JP2001226269A - Melanin-concentrating hormone antagonist - Google Patents

Abstract

PROBLEM TO BE SOLVED: To prepare a melanin-concentrating hormone antagonist useful as a prophylactic or therapeutic agent of obesity. SOLUTION: This melanin-concentrating hormone antagonist contains a compound represented by formula (I) [wherein, Ar is a (substituted) (condensed) aromatic ring; X1 is a (substituted) divalent liner group having 1-5 number of atoms in the main chain; X2 to X4 are each a bond or the like; and R2 is a basic substituent] or a salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a melanin-concentrating hormone antagonist useful as a medicament, more specifically, an appetite suppressant, or a prophylactic or therapeutic agent for obesity. The present invention also relates to novel piperidine derivatives useful as melanin-concentrating hormone antagonists and the like.

[0002]

2. Description of the Related Art Feeding behavior is an indispensable activity for many living things, including humans. For this reason, abnormalities in eating behavior often lead to disorder in normal life activities, leading to diseases in many cases. In recent years, obesity is becoming a social problem with changes in the eating environment. Obesity is not only a significant risk factor for lifestyle-related diseases such as diabetes, hypertension, and arteriosclerosis, but it is also widely known that weight gain overloads joints such as knees, resulting in arthritis and pain. Are known. There is also a large potential population who wants to lose weight due to the diet boom. On the other hand, a large number of eating disorders such as bulimia caused by genetic or neurotic disorders such as stress have been reported. Therefore, research and development of obesity preventive / therapeutic agents or food intake suppressants have been actively promoted since ancient times, and mazindol is commercially available as a central appetite suppressant.
On the other hand, a large number of appetite regulators represented by leptin have recently been found, and new antiobesity drugs or appetite suppressants that control the action of these appetite regulators are being developed. In particular, melanin-concentrating hormone (hereinafter MCH)
Is a hormone derived from the hypothalamus and is known to have an appetite-enhancing effect. Furthermore, it has been reported that MCH knockout mice have significantly reduced food intake and lighter weight compared to normal mice, despite their normal daily behavior [Nature, 396 670, 1998].

As the piperidine derivative, for example, the following compounds having cholinesterase or acetylcholinesterase inhibitory activity have been reported. 1) EP-A-607864 (JP-A-7-20684)
A compound of the following formula or a salt thereof according to 5).

Embedded image [Wherein, Ar is a tricyclic fused benzene ring group in which at least one heterocyclic ring is fused and may have a substituent, n represents an integer of 2 to 10, and R ¹ represents a hydrogen atom. Or a hydrocarbon group which may have a substituent, wherein n
And Y represents a 4-piperidinyl group, a 1-piperazinyl group or a 4-benzyl-1-piperidinyl group, each of which may have a substituent.] As a specific example, 8- [3 -[1- (phenylmethyl)
-4-piperidinyl] -1-oxopropyl] -1,
2,5,6-tetrahydro-4H-pyrrolo [3,2,1
-Ij] quinolin-4-one, 1- (1,2,2a,
3,4,5-hexahydrobenz [cd] indole-
6-yl) -3- [1- (phenylmethyl) -4-piperidinyl] -1-propanone and the like are described. 2) EP-A-655451 (JP-A-7-30983)
A compound of the following formula or a salt thereof according to 5).

Embedded image [In the formula, Ar represents a tetracyclic fused heterocyclic group which may have a substituent, n represents an integer of 1 to 10, and R ¹ may have a hydrogen atom or a substituent. A hydrocarbon group, which may be different in n repetitions,
Represents an amino group or a nitrogen-containing saturated heterocyclic group which may have a substituent.] As a specific example, 3- [3- [1- (phenylmethyl)-
4-piperidinyl] -1-oxopropyl] -7,11
b, 12,13-Tetrahydro-5H-isoindolo [2,1-b] [2] benzazepin-7-one, 2-
[1-oxo-3- [1- (phenylmethyl) -4-piperidinyl]]-4,5,7a, 8,9,10,11,
11a-octahydro-6H-pyrido [3,2,1-j
k] carbazol-6-one and the like. 3) EP-A-567090 (JP-A-6-20687)
A compound of the following formula or a salt thereof according to 5).

Embedded image [In the formula, the ring A is a benzene ring even if it further has a substituent, and the ring B is a non-aromatic heterocyclic ring containing two or more same or different heteroatoms and may have a substituent. Often,
R ¹ is a hydrogen atom or a hydrocarbon group which may have a substituent, may be different in repeating n, and Y may be an amino group or a substituent which may be substituted. A good nitrogen-containing saturated heterocyclic group, n represents an integer of 1 to 10] As specific examples, 3- [1- (phenylmethyl) piperidin-4-yl] -1- (2,3,4,5- And tetrahydro-1,4-benzoxazepin-7-yl) -1-propanone. 4) EP-A-487071 (JP-A-5-14014)
A compound of the following formula or a salt thereof according to 9).

Embedded image [Wherein, X represents R ¹ -N <(R ¹ represents a hydrogen atom, a hydrocarbon group which may have a substituent or an acyl group which may have a substituent), an oxygen atom or a sulfur atom; R ² represents a hydrogen atom or a hydrocarbon group which may have a substituent, ring A represents a benzene ring which may have a substituent, k represents an integer of 0 to 3, m is an integer of 1 to 8,
n represents an integer of 1 to 6] As a specific example, 3- [1- (phenylmethyl) piperidin-4-yl] -1- (2,3-dihydro-1H-indol-5-yl) -1- Propanone, 3- [1- (phenylmethyl) piperidin-4-yl] -1- (2,
3,4,5-tetrahydro-1H-1-benzazepin-8-yl) -1-propanone and the like are described. 5) A compound of the following formula described in WO 93/07140 or a salt thereof.

Embedded image Wherein ring A represents benzo, thieno, pyrido, pyrazino, pyrimido, furano, seleno, pyrrolo, thiazolo or imidazolo, and R ¹ is a substituent selected from C _1-6 alkyl, C _1-6 alkoxy and halogen. Phenyl, phenyl-C _1-6 alkyl, cinnamyl or heteroarylmethyl (which may be imidazolo, thiazolo, thieno, pyrido or isoxazolo, etc.) which may have 1 or 2 groups, respectively. , R
² and R ³ are each i) hydrogen atom, ii) C _1-6 alkoxy or iii) fluorine, benzyloxy, hydroxy, phenyl, benzyl, halogen, nitro, cyano and formulas: CO ₂ R ⁴ , CONHR ⁴ , NR ⁴ R ⁵ , NR ⁴ CO
R ⁵ or SO _p CH ₂ Ph (wherein R ⁴ and R ⁵ each represent a hydrogen atom or C _1-6 alkyl, or NR ⁴ R
R ⁴ and R ⁵ of ⁵ form a 4 to 8-membered ring together with the adjacent nitrogen atom containing at least one nitrogen atom (the other constituent atoms of the ring are carbon, oxygen or nitrogen), NR ⁴ COR of ⁵ R
⁴ and R ⁵ together with adjacent nitrogen and carbon atoms
A 8- to 8-membered lactam ring, and p represents 0, 1 or 2), or a C _1-6 alkyl optionally having 1 to 3 substituents selected from the group represented by ^Two
And R ³ is a 5- or 6-membered ring together with adjacent carbon atoms (the ring constituting atoms are selected from carbon, nitrogen and oxygen,
For example, a methylenedioxy, ethylenedioxy or lactam ring), X represents nitrogen or CH, Y represents oxygen, sulfur or NR ⁶ , R ⁶ is i) a hydrogen atom, ii) C _{1- 6-} alkyl, iii) COC _1-6 alkyl or iv) SO ₂ -phenyl which may have 1 to 5 C _1-4 alkyl, n is an integer of 1 to 4, and q is 1 Or 2 and Z represents oxygen or sulfur] As a specific example, 1- (2-methyl-1H-benzimidazol-5-yl) -3- [1- (phenylmethyl)
-4-piperidinyl] -1-propanone, 1- (6-methylbenzo [b] thi-2-yl) -3- [1- (phenylmethyl) -4-piperidinyl] -1-propanone,
1- (6-methylindol-2-yl) -3- [1-
(Phenylmethyl) -4-piperidinyl] -1-propanone and the like. 6) EP-A-562832 (JP-A-6-41070)
Or a salt thereof described below.

Embedded image [Wherein R ₁ and R ₂ each represent a hydrogen atom, a group selected from the following substituent group A, or 1 to 3 substituents (same or different) selected from the following substituent group A] An aryl group, an aralkyl group,
P represents an integer of 1 to 3; an aralkyloxycarbonyl group, an arylamino group, an arylaminoalkyl group, a heterocyclic group, a heterocyclic alkyl group or a heterocyclic aminoalkyl group; U is of the formula: -CO- or -CH (O
R ₃ ) — (wherein R ₃ represents a hydrogen atom or a hydroxyl-protecting group); V is a group represented by the formula: — (CH ＝ CH) m—
A group represented by (CH ₂ ) n- (wherein m represents an integer of 0 to 2 and n represents an integer of 0 to 7, provided that m and n are not simultaneously 0); V on the atom
A nitrogen-containing heterocyclic group having a bonding point with

Embedded image Wherein k and l are the same or different and each represents 1
And R 4 and R ₄ have the same meanings as R ₅ and R ₆ described below);
When forming a 6- or 6-membered ring, a group obtained by condensing an ethylene group in the 5- or 6-membered ring with one or two benzene rings, or a group represented by the formula: —NR ₅ R ₆ (wherein, R ₅ and R ₆ each have a hydrogen atom, a group selected from Substituent Group A below, or 1 to 3 substituents (identical or different) selected from Substituent Group A below. An aryl group, an arylcarbonyl group, an aralkyl group, a heterocyclic group or a heterocyclic alkyl group. Substituent group A: lower alkyl group, cycloalkyl group, aryl group, heterocyclic group, aralkyl group, halogen atom, amino group, lower alkylamino group, arylamino group, amino lower alkyl group, lower alkylaminoalkyl group, lower Alkynylaminoalkyl group, nitro group, cyano group,
Sulfonyl group, lower alkylsulfonyl group, halogenoalkylsulfonyl group, lower alkanoyl group, arylcarbonyl group, arylalkanoyl group, lower alkoxy group, lower alkoxycarbonyl group, halogeno lower alkyl group, N-lower alkynyl, N-cyanoamino group, N -Lower alkynyl and N-methylaminomethyl group] Specific examples include 1-methyl-3- [3- (1-benzyl-4-piperidyl) propionyl] indole,
Methyl-3- [3- [1- (3-fluorobenzyl)-
4-piperidyl] propionyl] -5-fluoroindole, 1-methyl-3- [3- [1- (2-chlorobenzyl) -4-piperidyl] propionyl] indazole and the like are described. 7) A compound of the following formula described in EP-A-0378207 or a salt thereof.

Embedded image [Wherein, B represents an optionally substituted saturated or unsaturated 5
Represents a 7-membered aza heterocyclic group, A represents a bond or a hydrocarbon residue, an alkylene group or an alkenylene group which may be substituted with an oxo group or a hydroxy group, ...
· Represents a single bond or a double bond (provided that when A represents a bond, the .... represents a single bond), have a hydrogen atom or a substituent R ₂ and R ₃ are each independently Represents a hydrocarbon residue which may be (but not simultaneously a hydrogen atom), or may form a cyclic amino group together with an adjacent nitrogen atom, and n represents 0, 1 or 2;
Represents 1 or 2.] As a specific example, 3- [1- (phenylmethyl) piperidin-4-yl] -1- [4- (pyrrolidin-1-yl)
Phenyl] -1-propanone, 1- [4- (N, N-dimethylamino) phenyl] -3- [1- (phenylmethyl) piperidin-4-yl] -1-propanone and the like are described. 8) EP-A-296560 (JP-A-64-7915)
A compound of the following formula or a salt thereof according to 1).

Embedded image [In the formula, J is (a) a substituted or unsubstituted group shown below;
(1) phenyl group, (2) pyridyl group, (3) pyrazyl group, (4) quinolyl group, (5) cyclohexyl group,
(6) quinoxalyl group or (7) furyl group, (b) monovalent or divalent group selected from the following group optionally substituted with phenyl group; (1) indanyl, (2) indanonyl, ( 3) indenyl, (4) indenonyl,
(5) indandionyl, (6) tetralonyl, (7)
Benzsuberonil, (8) indanolyl, formula (9)

Embedded image (C) a monovalent group derived from a cyclic amide compound, (d) a lower alkyl group, or (e) a compound represented by the formula R ₁
-CH = CH- (wherein, R ₁ represents a hydrogen atom or a lower alkoxycarbonyl group). B is a group represented by the formula-(CHR ₂ ) n-;
A group represented by-(CHR ₂ ) n-, a formula -NR _3- (CHR ₂ )
a group represented by n- (wherein, R ₃ represents a hydrogen atom, a lower alkyl group, an acyl group, a lower alkylsulfonyl group, an optionally substituted phenyl group or a benzyl group), a formula of -CO-NR ₄ - (CHR ₂₎ n- (wherein, R ₄ is a hydrogen atom, a lower alkyl group or a phenyl group)
A group represented by the formula -CH = CH- (CHR ₂₎ n- in the group represented the formula -O-COO- (CHR ₂₎ n- in the group represented the formula--O CO-NH- (CHR ₂ ) n- a group represented the formula -NH-CO- (CHR ₂₎ n- in the group represented the formula _{-CH 2 -CO-NH- (CHR 2} ) n- in the group represented,
Formula _{- (CH 2) 2 -CO-} NH- (CHR 2) n- in the group represented the formula _{-C (OH) H- (CHR 2} ) group (in the above equations represented by n-, n is 0 Or an integer of 1 to 10. R
₂ represents a hydrogen atom or a methyl group in such a manner that the alkylene group represented by the formula-(CHR ₂ ) n- has no substituent or one or more methyl groups. ), Formula = (CH-CH = CH) b- (where b is 1
A group represented by the formula: ＣＨCH- (C
H ₂₎ c- (wherein a group c is represented by an integer of 0 or 1-9), the formula = (CH-CH) d = ( wherein, d
The group represented by an integer of 0 or 1 to 5), the formula _{-CO-CH = CH-CH 2} - , a group of the formula -C
A group represented by O—CH ₂ —C (OH) H—CH ₂ —,
A group represented by C (CH ₃ ) H—CO—NH—CH ₂ —,
-CH = CH-CO-NH- ( CH 2) 2 - , a group represented by group of formula -NH-, a group represented by formula -O-, a group represented by the formula -S-, dialkylaminoalkyl It means a carbonyl group or a lower alkoxycarbonyl group. T means a nitrogen atom or a carbon atom. Q represents a nitrogen atom, a carbon atom or a group represented by the formula> N → O. K is a hydrogen atom, a substituted or unsubstituted phenyl group, an arylalkyl group optionally substituted with a phenyl group, a cinnamyl group optionally substituted with a phenyl group,
It means a lower alkyl group, a pyridylmethyl group, a cycloalkylalkyl group, an adamantanemethyl group, a furylmethyl group, a cycloalkyl group, a lower alkoxycarbonyl group or an acyl group. q means an integer of 1 to 3. In the formula, ... means a single bond or a double bond. As specific examples, 1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine, N- [4 ′-(1′-benzylpiperidyl) ethyl] -2-quinoxaline Carboxylic acid amide, 4- [4 ′
-(N-benzyl) piperidyl] -p-methoxybutyrophenone, 1- [4 '-(1'-benzylpiperidine) ethyl] -1,2,3,4-tetrahydro-5H-1-benzazepin-2-one And so on. Also,
As the piperidine derivative, for example, the following compounds having a heat production promoting action have been reported. 9) A compound of the following formula described in WO 98/46590 or a salt thereof.

Embedded image [In the formula, Ar represents a phenyl group which may have a substituent and may be condensed, n represents an integer of 1 to 10, and R represents a hydrogen atom or a substituent. A good hydrocarbon group, which may be different in repeating n, R may be bonded to Ar or a substituent of Ar, and Y is an amino group or a substituent which may have a substituent. And a nitrogen-containing saturated heterocyclic group which may have a group. As a specific example, 3-[[4- [4- [3-[(2-methylphenyl) methyl] -2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl] -4- Oxobutyl] -1-piperidinyl] methyl] -1-benzenecarboximidamide or 4- [1
-[[3- (4,5-dihydro-1H-2-imidazolyl) phenyl] methyl] -4-piperidinyl] -1- [3-[(2-methylphenyl) methyl] -2,3,4,5 -Tetrahydro-1H-3-
And benzazepin-7-yl] -1-butanone. However, it has not been reported that the above compounds are useful as melanin-concentrating hormone antagonists.

[0004]

Although MCH antagonists are expected to be excellent appetite suppressants or antiobesity agents, compounds having MCH antagonistic activity, particularly non-peptide compounds, have not yet been known. Under such circumstances, development of a melanin-concentrating hormone antagonist which is useful as an appetite suppressant or a prophylactic / therapeutic agent for obesity, has excellent oral absorbability and is safe has been desired.

[0005]

Means for Solving the Problems In view of such circumstances, the present inventors have conducted intensive studies on compounds having a melanin-concentrating hormone (MCH) antagonistic action. A different side chain having a unique chemical structure is substituted,

Embedded image [In the formula, Ar represents an aromatic ring which may have a substituent and may be condensed; X ¹ may have a substituent and has 1 to 5 atoms in the main chain. indicates certain divalent chain group; X ⁴ represents a non-cyclic hydrocarbon group which bond or a divalent may have a substituent, X ⁴ may be bonded with Ar, also , When Ar has a substituent, X ⁴ may be bonded to the substituent; X ² is a bond, CO or a divalent acyclic hydrocarbon optionally having a substituent X ³ represents a bond or a divalent acyclic hydrocarbon group which may have a substituent; R ² represents a basic substituent. Or a salt thereof (hereinafter, may be abbreviated as compound (I)) having excellent MCH antagonistic activity and the like, and exhibit excellent properties as a medicament. Was completed. That is, the present invention provides: 1) a melanin-concentrating hormone antagonist comprising compound (I);

Embedded image [Wherein, R ¹ represents a hydrogen atom, a hydrocarbon group which may have a substituent, an acyl group or a heterocyclic group which may have a substituent; and ring A has a substituent. A benzene ring; the B ′ ring may be further substituted with an oxo group;
Or a 9-membered nitrogen-containing heterocyclic ring]; 3) Ar is a group represented by the formula:

Embedded image [Wherein R ¹ represents a hydrogen atom, a hydrocarbon group which may have a substituent, an acyl group or a heterocyclic group which may have a substituent] ) agent according; 4) agent of the 1), wherein X ¹ is CO or O; 5) agent of the 1), wherein X ⁴ is C _1-3 alkylene; 6) X ² is CO or (CH _{2) p} (p is 1 to the a 3 represents an integer of) 1) agent according; 7) X ³ is a bond or (CH _{2) q (q} is 1 to 3
8) The agent according to the above 1), wherein the basic substituent represented by R ² is an amino group which may have a substituent, 5 to 5 which may have a substituent A 7-membered cyclic amino group, an amidino group which may have a substituent, a guanidino group which may have a substituent, or a 5- or 6-membered nitrogen-containing heterocyclic group which may have a substituent 9) An agent according to the above 1), wherein R ² is an amino group optionally substituted with 1 to 2 C _1-6 alkyl, a 5- to 7-membered cyclic amino group, an amidino group, or 4,5. The agent according to the above 1), which is -dihydro-1H-2-imidazolyl group; 10) Ar is a compound of the formula

Embedded image It is X ^1; [wherein, R ¹ represents a hydrogen atom may be an optionally substituted hydrocarbon group, a is also heterocyclic group optionally having an acyl group or a substituted group] groups represented by CO or O; X ⁴
Is C _1-3 alkylene; X ² is CO or CH ₂ ; X ³ is a bond or CH ₂ ; and R ² is dimethylamino, diethylamino, amidino, N-methylamidino, 4,5-dihydro-1H-2- Imidazolyl or 1-methyl-4,5-dihydro-
11) The agent according to the above 1), which is 1H-2-imidazolyl; 11) R ¹ is a halogen atom, an optionally halogenated C _1-6 alkyl, an optionally halogenated C
C- ₆ optionally having 1 to 3 substituents selected from alkoxy, nitro, cyano and hydroxy
The agent according to the above 10), which is a _7-16 aralkyl group; 12) the agent according to the above 1), which is a preventive / therapeutic agent for a disease caused by melanin-concentrating hormone; 13) the formula (Ia)

Embedded image [In the formula, R ¹ represents a hydrogen atom, a hydrocarbon group which may have a substituent, an acyl group or a heterocyclic group which may have a substituent; Ring A has a substituent. A benzene ring; a B ″ ring represents a 5- to 9-membered nitrogen-containing heterocyclic ring further substituted with one or two oxo groups; X ^1a represents O, NR ^3a , S, SO, SO ₂ , SO ₂ NR ^3a , SO ₂ N
HCONR ^3a , SO ₂ NHC (= NH) NR ^3a , CS,
CR ^3a R ^3b , C = CR ^3a R ^3b , C = NR ^3a or CO
NR ^3a wherein R ^3a and R ^3b are each independently
Hydrogen atom, cyano group, hydroxy group, amino group, C _1-6
It represents an alkyl group or a C _1-6 alkoxy group. X ⁴ represents a bond or a divalent acyclic hydrocarbon group which may have a substituent, X ⁴ may be bonded to ring A, and ring A is substituted. When it has a group, X ⁴ may be bonded to the substituent; X ² represents a bond, CO or a divalent acyclic hydrocarbon group which may have a substituent; X ³ represents a bond or a divalent acyclic hydrocarbon group which may have a substituent; R ² represents a basic substituent. Or a salt thereof (hereinafter sometimes abbreviated as compound (Ia)); 14) a pharmaceutical composition comprising compound (Ia); 15) a prodrug of compound (Ia) and the like. .

The "substituent" in the "aromatic ring which may have a substituent and may be condensed" represented by Ar is, for example, (i) a halogenated C
_1-6 alkyl group, (ii) halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), (iii) C _1-3 alkylenedioxy group (eg, methylenedioxy, ethylenedioxy, etc.), (iv ) Nitro group, (v) cyano group, (v
i) hydroxy group, (vii) optionally halogenated C _1-6 alkoxy group, (viii) C _3-6 cycloalkyl group (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), (ix) halogen Optionally substituted C _1-6 alkylthio group, (x) amino group, (x
i) a mono-C _1-6 alkylamino group (for example, methylamino, ethylamino, propylamino, etc.), (xii) a di-C _1-6 alkylamino group (for example, dimethylamino,
(Xiii) 5- to 7-membered cyclic amino group, (xiv) C _1-6 alkyl-carbonylamino group (eg, acetylamino, propionylamino, butyrylamino, etc.), (xv) C _1-6 alkylsulfonylamino Groups (eg, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, etc.), (xvi)
C _1-6 alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isobutoxycarbonyl, etc.), (xvii) carboxy group, (xviii) C _1-6 alkyl-carbonyl group (for example, methylcarbonyl, ethyl Carbonyl, butylcarbonyl, etc.), (xix) C _3-6 cycloalkyl-carbonyl (eg, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), (xx) carbamoyl group, (xxi)
Mono-C _1-6 alkyl-carbamoyl group (for example, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, etc.) (xxii) di-C _1-6
Alkyl-carbamoyl groups (eg, diethylcarbamoyl, dibutylcarbamoyl, etc.), (xxiii) C _1-6 alkylsulfonyl groups (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.), (xxiv) C
_3-6 cycloalkylsulfonyl (eg, cyclopentylsulfonyl, cyclohexylsulfonyl, etc.), (xx
v) C _6-14 aryl group (eg, phenyl, naphthyl, etc.), (xxvi) mono-C _6-14 aryl-C _1-6 alkyl group (eg, mono-phenyl-C _1-6 such as benzyl, phenylethyl, etc.) Alkyl group, etc.), (xxvii) di-C _6-14 aryl-C _1-6 alkyl group (for example, di-phenyl-C _1-6 alkyl group such as diphenylmethyl, diphenylethyl, etc.), (xxviii) mono- C _6-14 aryl-C
_1-6 alkyl - carbonyl group (e.g., phenyl methyl carbonyloxy, mono- phenylethyl carbonyloxy - phenyl -C _1-6 alkyl - carbonyl group), (xxix) di -C _{6 -14} aryl -C _{1 -6}
Alkyl-carbonyloxy group (eg, di-phenyl-C _1-6 alkyl-carbonyloxy group such as diphenylmethylcarbonyloxy, diphenylethylcarbonyloxy, etc.), (xxx) C _6-14 aryloxy group (eg, phenoxy, etc.) ), (Xxxi) mono-C _6-14 aryl-C _1-6 alkyl-carbonyl group (for example, mono-phenyl-C _1-6 alkyl-carbonyl group such as phenylmethylcarbonyl, phenylethylcarbonyl and the like), (x
xxii) di-C _6-14 aryl-C _1-6 alkyl-carbonyl group (for example, di-phenyl-C _1-6 alkyl-carbonyl group such as diphenylmethylcarbonyl, diphenylethylcarbonyl and the like), (xxxiii) C _{6 -14} aryl-
Carbonyl group (eg, benzoyl, etc.), (xxxiv) C
_6-14 aryloxy-carbonyl group (eg, phenoxycarbonyl, etc.), (xxxv) C _6-14 aryl-C _1-6 alkyl-carbamoyl group (eg, phenyl-C such as phenyl-methylcarbamoyl and phenyl-ethylcarbamoyl) _1-6 alkyl-carbamoyl group), (xxxvi)
A C _6-14 aryl-carbamoyl group (eg, phenylcarbamoyl, etc.), (xxxvii) a C _6-14 aryl-C _1-6 alkyl-carbonylamino group (eg, phenyl-methylcarbonylamino, phenyl-ethylcarbonylamino, etc.) phenyl -C _1-6 alkyl - carbonyl amino group), (xxxviii) C _6-14 aryl -C _1-6 alkylamino (e.g., phenyl - methylamino, phenyl - phenyl -C _1-6 alkyl, such as ethylamino an amino group), (xxxix) C _6-14 aryl -C _1-6 alkylsulfonyl group (e.g., phenyl - methyl sulfonyl, phenyl - phenyl -C _1-6 alkylsulfonyl group such as ethylsulfonyl), (xxxx) C _6-14 arylsulfonyl group (eg, phenylsulfonyl, etc.), (xxxxi) C
_6-14 aryl -C _1-6 alkylsulfinyl group (e.g., phenyl - methylsulfinyl, phenyl - phenyl -C _1-6 alkylsulfinyl group such as ethylsulfinyl), (XXXXII) C _6-14 aryl -C _{1- 6} alkylsulfonylamino group (for example, phenyl-C _1-6 alkylsulfonylamino group such as phenyl-methylsulfonylamino, phenyl-ethylsulfonylamino, etc.), (xxxxiii) C _6-14 arylsulfonylamino group (eg, phenylsulfonyl Amino) and the like.

The above-mentioned “optionally halogenated C _1-6”
Examples of the “alkyl group” include a C _1-6 alkyl group (for example, methyl, methyl) which may have 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.).
Ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), and specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2- Bromoethyl, 2,2,2-trifluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, Isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl and the like. Examples of the “optionally halogenated C _1-6 alkoxy group” include, for example,
1 to 3 halogen atoms (eg, fluorine, chlorine,
A C _1-6 alkoxy group optionally having bromine, iodine, etc. (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,
tert-butoxy) and the like. Specific examples thereof include, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,
4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like. As the aforementioned "optionally halogenated a C _1-6 alkylthio group", for example, 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine) may have a C _{1- 6} alkylthio groups (for example, methylthio, ethylthio, propylthio, isopropylthio,
Butylthio, isobutylthio, sec-butylthio, tert-
Butylthio, etc.), and specific examples thereof include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio,
Butylthio, 4,4,4-trifluorobutylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio and the like.

The "5- to 7-membered cyclic amino group" may have, for example, one to three heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to one nitrogen atom. Examples thereof include a 5- to 7-membered cyclic amino group, and specific examples include pyrrolidino, piperidino,
Examples include piperazino, morpholino, and thiomorpholino.

The above "C _6-14 aryl group", "mono-C
_6-14 aryl-C _1-6 alkyl group ”,“ di-C _6-14 aryl-C _1-6 alkyl group ”,“ mono-C _6-14 aryl-
C _1-6 alkyl-carbonyloxy group ”,“ di-C _6-14
Aryl-C _1-6 alkyl-carbonyloxy group ”,
“C _6-14 aryloxy group”, “mono-C _6-14 aryl-C _1-6 alkyl-carbonyl group”, “di-C _6-14 aryl-C _1-6 alkyl-carbonyl group”, “C _6-14 aryl - carbonyl group "," C _6-14 aryloxy - carbonyl group "," C _6-14 aryl -C _1-6 alkyl - carbamoyl group "," C _6-14 aryl - carbamoyl group ",
“C _6-14 aryl-C _1-6 alkyl-carbonylamino group”, “C _6-14 aryl-C _1-6 alkylamino”,
"C _6-14 aryl-C _1-6 alkylsulfonyl group",
“C _6-14 arylsulfonyl group”, “C _6-14 aryl-
C _1-6 alkylsulfinyl group ”,“ C _6-14 aryl-
“C _1-6 alkylsulfonylamino group” and “C _6-14 arylsulfonylamino group” further include, for example, C
_1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, Isobutoxy, sec-butoxy, tert-butoxy, etc.), halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), hydroxy, C _6-14 aryl-C _1-6 alkyloxy (eg, benzyloxy, etc.), amino Mono-C _1-6 alkylamino (eg, methylamino, ethylamino, propylamino, etc.), di-C _1-6 alkylamino (eg, dimethylamino, diethylamino, etc.), nitro, C _1-6 alkyl-carbonyl (For example,
It may have 1 to 4 substituents selected from methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), C _6-14 aryl-carbonyl (eg, benzoyl, etc.) and the like.

"Substituent" in the "aromatic ring which may have a substituent and may be condensed" represented by Ar
Are preferably (i) an amino group, (ii) a mono-C _1-6 alkylamino group (for example, methylamino, ethylamino, propylamino, etc.), (iii) a di-C _1-6 alkylamino group ( (Iv) dimethylamino, diethylamino, etc.), (iv) a 5- to 7-membered cyclic amino which may have 1 to 3 heteroatoms selected from nitrogen, oxygen, sulfur and the like in addition to one nitrogen atom Groups (eg, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, etc.), (v) C _1-6 alkyl-carbonylamino groups (eg, acetylamino, propionylamino, butyrylamino, etc.), (vi) C _1-6 alkyl sulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino, propylsulfonyl amino etc.), (vii) C _6-14 ants Le -C _1-6 alkylamino (e.g., phenyl - methylamino, phenyl - phenyl -C _1-6 alkylamino such as ethylamino), (viii) C _6-14 aryl -C _1-6 alkylsulfonylamino group (Eg, phenyl-C _1-6 alkylsulfonylamino such as phenyl-methylsulfonylamino, phenyl-ethylsulfonylamino), (ix) C
_6-14 arylsulfonylamino group (eg, phenylsulfonylamino, etc.), (x) halogen atom (eg, fluoro, chloro, etc.), (xi) optionally halogenated C _1-6 alkyl group (eg, methyl , Ethyl, isopropyl, tert-butyl, trifluoromethyl, etc.),
(Xii) an optionally halogenated C _1-6 alkoxy group (for example, methoxy, ethoxy, isopropoxy, tert.
-Butoxy, trifluoromethoxy, etc.).
Among them, a di-C _1-6 alkylamino group (eg, dimethylamino, diethylamino, etc.) has one to three heteroatoms selected from nitrogen, oxygen and sulfur in addition to one nitrogen atom. Optionally a 5- to 7-membered cyclic amino group (for example, pyrrolidino, piperidino,
Piperazino, morpholino, thiomorpholino and the like).

The "aromatic ring" in the "aromatic ring which may have a substituent and may be condensed" represented by Ar is, for example, a benzene ring, a 5- or 6-membered aromatic heterocyclic ring or the like. No. Said "5- or 6-membered aromatic heterocycle"
Examples thereof include a 5- or 6-membered aromatic heterocycle containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Specifically, pyridine, pyrazine, pyrimidine, imidazole, furan, thiophene, pyrrole, pyrazole, 1,2,3-triazole, oxazole, thiazole, isothiazole,
And isoxazole. The “aromatic ring” in Ar is preferably a benzene ring.

In the “aromatic ring optionally having substituent (s) and optionally condensed” represented by Ar, “aromatic ring”
Examples of condensed are, for example, when (1) an aromatic ring and a monocyclic heterocyclic ring which may have a substituent are condensed,
(2) When an aromatic ring and a bicyclic heterocyclic ring which may have a substituent are condensed, or two kinds of monocyclic rings which are the same or different from an aromatic ring (however, at least one ring is a monocyclic heterocyclic ring) And (3) a case where an aromatic ring and a tricyclic heterocyclic ring which may have a substituent are condensed.

Regarding the above (1), a specific example of the case where an aromatic ring (preferably a benzene ring) and a monocyclic heterocyclic ring which may have a substituent are condensed is, for example,

Embedded image [Wherein, ring A represents a benzene ring which may have a substituent, and ring B represents a heterocyclic ring which may have a substituent]. As the substituent in the “benzene ring optionally having substituent (s)” represented by ring A, “the substituent may be substituted” represented by the above Ar,
The "substituent" exemplified for the "benzene ring which may be condensed" is exemplified. The number of substituents is, for example, 1 to 3
Individual. The “heterocycle” in the “heterocycle optionally having substituent (s)” represented by ring B includes, for example, 4 to 14 containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. And a 5-membered (preferably 5- to 9-membered) aromatic or non-aromatic heterocyclic ring. Specifically, for example, pyridine, pyrazine, pyrimidine, imidazole, furan, thiophene, dihydropyridine, diazepine, oxazepine, pyrrolidine, piperidine, hexamethyleneimine, heptamethyleneimine,
Examples include tetrahydrofuran, piperazine, homopiperazine, tetrahydrooxazepine, morpholine, thiomorpholine, pyrrole, pyrazole, 1,2,3-triazole, oxazole, oxazolidine, thiazole, thiazolidine, isoxazole, imidazoline and the like. Among them, a 5- to 9-membered non-aromatic heterocyclic ring containing one hetero atom or two identical or different hetero atoms (for example, pyrrolidine, piperidine, hexamethyleneimine, heptamethyleneimine, tetrahydrofuran, piperazine, homopiperazine , Tetrahydrooxazepine, morpholine, thiomorpholine and the like). In particular, for example, a non-aromatic heterocycle containing one hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, one nitrogen atom and a nitrogen atom, and one hetero atom selected from an oxygen atom and a sulfur atom And a non-aromatic heterocycle containing

The "substituent" in the "heterocyclic ring optionally having substituent (s)" represented by ring B includes, for example, (i)
Halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), (ii) nitro group, (iii) cyano group, (iv) oxo group, (v) hydroxy group, (vi) C _1-6 alkyl group (for example, , Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, etc.) (vi
i) C _1-6 alkoxy group (for example, methoxy, ethoxy,
Propyloxy, isopropyloxy, butyloxy, etc.), (viii) C _1-6 alkylthio group (eg, methylthio, ethylthio, propylthio, etc.), (ix) amino group, (x) mono-C _1-6 alkylamino group (eg, , Methylamino, ethylamino, propylamino, etc.), (x
i) a di-C _1-6 alkylamino group (eg, dimethylamino, diethylamino, etc.); (xii) a heteroatom selected from nitrogen, oxygen, sulfur and the like in addition to carbon and one nitrogen atom, A 5- to 7-membered cyclic amino group optionally having 1 to 3 (eg, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, etc.), (xiii) a C _1-6 alkyl-carbonylamino group (eg, acetylamino , propionylamino, etc. butyrylamino), (xiv) C _1-6 alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino, etc.), (xv) C _1-6 alkoxy - carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl Carbonyl, propoxycarbonyl, etc.), (xvi)
Carboxy group, (xvii) C _1-6 alkylcarbonyl group (for example, methylcarbonyl, ethylcarbonyl, propylcarbonyl, etc.), (xviii) carbamoyl group, (x
ix) mono-C _1-6 alkylcarbamoyl group (for example, methylcarbamoyl, ethylcarbamoyl, etc.), (xx)
Di-C _1-6 alkylcarbamoyl group (for example, dimethylcarbamoyl, diethylcarbamoyl, etc.), (xxi)
And C _1-6 alkylsulfonyl groups (for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like). The number of substituents is, for example, 1 to 5, preferably 1 to 3. The substituent is preferably an oxo group, a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, te
rt-butyl, sec-butyl, etc.)
An oxo group is preferred.

When the ring B has a nitrogen atom as a ring-constituting atom, for example, the ring B has the formula> NR ¹ [wherein R ¹ may be a hydrogen atom or a substituent. A hydrocarbon group, an acyl group or a heterocyclic group which may have a substituent]. R ¹
As the "hydrocarbon group" in the "hydrocarbon group which may have a substituent" represented by, for example, a hydrocarbon group exemplified below, that is, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl Groups, aralkyl groups, groups obtained by combining these groups, and the like. The number of hydrocarbons in the hydrocarbon is preferably 1 to 16. (1) alkyl group (for example, C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, hexyl, etc.) (2) alkenyl group (for example, vinyl , allyl, isopropenyl, butenyl, isobutenyl, sec-C _2-6 an alkenyl group) (3) alkynyl groups such as butenyl (e.g., propargyl, ethynyl, butynyl, C _2-6 alkynyl groups such as 1-hexynyl) (4) a cycloalkyl group (for example, C, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.)
_3-6, such as a cycloalkyl group) (5) bridged cyclic C _8-14 saturated hydrocarbon group (e.g., bicyclo [3.2.1] oct-2-yl, bicyclo [3.3.
1] Bridged cyclic C _8-14 saturated hydrocarbon group such as non-2-yl and adamantane-1-yl) (6) aryl group (for example, phenyl, 1-naphthyl,
C _6-14 aryl groups such as 2-naphthyl, biphenyl, 2-indenyl, 2-anthryl and the like, preferably phenyl groups, etc. (7) aralkyl groups (for example, benzyl, phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl) Phenyl-C _1-10 alkyl such as phenylhexyl; naphthyl-C _1-6 alkyl such as α-naphthylmethyl; C _7-16 aralkyl group such as diphenyl-C _1-3 alkyl such as diphenylmethyl and diphenylethyl; (8) aryl-alkenyl groups (e.g. styryl, cinnamyl, 4-phenyl-2-butenyl, 4-phenyl-
A C _6-14 aryl-C _2-12 alkenyl group such as phenyl-C _2-12 alkenyl such as 3-butenyl, etc. (9) an aryl-C _2-12 alkynyl group (for example, phenylethynyl, 3 -Phenyl-2-propynyl, C _6-14 aryl-C _2-12 alkynyl group such as phenyl-C _2-12 alkynyl such as 3-phenyl-1-propynyl, etc.) (10) cycloalkyl-alkyl group ( For example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl,
Cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, cyclopropylpropyl, cyclobutylpropyl, cyclopentylpropyl, cyclohexylpropyl, cycloheptylpropyl, cyclopropylbutyl,
Cyclobutylbutyl, cyclopentylbutyl, cyclohexylbutyl, cycloheptylbutyl, cyclopropylpentyl, cyclobutylpentyl, cyclopentylpentyl, cyclohexylpentyl, cycloheptylpentyl, cyclopropylhexyl, cyclobutylhexyl,
Cycloalkyl pentylhexyl, such as C _3-7 cycloalkyl -C _1-6 alkyl group such as cyclohexyl hexyl) (11) aryl - aryl -C _1-10 alkyl group (e.g. a biphenyl methyl, C _6-14 ants, such as biphenyl ethyl - The "hydrocarbon group" in the "optionally substituted hydrocarbon group" represented by R ¹ is preferably C ₁ -C _6-14 aryl-C _1-10 alkyl group. _-6 alkyl,
C _3-6 cycloalkyl, C _7-16 aralkyl and the like.
Among them, a C _7-10 aralkyl group (for example, phenyl-C such as benzyl, phenylethyl, phenylpropyl, etc.)
_1-4 alkyl and the like).

The "substituent" in the "hydrocarbon group which may have a substituent" for R ¹ includes, for example,
(I) a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), (ii) a nitro group, (iii) a cyano group, (i.
v) oxo group, (v) hydroxy group, (vi) optionally halogenated C _1-6 alkyl group, (vii) optionally halogenated C _1-6 alkoxy group, (viii) halogenated An optionally substituted C _1-6 alkylthio group, (ix) amino group, (x) mono-C _1-6 alkylamino group (for example, methylamino, ethylamino, propylamino, etc.),
(Xi) di-C _1-6 alkylamino group (eg, dimethylamino, diethylamino, etc.), (xii) 5- to 7-membered cyclic amino group, (xiii) C _1-6 alkyl-carbonylamino group (eg, acetylamino , propionylamino, etc. butyrylamino), (xiv) C _1-6 alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino, etc.), (xv) C _1-6 alkoxy - carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl Carbonyl, propoxycarbonyl, etc.), (xvi)
Carboxy group, (xvii) C _1-6 alkyl-carbonyl group (for example, methylcarbonyl, ethylcarbonyl, propylcarbonyl, etc.), (xviii) carbamoyl group, (x
ix) mono-C _1-6 alkyl-carbamoyl group (for example,
Methylcarbamoyl, ethylcarbamoyl, etc.), (x
x) di-C _1-6 alkyl-carbamoyl group (for example, dimethylcarbamoyl, diethylcarbamoyl, etc.), (xx
i) a C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.),
(Xxii) a C _1-6 alkoxy-carbonyl-C _1-6 alkyl group (for example, methoxycarbonylmethyl, ethoxycarbonylmethyl, tert-butoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylethyl, methoxycarbonyl (dimethyl) methyl, ethoxy Carbonyl (dimethyl) methyl, tert-butoxycarbonyl (dimethyl) methyl, etc.), (xxiii) carboxy-C
_1-6 alkyl group (for example, carboxylmethyl, carboxylethyl, carboxyl (dimethyl) methyl and the like), (xxiv) a heterocyclic group optionally having a substituent,
(Xxv) a C _6-14 aryl group (eg, phenyl, naphthyl, etc.), (xxvi) a C _7-16 aralkyl group (eg, benzyl, etc.), (xxvii) a ureido group optionally having a substituent, xxviii) a thioureido group which may have a substituent, (xxix) an amidino group which may have a substituent, (xxx) a guanidino group which may have a substituent,
(Xxxi) a cyclic aminocarbonyl group optionally having a substituent, (xxxii) an aminothiocarbonyl group optionally having a substituent, (xxxiii) an aminosulfonyl group optionally having a substituent, (Xxxiv) optionally substituted C _6-14 arylsulfonylamino, (xxxv) sulfo group, (xxxvi) sulfino group, (xxxvii) sulfeno group, (xxxviii) C _1-6 alkylsulfo group (for example, , Methylsulfo, ethylsulfo, propylsulfo, etc.), (xx
xix) C _1-6 alkylsulfenyl fino group (e.g., methylsulfinyl Fino, ethylsulfamoyl Fino, etc. propylsulfanyl fino), (xxxx) C _1-6 alkylsulfenyl phenol group (e.g.,
Methylsulfeno, ethylsulfeno, propylsulfeno, etc.), (xxxxi) phosphono group, (xxxxii) di-C
_{And a 1-6} alkoxyphosphoryl group (eg, dimethoxyphosphoryl, diethoxyphosphoryl, dipropoxyphosphoryl, etc.). The number of substituents is, for example, 1 to 5, preferably 1 to 3.

Here, "C which may be halogenated"
_1-6 alkyl group "," C _{1-6 optionally} halogenated "
Alkoxy group "," C _1-6 which may be halogenated "
The “alkylthio group” and the “5- to 7-membered cyclic amino group” are exemplified as the “substituents” in the “optionally condensed and optionally condensed benzene ring” represented by Ar. Things are used.

The "heterocyclic group" in the "heterocyclic group optionally having substituent (s)" includes, for example, a heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom.
A group formed by removing one hydrogen atom from a 5- to 14-membered (monocyclic or 2- to 4-cyclic) heterocyclic ring containing from 6 to 6 (preferably from 1 to 4) is used. Here, as the monocyclic heterocycle, pyridine, pyrazine, pyrimidine, imidazole, furan, thiophene, dihydropyridine, diazepine, oxazepine, pyrrolidine, piperidine, hexamethylene imine, heptamethylene imine, tetrahydrofuran, piperazine, homopiperazine, tetrahydrooxa Zepine, morpholine, thiomorpholine, pyrrole, pyrazole, 1,2,3-triazole, oxazole, oxazolidine, thiazole, thiazolidine, isoxazole, imidazoline, triazole, thiadiazole, oxadiazole, oxathiadiazole, triazine, tetrazole and the like. Can be Examples of the bicyclic heterocycle include indole, dihydroindole, isoindole, dihydroisoindole, benzofuran, dihydrobenzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, indazole, quinoline,
Tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, tetrahydro-1H-1-benzazepine, tetrahydro-1H-2-benzazepine, tetrahydro-1H-3-benzazepine, tetrahydrobenzoxazepine, quinazoline, tetrahydroquinazoline, quinoxaline, tetrahydroquinoxaline, benzodioxane Benzodioxole, benzothiazine, imidazopyridine and the like. Examples of the tricyclic or tetracyclic heterocycle include acridine, tetrahydroacridine, pyrroloquinoline, pyrroloindole, cyclopentoindole, isoindolobenzazepine and the like. The “heterocyclic group” is preferably a group formed by removing one hydrogen atom from the above-mentioned monocyclic heterocyclic ring or bicyclic heterocyclic ring. As the “substituent” in the “heterocyclic group optionally having substituent (s)”, the “substituent” exemplified in the “heterocyclic ring optionally having substituent (s)” for the ring B can be mentioned. Can be The number of substituents is, for example, 1 to 5, preferably 1 to 3
Individual.

The "substituent" in the "ureido group which may have a substituent" and the "thioureido group which may have a substituent" may be, for example, (1) halogenated C _1-6 alkyl group, (2) C _7-16
Aralkyl groups (eg, benzyl, etc.), (3) halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), optionally halogenated C _1-6 alkyl groups, optionally halogenated C _{1 -6} alkoxy and C _6-14 aryl group (e.g., phenyl, naphthyl) 1 substituent to 3 substituents optionally having C _6-14 aryl group selected from (eg, phenyl, naphthyl, etc.), etc. Is mentioned. Here, as the “optionally halogenated C _1-6 alkyl group” and the “optionally halogenated C _1-6 alkoxy group”, each of the “optionally substituted C _1-6 alkyl group” And those exemplified as the "substituent" in the "benzene ring which may be condensed". Examples of the “ureido group which may have a substituent” include, for example, ureide, 3-methylureide, 3-ethylureide, 3-phenylureide, 3- (4-fluorophenyl) ureide, and 3- (2- Methylphenyl) ureido, 3- (4-methoxyphenyl) ureido, 3-
(2,4-difluorophenyl) ureido, 3- [3,
5-bis (trifluoromethyl) phenyl] ureido,
3-benzylureido, 3- (1-naphthyl) ureido, 3- (2-biphenylyl) ureido and the like. Examples of the "thioureido group which may have a substituent" include, for example, thioureido, 3-methylthioureido, 3-ethylthioureido, 3-phenylthioureido, 3- (4-fluorophenyl) thioureido, 3-
(4-methylphenyl) thioureido, 3- (4-methoxyphenyl) thioureide, 3- (2,4-dichlorophenyl) thioureide, 3-benzylthioureide,
3- (1-naphthyl) thioureido and the like.

