]

Embedded image

R ³⁰ , u and W are the same as defined in formula (1). Wherein R ³ has a group selected from the group consisting of a lower alkyl group as a substituent and an amino-lower alkoxy group which may have a hydroxyl group as a substituent on the phenyl ring. An amide derivative of the general formula (1), which is a substituted phenyl group, or a salt thereof.

(22) 1- (4-Nn-propylamino-2-chlorobenzoyl) -5-isopropylaminocarbonylmethyl-2,3,4,5-tetrahydro-1
H-thieno [3,2b] azepine.

(23) 1-methyl-4- [2-chloro-
4- (1-pyrrolidinyl) benzoyl] -1,4,5
6,7,8-Hexahydropyrrolo [3,2-b] azepine.

(24) 1-methyl-4- (2-chloro-
4-n-propylaminobenzoyl) -1,4,5
6,7,8-Hexahydropyrrolo [3,2-b] azepine.

(25) 1- [4- (1-pyrrolidinyl)
-2-chlorobenzoyl) -5-isopropylaminocarbonylmethyl-2,3,4,5-tetrahydro-1H
Thieno [3,2b] azepine.

Each group shown in the present specification is more specifically as follows.

As the lower alkyl group, for example, methyl,
Examples thereof include linear or branched alkyl groups having 1 to 6 carbon atoms, such as ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl groups.

Examples of the lower alkenyl group include straight-chain or branched alkenyl having 2 to 6 carbon atoms such as vinyl, allyl, 2-butenyl, 3-butenyl, 1-methylallyl, 2-pentenyl and 2-hexenyl. Groups.

A nitrogen atom, a sulfur atom or an oxygen atom
Examples of the 5- or 6-membered unsaturated heterocyclic residue having, for example, furyl, thienyl, pyrrolyl, 2H-pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 2H-pyranyl,
Pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,
Examples thereof include 2-pyrolinyl, 2-imidazolinyl, and 2-pyrazolinyl groups.

The group --CONR ⁴ R ⁵ (R ⁴ and R ⁵ are the same or different and represent a hydrogen atom, a lower alkenyl group or a phenyl group which may have a halogen atom as a substituent on the phenyl ring). As the heterocyclic residue having,
For example, 3- [N- (4-chlorophenyl) -N-allylaminocarbonyl] pyridyl, 3-allylaminocarbonylfuryl, 2-anilinocarbonylthienyl, 3-
(1-propenyl) aminocarbonylpyrrolyl, 4-
(3,4-dichloroanilinocarbonyl) oxazolyl, 2- (3,4,5-trichloroanilinocarbonyl) thiazolyl, 2- [N- (3-bromophenyl)-
N-allylaminocarbonyl] imidazolyl, 4- (2
-Butenyl) aminocarbonylpyrazolyl, 4- (2-
Fluoroanilinocarbonyl) pyridyl, 4- (3-pentenyl) aminocarbonylpyridazinyl, 5- (5-
Hexenyl) aminocarbonylpyrimidinyl, 3-
(3,4-dibromo anilinocarbonyl) group such as pyrazinyl group -CONR ⁴ R ⁵ (R ⁴ and R ⁵ are the same or different, a hydrogen atom, a straight-chain or branched alkenyl group having 2 to 6 carbon atoms Or a phenyl group which may have 1 to 3 halogen atoms as a substituent on the phenyl ring.).

The group —CONR ^4AA R ^5AA (R ^4AA and R ^4AA
5AA is the same or different and represents a hydrogen atom, a lower alkenyl group or a phenyl group having a halogen atom as a substituent on a phenyl ring. ) Is, for example, 3- [N- (4-chlorophenyl) -N-
Allylaminocarbonyl] pyridyl, 3-allylaminocarbonylfuryl, 4-[(4-chlorophenyl) aminocarbonyl] thienyl, 3- (1-propenyl) aminocarbonylpyrrolyl, 4- (3,4-dichloroanilinocarbonyl) Oxazolyl, 2- (3,4,5-trichloroanilinocarbonyl) thiazolyl, 2- [N-
(3-Bromophenyl) -N-allylaminocarbonyl] imidazolyl, 4- (2-butenyl) aminocarbonylpyrazolyl, 4- (2-fluoroanilinocarbonyl) pyridyl, 4- (3-pentenyl) aminocarbonylpyridazini , A group such as 5- (5-hexenyl) aminocarbonylpyrimidinyl, 3- (3,4-dibromoanilinocarbonyl) pyrazinyl group or the like -CONR ^4AA R ^5AA (R
^4AA and R ^5AA are the same or different and each have a hydrogen atom,
And a phenyl group having 1 to 3 halogen atoms as a substituent on a phenyl ring. ) Can be exemplified.

Examples of the phenyl group having a halogen atom on the phenyl ring include 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,
-Bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl,
-Iodophenyl, 3,4-dichlorophenyl, 2,6
-Dichlorophenyl, 2,3-dichlorophenyl, 2,
4-dichlorophenyl, 3,4-difluorophenyl,
A phenyl group having 1 to 3 halogen atoms as a substituent on a phenyl ring such as 3,5-dibromophenyl or 3,4,5-trichlorophenyl group can be exemplified.

Examples of the phenyl group which may have a halogen atom on the phenyl ring include phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl,
-Fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl,
3-iodophenyl, 4-iodophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,6-
Dichlorophenyl, 2,3-dichlorophenyl, 2,4
-Dichlorophenyl, 3,4-difluorophenyl,
Examples thereof include a phenyl group having from 1 to 3 halogen atoms as a substituent on a phenyl ring such as 3,5-dibromophenyl and 3,4,5-trichlorophenyl groups.

As the halogen atom, for example, a fluorine atom,
Examples include a chlorine atom, a bromine atom and an iodine atom.

Examples of the lower alkoxycarbonyl group include linear groups having 1 to 6 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl. Alternatively, a branched alkoxycarbonyl group can be exemplified.

The phenyl lower alkoxy group which may have on the phenyl ring a group selected from the group consisting of a carboxy group, a lower alkoxycarbonyl group as a substituent and an aminocarbonyl group which may have a lower alkyl group as a substituent includes: For example, benzyloxy, 2-phenylethoxy, 1-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 5-phenylpentyloxy, 6-phenylhexyloxy, 1,1-dimethyl-2-phenylethoxy, 2-methyl -3-phenylpropoxy, 4-isopropylaminocarbonylbenzyloxy, 3-aminocarbonylbenzyloxy, 2-
Dimethylaminocarbonylbenzyloxy, 2- (4-
Butylaminocarbonylphenyl) ethoxy, 3- (3
-Pentylaminocarbonylphenyl) propoxy, 4
-(2-hexylaminocarbonylphenyl) butoxy, 5- [4- (N-methyl-N-ethylaminocarbonyl) phenyl] pentyloxy, 6- [3- (N-ethyl-N-hexylaminocarbonyl) phenyl] Hexyloxy, 3,4-bis (methylamino) carbonylbenzyloxy, 3,4,5-tri (isopropylamino) benzyloxy, 3-carboxybenzyloxy,
4-carboxybenzyloxy, 2-carboxybenzyloxy, 4-methoxycarbonylbenzyloxy, 3
A straight-chain or branched alkoxy group having 1 to 6 carbon atoms in an alkoxy moiety such as an ethoxycarbonylbenzyloxy group or a 2-propoxycarbonylbenzyloxy group; a carboxy group as a substituent on the phenyl ring; ~ 6
A group selected from the group consisting of a straight-chain or branched alkoxycarbonyl group and an aminocarbonyl group which may have 1 to 2 alkyl groups having 1 to 6 carbon atoms as a substituent.
An example is a phenylalkoxy group which may have three.

Examples of the aminocarbonyl group which may have a lower alkyl group include, for example, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, butylaminocarbonyl, tert-butylaminocarbonyl, pentylamino Carbonyl, hexylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, dibutylaminocarbonyl, dipentylaminocarbonyl, dihexylaminocarbonyl, N-methyl-N-ethylaminocarbonyl, N-ethyl-N-propylaminocarbonyl, N-methyl-N-butylaminocarbonyl, N
A straight-chain or branched alkyl group having 1 to 6 carbon atoms as a substituent such as -methyl-N-hexylaminocarbonyl group;
Examples include aminocarbonyl groups that may have up to two aminocarbonyl groups.

Examples of the carboxy lower alkoxy group include carboxymethoxy, 2-carboxyethoxy,
-Carboxyethoxy, 3-carboxypropoxy, 4
An alkoxy moiety such as -carboxybutoxy, 5-carboxypentyloxy, 6-carboxyhexyloxy, 1,1-dimethyl-2-carboxyethoxy, or 2-methyl-3-carboxypropoxy, A carboxyalkoxy group which is a branched alkoxy group can be exemplified.

As the lower alkoxycarbonyl lower alkoxy group, for example, methoxycarbonylmethoxy, 3-
Methoxycarbonylpropoxy, ethoxycarbonylmethoxy, 3-ethoxycarbonylpropoxy, 4-ethoxycarbonylbutoxy, 5-methoxycarbonylpentyloxy, 5-ethoxycarbonylpentyloxy,
5-isopropoxycarbonylpentyloxy, 6-propoxycarbonylhexyloxy, 1,1-dimethyl-2-butoxycarbonylethoxy, 2-methyl-3-
Examples thereof include an alkoxycarbonylalkoxy group in which an alkoxy moiety such as tert-butoxycarbonylpropoxy, 2-pentyloxycarbonylethoxy, or hexyloxycarbonylmethoxy group is a linear or branched alkoxy group having 1 to 6 carbon atoms.

The lower alkylene group includes, for example, methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, hexamethylene C1 of group etc.
To 6 linear or branched alkylene groups.

Aminocarbonyl, which may have a lower alkyl group as a substituent, includes aminocarbonylmethyl, 2-aminocarbonylethyl,
-Aminocarbonylethyl, 3-aminocarbonylpropyl, 4-aminocarbonylbutyl, 5-aminocarbonylpentyl, 6-aminocarbonylhexyl, 1,1
-Dimethyl-2-aminocarbonylethyl, 2-methyl-3-aminocarbonylpropyl, methylaminocarbonylmethyl, 1-ethylaminocarbonylethyl, 2-
Propylaminocarbonylethyl, isopropylaminocarbonylmethyl, 3-isopropylaminocarbonylpropyl, 4-butylaminocarbonylbutyl, 5-pentylaminocarbonylpentyl, 6-hexylaminocarbonylhexyl, dimethylaminocarbonylmethyl, (N-ethyl-N- It may have 1-2 linear or branched alkyl groups having 1-6 carbon atoms as substituents such as propylamino) carbonylmethyl and 2- (N-methyl-N-hexylamino) carbonylethyl groups. Examples thereof include a linear or branched alkyl group having 1 to 6 carbon atoms and having an aminocarboxy group.

Examples of the pyridyl lower alkyl group include (4-pyridyl) methyl, 1- (3-pyridyl) ethyl, 2- (2-pyridyl) ethyl, 3- (2-pyridyl) propyl and 4- (3- Pyridyl) butyl, 5- (4
-Pyridyl) pentyl, 6- (2-pyridyl) hexyl, 1,1-dimethyl-2- (3-pyridyl) ethyl,
Examples thereof include a pyridylalkyl group in which an alkyl moiety such as a 2-methyl-3- (4-pyridyl) propyl group is a linear or branched alkyl group having 1 to 6 carbon atoms.

Together with the nitrogen atom to which R ¹¹ and R ¹² are attached,
Examples of the 5- to 7-membered saturated heterocyclic group formed by bonding to each other with or without a nitrogen atom or an oxygen atom include pyrrolidinyl, piperidinyl, piperazinyl, morpholino, and homopiperazinyl groups.

Examples of the above heterocyclic group substituted by a lower alkyl group include 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 3-ethylpyrrolidinyl, 2-propylpyrrolidinyl, 3,4 Linear or branched having 1 to 6 carbon atoms such as, 5-trimethylpiperidinyl, 4-butylpiperidinyl, 3-pentylmorpholino, 4-hexylpiperazinyl, 4-methylhomopiperazinyl group The heterocyclic group in which 1 to 3 alkyl groups have been substituted can be exemplified.

Examples of the lower alkynyl group include ethynyl, 2-propynyl, 2-butynyl, 3-butynyl,
Examples thereof include a linear or branched alkynyl group having 2 to 6 carbon atoms such as -methyl-2-propynyl, 2-pentynyl, and 2-hexynyl group.

Examples of the phenyl lower alkyl group include benzyl, 2-phenylethyl, 1-phenylethyl,
The alkyl moiety such as 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 1,1-dimethyl-2-phenylethyl, or 2-methyl-3-phenylpropyl has 1 to 6 carbon atoms. And a phenylalkyl group which is a linear or branched alkyl group.

Examples of the lower alkoxy group include straight-chain or branched-chain alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy and hexyloxy groups. it can.

Examples of the phenyl lower alkoxy group include benzyloxy, 2-phenylethoxy, 1-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 5-phenylpentyloxy, 6-phenylhexyloxy, 1,1- A phenylalkoxy group which is a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms in the alkoxy moiety such as dimethyl-2-phenylethoxy and 2-methyl-3-phenylpropoxy groups can be exemplified.

Examples of the halogen-substituted lower alkyl group include trifluoromethyl, trichloromethyl, chloromethyl,
Bromomethyl, fluoromethyl, iodomethyl, difluoromethyl, dibromomethyl, 2-chloroethyl, 2,
2,2-trifluoroethyl, 2,2,2-trichloroethyl, 3-chloropropyl, 2,3-dichloropropyl, 4,4,4-trichlorobutyl, 4-fluorobutyl, 5-chloropentyl, 3- Examples of the substituent such as chloro-2-methylpropyl, 5-bromohexyl, and 5,6-dichlorohexyl include a straight-chain or branched-chain alkyl group having 1 to 3 carbon atoms and having 1 to 3 halogen atoms. .

Examples of the amino group which may have a lower alkyl group as a substituent include, for example, amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, pentylamino, hexylamino, dimethylamino , Diethylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, N-methyl-N-ethylamino, N-ethyl-N-propylamino, N-methyl-
Examples of the substituent such as N-butylamino and N-methyl-N-hexylamino group include an amino group which may have 1 to 2 carbon atoms having 1 to 6 linear or branched alkyl groups.

The amino lower alkyl group which may have a lower alkyl group as a substituent includes aminomethyl,
2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1,1-dimethyl-2-aminoethyl,
2-methyl-3-aminopropyl, methylaminomethyl, 1-ethylaminoethyl, 2-propylaminoethyl, 3-isopropylaminopropyl, 4-butylaminobutyl, 5-pentylaminopentyl, 6-hexylaminohexyl, dimethyl Aminomethyl, (N-ethyl-N-propylamino) methyl, 2- (N-methyl-N
-Hexylamino) ethyl as a substituent having 1 carbon atom
Examples thereof include a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms and having an amino group which may have 1 to 2 straight-chain or branched-chain alkyl groups.

Examples of the phthalimido lower alkyl group include phthalimidomethyl, 2-phthalimidoethyl,
-Phthalimidoethyl, 3-phthalimidopropyl, 4
-Phthalimidobutyl, 5-phthalimidopentyl, 6
A phthalimidoalkyl group in which the alkyl moiety such as a phthalimidohexyl, 1,1-dimethyl-2-phthalimidoethyl, or 2-methyl-3-phthalimidopropyl group is a linear or branched alkyl group having 1 to 6 carbon atoms; Can be illustrated.

Examples of the tetrahydropyranyloxy lower alkyl group include (2-tetrahydropyranyl) oxymethyl, 2- (2-tetrahydropyranyl) oxyethyl, 1- (4-tetrahydropyranyl) oxyethyl, 3- (2 -Tetrahydropyranyl) oxypropyl, 4- (3-tetrahydropyranyl) oxybutyl,
5- (4-tetrahydropyranyl) oxypentyl, 6
-(2-tetrahydropyranyl) oxyhexyl, 1,
The alkyl moiety such as 1-dimethyl-2- (3-tetrahydropyranyl) oxyethyl and 2-methyl-3- (4-tetrahydropyranyl) oxypropyl has 1 to 1 carbon atoms.
And a tetrahydropyranyloxyalkyl group which is a straight or branched alkyl group of No. 6.

