JP2622673B2 - Osteoporosis drug and triazepine compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a remedy for osteoporosis containing a certain type of triazepine compound as an active ingredient, and a novel triazepine compound having an excellent bone resorption inhibiting action.
And intermediate compounds useful for producing those triazepine compounds.

[0002]

2. Description of the Related Art Osteoporosis is a syndrome that refers to a condition in which bone mass per unit volume is abnormally reduced without causing a change in the chemical composition (ratio between organic and inorganic substances) of bone itself. The reduction of protein, calcium and phosphorus in bone is its physiological characteristic. Since the loss of bone as a pathological condition is accompanied by the loss of bone due to physiological aging, the definition of bone loss is more pronounced than that due to physiological aging. It can be said that the patient presented clinical symptoms such as vertebral body deformation.

[0003] Osteoporosis increases with age and usually affects the spine, causing back and back pain and shortening of height. Especially in advanced cases, the long bones are also affected, and sometimes fractures may occur. It is said that the cause of the femoral fracture seen in the elderly is almost due to senile osteoporosis. The causes of this osteoporosis are various such as endocrine abnormalities including menopause, and nutritional disorders.

[0004] Known therapeutic agents for osteoporosis include vitamin preparations, calcium preparations, calcitonin preparations, bisphosphonate preparations, and isoflavone preparations. However, these therapeutic agents have not always been satisfactory in terms of side effects or methods of use. Therefore,
There is a strong demand for the development of a therapeutic agent for osteoporosis which is more effective, safer, and easier to use.

Recently, it has been reported that a benzothiadiazine derivative or a benzothiadiazepine derivative having a completely different chemical structure from the above-mentioned preparations is effective as a therapeutic agent for osteoporosis (JP-A-63-183572). No.). We have also found that a triazolobenzothiadiazine derivative or a triazolobenzothiadiazepine derivative has a bone resorption inhibiting effect, and filed a patent application (Japanese Patent Application No. 4-3573).
No. 69). Further, we have found that compounds having a diazepine skeleton also have a bone resorption inhibiting effect, and have also filed a patent application (WO 93/07129). However, these compounds are not yet active enough.
Since the above-mentioned demands are not sufficiently satisfied or the compound has asymmetric carbon, there are problems in practical use such as difficulty in optical resolution and elongation of the production process.

On the other hand, it has been reported that certain compounds having a triazepine skeleton have an anticonvulsant action, a muscle relaxing action, a sedative action, an anxiolytic action and a tranquilizing action, but they have an activity of inhibiting bone resorption. Have not been previously reported [U.S. Pat. No. 4,144,233.
No. 5,091,381; U.S. Pat. No. 3,891,666; U.S. Pat.
880,878].

[0007]

An object of the present invention is to provide a novel therapeutic agent for osteoporosis. Another object of the present invention is to provide a novel compound useful as an active ingredient of a drug for treating osteoporosis. Another object of the present invention is to provide an intermediate compound for producing a compound useful as an active ingredient of a therapeutic agent for osteoporosis.

[0008]

Means for Solving the Problems In view of the above problems, the present inventors have conducted intensive studies in search of useful therapeutic agents for osteoporosis. The present inventors have found that they have a bone resorption inhibiting action, and have completed the present invention. The present invention relates to a therapeutic agent for osteoporosis, comprising a triazepine compound represented by the following general formula [I] or a pharmaceutically acceptable salt thereof as an active ingredient. The present invention also relates to a novel triazepine compound represented by the following general formula [I '] or a pharmaceutically acceptable salt thereof, which is useful as such a medicament. Furthermore, the present invention
The present invention relates to intermediate compounds useful for producing such triazepine compounds. More specifically, the following (1) to (3)
As shown in 2).

(1) General formula [I]

[0010]

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[0011] wherein, R ¹ represents a optionally substituted aryl group or an optionally substituted heteroaryl group; R ²
Represents a hydrogen atom, a hydroxyl group, a halogen atom or a lower alkyl group, and R ⁴ represents a hydrogen atom or a halogen atom, or R ² and R ⁴ together form a carbonyl group together with the carbon atom to which they are bonded. R ³ is a hydrogen atom,
Lower alkyl group, a lower alkoxy group, a cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl ^{group, -CR 5 = CR 6 R 7} (R 5, R 6 and R ⁷ are the same or different A hydrogen atom, a halogen atom, a lower alkyl group or an optionally substituted aryl group), -OR ¹⁸ (R ¹⁸ is an optionally substituted aryl group),

[0012]

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(Wherein R ⁸ represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an optionally substituted aryl group,
It is an aralkyl group or a heteroaryl group which may be substituted, and R ⁹ and R ¹⁰ are the same or different and are a hydrogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a halogen atom, a nitro group or an amino group. ) Or -X-Y {wherein, X is _{- (CH 2) m - (} m is an integer of 1 to 4), -CO -., - COCH 2 -, - NH -, - NH
_{CH 2 -, - CH 2 NH} -, - CH 2 NHCO -, - O
CH ₂ —, — (CH ₂ ) _n O— (n is an integer of 1 to 4) or —CH ₂ S—; Y is a halogen atom,
A cycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group. Represents a ring A is a ring selected from the following:

[0014]

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Wherein R ¹¹ and R ¹² are the same or different and are each a hydrogen atom, a halogen atom, a lower alkyl group (the lower alkyl group is a halogen atom, a lower alkoxy group, a nitro group, an amino group, a lower alkyl group); Substituted amino group,
It may be substituted by a cyclic amino group, a hydroxyl group, an acyloxy group, a cyano group, a carbamoyl group, a carbamoyl group substituted by a lower alkyl group, a cyclic aminocarbonyl group, a carboxy group, a lower alkoxycarbonyl group or an aralkyloxycarbonyl group. ), Lower alkenyl group, aralkyl group, aralkyl group substituted with alkyl group, lower alkoxy group, nitro group, amino group, amino group substituted with lower alkyl group, cyclic amino group, hydroxyl group, acyloxy group, cyano group, A carbamoyl group, a carbamoyl group substituted with a lower alkyl group, a cyclic aminocarbonyl group, a carboxy group, a lower alkoxycarbonyl group or an aralkyloxycarbonyl group, and R ¹³ and R ¹⁴ are
Same or different hydrogen atom, halogen atom, lower alkyl group, lower alkenyl group, lower alkynyl group, haloalkyl group, lower alkoxy group, nitro group, amino group, amino group substituted with lower alkyl group, cyclic amino group, hydroxyl group An acyloxy group, a cyano group, a carbamoyl group, a carbamoyl group substituted with a lower alkyl group, a cyclic aminocarbonyl group, a carboxy group, a lower alkoxycarbonyl group, an aralkyloxycarbonyl group, a cycloalkyl group or a lower alkylcarbonyl group. Represents｝;

[0016]

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(Where R ¹⁵ is a lower alkyl group;
R ¹⁹ is a hydrogen atom or a lower alkyl group. ). Or a pharmaceutically acceptable salt thereof as an active ingredient.

(2) In the general formula [I], ring A is

[0019]

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(R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are as described in (1)). The therapeutic agent for osteoporosis according to (1).

(3) In the general formula [I]

[0022]

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The therapeutic agent for osteoporosis according to (R ¹⁵ is a lower alkyl group.) Is (2).

(4) The therapeutic agent for osteoporosis according to (3), wherein R ¹ in the general formula [I] is an optionally substituted aryl group.

(5) The therapeutic agent for osteoporosis according to (4), wherein R ¹ in the general formula [I] is an optionally substituted phenyl group.

(6) In the general formula [I], R ² and R
^The therapeutic agent for osteoporosis according to (5), wherein both ⁴ are hydrogen atoms.

(7) 6- (4-chlorophenyl) -4
-(4-methoxybenzyl) -1-methyl-4H-2,
3,4,5,10b-pentaazabenzo [e] azure
, 6- (4-chlorophenyl) -4- (3,4-dim
Toxibenzyl) -1-methyl-4H-2,3,4
5,10b-pentaazabenzo [e] azulene, 4-
(4-methoxybenzyl) -1-methyl-6-phenyl
-4H-2,3,4,5,10b-pentaazabenzo
[E] azulene, 4- (4-methoxybenzyl) -1,
9-dimethyl-6-phenyl-4H-2,3,4,5
10b-pentaazabenzo [e] azulene, 8-chloro
-4- (4-methoxybenzyl) -1-methyl-6-f
Enyl-4H-2,3,4,5,10b-pentaazabe
Nzo [e] azulene, 4- (4-methoxybenzyl)-
1-methyl-8-nitro-6-phenyl-4H-2,
3,4,5,10b-pentaazabenzo [e] azure
4- (4-methoxybenzyl) -1-methyl-6
(4-methylphenyl) -4H-2,3,4,5,10
b-pentaazabenzo [e] azulene, 8-chloro-6
-(2-chlorophenyl) -4- (4-methoxybenzyl)
L) -1-Methyl-4H-2,3,4,5,10b-pe
Nantazabenzo [e] azulene, 4- (4-chlorophene)
Nil) -6- (4-methoxybenzyl) -2,3,9-
Trimethyl-6H-5,6,7,8,9a-pentaaza
Thieno [2,3-e] azulene, 4- (4-chlorophene)
Nyl) -2-ethyl-6- (4-methoxybenzyl)-
9-methyl-6H-5,6,7,8,9a-pentaaza
Thieno [2,3-e] azulene, 6- (4-methoxy
Benzyl) -2,9-dimethyl-4-phenyl-6H-
5,6,7,8,9a-pentaazathieno [2,3-
e] azulene, 6- (4-methoxybenzyl) -2,
3,9-trimethyl-4-phenyl-6H-5,6,
7,8,9a-pentaazathieno [2,3-e] azure
, 2-ethyl-6- (4-methoxybenzyl) -9-
Methyl-4-phenyl-6H-5,6,7,8,9a-
Pentaazathieno [2,3-e] azulene, 6- (4-
Methoxybenzyl) -4- (4-methoxyphenyl)-
2,3,9-trimethyl-6H-5,6,7,8,9a
-Pentaazathieno [2,3-e] azulene, 6- (4
-Chlorophenyl) -1-methyl-4- (pyridine-3
-Ylmethyl) -4H-2,3,4,5,10b-pen
Taazabenzo [e] azulene, 4- (2-chlorophenyi
) -2,3,9-trimethyl-6- (pyridine-4-
Ylmethyl) -6H-5,6,7,8,9a-pentaa
Zathieno [2,3-e] azulene, 6- (4-chlorofu
Enyl) -4- (3-cyanobenzyl) -1-methyl-
4H-2,3,4,5,10b-pentaazabenzo
[E] azulene, 6- (4-chlorophenyl) -4-
(2-fluorobenzyl) -1-methyl-4H-2,
3,4,5,10b-pentaazabenzo [e] azure
, 6- (4-chlorophenyl) -4- (3-fluoro
Benzyl) -1-methyl-4H-2,3,4,5,10
b-pentaazabenzo [e] azulene, 6- (4-chloro
Rophenyl) -4- (4-fluorobenzyl) -1-me
Chill-4H-2,3,4,5,10b-pentaazaben
Zo [e] azulene, 6- (4-chlorophenyl) -4-
(2,4-difluorobenzyl) -1-methyl-4H-
2,3,4,5,10b-pentaazabenzo [e] az
Len, 6- (4-chlorophenyl) -4- (2,5-di
Fluorobenzyl) -1-methyl-4H-2,3,4
5,10b-pentaazabenzo [e] azulene, 6-
(4-chlorophenyl) -4- (3,5-difluorobe
Ndyl) -1-methyl-4H-2,3,4,5,10b
-Pentaazabenzo [e] azulene, 6- (4-chloro
Phenyl) -4- (3,4-difluorobenzyl) -1
-Methyl-4H-2,3,4,5,10b-pentaaza
Benzo [e] azulene, 6- (4-chlorophenyl)-
1-methyl-4- (2-trifluoromethylbenzyl)
-4H-2,3,4,5,10b-pentaazabenzo
[E] azulene, 6- (4-chlorophenyl) -1-me
Tyl-4- (4-trifluoromethylbenzyl) -4H
-2,3,4,5,10b-pentaazabenzo [e] a
Durene, 6- (4-chlorophenyl) -1-methyl-4
-(3-trifluoromethylbenzyl) -4H-2,
3,4,5,10b-pentaazabenzo [e] azure
, 6- (4-chlorophenyl) -1-methyl-4-
(4-trifluoromethoxybenzyl) -4H-2,
3,4,5,10b-pentaazabenzo [e] azure
, 6- (4-chlorophenyl) -1-methyl-4-
(3-nitrobenzyl) -4H-2,3,4,5,10
b-pentaazabenzo [e] azulene, 4- (2-chloro
(Robenzyl) -6- (4-chlorophenyl) -1-methyl
Ru-4H-2,3,4,5,10b-pentaazabenzo
[E] Azulene, 4- (3-chlorobenzyl) -6
(4-chlorophenyl) -1-methyl-4H-2,3,
4,5,10b-pentaazabenzo [e] azulene, 4
-(4-chlorobenzyl) -6- (4-chlorophenyl
L) -1-Methyl-4H-2,3,4,5,10b-pe
Ntazabenzo [e] azulene, 6- (4-chlorophene
Nil) -4- (2-cyanobenzyl) -1-methyl-4
H-2,3,4,5,10b-pentaazabenzo [e]
Azulene, 6- (4-chlorophenyl) -4- (4-si
Anobenzyl) -1-methyl-4H-2,3,4,5
10b-pentaazabenzo [e] azulene, 6- (4-
Chlorophenyl) -4- (2-methoxybenzyl) -1
-Methyl-4H-2,3,4,5,10b-pentaaza
Benzo [e] azulene, 6- (4-chlorophenyl)-
4- (3-methoxybenzyl) -1-methyl-4H-
2,3,4,5,10b-pentaazabenzo [e] az
Len, 6- (4-chlorophenyl) -4- (4-methoxy
Cibenzyl) -1-methyl-4H-2,3,4,5,1
0b-pentaazabenzo [e] azulene, 6- (4-c
(Rolophenyl) -4- (2,5-dimethoxybenzyl)
-1-methyl-4H-2,3,4,5,10b-penta
Azabenzo [e] azulene, 6- (4-chlorophenyl)
1) -methyl-4- (3,4,5-trimethoxy
Ndyl) -4H-2,3,4,5,10b-pentaaza
Benzo [e] azulene, 4- (5-acetyl-2-methoate)
Xybenzyl) -6- (4-chlorophenyl) -1-me
Chill-4H-2,3,4,5,10b-pentaazaben
Zo [e] azulene, 6- (4-chlorophenyl) -1-
Methyl-4- (3,4-methylenedioxybenzyl)-
4H-2,3,4,5,10b-pentaazabenzo
[E] azulene, 4- (2-chloro-4,5-methylene
Dioxybenzyl) -6- (4-chlorophenyl) -1
-Methyl-4H-2,3,4,5,10b-pentaaza
Benzo [e] azulene, 6- (4-chlorophenyl)-
4- (2-methoxy-5-nitrobenzyl) -1-methyl
Ru-4H-2,3,4,5,10b-pentaazabenzo
[E] azulene, 6- (4-chlorophenyl) -4-
(4-methoxy-3-nitrobenzyl) -1-methyl-
4H-2,3,4,5,10b-pentaazabenzo
[E] azulene, 4- (3-chloro-4-methoxybenz)
(Zyl) -6- (4-chlorophenyl) -1-methyl-4
H-2,3,4,5,10b-pentaazabenzo [e]
Azulene, 6- (4-chlorophenyl) -4- (3,5
-Dichloro-4-methoxybenzyl) -1-methyl-4
H-2,3,4,5,10b-pentaazabenzo [e]
Azulene, 6- (4-chlorophenyl) -1-methyl-
4- (2-methylbenzyl) -4H-2,3,4,5
10b-pentaazabenzo [e] azulene, 6- (4-
Chlorophenyl) -1-methyl-4- (3-methylben
Jill) -4H-2,3,4,5,10b-pentaazabe
Nzo [e] azulene, 6- (4-chlorophenyl) -1
-Methyl-4- (4-methylbenzyl) -4H-2,
3,4,5,10b-pentaazabenzo [e] azure
4- (4-tert-butylbenzyl) -6- (4
-Chlorophenyl) -1-methyl-4H-2,3,4
5,10b-pentaazabenzo [e] azulene, 6-
(4-chlorophenyl) -1-methyl-4- (naphthale
1-ylmethyl) -4H-2,3,4,5,10b
-Pentaazabenzo [e] azulene, 6- (4-chloro
Phenyl) -1-methyl-4- (naphthalen-2-yl
Methyl) -4H-2,3,4,5,10b-pentaaza
Benzo [e] azulene, 4- (4-benzyloxyben
(Zyl) -6- (4-chlorophenyl) -1-methyl-4
H-2,3,4,5,10b-pentaazabenzo [e]
Azulene, 4-benzyl-6- (4-chlorophenyl)
-1-methyl-4H-2,3,4,5,10b-penta
Azabenzo [e] azulene, 6- (4-chlorophenyl)
L) -1-Methyl-4- (4-phenylbenzyl) -4
H-2,3,4,5,10b-pentaazabenzo [e]
Azulene, 4- (4-chlorophenoxymethyl) -6
(4-chlorophenyl) -1-methyl-4H-2,3,
4,5,10b-pentaazabenzo [e] azulene, 6
-(4-chlorophenyl) -1-methyl-4- (pyridi
-2-Hylmethyl) -4H-2,3,4,5,10b
-Pentaazabenzo [e] azulene, 6- (4-chloro
Phenyl) -1-methyl-4- (pyridin-3-ylmeth
Chill) -4H-2,3,4,5,10b-pentaazabe
Nzo [e] azulene, 6- (4-chlorophenyl) -4
-[2- (Indol-3-yl) ethyl] -1-methyl
Ru-4H-2,3,4,5,10b-pentaazabenzo
[E] azulene, 6- (4-chlorophenyl) -4-
(2-methyl-1,3-thiazol-4-ylmethyl)
-1-methyl-4H-2,3,4,5,10b-penta
Azabenzo [e] azulene, 6- (4-chlorophenyl)
) -4- (5-chlorothiophen-2-ylmethyl)
-1-methyl-4H-2,3,4,5,10b-penta
Azabenzo [e] azulene, 6- (4-chlorophenyl)
) -1-methyl-4- (3,5-dimethylisoxa)
Zol-4-ylmethyl) -4H-2,3,4,5,1
0b-pentaazabenzo [e] azulene, 6- (4-c
(Rolophenyl) -1-methyl-4-phenethyl-4H-
2,3,4,5,10b-pentaazabenzo [e] az
Len, 6- (4-chlorophenyl) -1-methyl-4-
(3-phenylpropyl) -4H-2,3,4,5,1
0b-pentaazabenzo [e] azulene, 6- (4-c
(Rolophenyl) -4- (3,3-diphenylpropyl)
-1-methyl-4H-2,3,4,5,10b-penta
Azabenzo [e] azulene, 6- (4-chlorophenyl)
Ru) -4-cyclopropylmethyl-1-methyl-4H-
2,3,4,5,10b-pentaazabenzo [e] az
Len, 6- (4-chlorophenyl) -4-cyclohexyl
Lemethyl-1-methyl-4H-2,3,4,5,10b
-Pentaazabenzo [e] azulene, 6- (4-chloro
Phenyl) -4- (2-cyclohexylethyl) -1-
Methyl-4H-2,3,4,5,10b-pentaazabe
Nzo [e] azulene, 6- (4-chlorophenyl) -1
-Methyl-4- (3-phenyl-2-propenyl) -4
H-2,3,4,5,10b-pentaazabenzo [e]
Azulene, 4-allyl-6- (4-chlorophenyl)-
1-methyl-4H-2,3,4,5,10b-pentaa
Zabenzo [e] azulene, 6- (4-chlorophenyl)
-1-methyl-4- (2-methyl-2-propenyl)-
4H-2,3,4,5,10b-pentaazabenzo
[E] azulene, 6- (4-chlorophenyl) -4-
(2-chloro-2-propenyl) -1-methyl-4H-
2,3,4,5,10b-pentaazabenzo [e] az
Len, 4- (2-bromo-2-propenyl) -6- (4
-Chlorophenyl) -1-methyl-4H-2,3,4
5,10b-pentaazabenzo [e] azulene, 6-
(4-chlorophenyl) -4- (2,3-dichloro-2
-Propenyl) -1-methyl-4H-2,3,4,5
10b-pentaazabenzo [e] azulene, 6- (4-
Chlorophenyl) -4- (3,4-dibenzyloxybe
Ndyl) -1-methyl-4H-2,3,4,5,10b
-Pentaazabenzo [e] azulene, 4-benzyloxy
Cimethyl-6- (4-chlorophenyl) -1-methyl-
4H-2,3,4,5,10b-pentaazabenzo
[E] azulene, 6- (4-chlorophenyl) -1-me
Tyl-4- (3-phenoxypropyl) -4H-2,
3,4,5,10b-pentaazabenzo [e] azure
, 6- (4-chlorophenyl) -4- (3,3-dic
(Rolo-2-propenyl) -1-methyl-4H-2,3,
4,5,10b-pentaazabenzo [e] azulene, 6
-(4-chlorophenyl) -4- (4-methoxy-3-
Methylbenzyl) -1-methyl-4H-2,3,4
5,10b-pentaazabenzo [e] azulene, 6-
(4-chlorophenyl) -1-methyl-4- (pyridine
-4-ylmethyl) -4H-2,3,4,5,10b-
Pentaazabenzo [e] azulene, 6- (4-chlorofu
Enyl) -1-methyl-4- (4-methylsulfonylbe
Ndyl) -4H-2,3,4,5,10b-pentaaza
Benzo [e] azulene, 6- (4-chlorophenyl)-
1-methyl-4- (4-nitrobenzyl) -4H-2,
3,4,5,10b-pentaazabenzo [e] azure
, 6- (4-chlorophenyl) -4- (2,6-dic
(Rolopyridin-4-ylmethyl) -1-methyl-4H-
2,3,4,5,10b-pentaazabenzo [e] az
Len, 6- (4-chlorophenyl) -4- (2,2,2
-Trifluoroethyl) -1-methyl-4H-2,3.
4,5,10b-pentaazabenzo [e] azulene, 6
-(4-chlorophenyl) -4- (3,5-dinitrobe
Ndyl) -1-methyl-4H-2,3,4,5,10b
-Pentaazabenzo [e] azulene, 8-chloro-1-
Methyl-6-phenyl-4- (pyridin-4-ylmethy
Le) -4H-2,3,4,5,10b-pentaazaben
Zo [e] azulene, 8-chloro-1-methyl-6-fe
Nil-4- (pyridin-3-ylmethyl) -4H-2,
3,4,5,10b-pentaazabenzo [e] azure
1-methyl-6-phenyl-4- (pyridine-3-
Ylmethyl) -4H-2,3,4,5,10b-penta
Azabenzo [e] azulene, 1-methyl-6-phenyl
-4- (pyridin-4-ylmethyl) -4H-2,3,
4,5,10b-pentaazabenzo [e] azulene,
1,9-dimethyl-6-phenyl-4- (pyridine-3
-Ylmethyl) -4H-2,3,4,5,10b-pen
Taazabenzo [e] azulene, 1,9-dimethyl-6-
Phenyl-4- (pyridin-4-ylmethyl) -4H-
2,3,4,5,10b-pentaazabenzo [e] az
Len, 4- (3-cyanobenzyl) -1,9-dimethyl
-6-phenyl-4H-2,3,4,5,10b-pen
Taazabenzo [e] azulene, 1-methyl-8-nitro
-6-phenyl-4- (pyridin-3-ylmethyl)-
4H-2,3,4,5,10b-pentaazabenzo
[E] azulene, 1-methyl-8-nitro-6-phenyl
4- (pyridin-4-ylmethyl) -4H-2,
3,4,5,10b-pentaazabenzo [e] azure
1-methyl-6- (4-methylphenyl) -4-
(Pyridin-4-ylmethyl) -4H-2,3,4
5,10b-pentaazabenzo [e] azulene, 4-
(3-cyanobenzyl) -1-methyl-6- (4-methyl
Ruphenyl) -4H-2,3,4,5,10b-penta
Azabenzo [e] azulene, 8-chloro-6- (2-k
(Rolophenyl) -1-methyl-4- (pyridine-3-i
Methyl) -4H-2,3,4,5,10b-pentaa
Zabenzo [e] azulene, 8-chloro-6- (2-chloro
Rophenyl) -1-methyl-4- (pyridin-4-yl
Methyl) -4H-2,3,4,5,10b-pentaaza
Benzo [e] azulene, 4- (4-chlorophenyl)-
2,3,9-trimethyl-6- (pyridin-3-ylmeth
Chill) -6H-5,6,7,8,9a-pentaazatie
No [2,3-e] azulene, 4- (4-chlorophenyi)
) -2,3,9-trimethyl-6- (pyridine-4-
Ylmethyl) -6H-5,6,7,8,9a-pentaa
Zatieno [2,3-e] azulene, 4- (4-chlorofu
Enyl) -2-ethyl-9-methyl-6- (pyridine-
3-ylmethyl) -6H-5,6,7,8,9a-pen
Taazathieno [2,3-e] azulene, 4- (4-chloro
(Rophenyl) -2-ethyl-9-methyl-6- (pyridi
N-4-ylmethyl) -6H-5,6,7,8,9a-
Pentaazathieno [2,3-e] azulene, 2,9-di
Methyl-4-phenyl-6- (pyridin-3-ylmethy
Le) -6H-5,6,7,8,9a-pentaazathieno
[2,3-e] azulene, 2,9-dimethyl-4-fe
Nyl-6- (pyridin-4-ylmethyl) -6H-5,
6,7,8,9a-pentaazathieno [2,3-e] a
Durene, 2,3,9-trimethyl-4-phenyl-6
(Pyridin-3-ylmethyl) -6H-5,6,7,
8,9a-pentaazathieno [2,3-e] azulene,
2,3,9-trimethyl-4-phenyl-6- (pyridi
N-4-ylmethyl) -6H-5,6,7,8,9a-
Pentaazathieno [2,3-e] azulene, 2-ethyl
-9-Methyl-4-phenyl-6- (pyridine-3-i
Rumethyl) -6H-5,6,7,8,9a-pentaaza
Thieno [2,3-e] azulene, 2-ethyl-9-methyl
Ru-4-phenyl-6- (pyridin-4-ylmethyl)
-6H-5,6,7,8,9a-pentaazathieno
[2,3-e] azulene, 4- (4-methoxyphenyl)
) -2,3,9-trimethyl-6- (pyridine-3-
Ylmethyl) -6H-5,6,7,8,9a-pentaa
Zathieno [2,3-e] azulene, 4- (4-methoxy)
Phenyl) -2,3,9-trimethyl-6- (pyridine
-4-ylmethyl) -6H-5,6,7,8,9a-pe
Nantazathieno [2,3-e] azulene, 6- (4-k
(Rolophenyl) -1-methyl-4- (2-nitrobenzyl)
Le) -4H-2,3,4,5,10b-pentaazaben
Zo [e] azulene, 6- (4-chlorophenyl) -4-
Ethoxycarbonylmethyl-1-methyl-4H-2,
3,4,5,10b-pentaazabenzo [e] azure
, [6- (4-chlorophenyl) -1-methyl-4H
-2,3,4,5,10b-pentaazabenzo [e] a
Dulen-4-yl] acetic acid, 6- (4-chlorophenyl)
-1-methyl-4-phenylcarbamoylmethyl-4H
-2,3,4,5,10b-pentaazabenzo [e] a
Durene, 6- (4-chlorophenyl) -1-methyl-4
-(4-methylphenylcarbamoylmethyl) -4H-
2,3,4,5,10b-pentaazabenzo [e] az
Len, 6- (4-chlorophenyl) -4- (2-methoxy
(Ciphenylcarbamoylmethyl) -1-methyl-4H-
2,3,4,5,10b-pentaazabenzo [e] az
Len, 6- (4-chlorophenyl) -4- (2,5-di
Methoxyphenylcarbamoylmethyl) -1-methyl-
4H-2,3,4,5,10b-pentaazabenzo
[E] azulene, 4- (4-chloro-2,5-dimethoxy)
(Ciphenylcarbamoylmethyl) -6- (4-chlorofu
Enyl) -1-methyl-4H-2,3,4,5,10b
-Pentaazabenzo [e] azulene, 6- (4-chloro
Phenyl) -1-methyl-4- (naphthalen-1-yl
Carbamoylmethyl) -4H-2,3,4,5,10b
-Pentaazabenzo [e] azulene, 6- (4-chloro
Phenyl) -1-methyl-4- (pyridine-3-dolphin
Rubamoylmethyl) -4H-2,3,4,5,10b-
Pentaazabenzo [e] azulene, 6- (4-chlorofu
Enyl) -4- (cyclohexylcarbamoylmethyl)
-1-methyl-4H-2,3,4,5,10b-penta
Azabenzo [e] azulene, 6- (4-chlorophenyl)
L) -1-Methyl-4-n-propylcarbamoylmethyl
Ru-4H-2,3,4,5,10b-pentaazabenzo
[E] azulene, 4-bromoacetyl-6- (4-chloro
Rophenyl) -1-methyl-4H-2,3,4,5,1
0b-pentaazabenzo [e] azulene, 6- (4-c
(Rolophenyl) -4- (2-methoxyphenylaminoa
Cetyl) -1-methyl-4H-2,3,4,5,10b
-Pentaazabenzo [e] azulene, 6- (4-chloro
Phenyl) -1-methyl-4-phenylaminoacetyl
-4H-2,3,4,5,10b-pentaazabenzo
[E] azulene, 6- (4-chlorophenyl) -1-me
Tyl-4- (4-methylphenylaminoacetyl) -4
H-2,3,4,5,10b-pentaazabenzo [e]
Azulene, 6- (4-chlorophenyl) -4- (3-f
(Fluorophenylaminoacetyl) -1-methyl-4H-
2,3,4,5,10b-pentaazabenzo [e] az
Len, 6- (4-chlorophenyl) -4- (2,5-di
Methoxyphenylaminoacetyl) -1-methyl-4H
-2,3,4,5,10b-pentaazabenzo [e] a
Durene, 6- (4-chlorophenyl) -1-methyl-4
-Phenylthioacetyl-4H-2,3,4,5,10
b-pentaazabenzo [e] azulene, 6- (4-chloro
(Rophenyl) -1-methyl-4-phenylacetyl-4
H-2,3,4,5,10b-pentaazabenzo [e]
Azulene, 6- (4-chlorophenyl) -1-methyl-
4-phenyloxalyl-4H-2,3,4,5,10
b-pentaazabenzo [e] azulene, 6- (4-chloro
Rophenyl) -4-ethoxymethyl-1-methyl-4H
-2,3,4,5,10b-pentaazabenzo [e] a
Durene, [6- (4-chlorophenyl) -1-methyl-
4H-2,3,4,5,10b-pentaazabenzo
[E] azulen-4-ylmethyl] -phenyl-amido
4-benzylcarbamoyl-6- (4-chlorophene
Nyl) -1-methyl-4H-2,3,4,5,10b-
Pentaazabenzo [e] azulene, 6- (4-chlorofu
Enyl) -1-methyl-4- (3-methylphenylcarbyl
Bamoyl) -4H-2,3,4,5,10b-pentaa
Zabenzo [e] azulene, 6- (4-chlorophenyl)
-4- (4-hydroxybenzyl) -1-methyl-4H
-2,3,4,5,10b-pentaazabenzo [e] a
Durene, 6- (4-chlorophenyl) -4- (3,4-
Dihydroxybenzyl) -1-methyl-4H-2,3,
4,5,10b-pentaazabenzo [e] azulene, 6
-(4-chlorophenyl) -4- (4-ethoxybenzyl)
L) -1-Methyl-4H-2,3,4,5,10b-pe
Ntazabenzo [e] azulene, 6- (4-chlorophene
Nil) -1-methyl-4- (4-methylsulfonylfe
Nyl) hydroxymethyl-4H-2,3,4,5,10
b-pentaazabenzo [e] azulene, 4- (4-amido
Nobenzyl) -6- (4-chlorophenyl) -1-methyl
Ru-4H-2,3,4,5,10b-pentaazabenzo
[E] azulene, 6- (4-chlorophenyl) -4-
(4-formylaminobenzyl) -1-methyl-4H-
2,3,4,5,10b-pentaazabenzo [e] az
Len, 4- (4-acetylaminobenzyl) -6- (4
-Chlorophenyl) -1-methyl-4H-2,3,4
5,10b-pentaazabenzo [e] azulene, 6-
(4-chlorophenyl) -4- (4-methylsulfonyl)
Aminobenzyl) -1-methyl-4H-2,3,4
5,10b-pentaazabenzo [e] azulene, 4-
[4-bis (methylsulfonyl) aminobenzyl] -6
-(4-chlorophenyl) -4H-2,3,4,5,1
0b-pentaazabenzo [e] azulene, 6- (4-c
(Rolophenyl) -4- (4-dimethylaminobenzyl)
-1-methyl-4H-2,3,4,5,10b-penta
Azabenzo [e] azulene, 6- (4-chlorophenyl)
) -4- (2-hydroxy-2-phenylethyl)-
1-methyl-4H-2,3,4,5,10b-pentaa
Zabenzo [e] azulene, 6- (4-chlorophenyl)
-4- (2-oxo-2-phenylethyl) -1-methyl
Ru-4H-2,3,4,5,10b-pentaazabenzo
[E] azulene, 6- (4-chlorophenyl) -1-me
Tyl-4- [3-phenyl-2- (tetrahydropyran
-2-yloxy) propyl] -4H-2,3,4
5,10b-pentaazabenzo [e] azulene, 6-
(4-chlorophenyl) -4- [2- (2-methoxyphenyl)
Enyl) -2- (tetrahydropyran-2-yloxy
C) Ethyl] -1-methyl-4H-2,3,4,5,1
0b-pentaazabenzo [e] azulene, 6- (4-c
(Rolophenyl) -4- (2-hydroxy-3-phenyl)
Propyl) -1-methyl-4H-2,3,4,5,10
b-pentaazabenzo [e] azulene, 6- (4-chloro
Rophenyl) -4- (2-oxo-3-phenylpropy
L) -1-Methyl-4H-2,3,4,5,10b-pe
Ntazabenzo [e] azulene, 6- (4-chlorophene
Nil) -4- [2- (4-chlorophenyl) -2-oxo
Soethyl] -1-methyl-4H-2,3,4,5,10
b-pentaazabenzo [e] azulene, 6- (4-chloro
Rophenyl) -1-methyl-4- [2- (4-methylf
Enyl) -2-oxoethyl] -4H-2,3,4
5,10b-pentaazabenzo [e] azulene, 6-
(4-chlorophenyl) -4- [2- (2-methoxyphenyl
Enyl) -2-oxoethyl] -1-methyl-4H-
2,3,4,5,10b-pentaazabenzo [e] az
Len, 6- (4-chlorophenyl) -4- [2- (2,
5-dimethoxyphenyl) -2-oxoethyl] -1-
Methyl-4H-2,3,4,5,10b-pentaazabe
Nzo [e] azulene, 6- (4-chlorophenyl) -4
-[3- (2-methoxyphenyl) -2-oxopropyl
L] -1-methyl-4H-2,3,4,5,10b-pe
Ntazabenzo [e] azulene, 6- (4-chlorophene
Nil) -4- [3- (2,5-dimethoxyphenyl)-
2-oxopropyl] -1-methyl-4H-2,3,
4,5,10b-pentaazabenzo [e] azulene, 4
-Benzyl-6- (4-chlorophenyl) -1-methyl
-4H-2,3,4,5,10b-pentaazabenzo
[E] azulene and 6- (4-chlorophenyl) -4
-(4-methoxybenzyl) -4H-3,4,5,10
selected from the group consisting of b-tetraazabenzo [e] azulene
Triazepine compound or pharmaceutically acceptable salt thereof
The treatment for osteoporosis according to (1), comprising as an active ingredient
medicine.