The above-mentioned "amidino group optionally having substituent (s)" and "guanidino group optionally having substituent (s)"
Examples of the “substituent” in (1) include (1) a C _1-6 alkyl group (eg, methyl and ethyl), and (2) a C _6-14 aryl group _optionally having one or two nitro groups ( For example,
Phenyl, naphthyl, etc.). Examples of the “amidino group optionally having a substituent” include, for example, amidino, N ¹ -methylamidino, N ¹ -ethylamidino,
N ¹ -phenylamidino, N ¹ , N ¹ -dimethylamidino, N ¹ , N ² -dimethylamidino, N ¹ -methyl-N ^1-
Ethylamidino, N ¹ , N ¹ -diethylamidino, N ¹ −
Methyl-N ¹ -phenylamidino, N ¹ , N ¹ -di (4-
Nitrophenyl) amidino and the like. Examples of the “optionally substituted guanidino group” include guanidino, 3-methylguanidino, 3,3-dimethylguanidino, 3,3-diethylguanidino and the like.

"Cyclic aminocarbonyl group" in the above "Cyclic aminocarbonyl group optionally having substituent (s)"
As a group in which a 5- to 7-membered cyclic amino group (eg, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, etc.) and a carbonyl group are bonded, ie, pyrrolidinocarbonyl, piperidinocarbonyl, piperazinocarbonyl, Morpholinocarbonyl, thiomorpholinocarbonyl and the like. "Substituent" in "optionally substituted cyclic aminocarbonyl group"
Examples thereof include (1) a C _1-6 alkyl group (eg, methyl, ethyl, etc.), (2) a C _7-16 aralkyl group (eg, benzyl, etc.), and (3) one or two nitro groups. A C _6-14 aryl group (eg, phenyl, naphthyl, etc.), and (4) an optionally halogenated C _6-14 aryl-carbonyl group (eg, benzoyl, fluorobenzoyl, etc.). . Examples of the “optionally substituted cyclic aminocarbonyl group” include pyrrolidinocarbonyl, piperidinocarbonyl, (4-methylpiperidino) carbonyl, and (4-phenylpiperidino)
Carbonyl, (4-benzylpiperidino) carbonyl,
(4-benzoylpiperidino) carbonyl, [4- (4
-Fluorobenzoyl) piperidino] carbonyl, (4
-Methylpiperazino) carbonyl, (4-phenylpiperazino) carbonyl, [4- (4-nitrophenyl) piperazino] carbonyl, (4-benzylpiperazino) carbonyl, morpholinocarbonyl, thiomorpholinocarbonyl and the like.

The “substituent” in the “aminothiocarbonyl group optionally having substituent (s)” and “aminosulfonyl group optionally having substituent (s)” is, for example, a C _1-6 alkyl group ( For example, methyl, ethyl, etc.). Examples of the "optionally substituted aminothiocarbonyl group" include, for example, aminothiocarbonyl,
Methylaminothiocarbonyl, dimethylaminothiocarbonyl and the like can be mentioned. Examples of the “optionally substituted aminosulfonyl group” include aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl and the like.

The "substituent" in the "C _6-14 arylsulfonylamino _optionally having substituent (s)" includes, for example, (1) a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), ( 2) C _1-6 alkyl group (eg, methyl, ethyl, etc.), (3) C _1-6 alkoxy group (eg, methoxy, ethoxy, etc.), (4) C _1-6 alkyl-carbonylamino group (eg, Acetylamino) and (5) a C _6-14 aryl group _optionally having one or two nitro groups (eg, phenyl, naphthyl, etc.).
"C _6-14 arylsulfonylamino _optionally having substituent (s)" includes, for example, phenylsulfonylamino,
(4-methylphenyl) sulfonylamino, (4-chlorophenyl) sulfonylamino, (2,5-dichlorophenyl) sulfonylamino, (4-methoxyphenyl)
Sulfonylamino, (4-acetylaminophenyl) sulfonylamino, (4-nitrophenyl) phenylsulfonylamino and the like can be mentioned.

The “substituent” for R ¹ is preferably
Halogen atom, nitro group, cyano group, hydroxy group, optionally halogenated C _1-6 alkyl group, optionally halogenated C _1-6 alkoxy group, amino group, mono-C _1-6 alkyl An amino group, a di-C _1-6 alkylamino group, a 5- to 7-membered cyclic amino group, a C _1-6 alkyl-carbonylamino group, a C _1-6 alkylsulfonylamino group,
C _1-6 alkoxy-carbonyl group, carboxy group, carbamoyl group, mono-C _1-6 alkyl-carbamoyl group,
Di-C _1-6 alkyl-carbamoyl, aminothiocarbonyl, phenylsulfonylamino and the like.

The "optionally substituted hydrocarbon group" for R ¹ is preferably a halogen atom, an optionally halogenated C _1-6 alkyl, or an optionally halogenated group. And C _7-16 aralkyl group (preferably benzyl) which may have 1 to 3 substituents selected from C _1-6 alkoxy, nitro, cyano and hydroxy.

The "acyl group" represented by R ¹ is, for example, a group represented by the formula:-(C = O) -R ^4a ,-(C = O) -OR ^4a ,-
^{(C = O) -NR 4a R} 4b, -SO 2 -R 4a, -SO-R
^4a ,-(C = S) -OR ^4a or-(C = S) NR ^4a R ^4b
[Wherein, R ^4a and R ^4b each represent (i) a hydrogen atom,
i) a hydrocarbon group which may have a substituent or (iii)
A heterocyclic group which may have a substituent, or R ^4a and R ^{4a
And 4b} may be bonded to each other to form a nitrogen-containing heterocyclic group which may have a substituent together with an adjacent nitrogen atom]. Among them, preferably, a compound represented by the formula:-(C = O) -R ^4a or-(C = O) -NR
Wherein each symbol is as defined above] ^4a R ^{4 b} is an acyl group represented by. Examples of the “optionally substituted hydrocarbon group” represented by R ^4a or R ^4b include the “optionally substituted hydrocarbon group” exemplified as R ¹ above.
Is used. The “heterocyclic group optionally having substituent (s)” represented by R ^4a or R ^4b includes the “substituted hydrocarbon group” in the “hydrocarbon group optionally having substituent (s)” described above for R ^1. The “heterocyclic group which may have a substituent” exemplified as the “group” is used.

The “nitrogen-containing heterocyclic group optionally having substituent (s)” formed by R ^4a and R ^4b includes, for example, a nitrogen atom, an oxygen atom and a carbon atom and one nitrogen atom. 5- to 9-membered (preferably 5 to 7) members which may contain 1 to 3 heteroatoms selected from sulfur atoms
Membered) saturated nitrogen-containing heterocyclic group. More specifically, for example, the formula

Embedded image And the like.

As the "substituent" in the "nitrogen-containing heterocyclic group optionally having substituent (s)", the "substituted" in the "heterocyclic ring optionally having substituent (s)" for the ring B is referred to. Examples of the “group” include those exemplified above. The number of substituents is
For example, the number is 1 to 5, preferably 1 to 3.
R ^4a and R ^4b are preferably (i) a hydrogen atom, (i
i) optionally C _{1 -6} alkyl which may be halogenated, (ii
i) C _6-14 aryl optionally having 1 to 3 substituents selected from C _1-6 alkyl and C _1-6 alkoxy (eg, phenyl, etc.); (iii) C _7-16 aralkyl ( (Iv) 5- or 6-membered heterocyclic group (eg, pyridyl, thienyl, furyl, etc.).
The “acyl group” represented by R ¹ is preferably formyl, optionally halogenated C _1-6 alkyl-carbonyl (eg, acetyl, trifluoroacetyl, propionyl, etc.), and a 5- to 6-membered heterocyclic ring Carbonyl (eg,
Pyridylcarbonyl, thienylcarbonyl, furylcarbonyl, etc.), C _6-14 aryl-carbonyl (eg, benzoyl, 1-naphthoyl, 2-naphthoyl, etc.), C
_7-16 aralkyl-carbonyl (eg, phenylacetyl,
3-phenylpropionyl, etc.), C _6-14 arylsulfonyl (eg, phenylsulfonyl, naphthylsulfonyl, etc.) and the like.

R ¹ is preferably (1) a hydrogen atom,
(2) an optionally halogenated C _1-6 alkyl,
(3) Halogen atom, optionally halogenated C
_1-6 alkyl, optionally halogenated C _1-6 alkoxy optionally, nitro, cyano and 1 substituent selected from hydroxy to 3 substituents optionally having C _7-16 aralkyl group (preferably benzyl) , (4) C _1-6 alkyl-carbonyl which may be halogenated, and (5) C _6-14 aryl-carbonyl. R ¹ is more preferably a halogen atom, an optionally halogenated C
_1-6 alkyl, optionally halogenated C _1-6 alkoxy optionally, nitro, cyano and 1 substituent selected from hydroxy to 3 substituents optionally having C _7-16 aralkyl group (preferably benzyl) And so on.

The above equation

Embedded image Specific examples of the group represented by [the symbols in the formula are as defined above] include, for example, 2,3-dihydrobenzofuran;
3,4-dihydro-2H-1-benzothiopyran; 2,
1,3-dihydro-1H-indole; 1,2,3,4-tetrahydroquinoline; 2,3-dihydro-1H-isoindole; 1,2,3,4-tetrahydroisoquinoline;
3,4,5-tetrahydro-1H-1-benzazepine,
Benzazepines such as 2,3,4,5-tetrahydro-1H-2-benzazepine and 2,3,4,5-tetrahydro-1H-3-benzazepine; 1,2,3,4,5,6-hexahydro-1 -Benzazosin, 1,2,3,4,5,6-
Hexahydro-2-benzazocine, 1,2,3,4,5,
Benzazosin such as 6-hexahydro-3-benzazocine; 2,3,4,5,6,7-hexahydro-1H-1
-Benzazonin, 2,3,4,5,6,7-hexahydro-1H-2-benzazonin, 2,3,4,5,6,7-hexahydro-1H-3-benzazonin, 2,3,4,5 ,
Benzazonin such as 6,7-hexahydro-1H-4-benzazonin; benzoxazole such as 2,3-dihydrobenzoxazole; benzothiazole such as 2,3-dihydrobenzothiazole; 2,3-dihydro-1
Benzimidazoles such as H-benzimidazole; 3,
4-dihydro-1H-2,1-benzoxazine, 3,
4-dihydro-1H-2,3-benzoxazine, 3,
4-dihydro-2H-1,2-benzoxazine, 3,
4-dihydro-2H-1,4-benzoxazine, 3,
4-dihydro-2H-1,3-benzoxazine, 3,
Benzoxazines such as 4-dihydro-2H-3,1-benzoxazine; 3,4-dihydro-1H-2,1-benzothiazine, 3,4-dihydro-1H-2,3-benzothiazine, 3,4-dihydro -2H-1,2-benzothiazine, 3,4-dihydro-2H-1,4-benzothiazine, 3,4-dihydro-2H-1,3-benzothiazine, 3,4-dihydro-2H-3,1-benzothiazine Benzothiazines such as 1,2,3,4-tetrahydrocinnoline, 1,2,3,4-tetrahydrophthalazine, 1,2,3,4-tetrahydroquinazoline,
Benzodiazines such as 2,3,4-tetrahydroquinoxaline; 3,4-dihydro-1,2-benzoxathine; 3,4-dihydro-2,1-benzoxathine;
2,3-dihydro-1,4-benzoxatiin, 1,
4-dihydro-2,3-benzoxathiine, 4H-
Benzoxatiins such as 1,3-benzoxatiin, 4H-3,1-benzoxatiin; 3,4-dihydro-1,2-benzodioxin, 2,3-dihydro-1,
Benzodioxins such as 4-benzodioxin, 1,4-dihydro-2,3-benzodioxin, 4H-1,3-benzodioxin; 3,4-dihydro-1,2-benzdithiin, 2,3-dihydro-1 , 4-Benzdithiin, 1,4-dihydro-2,3-benzdithiin, 4H
Benzodithiin such as -1,3-benzdithiin; 2,
3,4,5-tetrahydro-1,2-benzoxazepine, 2,3,4,5-tetrahydro-1,3-benzoxazepine, 2,3,4,5-tetrahydro-1,4-
Benzoxazepine, 2,3,4,5-tetrahydro-
1,5-benzoxazepine, 1,3,4,5-tetrahydro-2,1-benzoxazepine, 1,3,4,5
-Tetrahydro-2,3-benzoxazepine, 1,
3,4,5-tetrahydro-2,4-benzoxazepine, 1,2,4,5-tetrahydro-3,1-benzoxazepine, 1,2,4,5-tetrahydro-3,2-
Benzoxazepine, 1,2,3,5-tetrahydro-
Benzoxazepines such as 4,1-benzoxazepine;
2,3,4,5-tetrahydro-1,2-benzothiazepine, 2,3,4,5-tetrahydro-1,4-benzothiazepine, 2,3,4,5-tetrahydro-1,5-
Benzothiazepine, 1,3,4,5-tetrahydro-
2,1-benzothiazepine, 1,3,4,5-tetrahydro-2,4-benzothiazepine, 1,2,4,5-tetrahydro-3,1-benzothiazepine, 1,2,4
5-tetrahydro-3,2-benzothiazepine, 1,
Benzothiazepines such as 2,3,5-tetrahydro-4,1-benzothiazepine; 2,3,4,5-tetrahydro-1H-1,2-benzothiazepine, 2,3,4,5-
Tetrahydro-1H-1,3-benzodiazepine, 2,
3,4,5-tetrahydro-1H-1,4-benzodiazepine, 2,3,4,5-tetrahydro-1H-1,5
-Benzodiazepine, 2,3,4,5-tetrahydro-
Benzodiazepines such as 1H-2,3-benzodiazepine and 2,3,4,5-tetrahydro-1H-2,4-benzodiazepine; 4,5-dihydro-1,3-benzodioxepin, 4,5-dihydro- 3H-1,2-benzodioxepin, 2,3-dihydro-5H-1,4-benzodioxepin, 3,4-dihydro-2H-1,5-benzodioxepin, 4,5-dihydro Benzodioxepins such as -1H-2,3-benzodioxepin and 1,5-dihydro-2,4-benzodioxepin; 4,5-dihydro-1H-2,3-benzothiepine; -Dihydro-2,4-benzodithiepine, 3,4-dihydro-2H
-1,5-benzodithiepine, 2,3-dihydro-5H
Benzodithiepine such as -1,4-benzodithiepine,
3,4,5,6-tetrahydro-2H-1,5-benzoxazosin, 3,4,5,6-tetrahydro-2H-
Benzoxazosins such as 1,6-benzoxazosin;
3,4,5,6-tetrahydro-2H-1,5-benzothiazocine, 3,4,5,6-tetrahydro-2H-
Benzothiazocine such as 1,6-benzothiazocine;
Benzodiazocine such as 2,3,4,5,6-hexahydro-1,6-benzodiazocine; benzooxathiocin such as 2,3,4,5-tetrahydro-1,6-benzooxathiocin; 2,3,4,5-tetrahydro-1,6
Benzodioxocins such as benzodioxocin; 1,
Benzotrioxepins such as 3,5-benzotrioxepin, 5H-1,3,4-benzotrioxepin;
-Dihydro-1H-5,2,1-benzoxathiazepine, 3,4-dihydro-2H-5,1,2-benzoxathiazepine, 4,5-dihydro-3,1,4-benzoxathi Azepine, 4,5-dihydro-3H-1,2,2
Benzoxathiazepines such as 5-benzoxathiazepine; benzoxadiazepines such as 2,3,4,5-tetrahydro-1,3,4-benzoxadiazepine; 2,
Benzthiadiazepines such as 3,4,5-tetrahydro-1,3,5-benzthiadiazepine; 2,3,4,5-
Benzotriazepines such as tetrahydro-1H-1,2,5-benzotriazepine; 4,5-dihydro-1,3;
2-benzoxathiepine, 4,5-dihydro-1H-
2,3-benzoxathiepine, 3,4-dihydro-2
H-1,5-benzoxathiepine, 4,5-dihydro-3H-1,2-benzoxathiepine, 4,5-dihydro-3H-2,1-benzoxathiepine, 2,3-
Dihydro-5H-1,4-benzoxathiepine, 2,
Examples include groups formed by removing one hydrogen atom from a bicyclic fused benzene ring such as 3-dihydro-5H-4,1-benzoxathiepine. Above all, 2,3,4,5-tetrahydro-1H-3-benzazepine, 2,3,4,5-
One hydrogen atom from a bicyclic fused benzene ring such as tetrahydro-1H-2-benzazepine, 2,3-dihydro-1H-indole, 2,3,4,5-tetrahydro-1,4-benzoxazepine Groups which can be removed are preferred.

"When an aromatic ring (preferably a benzene ring) is condensed with a monocyclic heterocyclic ring which may have a substituent"
As a preferable example of

Embedded image Wherein the ring B ′ is a 5- to 9-membered nitrogen-containing heterocyclic ring which may be further substituted with an oxo group, and other symbols have the same meanings as described above. .
The “5- to 9-membered nitrogen-containing heterocyclic ring” in the “5- to 9-membered nitrogen-containing heterocyclic ring which may be further substituted with an oxo group” for the ring B ′ is the “substituted for the above-mentioned ring B” Among the "heterocycles" exemplified in the "heterocycle optionally having a group", in addition to the carbon atom and one nitrogen atom, one to three heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom 5 to 9 which may be contained
Membered nitrogen-containing heterocyclic group. The "5- to 9-membered nitrogen-containing heterocyclic ring" is preferably a 5- to 9-membered non-aromatic nitrogen-containing heterocyclic ring, for example, pyrrolidine, piperidine, hexamethyleneimine, heptamethyleneimine, piperazine, homopiperazine, tetrahydrooxa. Zepin, morpholine, thiomorpholine and the like. In the “5- to 9-membered nitrogen-containing heterocyclic ring which may be further substituted with an oxo group” represented by the ring B ′, the number of oxo groups is, for example, 1
And three, preferably one or two.

"When an aromatic ring (preferably a benzene ring) and an optionally substituted monocyclic heterocycle are condensed"
As more preferred examples of

Embedded image [Wherein R ¹ has the same meaning as described above]. Above all, the expression

Embedded image [Wherein, R ¹ has the same meaning as described above], and the like are preferable.

Regarding the above (2), when an aromatic ring (preferably a benzene ring) and a bicyclic heterocyclic ring which may have a substituent are condensed, Specific examples of the case where two different types of monocycles (where at least one ring is a monocyclic heterocycle) are condensed include, for example,

Embedded image [Wherein, ring A has the same meaning as described above, one of ring C and ring D is a heterocyclic ring which may have a substituent, and the other is a 5- to 9-membered ring which may have a substituent. And the like are shown below.

The "optionally substituted heterocyclic ring" represented by ring C or D includes the "optionally substituted heterocyclic ring" exemplified as ring B above.
As the “5- to 9-membered ring” in the “5- to 9-membered ring optionally having substituent (s)” for the ring C or D, a 5- to 9-membered heterocyclic ring and a 5- to 9-membered carbocyclic ring are exemplified. Can be Here, as the “5- to 9-membered heterocycle”,
A 5- to 9-membered heterocyclic ring which may contain 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, for example, pyridine, pyrazine, pyrimidine, imidazole, furan, thiophene, dihydropyridine, diazepine, oxazepine, Examples include pyrrolidine, piperidine, hexamethyleneimine, heptamethyleneimine, tetrahydrofuran, piperazine, homopiperazine, tetrahydrooxazepine, morpholine, thiomorpholine and the like. As the "5- to 9-membered carbocycle", for example, benzene, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene, cycloheptadiene and the like can be mentioned. "5- to 9-membered ring" is preferably 5 to 7-membered ring.
And more preferably a 5- to 7-membered carbon ring. Especially, benzene, cyclohexane and the like are preferable. As the “substituent” in the “optionally substituted 5- to 9-membered ring” represented by ring C or D, the “optionally substituted heterocyclic ring” represented by ring B is referred to. "
And the "substituent" in the above.

The above equation

Embedded image [Wherein each symbol has the same meaning as described above], specific examples of the group represented by carbazole, 1,2,3,4,4
a, 9a-Hexahydrocarbazole, 9,10-dihydroacridine, 1,2,3,4-tetrahydroacridine, 10,11-dihydro-5H-dibenz [b,
f] azepine, 5,6,7,12-tetrahydrodibenz [b, g] azocine, 6,11-dihydro-5H-dibenz [b, e] azepine, 6,7-dihydro-5H-
Dibenz [c, e] azepine, 5,6,11,12-tetrahydrodibenz [b, f] azocine, dibenzofuran, 9H-xanthene, 10,11-dihydrodibenz [b, f] oxepin, 6,11- Dihydrodibenz [b, e] oxepin, 6,7-dihydro-5H-dibenz [b, g] oxocin, dibenzothiophene, 9H
-Thioxanthene, 10,11-dihydrodibenzo [b, f] thiepin, 6,11-dihydrodibenzo [b, e] thiepin, 6,7-dihydro-5H-dibenzo [b, g] thiocin, 10H-phenothiazine, 10
H-phenoxazine, 5,10-dihydrophenazine,
10,11-dibenzo [b, f] [1,4] thiazepine, 10,11-dihydrodibenz [b, f] [1,
4] oxazepine, 2,3,5,6,11,11a-hexahydro-1H-pyrrolo [2,1-b] [3] benzazepine, 10,11-dihydro-5H-dibenzo [b, e] [1, 4] diazepine, 5,11-dihydrodibenz [b, e] [1,4] oxazepine, 5,11
-Dihydrodibenzo [b, f] [1,4] thiazepine,
10,11-dihydro-5H-dibenzo [b, e]
[1,4] diazepine, 1,2,3,3a, 8,8a-
3 such as hexahydropyrrolo [2,3-b] indole
Examples include groups formed by removing one hydrogen atom from a cyclic fused benzene ring.

The above equation

Embedded image [Wherein each symbol has the same meaning as described above], specific examples of the group represented by 1H, 3H-naphtho [1,8-cd]
[1,2] oxazine, naphtho [1,8-de] -1,
3-oxazine, naphtho [1,8-de] -1,2-oxazine, 1,2,2a, 3,4,5-hexahydrobenz [cd] indole, 2,3,3a, 4,5,6 −
Hexahydro-1H-benzo [de] quinoline, 4H-
Pyrrolo [3,2,1-ij] quinoline, 1,2,5,6
-Tetrahydro-4H-pyrrolo [3,2,1-ij] quinoline, 5,6-dihydro-4H-pyrrolo [3,2,1
-Ij] quinoline, 1H, 5H-benzo [ij] quinolidine, azepino [3,2,1-hi] indole, 1,
2,4,5,6,7-hexahydroazepino [3,2
1-hi] indole, 1H-pyrido [3,2,1-j
k] [1] benzazepine, 5,6,7,8-tetrahydro-1H-pyrido [3,2,1-jk] [1] benzazepine, 1,2,5,6,7,8-hexahydro-1
H-pyrido [3,2,1-jk] [1] benzazepine, 2,3-dihydro-1H-benz [de] isoquinoline, 1,2,3,4,4a, 5,6,7-octahydronaphtho [1,8-bc] azepine, 2, 3, 5,
6,7,8-Hexahydro-1H-pyrido [3,2,1
-Jk] [1] a group formed by removing one hydrogen atom from a tricyclic fused benzene ring such as benzazepine.

The above equation

Embedded image [Wherein each symbol has the same meaning as described above], specific examples of the group represented by 1,2,3,5,6,7-hexahydrobenzo [1,2-b: 4,5 -B '] dipyrrole,
Examples include groups formed by removing one hydrogen atom from a tricyclic fused benzene ring such as 1,2,3,5,6,7-hexahydrocyclopent [f] indole.

The above equation

Embedded image [Wherein each symbol has the same meaning as described above], specific examples of the group represented by 1,2,3,6,7,8-hexahydrocyclopent [e] indole, 2,3,3 4,7,
Examples include groups formed by removing one hydrogen atom from a tricyclic fused benzene ring such as 8,9-hexahydro-1H-cyclopenta [f] quinoline.

"When an aromatic ring (preferably a benzene ring) is condensed with a bicyclic heterocyclic ring which may have a substituent, or two kinds of aromatic rings (preferably a benzene ring) which are the same as or different from an aromatic ring (preferably a benzene ring) Preferred examples of the case where a monocyclic ring is condensed with a monocyclic ring (where at least one ring is a monocyclic heterocyclic ring) include, for example, a compound represented by the formula

Embedded image [In the formula, the C ′ ring and the D ′ ring are the same or different and each represents a 5- to 9-membered nitrogen-containing heterocyclic ring which may be further substituted with an oxo group, and other symbols are as defined above. ]
And the like. The “5- to 9-membered nitrogen-containing heterocycle optionally further substituted with an oxo group” represented by the ring C ′ or the ring D ′ includes “ Or a 5- to 9-membered nitrogen-containing heterocyclic ring ". "When an aromatic ring (preferably a benzene ring) and an optionally substituted bicyclic heterocyclic ring are condensed, or two types of monocyclic rings (provided that they are the same or different from an aromatic ring (preferably a benzene ring)) And at least one ring is a monocyclic heterocycle).

Embedded image [Wherein each symbol has the same meaning as described above], and the like. Above all, the expression

Embedded image And the like are preferred.

Regarding the above (3), a specific example of the case where an aromatic ring (preferably a benzene ring) and a tricyclic heterocyclic ring which may have a substituent are condensed is, for example,

Embedded image [In the formula, ring A has the same meaning as described above, at least one of ring E, ring F and ring G is a heterocyclic ring which may have a substituent, and the other rings have a substituent. Which may represent a 5- to 9-membered ring]. E ring,
As the "heterocyclic ring optionally having substituent (s)" represented by ring F or ring G, "heterocyclic ring optionally having substituent (s)" exemplified as the aforementioned ring B can be mentioned. As the “optionally substituted 5- to 9-membered ring” represented by ring E, ring F or ring G, “optionally substituted 5-membered ring” exemplified as the aforementioned ring C or ring D Or a 9-membered ring ".

"When an aromatic ring (preferably a benzene ring) is condensed with an optionally substituted tricyclic heterocyclic ring"
As a preferred example of the formula (i)

Embedded image Wherein the ring A has the same meaning as described above, and the rings E ′, F ′ and G ′ are the same or different and are each a 5- to 9-membered nitrogen-containing heterocyclic ring which may be further substituted by an oxo group. , --
- is represented by a single bond or a double bond] group; (i
i) for example, fluoranthene, acephenanthrylene,
Aceanthrylene, triphenylene, pyrene, chrysene, naphthacene, preyadene, benzo [a] anthracene, indeno [1,2-a] indene, cyclopenta [a] phenanthrene, pyrido [1 ′, 2 ′: 1,2]
Groups formed by removing one hydrogen atom from a ring such as imidazo [4,5-b] quinoxaline, 1H-2-oxapyrene, spiro [piperidine-4.9′-xanthene], and dihydro and tetrahydro forms thereof , Hexahydro, octahydro and decahydro forms. The “5- to 9-membered nitrogen-containing heterocyclic ring which may be further substituted with an oxo group” represented by the ring E ′, the ring F ′ or the ring G ′ includes the “oxo group further exemplified by the ring B ′”. 5- to 9-membered nitrogen-containing heterocyclic ring which may be substituted ".

The above equation

Embedded image [Wherein each symbol has the same meaning as described above], specific examples of the group represented by 2H-isoindolo [2,1-e] purine, 1H-pyrazolo [4 ′, 3 ′: 3,4 Pyrid [2,
1-a] isoindole, 1H-pyrido [2 ', 3':
4,5] imidazo [2,1-a] isoindole, 2H,
6H-pyrido [1 ', 2': 3,4] imidazo [5,1-
a] Isoindole, 1H-isoindolo [2,1-a]
Benzimidazole, 1H-pyrido [3 ′, 4 ′: 4,
5] pyrrolo [2,1-a] isoindole, 2H-pyrido [4 ′, 3 ′: 4,5] pyrrolo [2,1-a] isoindole, 1H-isoindolo [2,1-a] indole, 2H
-Isoindolo [1,2-a] isoindole, 1H-cyclopenta [4,5] pyrimido [2,1-a] isoindole, 2H, 4H-pyrano [4 ′, 3 ′: 4,5] [1,
3] oxazino [2,3-a] isoindole, 2H-isoindolo [2,1-a] [3,1] benzoxazine,
7H-isoindolo [1,2-b] [1,3] benzoxazine, 2H-pyrido [2 ', 1': 3,4] pyrazino [2,1-a] isoindole, pyrido [2 ', 3' : 4,
5] pyrimido [2,1-a] isoindole, pyrido [3 ', 2': 5,6] pyrimido [2,1-a] isoindole, 1H-pyrido [1 ', 2': 3,4] Pyrimido [2,1-a] isoindole, isoindolo [2,1-
a] Quinazoline, isoindolo [2,1-a] quinoxaline, isoindolo [1,2-a] isoquinoline, isoindolo [2,1-b] isoquinoline, isoindolo [2,1
-A] quinoline, 6H-oxazino [3 ', 4': 3,
4] [1,4] diazepino [2,1-a] isoindole, azepino [2 ′, 1 ′: 3,4] pyrazino [2,1-
a] Isoindole, 2H, 6H-pyrido [2 ', 1':
3,4] [1,4] diazepino [2,1-a] isoindole, 1H-isoindolo [1,2-b] [1,3,4] benzotriazepine, 2H-isoindolo [2,1-a ]
[1,3,4] benzotriazepine, isoindolo [2,
1-d] [1,4] benzoxazepine, 1H-isoindolo [2,1-b] [2,4] benzodiazepine, 1H-
Isoindolo [2,1-c] [2,3] benzodiazepine, 2H-isoindolo [1,2-a] [2,4] benzodiazepine, 2H-isoindolo [2,1-d] [1,
4] Benzodiazepine, 5H-indolo [2,1-b]
[3] benzazepine, 2H-isoindolo [1,2-
a] [2] Benzazepine, 2H-isoindolo [1, 2
-B] [3] benzazepine, 2H-isoindolo [2,
1-b] [2] benzazepine, 2H-isoindolo [1,2-b] [1,3,4] benzooxadiazocine, isoindolo [2,1-b] [1,2,6] benzotriazocine, Groups formed by removing one hydrogen atom from a tetracyclic fused benzene ring such as 5H-4,8-methano-1H- [1,5] diazacycloundecino [1,11-a] indole; .

The above equation

Embedded image [Wherein each symbol has the same meaning as described above], specific examples of the group represented by 1H, 4H-pyrrolo [3 ′, 2 ′: 4,
5] pyrrolo [3,2,1-ij] quinoline, pyrrolo [3,2,
1-jk] carbazole, 1H-flo [2 ′, 3 ′: 4,
5] pyrrolo [3,2,1-ij] quinoline, 1H, 4H-cyclopenta [4,5] pyrrolo [1,2,3-de] quinoxaline, 1H, 4H-cyclopenta [4,5] pyrrolo [3,
2,1-ij] quinoline, pyrido [3 ', 4': 4,5] pyrrolo [1,2,3-de] benzoxazine, [1,4] oxazino [2,3,4-jk] carbazole, 1H, 3H-
[1,3] oxazino [5,4,3-jk] carbazole,
Pyrido [3 ', 4': 4,5] pyrrolo [1,2,3-de]
[1,4] benzothiazine, 4H-pyrrolo [3,2,1-d
e] phenanthridine, 4H, 5H-pyrido [3,2,1
-De] phenanthridine, 1H, 4H-3a, 6a-diazafluoroanthene, 1-oxa-4,6a-diazafluoroanthene, 4-oxa-2,10b-diazafluoroanthene, 1-thia- 4,6a-diazafluoroanthene, 1H-pyrazino [3,2,1-jk] carbazole,
1H-indolo [3,2,1-de] [1,5] naphthyridine, benzo [b] pyrano [2,3,4-hi] indolizine, 1H, 3H-benzo [b] pyrano [3,4, 5-hi]
Indolizine, 1H, 4H-pyrano [2 ', 3': 4,
5] pyrrolo [3,2,1-ij] quinoline, 1H, 3H-benzo [b] thiopyrano [3,4,5-hi] indolizine,
1H-pyrido [3,2,1-jk] carbazole, 4H-3
-Oxa-11b-azacyclohepta [jk] fluorene, 2H-azepino [1 ', 2': 1,2] pyrimidino [4,5-b] indole, 1H, 4H-cyclohepta [4,5] pyrrolo [1,2 , 3-de] quinoxaline, 5H
-Pyrido [3 ', 4': 4,5] pyrrolo [1,2,3-ef]
[1,5] benzoxazepine, 4H-pyrido [3 ',
4 ': 4,5] pyrrolo [3,2,1-jk] [4,1] benzothiazepine, 5H-pyrido [3', 4 ': 4,5] pyrrolo [1,2,3-ef] [1,5] benzothiazepine, 5H-
Pyrido [4 ', 3': 4,5] pyrrolo [1,2,3-ef]
[1,5] benzothiazepine, [1,2,4] triazepino [6,5,4-jk] carbazole, [1,2,4] triazepino [6,7,1-jk] carbazole, [1, 2,5] triazepino [3,4,5-jk] carbazole, 5H-
[1,4] oxazepino [2,3,4-jk] carbazole, 5H- [1,4] thiazepino [2,3,4-jk] carbazole, [1,4] diazepino [3,2,1-jk Carbazole, [1,4] diazepino [6,7,1-jk] carbazole, azepino [3,2,1-jk] carbazole, 1
H-cycloocta [4,5] pyrrolo [1,2,3-de] quinoxaline, 1H-cycloocta [4,5] pyrrolo [3,
[1,1-ij] quinoline, and other groups formed by removing one hydrogen atom from a tetracyclic fused benzene ring.

The above equation

Embedded image [Wherein each symbol is as defined above], specific examples of the group represented by 1H-indolo [1,2-a] benzimidazole, 1H-indolo [1,2-b] indazole, Pyrrolo [2 ', 1': 3,4] pyrazino [1,2-a]
Indole, 1H, 5H-pyrrolo [1 ', 2': 4,5]
Pyrazino [1,2-a] indole, 2H-pyrido [2 ′, 3 ′: 3,4] pyrrolo [1,2-a] indole,
1H-pyrrolo [2 ', 3': 3,4] pyrido [1,2-a]
Indole, 1H-indolo [1,2-a] indole,
6H-isoindolo [2,1-a] indole, 6H-indolo [1,2-c] [1,3] benzoxazine, 1H
-Indolo [1,2-b] [1,2] benzothiazine, pyrimido [4 ', 5': 4,5] pyrimido [1,6-a] indole, pyrazino [2 ', 3': 3,4] Pyrido [1,2-
a] indole, 6H-pyrido [1 ', 2': 3,4] pyrimido [1,6-a] indole, indolo [1,2-b] cinnoline, indolo [1,2-a] quinazoline, indolo [ 1,2-c] quinazoline, indolo [2,1-b] quinazoline, indolo [1,2-a] quinoxaline, indolo [1,2-a] [1,8] naphthyridine, indolo [1,2
-B] -2,6-naphthyridine, indolo [1,2-b]
[2,7] naphthyridine, indolo [1,2-h] -1,7
-Naphthyridine, indolo [1,2-b] isoquinoline,
Indolo [2,1-a] isoquinoline, Indolo [1,2
-A] quinoline, 2H, 6H-pyrido [2 ', 1': 3,
4] [1,4] diazepino [1,2-a] indole, 1
H-indolo [2,1-c] [1,4] benzodiazepine, 2H-indolo [1,2-d] [1,4] benzodiazepine, 2H-indolo [2,1-a] [2,3] benzodiazepine , 2H-indolo [2,1-b] [1,3] benzodiazepine, 1H-indolo [1,2-b] [2] benzazepine, 2H-indolo [1,2-a] [1] benzazepine, 2H- 4-cyclic fused benzene rings such as indolo [2,1-a] [2] benzazepine, indolo [1,2-e] [1,5] benzodiazocine, indolo [2,1-b] [3] benzazosin And a group formed by removing one hydrogen atom from the above.

The above equation

Embedded image [Wherein each symbol has the same meaning as described above], specific examples of the group represented by 1H-imidazo [1 ′, 2 ′: 1,2]
Pyrido [3,4-b] indole, 1H-imidazo [1 ′, 2 ′: 1,6] pyrido [4,3-b] indole,
1H-imidazo [1 ′, 5 ′: 1,2] pyrido [3,4-
b] indole, 1H-imidazo [1 ', 5': 1,6] pyrido [4,3-b] indole, 1H-pyrido [2 ',
1 ′: 2,3] imidazo [4,5-b] indole, imidazo [4,5-a] carbazole, imidazo [4,5-c] carbazole, pyrazolo [3,4-c] carbazole, 2H
-Pyrazino [1 ', 2': 1,5] pyrrolo [2,3-b] indole, 1H-pyrrolo [1 ', 2': 1,2] pyrimido [4,5-b] indole, 1H-indolizino [6,7
-B] indole, 1H-indolizino [8,7-b] indole, indolo [2,3-b] indole, indolo [3,2-b] indole, pyrrolo [2,3-a] carbazole, pyrrolo [2 , 3-b] carbazole, pyrrolo [2,
3-c] carbazole, pyrrolo [3,2-a] carbazole, pyrrolo [3,2-b] carbazole, pyrrolo [3,2
-C] carbazole, pyrrolo [3,4-a] carbazole, pyrrolo [3,4-b] carbazole, pyrrolo [3,4
-C] carbazole, 1H-pyrido [3 ', 4': 4,5]
Flow [3,2-b] indole, 1H-Flow [3,4-a]
Carbazole, 1H-furo [3,4-b] carbazole,
1H-furo [3,4-c] carbazole, 2H-furo [2,3-a] carbazole, 2H-furo [2,3-c] carbazole, 2H-furo [3,2-a] carbazole, 2
H-furo [3,2-c] carbazole, 1H-pyrido [3 ', 4': 4,5] thieno [2,3-b] indole,
Thieno [3 ', 2': 5,6] thiopyrano [4,3-b] indole, Thieno [3 ', 4': 5,6] thiopyrano [4,
3-b] indole, 1H- [1] benzothieno [2,3
-B] indole, 1H- [1] benzothieno [3,2-
b] indole, 1H-thieno [3,4-a] carbazole, 2H-thieno [2,3-b] carbazole, 2H-thieno [3,2-a] carbazole, 2H-thieno [3,2
−b] carbazole, cyclopenta [4,5] pyrrolo [2,3-f] quinoxaline, cyclopenta [5,6] pyrido [2,3-b] indole, pyrido [2 ′, 3 ′: 3,
4] cyclopenta [1,2-b] indole, pyrido [2 ′, 3 ′: 4.5] cyclopenta [1,2-b] indole, pyrido [3 ′, 4 ′: 3,4] cyclopenta [1, 2
-B] indole, pyrido [3 ', 4': 4,5] cyclopenta [1,2-b] indole, pyrido [4 ', 3': 4,
5] cyclopenta [1,2-b] indole, 1H-cyclopenta [5,6] pyrano [2,3-b] indole, 1
H-cyclopenta [5,6] thiopyrano [4,3-b] indole, cyclopenta [a] carbazole, cyclopenta [c] carbazole, indeno [1,2-b] indole, indeno [2,1-b] indole, [1,2,4]
Triazino [4 ', 3': 1,2] pyrido [3,4-b] indole, 1,3,5-triazino [1 ', 2': 1,1]
Pyrido [3,4-b] indole, 1H- [1,4] oxazino [4 ', 3': 1,2] pyrido [3,4-b] indole, 1H- [1,4] oxazino [4 ' , 3 ': 1,6]
Pyrido [3,4-b] indole, 4H- [1,3] oxazino [3 ′, 4 ′: 1,2] pyrido [3,4-b] indole, indolo [3,2-b] [1, 4] benzoxazine, 1,3-oxazino [6,5-b] carbazole, 2
H-pyrimido [2 ', 1': 2,3] [1,3] thiazino [5,6-b] indole, 2H- [1,3] thiazino [3 ', 2': 1,2] pyrido [ 3,4-b] indole,
4H- [1,3] thiazino [3 ', 4': 1,2] pyrido [3,4-b] indole, indolo [2,3-b] [1,
4] benzothiazine, indolo [3,2-b] [1, 4]
Benzothiazine, indolo [3,2-c] [2,1] benzothiazine, 1,4-thiazino [2,3-a] carbazole, [1,4] thiazino [2,3-b] carbazole,
[1,4] thiazino [2,3-c] carbazole, 1,4-
Thiazino [3,2-b] carbazole, 1,4-thiazino [3,2-c] carbazole, 1H-indolo [2,3-
g] pteridine, 1H-indolo [3,2-g] pteridine, pyrazino [1 ′, 2 ′: 1,2] pyrido [3,4-b]
Indole, pyrazino [1 ', 2': 1, 2] pyrido [4,
3-b] Indole, 1H-pyrido [2 ', 3': 5, 6]
Pyrazino [2,3-b] indole, 1H-pyrido [3 ', 2': 5.6] pyrazino [2,3-b] indole, 1H-pyrido [3 ', 4': 5.6] pyrazino [ A few
-B] indole, pyrido [1 ', 2': 1,2] pyrimido [4,5-b] indole, pyrido [1 ', 2': 1,2]
Pyrimido [5,4-b] indole, pyrido [2 ', 1':
2,3] pyrimido [4,5-b] indole, pyrimido [1 ′, 2 ′: 1,2] pyrido [3,4-b] indole,
Pyrimido [1 ', 2': 1,6] pyrido [3,4-b] indole, pyrimido [5 ', 4': 5,6] pyrano [2,3-
b] indole, pyridazino [4 ', 5': 5, 6] thiopyrano [4, 5-b] indole, 1H-indolo [3,2
-C] cinnoline, 1H-indolo [2,3-b] quinoxaline, 1H-pyrazino [2,3-a] carbazole, 1
H-pyrazino [2,3-b] carbazole, 1H-pyrazino [2,3-c] carbazole, 1H-pyridazino [3,
4-c] carbazole, 1H-pyridazino [4,5-b]
Carbazole, 1H-pyrimido [4,5-a] carbazole, 1H-pyrimido [4,5-c] carbazole, 1H-
Pyrimido [5,4-a] carbazole, 1H-pyrimido [5,4-b] carbazole, 1H-pyrimido [5,4-
c] carbazole, 7H-1,4-dioxino [2 ′,
3 ': 5,6] [1,2] dioxino [3,4-b] indole, 6H- [1,4] benzodioxino [2,3-b]
Indole, 6H- [1,4] benzodithiino [2,3-
b] indole, 1H-indolo [2,3-b] -1,5-
Naphthyridine, 1H-indolo [2,3-b] [1,6]
Naphthyridine, 1H-indolo [2,3-b] [1,8]
Naphthyridine, 1H-indolo [2,3-c] -1,5-
Naphthyridine, 1H-indolo [2,3-c] [1,6]
Naphthyridine, 1H-indolo [2,3-c] [1,7]
Naphthyridine, 1H-indolo [2,3-c] [1,8]
Naphthyridine, 1H-indolo [3,2-b] -1,5-
Naphthyridine, 1H-indolo [3,2-b] [1,7]
Naphthyridine, 1H-indolo [3,2-b] [1,8]
Naphthyridine, 1H-indolo [3,2-c] [1,8]
Naphthyridine, indolo [2,3-a] quinolidine, indolo [2,3-b] quinolizine, indolo [3,2-a] quinolizine, indolo [3,2-b] quinolizine, pyrano [4 ′, 3 ′]: 5,6] pyrido [3,4-b] indole,
Pyrido [4 ', 3': 4,5] pyrano [3,2-b] indole, pyrido [4 ', 3': 5,6] pyrano [2,3-b]
Indole, pyrido [4 ', 3': 5, 6] pyrano [3, 4
-B] indole, 1H-indolo [2,3-c] isoquinoline, 1H-indolo [3,2-c] isoquinoline, 1
H-indolo [2,3-c] quinoline, 1H-indolo [3,2-c] quinoline, 1H-pyrido [2,3-a] carbazole, 1H-pyrido [2,3-b] carbazole, 1
H-pyrido [2,3-c] carbazole, 1H-pyrido [3,2-a] carbazole, 1H-pyrido [3,2-b]
Carbazole, 1H-pyrido [3,2-c] carbazole, 1H-pyrido [3,4-a] carbazole, 1H-pyrido [3,4-b] carbazole, 1H-pyrido [3,4
-C] carbazole, 1H-pyrido [4,3-a] carbazole, 1H-pyrido [4,3-b] carbazole, 1H
-Pyrido [4,3-c] carbazole, 1H-kindrin, 1H-quinindrin, 1H-pyrano [3 ', 4':
5,6] pyrano [4,3-b] indole, [1] benzopyrano [2,3-b] indole, [1] benzopyrano [3,2-b] indole, [1] benzopyrano [3,4
-B] indole, [1] benzopyrano [4,3-b] indole, [2] benzopyrano [4,3-b] indole, pyrano [2,3-a] carbazole, pyrano [2,3
-B] carbazole, pyrano [2,3-c] carbazole, pyrano [3,2-a] carbazole, pyrano [3,2
-C] carbazole, pyrano [3,4-a] carbazole, 1H-phosphinolino [4,3-b] indole,
[1] benzothiopyrano [2,3-b] indole,
[1] benzothiopyrano [3,2-b] indole,
[1] benzothiopyrano [3,4-b] indole,
[1] benzothiopyrano [4,3-b] indole,
[2] Benzothiopyrano [4,3-b] indole, 1H
-Benzo [a] carbazole, 1H-benzo [b] carbazole, 1H-benzo [c] carbazole, [1,6,
2] oxathiazepino [2 ', 3': 1, 2] pyrido [3,
4-b] indole, 1H-azepino [1 ′, 2 ′: 1,
2] pyrido [3,4-b] indole, 1H-pyrido [1 ', 2': 1,2] azepino [4,5-b] indole, 2H-pyrido [1 ', 2': 1,2] Azepino [3,4
-B] indole, 1H-pyrido [3 ', 2': 5,6] oxepino [3,2-b] indole, 1H-pyrido [4 ', 3': 5,6] oxepino [3,2-b ] Indole, 2H-pyrido [2 ', 3': 5, 6] oxepino [2,
3-b] Indole, 2H-pyrido [2 ', 3': 5, 6]
Oxepino [3,2-b] indole, 2H-pyrido [3 ', 4': 5.6] oxepino [3,2-b] indole, pyrido [2 ', 3': 4.5] cyclohepta [1, 2-
b] indole, pyrido [3 ', 2': 3, 4] cyclohepta [1, 2-b] indole, pyrido [3 ', 4': 4,
5] cyclohepta [1,2-b] indole, pyrido [3 ′, 4 ′: 5.6] cyclohepta [1,2-b] indole, 2H-pyrano [3 ′, 2 ′: 2,3] azepino [ Four,
5-b] indole, 1H-indolo [3,2-b] [1,
5] benzoxazepine, 1H-indolo [3,2-d]
[1,2] benzoxazepine, 1H-indolo [2,3
−c] [1,5] benzothiazepine, [1,4] diazepino [2,3-a] carbazole, indolo [2,3-b]
[1,5] benzodiazepine, indolo [2,3-d]
[1,3] benzodiazepine, indolo [3,2-b]
[1,4] benzodiazepine, indolo [3,2-b]
[1,5] benzodiazepine, indolo [3,2-d]
[1,3] benzodiazepine, indolo [3,2-d]
[2,3] benzodiazepine, indolo [2,3-a]
[3] Benzazepine, indolo [2,3-c] [1] Benzazepine, indolo [2,3-d] [1] Benzazepine, indolo [2,3-d] [2] Benzazepine, indolo [3,2- b] [1] Benzazepine, indolo [3,2-c] [1] Benzazepine, indolo [3,2
-D] [1] benzazepine, 1H-indolo [2,1-
b] [3] benzazepine, 1H- [1] benzoxepino [5,4-b] indole, 1H- [2] benzoxepino [4,3-b] indole, 1H- [1] benzothiepino [4,5-b] Indole, 1H- [1] benzothiepino [5,4-b] indole, benzo [3,4] cyclohepta [1,2-b] indole, benzo [4,5] cyclohepta [1,2-b] indole, benzo [5,6]
Cyclohepta [1,2-b] indole, benzo [6,
7] cyclohepta [1,2-b] indole, cyclohepta [b] carbazole, 4H- [1,5] oxazocino [5 ′, 4 ′: 1,6] pyrido [3,4-b] indole,
Azocino [1 ', 2': 1,2] pyrido [3,4-b] indole, 2,6-methano-2H-azecino [4,3-b]
Indole, 3,7-methano-3H-azecino [5,4-
b] indole, pyrido [1 ', 2': 1,8] azosino [5,4-b] indole, pyrido [4 ', 3': 6, 7]
Oxosino [2,3-b] indole, pyrido [4 ',
3 ′: 6,7] oxono [4,3-b] indole, 1,
5-methano-1H-azecino [3,4-b] indole,
2,6-methano-1H-azecino [5,4-b] indole, 1H-pyrido [3 ', 4': 5.6] cycloocta [1,2-b] indole, 1,4-ethanooxocino [3, 4-b] Indole, pyrano [3 ', 4': 5, 6]
Cycloocta [1,2-b] indole, 1H-indolo [2,3-c] [1,2,5,6] benzotetrazocine, 1
H-indolo [2,3-c] [1,6] benzodiazocine, 6,13b-methano-13bH-azecino [5,4-
b] indole, oxocino [3,2-a] carbazole, 1H-benzo [g] cycloocta [b] indole,
6,3- (iminomethano) -2H-1,4-thiazono [9,8-b] indole, 1H, 3H- [1,4] oxazonino [4 ', 3': 1,2] pyrido [3,4 -B] indole, 2H-3,6-ethanoazonino [5,4-b] indole, 2H-3,7-methanoazacycloundesino [5,4-b] indole, 1H-6,12b-ethanoazonino [5 , 4-b] indole, indolo [3,2-e]
[2] benzazonin, 5,9-methanoazacycloundecino [5,4-b] indole, 3,6-ethano-3H
-Azecino [5,4-b] indole, 3,7-methano-
3H-azacycloundecino [5,4-b] indole,
Pyrano [4 ', 3': 8,9] azezino [5,4-b] indole, 1H-indolo [2,3-c] [1,7] benzodiazecin, 1H-indolo [3,2-e] [ 2] benzazecin, benzo [e] pyrrolo [3,2-b] indole, benzo [e] pyrrolo [3,2-g] indole, benzo [e] pyrrolo [3,2,1-hi] indole, benzo [ e] pyrrolo [3,4-b] indole, benzo [g] pyrrolo [3,4-b] indole, 1H-benzo [f] pyrrolo [1,2-a] indole, 1H-benzo [g] pyrrolo [ 1,2-a] indole, 2H-benzo [e] pyrrolo [1,2-a] indole, 1H-benzo [f] pyrrolo [2,1-a] isoindole, 1H-benzo [g] pyrrolo [2 , 1-a] isoindole, 2H-benzo [e] pyrrolo [2,1-a] isoindole, isoindolo [6,
7,1-cde] indole, spiro [cyclohexane-
1,5 '-[5H] pyrrolo [2,1-a] isoindole], isoindolo [7,1,2-hij] quinoline, 7.1
1-methanoazosino [1,2-a] indole, 7,11
-Methanoazosino [2,1-a] isoindole, dibenz [cd, f] indole, dibenz [cd, g] indole,
Dibenz [d, f] indole, 1H-dibenz [e, g] indole, 1H-dibenz [e, g] isoindole, naphtho [1,2,3-cd] indole, naphtho [1,8-e
f] indole, naphtho [1,8-fg] indole, naphtho [3,2,1-cd] indole, 1H-naphtho [1,2
-E] indole, 1H-naphtho [1,2-f] indole, 1H-naphtho [1,2-g] indole, 1H-naphtho [2,1-e] indole, 1H-naphtho [2,3-e ]
Indole, 1H-naphtho [1,2-f] isoindole, 1H-naphtho [2,3-e] isoindole, spiro [1H-carbazole-1,1′-cyclohexane], spiro [2H-carbazole-2, 1'-cyclohexane], spiro [3H-carbazole-3,1'-cyclohexane], cyclohepta [4,5] pyrrolo [3,2-f]
Quinoline, cyclohepta [4,5] pyrrolo [3,2-h]
Quinoline, azepino [4,5-b] benz [e] indole, 1H-azepino [1,2-a] benz [f] indole, 1H-azepino [2,1-a] benz [f] isoindole, benzo [E] Groups formed by removing one hydrogen atom from a tetracyclic fused benzene ring such as cyclohepta [b] indole and benzo [g] cyclohepta [b] indole.