Examples of the lower alkanoyloxy lower alkyl group include acetyloxymethyl, 2-propionyloxyethyl, 1-butyryloxyethyl, 3-acetyloxypropyl, 4-acetyloxybutyl,
Isobutyryloxybutyl, 5-pentanoyloxypentyl, 6-acetyloxyhexyl, 6-tert-
Butylcarbonyloxyhexyl, 1,1-dimethyl-
C2-C6 linear or branched alkanoyloxy group such as 2-hexanoyloxyethyl, 2-methyl-3-acetyloxypropyl group, etc. Substituted C1-C6 linear or branched alkyl Groups can be exemplified.

Examples of the hydroxyl-substituted lower alkyl group include hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxyethyl, 4-hydroxybutyl, 3,4-dihydroxybutyl, , 1-dimethyl-2-hydroxyethyl, 5-hydroxypentyl, 6-hydroxyhexyl, 2-methyl-3-hydroxypropyl, 2,3,4
A hydroxyl group as a substituent such as a trihydroxybutyl group;
Examples thereof include a linear or branched alkyl group having 1 to 6 carbon atoms and having 1 to 3 carbon atoms.

Examples of the lower alkoxycarbonyl lower alkyl group include methoxycarbonylmethyl, 3-methoxycarbonylpropyl, ethoxycarbonylmethyl,
3-ethoxycarbonylpropyl, 4-ethoxycarbonylbutyl, 5-isopropoxycarbonylpentyl,
6-propoxycarbonylhexyl, 1,1-dimethyl-2-butoxycarbonylethyl, 2-methyl-3-t
Alkoxy moieties such as tert-butoxycarbonylpropyl, 2-pentyloxycarbonylethyl, hexyloxycarbonylmethyl groups are linear or branched alkoxy groups having 1 to 6 carbon atoms, and alkyl portions are 1 to 6 carbon atoms.
And an alkoxycarbonylalkyl group which is a linear or branched alkyl group.

As the lower alkoxy lower alkyl group,
For example, methoxymethyl, 2-methoxyethyl, 3-methoxypropyl, ethoxymethyl, 3-ethoxypropyl, 4-ethoxybutyl, 5-isopropoxypentyl, 6-propoxyhexyl, 1,1-dimethyl-2-
Alkoxy moieties such as butoxyethyl, 2-methyl-3-tert-butoxypropyl, 2-pentyloxyethyl, and hexyloxymethyl groups are linear or branched alkoxy groups having 1 to 6 carbon atoms, and the alkyl moiety is Carbon number 1
And 6 alkoxyalkyl groups which are linear or branched alkyl groups.

Examples of the carboxy lower alkyl group include carboxymethyl, 2-carboxyethyl, 1-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl, 6-carboxyhexyl, and 1,1-dimethyl- 2-carboxyethyl, 2
And a carboxyalkyl group in which the alkyl moiety such as -methyl-3-carboxypropyl group is a linear or branched alkyl group having 1 to 6 carbon atoms.

Examples of the cyano lower alkyl group include cyanomethyl, 2-cyanoethyl, 1-cyanoethyl,
An alkyl moiety such as -cyanopropyl, 4-cyanobutyl, 5-cyanopentyl, 6-cyanohexyl, 1,1-dimethyl-2-cyanoethyl, or 2-methyl-3-cyanopropyl group having 1 to 6 carbon atoms; Or a cyanoalkyl group which is a branched alkyl group.

The tetrahydroisoquinolyl group which may have a lower alkyl group as a substituent on the tetrahydroisoquinolyl ring includes, for example, 1,2,3,4-tetrahydroisoquinolyl, 2-methyl-1,2 , 3,4-tetrahydroisoquinolyl, 1-ethyl-1,2,3,4
-Tetrahydroisoquinolyl, 3-propyl-1,2,2
3,4-tetrahydroisoquinolyl, 4-butyl-1,
2,3,4-tetrahydroisoquinolyl, 5-pentyl-1,2,3,4-tetrahydroisoquinolyl, 6-hexyl-1,2,3,4-tetrahydroisoquinolyl,
7-methyl-1,2,3,4-tetrahydroisoquinolyl, 8-propyl-1,2,3,4-tetrahydroisoquinolyl, 2-ethyl-1,2,3,4-tetrahydroisoquinolyl , 2,6-dimethyl-1,2,3,4-tetrahydroisoquinolyl, 1,2,4-trimethyl-
Tetrahydroisoquinolyl group having 1 to 3 carbon atoms having 1 to 3 linear or branched alkyl groups on a tetrahydroisoquinolyl ring such as 1,2,3,4-tetrahydroisoquinolyl Can be mentioned.

Examples of the furyl lower alkyl group include (2-furyl) methyl, 2- (3-furyl) ethyl,
-(2-furyl) ethyl, 3- (3-furyl) propyl, 4- (2-furyl) butyl, 5- (3-furyl) pentyl, 6- (2-furyl) hexyl, 1,1-dimethyl- 2- (3-furyl) ethyl, 2-methyl-3- (2
An alkyl moiety such as -furyl) propyl group has 1 to 6 carbon atoms
And a furylalkyl group which is a linear or branched alkyl group.

Examples of the lower alkanoyl group include linear or branched alkanoyl groups having 1 to 6 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl and hexanoyl groups.

[0129]

Embedded image

Examples of the heterocyclic group represented by are furyl, thienyl, pyrrolyl, 2H-pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
Examples thereof include imidazolyl, pyrazolyl, 2H-pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 2-pyrolinyl, and 2-imidazolinyl groups.

Group

[0132]

Embedded image

As the heterocyclic group represented by
6,7,8-tetrahydro-4H-furo [3,2-b]
Azepinyl, 2,3,4,5-tetrahydro-1H-pyrido [2,3-b] azepinyl, 1,4,5,6,7,
8-hexahydropyrrolo [3,2-b] azepinyl,
2,3,4,5-tetrahydro-1H-thieno [3,2
-B] azepinyl, 4,5,6,7-tetrahydrothieno [3,2-b] pyridyl, 4,5,6,7-tetrahydro-1H-pyrrolo [3,2-b] pyridyl, 4,5
6,7-tetrahydrofuro [3,2-b] pyridyl,
5,6-dihydro-4H-thieno [3,2-b] pyrrolyl, 5,6-dihydro-4H-furo [3,2-b] pyrrolyl, 1,2,3,4-tetrahydropyrrolo [3,2 −
b] pyrrolyl, 4,5,6,7,8,9-hexahydrothieno [3,2-b] azocinyl, 4,5,6,7,
8,9-hexahydro-1H-pyrrolo [3,2-b] azocinyl, 4,5,6,7,8,9-hexahydrofuro [3,2-b] azocinyl, 1,2,3,4- Tetrahydro [1,8] naphthyridinyl, 1,2,3,4-tetrahydro [1,5] naphthyridinyl, 2,3-dihydro-1H-pyrrolo [2,3-b] pyridyl, 2,3-dihydro-1H- Pyrrolo [3,2-b] pyridyl, 5,6
7,8,9,10-hexahydropyrido [2,3-b]
Azocinyl, 1,2,3,4-tetrahydrothieno [2,3-b] pyrazinyl, 5,6,7,8-tetrahydro-4H-thieno [2,3-b] [1,4] diazepinyl, 5,6,7,8,9-hexahydrothieno [2,3-b] [1,4] diazosinyl, 5,6,7,
8-tetrahydro-4H-thieno [2,3-b] [1,
4] oxazosinyl, 2,3-dihydro-1H-thieno [2,3-b] imidazolyl, 4,5-dihydro-1H
-Pyrrolo [3,2-b] pyridyl, 4,5,6,7-tetrahydrothieno [3,2-b] azocinyl, 1,2-
Dihydro [1,8] naphthyridinyl, 1,2-dihydro [1,5] naphthyridinyl, 1H-thieno [2,3-
b] imidazolyl, 4,5-dihydrothieno [3,2-
b] pyridyl, 4,5-dihydrofuro [3,2-b] pyridyl, 4H-thieno [3,2-b] pyrrolyl, 4H-
Furo [3,2-b] pyrrolyl, 4,5,6,7-tetrahydro-1H-pyrrolo [3,2-b] azocinyl, 4,
5,6,7-tetrahydrofuro [3,2-b] azocinyl, 1H-pyrrolo [2,3-b] pyridyl, 1H-pyrrolo [3,2-b] pyrrolyl, 1H-pyrrolo [3,2-
b] pyridyl, 5,6-dihydro-4H-thieno [2,
3-b] [1,4] diazepinyl, 5,6,7,8-tetrahydro [2,3-b] azocinyl, 1,2-dihydrothieno [2,3-b] pyrazinyl, 4,5,6,7 −
Examples thereof include a tetrahydrothieno [2,3-b] [1,4] diazosynyl group.

A halogen atom, a lower alkyl group and a group NR ³¹ R ³² (R ³¹ and R
³² is the same or different and represents a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or a phenyl lower alkoxycarbonyl group. R ³¹ and R ³² may form a 5- or 6-membered saturated heterocycle with or without a nitrogen atom or an oxygen atom together with the nitrogen atom to which they are bonded. The heterocyclic ring may be substituted by a lower alkyl group as a substituent. Groups 1-3 selected from the group
Examples of the phenyl group having two or more phenyl groups include phenyl, 2- (1-pyrrolidinyl) phenyl, and 3- (1-
Pyrrolidinyl) phenyl, 4- (4-methyl-1-piperazinyl) phenyl, 3- (1-piperidinyl) phenyl, 2-morpholinophenyl, 4- (1-pyrrolidinyl) phenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 4-methylaminophenyl,
4-ethylaminophenyl, 2,4-diaminophenyl, 4-propylaminophenyl, 3,4-dipropylaminophenyl, 3-amino-4-butylaminophenyl, 3,4,5-triaminophenyl, 2- Chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-
Fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4-difluorophenyl, 3,5-
Dibromophenyl, 3,4,5-trichlorophenyl,
2-methoxy-3-chlorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-butylphenyl,
4-pentylphenyl, 4-hexylphenyl, 3,4
-Dimethylphenyl, 3,4-diethylphenyl, 2,
4-dimethylphenyl, 2,5-dimethylphenyl,
2,6-dimethylphenyl, 3,4,5-trimethylphenyl, 2-chloro-4- (1-pyrrolidinyl) phenyl, 3-amino-4-methyl-5-iodophenyl,
-Chloro-4-aminophenyl, 2-chloro-4-propylaminophenyl, 3,4-diamino-5-bromophenyl, 3,5-diiodo-4- (1-pyrrolidinyl)
Phenyl, 2-chloro-4- (N-propyl-N-te
A halogen atom as a substituent on a phenyl ring such as rt-butoxycarbonylamino) phenyl, 2-chloro-4- (N-propyl-N-benzyloxycarbonylamino) phenyl group, a straight-chain or branched carbon having 1 to 6 carbon atoms. A branched alkyl group and a group NR ³¹ R ³² (R ³¹ and R ³² are the same or different and each are a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, and an alkoxy moiety having 1 to 6 carbon atoms. alkoxycarbonyl group or a straight-chain or branched alkoxy group represents phenyl alkoxycarbonyl group the alkoxy moiety is a straight or branched alkoxy group having 1 to 6 carbon atoms. the R ³¹ and R ³² May form a 5- or 6-membered saturated heterocycle with or without a nitrogen atom or an oxygen atom together with the nitrogen atom to which they are bonded. Linear or branched alkyl group of prime 1-6 may be substituted.) Made can be exemplified phenyl group which may have one to three more group selected group.

Examples of the 5- or 6-membered saturated heterocyclic group formed by bonding R ³¹ and R ³² together with or without a nitrogen atom to which they are bonded, include, for example, pyrrolidinyl, piperidinyl, Examples include piperazinyl and morpholino groups.

Examples of the above heterocyclic group substituted by a lower alkyl group include 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 3-ethylpyrrolidinyl, 2-propylpyrrolidinyl, 3,4 1,3-trimethylpiperidinyl, 4-butylpiperidinyl, 3-pentylmorpholino, 4-hexylpiperazinyl group, etc. are substituted with 1 to 3 straight or branched alkyl groups having 1 to 6 carbon atoms. The above-mentioned heterocyclic groups can be exemplified.

Examples of the phenyl lower alkoxycarbonyl group include benzyloxycarbonyl, 2-phenylethoxycarbonyl, 1-phenylethoxycarbonyl, 3-phenylpropoxycarbonyl, 4-phenylbutoxycarbonyl, 5-phenylpentyloxycarbonyl, 6-phenyl Hexyloxycarbonyl, 1,
1-dimethyl-2-phenylethoxycarbonyl, 2-
A phenylalkoxycarbonyl group which is a linear or branched alkoxy group having 1 to 6 carbon atoms in the alkoxy moiety such as a methyl-3-phenylpropoxycarbonyl group can be exemplified.

Examples of the cycloalkyl group include those having 3 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups.
To 8 cycloalkyl groups.

Examples of the amino lower alkoxy group which may have a lower alkyl group which may have a hydroxyl group as a substituent include, for example, aminomethoxy, 2-aminoethoxy, 1-aminoethoxy, 3-aminopropoxy,
Aminobutoxy, 5-aminopentyloxy, 6-aminohexyloxy, 1,1-dimethyl-2-aminoethoxy, 2-methyl-3-aminopropoxy, methylaminomethoxy, 1-ethylaminoethoxy, 2-propylaminoethoxy , 3-isopropylaminopropoxy,
3-ethylaminopropoxy, 4-butylaminobutoxy, 5-pentylaminopentyloxy, 6-hexylaminohexyloxy, dimethylaminomethoxy, (N
-Methyl-N-propylamino) methoxy, 2- (N-
Methyl-N-hexylamino) ethoxy, 3-{(2-
(Hydroxyethyl) amino} propoxy, 3- {N-
(2-hydroxyethyl) -N- (2-hydroxyethyl) amino} propoxy, (N-hydroxymethyl-N
-Ethylamino) a carbon having an amino group which may have 1 to 2 linear or branched alkyl groups having 1 to 6 carbon atoms and may have 1 to 3 hydroxyl groups as a substituent such as a methoxy group or the like. There may be mentioned straight-chain or branched alkoxy groups of formulas 1 to 6.