(8) Formula [I ']

[0029]

Embedded image

[0030] wherein, R ¹ represents a optionally substituted aryl group or an optionally substituted heteroaryl group; R ²
Represents a hydrogen atom, a hydroxyl group or a halogen atom, R ⁴ represents a hydrogen atom or a halogen atom, or R ² and R ⁴
There together form a carbonyl group together with the carbon atoms to which they are attached; R ³ is a lower alkoxy group, a cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, -CR ⁵ = CR ⁶ R ⁷ (R ⁵ ,
R ⁶ and R ⁷ are the same or different and are a hydrogen atom, a halogen atom, a lower alkyl group or an optionally substituted aryl group. ), -OR ¹⁸ (R ¹⁸ is an optionally substituted aryl group),

[0031]

Embedded image

(Where R ⁸ is a hydrogen atom, a lower alkyl group, a cycloalkyl group, an optionally substituted aryl group,
An aralkyl group or an optionally substituted heteroaryl group, R ⁹ and R ¹⁰ are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a halogen atom, a nitro group or amino group, R ²⁰ Is an optionally substituted aryl group, an aralkyl group or an optionally substituted heteroaryl group. ) Or -X-Y {wherein, X is _{- (CH 2) m - (} m is an integer of 1 to 4). -
_{CO -, - COCH 2 -,} - NH -, - NHCH 2 -,
_{-CH 2 NH -, - CH 2} NHCO -, - OCH 2 -,
— (CH ₂ ) _n O— (n is an integer of 1 to 4) or —CH ₂ S—; Y represents a halogen atom, a cycloalkyl group, an optionally substituted aryl group, or an optionally substituted A good heteroaryl group. Represents a ring A is a ring selected from the following:

[0033]

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Wherein R ¹¹ and R ¹² are the same or different and are each a hydrogen atom, a halogen atom, a lower alkyl group (the lower alkyl group is a halogen atom, a lower alkoxy group, a nitro group, an amino group, a lower alkyl group, Substituted amino group,
It may be substituted by a cyclic amino group, a hydroxyl group, an acyloxy group, a cyano group, a carbamoyl group, a carbamoyl group substituted by a lower alkyl group, a cyclic aminocarbonyl group, a carboxy group, a lower alkoxycarbonyl group or an aralkyloxycarbonyl group. ), Lower alkenyl group, aralkyl group, aralkyl group substituted with alkyl group, lower alkoxy group, nitro group, amino group, amino group substituted with lower alkyl group, cyclic amino group, hydroxyl group, acyloxy group, cyano group, A carbamoyl group, a carbamoyl group substituted with a lower alkyl group, a cyclic aminocarbonyl group, a carboxy group, a lower alkoxycarbonyl group or an aralkyloxycarbonyl group, and R ¹³ and R ¹⁴ are
Same or different hydrogen atom, halogen atom, lower alkyl group, lower alkenyl group, lower alkynyl group, haloalkyl group, lower alkoxy group, nitro group, amino group, amino group substituted with lower alkyl group, cyclic amino group, hydroxyl group An acyloxy group, a cyano group, a carbamoyl group, a carbamoyl group substituted with a lower alkyl group, a cyclic aminocarbonyl group, a carboxy group, a lower alkoxycarbonyl group, an aralkyloxycarbonyl group, a cycloalkyl group or a lower alkylcarbonyl group. Represents｝;

[0035]

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(Where R ¹⁵ is a lower alkyl group,
R ¹⁹ is a hydrogen atom or a lower alkyl group. ). Or a pharmaceutically acceptable salt thereof.

(9) Ring A is

[0038]

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[0039] ^{(R 11, R 12, R} 13 and R ¹⁴ are as described. (8)) triazepine compound or a pharmaceutically acceptable salt thereof according to a (8).

(10)

[0041]

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The triazepine compound or a pharmaceutically acceptable salt thereof according to (9), wherein R ¹⁵ is a lower alkyl group.

(11) The triazepine compound or a pharmaceutically acceptable salt thereof according to (10), wherein R ¹ is an optionally substituted aryl group.

(12) The triazepine compound or a pharmaceutically acceptable salt thereof according to (11), wherein R ¹ is a phenyl group which may be substituted.

(13) The triazepine compound or a pharmaceutically acceptable salt thereof according to (12), wherein both R ² and R ⁴ are hydrogen atoms.

(14) The triazepine compound or a pharmaceutically acceptable salt thereof according to (13), wherein R ³ is a pyridyl group or an optionally substituted phenyl group.

(15) A triazepine compound selected from the group consisting of the compounds described in (7) or a pharmaceutically acceptable salt thereof.

(16) Formula [I ']

[0049]

Embedded image

(Wherein R ¹ , R ² , R ³ , R ⁴ , ring A and

[0051]

Embedded image

Is as described in (8). A) a pharmaceutical composition comprising a triazepine compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

(17) In the general formula [I '], ring A is

[0054]

Embedded image

The pharmaceutical composition according to (16), wherein (R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are as described in (8)).

(18) In the general formula [I ']

[0057]

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The pharmaceutical composition according to (17), wherein (R ¹⁵ is a lower alkyl group).

(19) The pharmaceutical composition according to (18), wherein R ¹ in the general formula [I ′] is an optionally substituted aryl group.

(20) The pharmaceutical composition according to (19), wherein R ¹ is a phenyl group which may be substituted in the general formula [I '].

(21) The pharmaceutical composition according to (20), wherein R ² and R ⁴ in the formula [I ′] are both hydrogen atoms.

(22) In the general formula [I '], R ³ is a pyridyl group or an optionally substituted phenyl group (2
The pharmaceutical composition according to 1).

(23) A pharmaceutical composition comprising a triazepine compound selected from the group consisting of the compounds described in (7) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

(24) Formula [II ']

[0065]

Embedded image

Wherein R ¹ , R ² , R ³ , R ⁴ and ring A
Is as described in (8). Or a salt thereof.

(25) Ring A is

[0068]

Embedded image (R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are as described in (8)), R ¹ is a phenyl group which may be substituted, and R ² and R ⁴ are both hydrogen atoms The triazepinethione compound or a salt thereof according to (24).

(26) 5- (4-chlorophenyl)-
3- (3,4-dimethoxybenzyl) -1,3-dihydrobenzo [e] [1,2,4] triazepine-2-thione, 3- (4-methoxybenzyl) -5-phenyl-
1,3-dihydrobenzo [e] [1,2,4] triazepine-2-thione, 5- (4-chlorophenyl) -3-
(4-methoxybenzyl) -1,3-dihydrobenzo [e] [1,2,4] triazepine-2-thione, 7-
Chloro-3- (4-methoxybenzyl) -5-phenyl-1,3-dihydrobenzo [e] [1,2,4] triazepin-2-thione, 3- (4-methoxybenzyl)-
7-nitro-5-phenyl-1,3-dihydrobenzo [e] [1,2,4] triazepine-2-thione, 3-
(4-methoxybenzyl) -5- (4-methylphenyl) -1,3-dihydrobenzo [e] [1,2,4] triazepin-2-thione, 7-chloro-5- (2-chlorophenyl)- 3- (4-methoxybenzyl) -1,3
-Dihydrobenzo [e] [1,2,4] triazepine-
2-thione, 5- (4-chlorophenyl) -3- (pyridin-3-ylmethyl) -1,3-dihydrobenzo [e] [1,2,4] triazepine-2-thione, 4-
(4-chlorophenyl) -6- (4-methoxybenzyl) -2,3-dimethyl-6,8-dihydro-1-thia-5,6,8-triaza-azulene-7-thione, 4-
(4-chlorophenyl) -2-ethyl-6- (4-methoxybenzyl) -6,8-dihydro-1-thia-5
6,8-triaza-azulene-7-thione, 6- (4-
Methoxybenzyl) -2-methyl-4-phenyl-6,
8-dihydro-1-thia-5,6,8-triaza-azulene-7-thione, 6- (4-methoxybenzyl)-
2,3-dimethyl-4-phenyl-6,8-dihydro-
1-thia-5,6,8-triaza-azulene-7-thione, 2-ethyl-6- (4-methoxybenzyl) -4-
Phenyl-6,8-dihydro-1-thia-5,6,8-
Triaza-azulene-7-thione, 6- (4-methoxybenzyl) -4- (4-methoxyphenyl) -2,3-
Dimethyl-6,8-dihydro-1-thia-5,6,8-
Triaza-azulene-7-thione, 4- (2-chlorophenyl) -2,3-dimethyl-6- (pyridin-4-ylmethyl) -6,8-dihydro-1-thia-5,6,8
-Triaza-azulene-7-thione, 3- (4-methoxybenzyl) -8-methyl-5-phenyl-1,3-dihydrobenzo [e] [1,2,4] triazepine-2-
Selected from the group consisting of thione and 3-benzyl-5- (4-chlorophenyl) -1,3-dihydrobenzo [e] [1,2,4] triazepin-2-thione (2
The triazepinethione compound or a salt thereof according to 5).

(27) General formula [III ']

[0071]

Embedded image

(Wherein R ¹ , R ² , R ³ , R ⁴ and ring A
Is as described in (8), and R ¹⁶ represents a lower alkyl group. Or a salt thereof.

(28) Ring A is

[0074]

Embedded image

(R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are as described in (8)), R ¹ is a phenyl group which may be substituted, and R ² and R ⁴ are both The alkylthiotriazepine compound or a salt thereof according to (27), which is a hydrogen atom.

(29) 5- (4-chlorophenyl)-
3- (3,4-dimethoxybenzyl) -2-methylthio-3H-benzo [e] [1,2,4] triazepine,
-(4-methoxybenzyl) -2-methylthio-5-phenyl-3H-benzo [e] [1,2,4] triazepine, 7-chloro-3- (4-methoxybenzyl) -2-
Methylthio-5-phenyl-3H-benzo [e] [1,
2,4] triazepine, 3- (4-methoxybenzyl)
-8-methyl-2-methylthio-5-phenyl-3H-
Benzo [e] [1,2,4] triazepine, 3- (4-
Methoxybenzyl) -7-nitro-2-methylthio-5
-Phenyl-3H-benzo [e] [1,2,4] triazepine, 3- (4-methoxybenzyl) -5- (4-methylphenyl) -2-methylthio-3H-benzo [e]
[1,2,4] triazepine, 7-chloro-5- (2-
Chlorophenyl) -3- (4-methoxybenzyl) -2
-Methylthio-3H-benzo [e] [1,2,4] triazepine, 5- (4-chlorophenyl) -2-methylthio-3- (pyridin-3-ylmethyl) -3H-benzo [e] [1,2 , 4] Triazepine, 4- (4-chlorophenyl) -6- (4-methoxybenzyl) -2,3-
Dimethyl-7-methylthio-6H-1-thia-5,6,
8-triazaazulene, 4- (4-chlorophenyl)-
2-ethyl-6- (4-methoxybenzyl) -7-methylthio-6H-1-thia-5,6,8-triazaazulene, 6- (4-methoxybenzyl) -2-methyl-7-
Methylthio-4-phenyl-6H-1-thia-5,6,
8-triazaazulene, 6- (4-methoxybenzyl)
-2,3-dimethyl-7-methylthio-4-phenyl-
6H-1-thia-5,6,8-triazaazulene, 2-
Ethyl-6- (4-methoxybenzyl) -7-methylthio-4-phenyl-6H-1-thia-5,6,8-triazaazulene, 6- (4-methoxybenzyl) -4-
(4-methoxyphenyl) -2,3-dimethyl-7-methylthio-6H-1-thia-5,6,8-triazaazulene, 4- (2-chlorophenyl) -2,3-dimethyl-7-methylthio -6- (pyridin-4-ylmethyl)
-6H-1-thia-5,6,8-triazaazulene and 5- (4-chlorophenyl) -3- (4-methoxybenzyl) -2-methylthio-3H-benzo [e] [1,
2,4] triazepine (the alkylthiotriazepine compound or salt thereof according to 28.

(30) Formula [IV ']

[0078]

Embedded image

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ¹⁵ and ring A are as described in (8)) or a salt thereof.

(31) When ring A is

[0081]

Embedded image

(R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are as described in (8)), R ¹ is a phenyl group which may be substituted, and R ² and R ⁴ are both The acylhydrazotriazepine compound or a salt thereof according to (30), which is a hydrogen atom.

(32) N '-[5- (4-Chlorophenyl) -3-acetic acid acetate (3,4-dimethoxybenzyl) -3
H-benzo [e] [1,2,4] triazepin-2-yl] hydrazide, acetate N '-[3- (4-methoxybenzyl) -5-phenyl-3H-benzo [e] [1,2,2
4] Triazepin-2-yl] hydrazide and N '-[3- (4-methoxybenzyl) -8-methyl-acetate
The acylhydrazotriazepine compound or a salt thereof according to (31), which is selected from the group consisting of 5-phenyl-3H-benzo [e] [1,2,4] triazepin-2-yl] hydrazide.

The definition of each substituent used in the present specification is as follows.

The "optionally substituted aryl group" means a phenyl group, a naphthyl group or a biphenylyl group which may have 1 to 3 substituents on the ring. For example, as a substituent, a halogen atom (chlorine, bromine, fluorine, iodine), a lower alkyl group (a methyl group having 1 to 6 carbon atoms,
Ethyl group, propyl group, isopropyl group, butyl group, t
tert-butyl group, isobutyl group, pentyl group, isopentyl group, hexyl group, etc.), lower alkoxy group (methoxy group having 1 to 6 carbon atoms, ethoxy group, propoxy group,
An isopropoxy group, a butoxy group, a tert-butoxy group, a hexyloxy group, etc., an aralkyloxy group (such as a benzyloxy group), a methylenedioxy group, a haloalkyl group (a chloromethyl group having an alkyl portion having 1 to 4 carbon atoms,
Bromomethyl group, fluoromethyl group, trifluoromethyl group, trifluoroethyl group, pentafluoropropyl group, chlorobutyl group, etc., haloalkyloxy group (trifluoromethoxy group, trifluoroethoxy group, etc.), haloalkylsulfonylamino group (trifluoromethane, etc.) Sulfonylamino group), hydroxyl group, nitro group, amino group,
Mono- or di-substituted amino group ｛alkylamino group (methylamino group, dimethylamino group, etc.), acylamino group (acetylamino group, formylamino group, etc.), alkylsulfonylamino group (methanesulfonylamino group, etc.),
Bisalkylsulfonylamino group (bismethanesulfonylamino group, etc.), cyano group, alkylsulfonyl group (methanesulfonyl group, etc.), acyl group (acetyl group, propionyl group, butyryl group, pivaloyl group, etc.), acyloxy group [acyl moiety Is an alkanoyl group having 2 to 5 carbon atoms (acetyl group, propionyl group, butyryl group, pivaloyl group, etc.) or an aroyl group: a halogen atom on the ring (as defined above), a lower alkyl group (as defined above), a lower alkoxy group Benzoyl group (benzoyl group, chlorobenzoyl group, methylbenzoyl group, methoxybenzoyl group and the like) which may have 1 to 3 substituents selected from a group (as defined above), a haloalkyl group (as defined above), and a hydroxyl group )
Means Or an aralkyl group having 1 to 6 carbon atoms in the alkyl portion, and a halogen atom (as defined above), a lower alkyl group (as defined above), a lower alkoxy group (as defined above), a hydroxyl group on the ring And a benzyl group optionally having 1 to 3 substituents, a 2-phenylethyl group, a 3-phenylpropyl group, and the like. Preferably, a phenyl group, a biphenylyl group, a naphthyl group or a halogen atom (as defined above), a lower alkyl group (as defined above), a lower alkoxy group (as defined above) as a substituent,
Aralkyloxy group (same as above), haloalkyl group (same as above), haloalkyloxy group (same as above), haloalkylsulfonylamino group (same as above), nitro group, amino group, mono- or di-substituted amino group (same as above) Phenyl having an alkylsulfonylamino group (as defined above), a bisalkylsulfonylamino group (as defined above), an alkylsulfonyl group (as defined above), an acyloxy group (as defined above), a cyano group or a hydroxyl group And the like. Particularly preferably, a phenyl group,
2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2,5-dimethoxyphenyl group, 3,4-dimethoxyphenyl Group,
3,4,5-trimethoxyphenyl group, 5-acetyl-
2-methoxyphenyl group, 4-ethoxyphenyl group,
3,4-methylenedioxyphenyl group, 2-chloro-
4,5-methylenedioxyphenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2,4-difluorophenyl group, 2,5-difluorophenyl group, 3,4-difluorophenyl Group,
3,5-difluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 3
-Chloro-4-methoxyphenyl group, 3,5-dichloro-4-methoxyphenyl group, 4-chloro-2,5-dimethoxyphenyl group, 2-trifluoromethylphenyl group, 3-trifluoromethylphenyl group, -Trifluoromethylphenyl group, 4-trifluoromethoxyphenyl group, 2-nitrophenyl group, 3-nitrophenyl group, 4-nitrophenyl group, 2-methoxy-5-nitrophenyl group, 4-methoxy-3-nitro Phenyl group, 2
-Cyanophenyl group, 3-cyanophenyl group, 4-cyanophenyl group, 4-aminophenyl group, 4-formylaminophenyl group, 4-acetylaminophenyl group, 4-
Dimethylaminophenyl group, 4-methanesulfonylaminophenyl group, 4-bismethanesulfonylaminophenyl group, 4-trifluoromethanesulfonylaminophenyl group, 4-methylsulfonylphenyl group, 4-hydroxyphenyl group, 3,4-dihydroxyphenyl Group, 4-
Benzyloxyphenyl group, 3,4-dibenzyloxyphenyl group, 3-benzyloxy-4-methoxyphenyl group, 4-hydroxy-3-methoxyphenyl group, 4-
Benzyloxy-3-hydroxyphenyl group, 3-benzyloxy-4-hydroxyphenyl group, 4-benzyloxy-3-methoxyphenyl group, biphenylyl group, 1
-Naphthyl group or 2-naphthyl group.

“Heteroaryl group which may be substituted”
The term means a pyridyl group, a thienyl group, a thiazolyl group, an isoxazolyl group or the like, and may have 1 to 3 substituents on a ring. For example, as a substituent, a halogen atom (chlorine, bromine, fluorine, iodine), a lower alkyl group (a methyl group having 1 to 6 carbon atoms, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group, an isobutyl group) , A pentyl group, an isopentyl group, a hexyl group, etc.), a lower alkoxy group (a methoxy group having 1 to 6 carbon atoms, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a tert-butoxy group, a hexyloxy group, etc.), Aralkyloxy group (benzyloxy group, etc.), methylenedioxy group, haloalkyl group (chloromethyl group having 1 to 4 carbon atoms, bromomethyl group, fluoromethyl group, trifluoromethyl group, trifluoroethyl group, pentaethyl group, Fluoropropyl group, chlorobutyl group, etc.), haloalkyloxy group (trifluoromethyl Alkoxy group, trifluoroethoxy group, etc.), haloalkylsulfonyl amino group (trifluoromethanesulfonyl amino group, etc.), a hydroxyl group, a nitro group, an amino group, a mono- or di-substituted amino group {an alkylamino group (methylamino group,
Dimethylamino group, etc.), acylamino group (acetylamino group, formylamino group, etc.), alkylsulfonylamino group (methanesulfonylamino group, etc.), bisalkylsulfonylamino group (bismethanesulfonylamino group, etc.), cyano group, alkyl Sulfonyl group (methanesulfonyl group, etc.), acyl group (acetyl group, propionyl group, butyryl group, pivaloyl group, etc.), acyloxy group [alkanoyl group having 2 to 5 carbon atoms (acetyl group, propionyl group, butyryl group) , A pivaloyl group, etc.) or an aroyl group: a halogen atom (as defined above), a lower alkyl group (as defined above), a lower alkoxy group (as defined above), a haloalkyl group (as defined above) on the ring,
It means a benzoyl group (benzoyl group, chlorobenzoyl group, methylbenzoyl group, methoxybenzoyl group, etc.) which may have 1 to 3 substituents selected from a hydroxyl group. Or an aralkyl group, wherein the alkyl moiety has 1 to 6 carbon atoms, and a halogen atom (as defined above) on the ring;
A lower alkyl group (as defined above), a lower alkoxy group (as defined above), a benzyl group optionally having 1 to 3 substituents selected from a hydroxyl group, a 2-phenylethyl group,
And a phenylpropyl group. Preferred are a pyridyl group, a thienyl group, a thiazolyl group or an isoxazolyl group, and these heteroaryl groups are a halogen atom (as defined above), a lower alkyl group (as defined above), a lower alkoxy group (as defined above), Aralkyloxy group (same as above), haloalkyl group (same as above), haloalkyloxy group (same as above), haloalkylsulfonylamino group (same as above), nitro group, amino group, mono- or di-substituted amino group (same as above) Synonymous with)
1 to 3 selected from an alkylsulfonylamino group (as defined above), a bisalkylsulfonylamino group (as defined above), an alkylsulfonyl group (as defined above), an acyloxy group (as defined above), a cyano group, a hydroxyl group, and the like May have a substituent. More preferably, a pyridyl group, a 2-methylpyridyl group, a 3-methylpyridyl group,
-Methylpyridyl group, 2,5-dimethylpyridyl group,
2,6-dimethylpyridyl group, 3,5-dimethylpyridyl group, 2-methoxypyridyl group, 3-methoxypyridyl group, 4-methoxypyridyl group, 2,5-dimethoxypyridyl group, 2,6-dimethoxypyridyl group, 3,5-dimethoxypyridyl group, 2-fluoropyridyl group, 3-fluoropyridyl group, 4-fluoropyridyl group, 2,5-difluoropyridyl group, 2,6-difluoropyridyl group,
3,5-difluoropyridyl group, 2-chloropyridyl group, 3-chloropyridyl group, 4-chloropyridyl group,
2,5-dichloropyridyl group, 2,6-dichloropyridyl group, 3,5-dichloropyridyl group, 4-trifluoromethylpyridyl group, 4-trifluoromethoxypyridyl group, 2-nitropyridyl group, 3-nitropyridyl Group, 4
-Nitropyridyl group, 2-cyanopyridyl group, 3-cyanopyridyl group, 4-cyanopyridyl group, 4-aminopyridyl group, 4-formylaminopyridyl group, 4-acetylaminopyridyl group, 4-dimethylaminopyridyl group, 4
-Methanesulfonylaminopyridyl group, 4-bismethanesulfonylaminopyridyl group, 4-trifluoromethanesulfonylaminopyridyl group, 2-hydroxypyridyl group, 3-hydroxypyridyl group, 4-hydroxypyridyl group, 2-benzyloxypyridyl group, 3-benzyloxypyridyl group, 4-benzyloxypyridyl group, thienyl group, 2-methylthienyl group, 3-methylthienyl group, 2,3-dimethylthienyl group, 3,4-dimethylthienyl group, 2-methoxythienyl group , 3-methoxythienyl group, 2-fluorothienyl group, 3-fluorothienyl group, 2,3-difluorothienyl group, 3,4-difluorothienyl group, 2-chlorothienyl group, 3-chlorothienyl group, 2,3 -Dichlorothienyl group, 3,4-dichlorothienyl group, 2 Trifluoromethyl thienyl group,
3-trifluoromethylthienyl group, 2-trifluoromethoxythienyl group, 3-trifluoromethoxythienyl group, 2-nitrothienyl group, 3-nitrothienyl group,
2-cyanothienyl group, 3-cyanothienyl group, 2-aminothienyl group, 3-aminothienyl group, 2-formylaminothienyl group, 3-formylaminothienyl group, 2
-Acetylaminothienyl group, 3-acetylaminothienyl group, 2-dimethylaminothienyl group, 3-dimethylaminothienyl group, 2-methanesulfonylaminothienyl group, 3-methanesulfonylaminothienyl group, 2-bismethanesulfonylaminothienyl Group, 3-bismethanesulfonylaminothienyl group, 2-trifluoromethanesulfonylaminothienyl group, 3-trifluoromethanesulfonylaminothienyl group, 2-hydroxythienyl group, 3-hydroxythienyl group , 2 -benzyloxythienyl group, 3- Benzyloxythienyl group, isoxazolyl group, 3-methylisoxazolyl group, 4-methylisoxazolyl group, 5-methylisoxazolyl group,
3,4-dimethylisoxazolyl group, 3,5-dimethylisoxazolyl group, 4,5-dimethylisoxazolyl group, 3-chloroisoxazolyl group, 4-chloroisoxazolyl group , A 5-chloroisoxazolyl group,
3,4-dichloroisoxazolyl group, 3,5-dichloroisoxazolyl group, 4,5-dichloroisoxazolyl group, thiazolyl group, 2-methylthiazolyl group, 4-
Methylthiazolyl group, 5-methylthiazolyl group, 2,4
-Dimethylthiazolyl group, 2,5-dimethylthiazolyl group, 4,5-dimethylthiazolyl group, 2-chlorothiazolyl group, 4-chlorothiazolyl group, 5-chlorothiazolyl group, 2,4-dichlorothiazolyl A 2,5-dichlorothiazolyl group, a 4,5-dichlorothiazolyl group and the like.