The above equation

Embedded image [Wherein each symbol has the same meaning as described above], specific examples of the group represented by 1H-dipyrrolo [2,3-b: 3 ′,
2 ', 1'-hi] indole, spiro [cyclopentane-1,2'(1'H) -pyrrolo [3,2,1-hi] indole], spiro [imidazolidine-4,1 '(2' H)
-[4H] pyrrolo [3,2,1-ij] quinoline], pyrido [2,3-b] pyrrolo [3,2,1-hi] indole, pyrido [4,3-b] pyrrolo [3,2 , 1-h
i] indole, benzo [de] pyrrolo [3,2,1-
ij] quinoline, 3H-pyrrolo [3,2,1-de] acridine, 1H-pyrrolo [3,2,1-de] phenanthridine, spiro [cyclohexane-1,6 ′-[6
H] pyrrolo [3,2,1-ij] quinoline], 4,9-
Methanopyrrolo [3,2,1-lm] [1] benzoazosin, spiro [cycloheptane-1,6 ′-[6H] pyrrolo [3,2,1-ij] quinoline], 1H-pyrano [3,4-d ] Pyrrolo [3,2,1-jk] [1] benzazepine, 3H-benzo [b] pyrrolo [3,2,1-
jk] [4,1] benzoxazepine, 7H-indolo [1,7-ab] [4,1] benzoxazepine, benzo [b] pyrrolo [3,2,1-jk] [1,4 Benzodiazepine, indolo [1,7-ab] [1,4] benzodiazepine, indolo [1,7-ab] [1] benzazepine, indolo [7,1-ab] [3] benzazepine, 1H-cyclohepta [d] [3,2,1-jk]
[1] benzazepine, spiro [azepino [3,2,1
-Hi] indole-7 (4H), 1'-cycloheptane], 4H-5,11-methanopyrrolo [3,2,1-n
o] [1] benzazacycloundesine, spiro [azepino [3,2,1-hi] indole-7 (4H),
[1'-cyclooctane], and the like, which can be obtained by removing one hydrogen atom from a tetracyclic fused benzene ring.

"When an aromatic ring (preferably a benzene ring) and an optionally substituted tricyclic heterocycle are condensed"
As a particularly preferred example of

Embedded image And the like.

Ar is preferably of the formula

Embedded image Wherein the symbols in the formula are as defined above, and more preferably a group represented by the formula

Embedded image [The symbols in the formula are as defined above].

Preferred specific examples of Ar include a compound represented by the formula

Embedded image [The symbols in the formula are as defined above]. Above all, the expression

Embedded image [The symbols in the formula have the same meanings as described above] are preferable.

The “substituent” in the “divalent chain group which may have a substituent and has 1 to 5 atoms in the main chain” represented by X ¹ includes, for example, (i) halogen _Optionally substituted C _1-6 alkyl group, (ii) halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), (ii)
i) a C _1-3 alkylenedioxy group (eg, methylenedioxy, ethylenedioxy, etc.), (iv) a nitro group,
(V) a cyano group, (vi) a hydroxy group, (vii) an optionally halogenated C _1-6 alkoxy group, (viii) C _3-6
Cycloalkyl groups (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), (vii
i) an optionally halogenated C _1-6 alkylthio group,
(Ix) C _6-14 aryl group (eg, phenyl, naphthyl, etc.), (x) mono-C _6-14 aryl-C _1-6 alkyl group (eg, mono-phenyl-C _1- such as benzyl, phenylethyl, etc.) _And (xi) di-C _6-14 aryl-C _1-6 alkyl group (for example, di-phenyl-C _1-6 alkyl group such as diphenylmethyl and diphenylethyl). Here, “optionally halogenated C _1-6 alkyl group”, “optionally halogenated C _1-6 alkoxy group” and “optionally halogenated C _1-6 alkylthio group” The above-mentioned A
What was illustrated as a substituent in r is used.

X¹Represented by `` may have a substituent
And a divalent chain group having 1 to 5 atoms in the main chain.
"The divalent chain having 1 to 5 atoms in the main chain
As the group, for example, O, S, CO, SO, SO, NR
^3a, CR^3aR^3b, C = CR^3aR ^3b(R^3aAnd R^3bHaso
Each independently represents a hydrogen atom, a cyano group, a hydroxy group,
Amino group, C_1-6Alkyl group or C_1-6Alkoxy group
Represents 1) to 5 divalent groups selected from
And the resulting divalent chain group. here
And R^3aOr R^3bC indicated by_1-6As an alkyl group
Is, for example, methyl, ethyl, propyl, isopropyl
Butyl, sec-butyl, tert-butyl, pentyl, f
Xyl and the like. R^3aOr R^3bC indicated by
_1-6As the alkoxy group, for example, methoxy, ethoxy
Si, propoxy, isopropoxy, butoxy, isobut
Xy, sec-butoxy, tert-butoxy, etc.
You. X¹Is preferably CO, O, NR^3a, S, SO,
SO_Two, SO_TwoNR^3a, SO_TwoNHCONR^3a, SO_TwoNH
C (= NH) NR^3a, CS, CR^3aR^3b, C = CR^3aR
^3b, C = NR^3aOr CONR^3a(R^3aAnd R^3bIs
And the same meaning as described above). X¹Is even more preferred
Or CO, O, NR^3a, S, SO, SO_Two, SO_TwoN
R^3aOr CONR^3a(R^3aIs the same as above)
What is it? Among them, CO or O is preferable. Ma
T, X¹Is any position on Ar as long as it is a substitutable position
May be replaced by a replacement.

[0052] As the "substituent" in the "optionally substituted divalent acyclic hydrocarbon group" represented by X ^4, for example, exemplified substituents in the X ¹ can be mentioned. Examples of the “divalent acyclic hydrocarbon group” in the “optionally substituted bivalent acyclic hydrocarbon group” include, for example, a divalent C _1-4 acyclic hydrocarbon group Is mentioned. The “divalent C _1-4 acyclic hydrocarbon group” is preferably (1) C _1-4 alkylene [eg, CH ₂ , (CH ₂ ) ₂ ,
(CH ₂ ) ₃ , (CH ₂ ) ₄ , CH (CH ₃ ), CH (CH ₃ ) ₂ , (C
H (CH ₃ )) ₂ etc.]; (2) C _2-4 alkenylene [for example, CHＣＨCH, CH
_{2 -CH = CH, CH 2 -CH} = CH-CH 2, CH = C
_{H-CH 2 -CH 2, CH} 2 -CH 2 -CH = CH, CH =
(3) C _2-4 alkynylene [for example, C≡C, CH _2-
C≡C, C≡C-CH ₂ , CH ₂ -C≡C-CH ₂ , C≡
Such as _{C-CH 2 -CH 2, CH} 2 -CH 2 -C≡C] and the like. X ⁴ is preferably a bond or C _1-3 alkylene, more preferably C _1-3 alkylene.

[0053] X as a "non-cyclic hydrocarbon group which may have a substituent" represented by ^2, for example, the X ⁴
And "a divalent acyclic hydrocarbon group which may have a substituent". X ² is preferably CO 2
Or (CH ₂ ) _p (p is an integer of 1 to 3). Especially, CO or CH ₂ is preferable. As the "optionally substituted divalent acyclic hydrocarbon group" represented by X ^3, for example, illustrated "acyclic divalent may have a substituent group as the X ⁴ Formula hydrocarbon group ". X ³ is preferably a bond or (CH ₂ ) _q (q
Represents an integer of 1 to 3). Especially, a bond or CH ₂ is preferable.

The “basic substituent” represented by R ² is not particularly limited as long as it is a basic substituent. Examples of the basic substituent include an amino group which may have a substituent, a 5- to 7-membered cyclic amino group which may have a substituent, an amidino group which may have a substituent, Examples thereof include a guanidino group which may have a group, and a 5- or 6-membered nitrogen-containing heterocyclic group which may have a substituent. "Optionally substituted amino group", "optionally substituted 5- to 7-membered cyclic amino group", "optionally substituted amidino group", "substituent the "substituent" in the optionally may guanidino group which may "and" 5- or substituted 6-membered nitrogen-containing heterocyclic group "has, for example, a" substituent represented by R ¹ Examples of the "hydrocarbon group which may be possessed" are exemplified.
The substituent is preferably nitro, amino, mono-C _1-6
Alkylamino, the (preferably methyl, ethyl, propyl, etc.) a C _1-6 alkyl group optionally having respectively 1 to 2 substituents selected from and di -C _1-6 alkylamino, C _{6 -14} aryl group (preferably phenyl and the like), C _7-16 aralkyl group (preferably benzyl and the like) and the like.

"Amino group optionally having substituent (s)"
Is preferably an amino group optionally substituted by one or two C _1-6 alkyl. Among them, amino, methylamino, ethylamino, propylamino, dimethylamino, diethylamino and the like are preferable. The “5- to 7-membered cyclic amino group” in the “5- to 7-membered cyclic amino group which may have a substituent” includes the “optionally substituted and condensed Examples of the “substituent” in the “optionally substituted benzene ring” may be mentioned. "5 to 7 optionally having substituent (s)
A "membered cyclic amino group" is preferably one to two C
Examples include pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, and the like, each of which may have a _1-6 alkyl group (preferably, methyl, ethyl, propyl, etc.). Examples of the “amidino group optionally having a substituent” and the “guanidino group optionally having a substituent” include the “hydrocarbon group optionally having a substituent” represented by R ¹ above. And the "substituent" in the above.

As the “5- to 6-membered nitrogen-containing heterocyclic group” in the “optionally substituted 5- or 6-membered nitrogen-containing heterocyclic group”, for example, in addition to a carbon atom and one nitrogen atom, Examples thereof include a 5- or 6-membered nitrogen-containing heterocyclic group which may contain 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and which is basic. Such groups include, for example, pyridyl, pyrazyl, pyrazinyl, pyridazinyl, imidazolyl,
4,5-dihydro-1H-2-imidazolyl, pyrazolyl, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, piperazinyl and the like. The “optionally substituted 5- or 6-membered nitrogen-containing heterocyclic group” is preferably a C _1-6 alkyl group (preferably methyl, ethyl, propyl and the like) and a C _6-14 aryl group ( 4,5-dihydro-1H-2-imidazolyl which may have one or two substituents selected from phenyl and the like. In particular, 4,5-dihydro-1H-2-imidazolyl, 1-
Methyl-4,5-dihydro-1H-2-imidazolyl, 1-ethyl-
4,5-dihydro-1H-2-imidazolyl, 1-phenyl-4,5
-Dihydro-1H-2-imidazolyl and the like are preferred.

R ² is preferably 1 to 2
Amino groups _optionally substituted with C _1-6 alkyl,
5- to 7-membered cyclic amino group, amidino group, or 4,5-
It is a dihydro-1H-2-imidazolyl group. Among them, dimethylamino, diethylamino, amidino, N-methylamidino, 4,5-dihydro-1H-2-imidazolyl, 1-methyl
-4,5-dihydro-1H-2-imidazolyl and the like are preferred.
Compound (I) is preferably a compound wherein Ar is of the formula

Embedded image Wherein R ¹ is as defined above; X ¹
Is CO or O; X ⁴ is C _1-3 alkylene; X ² is CO or CH ₂ ; X ³ is a bond or CH ₂ ; and R ² is dimethylamino, diethylamino, amidino, N-methylamidino, 4.5 A compound which is -dihydro-1H-2-imidazolyl or 1-methyl-4,5-dihydro-1H-2-imidazolyl or a salt thereof. Here, R ¹ is preferably
A halogen atom, an optionally halogenated C _1-6 alkyl, an optionally halogenated C _1-6 alkoxy,
C _7-16 aralkyl group (preferably benzyl) which may have 1 to 3 substituents selected from nitro, cyano and hydroxy.

In the compound (I), Ar represents a compound of the formula

Embedded image Wherein the ring B ″ is a 5- to 9-membered nitrogen-containing heterocyclic ring further substituted with one or two oxo groups, and other symbols are as defined above. And X is X ^1a (X ^1a is O, NR ^3a , S, SO, SO ₂ , SO ₂ NR
^3a , SO ₂ NHCONR ^3a , SO ₂ NHC (= NH) NR
^3a , CS, CR ^3a R ^3b , C = CR ^3a R ^3b , C = NR ^3a
Or CONR ^3a (R ^3a and R ^3b are as defined above). ), That is, the compound (Ia)
Is a novel compound. Here, the “5- to 9-membered nitrogen-containing heterocyclic ring further substituted by one or two oxo groups” represented by the ring B ″ is the “substituted by an oxo group further exemplified by the aforementioned B ′ ring”. And the optionally substituted 5- to 9-membered nitrogen-containing heterocyclic ring "includes a 5- to 9-membered nitrogen-containing heterocyclic ring substituted with one or two oxo groups.

The above equation

Embedded image [The symbols in the formula are as defined above.]
Preferably, the formula

Embedded image Wherein k is an integer of 1 to 4, m is an integer of 0 to 5, (m + n) is 1 to 5, and R ¹ has the same meaning as described above. k is preferably 2
Or 3, more preferably 3. m is preferably 0 or 1, and more preferably 0. X ^1a is preferably O.

Hereinafter, the compound (I) will be described in more detail. Here, since the compound (Ia) is included in the compound (I), the following description also applies to the compound (Ia). Examples of the salt of compound (I) include salts with inorganic bases, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids. . Preferable examples of the salt with an inorganic base include an alkali metal salt such as a sodium salt and a potassium salt; an alkaline earth metal salt such as a calcium salt, a magnesium salt and a barium salt; an aluminum salt. Suitable examples of the salt with an organic base include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine, and the like. Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, Salts with p-toluenesulfonic acid and the like can be mentioned. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine, and preferred examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. Is mentioned. Among these salts, pharmaceutically acceptable salts are preferred. For example, when the compound (I) has an acidic functional group, an alkali metal salt (eg, sodium salt, potassium salt, etc.), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt, etc.)
Inorganic salts, ammonium salts and the like. When compound (I) has a basic functional group, it may be an inorganic salt such as hydrochloride, sulfate, phosphate, hydrobromide; or acetate, maleate, fumarate, or succinic acid. Organic salts such as salts, methanesulfonate, p-toluenesulfonate, citrate, tartrate and the like may be formed.

The compound (I) may be either an anhydride or a hydrate. In the case of a hydrate, it may have 0.5 to 3 water molecules. Further, compound (I) may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, etc.). .

When compound (I) has optical isomers, stereoisomers, positional isomers, and rotamers, these are also included as compound (I), as well as synthesis methods and separation methods known per se. Thus, each can be obtained as a single item. For example, when the compound (I) has an optical isomer, the compound (I) includes an optical isomer resolved from the racemate. The optical isomer can be produced by a method known per se. Specifically, an optical isomer is obtained by using an optically active synthetic intermediate or by optically resolving the final racemic mixture according to a conventional method. As the optical resolution method, a method known per se, for example, a fractional recrystallization method described in detail below, a chiral column method,
The diastereomer method or the like is used. 1) fractional recrystallization method Racemic and optically active compounds (e.g., (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-tartaric acid,
((+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine, etc.)
To form a salt, which is separated by fractional recrystallization,
A method of obtaining a free optical isomer through a neutralization step, if desired. 2) Chiral column method

A method in which a racemate or a salt thereof is applied to an optical isomer separation column (chiral column) to separate the racemate or a salt thereof. For example, in the case of liquid chromatography, a mixture of optical isomers is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) or CHIRAL series manufactured by Daicel Corporation, and water, various buffers (e.g., phosphate buffer), organic The optical isomers are separated by developing a solvent (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.) alone or as a mixed solution. For example, in the case of gas chromatography, separation is performed using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Sciences). 3) Diastereomer method A racemic mixture is formed into a diastereomer mixture by a chemical reaction with an optically active reagent, which is then separated by a conventional separation method.
(Eg, fractional recrystallization, chromatography, etc.) to obtain a single substance, and then obtain optical isomers by separating optically active reagent sites by a chemical treatment such as a hydrolysis reaction. For example, when the compound of the present invention has hydroxy or primary or secondary amino in the molecule, the compound and an optically active organic acid (for example, MTPA [α-methoxy-α- (trifluoromethyl) phenylacetic acid], (− ) -Menthoxyacetic acid or the like) to give a diastereomer of an ester form or an amide form, respectively. On the other hand, when the compound of the present invention has a carboxylic acid group, an amide or ester diastereomer can be obtained by subjecting the compound to an optically active amine or alcohol reagent for a condensation reaction. The separated diastereomer is converted into an optical isomer of the original compound by subjecting it to acid hydrolysis or basic hydrolysis reaction.

Compound (I) may be used as a prodrug. The prodrug of the compound (I) is a compound which is converted into the compound (I) by a reaction with an enzyme or a stomach acid under physiological conditions in a living body, that is, the compound (I) which is enzymatically oxidized, reduced, hydrolyzed, or the like. ), A compound (I) which is hydrolyzed by gastric acid and the like.
A compound that changes to As a prodrug of the compound (I), a compound in which the amino group of the compound (I) is acylated, alkylated or phosphorylated [eg, the amino group of the compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compound, etc.]; The hydroxyl group of compound (I) is acylated, alkylated,
Phosphorylated or borated compounds (eg, compounds in which the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated, etc.); The carboxyl group of compound (I) is esterified,
Amidated compound [eg, carboxyl group of compound (I) is ethyl-esterified, phenyl-esterified, carboxymethyl-esterified, dimethylaminomethyl-esterified, pivaloyloxymethyl-esterified, ethoxycarbonyloxyethyl-esterified, Phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compound, etc.]. These compounds can be produced from compound (I) by a method known per se. The prodrug of compound (I) is available from Hirokawa Shoten 1
The compound may be converted into the compound (I) under physiological conditions, as described in “Development of Pharmaceuticals”, Vol. 7, pp. 163 to 198, 990.

Next, a method for producing the compound (I) or a salt thereof will be described. The following production methods are applied to a free form of compound (I) and a salt thereof, but in the following description, these may be simply abbreviated as compound (I). The starting compound or the synthetic intermediate of the compound (I) used in each of the following steps may be either a free form or a salt, but in the following description, these may be simply abbreviated as a compound. As the salts of these starting compounds or synthetic intermediates, the salts exemplified as the salts of compound (I) are used.

When the starting compound or the synthetic intermediate of the compound (I) is a free form, it can be converted into a salt according to a conventional method. When a salt is formed, the free form or another salt can be formed according to a conventional method. Can also be converted to These starting compounds or synthetic intermediates may be hydrates or anhydrides. Further, as in the case of the compound (I), the starting compound or the synthetic intermediate of the compound (I) may be an optical isomer, a stereoisomer, a positional isomer or a rotational isomer, or a mixture thereof. Good.

The following reactions can be carried out without using a solvent or, if necessary, using an appropriate solvent. The solvent may be any solvent that can be generally used for a chemical reaction, as long as it does not hinder the reaction, such as a hydrocarbon solvent (eg, hexane, toluene, etc.), an ether solvent (eg, ethyl ether, tetrahydrofuran, dioxane, Dimethoxyethane), amide solvents (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide, etc.), urea solvents (eg, 1,3-dimethyl-2)
-Imidazolidinone, etc.), sulfoxide solvents (e.g., dimethyl sulfoxide), alcohol solvents (e.g., methanol, ethanol, isopropanol, t-butanol, etc.), nitrile solvents (e.g., acetonitrile,
Organic solvents such as propionitrile) and pyridine; or water. The amount of the solvent to be used is generally about 0.5 ml to about 100 ml, preferably about 3 ml to about 30 ml, per 1 mmol of the starting compound. The reaction temperature varies depending on the type of the solvent used, but is usually about -30 ° C to about 180 ° C, preferably about 0 ° C to about 120 ° C.
It is about ° C. The reaction time depends on the reaction temperature,
Usually about 0.5 hour to about 72 hours, preferably about 1 hour to about 24 hours. The reaction is usually carried out under normal pressure, but may be carried out under a pressure of about 1 atm to about 100 atm, if necessary.

The compound obtained in each of the following steps can be prepared by a known method, for example, concentration, liquid conversion, phase transfer, solvent extraction, fractionation,
It is isolated and purified by distillation, crystallization, recrystallization, chromatography, preparative high performance liquid chromatography, etc., and used as a raw material for the next reaction, but is used as a raw material in the reaction mixture without isolation or purification. You may. In the following description, the “condensation reaction” can be performed in the presence of a base, if necessary. Examples of the base include inorganic bases such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, potassium hydride, sodium hydride, sodium methoxide, potassium t-butoxide; pyridine; Organic bases such as lutidine, collidine and triethylamine are used. The amount of the base to be used is generally equimolar to excess, preferably about 1 molar equivalent to about 5 moles, relative to the starting compound.
Double molar equivalents. Further, in this reaction, a catalytic amount of an iodide compound, for example, sodium iodide, potassium iodide, 4-dimethylaminopyridine or the like may be added for the purpose of accelerating the reaction. In the reactions in the following steps, the reaction may be carried out after protecting the functional group according to a conventional method, if necessary, and after the reaction, the reaction may be optionally deprotected according to a conventional method. The protecting group introduction reaction and the deprotection reaction are carried out by a means known per se or a means analogous thereto. Specifically, Protective groups in Organic Synthesis
ganic Synthesis; John Wiley & Sons, INC.). For example, as the deprotection reaction, for example, a method of treating with acid, base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate or the like is used.

1) Compound (I) is, for example,

Embedded image [Wherein the symbols have the same meanings as described above. Or a salt thereof (hereinafter sometimes abbreviated as compound (II)) and a compound represented by the formula

Embedded image [In the formula, Z ¹ represents a leaving group, and other symbols have the same meanings as described above. Or a salt thereof (hereinafter, also abbreviated as compound (III)) in a condensation reaction. Examples of the leaving group represented by Z ¹ include a halogen atom (eg, chlorine, bromine, iodine, etc.), an optionally halogenated C _1-6 alkylsulfonyloxy group (eg, methanesulfonyloxy, ethanesulfonyloxy, For example, trifluoromethanesulfonyloxy), C _6-10 arylsulfonyloxy group (for example, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.) are used. Of these, a halogen atom (preferably, bromine, iodine, etc.) is preferred.

This reaction is preferably carried out in an alcoholic solvent such as ethanol or a nitrile solvent such as acetonitrile. The reaction temperature varies depending on the type of the solvent used, but is preferably about 0 ° C. to about 120 ° C. The reaction time varies depending on the reaction temperature, but is preferably about 1 hour to about 24 hours. This reaction is preferably performed in the presence of a base such as sodium carbonate, potassium carbonate, and triethylamine. The amount of the base to be used is preferably about 1 equivalent to about 3 equivalents relative to compound (III). Further, if necessary, for the purpose of accelerating the reaction, a catalytic amount of an iodide compound (for example, sodium iodide, potassium iodide or the like) or 4-dimethylaminopyridine or the like may be used for compound (III). Good.

Compound (III) can be produced by a method known per se or a method analogous thereto. Among the compounds (II), those in which X ¹ is CO can be produced by a method known per se, for example, the method described in JP-A-10-107257 or a method analogous thereto. Also,
Among the compounds (II), those in which X ¹ is other than CO can be produced, for example, by the following synthesis method.

1-1) In the compound (II), X ¹ is O
(Hereinafter sometimes abbreviated as compound (IIa)) can be produced, for example, according to the following reaction formula 1-1. Step (aa): a compound represented by the formula (IVa) (hereinafter sometimes abbreviated as the compound (IVa)) and a compound represented by the formula (Va) (hereinafter abbreviated as the compound (Va)) Step (ab): a deprotection reaction of a compound represented by the formula (VIa) (hereinafter sometimes abbreviated as compound (VIa))
Compound (IIa) can be produced by performing the steps sequentially. Reaction formula 1-1

Embedded image [In the formula, Z ² represents a leaving group, W ¹ represents a protecting group for an amino group, and the other symbols have the same meanings as described above. ]

In the step (aa), the compound (VIa) can be produced by a condensation reaction between the compound (IVa) and the compound (Va). Examples of the amino-protecting group represented by W ¹ include amino-group protecting groups generally used in the field of peptide chemistry. As such a protective group, for example, the “hydrocarbon group which may have a substituent” or the “acyl group” represented by R ² can be used. Specifically, for example, a formyl group, an optionally substituted C _1-6 alkyl-carbonyl group (eg, acetyl, ethylcarbonyl, etc.), a benzoyl group, a C _1-6 alkyl-oxycarbonyl group (eg, Methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.), C _6-14 aryloxycarbonyl group (eg, phenoxycarbonyl), C _7-15 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, fluorenyloxy) Acyl groups such as carbonyl; and hydrocarbon groups such as trityl and phthaloyl. Among them, a t-butoxycarbonyl group and the like are preferable. Examples of the “substituent” in the aforementioned “optionally substituted hydrocarbon group” include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl-carbonyl (eg, methylcarbonyl , Ethylcarbonyl, butylcarbonyl, etc.), nitro and the like. The number of substituents is preferably about 1 to 3. Z ²
In Examples of the leaving group represented, the leaving group is used exemplified for the aforementioned Z ^1. Of these, a halogen atom (preferably, bromine, iodine, etc.) is preferred. The condensation reaction can be performed, for example, in the same manner as the condensation reaction between compound (II) and compound (III). This reaction can be performed, for example, in a solvent such as N, N-dimethylformamide in the presence of a base such as potassium carbonate or sodium hydride.
The amount of the base to be used is preferably about 1 equivalent to about 3 equivalents relative to compound (Va). Compound (Va)
Can be produced by a method known per se or a method analogous thereto. Compound (Va) can be obtained, for example, from Journal of Medicinal Chemistry (J. Med.
m.), 40 , 1779-1788 (1997), or JP-A-58-20.
It can be produced by the method described in 8289 or the like or a method analogous thereto.

[0074] In step (ab), the compound (VIa) is subjected to deprotection reaction, by removing the W ^1, can be prepared a compound (IIa). The deprotection reaction can be performed, for example, according to a method generally used in the field of peptide chemistry. In the deprotection reaction, for example, compound (VIa) is converted from an acid such as a mineral acid (eg, hydrochloric acid, sulfuric acid, hydrobromic acid, iodic acid, periodic acid, etc.) or an alkali metal hydroxide (eg, sodium hydroxide, The reaction is preferably carried out in an aqueous solution of a base such as potassium hydroxide or lithium hydroxide, preferably at about 20 ° C. to about 140 ° C. The amount of the acid or base to be used is generally about 1-about 100 equivalents, preferably about 1-equivalent, relative to compound (VIa).
To about 40 equivalents. The strength of the acid or base is usually about 0.1 normal to about 18 normal, preferably about 1 normal to about 12 normal. Although the reaction time depends on the reaction temperature, it is generally about 1 hour to about 48 hours, preferably about 2 hours to about 24 hours. The deprotection reaction is carried out using palladium, palladium-carbon, Raney-nickel, Raney- It is also carried out by subjecting to a catalytic reduction reaction in the presence of a catalyst such as cobalt or platinum oxide, for example, in an alcoholic solvent such as ethanol or a solvent such as acetic acid at normal pressure or, if necessary, under pressure. When W ¹ is a t-butoxycarbonyl group, the deprotection reaction is carried out in the presence of an aromatic or tertiary amine such as 2,6-lutidine or triethylamine, for example, trimethylsilyl-trifluoromethanesulfonate, triethylsilyl-trifluoro. It can also be carried out using a trialkylsilyltrifluoromethanesulfonate derivative such as methanesulfonate or t-butyldimethylsilyl-trifluoromethanesulfonate. This reaction is preferably performed in a nonpolar solvent such as dichloromethane or the like, or in a polar aprotic solvent such as tetrahydrofuran, diethyl ether or N, N-dimethylformamide. The reaction temperature is preferably from about -20 ° C to room temperature. The deprotection reaction is particularly preferably carried out in dichloromethane at about 0 ° C. to about room temperature with trimethylsilyl-trifluoromethanesulfonate and 2,6
-Performed using lutidine.

The starting compound (IVa) in the step (aa) is
It can be produced by a method known per se or a method analogous thereto. Further, among the starting compounds (IVa),
Ar is

Embedded image Wherein each symbol is as defined above (hereinafter, sometimes abbreviated as compound (IVA)),
For example, it can be produced by the following reaction formula 1-2. That is, step (ac): a compound represented by the formula (VIIA) (hereinafter, referred to as
Compound (VIIA)) and formula (Xa)
And a condensation reaction with a compound represented by the formula (hereinafter sometimes abbreviated as compound (Xa)), and step (ad): a compound represented by the formula (VIIIA) (hereinafter abbreviated as compound (VIIIA)) Compound (IVA) can be produced by sequentially performing the deprotection reaction of Reaction formula 1-2

Embedded image [Wherein, W ² is a protecting group for a phenolic hydroxyl group, and other symbols are as defined above]

Examples of the phenolic hydroxyl-protecting group represented by W ² include phenolic hydroxyl-protecting groups generally used in the field of peptide chemistry.
Such protecting groups include, for example, Protective Groups in Organic Synthesis (Protectiv
e groups in Organic Synthesis; John Wiley & Sons,
INC.) Is used. Especially, a methyl group, a benzyl group, etc. are preferable. Compound (VIIA) can be produced by a method known per se or a method analogous thereto. Compound (VIIA) can be obtained, for example, from Journal of the Chemical Society (J. Chem. Soc.
(C)), 183-188 (1969) or US Pat. No. 4,080,449 or a method analogous thereto.

In the step (ac), the compound (VIIA)
By the condensation reaction of the compound (Xa) with the compound (VIII)
A) can be produced. The condensation reaction can be performed, for example, in the same manner as the condensation reaction between compound (II) and compound (III). This reaction is preferably performed in a solvent such as an alcoholic solvent such as ethanol or a nitrile solvent such as acetonitrile in the presence of a base such as sodium carbonate, potassium carbonate and triethylamine.
In this reaction, if desired, a catalytic amount of an iodide compound (eg, sodium iodide, potassium iodide, etc.) or 4
-Dimethylaminopyridine or the like may be used.

In the step (ad), the compound (VIIIA)
) Is subjected to a deprotection reaction to remove W ² , whereby compound (IVA) can be produced. The deprotection reaction can be performed according to a deprotection reaction generally used in the field of peptide chemistry. For example, W ²
When is a methyl group, the deprotection reaction is performed by the journal of the Chemical Society of Japan (Bull.
Chem. Soc. Jpn), 44 , 1986 (1971), tetrahedron
(Tetrahedron), can be carried out according to 4 2, 3259 (1986) method, or a method analogous thereto according to such.

1-2) Among compounds (II), a compound in which X ¹ is NR ^3a (hereinafter sometimes abbreviated as compound (IIb)) can be produced by the following reaction formula 2-1. it can. That is, step (ba): a compound represented by the formula (IVb)
Compound (IVb)) and Compound (V
a) a condensation reaction with a), and step (bb): a compound represented by the formula (VIb)
Compound (IIb) can be produced by sequentially performing the deprotection reaction of compound (VIb)). Reaction formula 2-1

Embedded image [Wherein the symbols have the same meanings as described above]. In the step (ba), the compound (IVb) and the compound (V
Compound (VIb) can be produced by a condensation reaction with a). The condensation reaction can be performed, for example, in the same manner as the condensation reaction between compound (II) and compound (III). This reaction can be performed, for example, in a solvent such as N, N-dimethylformamide in the presence of a base such as potassium carbonate or sodium hydride. The amount of the base to be used is preferably about 1 equivalent to about 3 equivalents relative to compound (Va).

In step (bb), compound (VIb)
Is subjected to a deprotection reaction to remove W ¹ , whereby compound (IIb) can be produced. This reaction can be carried out, for example, in the same manner as in the deprotection reaction of compound (VIa).

Further, the starting compound (IV) in the step (ba)
b) can be produced, for example, by the following reaction formula 2-2. Step (bc): a nitration reaction of a compound represented by the formula (VIIb) (hereinafter sometimes abbreviated as compound (VIIb)), Step (bd): a compound represented by the formula (VIIIb) ( Step (be): a compound represented by the formula (IXb) (hereinafter, may be abbreviated as compound (VIIIb)).
Compound (IXb)) and formula (Xb)
(Hereinafter sometimes abbreviated as compound (Xb)), the compound (IVb) can be produced by sequentially performing the condensation reaction. Reaction formula 2-2

Embedded image [Wherein the symbols have the same meanings as described above]. Compound (VIIIb) can be produced by nitrating compound (VIIb) in step (bc). This reaction is carried out using a suitable nitrating reagent (for example, nitric acid, nitric acid-sulfuric acid, nitronium trifluoroborate, etc.) by a known method (for example, synthesis (Synth
esis), 217-238 (1977), Chemistry of the Nitro and Nitroso Groups
Nitro and Nitroso Groups), p.1-48 Wiley (1970), etc.) or a method analogous thereto. Nitro groups can be introduced at any of the reactive positions.

Compound (VIIb) can be produced by a method known per se or a method analogous thereto.
Compound (VIIb) is, for example, a compound of the journal
Organic Chemistry (J. Org. Chem.), 3
4 , 2235 (1969), Journal of the Organic Chemistry (J. Org. Chem.), 54 , 5
574 (1989), Tetrah Letters
edron Lett.), 35 , 3023 (1977), Bulletin of the Chemical Society of Japan (Bull. Chem. Soc. Jpn.), 56 , 2300 (198)
3), Indian Journal of Chemistry (Indian. J. Chem.), 2 , 211 (1964), Indian Journal of Chemistry (Indian. J. Che.)
m.), 12 , 247 (1974), Bulletin of the Chemical Society of Japan (Bull. Chem. S.
oc., Jpn.), 43 , 1824 (1970), Chemical Pharmaceutical Bulletin (Chem. Pharm. Bull.),
20, 1328 (1972), Chemical Faculty Pharmaceutical Bulletin (Chem.Pharm.Bull.), 27, 1982 (1979), Heruhe Bu Chika Himika actor (Helv. Chem. Acra), 46, 1696 (196
3), Synthesis, 541 (1979), US
3,682,962, US 3,911,126., Ger. Offen. 2,314,39
2, Ger. 1,545,805, Journal of Chemical Society (J. Chem. Soc.), 1381 (1949), Canadian Journal of Chemistry (Can. J. Ch.
em.), 42 , 2904 (1964), Journal of Organism
J. Org. Chem., 28 , 3058 (196
3), Journal of American Chemical Society (J. Am. Chem. Soc.), 76 , 3194 (1954), 87 , 1
397 (1965), 88 , 4061 (1966), JP-A-49-41539.
Etc. or a method analogous thereto.

In step (bd), compound (VIII)
Compound (IXb) can be produced by the reduction reaction of b). This reaction can be carried out by a known reduction reaction (for example, a catalytic reduction reaction using a transition metal catalyst, a reduction reaction using a metal such as tin in an acidic solvent, and the like). This reaction can be performed, for example, by using Organic Synth
Vol. 5, 829-833 (1973), Organic Synthesis, Coll. Vol. 1, 455
(1941), Journal of the American Chemical Society (J. Am. Chem. Soc.), 66 , 1781 (1
944) or a method analogous thereto.

In step (be), compound (IXb)
By the condensation reaction of the compound (Xb) with the compound (IV)
b) can be produced. The condensation reaction can be performed, for example, in the same manner as the condensation reaction between compound (II) and compound (III). Further, compound (IVb) can be prepared by reacting compound (IXb) with, for example, a reductive alkylation reaction (for example, Journal of the American Chemical Society (J. Am. Chem. Soc.), 87 , 2767 (1965),
Organic Synthesis, Coll.
Vol. 4, 283-285 (1963), etc.) or a Michael addition reaction (for example, Helvetica Himica Actor (H
elv. Chem. Acta), 43, 1898 (1960), Journal of Organic Chemistry (J. Org. Chem.), 3
9,2044 (1974), Synthesis, 5, 375 (198
Etc.) or a reaction according to them.

1-3) Of the starting compound (II), X
A compound wherein ¹ is NR ^3a CO (hereinafter, compound (IIc)
May be abbreviated as follows), for example, according to the following reaction formula 3. Step (ca): an amidation reaction between the compound (IVb) and the compound represented by the formula (Vc) (hereinafter sometimes abbreviated as compound (Vc)); Step (cb): a compound represented by the formula (VIc) The compound represented (hereinafter, referred to as
Compound (IIc) can be produced by sequentially performing the deprotection reaction of compound (VIc)). Reaction formula 3

Embedded image [Wherein, Z ³ represents a leaving group, and other symbols have the same meanings as described above.] In step (ca), compound (IVb) and compound (V
Compound (VIc) can be produced by amidation reaction of c). Examples of the leaving group represented by Z ³ include a halogen atom (eg, chlorine, bromine, iodine, etc.), C
_1-6 alkyloxy group (eg, methoxy, ethoxy, etc.), C _7-15 aralkyloxy group (eg, benzyloxy, etc.), C _6-10 aryloxy group _optionally substituted by nitro group (eg, phenoxy, p-nitrophenoxy, etc.), a hydroxyl group and the like. Among them, for example, a halogen atom (preferably chlorine or the like), a hydroxyl group and the like are preferable.

The amidation reaction between compound (IVb) and compound (Vc) can be carried out using an appropriate condensing agent or base. For example, when Z ³ is a hydroxyl group, the amidation reaction is performed using, for example, a condensing agent commonly used in the field of peptide chemistry. The condensing agent is preferably dicyclohexylcarbodiimide, 1-ethyl-3
Carbodiimides such as-(3-dimethylaminopropyl) carbodiimide; phosphonic acids such as diphenylphosphoryl azide and diethyl cyanophosphonate; and phosgene equivalents such as 1-1'-carbonylbis-1H-imidazole. The amount of the condensing agent to be used is generally about 1 equivalent-about 5 equivalents, preferably about 1 equivalent-about 1.5 equivalents, per 1 mmol of compound (IVb). Also, for example, Z ³
When is a halogen atom, the amidation reaction is carried out by using a suitable base,
For example, the reaction is performed using sodium carbonate, potassium carbonate, triethylamine, or the like. The amount of the base used is the same as that of the compound (I
It is generally about 1 equivalent to about 10 equivalents, preferably about 1 equivalent to about 2 equivalents, relative to Vb).

In step (cb), compound (VIc)
Is subjected to a deprotection reaction to remove W ¹ , whereby compound (IIc) can be produced. The deprotection reaction is
For example, the reaction can be carried out in the same manner as in the deprotection reaction of compound (VIa).

1-4) Of the starting compound (II), X
^A compound in which ¹ is S, SO or SO ₂ (hereinafter sometimes abbreviated as compound (IId)) can be produced, for example, by the following reaction formula 4-1. That is, step (da): a compound represented by the formula (IVd)
Compound (IVd)) and compound (V
a) condensation reaction with a), step (db): a compound represented by the formula (VId)
Step (dc): Deoxidation of a compound represented by the formula (VIId) (hereinafter sometimes abbreviated as compound (VIId)) of compound (VId). Compound (IId) can be produced by sequentially performing the protection reaction. Reaction formula 4-1

Embedded image [Wherein, X ^1a represents S, SO or SO ₂ , and other symbols have the same meanings as described above.] In step (da), compound (IVd) and compound (V
Compound (VId) can be produced by a condensation reaction with a). The condensation reaction can be performed, for example, in the same manner as the condensation reaction between compound (II) and compound (III). The condensation reaction can be performed, for example, in a solvent such as N, N-dimethylformamide in the presence of a base such as potassium carbonate or sodium hydride. The amount of the base used is
Preferably, it is about 1 equivalent to about 3 equivalents relative to compound (Va).

In step (db), compound (VId)
Is subjected to an oxidation reaction as required, whereby compound (VIId) can be produced. The oxidation reaction is usually performed using an oxidizing agent. As the oxidizing agent, any one can be used as long as it is used as an oxidizing agent for sulfide. Can be Among them, metachloroperbenzoic acid and hydrogen peroxide are preferred. In the case of oxidizing S to SO, the amount of the oxidizing agent is preferably a compound (V
It is about 1 equivalent to about 1.1 equivalent based on Id).
In the case of oxidation of S to SO ₂ , the amount is preferably about 2 to about 2.5 equivalents based on compound (VId).
This reaction is preferably performed in a solvent such as dichloromethane, chloroform, acetic acid, ethyl acetate and the like.

In step (dc), compound (VII)
subjecting d) to a deprotection reaction to remove W ¹ ,
Compound (IId) can be produced. The reaction is
For example, the reaction can be carried out in the same manner as in the deprotection reaction of compound (VIa).

The starting compound (IVd) in the step (da) is
For example, it can be produced by the following reaction formula 4-2. That is, step (dd): a chlorosulfonylation reaction of compound (VIIb), and step (de): a reduction reaction of a compound represented by formula (VIIId) (hereinafter sometimes abbreviated as compound (VIIId)). And compound (IVd). Reaction formula 4-2

Embedded image [Wherein the symbols have the same meanings as described above] In step (dd), compound (VIIId) can be produced by subjecting compound (VIIb) to chlorosulfonylation. This reaction is carried out using a chlorosulfonylating reagent such as chlorosulfonic acid, sulfuryl chloride, sulfur dioxide-copper chloride and the like. Among them, chlorosulfonic acid and the like are preferable. The amount of the chlorosulfonylation reagent used is, for example, about 1 equivalent to a large excess. This reaction can be carried out without a solvent or with a solvent, but the reaction without a solvent is particularly preferred. When a solvent is used, the solvent is preferably, for example, dichloromethane, 1,2-dichloroethane, carbon disulfide or the like. The reaction temperature is preferably from about -20C to about 100C. Further, the chlorosulfonyl group is introduced at any of the reactable positions.

In the step (de), the compound (VIII)
Compound (IVd) can be produced by subjecting d) to a reduction reaction. This reduction reaction is a method known per se, for example, a reduction reaction using a combination of a metal and an acid such as zinc-acetic acid, tin-hydrochloric acid; a catalytic reduction reaction using a transition metal catalyst; a metal hydride such as lithium aluminum hydride And the like. Among them, a reduction reaction using zinc-acetic acid is preferable.

1-5) Of the starting compound (II), X
^A compound in which ¹ is SO ₂ NR ^3a (hereinafter, compound (IIe)
May be abbreviated as follows), for example, according to the following reaction formula 5. Step (ea): condensation reaction between compound (VIIId) and a compound represented by formula (IVe) (hereinafter sometimes abbreviated as compound (IVe)), and step (eb): formula (Ve) (Hereinafter may be abbreviated as compound (Ve))
Compound (IIe) can be produced by performing the steps sequentially. Reaction formula 5

Embedded image [Wherein the symbols have the same meanings as described above] In step (ea), compound (Ve) can be produced by a condensation reaction between compound (VIIId) and compound (IVe). The condensation reaction is carried out, for example, using the compound (IV
The reaction can be carried out in the same manner as in the amidation reaction between b) and compound (Vc). Compound (IVe) can be produced by a method known per se or a method analogous thereto.
Compound (IVe) or a salt thereof is described in, for example, Journal
Obj Medicinal Chemistry (J. Med. Che
m.), 33 , 1880 (1990) or a method analogous thereto.

[0094] In step (eb), the compound (Ve) is subjected to deprotection reaction, by removing the W ^1, can be prepared a compound (IIe). The deprotection reaction can be performed, for example, in the same manner as in the deprotection reaction of compound (VIa).