Benzoylamino substitution which may have on the phenyl ring a lower alkyl group as a substituent and an amino-lower alkoxy group which may have a lower alkyl group which may have a hydroxyl group as a substituent. Examples of the phenyl group include 4-benzoylaminophenyl, 4- (2-methylbenzoylamino) phenyl, 3- (3-methylbenzoylamino) phenyl,
2- (4-methylbenzoylamino) phenyl, 4-
(2-ethylbenzoylamino) phenyl, 3- (3-
Ethylbenzoylamino) phenyl, 2- (4-ethylbenzoylamino) phenyl, 4- (4-isopropylbenzoylamino) phenyl, 2- (3-butylbenzoylamino) phenyl, 3- (4-pentylbenzoylamino) phenyl, 4- (4-hexylbenzoylamino) phenyl, 4- (3,4-dimethylbenzoylamino) phenyl, 4- (3,4,5-trimethylbenzoylamino) phenyl, 4- [4- (5-pentylaminopentyl) Oxy) benzoylamino] phenyl, 4-
[2- (3-isopropylaminopropoxy) benzoylamino] phenyl, 3- [2- (4-isopropylaminobutoxy) benzoylamino] phenyl, 2- [2
-(3-ethylaminopropoxy) benzoylamino]
Phenyl, 4- [3- (methylaminomethoxy) benzoylamino] phenyl, 4- [2-methyl-4- (3-
Isopropylaminopropoxy) benzoylamino] phenyl, 4- [2- {3- [N- (2-hydroxyethyl) -N- (2-hydroxyethyl) amino] propoxy} benzoylamino] phenyl, 4- {2- [ 6-
(N-hydroxymethyl-N-isopropylamino) hexyloxy] benzoylaminodiphenyl, 3- [2
C1 to C6 as a substituent on a phenyl ring such as-(3-aminopropoxy) benzoylamino] phenyl or 4- [2- {3-[(2-hydroxyethyl) amino] propoxy} benzoylamino] phenyl group; A linear or branched alkyl group and an amino group which may have 1 to 2 straight or branched alkyl groups having 1 to 6 carbon atoms which may have 1 to 3 hydroxyl groups as substituents And a phenyl group having a benzoylamino group which may have 1 to 3 groups selected from the group consisting of linear or branched alkoxy groups having 1 to 6 carbon atoms having

A benzoylamino-substituted phenyl group having on the phenyl ring a lower alkyl group as a substituent and an amino-lower alkoxy group which may have a lower alkyl group which may have a hydroxyl group as a substituent. Is, for example, 4- (2-methylbenzoylamino) phenyl, 3- (3-methylbenzoylamino)
Phenyl, 2- (4-methylbenzoylamino) phenyl, 4- (2-ethylbenzoylamino) phenyl, 3
-(3-ethylbenzoylamino) phenyl, 2- (4
-Ethylbenzoylamino) phenyl, 4- (4-isopropylbenzoylamino) phenyl, 2- (3-butylbenzoylamino) phenyl, 3- (4-pentylbenzoylamino) phenyl, 4- (4-hexylbenzoylamino) phenyl 4- (3,4-dimethylbenzoylamino) phenyl, 4- (3,4,5-trimethylbenzoylamino) phenyl, 4- [4- (5-pentylaminopentyloxy) benzoylamino] phenyl, 4- [ 2- (3-isopropylaminopropoxy)
Benzoylamino] phenyl, 3- [2- (4-isopropylaminobutoxy) benzoylamino] phenyl,
2- [2- (3-ethylaminopropoxy) benzoylamino] phenyl, 4- [3- (methylaminomethoxy) benzoylamino] phenyl, 4- [2-methyl-
4- (3-isopropylaminopropoxy) benzoylamino] phenyl, 4- [2- {3- [N- (2-hydroxyethyl) -N- (2-hydroxyethyl) amino] propoxy} benzoylamino] phenyl, 4 −
{2- [6- (N-hydroxymethyl-N-isopropylamino) hexyloxy] benzoylamino} phenyl, 3- [2- (3-aminopropoxy) benzoylamino] phenyl, 4- [2- {3- [ (2-Hydroxyethyl) amino] propoxy {benzoylamino] phenyl has a linear or branched alkyl group having 1 to 6 carbon atoms as a substituent on a phenyl ring and 1 to 3 hydroxyl groups as a substituent Selected from the group consisting of straight-chain or branched alkoxy groups having 1 to 6 carbon atoms having an amino group which may have 1 to 2 straight-chain or branched alkyl groups having 1 to 6 carbon atoms. And a phenyl group having a benzoylamino group having 1 to 3 groups.

The compound of the present invention can be produced by various methods.

[0143]

Embedded image

Wherein R ¹ , R ² and R ³ are as defined above. The method represented by the reaction formula-1 is a method in which an amine of the general formula (2) and a carboxylic acid of the general formula (3) are reacted by a usual amide bond formation reaction. Known conditions for the amide bond formation reaction can be easily applied to the acid amide bond formation reaction. For example, (a) a mixed acid anhydride method, that is, a method in which a carboxylic acid (3) is reacted with an alkylhalocarbonate to form a mixed acid anhydride, and the mixed acid anhydride is reacted with an amine (2);
(B) Active ester method, that is, a method in which the carboxylic acid (3) is converted into an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester and the like and reacted with the amine (2). (C) a carbodiimide method, that is, a method of subjecting a carboxylic acid (3) to a condensation reaction of an amine (2) in the presence of an activator such as dicyclohexylcarbodiimide, carbonyldiimidazole, or the like; 3) converting carboxylic acid anhydride to a carboxylic anhydride with a dehydrating agent such as acetic anhydride, and reacting the carboxylic anhydride with an amine (2); and reacting the amine (2) with an ester of a carboxylic acid (3) and a lower alcohol under high pressure and high temperature. Method of reacting acid halide of carboxylic acid (3), ie, carboxylic acid halide with amine (2) It can be mentioned.

The mixed acid anhydride used in the above mixed acid anhydride method (a) is obtained by a reaction similar to the usual Schotten-Baumann reaction, and this is usually reacted with the amine (2) without isolation. Thereby, the compound of the present invention of the general formula (1) is produced. The Schotten-Baumann reaction is performed in the presence of a basic compound. As the basic compound to be used, compounds commonly used in the Schotten-Baumann reaction, for example, triethylamine, trimethylamine,
Diisopropylethylamine, pyridine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] nonene-5 (DBN), 1,8-diazabicyclo [5.4.0] undecene-7 (DBU) ,
1,4-diazabicyclo [2.2.2] octane (DA
Organic bases such as BCO) and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate and sodium hydrogen carbonate. The reaction is usually performed at about -20 to 100 ° C, preferably about 0 to 50 ° C, and the reaction time is about 5 minutes to 10 hours, preferably about 5 minutes to 2 hours. The reaction between the obtained mixed acid anhydride and the amine (2) is usually about -20 to 150 ° C, preferably 10 to 50 ° C.
The reaction time is about 5 minutes to 10 hours,
Preferably, it is about 5 minutes to 5 hours. The mixed anhydride method is generally performed in a solvent. As the solvent to be used, any of the solvents commonly used in the mixed acid anhydride method can be used. Specifically, chloroform, dichloromethane, halogenated hydrocarbons such as dichloroethane, benzene, p-chlorobenzene, toluene, xylene and the like can be used. Aromatic hydrocarbons, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dimethoxyethane, esters such as methyl acetate and ethyl acetate, 1-methyl-2-pyrrolidinone (NMP), N, N-dimethylformamide,
Examples include aprotic polar solvents such as dimethyl sulfoxide, acetonitrile, and hexamethylphosphoric acid triamide, and the like, and mixed solvents thereof. Examples of the alkyl halocarbonate used in the mixed acid anhydride method include methyl chloroformate, methyl bromoformate, ethyl chloroformate,
Examples include ethyl bromoformate, isobutyl chloroformate, and pivaloyl chloride. The ratio of the carboxylic acid (3), the alkyl halocarbonate and the amine (2) used in the method is usually preferably equimolar, but the ratio of the alkylhalocarbonate and the carboxylic acid (3) to the amine (2) is relatively small. Each can be used in the range of about 1 to 1.5 times the molar amount.

When the method of reacting the carboxylic acid halide with the amine (2) is employed among the other methods (d), the reaction is carried out in the presence of a basic compound in a suitable solvent. As the basic compound to be used, known compounds can be widely used.For example, in addition to the basic compound used for the above-mentioned Schotten-Baumann reaction, for example, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride and the like can be used. Can be illustrated. Examples of the solvent used include, in addition to the solvent used in the mixed acid anhydride method, alcohols such as methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve; pyridine; Acetone, water and the like can be exemplified. The use ratio of the amine (2) and the carboxylic acid halide is not particularly limited and can be appropriately selected within a wide range. Usually, the amount of the latter is at least about 0.1 mol, preferably about 0.1 mol to 5 mol, based on the former. It is preferable to use about twice the molar amount. The reaction is usually carried out at -20 to 180 ° C.
The reaction is carried out at about 0 ° C., preferably about 0 ° C. to 150 ° C., and the reaction is generally completed in about 5 minutes to 30 hours.

Further, in the amide bond forming reaction shown in the above reaction formula-1, the carboxylic acid (3) and the amine (2) are reacted with phenylphosphine-2,2'-dithiodipyridine, diphenylphosphinyl chloride, phenyl- N-phenylphosphoramide chloridate, diethyl chlorophosphate,
It can also be carried out by a method in which the reaction is carried out in the presence of a condensing agent for a phosphorus compound such as diethyl cyanophosphate, azide diphenylphosphate, bis (2-oxo-3-oxazolidinyl) phosphinic chloride.

The reaction is usually carried out at about -20 to 150 ° C., preferably about 0 to 100 ° C., in the presence of a solvent and a basic compound used in the method for reacting the carboxylic acid halide with the amine (2). 5 minutes to 3 days
The reaction is completed in about 0 hours. The condensing agent and the carboxylic acid (3) are used in an amount of at least about 0.1 mole, preferably about 0.1 to 2 times the mole of the amine (2).

[0149]

Embedded image

Wherein R ³ is as defined above. X represents a halogen atom. R ^2a is a group together with a nitrogen atom to which R ¹ and R ² are bonded.

[0151]

Embedded image

Shows a R ² other than that forming the [0152]. R ¹³ and R
¹⁴ is the same or different and represents a hydrogen atom or a lower alkyl group. R ^1a represents a lower alkyl group or a lower alkenyl group. The reaction between compound (4) and compound (5) is generally performed in a suitable inert solvent in the presence or absence of a basic compound. Examples of the inert solvent used include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and diethylene glycol dimethyl ether; halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; methanol and ethanol. , Isopropanol, butanol, t
Examples thereof include lower alcohols such as ert-butanol, acetic acid, ethyl acetate, acetone, acetonitrile, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, and a mixed solvent thereof. Examples of the basic compound include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, carbonates such as potassium hydrogen carbonate, sodium hydroxide, metal hydroxides such as potassium hydroxide, sodium hydride, potassium, sodium, sodium amide, and the like. Metal alcoholates such as sodium methylate and sodium ethylate, pyridine,
N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine, 1,5-diazabicyclo [4.3.0] nonene-5 (DBN), 1,8-diazabicyclo [5.4.0] undecene-7 (DBU),
1,4-diazabicyclo [2.2.2] octane (DA
And organic bases such as BCO). The ratio of the compound (4) to the compound (5) is not particularly limited and may be appropriately selected in a wide range. The amount of the latter is at least about equimolar to the former, preferably about 1 to 1 mol.
It is preferable to use about 0 times the molar amount. The reaction is generally carried out at 0 to 20
The reaction is carried out at about 0 ° C., preferably about 0-170 ° C., and the reaction is generally completed in about 30 minutes to 75 hours. An alkali metal halide such as sodium iodide and potassium iodide, copper powder and the like may be added to the reaction system.

[0153]

Embedded image

[Wherein R ¹ , R ² , R ¹³ , R ¹⁴ and X are as defined above. R ¹⁵ represents a halogen atom, a lower alkyl group or a group NR ³¹ R ³² (R ³¹ and R ³² are as defined above). q shows the integer of 0-2. R ¹⁷ represents a lower alkyl group. R
¹⁸ represents a lower alkoxycarbonyl group or a phenyl lower alkoxycarbonyl group. R ¹⁶ represents a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or a phenyl lower alkoxycarbonyl group. The reaction between compound (1a) and compound (6) is carried out without a solvent or in a suitable solvent in the presence of a reducing agent. Examples of the solvent used herein include water, alcohols such as methanol, ethanol, and isopropanol; acetonitrile, formic acid, acetic acid, dioxane, diethyl ether, diglyme, and ethers such as tetrahydrofuran; and aromatic hydrocarbons such as benzene, toluene, and xylene. Examples thereof include hydrogens and a mixed solvent thereof. As the reducing agent, for example, formic acid, ammonium formate, alkali metal salts of fatty acids such as sodium formate, hydride reducing agents such as sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, palladium-black, palladium-carbon, oxidized platinum,
Examples thereof include a contact reducing agent such as platinum black and Raney nickel.

When formic acid is used as a reducing agent, the reaction temperature is usually from room temperature to about 200 ° C., preferably from 50 to 150 ° C.
C. is appropriate, and the reaction is completed in about 1 to 10 hours. The amount of formic acid used is preferably a large excess with respect to compound (1a).

When a hydride reducing agent is used, the reaction temperature is usually about -30 to 100 ° C, preferably 0 to 70 ° C.
The reaction is properly performed, and the reaction is completed in about 30 minutes to 12 hours. The amount of the reducing agent to be used is generally about equimolar to about 20-fold molar quantity, preferably about 1- to 6-fold molar quantity, relative to compound (1a). In particular, when lithium aluminum hydride is used as the reducing agent, it is preferable to use ethers such as diethyl ether, dioxane, tetrahydrofuran, and diglyme as solvents, and aromatic hydrocarbons such as benzene, toluene, and xylene.

Further, when a catalytic reducing agent is used, it is usually in a hydrogen atmosphere at normal pressure to about 20 atm, preferably normal pressure to about 10 atm, or a hydrogen donor such as formic acid, ammonium formate, cyclohexene or hydrazine hydrate. The reaction is usually carried out at a temperature of about -30 to 100 ° C, preferably about 0 to 60 ° C, and the reaction is usually completed in about 1 to 12 hours. The amount of the catalytic reducing agent used may be the compound (1
0.1 to 40% by weight, preferably 1 to 40% by weight based on a)
The content is preferably about 20% by weight. The amount of the hydrogen donor to be used is generally preferably a large excess with respect to the compound (1a).

The amount of compound (6) to be used is usually at least equimolar, preferably equimolar to large excess with respect to compound (1a).

The reaction between the compound (1a) and the compound (7) is carried out under the same reaction conditions as the reaction between the compound (4) and the compound (5) in the aforementioned Reaction Formula-2.

The reaction between the compound (1a) and the compound (8) is carried out under the same reaction conditions as the reaction between the compound (2) and the compound (3) in the above Reaction Scheme-1.

The reaction for converting a compound in which R ¹⁸ is a lower alkoxycarbonyl group among the compounds (1c) into a compound (1a) is the same as the reaction for converting a compound (1i) into a compound (1j) in Reaction Scheme-7 described below. Performed under reaction conditions.

Compound (1c) wherein R ¹⁸ is a phenyl lower alkoxycarbonyl group is compound (1a)
Is carried out under the same reaction conditions as the reaction using a reduction catalyst of (1) in Reaction Formula -15 described later.

[0163]

Embedded image

Wherein R ¹ , R ² , R ¹⁵ and q are as defined above. X ¹ and X ² are the same or different and represent a halogen atom. The reaction between the compound (1a) and the compound (9) is performed under the same reaction conditions as the reaction between the compound (4) and the compound (5) in the aforementioned Reaction Formula-2.

[0165]

Embedded image

[Wherein R ¹ and R ² are as defined above. R ¹⁹ is
A benzoyl group which may have on the phenyl ring a lower alkyl group as a substituent and an amino-lower alkoxy group which may have a lower alkyl group which may have a hydroxyl group as a substituent. The reaction between the compound (1f) and the compound (10) is carried out under the same reaction conditions as in the reaction between the compound (2) and the compound (3) in the aforementioned Reaction Formula-1.

[0167]

Embedded image

[Wherein R ¹ , R ² and q are as defined above. R ²¹
Represents a halogen-substituted lower alkoxy group. R ²² represents an amino group which may have lower alkyl group which may have a hydroxyl group as a substituent. R ²⁰ represents a lower alkyl group or an amino-lower alkoxy group which may have a lower alkyl group which may have a hydroxyl group as a substituent.
R ^22a represents an amino-lower alkoxy group which may have a lower alkyl group which may have a hydroxyl group as a substituent. Here, examples of the halogen-substituted lower alkoxy group include trifluoromethoxy, trichloromethoxy, chloromethoxy, bromomethoxy, fluoromethoxy, iodomethoxy, difluoromethoxy, dibromomethoxy,
Chloroethoxy, 2,2,2-trifluoroethoxy,
2,2,2-trichloroethoxy, 3-chloropropoxy, 2,3-dichloropropoxy, 4,4,4-trichlorobutoxy, 4-fluorobutoxy, 5-chloropentyloxy, 3-chloro-2-methylpropoxy, 6-
Examples thereof include straight-chain or branched-chain alkoxy groups having 1 to 3 carbon atoms and having 1 to 3 halogen atoms, such as bromohexyloxy and 5,6-dichlorohexyloxy groups.

The reaction between the compound (11) and the compound (12) is carried out under the same reaction conditions as the reaction between the compound (4) and the compound (5) in the aforementioned Reaction Formula-2.