The “lower alkyl group” is a group having 1 to 6 carbon atoms.
Represents a linear or branched alkyl group, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group,
It is a tert-pentyl group or a hexyl group, particularly preferably a methyl group having 1 to 4 carbon atoms, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group or a tert-butyl group.

The “halogen atom” is chlorine, bromine, fluorine or iodine, preferably chlorine.

The "aralkyl group" is an arylalkyl group in which the aryl group is a phenyl group and the alkyl part is an alkyl group having 1 to 6 carbon atoms, and is a benzyl group, a phenylethyl group, a phenylpropyl group. Group, a phenylbutyl group or a phenylhexyl group, and a halogen atom (chlorine, bromine, fluorine, etc.) on the phenyl ring,
An alkyl group (an alkyl group having 1 to 6 carbon atoms,
A methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group, an isobutyl group, a pentyl group, an isopentyl group, a hexyl group, etc.), an alkoxy group (an alkoxy group having 1 to 6 carbon atoms, A methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a tert-butoxy group, a hexyloxy group, etc., a haloalkyl group (where the alkyl part is an alkyl group having 1 to 4 carbon atoms, and a chloromethyl group; Bromomethyl group, fluoromethyl group, trifluoromethyl group, trifluoroethyl group, pentafluoropropyl group, chlorobutyl group, etc.), hydroxyl group, nitro group, amino group, cyano group,
An acyloxy group [an alkanoyl group having an acyl moiety of 2 to 5 carbon atoms (acetyl group, propionyl group, butyryl group,
A halogen atom (as defined above), an alkyl group (as defined above), an alkoxy group (as defined above), a haloalkyl group (as defined above),
It means benzoyl (benzoyl group, chlorobenzoyl group, methylbenzoyl group, methoxybenzoyl group, etc.) which may have 1 to 3 substituents selected from a hydroxyl group. ｝] May have 1 to 3 substituents selected from Preferably, a phenyl group or a substituent is a halogen atom (as defined above), an alkyl group (as defined above), an alkoxy group (as defined above), a haloalkyl group (as defined above), a hydroxyl group, a nitro group, an amino group, or a cyano group And an aralkyl group having an alkyl group having 1 to 4 carbon atoms. Particularly preferably, a phenyl group or a phenyl group substituted with a halogen atom (as defined above), an alkyl group (as defined above), an alkoxy group (as defined above), or the like as a substituent has 1 to 4 carbon atoms. It is an aralkyl group having an alkyl group.

The term "lower alkoxy group" means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy. , A pentyloxy group, a tert-pentyloxy group or a hexyloxy group, preferably a methoxy group having 1 to 4 carbon atoms, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group or a tert-butoxy group. . Particularly preferred are a methoxy group, an ethoxy group, a propoxy group and a butoxy group.

The "cycloalkyl group" has 3 to 10 carbon atoms and includes, for example, a cyclopropyl group, a 2,3-dimethylcyclopropyl group, a cyclobutyl group, a 3-methylcyclobutyl group, a cyclopentyl group, 4-dimethylcyclopentyl group, cyclohexyl group, 4-methylcyclohexyl group, cycloheptyl group, cyclooctyl group, norbornyl group, adamantyl group, bicyclo [3.3.
0] octan-1-yl group or bicyclo [3.3.1]
And a nonan-9-yl group. Preferred are a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group, and particularly preferred are a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group.

"Amino group substituted by lower alkyl group"
Represents an alkylamino group mono- or di-substituted with alkyl having 1 to 5 carbon atoms, such as a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group, a propylamino group, and a dipropylamino group. Preferred are a methylamino group, a dimethylamino group, an ethylamino group and a diethylamino group.

"Cyclic amino group" means a pyrrolidinyl group,
Examples include a piperidino group, a morpholino group having an oxygen, sulfur, or nitrogen atom as a hetero atom, a thiomorpholino group, or a piperazinyl group. The nitrogen atom at the 4-position of the piperazinyl group may be substituted with a lower alkyl group, an aralkyl group, or the like.

The "acyl group" includes an alkanoyl group having 2 to 5 carbon atoms, such as an acetyl group, a propionyl group, a butyryl group or a pivaloyl group, or a benzoyl group. Preferred are a formyl group, an acetyl group, a propionyl group and a benzoyl group.

The term "acyloxy group" means an alkanoyloxy group having 2 to 5 carbon atoms such as an acetyloxy group, a propionyloxy group, a butyryloxy group or a pivaloyloxy group, or a benzoyloxy group. Preferred are an acetyloxy group, a propionyloxy group and a benzoyloxy group.

The term "carbamoyl group substituted with a lower alkyl group" refers to a carbamoyl group having 1 to 5 carbon atoms such as a methylcarbamoyl group, a dimethylcarbamoyl group, an ethylcarbamoyl group, a diethylcarbamoyl group, a propylcarbamoyl group or a dipropylcarbamoyl group. Represents an alkylcarbamoyl group mono- or disubstituted with an alkyl group. Preferred are a methylcarbamoyl group, a dimethylcarbamoyl group, an ethylcarbamoyl group and a diethylcarbamoyl group.

"Cyclic aminocarbonyl group" means a compound having a cyclic amino moiety as described above, for example, pyrrolidinylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperazinylcarbonyl or Represents a 4-methyl-1-piperazinylcarbonyl group or the like. Preferred are a pyrrolidinylcarbonyl group, a piperidinocarbonyl group, a morpholinocarbonyl group and a piperazinylcarbonyl group.

The term "lower alkoxycarbonyl group" means a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group or
An alkoxy moiety such as a t-butoxycarbonyl group has 1 carbon atom
Represents from 5 to 5 alkoxycarbonyl groups. Preferred are a methoxycarbonyl group, an ethoxycarbonyl group and a propoxycarbonyl group.

An “aralkyloxycarbonyl group” is
A benzyloxycarbonyl group, a phenylalkoxycarbonyl group having 1 to 5 carbon atoms such as a 2-phenylethoxycarbonyl group or a 3-phenylpropoxycarbonyl group, and a halogen atom, a nitro group, an alkyl group, It may have an alkoxy group or a trifluoromethyl group.

“Lower alkenyl group” means an alkenyl group having 2 to 6 carbon atoms, for example, ethenyl group, 1-
Propenyl group, 1-butenyl group, 2-butenyl group, 3-
Butenyl group, 2-methyl-1-propenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 2-
A methyl-1-butenyl group, a 3-methyl-1-butenyl group, a 1-hexenyl group, a 2-hexenyl group, a 3-hexenyl group, a 4-hexenyl group, a 5-hexenyl group, a 2-methyl-1-pentenyl group, A 3-methyl-1-pentenyl group, a 4-methyl-1-pentenyl group, a 2,3-dimethyl-1-butenyl group or a 3,3-dimethyl-1-butenyl group, preferably having 2 to 4 carbon atoms. An ethenyl group of
1-propenyl group, 1-butenyl group, 2-butenyl group,
A 3-butenyl group or a 2-methyl-1-propenyl group.

The "aralkyl group substituted with a lower alkyl group" refers to an aralkyl group in which the above aralkyl group is substituted with an alkyl group having 1 to 6 carbon atoms. -Ethylbenzyl group, 4-propylbenzyl group, 4-isopropylbenzyl group, 4-methylphenylethyl group, 4-ethylphenylethyl group or 4-
And a propylphenylethyl group and the like, preferably a 4-methylbenzyl group, a 4-ethylbenzyl group or a 4-isopropylbenzyl group.

[0102] The "lower alkynylene Le group", represents the number 2 or 6 alkynyl group having a carbon such as ethynyl group, 1-
Propynyl group, 1-butynyl group, 2-butynyl group, 3-
Butynyl group, 1-pentynyl group, 2-pentynyl group, 3
-Pentynyl group, 3-methyl-1-butynyl group, 1-hexynyl group, 2-hexynyl group, 3-hexynyl group, 4
-Hexynyl group, 5-hexynyl group, 3-methyl-1-
Pentynyl group, 4-methyl-1-pentynyl group or 3,
3-dimethyl-1 a butynyl group and the like, preferably an ethynyl group having 2 to 4 carbon atoms, 1-propynyl group, 1-butynyl group, 2-butynyl or 3-butynyl group.

The “haloalkyl group” is an alkyl group having an alkyl portion of 1 to 4 carbon atoms, and specifically includes a chloromethyl group, a bromomethyl group, a fluoromethyl group, a trifluoromethyl group, a trichloromethyl group, A trifluoroethyl group, a trichloroethyl group, a pentafluoropropyl group or a chlorobutyl group, preferably a chloromethyl group, a bromomethyl group, a fluoromethyl group, a trifluoromethyl group or a trichloromethyl group;

The term "lower alkylcarbonyl group" means an alkylcarbonyl group having 1 to 5 carbon atoms in the alkyl portion such as an acetyl group, a propionyl group, a butyryl group, an isobutyryl group or a pivaloyl group.

“Pharmaceutically acceptable salts” include, for example, various inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate and nitrate; acetate, propionate, succinate , Glycolate, lactate, malate, oxalate, tartrate, citrate, maleate, fumarate, methanesulfonate, benzenesulfonate, p-
Various organic acid addition salts such as toluenesulfonate or ascorbate; salts with various amino acids such as aspartate or glutamate, but are not limited thereto. Further, depending on the case, it may be a hydrate or a hydrate.

The salts of compounds [II '], [III'] and [IV '] include inorganic acid addition salts, organic acid addition salts and amino acid addition salts as exemplified in the above-mentioned "pharmaceutically acceptable salts". Salts include, but are not limited to. In some cases, it may be a hydrate or a hydrate.

Next, the various substituents will be described in more detail.

R ¹ represents an optionally substituted aryl group or an optionally substituted heteroaryl group, and is preferably a phenyl group, a 2-methylphenyl group, a 3-methylphenyl group, a 4-methylphenyl group, -Methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group,
3-chlorophenyl group, 4-chlorophenyl group, 2-trifluoromethylphenyl group, 3-trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 2-
Nitrophenyl group, 3-nitrophenyl group, 4-nitrophenyl group, 2-hydroxyphenyl group, 3-hydroxyphenyl group, 4-hydroxyphenyl group, 2-benzyloxyphenyl group, 3-benzyloxyphenyl group,
4-benzyloxyphenyl group, 2-cyanophenyl group, 3-cyanophenyl group, 4-cyanophenyl group, 2
-Aminophenyl group, 3-aminophenyl group, 4-aminophenyl group, 2-dimethylaminophenyl group, 3-dimethylaminophenyl group, 4-dimethylaminophenyl group, pyridyl group, 2-methylpyridyl group, 3-methyl Pyridyl group, 4-methylpyridyl group, 2-methoxypyridyl group, 3-methoxypyridyl group, 4-methoxypyridyl group, 2-fluoropyridyl group, 3-fluoropyridyl group, 4-fluoropyridyl group, 2-chloropyridyl group ,
3-chloropyridyl group, 4-chloropyridyl group, 2-trifluoromethylpyridyl group, 3-trifluoromethylpyridyl group, 4-trifluoromethylpyridyl group, 2-
Nitropyridyl, 3-nitropyridyl, 4-nitropyridyl, 2-hydroxypyridyl, 3-hydroxypyridyl, 4-hydroxypyridyl, 2-benzyloxypyridyl, 3-benzyloxypyridyl,
4-benzyloxypyridyl group, 2-cyanopyridyl group, 3-cyanopyridyl group, 4-cyanopyridyl group, 2
-Aminopyridyl group, 3-aminopyridyl group, 4-aminopyridyl group, 2-dimethylaminopyridyl group, 3-dimethylaminopyridyl group or 4-dimethylaminopyridyl group, and more preferably phenyl group, 2-methyl Phenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group , 2-chlorophenyl group, 3-chlorophenyl group, 4
-Chlorophenyl group, 2-trifluoromethylphenyl group, 3-trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 2-nitrophenyl group, 3-nitrophenyl group, 4-nitrophenyl group, 2-hydroxyphenyl Group, 3-hydroxyphenyl group, 4-hydroxyphenyl group, 2-aminophenyl group, 3-aminophenyl group or 4-aminophenyl group, and particularly preferably phenyl group, 2-methylphenyl group, 3-methyl Phenyl group, 4-methylphenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group,
Examples thereof include a 2-methoxyphenyl group, a 3-methoxyphenyl group, and a 4-methoxyphenyl group.

R ² represents a hydrogen atom, a hydroxyl group, a halogen atom or a lower alkyl group, or R ² and R ⁴ together form a carbonyl group together with the carbon atom to which they are bonded. Preferably, R ² represents a hydrogen atom or a hydroxyl group, or R ² and R ⁴ together form a carbonyl group with the carbon atom to which they are attached. More preferably, R ² represents a hydrogen atom or R ² and R ⁴ together form a carbonyl group together with the carbon atom to which they are attached, particularly preferably R ² is a hydrogen atom.

R ³ is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, —CR ^{5
= CR 6 R 7 (R 5} , R 6 and R ⁷ are the same or different and each is a hydrogen atom, a halogen atom, a lower alkyl group or an optionally substituted aryl ^{group.), - OR 18 (R} 18 is substituted An aryl group that may be present).

[0111]

Embedded image

(Where R ⁸ represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an optionally substituted aryl group,
It is an aralkyl group or a heteroaryl group which may be substituted, and R ⁹ and R ¹⁰ are the same or different and are a hydrogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a halogen atom, a nitro group or an amino group. ) Or -X-Y {wherein, X is _{- (CH 2) m - (} m is an integer of 1 to 4), -CO -., - COCH 2 -, - NH -, - NH
_{CH 2 -, - CH 2 NH} -, - CH 2 NHCO -, - O
CH ₂ —, — (CH ₂ ) _n O— (n is an integer of 1 to 4) or —CH ₂ S—; Y is a halogen atom,
A cycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group. Represents 、,
Preferably a phenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-ethylphenyl group, 3-ethylphenyl group, 4-ethylphenyl group, 2-tert-butylphenyl group, 3 -Tert-
Butylphenyl group, 4-tert-butylphenyl group,
2-methoxyphenyl group, 3-methoxyphenyl group, 4
-Methoxyphenyl group, 2,4-dimethoxyphenyl group, 2,5-dimethoxyphenyl group, 3,4-dimethoxyphenyl group, 3,5-dimethoxyphenyl group, 3,
4,5-trimethoxyphenyl group, 2-ethoxyphenyl group, 3-ethoxyphenyl group, 4-ethoxyphenyl group, 2-hydroxyphenyl group, 3-hydroxyphenyl group, 4-hydroxyphenyl group, 2,4-dihydroxy Phenyl group, 2,5-dihydroxyphenyl group, 3,
4-dihydroxyphenyl group, 3,5-dihydroxyphenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2,4-difluorophenyl group, 2,5-difluorophenyl group, 3, 4-
Difluorophenyl group, 3,5-difluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4
-Chlorophenyl group, 2-trifluoromethylphenyl group, 3-trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 2-trifluoromethoxyphenyl group, 3-trifluoromethoxyphenyl group, 4-trifluoromethoxyphenyl Group, 2-aminophenyl group, 3-aminophenyl group, 4-aminophenyl group, 2
-Methylaminophenyl group, 3-methylaminophenyl group, 4-methylaminophenyl group, 2-dimethylaminophenyl group, 3-dimethylaminophenyl group, 4-dimethylaminophenyl group, 2-cyanophenyl group, 3-cyano Phenyl, 4-cyanophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-chloro-4-methoxyphenyl, 3-chloro-5-methoxyphenyl, 4-chloro -5-methoxyphenyl group, 3,5-dichloro-4-methoxyphenyl group, 4-chloro-2,5-dimethoxyphenyl group, 2-
Methoxy-3-nitrophenyl group, 2-methoxy-4-
Nitrophenyl group, 2-methoxy-5-nitrophenyl group, 3-methoxy-4-nitrophenyl group, 3-methoxy-5-nitrophenyl group, 4-methoxy-2-nitrophenyl group, 4-methoxy-3- Nitrophenyl group, 2
-Acetyl-3-methoxyphenyl group, 2-acetyl-
4-methoxyphenyl group, 5-acetyl-2-methoxyphenyl group, 3-acetyl-4-methoxyphenyl group,
3-acetyl-5-methoxyphenyl group, 3,4-methylenedioxyphenyl group, 2-chloro-4,5-methylenedioxyphenyl group, 3-chloro-4,5-methylenedioxyphenyl group, 2- Benzyloxyphenyl group,
3-benzyloxyphenyl group, 4-benzyloxyphenyl group, 3,4-dibenzyloxyphenyl group, 3,
5-dibenzyloxyphenyl group, 2-formylaminophenyl group, 3-formylaminophenyl group, 4-formylaminophenyl group, 2-acetylaminophenyl group, 3-acetylaminophenyl group, 4-acetylaminophenyl group, 2-methylsulfonylphenyl group, 3-
Methylsulfonylphenyl group, 4-methylsulfonylphenyl group, 2-methylsulfonylaminophenyl group, 3
-Methylsulfonylaminophenyl group, 4-methylsulfonylaminophenyl group, 2-bis (methylsulfonyl) aminophenyl group, 3-bis (methylsulfonyl)
Aminophenyl group, 4-bis (methylsulfonyl) aminophenyl group, 2-phenylphenyl group, 3-phenylphenyl group, 4-phenylphenyl group, 1-naphthyl group, 2-naphthyl group, 2-pyridyl group, 3- Pyridyl group, 4-pyridyl group, 2-methylpyridyl group, 3-methylpyridyl group, 4-methylpyridyl group, 2-methoxypyridyl group, 3-methoxypyridyl group, 4-methoxypyridyl group, 2-hydroxypyridyl group, 3-hydroxypyridyl group, 4-hydroxypyridyl group, 2-fluoropyridyl group, 3-fluoropyridyl group, 4-fluoropyridyl group, 2-chloropyridyl group, 3-chloropyridyl group, 4-chloropyridyl group, 2, 5-dichloropyridyl group, 2,6-dichloropyridyl group, 3,5-dichloropyridyl group, 4-trifur Romechirupirijiru group, 4-trifluoromethoxy pyridyl group, 2-nitropyridyl, 3-nitropyridyl group, 4-nitropyridyl group, 2
-Cyanopyridyl group, 3-cyanopyridyl group, 4-cyanopyridyl group, 4-aminopyridyl group, 4-dimethylaminopyridyl group, 4-formylaminopyridyl group, 4-
Acetylaminopyridyl group, 4-methanesulfonylaminopyridyl group, 4-bismethanesulfonylaminopyridyl group, thienyl group, 2-methylthienyl group, 3-methylthienyl group, 2,3-dimethylthienyl group, 3,4-dimethyl Thienyl group, 2-chlorothienyl group, 3-chlorothienyl group, 2,3-dichlorothienyl group, 3,4-dichlorothienyl group, isoxazolyl group, 3-methylisoxazolyl group, 4-methylisoxazolyl Group, 5
-Methylisoxazolyl group, 3,4-dimethylisoxazolyl group, 3,5-dimethylisoxazolyl group,
4,5-dimethylisoxazolyl group, 3-chloroisoxazolyl group, 4-chloroisoxazolyl group, 5-
Chloroisoxazolyl group, 3,4-dichloroisoxazolyl group, 3,5-dichloroisoxazolyl group,
4,5-dichloroisoxazolyl group, thiazolyl group,
2-methylthiazolyl group, 4-methylthiazolyl group, 5
-Methylthiazolyl group, 2,4-dimethylthiazolyl group, 2,5-dimethylthiazolyl group, 4,5-dimethylthiazolyl group, 2-chlorothiazolyl group, 4-chlorothiazolyl group, 5-chlorothiazolyl group, 2 4,4-dichlorothiazolyl group, 2,5-dichlorothiazolyl group, 4,
5-dichlorothiazolyl group, ethenyl group, 1-methylethenyl group, propenyl group, 2-phenylethenyl group, 1
-Chloroethenyl group, 2-chloroethenyl group, 1,2-
Dichloroethenyl group, 2,2-dichloroethenyl group,
1,2,2-trichloroethenyl group, 1-bromoethenyl group, 2-bromoethenyl group, phenylhydroxymethyl group, 2-phenyl-1-hydroxyethyl group, 2-
(2-methoxyphenyl) -1-hydroxyethyl group,
2- (3-methoxyphenyl) -1-hydroxyethyl group, 2- (4-methoxyphenyl) -1-hydroxyethyl group, benzoyl group, 2-methylbenzoyl group, 3-
Methylbenzoyl group, 4-methylbenzoyl group, 2-methoxybenzoyl group, 3-methoxybenzoyl group, 4-
Methoxybenzoyl group, 2,3-dimethoxybenzoyl group, 2,4-dimethoxybenzoyl group, 2,5-dimethoxybenzoyl group, 3,5-dimethoxybenzoyl group,
2-fluorobenzoyl group, 3-fluorobenzoyl group, 4-fluorobenzoyl group, 2-chlorobenzoyl group, 3-chlorobenzoyl group, 4-chlorobenzoyl group, 2-phenyl-1-oxoethyl group, 2- (2- (Methoxyphenyl) -1-oxoethyl group, 2- (3-methoxyphenyl) -1-oxoethyl group, 2- (4-methoxyphenyl) -1-oxoethyl group, 2- (2,3
-Dimethoxyphenyl) -1-oxoethyl group, 2-
(2,4-dimethoxyphenyl) -1-oxoethyl group, 2- (2,5-dimethoxyphenyl) -1-oxoethyl group, 2- (3,5-dimethoxyphenyl) -1-
Oxoethyl group, (2-methoxyphenyl) (2-tetrahydropyranyloxy) methyl group, (3-methoxyphenyl) (2-tetrahydropyranyloxy) methyl group, (4-methoxyphenyl) (2-tetrahydropyranyloxy ) Methyl group, 2-phenyl-1- (2-tetrahydropyranyloxy) ethyl group, 2,2-diphenylethyl group, 2,2-bis (2-methylphenyl) ethyl group, 2,2-bis (3 -Methylphenyl) ethyl group,
2,2-bis (4-methylphenyl) ethyl group, 2,2
-Bis (2-methoxyphenyl) ethyl group, 2,2-bis (3-methoxyphenyl) ethyl group, 2,2-bis (4-methoxyphenyl) ethyl group, 3-indolylmethyl group, 4-methoxyindole -3-ylmethyl group,
5-methoxyindol-3-ylmethyl group, 6-methoxyindol-3-ylmethyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group Benzyl group, phenethyl group, methoxy group, ethoxy group, propoxy group, butoxy group, tert-butoxy group, 2-chlorophenoxy group, 3-chlorophenoxy group, 4-chlorophenoxy group, benzyloxy group, fluoromethyl group, Chloromethyl group, bromomethyl group, carboxy group, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group,
tert-butoxycarbonyl group, phenylaminocarbonyl group, 2-methylphenylaminocarbonyl group, 3
-Methylphenylaminocarbonyl group, 4-methylphenylaminocarbonyl group, 2-methoxyphenylaminocarbonyl group, 3-methoxyphenylaminocarbonyl group, 4-methoxyphenylaminocarbonyl group, 2,3
-Dimethoxyphenylaminocarbonyl group, 2,4-dimethoxyphenylaminocarbonyl group, 2,5-dimethoxyphenylaminocarbonyl group, 3,4,5-trimethoxyphenylaminocarbonyl group, 1-naphthylaminocarbonyl group, 2-naphthyl Aminocarbonyl group, 2
-Pyridylaminocarbonyl group, 3-pyridylaminocarbonyl group, 4-pyridylaminocarbonyl group, cyclopropylaminocarbonyl group, cyclobutylaminocarbonyl group, cyclopentylaminocarbonyl group, cyclohexylaminocarbonyl group, methylaminocarbonyl group, ethylaminocarbonyl group, propyl Aminocarbonyl group, butylaminocarbonyl group, tert-butylaminocarbonyl group, phenylamino group, benzylamino group, phenylaminomethyl group, 2-methylphenylaminomethyl group, 3-methylphenylaminomethyl group, 4
-Methylphenylaminomethyl group, 2-methoxyphenylaminomethyl group, 3-methoxyphenylaminomethyl group, 4-methoxyphenylaminomethyl group, 2,3-dimethoxyphenylaminomethyl group, 2,4-dimethoxyphenylaminomethyl group 2,5-dimethoxyphenylaminomethyl group, 2-fluorophenylaminomethyl group, 3-fluorophenylaminomethyl group, 4-fluorophenylaminomethyl group, 2-chlorophenylaminomethyl group, 3-chlorophenylaminomethyl group, 4 -Chlorophenylaminomethyl group, 2-bromophenylaminomethyl group, 3-bromophenylaminomethyl group, 4-
A bromophenylaminomethyl group, a 2-phenoxyethyl group, a 3-phenoxyethyl group, a 4-phenoxyethyl group or a phenylthiomethyl group, more preferably a phenyl group, a 2-methylphenyl group, a 3-methylphenyl group, -Methylphenyl group, 4-tert-butylphenyl group, 4-methoxyphenyl group, 2,4-dimethoxyphenyl group, 2,5-dimethoxyphenyl group, 3,4-
Dimethoxyphenyl group, 3,4,5-trimethoxyphenyl group, 4-ethoxyphenyl group, 4-hydroxyphenyl group, 3,4-dihydroxyphenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluoro Phenyl group, 2,4-difluorophenyl group, 2,5-
Difluorophenyl group, 3,4-difluorophenyl group, 3,5-difluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group,
2-trifluoromethylphenyl group, 3-trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 4-trifluoromethoxyphenyl group, 4-aminophenyl group, 4-dimethylaminophenyl group, 2-cyanophenyl group , 3-cyanophenyl, 4-cyanophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-chloro-4-methoxyphenyl, 3,5-dichloro-4-methoxy Phenyl group, 2-methoxy-5-nitrophenyl group, 4-methoxy-3-nitrophenyl group, 5-acetyl-2-methoxyphenyl group, 3,4-methylenedioxyphenyl group,
2-chloro-4,5-methylenedioxyphenyl group, 4
-Benzyloxyphenyl group, 3,4-dibenzyloxyphenyl group, 4-formylaminophenyl group, 4-acetylaminophenyl group, 4-methylsulfonylphenyl group, 4-methylsulfonylaminophenyl group, 4-bis (methyl Sulfonyl) aminophenyl group, 4-phenylphenyl group, 1-naphthyl group, 2-naphthyl group, 2-
Pyridyl group, 3-pyridyl group, 4-pyridyl group, 2,6
-Dichloropyridin-4-yl group, 3,5-dimethylisoxazolin-3-yl group, 2-methyl-1,3-thiazolin-3-yl group, 2-chloro-4-thienyl group,
Ethenyl group, 1-methylethenyl group, 2-phenylethenyl group, 1-chloroethenyl group, 1,2-dichloroethenyl group, 2,2-dichloroethenyl group, 1-bromoethenyl group, phenylhydroxymethyl group, 2-phenyl-
1-hydroxyethyl group, 2- (2-methoxyphenyl) -1-hydroxyethyl group, benzoyl group, 2-methoxybenzoyl group, 4-methoxybenzoyl group, 4-
Methylbenzoyl group, 2,5-dimethoxybenzoyl group, 4-chlorobenzoyl group, 2-phenyl-1-oxoethyl group, 2- (2-methoxyphenyl) -1-oxoethyl group, 2- (2,5-dimethoxyphenyl) ) -1
-Oxoethyl group, (2-methoxyphenyl) (2-tetrahydropyranyloxy) methyl group, 2-phenyl-
A 1- (2-tetrahydropyranyloxy) ethyl group,
2,2-diphenylethyl group, 3-indolylmethyl group, cyclopropyl group, cyclohexyl group, cyclohexylmethyl group, benzyl group, phenethyl group, ethoxy group, 4-chlorophenoxy group, benzyloxy group, bromomethyl group, carboxy group Ethoxycarbonyl group, phenylaminocarbonyl group, 4-methylphenylaminocarbonyl group, 2-methoxyphenylaminocarbonyl group, 2,5-dimethoxyphenylaminocarbonyl group,
3,4,5-trimethoxyphenylaminocarbonyl group, 1-naphthylaminocarbonyl group, 3-pyridylaminocarbonyl group, cyclohexylaminocarbonyl group, propylaminocarbonyl group, phenylamino group,
Benzylamino group, phenylaminomethyl group, 4-methylphenylaminomethyl group, 2-methoxyphenylaminomethyl group, 2,5-dimethoxyphenylaminomethyl group, 3-fluorophenylaminomethyl group, 2-phenoxyethyl group or phenyl Thiomethyl group, particularly preferably phenyl group, 4-methoxyphenyl group, 2,4
-Dimethoxyphenyl group, 3,4-dimethoxyphenyl group, 3,4,5-trimethoxyphenyl group, 4-ethoxyphenyl group, 4-hydroxyphenyl group, 3,4-dihydroxyphenyl group, 2-fluorophenyl group, 3-
Fluorophenyl group, 4-fluorophenyl group, 2,4
-Difluorophenyl group, 2,5-difluorophenyl group, 3,4-difluorophenyl group, 3,5-difluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 4-aminophenyl group, 4-dimethylaminophenyl group, 2-cyanophenyl group, 3-cyanophenyl group, 4-cyanophenyl group,
2-nitrophenyl group, 3-nitrophenyl group, 4-nitrophenyl group, 4-formylaminophenyl group, 4-
Acetylaminophenyl, 4-methylsulfonylphenyl, 4-methylsulfonylaminophenyl, 4-
Bis (methylsulfonyl) aminophenyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2,6-dichloropyridin-4-yl group, ethenyl group, 1-methylethenyl group, 2-phenylethenyl group , 1-chloroethenyl group, 1-bromoethenyl group, 1,2-dichloroethenyl group, 2,2-dichloroethenyl group, phenylhydroxymethyl group, 2-phenyl-1-hydroxyethyl group, 2- (2-methoxyphenyl) -1-hydroxyethyl group, benzoyl group, 2-methoxybenzoyl group, 4
-Methoxybenzoyl group, 2,5-dimethoxybenzoyl group, 4-chlorobenzoyl group, 2-phenyl-1-oxoethyl group, 2- (2-methoxyphenyl) -1-oxoethyl group, 2- (2,5-dimethoxy Phenyl)-
1-oxoethyl group, 2,2-diphenylethyl group, 3
-Indolylmethyl, cyclopropyl, cyclohexyl, cyclohexylmethyl, benzyl, phenethyl, ethoxy, 4-chlorophenoxy, benzyloxy, bromomethyl, carboxy, ethoxycarbonyl, phenylaminocarbonyl , 4-methylphenylaminocarbonyl, 2-methoxyphenylaminocarbonyl, 2,5-dimethoxyphenylaminocarbonyl, 3,4,5-trimethoxyphenylaminocarbonyl, phenylamino, benzylamino, phenylamino A methyl group, a 2-methoxyphenylaminomethyl group, a 2,5-dimethoxyphenylaminomethyl group, a 3-fluorophenylaminomethyl group or a phenylthiomethyl group.