1-6) Of the starting compound (II), X
^A compound in which ¹ is SO ₂ NHCONR ^3a (hereinafter sometimes abbreviated as compound (IIf)) can be produced, for example, by the following reaction formula 6. Step (fa): Compound (VIIId) and Compound (IV)
e) the condensation reaction and step (fb): a deprotection reaction of a compound represented by the formula (Vf) (hereinafter sometimes abbreviated as compound (Vf))
Compound (IIf) can be produced by performing the steps sequentially. Reaction formula 6

Embedded image [Wherein each symbol has the same meaning as described above] In the step (fa), after reacting the compound (VIIId) with an alkali metal isocyanate (MOCN; M represents an alkali metal), Further, the compound (IV
Compound (Vf) can be produced by reacting e). This reaction is carried out, for example, in EP-A-759.
431, JP-A-7-118267 and the like or a method analogous thereto. The reaction of compound (VIIId) with an alkali metal isocyanate is carried out in the presence of a base, if necessary. here,
The alkali metal is preferably potassium or the like. The base is preferably pyridine, triethylamine and the like. The amount of the base to be used is preferably the compound (VIII)
It is about 1 equivalent to about 5 equivalents to d). This reaction is preferably performed in a solvent such as acetonitrile.

[0096] In step (fb), the compound (Vf) is subjected to deprotection reaction, by removing the W ^1, can be prepared a compound (IIf). This reaction can be carried out, for example, in the same manner as in the deprotection reaction of compound (VIa).

1-7) Of the starting compound (II), X
^A compound in which ¹ is SO ₂ NHC (3NH) NR ^3a (hereinafter, referred to as
Compound (IIg)) can be produced, for example, according to the following reaction formula 7. Step (ga): condensation reaction between compound (VIIId) and a compound represented by formula (IVg) (hereinafter sometimes abbreviated as compound (IVg)), and step (gb): formula (Vg) (Hereinafter may be abbreviated as compound (Vg)),
Compound (IIg) can be produced by performing the steps sequentially. Reaction formula 7

Embedded image [Wherein each symbol is as defined above]

In the step (ga), the compound (VIII)
Compound (Vg) can be produced by a condensation reaction between d) and compound (IVg). The condensation reaction can be performed, for example, in the same manner as in the amidation reaction between compound (IVb) and compound (Vc). Compound (IVg) can be produced using compound (IVe) by a method known per se or a method analogous thereto. Compound (IV
g) is, for example, the reaction of compound (IVe) with S-methylisothiourea (for example, Journal of the Organic Chemistry (J. Org. Chem.) 13 , 924 (1)
948)), reaction with cyanamide (for example,
Helvetica Chem. Acra, 29 ,
324 (1946)) and 1,3-bis (t-butoxycarbonyl) -2-methyl-2-thiopsoidurea (1,3-Bis (tert-butoxycarbonyl) -2-methyl
-2-thiopseudourea) (for example, Tetrahedron Lett., 33 , 6541-6542 (199)
2), the method described in Journal Obge Organic Chemistry (J. Org. Chem.), 52 , 1700-1703 (1987), etc.) and the like.

[0098] In step (gb), the compound (Vg) is subjected to deprotection reaction, by removing the W ^1, can be prepared a compound (IIg). This reaction can be carried out, for example, in the same manner as in the deprotection reaction of compound (VIa).

1-8) Of the starting compound (II), X
Compounds in which ¹ is CR ^3a R ^3b (hereinafter, compound (IIh)
May be abbreviated as follows), for example, according to the following reaction formula 8. That is, step (ha): a compound represented by the formula (IVh) (hereinafter, referred to as
Step (hb): Deprotection of a compound represented by the formula (Vh) (hereinafter sometimes abbreviated as compound (Vh)) The reaction,
Compound (IIh) can be produced by performing the steps sequentially. Reaction formula 8

Embedded image [Wherein each symbol is as defined above]

In step (ha), compound (IVh)
Is reacted with an appropriate reagent to convert the carbonyl group, whereby the compound (Vh) can be produced. Examples of such a reagent include reducing agents such as sodium borohydride, lithium aluminum hydride, and triethylsilane; organometallic reagents such as alkyllithium and alkylmagnesium halides; and nucleophilic reactants such as hydrogen cyanide. Can be Specifically, the conversion of the carbonyl group to —CH (OH) — or —CH ₂ — is performed by using a reducing agent such as sodium borohydride, lithium aluminum hydride, triethylsilane, or the like, under appropriate reduction conditions ( For example, triethylsilane-trifluoroacetic acid,
Reduction using a combination of lithium aluminum hydride-aluminum chloride, zinc-hydrochloric acid, etc.). This reaction is carried out, for example, with Reduction with Complex Metal Hydride (Reduction with Co
mplex Metal Hydrides) Interscience, New York
(1956), Chemical Society Reviews (Ch
em. Soc. Rev.), 5 , 23 (1976), Synthesi
s), 633 (1974), Journal of the American Chemical Society (J. Am. Chem. Soc.) 91 ,
2967 (1969), Journal of Organic Chemistry (J. Org. Chem.), 29 , 121 (1964), Organic Reactions (Org. Reactons), 1 , 155 (1942), Angevante
Hemy (Angew. Chem.), 71 , 726 (1956), synthesis (S
ynthesis), 633 (1974), Journal of the American Chemical Society (J. Am. Chem. So
c.), 8 0, 2896 (1958), Organic Reactions (Org. Reactons), 4, 378 (1948), Journal of the American Chemical Society (J. Am.
Chem. Soc.), 108 , 3385 (1986) and the like or a method analogous thereto.

Further, the carbonyl group represented by —CR ^3C (OH) —
(Here, R ^3C represents a C _1-6 alkyl group.) For example, Grignard Reactions of Nonmetallic Substances is used by using an organometallic reagent such as alkyllithium and alkylmagnesium halide. Substance
s), Prentice-Hall: Englewood Cliffs, NJ, 1954, pp.
138-528, Organolithium Method
Methods), Academic Press: New York, 1988, pp. 67-
The method can be carried out according to the method described in 75, etc., or a method analogous thereto. The conversion of the carbonyl group is
Advanced Organic Chemistry
Organic Chemistry), 5th ed.Wiley-Interscience: N
ew York, 1992, pp. 879-981, or the like, or a method analogous thereto. Compound (IVh) can be obtained by a method known per se or a method analogous thereto, for example, JP-A-5-140149, JP-A-6-206
875, Journal of Medicinal Chemistry (J. Med. Chem.), 37 , 2292 (1994), etc., or a method analogous thereto. In step (hb), compound (Vh) is subjected to a deprotection reaction to remove W ¹ , whereby compound (I)
Ih) can be produced. This reaction can be carried out, for example, in the same manner as in the deprotection reaction of compound (VIa).

1-9) Of the starting compound (II), X
^A compound in which ¹ is C = CR ^3a R ^3b (the symbols in the formula have the same meanings as described above) (hereinafter, sometimes abbreviated as compound (IIi)) can be produced, for example, according to the following reaction formula 9. Can be. That is, step (ia): a conversion reaction of the carbonyl group of compound (IVh), and step (ib): deprotection of a compound represented by formula (Vi) (hereinafter sometimes abbreviated as compound (Vi)). The reaction
Compound (IIi) can be produced by performing the steps sequentially. Reaction formula 9

Embedded image [In the formula, each symbol has the same meaning as described above.] In the step (ia), the compound (IVh) may be reacted with an appropriate reagent to convert the carbonyl group to produce the compound (Vi). it can. Examples of the conversion reaction of the carbonyl group include, for example, a Wittig reaction,
Horner-Wadsworth-Em
mons) reaction, Peterson olefination reaction, Knoevenagel reaction, and the like, and a common reagent used in these reactions is used as a reagent. This reaction is performed, for example, by using Advanced Organic Chemistr
y), 5th ed. Wiley-Interscience: New York, 1992, p
p. 879-981, Organic Synth
esis), coll. vol. 5, 751 (1973), Organic Synthesis, coll. vol. 5, 509 (1973)
3), Synthesis, 384 (1984), Organic Reactions (Org. Reactons), 15 , 204 (1967)
And the like, or a method analogous thereto. In step (ib), the compound (Vi) is subjected to deprotection reaction, by removing the W ^1, can be prepared a compound (IIi). This reaction can be carried out, for example, in the same manner as in the deprotection reaction of compound (VIa).

1-10) Of the starting compound (II),
A compound wherein X ¹ is C = NR ^3a (hereinafter, compound (II)
j) may be abbreviated to, for example, the following reaction formula 1
0. That is, step (ja): a conversion reaction of a carbonyl group of compound (IVh), and step (jb): deprotection of a compound represented by the formula (Vj) (hereinafter sometimes abbreviated as compound (Vj)). The reaction,
Compound (IIj) can be produced by performing the steps sequentially. Reaction formula 10

Embedded image [Wherein the symbols have the same meanings as described above.] In the step (ja), the compound (Vj) can be produced by reacting the compound (IVh) with an appropriate reagent to convert the carbonyl group. it can. Examples of the reagent used for the carbonyl group conversion reaction include hydrazine which may be substituted, hydroxylamine which may be substituted, and the like. Here, examples of the substituent in “optionally substituted hydrazine” and “optionally substituted hydroxylamine” include C _1-6
An alkyl group or the like is used. This reaction can be performed, for example, by using Advanced Organic Chemistry (Advanced Organ Chemistry).
ic Chemistry), 5th ed. Wiley-Interscience: New Yor
k, 1992, pp. 904-907, Organic Functional Group Preparations
Group Preparations), vol. III, Academic (1983), Rod Chemistry of Carbon Compounds
(Rodd's Chemistory of Carbon Compounds), vol. 1, p
art C, Elsevier Publishing co. (1965) or the like, or a method analogous thereto. In the step (jb), the compound (Vj) is subjected to a deprotection reaction to remove W ¹ , whereby the compound (I)
Ij) can be produced. This reaction can be carried out, for example, in the same manner as in the deprotection reaction of compound (VIa).

1-11) Of the starting compound (II),
A compound in which X ¹ is CS (hereinafter sometimes abbreviated as compound (IIk)) can be produced, for example, according to the following reaction formula 11. Step (ka): conversion reaction of the carbonyl group of the compound (IVh), and Step (kb): deprotection of the compound represented by the formula (Vk) (hereinafter sometimes abbreviated as compound (Vk)). The reaction,
Compound (IIk) can be produced by performing the steps sequentially. Reaction formula 11

Embedded image [Wherein the symbols have the same meanings as described above] In step (ka), compound (IVh) is reacted with an appropriate reagent to convert a carbonyl group into a thiocarbonyl group, thereby converting compound (Vk). Can be manufactured. Examples of the reagent used for converting a carbonyl group to a thiocarbonyl group include a sulfurizing reagent and the like, preferably a Lawesson reagent, diphosphorus pentasulfide, hydrogen sulfide-hydrochloric acid and the like. This reaction is performed by Synthesis,
7, 543 (1991), Journal of the American Chemical Society (J. Am. Chem. Soc.), 106, 9
34 (1984), Journal of the American Chemical Society (J. Am. Chem. Soc.) 68, 769 (1
946) or a method similar thereto. In the step (kb), the compound (Vk)
Is subjected to a deprotection reaction to remove W ¹ , whereby compound (IIk) can be produced. This reaction can be carried out, for example, in the same manner as in the deprotection reaction of compound (VIa).

1-12) Of the starting compound (II),
A compound wherein X ¹ is CONR ^3a (hereinafter referred to as compound (II)
m) may be represented by the following reaction formula 12-1
Can be manufactured. That is, step (ma): a compound represented by the formula (Vm) (hereinafter sometimes abbreviated as compound (Vm)) and a compound (IV
Step (mb): a compound represented by the formula (VIm)
Compound (IIm) can be produced by sequentially performing the deprotection reaction of compound (VIm)). Reaction formula 12-1

Embedded image [Wherein the symbols have the same meanings as described above] In the step (ma), the compound (Vm) and the compound (IV
Compound (VIm) can be produced by a condensation reaction with e). The condensation reaction is carried out, for example, by reacting the compound (IVb)
And the compound (Vc). In step (mb), the compound (VIm) subjected to deprotection reaction, by removing the W ^1, can be prepared a compound (IIm). This reaction can be carried out, for example, in the same manner as in the deprotection reaction of compound (VIa).

The starting compound (Vm) in the step (ma) can be produced, for example, according to the following reaction formula 12-2. Step (mc): acetylation reaction of compound (VIIb)
And step (md): performing an oxidation reaction of a compound represented by the formula (VIIIm) (hereinafter sometimes abbreviated as compound (VIIIm)), and optionally converting a functional group, to obtain a compound ( Vm). Reaction formula 12-2

Embedded image [Wherein the symbols have the same meanings as described above] In the step (mc), the compound (VIIIm) can be produced by acetylating the compound (VIIb). This reaction is a general Friedel-Crafts
(Friedel-Crafts) reaction. Acetylation is performed using, for example, acetyl chloride or acetic anhydride. This reaction is carried out, for example, as described in
49, JP-A-6-206875, Journal of Medicinal Chemistry (J. Med. Chem.), 37 , 2292
(1994) or the like, or a method analogous thereto. An acetyl group is introduced at any of the reactable positions.

In step (md), compound (VIII)
By oxidizing m), compound (Vm), especially Z ³
Is a hydroxyl group. This reaction is generally performed using an oxidizing agent. Examples of the oxidizing agent include hypochlorite, hypobromite, and a simple halogen (eg, bromine, iodine, etc.) in the presence of a suitable base (eg, sodium hydroxide, etc.). . This reaction is performed, for example, using organic synthesis (O
rg. Synthesis), Coll. Vol. 2, 428 (1943), Journal of the American Chemical Society
(J. Am. Chem. Soc.), 66 , 894 (1944) and the like or a method analogous thereto. If necessary, the hydroxyl group of the compound (Vm) in which Z ³ is a hydroxyl group is subjected to a functional group conversion, whereby Z ³ is a halogen atom (for example, chlorine, bromine, iodine, etc.), a C _1-6 alkoxy group (Eg, methoxy, ethoxy, etc.), a C _7-16 aralkyloxy group (eg, benzyloxy, etc.), or C which may be substituted by nitro
Compound (Vm) which is a _6-10 aryloxy group (for example, phenoxy, p-nitrophenoxy, etc.) can be produced. Functional group conversion can be performed, for example, by using Advanced Organic Chemistry, 5t.
h ed. Wiley-Interscience: New York, 1992, pp. 393-
396,437-438, Comprehensive Organic Transformations
nsformations), VCH Publishers Inc. (1989), and the like, or a method analogous thereto.

2) Compound (I) can also be produced by the following method and the like. 2-1) Among compounds (I), a compound in which X ¹ is SO ₂ NR ^3a (hereinafter sometimes abbreviated as compound (Iee)) can be produced by the following reaction formula 2-1. . That is, compound (VIIId) and formula (IVee)
(Hereinafter sometimes abbreviated as compound (IVee)) by the condensation reaction of compound (Iee)
Can be manufactured. Reaction formula 2-1

Embedded image [Wherein the symbols have the same meanings as described above] The condensation reaction is performed, for example, with compound (IVb) and compound (Vc).
In the same manner as in the amidation reaction of Compound (IVee) can be produced by a method known per se or a method analogous thereto. Compound (IVee)
Or a salt thereof is described, for example, in Journal of the Medicinal Chemistry (J. Med. Chem.), 33 , 18
80 (1990) or a method analogous thereto.

2-2) In the compound (I), X ¹ is S
O ₂ NHCONR ^3a (hereinafter referred to as compound (If
f) may be represented, for example, by the following reaction formula 2.
-2. That is, compound (VIIId) and alkali metal isocyanate (MOC
N; where M represents an alkali metal. ), And then the compound (IVee) is further reacted to produce the compound (Iff). Reaction formula 2-2

Embedded image [Wherein the symbols have the same meanings as described above.] In this reaction, for example, compound (VI) described in the above 1-6)
It can be carried out in the same manner as in the condensation reaction between IId) and compound (IVe).

2-3) In compound (I), X ¹ is S
The compound of O ₂ NHC (＝ NH) NR ^3a (hereinafter sometimes abbreviated as compound (Igg)) can be produced, for example, by the following reaction formula 2-3. Compound (V
IIId) and a compound represented by the formula (IVgg)
Compound (Igg) can be produced by a condensation reaction with compound (IVgg). Reaction formula 2-3

Embedded image [Wherein the symbols have the same meanings as described above] The condensation reaction is performed, for example, with compound (IVb) and compound (Vc).
In the same manner as in the amidation reaction of Compound (IVgg) can be obtained, for example, using compound (IVee)
It can be produced in the same manner as for compound (IVg).

2-4) In compound (I), X ¹ is C
Compound (Ihh) which is R ^3a R ^3b (hereinafter, compound (Ih)
h) may be represented, for example, by the following reaction formula 2
-4. That is, the formula (IV
Compound (Ihh) can be produced by reacting a compound represented by formula (hh) (hereinafter sometimes abbreviated as compound (IVhh)) with an appropriate reagent to convert a carbonyl group. Reaction formula 2-4

Embedded image [Wherein the symbols have the same meanings as described above.] The present reaction is carried out, for example, using compound (IV) described in the above 1-8).
The reaction can be carried out in the same manner as in the conversion reaction of h) into compound (Vh). Compound (IVhh) can be obtained by a method known per se or a method analogous thereto, for example, JP-A-5-14014
9, JP-A-6-206875, Journal of Medicinal Chemistry (J. Med. Chem.), 37 , 2292 (1
994), or a method analogous thereto.

2-5) In compound (I), X ¹ is C
A compound in which ＝ CR ^3a R ^3b (hereinafter sometimes abbreviated as compound (Iii)) can be produced, for example, by the following reaction formula 2-5. That is, the compound (IVh
The compound (Iii) can be produced by reacting h) with an appropriate reagent to convert the carbonyl group. Reaction formula 2-5

Embedded image [Wherein the symbols have the same meanings as described above]. This reaction is carried out, for example, using compound (IV) described in the above 1-9).
The reaction can be carried out in the same manner as in the conversion reaction of h) into compound (Vi).

2-6) In the compound (I), X ¹ is C
= N—R ^3a (the symbols have the same meanings as described above) (hereinafter sometimes abbreviated as compound (Ijj)):
For example, it can be produced by the following reaction formula 2-6. That is, by reacting the compound (IVhh) with an appropriate reagent, the carbonyl group can be converted to produce the compound (Ijj). Reaction formula 2-6

Embedded image [Wherein the symbols have the same meanings as described above.] In this reaction, for example, compound (I) described in the above 1-10)
The reaction can be carried out in the same manner as in the conversion reaction of Vh) into compound (Vj).

2-7) In compound (I), X ¹ is C
The compound represented by S (hereinafter sometimes abbreviated as compound (Ikk)) can be produced, for example, according to the following reaction formula 2-7. That is, the compound (Ikk) can be produced by reacting the compound (IVhh) with a suitable reagent to convert the carbonyl group into a thiocarbonyl group. Reaction formula 2-7

Embedded image [Wherein the symbols have the same meanings as described above.] In this reaction, for example, compound (I) described in the above 1-11)
Vh) can be carried out in the same manner as in the conversion reaction to compound (Vk).

2-8) In compound (I), X ¹ is C
The compound that is ONR ^3a (hereinafter sometimes abbreviated as compound (Imm)) can be produced, for example, according to the following Reaction Formula 2-8. That is, the compound (Im) is obtained by a condensation reaction between the compound (Vm) and the compound (IVee).
m) can be manufactured. Reaction formula 2-8

Embedded image [Wherein the symbols have the same meanings as described above] This reaction can be carried out, for example, in the same manner as in the amidation reaction of compound (IVb) with compound (Vc).

3) Compound (I) has the formula

Embedded image [Wherein, R ^2A is a synthetic precursor of R ² , and other symbols are as defined above. Can be produced by subjecting the compound represented by the formula [1] to various conversion reactions. As the “synthesis precursor of R ² ” represented by R ^2A , for example, a nitro group, a leaving group exemplified as the aforementioned Z ¹ , a cyano group and the like can be mentioned. The conversion reaction is performed according to a method known per se.

3-1) Among the compounds (I), those in which R ² is an amino group include, for example, those represented by the formula

Embedded image [Wherein each symbol has the same meaning as described above. ] Can be produced by reducing the nitro group of the compound represented by the formula: This reduction reaction can be performed, for example, in the same manner as in the reduction reaction of compound (VIIb) in the above step (bd). 3-2) In compound (I), R ² is C
_An amino group optionally substituted with _1-6 alkyl or 5
The compound having a 7-membered cyclic amino group is, for example, a compound represented by the formula

Embedded image [Wherein each symbol has the same meaning as described above. And a compound represented by the formula ^{HR 2Ab} (III) wherein R ^2Ab is an amino group optionally substituted with C _1-6 alkyl or a 5- to 7-membered cyclic amino group, The symbols are as defined above. To a condensation reaction. Regarding R ^2Ab , as the “amino group or 5- to 7-membered cyclic amino group optionally substituted with C _1-6 alkyl”, those exemplified as the aforementioned R ² can be mentioned. This condensation reaction is carried out, for example, by reacting compound (II) with compound (II)
It can be carried out in the same manner as in the condensation reaction with I).

3-3) In the compound (I), R ² is an optionally substituted amidino group or an optionally substituted 5- or 6-membered nitrogen-containing heterocyclic group (preferably The compound which is an imidazolinyl group) is, for example, a compound represented by the formula

Embedded image [Wherein each symbol has the same meaning as described above. Can be produced by reacting a compound represented by the formula [1] with an alcohol in the presence of hydrogen chloride and then reacting with various amines. This reaction is performed, for example, by using Organic Synthesis (Org.
th.), I, 5 (1941) and Methoden der Organischen Chemie
(Houben-Weyl), Band XI / 2, Georg Thieme (1958), p3
It can be carried out by the method described in 8-72 or a method analogous thereto.

Compound (I) or a salt thereof (hereinafter sometimes abbreviated as the compound of the present invention) has excellent MCH receptor antagonistic activity and is therefore useful as an agent for preventing or treating diseases caused by MCH. . In addition, the compounds of the present invention have low toxicity, and are excellent in oral absorption and brain localization. Therefore, melanin-concentrating hormone antagonists (hereinafter sometimes abbreviated as MCH antagonists) containing the compound of the present invention can be used in mammals (eg, rats, mice, guinea pigs, rabbits, sheep, horses, pigs, cows, monkeys). , Humans, etc.) as a preventive or therapeutic agent for diseases caused by MCH. Here, as a disease caused by MCH, for example, obesity [eg, malignant mastocytosis (malignant mastocytosis)
sis), exogenous obesity, hyperinsulin obesity, hyperplasmic obesity (h
yperplasmic obesity), hypophyseal adi
posity), hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatism
ic obesity), childhood obesity (infantile obesity), upper body obesity (upper body obesity), dietary obesity (alimentary)
obesity), hypogonadal obesity,
Systemic mastocytosis, simple obesity, central obesity, etc.], hyperphagia, affective disorder, sexual dysfunction and the like.

The compound of the present invention is useful for the treatment of diabetes and diabetic complications.
(Eg, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, etc.), and is also useful as a prophylactic / therapeutic agent for lifestyle-related diseases such as arteriosclerosis and knee arthritis. Further, the compound of the present invention is also useful as an antifeedant. The MCH antagonist and the pharmaceutical composition of the present invention can also be used in combination with diet therapy (eg, diet therapy for diabetes, etc.) and exercise therapy.

The MCH antagonist and the pharmaceutical composition of the present invention include:
It is produced by formulating compound (I) or (Ia) as it is or together with a pharmacologically acceptable carrier according to a means known per se.

Here, the pharmacologically acceptable carrier includes various organic or inorganic carrier substances commonly used as pharmaceutical materials, such as excipients, lubricants, binders, disintegrants in solid preparations, and liquid preparations. Solvents, dissolution aids, suspending agents, isotonic agents, buffers, soothing agents and the like.
At the time of formulation, additives such as preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents and the like can be used, if necessary. Examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, and the like. Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. As the binder, for example, crystalline cellulose,
Examples include sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like. As a disintegrant, for example,
Examples include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethylstarch sodium, low-substituted hydroxypropylcellulose (L-HPC), and the like.

As the solvent, for example, water for injection, alcohol, propylene glycol, macrogol, sesame oil,
Corn oil and the like. Examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; for example, polyvinyl alcohol,
Examples include hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.

Examples of the tonicity agent include glucose, D
-Sorbitol, sodium chloride, glycerin, D-mannitol and the like. Examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate. Examples of the soothing agent include benzyl alcohol and the like. Examples of the preservative include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like. Examples of the antioxidant include sulfite and ascorbic acid.

The dosage forms of the MCH antagonist and the pharmaceutical composition of the present invention include, for example, oral preparations such as tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules (including soft capsules), and liquids Injections (eg, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, etc.), external preparations (eg, transnasal preparations, transdermal preparations, ointments, etc.), suppositories (eg, Orally or parenterally as parenteral preparations such as rectal suppositories, vaginal suppositories, sustained-release preparations (eg, sustained-release microcapsules, etc.), pellets, drops, etc.
(Eg, topical, rectal, intravenous administration, etc.).

The content of the compound (I) in the MCH antagonist of the present invention and the content of the compound (Ia) in the pharmaceutical composition of the present invention are, for example, about the same as that of the MCH antagonist or the whole pharmaceutical composition, respectively. 0.1 to 100% by weight. The dose of the MCH antagonist and the pharmaceutical composition of the present invention is appropriately selected depending on the administration subject, administration route, disease and the like. For example, the present invention
The daily dose when an MCH antagonist or a pharmaceutical composition is orally administered to an obese adult patient (body weight about 60 kg) is as follows:
The compound (I) or (Ia) as an active ingredient is about 0.1 to about 500 mg, preferably about 1 to about 100 mg, respectively.
mg, more preferably about 5 to about 100 mg, which can be administered in one or several divided doses per day.

The MCH antagonist and the pharmaceutical composition of the present invention include:
For example, a combination drug that does not adversely affect the MCH antagonist and the pharmaceutical composition of the present invention can be used for the purpose of “enhancing the therapeutic effect of obesity”, “reducing the amount of MCH antagonist”, and the like. Examples of such concomitant drugs include "diabetes therapeutics", "diabetic complications", "MCH
Other examples include anti-obesity drugs other than antagonists, "hypertensive drugs", "hyperlipidemic drugs", "arthritis drugs", "anti-anxiety drugs", and "anti-depressants". Two or more of these concomitant drugs may be used in combination at an appropriate ratio.

Examples of the above "agents for treating diabetes" include insulin sensitizers, insulin secretagogues, biguanides, insulin, α-glucosidase inhibitors, β
3 adrenergic receptor agonists and the like. Examples of the insulin sensitizer include pioglitazone or a salt thereof (preferably hydrochloride), troglitazone, rosiglitazone or a salt thereof (preferably maleate),
JTT-501, GI-262570, MCC-55
5, YM-440, DRF-2593, BM-13-1
258, KRP-297, CS-011 and the like. Examples of the insulin secretagogue include a sulfonylurea agent. Specific examples of the sulfonylurea agent include, for example, tolbutamide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide and its ammonium salt, glibenclamide, gliclazide, glimepiride and the like. In addition to the above, examples of the insulin secretagogue include repaglinide, nateglinide, KAD-1229, JTT-608 and the like.

The biguanides include, for example, metformin, buformin and the like. Examples of the insulin include animal insulin extracted from bovine and porcine pancreas; semi-synthetic human insulin enzymatically synthesized from insulin extracted from porcine pancreas; human insulin genetically synthesized using Escherichia coli and yeast. And the like. 0.45 to 0.9 as insulin
Insulin zinc containing (w / w)% zinc; zinc chloride;
Protamine insulin zinc produced from protamine sulfate and insulin is also used. Further, insulin is a fragment or derivative thereof (eg, INS-1
Etc.). Insulin includes various types such as super fast-acting type, fast-acting type, two-phase type, intermediate type and continuous type, and these can be appropriately selected depending on the condition of the patient. Examples of the α-glucosidase inhibitor include acarbose, voglibose, miglitol, emiglitate and the like. Examples of β3 adrenergic receptor agonists include, for example, AJ-9677, BMS-196085,
SB-226552, SR-58611-A, CP-1
14271, L-755507 and the like. In addition to the above, examples of the "agent for treating diabetes" include ergoset, pramlintide, leptin, BAY-27-9955 and the like.

Examples of the "agent for treating diabetic complications" include aldose reductase inhibitors, glycation inhibitors, protein kinase C inhibitors and the like. Examples of aldose reductase inhibitors include tolrestat; epalrestat; imirestat; zenarestat; SNK-860; zopolrestat; ARI-50.
9; AS-3201 and the like. Examples of the glycation inhibitor include pimagedine and the like.
Examples of protein kinase C inhibitors include NGF, LY-
333531 and the like. In addition to the above, examples of the "agent for treating diabetic complications" include alprostadil, tiapride hydrochloride, cilostazol, mexiletine hydrochloride, ethyl icosapentate, memantine, pimagedline (pimagedline; ALT-711) and the like.

Examples of the above-mentioned "anti-obesity drugs other than MCH antagonists" include lipase inhibitors, appetite suppressants and the like. Examples of lipase inhibitors include orlistat,
AZM-131 and the like. Appetite suppressants include, for example, mazindol, dexfenfuramine, fluoxetine, sibutramine, biamine and the like. In addition to the above, “anti-obesity drugs other than MCH antagonists” include, for example, lipstatin, FPL-15849, ER
-230, OB protein, AZM-090, P
-57, LY-355101 and the like. Also,
The β3 adrenergic receptor agonist and leptin exemplified as the above-mentioned “therapeutic agent for diabetes” may be used as the “anti-obesity drug other than the MCH antagonist”.

Examples of the "agent for treating hypertension" include angiotensin converting enzyme inhibitors, calcium antagonists, potassium channel openers, angiotensin II antagonists and the like. Examples of the angiotensin converting enzyme inhibitor include captopril, enalapril, alacepril, delapril (hydrochloride), lisinopril, imidapril, benazepril, cilazapril, temocapril, trandolapril, and manidipine (hydrochloride).
Examples of the calcium antagonist include nifedipine, amlodipine, efonidipine, nicardipine and the like. Examples of potassium channel openers include Levcromakalim, L-27152, AL0671, NIP-121 and the like. Examples of the angiotensin II antagonist include losartan, candesartan cilexitil, valsartan, irbesartan, CS-866, E4177 and the like.

Examples of the "agent for treating hyperlipidemia" include HMG-CoA reductase inhibitors, fibrate compounds and the like. Examples of the HMG-CoA reductase inhibitor include pravastatin (sodium salt), cerivastatin (sodium salt), simvastatin, lovastatin, atorvastatin, fluvastatin, lipanthryl, and the like. Examples of the fibrate compounds include bezafibrate, clinofibrate, clofibrate, and simfibrate.

Examples of the "agent for treating arthritis" include ibuprofen. Examples of the above-mentioned "anxiolytics" include chlordiazepoxide, diazepam, oxazolam, medazepam, cloxazolam, bromazepam, lorazepam, alprazolam, fludiazepam and the like. Examples of the above-mentioned "antidepressant" include fluoxetine, fluvoxamine, imipramine, paroxetine, sertraline and the like.

The administration time of the above-mentioned concomitant drug is not limited, and the MCH antagonist or the pharmaceutical composition and the concomitant drug may be administered to the subject at the same time or may be administered with a time lag. Is also good. The dose of the concomitant drug may be in accordance with the dose clinically used, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like. The administration form of the concomitant drug is not particularly limited as long as the MCH antagonist or the pharmaceutical composition and the concomitant drug are combined at the time of administration. Such dosage forms include:
For example, 1) administration of a single preparation obtained by simultaneously preparing an MCH antagonist or a pharmaceutical composition and a concomitant drug, 2)
Simultaneous administration of the two preparations obtained by separately formulating the MCH antagonist or the pharmaceutical composition and the concomitant drug by the same administration route; 3) Separately administering the MCH antagonist or the pharmaceutical composition and the concomitant drug separately Administration of two preparations obtained by formulation at different times by the same administration route. 4) Difference between two preparations obtained by separately preparing an MCH antagonist or a pharmaceutical composition and a concomitant drug. 5) simultaneous administration by administration route, 5) administration of two formulations obtained by separately formulating an MCH antagonist or a pharmaceutical composition and a concomitant drug with different administration routes at different times (for example, MCH antagonist Or a pharmaceutical composition; administration of the concomitant drugs in the order of administration, or administration in the reverse order). The mixing ratio of the MCH antagonist or the pharmaceutical composition to the concomitant drug can be appropriately selected depending on the administration subject, administration route, disease and the like.

[0136]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention further includes the following reference examples,
Examples, formulation examples, experimental examples will be described in detail,
These do not limit the present invention, and may be changed without departing from the scope of the present invention. “Room temperature” in the following Reference Examples and Examples indicates 0 to 30 ° C., and anhydrous magnesium sulfate or anhydrous sodium sulfate was used for drying the organic layer. "%" Means weight percent unless otherwise specified. The infrared absorption spectrum was measured by a diffuse reflection method using a Fourier transform infrared spectrophotometer.

Other abbreviations used herein have the following meanings. s: singlet d: doublet t: triplet q: quartet m: multiplet br: broad J: coupling constant (co)
nstant) Hz: Hertz CDCl ₃ : heavy chloroform DMSO-d ₆ : heavy dimethyl sulfoxide THF: tetrahydrofuran DMF: N, N-dimethylformamide DMSO: dimethyl sulfoxide WSCD: 1-ethyl-3- (3-dimethylaminopropyl) ) Carbodiimide WSC: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride ¹ H-NMR: Proton nuclear magnetic resonance
Measured in DCl ₃ . ) IR: infrared absorption spectrum Me: methyl Et: ethyl HOBt: 1-hydroxy-1H-benzotriazole IPE: diisopropyl ether DMAP: 4-dimethylaminopyridine

In the present specification, when bases, amino acids, and the like are represented by abbreviations, these abbreviations are represented by IUPAC-IUB.
Commission on Biochemical N
This is based on the abbreviation by omenclature or the abbreviation commonly used in the art, examples of which are described below. When amino acids may have optical isomers,
Unless otherwise specified, it indicates the L-form. DNA: deoxyribonucleic acid cDNA: complementary deoxyribonucleic acid A: adenine T: thymine G: guanine C: cytosine RNA: ribonucleic acid mRNA: messenger ribonucleic acid dATP: deoxyadenosine triphosphate dTTP: deoxythymidine triphosphate dGTP: deoxyguanosine triphosphate Phosphate dCTP: Deoxycytidine triphosphate ATP: Adenosine triphosphate EDTA: Ethylenediaminetetraacetic acid SDS: Sodium dodecyl sulfate EIA: Enzyme immunoassay Gly: Glycine Ala: Alanine Val: Valine Leu: Leucine Ile: Isoleucine Serin: Isoleucine Serine Cys: cysteine Met: methionine Glu: glutamic acid Asp: aspartic acid Lys: lysine Arg: al Nin His: Histidine Phe: Phenylalanine Tyr: Tyrosine Trp: Tryptophan Pro: Proline Asn: Asparagine Gln: Glutamine pGl: Pyroglutamic acid Me: Methyl group Et: Ethyl group Bu: ThiR phenyl group PhC: ThiP phenyl group -Carboxamide group

The substituents, protecting groups and reagents frequently used in the present specification are represented by the following symbols. Tos: p-toluenesulfonyl CHO: formyl Bzl: benzyl Cl ₂ Bzl: 2,6-dichlorobenzyl Bom: benzyloxymethyl Z: benzyloxycarbonyl Cl-Z: 2-chlorobenzyloxycarbonyl Br-Z: 2-bromobenzyl Oxycarbonyl Boc: t-butoxycarbonyl DNP: dinitrophenol Trt: trityl Bum: t-butoxymethyl Fmoc: N-9-fluorenylmethoxycarbonyl HOBt: 1-hydroxybenztriazole HOOBT: 3,4-dihydro-3-hydroxy -4-oxo-1,2,3-benzotriazine HONB: 1-hydroxy-5-norbornene-2,3-dicarbodiimide DCC: N, N'-dicyclohexylcarbodiimide

The sequence numbers in the sequence listing in the present specification indicate the following sequences. [SEQ ID NO: 1] This shows the synthetic DNA used for screening of cDNA encoding rat SLC-1. [SEQ ID NO: 2] This shows the synthetic DNA used for screening of cDNA encoding rat SLC-1. [SEQ ID NO: 3] This shows the entire amino acid sequence of rat SLC-1. [SEQ ID NO: 4] This shows the entire nucleotide sequence of rat SLC-1 cDNA having a Sal I recognition sequence added to the 5 ′ side and a Spe I recognition sequence added to the 3 ′ side. [SEQ ID NO: 5] This shows the riboprobe used for measuring the expression level of SLC-1 mRNA in each clone of rat SLC-1 expression CHO cells. [SEQ ID NO: 6] This shows the synthetic DNA used to obtain cDNA encoding human SLC-1. [SEQ ID NO: 7] This shows the primer used to make cDNA encoding human SLC-1 double-stranded. [SEQ ID NO: 8] This shows the entire nucleotide sequence of cDNA encoding human SLC-1. [SEQ ID NO: 9] This shows the entire amino acid sequence of human SLC-1. [SEQ ID NO: 10] This shows the synthetic DNA used for screening of cDNA encoding human SLC-1 (S). [SEQ ID NO: 11] This shows the synthetic DNA used for screening of cDNA encoding human SLC-1 (S). [SEQ ID NO: 12] This shows the synthetic DNA used for screening of cDNA encoding human SLC-1 (L). [SEQ ID NO: 13] This shows the synthetic DNA used for screening of cDNA encoding human SLC-1 (L). [SEQ ID NO: 14] Sal I recognition sequence was added to the 5 ′ side,
Human SLC-1 (S) cD with Spe I recognition sequence added to the 3 'side
Shows the entire nucleotide sequence of NA. [SEQ ID NO: 15] A Sal I recognition sequence is added to the 5 ′ side,
Human SLC-1 (L) cD with Spe I recognition sequence added to the 3 'side
Shows the entire nucleotide sequence of NA. [SEQ ID NO: 16] SLC-1mRN in each clone of human SLC-1 (S) -expressing CHO cells and human SLC-1 (L) -expressing CHO cells
Riboprobe (rib) used to measure the expression level of A
oprobe).

SEQ ID NO: obtained in Reference Example 1-6 described below:
Transformant Escherichia coli DH10B / phSLC1L8 with plasmid containing DNA encoding base sequence represented by 9
Was deposited with the National Institute of Advanced Industrial Science and Technology (NIBH) on February 1, 1999 under the deposit number FERM.
No. IFO 162 as BP-6632 from the Fermentation Research Institute (IFO) from January 21, 1999
Deposited as No. 54.

[0142]

Reference Example 1 The following compound was obtained according to a method known per se (a method described in WO 98/46590 or a method analogous thereto). 1) 4- [1-[[3- (4,5-dihydro-1H-2-imidazolyl) phenyl] methyl] -4-piperidinyl] -1- [3-[(2-methylphenyl) methyl] -2 , 3,4,5-Tetrahydro-1H-3-benzazepin-7-yl] -1-butanone trihydrochloride

Embedded image Colorless powder. 183-185 ° C. ¹ H NMR (CDCl ₃ , free base) δ 1.10-1.40 (5H, m), 1.6
0-1.80 (4H, m), 1.80-2.00 (2H, m), 2.39 (3H, s),
2.55-2.70 (4H, m), 2.75-3.00 (9H, m), 3.49 (2H,
s), 3.54 (2H, s), 3.78 (4H, s), 7.10-7.20 (4H, m),
7.25-7.45 (3H, m), 7.60-7.75 (4H, m). 2) 3-[[4- [4- [3-[(2-methylphenyl) methyl] -2,3,4,5
-Tetrahydro-1H-3-benzazepin-7-yl] -4-oxobutyl] -1-piperidinyl] methyl] -1-benzenecarboximidamide

Embedded image Colorless crystals. 150-152 ° C. ¹ H NMR (CDCl ₃ ) δ 1.10-1.40 (5H,
m), 1.60-1.82 (4H, m), 1.
84-2.05 (5H, m), 2.39 (3
H, s), 2.55-2.70 (4H, m),
2.74-3.02 (8H, m), 3.45-
3.60 (4H, m), 7.10-7.37 (5
H, m), 7.40-7.80 (6H, m). Elemental analysis: calculated as C ₃₅ H ₄₄ N ₄ O.3H ₂ O: C, 71.15; H, 8.53; N, 9.48. Experimental: C, 71.52; H, 8.19; N, 8.98.

Reference Example 2 t-butyl 4- [3-[[2-[(4-fluorophenyl) methyl] -2,
3,4,5-tetrahydro-1H-2-benzazepin-8-yl] oxy] propyl] -1-piperidinecarboxylate

Embedded image 1) 4-Fluorobenzyl chloride (2.87 ml) was added to 8
-Methoxy-2,3,4,5-tetrahydro-1H-2
-To a suspension of benzazepine (3.89 g), potassium carbonate (4.0 g) and potassium iodide (catalytic amount) in ethanol (150 ml) at room temperature. The mixture was heated under reflux for 3 hours, the solvent was distilled off under reduced pressure, and the residue was dissolved in water-ethyl acetate.
Extracted with ethyl acetate. Wash the extract with saturated saline,
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate = 4: 1) to give 2-[(4-fluorophenyl) methyl] -8-methoxy-2,3,4, 5-tetrahydro-1H-2-benzazepine (5.52
g) was obtained as a colorless oil. ¹ H NMR (CDCl ₃ ) δ1.60-1.80 (2H, m), 2.80-2.95 (2H,
m), 3.10 (2H, t-like, J = 5.2 Hz), 3.50 (2H, s), 3.7
5 (2H, s), 3.82 (2H, s), 6.49 (1H, d, J = 2.8Hz), 6.
69 (1H, dd, J = 2.8, 8.2Hz), 6.90-7.10 (3H, m), 7.20
-7.30 (2H, m). 2) 2-[(4-Fluorophenyl) methyl] obtained in 1) above
A mixture of -8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepine (5.32 g) and a 48% hydrobromic acid solution (80 ml) was added to 14
The mixture was stirred at 0 ° C for 2 hours. After cooling to room temperature, weak alkaline (pH approx.
10) and extracted twice with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 2-[(4-fluorophenyl) methyl] -8-.
Hydroxy-2,3,4,5-tetrahydro-1H-2-benzazepine (5.69 g) was obtained as a colorless powder. ¹ H NMR (CDCl ₃ ) δ1.65-1.80 (2H, m), 2.70-2.85 (2H,
m), 3.04 (2H, t-like, J = 5.2 Hz), 3.54 (2H, s), 3.7
1 (2H, s), 6.24 (1H, d, J = 2.6Hz), 6.55 (1H, dd, J =
2.2, 8.0Hz), 6.91 (1H, d, J = 8.0Hz), 7.20-7.35 (5H,
m). 3) 2-[(4-fluorophenyl) methyl] obtained in 2) above
-8-hydroxy-2,3,4,5-tetrahydro-1H-2-benzazepine (5.0 g) and t-butyl 4- (3-iodopropyl) -1-piperidinecarboxylate (6.3 g) N,
Potassium carbonate (10.0 g) was added to a N-dimethylformamide (80 ml) solution, and the mixture was stirred at 80 ° C. for 12 hours. After evaporating the solvent under reduced pressure, the residue was dissolved in water-ethyl acetate and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The obtained residue was purified by silica gel column chromatography (eluent; hexane-ethyl acetate = 19: 1) to give the title compound (7.2 g) as a colorless oil. ¹ H NMR (CDCl ₃ ) δ1.00-1.25 (2H, m), 1.46 (9H, s),
1.60-1.90 (7H, m), 2.55-2.80 (2H, m), 2.80-2.90 (2
H, m), 3.08 (2H, t-like, J = 5.4Hz), 3.48 (2H, s),
6.70-6.80 (2H, m), 3.80 (2H, s), 3.87 (2H, t, J =
6.4Hz), 4.00-4.20 (2H, m), 6.48 (1H, d, J = 2.6H
z), 6.67 (1H, dd, J = 8.0, 2.6Hz), 6.90-7.10 (3H,
m), 7.20-7.30 (2H, m).

Reference Example 3 2-[(4-fluorophenyl) methyl] -8- [3-
(4-Piperidinyl) propoxy] -2,3,4,5-
Tetrahydro-1H-2-benzazepine

Embedded image T-butyl 4- [3-[[2-[(4-fluorophenyl) methyl] -2,3,4,5-tetrahedro-1H-2-benzazepine-8- obtained in Reference Example 2
Yl] oxy] propyl] -1-piperidinecarboxylate
(7.1g) in ethyl acetate solution (30ml) in 4N hydrogen chloride-
An ethyl acetate solution (100 ml) was added at room temperature and stirred for 2 hours. After the solvent was distilled off under reduced pressure, the residue was made alkaline with an aqueous potassium carbonate solution and extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous potassium carbonate, and the solvent was distilled off under reduced pressure to give the title compound (5.1 g).
Obtained as colorless crystals of mp 88-89 ° C. ¹ H NMR (CDCl ₃ ) δ1.00-1.25 (2H, m), 1.30-1.50 (2H,
m), 1.60-1.85 (7H, m), 1.90-2.10 (1H, br), 2.50-
2.70 (2H, m), 2.80-2.90 (2H, m), 3.00-3.20 (4H,
m), 3.49 (2H, s), 3.81 (2H, s), 3.87 (2H, t, J =
6.4Hz), 6.48 (1H, d, J = 2.6Hz), 6.67 (1H, dd, J =
8.0, 2.6Hz), 6.90-7.10 (3H, m), 7.20-7.30 (2H, m). Elemental analysis: C ₂₄ H ₃₃ FN ₂ O ・ 0.5H ₂ O Calculated: C, 74.04; H, 8.45 N, 6.91. Found: C, 73.82; H, 8.10; N, 6.74.

Reference Example 4 8- [3- [1-[(3-cyanophenyl) methyl] -4-piperidinyl] propoxy] -2-[(4-fluorophenyl)
Methyl] -2,3,4,5-tetrahydro-1H-2-benzazepine

Embedded image 2-[(4-fluorophenyl) methyl] obtained in Reference Example 2
-8- [3- (4-piperidinyl) propoxy] -2,
3,4,5-tetrahydro-1H-2-benzazepine
(500mg) and potassium carbonate (500mg) in acetonitrile (25m
l) To the suspension was added α-bromo-m-tolunitrile (198 mg,
0.83 mmol) was added dropwise at room temperature. The mixture was stirred at room temperature for 10 hours, and the solvent was distilled off under reduced pressure. The residue was dissolved in water-ethyl acetate and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (developing solvent; hexane-ethyl acetate = 4:
Purify by 1) to give the free base of the title compound (356m
g) was obtained as colorless crystals, mp 97-98 ° C. ¹ H NMR (CDCl ₃ ) δ 1.10-1.45 (4H, m), 1.50-1.80 (7
H, m), 1.85-2.05 (2H, m), 2.75-2.90 (4H, m), 3.09
(2H, t-like, J = 5.2 Hz), 3.49 (4H, s), 3.81 (2H,
s), 3.87 (2H, t, J = 6.4 Hz), 6.48 (1H, d, J = 2.6
Hz), 6.67 (1H, dd, J = 8.3, 2.6 Hz), 6.95-7.10 (3
H, m), 7.20-7.30 (2H, m), 7.40 (1H, t, J = 7.4 Hz),
7.50-7.60 (2H, m), 7.65 (1H, s). Elemental analysis calculated as C ₃₃ H ₃₈ FN ₃ O Calculated: C, 77.46; H, 7.49; N, 8.21. Experimental: C, 77.30; H , 7.57; N, 8.21.