[0170]

Embedded image

[Wherein R ¹ , R ³ , R ⁶ , R ⁷ and R ⁸ are the same as above. R ²³ represents a lower alkoxycarbonyl group.
r represents 0 or 1. The reaction for converting the compound (1i) to the compound (1j) can be carried out in a suitable solvent or without a solvent in the presence of an acid or a basic compound. Examples of the solvent used include water, lower alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; ethers such as dioxane, tetrahydrofuran and ethylene glycol dimethyl ether; fatty acids such as acetic acid and formic acid; And the like. Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and organic acids such as formic acid, acetic acid, and aromatic sulfonic acid.Examples of the basic compound include sodium carbonate and potassium carbonate. And metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide and lithium hydroxide. The reaction is carried out usually at room temperature to about 200 ° C., preferably at room temperature to 150 ° C.
The process suitably proceeds at about ° C, and generally ends in about 10 minutes to 25 hours.

The esterification of compound (1i) is carried out, for example, by reacting the starting compound with methanol and methanol in the presence of a mineral acid such as hydrochloric acid or sulfuric acid, or a halogenating agent such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride or phosphorus trichloride. The reaction is carried out by reacting with alcohols such as ethanol and isopropanol usually at 1 to 150 ° C, preferably 50 to 100 ° C for about 1 to 10 hours.

The reaction between compound (1j) and compound (13) is carried out by reacting compound (2) and compound (3) in the aforementioned reaction formula-1.
Under the same reaction conditions as in the reaction with

[0174]

Embedded image

[Wherein R ¹ , R ³ , R ⁶ , R ²³ , r, A ₁ ,
R ¹¹ and R ¹² are the same as above. The reaction for converting the compound (1l) into the compound (1m) is carried out under the same reaction conditions as the reaction for converting the compound (1i) into the compound (1j) in the aforementioned Reaction Formula-7.

The reaction for converting the compound (1m) into the compound (1l) is carried out under the same reaction conditions as the reaction for converting the compound (1j) into the compound (1i) in the aforementioned Reaction Formula-7.

The reaction between the compound (1m) and the compound (14) is carried out under the same reaction conditions as those for the reaction between the compound (2) and the compound (3) in the aforementioned reaction formula-1.

[0178]

Embedded image

[Wherein R ¹ , R ³ , R ⁶ , r, R ⁷ , A ₁ ,
R ²³ , R ⁹ and R ¹⁰ are the same as described above. The reaction for converting the compound (1o) into the compound (1p) is carried out under the same reaction conditions as the reaction for converting the compound (1i) into the compound (1j) in the aforementioned Reaction Formula-7.

The reaction for converting the compound (1p) into the compound (1o) is carried out under the same reaction conditions as the reaction for converting the compound (1j) into the compound (1i) in the above Reaction Scheme-7.

The reaction between the compound (1p) and the compound (15) is carried out under the same reaction conditions as the reaction between the compound (2) and the compound (3) in the above Reaction Scheme-1.

[0182]

Embedded image

Wherein R ¹ , R ³ , R ⁶ , R ⁷ and r are as defined above. R ²⁴ represents a phthalimide lower alkyl group. The reaction for converting the compound (1r) to the compound (1s) can be carried out by reacting the compound (1r) with hydrazine or hydrolyzing the compound (1r) in a suitable solvent. As the solvent used in the reaction of hydrazine, in addition to water, any of the same solvents as those used in the reaction between compound (2) and compound (3) in the aforementioned reaction formula-1 can be used. The reaction is usually carried out at room temperature to about 120 ° C., preferably 0 to 120 ° C.
The process is performed at about 100 ° C., and is generally completed in about 0.5 to 5 hours. The amount of hydrazine to be used is at least about an equimolar amount, preferably about equimolar to about 5-fold molar amount, relative to compound (1r).

The hydrolysis can be carried out in a suitable solvent or without a solvent in the presence of an acid or a basic compound. Examples of the solvent used include water, lower alcohols such as methanol, ethanol and isopropanol; ketones such as acetone and methyl ethyl ketone; ethers such as diethyl ether, dioxane, tetrahydrofuran and ethylene glycol dimethyl ether; and fatty acids such as acetic acid and formic acid. And mixed solvents thereof. Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid and hydrobromic acid, and organic acids such as formic acid, acetic acid and aromatic sulfonic acid.Examples of the basic compound include sodium carbonate and potassium carbonate. Examples thereof include metal carbonates and metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide. The reaction is usually carried out at room temperature to 200
C., preferably at room temperature to about 150.degree. C., and generally completes in about 10 minutes to 25 hours.

[0185]

Embedded image

[Wherein R ¹ , R ³ , R ⁶ , r, R ⁷ , A, l,
R ⁹ , R ¹³ , R ¹⁴ , R ¹⁷ and X are the same as described above. R ^8a represents a lower alkyl group, a lower alkenyl group, a lower alkynyl group,
Phenyl lower alkyl group, phthalimide lower alkyl group, tetrahydropyranyloxy lower alkyl group, lower alkanoyloxy lower alkyl group, hydroxyl-substituted lower alkyl group, lower alkoxycarbonyl lower alkyl group,
Lower alkoxy lower alkyl group, carboxy lower alkyl group, cyano lower alkyl group, tetrahydroisoquinolyl group which may have a lower alkyl group as a substituent on a tetrahydroisoquinolyl ring, pyridyl group, thiazolyl group, furyl lower alkyl group Or a group -A (CO) _l -N
R ⁹ R ¹⁰ (A, 1, R ⁹ and R ¹⁰ are the same as above). R ²⁵ represents a lower alkanoyl group or a lower alkoxycarbonyl group. The reaction between the compound (1t) and the compound (7) or the compound (6) and the reaction between the compound (1w) and the compound (17) or the compound (6) are carried out by the compound (4) and the compound The reaction is performed under the same reaction conditions as in the reaction with (5) or compound (6).

The reaction between the compound (1t) and the compound (16) is carried out under the same reaction conditions as in the reaction between the compound (2) and the compound (3) in the above-mentioned reaction formula-1.

The reaction for converting the compound (1v) to the compound (1t) is carried out under the same reaction conditions as the reaction for converting the compound (1i) to the compound (1j) in the above Reaction Scheme-7.

[0189]

Embedded image

[Wherein R ¹ , R ³ , R ⁶ , r, R ⁷ and X are as defined above. R ²⁵ represents a hydroxyl-substituted lower alkyl group. R
²⁶ represents a lower alkanoyl group. R ²⁷ represents a lower alkanoyloxy lower alkyl group. The reaction between the compound (1x) and the compound (17) is carried out under the same reaction conditions as the reaction between the compound (4) and the compound (5) in the aforementioned Reaction Formula-2.

The reaction for converting the compound (1y) into the compound (1x) is carried out under the same reaction conditions as the reaction for converting the compound (1i) into the compound (1j) in the above Reaction Scheme-7.

[0192]

Embedded image

Wherein R ¹ , R ³ , R ⁶ , r, R ⁷ and R ²⁵ are as defined above. R ²⁸ represents a tetrahydropyranyloxy lower alkyl group. The reaction for converting the compound (1z) into the compound (1x) is carried out under the same reaction conditions as the reaction for converting the compound (1i) into the compound (1j) in the aforementioned Reaction Formula-7. In the reaction, a pyridinium salt such as pyridinium / p-toluenesulfonate can be used as an acid.

[0194]

Embedded image

[Wherein the formula

[0196]

Embedded image

W, R ³ and R ³⁰ are the same as described above. v is 0
2 to 2. R ³³ represents a carboxy lower alkyl group. R ³¹ represents an amino group which may have a lower alkyl group as a substituent. R ³² represents an aminocarbonyl lower alkyl group which may have a lower alkyl group as a substituent. The reaction between the compound (1A) and the compound (18) is carried out under the same reaction conditions as in the reaction between the compound (2) and the compound (3) in the aforementioned Reaction Formula-1.

Compounds (2), (1d) and (1f) used as starting materials in the above reaction formulas
And compound (11) are produced, for example, by the method shown in the following reaction formula.

[0199]

Embedded image

Wherein R ^2a is as defined above. The reduction reaction may be, for example, (1) reduction using a catalytic reduction catalyst in a suitable solvent using a reduction catalyst, or (2) metal or metal salt and acid or metal or metal salt in a suitable inert solvent. The reaction is carried out by reducing a mixture of the compound with an alkali metal hydroxide, sulfide, ammonium salt or the like as a reducing agent.

When the reduction catalyst (1) is used, examples of the solvent used include water, acetic acid, alcohols such as methanol, ethanol, and isopropanol; hexane;
Hydrocarbons such as cyclohexane; ethers such as dioxane, tetrahydrofuran, diethyl ether and diethylene glycol dimethyl ether; esters such as ethyl acetate and methyl acetate; aprotic polar solvents such as N, N-dimethylformamide; Mixed solvents and the like can be mentioned. As the catalytic reduction catalyst used, for example, palladium, palladium-black, palladium-carbon, platinum,
Platinum oxide, copper chromite, Raney nickel and the like can be mentioned. Generally, the catalyst is preferably used in an amount of about 0.02 to 1 times the amount of the starting material. The reaction temperature is usually -20 to 150
℃, preferably 0-100 ℃, hydrogen pressure is usually 1
The reaction is generally between 0.5 and 1 atmosphere.
It ends in about 0 hours. Further, an acid such as hydrochloric acid may be added to the reaction.

When the method (2) is used, iron, zinc, tin or stannous chloride and a mineral acid such as hydrochloric acid or sulfuric acid, or iron, ferrous sulfate, zinc or tin and an alkali such as sodium hydroxide or the like are used. Mixtures with metal hydroxides, sulfides such as ammonium sulfide, ammonia water, and ammonium salts such as ammonium chloride are used as reducing agents. Examples of the inert solvent used include water, acetic acid, methanol, ethanol, dioxane and the like. Conditions for the reduction reaction may be appropriately selected depending on the reducing agent used. For example, when stannous chloride and hydrochloric acid are used as the reducing agent, the temperature is preferably 0 ° C. to around room temperature, about 0.5 to 10 hours. The reaction is preferably performed. The reducing agent is used at least in an equimolar amount, usually in an equimolar to 5-fold molar amount, relative to the raw material compound.

[0203]

Embedded image

Wherein R ¹ , R ² , R ¹⁵ and q are as defined above. Compound (2) and compound (20a) or compound (20b)
Is carried out under the same reaction conditions as in the reaction of the compound (2) with the compound (3) in the aforementioned reaction formula-1.

The reduction reaction of the compound (21a) and the compound (21b) is carried out by reacting the compound (19) in the aforementioned reaction formula-15.
Under the same reaction conditions as in the reduction reaction of

[0206]

Embedded image

Wherein R ¹ , R ² , R ²⁰ , R ²¹ and q are as defined above. The reaction between the compound (1f) and the compound (22) is carried out under the same reaction conditions as the reaction between the compound (2) and the compound (3) in the aforementioned Reaction Formula-1.

[0208]

Embedded image

[Wherein the formula

[0210]

Embedded image

R ³⁰ , u and W are the same as described above. R ²⁹ represents a phenylsulfonyl group which may have a lower alkyl group as a substituent on the phenyl ring. The reaction for converting the compound (23) into the compound (2b) is carried out by reacting the compound (23) with metallic magnesium in a suitable solvent. As the solvent used here,
For example, alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and methyl ethyl ketone, ethers such as dioxane, tetrahydrofuran and ethylene glycol dimethyl ether, aromatic hydrocarbons such as benzene, toluene and xylene, hexane, cyclohexane, heptane and the like And aprotic polar solvents such as dimethylformamide, dimethylsulfoxide and hexamethylphosphoric acid triamide, and mixed solvents thereof. The amount of magnesium metal used is usually a large excess with respect to compound (23),
The molar amount is preferably 5 to 20 times. The reaction is usually carried out at room temperature to around 120 ° C, preferably at room temperature to 100 ° C.
The reaction suitably proceeds at around ℃, and the reaction is generally completed in about 1 to 15 hours.

The compound (2) can also be obtained by treating the compound (23) in a suitable solvent in the presence of an acid such as sulfuric acid.
b) is manufactured. As the solvent used here, in addition to aromatic hydrocarbons such as benzene, toluene and xylene, the above-mentioned alcohols, ethers, aliphatic hydrocarbons, aprotic polar solvents or mixed solvents thereof and the like Can be mentioned. The amount of the acid used is the same as that of compound (23)
It is usually good to use a large excess amount. The reaction is usually carried out at room temperature to 150 ° C, preferably at around 50 to 120 ° C.
Generally, it is completed in about 1 to 10 hours. The reaction proceeds advantageously by adding anisole or the like to the reaction system.

Of the compounds (1) of the present invention, those having an acidic group can form salts with pharmacologically acceptable basic compounds. Examples of such a basic compound include metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and calcium hydroxide, alkali metal carbonates and bicarbonates such as sodium carbonate and sodium hydrogen carbonate, and sodium methylate. And alkali metal alcoholates such as potassium ethylate. In addition, among the compounds (1) of the present invention, a compound having basicity can easily form a salt with a usual pharmacologically acceptable acid. Such acids include, for example, inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, hydrobromic acid, acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, fumaric acid, citric acid,
Organic acids such as succinic acid and benzoic acid can be exemplified. These salts can also be used as the active ingredient compound in the present invention, like the compound (1) in a free form. The compound (1) includes stereoisomers and optical isomers, and these can also be used as the active ingredient compound.

The target compound obtained by the method shown in each of the above reaction schemes can be separated from the reaction system by a usual separation means and further purified. Such separation and purification means include, for example, distillation, recrystallization, column chromatography, ion exchange chromatography,
Gel chromatography, affinity chromatography, preparative thin-layer chromatography, solvent extraction and the like can be employed.

The active compound thus obtained is effective as a vasopressin antagonist, an oxytocin antagonist and a vasopressin agonist, and these agents are used in the form of general pharmaceutical preparations. The preparation is prepared using a commonly used diluent or excipient such as a filler, a bulking agent, a binder, a humectant, a disintegrant, a surfactant and a lubricant. Various forms can be selected as the pharmaceutical preparation depending on the purpose of treatment, and typical examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections ( Liquid, suspension, etc.). In molding into tablets, various carriers well-known in the art can be widely used as carriers. Examples include lactose, sucrose, sodium chloride, glucose, urea, starch, potassium carbonate, kaolin,
Excipients such as crystalline cellulose and silicic acid, water, ethanol,
Propanol, simple syrup, glucose solution, starch solution,
Gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dried starch, sodium alginate, agar powder, laminaran powder, sodium hydrogencarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, lauryl sulfate Disintegrants such as sodium, monoglyceride stearate, starch, lactose, sucrose,
Disintegration inhibitors such as stearin, cocoa butter, hydrogenated oil and the like, quaternary ammonium bases, absorption promoters such as sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, kaolin, bentonite, colloidal silicic acid and the like Adsorbents, lubricating agents such as purified talc, stearates, boric acid powder, polyethylene glycol and the like. Further tablets are tablets coated with normal skin as needed,
For example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or double tablets or multilayer tablets can be prepared. In molding into the form of pills, a wide variety of carriers conventionally known in this field can be used. Examples thereof include excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, etc., gum arabic powder, tragacanth powder, gelatin, binders such as ethanol,
Disintegrators such as laminaran and agar can be used. In the case of molding into a suppository form, conventionally known carriers can be widely used. Examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides. Capsules are prepared according to a conventional method, usually by mixing the active ingredient compound with the various carriers exemplified above and filling the mixture into hard gelatin capsules, soft capsules and the like. When prepared as an injection, the solutions, emulsions and suspensions are preferably sterile and isotonic with blood,
When molding into these forms, any of those commonly used in this field can be used as a diluent, such as water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, Oxyethylene sorbitan fatty acid esters and the like can be used. In this case, a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution may be included in the pharmaceutical preparation, and a usual solubilizer, buffer, soothing agent, etc. may be added. You may. Further, a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent and the like and other pharmaceuticals can be contained in the pharmaceutical preparation as required.

The amount of the active ingredient compound to be contained in the pharmaceutical preparation of the present invention is not particularly limited and may be appropriately selected from a wide range, but is usually about 1 to 70% by weight, preferably about 1 to 70% by weight in the pharmaceutical composition. The content is preferably 5 to 50% by weight.