R ⁴ represents a hydrogen atom or a halogen atom, preferably a hydrogen atom.

Ring A is a ring selected from the following:

[0115]

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Wherein R ¹¹ and R ¹² are the same or different and each represents a hydrogen atom, a halogen atom, or a lower alkyl group (the lower alkyl group is substituted with a halogen atom, a lower alkoxy group, a nitro group, an amino group, or a lower alkyl group); Amino group,
It may be substituted by a cyclic amino group, a hydroxyl group, an acyloxy group, a cyano group, a carbamoyl group, a carbamoyl group substituted by a lower alkyl group, a cyclic aminocarbonyl group, a carboxy group, a lower alkoxycarbonyl group or an aralkyloxycarbonyl group. ), Lower alkenyl group, aralkyl group, aralkyl group substituted with lower alkyl group, lower alkoxy group, nitro group, amino group, amino group substituted with lower alkyl group, cyclic amino group, hydroxyl group,
An acyloxy group, a cyano group, a carbamoyl group, a carbamoyl group substituted with a lower alkyl group, a cyclic aminocarbonyl group, a carboxy group, a lower alkoxycarbonyl group or an aralkyloxycarbonyl group, and R ¹³ and R ¹⁴
Are the same or different and are a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a haloalkyl group, a lower alkoxy group, a nitro group, an amino group,
An amino group substituted with a lower alkyl group, a cyclic amino group,
Hydroxyl group, acyloxy group, cyano group, carbamoyl group,
A carbamoyl group, a cyclic aminocarbonyl group, a carboxy group, a lower alkoxycarbonyl group, an aralkyloxycarbonyl group, a cycloalkyl group, and a lower alkylcarbonyl group substituted with a lower alkyl group. ), But
Preferably

[0117]

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[0118]

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[0119]

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[0120]

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And more preferably

[0122]

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[0123]

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And particularly preferably

[0125]

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[0126]

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Is as follows.

[0128]

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(Where R ¹⁵ represents a lower alkyl group;
¹⁹ represents a hydrogen atom or a lower alkyl group. ), But
Preferably

[0130]

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(R ¹⁵ and R ¹⁹ have the same meanings as described above), and particularly preferably.

[0132]

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(R ¹⁵ has the same meaning as described above.)

Next, a method for producing the compound of the present invention will be described. Production method 1 Here, among the compounds represented by the general formula [I],

[0135]

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(R ¹⁵ has the same meaning as described above), and shows a method for producing the target compound [I-1] in which both R ² and R ⁴ are hydrogen atoms.

[0137]

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[0138]

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Step ¹ A ketone compound (viii) (R ¹ and A each represent the same meaning as described above), which is known or obtained by the method described in JP-A-2-256681, is treated with dichloromethane and
In a solvent such as chloroform, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, n-propanol, isopropanol, ethyl acetate, acetone, acetonitrile, toluene, water or a mixed solvent thereof, thiophosgene, thiocarbonyldiimidazole, di- By reacting with 2-pyridylthiocarbonate, diethylthiocarbamyl chloride or carbon disulfide,
Compound (ix) (R ¹ and A each have the same meaning as described above) is obtained. The thionation reaction used here is
As possible out also be used in addition to isothiocyanate synthesis method it is also commonly used above.

Step 1 ′ This step is the same as the hydrazine compound (vii) used in the second step.
This is a step for preparing (). Carbazic acid ter
A Schiff base formed by reacting t-butyl (tert-butoxycarbonylhydrazine) (v) and an aldehyde compound (vi) (R ³ has the same meaning as described above) is converted to palladium carbon, palladium black, palladium hydroxide. The catalytic reduction is carried out using a catalyst such as carbon or Raney nickel. Then, the tert-butoxycarbonyl group is deprotected using an acid such as hydrochloric acid to obtain a desired hydrazine compound (vii) (R ³ has the same meaning as described above) or a salt thereof. The solvent used in these reactions may be any solvent that does not participate in the reaction,
For example, methanol, ethanol, n-propanol, isopropanol, water, acetic acid and the like or a mixed solvent thereof can be used. The protecting group may be any one other than a tert-butoxycarbonyl group, as long as it is usually used as a protecting group for an amino group, and the deprotection method may be a method usually used for deprotecting the protecting group. Just do it. Also, hydrazine monohydrate (v ') can be used in place of protected hydrazine such as tert-butoxycarbonylhydrazine. in this case,
The operation of deprotection need not be performed.

Second Step The compound (ix) obtained in the first step is converted into dichloromethane, chloroform, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 1,4-
In a solvent such as dioxane, acetone, ethyl acetate, water or the like or a mixed solvent thereof, the hydrazine compound (vii) or its salt obtained in the first step is cooled with ice or heated, preferably with ice cooled to room temperature. To obtain a compound (x) (R ¹ , R ³ , and A each have the same meaning as described above). When a salt of a hydrazine compound is used, it is desirable to add an organic base such as triethylamine or N, N-diisopropylethylamine and an inorganic base such as sodium hydrogen carbonate.

Step 3 The compound (x) obtained in the step 2 is treated with hydrochloric acid in a solvent such as methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 1,4-dioxane, benzene, toluene or a mixed solvent thereof. By heating in the presence of an inorganic acid such as sulfuric acid or hydrobromic acid or an organic acid such as p-toluenesulfonic acid or trifluoroacetic acid, the compound [II] (R ¹ , R ³ , A Or a salt thereof is obtained.

Fourth Step The compound [II] obtained in the third step is treated with hydrazine or its water in a solvent such as tetrahydrofuran, N, N-dimethylformamide, methanol, ethanol, n-propanol, isopropanol or a mixture thereof. The compound (xi) (R ¹ , R ³ , and A have the same meanings as described above) can be obtained by reacting the compound with the hydrate at room temperature or under heating.

Fifth Step The compound (xi) obtained in the fourth step is dissolved in a solvent such as benzene, toluene, N, N-dimethylformamide or a mixed solvent thereof with R ¹⁵ -C (OEt) ₃ (R ¹⁵ An orthoester represented by the same meaning as above);
The target compound [I-1] (R ¹ , R ³ , R ¹⁵ , and A each have the same meaning as described above) can be obtained by reacting the mixture under heating, preferably under reflux. In this reaction, it may be preferable to add an acid such as acetic acid, p-toluenesulfonic acid or silica gel.

Sixth Step This step and the next step are steps for obtaining the desired compound [I-1] from the compound [II] via another route.

The compound [II] obtained in the third step is converted to N, N
-Dissolve or suspend in a solvent such as dimethylformamide or tetrahydrofuran and add sodium hydride. Then, by reacting with a halogenated alkyl represented by R ¹⁶ -Hal (R ¹⁶ represents a lower alkyl group and Hal represents a halogen atom), the compound [III] (R ¹ ,
R ³ , R ¹⁶ and A each have the same meaning as described above. )
Is obtained. Alternatively, the compound [II] is reacted with R ^16-in a solvent such as acetone, methyl ethyl ketone or toluene, or in a solvent such as methanol, ethanol, or a mixed solvent thereof with water in the presence of a base such as sodium carbonate or potassium carbonate, or an aqueous solution of sodium hydroxide. Hal or

[0147]

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(R ¹⁶ and Hal have the same meanings as described above).

Seventh Step The compound [III] obtained in the sixth step is converted to ethanol, n-
Dissolved or suspended in a solvent such as propanol, isopropanol, n-butanol, toluene or a mixed solvent thereof,

[0150]

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The compound [IV] (R ¹ , R ³ , R ¹⁵ and A are each as defined above) by adding (R ¹⁵ has the same meaning as described above) and heating, preferably heating to reflux. .) Is obtained. In this case, it may be preferable to add an acid such as acetic acid, p-toluenesulfonic acid or trifluoroacetic acid.

Step 7 ′ The compound [III] obtained in the step 6 was treated with ethanol, n
-Propanol, isopropanol, n-butanol,
Dissolved or suspended in a solvent such as toluene,

[0153]

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(R ¹⁵ has the same meaning as described above), and the mixture is heated, preferably at a temperature of 90 ° C. to 110 ° C. or higher, to give the desired compound [I-1]
(R ¹ , R ³ , R ¹⁵ and A each have the same meaning as described above). Also in this case, it is preferable to add an acid such as acetic acid, p-toluenesulfonic acid or trifluoroacetic acid. When one or more equivalents of these acids are added to compound [III], a salt of compound [I-1] can be directly obtained.

Step 7 "This step is another method for obtaining the compound (xi). The compound [III] can be prepared in a solvent such as methanol, ethanol, n-propanol, isopropanol, n-butanol or a mixture thereof. , The seventh step.

[0156]

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Compound (xi) is obtained by reacting with hydrazine instead of hydrazine.

Eighth Step The target compound [I-1] can be obtained by heating the compound [IV] obtained in the seventh step in a solvent such as benzene or toluene, preferably by heating to reflux. In this reaction, it may be preferable to add an acid such as acetic acid, p-toluenesulfonic acid or hydrochloric acid.

Ninth Step In this step and the next step, R ² and R ⁴ are hydrogen atoms,
³ is a 4-methoxyphenyl group or a 3,4-dimethoxyphenyl group

[0160]

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This is a step of replacing a portion.

In the compound [I-1], R ² and R ⁴ are hydrogen atoms, and R ³ is a 4-methoxyphenyl group or 3,4
A compound [I-1 ′] which is a dimethoxyphenyl group (in the reaction scheme, R ′ represents a hydrogen atom or a methoxy group;
¹ , R ¹⁵ and A have the same meanings as described above. ) In a solvent such as chloroform, 1,4-dioxane, acetic acid, trifluoroacetic acid or a mixed solvent thereof in the presence of a strong acid such as sulfuric acid, hydrochloric acid or hydrobromic acid to give compound (xii) ( R ¹ , R ¹⁵ and A have the same meanings as described above). In this reaction, it may be preferable to add a benzyl cation scavenger such as phenol, anisole or thioanisole.

Step 10-1 The compound (xii) obtained in the ninth step is treated with a solvent such as N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, acetone, methyl ethyl ketone, dichloromethane, chloroform, water or a mixture thereof. , Sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, triethylamine, N, N-diisopropylethylamine, pyridine or N, N-dimethylaminopyridine in the presence of a base and under ice-cooling To under heating, preferably under ice cooling to room temperature

[0164]

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(Hal represents a halogen atom, R ² , R
³ and R ⁴ each have the same meaning as described above. ) To give the desired compound [I-1 ″] (R ¹ , R
² , R ³ , R ⁴ , R ¹⁵ and A each have the same meaning as described above. ) Is obtained. In this reaction, react

[0166]

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The base to be used may be appropriately selected depending on the reactivity and stability, and in some cases, these bases may be used in an appropriate combination.

Tenth Step 2 R ² and R ⁴ shown in the tenth step 1 are hydrogen atoms.

[0169]

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When performing the reaction using , one of the tenth steps
When the reaction is carried out in the presence of air (oxygen) using the same solvent and base as described above, the target compound [I-1 ″] in which R ² is a hydroxyl group and R ⁴ is a hydrogen atom may be produced.

Step 10-3. The method of Edward et al. [Tetrahedron Letters, 31
Volume, 3417 (1990) [Tetrahedron Lett.,Three
1, 3417 (1990)] to give compound (xii)
Lofuran, diethyl ether, 1,4-dioxane or
In a solvent such as N, N-dimethylformamide, R^ThreeR^Four
CHOH (R^Three, R^FourRepresents the same meaning as above.
You. ) Alcohol compound represented by the formula
React with sphing. Then, the dialki
Add luazodicarboxylate, under ice cooling to 40 ° C,
Preferably, the reaction is carried out at room temperature or 25 ° C.
^TwoRepresents a hydrogen atom, the target compound [I-1 ″] is obtained.
You.

Fourth Step 4 Compound (xii) was treated with a solvent such as methanol, ethanol, n-propanol, or isopropanol using an aqueous formaldehyde solution and a solvent (R ³ 'CH ₂ OH) (R
³ ′ represents a lower alkyl group. ) As a reagent, or by reacting with an aqueous formaldehyde solution and Y′NH ₂ (Y ′ represents an optionally substituted aryl group or an optionally substituted heteroaryl group) at room temperature or under reflux with heating. ^The target compound [I-1 ″] is obtained, in which both ² and R ⁴ represent a hydrogen atom, and R ³ represents a lower alkoxy group or —NHY ′ (Y ′ has the same meaning as described above).

Step 10-5 Compound (xii) was converted to dichloromethane, chloroform, N, N
Y'NCO in a solvent such as dimethylformamide or tetrahydrofuran or anhydrous acetonitrile, if necessary, in the presence of an inorganic base such as sodium hydroxide or potassium hydroxide, or an organic base such as triethylamine or N, N-diisopropylethylamine. (Y ′ has the same meaning as described above.), R ² and R ⁴ together form a carbonyl group together with the carbon atom to which they are bonded, and R ³ Is -NHY '(Y' has the same meaning as described above) to obtain the target compound [I-1 "].

Step 10 Step 6: Compound (xii) was dissolved in a solvent such as N, N-dimethylformamide, dimethyl sulfoxide or tetrahydrofuran.
In the presence of a base such as sodium hydride or potassium hydride

[0175]

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By reacting with an oxirane compound represented by the formula (R ⁸ has the same meaning as described above), R ²
And R ⁴ are both hydrogen, R ³ is

[0177]

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The desired compound [I-1 ″] represented by (R ⁸ has the same meaning as described above) is obtained.

Tenth Step 7 Of those obtained in the tenth step 1, R ³ is

[0180]

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[0181] (R ¹⁷ represents a protecting group for a hydroxyl group, Y represents. The same as defined above) by removing the protecting group of the compound represented by, R ³ is

[0182]

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The desired compound [I-1 ″] represented by the formula (Y represents the same meaning as described above) is obtained.A protective group for a hydroxyl group may be any commonly used one. When using a tetrahydropyranyl group,
The solvent may be any solvent that does not participate in the reaction, such as methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, etc., and the reagent is an organic acid such as p-toluenesulfonic acid or trifluoroacetic acid. Alternatively, an inorganic acid such as hydrochloric acid, sulfuric acid or hydrobromic acid can be used.

[0184] obtained in the 6 or 7 of 8 tenth step of the 10 steps, the R ³

[0185]

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In a solvent such as acetic acid, pyridine, dichloromethane, water or a mixture thereof, chromium trioxide, pyridinium chlorochromate, pyridinium chromate, Jones reagent (chromium trioxide, sulfuric acid mixture) or dimethyl By subjecting it to an oxidation reaction with an oxidizing agent such as an oxidizing agent prepared from sulfoxide and oxalyl chloride, R ³

[0187]

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The desired compound [I-1 ″] represented by the formula (Y represents the same meaning as described above) is obtained.

Tenth Step 9 Among the compounds obtained in the tenth step 1, R ³ is —CO ₂ E
The compound represented by the t group is methanol, ethanol, n-
By reacting with a base such as sodium hydroxide or potassium hydroxide in a solvent such as propanol, isopropanol, tetrahydrofuran, 1,4-dioxane, water or a mixture thereof, R ³ is represented by a —CO ₂ H group. The desired compound [I-1 ″] is obtained.

Tenth Step 10 The compound in which R ³ is —CO ₂ H group obtained in the tenth step 9 is converted to a solvent such as N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, acetone, dichloromethane or the like. In these mixed solvents, alkyl halides such as ethyl chlorocarbonate or isobutyl chlorocarbonate and R ⁸ NH ₂ (R ₂ ) in the presence of a base such as triethylamine or N, N-diisopropylethylamine.
⁸ represents the same meaning as described above. ) To obtain the target compound [I-1 ″] in which R ³ is —CONHR ⁸ (R ⁸ has the same meaning as described above), or according to a usual peptide bond formation method. To obtain the target compound [I-1 ″] in which R ³ is —CONHR ⁸ (“Basic and Experimental Peptide Synthesis”, Nobuo Izumiya, Maruzen Co., Ltd., 1985).

Tenth Step 11 Of the compounds obtained in the tenth step 1, R ³ is --CH _2-
A compound represented by a Hal group (Hal represents a halogen atom) is treated with sodium hydride, hydrogen in a solvent such as ethanol, dichloromethane, N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, water or a mixed solvent thereof. Potassium hydroxide, sodium hydroxide,
In the presence of a base such as potassium hydroxide, potassium carbonate, triethylamine or N, N-diisopropylethylamine,
By reacting with Y′NH ₂ (Y ′ has the same meaning as described above) or Y′SH (Y ′ has the same meaning as described above), R ³ is a —CH ₂ NHY ′ group ( Y ′ has the same meaning as described above) or —CH ₂ SY ′ group (Y ′
Represents the same meaning as described above. ) Is obtained.

Tenth Step 12 A compound in which R ³ is an optionally substituted aryl group or an optionally substituted heteroaryl group among those obtained in the tenth step 1 and the substituent is a nitro group In a solvent such as methanol, ethanol, n-propanol, isopropanol, 1,4-dioxane, acetic acid, water or a mixture thereof in the presence of a catalyst such as palladium carbon, palladium hydroxide carbon, palladium black or Raney nickel, Or catalytic reduction using formic acid, ammonium formate, cyclohexene or cyclohexadiene in the presence of the catalyst. Or in the solvent,
When subjected to a reduction reaction using a reducing agent such as sodium borohydride or lithium borohydride, R ³ is an optionally substituted aryl group or an optionally substituted heteroaryl group, wherein the substituent is an amino group. Thus, the target compound [I-1 ″] or the target compound [I-1 ″] wherein the substituent is a formylamino group is obtained. In some cases, a mixture of these may be obtained. In such a case, a conventional separation method may be used.

Step 10-13 The compound obtained in Step 10-12, wherein R ³ is an optionally substituted aryl group or an optionally substituted heteroaryl group, wherein the substituent is an amino group, Dichloromethane, chloroform, pyridine, ethanol, acetone,
By reacting in a solvent such as tetrahydrofuran with acetic anhydride, acetic anhydride and formic acid, an acylating agent such as acetyl chloride, or an alkylsulfonyl halide such as methanesulfonyl chloride, an aryl group or a substituted group in which R ³ may be substituted. And the substituent is an acylamino group, an alkylsulfonylamino group, a bis (alkylsulfonyl) amino group or a halogenoalkylsulfonylamino group, whereby the target compound [I-1 ″] is obtained. In some cases, triethylamine, N,
It is preferable to add a base such as N-diisopropylethylamine.

Step 10-14 The compound obtained in Step 10-12, wherein R ³ is an optionally substituted aryl group or an optionally substituted heteroaryl group, wherein the substituent is an amino group, Methanol,
In a solvent such as ethanol, n-propanol, isopropanol, water or a mixed solvent thereof, subjected to a reduction reaction in a hydrogen atmosphere using palladium carbon, palladium hydroxide carbon or palladium black as a catalyst in the presence of an aqueous formaldehyde solution. Gives the target compound [I-1 ″], wherein R ³ is an optionally substituted aryl group or an optionally substituted heteroaryl group, and the substituent is a methylamino group or a dimethylamino group. In some cases, a mixture of these may be obtained. In such a case, a conventional separation method may be used.

Step 15 of Step 10 Among the compounds obtained in Step 10 1, R ³ is an optionally substituted aryl group or an optionally substituted heteroaryl group, and the substituent is a benzyloxy group. The compound is reduced in a solvent such as methanol, ethanol, n-propanol, isopropanol, 1,4-dioxane, acetic acid or a mixture thereof in a hydrogen atmosphere using palladium carbon, palladium hydroxide carbon or palladium black as a catalyst. R ³ may be substituted by subjecting it to a reaction or subjecting it to catalytic reduction using formic acid, ammonium formate, cyclohexene or cyclohexadiene in the presence of a catalyst such as palladium carbon, palladium hydroxide carbon, palladium black or Raney nickel. An aryl group or an optionally substituted heteroaryl group, If the target compound substituent is a hydroxyl group [I-1 "] are obtained. The substituent of the di-benzyloxy obtain the catechol compound corresponding with the above reaction.

Step 10-16 The compound obtained in Step 10-15, wherein R ³ is an optionally substituted aryl group or an optionally substituted heteroaryl group, wherein the substituent is a hydroxyl group, is selected from tetrahydrofuran, In a solvent such as diethyl ether or 1,4-dioxane, by reacting with a diazoalkyl such as diazomethane or diazoethane, R ³ is an optionally substituted aryl group or an optionally substituted heteroaryl group, The compound of interest wherein the substituent is a lower alkoxy group [I
-1 "] is obtained.

Production Method 2 Here, a method for producing the target compound [I-2] by another method of the production method shown in Production Method 1 is shown.

[0198]

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Eleventh Step: Compound (viii) was treated with diethylene glycol, ethylene glycol monomethyl ether, dimethyl sulfoxide,
By reacting with hydrazine in a solvent such as N, N-dimethylformamide under heating, preferably at 150 ° C. or higher, compound (xiii) (R ¹ and A each have the same meaning as described above) is obtained. Can be

Twelfth Step The compound (xiii) obtained in the eleventh step is treated with sodium hydroxide, potassium hydroxide, lithium hydroxide in a solvent such as diethylene glycol, ethylene glycol monomethyl ether, dimethyl sulfoxide and N, N-dimethylformamide. By heating, preferably at 80 ° C. to 150 ° C. in the presence of a base such as the compound (xiv) (R
¹ and A each have the same meaning as described above. ) Is obtained.

Thirteenth Step The compound (xiv) obtained in the twelfth step is reacted with a tri-lower alkyl orthoformate such as triethyl orthoformate under heating, preferably at 100 to 150 ° C. Then, in a solvent such as methanol, ethanol, n-propanol, or isopropanol, R ¹⁵ CONHNH
Compound (xv) (R ¹ , R ¹⁵ , and A have the same meanings as described above) by reacting with an acylhydrazide compound represented by ₂ (R ¹⁵ has the same meaning as described above), preferably at room temperature. Is obtained.)

Fourteenth Step The compound (xv) obtained in the thirteenth step is heated in a solvent such as diethylene glycol dimethyl ether, ethylene glycol monomethyl ether, dimethyl sulfoxide, N, N-dimethylformamide, pyridine, water or a mixed solvent thereof. The compound (xvi) (R ¹ , R ¹⁵ and A have the same meanings as described above) can be obtained by reacting the mixture under heating, preferably under reflux.

Fifteenth Step The compound (xvi) obtained in the fourteenth step is treated with an oxidizing agent such as chromium trioxide, pyridinium chlorochromate or Jones reagent in a solvent such as acetic acid, pyridine, dichloromethane, water or a mixture thereof. The compound (xvii) (R ¹ , R ¹⁵ , and A each have the same meaning as described above) can be obtained by subjecting the compound to the oxidation reaction.

Sixteenth Step Compound (xvii) was heated in a solvent such as carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane or the like under heating, preferably under reflux, under heating with N-bromosuccinimide, N-chlorosuccinic acid. By halogenating using a halogenating agent such as imide, N-iodosuccinimide, carbon tetrabromide or the like, compound (xviii) (R ¹ , R ¹⁵ , A represents the same meaning as above, and Hal represents halogen Represents an atom).

Step 17 The compound (xviii) is heated under heating in a solvent such as methanol, ethanol, n-propanol or isopropanol or a mixture thereof in the presence of a weak base such as sodium acetate, potassium acetate or lithium acetate. Is reacted with hydrazine sulfate under heating and reflux to give the compound (xi
i) (R ¹ , R ¹⁵ and A each have the same meaning as described above). This compound was obtained by using the method shown in the tenth step to obtain the target compound [I-2] (R ¹ ,
R ² , R ³ , R ⁴ , R ¹⁵ and A each have the same meaning as described above. ). Production Method 3 Here, a novel production method of the target compound [I-3] by a production method different from the production methods shown in Production Method 1 and Production Method 2 is shown.

[0206]

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[0207]

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Step 18 Compound (viii) was heated in a solvent such as methanol, ethanol, n-propanol, isopropanol or a mixture thereof in the presence of p-toluenesulfonic acid under heating.
The compound (xix) (R ¹ and A each represent the same meaning as described above) is preferably obtained by reacting with methyl carbazate under reflux with heating.

Step 19 The compound (xix) obtained in the step 18 is dissolved in a solvent such as dimethyl sulfoxide or N, N-dimethylformamide.
By carrying out the reaction under heating, preferably under heating to reflux, compound (xx) (R ¹ and A each have the same meaning as described above) can be obtained.

Step 18 'This is a step in which the steps 18 and 19 are performed in one step. Compound (viii) is dimethyl sulfoxide,
In a solvent such as N, N-dimethylformamide under heating,
The compound (xx) is obtained preferably by reacting with methyl carbazate under reflux with heating.

Step 20 This step is a step of selectively protecting the 1-position nitrogen atom of the triazepine ring of the compound (xx), and any protecting group may be used as long as it can be selectively protected. A method for protecting using a methoxymethyl group will be described. Nineteenth
The compound (xx) obtained in the step or the step 18 ′ is converted to N, N
By reacting with chloromethyl methyl ether in a solvent such as dimethylformamide or tetrahydrofuran in the presence of a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate or potassium carbonate to obtain a compound (xxi) ( R ¹ and A each have the same meaning as described above).

Twenty First Step The compound (xxi) obtained in the twentieth step is converted into a compound of the tenth step
According to the method shown in

[0213]

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By reacting (R ² , R ³ , R ⁴ , and Hal have the same meanings as described above), compound (xxii) (R ¹ , R ² , R ³ , R ⁴ , A is converted to Each has the same meaning as described above.)

Step 22 This step is a step of removing the protecting group at the 1-position nitrogen atom of the triazepine ring of compound (xxii), and may be carried out by a method usually used to remove the protecting group. The method for deprotection of a methoxymethyl group will be described. Compound (xxii) obtained in the 21st step was converted to methanol, ethanol, n-
The reaction is carried out in a solvent such as propanol, isopropanol, tetrahydrofuran, 1,4-dioxane, water, or a mixture thereof in the presence of an acid such as hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid. Thus, compound (xxiii) (R ¹ , R ² ,
R ³ , R ⁴ and A each have the same meaning as described above. )
Is obtained.

Step 23 The compound (xxiii) obtained in the step 22 is dissolved in a solvent such as diethylene glycol, diethylene glycol dimethyl ether, ethylene glycol monomethyl ether, dimethyl sulfoxide, N, N-dimethylformamide and the like.
The compound [II] (R ¹ , R ² , R ³ , R ² , R ³ , R ² , R ³ , R ² ,
R ³ , R ⁴ and A each have the same meaning as described above. )
Is obtained. This compound [II] was obtained by using the method shown in the fourth step and the fifth step, or the sixth step, the seventh step and the eighth step, and further, if necessary, the ninth step and the tenth step. Compound [I-3] (R ¹ , R ² ,
R ³ , R ⁴ , R ¹⁵ and A each have the same meaning as described above. ).

Production method 4 Here, among the compounds represented by the general formula [I],

[0218]

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The production method of the target compound [I-4] represented by the following formula is shown below.

[0220]

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[0221] The compound obtained in the 24th step sixth step [III] or methanol salts thereof, ethanol, n- propanol, in a solvent such as isopropanol, and hydrin La gin or a hydrate under room temperature to heating under reflux By reacting, the compound (xxi
v) (R ¹ , R ² , R ³ , R ⁴ , and A each have the same meaning as described above) are obtained.

Twenty-Fifth Step The compound (xxiv) or its salt obtained in the twenty-fourth step is dissolved in a solvent such as water under ice-cooling to room temperature, preferably 0 ° C. to 10 ° C.
C. by reacting with sodium nitrite in the presence of an acid such as hydrochloric acid or acetic acid to obtain the desired compound [I-4] (R ¹ , R 2
² , R ³ , R ⁴ and A each have the same meaning as described above. ) Is obtained.

Production method 5 Here, among the compounds represented by the general formula [I],

[0224]

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[0225] (R ¹⁹ represents. The same as defined above) showing a manufacturing method of the target compound represented by [I-5].

[0226]

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Step 26 The compound [III] or its salt obtained in the step 6 is treated with aminoacetaldehyde dimethyl acetal in a solvent such as diethylene glycol, ethylene glycol monomethyl ether or 2-ethoxyethanol under heating, preferably under reflux with heating. By reacting with an aminoketone dialkyl acetal such as the above, the compound (xxv) (R ²¹ represents a lower alkyl group, and R ¹ , R ² , R ³ , R ⁴ , R ¹⁹ and A have the same meanings as described above. ) Is obtained. In this reaction, it may be preferable to add an acid such as acetic acid, p-toluenesulfonic acid or trifluoroacetic acid.

Step 27 The compound (xxv) or a salt thereof obtained in the step 26 is
By reacting with a strong acid such as hydrochloric acid, sulfuric acid, hydrobromic acid or the like in a solvent such as 4-dioxane, acetic acid, water or a mixed solvent thereof under heating, preferably under reflux, the desired compound [I-5] (R ¹ , R ² , R ³ , R ⁴ , R ¹⁹ , A
Represents the same meaning as described above. ) Is obtained.