Reference Example 5 8-Hydroxy-2-[(2-methylphenyl) methyl]
-2,3,4,5-tetrahydro-1H-2-benzazepine

Embedded image 1) The same as 1) in Reference Example 2 using α-bromo-o-xylene (3.16 ml) and 8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepine (3.80 g). By performing the operation, 8-methoxy-2-[(2-
Methylphenyl) methyl] -2,3,4,5-tetrahydro-1H-2-benzazepine (4.63 g) was obtained as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 1.60-1.70 (2H,
m), 2.19 (3H, s), 2.78 (2
H, t-like, J = 5.4 Hz), 3.
00 (2H, t-like, J = 5.4H
z), 3.41 (2H, s), 3.67 (3
H, s), 3.73 (2H, s), 6.46.
(1H, d, J = 2.6 Hz), 6.60
(1H, dd, J = 8.0, 2.6H
z), 6.98 (1H, d, J = 8.0H)
z), 7.00-7.20 (4H, m). 2) Reference Example 2 using 8-methoxy-2-[(2-methylphenyl) methyl] -2,3,4,5-tetrahydro-1H-2-benzazepine (4.63 g) obtained in 1) above. By performing the same operation as in 2), 8-hydroxy-2-[(2-methylphenyl) methyl] -2,3,3
4,5-tetrahydro-1H-2-benzazepine (4.
37g) was obtained as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 1.75-1.85 (2H, m), 2.26 (3H, s),
2.80 (2H, t-like, J = 5.0 Hz), 3.03 (2H, t-like, J
= 5.0 Hz), 3.48 (2H, s), 3.70 (2H, s), 6.19 (1H,
d, J = 2.6 Hz), 6.46 (1H, dd, J = 8.0, 2.6 Hz), 6.
88 (1H, d, J = 8.0 Hz), 7.00-7.30 (4H, m).

Reference Example 6 t-butyl 4- [2-[[2-[(2-methylphenyl) methyl] -2,3,4,5-tetrahydro-1H-
2-benzazepin-8-yl] oxy] ethyl] -1-
Piperidine carboxylate

Embedded image 8-Hydroxy-2-[(2-methylphenyl) methyl] -2,3,4,5-tetrahydro- obtained in Reference Example 5.
The title compound (4.81 g) was obtained as a viscous oil by performing the same operation as in 3) of Reference Example 2 using 1H-2-benzazepine (3.94 g). ¹ H NMR (CDCl ₃ ) δ 1.05-1.30 (2H,
m), 1.46 (9H, s), 1.60-1.
80 (7H, m), 2.28 (3H, s),
2.60-2.80 (2H, m), 2.86
(2H, t-like, J = 5.4 Hz),
3.07 (2H, t-like, J = 5.2
Hz), 3.49 (2H, s), 3.81
(2H, s), 3.95 (2H, t, J =
5.8 Hz), 4.00-4.20 (2H,
m), 6.54 (1H, d, J = 2.6)
Hz), 6.67 (1H, dd, J = 8).
0, 2.6 Hz), 7.05 (1H, d,
J = 8.0 Hz), 7.10-7.30 (4
H, m).

Reference Example 7 2-[(2-methylphenyl) methyl] -8- [2-
(4-Piperidinyl) ethoxy] -2,3,4,5-tetrahydro-1H-2-benzazepine

Embedded image T-butyl 4- [2-[[2-[(2-
Methylphenyl) methyl] -2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl] oxy] ethyl] -1-piperidinecarboxylate (4.81 g, 10.1
The title compound (3.61 g) was obtained as colorless crystals having a mp of 74-75 ° C. by performing the same operation as in Reference Example 3 using the compound (mmol). ¹ H NMR (CDCl ₃ ) δ 1.05-1.30 (2H, m), 1.50-1.95 (8
H, m), 2.28 (3H, s), 2.50-2.70 (2H, m), 2.86 (2H,
t-like, J = 5.4 Hz), 3.00-3.15 (4H, m), 3.46 (2H,
s), 3.81 (2H, s), 3.94 (2H, t, J = 6.2 Hz), 6.54
(1H, d, J = 2.6 Hz), 6.67 (1H, dd, J = 8.1, 2.6 H
z), 7.04 (1H, d, J = 8.1 Hz), 7.09-7.32 (4H, m). Elemental analysis: Calculated for C ₂₅ H ₃₄ N ₂ O. Calculated: C, 79.32; H, 9.05; N, 7.40. Found: C, 79.00; H, 9.15; N, 7.32.

Reference Example 8 8- [2- [1-[(4-cyanophenyl) methyl] -4-piperidinyl] ethoxy] -2-[(2-methylphenyl) methyl] -2,3,4,5 -Tetrahydro-1H-2-benzazepine

Embedded image 2-[(2-methylphenyl) methyl]-obtained in Reference Example 7
8- [2- (4-piperidinyl) ethoxy] -2,3,
The title compound was obtained as a colorless amorphous powder by performing the same operation as in Reference Example 4 using 4,5-tetrahydro-1H-2-benzazepine. ¹ H NMR (CDCl ₃ ) δ 1.20-1.80 (9H, m), 1.90-2.05 (2H,
m), 2.27 (3H, s), 2.75-2.90 (4H, m), 3.07 (2H, t-
like, J = 5.2 Hz), 3.48 (2H, s), 3.51 (2H, s), 3.8
0 (2H, s), 3.93 (2H, t, J = 6.4 Hz), 6.54 (1H, d,
J = 2.6 Hz), 6.66 (1H, dd, J = 8.2, 2.6 Hz), 7.04
(1H, d, J = 8.0 Hz), 7.10-7.30 (4H, m), 7.44 (2H,
d, J = 8.4 Hz), 7.59 (2H, d, J = 8.4 Hz).

Reference Example 9 Ethyl 4-[[4- [2-[[2-[(2-methylphenyl) methyl] -2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl] [Oxy] ethyl] -1-piperidinyl] methyl] -1-benzenecarboximidate

Embedded image 8- [2- [1-[(4-cyanophenyl) methyl] -4-piperidinyl] ethoxy] -2-[(2-methylphenyl) methyl] -2,3,4,5 obtained in Reference Example 8. -Tetrahydro-1H-2-
The title compound was obtained as colorless crystals having a mp of 103 to 104 ° C by performing the same operation as in 1) of Reference Example 97 using benzazepine. ¹ H NMR (CDCl ₃ ) δ 1.20-1.85 (9H, m), 1.42 (3H, t, J
= 7.0 Hz), 1.90-2.10 (2H, m), 2.27 (3H, s), 2.75-
2.90 (4H, m), 3.07 (2H, t-like, J = 5.2 Hz), 3.48
(2H, s), 3.53 (2H, s), 3.81 (2H, s), 3.93 (2H, t,
J = 6.4 Hz), 4.33 (2H, q, J = 7.0 Hz), 6.54 (1H,
d, J = 2.6 Hz), 6.66 (1H, dd, J = 8.2, 2.6 Hz), 7.0
4 (1H, d, J = 8.0 Hz), 7.10-7.30 (4H, m), 7.38 (2
H, d, J = 8.4 Hz), 7.69 (2H, d, J = 8.4 Hz). Elemental analysis: C ₃₅ H ₄₅ N ₃ O ₂ · 0.5 H ₂ O Calculated: C, 76.61; H, 8.45; N, 7.29. Found: C, 76.72; H, 8.13; N, 7.61.

Reference Example 10 2-[(2-methylphenyl) methyl] -8- [2-
[1-[(3-cyanophenyl) methyl] -4-piperidinyl] ethoxy] -2,3,4,5-tetrahydro-
1H-2-benzazepine dihydrochloride

Embedded image 2-[(2-methylphenyl) methyl] obtained in Reference Example 7
-8- [2- (4-piperidinyl) ethoxy] -2,
The title compound was obtained as a colorless amorphous powder by performing the same operation as in Reference Example 4 using 3,4,5-tetrahydro-1H-2-benzazepine. ¹ H NMR (CDCl ₃ , free base) δ 1.20-1.90 (9H, m), 1.
90-2.10 (2H, m), 2.28 (3H, s), 2.75-2.95 (4H, m),
3.07 (2H, t-like, J = 5.2 Hz), 3.49 (4H, s), 3.81
(2H, s), 3.94 (2H, t, J = 6.2 Hz), 6.54 (1H, d, J
= 2.6 Hz), 6.67 (1H, dd, J = 8.1, 2.6 Hz), 7.00-7.7
0 (9H, m). Elemental analysis: C ₃₃ H ₃₉ N ₃ O.2HCl. H ₂ O Calculated: C, 67.80; H, 7.41; N, 7.19. Experimental: C, 67.95; H, 7.57; N, 7.20.

Reference Example 11 2-[(2-methylphenyl) methyl] -8- [2-
[1- (4-cyanobenzoyl) -4-piperidinyl]
Ethoxy] -2,3,4,5-tetrahydro-1H-2-
Benzazepine hydrochloride

Embedded image 2-[(2-methylphenyl) methyl] obtained in Reference Example 7
-8- [2- (4-piperidinyl) ethoxy] -2,
The title compound was obtained as a colorless amorphous powder by performing the same operation as in Reference Example 4 using 3,4,5-tetrahydro-1H-2-benzazepine. ¹ H NMR (CDCl ₃ , free base) δ 1.00-1.50 (2H, m), 1.
60-2.00 (7H, m), 2.28 (3H, s), 2.70-3.20 (2H, br),
2.80-2.95 (2H, m), 3.07 (2H, t-like, J = 5.2 Hz),
3.49 (2H, s), 3.50-3.70 (1H, br), 3.81 (2H, s), 3.
96 (2H, t, J = 6.0 Hz), 4.60-4.80 (1H, br), 6.54 (1
H, d, J = 2.6 Hz), 6.66 (1H, dd, J = 8.0, 2.6 Hz),
7.00-7.30 (5H, m), 7.50 (2H, d, J = 8.0 Hz), 7.71
(2H, d, J = 8.0 Hz). Elemental analysis: C ₃₃ H ₃₇ N ₃ O ₂ · HCl · 0.5H ₂ O Calculated: C, 71.66; H, 7.11; N, 7.60. Experimental: C, 71.39; H, 7.16; N, 7.61.

Reference Example 12 2- (phenylmethyl) -7-[(4-piperidinyl)
Methoxy] -2,3,4,5-tetrahydro-1H-2-
Benzazepine dihydrochloride

Embedded image 1) 7-methoxy-2,3,4,5-tetrahydro-
By using 1H-2-benzazepine and performing the same operation as in Reference Example 2, t-butyl 4-[[2- (phenylmethyl) -2,3,4,5-tetrahydro-1H-2) was obtained.
-Benzazepin-7-yl] oxymethyl] -1-piperidinecarboxylate was obtained as colorless crystals, mp 103-104 ° C. ¹ H NMR (CDCl ₃ ) δ 1.10-2.10 (7H, m), 1.47 (9H, s),
2.65-2.90 (4H, m), 3.09 (2H, t-like, J = 5.2 Hz),
3.51 (2H, s), 3.79 (2H, d, J = 7.6 Hz), 3.81 (2H, s)
s), 4.05-4.25 (2H, br), 6.59 (1H, dd, J = 8.2, 2.6
Hz), 6.71 (1H, d, J = 2.6 Hz), 6.84 (1H, d, J = 8.
2 Hz), 7.20-7.40 (5H, m). Elemental analysis: C ₂₈ H ₃₈ N ₂ O ₃ Calculated: C, 74.63; H, 8.50; N, 6.22. Experimental: C, 74.56; H, 8.40 N, 6.43.2) t-butyl 4-[[2- (phenylmethyl) -2,3,4,5-tetrahydro-1H-2 obtained in 1) above.
The title compound was obtained as a colorless amorphous powder by performing the same operation as in Reference Example 3 using -benzazepin-7-yl] oxymethyl] -1-piperidinecarboxylate. ¹ H NMR (CDCl ₃ , free base) δ 1.15-1.40 (2H, m), 1.
65-2.00 (6H, m), 2.64 (2H, dt, J = 8.2, 2.6 Hz), 2.
80-2.90 (2H, m), 3.00-3.20 (4H, m), 3.50 (2H, s),
3.76 (2H, d, J = 6.2 Hz), 3.81 (2H, s), 6.59 (1H,
dd, J = 8.2, 2.6 Hz), 6.71 (1H, d, J = 2.6 Hz), 6.
83 (1H, d, J = 8.2 Hz), 7.20-7.40 (5H, m).

Reference Example 13 2- (phenylmethyl) -7-[[1-[(4-cyanophenyl) methyl] -4-piperidinyl] methoxy]-
2,3,4,5-tetrahydro-1H-2-benzazepine dihydrochloride

Embedded image 2- (phenylmethyl) -7-[(4
-Piperidinyl) methoxy] -2,3,4,5-tetrahydro-1H-2-benzazepine dihydrochloride and the same operation as in Reference Example 4 to give the title compound as a colorless amorphous powder. Was. ¹ H NMR (CDCl ₃ , free base) δ 1.20-1.55 (2H, m), 1.
65-1.90 (5H, m), 1.95-2.15 (2H, m), 2.80-2.95 (4H,
m), 3.09 (2H, t-like, J = 5.2 Hz), 3.51 (2H, s),
3.54 (2H, s), 3.79 (2H, d, J = 6.2 Hz), 3.80 (2H,
s), 6.59 (1H, dd, J = 8.2, 2.6 Hz), 6.71 (1H, d, J
= 2.6 Hz), 6.83 (1H, d, J = 8.2 Hz), 7.20-7.40 (5
H, m), 7.45 (2H, d, J = 8.4 Hz), 7.60 (2H, d, J =
8.4 Hz). Elemental analysis: C ₃₁ H ₃₅ N ₃ O · 2HCl · 1.5H ₂ O Calculated: C, 65.83; H, 7.13; N, 7.43. Experimental: C, 65.90; H, 7.22; N, 7.37.

Reference Example 14 t-butyl 4-[[2- (phenylmethyl) -2,
3,4,5-tetrahydro-1H-2-benzazepine-
8-yl] oxymethyl] -1-piperidinecarboxylate

Embedded image 8-methoxy-2,3,4,5-tetrahydro-1H-2
The title compound was converted to mp 11 by sequentially performing the same operation as in Reference Example 2 and Reference Example 8 using -benzazepine.
Obtained as colorless crystals at 6-118 ° C. ¹ H NMR (CDCl ₃ ) δ 1.10-1.40 (2H, m), 1.47 (9H, s),
1.50-2.00 (5H, m), 2.65-2.90 (4H, m), 3.09 (2H, t-
like, J = 5.2 Hz), 3.54 (2H, s), 3.73 (2H, d, J =
6.2 Hz), 3.82 (2H, s), 4.05-4.25 (2H, br), 6.49 (1
H, d, J = 2.4 Hz), 6.65 (1H, dd, J = 8.2, 2.4 Hz),
7.04 (1H, d, J = 8.2 Hz), 7.20-7.40 (5H, m). Elemental analysis calculated as C ₂₈ H ₃₈ N ₂ O ₃ Calculated: C, 74.63; H, 8.50; N, 6.22. Experimental : C, 74.44; H, 8.55; N, 6.10.

Reference Example 15 2- (phenylmethyl) -8-[(4-piperidinyl)
Methoxy] -2,3,4,5-tetrahydro-1H-2-
Benzazepine dihydrochloride

Embedded image T-butyl 4-[[2- (phenylmethyl) -2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl] oxymethyl] -1-piperidinecarboxylate obtained in Reference Example 14 The title compound was obtained as colorless crystals having a mp of 103 to 105 ° C by performing the same operation as in Reference Example 3 using the compound. ¹ H NMR (CDCl ₃ ) δ 1.15-1.40 (2H, m), 1.65-2.00 (6H,
m), 2.65 (2H, dt, J = 8.2, 2.6 Hz), 2.80-2.90 (2H,
m), 3.00-3.20 (4H, m), 3.54 (2H, s), 3.72 (2H, d,
J = 5.8 Hz), 3.83 (2H, s), 6.51 (1H, d, J = 2.6 H
z), 6.67 (1H, dd, J = 8.2, 2.6 Hz), 7.04 (1H, d, J
= 8.2 Hz), 7.20-7.40 (5H , m) Elemental analysis _{C 23 H 30 N 2 O ·} 2HCl · H 2 O Calculated:. C, 62.58; H, 7.76;
N, 6.35. Experimental value: C, 62.64; H, 8.03;
N, 6.07.

Reference Example 16 2- (phenylmethyl) -8-[[1-[(4-cyanophenyl) methyl] -4-piperidinyl] methoxy]-
2,3,4,5-tetrahydro-1H-2-benzazepine dihydrochloride

Embedded image 2- (phenylmethyl) -8-[(4
-Piperidinyl) methoxy] -2,3,4,5-tetrahydro-1H-2-benzazepine dihydrochloride and the same procedure as in Reference Example 4 to give the title compound as mp
Obtained as colorless crystals at 105-107 ° C. ¹ H NMR (CDCl ₃ ) δ 1.20-1.55 (2H, m), 1.60-1.90 (5H,
m), 1.95-2.15 (2H, m), 2.80-2.95 (4H, m), 3.09 (2
H, t-like, J = 5.2 Hz), 3.54 (4H, s), 3.74 (2H, d,
J = 6.0 Hz), 3.83 (2H, s), 6.50 (1H, d, J = 2.6 H
z), 6.66 (1H, dd, J = 8.2, 2.6 Hz), 7.04 (1H, d, J
= 8.2 Hz), 7.20-7.35 (5H, m), 7.45 (2H, d, J = 8.
2 Hz), 7.61 (2H, d, J = 8.2 Hz). Elemental analysis: C ₃₁ H ₃₅ N ₃ O ・ 2HCl ・ 1.5H ₂ O Calculated: C, 65.83; H, 7.13; N, 7.43. Values: C, 65.90; H, 7.22; N, 7.37.

Reference Example 17 2- (phenylmethyl) -8- [2- [1-[(4-cyanophenyl) methyl] -4-piperidinyl] ethoxy] -2,3,4,5-tetrahydro-1H- 2-benzazepine

Embedded image 1) 8-methoxy-2,3,4,5-tetrahydro-
The same operation as in Reference Example 2 was carried out using 1H-2-benzazepine to give t-butyl 4- [2-[[2-
(Phenylmethyl) -2,3,4,5-tetrahydro-
1H-2-benzazepin-8-yl] oxy] ethyl]
-1-Piperidine carboxylate was obtained as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 1.00-1.90 (9H, m), 1.46 (9H, s),
2.60-2.80 (2H, m), 2.80-2.90 (2H, m), 3.09 (2H, t-
like, J = 5.2Hz), 3.54 (2H, s), 3.83 (2H, s), 3.94
(2H, t, J = 5.8Hz), 4.00-4.20 (2H, m), 6.50 (1H,
d, J = 2.6Hz), 6.66 (1H, dd, J = 8.0, 2.6Hz), 7.04
(1H, d, J = 8.0 Hz), 7.10-7.40 (5H, m). 2) t-butyl 4- [2-[[2-
(Phenylmethyl) -2,3,4,5-tetrahydro-
1H-2-benzazepin-8-yl] oxy] ethyl]
Reference Example 3 using -1-piperidine carboxylate
By performing the same operation as described above, 2- (phenylmethyl) -8-[[2- (4-piperidinyl) ethyl] oxy] -2,3,4,5-tetrahydro-1H-2-benzazepine was converted to mp43. Obtained as colorless crystals at -44 ° C. ¹ H NMR (CDCl ₃ ) δ 1.05-1.30 (2H, m), 1.50-1.80 (7H,
m), 1.85-2.05 (1H, br), 2.55-2.70 (2H, m), 2.80-
2.95 (2H, m), 3.00-3.20 (4H, m), 3.54 (2H, s), 3.8
4 (2H, s), 3.94 (2H, t, J = 6.0Hz), 6.52 (1H, d, J
= 2.6Hz), 6.67 (1H, dd, J = 8.2, 2.6Hz), 7.05 (1H,
d, J = 8.2 Hz), 7.20-7.40 (5H, m). 3) 2- (phenylmethyl) -8- obtained in 2) above
[[2- (4-piperidinyl) ethyl] oxy] -2,
The same operation as in Reference Example 4 was carried out using 3,4,5-tetrahydro-1H-2-benzazepine to give the title compound as colorless crystals having a mp of 83-85 ° C. ¹ H NMR (CDCl ₃ ) δ 1.20-1.85 (9H, m), 1.90-2.05 (2H,
m), 2.75-2.90 (4H, m), 3.09 (2H, t-like, J = 5.2
Hz), 3.51 (2H, s), 3.53 (2H, s), 3.82 (2H, s), 3.9
3 (2H, t, J = 6.4 Hz), 6.50 (1H, d, J = 2.6 Hz),
6.66 (1H, dd, J = 8.0, 2.6 Hz), 7.04 (1H, d, J = 8.
0 Hz), 7.15-7.35 (5H, m), 7.44 (2H, d, J = 8.4 Hz),
7.59 (2H, d, J = 8.4 Hz) Elemental analysis C ₃₂ H ₃₇ N ₃ O Calculated:.. C, 80.13; H , 7.78; N, 8.76 Found: C, 79.93; H, 7.95 ; N , 8.91.

Reference Example 18 8-methoxy-2- (phenylmethyl) -2,3,4
5-tetrahydro-2-benzazepin-1-one

Embedded image The title compound was obtained as a colorless powder by performing the same operation as 1) of Reference Example 2 using 8-methoxy-2,3,4,5-tetrahydro-2-benzazepin-1-one. ¹ H NMR (CDCl ₃ ) δ 1.74 (2H, tt, J = 7.0, 6.6 Hz),
2.67 (2H, t, J = 7.0 Hz), 3.18 (2H, t, J = 6.6 H
z), 3.83 (3H, s), 4.78 (2H, s), 6.90 (1H, dd, J =
8.4, 2.8 Hz), 7.02 (1H, d, J = 8.4 Hz), 7.20-7.45
(6H, m).

Reference Example 19 8-Hydroxy-2- (phenylmethyl) -2,3
4,5-tetrahydro-2-benzazepin-1-one

Embedded image The same operation as in 2) of Reference Example 2 is performed using 8-methoxy-2- (phenylmethyl) -2,3,4,5-tetrahydro-2-benzazepin-1-one obtained in Reference Example 18. This gave the title compound as colorless crystals, mp 153-155 ° C. ¹ H NMR (CDCl ₃ ) δ 1.74 (2H, tt, J = 7.0, 6.6 Hz),
2.63 (2H, t, J = 7.0 Hz), 3.21 (2H, t, J = 6.6 H
z), 4.80 (2H, s), 6.90 (1H, ddd, J = 8.4, 2.8,0.8
Hz), 6.95 (1H, d, J = 8.4 Hz), 7.25-7.45 (6H, m),
3.21 (1H, d, J = 2.6 Hz).

Reference Example 20 t-butyl 4- [2-[[1-oxo-2- (phenylmethyl) -2,3,
4,5-tetrahydro-2-benzazepin-8-yl] oxy] ethyl] -1-piperidinecarboxylate

Embedded image The same operation as 3) of Reference Example 2 is performed using 8-hydroxy-2- (phenylmethyl) -2,3,4,5-tetrahydro-2-benzazepin-1-one obtained in Reference Example 19. As a result, the title compound was obtained as colorless crystals having a mp of 111 to 112 ° C. ¹ H NMR (CDCl ₃ ) δ 1.00-1.40 (2H, m), 1.46 (9H, s),
1.50-1.85 (7H, m), 2.60-2.80 (4H, m), 3.18 (2H, t,
J = 6.4 Hz), 4.00-4.20 (4H, m), 4.78 (2H, s), 6.8
9 (1H, dd, J = 8.2, 2.8 Hz), 7.02 (1H, d, J = 8.2
Hz), 7.20-7.45 (6H, m). Elemental analysis: C ₂₉ H ₃₈ N ₂ O ₄ Calculated: C, 72.77; H, 8.00; N, 5.85. Experimental: C, 72.71; H, 8.09; N, 5.84.

Reference Example 21 2- (phenylmethyl) -8- [2- (4-piperidinyl) ethoxy] -2,3,4,5-tetrahydro-2-
Benzazepine-1-one

Embedded image T-butyl 4- [2-[[1-oxo-2- (phenylmethyl) -2,3,4,5-tetrahydro-2-benzazepine- obtained in Reference Example 20
The title compound was obtained as colorless crystals having a mp of 82 to 83 ° C by performing the same operation as in Reference Example 3 using 8-yl] oxy] ethyl] -1-piperidinecarboxylate. ¹ H NMR (CDCl ₃ ) δ 1.05-1.30 (2H, m), 1.50-1.85 (8H,
m), 2.50-2.75 (4H, m), 3.00-3.15 (2H, m), 3.18 (2
H, t, J = 6.4 Hz), 4.04 (2H, t, J = 6.2 Hz), 4.78
(2H, s), 6.89 (1H, dd, J = 8.2, 2.8 Hz), 7.01 (1H,
d, J = 8.2 Hz), 7.20-7.45 (6H, m). Elemental analysis calculated as C ₂₄ H ₃₀ N ₂ O ₂ Calculated: C, 76.16; H, 7.99; N, 7.40. Experimental: C, 76.11 ; H, 8.04; N, 7.40.

Reference Example 22 8- [2- [1-[(4-cyanophenyl) methyl] -4-piperidinyl] ethoxy] -2- (phenylmethyl) -2,
3,4,5-tetrahydro-2-benzazepine-1-
on

Embedded image 2- (phenylmethyl) -8- [2-
(4-Piperidinyl) ethoxy] -2,3,4,5-tetrahydro-2-benzazepin-1-one,
By performing the same operation as in Reference Example 4, the title compound was obtained.
Obtained as colorless crystals of mp 134-136 ° C. ¹ H NMR (CDCl ₃ ) δ 1.20-1.85 (9H, m), 1.90-2.10 (2H,
m), 2.67 (2H, t, J = 7.0 Hz), 2.75-2.90 (2H, m),
3.18 (2H, t, J = 6.4 Hz), 3.52 (2H, s), 4.03 (2H,
t, J = 6.2 Hz), 4.78 (2H, s), 6.89 (1H, dd, J = 8.
2, 2.8 Hz), 7.01 (1H, d, J = 8.2 Hz), 7.20-7.40 (6
H, m), 7.45 (2H, d, J = 8.0 Hz), 7.60 (2H, d, J =
8.0 Hz). Elemental analysis: C ₃₂ H ₃₅ N ₃ O ₂ Calculated: C, 77.86; H, 7.15; N, 8.51. Experimental: C, 77.64; H, 7.29; N, 8.46.

Reference Example 23 t-butyl 4-[[2- (phenylmethyl) -2,
3,4,5-tetrahydro-1H-2-benzazepin-7-yl] oxy] -1-piperidinecarboxylate

Embedded image 7-methoxy-2,3,4,5-tetrahydro-1H-2
The title compound was converted to mp 99 by sequentially performing the same operation as in Reference Examples 2 and 3 using
Obtained as colorless crystals at -100 ° C. ¹ H NMR (CDCl ₃ ) δ 1.47 (9H, s), 1.60-2.00 (6H, m),
2.80-2.95 (2H, m), 3.09 (2H, t-like, J = 5.2 Hz),
3.25-3.45 (2H, m), 3.52 (2H, s), 3.60-3.85 (2H,
m), 3.80 (2H, s), 4.44 (1H, tt, J = 6.8, 3.4 Hz),
6.61 (1H, dd, J = 8.4, 2.6 Hz), 6.73 (1H, d, J = 2.
6 Hz), 6.84 (1H, d, J = 8.4 Hz), 7.20-7.40 (5H,
m).

Reference Example 24 2- (phenylmethyl) -7-[(4-piperidinyl)
Oxy] -2,3,4,5-tetrahydro-1H-2-
Benzazepine dihydrochloride

Embedded image T-butyl 4-[[2- (phenylmethyl) -2,3,4,5-tetrahydro-1H-2- obtained in Reference Example 23
The title compound was obtained as a colorless amorphous powder by performing the same operation as in Reference Example 3 using benzazepin-7-yl] oxy] -1-piperidinecarboxylate. ¹ H NMR (CDCl ₃ , free base) δ 1.55-1.85 (7H, m), 1.
90-2.10 (2H, m), 2.75 (2H, ddd, J = 12.6, 9.4, 3.0
Hz), 2.80-2.95 (2H, m), 3.05-3.25 (4H, m), 3.51 (2
H, s), 3.80 (2H, s), 4.34 (1H, tt, J = 8.4, 4.0 H
z), 6.61 (1H, dd, J = 8.2, 2.4 Hz), 6.73 (1H, d, J
= 2.4 Hz), 6.83 (1H, d, J = 8.2 Hz), 7.20-7.40 (5
H, m).

Reference Example 25 2- (phenylmethyl) -7-[[1-[(4-cyanophenyl) methyl] -4-piperidinyl] oxy] -2,
3,4,5-tetrahydro-1H-2-benzazepine dihydrochloride

Embedded image 2- (phenylmethyl) -7-[(4
-Piperidinyl) oxy] -2,3,4,5-tetrahydro-1H-2-benzazepine dihydrochloride,
By performing the same operation as in Reference Example 4, the title compound was obtained as a colorless amorphous powder. ¹ H NMR (CDCl ₃ , free base) δ 1.65-2.05 (7H, m), 2.
31 (1H, ddd, J = 11.5,8.4, 3.2 Hz), 2.65-2.75 (2H,
m), 2.80-2.90 (2H, m), 3.08 (2H, t-like, J = 5.2 H
z), 3.51 (2H, s), 3.56 (2H, s), 3.79 (2H, s), 4.31
(1H, tt, J = 7.2, 3.6 Hz), 6.60 (1H, dd, J = 8.2,
2.6 Hz), 6.72 (1H, d, J = 2.6 Hz), 6.82 (1H, d, J =
8.2 Hz), 7.20-7.35 (5H, m), 7.45 (2H, d, J = 8.2
Hz), 7.60 (2H, d, J = 8.2 Hz). Elemental analysis: C ₃₀ H ₃₃ N ₃ O · 2HCl · H ₂ O Calculated: C, 66.41; H, 6.87; N, 7.75. Experimental: C, 66.28; H, 6.98; N, 7.53.

Reference Example 26 t-butyl 4-[[2- (phenylmethyl) -2,
3,4,5-tetrahydro-1H-2-benzazepin-8-yl] oxy] -1-piperidinecarboxylate

Embedded image 8-methoxy-2,3,4,5-tetrahydro-1H-2
The title compound was obtained as an oil by sequentially performing the same operation as in Reference Example 2 and Reference Example 3 using -benzazepine. ¹ H NMR (CDCl ₃ ) δ 1.47 (9H, m), 1.50-2.00 (6H, m),
2.80-2.90 (2H, m), 3.05-3.20 (2H, m), 3.20-3.40 (2
H, m), 3.54 (2H, s), 3.60-3.80 (2H, m), 3.81 (2H,
s), 4.25-4.40 (1H, m), 6.50 (1H, d, J = 2.6 Hz),
6.69 (1H, dd, J = 8.2, 2.6 Hz), 7.04 (1H, d, J = 8.
2 Hz), 7.20-7.40 (5H, m).

Reference Example 27 2- (phenylmethyl) -8-[(4-piperidinyl)
Oxy] -2,3,4,5-tetrahydro-1H-2-
Benzazepine

Embedded image T-butyl 4-[[2- (phenylmethyl) -2,3,4,5-tetrahydro-1H-2- obtained in Reference Example 26
The title compound was obtained as colorless crystals having a mp of 78-80 ° C by performing the same operation as in Reference Example 3 using benzazepin-8-yl] oxy] -1-piperidinecarboxylate. ¹ H NMR (CDCl ₃ ) δ 1.50-1.80 (5H, m), 1.90-2.10 (2H,
m), 2.69 (2H, ddd, J = 12.6, 9.6, 3.0 Hz), 2.80-2.
90 (2H, m), 3.05-3.20 (4H, m), 3.54 (2H, s), 3.82
(2H, s), 4.25 (1H, tt, J = 8.4, 4.0 Hz), 6.51 (1H,
d, J = 2.6 Hz), 6.69 (1H, dd, J = 8.2, 2.6 Hz),
7.04 (1H, d, J = 8.2 Hz), 7.20-7.40 (5H, m) Elemental analysis C ₂₂ H ₂₈ N ₂ O Calculated:.. C, 78.53; H , 8.39; N, 8.33 Found: C, 77.93; H, 8.20; N, 8.42.

Reference Example 28 2- (phenylmethyl) -8-[[1-[(4-cyanophenyl) methyl] -4-piperidinyl] oxy] -2,
3,4,5-tetrahydro-1H-2-benzazepine dihydrochloride

Embedded image 2- (phenylmethyl) -8-[(4
-Piperidinyl) oxy] -2,3,4,5-tetrahydro-1H-2-benzazepine dihydrochloride,
By performing the same operation as in Reference Example 4, the title compound was obtained as a colorless amorphous powder. ¹ H NMR (CDCl ₃ ) δ 1.60-2.10 (6H, m), 2.10-2.40 (2H,
m), 2.60-2.80 (2H, m), 2.80-2.90 (2H, m), 3.10 (2
H, t-like, J = 5.2 Hz), 3.55 (2H, s), 3.56 (2H,
s), 3.82 (2H, s), 4.10-4.30 (1H, m), 6.51 (1H, d,
J = 2.6 Hz), 6.69 (1H, dd, J = 8.2, 2.6 Hz), 7.04
(1H, d, J = 8.2 Hz), 7.20-7.40 (5H, m) 7.42 (2H,
d, J = 8.2 Hz), 7.62 (2H, d, J = 8.2 Hz). Elemental analysis: C ₃₀ H ₃₃ N ₃ O · 2HCl · 1.5H ₂ O Calculated: C, 65.33; H, 6.94; N , 7.62. Found: C, 65.39; H, 6.97; N, 7.39.

Reference Example 29 7-Hydroxy-2- (phenylmethyl) -2,3
4,5-tetrahydro-2-benzazepin-1-one

Embedded image By using 7-methoxy-2,3,4,5-tetrahydro-2-benzazepin-1-one, the same operations as in 1) of Reference Example 2 and 2) of Reference Example 2 were sequentially performed to obtain
The title compound was obtained as a colorless powder, mp 168-170 ° C. ¹ H NMR (CDCl ₃ ) δ 1.60-1.85 (2H, m), 2.55 (2H, t, J
= 7.0 Hz), 3.17 (2H, t, J = 6.2 Hz), 4.77 (2H, s),
6.56 (1H, d, J = 2.6 Hz), 6.69 (1H, dd, J = 8.2,
2.6 Hz), 7.20-7.40 (6H, m), 7.50 (1H, d, J = 8.4 H
z).

Reference Example 30 2- (phenylmethyl) -8- [2- (4-piperidinyl) ethoxy] -2,3,4,5-tetrahydro-2-
Benzazepine-1-one

Embedded image Using 7-hydroxy-2- (phenylmethyl) -2,3,4,5-tetrahydro-2-benzazepin-1-one obtained in Reference Example 29, as in 3) of Reference Example 2 and Reference Example 3 The title compound was obtained as an oil by sequentially performing the above operations. ¹ H NMR (CDCl ₃ ) δ 1.05-1.30 (2H, m), 1.50-2.00 (8H,
m), 2.50-2.75 (4H, m), 3.00-3.15 (2H, m), 3.18 (2
H, t, J = 6.4 Hz), 4.02 (2H, t, J = 6.0 Hz), 4.79
(2H, s), 6.63 (1H, d, J = 2.6 Hz), 6.82 (1H, dd, J
= 8.4, 2.6 Hz), 7.20-7.40 (5H, m), 7.68 (1H, d, J
= 8.4 Hz).

Reference Example 31 7- [2- [1-[(4-cyanophenyl) methyl] -4-piperidinyl] ethoxy] -2- (phenylmethyl) -2,
3,4,5-tetrahydro-2-benzazepine-1-
on

Embedded image 2- (phenylmethyl) -8- [2-
(4-Piperidinyl) ethoxy] -2,3,4,5-tetrahydro-2-benzazepin-1-one,
By performing the same operation as in Reference Example 4, the title compound was obtained.
mp 111-113 ° C. as colorless crystals. ¹ H NMR (CDCl ₃ ) δ 1.20-1.85 (9H, m), 1.90-2.10 (2H,
m), 2.69 (2H, t, J = 7.0 Hz), 2.75-2.90 (2H, m),
3.19 (2H, t, J = 6.4 Hz), 3.52 (2H, s), 4.02 (2H,
t, J = 6.2 Hz), 4.77 (2H, s), 6.63 (1H, d, J = 2.8
Hz), 6.82 (1H, dd, J = 8.2, 2.8 Hz), 7.20-7.50 (7
H, m), 7.60 (2H, d, J = 8.4 Hz), 7.68 (1H, d, J =
8.8 Hz). Elemental analysis: Calculated for C ₃₂ H ₃₅ N ₃ O ₂ Calculated: C, 77.86; H, 7.15; N, 8.81. Experimental: C, 77.72; H, 7.04; N, 8.54.

Reference Example 32 8-Hydroxy-2-[[2- (trifluoromethyl)
[Phenyl] methyl] -2,3,4,5-tetrahydro-
1H-2-benzazepine

Embedded image 1) 8-methoxy-2,3,4,5-tetrahydro-
By performing the same operation as 1) of Reference Example 5 using 1H-2-benzazepine, 8-methoxy-2-[[2
-(Trifluoromethyl) phenyl] methyl] -2,
3,4,5-Tetrahydro-1H-2-benzazepine was obtained as a colorless powder. _{^{1 H NMR (CDCl 3) δ1.70-1.85}} (2H, m), 1.80-1.90 (2H,
m), 3.06 (2H, t-like, J = 5.6 Hz), 3.74 (5H, s), 3.
77 (2H, s), 6.69 (1H, d, J = 2.8 Hz), 6.68 (1H, dd,
J = 8.2, 2.8 Hz), 7.06 (1H, d, J = 8.2 Hz), 7.31
(1H, t, J = 7.6 Hz), 7.50 (1H, t, J = 7.6 Hz), 7.
61 (1H, d, J = 7.6 Hz), 7.81 (1H, d, J = 7.6 Hz). 2) 8-Methoxy-2-[[2- (trifluoromethyl) phenyl] methyl obtained in 1) above ] -2,3,4
The title compound was obtained as colorless crystals of mp 205-207 ° C by performing the same operation as in 2) of Reference Example 5 using 5-tetrahydro-1H-2-benzazepine. ¹ H NMR (CDCl ₃ ) δ 1.80-2.00 (2H, m), 2.80-3.00 (2H,
m), 3.30-3.60 (2H, m), 4.25-4.70 (4H, m), 6.58 (1H,
d, J = 2.2 Hz), 6.74 (1H, dd, J = 8.2, 2.2Hz), 7.
07 (1H, d, J = 8.2 Hz), 7.69 (1H, t, J = 7.8 Hz),
7.80-7.95 (2H, m), 8.22 (1H, d, J = 7.8 Hz), 9.30-
9.80 (1H, br.).

Reference Example 33 t-butyl 4- [2-[[2-[[2- (trifluoromethyl) phenyl] methyl] -2,3,4,5-tetrahydro-1H-2-benzazepine-8- Il] oxy]
Ethyl] -1-piperidinecarboxylate

Embedded image 8-hydroxy-2-[[2- (trifluoromethyl) phenyl] methyl] -2,3,4, obtained in Reference Example 32.
The title compound was obtained as a viscous oil by performing the same operation as in 3) of Reference Example 2 using 5-tetrahydro-1H-2-benzazepine. ¹ H NMR (CDCl ₃ ) δ1.00-1.30 (2H, m), 1.46 (9H, s),
1.60-1.80 (7H, m), 2.60-2.80 (2H, m), 2.80-2.90 (2
H, m), 3.06 (2H, t-like, J = 5.4 Hz), 3.73 (2H,
s), 3.76 (2H, s), 3.93 (2H, t, J = 5.8 Hz), 4.00-
4.20 (2H, m), 6.48 (1H, d, J = 2.8 Hz), 6.66 (1H,
dd, J = 8.2, 2.8 Hz), 7.05 (1H, d, J = 8.2Hz), 7.3
2 (1H, t, J = 7.6 Hz), 7.50 (1H, t, J = 7.6 Hz),
7.61 (1H, d, J = 8.0 Hz), 7.82 (1H, d, J = 8.0 Hz).

Reference Example 34 2-[[2- (trifluoromethyl) phenyl] methyl]
-8- [2- (4-piperidinyl) ethoxy] -2,
3,4,5-tetrahydro-1H-2-benzazepine

Embedded image T-butyl 4- [2-[[2-[[2
-(Trifluoromethyl) phenyl] methyl] -2,
The title compound was obtained as a colorless oil by performing the same operation as in Reference Example 3 using 3,4,5-tetrahydro-1H-2-benzazepin-8-yl] oxy] ethyl] -1-piperidinecarboxylate. As obtained. ¹ H NMR (CDCl ₃ ) δ1.05-1.30 (2H, m), 1.50-1.80 (6H,
m), 2.50-2.70 (4H, m), 2.80-2.90 (2H, m), 3.00-3.
15 (4H, m), 3.74 (2H, s), 3.78 (2H, s), 3.93 (2H,
t, J = 5.8 Hz), 6.49 (1H, d, J = 2.8 Hz), 6.67 (1
H, dd, J = 8.2, 2.8 Hz), 7.05 (1H, d, J = 8.2 Hz),
7.32 (1H, t, J = 7.6 H), 7.50 (1H, t, J = 7.6 H)
z), 7.61 (1H, d, J = 7.8 Hz), 7.82 (1H, d, J = 7.8
Hz).

Reference Example 35 8- [2- [1-[(4-cyanophenyl) methyl] -4-piperidinyl] ethoxy] -2-[[2- (trifluoromethyl) phenyl] methyl] -2,3 , 4,5-tetrahydro-1H
−2-Benzazepine

Embedded image 2-[[2- (trifluoromethyl) obtained in Reference Example 34
[Phenyl] methyl] -8- [2- (4-piperidinyl)
Ethoxy] -2,3,4,5-tetrahydro-1H-2
-The title compound was obtained as a colorless oil by performing the same operation as in Reference Example 4 using benzazepine. ¹ H NMR (CDCl ₃ ) δ 1.20-1.80 (9H, m), 1.85-2.05 (2H,
m), 2.75-2.90 (4H, m), 3.06 (2H, t-like, J = 5.4 H
z), 3.51 (2H, s), 3.74 (2H, s), 3.77 (2H, s), 3.92
(2H, t, J = 6.2 Hz), 6.49 (1H, d, J = 2.6 Hz), 6.
66 (1H, dd, J = 8.2, 2.6Hz), 7.04 (1H, d, J = 8.2H
z), 7.31 (1H, t, J = 7.6 Hz), 7.40-7.65 (6H, m),
7.82 (1H, d, J = 7.6 Hz).

Reference Example 36 8- [2- [1-[(2-chloro-4-cyanophenyl) methyl] -4-piperidinyl] ethoxy] -2-[[2- (trifluoromethyl) phenyl] methyl] -2,3,4,5-tetrahydro-1H-2-benzazepine

Embedded image 2-[[2- (trifluoromethyl) obtained in Reference Example 34
[Phenyl] methyl] -8- [2- (4-piperidinyl)
Ethoxy] -2,3,4,5-tetrahydro-1H-2
-The title compound was obtained as a colorless oil by performing the same operation as in Reference Example 4 using benzazepine. ¹ H NMR (CDCl ₃ ) δ 1.20-1.95 (9H, m), 2.00-2.20 (2H,
m), 2.70-2.95 (4H, m), 3.06 (2H, t-like, J = 5.2 H
z), 3.60 (2H, s), 3.74 (2H, s), 3.78 (2H, s), 3.93
(2H, t, J = 6.4 Hz), 6.49 (1H, d, J = 2.6 Hz), 6.
67 (1H, dd, J = 8.0, 2.6 Hz), 7.04 (1H, d, J = 8.0
Hz), 7.31 (1H, t, J = 7.6 Hz), 7.45-7.65 (4H, m),
7.68 (1H, d, J = 8.0 Hz), 7.82 (1H, d, J = 7.6 H
z).

Reference Example 37 2- (phenylmethyl) -8- [3- (4-piperidinyl) propoxy] -2,3,4,5-tetrahydro-1
H-2-Benzazepine

Embedded image 1) 8-methoxy-2,3,4,5-tetrahydro-
By performing the same operation as in Reference Example 2 using 1H-2-benzazepine, t-butyl 4- [3-[[2-
(Phenylmethyl) -2,3,4,5-tetrahydro-
1H-2-Benzazepin-8-yl] oxy] propyl] -1-piperidinecarboxylate was obtained as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 1.00-1.45 (4H, m), 1.46 (9H, s),
1.60-1.85 (7H, m), 2.60-2.80 (2H, m), 2.80-2.90 (2
H, m), 3.10 (2H, t-like, J = 5.4 Hz), 3.54 (2H,
s), 3.83 (2H, s), 3.88 (2H, t, J = 6.4 Hz), 4.00-
4.20 (2H, m), 6.50 (1H, d, J = 2.6 Hz), 6.66 (1H, d
d, J = 8.2, 2.6 Hz), 7.04 (1H, d, J = 8.2 Hz), 7.2
0-7.35 (5H, m). 2) t-butyl 4- [3-[[2-
(Phenylmethyl) -2,3,4,5-tetrahydro-
The title compound was obtained as a colorless oil by performing the same operation as in Reference Example 3 using 1H-2-benzazepin-8-yl] oxy] propyl] -1-piperidinecarboxylate. ¹ H NMR (CDCl ₃ ) δ1.00-1.50 (4H, m), 1.65-1.85 (6H,
m), 2.25-2.40 (2H, m), 2.60 (2H, dt, J = 12.0, 2.2
Hz), 2.80-2.90 (2H, m), 3.05-3.20 (4H, m), 3.54 (2
H, s), 3.83 (2H, s), 3.88 (2H, t, J = 6.6Hz), 6.51
(1H, d, J = 2.6 Hz), 6.67 (1H, dd, J = 8.2, 2.6 H
z), 7.04 (1H, d, J = 8.2 Hz), 7.20-7.35 (5H, m).

Reference Example 38 8- [3- [1-[(4-cyanophenyl) methyl] -4-piperidinyl] propoxy] -2- (phenylmethyl) -2,3,
4,5-tetrahydro-1H-2-benzazepine

Embedded image 2- (phenylmethyl) -8- [3-
(4-Piperidinyl) propoxy] -2,3,4,5-
The title compound was obtained as a colorless oil by performing the same operation as in Reference Example 4 using tetrahydro-1H-2-benzazepine. _{^{1 H NMR (CDCl 3) δ1.20-1.80}} (11H, m), 1.85-2.05 (2H,
m), 2.75-2.90 (4H, m), 3.10 (2H, t-like, J = 5.4
Hz), 3.51 (2H, s), 3.54 (2H, s), 3.84 (2H, s), 3.8
7 (2H, t, J = 6.6 Hz), 6.51 (1H, d, J = 2.6 Hz),
6.66 (1H, dd, J = 8.2, 2.6 Hz), 7.04 (1H, d, J = 8.
2 Hz), 7.20-7.55 (5H, m), 7.44 (2H, d, J = 8.4 Hz),
7.60 (2H, d, J = 8.4 Hz).