The administration method of the pharmaceutical preparation of the present invention is not particularly limited, and may be various preparation forms, patient age, gender and other conditions,
The drug is administered according to the degree of the disease. For example, tablets,
In the case of pills, solutions, suspensions, emulsions, granules and capsules, they are administered orally. In the case of an injection, it is administered intravenously, alone or in combination with a normal replenisher such as glucose or amino acid, and if necessary, intramuscularly, intradermally, subcutaneously or intraperitoneally. In the case of suppositories, they are administered rectally.

The dose of the pharmaceutical preparation of the present invention is appropriately selected depending on the usage, the age of the patient, gender and other conditions, the degree of the disease, and the like.
The amount is preferably about 0.6 to 50 mg per kg. The active ingredient compound may be present in the dosage unit form in an amount of about 10 to about 10.
Desirably, it is contained in the range of 1000 mg.

[0219]

EXAMPLES Hereinafter, in order to explain the present invention in more detail, preparation examples of the pharmaceutical preparation of the present invention will be given, followed by production examples of the above-mentioned active ingredient compounds, and test examples of the active ingredient compounds.

Formulation Example 1 1- (4-Nn-propylamino-2-chlorobenzoyl) -5-isopropylaminocarbonylmethyl-2,3,4,5-tetrahydro-1H-thieno [3,2b] azepine 150 g citric acid 1.0 g lactose 33.5 g dicalcium phosphate 70.0 g Pluronic F-68 30.0 g sodium lauryl sulfate 15.0 g polyvinylpyrrolidone 15.0 g polyethylene glycol (Carbowax 1500) 4.5 g polyethylene glycol (carbo) Wax 6000) 45.0 g Corn starch 30.0 g Dry sodium stearate 3.0 g Dry magnesium stearate 3.0 g Ethanol Appropriate amount Active compound of the present invention, citric acid, lactose, dicalcium phosphate, Pluronic F- Mix 68 and sodium lauryl sulfate.

The above mixture was designated as No. The mixture is sieved with a 60 screen and wet granulated with an alcohol solution containing polyvinylpyrrolidone, carbowax 1500 and 6000. If necessary, alcohol is added to make the powder into a pasty mass. Add corn starch and continue mixing until uniform particles are formed. The mixture was no. Pass through 10 screens, place in trays and dry at 100 ° C open for 12-14 hours. The dried particles were no. Sieve through 16 screens, add dry sodium lauryl sulfate and dry magnesium stearate, mix and compress to desired shape on tablet press.

The above core is treated with varnish, and talc is sprayed to prevent moisture absorption. An undercoat layer is coated around the core. Apply enough varnish coating for internal use. A further subbing layer and a smooth coating are applied to make the tablet completely round and smooth. Color coating is carried out until the desired hue is obtained. After drying, the coated tablets are polished into tablets of uniform gloss.

Formulation Example 2 1-Methyl-4- [2-chloro-4- (1-pyrrolidinyl) benzoyl] -1,4,5,6,7,8-hexahydropyrrolo [3,2-b] azepine 5 g polyethylene glycol (molecular weight: 4000) 0.3 g sodium chloride 0.9 g polyoxyethylene-sorbitan monooleate 0.4 g sodium metabisulfite 0.1 g methyl-paraben 0.18 g propyl-paraben 0.02 g distillation for injection Water 10.0 ml The above parabens, sodium metabisulfite and sodium chloride are dissolved in about half of the above distilled water at 80 ° C. with stirring. The obtained solution is cooled to 40 ° C., and the active ingredient compound of the present invention, and then polyethylene glycol and polyoxyethylene sorbitan monooleate are dissolved in the above solution. Next, distilled water for injection is added to the solution to make the final volume, and the solution is sterilized by sterile filtration using an appropriate filter paper to prepare an injection.

Reference Example 1 9.1 g of 2-chloro-4-nitrobenzoic acid was suspended in 100 ml of thionyl chloride, and the mixture was refluxed for 1 hour. The reaction was concentrated to give 2-chloro-4-nitrobenzoyl chloride. 5-methoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-thieno [3,
2b] Azepine (7.8 g) was dissolved in dichloromethane (200 ml), pyridine (14 ml) was added thereto, and the above-mentioned 2-chloro-4-nitrobenzoyl chloride (50 ml) dichloromethane solution was gradually added to the mixture under ice-cooling and stirring. After stirring at room temperature overnight, the reaction was poured into water and extracted with dichloromethane. After drying over sodium carbonate,
Purification by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 4: 1 → 1: 1), crystallization with diethyl ether, and 1- (4′-nitro-
5.53 g of 2'-chlorobenzoyl) -5-methoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-thieno [3,2b] azepine was obtained.

Property: white powder ¹ H-NMR (200 MHz, CDCl ₃ ) δ ppm:
1.48-2.21 (4H, m), 2.61-2.97
(2H, m), 2.98-4.90 (3H, m), 3.
74 (3H, s), 6.38-6.52 (1H, m),
6.74 (1H, d, J = 5.3 Hz), 7.31-
7.45 (1H, m), 7.99 (1H, dd, J =
8.4 Hz, J = 2.1 Hz), 8.19 (1H, d,
J = 2.1 Hz).

Reference Example 2 1 g of 6-nitronicotinic acid was suspended in 20 ml of dichloromethane, and 1.3 ml of oxalyl chloride was added thereto.
After heating under reflux, the mixture was concentrated to obtain 6-nitronicotinic acid chloride. To a solution of 0.83 g of N-allyl-4-chloroaniline in 20 ml of dichloromethane was added 2 g of pyridine, and the above-mentioned 6-nitronicotinic acid chloride was added, followed by stirring at room temperature for 30 minutes. Water was added to the reaction solution, extracted with ethyl acetate,
After washing with a 0.1N hydrochloric acid aqueous solution, washing with water, and drying over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 1: 1) to give N- (4′-chlorophenyl) -1-propenylamino- (6 1.2 g of '-nitro) nicotinamide were obtained.

Properties: yellow oil.

Reference Example 3 To 9 g of reduced iron, 30 ml of 2N hydrochloric acid was added, and the mixture was allowed to stand for 10 minutes, filtered, washed with water and acetone, and dried. N-
(4'-chlorophenyl) -1-propenylamino-
90 ml of acetic acid was added to 9 g of (6′-nitro) nicotinamide, and reduced iron was gradually added thereto while stirring at 80 ° C. After 30 minutes, the reaction solution was filtered through a celite layer, and the filtrate was neutralized with an aqueous solution of sodium hydrogen carbonate, extracted with dichloromethane, washed with water, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 1: 1) and recrystallized from dichloromethane-diethyl ether to give N- (4'- 2.4 g of (chlorophenyl) -1-propenylamino- (6′-amino) nicotinamide were obtained.

Properties: white powder Melting point: 171-172.5 ° C.

Using the appropriate starting materials, the compounds shown in Tables 1 to 4 below were obtained in the same manner as in Reference Example 1 or 2.

[0231]

[Table 1]

[0232]

[Table 2]

[0233]

[Table 3]

[0234]

[Table 4]

(1) ¹ H-NMR (200 MHz, CD
Cl ₃ ) δ ppm: 1.25 (3H, t, J = 7.1H)
z), 1.40-1.88 (6H, m), 2.18-
2.50 (4H, m), 2.26 (3H, s), 3.7
4 (2H, t, J = 6.1 Hz), 3.66-3.95
(2H, m), 4.12 (2H, q, J = 7.1H
z), 4.04-4.22 (1H, m), 4.37 (2
H, t, J = 6.1 Hz), 4.50-4.69 (1
H, m), 5.02-5.19 (2H, m), 5.81
−6.07 (1H, m), 6.48−6.62 (2H,
m), 6.80-7.19 (3H, m), 7.28-
7.55 (5H, m), 8.20 (1H, dd, J =
7.8 Hz, J = 1.8 Hz), 9.73 (1 H, br
s).

(2) ¹ H-NMR (200 MHz, CD
Cl ₃ ) δ ppm: 1.13 (3H, s), 1.16
(3H, s), 1.39-1.92 (6H, m), 2.
09-2.27 (2H, m), 2.26 (3H, s),
2.39 (2H, quint, J = 6.2 Hz);
65-3.94 (2H, m), 3.73 (2H, t, J
= 6.1 Hz), 3.95-4.23 (2H, m),
4.38 (2H, t, J = 6.1 Hz), 4.48−
4.73 (1H, m), 5.00-5.18 (2H,
m), 5.60-6.07 (2H, m), 6.50-
6.70 (2H, m), 6.86-7.21 (3H,
m), 7.28-7.60 (5H, m), 8.20 (1
H, dd, J = 7.8 Hz, J = 1.8 Hz), 9.7
3 (1H, brs).

(3) ¹ H-NMR (200 MHz, CD
_{Cl 3) δppm: 3.52 (3H} , s), 7.06-
7.38 (6H, m), 7.93 (1H, dd, J =
8.4 Hz, J = 2.2 Hz), 8.08 (1H, d,
J = 2.2 Hz).

(4) ¹ H-NMR (200 MHz, CD
_{Cl 3) δppm: 4.47-4.60 (2H} , m),
5.13-5.32 (2H, m), 5.85-6.11
(1H, m), 7.05-7.36 (6H, m), 7.
92 (1H, dd, J = 8.4 Hz, J = 2.2H
z), 8.08 (1H, d, J = 2.2 Hz).

(5) ¹ H-NMR (200 MHz, CD
_{Cl 3) δppm: 7.13-7.50 (3H} , m),
7.53-7.70 (2H, m), 7.75-8.02
(2H, m), 8.19 (1H, dd, J = 8.5H
z, J = 2.1 Hz), 8.30 (1H, d, J = 2.
1 Hz), (6) ¹ H-NMR (200 MHz, CDCl ₃ ) δpp
m: 1.24 (3H, t, J = 7.1 Hz), 1.43
-1.97 (6H, m), 2.26-2.40 (5H,
m), 4.03-4.18 (4H, m), 6.72-
6.87 (2H, m), 7.98-8.13 (2H,
m), 8.28-8.43 (3H, m), 8.55 (1
H, brs).

(7) ¹ H-NMR (200 MHz, CD
Cl ₃ ) δ ppm: 1.26 (3H, t, J = 7.1H)
z), 1.41-1.95 (6H, m), 2.26 (3
H, s), 2.26-2.46 (2H, m), 3.35.
(3H, s), 3.82-3.98 (2H, m), 4.
14 (2H, q, J = 7.1 Hz), 6.52-6.6
3 (2H, m), 6.79-6.89 (1H, m),
7.36-7.50 (2H, m), 7.93-8.05
(2H, m).

(8) ¹ H-NMR (200 MHz, CD
_{Cl 3) δppm: 1.43-1.96 (6H} , m),
2.25 (3H, s), 2.42 (2H, t, J = 7.
2Hz), 3.35 (3H, s), 3.78-3.96
(2H, m), 6.53-6.68 (2H, m), 6.
82-6.92 (1H, m), 7.38-7.53 (2
H, m), 7.93-8.08 (2H, m).

(9) ¹ H-NMR (200 MHz, CD
Cl ₃ ) δ ppm: 1.27 (3H, t, J = 7.1H)
z), 1.41-1.93 (6H, m), 2.25 (3
H, s), 2.36 (2H, t, J = 7.4 Hz),
3.71-3.93 (2H, m), 4.05-4.26
(3H, m), 4.53-4.68 (1H, m), 5.
06-5.23 (2H, m), 5.83-6.05 (1
H, m), 6.48-6.63 (2H, m), 6.82.
−6.93 (1H, m), 7.40−7.53 (2H,
m), 7.92-8.06 (2H, m).

(10) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 1.15 (3H, d, J = 6.5)
Hz), 1.16 (3H, d, J = 6.5 Hz), 1.
42-1.93 (6H, m), 2.19 (2H, t, J
= 7.7 Hz), 2.26 (3H, s), 3.34 (3
H, s), 3.77-3.98 (2H, m), 3.99.
-4.20 (1H, m), 5.37-5.61 (1H,
m), 6.53-6.67 (2H, m), 6.83-
6.93 (1H, m), 7.38-7.52 (2H,
m), 7.92-8.06 (2H, m).

(11) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 1.41-1.88 (6H,
m), 2.20-2.48 (6H, m), 2.26 (3
H, s), 2.31 (3H, s), 3.35 (3H,
s), 3.42-3.70 (4H, m), 3.78-
4.00 (2H, m), 6.50-6.64 (2H,
m), 6.79-6.90 (1H, m), 7.38-
7.52 (2H, m), 7.93-8.07 (2H,
m).

(12) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 1.29 (3H, s), 1.16
(3H, s), 1.36-1.90 (6H, m), 2.
18 (2H, t, J = 7.8 Hz), 2.27 (3H,
s), 2.39 (2H, quint, J = 6.1H)
z), 3.33 (3H, s), 3.73 (2H, t, J
= 6.1 Hz), 3.77-4.21 (3H, m),
4.38 (2H, t, J = 6.1 Hz), 5.58-
5.77 (1H, m), 6.52-6.67 (2H,
m), 6.85-7.17 (3H, m), 7.28-
7.51 (5H, m), 8.20 (1H, dd, J =
7.8 Hz, J = 1.8 Hz), 9.23 (1 H, br
s).

(13) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 1.40-1.90 (6H,
m), 2.05-2.84 (8H, m), 2.27 (3
H, s), 2.34 (3H, s), 3.32 (3H,
s), 3.40-4.07 (8H, m), 4.38 (2
H, t, J = 6.1 Hz), 6.51-6.68 (2
H, m), 6.79-7.17 (3H, m), 7.23.
−7.57 (5H, m), 8.20 (1H, dd, J =
7.8 Hz, J = 1.8 Hz), 9.73 (1 H, br
s).

(14) ¹ H-NMR (200 MHz, C
_{DCl 3) δppm: 1.41-1.92 (6H} ,
m), 2.26 (3H, s), 2.20-2.48 (4
H, m), 3.62-3.94 (4H, m), 3.71.
(3H, s), 4.07-4.69 (4H, m), 4.
90-5.63 (3H, m), 5.82-6.07 (1
H, m), 6.48-6.67 (2H, m), 6.85.
−7.20 (3H, m), 7.28-7.55 (5H,
m), 8.12-8.25 (1H, m), 9.75 (1
H, brs).

(15) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 0.97 (3H, t, J = 7.4)
Hz), 1.67 (2H, sex, J = 7.4 Hz),
3.91 (2H, t, J = 7.4 Hz), 7.24 (1
H, dd, J = 4.7 Hz, J = 8.1 Hz), 7.3
3-7.61 (1H, m), 7.43 (2H, d, J =
8.7 Hz), 8.06 (2H, d, J = 8.7H)
z), 8.32 (1H, d, J = 2.3 Hz), 8.4
4 (1H, dd, J = 1.5 Hz, J = 4.7 Hz).

(16) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 5.05 (2H, s), 6.20
−6.35 (1H, m), 6.32 (1H, dd, J =
1.8 Hz, J = 3.2 Hz), 6.90 (1H, d,
J = 8.8 Hz), 7.19 (2H, d, J = 8.8H)
z), 7.38 (1H, dd, J = 0.9 Hz, J =
1.8Hz), 7.47 (2H, d, J = 8.8H)
z), 8.05 (2H, d, J = 8.8 Hz).

Reference Example 20 The following compounds were obtained in the same manner as in Reference Example 3, using appropriate starting materials.

2- (4-methoxycarbonylbenzyloxy) aniline Property: Light brown acicular ¹ H-NMR (200 MHz, CDCl ₃ ) δ ppm:
3.65-4.02 (2H, m), 3.92 (3H,
s), 5.15 (2H, s), 6.60-6.87 (4
H, m), 7.43-7.54 (2H, m), 7.97
-8.13 (2H, m).

2- (5-ethoxycarbonylpentyloxy) -4-methylaniline Property: pale brown oil ¹ H-NMR (200 MHz, CDCl ₃ ) δ ppm:
1.25 (3H, t, J = 7.1 Hz), 1.42-
1.97 (6H, m), 2.25 (3H, s), 2.3
3 (2H, t, J = 7.6 Hz), 3.97 (2H,
t, J = 6.4 Hz), 3.93-4.26 (4H,
m), 6.56-6.76 (3H, m).