The compound of the present invention represented by the general formula [I] thus obtained has a pharmacological action such as an action of inhibiting bone resorption and an action of promoting bone formation, and is useful as a drug for treating osteoporosis or rheumatoid arthritis. When the compound of the present invention is used as a therapeutic agent for osteoporosis or a therapeutic agent for rheumatoid arthritis, it is usually administered systemically or locally, orally or parenterally.

The dose varies depending on the age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but it is usually within the range of 0.01 mg to 100 mg per adult, once to several times a day, orally or parenterally. Is administered.

When the compound of the present invention is made into a solid composition for oral administration, it can be formulated into dosage forms such as tablets, pills, powders and granules. In such a solid composition, the one or more active substances comprise at least one inert diluent, dispersant or adsorbent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose. , Starch, polyvinylpyrrolidone, magnesium metasilicate aluminate or anhydrous silicate powder. Further, the composition may be mixed with additives other than the diluent according to a conventional method.

When preparing tablets or pills, they may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose or hydroxymethylcellulose phthalate, if necessary, or in two or more layers. It may be coated. In addition, the capsule may be made of a substance such as gelatin or ethyl cellulose.

When a liquid composition for oral administration is prepared, it can be formulated into pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. The diluent used includes, for example, purified water, ethanol, vegetable oil and emulsifier. In addition, the composition may contain adjuvants such as wetting agents, suspending agents, sweetening agents, flavoring agents, flavoring agents, preservatives and the like in addition to the diluent.

When preparing parenteral injections,
Sterile aqueous or non-aqueous solvents, solubilizers, suspending agents or emulsifiers are used. Examples of aqueous solvents, solubilizing agents, and suspending agents include distilled water for injection, physiological saline, cyclodextrin and its derivatives, organic amines such as triethanolamine, diethanolamine, monoethanolamine, and triethylamine, or inorganic alkali solutions. Etc. As the non-aqueous solvent, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and the like may be used. As the solubilizing agent, for example, a surfactant such as polyoxyethylene hydrogenated castor oil and sucrose fatty acid ester (mixed micelle formation), or lecithin or hydrogenated lecithin (liposome formation) is also used. Also, an emulsion preparation comprising a non-aqueous solvent such as vegetable oil and lecithin, polyoxyethylene hydrogenated castor oil or polyoxyethylene polyoxypropylene glycol can be prepared.

Other compositions for parenteral administration include topical solutions, ointments and other suppositories, suppositories or pessaries containing one or more active substances and formulated according to methods known per se. And so on.

The compound represented by the general formula [II], [III] or [IV] is useful as an intermediate for producing the triazepine compound represented by the general formula [I]. According to the production method described above using these intermediate compounds,
The target compound [I] can be produced. In particular, among the intermediate compounds represented by the general formula (II), (III) or (IV), the compound represented by the general formula (II ′), (III ′) or (IV ′) is a novel compound, It is useful as an intermediate for producing the triazepine compound represented by the general formula [I].

[0237]

EXAMPLES Next, the compounds represented by the general formula [I] according to the present invention and the method for producing the same will be specifically described with reference to Examples. However, it goes without saying that the present invention is not limited by these examples.

Reference Example 1 (Step 1 ') 3,4-Dimethoxybenzylhydrazine hydrochloride

[0239]

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Dissolve tert-butyl carbazate (59.65 g) and 3,4-dimethoxybenzaldehyde (75 g) in ethanol (1.3 l), add acetic acid (77 ml) and 10% palladium on carbon (1.5 g), and add hydrogen Catalytic reduction was carried out for 2 days with vigorous stirring at 1 atm under an atmosphere. After the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and anisole (54 ml) and 1,4-dioxane (100 ml) were added to the obtained oil. This was cooled in an ice bath, a 4N hydrogen chloride-dioxane solution (360 ml) was added, and the mixture was stirred under ice cooling for 1 hour and at room temperature for 4 hours. After completion of the reaction, diethyl ether (800 ml) was slowly added, and the viscous solid deposited was collected by filtration. This solid was dissolved in methanol (1.5 L) heated to 50 ° C., and concentrated to about a half amount to precipitate crystals. This was collected by filtration, washed with cold methanol and then with diethyl ether, and dried to give the title compound (57.8 g) as colorless needles. 178-180 ° C

Reference Example 2 (Step 1 ') 3-Pyridylmethylhydrazine dihydrochloride

[0242]

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Tert-butyl carbazate (13.22 g),
3-pyridinecarboxaldehyde (9.44 ml) and acetic acid (1
1.5 ml) in methanol (230 ml) under ice-cooling.
Stirred for hours. After replacing the inside of the reactor with argon gas, 10% palladium carbon (1.0 g) suspended in an appropriate amount of methanol was similarly added under an argon gas atmosphere. After replacing the inside of the reactor with hydrogen, catalytic reduction was performed for 2 days while stirring vigorously. The filtrate obtained by filtering off the catalyst (1.7 liter) (containing about 0.93 mol) and 101 ml of anisole (0.93 mol)
l) was mixed and cooled on ice. A 4N-hydrochloric acid / dioxane solution (0.93 liter) was added to this mixture while stirring with ice cooling, and then the mixture was stirred at 50 ° C. for 1 hour and at 60 ° C. for 3 hours. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound.
(8.68 g) was obtained as pale yellow needle-like crystals. Melting point 189-191 ° C ¹ H NMR (300 MHz, δ ppm, DMSO-d ₆ ) 4.27 (2 H, s), 8.03 (1 H, dd, J = 7.8 and 5.7 Hz), 8.55 (1 H,
d, J = 7.8Hz), 8.86 (1H, d, J = 5.7Hz), 8.91 (1H, s)

Reference Examples 3, 4 (Step 1 ') In the same manner as in Reference Example 1, the compound of Reference Example 3 was prepared from tert-butyl carbazate and 4-methoxybenzaldehyde in the same manner as in Reference Example 2. tert-
The compound of Reference Example 4 was obtained from butyl and 4-pyridinecarboxaldehyde. These are shown in Table 1.

[0245]

[Table 1]

Reference Example 5 (first step) 2- (4-chlorobenzoyl) phenylisothiocyanate

[0247]

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According to the method described in US Pat. No. 4,144,233, the title compound (74.1 g) was obtained from thiophosgene (22.6 ml) and 2-aminophenyl 4-chlorophenyl ketone (62.6 g) (manufactured by Tokyo Chemical Industry Co., Ltd.). ) Was obtained as yellow crystals. Melting point 80-82 ° C Mass spectrometry (low resolution) 274.1

Reference Examples 6 to 11 (First Step) In the same manner as in Reference Example 5, the compound of Reference Example 6 was converted from 2-aminophenyl phenyl ketone to the compound of Reference Example 7 from 2-amino-5-chlorophenyl phenyl ketone. To 2-amino-4-methylphenyl phenyl ketone, the compound of Reference Example 9 from 2-amino-5-nitrophenyl phenyl ketone,
The compound of Reference Example 10 was obtained from -aminophenyl 4-methylphenyl ketone, and the compound of Reference Example 11 was obtained from 2-amino-5-chlorophenyl 2-chlorophenyl ketone. These are shown in Table 2.

[0250]

[Table 2]

Reference Example 12 (First step) 3- (4-chlorobenzoyl) -4,5-dimethylthiophen-2-isothiocyanate

[0252]

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2-Amino-3- (4-chlorobenzoyl) obtained by the method described in JP-A-2-256681
-4,5-dimethylthiophene (1 g) and thiophosgene (316
μl) to give the title compound (1.16 g) as a crude oil in the same manner as in Reference Example 5.

Reference Examples 13 to 18 In the same manner as in Reference Example 12, 2-amino-3- (4-chlorobenzoyl) -5-ethylthiophene was used.
From 2-amino-3-benzoyl-5-methylthiophene to 2-amino-3
-Benzoyl-4,5-dimethylthiophene, the compound of Reference Example 15 from 2-amino-3-benzoyl-5-ethylthiophene, and the compound of Reference Example 16 from 2-amino-3- (4-methoxybenzoyl)- The compound of Reference Example 17 was converted from 4,5-dimethylthiophene to 2-amino-3
The compound of Reference Example 18 was obtained from-(2-chlorobenzoyl) -4,5-dimethylthiophene. These are shown in Tables 3 and 4.
It was shown to.

[0255]

[Table 3]

[0256]

[Table 4]

Reference Example 19 (Second step) N- [2- (4-chlorobenzoyl) phenyl] -1-
(3,4-dimethoxybenzyl) hydrazinecarbothioamide

[0258]

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The 3,4-dimethoxybenzylhydrazine hydrochloride (22.99 g) obtained in Reference Example 1 was treated with methanol (460 m
l), and after cooling with ice, triethylamine (14.8 ml) was added dropwise over 5 minutes. To this reaction mixture, a solution of 2- (4-chlorobenzoyl) phenylisothiocyanate (24.2 g) obtained in Reference Example 5 in tetrahydrofuran (240 ml) was added under ice cooling, and the mixture was cooled under ice cooling for 15 minutes and at room temperature for 40 minutes. Stirred for minutes. After completion of the reaction, the residue obtained by evaporating the solvent under reduced pressure was dissolved in dichloromethane (500 ml) and washed twice with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was crystallized from diethyl ether to give the title compound (34.7 g) as pale yellow needles. 162-166 ° C

Reference Examples 20 to 25 (Second Step) In the same manner as in Reference Example 19, the compound of Reference Example 20 was replaced with the compound of Reference Example 20 from the compound of Reference Example 3 and the compound of Reference Example 6. The compound of Reference Example 21 was compared with the compound of Reference Example 21 from the compound of Reference Example 3, the compound of Reference Example 22, and the compound of Reference Example 23 from the compound of Reference Example 3 and the compound of Reference Example 9. And Reference Example 1
The compound of Reference Example 24 was obtained from the compound of Reference Example 24, and the compound of Reference Example 25 was obtained from the compound of Reference Example 3 and the compound of Reference Example 11. These are shown in Tables 5 and 6.

[0261]

[Table 5]

[0262]

[Table 6]

Reference Example 26 N- [2- (4-chlorobenzoyl) phenyl] -1-
(Pyridin-3-ylmethyl) hydrazinecarbothioamide

[0264]

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The 3-pyridylmethylhydrazine dihydrochloride (11.8 g) obtained in Reference Example 2 was dissolved in water (25 ml), and sodium hydrogen carbonate (10.08 g) was added, followed by cooling with ice. To this solution, a solution of 2- (4-chlorobenzoyl) phenylisothiocyanate (16.4 g) obtained in Reference Example 5 in tetrahydrofuran (30 ml) was added after cooling with ice, and the mixture was stirred for 30 minutes under ice cooling. The reaction solution was returned to room temperature, ethanol (30 ml) was added, and the precipitated crystals were collected by filtration.
After washing with a mixed solvent of No. 20 and drying under reduced pressure, the title compound (19.9 g) was obtained as colorless crystals. 165-166 ° C

Reference Example 27 N- [3- (4-Chlorobenzoyl) -4,5-dimethylthiophen-2-yl] -1- (4-methoxybenzyl) hydrazinecarbothioamide

[0267]

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The 4-methoxybenzylhydrazine hydrochloride (745 mg) obtained in Reference Example 3 was dissolved in methanol (10 ml), cooled on ice, and then triethylamine (550 μl) was added dropwise. The 3- (4) obtained in Reference Example 12 was added to the reaction mixture.
-Chlorobenzoyl) -4,5-dimethylthiophene-
Tetrahydrofuran of 2-isothiocyanate (1.16g)
(10 ml) The solution was added with ice cooling, and the mixture was stirred under ice cooling for 30 minutes and at room temperature for 30 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue obtained was subjected to silica gel column chromatography, and the fraction obtained by elution with hexane: ethyl acetate 3: 1 was crystallized with diethyl ether to give the residue. The compound (830 mg) was obtained as yellow crystals. 157-160 ° C

Reference Examples 28 to 33 (Second Step) In the same manner as in Reference Example 27, the compound of Reference Example 28 was replaced with the compound of Reference Example 28 from the compound of Reference Example 3 and the compound of Reference Example 13. The compound of Reference Example 29 from the compound of Reference Example 29, the compound of Reference Example 30 from the compound of Reference Example 3 and the compound of Reference Example 15, the compound of Reference Example 31 from the compound of Reference Example 3, and the compound of Reference Example 3 from the compound of Reference Example 3. The compound of Reference Example 32 was obtained from the compound of Reference Example 17 and the compound of Reference Example 17, and the compound of Reference Example 33 was obtained from the compound of Reference Example 3 and the compound of Reference Example 18. These are shown in Tables 7 and 8.

[0270]

[Table 7]

[0271]

[Table 8]

Example 1 (third step) 5- (4-chlorophenyl) -3- (3,4-dimethoxybenzyl) -1,3-dihydrobenzo [e] [1,
2,4] triazepine-2-thione

[0273]

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The N- [2- (4-chlorobenzoyl) phenyl] -1- (3,4-dimethoxybenzyl) hydrazinecarbothioamide (35.75 g) obtained in Reference Example 19 was suspended in ethanol (360 ml). p-Toluenesulfonic acid monohydrate (0.45 g) was added, and the mixture was heated under reflux for 1 hour. After completion of the reaction, the residue obtained by concentration under reduced pressure was treated with diethyl ether.
(500 ml), and washed successively with water, a saturated aqueous solution of sodium hydrogen carbonate and water. The organic layer was dried, filtered, concentrated, and the precipitated crystals were collected by filtration to give the title compound (28.
6g) was obtained as yellow crystals. 136-137 ° C

Example 2 (third step) 3- (4-methoxybenzyl) -5-phenyl-1,3
-Dihydrobenzo [e] [1,2,4] triazepine-
2-thione

Example 3 (3rd step) 5- (4-chlorophenyl) -3- (4-methoxybenzyl) -1,3-dihydrobenzo [e] [1,2,4]
Triazepine-2-thione

Example 4 (3rd step) 7-chloro-3- (4-methoxybenzyl) -5-phenyl-1,3-dihydrobenzo [e] [1,2,4] triazepine-2-thione

Example 5 (third step) 3- (4-methoxybenzyl) -7-nitro-5-phenyl-1,3-dihydrobenzo [e] [1,2,4] triazepine-2-thione

Example 6 (3rd step) 3- (4-methoxybenzyl) -5- (4-methylphenyl) -1,3-dihydrobenzo [e] [1,2,4]
Triazepine-2-thione

Example 7 (third step) 7-chloro-5- (2-chlorophenyl) -3- (4-
Methoxybenzyl) -1,3-dihydrobenzo [e]
[1,2,4] Triazepine-2-thione Reference Examples 20, 21, 22, 23, 24, 25 as in Example 1.
The compounds of Examples 2, 3, 4, 5, 6, and 7 were obtained from the compound of the above. These are shown in Tables 9 and 10.

[0281]

[Table 9]

[0282]

[Table 10]

Example 8 (3rd step) 5- (4-chlorophenyl) -3- (pyridin-3-ylmethyl) -1,3-dihydrobenzo [e] [1,2,2
4] Triazepine-2-thione hydrochloride

[0284]

Embedded image

N- [2- (4-chlorobenzoyl) phenyl] -1- (pyridin-3-ylmethyl) hydrazinecarbothioamide (1.0 g) obtained in Reference Example 26 was suspended in 2-propanol, and Hydrochloric acid / 1,4-dioxane
(0.63 ml) was added and the mixture was stirred at 60 ° C. for 1 hour. The reaction solution was returned to room temperature, diethyl ether (20 ml) was added, and the mixture was allowed to stand for 2 hours. The resulting crystals were collected by filtration and washed with diethyl ether to give the title compound (985 mg) as yellow crystals. 136-137 ° C

Example 9 (3rd step) 5- (4-chlorophenyl) -3- (pyridin-3-ylmethyl) -1,3-dihydrobenzo [e] [1,2,2
4] Triazepine-2-thione p-toluenesulfonate The title compound was obtained in the same manner as in Example 8. This is shown in Table 1.
1 is shown.

[0287]

[Table 11]

Example 10 (3rd step) 4- (4-chlorophenyl) -6- (4-methoxybenzyl) -2,3-dimethyl-6,8-dihydro-1-thia-5,6,8- Triaza-azulene-7-thione

[0289]

Embedded image

The N- [3- (4-chlorobenzoyl) -4,5-dimethylthiophene-2- obtained in Reference Example 27
Yl] -1- (4-methoxybenzyl) hydrazinecarbothioamide (750 mg) was suspended in ethanol (15 ml).
-Toluenesulfonic acid monohydrate was added and heated to reflux for 1 hour. After completion of the reaction, the residue obtained by concentration under reduced pressure was dissolved in chloroform, and washed sequentially with water, a saturated aqueous solution of sodium hydrogencarbonate and water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography (hexane: ethyl acetate).
Purification by 3: 1) gave the title compound (530 mg) as yellow crystals. Melting point 108-110 ° C

Example 11 (3rd step) 4- (4-chlorophenyl) -2-ethyl-6- (4-
(Methoxybenzyl) -6,8-dihydro-1-thia-
5,6,8-triaza-azulene-7-thione

Example 12 (third step) 6- (4-methoxybenzyl) -2-methyl-4-phenyl-6,8-dihydro-1-thia-5,6,8-triaza-azulene-7- Zion

Example 13 (3rd step) 6- (4-methoxybenzyl) -2,3-dimethyl-4
-Phenyl-6,8-dihydro-1-thia-5,6,8
-Triaza-azulene-7-thione

Example 14 (3rd step) 2-ethyl-6- (4-methoxybenzyl) -4-phenyl-6,8-dihydro-1-thia-5,6,8-triaza-azulene-7- Zion

Example 15 (third step) 6- (4-methoxybenzyl) -4- (4-methoxyphenyl) -2,3-dimethyl-6,8-dihydro-1-
Thia-5,6,8-triaza-azulene-7-thione

Example 16 (3rd step) 4- (2-chlorophenyl) -2,3-dimethyl-6-
(Pyridin-4-ylmethyl) -6,8-dihydro-1
-Thia-5,6,8-triaza-azulene-7-thione Reference Examples 28, 29, 30, 3 in the same manner as in Example 10.
Examples 11, 12, 13, from the compounds of 1, 32 and 33,
Compounds 14, 15, and 16 were obtained, respectively. These are shown in Tables 12 and 13.

[0297]

[Table 12]

[0298]

[Table 13]

Example 17 (2nd and 3rd steps) 3- (4-methoxybenzyl) -8-methyl-5-phenyl-1,3-dihydrobenzo [e] [1,2,4] triazepine- 2-thione

[0300]

Embedded image

According to a method similar to that of Reference Example 19, Reference Example 8
Were reacted with the 2-benzoyl-5-methylphenylisothiocyanate (4.2 g) obtained in the above, 4-methoxybenzylhydrazine hydrochloride (3.3 g) obtained in Reference Example 3, and triethylamine (2.44 ml). . The reaction solvent was distilled off, and the obtained residue (oil) was heated at 50 ° C. for 2 hours. This was subjected to the extraction procedure described in Example 1 and crystallized from chloroform-diethyl ether to give the title compound (1.78
g) was obtained as yellow crystals. 190-191 ° C

Example 18 (Fourth Step) 5- (4-Chlorophenyl) -3- (4-methoxybenzyl) -3H-benzo [e] [1,2,4] triazepin-2-ylhydrazine

[0303]

Embedded image

The 5- (4-chlorophenyl) -3- (4-methoxybenzyl) -1,3-dihydrobenzo [e] [1,2,4] triazepine-2-thione obtained in Example 3 (41 mg) ) Was dissolved in tetrahydrofuran (0.4 ml), hydrazine monohydrate (49 μl) was added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the residue obtained by concentration under reduced pressure was dissolved in ethyl acetate, and washed with water three times. The organic layer was dried, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography (chloroform: methanol 20: 1) to give the title compound (27 mg) as a pale yellow powder. . ^{1 H NMR (300MHz, δppm,} CDCl 3) 3.78 (3H, s), 4.71 (2H, s), 6.82 (2H, d, J = 8.8Hz), 7.00 (3
H, m), 7.15-7.28 (6H, m), 7.41 ((1H, m)

Example 19 (Sixth Step) 5- (4-Chlorophenyl) -3- (3,4-dimethoxybenzyl) -2-methylthio-3H-benzo [e]
[1,2,4] triazepine

[0306]

Embedded image

The 5- (4-chlorophenyl) -3- (3,4-dimethoxybenzyl) -1,3 obtained in Example 1
-Dihydrobenzo [e] [1,2,4] triazepine-
2-thione (41 g) was added to anhydrous N, N-dimethylformamide
(200ml) and sodium hydride (oil 60%)
(3.51 g), and the mixture was stirred at room temperature for 30 minutes under an argon atmosphere. After cooling with ice, methyl iodide (5.47 ml) was added, and the mixture was stirred under ice cooling for 30 minutes and at room temperature for 1 hour. After completion of the reaction, the mixture was ice-cooled, acetic acid (1.67 ml) was added, and the mixture was concentrated under reduced pressure.
The obtained residue was dissolved in ethyl acetate, and washed sequentially with a 5% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and water. The ethyl acetate layer was dried, filtered, and concentrated under reduced pressure. The obtained oil was crystallized from diethyl ether-n-hexane to give the title compound (30.43 g) as pale-yellow crystals. 136-137 ° C

Example 20 (Sixth step) 3- (4-methoxybenzyl) -2-methylthio-5-
Phenyl-3H-benzo [e] [1,2,4] triazepine

Example 21 (sixth step) 7-chloro-3- (4-methoxybenzyl) -2-methylthio-5-phenyl-3H-benzo [e] [1,2,2
4] Triazepine

Example 22 (Sixth step) 3- (4-methoxybenzyl) -8-methyl-2-methylthio-5-phenyl-3H-benzo [e] [1,2,2
4] Triazepine

Example 23 (sixth step) 3- (4-methoxybenzyl) -2-methylthio-7-
Nitro-5-phenyl-3H-benzo [e] [1,2,
4] Triazepine

Example 24 (Sixth step) 3- (4-methoxybenzyl) -5- (4-methylphenyl) -2-methylthio-3H-benzo [e] [1,
2,4] triazepine

Example 25 (sixth step) 7-chloro-5- (2-chlorophenyl) -3- (4-
Methoxybenzyl) -2-methylthio-3H-benzo [e] [1,2,4] triazepine In the same manner as in Example 19, Examples 2, 4, 17, 5,
Examples 20, 21, 22, 23, 2 from the compounds of 6, 7
4, 25 compounds were obtained. These are shown in Tables 14 and 15.

[0314]

[Table 14]

[0315]

[Table 15]

Example 26 (sixth step) 5- (4-chlorophenyl) -2-methylthio-3-
(Pyridin-3-ylmethyl) -3H-benzo [e]
[1,2,4] triazepine

[0317]

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The 5- (4-chlorophenyl) -3- (pyridin-3-ylmethyl) -1,3 obtained in Example 8
-Dihydrobenzo [e] [1,2,4] triazepine-
2-Thion hydrochloride (1.97 g) was dissolved in anhydrous N, N-dimethylformamide (20 ml), sodium hydride (380 mg) was added under ice cooling and stirring, and the mixture was returned to room temperature and stirred for 30 minutes. Cool again with ice, add methyl iodide (296 μl), return to room temperature, and add
After stirring for 0 minutes, the reaction was poured into water (50 ml) and neutralized with citric acid. The reaction mixture was extracted with ethyl acetate (50ml),
After washing five times with water, the extract was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain the title compound (1.79 g) as a yellow oil. ^{1 H NMR (300MHz, δppm,} CDCl 3) 2.56 (3H, s), 4.77 (2H, s), 6.92-7.02 (2H, m), 7.15-7.32
(6H, m), 7.43 (1H, m), 7.61 (1H, m), 8.50 (1H, dd, J = 4.8 a
nd 1.7Hz), 8.59 (1H, d, J = 1.7Hz)

Example 27 (sixth step) 5- (4-chlorophenyl) -2-methylthio-3-
(Pyridin-3-ylmethyl) -3H-benzo [e]
[1,2,4] triazepine

[0320]

Embedded image

In the same manner as in Example 26, 5- (4-chlorophenyl) -3- (pyridine-
3-ylmethyl) -1,3-dihydrobenzo [e]
[1,2,4] triazepine-2-thione The title compound was obtained as an amorphous substance from p-toluenesulfonate. The NMR of this compound was consistent with the NMR of Example 26 . Example 28 (sixth step) 4- (4-chlorophenyl) -6- (4-methoxybenzyl) -2,3-dimethyl-7-methylthio-6H-1
-Thia-5,6,8-triazaazulene

[0322]

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The 4- (4-chlorophenyl) -6- (4-methoxybenzyl) -2,3-dimethyl-6,8-dihydro-1-thia-5,6,8-triaza obtained in Example 10 -Azulene-7-thione (442 mg) in acetone (5 m
l), anhydrous potassium carbonate (1.38 g) and methyl iodide (74.7 μl) were added, and the mixture was stirred at room temperature for 1 hour. After filtering off potassium carbonate, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound.
(430 mg) was obtained as an amorphous.

Example 29 (sixth step) 4- (4-chlorophenyl) -2-ethyl-6- (4-
(Methoxybenzyl) -7-methylthio-6H-1-thia-5,6,8-triaza-azulene

Example 30 (Sixth step) 6- (4-methoxybenzyl) -2-methyl-7-methylthio-4-phenyl-6H-1-thia-5,6,8-
Triaza-azulene

Example 31 (Sixth step) 6- (4-methoxybenzyl) -2,3-dimethyl-7
-Methylthio-4-phenyl-6H-1-thia-5,
6,8-triaza-azulene

Example 32 (Sixth step) 2-Ethyl-6- (4-methoxybenzyl) -7-methylthio-4-phenyl-6H-1-thia-5,6,8-
Triaza-azulene

Example 33 (sixth step) 6- (4-methoxybenzyl) -4- (4-methoxyphenyl) -2,3-dimethyl-7-methylthio-6H-
1-thia-5,6,8-triaza-azulene

Example 34 (sixth step) 4- (2-chlorophenyl) -2,3-dimethyl-7-
Methylthio-6- (pyridin-4-ylmethyl) -6H
-1-Thia-5,6,8-triaza-azulene Example 2
In the same manner as in Example 8, Examples 11, 12, 13, 14, 1
Examples 29, 30, 31, 32 from the compounds of 5, 16
Compounds 33 and 34 were obtained, respectively. These are shown in Table 16,
17 is shown.

[0330]

[Table 16]

[0331]

[Table 17]

Example 35 (Sixth Step) 5- (4-Chlorophenyl) -3- (4-methoxybenzyl) -2-methylthio-3H-benzo [e] [1,
2,4] triazepine

[0333]

Embedded image

The 5- (4-chlorophenyl) -3- (4-methoxybenzyl) -1,3-dihydrobenzo [e] [1,2,4] triazepine-2-thione obtained in Example 3 (100 mg) Was dissolved in acetone (1 ml), anhydrous potassium carbonate (339 mg) and methyl iodide (18 μl) were added, and the mixture was stirred at room temperature for 2 hours. After filtering off potassium carbonate, the residue obtained by concentrating the filtrate under reduced pressure was dissolved in diethyl ether,
Washing was sequentially performed with water, a 5% citric acid aqueous solution, and water. The organic layer is dried, filtered, and concentrated under reduced pressure. The obtained residue is subjected to preparative thin-layer chromatography (n-hexane: ethyl acetate 3:
The title compound (97 mg) was obtained by purification in 1). ^{1 H NMR (300MHz, δppm,} CDCl 3) 2.53 (3H, s), 3.78 (3H, s), 4.70 (2H, s), 6.82 (2H, d, J = 8.
7Hz), 6.96 (2H, m), 7.15 (1H, d, J = 7.9Hz), 7.21-7.28 (6
H, m), 7.40 (1H, m)

Example 36 (7th step) 5- (4-chlorophenyl) -3- (4-methoxybenzyl) -3H-benzo [e] [1,2,4] triazepin-2-ylhydrazine

[0336]

Embedded image

The 5- (4-chlorophenyl) -3- (4-methoxybenzyl) -2-methylthio-3H-benzo [e] [1,2,4] triazepine obtained in Example 35
(42.2 mg) and hydrazine monohydrate (10 μl) in ethanol
(0.4 ml), and the mixture was heated and stirred at 70 ° C. for 24 hours. After completion of the reaction, the residue obtained by concentration under reduced pressure was dissolved in ethyl acetate, and washed with water three times. The organic layer was dried, filtered, and concentrated under reduced pressure, and the resulting residue was subjected to preparative thin-layer chromatography.
(Chloroform: methanol 20: 1) gave the title compound (10.8 mg). The spectral data of this compound was consistent with the compound of Example 18.

Example 37 (seventh step) N '-[5- (4-chlorophenyl) -3-acetic acid acetate
4-dimethoxybenzyl) -3H-benzo [e] [1,
2,4] Triazepin-2-yl] hydrazide

[0339]

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The 5- (4-chlorophenyl) -3- (3,4-dimethoxybenzyl) -2- obtained in Example 19
Methylthio-3H-benzo [e] [1,2,4] triazepine (51.5 g) was dissolved in n-butanol (110 ml), acetylhydrazine (16.89 g) was added, and the mixture was stirred at 110 ° C. for 3 hours. The reaction solution was cooled, and the precipitated solid was collected by filtration and washed sequentially with diethyl ether and water. This solid was dissolved in dichloromethane (11) and dried over anhydrous sodium sulfate. After the drying agent was filtered off, the filtrate was concentrated to give a concentrated solution, and diethyl ether was added to obtain crystals of the title compound (48.1 g). 145-146 ° C

Example 38 (Seventh Step) N '-[3- (4-methoxybenzyl) -5-phenyl-3H-benzo [e] [1,2,4] triazepin-2-yl] hydrazide acetate

Example 39 (seventh step) N ′-[3- (4-methoxybenzyl) -8-methyl-5-phenyl-3H-benzo [e] acetate [1,2,4] acetate
Triazepin-2-yl] hydrazide In the same manner as in Example 37, the compounds of Examples 38 and 39 were obtained from the compounds of Examples 20 and 22, respectively. These are shown in Table 18.