Reference Example 39 7-Hydroxy-2-[(2-methylphenyl) methyl]
-2,3,4,5-tetrahydro-1H-2-benzazepine

Embedded image 1) α-bromo-o-xylene (3.97 ml, 29.6 mmol)
With 7-methoxy-2,3,4,5-tetrahydro-1
H-2-Benzazepine (5.00 g, 28.2 mmol), potassium carbonate (4.0 g) and a suspension of potassium iodide (catalytic amount) in ethanol (150 ml) were added dropwise at room temperature. The mixture was heated under reflux for 3 hours, and the solvent was distilled off under reduced pressure. The residue was dissolved in water-ethyl acetate and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (developing solvent; hexane-ethyl acetate =
4: 1) to give 7-methoxy-2-[(2-
Methylphenyl) methyl] -2,3,4,5-tetrahydro-1H-2-benzazepine (6.71 g) was obtained as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 1.60-1.90 (2H, m), 2.28 (3H, s),
2.88 (2H, t-like, J = 5.4 Hz), 3.07 (2H, t-like, J
= 5.4 Hz), 3.46 (2H, s), 3.80 (3H, s), 3.81 (2H,
s), 6.62 (1H, dd, J = 8.0, 2.6 Hz), 6.73 (1H, d, J
= 2.6 Hz), 6.90 (1H, d, J = 8.0Hz), 7.10-7.35 (4
H, m). 2) 7-methoxy-2-[(2-methylphenyl) methyl] -2,3,4,5-tetrahydro-1H-2-benzazepine obtained in 1) above (6.71 g, 23.8 mmol) ) And 48%
A mixture of the hydrobromic acid solution (80 ml) was stirred at 140 ° C. for 2 hours. After cooling to room temperature, the mixture was made weakly alkaline (pH about 10) using an 8 N aqueous sodium hydroxide solution under ice cooling, and extracted twice with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the title compound (5.69 g) as colorless crystals, mp 148-149 ° C. ¹ H NMR (CDCl ₃ ) δ 1.70-1.85 (2H, m), 2.27 (3H, s),
2.83 (2H, t-like, J = 5.4 Hz), 3.08 (2H, t-like, J
= 5.2 Hz), 3.48 (2H, s), 3.80 (2H, s), 6.50 (1H,
dd, J = 8.0, 2.6 Hz), 6.61 (1H, d, J = 2.6 Hz), 6.
82 (1H, d, J = 8.0 Hz), 7.10-7.30 (4H, m).

Reference Example 40 7-methoxy-3- (phenylmethyl) -2,3,4
5-tetrahydro-1H-3-benzazepine

Embedded image 1) 8-Methoxy-2,3-dihydro-1H-3-benzazepin-2-one (9.0 g, 47.5 mmol
l) ethanol solution (200 ml) was added to 5% Pd / C
, A catalytic hydrogenation reaction was performed at room temperature, and 8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one (8.3 g) was added to mp 162
Obtained as colorless needles at -163 ° C. ¹ H NMR (CDCl ₃ ) δ 3.06 (2H, t, J = 6.2 H
z), 3.49-3.60 (2H, m), 3.78 (3H, s), 3.81 (2H,
s), 6.0 (1H, br, NH), 6.69 (1H, d, J = 2.6 Hz), 6.7
6 (1H, dd, J = 2.6, 8.4 Hz), 7.04 (1H, d, J = 8.4
Hz). 2) 8-Methoxy-2,3,4,5- obtained in 1) above
To a solution of tetrahydro-1H-3-benzazepin-2-one (3.5 g, 18.5 mmol) in tetrahydrofuran (300 ml), lithium aluminum hydride (1.4 g, 36.8 mmol) was added little by little at room temperature. The mixture was heated under reflux for 4 hours, allowed to cool, and water (2.8 ml) and then a 10% aqueous sodium hydroxide solution (2.24 ml) were added dropwise with stirring. After stirring at room temperature for 14 hours, the formed precipitate was removed by filtration, and the solvent was distilled off under reduced pressure to give 7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (3.0 g). ) Was obtained as a viscous oil. 3) 7-methoxy-2,3,4,5- obtained in 2) above
Tetrahydro-1H-3-benzazepine (1.0 g
The title compound (1.05 g) was obtained as an oil by performing the same operation as in 1) of Reference Example 1). ¹ H NMR (CDCl ₃ ) δ 2.55-2.68 (4H, m), 2.8
1-2.91 (4H, m), 3.64 (2H, s), 3.77 (3H, s), 6.58
-6.68 (2H, m), 6.99 (1H, d, J = 8.4 Hz), 7.18-
7.40 (5H, m).

Reference Example 41 7-Hydroxy-3- (phenylmethyl) -2,3
4,5-tetrahydro-1H-3-benzazepine

Embedded image Using 7-methoxy-3- (phenylmethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine (0.7 g) obtained in Reference Example 40, the same as 2) in Reference Example 2 By performing the operation, the title compound (0.6 g) was obtained.
Was obtained as a colorless powder of mp 134-137 ° C. ¹ H NMR (CDCl ₃ ) δ 2.53-2.70 (4H, m), 2.7
5-2.92 (4H, m), ca.3.2 (1H, br, OH), 3.65 (2H,
s), 6.49-6.60 (2H, m), 6.92 (1H, d, J = 8.8 Hz),
7.18-7.40 (5H, m).

Reference Example 42 7-methoxy-3-[(2-methylphenyl) methyl]
-2,3,4,5-tetrahydro-1H-3-benzazepine

Embedded image Using 7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (1.5 g) obtained in Reference Example 40, the same operation as 1) of Reference Example 2 was carried out to obtain
The title compound (1.8 g) was obtained as an oil. ¹ H NMR (CDCl ₃ ) δ 2.39 (3H, s), 2.55-2.6
8 (4H, m), 2.77-2.89 (4H, m), 3.53 (2H, s), 3.77
(3H, s), 6.58-6.67 (2H, m), 6.99 (1H, d, J = 8.4
Hz), 7.10-7.37 (4H, m).

Reference Example 43 7-Hydroxy-3-[(2-methylphenyl) methyl] -2,3,4,5-tetrahydro-1H-3-benzazepine

Embedded image 7-methoxy-3-[(2-methylphenyl) methyl] -2,3,4,5-tetrahydro-1 obtained in Reference Example 42
The same operation as in Reference Example 2-2) was performed using H-3-benzazepine (0.85 g) to give the title compound (0.7 g) as an oil. ¹ H NMR (CDCl ₃ ) δ 2.38 (3H, s), 2.53-2.6
8 (4H, m), 2.72-2.87 (4H, m), 3.54 (2H, s), ca.
3.7 (1H, br, OH), 6.48-6.58 (2H, m), 6.91 (1H, d,
J = 8.8 Hz), 7.05-7.37 (4H, m).

Reference Example 44 t-butyl 4- [2-[[2-[(2-methylphenyl) methyl] -2,3,4,5-tetrahydro-1H-
2-benzazepin-7-yl] oxy] ethyl] -1-
Piperidine carboxylate

Embedded image 7-hydroxy-2-[(2-methylphenyl) methyl] -2,3,4,5-tetrahydro- obtained in Reference Example 39
1H-2-benzazepine (5.00 g, 18.7 mmol) and t-
To a solution of butyl 4- (2-iodoethyl) -1-piperidinecarboxylate (6.34 g, 18.7 mmol) in N, N-dimethylformamide (80 ml) was added potassium carbonate (10.0).
g) was added and stirred at 80 ° C. for 12 hours. After evaporating the solvent under reduced pressure, the residue was dissolved in water-ethyl acetate and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate = 19: 1) to give the title compound (7.46 g) as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 1.00-1.30 (2H,
m), 1.46 (9H, s), 1.60-1.
80 (7H, m), 2.28 (3H, s),
2.60-2.80 (2H, m), 2.86
(2H, t-like, J = 5.2 Hz),
3.06 (2H, t-like, J = 5.
2Hz), 3.46 (2H, s), 3.79
(2H, s), 3.98 (2H, t, J =
5.6 Hz), 4.00-4.20 (2H,
m), 6.59 (1H, dd, J = 8.
0, 2.4 Hz), 6.71 (1H, d,
J = 2.4 Hz), 6.88 (1H, d,
J = 8.0 Hz), 7.05-7.30 (4
H, m).

Reference Example 45 2-[(2-methylphenyl) methyl] -7- [2-
(4-Piperidinyl) ethoxy] -2,3,4,5-tetrahydro-1H-2-benzazepine

Embedded image T-butyl 4- [2-[[2-[(2
-Methylphenyl) methyl] -2,3,4,5-tetrahydro-1H-2-benzazepin-7-yl] oxy]
Ethyl] -1-piperidinecarboxylate (7.46 g, 1
To a solution of 5.6 mmol) in ethyl acetate (30 ml) was added a 4N solution of hydrogen chloride-ethyl acetate (100 ml) at room temperature, followed by stirring for 2 hours. After the solvent was distilled off under reduced pressure, the residue was made alkaline with an aqueous potassium carbonate solution and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous potassium carbonate.
The solvent was evaporated under reduced pressure to give the title compound (5.20
g) was obtained as a colorless oil. This crude product was used for the next reaction without further purification. ¹ H NMR (CDCl ₃ ) δ1.00-1.30 (2H, m), 1.60-1.80 (8H,
m), 2.27 (3H, s), 2.60-2.80 (2H, m), 2.87 (2H, t-
like, J = 5.2 Hz), 3.05 (2H, t-like, J = 5.2Hz),
3.46 (2H, s), 3.79 (2H, s), 3.97 (2H, t, J = 5.6 H
z), 4.00-4.20 (2H, m), 6.58 (1H, dd, J = 8.0, 2.4
Hz), 6.72 (1H, d, J = 2.4 Hz), 6.88 (1H, d, J = 8.
0 Hz), 7.05-7.30 (4H, m).

Reference Example 46 t-butyl 4- [2-[[3-[(2-methylphenyl) methyl] -2,3,4,5-tetrahydro-1H-
3-Benzazepin-7-yl] oxy] ethyl] -1
―Piperidine carboxylate

Embedded image 7-Hydroxy-3-[(2-methylphenyl) methyl] -2,3,4,5-tetrahydro- obtained in Reference Example 43
The title compound (0.29 g) was obtained as a viscous oil by performing the same operation as 3) in Reference Example 2 using 1H-3-benzazepine (0.23 g). ¹ H NMR (CDCl ₃ ) δ 1.02-1.27 (2H, m), 1.4
6 (9H, s), 1.55-1.79 (5H, m), 2.39 (3H, s), 2.56
-2.89 (10H, m), 3.54 (2H, s), 3.92-4.17 (4H, m),
6.57-6.67 (2H, m), 6.98 (1H, d, J = 8.1 Hz), 7.
05-7.37 (4H, m).

Reference Example 47 3-[(2-Methylphenyl) methyl] -7- [2-
(4-Piperidinyl) ethoxy] -2,3,4,5-tetrahydro-1H-3-benzazepine

Embedded image T-butyl 4- [2-[[3-[(2
-Methylphenyl) methyl] -2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl] oxy] ethyl] -1-piperidinecarboxylate (0.
The title compound (0.185 g) was obtained as an oil by performing the same operation as in Reference Example 3 using 23 g). ¹ H NMR (CDCl ₃ ) δ 1.10-1.33 (2H, m), 1.6
0-1.83 (3H, m), 1.92- 2.08 (2H, m), 2.39 (3H, m
s), 2.50-2.77 (7H, m), 2.78-2.90 (4H, m), 3.02
-3.17 (2H, m), 3.53 (2H, s), 3.97 (2H, t, J = 5.9
Hz), 6.57-6.69 (2H, m), 6.98 (1H, d, J = 8.0 H
z), 7.11-7.22 (3H, m), 7.25-7.37 (1H, m).

Reference Example 48 t-butyl 4- [3-[[3- (phenylmethyl)-
2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl] oxy] propyl] -1-piperidinecarboxylate

Embedded image Using 7-hydroxy-3-phenylmethyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.11 g) obtained in Reference Example 41, the same operation as 3) of Reference Example 2 was performed. This gave the title compound (0.17 g) as a viscous oil. ¹ H NMR (CDCl ₃ ) δ 0.97-1.23 (2H, m), 1.3
0-1.48 (12H, m), 1.58-1.86 (4H, m), 2.54-2.7
7 (6H, m), 2.80-2.92 (4H, m), 3.63 (2H, s), 3.91
(2H, t, J = 6.4 Hz), 3.98-4.16 (2H, m), 6.57-
6.66 (2H, m), 6.97 (1H, d, J = 7.7 Hz), 7.21-7.3
8 (5H, m).

Reference Example 49 3- (Phenylmethyl) -7- [3- (4-piperidinyl) propoxy] -2,3,4,5-tetrahydro-1
H-3-Benzazepine

Embedded image T-butyl 4- [3-[[3-
(Phenylmethyl) -2,3,4,5-tetrahydro-
1H-3-Benzazepin-7-yl] oxy] propyl] -1-piperidinecarboxylate (0.15 g)
The title compound (0.11 g) was obtained as an oil by performing the same operation as in Reference Example 3 using ¹ H NMR (CDCl ₃ ) δ 1.03-1.49 (5H, m), 1.6
3-1.99 (5H, m), 2.49- 2.69 (6H, m), 2.78-2.93
(4H, m), 3.01-3.19 (2H, m), 3.63 (2H, s), 3.90 (2
H, t, J = 6.2 Hz), 6.56-6.68 (2H, m), 6.97 (1H,
d, J = 7.7 Hz), 7.20-7.40 (5H, m).

Reference Example 50 t-butyl 4- [3-[[3-[(2-methylphenyl) methyl] -2,3,4,5-tetrahydro-1H-
3-Benzazepin-7-yl] oxy] propyl]-
1-piperidine carboxylate

Embedded image 7-Hydroxy-3-[(2-methylphenyl) methyl] -2,3,4,5-tetrahydro- obtained in Reference Example 43
The title compound (0.15 g) was obtained as a viscous oil by performing the same operation as 3) in Reference Example 2 using 1H-3-benzazepine (0.11 g). ¹ H NMR (CDCl ₃ ) δ 0.99-1.22 (2H, m), 1.2
9-1.50 (12H, m), 1.53-1.87 (4H, m), 2.39 (3H, m
s), 2.54-2.90 (10H, m), 3.53 (2H, s), 3.91 (2H,
t, J = 6.4 Hz), 4.00- 4.17 (2H, m), 6.57-6.67 (2
H, m), 6.98 (1H, d, J = 8.1 Hz), 7.10-7.22 (3H,
m), 7.24-7.36 (1H, m).

Reference Example 51 3-[(2-methylphenyl) methyl] -7- [3-
(4-Piperidinyl) propoxy] -2,3,4,5-
Tetrahydro-1H-3-benzazepine

Embedded image T-butyl 4- [3-[[3-[(2
-Methylphenyl) methyl] -2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl] oxy] propyl] -1-piperidinecarboxylate (0.14 g), By performing the same operation, the title compound (0.105 g) was obtained as an oil. ¹ H NMR (CDCl ₃ ) δ 1.00-1.46 (5H, m), 1.5
8-2.03 (5H, m), 2.39 (3H, s), 2.42-2.89 (10H,
m), 3.02-3.18 (2H, m), 3.53 (2H, s), 3.91 (2H, t,
J = 6.4 Hz), 6.56-6.67 (2H, m), 6.98 (1H, d, J
= 7.7 Hz), 7.02- 7.21 (3H, m), 7.24-7.37 (1H,
m).

Reference Example 52 t-butyl 4- [2-[[3- (phenylmethyl)-
2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl] oxy] ethyl] -1-piperidinecarboxylate

Embedded image Using 7-hydroxy-3-phenylmethyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.25 g) obtained in Reference Example 41, the same operation as in 3) of Reference Example 2 was performed. This gave the title compound (0.36 g) as a viscous oil. ¹ H NMR (CDCl ₃ ) δ 1.03-1.28 (2H, m), 1.4
5 (9H, s), 1.50-1.79 (5H, m), 2.55-2.92 (10H,
m), 3.64 (2H, s), 3.91-4.16 (4H, m), 6.56- 6.67
(2H, m), 6.97 (1H, d, J = 8.1 Hz), 7.21-7.38 (5
H, m).

Reference Example 53 3- (phenylmethyl) -7- [2- (4-piperidinyl) ethoxy] -2,3,4,5-tetrahydro-1H
―3-Benzazepine

Embedded image T-butyl 4- [2-[[3- (phenylmethyl) -2,3,4,5-tetrahydro-1H- obtained in Reference Example 52
3-Benzazepin-7-yl] oxy] ethyl] -1
The title compound (0.265 g) was obtained as an oil by performing the same operation as in Reference Example 3 using -piperidinecarboxylate (0.34 g). ¹ H NMR (CDCl ₃ ) δ1.40-2.08 (8H, m), 2.6
8-3.00 (10H, m), 3.30-3.46 (2H, m), 3.81 (2H,
s), 3.95 (2H, t, J = 5.7 Hz), 6.55-6.65 (2H, m),
6.97 (1H, d, J = 8.4 Hz), 7.28-7.38 (5H, m).

Reference Example 54 2,2,2-trifluoro-1- (7-sulfanyl-
2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl) -1-ethanone

Embedded image Zinc powder (10 g, 153 mmol) was added to a solution of 3- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonyl chloride (10.0 g, 29.3 mmol) in acetic acid (80 ml). The mixture was heated under reflux for 10 minutes. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in water-ethyl acetate and extracted with ethyl acetate. The extract was washed successively with an aqueous sodium hydrogen carbonate solution and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the title compound (6.35 g) as colorless crystals having a mp of 81-85 ° C. ¹ H NMR (CDCl ₃ ) δ 2.85-3.00 (4H, m), 3.42 (1H, s),
3.60-3.80 (4H, m), 6.95-7.15 (3H, m). Elemental analysis calculated as C ₁₂ H ₁₂ F ₃ NOS ・ H ₂ O Calculated: C, 49.14; H, 4.81; N, 4.78. Experimental For: C, 49.22; H, 4.06; N, 4.85.

Reference Example 55 t-butyl 4- [2-[[3- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl] sulfanyl] ethyl] -1 −
Piperidine carboxylate

Embedded image The 2,2,2-trifluoro-1- (7) obtained in Reference Example 54
-Sulfanyl-2,3,4,5-tetrahydro-1H
-3-benzazepin-3-yl) -1-ethanone (2.
To a solution of 41 g, 8.75 mmol) in N, N-dimethylformamide were added t-butyl 4- (2-iodoethyl) -1-piperidinecarboxylate (2.97 g, 8.76 mmol) and anhydrous potassium carbonate (1 g). Stir for 2 hours. After evaporating the solvent under reduced pressure, the residue was dissolved in water-ethyl acetate and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate = 4: 1) to give the title compound (3.49 g) as colorless crystals with a mp of 100-102 ° C. ¹ H NMR (CDCl ₃ ) δ 1.00-1.20 (2H,
m), 1.45 (9H, s), 1.50-1.
75 (5H, m), 2.55-2.80 (2
H, m), 2.85-3.00 (6H, m),
3.60-3.80 (4H, m), 4.00-
4.15 (2H, m), 7.00-7.20
(3H, m). Elemental analysis: C ₂₄ H ₃₃ F ₃ N ₂ O ₃ S Calculated: C, 59.24; H, 6.84; N, 5.76. Experimental: C, 59.21; H, 6.79; N, 5.75.

Reference Example 56 t-butyl 4- [2-[(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl) sulfanyl] ethyl] -1-piperidinecarboxylate

Embedded image T-butyl 4- [2-[[3- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl] sulfanyl] ethyl] -1 obtained in Reference Example 55 -Piperidine carboxylate (1.70
g, 3.49 mmol) in methanol (20 ml) and water (10 ml)
And a saturated aqueous solution of potassium carbonate (10 ml) were added, and the mixture was stirred at room temperature for 2 hours. After the methanol was distilled off under reduced pressure, the residue was dissolved in water-ethyl acetate and extracted twice with ethyl acetate. The extract was washed with brine, dried over anhydrous potassium carbonate, and the solvent was distilled off under reduced pressure to give the title compound.
(1.50 g) was obtained as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 1.00-1.20 (2H, m), 1.45 (9H, s),
1.50-1.75 (5H, m), 2.00-2.20 (1H, br), 2.55-2.80
(2H, m), 2.80-3.00 (10H, m), 3.95-4.15 (2H, m), 7.0
0-7.10 (3H, m).

Reference Example 57 t-butyl 4- [2-[[3- (phenylmethyl)-
2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl] sulfanyl] ethyl] -1-piperidinecarboxylate

Embedded image Benzyl bromide (0.503 ml, 4.23 mmol) was converted to t-butyl 4- [2-[(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl) sulfanyl] obtained in Reference Example 56. Ethyl] -1-piperidinecarboxylate
(1.50 g, 3.84 mmol) and a suspension of potassium carbonate (2.5 g) in ethanol (50 ml) were added dropwise at room temperature. The mixture was stirred at room temperature for 10 hours, and the solvent was distilled off under reduced pressure.
Dissolved in ethyl acetate and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate = 3: 1) to give the title compound (1.52 g) as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 1.00-1.20 (2H, m), 1.45 (9H, s),
1.50-1.80 (5H, m), 2.50-2.80 (6H, m), 2.80-3.00
(6H, m), 3.63 (2H, s), 3.95-4.15 (2H, m), 6.95-7.1
0 (3H, m), 7.20-7.40 (5H, m).

Reference Example 58 3- (Phenylmethyl) -7-[[2- (4-piperidinyl) ethyl] sulfanyl] -2,3,4,5-tetrahydro-1H-3-benzazepine dihydrochloride

Embedded image T-butyl 4- [2-[[3-phenylmethyl- (2,3,4,5-tetrahydro-1H-) obtained in Reference Example 57
3-benzazepin-7-yl)] sulfanyl] ethyl] -1-piperidinecarboxylate (1.52 g, 3.16 m
mol) in ethanol (30 ml), 4N hydrogen chloride (ethyl acetate solution, 30 ml) was added, and the mixture was stirred at room temperature for 1 hour.
After the solvent was distilled off under reduced pressure, the residue was made alkaline with aqueous potassium carbonate, then dissolved in water-ethyl acetate, and extracted twice with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous potassium carbonate, and the solvent was distilled off under reduced pressure to obtain a free base of the title compound (1.21 g) as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 0.95-1.20 (2H, m), 1.40-1.75 (5
H, m), 1.80-1.90 (1H, br), 2.45-2.70 (6H, m), 2.8
0-3.10 (8H, m), 3.62 (2H, s), 6.95-7.10 (3H, m), 7.
20-7.40 (5H, m). A solution of the above free base (240 mg) in ethanol was treated with 2 equivalents of hydrogen chloride (ethanol solution) to give the title compound.
(240 mg) was obtained as colorless crystals having an mp of 246 ° C. (dec.). Elemental analysis: C ₂₄ H ₃₂ N ₂ S · 2HCl · 0.5H ₂ O Calculated: C, 62.32; H, 7.63; N, 6.06. Experimental: C, 62.83; H, 7.65; N, 6.44.

Reference Example 59 t-butyl 4- [2-[[3- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl] sulfinyl] ethyl] -1 −
Piperidine carboxylate

Embedded image m-Chloroperbenzoic acid (683 mg, 3.95 mmol) was added to the t-butyl 4- [2-[[3- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-) obtained in Reference Example 55.
3-benzazepin-7-yl] sulfanyl] ethyl] -1-piperidinecarboxylate (1.70 g, 3.49 m
mol) in chloroform (30 ml) at room temperature. After stirring the mixture at room temperature for 30 minutes, it was dissolved in water-ethyl acetate and extracted with ethyl acetate. The extract was washed successively with an aqueous sodium thiosulfate solution, an aqueous sodium hydrogen carbonate solution and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate = 1: 4) to give the title compound (1.71).
g) was obtained as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 1.00-1.20 (2H, m), 1.44 (9H, s),
1.50-1.80 (5H, m), 2.55-2.90 (4H, m), 3.00-3.15
(4H, m), 3.65-3.90 (4H, m), 4.00-4.15 (2H, m), 7.2
5-7.45 (3H, m).

Reference Example 60 t-butyl 4- [2-[(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl) sulfinyl] ethyl] -1-piperidinecarboxylate

Embedded image T-Butyl 4- [2-[[3- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl] sulfinyl] ethyl] obtained in Reference Example 59 -Piperidine carboxylate (1.70
g, 3.38 mmol) to give the title compound (1.50 g) as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 1.00-1.20 (2H, m), 1.44 (9H, s),
1.50-1.80 (5H, m), 2.00-2.10 (1H, br), 2.55-3.10
(12H, m), 4.00-4.15 (2H, m), 7.20-7.40 (3H, m).

Reference Example 61 t-butyl 4- [2-[[3- (phenylmethyl)-
2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl] sulfinyl] ethyl] -1-piperidinecarboxylate

Embedded image T-butyl 4- [2-[(2,3, obtained in Reference Example 60
4,5-tetrahydro-1H-3-benzazepine-7
-Yl) sulfinyl] ethyl] -1-piperidinecarboxylate (1.50 g, 3.69 mmol) and benzyl bromide (0.483 ml, 4.06 mmol) by performing the same operation as in Reference Example 22. (1.39 g) was obtained as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 0.95-1.20 (2H, m), 1.44 (9H, s),
1.50-1.80 (5H, m), 2.50-2.85 (8H, m), 2.90-3.05
(4H, m), 3.63 (2H, s), 3.95-4.15 (2H, m), 7.15-7.4
0 (8H, m).

Reference Example 62 3- (Phenylmethyl) -7-[[2- (4-piperidinyl) ethyl] sulfinyl] -2,3,4,5-tetrahydro-1H-3-benzazepine dihydrochloride

Embedded image T-butyl 4- [2-[[3- (phenylmethyl) -2,3,4,5-tetrahydro-1H obtained in Reference Example 61
-3-benzazepin-7-yl] sulfinyl] ethyl] -1-piperidinecarboxylate (1.39 g, 2.77 m
mol) and the same operation as in Reference Example 58, to give a free base (1.03 g) of the title compound as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 1.00-1.20 (2H, m), 1.40-1.75 (5
H, m), 1.80-2.00 (1H, br), 2.45-2.70 (6H, m), 2.75
-3.20 (8H, m), 3.63 (2H, s), 6.95-7.10 (3H, m), 7.
15-7.40 (5H, m). A solution of the above free base (200 mg) in ethanol was treated with 2 equivalents of hydrogen chloride (ethanol solution) to give the title compound.
(224 mg) was obtained as a colorless amorphous powder. Elemental analysis: C ₂₄ H ₃₂ N ₂ OS · 2HCl · H ₂ O Calculated: C, 59.13; H, 7.44; N, 5.75. Experimental: C, 59.05; H, 7.46; N, 5.34.

Reference Example 63 t-butyl 4- [2-[[3- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl] sulfonyl] ethyl] -1 -Piperidine carboxylate

Embedded image m-Chloroperbenzoic acid (1.24 g, 7.18 mmol) was added to t-butyl 4- [2-[[3- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H obtained in Reference Example 55. −
3-benzazepin-7-yl] sulfanyl] ethyl] -1-piperidinecarboxylate (1.40 g, 2.88 m
mol) in chloroform (10 ml) at room temperature. After stirring the mixture at room temperature for 2 hours, it was dissolved in water-ethyl acetate and extracted with ethyl acetate. The extract was washed successively with an aqueous sodium thiosulfate solution, an aqueous sodium hydrogen carbonate solution and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate = 1: 1) to give the title compound (1.49 g).
Was obtained as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 1.00-1.20 (2H,
m), 1.44 (9H, s), 1.50-1.
80 (5H, m), 2.50-2.75 (2
H, m), 3.05-3.20 (6H, m),
3.70-3.85 (4H, m), 4.00-
4.15 (2H, m), 7.37 (1H, d
d, J = 8.2, 5.6 Hz), 7.65
-7.75 (2H, m).

Reference Example 64 t-butyl 4- [2-[(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl) sulfonyl] ethyl] -1-piperidinecarboxylate

Embedded image T-Butyl 4- [2-[[3- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl] sulfonyl] obtained in Reference Example 63
Ethyl] -1-piperidinecarboxylate (1.53 g,
The title compound (1.25 g) was obtained as colorless crystals having a mp of 102-103 ° C by the same operation as in Reference Example 56 using 2.95 mmol). ¹ H NMR (CDCl ₃ ) δ 0.95-1.20 (2H, m), 1.44 (9H, s),
1.50-1.75 (5H, m), 1.80-1.90 (1H, br), 2.55-2.75
(2H, m), 2.85-3.15 (10H, m), 4.00-4.15 (2H, m), 7.2
5-7.30 (1H, m), 7.60-7.65 (2H, m) Elemental analysis _{C 22 H 34 N 2 O 4} S Calculated:.. C, 62.53; H , 8.11; N, 6.63 Experimental: C, , 62.63; H, 8.18; N, 6.45.

Reference Example 65 t-butyl 4- [2-[[3- (phenylmethyl)-
2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl] sulfonyl] ethyl] -1-piperidinecarboxylate

Embedded image T-butyl 4- [2-[(2,3, obtained in Reference Example 64
4,5-tetrahydro-1H-3-benzazepine-7
-Yl) sulfonyl] ethyl] -1-piperidinecarboxylate (1.43 g, 3.38 mmol) and benzyl bromide
The title compound (1.35 g) was obtained as a colorless oil by performing the same operation as in Reference Example 57 using (0.443 ml, 3.72 mmol). ¹ H NMR (CDCl ₃ ) δ 0.95-1.20 (2H, m), 1.44 (9H, s),
1.50-1.80 (5H, m), 2.55-2.75 (6H, m), 2.95-3.15
(6H, m), 3.64 (2H, s), 3.95-4.15 (2H, m), 7.20-7.4
0 (6H, m), 7.55-7.70 (2H, m).

Reference Example 66 3- (Phenylmethyl) -7-[[2- (4-piperidinyl) ethyl] sulfonyl] -2,3,4,5-tetrahydro-1H-3-benzazepine

Embedded image T-butyl 4- [2-[[3- (phenylmethyl) -2,3,4,5-tetrahydro-1H obtained in Reference Example 65
-3-benzazepin-7-yl] sulfonyl] ethyl] -1-piperidinecarboxylate (1.35 g, 2.63 m
mol), to give the title compound (1.08 g) as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 0.95-1.20 (2H, m), 1.35-2.00 (6
H, m), 2.40-2.75 (6H, m), 2.90-3.20 (8H, m), 3.64
(2H, s), 7.20-7.40 (6H, m), 7.55-7.70 (2H, m).

Reference Example 67 8-Nitro-1,3,4,5-tetrahydro-2H-2
-Benzazepine-2-carbaldehyde

Embedded image To a solution of 1,3,4,5-tetrahydro-2H-2-benzazepine-2-carbaldehyde (10.0 g, 57.1 mmol) in concentrated sulfuric acid (100 ml) was added potassium nitrate (6.4 g, 63.3 mmol).
Was added little by little at 0 ° C. and stirred for 3 hours. The reaction mixture was added to ice-sodium bicarbonate, the aqueous layer was made alkaline, and extracted with ethyl acetate. The extract was washed successively with an aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product of the title compound (7.36 g) as a pale yellow solid. ¹ H NMR (CDCl ₃ ) δ 1.80-1.95 (2H, m), 3.11 (2H, tl
ike, J = 5.4 Hz), 3.71 (2H, t-like, J = 5.4 Hz), 4.
62 (2H, s), 7.31 (1H, d, J = 8.4 Hz), 8.00-8.10 (2
H, m), 8.23 (1H, s).

Reference Example 68 8-Nitro-2,3,4,5-tetrahydro-1H-2
-Benzazepine

Embedded image To a solution of 8-nitro-1,3,4,5-tetrahydro-2H-2-benzazepine-2-carbaldehyde (3.00 g, 13.6 mmol) obtained in Reference Example 67 in methanol (30 ml) was added concentrated hydrochloric acid (70 ml). In addition, the mixture was heated under reflux for 2 hours. After the methanol was distilled off under reduced pressure, the residue was made alkaline with sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product of the title compound (2.22 g) as a yellow oil. ¹ H NMR (CDCl ₃ ) δ 1.50-1.90 (3H,
m), 3.04 (2H, t-like, J =
5.4 Hz), 3.24 (2H, t-like)
e, J = 5.4 Hz), 4.02 (2H,
s), 7.30 (1H, d, J = 9.2)
Hz), 7.95-8.05 (2H, m).

Reference Example 69 8-Nitro-2- (phenylmethyl) -2,3,4,5
-Tetrahydro-1H-2-benzazepine

Embedded image Crude product of 8-nitro-2,3,4,5-tetrahydro-1H-2-benzazepine obtained in Reference Example 68
(2.22 g, 11.5 mmol) and benzyl bromide (1.51 ml, 13.9 mmol) were subjected to the same operation as in Reference Example 57 to give the title compound (520 mg) as a yellow solid. ¹ H NMR (CDCl ₃ ) δ 1.70-1.90 (2H, m), 3.02 (2H, tl
ike, J = 5.4 Hz), 3.13 (2H, t-like, J = 5.4 Hz), 3.
55 (2H, s), 3.92 (2H, s), 7.20-7.40 (6H, m), 7.79
(1H, d, J = 2.6 Hz), 8.02 (1H, dd, J = 8.0, 2.6 H
z).

Reference Example 70 8-amino-2- (phenylmethyl) -2,3,4,5
-Tetrahydro-1H-2-benzazepine

Embedded image 8-Nitro-2- (phenylmethyl) obtained in Reference Example 69
To a solution of -2,3,4,5-tetrahydro-1H-2-benzazepine (200 mg, 0.79 mmol) in acetic acid (10 ml) was added zinc dust (3 g, 47 mmol), and the mixture was heated under reflux for 30 minutes. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was made alkaline with an aqueous potassium carbonate solution and extracted with ethyl acetate. The extract was washed successively with an aqueous potassium carbonate solution and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give the title compound (138 mg) as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 1.60-1.80 (2H, m), 2.80 (2H, tl
ike, J = 5.4 Hz), 3.07 (2H, t-like, J = 5.4 Hz), 3.
20-3.60 (2H, br), 3.53 (2H, s), 3.78 (2H, s), 6.31
(1H, d, J = 2.6 Hz), 6.47 (1H, dd, J = 8.0, 2.6 H
z), 6.92 (1H, d, J = 8.0 Hz), 7.20-7.40 (5H, m).

Reference Example 71 8-acetyl-1,3,4,5-tetrahydro-2H-
2-benzazepine-2-carbaldehyde

Embedded image Dichloroethane of 1,3,4,5-tetrahydro-2H-2-benzazepine-2-carbaldehyde (5.00 g, 28.5 mmol) and acetyl chloride (2.23 ml, 31.4 mmol)
(25ml) solution, aluminum chloride (13.3g, 99.7mmo
l) was added little by little at room temperature and stirred for 12 hours. The reaction mixture was added to ice and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give the title compound (3.04 g) as a colorless solid. ¹ H NMR (CDCl ₃ ) δ 1.80-1.95 (2H, m), 2.59 (3H, s),
3.00-3.10 (2H, m), 3.68 (2H, t-like, J = 5.6 Hz),
4.61 (2H, s), 7.20-7.30 (1H, m), 7.81 (1H, dd, J =
7.8, 2.0 Hz), 7.94 (1H, d, J = 2.0 Hz), 8.03 (1H,
s).

Reference Example 72 2-Formyl-2,3,4,5-tetrahydro-1H-
2-benzazepine-8-carboxylic acid

Embedded image 8-acetyl-1,3,4,5-tetrahydro-2H-2-benzazepine-2-carbaldehyde (5.00 g, 28.5 mmol) obtained in Reference Example 71 was dissolved in 1,4-dioxane (50 m
l) An aqueous solution of sodium hydroxide (4.8 g / 70 ml) was added to the solution. Next, bromine (2.14 ml, 41.6 mmol) was added dropwise at -15 ° C, and the mixture was stirred at 0 ° C for 30 minutes. After adding acetone (5 ml) and stirring for 10 minutes, the mixture was concentrated under reduced pressure, and washed with ethyl acetate. The aqueous layer was acidified with 5N hydrochloric acid, and the precipitated solid was filtered, washed successively with water and ethyl ether, and air-dried to obtain the title compound (1.95 g) as a colorless solid. ¹ H NMR (CDCl ₃ ) δ 1.80-1.95 (2H, m), 3.00-3.10 (2
H, m), 3.69 (2H × 3/5, t-like, J = 5.4 Hz), 3.85 (2
H × 2/5, t-like, J = 5.4 Hz), 4.53 (2H × 2/5, s), 4.
63 (2H × 3/5, s), 7.20-7.30 (1H, m), 7.85-8.20 (3H,
m).

Reference Example 73 2- (phenylmethyl) -2,3,4,5-tetrahydro-1H-2-benzazepine-8-carboxylic acid

Embedded image 1) 2-Formyl-2,3,4,5 obtained in Reference Example 72
Concentrated hydrochloric acid (100 ml) was added to tetrahydro-1H-2-benzazepine-8-carboxylic acid (1.90 g, 8.67 mmol),
Stirred at 0 ° C. for 2 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to give 2,3,4,5-tetrahydro-1H-
2-benzazepine-8-carboxylate hydrochloride (1.81 g)
Was obtained as a colorless solid. 2) 2,3,4,5-tetrahydro-1H-2-benzazepine-8-carboxylic acid hydrochloride obtained in 1) above
(1.50 g, 6.59 mmol) and benzyl bromide (0.823 ml, 6.
The same operation as in Reference Example 57 was carried out using 92 mmol) to give 2- (phenylmethyl) -2,3,4,5-tetrahydro-1H-2-benzazepine-8-carboxylic acid benzyl ester (1.24 g). ) Was obtained as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 1.80-1.95 (2H, m), 2.85-3.00 (2
H, m), 3.15 (2H, t-like, J = 5.4 Hz), 3.53 (2H,
s), 3.93 (2H, s), 5.35 (2H, s), 7.20-7.90 (13H, m). 3) 2- (phenylmethyl) -2, obtained in 2) above
3,4,5-tetrahydro-1H-2-benzazepine-8-carboxylic acid benzyl ester (1.23 g, 3.31 mmol
To a solution of l) in ethanol (50 ml) was added a 1N aqueous sodium hydroxide solution (50 ml), and the mixture was heated under reflux for 1 hour. After concentrating the ethanol under reduced pressure, the residue was adjusted to pH using 2N hydrochloric acid.
It was adjusted to about 5 and extracted three times with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (804 mg) as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 1.80-2.10 (2H, m), 2.80-3.10 (2
H, m), 3.30-3.60 (2H, m), 4.05 (2H, s), 4.70 (2H,
s), 7.10-8.10 (8H, m).

Reference Example 74 2-[(4-fluorophenyl) methyl] -8- [2-
(4-Piperidinyl) ethoxy] -2,3,4,5-tetrahydro-1H-2-benzazepine dihydrochloride

Embedded image 2-[(4-fluorophenyl) methyl] obtained in 2) of Reference Example 2
Using -8-hydroxy-2,3,4,5-tetrahydro-1H-2-benzazepine, the same procedure as in 3) and 3) of Reference Example 2 was carried out to give the title compound as a colorless amorphous substance. Obtained as a powder. ¹ H NMR (CDCl ₃ , free base) δ 1.05-
1.30 (2H, m), 1.50-1.90 (6H, m), 2.50-2.70 (2H,
m), 2.85 (2H, t-like, J = 5.4 Hz), 3.00-3.15 (4H,
m), 3.49 (2H, s), 3.70-3.85 (4H, m), 3.94 (2H, t,
J = 6.2 Hz), 6.48 (1H, d, J = 2.6Hz), 6.67 (1H, d
d, J = 8.2, 2.6 Hz), 6.90-7.10 (3H, m), 7.20-7.30
(2H, m). Elemental analysis: C ₂₄ H ₃₁ FN ₂ O · 2HCl · 0.5H ₂ O Calculated: C, 62.07; H, 7.38; N, 6.03. Experimental: C, 61.99; H, 7.70; N, 5.78.

Reference Example 75 2-[(4-fluorophenyl) methyl] -7- [2-
(4-Piperidinyl) ethoxy] -2,3,4,5-tetrahydro-1H-2-benzazepine dihydrochloride

Embedded image 4-fluorobenzyl bromide and 7-methoxy-2,
The title compound was obtained as a colorless amorphous powder by sequentially performing the same operation as in Reference Example 2 and Reference Example 3 using 3,4,5-tetrahydro-1H-2-benzazepine. ¹ H NMR (CDCl ₃ , free base) δ 1.05-1.30 (2H, m),
1.50-1.90 (6H, m), 2.50-2.70 (2H, m), 2.86 (2H, t-
like, J = 5.4 Hz), 3.00-3.15 (4H, m), 3.46 (2H,
s), 3.65-3.80 (4H, m), 3.99 (2H, t, J = 6.2 Hz),
6.59 (1H, dd, J = 8.0, 2.6 Hz), 6.72 (1H, d, J =
2.6 Hz), 6.81 (1H, d, J = 8.0 Hz), 6.80-7.05 (2H,
m), 7.40-7.50 (2H, m). Elemental analysis: C ₂₄ H ₃₁ FN ₂ O, 2HCl, 1.5 H ₂ O Calculated: C, 59.75; H, 7.52; N, 5.81. Experimental: C, H, 7.57;
N, 5.32.

Reference Example 76 2-[[2- (trifluoromethyl) phenyl] methyl]
-7- [2- (4-piperidinyl) ethoxy] -2,
3,4,5-tetrahydro-1H-2-benzazepine

Embedded image By using 2- (trifluoromethyl) benzyl bromide and 7-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepine, the same operation as in Reference Examples 2 and 3 was sequentially performed to obtain The title compound was obtained as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 1.05-1.30 (2H, m), 1.65-1.85 (6
H, m), 2.50-3.20 (10H, m), 3.72 (2H, s), 3.75 (2H,
s), 3.99 (2H, t, J = 6.2 Hz), 6.59 (1H, dd, J = 8.
2, 2.6 Hz), 6.72 (1H, d, J = 2.6 Hz), 6.83 (1H, d,
J = 8.2 Hz), 7.31 (1H, t, J = 7.6 Hz), 7.50 (1H,
t, J = 7.6 Hz), 7.61 (1H, d, J = 7.8 Hz), 7.81 (1
(H, d, J = 7.8 Hz).

Reference Example 77 t-butyl 4- [3-[[3- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl] sulfanyl] propyl] -1 −
Piperidine carboxylate

Embedded image The 2,2,2-trifluoro-1- (7) obtained in Reference Example 54
-Sulfanyl-2,3,4,5-tetrahydro-1H-
The title compound was obtained as colorless crystals having a mp of 104 to 105 ° C by performing the same operation as in Reference Example 55 using 3-benzazepin-3-yl) -1-ethanone. ¹ H NMR (CDCl ₃ ) δ 1.00-1.75 (9H, m), 1.45 (9H, s),
2.55-2.75 (2H, m), 2.85-3.00 (6H, m), 3.65-3.85 (4
H, m), 4.00-4.15 (2H, m), 7.00-7.20 (2H, m), 7.27
(1H, s).

Reference Example 78 t-butyl 4- [3-[[3- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl] sulfonyl] propyl] -1 -Piperidine carboxylate

Embedded image T-butyl 4- [3-[[3- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl] sulfanyl] obtained in Reference Example 77
The title compound was obtained as a colorless oil by performing the same operation as in Reference Example 63 using propyl] -1-piperidinecarboxylate. ¹ H NMR (CDCl ₃ ) δ 0.90-1.85 (9H, m), 1.45 (9H, s),
2.55-2.75 (2H, m), 3.00-3.20 (6H, m), 3.65-3.85 (4
H, m), 3.95-4.15 (2H, m), 7.30-7.45 (1H, m), 7.65
7.80 (2H, m).

Reference Example 79 t-butyl 4- [3-[(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl) sulfonyl] propyl] -1-piperidinecarboxylate

Embedded image T-butyl 4- [3-[[3- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl] sulfonyl] propyl obtained in Reference Example 78 Using piperidine carboxylate,
The title compound was obtained as a colorless oil by performing the same operation as in Reference Example 56. _{^{1 H NMR (CDCl 3) δ}} 0.90-1.85 (9H, m), 1.44 (9H, s),
2.10-2.30 (1H, br), 2.50-2.75 (2H, m), 2.90-3.10
(10H, m), 3.95-4.20 (2H, m), 7.20-7.35 (1H, m), 7.
60-7.65 (2H, m).

Reference Example 80 t-butyl 4- [3-[[3- (phenylmethyl)-
2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl] sulfonyl] propyl] -1-piperidinecarboxylate

Embedded image T-butyl 4- [3-[[2,3] obtained in Reference Example 79
4,5-tetrahydro-1H-3-benzazepine-7-
The title compound was obtained as a colorless oil by performing the same operation as in Reference Example 57 using yl] sulfonyl] propyl] -1-piperidinecarboxylate. ¹ H NMR (CDCl ₃ ) δ 0.90-1.85 (9H,
m), 1.45 (9H, s), 2.50-2.
75 (6H, m), 2.95-3.10 (6
H, m), 3.64 (2H, s), 3.95
-4.15 (2H, m), 7.20-7.40
(6H, m), 7.60-7.65 (2H,
m).

Reference Example 81 t-butyl 4- [3-[[3-[(2-methylphenyl) methyl] -2,3,4,5-tetrahydro-1H-3
-Benzazepin-7-yl] sulfonyl] propyl]
-1-piperidine carboxylate

Embedded image T-butyl 4- [3-[(2,3) obtained in Reference Example 79
4,5-tetrahydro-1H-3-benzazepine-7-
The title compound was obtained as a colorless oil by performing the same operation as in Reference Example 57 using yl) sulfonyl] propyl] -1-piperidinecarboxylate. ¹ H NMR (CDCl ₃ ) δ 0.90-2.00 (9H, m), 1.45 (9H, s),
2.39 (3H, s), 2.50-2.75 (6H, m), 2.90-3.10 (6H,
m), 3.54 (2H, s), 3.95-4.15 (2H, m), 7.10-7.35 (5H,
m), 7.60-7.65 (2H, m).

Reference Example 82 3- (Phenylmethyl) -7-[[3- (4-piperidinyl) propyl] sulfonyl] -2,3,4,5-tetrahydro-1H-3-benzazepine

Embedded image T-butyl 4- [3-[[3- (phenylmethyl) -2,3,4,5-tetrahydro-1H- obtained in Reference Example 80
The title compound was obtained as a colorless oil by performing the same operation as in Reference Example 58 using 3-benzazepin-7-yl] sulfonyl] propyl] -1-piperidinecarboxylate. ¹ H NMR (CDCl ₃ ) δ 0.90-1.40 (5H, m), 1.50-1.95 (4H,
m), 2.10-2.70 (1H, br), 2.53 (2H, dt, J = 12.2,
2.6 Hz), 2.55-2.70 (4H, m), 2.90-3.10 (8H, m), 3.6
4 (2H, s), 7.20-7.40 (6H, m), 7.60-7.65 (2H, m).

Reference Example 83 3-[(2-methylphenyl) methyl] -7-[[3-
(4-piperidinyl) propyl] sulfonyl] -2,
3,4,5-tetrahydro-1H-3-benzazepine

Embedded image T-butyl 4- [3-[[3-
[(2-methylphenyl) methyl] -2,3,4,5-
The title compound was obtained as a colorless oil by performing the same operation as in Reference Example 58 using tetrahydro-1H-3-benzazepin-7-yl] sulfonyl] propyl] -1-piperidinecarboxylate. ¹ H NMR (CDCl ₃ ) δ 0.90-1.40 (5H, m), 1.50-1.90 (4H,
m), 1.90-2.05 (1H, br), 2.39 (3H, s), 2.45-2.75
(6H, m), 2.90-3.10 (8H, m), 3.54 (2H, s), 7.15-7.3
5 (5H, m), 7.60-7.65 (2H, m).

Reference Example 84 2,2,2-trifluoro-1- (7-sulfanyl-
2,3,4,5-tetrahydro-1H-2-benzazepin-2-yl) -1-ethanone

Embedded image The title compound was converted to mp 94- by performing the same operation as in Reference Example 54 using 2- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-2-benzazepine-8-sulfonyl chloride. Obtained as colorless crystals at 95 ° C. ¹ H NMR (CDCl ₃ ) δ 1.80-2.00 (2H, m), 2.41 (1H, s),
2.95-3.10 (2H, m), 3.80-4.00 (2H, m), 4.61 and 4.6
8 (2H, s and s), 7.15-7.45 (3H, m). Elemental analysis calculated as C ₁₂ H ₁₂ F ₃ NOS Calculated: C, 52.35; H, 4.39; N, 5.09. Experimental: C, 53.10 ; H, 4.47; N, 4.50.