Example 1 A solution of 1.96 g of 2-chloro-4-pyrrolidylbenzoic acid in 10 ml of thionyl chloride was stirred at room temperature overnight. Thionyl chloride was distilled off under reduced pressure, and azeotropic distillation with dehydrated methylene chloride was repeated three times to obtain a methylene chloride 20 ml solution. This is 5,
6,7,8-tetrahydro-4H-furo [3,2-b]
The solution was added to a solution of 800 mg of azepine and 10 ml of pyridine in 30 ml of methylene chloride, followed by stirring at room temperature for 20 minutes. Saturated sodium carbonate aqueous solution, saturated sodium hydrogen sulfate aqueous solution,
The extract was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was recrystallized from chloroform / diisopropyl ether to give 4-
(2-chloro-4-pyrrolidylbenzoyl) -5,6
1.7 g of 7,8-tetrahydro-4H-furo [3,2-b] azepine was obtained.

Properties: pale yellow powder Melting point: 147.5-149.0 ° C.

Example 2 A solution of 0.94 g of 4- (3,5-dichlorobenzoyl) aminobenzoic acid in 10 ml of thionyl chloride was stirred under reflux for 1.5 hours. After distilling off thionyl chloride, the mixture was azeotroped three times with dehydrated methylene chloride to obtain a 10 ml methylene chloride solution. This was mixed with 1 g of N-methylaniline and 0.47 of triethylamine.
ml of methylene chloride in 10 ml of a solution,
Stirred for a while. The extract was washed successively with a saturated aqueous solution of sodium carbonate, a saturated aqueous solution of sodium hydrogen sulfate, water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and recrystallized with ethanol / water to give 4- (3,5-dichlorobenzoyl) amino
0.33 g of N-methyl-N-phenyl-benzamide was obtained.

Properties: colorless plate Melting point: 214.5-215.0 ° C.

Example 3 1- (4 '-(Nn-propyl-Nt-butoxycarbonyl) amino-2'-chlorobenzoyl) -5-hydroxycarbonylmethyl-2,3,4,5- 2.0 g of tetrahydro-1H-thieno [3,2b] azepine
Was dissolved in 50 ml of dichloromethane, and 1.51 g of bis (2-oxo-3-oxazolidinyl) phosphinic chloride and 2.1 ml of diisopropylethylamine were sequentially added. After stirring for 30 minutes as it was, 0.5 ml of isopropylamine was added, and the mixture was stirred at room temperature overnight. The reaction product was poured into water, extracted with dichloromethane, dried over sodium carbonate, and then subjected to silica gel column chromatography (eluent; n-hexane: ethyl acetate = 3: 1).
→ 1: 1) purification and 1- (4 ′-(Nn-propyl-Nt-butoxycarbonyl) amino-2′-chlorobenzoyl) -5-isopropylaminocarbonylmethyl-2,3, 0.7 g of 4,5-tetrahydro-1H-thieno [3.2b] azepine was obtained.

Properties: colorless oil ¹ H-NMR (200 MHz, CDCl ₃ ) δ ppm:
0.76-3.93 (32H, m), 5.30-7.4
6 (6H, m).

Example 4 4- (3,5-dichlorobenzoyl) amino-N- (3
2 ml of concentrated hydrochloric acid was added to a solution of 2.46 g of -t-butoxycarbonylaminopropyl) -N-phenyl-benzamide in 30 ml of methanol, followed by stirring at room temperature overnight. ice water,
Then, a saturated aqueous sodium carbonate solution was added to make the mixture basic.
Washed sequentially with water and saturated saline, dried over anhydrous magnesium sulfate, recrystallized from ethanol, and 4- (3,5-dichlorobenzoyl) amino-N- (3-aminopropyl) -N-phenyl-benzamide 2.87 g were obtained.

Properties: colorless needles Melting point: 191 ° -192 ° C.

The following Examples 15 to 17, 39, 40, 42, 47, and 47 were prepared in the same manner as in Example 4 using appropriate starting materials.
48, 51-53, 68, 109, 110 and 128 were obtained.

Example 5 1- (2-Chloro-4- (Nn-propyl-N-benzyloxycarbonyl) -aminobenzoyl) -2,
3,4,5-tetrahydro-1H-pyrido [2,3-
b] To a solution of 1.79 g of azepine in 20 ml of acetic acid was added 5 mg of palladium / 170 mg of carbon, and the mixture was stirred under a hydrogen atmosphere for 2 hours. Palladium was filtered off, and ethyl acetate was added to the filtrate, which was washed successively with a saturated aqueous solution of sodium carbonate, a saturated aqueous solution of sodium hydrogen sulfate, water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent; dichloromethane: methanol = 50: 1) to give 1- (2-chloro-4-n -Propylaminobenzoyl) -2,3,4,5-tetrahydro-1H-pyrido [2,3-b] azepine 1.12 g was obtained.

Property: pale yellow amorphous ¹ H-NMR (200 MHz, CDCl ₃ ) δ ppm:
0.94 (3H, t, J = 7.3 Hz), 1.56 (2
H, q, J = 7.3 Hz), 1.66-2.10 (4
H, m), 2.73-3.08 and 3.35-4.25.
(Total 7H, m), 6.24 (1H, d, J = 7.8H)
z), 6.37 (1H, s), 6.81-7.11 (2
H, m), 7.36-7.55 (1H, m), 8.06
(1H, brs).

The following Examples 15 to 17, 39, 40, 42, 47, and 47 were prepared in the same manner as in Example 5 using appropriate starting materials.
48, 51-53 and 126 were obtained.

Example 6 1- (4'-Nitro-2'-chlorobenzoyl) -5
5.53 g of methoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-thieno [3,2b] azepine and 12.2 g of stannic chloride dihydrate were mixed in ethanol and heated to reflux for 8 hours. The reaction product was concentrated, basified with a 6N aqueous sodium hydroxide solution, and extracted with dichloromethane. After drying over sodium carbonate and concentration, 1- (4'-amino-2'-chlorobenzoyl)-
6 g of 5-methoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-thieno [3,2b] azepine was obtained. Properties: orange oil ¹ H-NMR (200 MHz, CDCl ₃ ) δ ppm:
1.48-2.18 (5H, m), 2.58-2.99
(2H, m), 3.23-4.03 (3H, m), 3.
72 (3H, s), 6.34 (1H, dd, J = 8.3)
Hz, J = 2.2 Hz), 6.42 (1H, d, J =
5.2Hz), 6.57 (1H, d, J = 2.2H)
z), 6.70 (1H, d, J = 5.3 Hz), 6.8
9 (1H, d, J = 8.3 Hz).

The following Examples 39, 40, 42, 47, 48 and 51 were prepared in the same manner as in Example 6 using appropriate starting materials.
~ 53 compounds were obtained.

Example 7 1- (4 '-(Nn-propyl-Nt-butoxycarbonyl) amino-2'-chlorobenzoyl) -5-methoxycarbonylmethyl-2,3,4,5-tetrahydro 2.2 g of -1H-thieno [3,2b] azepine was dissolved in 50 ml of tetrahydrofuran, 10 ml of water and 0.25 g of lithium hydroxide monohydrate were added, and the mixture was stirred at room temperature overnight. The reaction product was acidified by adding a 5% aqueous citric acid solution, extracted with ethyl acetate, dried over calcium sulfate, and dried with 1- (4 ′-(Nn-propyl-Nt-butoxycarbonyl) amino acid. -2'-chlorobenzoyl)-
2.0 g of 5-carboxymethyl-2,3,4,5-tetrahydro-1H-thieno [3.2b] azepine was obtained.

Property: colorless oil ¹ H-NMR (200 MHz, CDCl ₃ ) δ ppm:
0.76-2.19 (20H, m), 2.60-3.0
2 (2H, m), 3.15-4.48 (4H, m),
6.40-7.53 (5H, m).

By using appropriate starting materials, the compounds of Examples 36, 38 and 120 described below were obtained in the same manner as in Example 7.

Example 8 1- (4'-amino-2'-chlorobenzoyl) -5
Dissolve 6.0 g of methoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-thieno [3,2b] azepine in 100 ml of toluene, add 17.3 g of di-t-butyl dicarbonate and heat for 4 hours Reflux. The reaction product was concentrated and then purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 4: 1 → 2: 1) to give 1- (4′-t-butoxycarbonylamino-2′-chloroform). 6.4 g of (benzoyl) -5-methoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-thieno [3,2b] azepine were obtained.

Property: colorless oil ¹ H-NMR (200 MHz, CDCl ₃ ) δ ppm:
1.36 (9H, s), 1.55-2.18 (5H,
m), 2.57-2.98 (2H, m), 3.25-
4.78 (3H, m), 3.72 (3H, s), 6.4
8 (1H, d, J = 5.3 Hz), 6.64 (1H,
d, J = 5.3 Hz), 6.88 (1H, dd, J =
8.1 Hz, J = 2.0 Hz), 7.05-7.25
(3H, m).

Using the appropriate starting materials, compounds of Examples 56, 101, 128 and 129 described below were obtained in the same manner as in Example 8.

Example 9 1- (4'-tert-butoxycarbonylamino-2'-chlorobenzoyl) -5-methoxycarbonylmethyl-
2,3,4,5-tetrahydro-1H-thieno [3,2
b] 4.6 g of azepine in 100 m of dimethyl sulfoxide
and 0.77 g of sodium hydroxide powder at room temperature
And 1.4 ml of n-propyl iodide, and the mixture was stirred at room temperature overnight. The reaction product was poured into water, extracted with ethyl acetate, dried over sodium carbonate, and purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 3: 1 → 1: 1). , 1- (4 ′-(N
2.2 g of -n-propyl-NT-butoxycarbonyl) amino-2'-chlorobenzoyl) -5-methoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-thieno [3,2b] azepine Obtained.

Property: colorless oil ¹ H-NMR (200 MHz, CDCl ₃ ) δ ppm:
0.87-2.18 (19H, m), 2.59-3.0
0 (2H, m), 3.21-4.25 (7H, m),
6.38-7.42 (6H, m).

The following Examples 11 to 15, 35 to 40, 42 to 42 were prepared in the same manner as in Example 9 using appropriate starting materials.
44, 47, 48, 50-58, 60-125 and 12
9 compounds were obtained.

Example 10 O-Toluoyl chloride 0.2 was added to a solution of 0.4 g of N- (4'-chlorophenyl) -1-propenylamino- (6'-amino) nicotinamide in 4 ml of pyridine under ice-cooling and stirring.
8 g was added, and the mixture was stirred at room temperature for 2 hours. After the reaction, a 0.1 N aqueous solution of hydrochloric acid was added to the mixture, extracted with dichloromethane, washed with water, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 1: 1) and recrystallized from dichloromethane-diethyl ether to give N- (4'- 0.3 g of (chlorophenyl) -1-propenylamino- [6 '-(2-methylbenzoyl) -amino] nicotinamide was obtained.

Properties: white powder Melting point: 130-132 ° C.

Using the appropriate starting materials, the compounds shown in the following Tables 5 to 34 were obtained in the same manner as in Examples 1 to 3 or 10.

[0279]

[Table 5]

[0280]

[Table 6]

[0281]

[Table 7]

[0282]

[Table 8]

[0283]

[Table 9]

[0284]

[Table 10]

[0285]

[Table 11]

[0286]

[Table 12]

[0287]

[Table 13]

[0288]

[Table 14]

[0289]

[Table 15]

[0290]

[Table 16]

[0291]

[Table 17]

[0292]

[Table 18]

[0293]

[Table 19]

[0294]

[Table 20]

[0295]

[Table 21]

[0296]

[Table 22]

[0297]

[Table 23]

[0298]

[Table 24]

[0299]

[Table 25]

[0300]

[Table 26]

[0301]

[Table 27]

[0302]

[Table 28]

[0303]

[Table 29]

[0304]

[Table 30]

[0305]

[Table 31]

[0306]

[Table 32]

[0307]

[Table 33]

[0308]

[Table 34]

(1) ¹ H-NMR (200 MHz, CD
_{Cl 3) δppm: 1.78-2.06 (4H} , m),
2.23-2.62 (4H, m), 2.34 (3H,
s), 3.03-3.96 (8H, m), 3.39 (3
H, s), 5.12 (2H, s), 5.98-6.13.
(1H, m), 6.25-6.35 (1H, m), 6.
72-7.23 (4H, m), 7.38-7.56 (4
H, m).

(2) ¹ H-NMR (200 MHz, CD
_{Cl 3) δppm: 1.83-2.07 (4H} , m),
3.04-3.28 (4H, m), 4.38-4.57
(2H, m), 5.08-5.28 (2H, m), 5.
84-6.08 (1H, m), 6.11-6.22 (1
H, m), 6.33 (1H, d, J = 2.3 Hz),
6.94 (1H, d, J = 8.5 Hz), 7.02-
7.28 (5H, m).

(3) ¹ H-NMR (200 MHz, CD
Cl ₃ ) δ ppm: 1.11 (3H, s), 1.14
(3H, s), 1.33-2.98 (18H, m),
2.21 (3H, s), 3.31 (3H, s), 3.5
3 (4H, t, J = 5.3 Hz), 3.70-4.13
(3H, m), 4.25 (2H, t, J = 6.2H
z), 5.85-6.03 (1H, m), 6.52-
6.67 (2H, m), 6.83-7.14 (3H,
m), 7.25-7.54 (5H, m), 8.16 (1
H, dd, J = 7.8 Hz, J = 1.8 Hz), 9.8
8 (1H, brs).

(4) ¹ H-NMR (200 MHz, CD
_{Cl 3) δppm: 1.43-2.83 (28H} ,
m), 3.32 (3H, s), 3.36-4.37 (1
2H, m), 6.50-6.66 (2H, m), 6.7
8-7.14 (4H, m), 7.28-7.56 (5
H, m), 8.18 (1H, dd, J = 7.8, 1.8)
Hz), 9.87 (1H, brs).

(5) ¹ H-NMR (200 MHz, CD
Cl ₃ ) δ ppm: 1.01 (3H, s), 1.04
(3H, s), 1.13 (3H, s), 1.16 (3
H, s), 1.39-1.88 (8H, m), 2.02
-2.30 (4H, m), 2.27 (3H, s), 3.
32 (3H, s), 3.00-4.17 (4H, m),
4.27 (4H, t, J = 6.4 Hz), 5.67 −
5.84 (1H, m), 6.53-6.18 (2H,
m), 6.85-7.15 (3H, m), 7.29-
7.58 (5H, m), 8.23 (1H, dd, J =
7.8 Hz, J = 1.8 Hz), 10.00 (1 H, b
rs).

(6) ¹ H-NMR (200 MHz, CD
Cl ₃ ) δ ppm: 1.08 (3H, t, J = 7.1H)
z), 1.42-1.92 (7H, m), 2.02-
2.45 (12H, m), 2.64 (2H, q, J =
7.1 Hz), 2.85 (2H, t, J = 6.8H)
z), 3.32 (3H, s), 3.38-3.68 (4
H, m), 3.76-4.00 (2H, m), 4.28
(2H, t, J = 6.4 Hz), 6.49-6.67
(2H, m), 6.77-6.90 (1H, m), 6.
98-7.16 (2H, m), 7.27-7.53 (5
H, m), 8.22 (1H, dd, J = 7.8 Hz, J
= 1.8 Hz), 10.02 (1H, brs).

(7) ¹ H-NMR (200 MHz, CD
Cl ₃ ) δ ppm: 0.96-1.22 (12H,
m), 1.37-1.88 (7H, m), 2.00-
2.32 (4H, m), 2.26 (3H, s), 2.7
0-2.91 (3H, m), 3.63-4.33 (6
H, m), 4.49-5.19 (2H, m), 5.71.
-6.10 (2H, m), 6.90-7.18 (3H,
m), 7.32-7.57 (5H, m), 8.17-
8.29 (1H, m), 10.02 (1H, brs).

(8) ¹ H-NMR (200 MHz, CD
_{Cl 3) δppm: 1.37-1.88 (6H} , m),
2.00-2.53 (15H, m), 3.38-3.9
9 (6H, m), 4.03-4.23 (1H, m),
4.45-4.67 (1H, m), 5.00-5.20
(2H, m), 5.80-6.07 (1H, m), 6.
50-6.67 (2H, m), 6.82-6.97 (1
H, m), 7.13-7.56 (8H, m), 7.88.
(1H, brs).