[0343]

[Table 18]

Example 40 (Fifth Step) 6- (4-Chlorophenyl) -4- (4-methoxybenzyl) -1-methyl-4H-2,3,4,5,10b-
Pentaazabenzo [e] azulene

[0345]

Embedded image

The compound obtained in Example 18 or Example 36
(4-chlorophenyl) -3- (4-methoxybenzyl) -3H-benzo [e] [1,2,4] triazepin-2-ylhydrazine (23 mg), triethyl orthoacetate (15 μl) and p-toluene Sulfonic acid monohydrate
(2.4 mg) was suspended in toluene (0.5 ml) and heated under reflux for 3 hours. After cooling, ethyl acetate was added, and the organic layer was washed successively with an aqueous solution of sodium hydrogen carbonate and water. The organic layer was dried, filtered and concentrated under reduced pressure.The residue obtained was crystallized from ethyl acetate-diethyl ether to give the title compound (16 m
g) was obtained as colorless needles. Melting point 192-193 ° C ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.60 (3H, s), 3.79 (3H, s), 4.89-5.04 (2H, m), 6.83-6.85
(2H, m), 6.96 (2H, m), 7.18-7.37 (9H, m), 7.59-7.64 (1H,
m)

Example 41 (8th step) 6- (4-chlorophenyl) -4- (3,4-dimethoxybenzyl) -1-methyl-4H-2,3,4,5,1
0b-pentaazabenzo [e] azulene

[0348]

Embedded image

The acetic acid N '-[5-
(4-chlorophenyl) -3- (3,4-dimethoxybenzyl) -3H-benzo [e] [1,2,4] triazepin-2-yl] hydrazide (48 g) and p-toluenesulfonic acid monohydrate (2.1 g) suspended in toluene, 110 ° C.
For 30 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained residue was dissolved in dichloromethane and washed sequentially with saturated sodium hydrogen carbonate and water. The dichloromethane layer was dried and filtered, and the residue obtained by concentrating the filtrate was crystallized from diethyl ether to give the title compound (42.
4g) was obtained as colorless crystals. 235-237 ° C

Example 42 (8th step) 4- (4-methoxybenzyl) -1-methyl-6-phenyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene

Example 43 (8th step) 4- (4-methoxybenzyl) -1,9-dimethyl-6
-Phenyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene In the same manner as in Example 41, the compounds of Examples 42 and 43 were obtained from the compounds of Examples 38 and 39, respectively. These are shown in Table 19.

[0352]

[Table 19]

Example 44 (Step 7 ′) 8-chloro-4- (4-methoxybenzyl) -1-methyl-6-phenyl-4H-2,3,4,5,10b-pentaazabenzo [e Azulene

[0354]

Embedded image

The 7-chloro-3- obtained in Example 21
(4-methoxybenzyl) -2-methylthio-5-phenyl-3H-benzo [e] [1,2,4] triazepine
(600 mg), acetylhydrazine (220 mg) and p-toluenesulfonic acid monohydrate (80 mg) were dissolved in n-butanol (6 ml) and heated and stirred at 90 ° C. for 2 hours and at 110 ° C. for 1.5 hours. did. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained residue was dissolved in ethyl acetate and washed sequentially with water, a saturated aqueous solution of sodium hydrogen carbonate and water. The organic layer was dried, filtered, concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography. The fraction obtained by elution with chloroform: acetone 5: 1 was crystallized from diethyl ether to give a residue. The title compound (100.7 mg) was obtained as crystals. Melting point 116-118 ° C

Example 45 (Step 7 ′) 4- (4-Methoxybenzyl) -1-methyl-8-nitro-6-phenyl-4H-2,3,4,5,10b-pentaazabenzo [e Azulene

Example 46 (Step 7 ′) 4- (4-methoxybenzyl) -1-methyl-6- (4
-Methylphenyl) -4H-2,3,4,5,10b-
Pentaazabenzo [e] azulene

Example 47 (Step 7 ′) 8-chloro-6- (2-chlorophenyl) -4- (4-
(Methoxybenzyl) -1-methyl-4H-2,3,4
5,10b-Pentazaazabenzo [e] azulene Example 4
In the same manner as in Example 4, the compounds of Examples 45, 46, and 47 were obtained from the compounds of Examples 23, 24, and 25, respectively. These are shown in Table 20.

[0359]

[Table 20]

Example 48 (Step 7 ′) 4- (4-Chlorophenyl) -6- (4-methoxybenzyl) -2,3,9-trimethyl-6H-5,6,7,
8,9a-pentaazathieno [2,3-e] azulene

[0361]

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The 4- (4-chlorophenyl) -6- (4-methoxybenzyl) -2,3- obtained in Example 28
Dimethyl-7-methylthio-6H-1-thia-5,6,
8-Triaza-azulene (350 mg), acetylhydrazine (114 mg) and p-toluenesulfonic acid monohydrate (14.6 mg) were added to n-butanol (13.5 m).
1) and stirred under heating at 110 ° C. for 12 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained residue was dissolved in ethyl acetate and washed sequentially with water, a saturated aqueous solution of sodium hydrogen carbonate and water. The organic layer was dried, filtered, and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography, and the fraction obtained by eluting with chloroform: methanol 5: 1 was subjected to ethyl acetate: diethyl ether 1:
By crystallizing with the mixed solvent of No. 3, the title compound (16
0 mg) as colorless crystals. 214-216 ° C ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 1.26 (3H, s), 2.36 (3H, s), 2.6
5 (3H, s), 3.81 (3H, s), 4.95 (2
H, m), 6.86 (2H, d, J = 8.7 Hz),
7.23-7.31 (4H, m), 7.35 (2H,
d , J = 8.7 Hz)

Example 49 (Step 7 ′) 4- (4-Chlorophenyl) -2-ethyl-6- (4-
Methoxybenzyl) -9-methyl-6H-5,6,7,
8,9a-pentaazathieno [2,3-e] azulene

Example 50 (Step 7 ′) 6- (4-methoxybenzyl) -2,9-dimethyl-4
-Phenyl-6H-5,6,7,8,9a-pentaazathieno [2,3-e] azulene

Example 51 (Step 7 ′) 6- (4-Methoxybenzyl) -2,3,9-trimethyl-4-phenyl-6H-5,6,7,8,9a-pentaazathieno [2,3 -E] azulene

Example 52 (Step 7 ') 2-Ethyl-6- (4-methoxybenzyl) -9-methyl-4-phenyl-6H-5,6,7,8,9a-pentaazathieno [2,3 -E] azulene

Example 53 (Step 7 ′) 6- (4-methoxybenzyl) -4- (4-methoxyphenyl) -2,3,9-trimethyl-6H-5,6,6
7,8,9a-pentaazathieno [2,3-e] azulene In the same manner as in Example 48, Examples 29, 30, 31, 3
Examples 49, 50, 51, 52 from the compounds of 2, 33,
53 compounds were each obtained. These are shown in Tables 21 and 22.

[0368]

[Table 21]

[0369]

[Table 22]

Example 54 (Step 7 ′) 6- (4-Chlorophenyl) -1-methyl-4- (pyridin-3-ylmethyl) -4H-2,3,4,5,10
b-pentaazabenzo [e] azulene

[0371]

Embedded image

The 5- (4-chlorophenyl) -2-methylthio-3- (pyridin-3-ylmethyl) -3H-benzo [e] [1,2,4] triazepine (800 mg) obtained in Example 26 was added. It was dissolved in 1-butanol (4 ml), acetohydrazine (151 mg) and p-toluenesulfonic acid monohydrate (19.4 mg) were added, and the mixture was stirred on a hot water bath at 100 ° C for 3 hours. The reaction solution was returned to room temperature, diethyl ether (10 ml) was slowly added, and the mixture was allowed to stand for 1 hour. The precipitated crystals were collected by filtration and washed with diethyl ether to give the title compound (488 mg) as colorless crystals. 240-243 ° C

¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.62 (3 H, s), 4.98 (1 H, m), 5.11 (1 H, m), 7.18-7.40 (8H,
m), 7.64 (1H, dt, J = 7.8 and 1.4Hz), 7.72 (1H, dt, J = 7.8
and 1.9Hz), 8.51 (1H, dd, J = 4.8 and 1.6Hz), 8.65 (1H,
d, J = 1.6 Hz) The title compound can also be synthesized in the same manner as in Example 56 (see Example 98).

Example 55 (Step 7 ′) 4- (2-Chlorophenyl) -2,3,9-trimethyl-6- (pyridin-4-ylmethyl) -6H-5,6,6
7,8,9a-Pentazaazathieno [2,3-e] azulene In the same manner as in Example 54, the title compound was obtained from the compound of Example 34. This is shown in Table 23.

[0375]

[Table 23]

Reference Example 34 (ninth step) 6- (4-chlorophenyl) -1-methyl-4H-2,
3,4,5,10b-pentaazabenzo [e] azulene

[0377]

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6- (4-Chlorophenyl) -4- (3,4-dimethoxybenzyl) -1- obtained in Example 41
Methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene (2.02 g) and anisole (1.4 ml) were dissolved in trifluoroacetic acid (8 ml), and concentrated sulfuric acid (1.3 ml) was added. After stirring for 10 minutes, concentrated sulfuric acid (3.9 ml) was added and the mixture was stirred for 45 minutes. Further, concentrated sulfuric acid (1.3 ml) was added, and the mixture was stirred for 1.5 hours. The reaction solution was poured into ice water (300 ml) and extracted with ethyl acetate. The organic layer was washed successively with an aqueous sodium hydrogen carbonate solution and water, dried, filtered, and concentrated, and the residue obtained was crystallized from diethyl ether to give the title compound (748 m
g) was obtained as colorless crystals. Melting point 231-233 ° C

Reference Example 35 (ninth step) 1-methyl-6- (4-methylphenyl) -4H-2,
3,4,5,10b-pentaazabenzo [e] azulene

[0380]

Embedded image

4- (4-methoxybenzyl) -1-methyl-6- (4-methylphenyl) obtained in Example 46
-4H-2,3,4,5,10b-pentaazabenzo [e] azulene (800 mg) in 25% hydrobromic acid / acetic acid solution
(8 ml), anisole (0.22 ml) was added, and the mixture was heated and stirred at 40 ° C. for 3 hours. Diisopropyl ether (200ml)
Was added, and the crystals were collected by filtration. The crystals were dissolved in water (10 ml) and neutralized with sodium bicarbonate. The precipitated crystals were collected by filtration, dissolved in methylene chloride (30 ml), washed with water, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was crystallized from ethyl acetate to give the title compound (345 m
g) was obtained. Melting point 259-261 ° C

Reference Example 36 (ninth step) 7-nitro-1-methyl-6-phenyl-4H-2,
3,4,5,10b-pentaazabenzo [e] azulene

Reference Example 37 (ninth step) 8-Chloro-6- (2-chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene Reference Example 34 Similarly, the compounds of Reference Examples 36 and 37 were obtained from the compounds of Examples 45 and 47, respectively. These are shown in Table 24.

[0384]

[Table 24]

Reference Example 38 (9th step) 1-methyl-6-phenyl-4H-2,3,4,5,1
0b-pentaazabenzo [e] azulene

[0386]

Embedded image

The 4- (4-methoxybenzyl) -1-methyl-6-phenyl-4H-2, obtained in Example 42,
3,4,5,10b-pentaazabenzo [e] azulene
(94 mg) and anisole (20 μl) were dissolved in a 25% hydrobromic acid / acetic acid solution (6.9 ml) and stirred at room temperature for 32 hours. After the reaction solvent was concentrated under reduced pressure, ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate were added to the residue, and the organic layer was separated. The organic layer
After washing with water, drying, filtration and concentration under reduced pressure, the residue obtained is purified by preparative thin-layer chromatography (chloroform: methanol 20: 1) and crystallized from diethyl ether to give the title compound (48.5). mg) as colorless needles. 227-230 ° C

Reference Example 39 (ninth step) 1,9-dimethyl-6-phenyl-4H-2,3,4
5,10b-pentaazabenzo [e] azulene In the same manner as in Reference Example 38, the compound of Reference Example 39 was obtained from the compound of Example 43. This is shown in Table 25.

[0389]

[Table 25]

Reference Example 40 (ninth step) 8-chloro-1-methyl-6-phenyl-4H-2,
3,4,5,10b-pentaazabenzo [e] azulene hydrobromide

[0391]

Embedded image

8-Chloro-4- obtained in Example 44
(4-Methoxybenzyl) -1-methyl-6-phenyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene (105 mg) was reacted in the same manner as in Reference Example 38, and the solvent was removed. Is distilled off under reduced pressure to obtain crystals.
This was washed with diethyl ether and dried to obtain the title compound (108.2 mg). Melting point 191-192 ° C (decomposition)

Reference Example 41 (ninth step) 8-chloro-1-methyl-6-phenyl-4H-2,
3,4,5,10b-pentaazabenzo [e] azulene

[0394]

Embedded image

The 8-chloro-1-methyl-6-phenyl-4H-2,3,4,5,10b- obtained in Reference Example 40
Pentaazabenzo [e] azulene hydrobromide (102m
g) was subjected to the extraction procedure described in Reference Example 34 and crystallized from diethyl ether to give the title compound as crystals. 140-142 ° C

Reference Example 42 (ninth step) 4- (4-chlorophenyl) -2,3,9-trimethyl-6H-5,6,7,8,9a-pentaazathieno [2,3-e] azulene

[0397]

Embedded image

The 4- (4-chlorophenyl) -6- (4-methoxybenzyl) -2,3,9 obtained in Example 48
-Trimethyl-6H-5,6,7,8,9a-pentaazathieno [2,3-e] azulene (100 mg) and anisole (24 μl) were dissolved in a 25% hydrobromic acid / acetic acid solution (1 ml), Stirred at 40 ° C. for 5 hours. The reaction solution was returned to room temperature, diisopropyl ether (30 ml) was added, and the oil deposited in the reaction vessel and the organic solvent were separated. The oil was dissolved in chloroform, washed successively with water, a saturated aqueous solution of sodium hydrogen carbonate and water, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was crystallized from diethyl ether to give the title compound (68 mg) as yellow crystals. Melting point 247 ° C ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 1.58 (3H, s), 2.36 (3H, s), 2.62 (3H, s), 7.35 (2H, d, J = 8.
9Hz), 7.43 (2H, d, J = 8.9Hz), 7.83 (1H, s)

Reference Example 43 (ninth step) 4- (4-chlorophenyl) -2-ethyl-9-methyl-6H-5,6,7,8,9a-pentaazathieno [2,3-e] azulene

Reference Example 44 (ninth step) 2,9-dimethyl-4-phenyl-6H-5,6,7,
8,9a-pentaazathieno [2,3-e] azulene

Reference Example 45 (ninth step) 2,3,9-trimethyl-4-phenyl-6H-5
6,7,8,9a-pentaazathieno [2,3-e] azulene

Reference Example 46 (ninth step) 2-ethyl-9-methyl-4-phenyl-6H-5
6,7,8,9a-pentaazathieno [2,3-e] azulene

Reference Example 47 (ninth step) 4- (4-methoxyphenyl) -2,3,9-trimethyl-6H-5,6,7,8,9a-pentaazathieno [2,3-e] azulene In the same manner as in Example 42, Examples 49, 50, 51, and 5
Reference Examples 43, 44, 45, 46 from the compounds of 2, 53
47 compounds were each obtained. This is shown in Tables 26 and 27.

[0404]

[Table 26]

[0405]

[Table 27]

Example 56 (10th step 1) 6- (4-chlorophenyl) -4- (3-cyanobenzyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [ e] Azulene

[0407]

Embedded image

6- (4-Chlorophenyl) -1-methyl-4H-2,3,4,5,10b obtained in Reference Example 34
-Pentaazabenzo [e] azulene (20 mg) was added under an argon gas atmosphere to anhydrous N, N-dimethylformamide (0.4 m
l) and cooled on ice. To this, potassium hydroxide (13 mg) crushed in a mortar was added all at once, and 3- (chloromethyl) benzonitrile (15.2 mg) was further added thereto.
And stirred at room temperature for 1 hour. After the reaction, cool on ice and 5%
An aqueous solution of citric acid and ethyl acetate were added, and the organic layer was separated, and washed sequentially with a saturated aqueous solution of sodium hydrogen carbonate and water. The organic layer was dried, filtered, and concentrated under reduced pressure, and the obtained residue was crystallized from diethyl ether to give the title compound (8.4 mg). 140-141 ° C ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.62 (3H, s), 4.92-5.16 (2H, m), 7.24-7.69 (12H, m)

Examples 57 to 119 (10th step 1) In the same manner as in Example 56, the following compounds of Examples 57 to 119 were obtained from the compound of Reference example 34. These are shown in Table 28.
To Table 32.

Example 57 6- (4-Chlorophenyl) -4- (2-fluorobenzyl) -1-methyl-4H-2,3,4,5,10b-
Pentaazabenzo [e] azulene

Example 58 6- (4-Chlorophenyl) -4- (3-fluorobenzyl) -1-methyl-4H-2,3,4,5,10b-
Pentaazabenzo [e] azulene

Example 59 6- (4-Chlorophenyl) -4- (4-fluorobenzyl) -1-methyl-4H-2,3,4,5,10b-
Pentaazabenzo [e] azulene

Example 60 6- (4-Chlorophenyl) -4- (2,4-difluorobenzyl) -1-methyl-4H-2,3,4,5,1
0b-pentaazabenzo [e] azulene

Example 61 6- (4-Chlorophenyl) -4- (2,5-difluorobenzyl) -1-methyl-4H-2,3,4,5,1
0b-pentaazabenzo [e] azulene

Example 62 6- (4-Chlorophenyl) -4- (3,5-difluorobenzyl) -1-methyl-4H-2,3,4,5,1
0b-pentaazabenzo [e] azulene

Example 63 6- (4-Chlorophenyl) -4- (3,4-difluorobenzyl) -1-methyl-4H-2,3,4,5,1
0b-pentaazabenzo [e] azulene

Example 64 6- (4-Chlorophenyl) -1-methyl-4- (2-
Trifluoromethylbenzyl) -4H-2,3,4
5,10b-pentaazabenzo [e] azulene

Example 65 6- (4-Chlorophenyl) -1-methyl-4- (4-
Trifluoromethylbenzyl) -4H-2,3,4
5,10b-pentaazabenzo [e] azulene

Example 66 6- (4-Chlorophenyl) -1-methyl-4- (3-
Trifluoromethylbenzyl) -4H-2,3,4
5,10b-pentaazabenzo [e] azulene

Example 67 6- (4-Chlorophenyl) -1-methyl-4- (4-
Trifluoromethoxybenzyl) -4H-2,3,4
5,10b-pentaazabenzo [e] azulene

Example 68 6- (4-Chlorophenyl) -1-methyl-4- (3-
Nitrobenzyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulene

Example 69 4- (2-chlorobenzyl) -6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene

Example 70 4- (3-chlorobenzyl) -6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene

Example 71 4- (4-chlorobenzyl) -6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene

Example 72 6- (4-Chlorophenyl) -4- (2-cyanobenzyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene

Example 73 6- (4-Chlorophenyl) -4- (3-cyanobenzyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene

Example 74 6- (4-Chlorophenyl) -4- (4-cyanobenzyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene

Example 75 6- (4-Chlorophenyl) -4- (2-methoxybenzyl) -1-methyl-4H-2,3,4,5,10b-
Pentaazabenzo [e] azulene

Example 76 6- (4-Chlorophenyl) -4- (3-methoxybenzyl) -1-methyl-4H-2,3,4,5,10b-
Pentaazabenzo [e] azulene

Example 77 6- (4-Chlorophenyl) -4- (4-methoxybenzyl) -1-methyl-4H-2,3,4,5,10b-
Pentaazabenzo [e] azulene

Example 78 6- (4-Chlorophenyl) -4- (2,5-dimethoxybenzyl) -1-methyl-4H-2,3,4,5,1
0b-pentaazabenzo [e] azulene

Example 79 6- (4-Chlorophenyl) -1-methyl-4- (3
4,5-trimethoxybenzyl) -4H-2,3,4
5,10b-pentaazabenzo [e] azulene

Example 80 4- (5-acetyl-2-methoxybenzyl) -6
(4-chlorophenyl) -1-methyl-4H-2,3,
4,5,10b-pentaazabenzo [e] azulene

Example 81 6- (4-Chlorophenyl) -1-methyl-4- (3
4-methylenedioxybenzyl) -4H-2,3,4
5,10b-pentaazabenzo [e] azulene

Example 82 4- (2-chloro-4,5-methylenedioxybenzyl) -6- (4-chlorophenyl) -1-methyl-4H
-2,3,4,5,10b-Pentazabenzo [e] azulene

Example 83 6- (4-Chlorophenyl) -4- (2-methoxy-5
-Nitrobenzyl) -1-methyl-4H-2,3,4
5,10b-pentaazabenzo [e] azulene

Example 84 6- (4-Chlorophenyl) -4- (4-methoxy-3)
-Nitrobenzyl) -1-methyl-4H-2,3,4
5,10b-pentaazabenzo [e] azulene

Example 85 4- (3-chloro-4-methoxybenzyl) -6- (4
-Chlorophenyl) -1-methyl-4H-2,3,4
5,10b-pentaazabenzo [e] azulene

Example 86 6- (4-Chlorophenyl) -4- (3,5-dichloro-4-methoxybenzyl) -1-methyl-4H-2,
3,4,5,10b-pentaazabenzo [e] azulene

Example 87 6- (4-Chlorophenyl) -1-methyl-4- (2-
Methylbenzyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulene

Example 88 6- (4-Chlorophenyl) -1-methyl-4- (3-
Methylbenzyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulene

Example 89 6- (4-Chlorophenyl) -1-methyl-4- (4-
Methylbenzyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulene

Example 90 4- (4-tert-butylbenzyl) -6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5
10b-pentaazabenzo [e] azulene

Example 91 6- (4-Chlorophenyl) -1-methyl-4- (naphthalen-1-ylmethyl) -4H-2,3,4,5,1
0b-pentaazabenzo [e] azulene

Example 92 6- (4-Chlorophenyl) -1-methyl-4- (naphthalen-2-ylmethyl) -4H-2,3,4,5,1
0b-pentaazabenzo [e] azulene

Example 93 4- (4-benzyloxybenzyl) -6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,1
0b-pentaazabenzo [e] azulene

Example 94 4-Benzyl-6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene

Example 95 6- (4-Chlorophenyl) -1-methyl-4- (4-
Phenylbenzyl) -4H-2,3,4,5,10b-
Pentaazabenzo [e] azulene

Example 96 4- (4-chlorophenoxymethyl) -6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,1
0b-pentaazabenzo [e] azulene

Example 97 6- (4-Chlorophenyl) -1-methyl-4- (pyridin-2-ylmethyl) -4H-2,3,4,5,10
b-pentaazabenzo [e] azulene

Example 98 6- (4-Chlorophenyl) -1-methyl-4- (pyridin-3-ylmethyl) -4H-2,3,4,5,10
b-pentaazabenzo [e] azulene

Example 99 6- (4-Chlorophenyl) -4- [2- (indol-3-yl) ethyl] -1-methyl-4H-2,3
4,5,10b-pentaazabenzo [e] azulene

Example 100 6- (4-Chlorophenyl) -4- (2-methyl-1,
3-thiazol-4-ylmethyl) -1-methyl-4H
-2,3,4,5,10b-Pentazabenzo [e] azulene

Example 101 6- (4-Chlorophenyl) -4- (5-chlorothiophen-2-ylmethyl) -1-methyl-4H-2,3
4,5,10b-pentaazabenzo [e] azulene

Example 102 6- (4-Chlorophenyl) -1-methyl-4- (3
5-dimethylisoxazol-4-ylmethyl) -4
H-2,3,4,5,10b-pentaazabenzo [e]
Azulene

Example 103 6- (4-Chlorophenyl) -1-methyl-4-phenethyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene

Example 104 6- (4-Chlorophenyl) -1-methyl-4- (3-
Phenylpropyl) -4H-2,3,4,5,10b-
Pentaazabenzo [e] azulene

Example 105 6- (4-Chlorophenyl) -4- (3,3-diphenylpropyl) -1-methyl-4H-2,3,4,5,1
0b-pentaazabenzo [e] azulene

Example 106 6- (4-Chlorophenyl) -4-cyclopropylmethyl-1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene

Example 107 6- (4-Chlorophenyl) -4-cyclohexylmethyl-1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene

Example 108 6- (4-Chlorophenyl) -4- (2-cyclohexylethyl) -1-methyl-4H-2,3,4,5,10
b-pentaazabenzo [e] azulene

Example 109 6- (4-Chlorophenyl) -1-methyl-4- (3-
Phenyl-2-propenyl) -4H-2,3,4,5
10b-pentaazabenzo [e] azulene

Example 110 4-Allyl-6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene

Example 111 6- (4-Chlorophenyl) -1-methyl-4- (2-
Methyl-2-propenyl) -4H-2,3,4,5,1
0b-pentaazabenzo [e] azulene

Example 112 6- (4-Chlorophenyl) -4- (2-chloro-2-
Propenyl) -1-methyl-4H-2,3,4,5,1
0b-pentaazabenzo [e] azulene

Example 113 4- (2-bromo-2-propenyl) -6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,1
0b-pentaazabenzo [e] azulene

Example 114 6- (4-Chlorophenyl) -4- (2,3-dichloro-2-propenyl) -1-methyl-4H-2,3,4
5,10b-pentaazabenzo [e] azulene

Example 115 6- (4-Chlorophenyl) -4- (3,4-dibenzyloxybenzyl) -1-methyl-4H-2,3,4
5,10b-pentaazabenzo [e] azulene

Example 116 4-Benzyloxymethyl-6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene

Example 117 6- (4-Chlorophenyl) -1-methyl-4- (3-
Phenoxypropyl) -4H-2,3,4,5,10b
-Pentaazabenzo [e] azulene

Example 118 6- (4-Chlorophenyl) -4- (3,3-dichloro-2-propenyl) -1-methyl-4H-2,3,4
5,10b-pentaazabenzo [e] azulene

Example 119 6- (4-Chlorophenyl) -4- (4-methoxy-3)
-Methylbenzyl) -1-methyl-4H-2,3,4
5,10b-pentaazabenzo [e] azulene

[0473]

[Table 28]

[0474]

[Table 29]

[0475]

[Table 30]

[0476]

[Table 31]

[0477]

[Table 32]

Example 120 (10th step 1) 6- (4-Chlorophenyl) -1-methyl-4- (pyridin-4-ylmethyl) -4H-2,3,4,5,10
b-pentaazabenzo [e] azulene

[0479]

Embedded image

6- (4-Chlorophenyl) -1-methyl-4H-2,3,4,5,10b obtained in Reference Example 34
-Pentaazabenzo [e] azulene (783 mg) was added under an argon gas atmosphere to anhydrous N, N-dimethylformamide (8 m
l) and cooled on ice, then sodium hydride (oily 6
0%) (120 mg) and 10 minutes at room temperature under ice-cooling for 5 minutes.
Stirred for minutes. The reaction mixture was again cooled with ice, 4-picolyl chloride hydrochloride (415 mg) was added as a solid, and the mixture was stirred under ice cooling for 25 minutes. After completion of the reaction, ice water (50 ml) and ethyl acetate (40 ml) were added, and the organic layer was separated. Organic layer with water 3
After washing twice, drying over anhydrous sodium sulfate and filtration, the filtrate was concentrated under reduced pressure, and the obtained oil was crystallized from diethyl ether to give the title compound (760 mg). Melting point 223-225 ° C ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 2.63 (3H, s), 4.98-5.14 (2H, m), 7.25-7.70 (10 H, m), 8.5
4 (2H, dd, J = 4.5 and 3.0Hz)

Examples 121 to 138 (10th step 1) In the same manner as in Example 120, the compounds of Examples 121 to 125 were substituted for the compound of Reference Example 34, and the compounds of Examples 126 and 127 were substituted for the compound of Reference Example 41. Compounds of the compounds of Examples 128 and 129 from the compound of Reference Example 38, compounds of Examples 130, 131 and 132 from the compound of Reference Example 39,
The compounds of Examples 133 and 134 were obtained from the compound of Reference Example 36, the compounds of Examples 135 and 136 were obtained from the compound of Reference Example 35, and the compounds of Examples 137 and 138 were obtained from the compound of Reference Example 37.
Were obtained, respectively. These are shown in Tables 33, 34, and 3
5 and 36.

Example 121 6- (4-Chlorophenyl) -1-methyl-4- (4-
Methylsulfonylbenzyl) -4H-2,3,4,5
10b-pentaazabenzo [e] azulene

Example 122 6- (4-Chlorophenyl) -1-methyl-4- (4-
Nitrobenzyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulene

Example 123 6- (4-Chlorophenyl) -4- (2,6-dichloropyridin-4-ylmethyl) -1-methyl-4H-2,
3,4,5,10b-pentaazabenzo [e] azulene

Example 124 6- (4-Chlorophenyl) -4- (2,2,2-trifluoroethyl) -1-methyl-4H-2,3,4
5,10b-pentaazabenzo [e] azulene

Example 125 6- (4-Chlorophenyl) -4- (3,5-dinitrobenzyl) -1-methyl-4H-2,3,4,5,10
b-pentaazabenzo [e] azulene

Example 126 8-Chloro-1-methyl-6-phenyl-4- (pyridin-4-ylmethyl) -4H-2,3,4,5,10b
-Pentaazabenzo [e] azulene

Example 127 8-Chloro-1-methyl-6-phenyl-4- (pyridin-3-ylmethyl) -4H-2,3,4,5,10b
-Pentaazabenzo [e] azulene

Example 128 1-Methyl-6-phenyl-4- (pyridin-3-ylmethyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulene

Example 129 1-Methyl-6-phenyl-4- (pyridin-4-ylmethyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulene

Example 130 1,9-Dimethyl-6-phenyl-4- (pyridine-3
-Ylmethyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulene

Example 131 1,9-Dimethyl-6-phenyl-4- (pyridine-4
-Ylmethyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulene

Example 132 4- (3-cyanobenzyl) -1,9-dimethyl-6-
Phenyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene

Example 133 1-Methyl-8-nitro-6-phenyl-4- (pyridin-3-ylmethyl) -4H-2,3,4,5,10b
-Pentaazabenzo [e] azulene

Example 134 1-Methyl-8-nitro-6-phenyl-4- (pyridin-4-ylmethyl) -4H-2,3,4,5,10b
-Pentaazabenzo [e] azulene

Example 135 1-Methyl-6- (4-methylphenyl) -4- (pyridin-4-ylmethyl) -4H-2,3,4,5,10
b-pentaazabenzo [e] azulene

Example 136 4- (3-cyanobenzyl) -1-methyl-6- (4-
Methylphenyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulene

Example 137 8-Chloro-6- (2-chlorophenyl) -1-methyl-4- (pyridin-3-ylmethyl) -4H-2,3,3
4,5,10b-pentaazabenzo [e] azulene

Example 138 8-Chloro-6- (2-chlorophenyl) -1-methyl-4- (pyridin-4-ylmethyl) -4H-2,3
4,5,10b-pentaazabenzo [e] azulene

[0500]

[Table 33]

[0501]

[Table 34]

[0502]

[Table 35]

[0503]

[Table 36]

Example 139 (10th step 1) 4- (4-Chlorophenyl) -2,3,9-trimethyl-6- (pyridin-3-ylmethyl) -6H-5,6,6
7,8,9a-pentaazathieno [2,3-e] azulene

[0505]

Embedded image

The 4- (4-chlorophenyl) -2,3,9-trimethyl-6H-5,6 obtained in Reference Example 42
7,8,9a-Pentazaazaeno [2,3-e] azulene (1 g) was dissolved in anhydrous N, N-dimethylformamide (10 ml) under an argon gas atmosphere, cooled on ice, and then sodium hydride (60% oily). ) (244 mg), and the mixture was stirred under ice cooling for 5 minutes and at room temperature for 30 minutes. The reaction mixture was cooled again with ice, and 3-picolyl chloride was added.