Reference Example 85 t-butyl 4- [2-[[2- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl] sulfanyl] ethyl] -1 -Piperidine carboxylate

Embedded image The 2,2,2-trifluoro-1- (7) obtained in Reference Example 84
-Sulfanyl-2,3,4,5-tetrahydro-1H-
The title compound was obtained as a colorless oil by performing the same operation as in Reference Example 55 using 2-benzazepin-2-yl) -1-ethanone. ¹ H NMR (CDCl ₃ ) δ 1.00-1.25 (2H, m), 1.45 (9H, s),
1.45-1.75 (9H, m), 2.55-2.80 (2H, m), 2.85-3.10 (2
H, m), 3.80-4.20 (4H, m), 4.50-4.70 (2H, m), 7.00-
7.25 (3H, m).

Reference Example 86 t-butyl 4- [2-[(2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl) sulfanyl] ethyl] -1-piperidinecarboxylate

Embedded image T-butyl 4- [2-[[2- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl] sulfanyl] obtained in Reference Example 85
Ethyl] -1-piperidinecarboxylate,
The title compound was obtained as a colorless oil by performing the same operation as in Reference Example 56. ¹ H NMR (CDCl ₃ ) δ 1.00-1.30 (2H, m), 1.40-1.80 (19
H, m), 2.30-2.45 (1H, br), 2.55-2.80 (2H, m), 2.85
-3.00 (2H, m), 3.19 (1H, t, J = 5.2Hz), 3.67 (1H,
t, J = 6.4Hz), 3.90 (1H, s), 4.00-4.20 (2H, m), 7.
00-7.30 (3H, m).

Reference Example 87 t-butyl 4- [2-[[2- (phenylmethyl)-
2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl] sulfanyl] ethyl] -1-piperidinecarboxylate

Embedded image T-butyl 4- [2-[(2,3) obtained in Reference Example 86
4,5-tetrahydro-1H-2-benzazepine-8-
The title compound was obtained as a colorless oil by performing the same operation as in Reference Example 57 using yl) sulfanyl] ethyl] -1-piperidinecarboxylate. ¹ H NMR (CDCl ₃ ) δ 1.00-1.20 (2H,
m), 1.45 (9H, s), 1.50-1.
95 (7H, m), 2.55-2.80 (2
H, m), 2.80-2.95 (4H, m),
3.11 (2H, t-like, J = 5.
2Hz), 3.52 (2H, s), 3.82
(2H, s), 4.00-4.20 (2H, s)
m), 6.85-6.90 (1H, m), 7.
00-7.15 (2H, m), 7.20-7.4
0 (5H, m).

Reference Example 88 2- (phenylmethyl) -8-[[2- (4-piperidinyl) ethyl] sulfanyl] -2,3,4,5-tetrahydro-1H-2-benzazepine

Embedded image The t-butyl 4- [2-[[2- (phenylmethyl) -2,3,4,5-tetrahydro-1H-) obtained in Reference Example 87
The title compound was obtained as a colorless oil by performing the same operation as in Reference Example 58 using 2-benzazepin-8-yl] sulfanyl] ethyl] -1-piperidinecarboxylate. ¹ H NMR (CDCl ₃ ) δ 0.95-1.25 (2H, m), 1.40-1.80 (8H,
m), 2.45-2.70 (2H, m), 2.80-2.95 (4H, m), 2.95-3.
20 (4H, m), 3.53 (2H, s), 3.83 (2H, s), 6.85-6.95
(1H, m), 7.00-7.15 (2H, m), 7.20-7.40 (5H, m).

Reference Example 89 t-butyl 4- [2-[[2- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl] sulfinyl] ethyl] -1 -Piperidine carboxylate

Embedded image T-butyl 4- [2-[[2- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl] sulfanyl] obtained in Reference Example 85
Ethyl] -1-piperidinecarboxylate,
The title compound was obtained as a colorless oil by performing the same operation as in Reference Example 59. ¹ H NMR (CDCl ₃ ) δ 0.90-1.20 (2H, m), 1.30-1.80 (5H,
m), 1.44 (9H, s), 1.85-2.00 (2H, m), 2.55-2.90 (4
H, m), 3.00-3.15 (2H, m), 3.80-4.20 (4H, m), 4.55-
4.80 (2H, m), 7.30-7.60 (3H, m).

Reference Example 90 t-butyl 4- [2-[(2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl) sulfinyl] ethyl] -1-piperidinecarboxylate

Embedded image T-butyl 4- [2-[[2- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl] sulfinyl] obtained in Reference Example 89
Ethyl] -1-piperidinecarboxylate,
The title compound was obtained as a colorless oil by performing the same operation as in Reference Example 56. ¹ H NMR (CDCl ₃ ) δ 1.00-1.20 (2H, m), 1.44 (9H, s),
1.50-1.90 (8H, m), 2.55-2.85 (4H, m), 2.95-3.10 (2
H, m), 3.23 (2H, t-like, J = 4.6Hz), 3.95-4.20 (4
H, m), 7.25-7.40 (3H, m).

Reference Example 91 t-butyl 4- [2-[[2- (phenylmethyl)-
2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl] sulfinyl] ethyl] -1-piperidinecarboxylate

Embedded image T-butyl 4- [2-[(2,3, obtained in Reference Example 90
4,5-tetrahydro-1H-2-benzazepine-8-
The title compound was obtained as a colorless oil by performing the same operation as in Reference Example 57 using yl) sulfinyl] ethyl] -1-piperidinecarboxylate. ¹ H NMR (CDCl ₃ ) δ 1.00-1.20 (2H, m), 1.44 (9H, s),
1.50-2.10 (7H, m), 2.55-2.85 (4H, m), 2.90-3.05 (2
H, m), 3.12 (2H, t-like, J = 5.4Hz), 3.54 (2H, s),
3.91 (2H, s), 3.95-4.20 (2H, m), 7.13 (1H, d, J =
1.8Hz), 7.20-7.35 (6H, m), 7.42 (1H, dd, J = 7.6,
1.8Hz).

Reference Example 92 2- (phenylmethyl) -8-[[2- (4-piperidinyl) ethyl] sulfinyl] -2,3,4,5-tetrahydro-1H-2-benzazepine

Embedded image T-butyl 4- [2-[[2- (phenylmethyl) -2,3,4,5-tetrahydro-1H-) obtained in Reference Example 91
The title compound was obtained as a colorless oil by performing the same operation as in Reference Example 58 using 2-benzazepin-8-yl] sulfinyl] ethyl] -1-piperidinecarboxylate. ¹ H NMR (CDCl ₃ ) δ 1.00-1.20 (2H, m), 1.45-2.10 (8H,
m), 2.50-2.70 (2H, m), 2.80-2.95 (4H, m), 3.00-3.
20 (4H, m), 3.52 (2H, s), 3.83 (2H, s), 6.85-7.15
(3H, m), 7.20-7.40 (5H, m).

Reference Example 93 t-butyl 4- [2-[[2- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl] sulfonyl] ethyl] -1 -Piperidine carboxylate

Embedded image T-butyl 4- [2-[[2- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl] sulfanyl] obtained in Reference Example 85
Ethyl] -1-piperidinecarboxylate,
By performing the same operation as in Reference Example 63, the title compound was obtained as colorless crystals having a mp of 129-131 ° C. ¹ H NMR (CDCl ₃ ) δ 0.95-1.20 (2H, m), 1.30-1.80 (5H,
m), 1.44 (9H, s), 1.85-2.05 (2H, m), 2.50-2.75 (2
H, m), 3.00-3.20 (4H, m), 3.80-4.20 (4H, m), 4.67 a
nd 4.76 (2H, s and s), 7.38 (1H, d, J = 7.38Hz),
7.76 (1H, dd, J = 8.2, 1.8 Hz), 7.91 (1H, d, J = 1.
8 Hz). Elemental analysis: C ₂₄ H ₃₃ F ₃ N ₂ O ₅ S Calculated: C, 55.58; H, 6.41; N, 5.40. Experimental: C, 55.52; H, 6.31; N, 5.48.

Reference Example 94 t-butyl 4- [2-[(2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl) sulfonyl] ethyl] -1-piperidinecarboxylate

Embedded image T-butyl 4- [2-[[2- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl] sulfonyl] ethyl] obtained in Reference Example 93 The title compound was obtained as a colorless oil by performing the same operation as in Reference Example 56 using -piperidinecarboxylate. ¹ H NMR (CDCl ₃ ) δ 0.95-1.25 (2H, m), 1.44 (9H, s),
1.50-1.95 (8H, m), 2.55-2.75 (2H, m), 2.90-3.15 (4
H, m), 3.24 (2H, t-like, J = 5.2Hz), 3.95-4.15 (2
H, m), 4.00 (2H, s), 7.34 (1H, d, J = 7.4Hz), 7.60
-7.75 (2H, m).

Reference Example 95 t-butyl 4- [2-[[2- (phenylmethyl)-
2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl] sulfonyl] ethyl] -1-piperidinecarboxylate

Embedded image T-butyl 4- [2-[(2,3) obtained in Reference Example 94
4,5-tetrahydro-1H-2-benzazepine-8-
The title compound was obtained as a colorless oil by performing the same operation as in Reference Example 57 using yl) sulfonyl] ethyl] -1-piperidinecarboxylate. ¹ H NMR (CDCl ₃ ) δ 0.95-1.20 (2H, m), 1.44 (9H, s),
1.50-1.90 (7H, m), 2.55-2.75 (2H, m), 2.95-3.10 (4
H, m), 3.13 (2H, t-like, J = 5.2Hz), 3.54 (2H, s),
3.91 (2H, s), 3.95-4.20 (2H, m), 7.20-7.40 (6H,
m), 7.43 (1H, d, J = 1.8Hz), 7.68 (1H, dd, J = 7.7,
1.8Hz).

Reference Example 96 2- (phenylmethyl) -8-[[2- (4-piperidinyl) ethyl] sulfinyl] -2,3,4,5-tetrahydro-1H-2-benzazepine

Embedded image T-butyl 4- [2-[[2- (phenylmethyl) -2,3,4,5-tetrahydro-1H- obtained in Reference Example 95
2-benzazepin-8-yl] sulfonyl] ethyl]
Reference Example 5 using -1-piperidinecarboxylate
By performing the same operation as in Step 8, the title compound was converted to mp 83
Obtained as colorless crystals at -85 ° C. ¹ H NMR (CDCl ₃ ) δ 0.95-1.90 (12H, m), 2.45-2.65 (2
H, m), 2.90-3.20 (6H, m), 3.54 (2H, s), 3.91 (2H,
s), 7.20-7.40 (6H, m), 7.40-7.45 (1H, m), 7.65-7.7
5 (1H, m).

Reference Example 97 N-methyl 3-[[4- [3-[[2-[(4-fluorophenyl) methyl] -2,3,4,5-tetrahydro-1H-2-benzazepine-8- Yl] oxy] propyl] -1-piperidinyl] methyl] -1-benzenecarboximidamide trihydrochloride

Embedded image 1) 8- [3- [1-[(3-cyanophenyl) methyl] -4-piperidinyl] propoxy] -2-[(4
-Fluorophenyl) methyl] -2,3,4,5-tetrahydro-1H-2-benzazepine (1.8 g) and 9.8 N hydrochloric acid (ethanol solution, 80 ml) were stirred at room temperature for 16 hours. After evaporating the solvent under reduced pressure, the residue was dissolved in water-ethyl acetate and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give ethyl 3-[[4- [3-[[2-[(4-fluorophenyl) methyl]-. 2,3,4,5-tetrahydro-1H-2-
Benzazepin-8-yl] oxy] propyl] -1-piperidinyl] methyl] -1-benzenecarboximidate (2.18 g) was obtained as a colorless oil. 2) The ethyl 3-[[4- [3-[[2-[(4
-Fluorophenyl) methyl] -2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl] oxy] propyl]
A methanol solution (10 ml) of 1-piperidinyl] methyl] -1-benzenecarboximidate (500 mg) and 40% methylamine (methanol solution, 10 ml) was heated at 120 ° C. for 30 minutes in a stainless steel pressure tube. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate-1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with brine, dried over potassium carbonate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography using basic activated alumina (developing solvent; ethyl acetate-methanol-NH4OH = 1: 1: 0.03) to obtain a free base of the title compound. An ethanol solution of the free base is treated with 3 equivalents of hydrogen chloride (ethanol solution),
The title compound (512 mg) was obtained as a colorless amorphous powder. ¹ H NMR (CDCl ₃ , free base) δ 1.15-1.45 (5H, m),
1.55-2.05 (9H, m), 2.75-2.90 (4H, m), 2.98 (3H,
s), 3.08 (2H, t-like, J = 5.2 Hz), 3.49 (4H, s),
3.80 (2H, s), 3.87 (2H, t, J = 6.4 Hz), 5.60-6.20
(1H, br), 6.47 (1H, d, J = 2.6 Hz), 6.66 (1H, dd, J
= 8.0, 2.6 Hz), 6.90-7.05 (3H, m), 7.20-7.50 (5H,
m), 7.53 (1H, s). Elemental analysis: C ₃₄ H ₄₃ FN ₄ O.3HCl.2H ₂ O Calculated: C, 59.34; H, 7.32; N, 8.14. Experimental: C, 59.27; H , 7.74; N, 8.41.

Reference Example 98 8- [3- [1-[[3- (4,5-dihydro-1H-2-imidazolyl) phenyl] methyl] -4-piperidinyl] propoxy] -2-[(4-fluoro Phenyl) methyl] -2,3,4,5-
Tetrahydro-1H-2-benzazepine

Embedded image The ethyl 3-[[4- [3-[[2-
[(4-Fluorophenyl) methyl] -2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl] oxy] propyl] -1-piperidinyl] methyl] -1-benzenecarboximidate and ethylenediamine Using Reference Example 9
By performing the same operation as in 7-2), the title compound was obtained.
Obtained as colorless crystals of mp 119-121 ° C. ¹ H NMR (CDCl ₃ ) δ 1.15-1.45 (5H, m), 1.55-2.05 (9
H, m), 2.80-2.90 (4H, m), 3.08 (2H, t-like, J = 5.
2 Hz), 3.49 (4H, s), 3.50 (2H, s), 3.70-3.95 (6H,
m), 6.48 (1H, d, J = 2.6 Hz), 6.66 (1H, dd, J = 8.
0, 2.6 Hz), 6.90-7.05 (3H, m), 7.20-7.45 (4H, m),
7.66 (1H, d, J = 7.0 Hz), 7.74 (1H, s). Elemental analysis: C ₃₅ H ₄₃ FN ₄ O Calculated: C, 75.78; H, 7.81; N, 10.10. Experimental: C, 75.33; H, 7.59; N, 10.05.

Reference Example 99 4-[[4- [2-[[2-[(2-methylphenyl) methyl] -2,
3,4,5-tetrahydro-1H-2-benzazepin-8-yl] oxy] ethyl] -1-piperidinyl] methyl] -1-benzenecarboximidamide

Embedded image Ethyl 4-[[4- [2-[[2-[(2-methylphenyl) methyl] -2,3,4,5-tetrahydro-1H-2) obtained in Reference Example 9.
Reference Example 97 using -benzazepin-8-yl] oxy] ethyl] -1-piperidinyl] methyl] -1-benzenecarboximidate and ammonia (ethanol solution).
By performing the same operation as in 2), the title compound was converted to mp
Obtained as colorless crystals at 107-108 ° C. ¹ H NMR (CDCl ₃ ) δ 1.20-1.80 (9H,
m), 1.90-2.10 (2H, m), 2.
28 (3H, s), 2.75-2.90 (4
H, m), 3.07 (2H, t-like,
J = 5.2 Hz), 3.48 (2H,
s), 3.51 (2H, s), 3.60-4.
40 (3H, br), 3.81 (2H, br)
s), 3.93 (2H, t, J = 6.2)
Hz), 6.54 (1H, d, J = 2.6)
Hz), 6.66 (1H, dd, J = 8.
0, 2.6 Hz), 7.04 (1H, d,
J = 8.0 Hz), 7.10-7.30 (4
H, m), 7.37 (2H, d, J =
8.0 Hz), 7.55 (2H, d, J =
8.0 Hz). Elemental analysis _{C 33 H 42 N 4 O ·} 0.5H 2 O Calculated:. C, 76.26; H, 8.34; N, 10.78 Found: C, 76.39; H, 8.13 ; N, 10.80.

Reference Example 100 8- [2- [1-[[4- (4,5-dihydro-1H-2-imidazolyl) phenyl] methyl] -4-piperidinyl] ethoxy]
-2-[(2-methylphenyl) methyl] -2,3,4,5-tetrahydro-1H-2-benzazepine

Embedded image Ethyl 4-[[4- [2-[[2-[(2-methylphenyl) methyl] -2,3,4,5-tetrahydro-1H-2) obtained in Reference Example 9.
-Benzazepin-8-yl] oxy] ethyl] -1-piperidinyl] methyl] -1-benzenecarboximidate and ethylenediamine were subjected to the same operation as in 2) of Reference Example 97 to convert the title compound to mp150. Obtained as colorless crystals at -151 ° C. ¹ H NMR (CDCl ₃ ) δ 1.20-1.80 (9H, m), 1.90-2.05 (2H,
m), 2.27 (3H, s), 2.80-2.90 (4H, m), 3.07 (2H, t-
like, J = 5.2 Hz), 3.48 (2H, s), 3.51 (2H, s), 3.7
8 (4H, s), 3.81 (2H, s), 3.93 (2H, t, J = 6.2 Hz),
6.54 (1H, d, J = 2.6 Hz), 6.66 (1H, dd, J = 8.0,
2.6 Hz), 7.04 (1H, d, J = 8.0 Hz), 7.10-7.30 (4H,
m), 7.36 (2H, d, J = 8.0 Hz), 7.52 (2H, d, J = 8.0
Hz). Elemental analysis: C ₃₅ H ₄₄ N ₄ O Calculated: C, 78.32; H, 8.26; N, 10.44. Experimental: C, 78.30; H, 8.12; N, 10.45.

Reference Example 101 2-[(2-methylphenyl) methyl] -8- [2-
[1-[[3- (4,5-Dihydro-1H-2-imidazolyl) phenyl] methyl] -4-piperidinyl] ethoxy] -2,3,4,5-tetrahydro-1H-2-benzazepine trihydrochloride

Embedded image 2-[(2-methylphenyl) methyl] -8- [2- [1-[(3-cyanophenyl) methyl] -4-piperidinyl] ethoxy] -2,3,4,5 obtained in Reference Example 10.
The title compound was obtained as a colorless amorphous powder by performing the same operation as in Reference Example 97 using -tetrahydro-1H-2-benzazepine dihydrochloride. ¹ H NMR (CDCl ₃ , free base) δ 1.20-1.80 (9H, m), 1.
85-2.10 (2H, m), 2.27 (3H, s), 2.80-2.90 (4H, m),
3.06 (2H, t-like, J = 5.2 Hz), 3.48 (4H, s), 3.60-
4.00 (1H, br), 3.76 (4H, s), 3.80 (2H, s), 3.92 (2
H, t, J = 6.2 Hz), 6.53 (1H, d, J = 2.6 Hz), 6.65
(1H, dd, J = 8.2, 2.6 Hz), 7.03 (1H, d, J = 8.0 H
z), 7.10-7.45 (6H, m), 7.65 (1H, d, J = 7.4 Hz),
7.73 (1H, s). Elemental analysis: Calculated for C ₃₅ H ₄₄ N ₄ O.3HCl.1.5H ₂ O Calculated: C, 62.45; H, 7.49; N, 8.32. Experimental: C, 62.25; H, 7.65 ; N, 7.76.

Reference Example 102 2-[(2-methylphenyl) methyl] -8- [2-
[1- [4- (4,5-Dihydro-1H-2-imidazolyl) benzoyl] -4-piperidinyl] ethoxy]-
2,3,4,5-tetrahydro-1H-2-benzazepine

Embedded image 2-[(2-methylphenyl) methyl] -8- [2- [1- (4-cyanobenzoyl) -4 obtained in Reference Example 11
-Piperidinyl] ethoxy] -2,3,4,5-tetrahydro-1H-2-benzazepine hydrochloride and the same procedure as in Reference Example 97 to give the title compound as mp
Obtained as colorless crystals at 145-146 ° C. ¹ H NMR (CDCl ₃ ) δ 1.00-1.50 (2H, m), 1.60-2.00 (8H,
m), 2.28 (3H, s), 2.70-3.20 (2H, br), 2.80-2.95
(2H, m), 3.07 (2H, t-like, J = 5.2 Hz), 3.49 (2H,
s), 3.60-4.00 (5H, br), 3.81 (2H, s), 3.96 (2H, t,
J = 6.0 Hz), 4.60-4.80 (1H, br), 6.53 (1H, d, J =
2.6 Hz), 6.66 (1H, dd, J = 8.0, 2.6 Hz), 7.05 (1
H, d, J = 8.0 Hz), 7.10-7.30 (4H, m), 7.42 (2H, d,
J = 8.0 Hz), 7.81 (2H, d, J = 8.0 Hz). Elemental analysis: C ₃₅ H ₄₂ N ₄ O ₂ Calculated: C, 76.33; H, 7.69; N, 10.17. Experimental: C, 75.97; H, 7.25; N, 10.03.

Reference Example 103 2- (phenylmethyl) -7-[[1-[[4- (4
5-dihydro-1H-2-imidazolyl) phenyl] methyl] -4-piperidinyl] methoxy] -2,3,4,5
-Tetrahydro-1H-2-benzazepine

Embedded image 2- (phenylmethyl) -7-[[1
-[(4-cyanophenyl) methyl] -4-piperidinyl] methoxy] -2,3,4,5-tetrahydro-1H-
The title compound was converted to mp 152-154 by performing the same operation as in Reference Example 97 using 2-benzazepine dihydrochloride.
Obtained as colorless crystals at ° C. ¹ H NMR (CDCl ₃ ) δ 1.30-1.95 (8H, m), 1.95-2.10 (2H,
m), 2.80-3.00 (4H, m), 3.11 (2H, t-like, J = 5.2
Hz), 3.53 (2H, s), 3.56 (2H, s), 3.81 (2H, d, J =
6.2 Hz), 3.83 (6H, s), 6.60 (1H, dd, J = 8.2, 2.6
Hz), 6.73 (1H, d, J = 2.6 Hz), 6.85 (1H, d, J = 8.
2 Hz), 7.20-7.35 (5H, m), 7.39 (2H, d, J = 8.0 Hz),
7.75 (2H, d, J = 8.0 Hz) Elemental analysis C ₃₃ H ₄₀ N ₄ O Calculated:.. C, 77.92; H , 7.93; N, 11.01 Found: C, 77.42; H, 7.93 ; N , 10.93.

Reference Example 104 2- (phenylmethyl) -8-[[1-[[4- (4
5-dihydro-1H-2-imidazolyl) phenyl] methyl] -4-piperidinyl] methoxy] -2,3,4,5
-Tetrahydro-1H-2-benzazepine

Embedded image 2- (phenylmethyl) -8-[[1
-[(4-cyanophenyl) methyl] -4-piperidinyl] methoxy] -2,3,4,5-tetrahydro-1H-
The title compound was converted to mp 137-139 by performing the same operation as in Reference Example 97 using 2-benzazepine dihydrochloride.
Obtained as colorless crystals at ° C. ¹ H NMR (CDCl ₃ ) δ 1.25-1.50 (2H, m), 1.60-2.10 (8H,
m), 2.80-3.00 (4H, m), 3.09 (2H, t-like, J = 5.2
Hz), 3.40-4.20 (4H, br), 3.53 (4H, s), 3.73 (2H, d,
J = 5.8 Hz), 3.82 (2H, s), 6.50 (1H, d,
J = 2.6 Hz), 6.65 (1H, dd,
J = 8.2, 2.6 Hz), 7.03
(1H, d, J = 8.2 Hz), 7.20
−7.35 (5H, m), 7.37 (2H,
d, J = 8.0 Hz), 7.73 (2H,
d, J = 8.0 Hz). Elemental analysis: C ₃₃ H ₄₀ N ₄ O Calculated: C, 77.92; H, 7.93; N, 11.01. Experimental: C, 77.87; H, 7.91; N, 10.85.

Reference Example 105 2- (phenylmethyl) -8- [2- [1-[[4-
(4,5-dihydro-1H-2-imidazolyl) phenyl]
Methyl] -4-piperidinyl] ethoxy] -2,3,
4,5-tetrahydro-1H-2-benzazepine

Embedded image 2- (phenylmethyl) -8- [2-
[1-[(4-cyanophenyl) methyl] -4-piperidinyl] ethoxy] -2,3,4,5-tetrahydro-
The same procedure as in Reference Example 97 was carried out using 1H-2-benzazepine to give the title compound at mp 151-153 ° C.
As colorless crystals of ¹ H NMR (CDCl ₃ ) δ 1.20-2.10 (12H, m), 2.80-2.90 (4
H, m), 3.09 (2H, t-like, J = 5.2 Hz), 3.50 (2H,
s), 3.53 (2H, s), 3.60-4.00 (4H, br), 3.82 (2H, s),
3.92 (2H, t, J = 6.4 Hz), 6.50 (1H, d, J = 2.6 H
z), 6.66 (1H, dd, J = 8.0, 2.6 Hz), 7.03 (1H, d, J
= 8.0 Hz), 7.20-7.50 (5H, m), 7.35 (2H, d, J = 8.4
Hz), 7.72 (2H, d, J = 8.4 Hz). Elemental analysis: Calculated for C ₃₄ H ₄₂ N ₄ O Calculated: C, 78.12; H, 8.10; N, 10.72. Experimental: C, 77.64; H, 8.02; N, 10.49.

Reference Example 106 2- (phenylmethyl) -8- [2- [1-[(4-dimethylaminophenyl) methyl] -4-piperidinyl]
Ethoxy] -2,3,4,5-tetrahydro-1H-2-
Benzazepine trihydrochloride

Embedded image 8-methoxy-2,3,4,5-tetrahydro-1H-2
The title compound was obtained as a colorless amorphous powder by sequentially performing the same operation as in Reference Example 2, Reference Example 3, and Reference Example 4 using -benzazepine. ¹ H NMR (CDCl ₃ , free base) δ 1.20-1.80 (9H, m), 1.
85-2.05 (2H, m), 2.80-2.90 (4H, m), 2.93 (6H, s),
3.10 (2H, t-like, J = 5.2 Hz), 3.43 (2H, s), 3.53
(2H, s), 3.83 (2H, s), 3.91 (2H, t, J = 6.4 Hz),
6.49 (1H, d, J = 2.6 Hz), 6.60-6.75 (2H m), 7.03 (1
H, d, J = 8.0 Hz), 7.10-7.35 (8H, m). Elemental analysis: C ₃₃ H ₄₃ N ₃ O.3HCl Calculated: C, 62.50; H, 7.79; N, 6.63. Experimental: C, 62.20; H, 7.97; N, 6.34.

Reference Example 107 2- (phenylmethyl) -8- [2- [1-[[4-
(N, N-diethylaminomethyl) phenyl] methyl] -4
-Piperidinyl] ethoxy] -2,3,4,5-tetrahydro-1H-2-benzazepine trihydrochloride

Embedded image 8-methoxy-2,3,4,5-tetrahydro-1H-2
The title compound was obtained as a colorless amorphous powder by sequentially performing the same operation as in Reference Example 2, Reference Example 3, and Reference Example 4 using -benzazepine. ¹ H NMR (CDCl ₃ , free base) δ 1.04 (6H, t, J = 7.0
Hz), 1.20-1.80 (8H, m), 1.85-2.10 (3H, m), 2.51 (4
H, q, J = 7.0 Hz), 2.80-2.95 (4H, m), 3.09 (2H, t-
like, J = 5.2 Hz), 3.46 (2H, s), 3.53 (2H, s), 3.5
4 (2H, s), 3.82 (2H, s), 3.92 (2H, t, J = 6.4 Hz),
6.49 (1H, d, J = 2.6 Hz), 6.65 (1H, dd, J = 8.3,
2.6 Hz), 7.03 (1H, d, J = 8.3 Hz), 7.20-7.35 (9H,
m). Elemental analysis: C ₃₆ H ₄₉ N ₃ O.3HCl.H ₂ O Calculated: C, 64.81; H, 8.16; N, 6.30. Experimental: C, 64.44; H, 8.48; N, 6.36.

Reference Example 108 2- (phenylmethyl) -7-[[1-[[4- (4,5
-Dihydro-1H-2-imidazolyl) phenyl] methyl]
-4-Piperidinyl] oxy] -2,3,4,5-tetrahydro-1H-2-benzazepine

Embedded image 2- (phenylmethyl) -7-[[1-
By using [(4-cyanophenyl) methyl] -4-piperidinyl] oxy] -2,3,4,5-tetrahydro-1H-2-benzazepine dihydrochloride, the same operation as in Reference Example 97 was performed. Mp 122-124 ° C
As colorless crystals of ¹ H NMR (CDCl ₃ ) δ 1.65-2.05 (6H, m), 2.20-2.40 (2H,
m), 2.65-2.90 (5H, m), 3.08 (2H, t-like, J = 5.2
Hz), 3.51 (2H, s), 3.55 (2H, s), 3.60-3.95 (4H, b
r), 3.79 (2H, s), 4.29 (1H, tt, J = 7.4, 3.6 Hz),
6.60 (1H, dd, J = 8.2, 2.6 Hz), 6.71 (1H, d, J = 2.
6 Hz), 6.82 (1H, d, J = 8.2 Hz), 7.20-7.35 (5H,
m), 7.37 (2H, d, J = 8.4 Hz), 7.73 (2H, d, J = 8.4 Hz)
. Hz) Elemental analysis _{C 32 H 38 N 4 O ·} 0.5H 2 O Calculated:. C, 76.31; H, 7.80; N, 11.12 Found: C, 76.75; H, 7.71 ; N, 11.17.

Reference Example 109 2- (phenylmethyl) -8-[[1-[[4- (4,5
-Dihydro-1H-2-imidazolyl) phenyl] methyl]
-4-Piperidinyl] oxy] -2,3,4,5-tetrahydro-1H-2-benzazepine

Embedded image 2- (phenylmethyl) -8-[[1-
By using [(4-cyanophenyl) methyl] -4-piperidinyl] oxy] -2,3,4,5-tetrahydro-1H-2-benzazepine dihydrochloride, the same operation as in Reference Example 97 was performed. Mp 131-133 ° C
As colorless crystals of ¹ H NMR (CDCl ₃ ) δ 1.65-2.00 (7H, m), 2.27 (2H, ddd,
J = 11.5, 8.3, 3.2 Hz), 2.65-2.80 (2H, m), 2.80-
2.90 (2H, m), 3.10 (2H, t-like, J = 5.2 Hz), 3.53
(2H, s), 3.55 (2H, s), 3.60-4.00 (4H, br), 3.81 (2
H, s), 4.21 (1H, tt, J = 7.6, 3.6 Hz), 6.50 (1H, d,
J = 2.6 Hz), 6.67 (1H, dd, J = 8.4, 2.6 Hz), 7.03
(1H, d, J = 8.4 Hz), 7.20-7.35 (5H, m), 7.37 (2H,
d, J = 8.4 Hz), 7.73 (2H, d, J = 8.4 Hz). Elemental analysis calculated as C ₃₂ H ₃₈ N ₄ O Calculated: C, 77.70; H, 7.74; N, 11.33. Experimental: C , 77.29; H, 7.66; N, 11.33.

Reference Example 110 3-[[4- [2-[[2-[[2- (trifluoromethyl) phenyl] methyl] -2,3,4,5-tetrahydro-1H-2-benzazepine-8] -Yl] oxy] ethyl] -1-piperidinyl] methyl] -1-benzenecarboximidamide trihydrochloride

Embedded image 8- [2- [1-[(4-cyanophenyl) obtained in Reference Example 35
Reference Example 9 using methyl] -4-piperidinyl] ethoxy] -2-[[2- (trifluoromethyl) phenyl] methyl] -2,3,4,5-tetrahydro-1H-2-benzazepine.
By performing the same operation as in 7, the title compound was obtained as a colorless amorphous powder. ¹ H NMR (CDCl ₃ ) δ 1.20-1.80 (9H, m), 1.85-2.05 (2H,
m), 2.75-2.90 (4H, m), 3.05 (2H, t-like, J = 5.4 H
z), 3.50 (2H, s), 3.73 (2H, s), 3.77 (2H, s), 3.91
(2H, t, J = 6.2 Hz), 4.00-4.70 (3H, br.), 6.48 (1
H, d, J = 2.6 Hz), 6.66 (1H, dd, J = 8.2, 2.6 Hz),
7.04 (1H, d, J = 8.2 Hz), 7.25-7.65 (7H, m), 7.81
(1H, d, J = 7.6Hz).

Reference Example 111 8- [2- [1-[[4- (4,5-dihydro-1H-2-imidazolyl) phenyl] methyl] -4-piperidinyl] ethoxy]
-2-[[2- (trifluoromethyl) phenyl] methyl] -2,3,4,5-tetrahydro-1H-2-benzazepine

Embedded image 8- [2- [1-[(4-cyanophenyl) obtained in Reference Example 35
Reference Example 9 using methyl] -4-piperidinyl] ethoxy] -2-[[2- (trifluoromethyl) phenyl] methyl] -2,3,4,5-tetrahydro-1H-2-benzazepine.
By performing the same operation as in 7, the title compound was converted to mp 11
Obtained as colorless crystals at 4-117 ° C. _{^{1 H NMR (CDCl 3) δ1.20-1.80}} (10H, m), 1.85-2.05 (2H,
m), 2.75-2.90 (4H, m), 3.03 (2H, t-like, J = 5.4
Hz), 3.50 (2H, s), 3.73 (2H, s), 3.77 (6H, s), 3.9
1 (2H, t, J = 6.2 Hz), 6.48 (1H, d, J = 2.6 Hz),
6.66 (1H, dd, J = 8.0, 2.6 Hz), 7.04 (1H, d, J = 8.
0 Hz), 7.25-7.40 (4H, m), 7.50 (1H, t, J = 7.2 Hz),
7.61 (1H, d, J = 7.6 Hz), 7.72 (1H, d, J = 8.0 H
z), 7.81 (1H, d, J = 7.6 Hz).

Reference Example 112 8- [2- [1-[[4- (1-methyl-4,5-dihydro-1H-
2-imidazolyl) phenyl] methyl] -4-piperidinyl] ethoxy] -2-[[2- (trifluoromethyl) phenyl] methyl] -2,3,4,5-tetrahydro-1H-2-benzazepine trihydrochloride

Embedded image 8- [2- [1-[(4-cyanophenyl) obtained in Reference Example 35
Reference Example 9 using methyl] -4-piperidinyl] ethoxy] -2-[[2- (trifluoromethyl) phenyl] methyl] -2,3,4,5-tetrahydro-1H-2-benzazepine.
By performing the same operation as in 7, the title compound was converted to mp 11
Obtained as colorless crystals at 4-117 ° C. ¹ H NMR (CDCl ₃ ) δ 1.20-2.00 (9H, m), 2.20-2.55 (2H,
m), 2.80-2.95 (4H, m), 3.06 (2H, t-like, J = 5.4 H
z), 3.45-3.65 (5H, m), 3.74 (2H, s), 3.77 (2H, s),
3.80-4.00 (4H, m), 4.34 (2H, t, J = 7.0 Hz), 6.48
(1H, d, J = 2.6Hz), 6.66 (1H, dd, J = 8.0, 2.6 H
z), 7.04 (1H, d, J = 8.0 Hz), 7.25-7.55 (6H, m), 7.
61 (1H, d, J = 7.6 Hz), 7.81 (1H, d, J = 7.6 Hz).

Reference Example 113 3-Chloro-4-[[4- [2-[[2-[[2- (trifluoromethyl) phenyl] methyl] -2,3,4,5-tetrahydro-1H-2] -Benzazepin-8-yl] oxy] ethyl]-
1-piperidinyl] methyl] -1-benzenecarboximidamide trihydrochloride

Embedded image 8- [2- [1-[(2-Chloro-4-cyanophenyl) methyl] -4-piperidinyl] ethoxy] -2- obtained in Reference Example 36
[[2- (trifluoromethyl) phenyl] methyl] -2,
The title compound was obtained as a colorless amorphous powder by performing the same operation as in Reference Example 97 using 3,4,5-tetrahydro-1H-2-benzazepine. _{^{1 H NMR (CDCl 3) δ1.20-1.90}} (9H, m), 2.00-2.20 (2H,
m), 2.75-2.95 (4H, m), 3.06 (2H, t-like, J = 5.2 H
z), 3.60 (2H, s), 3.74 (2H, s), 3.77 (2H, s), 3.93
(2H, t, J = 6.4 Hz), 3.80-4.80 (3H, br.), 6.49 (1
H, d, J = 2.6 Hz), 6.67 (1H, dd, J = 8.0, 2.6 Hz),
7.05 (1H, d, J = 8.0 Hz), 7.32 (1H, t, J = 7.6 H
z), 7.40-7.65 (5H, m), 7.81 (1H, d, J = 7.6 Hz).

Reference Example 114 8- [2- [1-[[2-chloro-4- (4,5-dihydro-1H-2
-Imidazolyl) phenyl] methyl] -4-piperidinyl]
Ethoxy] -2-[[2- (trifluoromethyl) phenyl] methyl] -2,3,4,5-tetrahydro-1H-2-benzazepine trihydrochloride

Embedded image 8- [2- [1-[(2-Chloro-4-cyanophenyl) methyl] -4-piperidinyl] ethoxy] -2- obtained in Reference Example 36
[[2- (trifluoromethyl) phenyl] methyl] -2,
The title compound was obtained as colorless crystals having a mp of 209-211 ° C. by the same operation as in Reference Example 97 using 3,4,5-tetrahydro-1H-2-benzazepine. ¹ H NMR (CDCl ₃ ) δ 1.20-1.95 (9H, m), 2.00-2.20 (2H,
m), 2.70-3.40 (1H, br.), 2.80-2.95 (4H, m), 3.06
(2H, t-like, J = 5.2 Hz), 3.60 (2H, s), 3.74 (2H,
s), 3.78 (6H, s), 3.92 (2H, t, J = 6.4 Hz), 6.49
(1H, d, J = 2.6 Hz), 6.67 (1H, dd, J = 8.0, 2.6 H
z), 7.04 (1H, d, J = 8.0 Hz), 7.32 (1H, t, J = 7.6
Hz), 7.40-7.70 (4H, m), 7.76 (1H, d, J = 1.6 Hz),
7.81 (1H, d, J = 7.6 Hz).

Reference Example 115 8- [2- [1-[[2-Chloro-4- (1-methyl-4,5-dihydro-1H-2-imidazolyl) phenyl] methyl] -4-]
Piperidinyl] ethoxy] -2-[[2- (trifluoromethyl) phenyl] methyl] -2,3,4,5-tetrahydro-1
H-2-benzazepine trihydrochloride

Embedded image 8- [2- [1-[(2-Chloro-4-cyanophenyl) methyl] -4-piperidinyl] ethoxy] -2- obtained in Reference Example 36
[[2- (trifluoromethyl) phenyl] methyl] -2,
The title compound was obtained as a colorless amorphous powder by performing the same operation as in Reference Example 97 using 3,4,5-tetrahydro-1H-2-benzazepine. ¹ H NMR (CDCl ₃ ) δ 1.20-1.95 (9H,
m), 2.00-2.20 (2H, m), 2.
79 (3H, s), 2.80-2.95 (4
H, m), 3.06 (2H, t-like,
J = 5.2 Hz), 3.44 (2H, t,
J = 9.6 Hz), 3.60 (2H,
s), 3.74 (2H, s), 3.77 (2
H, s), 3.86 (2H, t, J =
9.6 Hz), 3.93 (2H, t, J =
6.4 Hz), 6.49 (1H, d, J =
2.6 Hz), 6.67 (1H, dd, J
= 8.0, 2.6 Hz), 7.04 (1
H, d, J = 8.0 Hz), 7.25-
7.65 (6H, m), 7.81 (1H,
d, J = 7.6 Hz).

Reference Example 116 8- [3- [1-[[4- (4,5-dihydro-1H-2-imidazolyl) phenyl] methyl] -4-piperidinyl] propoxy] -2- (phenylmethyl)- 2,3,4,5-tetrahydro-1H-2-benzazepine

Embedded image Reference Example 38 8- [3- [1-[(4-cyanophenyl) methyl] -4-piperidinyl] propoxy] -2- (phenylmethyl) -2,3,4,5-tetrahydro-1H-2- The same operation as in Reference Example 97 was performed using benzazepine to give the title compound as colorless crystals, mp 131-134 ° C. _{^{1 H NMR (CDCl 3) δ1.20-1.45}} (4H, m), 1.60-2.00 (9H,
m), 2.80-2.90 (4H, m), 3.09 (2H, t-like, J = 5.2 H
z), 3.40-4.20 (4H, br.), 3.50 (2H, s), 3.53 (2H,
s), 3.83 (2H, s), 3.86 (2H, t, J = 6.6 Hz), 4.60-
4.90 (1H, br.), 6.50 (1H, d, J = 2.6 Hz), 6.66 (1
H, dd, J = 8.0, 2.6 Hz), 7.03 (1H, d, J = 8.0 Hz),
7.20-7.40 (7H, m), 7.72 (2H, d, J = 6.6 Hz).

Reference Example 117 2- (phenylmethyl) -8- [2- [1-[[4-
(N, N-dimethylaminomethyl) phenyl] methyl] -4
-Piperidinyl] ethoxy] -2,3,4,5-tetrahydro-1H-2-benzazepine trihydrochloride

Embedded image 8-methoxy-2,3,4,5-tetrahydro-1H-2
The title compound was obtained as a colorless amorphous powder by sequentially performing the same operation as in Reference Example 2, Reference Example 3, and Reference Example 4 using -benzazepine. ¹ H NMR (CDCl ₃ , free base) δ 1.20-1.80 (9H, m), 1.
85-2.05 (2H, m), 2.23 (6H, s), 2.80-2.95 (4H, m),
3.10 (2H, t-like, J = 5.4 Hz), 3.40 (2H, s), 3.47
(2H, s), 3.53 (2H, s), 3.82 (2H, s), 3.92 (2H, t,
J = 6.4 Hz), 6.50 (1H, d, J = 2.8 Hz), 6.66 (1H, d
d, J = 8.2, 2.8 Hz), 7.03 (1H, d, J = 8.2 Hz), 7.20
-7.35 (9H, m).

Example 1 8- [2- [1-[[4- (4,5-dihydro-1H-2-imidazolyl) phenyl] methyl] -4-piperidinyl] ethoxy] -2- (phenylmethyl)- 2,3,4,5-tetrahydro-2-benzazepin-1-one

Embedded image 8- [2- [1-[(4-cyanophenyl) methyl] -4-piperidinyl] ethoxy] -2- (phenylmethyl) -2,3,4,5-tetrahydro-2- obtained in Reference Example 22 The same operation as in Reference Example 97 was performed using benzazepin-1-one to give the title compound as colorless crystals having an mp of 86-89 ° C. ¹ H NMR (CDCl ₃ ) δ 1.20-1.85 (9H, m), 1.85-2.05 (2H,
m), 2.00-2.80 (1H, br), 2.66 (2H, t, J = 7.0 Hz),
2.75-2.90 (2H, m), 3.17 (2H, t, J = 6.4 Hz), 3.51
(2H, s), 3.78 (4H, s), 4.02 (2H, t, J = 6.4 Hz),
4.78 (2H, s), 6.88 (1H, dd, J = 8.4, 2.8 Hz), 7.00
(1H, d, J = 8.4 Hz), 7.20-7.40 (8H, m), 7.72 (2H,
d, J = 8.2 Hz). Elemental analysis: calculated as C ₃₄ H ₄₀ N ₄ O ₂ .0.5H ₂ O Calculated: C, 74.83; H, 7.57; N, 10.27. Experimental: C, 74.87; H, 7.77 ; N, 10.44.

Example 2 4-[[4- [2-[[1-oxo-2- (phenylmethyl) -2,
3,4,5-tetrahydro-1H-2-benzazepin-7-yl] oxy] ethyl] -1-piperidinyl] methyl] -1-benzenecarboximidamide trihydrochloride

Embedded image 7- [2- [1-[(4-cyanophenyl) methyl] -4-piperidinyl] ethoxy] -2- (phenylmethyl) -2,3,4,5-tetrahydro-2- obtained in Reference Example 31 The title compound was obtained as a colorless amorphous powder by performing the same operation as in Reference Example 97 using benzazepin-1-one. ¹ H NMR (CDCl ₃ , free base) δ 1.20-1.85 (11H, m),
1.90-2.05 (2H, m), 2.69 (2H, t, J = 7.0 Hz), 2.75-
2.95 (2H, m), 3.18 (2H, t, J = 6.6 Hz), 3.50 (2H,
s), 4.02 (2H, t, J = 6.6 Hz), 4.77 (2H, s), 5.00-
5.40 (3H, br), 6.63 (1H, d, J = 2.6 Hz), 6.82 (1H,
dd, J = 8.4, 2.6 Hz), 7.20-7.45 (7H, m), 7.55 (2
. H, d, J = 8.0 Hz), 7.68 (1H, d, J = 8.4 Hz) Elemental analysis _{C 32 H 40 N 4 O 2} · 3HCl · 1.5H 2 O Calculated: C, 62.94; H, 7.10; N, 9.18. Found: C, 63.27; H, 7.20; N, 9.21.

Example 3 7- [2- [1-[[4- (4,5-Dihydro-1H-2-imidazolyl) phenyl] methyl] -4-piperidinyl] ethoxy] -2-[(4-fluoro Phenyl) methyl] -2,3,4,5-
Tetrahydro-2-benzazepin-1-one

Embedded image 7- [2- [1-[(4-cyanophenyl) methyl] -4-piperidinyl] ethoxy] -2- (phenylmethyl) -2,3,4,5-tetrahydro-2- obtained in Reference Example 31 The same procedure as in Reference Example 97 was carried out using benzazepin-1-one to convert the title compound to mp 135-136 ° C.
As colorless crystals of ¹ H NMR (CDCl ₃ ) δ 1.20-1.85 (10H, m), 1.90-2.05 (2
H, m), 2.69 (2H, t, J = 7.0 Hz), 2.75-2.95 (2H, m),
3.18 (2H, t, J = 6.6 Hz), 3.51 (2H, s), 3.60-4.00
(4H, br), 4.01 (2H, t, J = 6.6 Hz), 4.77 (2H, s),
6.62 (1H, d, J = 2.6 Hz), 6.82 (1H, dd, J = 8.4, 2.
6 Hz), 7.20-7.40 (7H, m), 7.67 (1H, d, J = 8.4 H
z), 7.72 (2H, d, J = 8.4 Hz). Elemental analysis: calculated as C ₃₄ H ₄₀ N ₄ O ₂ · 0.5 H ₂ O Calculated: C, 74.83; H, 7.57; N, 10.27. Experimental: C, 75.35; H, 7.59; N, 10.27.

Example 4 7- [2- [1-[[4- (1-Methyl-4,5-dihydro-1H-2)
-Imidazolyl) phenyl] methyl] -4-piperidinyl]
Ethoxy] -2-[(4-fluorophenyl) methyl] -2,
3,4,5-tetrahydro-2-benzazepin-1-one

Embedded image 7- [2- [1-[(4-cyanophenyl) methyl] -4-piperidinyl] ethoxy] -2- (phenylmethyl) -2,3,4,5-tetrahydro-2- obtained in Reference Example 31 The same procedure as in Reference Example 97 was carried out using benzazepin-1-one to give the title compound at mp 139-141 ° C.
As colorless crystals of ¹ H NMR (CDCl ₃ ) δ 1.20-1.85 (9H, m), 1.85-2.05 (2H,
m), 2.69 (2H, t, J = 7.0 Hz), 2.75-2.95 (2H, m),
2.80 (3H, s), 3.19 (2H, t, J = 6.6 Hz), 3.35-3.55
(4H, m), 3.86 (2H, t, J = 9.6 Hz), 4.01 (2H, t, J
= 6.6 Hz), 4.77 (2H, s), 6.63 (1H, d, J = 2.2 Hz),
6.82 (1H, dd, J = 8.6, 2.2 Hz), 7.20-7.40 (7H, m),
7.50 (2H, d, J = 8.0 Hz), 7.68 (1H, d, J = 8.4 H
z). Elemental analysis: Calculated for C ₃₅ H ₄₂ N ₄ O ₂ .0.5H ₂ O: C, 75.10; H, 7.74; N, 10.01. Experimental: C, 75.36; H, 7.70; N, 9.76.