(9) ¹ H-NMR (200 MHz, CD
Cl ₃ ) δ ppm: 1.35-2.01 (8H, m),
2.06-2.69 (15H, m), 3.41-3.9
7 (6H, m), 4.02-4.23 (1H, m),
4.43-4.68 (1H, m), 5.00-5.20
(2H, m), 5.78-6.08 (1H, m), 6.
50-6.68 (2H, m), 6.81-6.96 (1
H, m), 7.11-7.52 (8H, m), 7.99
(1H, brs).

(10) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 0.93-1.08 (6H,
m), 1.38-1.97 (6H, m), 2.10-
2.30 (2H, m), 2.28 (3H, s), 2.4
0-2.67 (6H, m), 2.46 (3H, s),
3.17-3.32 (2H, m), 3.67-3.97
(2H, m), 4.05-4.23 (1H, m), 4.
48-4.68 (1H, m), 5.02-5.19 (2
H, m), 5.81-6.09 (1H, m), 6.23.
−6.40 (1H, m), 6.52-6.70 (2H,
m), 6.87-6.99 (1H, m), 7.16-
7.50 (8H, m), 7.79 (1H, brs).

(11) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 1.32-1.87 (6H,
m), 2.17 (2H, t, J = 7.7 Hz), 2.2
7 (3H, s), 2.45 (3H, s), 2.93 (2
H, t, J = 6.3 Hz), 3.48-3.93 (4
H, m), 4.05-4.23 (1H, m), 4.47.
-4.65 (1H, m), 5.02-5.18 (2H,
m), 5.80-6.05 (1H, m), 6.50-
6.68 (3H, m), 6.88-6.98 (1H,
m), 7.06-7.52 (10H, m), 7.63-
7.67 (1H, m), 7.80-8.00 (1H,
m), 8.42-8.52 (1H, m).

(12) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 1.90-2.13 (4H,
m), 3.20-3.43 (4H, m), 3.93 (3
H, s), 5.17 (2H, s), 6.32-6.58.
(2H, m), 6.84-7.08 (2H, m), 7.
43-7.56 (2H, m), 7.85-7.95 (1
H, m), 8.00-8.12 (2H, m), 8.55.
-8.68 (1H, m), 9.24 (1H, brs).

(13) ¹ H-NMR (200 MHz, C
_{DCl 3) δppm: 1.83-2.11 (4H} ,
m), 3.05-3.29 (4H, m), 3.40 (3
H, s), 3.93 (3H, s), 5.17 (2H,
s), 6.00-7.20 (7H, m), 7.38-
7.53 (2H, m), 8.00-8.13 (2H,
m).

(14) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 1.85-2.20 (4H,
m), 3.05-3.35 (4H, m), 3.40 (3
H, s), 5.18 (2H, s), 6.00-7.60.
(10H, m), 8.00-8.20 (2H, m).

(15) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 1.25 (3H, t, J = 7.1)
Hz), 1.38-1.88 (6H, m), 2.28
(3H, s), 2.34 (2H, t, J = 7.2H
z), 2.47 (3H, s), 3.70-3.95 (2
H, m), 4.02-4.22 (1H, m), 4.11
(2H, q, J = 7.1 Hz), 4.49-4.68
(1H, m), 4.98-5.18 (2H, m), 5.
82-6.08 (1H, m), 6.53-6.66 (2
H, m), 6.80-6.92 (1H, m), 7.18
-7.59 (8H, m).

(16) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 1.40-1.88 (6H,
m), 2.27 (3H, s), 2.28-2.48 (2
H, m), 2.45 (3H, s), 3.63-4.80.
(4H, m), 5.02-5.18 (2H, m), 5.
82-6.07 (1H, m), 6.52-6.67 (2
H, m), 6.84-6.95 (1H, m), 7.13
-7.52 (8H, m).

(17) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 3.45 (3H, s), 3.74
(2H, brs), 6.21-6.57 (2H, m),
6.81-7.32 (6H, m).

(18) ¹ H-NMR (250 MHz, C
DCl ₃ ) δ ppm: 1.95-2.15 (4H,
m), 3.25-3.45 (4H, m), 6.47-
6.58 (2H, m), 6.93 (1H, d, J = 2.
9Hz), 7.23-7.32 (1H, m), 7.99
(1H, d, J = 6.9 Hz), 11.08 (1H, b
rs).

(19) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 1.26 (3H, t, J = 7.1)
Hz), 1.38-1.88 (6H, m), 2.27
(3H, s), 2.21-2.29 (2H, m), 3.
29 (3H, s), 3.60-3.98 (4H, m),
4.13 (2H, q, J = 7.1 Hz), 6.31−
6.43 (2H, m), 6.51-6.63 (2H,
m), 6.79-6.92 (1H, m), 7.08-
7.21 (2H, m).

(20) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 1.26 (3H, t, J = 7.1)
Hz), 1.37-1.86 (6H, m), 1.88-
2.30 (1H, m), 2.27 (3H, s), 2.3
3 (2H, t, J = 7.1 Hz), 3.53-3.95
(4H, m), 4.14 (2H, q, J = 7.1H
z), 4.47-4.68 (1H, m), 4.98-
5.18 (2H, m), 5.81-6.06 (1H,
m), 6.32-6.44 (2H, m), 6.52-
6.68 (2H, m), 6.82-6.95 (1H,
m), 7.09-7.23 (2H, m).

(21) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 1.13 (3H, s), 1.17
(3H, s), 1.34-1.83 (6H, m), 2.
03-2.22 (2H, m), 2.28 (3H, s),
3.00-3.18 (1H, m), 3.29 (3H,
s), 3.46-4.02 (4H, m), 5.56-
5.76 (1H, m), 6.38-6.48 (2H,
m), 6.52-6.67 (2H, m), 6.85-
6.94 (1H, m), 7.07-7.22 (2H,
m).

(22) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 1.36-1.90 (6H,
m), 2.20-2.43 (2H, m), 2.28 (3
H, s), 2.72 (3H, s), 2.79-3.12.
(4H, m), 3.39-4.13 (8H, m), 6.
35-6.48 (2H, m), 6.52-6.68 (2
H, m), 6.77-6.89 (1H, m), 7.02.
-7.15 (2H, m).

(23) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 0.94 (3H, t, J = 7.3)
Hz), 1.56 (2H, q, J = 7.3 Hz), 1.
66-2.10 (4H, m), 2.73-3.08,
3.35-4.25 (7H, m in total), 6.24 (1H,
d, J = 7.8 Hz), 6.37 (1H, s), 6.8
1-7.11 (2H, m), 7.36-7.55 (1
H, m), 8.06 (1H, brs).

(24) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 0.81 (3H, t, J = 7.3)
Hz), 1.44 (2H, q, J = 7.3 Hz),
58-2.11, 3.72-4.15 (all 6H, m),
2.81-3.01 (2H, m), 3.55 (2H,
t, J = 7.3 Hz), 5.09 (2H, s), 6.7
8-6.99 (2H, m), 7.04 (1H, s),
7.10-7.51, 7.75-7.90 (8H,
m).

(25) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 0.84 (3H, t, J = 7.4)
Hz), 1.49 (2H, sept, J = 7.4H)
z), 1.65-2.12, 3.48-4.05 (8
H, m), 2.61-2.81 (2H, m), 3.40.
(3H, s), 5.12, 5.17 (2H, each s),
5.35, 5.91, 6.34, 6.46 (2H, each d, J = 3.0 Hz), 6.95-7.40 (8H,
m).

(26) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 1.44 (9H, s), 1.71
(2H, quint, J = 6.2 Hz), 3.19 (2
H, q, J = 6.2 Hz), 4.03 (2H, t, J =
6.6Hz), 5.42 (1H, brs), 6.97-
7.07 (2H, m), 7.10-7.33 (5H,
m), 7.41 (2H, d, J = 8.7 Hz), 7.5
1 (1H, t, J = 1.9 Hz), 7.70 (2H,
d, J = 1.9 Hz), 8.05 (1H, s).

(27) ¹ H-NMR (200 MHz, D
_{MSO-d 6) δppm: 7.08} (1H, t, J =
7.3 Hz), 7.34 (2H, t, J = 7.6H)
z), 7.77 (2H, d, J = 7.4 Hz), 7.8
5-8.05 (7H, m), 10.17 (1H, s),
10.66 (1H, s).

(28) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 1.22 (3H, t, J = 7.1)
Hz), 3.98 (2H, d, J = 7.1 Hz), 7.
00-7.45 (9H, m), 7.52 (1H, t, J
= 1.9 Hz), 7.72 (2H, d, J = 1.9H)
z), 8.05 (1H, brs).

(29) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 0.93 (3H, t, J = 7.4)
Hz), 1.49-1.75 (2H, m), 3.80-
3.95 (2H, m), 6.99-7.29 (7H,
m), 7.35 (2H, d, J = 8.6 Hz), 7.5
1 (1H, t, J = 1.9 Hz), 7.73 (2H,
d, J = 1.9 Hz), 8.28 (1H, brs).

(30) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 0.86 (3H, t, J = 6.8)
Hz), 1.30-1.45 (4H, m), 1.50-
1.75 (2H, m), 3.89 (2H, t, J = 7.
6Hz), 6.99-7.06 (2H, m), 7.11
−7.28 (5H, m), 7.35 (2H, d, J =
8.7 Hz), 7.73 (2H, d, J = 1.9H)
z), 8.38 (1H, brs).

(31) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 2.24 (1H, t, J = 2.4)
Hz), 4.66 (2H, d, J = 2.4 Hz), 7.
1-7.35 (7H, m), 7.40 (2H, d, J =
8.8 Hz), 7.49 (1H, t, J = 1.9H)
z), 7.72 (2H, d, J = 1.9 Hz), 8.4
3 (1H, s).

(32) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 1.65-1.80 (2H,
m), 2.04 (3H, s), 3.32 (2H, q, J
= 5.7 Hz), 4.05 (2H, t, J = 6.3H)
z), 6.88 (1H, brs), 6.99-7.07
(2H, m), 7.15-7.35 (5H, m), 7.
46 (2H, d, J = 8.8 Hz), 7.53 (1H,
t, J = 1.9 Hz), 7.69 (2H, d, J = 1.
9 Hz), 7.90 (1H, s).

(33) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 1.40-1.95 (6H,
m), 3.40-3.55 (1H, m), 3.65-
4.26 (5H, m), 4.57-4.63 (1H,
m), 7.05-7.35 (7H, m), 7.39 (2
H, d, J = 8.7 Hz), 7.51 (1H, t, J =
1.9 Hz), 7.72 (2H, d, J = 1.9H)
z), 8.10 (1H, s).

(34) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 1.19 (3H, t, J = 7.1)
Hz), 3.91 (2H, sept, J = 7.1H)
z), 4.95 (2H, dd, J = 11.8 Hz, 2
8.5Hz), 6.85 (2H, t, J = 7.8H)
z), 7.05-7.45 (11H, m), 7.51
(1H, t, J = 1.8 Hz), 7.74 (2H, d,
J = 1.7 Hz), 8.17 (1H, brs).

(35) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 0.92 (3H, t, J = 7.4)
Hz), 1.55-1.80 (2H, m), 3.80-
4.05 [including 5H, m, 3.88 (s)], 7.0
8 (2H, d, J = 8.5 Hz), 7.20 (2H,
d, J = 8.6 Hz), 7.40 (2H, d, J = 8.
7Hz), 7.49 (1H, t, J = 1.9Hz),
7.73 (2H, d, J = 1.9 Hz), 7.90 (2
H, d, J = 8.5 Hz), 8.49 (1H, s).

(36) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 2.47 (3H, s), 4.45
-4.60 (2H, m), 5.15-5.27 (2H,
m), 5.85-6.10 (1H, m), 7.05-
7.65 (13H, m).

(37) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 4.50-4.65 (2H,
m), 5.15-5.25 (2H, m), 5.85-
6.10 (1H, m), 7.16 (2H, d, J = 8.
3Hz), 7.33-7.60 (9H, m), 7.75
(1H, d, J = 6.3 Hz), 7.94 (1H, br)
s).

(38) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 2.48 (3H, s), 4.56
(2H, d, J = 5.8 Hz), 5.13-5.30
(2H, m), 5.82-6.08 (1H, m), 7.
14 (2H, d, J = 8.6 Hz), 7.20-7.6
2 (1H, m).

(39) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 4.50-4.65 (2H,
m), 5.15-5.35 (2H, m), 7.85-
6.10 (1H, m), 7.14 (2H, d, J = 8.
7 Hz), 7.21-8.15 (11H, m).

(40) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 4.49 (2H, d, J = 6.1)
Hz), 5.16 (1H, dd, J = 1.3 Hz, J =
7.9 Hz), 5.23 (1H, s), 5.85-6.
05 (1H, m), 6.80-7.10 (2H, m),
7.20-7.70 (7H, m), 7.99 (1H,
d, J = 2.1 Hz), 8.21 (1H, d, J = 8.
3 Hz), 9.25 (1H, s).

(41) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 4.48 (2H, d, J = 6.1)
Hz), 5.16 (1H, dd, J = 1.3 Hz, J =
8.1 Hz), 5.23 (1H, s), 5.85-6.
06 (1H, m), 6.90-7.00 (2H, m),
7.10-7.70 (7H, m), 7.96 (1H,
d, J = 1.6 Hz), 8.20 (1H, d, J = 8.
8 Hz), 9.12 (1H, s).

(42) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 0.94 (3H, t, J = 7.4)
Hz), 1.64 (2H, sext, J = 7.4H)
z), 3.86 (2H, t, J = 7.4 Hz), 7.0
8-7.57 (9H, m), 7.58-7.82 (1
H, m), 8.09-8.58 (1H, m), 8.29
(1H, d, J = 2.3 Hz), 8.36 (1H, d,
J = 4.7 Hz).

(43) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 0.72-1.25 (11H,
m), 1.46-4.30 (12H, m), 5.37-
7.03 (6H, m), 7.12-7.21 (1H,
m).

(44) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 0.76-3.93 (32H,
m), 5.30-7.46 (6H, m).

(45) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 0.82 (3H, d, J = 7.4)
Hz), 1.75 (2H, sext, J = 7.4H)
z), 4.15 (2H, t, J = 7.4 Hz), 7.0
6 (1H, d, J = 3.6 Hz), 7.34-7.56
(5H, m), 7.57 (1H, d, J = 3.6H
z), 7.67-7.86 (3H, m), 8.20 (1
H, brs).

(46) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 0.94 (3H, t, J = 7.4)
Hz), 1.64 (2H, sex, J = 7.4 Hz),
3.86 (2H, t, J = 7.4 Hz), 7.08−
7.57 (9H, m), 7.58-7.82 (1H,
m), 8.09-8.58 (1H, m), 8.29 (1
H, d, J = 3.3 Hz), 8.36 (1H, d, J =
4.7 Hz).

(47) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 2.43 (3H, s), 4.58
(2H, s), 6.90-7.61 (17H, m),
7.73-7.97 (1H, m), 8.78 (1H, b
rs).

(48) ¹ H-NMR (200 MHz, D
_{MSO-d 6) δppm: 4.63} (2H, s), 7.
04 (1H, t, J = 7.4 Hz), 7.13-7.7
4 (16H, m), 10.18 (1H, s), 10.6
3 (1H, s).

(49) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 2.44 (3H, s), 5.06
(2H, s), 6.84 (2H, d, J = 6.7H
z), 7.04-7.55 (13H, m), 7.13
(2H, d, J = 6.7 Hz), 7.69-7.90
(1H, m), (50) ¹ H-NMR (200 MHz, CDCl ₃ ) δp
pm: 5.07 (2H, s), 6.84 (2H, d, J
= 8.7 Hz), 7.13 (2H, d, J = 8.7H)
z), 7.20-7.57 (12H, m), 7.67
(1H, d, J = 6.7 Hz), 8.03-8.32
(1H, m).