[0507] Hydrochloride (525 mg) was added, and the mixture was stirred for 4 hours under ice-cooling. After completion of the reaction, a 1% aqueous citric acid solution (50 ml) and ethyl acetate (50 ml) were added, and the organic layer was separated. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
The solid obtained by concentrating the fraction eluted in was crystallized with ethyl acetate: diethyl ether 1: 3,
The title compound (936 mg) was obtained as colorless crystals. Melting point 195-196 ° C ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 1.53 (3H, s), 2.37 (3H, s), 2.62 (3H, s), 5.03 (2H, s), 7.
23-7.32 (5H, m), 7.77 (1H, m), 8.54 (1H, dd, J = 5.0 and 1.
7Hz), 8.70 (1H, d, J = 2.0Hz)

Examples 140 to 150 (10th step 1) In the same manner as in Example 139, the compound of Example 140 was replaced with the compound of Reference Example 42, and the compounds of Examples 141 and 142 were replaced with the compound of Reference Example 43. The compounds of Examples 143 and 144 from the compound of Reference Example 44, the compounds of Examples 145 and 146 from the compound of Reference Example 45, the compounds of Examples 147 and 148 from the compound of Reference Example 46, and the compounds of Reference Example 47. The compounds of Examples 149 and 150 were obtained from the compounds. These are shown in Tables 37 and 38.

Example 140 4- (4-Chlorophenyl) -2,3,9-trimethyl-6- (pyridin-4-ylmethyl) -6H-5,6
7,8,9a-pentaazathieno [2,3-e] azulene

Example 141 4- (4-Chlorophenyl) -2-ethyl-9-methyl-6- (pyridin-3-ylmethyl) -6H-5,6,6
7,8,9a-pentaazathieno [2,3-e] azulene

Example 142 4- (4-Chlorophenyl) -2-ethyl-9-methyl-6- (pyridin-4-ylmethyl) -6H-5,6,6
7,8,9a-pentaazathieno [2,3-e] azulene

Example 143 2,9-Dimethyl-4-phenyl-6- (pyridine-3
-Ylmethyl) -6H-5,6,7,8,9a-pentaazathieno [2,3-e] azulene

Example 144 2,9-Dimethyl-4-phenyl-6- (pyridine-4
-Ylmethyl) -6H-5,6,7,8,9a-pentaazathieno [2,3-e] azulene

Example 145 2,3,9-Trimethyl-4-phenyl-6- (pyridin-3-ylmethyl) -6H-5,6,7,8,9a-
Pentaazathieno [2,3-e] azulene

Example 146 2,3,9-Trimethyl-4-phenyl-6- (pyridin-4-ylmethyl) -6H-5,6,7,8,9a-
Pentaazathieno [2,3-e] azulene

Example 147 2-Ethyl-9-methyl-4-phenyl-6- (pyridin-3-ylmethyl) -6H-5,6,7,8,9a-
Pentaazathieno [2,3-e] azulene

Example 148 2-Ethyl-9-methyl-4-phenyl-6- (pyridin-4-ylmethyl) -6H-5,6,7,8,9a-
Pentaazathieno [2,3-e] azulene

Example 149 4- (4-Methoxyphenyl) -2,3,9-trimethyl-6- (pyridin-3-ylmethyl) -6H-5
6,7,8,9a-pentaazathieno [2,3-e] azulene

Example 150 4- (4-methoxyphenyl) -2,3,9-trimethyl-6- (pyridin-4-ylmethyl) -6H-5
6,7,8,9a-pentaazathieno [2,3-e] azulene

[0520]

[Table 37]

[0521]

[Table 38]

Example 151 6- (4-Chlorophenyl) -1-methyl-4- (pyridin-3-ylmethyl) -4H-2,3,4,5,10
b-pentaazabenzo [e] azulene monohydrochloride monohydrate

[0523]

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The 6- (4-) obtained in Example 54 or 98
Chlorophenyl) -1-methyl-4- (pyridine-3-
Ylmethyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulene (501 mg) in ethanol (10 ml)
And a 4N hydrochloric acid / ethyl acetate solution (0.4 ml) was added. The solution was concentrated to 3 ml, and the precipitated crystals were collected by filtration. The crystals were suspended in ethanol (10 ml), heated, and allowed to stand at room temperature to give the title compound (395 mg) as colorless needles. 238-240 ° C ¹ H NMR (300 MHz, δ ppm, DMSO-d ₆ ) 2.49 (3 H, s), 4.98 (1 H, m), 5.08 (1 H, m), 7.15 (1 H, d, J = 7.
2Hz), 7.33-7.47 (5H, m), 7.69 (2H, m), 7.84 (1H, dd, J = 7.2
and 4.8Hz), 8.38 (1H, d, J = 7.5Hz), 8.72 (1H, d, J = 4.8H
z), 8.87 (1H, s)

Examples 152 to 156 In the same manner as in Example 151, the compound of Example 54 or 98 and p-toluenesulfonic acid monohydrate were used.
Of the compound of Example 153 from methanesulfonic acid, the compound of Example 154 from benzenesulfonic acid, the compound of Example 155 from the compound of Example 126 and 4N hydrochloric acid / ethyl acetate solution, and the compound of Example 143 from the 4N hydrochloric acid / ethyl acetate solution. The compound of Example 156 was obtained from the compound and p-toluenesulfonic acid monohydrate. These are shown in Tables 39 and 40.

Example 152 6- (4-Chlorophenyl) -1-methyl-4- (pyridin-3-ylmethyl) -4H-2,3,4,5,10
b-pentaazabenzo [e] azulene p-toluenesulfonate

Example 153 6- (4-Chlorophenyl) -1-methyl-4- (pyridin-3-ylmethyl) -4H-2,3,4,5,10
b-pentaazabenzo [e] azulene dimethanesulfonate

Example 154 6- (4-Chlorophenyl) -1-methyl-4- (pyridin-3-ylmethyl) -4H-2,3,4,5,10
b-pentaazabenzo [e] azulene 1.5 benzenesulfonate

Example 155 8-Chloro-1-methyl-6-phenyl-4- (pyridin-4-ylmethyl) -4H-2,3,4,5,10b
-Pentazabenzo [e] azulene hydrochloride

Example 156 2,9-Dimethyl-4-phenyl-6- (pyridine-3
-Ylmethyl) -6H-5,6,7,8,9a-pentaazathieno [2,3-e] azulene p-toluenesulfonate

Example 157 8-Chloro-1-methyl-6-phenyl-4- (pyridin-4-ylmethyl) -4H-2,3,4,5,10b
-Pentazabenzo [e] azulene p-toluenesulfonate

[0532]

[Table 39]

[0533]

[Table 40]

Example 158 6- (4-Chlorophenyl) -1-methyl-4- (pyridin-3-ylmethyl) -4H-2,3,4,5,10
b-pentaazabenzo [e] azulene citrate

[0535]

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The 6- (4-) obtained in Example 54 or 98
Chlorophenyl) -1-methyl-4- (pyridine-3-
Ylmethyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulene (401 mg) in ethanol (20 ml)
And added with citric anhydride (192 mg) and heated. The solution was concentrated to 10 ml, 7 ml of diethyl ether was added, and the mixture was allowed to stand at room temperature. The precipitated crystals were collected by filtration, suspended in ethanol (20 ml), heated, and allowed to stand at room temperature to give the title compound (395 mg) as colorless needles. Melting point 208-209 ° C ¹ H NMR (300 MHz, δ ppm, DMSO-d ₆ ) 2.53 (3H, s), 2.66 (2H, d, J = 15.3 Hz), 2.75 (2H, d, J = 15.3 H)
z), 4.86 (1H, m), 5.01 (1H, m), 7.20 (1H, d, J = 7.8Hz), 7.
35-7.53 (6H, m), 7.69-7.81 (3H, m), 8.48 (1H, dd, J = 4.7 a
nd 1.4Hz), 8.60 (1H, d, J = 1.4Hz)

Example 159 (10th step 1) 6- (4-Chlorophenyl) -1-methyl-4- (2-
Nitrobenzyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulene

[0538]

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6- (4-Chlorophenyl) -1-methyl-4H-2,3,4,5,10b obtained in Reference Example 34
-Pentaazabenzo [e] azulene (217 mg) was added under an argon gas atmosphere to dry N, N-dimethylformamide (3 m
l), 2-nitrobenzyl bromide (756 mg) and potassium carbonate (967 mg) were added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, insolubles were filtered off, and the filtrate was added with ethyl acetate (5%).
0 ml) and water (40 ml) were added and the organic layer was separated. The organic layer was sequentially washed with a 5% aqueous citric acid solution, saturated sodium hydrogen carbonate, and water, dried, filtered, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and eluted with chloroform: acetone 10: 1. The residue obtained by concentrating the fraction was crystallized from diethyl ether to give the title compound (46 mg) as yellow crystals. 204-205 ° C

Example 160 (10th step 1) 6- (4-Chlorophenyl) -4-ethoxycarbonylmethyl-1-methyl-4H-2,3,4,5,10b-
Pentaazabenzo [e] azulene In the same manner as in Example 159, the compound of Example 160 was obtained from the compound of Reference Example 34. This is shown in Table 41.

[0541]

[Table 41]

Example 161 (10th step 9) [6- (4-Chlorophenyl) -1-methyl-4H-
2,3,4,5,10b-pentaazabenzo [e] azulen-4-yl] acetic acid

[0543]

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6- (4-Chlorophenyl) -4-ethoxycarbonylmethyl-1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene obtained in Example 160 (151 mg) Was dissolved in ethanol (1.5 ml) and cooled on ice, and then 1N aqueous sodium hydroxide solution (0.37 m
l) was added, and the mixture was stirred under ice cooling for 1 hour and at room temperature for 2 hours.
The reaction solution was ice-cooled again, 1N hydrochloric acid (0.2 ml) was added, and the mixture was stirred for a while. To this, ethyl acetate (10 ml) and a saturated aqueous solution of sodium chloride (5 ml) were added, and the organic layer was separated.
The organic layer was further washed three times with a saturated aqueous solution of sodium chloride, dried and filtered. The residue obtained by concentrating the filtrate under reduced pressure was crystallized from diethyl ether to give the title compound (129 mg) as crystals. 274-275 ° C

Example 162 (10th step 10) 6- (4-Chlorophenyl) -1-methyl-4-phenylcarbamoylmethyl-4H-2,3,4,5,10b
-Pentaazabenzo [e] azulene

[0546]

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[6- (4-Chlorophenyl) -1-methyl-4H-2,3,4,5,1 obtained in Example 161
Ob-pentaazabenzo [e] azulen-4-yl] acetic acid (114 mg) was added to anhydrous N, N-dimethylformamide (2.2 m
l), and triethylamine (0.05 ml) was added.
After cooling to −15 ° C. in a dry ice acetone bath, isobutyl chlorocarbonate (0.4 ml) was added over 1 minute. -15 ° C
After stirring for 40 minutes while maintaining the internal temperature at -10 ° C, aniline (0.34 ml) was added. The internal reaction temperature was raised to 0 ° C. in 30 minutes, and the mixture was further stirred for 30 minutes. Ethyl acetate (15 ml) and water (10 ml) were added to the reaction solution, and the organic layer was separated. The organic layer was further washed with water, dried, filtered, and concentrated under reduced pressure.The residue obtained was dissolved in a small amount of chloroform, and diethyl ether was added for crystallization to obtain the title compound (111 mg) as crystals. . 249-252 ° C

Examples 163 to 170 (1 of the tenth step)
0) In the same manner as in Example 162, compounds of Examples 163 to 170 were obtained from the compound of Example 161. These are shown in Table 42.

Example 163 6- (4-Chlorophenyl) -1-methyl-4- (4-
Methylphenylcarbamoylmethyl) -4H-2,3
4,5,10b-pentaazabenzo [e] azulene

Example 164 6- (4-Chlorophenyl) -4- (2-methoxyphenylcarbamoylmethyl) -1-methyl-4H-2,
3,4,5,10b-pentaazabenzo [e] azulene

Example 165 6- (4-Chlorophenyl) -4- (2,5-dimethoxyphenylcarbamoylmethyl) -1-methyl-4H-
2,3,4,5,10b-pentaazabenzo [e] azulene

Example 166 4- (4-Chloro-2,5-dimethoxyphenylcarbamoylmethyl) -6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [E] Azulene

Example 167 6- (4-Chlorophenyl) -1-methyl-4- (naphthalen-1-ylcarbamoylmethyl) -4H-2,
3,4,5,10b-pentaazabenzo [e] azulene

Example 168 6- (4-Chlorophenyl) -1-methyl-4- (pyridin-3-ylcarbamoylmethyl) -4H-2,3
4,5,10b-pentaazabenzo [e] azulene

Example 169 6- (4-Chlorophenyl) -4- (cyclohexylcarbamoylmethyl) -1-methyl-4H-2,3,4
5,10b-pentaazabenzo [e] azulene

Example 170 6- (4-Chlorophenyl) -1-methyl-4-n-propylcarbamoylmethyl-4H-2,3,4,5,1
0b-pentaazabenzo [e] azulene

[0557]

[Table 42]

Example 171 (10th step 1) 4-bromoacetyl-6- (4-chlorophenyl) -1
-Methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene

[0559]

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6- (4-Chlorophenyl) -1-methyl-4H-2,3,4,5,10b obtained in Reference Example 34
-Pentazabenzo [e] azulene (100 mg) was dissolved in anhydrous dichloromethane (1 ml), anhydrous pyridine (52 µl) was added, and the mixture was cooled on ice and bromoacetyl bromide (42 µl) was added. After stirring for 30 minutes under ice-cooling and for 1.5 hours at room temperature, water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a 5% aqueous citric acid solution and water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography to obtain the title compound (70 mg) as white crystals. Was. ^{1 H NMR (300MHz, δppm,} CDCl 3) 2.70 (3H, s), 4.23-4.42 (2H, m), 7.36-7.52 (5H, m), 7.62
-7.65 (2H, m), 7.72-7.78 (1H, m)

Example 172 (10th step 11) 6- (4-Chlorophenyl) -4- (2-methoxyphenylaminoacetyl) -1-methyl-4H-2,3
4,5,10b-pentaazabenzo [e] azulene

[0562]

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The 4-bromoacetyl-6- (4-chlorophenyl) -1-methyl-4H- obtained in Example 171
2,3,4,5,10b-Pentazaazabenzo [e] azulene (8 mg) was suspended in ethanol and 2-anisidine (12.
5 μl) and stirred at 80 ° C. for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, water (20 ml) was added to the residue, and extracted with ethyl acetate (20 ml). The organic layer was further washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by preparative thin-layer chromatography to give the title compound (2.4 mg) as an oil. . ^{1 H NMR (300MHz, δppm,} CDCl 3) 2.67 (3H, s), 3.82 (3H, s), 4.35 (2H, m), 6.37 (1H, m), 6.
60-6.72 (3H, m), 7.29-7.43 (6H, m), 7.61-7.64 (3H, m)

Examples 173 to 176 (1 of the tenth step)
1) In the same manner as in Example 172, the compounds of Examples 173 to 176 were obtained from the compound of Example 171. These are shown in Table 43.
It was shown to.

Example 173 6- (4-Chlorophenyl) -1-methyl-4-phenylaminoacetyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene

Example 174 6- (4-Chlorophenyl) -1-methyl-4- (4-
Methylphenylaminoacetyl) -4H-2,3,4
5,10b-pentaazabenzo [e] azulene

Example 175 6- (4-Chlorophenyl) -4- (3-fluorophenylaminoacetyl) -1-methyl-4H-2,3
4,5,10b-pentaazabenzo [e] azulene

Example 176 6- (4-Chlorophenyl) -4- (2,5-dimethoxyphenylaminoacetyl) -1-methyl-4H-2,
3,4,5,10b-pentaazabenzo [e] azulene

[0569]

[Table 43]

Example 177 (Step 10 of 11) 6- (4-chlorophenyl) -1-methyl-4-phenylthioacetyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene

[0571]

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The 4-bromoacetyl-6- (4-chlorophenyl) -1-methyl-4H- obtained in Example 171
2,3,4,5,10b-Pentazabenzo [e] azulene (8 mg) was dissolved in anhydrous dichloromethane (0.8 ml), thiophenol (2 μl) and triethylamine (2.8 μl) were added, and the mixture was stirred at room temperature for 2 hours. did. After the reaction, add water (2
0 ml) and extracted with ethyl acetate (20 ml). 5 organic layers
% Citric acid aqueous solution, water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue obtained was purified by preparative thin-layer chromatography to give the title compound (2.1 mg). Obtained as a crystalline solid. ^{1 H NMR (300MHz, δppm,} CDCl 3) 2.69 (3H, s), 3.96-4.12 (2H, m), 7.03-7.76 (13H, m)

Example 178 (10th step 1) 6- (4-chlorophenyl) -1-methyl-4-phenylacetyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene

[0574]

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6- (4-Chlorophenyl) -1-methyl-4H-2,3,4,5,10b obtained in Reference Example 34
-Dissolve pentaazabenzo [e] azulene (20 mg) in anhydrous dichloromethane (0.2 ml), add pyridine (21 μl), 4-dimethylaminopyridine (1.5 mg) and phenylacetyl chloride (25.6 μl) and cool on ice. 30 minutes under, 16 at room temperature
Stirred for hours. After completion of the reaction, water (30 ml) was added, and the mixture was extracted with dichloromethane (30 ml). The organic layer is washed successively with a 5% aqueous citric acid solution and water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by preparative thin-layer chromatography and crystallized with diethyl ether. This gave the title compound (6 mg) as colorless crystals. 89-90 ° C

Example 179 (10th step 1) 6- (4-chlorophenyl) -1-methyl-4-phenyloxalyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene

In a similar manner to Example 178, the compound of Example 179 was obtained from the compound of Reference Example 34. This is shown in Table 44.

[0578]

[Table 44]

Example 180 (10th step 4) 6- (4-Chlorophenyl) -4-ethoxymethyl-1
-Methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene

[0580]

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The 6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,10b obtained in Reference Example 34
Pentaazabenzo [e] azulene (84 mg) in ethanol
(1 ml) and a 37% aqueous formaldehyde solution (0.12m
l) was added and the mixture was heated under reflux for 3 days. The reaction solvent was evaporated under reduced pressure, the residue was purified by preparative thin-layer chromatography, and crystallized from ethyl acetate-diethyl ether to give the title compound (70 mg) as colorless crystals. Melting point 98-100 ° C

Example 181 (10th step 4) [6- (4-Chlorophenyl) -1-methyl-4H-
2,3,4,5,10b-pentaazabenzo [e] azulen-4-ylmethyl] -phenyl-amine

[0583]

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6- (4-Chlorophenyl) -1-methyl-4H-2,3,4,5,10b obtained in Reference Example 34
-Pentazabenzo [e] azulene (20mg) in ethanol
(0.1 ml) and 37% formaldehyde solution (6 μl)
And aniline (7.6 μl) were added, and the mixture was heated and stirred for 2 hours.
By cooling the reaction solution and collecting the precipitated crystals by filtration,
The title compound (13.8 mg) was obtained as colorless crystals. Melting point 223-224 ° C

Example 182 (10th step 5) 4-benzylcarbamoyl-6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene

[0586]

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6- (4-Chlorophenyl) -1-methyl-4H-2,3,4,5,10b obtained in Reference Example 34
-Pentazabenzo [e] azulene (206 mg) was suspended in anhydrous acetonitrile, sodium hydroxide (52 mg) and benzyl isocyanate (100 μl) ground in a mortar were added, and the mixture was stirred at room temperature for 2 hours and at 50 ° C. for 2 hours. did. After completion of the reaction, the reaction solution was concentrated under reduced pressure, water (30 ml) was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography and crystallized from ethyl acetate-diethyl ether to give the title compound.
(80 mg) was obtained. 146-149 ° C

Example 183 (10th step 5) 6- (4-Chlorophenyl) -1-methyl-4- (3-
Methylphenylcarbamoyl) -4H-2,3,4
5,10b-Pentazaazabenzo [e] azulene Example 1
In the same manner as in Example 82, the compound of Reference Example 34 was used to obtain Example 18
Compound 3 was obtained. This is shown in Table 45.

[0589]

[Table 45]

Example 184 (15th step 15) 6- (4-chlorophenyl) -4- (4-hydroxybenzyl) -1-methyl-4H-2,3,4,5,10b
-Pentaazabenzo [e] azulene

[0591]

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4- (4-benzyloxybenzyl) -6- (4-chlorophenyl) -1- obtained in Example 93
Methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene (80 mg) was dissolved in ethanol (1 ml), and palladium black (4 mg) was added. Stirred for days. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by preparative thin-layer chromatography (chloroform: methanol 20: 1) and crystallized from ethyl acetate-diethyl ether to give the title compound.
(29 mg) was obtained. Melting point 254-257 ° C

Example 185 (10th step 15) 6- (4-Chlorophenyl) -4- (3,4-dihydroxybenzyl) -1-methyl-4H-2,3,4,5
10b-pentaazabenzo [e] azulene In the same manner as in Example 184, the compound of Example 185 was obtained from the compound of Example 115. This is shown in Table 46.

[0594]

[Table 46]

Example 186 (10th step 16) 6- (4-Chlorophenyl) -4- (4-ethoxybenzyl) -1-methyl-4H-2,3,4,5,10b-
Pentaazabenzo [e] azulene

[0596]

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6- (4-Chlorophenyl) -4- (4-hydroxybenzyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene obtained in Example 184 (15 mg) was dissolved in tetrahydrofuran (2 ml), and after cooling with ice, a diazoethane solution was added and the mixture was stirred at 0 ° C. overnight. The residue obtained by concentrating the reaction solution under reduced pressure was purified by preparative thin-layer chromatography to obtain the title compound (12 mg). ^{1 H NMR (300MHz, δppm,} CDCl 3) 1.40 (3H, t, J = 7.2Hz), 2.60 (3H, s), 4.02 (2H, q, J = 7.2H
z), 4.88-5.03 (2H, m), 6.83 (2H, d, J = 9.0Hz), 7.18-7.64
(10H, m)

Example 187 (10th step 2) 6- (4-chlorophenyl) -1-methyl-4- (4-
Methylsulfonylphenyl) hydroxymethyl-4H-
2,3,4,5,10b-pentaazabenzo [e] azulene

[0599]

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6- (4-Chlorophenyl) -1-methyl-4H-2,3,4,5,10b obtained in Reference Example 34
-Pentazabenzo [e] azulene (93 mg) was dissolved in N, N-dimethylformamide (1 ml), crushed potassium hydroxide (100 mg) was added, and the mixture was stirred under dry air at room temperature for 5 minutes. Then p-methylsulfonylbenzyl chloride
(68 mg) and the mixture was stirred at room temperature for 5 minutes. After completion of the reaction, the mixture was cooled on ice, and a 5% aqueous solution of citric acid and ethyl acetate were added to separate an organic layer. The organic layer was dried, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography, and crystallized from ethyl acetate-diethyl ether to obtain the title compound (34 mg). 142-144 ° C

Example 188 (10th step 12) 4- (4-aminobenzyl) -6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [ e] azulene and 6- (4-chlorophenyl) -4- (4-formylaminobenzyl) -1-
Methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene

[0602]

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6- (4-Chlorophenyl) -1-methyl-4- (4-nitrobenzyl) obtained in Example 122
-4H-2,3,4,5,10b-pentaazabenzo [e] azulene (680 mg) was treated with methanol (20 ml) and formic acid (6 ml).
ml), and palladium black (68 mg) was added thereto.
Stirred for hours. The catalyst was filtered off, and the residue obtained by concentrating the filtrate under reduced pressure was dissolved in ethyl acetate, and water was added to separate an organic layer. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and water, dried, filtered and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography and crystallized from diethyl ether to give 4- (4-amino (Benzyl) -6- (4-chlorophenyl) -1-methyl-4H
-2,3,4,5,10b-pentaazabenzo [e] azulene (120 mg) (melting point: 234 to 237 ° C) and 6- (4
-Chlorophenyl) -4- (4-formylaminobenzyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene (340 mg) (mp 215-
216 ° C).

Example 189 (10th step 13) 4- (4-acetylaminobenzyl) -6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,1
0b-pentaazabenzo [e] azulene

[0605]

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4- (4-aminobenzyl) -6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene obtained in Example 188 (12.4 mg) was dissolved in dichloromethane (1 ml), cooled with ice, and acetyl chloride (2.4 μm) was added.
Stirred for 0 minutes and room temperature for 20 minutes. After completion of the reaction, the residue obtained by evaporating dichloromethane under reduced pressure was crystallized from ethyl acetate-diethyl ether to give the title compound (11.1 m
g) was obtained. 245-249 ° C

Example 190 (10th step 13) 6- (4-Chlorophenyl) -4- (4-methylsulfonylaminobenzyl) -1-methyl-4H-2,3
4,5,10b-pentaazabenzo [e] azulene and 4- [4-bis (methylsulfonyl) aminobenzyl]
-6- (4-chlorophenyl) -4H-2,3,4
5,10b-pentaazabenzo [e] azulene

[0608]

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4- (4-aminobenzyl) -6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene obtained in Example 188 (24.8 mg) was dissolved in dichloromethane (2 ml), triethylamine (30 μl) was added, the mixture was cooled on ice, methanesulfonyl chloride (7 μl) was added, and 10
And stirred at room temperature for 2 hours. After concentrating the reaction solution under reduced pressure, 5%
An aqueous citric acid solution and ethyl acetate were added thereto, and the organic layer was separated and washed sequentially with a saturated aqueous sodium hydrogen carbonate solution and water. The organic layer was dried, filtered, and concentrated under reduced pressure, and the obtained residue was separated and purified by preparative thin-layer chromatography. The two compounds were each crystallized from ethyl acetate-diethyl ether to give 6- (4-chlorophenyl) -4-
(4-methylsulfonylaminobenzyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene (8 mg) (melting point 273-275 ° C.) and 4
-[4-bis (methylsulfonyl) aminobenzyl]-
6- (4-chlorophenyl) -4H-2,3,4,5
There was obtained 10b-pentaazabenzo [e] azulene (16 mg) (melting point: 220-221 ° C).

Example 191 (10th step 14) 6- (4-Chlorophenyl) -4- (4-dimethylaminobenzyl) -1-methyl-4H-2,3,4,5,1
Ob-pentaazabenzo [e] azulene hydrochloride

[0611]

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The 4- (4-aminobenzyl) -6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene obtained in Example 188 (124 mg) was dissolved in ethanol (5 ml).
A 25% aqueous formaldehyde solution (0.15 ml) and palladium black (10 mg) were added, and the mixture was stirred under a hydrogen atmosphere for 2 days. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to preparative thin-layer chromatography (chloroform: acetone 3:
Purification was performed in 1), and the obtained solid was dissolved in diethyl ether, and a 1N hydrogen chloride-diethyl ether solution (0.1 ml) was added to form crystals. This was collected by filtration and washed with diethyl ether to give the title compound (34 mg)
I got Melting point 169-175 ° C

Example 192 (10th step 6) 6- (4-Chlorophenyl) -4- (2-hydroxy-
2-phenylethyl) -1-methyl-4H-2,3,
4,5,10b-pentaazabenzo [e] azulene

[0614]

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6- (4-Chlorophenyl) -1-methyl-4H-2,3,4,5,10b obtained in Reference Example 34
-Pentazabenzo [e] azulene (103 mg) was added to N, N-
The residue was dissolved in dimethylformamide (10 ml), cooled with ice, sodium hydride (60% oil) (15.9 mg) was added, and the mixture was stirred under ice cooling for 5 minutes and at room temperature for 10 minutes. Then, styrene oxide (46 μl) was added, and the mixture was stirred at 50 ° C. for 1 hour. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, filtered, and purified by silica gel column chromatography to give the title compound (62 m
g) was obtained as an amorphous solid. ^{1 H NMR (300MHz, δppm,} CDCl 3) 2.61 (3H, s), 4.08 (2H, m), 5.34 (1H, m), 7.27-7.72 (13H,
m)

Example 193 (tenth step 8) 6- (4-Chlorophenyl) -4- (2-oxo-2-
Phenylethyl) -1-methyl-4H-2,3,4
5,10b-pentaazabenzo [e] azulene

[0617]

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6- (4-Chlorophenyl) -4- (2-hydroxy-2-phenylethyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo obtained in Example 192 [E] Azulene (31 mg) was dissolved in anhydrous dichloromethane (0.3 ml) and pyridinium dichromate (54.
4 mg) and stirred at room temperature. The reaction solution was filtered using celite, washed with water, and dried over anhydrous sodium sulfate.
The residue obtained by concentration under reduced pressure was purified by preparative thin-layer chromatography to give the title compound (2.0 mg).
Was obtained as an amorphous solid.