Formulation Example 1 (1) Compound obtained in 1) of Reference Example 1 50 mg (2) Lactose 34 mg (3) Corn starch 10.6 mg (4) Corn starch (paste-like) 5 mg (5) Magnesium stearate 0.4 mg (6) Carboxymethylcellulose calcium 20 mg Total 120 mg A tablet is obtained by mixing the above (1) to (6) according to a conventional method and tableting using a tablet machine. Formulation Example 2 (1) Compound obtained in Reference Example 99 50 mg (2) Lactose 34 mg (3) Corn starch 10.6 mg (4) Corn starch (paste-like) 5 mg (5) Magnesium stearate 0.4 mg (6) Carboxymethylcellulose calcium 20 mg Total 120 mg Tablets are obtained by mixing the above (1) to (6) according to a conventional method and tableting using a tablet machine. Formulation Example 3 (1) Compound obtained in Example 1 50 mg (2) Lactose 34 mg (3) Maize starch 10.6 mg (4) Maize starch (paste-like) 5 mg (5) Magnesium stearate 0.4 mg (6) Carboxymethylcellulose calcium 20 mg Total 120 mg Tablets are obtained by mixing the above (1) to (6) according to a conventional method and tableting using a tablet machine.

Reference Example 1-1 Using cDNA derived from rat brain
Amplification of rat SLC-1 receptor cDNA by PCR A reverse transcription reaction was performed using rat brain-derived poly (A) ⁺ RNA (Clontech) as a template and random primers. For the reverse transcription reaction, reagents of Takara RNA PCR ver. 2 kit were used. Next, using the reverse transcription product as a template, amplification was performed by PCR using the synthetic DNA primers of SEQ ID NOs: 1 and 2. The synthetic DNA primer was constructed so that the gene in the region translated into the receptor protein was amplified.At that time, a nucleotide sequence recognized by the restriction enzyme Sal I was added to the 5 ′ side of the gene, and the 3 ′ side was added. Restriction enzyme Spe
As the base sequence recognized by I is added,
Recognition sequences for each restriction enzyme were added to the 3 'side. The composition of the reaction solution was 5 μl of the cDNA template and 0.4 of each synthetic DNA primer.
μM, 0.25 mM dNTPs, 0.5 μl of pfu (Stratagene) DNA polymerase and the buffer attached to the enzyme were used, and the total reaction volume was 50 μl. The cycle for amplification was performed using a thermal cycler (PerkinElmer) at 94 ° C and 60 ° C.
After heating for 2 seconds, a cycle of 94 ° C. for 60 seconds, 60 ° C. for 30 seconds, and 72 ° C. for 150 seconds was repeated 35 times, and finally the reaction was performed at 72 ° C. for 10 minutes. Confirmation of the amplification product was performed by ethidium bromide staining after electrophoresis on 0.8% agarose gel.

Reference Example 1-2 Confirmation of Amplified cDNA Sequence by Subcloning PCR Product into Plasmid Vector and Decoding Base Sequence of Inserted cDNA Part The reaction product after PCR performed in Reference Example 1-1 has a low melting point of 0.8%. Separation was performed using agarose gel, and the band was cut out with a razor, followed by fragmentation, phenol extraction, phenol / chloroform extraction, and ethanol precipitation.
DNA was recovered. Recovered DN according to the prescription of PCR-Script ^™ Amp SK (+) Cloning Kit (Stratagene)
A was subcloned into the plasmid vector pCR-Script Amp SK ( ⁺ ). This is called Escheric
hia coli ) XL-1 Blue (Stratagene) and transformed, clones containing cDNA insert were selected in LB agar medium containing ampicillin and X-gal, and only white clones were sterilized. Separation was performed using a toothpick to obtain a transformant E. coli XL-1 Blue / rat SLC-1. Each clone was cultured overnight in an LB medium containing ampicillin, and plasmid DNA was prepared using QIA prep8 miniprep (Qiagen). A portion of the prepared DNA was digested with restriction enzymes Sal I and Spe I to confirm the size of the inserted receptor cDNA fragment. The reaction for determining the nucleotide sequence is DyeDeoxy Terminator Cycle Sequen
This was performed using ce Kit (PerkinElmer), and decoding was performed using a fluorescent automatic sequencer. Rat SL in which the sequences of the three clones obtained were analyzed and all sequences were reported
A cDNA sequence encoding the C-1 protein (SEQ ID NO: 3) (Lakaye, B. et al. Biochim. Biophys. Acta, Vol. 1).
401, pp. 216-220 (1998), accession No. AF08650)
It was confirmed that the Sal I recognition sequence was added to the 5 'side and the gene sequence was identical to the gene sequence with the Spe I recognition sequence added to the 3' side (SEQ ID NO: 4).

Reference Example 1-3 Preparation of Rat SLC-1 Expressing CHO Cells SLC-1 derived from rat brain whose sequence was confirmed in Reference Example 1-2
E. col transformed with a plasmid into which a gene encoding a full-length amino acid sequence of 5 ′, a Sal I recognition sequence was added on the 5 ′ side, and a Spe I recognition sequence was added on the 3 ′ side.
A plasmid was prepared from the clone i using a Plasmid Midi Kit (Qiagen), and cut with restriction enzymes Sal I and Spe I to cut out the insert. Insert DNA
Was electrophoresed, cut out from an agarose gel with a razor, and then recovered by fragmentation, phenol extraction, phenol / chloroform extraction, and ethanol precipitation. This insert DNA was digested with Sal I and Spe I, and vector plasmid pAKKO-111H for animal cell expression (Hinuma, S. et.
al. Biochim. Biophys. Acta, Vol. 1219, pp. 251-259
(The same vector plasmid as pAKKO1.11H described in (1994)) and ligation was performed using T4 ligase (Takara Shuzo) to construct a plasmid pAKKO-SLC-1 for protein expression. E. coli DH5 transformed with pAKKO- SLC-1
After culturing (Toyo Bo), plasmid DNA of pAKKO-SLC-1 was prepared using PlasmidMidi Kit (Qiagen). This was introduced into CHO dhfr ⁻ cells using CellPhect Transfection Kit (Amersham Pharmacia Biotech) according to the attached protocol. 10 μg of DNA was co-precipitated with calcium phosphate and added to a 10 cm dish seeded with 5 × 10 ⁵ or 1 × 10 ⁶ CHO dhfr ⁻ cells 24 hours before. After culturing for 1 day in MEMα medium containing 10% fetal bovine serum, the cells were subcultured and cultured in nucleic acid-free MEMα medium containing 10% dialyzed fetal bovine serum as a selective medium. 56 clones of transformed cell colonies, which are SLC-1-expressing CHO cells growing in the selection medium, were selected.

Reference Example 1-4 Selection of CHO / SLC-1 Cell Line with High Expression of Full-length Rat SLC-1 Receptor Protein mRNA Full-length rat of 56 clones of CHO / SLC-1 strain established in Reference Example 1-3 Cytosta expression level of SLC-1 receptor protein mRNA
Using rT Plate (Amersham Pharmacia Biotech), measurement was performed as follows according to the attached protocol. Each clone of the CHO / SLC-1 strain was
After seeding 2.5 x 10 ⁴ cells per well and culturing for 24 hours, 10
Cells were fixed with% formalin. 0.25% for each well
After adding Triton X-100 to increase cell permeability, ³⁵ S
The labeled riboprobe of SEQ ID NO: 5 was added and hybridized. Free riboprobe was digested by adding 20 mg / ml RNaseA to each well, the plate was washed well, and the radioactivity of the hybridized riboprobe was measured with a Topcounter. Strain with higher radioactivity has higher mRNA expression level. mRNA
Among the three clones with high expression levels, especially clone number 44
Was mainly used.

Reference Example 1-5 Isolation of Plasmid Containing Human SLC-1 cDNA A cDNA library derived from human fetal brain (SUPERSCRIPT ^™ cDNA Lib
rary; GIBCO BRL) and Genetrapper cDNA positive sele
After nicking the DNA using phage F1 endonuclease according to the manual of the ction system (GIBCOBRL), Escherichia coli exonuclease I
By digestion with II, single-stranded human fetal brain-derived cDNA
brary was prepared. Kolakowski Jr., et al. (Kolakowski Jr.,
et al (1996) FEBS Lett. Vol. 398, pp. 253-258) and the synthetic oligonucleotide of SEQ ID NO: 6 (corresponding to 1434-1451 of accession No. U71092).
Biotin-14-dCTP at the 3 'end of Terminal Deoxynucleotidy
l Using transferase, a biotinylated oligonucleotide was prepared. The composition and reaction time of the reaction solution were in accordance with the manual. 4 μg of single-stranded human fetal brain-derived cDNA library
After keeping at 95 ° C for 1 minute, the mixture was rapidly cooled on ice, 20 ng of biotinylated oligonucleotide was added, and hybridized at 37 ° C for 1 hour with the attached hybridization buffer. Add streptavidin beads and use MAGNA-SEP Magnetic Par
Using a ticle Separator (GIBCOBRL), a cDNA derived from a single-stranded human fetal brain hybridized to a biotinylated oligonucleotide was isolated and reported by Kolacowski Jr. et al. (Kolakows
ki Jr., et al (1996) FEBS Lett. Vol. 398, pp. 253-
258), a complementary strand was synthesized according to the manual using 50 ng of the synthetic oligonucleotide of SEQ ID NO: 7 (corresponding to 1011-1028 of accession No. U71092) as a primer to prepare a double-stranded plasmid.

Reference Example 1-6 Determination of Base Sequence of Plasmid Containing Isolated Human SLC-1 cDNA The plasmid obtained in Reference Example 1-5 was replaced with ELECTROMAX ^™ DH10
After transformation by introducing electroporation method B ^TM Cells, clones having a cDNA insert fragment was selected on LB agar medium containing ampicillin and X-gal, were sterilized only clones exhibiting white toothpick Detsu Then, a transformant E. coli. DH10B / hSLC-1 was obtained. Individual clones were cultured overnight in LB medium containing ampicillin and QIA prep
Plasmid DNA was purified using 8 mini prep (Qiagen). The reaction for base sequence determination is DyeDeoxy Termi
This was performed using a nator Cycle Sequence Kit (PerkinElmer), and decoding was performed using a fluorescent automatic sequencer. As a result, the sequence shown in SEQ ID NO: 8 was obtained. The amino acid sequence encoded by the nucleotide sequence obtained here (SEQ ID NO: 9) is reported by Lakaye et al. (Lakaye, B. et al. (1
998) Biochem. Biophys. Acta, vol. 1401, pp. 216-22
0), the rat SLC was determined based on the human chromosomal DNA sequence (accession number: Z86090) containing the sequence of human SLC-1.
Human SLC-1 estimated as a sequence deduced from -1
It differs from the amino acid sequence, indicating that ATG, the start codon, is present on the mRNA further 69 and 64 amino acids upstream of the deduced sequence. Transformant Escherichia coli DH1 with plasmid containing DNA encoding this sequence
0B / phSLC1L8 was deposited with IFO and NIBH.

Reference Example 1-7 Amplification of human SLC-1 cDNA by PCR using cDNA derived from human fetal brain Human SLC-1 cloned by the gene trap method
Using a plasmid containing the DNA sequence as a template, SEQ ID NO: 1
Amplification by the PCR method was performed using the synthetic DNA primers 0 and 11 and the synthetic DNA primers of SEQ ID NOs: 12 and 13, respectively. The former amplified DNA was converted to human SLC-1 (S)
And the latter amplified DNA was designated as human SLC-1 (L). Synthesis
The DNA primer was constructed so that the gene in the region translated into the receptor protein was amplified.At that time, a nucleotide sequence recognized by the restriction enzyme Sal I was added to the 5 ′ side of the gene, and
Recognition sequences of the respective restriction enzymes were added to the 5 ′ and 3 ′ sides such that the base sequence recognized by the restriction enzyme Spe I was added to the 3 ′ side. The composition of the reaction solution for human SLC-1 (S) amplification was 5 μl of plasmid template containing human SLC-1 DNA sequence, synthetic DN
A primer 0.4 μM each, 0.2 mM dNTPs, 0.5 μl of pfu DNA polymerase and the buffer attached to the enzyme, and the total reaction volume was 50 μl. A cycle for amplification was performed using a thermal cycler (PerkinElmer), and after heating at 94 ° C for 60 seconds, a cycle of 94 ° C for 60 seconds, 57 ° C for 60 seconds, and 72 ° C for 150 seconds was repeated 25 times. Finally, it was kept at 72 ° C for 10 minutes. The composition of the reaction solution for human SLC-1 (L) amplification was human SLC-1D.
Plasmid template containing NA sequence 5 μl, synthetic DNA primers 0.4 μM each, 0.2 mM dNTPs, pfu DNA polymerase 0.5 μl
l and the buffer provided with the enzyme, for a total reaction volume of 50 μl
And The cycle for amplification was performed using a thermal cycler (PerkinElmer) at 94 ° C for 60 seconds, followed by a cycle of 94 ° C for 60 seconds, 60 ° C for 60 seconds, and 72 ° C for 3 minutes.
This was repeated 25 times and finally kept at 72 ° C. for 10 minutes. Confirmation of the amplification product was performed by ethidium bromide staining after electrophoresis on 0.8% agarose gel.

Reference Example 1-8 Confirmation of Amplified cDNA Sequence by Subcloning PCR Product into Plasmid Vector and Decoding Base Sequence of Inserted cDNA Portion The reaction product after PCR performed in Reference Example 1-7 had a low melting point of 0.8%. Separation was performed using agarose gel, and the band was cut out with a razor, followed by fragmentation, phenol extraction, phenol / chloroform extraction, and ethanol precipitation.
DNA was recovered. Recovered DN according to the prescription of PCR-Script ^™ Amp SK ( ⁺ ) Cloning Kit (Stratagene)
A was subcloned into the plasmid vector pCR-Script Amp SK ( ⁺ ). This is called Escheric
hia coli ) into a DH5α competent cell (Toyo Bo) for transformation, and then select a clone having a cDNA insert in an LB agar medium containing ampicillin and X-gal. E. coli DH5α transformant of human SLC-1 (S)
/ hSLC-1 (S) and human SLC-1 (L) transformant E. coli DH5α
/ hSLC-1 (L) was obtained. Each clone was cultured overnight in an LB medium containing ampicillin, and plasmid DNA was prepared using QIA prep8 mini prep (Qiagen). Prepared DNA
Was digested with the restriction enzymes Sal I and Spe I to confirm the size of the inserted receptor cDNA fragment. Reaction for nucleotide sequence determination is DyeDeoxy Termina
This was performed using a tor Cycle Sequence Kit (PerkinElmer), and decoding was performed using a fluorescent automatic sequencer.
The sequence of the obtained clone was determined using the human SLC-1 gene as a template, the DNA sequence to be amplified with the synthetic DNA primers of SEQ ID NOs: 10 and 11 (SEQ ID NO: 14), and the human SLC-1 gene as a template. : 12 and 13
Respectively corresponded to the DNA sequence to be amplified by the synthetic DNA primer (SEQ ID NO: 15).

Reference Example 1-9 Preparation of Human SLC-1 (S) -Expressing CHO Cells and Human SLC-1 (L) -Expressing CHO Cells The human SLC-1 (S) whose sequence was confirmed in Reference Example 1-8 , Human
Plasmids were prepared using the SLC-1 (L) Plasmid from clones E. col i transformed by the introduced plasmid Midi Kit (Qiagen), the insert was cleaved with restriction enzymes Sal I and Spe I The part was cut out. After the electrophoresis, the insert DNA was cut out from the agarose gel with a razor, and then recovered by performing fragmentation, phenol extraction, phenol / chloroform extraction, and ethanol precipitation. Vector plasmid pAKKO-111H (Hinum
a, S. et al. Biochim. Biophys. Acta, Vol. 1219, pp.
251-259 (1994), the same vector plasmid as pAKKO1.11H), and ligated using T4 ligase (Takara Shuzo) to obtain a plasmid pAKKO-hS for protein expression.
LC-1 (S) and pAKKO-hSLC-1 (L) were constructed. pAKKO-hSLC-1
(S) and pAKKO-hSLC-1 E. co li DH5 transformed with (L)
After culturing α (Toyo Bo), plasmid DNAs of pAKKO-hSLC-1 (S) and pAKKO-hSLC-1 (L) were prepared using Plasmid Midi Kit (Qiagen). This is CellPhect Transfect
The cells were introduced into CHO dhfr ^- cells using an ion Kit (Amersham Pharmacia Biotech) according to the attached protocol. 10 μg of DNA was co-precipitated with calcium phosphate and added to a 10 cm dish seeded with 5 × 10 ⁵ or 1 × 10 ⁶ CHO dhfr ⁻ cells 24 hours before. After culturing for 1 day in MEMα medium containing 10% fetal bovine serum, it is subcultured and nucleic acid-free MEMα containing 10% dialyzed fetal bovine serum as a selection medium
The cells were cultured in a medium. Human SLC-1 growing in selective medium
(S) Transformed cell colony 5 as a transfected CHO cell
Six clones and 61 clones of colonies of transformed cells, which are human SLC-1 (L) gene transfected CHO cells, were selected.

Reference Example 1-10 Human SLC-1 (S) and human
Selection of a transgenic cell line having a high expression level of SLC-1 (L) mRNA 56 clones of CHO / hSLC-1 (S) strain and 61 clones of CHO / hSLC-1 (L) strain established in Reference Example 1-9 Cyt expression level of mRNA
Using an ostar T Plate (Amersham Pharmacia Biotech), measurement was performed as follows according to the attached protocol. Each clone of the CHO / hSLC-1 (S) and CHO / hSLC-1 (L) strains was seeded at 2.5 × 10 ^{4 in} each well of a Cytostar T plate, cultured for 24 hours, and then cultured with 10% formalin. Was fixed. After adding 0.25% Triton X-100 to each well to increase cell permeability, ³⁵ S-labeled SEQ ID NO:
Sixteen riboprobes were added and hybridized. 20 mg
/ ml of RNaseA was added to each well to digest free riboprobe, and the plate was washed well and hybridized ri
The radioactivity of boprobe was measured by Topcounter. Strain with higher radioactivity has higher mRNA expression level. Of the 7 clones with high mRNA expression, clone number 57 was mainly used.

Experimental Example 1 Measurement of Antagonist Activity of Test Compound Using GTPγS Binding Assay Human SLC-1 expressing CHO cell clone 57 obtained in Reference Example 1-10 and rat SLC-Clone obtained in Reference Example 1-4 1 expression CHO
Using cell clone 44, a membrane fraction was prepared by the following method. Human and rat SLC-1 expressing CHO cells (1 × 10 ⁸ ) were suspended in phosphate buffered saline (pH 7.4) supplemented with 5 mM EDTA (ethylenediaminetetraacetic acid) and centrifuged.
Add a homogenate buffer (10 mM NaHCO3) to the cell pellet.
10 ml of 3,5 mM EDTA (pH 7.5) was added and homogenized using a Polytron homogenizer. The supernatant obtained by centrifugation at 400 × g for 15 minutes was further centrifuged at 100,000 × g for 1 hour to obtain a membrane fraction precipitate. The precipitate was added to 2 ml of assay buffer [50 mM Tris-HCl (pH 7.5), 1 mM EDTA, 0.1 mM
1% BSA (bovine serum albumin), 10 mM MgCl2, 100 mM Na
Cl, 1 mM GDP (guanosine 5'-diphosphate), 0.25 mM PMSF
(Phenylmethylsulfonyl fluoride), 1 mg / ml pepstatin, 20 mg / ml leupeptin, 10 mg / ml phosphoramidon] and centrifuged at 100,000 × g for 1 hour.
The membrane fraction recovered as a precipitate is again assayed in 20 ml.
After suspending in a buffer and dispensing, it was stored at -80 ° C, and thawed before use. The antagonist activity of the test compound was measured as follows. SLC-1 expression C diluted in assay buffer in a 96-well polypropylene plate
After dispensing 171 μl of HO cell membrane fraction, it was diluted with DMSO solution
2 ml of 3x10 ^-10 M MCH, 2 ml of test compound solution diluted to various concentrations, and [ ³⁵ S] -Guanosine 5 '-(γ-thio) triph
osphate (Daiichi Pure Chemicals Co., Ltd.) (25 ml) was added thereto (cell membrane final concentration: 20 mg / ml, [ ³⁵ S] -Guanosine 5 '-(γ-th
io) Triphosphate final concentration: 0.33 nM). After reacting this reaction solution at 25 ° C. for 1 hour while stirring, a glass filter was used.
(GF-C), filter with suction, and wash with 50 mM Tris-
Washed three times with 300 ml of HCl buffer (pH 7.5). 50 ml of liquid scintillator was added to the glass filter, and the remaining radioactivity was measured with a liquid scintillation counter. Binding inhibition rate (%) = (radioactivity when compound and MCH are added-radioactivity when DMSO solution is added) / (radioactivity when MCH is added-radioactivity when DMSO solution is added) As x100, the compound inhibition rate (%)
IC ₅₀ values were calculated.

The results are shown below.

Compound (I) or a salt thereof has excellent MC
It has H receptor antagonism and is useful as a prophylactic / therapeutic agent for obesity and the like.

[0277]

[Sequence List] [SEQUENCE LISTING] <110> Takeda Chemical Industries, Ltd. <120> Melanin Concentrating Hormone Antagonist <130> B00022 <160> 16 <210> 1 <211> 32 <212> DNA <213> Artificial Sequence <220><223><400> 1 GTCGACATGG ATCTGCAAAC CTCGTTGCTG TG 32 <210> 2 <211> 32 <212> DNA <213> Artificial Sequence <220><223><400> 2 ACTAGTTCAG GTGCCTTTGC TTTCTGTCCT CT 32 <210> 3 <211> 353 <212> PRT <213> Rat <400> 3 Met Asp Leu Gln Thr Ser Leu Leu Ser Thr Gly Pro Asn Ala Ser Asn 1 5 10 15 Ile Ser Asp Gly Gln Asp Asn Leu Thr Leu Pro Gly Ser Pro Pro Arg 20 25 30 Thr Gly Ser Val Ser Tyr Ile Asn Ile Ile Met Pro Ser Val Phe Gly 35 40 45 Thr Ile Cys Leu Leu Gly Ile Val Gly Asn Ser Thr Val Ile Phe Ala 50 55 60 Val Val Lys Lys Ser Lys Leu His Trp Cys Ser Asn Val Pro Asp Ile 65 70 75 80 Phe Ile Ile Asn Leu Ser Val Val Asp Leu Leu Phe Leu Leu Gly Met 85 90 95 Pro Phe Met Ile His Gln Leu Met Gly Asn Gly Val Trp His Phe Gly 100 105 110 Glu Thr Met Cys Thr Leu Ile Thr Ala Met Asp Ala Asn Ser Gln Phe 115 1 20 125 Thr Ser Thr Tyr Ile Leu Thr Ala Met Thr Ile Asp Arg Tyr Leu Ala 130 135 140 Thr Val His Pro Ile Ser Ser Thr Lys Phe Arg Lys Pro Ser Met Ala 145 150 155 160 Thr Leu Val Ile Cys Leu Leu Trp Ala Leu Ser Phe Ile Ser Ile Thr 165 170 175 Pro Val Trp Leu Tyr Ala Arg Leu Ile Pro Phe Pro Gly Gly Ala Val 180 185 190 Gly Cys Gly Ile Arg Leu Pro Asn Pro Asp Thr Asp Leu Tyr Trp Phe 195 200 205 Thr Leu Tyr Gln Phe Phe Leu Ala Phe Ala Leu Pro Phe Val Val Ile 210 215 220 Thr Ala Ala Tyr Val Lys Ile Leu Gln Arg Met Thr Ser Ser Val Ala 225 230 235 240 Pro Ala Ser Gln Arg Ser Ile Arg Leu Arg Thr Lys Arg Val Thr Arg 245 250 255 Thr Ala Ile Ala Ile Cys Leu Val Phe Phe Val Cys Trp Ala Pro Tyr 260 265 270 Tyr Val Leu Gln Leu Thr Gln Leu Ser Ile Ser Arg Pro Thr Leu Thr 275 280 285 Phe Val Tyr Leu Tyr Asn Ala Ala Ile Ser Leu Gly Tyr Ala Asn Ser 290 295 300 Cys Leu Asn Pro Phe Val Tyr Ile Val Leu Cys Glu Thr Phe Arg Lys 305 310 315 320 Arg Leu Val Leu Ser Val Lys Pro Ala Ala Gln Gly Gln Leu Arg Thr 325 Three 30 335 Val Ser Asn Ala Gln Thr Ala Asp Glu Glu Arg Thr Glu Ser Lys Gly 340 345 350 Thr <210> 4 <211> 1074 <212> DNA <213> Rat <400> 4 GTCGACATGG ATCTGCAAAC CTCGTTGCTG TCCACTGGCC CCAATGCCAG CAACATCTCC 60 GATGGCCAGG ATAATCTCAC ATTGCCGGGG TCACCTCCTC GCACAGGGAG TGTCTCCTAC 120 ATCAACATCA TTATGCCTTC CGTGTTTGGT ACCATCTGTC TCCTGGGCAT CGTGGGAAAC 180 TCCACGGTCA TCTTTGCTGT GGTGAAGAAG TCCAAGCTAC ACTGGTGCAG CAACGTCCCC 240 GACATCTTCA TCATCAACCT CTCTGTGGTG GATCTGCTCT TCCTGCTGGG CATGCCTTTC 300 ATGATCCACC AGCTCATGGG GAACGGCGTC TGGCACTTTG GGGAAACCAT GTGCACCCTC 360 ATCACAGCCA TGGACGCCAA CAGTCAGTTC ACTAGCACCT ACATCCTGAC TGCCATGACC 420 ATTGACCGCT ACTTGGCCAC CGTCCACCCC ATCTCCTCCA CCAAGTTCCG GAAGCCCTCC 480 ATGGCCACCC TGGTGATCTG CCTCCTGTGG GCGCTCTCCT TCATCAGTAT CACCCCTGTG 540 TGGCTCTACG CCAGGCTCAT TCCCTTCCCA GGGGGTGCTG TGGGCTGTGG CATCCGCCTG 600 CCAAACCCGG ACACTGACCT CTACTGGTTC ACTCTGTACC AGTTTTTCCT GGCCTTTGCC CGTC TGCT CGTC CGTC TGCT CGTC CGTC TGCT TAG TCCGG CTTCGGACAA AGAGGGTGAC CCGCACGGCC 780 ATTGCCATCT GTCTGGTCTT CTTTGTGTGC TGGGCACCCT ACTATGTGCT GCAGCTGACC 840 CAGCTGTCCA TCAGCCGCCC GACCCTCACG TTTGTCTACT TGTACAACGC GGCCATCAGC 900 TTGGGCTATG CTAACAGCTG CCTGAACCCC TTTGTGTACA TAGTGCTCTG TGAGACCTTT 960 CGAAAACGCT TGGTGTTGTC AGTGAAGCCT GCAGCCCAGG GGCAGCTCCG CACGGTCAGC 1020 AACGCTCAGA CAGCTGATGA GGAGAGGACA GAAAGCAAAG GCACCTGAAC TAGT 1074 <210> 5 <211> 262 <212 > RNA <213> Rat <400> 5 GCGAAUUGGG UACCGGGCCC CCCCUCGAGG UCGACGGUAU CGAUAAGCUU GAUAUCGAAU 60 UCCUGCAGCC CGGGGGAUCC GCCCACUAGU UCAGGUGCCU UUGCUUUCUG UCCUCUCCUC 120 AUCAGCUGUC UGAGCGUUGC UGACCGUGCG GAGCUGCCCC UGGGCUGCAG GCUUCACUGA 180 CAACACCAAG CGUUUUCGAA AGGUCUCACA GAGCACUAUG UACACAAAGG GGUUCAGGCA 240 GCUGUUAGCA UAGCCCAAGC UG 262 <210> 6 <211> 18 <212> DNA <213> Artificial Sequence <220><223><400> 6 CAACAGCTGC CTCAACCC 18 <210> 7 <211> 18 <212> DNA <213> Artificial Sequence <220><223><400> 7 CCTGGTGATC TGCCTCCT 18 <210> 8 <211> 1275 <212> DNA <213> Human <400> 8 TAGGTGATGT CAGTG GGAGC CATGAAGAAG GGAGTGGGGA GGGCAGTTGG GCTTGGAGGC 60 GGCAGCGGCT GCCAGGCTAC GGAGGAAGAC CCCCTTCCCA ACTGCGGGGC TTGCGCTCCG 120 GGACAAGGTG GCAGGCGCTG GAGGCTGCCG CAGCCTGCGT GGGTGGAGGG GAGCTCAGCT 180 CGGTTGTGGG AGCAGGCGAC CGGCACTGGC TGGATGGACC TGGAAGCCTC GCTGCTGCCC 240 ACTGGTCCCA ACGCCAGCAA CACCTCTGAT GGCCCCGATA ACCTCACTTC GGCAGGATCA 300 CCTCCTCGCA CGGGGAGCAT CTCCTACATC AACATCATCA TGCCTTCGGT GTTCGGCACC 360 ATCTGCCTCC TGGGCATCAT CGGGAACTCC ACGGTCATCT TCGCGGTCGT GAAGAAGTCC 420 AAGCTGCACT GGTGCAACAA CGTCCCCGAC ATCTTCATCA TCAACCTCTC GGTAGTAGAT 480 CTCCTCTTTC TCCTGGGCAT GCCCTTCATG ATCCACCAGC TCATGGGCAA TGGGGTGTGG 540 CACTTTGGGG AGACCATGTG CACCCTCATC ACGGCCATGG ATGCCAATAG TCAGTTCACC 600 AGCACCTACA TCCTGACCGC CATGGCCATT GACCGCTACC TGGCCACTGT CCACCCCATC 660 TCTTCCACGA AGTTCCGGAA GCCCTCTGTG GCCACCCTGG TGATCTGCCT CCTGTGGGCC 720 CTCTCCTTCA TCAGCATCAC CCCTGTGTGG CTGTATGCCA GACTCATCCC CTTCCCAGGA 780 GGTGCAGTGG GCTGCGGCAT ACGCCTGCCC AACCCAGACA CTGACCTCTA CTGGTTCACC 840 CTGTACCAGT TTTTCCTGGC CTTTGCCCTG CCTT TTGTGG TCATCACAGC CGCATACGTG 900 AGGATCCTGC AGCGCATGAC GTCCTCAGTG GCCCCCGCCT CCCAGCGCAG CATCCGGCTG 960 CGGACAAAGA GGGTGACCCG CACAGCCATC GCCATCTGTC TGGTCTTCTT TGTGTGCTGG 1020 GCACCCTACT ATGTGCTACA GCTGACCCAG TTGTCCATCA GCCGCCCGAC CCTCACCTTT 1080 GTCTACTTAT ACAATGCGGC CATCAGCTTG GGCTATGCCA ACAGCTGCCT CAACCCCTTT 1140 GTGTACATCG TGCTCTGTGA GACGTTCCGC AAACGCTTGG TCCTGTCGGT GAAGCCTGCA 1200 GCCCAGGGGC AGCTTCGCGC TGTCAGCAAC GCTCAGACGG CTGACGAGGA GAGGACAGAA 1260 AGCAAAGGCA CCTGA 1275 <210> 9 <211> 422 <212> PRT <213> Human <400> 9 MeT Ser Val Gly Ala MeT Lys Lys Gly Val Gly Arg Ala Val Gly Leu 1 5 10 15 Gly Gly Gly Ser Gly Cys Gln Ala Thr Glu Glu Asp Pro Leu Pro Asn 20 25 30 Cys Gly Ala Cys Ala Pro Gly Gln Gly Gly Arg Arg Trp Arg Leu Pro 35 40 45 Gln Pro Ala Trp Val Glu Gly Gly Ser Ser Ala Arg Leu Trp Glu Gln Ala 50 55 60 Thr Gly Thr Gly Trp MeT Asp Leu Glu Ala Ser Leu Leu Pro Thr Gly 65 70 75 80 Pro Asn Ala Ser Asn Thr Ser Asp Gly Pro Asp Asn Leu Thr Ser Ala 85 90 95 Gly Ser Pro Pro Arg Thr Gly Se r Ile Ser Tyr Ile Asn Ile Ile MeT 100 105 110 Pro Ser Val Phe Gly Thr Ile Cys Leu Leu Gly Ile Ile Gly Asn Ser 115 120 125 Thr Val Ile Phe Ala Val Val Lys Lys Ser Lys Leu His Trp Cys Asn 130 135 140 Asn Val Pro Asp Ile Phe Ile Ile Asn Leu Ser Val Val Asp Leu Leu 145 150 155 160 Phe Leu Leu Gly MeT Pro Phe MeT Ile His Gln Leu MeT Gly Asn Gly 165 170 175 Val Trp His Phe Gly Glu Thr MeT Cys Thr Leu Ile Thr Ala MeT Asp 180 185 190 Ala Asn Ser Gln Phe Thr Ser Thr Tyr Ile Leu Thr Ala MeT Ala Ile 195 200 205 Asp Arg Tyr Leu Ala Thr Val His Pro Ile Ser Ser Ser Thr Lys Phe Arg 210 215 220 Lys Pro Ser Val Ala Thr Leu Val Ile Cys Leu Leu Trp Ala Leu Ser 225 230 235 240 Phe Ile Ser Ile Thr Pro Val Trp Leu Tyr Ala Arg Leu Ile Pro Phe 245 250 255 Pro Gly Gly Aly Val Gly Cys Gly Ile Arg Leu Pro Asn Pro Asp Thr 260 265 270 Asp Leu Tyr Trp Phe Thr Leu Tyr Gln Phe Phe Leu Ala Phe Ala Leu 275 280 285 Pro Phe Val Val Ile Thr Ala Ala Tyr Val Arg Ile Leu Gln Arg MeT 290 295 300 Thr Ser Ser Val Ala Pro Ala Ser Gl n Arg Ser Ile Arg Leu Arg Thr 305 310 315 320 Lys Arg Val Thr Arg Thr Ala Ile Ala Ile Cys Leu Val Phe Phe Val 325 330 335 Cys Trp Ala Pro Tyr Tyr Val Leu Gln Leu Thr Gln Leu Ser Ile Ser 340 345 350 Arg Pro Thr Leu Thr Phe Val Tyr Leu Tyr Asn Ala Ala Ile Ser Leu 355 360 365 Gly Tyr Ala Asn Ser Cys Leu Asn Pro Phe Val Tyr Ile Val Leu Cys 370 375 380 Glu Thr Phe Arg Lys Arg Leu Val Leu Ser Val Lys Pro Ala Ala Gln 385 390 395 400 400 Gly Gln Leu Arg Ala Val Ser Asn Ala Gln Thr Ala Asp Glu Glu Arg 405 410 415 Thr Glu Ser Lys Gly Thr 420 <210> 10 <211> 31 <212> DNA <213> Artificial Sequence <220><223><400> 10 GTCGACaTGG aCCTGGaaGC CTCGCTGCTG C 31 <210> 11 <211> 31 <212> DNA <213> Artificial Sequence <220><223><400> 11 ACTAGTTCAG GTGCCTTTGC TTTCTGTCCT C 31 <210 > 12 <211> 33 <212> DNA <213> Artificial Sequence <220><223><400> 12 AGTCGACATG TCAGTGGGAG CCATGAAGAA GGG 33 <210> 13 <211> 33 <212> DNA <213> Artificial Sequence <220><223><400> 13 AACTAGTTCA GGTGCCTTTG CTTTCTGTCC TCT 33 <210> 14 <211> 1074 <212> DNA <213> Human <400> 14 GTCGACATGG ACCTGGAAGC CTCGCTGCTG CCCACTGGTC CCAACGCCAG CAACACCTCT 60 GATGGCCCCG ATAACCTCAC TTCGGCAGGA TCACCTCCTC GCACGGGGAG CATCTCCTAC 120 ATCAACATCA TCATGCCTTC GGTGTTCGGC ACCATCTGCC TCCTGGGCAT CATCGGGAAC 180 TCCACGGTCA TCTTCGCGGT CGTGAAGAAG TCCAAGCTGC ACTGGTGCAA CAACGTCCCC 240 GACATCTTCA TCATCAACCT CTCGGTAGTA GATCTCCTCT TTCTCCTGGG CATGCCCTTC 300 ATGATCCACC AGCTCATGGG CAATGGGGTG TGGCACTTTG GGGAGACCAT GTGCACCCTC 360 ATCACGGCCA TGGATGCCAA TAGTCAGTTC ACCAGCACCT ACATCCTGAC CGCCATGGCC 420 ATTGACCGCT ACCTGGCCAC TGTCCACCCC ATCTCTTCCA CGAAGTTCCG GAAGCCCTCT 480 GTGGCCACCC TGGTGATCTG CCTCCTGTGG GCCCTCTCCT TCATCAGCAT CACCCCTGTG 540 TGGCTGTATG CCAGACTCAT CCCCTTCCCA GGAGGTGCAG TGGGCTGCGG CATACGCCTG 600 CCCAACCCAG ACACTGACCT CTACTGGTTC ACCCTGTACC AGTTTTTCCT GGCCTTTGCC 660 CTGCCTTTTG TGGTCATCAC AGCCGCATAC GTGAGGATCC TGCAGCGCAT GACGTCCTCA 720 GTGGCCCCCG CCTCCCAGCG CAGCATCCGG CTGCGGACAA AGAGGGTGAC CCGCACAGCC 780 ATCGCCATCT GTCTGGTCTT CTTTGTGTGC TGGGCACCCT ACTATG TGCT ACAGCTGACC 840 CAGTTGTCCA TCAGCCGCCC GACCCTCACC TTTGTCTACT TATACAATGC GGCCATCAGC 900 TTGGGCTATG CCAACAGCTG CCTCAACCCC TTTGTGTACA TCGTGCTCTG TGAGACGTTC 960 CGCAAACGCT TGGTCCTGTC GGTGAAGCCT GCAGCCCAGG GGCAGCTTCG CGCTGTCAGC 1020 AACGCTCAGA CGGCTGACGA GGAGAGGACA GAAAGCAAAG GCACCTGAAC TAGT 1074 <210> 15 <211> 1283 <212> DNA <213> Human <400> 15 AGTCGACATG TCAGTGGGAG CCATGAAGAA GGGAGTGGGG AGGGCAGTTG GGCTTGGAGG 60 CGGCAGCGGC TGCCAGGCTA CGGAGGAAGA CCCCCTTCCC AACTGCGGGG CTTGCGCTCC 120 GGGACAAGGT GGCAGGCGCT GGAGGCTGCC GCAGCCTGCG TGGGTGGAGG GGAGCTCAGC 180 TCGGTTGTGG GAGCAGGCGA CCGGCACTGG CTGGATGGAC CTGGAAGCCT CGCTGCTGCC 240 CACTGGTCCC AACGCCAGCA ACACCTCTGA TGGCCCCGAT AACCTCACTT CGGCAGGATC 300 ACCTCCTCGC ACGGGGAGCA TCTCCTACAT CAACATCATC ATGCCTTCGG TGTTCGGCAC 360 CATCTGCCTC CTGGGCATCA TCGGGAACTC CACGGTCATC TTCGCGGTCG TGAAGAAGTC 420 CAAGCTGCAC TGGTGCAACA ACGTCCCCGA CATCTTCATC ATCAACCTCT CGGTAGTAGA 480 TCTCCTCTTT CTCCTGGGCA TGCCCTTCAT GATCCACCAG CTCATGGGCA ATGGGGTGTG 540 GCACTTTGGG GAGACCATGT GC ACCCTCAT CACGGCCATG GATGCCAATA GTCAGTTCAC 600 CAGCACCTAC ATCCTGACCG CCATGGCCAT TGACCGCTAC CTGGCCACTG TCCACCCCAT 660 CTCTTCCACG AAGTTCCGGA AGCCCTCTGT GGCCACCCTG GTGATCTGCC TCCTGTGGGC 720 CCTCTCCTTC ATCAGCATCA CCCCTGTGTG GCTGTATGCC AGACTCATCC CCTTCCCAGG 780 AGGTGCAGTG GGCTGCGGCA TACGCCTGCC CAACCCAGAC ACTGACCTCT ACTGGTTCAC 840 CCTGTACCAG TTTTTCCTGG CCTTTGCCCT GCCTTTTGTG GTCATCACAG CCGCATACGT 900 GAGGATCCTG CAGCGCATGA CGTCCTCAGT GGCCCCCGCC TCCCAGCGCA GCATCCGGCT 960 GCGGACAAAG AGGGTGACCC GCACAGCCAT CGCCATCTGT CTGGTCTTCT TTGTGTGCTG 1020 GGCACCCTAC TATGTGCTAC AGCTGACCCA GTTGTCCATC AGCCGCCCGA CCCTCACCTT 1080 TGTCTACTTA TACAATGCGG CCATCAGCTT GGGCTATGCC AACAGCTGCC TCAACCCCTT 1140 TGTGTACATC GTGCTCTGTG AGACGTTCCG CAAACGCTTG GTCCTGTCGG TGAAGCCTGC 1200 AGCCCAGGGG CAGCTTCGCG CTGTCAGCAA CGCTCAGACG GCTGACGAGG AGAGGACAGA 1260 AAGCAAAGGC ACCTGAACTA GTT 12
83 <210> 16 <211> 420 <212> RNA <213> Human <400> 16 CAAAAGCUGG AGCUCCACCG CGGUGGCGGC CGC
UCUAGCC CACUAUGUCA GGUGCUCUUG 60 CUUCUCUGUC UCUCCUCGUC AGCCGUCUGA GCG
UUGCUGA CAGCGCGAAG CUGCCCCUGG 120 GCUGCAGGCU UCACCGACAG GACCAAGCGU UUG
CGGAACG UCUCACAGAG CACGAUGUAC 180 ACAAAGGGGU UGAGGCAGCU GUUGGCAUAG CCC
AAGCUGA UGGCCGCAUU GUAUAAGUAG 240 ACAAAGGUGA GGGUCGGGCG GCUGAUGGAC AAC
UGGGUCA GCUGAGACAC AUAGUAGGGGU 300 GCCCAGCACA CAAAGAAGAC CAGACAGAUG GCG
AUGGCUG UGCGGGUCAC CCUCUUUGUC 360 CGCAGCCGGA UGCUGCGCUG GGAGGCGGGGG GCC
ACUGAGGG ACGUCAUGCG CUGCAGGAUC 420

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 9/10 101 A61P 9/10 101 19/02 19/02 C07D 401/12 C07D 401/12 401/14 401/14 F-term (Reference) 4C063 AA01 AA03 BB08 CC19 CC23 DD10 EE01 4C076 CC21 CC30 CC42 4C086 AA01 AA02 AA03 BC38 GA07 MA01 NA14 NA15 ZA45 ZA70 ZA96 ZC03 ZC35 ZC54

Claims (15)

[Claims] 1. A compound of the formula (I) [In the formula, Ar represents an aromatic ring which may have a substituent and may be condensed; X ¹ may have a substituent and has 1 to 5 atoms in the main chain. indicates certain divalent chain group; X ⁴ represents a non-cyclic hydrocarbon group which bond or a divalent may have a substituent, X ⁴ may be bonded with Ar, also , When Ar has a substituent, X ⁴ may be bonded to the substituent; X ² is a bond, CO or a divalent acyclic hydrocarbon optionally having a substituent X ³ represents a bond or a divalent acyclic hydrocarbon group which may have a substituent; R ² represents a basic substituent. ] Or a salt thereof, a melanin-concentrating hormone antagonist. 2. Ar is a compound of the formula [Wherein, R ¹ represents a hydrogen atom, a hydrocarbon group which may have a substituent, an acyl group or a heterocyclic group which may have a substituent; and ring A has a substituent. A benzene ring; the B ′ ring may be further substituted with an oxo group;
Or a 9-membered nitrogen-containing heterocyclic ring]. 3. Ar is a compound of the formula Wherein R ¹ is a hydrogen atom, a hydrocarbon group which may have a substituent, an acyl group or a heterocyclic group which may have a substituent. The agent according to 1. 4. The agent according to claim 1, wherein X ¹ is CO or O. 5. The agent according to claim 1, wherein X ⁴ is C _1-3 alkylene. 6. The agent according to claim 1, wherein X ² is CO or (CH ₂ ) _p (p is an integer of 1 to 3). 7. X ³ is a bond or (CH ₂ ) _q (q is 1
Or an integer of from 3 to 3). 8. The basic substituent represented by R ² has an amino group which may have a substituent, a 5- to 7-membered cyclic amino group which may have a substituent, and a substituent. An amidino group which may be, a guanidino group which may have a substituent,
2. The agent according to claim 1, which is a 5- or 6-membered nitrogen-containing heterocyclic group which may have a substituent. 9. R ² are each 1 to two C _1-6 alkyl optionally substituted amino group, 5 to 7-membered cyclic amino group, amidino group or 4,5-dihydro,-1H-
The agent according to claim 1, which is a 2-imidazolyl group. 10. Ar is a compound of the formula It is X ^1; [wherein, R ¹ represents a hydrogen atom may be an optionally substituted hydrocarbon group, a is also heterocyclic group optionally having an acyl group or a substituted group] groups represented by CO or O; X ⁴
Is C _1-3 alkylene; X ² is CO or CH ₂ ; X ³ is a bond or CH ₂ ; and R ² is dimethylamino, diethylamino, amidino, N-methylamidino, 4,5-dihydro-1H-2- Imidazolyl or 1-methyl-4,5-dihydro-
The agent according to claim 1, which is 1H-2-imidazolyl. 11. R ¹ is a substituent selected from a halogen atom, an optionally halogenated C _1-6 alkyl, an optionally halogenated C _1-6 alkoxy, nitro, cyano and hydroxy. The agent according to claim 10, which is a _C7-16 aralkyl group which may have 3 to 3 groups. 12. The agent according to claim 1, which is a prophylactic / therapeutic agent for a disease caused by melanin-concentrating hormone. 13. A compound of the formula (Ia) [In the formula, R ¹ represents a hydrogen atom, a hydrocarbon group which may have a substituent, an acyl group or a heterocyclic group which may have a substituent; Ring A has a substituent. A benzene ring; a B ″ ring represents a 5- to 9-membered nitrogen-containing heterocyclic ring further substituted with one or two oxo groups; X ^1a represents O, NR ^3a , S, SO, SO ₂ , SO ₂ NR ^3a , SO ₂ N
HCONR ^3a , SO ₂ NHC (= NH) NR ^3a , CS,
CR ^3a R ^3b , C = CR ^3a R ^3b , C = NR ^3a or CO
NR ^3a wherein R ^3a and R ^3b are each independently
Hydrogen atom, cyano group, hydroxy group, amino group, C _1-6
It represents an alkyl group or a C _1-6 alkoxy group. X ⁴ represents a bond or a divalent acyclic hydrocarbon group which may have a substituent, X ⁴ may be bonded to ring A, and ring A is substituted. When it has a group, X ⁴ may be bonded to the substituent; X ² represents a bond, CO or a divalent acyclic hydrocarbon group which may have a substituent; X ³ represents a bond or a divalent acyclic hydrocarbon group which may have a substituent; R ² represents a basic substituent. Or a salt thereof. 14. A pharmaceutical composition comprising the compound according to claim 13 or a salt thereof. (15) a prodrug of the compound according to the above (13);