(51) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 3.19 (3H, s), 4.25
(2H, s), 7.04 (2H, d, J = 8.8H)
z), 7.14 (2H, d, J = 8.8 Hz), 7.2
0-7.64 (13H, m), 8.62 (1H, br
s).

(52) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 2.89 (3H, s), 3.01
(3H, s), 4.60 (2H, s), 7.10 (2
H, d, J = 8.9 Hz), 7.17 (2H, d, J =
8.1 Hz), 7.23-7.45 (5H, m), 7.
45-7.70 (3H, m), 8.25-8.55 (1
H, m).

(53) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 0.94 (3H, t, J = 7.4)
Hz), 1.51-1.82 (2H, m), 2.19
(6H, s), 3.09 (1H, d, J = 14.5H)
z), 3.26-3.47 (1H, m), 3.29 (1
H, d, J = 14.5 Hz), 3.99-4.20 (1
H, m), 7.04 (1H, d, J = 8.4 Hz),
7.17 (1H, d, J = 8.4 Hz), 7.22-
7.86 (9H, m), 7.96 (1H, brs).

(54) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 4.73 (2H, s), 7.11
(2H, d, J = 8.8 Hz), 7.33 (2H, d,
J = 8.8 Hz), 7.34-7.50 (5H, m),
7.54 (2H, d, J = 8.6 Hz), 7.74 (1
H, d, J = 8.1 Hz), 7.98 (1H, br)
s).

(55) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 2.42 (3H, s), 4.54
(2H, s), 6.98-7.61 (15H, m),
7.66-8.12 (1H, m), 7.74 (1H,
s), 8.45-8.81 (1H, m).

(56) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 4.55 (2H, s), 6.86
−7.68 (15H, m), 7.74 (1H, br)
s), 8.17-8.54 (1H, m), 8.54-
8.85 (1H, m).

(57) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 1.48-2.18 (5H,
m), 2.58-2.99 (2H, m), 3.23-
4.03 (3H, m), 3.72 (3H, s), 6.3
4 (1H, dd, J = 8.3 Hz, J = 2.2 Hz),
6.42 (1H, d, J = 5.2 Hz), 6.57 (1
H, d, J = 2.2 Hz), 6.70 (1H, d, J =
5.3 Hz), 6.89 (1H, d, J = 8.3H)
z).

(58) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 1.36 (9H, s), 1.55
−2.18 (5H, m), 2.57-2.98 (2H,
m), 3.25-4.78 (3H, m), 3.72 (3
H, s), 6.48 (1H, d, J = 5.3 Hz),
6.64 (1H, d, J = 5.3 Hz), 6.88 (1
H, dd, J = 8.1 Hz, J = 2.0 Hz), 7.0
5-7.25 (3H, m).

(59) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 0.87-2.18 (19H,
m), 2.59-3.00 (2H, m), 3.21-
4.25 (7H, m), 6.38-7.42 (6H,
m).

(60) ¹ H-NMR (200 MHz, C
DCl ₃ ) δ ppm: 0.76-2.19 (20H,
m), 2.60-3.02 (2H, m), 3.15-
4.48 (4H, m), 6.40-7.53 (5H,
m).

Example 130 4- (3,5-Dichlorobenzoyl) amino-N- [3
-Tetrahydropyranyl) oxypropyl] -N-phenyl-benzamide (0.93 g) was suspended in ethanol, and pyridinium-p-toluenesulfonate (0.
046 g) and stirred at 55 ° C. overnight. The solvent was distilled off under reduced pressure, recrystallized from ethanol,
0.62 g of dichlorobenzoyl) amino-N- (3-hydroxypropyl) -N-phenyl-benzamide was obtained.

Property: colorless columnar crystals Melting point: 172-173 ° C.

Pharmacological test The gene encoding the human V ₂ receptor was introduced into HeLa cells derived from human cervical cancer, and cells expressing the human V ₂ receptor stably (V ₂ -HeLa) were used. The agonist activity was measured using the amount of cAMP produced by the test compound as an index.

D previously adjusted to pH 7.4 with 10 mM Hepes containing 1 mM MIBMX (isobutylmethylxanthine) and 0.3% BSA (bovine serum albumin).
A MEM solution (Dulbecco's modified Eagle's medium) was prepared. The V ₂ -HeLa passaged cultures were cultured in a dish of 24 wells. After 2 to 3 days of culture, the cells were washed twice with ice-cold physiological phosphate buffer (PBS), and 200 μl and 50 μl of the DMEM solution prepared above was added to the test compound (the compound obtained in Example 45). ) Was added thereto and reacted at 37 ° C. for 10 minutes. When the test compound was not added, 250 µl of the DMEM solution was used instead of 200 µl of the DMEM solution, and the reaction was performed at 37 ° C for 10 minutes. After completion of the reaction, the reaction solution was removed by suction, washed once with ice-cooled PBS, and further added with a 0.1N hydrochloric acid aqueous solution
Extract cAMP from cells in μl, and measure at −20 ° C.
And stored frozen. cAMP was measured with a cAMP kit manufactured by Yamasa Corporation. The above D to which the test compound was not added
The amount of cAMP when only the MEM solution was used was used as a reference (1
00%), the cAMP when the test compound was added
The amount was determined and the rate of increase was calculated. The results are shown in Table 35.

[0372]

[Table 35]

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/34 ACV A61K 31/34 ACV 31/35 ACS 31/35 ACS 31/40 ADS 31/40 ADS 31/425 ACB 31 / 425 ACB 31/47 AAM 31/47 AAM 31/495 ACX 31/495 ACX 31/55 ACJ 31/55 ACJ C07C 237/42 C07C 237/42 271/20 271/20 C07D 213/40 C07D 213/40 213 / 75 213/75 213/82 213/82 215/08 215/08 277/48 277/48 295/06 295/06 Z 295/18 295/18 A Z 307/52 307/52 309/12 309/12 471 / 04 121 471/04 121 487/04 150 487/04 150 491/048 491/048 495/04 105 495/04 105A 108 108 (72) Inventor Yuichi Shinohara 140 Maehama, Kokuwajima, Fuyo-cho, Naruto City, Tokushima Prefecture Address (72) Inventor Keizo Suga 5-2 Kanaoka, Kawauchi-cho, Tokushima City, Tokushima Prefecture (72) Inventor of Hidenori Ogawa Tokushima Prefecture Itano-gun, Matsushige-cho, Nakagirai character in SenishinoEtsu 25 address 18 (72) of the invention's Tokushima Prefecture Naruto City Muyachokitahama 101 address west of the temple Toyoki Mori 8

Claims (2)

[Claims] 1. A compound of the general formula [In the formula, R ¹ represents a hydrogen atom, a lower alkyl group or a lower alkenyl group. R ^2AA is a ^5- to 6-membered unsaturated heterocyclic residue having one or two nitrogen, sulfur or oxygen atoms (the heterocyclic residue has a substituent —CONR
^4AA R ^5AA (R ^4AA and R ^5AA are the same or different, a hydrogen atom, a lower alkenyl or. To a phenyl group having a halogen atom as a substituent on the phenyl ring) may have. ) Or group (P represents 1 or 2. R ^6AA is the same or different and is a hydrogen atom, a halogen atom, a lower alkyl group, a carboxy group, a lower alkoxycarbonyl group, a carboxy group or a lower alkoxycarbonyl as a substituent on a phenyl ring. A phenyl lower alkoxy group, a carboxy lower alkoxy group, a lower alkoxycarbonyl lower alkoxy group, which may have a group selected from an aminocarbonyl group which may have a lower alkyl group as a group or a substituent, -OA ₁ CONR ¹¹ R ¹² (A ₁ represents a lower alkylene group. R ¹¹ and R ¹² may be the same or different and are each a hydrogen atom,
It represents a lower alkyl group, an amino lower alkyl group or a pyridyl lower alkyl group which may have a lower alkyl group as a substituent. R ¹¹ and R ¹² may form a 5- to 7-membered saturated heterocyclic ring with or without a nitrogen atom or an oxygen atom together with the nitrogen atom to which they are bonded.
The heterocyclic ring may be substituted by a lower alkyl group as a substituent. ) Or a group -CONR ^7AA R ^8AA (R ^7AA
And R ^8AA are the same or different and are a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a phenyl lower alkyl group, a lower alkyl group as a substituent on a phenyl ring, a halogen atom, a lower alkoxy group, a phenyl lower group. Selected from the group consisting of an alkoxy group, a lower alkoxycarbonyl group, a cyano group, a halogen-substituted lower alkyl group, an amino group having a lower alkyl group as a substituent and an amino lower alkyl group having a lower alkyl group as a substituent. Phenyl group, phthalimide lower alkyl group, tetrahydropyranyloxy lower alkyl group, lower alkanoyloxy lower alkyl group, hydroxyl-substituted lower alkyl group, lower alkoxycarbonyl lower alkyl group, lower alkoxy lower group Alkyl group, Ruboxy lower alkyl group, cyano lower alkyl group, furyl lower alkyl group or group -A (C
O) _l -NR ⁹ R ¹⁰ (l represents 0 or 1. A represents a lower alkylene group. R ⁹ and R ¹⁰ may be the same or different and are a hydrogen atom, a lower alkyl group, a lower alkanoyl group,
Shows a lower alkoxycarbonyl group or a phenyl group. )
Is shown. ). R ¹ and R ^2AA are a group together with the nitrogen atom to which they are bonded. (Where: Represents a 5- to 6-membered unsaturated heterocyclic residue having 1 to 2 nitrogen, sulfur or oxygen atoms. R ³⁰ is the same or different and represents a lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a carboxy lower alkyl group and an aminocarbonyl lower alkyl group which may have a lower alkyl group as a substituent. u shows the integer of 0-3. W
Is - (CH ₂₎ s-group (s is an integer of 2-5) or -CH = (CH ₂₎ t- group (t is an integer of 0 to 3)
Is shown. - (CH ₂₎ s- groups and -CH = (CH ₂₎ t-
The carbon atom in the group may be replaced by an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group or a —NH— group, and the above R ³⁰ may be substituted on the —NH— group. )
May be formed. R ^3AA represents a halogen atom, a lower alkyl group or a group NR ³¹ R as a substituent on the phenyl ring.
³² (R ³¹ and R ³² are the same or different and each represent a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or a phenyl lower alkoxycarbonyl group; and R ³¹ and R ³²
May form a 5- or 6-membered saturated heterocycle with or without a nitrogen atom or an oxygen atom together with the nitrogen atom to which they are bonded. The heterocyclic ring may be substituted by a lower alkyl group as a substituent. A) a phenyl group, cycloalkyl group or cycloalkyl group which may have 1 to 3 groups selected from the group consisting of a lower alkyl group as a substituent and a lower alkyl group which may have a hydroxyl group as a substituent. A benzoylamino-substituted phenyl group having a group selected from a certain amino lower alkoxy group is shown. However, R ¹ represents a hydrogen atom, R ^7AA represents a lower alkyl group or phenyl which may have a lower alkyl group as a substituent on the phenyl ring, and R ^8AA represents a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group. ,
Hydroxyl-substituted lower alkyl group, lower alkoxycarbonyl lower alkyl group, carboxy lower alkyl group or group -A
(CO) _l -NR ⁹ R ¹⁰ (A is the same as above. _L is 1, R
⁹ and R ¹⁰ are the same or different and each represent a hydrogen atom or a lower alkyl group. ), And R ¹ and R
^2AA is ^grouped together with the nitrogen atom to which they are attached. (Where: , U and W are the same as above. R ³⁰ represents a lower alkyl group. )), R ^3AA is a halogen atom, a lower alkyl group or a group NR ³¹ as a substituent on the phenyl ring.
R ³² (R ³¹ and R ³² may be the same or different and each represent a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or a phenyl lower alkoxycarbonyl group.) Must not be a phenyl group. Or a salt thereof. 2. A compound of the general formula [In the formula, R ¹ represents a hydrogen atom, a lower alkyl group or a lower alkenyl group. R ² is a 5- to 6-membered unsaturated heterocyclic residue having one or ^two nitrogen atoms, sulfur atoms or oxygen atoms (the heterocyclic residue has a group —CONR ⁴ R ⁵ as a substituent;
(R ⁴ and R ⁵ may be the same or different and each represent a hydrogen atom, a lower alkenyl group, or a phenyl group which may have a halogen atom as a substituent on the phenyl ring.) ) Or group (P represents 1 or 2. R ⁶ is the same or different,
A hydrogen atom, a halogen atom, a lower alkyl group, a carboxy group, a lower alkoxycarbonyl group, a carboxy group as a substituent on a phenyl ring, a lower alkoxycarbonyl group, and an aminocarbonyl group which may have a lower alkyl group as a substituent. A phenyl lower alkoxy group which may have a selected group, a carboxy lower alkoxy group, a lower alkoxycarbonyl lower alkoxy group,-
OA ₁ CONR ¹¹ R ¹² (A ₁ represents a lower alkylene group.
R ¹¹ and R ¹² are the same or different and represent a hydrogen atom, a lower alkyl group, an amino lower alkyl group or a pyridyl lower alkyl group which may have a lower alkyl group as a substituent. R ¹¹ and R ¹² may form a 5- to 7-membered saturated heterocyclic ring with or without a nitrogen atom or an oxygen atom together with the nitrogen atom to which they are bonded. The heterocyclic ring may be substituted by a lower alkyl group as a substituent. ) Or a group —CONR ⁷ R ⁸ (R ⁷ and R ⁸ are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a phenyl lower alkyl group, An alkyl group, a halogen atom, a lower alkoxy group, a phenyl lower alkoxy group, a lower alkoxycarbonyl group, a cyano group, a halogen-substituted lower alkyl group, an amino group which may have a lower alkyl group as a substituent and a lower alkyl group as a substituent A phenyl group, a phthalimide lower alkyl group, a tetrahydropyranyloxy lower alkyl group, a lower alkanoyloxy lower alkyl group, a hydroxyl-substituted lower alkyl group which may have 1 to 3 groups selected from the group consisting of an amino lower alkyl group which may have Group, lower alkoxycarbonyl lower alkyl group, lower Lower alkoxy lower alkyl group, carboxy lower alkyl group, cyano lower alkyl group, tetrahydroisoquinolyl group which may have a lower alkyl group as a substituent on a tetrahydroisoquinolyl ring, pyridyl group, thiazolyl group, furyl lower alkyl group Or a group -A (CO) _l -NR ⁹ R ¹⁰ (l represents 0 or 1. A represents a lower alkylene group. R ⁹ and R ¹⁰ are
The same or different, and represents a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group or a phenyl group. ). ). R ¹ and R ² are
Together with the nitrogen atom to which they are attached, the group (Where: Represents a 5- to 6-membered unsaturated heterocyclic residue having 1 to 2 nitrogen, sulfur or oxygen atoms. R ³⁰ is the same or different and represents a lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a carboxy lower alkyl group, and an aminocarbonyl lower alkyl group which may have a lower alkyl group as a substituent. u shows the integer of 0-3. W
Is - (CH ₂₎ s-group (s is an integer of 2-5) or -CH = (CH ₂₎ t- group (t is an integer of 0 to 3)
Is shown. - (CH ₂₎ s- groups and -CH = (CH ₂₎ t-
The carbon atom in the group may be replaced by an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group or a —NH— group, and the above R ³⁰ may be substituted on the —NH— group. )
May be formed. R ³ represents a halogen atom, a lower alkyl group or a group NR ³¹ R ³² (R
³¹ and R ³² are the same or different and represent a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or a phenyl lower alkoxycarbonyl group. R ³¹ and R ³² may form a 5- or 6-membered saturated heterocycle with or without a nitrogen atom or an oxygen atom together with the nitrogen atom to which they are bonded. The heterocyclic ring may be substituted by a lower alkyl group as a substituent. A) a phenyl group, a cycloalkyl group, which may have 1 to 3 groups selected from the group consisting of a lower alkyl group as a substituent and a lower alkyl group, which may have a hydroxyl group as a substituent, on the phenyl ring; A benzoylamino-substituted phenyl group which may have a group selected from a certain amino lower alkoxy group is shown. A vasopressin agonist comprising as an active ingredient at least one selected from the group consisting of the amide derivative represented by the formula (1) and salts thereof.