[0619] ^{1 H NMR (300MHz, δppm,} CDCl 3) 2.63 (3H, s), 5.40 (2H, s), 7.28-7.67 (11H, m), 8.03-8.0
7 (2H, m)

Example 194 (10th step 1) 6- (4-Chlorophenyl) -1-methyl-4- [3-
Phenyl-2- (tetrahydropyran-2-yloxy) propyl] -4H-2,3,4,5,10b-pentaazabenzo [e] azulene

[0621]

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According to a method similar to that of Example 56, Reference Example 3
The title compound (156 mg) was obtained from 6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene (100 mg) obtained in 4 above. However, 2- (1-benzyl-2-bromoethoxy) tetrahydropyran was used instead of 3- (chloromethyl) benzonitrile.

¹ H NMR (300 MHz, δppm, CDCl ₃ ) 0.96-1.66 (7H, m), 2.57 (3H, s), 2.88-3.47 (3H, m), 3.95
-4.78 (4H, m), 7.13-7.65 (13H, m)

Example 195 (10th step 1) 6- (4-Chlorophenyl) -4- [2- (2-methoxyphenyl) -2- (tetrahydropyran-2-yloxy) ethyl] -1-methyl- 4H-2,3,4,5
10b-pentaazabenzo [e] azulene In the same manner as in Example 194, the compound of Example 195 was obtained from the compound of Reference Example 34. This is shown in Table 47.

[0625]

[Table 47]

Example 196 (10th step 7) 6- (4-Chlorophenyl) -4- (2-hydroxy-
3-phenylpropyl) -1-methyl-4H-2,3,
4,5,10b-pentaazabenzo [e] azulene

[0627]

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The 6- (4-chlorophenyl) -1-methyl-4- [3-phenyl-2- obtained in Example 194
(Tetrahydropyran-2-yloxy) propyl]-
4H-2,3,4,5,10b-Pentazaazabenzo [e] azulene (146 mg) was dissolved in ethanol (0.7 ml), and pyridinium-p-toluenesulfonic acid (218 mg) was added. Stir for 18 hours. After allowing to cool to room temperature, water (30 ml) was added, and the mixture was extracted with ethyl acetate (30 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound (112 mg) as an amorphous solid. ^{1 H NMR (300MHz, δppm,} CDCl 3) 2.59 (3H, s) 2.73-2.88 (2H, m), 3.81-3.98 (2H, m), 4.44-
4.61 (1H, m), 7.22-7.44 (12H, m), 7.60-7.65 (1H, t, J = 7.5
Hz)

Example 197 (10th step 8) 6- (4-Chlorophenyl) -4- (2-oxo-3-
Phenylpropyl) -1-methyl-4H-2,3,4
5,10b-pentaazabenzo [e] azulene

[0630]

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The 6- (4-chlorophenyl) -4- (2-hydroxy-3-phenylpropyl) -1-methyl-4H-2,3,4,5,10b- obtained in Example 196
Dissolve pentaazabenzo [e] azulene (89 mg) in anhydrous dichloromethane (1 ml) and add pyridinium chlorochromate.
(130 mg) and the mixture was stirred at room temperature for 12 hours. After the completion of the reaction, the reaction solution was purified by silica gel column chromatography, and crystallized from diethyl ether to obtain the title compound (23 mg) as white crystals. 81-84 ° C

Examples 198 to 203 The compounds of Examples 198 to 203 were obtained from the compound of Reference Example 34 in the same manner as in Examples 192 to 197. This is shown in Table 48.

Example 198 6- (4-Chlorophenyl) -4- [2- (4-chlorophenyl) -2-oxoethyl] -1-methyl-4H-
2,3,4,5,10b-pentaazabenzo [e] azulene

Example 199 6- (4-Chlorophenyl) -1-methyl-4- [2-
(4-methylphenyl) -2-oxoethyl] -4H-
2,3,4,5,10b-pentaazabenzo [e] azulene

Example 200 6- (4-Chlorophenyl) -4- [2- (2-methoxyphenyl) -2-oxoethyl] -1-methyl-4H
-2,3,4,5,10b-Pentazabenzo [e] azulene

Example 201 6- (4-Chlorophenyl) -4- [2- (2,5-dimethoxyphenyl) -2-oxoethyl] -1-methyl-4H-2,3,4,5,10b-penta Azabenzo [e] azulene

Example 202 6- (4-Chlorophenyl) -4- [3- (2-methoxyphenyl) -2-oxopropyl] -1-methyl-4
H-2,3,4,5,10b-pentaazabenzo [e]
Azulene

Example 203 6- (4-Chlorophenyl) -4- [3- (2,5-dimethoxyphenyl) -2-oxopropyl] -1-methyl-4H-2,3,4,5,10b- Pentaazabenzo [e] azulene

[0639]

[Table 48]

Reference Example 48 (11th step) 2-[(4-chlorophenyl) hydrazonomethyl] phenylamine

[0641]

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2-Aminophenyl 4-chlorophenyl ketone (27.2 g) was suspended in diethylene glycol (170 ml), 100% hydrazine hydrate (23 ml) was added, and the mixture was heated under reflux for 7 hours. The reaction solution was allowed to cool to room temperature, water (400 ml) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure.The obtained residue was subjected to silica gel column chromatography, and the obtained solid was crystallized from petroleum ether-diethyl ether to give the title compound ( 20.25 g). 85-86 ° C

Reference Example 49 (12th step) 2- (4-chlorobenzyl) phenylamine

[0644]

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Potassium hydroxide (12.15 g) was dissolved in diethylene glycol (128 ml) and the volatiles were distilled until the temperature of the solution reached 200 ° C. This solution was allowed to cool to room temperature, and 2-[(4-chlorophenyl) hydrazonomethyl] phenylamine (20.25 g) obtained in Reference Example 48 was added, and the mixture was slowly heated to 150 ° C. After heating at the same temperature for 90 minutes until gas evolution ceased, the solution was cooled to 120 ° C., poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography to give the title compound (17 g) as an oil. ^{1 H NMR (300MHz, δppm,} CDCl 3) 3.47 (2H, s), 3.86 (2H, s), 6.66-7.27 (8H, m)

Reference Example 50 (13th step) Acetic acid [2- (4-chlorobenzyl) phenylaminomethylene] hydrazide

[0647]

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A mixture of 2- (4-chlorobenzyl) phenylamine (17 g) obtained in Reference Example 49 and triethyl orthoformate (27.9 g) was heated under reflux for 5 hours. The reaction solution was allowed to cool to room temperature, and anhydrous ethanol (160 ml) and acetohydrazide (11.6 g) were added, followed by stirring for 13 hours. The precipitated crystals were collected by filtration, washed with hexane-ethanol, and dried to give the title compound (25 g) as colorless crystals. Melting point 163-165 ° C

Reference Example 51 (14th step) 4- [2- (4-chlorobenzyl) phenyl] -3-methyl-4H- [1,2,4] triazole

[0650]

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The acetic acid [2- (4-chlorobenzyl) phenylaminomethylene] hydrazide (1
1.6 g) in diethylene glycol dimethyl ether (250 m
l) and heated under reflux for 14 hours. The mixture was allowed to cool to room temperature, the solvent was distilled off under reduced pressure, and the obtained crystals were collected by filtration, washed with diethyl ether, and dried to give the title compound (6 g) as colorless crystals. 137-139 ° C

Reference Example 52 (15th step) 4-Chlorophenyl 2- (3-methyl- [1,2,2
4] triazol-4-yl) phenyl ketone

[0653]

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The 4- [2- (4-chlorobenzyl) phenyl] -3-methyl-4H- [1,1 obtained in Reference Example 51
[2,4] Triazole (290 mg) was dissolved in glacial acetic acid (1 ml), Jones reagent (1.2 ml) was added dropwise under ice cooling, and the mixture was heated under reflux for 4 hours. Further, Jones reagent (0.2 ml) was added, and the mixture was heated under reflux for 2 hours. After completion of the reaction, the mixture was poured into a 5% aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give the title compound (185 mg) as crystals. 140-141 ° C

Reference Example 53 (16th step) 2- (3-bromo-5-methyl- [1,2,4] triazol-4-yl) phenyl 4-chlorophenyl ketone

[0656]

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4-Chlorophenyl 2- (3-methyl- [1,2,4] triazole-4 obtained in Reference Example 52
-Yl) phenyl ketone (165 mg) was dissolved in carbon tetrachloride, N-bromosuccinimide (110 mg) was added, and the mixture was refluxed under a nitrogen atmosphere for 3 hours. After completion of the reaction, the reaction solution was allowed to cool to room temperature, and chloroform was added to dissolve an insoluble oily substance, followed by washing with water. The organic layer is dried over anhydrous magnesium sulfate,
After filtration, the residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography to give the title compound (65 mg) as crystals. 177-179 ° C

Reference Example 54 (17th step) 6- (4-chlorophenyl) -1-methyl-4H-2,
3,4,5,10b-pentaazabenzo [e] azulene

[0659]

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The 2- (3-bromo-) obtained in Reference Example 53
5-methyl- [1,2,4] triazol-4-yl)
Phenyl 4-chlorophenyl ketone (1.55 g) was dissolved in absolute ethanol (30 ml), and hydrazine sulfate (1.95 g) and sodium acetate (2.87 g) were added.
The mixture was heated under reflux for 60 hours. After the reaction, allow to cool to room temperature,
A 5% aqueous sodium hydrogen carbonate solution was added to the residue obtained by concentration under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.The resulting residue was subjected to silica gel column chromatography, and the obtained residue was crystallized from diethyl ether. The title compound (670m
g) was obtained as needles. Melting point 231-233 ° C

Reference Example 55 (18th step) 2-[(4-chlorophenyl) carbomethoxyhydrazonomethyl] phenylamine

[0662]

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2-Aminophenyl 4-chlorophenyl ketone (25 g) was dissolved in ethanol (300 ml), and methyl carbazate (19.44 g) and p-toluenesulfonic acid monohydrate (6.16 g) were added. Heated to reflux for an hour. The reaction solution was cooled to room temperature, and the resulting crystals were collected by filtration and washed with ethanol to give the title compound (32 g) as white crystals. 217-218 ° C

Reference Example 56 (19th step) 5- (4-chlorophenyl) -1,3-dihydrobenzo [e] [1,2,4] triazepin-2-one

[0665]

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The 2-[(4-chlorophenyl) carbomethoxyhydrazonomethyl] phenylamine (32 g) obtained in Reference Example 55 was dissolved in dimethyl sulfoxide (100 ml) and heated at 180 ° C. for 1.5 hours. The reaction solution was cooled to room temperature, poured into water (1 l), and the resulting crystals were collected by filtration and washed with water to give the title compound (26 g) as yellow crystals. 257-259 ° C

Reference Example 57 (Step 18 ') 5- (4-Chlorophenyl) -1,3-dihydrobenzo [e] [1,2,4] triazepin-2-one

[0668]

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2-Aminophenyl 4-chlorophenyl ketone (25 g) was added to dimethyl sulfoxide (100
ml), and methyl carbazate (22.4 g) was added thereto, followed by heating and stirring at 180 ° C for 18 hours. The reaction solution was cooled to room temperature, poured into water (31), and the resulting crystals were collected by filtration and washed with water to give the title compound (24 g).
Was obtained as yellow crystals. The melting point of this compound is shown in Reference Example 56.
And matched.

Reference Example 58 (20th step) 5- (4-chlorophenyl) -1-methoxymethyl-
1,3-dihydrobenzo [e] [1,2,4] triazepin-2-one

[0671]

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[0672] 5 obtained in Reference Example 56 or Reference Example 57
-( 4 -Chlorophenyl) -1,3-dihydrobenzo [e] [1,2,4] triazepin-2-one (1 g)
Was suspended in N, N-dimethylformamide (20 ml), and potassium hydroxide (413 mg) was added.
Stir for 5 minutes. Chloromethyl methyl ether (419 μl) was added to the reaction solution, and the mixture was further stirred at room temperature for 30 minutes. The reaction solution was poured into water (50 ml) and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was crystallized from ethyl acetate-diethyl ether to give the title compound (350 mg) as yellow crystals. 177-180 ° C

Reference Example 59 (21st step) 3-benzyl-5- (4-chlorophenyl) -1-methoxymethyl-1,3-dihydrobenzo [e] [1,2,2
4] Triazepin-2-one

[0674]

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The 5- (4-chlorophenyl) -1-methoxymethyl-1,3-dihydrobenzo [e] [1,2,4] triazepin-2-one obtained in Reference Example 58 (350 m
g) was dissolved in dimethyl sulfoxide (3.5 ml), sodium hydride (60% oily) (53.2 mg) was added, and the mixture was added at room temperature for 3 hours.
Stirred for 0 minutes. Benzyl bromide (158 μl) was added, and the mixture was further stirred for 1 hour. The reaction solution was poured into water, neutralized with glacial acetic acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue obtained was subjected to silica gel chromatography to give the title compound.
(374 mg) was obtained as an oil. ^{1 H NMR (300MHz, δppm,} CDCl 3) 3.47 (3H, s), 4.62-5.17 (4H, m), 7.04-7.57 (13H, m)

Reference Example 60 (22nd step) 3-benzyl-5- (4-chlorophenyl) -1,3-
Dihydrobenzo [e] [1,2,4] triazepine-2
-ON

[0677]

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The 3-benzyl-5 obtained in Reference Example 59
(4-chlorophenyl) -1-methoxymethyl-1,3
-Dihydrobenzo [e] [1,2,4] triazepine-
2-One (370 mg) was dissolved in ethanol (1 ml), 5N hydrochloric acid (2 ml) was added, and the mixture was heated under reflux for 3 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. 5%
The residue was washed with an aqueous sodium hydrogen carbonate solution and water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.The residue obtained was washed with diethyl ether to give the title compound (260 mg) as white crystals. . 200-202 ° C

Example 204 (23rd step) 3-benzyl-5- (4-chlorophenyl) -1,3-
Dihydrobenzo [e] [1,2,4] triazepine-2
−Thion

[0680]

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The 3-benzyl-5 obtained in Reference Example 60
(4-Chlorophenyl) -1,3-dihydrobenzo [e] [1,2,4] triazepin-2-one (100 mg)
Was suspended in diethylene glycol dimethyl ether (2 ml), diphosphorus pentasulfide (74 mg) and sodium hydrogen carbonate (74 mg)
Was added and the mixture was heated and stirred at 100 ° C. for 22 hours. Further, diphosphorus pentasulfide (64 mg) was added, and the mixture was heated and stirred at 100 ° C. for 24 hours. The reaction solution was cooled to room temperature, poured into a 5% aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.The obtained residue was purified by preparative thin-layer chromatography to give the title compound (60 mg) as yellow crystals. As obtained. 159-160 ° C

Example 205 (4th step) 3-benzyl-5- (4-chlorophenyl) -3H-benzo [e] [1,2,4] triazepin-2-ylhydrazine

[0683]

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The 3-benzyl-5 obtained in Example 204
-(4-Chlorophenyl) -1,3-dihydrobenzo [e] [1,2,4] triazepine-2-thione (40 mg)
Was dissolved in anhydrous tetrahydrofuran (0.4 ml), 100% hydrazine hydrate (10 μl) was added, and the mixture was stirred at room temperature for 4 hours. The temperature of the reaction solution was raised to 40 ° C., and the mixture was further stirred for 4 hours. The residue was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.The residue obtained was purified by preparative thin-layer chromatography to give the title compound (1
7 mg) as a yellow powder. ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 4.79 (2H, s), 6.99-7.50 (16H, m)

Example 206 (Fifth Step) 4-Benzyl-6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene

[0686]

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The 3-benzyl-5 obtained in Example 205
-(4-chlorophenyl) -3H-benzo [e] [1,
[2,4] Triazepin-2-ylhydrazine (14 mg) was dissolved in toluene (1 ml), ethyl orthoacetate (14 μl) was added, and the mixture was heated under reflux for 2 days. Cool the reaction to room temperature,
Poured into water (10 ml) and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.The residue obtained was purified by preparative thin-layer chromatography to give the title compound.
(5 mg) was obtained as white crystals. 234-238 ° C

Reference Example 61 (26th step) 5- (4-chlorophenyl) -2- (2,2-dimethoxyethylamino) -3- (4-methoxybenzyl) -3
H-benzo [e] [1,2,4] triazepine

[0689]

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5- (4-chlorophenyl) -3- (4-methoxybenzyl) -2-methylthio-3H-benzo [e] [1,2,4] triazepine obtained in Example 35
(300 mg) was dissolved in 2-ethoxyethanol (1 ml), and aminoacetaldehyde dimethyl acetal (85.2 μl) and p-toluenesulfonic acid (14 mg) were added. Reaction solution 3
The mixture was heated from 80 ° C. to the reflux temperature over a period of time, and further heated and refluxed for 1 hour. After the reaction is completed, allow to cool to room temperature, and add water (20m
l) was added and extracted with ethyl acetate (30 ml). Water the organic layer,
The residue was washed with a 5% aqueous sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was crystallized from n-hexane: diethyl ether 5: 1 to give the title compound. (160 mg) was obtained as white crystals. 114-115 ° C

Example 207 (Step 27) 6- (4-chlorophenyl) -4- (4-methoxybenzyl) -4H-3,4,5,10b-tetraazabenzo [e] azulene

[0692]

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The 5- (4-chlorophenyl) -2- (2,2-dimethoxyethylamino)-obtained in Reference Example 61
3- (4-methoxybenzyl) -3H-benzo [e]
[1,2,4] Triazepine (100 mg) was dissolved in a 1N hydrochloric acid-acetic acid solution and heated under reflux for 7 hours. The reaction solution was allowed to cool, concentrated under reduced pressure, added with water (20 ml), and extracted with ethyl acetate (20 ml). The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.The residue obtained was purified by preparative thin-layer chromatography to give the title compound (3
2 mg) was obtained as an amorphous solid. ^{1 H NMR (300MHz, δppm,} CDCl 3) 3.79 (3H, s), 4.92 (2H, s), 6.83-6.87 (2H, m), 6.97 (1H,
d, J = 1.8Hz), 7.06-7.41 (9H, m), 7.51-7.57 (1H, m)

(Test Example) Next, the results of a test performed on the bone resorption inhibiting action of the triazepine compound represented by the above general formula [I] according to the present invention will be shown.

Test Example 1 Bone Resorption Inhibitory Effect The bone resorption inhibitory effect was basically measured by the method of Lois [Journal of Clinical Investigation (J. Clin. Invest.) Vol.
116, 1965]. I for 1 or 2 days after birth
1.5 CaCi was intraperitoneally administered with ⁴⁵ Ca (a calcium isotope, CaCl ₂ solution) to one newborn CR mouse, and the parietal bone was aseptically removed the next day. The parietal bone was divided into two along the central suture line, one of which was a control group and the other was an experimental group. Test compounds were used at 0.04 μM, 0.2 μM and 1 μM
0.5 ml of BGJb medium (Fit
ton-Jackson modification,
[GIBCO Laboratories (USA)] containing bovine serum albumin 1 mg / ml) at 37 ° C.
After pre-culture for one day, the culture was continued for another three days in the above medium containing 50 nM hPTH (1-34). After cultivation,
The radioactivity of ⁴⁵ Ca in the medium and in the bone was measured, and the ratio (%) of ⁴⁵ Ca released from the bone into the medium was determined according to the following equation.

[0696]

(Equation 1)

A bone obtained from the same mouse was treated in the same manner without adding the test compound, and the ratio (%) to the control group was determined according to the following formula.

[0698]

(Equation 2)

The average of these values obtained from 4 pairs of bones in each group was determined, and the IC ₅₀ value was calculated from the results. The results are shown in Table 49.

[0700]

[Table 49]

Test Example 2 Inhibitory Effect on Bone Loss [0707] Using an ovariectomized rat (osteoporosis model rat), the compound of the present invention was tested for its inhibitory effect on bone loss. 13-week-old SD female rats were treated with Nembutal (50 mg / kg / m
l, i. p. Dainippon Pharmaceutical Co., Ltd.) Underwent bilateral ovariectomy under anesthesia. At this time, a sham operation group in which ovaries were not removed was provided as a normal control. Based on the lumbar vertebra (L4-5) bone density (hereinafter abbreviated as BMD) of each rat measured with a bone mineral analyzer DCS-600R (Aloka) under ether anesthesia the day before the treatment, the BMD of each group was treated on the day after the treatment. Were grouped so as to average. The test compound was suspended in 0.5% hydroxypropylmethylcellulose (hereinafter abbreviated as HPMC; Shin-Etsu Chemical Co., Ltd.) and 0.3, 1.0 or 3.0 mg / 5.
ml / kg (5 ml / kg) was orally administered every day for 12 weeks from the day after the operation. As a positive control, 17β-estradiol (Sigma) was added to 5% benzyl alcohol and 95%
It was dissolved in corn oil and subcutaneously administered at 50 μg / kg (1 ml / kg) twice a week for 12 weeks. Normal control and control were orally administered 0.5% HPMC at 5 ml / kg daily for 12 weeks. On the day after the final administration, the rats were exsanguinated and killed under ether anesthesia, and the lumbar spine (L4-5) was collected. After removing soft tissues and processes from the collected lumbar spine, BMD of the vertebral body (L4-5)
Was measured with a bone mineral analyzer DCS-600R (Aloka). The results are the mean ± SEM of each group. E. FIG. The test was performed by one-way analysis of variance for comparison between groups. Note that a significance level of less than 5% was defined as significant. The results are shown in Table 50.

[0702]

[Table 50]

[0703]

Industrial Applicability The triazepine compound represented by the above general formula [I] according to the present invention has an excellent inhibitory action on bone resorption and has low toxicity. From the results of the bone resorption inhibitory test, it is also clear that these compounds have an effect of reducing serum calcium caused by bone resorption.
Therefore, these compounds are considered to be associated with diseases such as Paget's disease, hypercalcemia, osteoporosis or inflammatory joint diseases such as rheumatoid arthritis, in which enhanced bone resorption is considered to be importantly involved in the pathological condition. Effectively suppresses bone resorption against pathological conditions such as enhanced resorption (osteoporosis) and prevents bone loss, or prevents or reduces serum calcium levels associated with increased bone resorption. It can be used as a medicament.

The compounds represented by the above general formulas [II '] and [II]
The compound represented by I ′] or [IV ′] is useful as an intermediate for producing the triazepine compound represented by the general formula [I].

──────────────────────────────────────────────────の Continuation of the front page (51) Int.Cl. ⁶ Identification number Agency reference number FI Technical display location C07D 495/04 108 C07D 495/04 108 495/14 495/14 E // (C07D 487/04 249 : 08 255: 04) (C07D 487/04 233: 88 255: 04) (C07D 487/04 255: 04 257: 04) (C07D 495/04 255: 04 333: 10) (C07D 495/14 233: 88 255: 04 333: 10) (C07D 495/14 249: 08 255: 04 333: 10) (C07D 495/14 255: 04 257: 04 333: 10)

Claims (32)

(57) [Claims] 1. A compound of the general formula [I] [Wherein, R ¹ represents an optionally substituted aryl group or an optionally substituted heteroaryl group; R ² represents a hydrogen atom,
A hydroxyl group, a halogen atom or a lower alkyl group, R ⁴
Represents a hydrogen atom or a halogen atom, or R ² and R ⁴ together form a carbonyl group together with the carbon atom to which they are attached; R ³ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl ^{group, -CR 5 = CR 6 R 7} (R 5, R 6 and R ⁷ are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group Or an aryl group which may be substituted.), —OR ¹⁸
(R ¹⁸ is an optionally substituted aryl group.), (Where R ⁸ is a hydrogen atom, a lower alkyl group, a cycloalkyl group, an optionally substituted aryl group, an aralkyl group or an optionally substituted heteroaryl group, and R ⁹ and R ¹⁰ are the same or different. Hydrogen atom, lower alkyl group,
It is a lower alkoxy group, a hydroxyl group, a halogen atom, a nitro group or an amino group. ) Or -XY ｛where X is-(
CH ₂ ) _m- (m is an integer of 1 to 4), -CO
_{-, - COCH 2 -, -} NH -, - NHCH 2 -, - C
_{H 2 NH -, - CH 2} NHCO -, - OCH 2 -, -
(CH ₂ ) _n O— (n is an integer of 1 to 4) or —CH ₂ S—; Y is a halogen atom, a cycloalkyl group, an optionally substituted aryl group, or an optionally substituted It is a heteroaryl group. Represents a ring A is a ring selected from the following: ｛Wherein, R ¹¹ and R ¹² are the same or different and each represent a hydrogen atom,
Halogen atom, lower alkyl group (the lower alkyl group is
Halogen atom, lower alkoxy group, nitro group, amino group, amino group substituted with lower alkyl group, cyclic amino group, hydroxyl group, acyloxy group, cyano group, carbamoyl group, carbamoyl group substituted with lower alkyl group, cyclic amino It may be substituted by a carbonyl group, a carboxy group, a lower alkoxycarbonyl group or an aralkyloxycarbonyl group. ), Lower alkenyl group, aralkyl group, aralkyl group substituted with alkyl group, lower alkoxy group, nitro group, amino group, amino group substituted with lower alkyl group, cyclic amino group, hydroxyl group, acyloxy group, cyano group, A carbamoyl group, a carbamoyl group substituted with a lower alkyl group, a cyclic aminocarbonyl group, a carboxy group, a lower alkoxycarbonyl group or an aralkyloxycarbonyl group, R ¹³ and R ¹⁴ are the same or different and are a hydrogen atom, a halogen atom, Lower alkyl group, lower alkenyl group, lower alkynyl group, haloalkyl group,
Lower alkoxy group, nitro group, amino group, amino group substituted with lower alkyl group, cyclic amino group, hydroxyl group, acyloxy group, cyano group, carbamoyl group, carbamoyl group substituted with lower alkyl group, cyclic aminocarbonyl group, A carboxy group, a lower alkoxycarbonyl group, an aralkyloxycarbonyl group, a cycloalkyl group or a lower alkylcarbonyl group. Represents｝; (Where R ¹⁵ is a lower alkyl group and R ¹⁹ is a hydrogen atom or a lower alkyl group). Or a pharmaceutically acceptable salt thereof as an active ingredient. 2. In the general formula [I], the ring A is (R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are as defined in claim 1). The therapeutic agent for osteoporosis according to claim 1. 3. A compound represented by the general formula [I]: 3. The therapeutic agent for osteoporosis according to claim 2, wherein R ¹⁵ is a lower alkyl group. 4. The therapeutic agent for osteoporosis according to claim 3, wherein R ¹ in the general formula [I] is an optionally substituted aryl group. 5. The therapeutic agent for osteoporosis according to claim 4, wherein R ¹ in the general formula [I] is an optionally substituted phenyl group. 6. The therapeutic agent for osteoporosis according to claim 5, wherein in formula [I], R ² and R ⁴ are both hydrogen atoms. 7. 6- (4-chlorophenyl) -4- (4
-Methoxybenzyl) -1-methyl-4H-2,3,
4,5,10b-pentaazabenzo [e] azulene, 6
-(4-chlorophenyl) -4- (3,4-dimethoxybenzyl) -1-methyl-4H-2,3,4,5,10
b-pentaazabenzo [e] azulene, 4- (4-methoxybenzyl) -1-methyl-6-phenyl-4H-
2,3,4,5,10b-pentaazabenzo [e] azulene, 4- (4-methoxybenzyl) -1,9-dimethyl-6-phenyl-4H-2,3,4,5,10b-penta Azabenzo [e] azulene, 8-chloro-4- (4
-Methoxybenzyl) -1-methyl-6-phenyl-4
H-2,3,4,5,10b-pentaazabenzo [e]
Azulene, 4- (4-methoxybenzyl) -1-methyl-8-nitro-6-phenyl-4H-2,3,4,5
10b-pentaazabenzo [e] azulene, 4- (4-
Methoxybenzyl) -1-methyl-6- (4-methylphenyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 8-chloro-6- (2-chlorophenyl) -4 -(4-methoxybenzyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 4- (4-chlorophenyl) -6
(4-methoxybenzyl) -2,3,9-trimethyl-
6H-5,6,7,8,9a-pentaazathieno [2,
3-e] azulene, 4- (4-chlorophenyl) -2-
Ethyl-6- (4-methoxybenzyl) -9-methyl-
6H-5,6,7,8,9a-pentaazathieno [2,
3-e] azulene, 6- (4-methoxybenzyl)-
2,9-dimethyl-4-phenyl-6H-5,6,7,
8,9a-pentaazathieno [2,3-e] azulene,
6- (4-methoxybenzyl) -2,3,9-trimethyl-4-phenyl-6H-5,6,7,8,9a-pentaazathieno [2,3-e] azulene, 2-ethyl-6
-(4-methoxybenzyl) -9-methyl-4-phenyl-6H-5,6,7,8,9a-pentaazathieno [2,3-e] azulene, 6- (4-methoxybenzyl) -4- ( 4-methoxyphenyl) -2,3,9-trimethyl-6H-5,6,7,8,9a-pentaazathieno [2,3-e] azulene, 6- (4-chlorophenyl) -1-methyl-4- (Pyridin-3-ylmethyl)
-4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 4- (2-chlorophenyl) -2,
3,9-trimethyl-6- (pyridin-4-ylmethyl) -6H-5,6,7,8,9a-pentaazathieno [2,3-e] azulene, 6- (4-chlorophenyl)
-4- (3-cyanobenzyl) -1-methyl-4H-
2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -4- (2-fluorobenzyl) -1-methyl-4H-2,3,4,5,1
0b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -4- (3-fluorobenzyl) -1-
Methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -4
-(4-fluorobenzyl) -1-methyl-4H-2,
3,4,5,10b-Pentazaazabenzo [e] azulene, 6- (4-chlorophenyl) -4- (2,4-difluorobenzyl) -1-methyl-4H-2,3,4
5,10b-pentaazabenzo [e] azulene, 6-
(4-Chlorophenyl) -4- (2,5-difluorobenzyl) -1-methyl-4H-2,3,4,5,10b
-Pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -4- (3,5-difluorobenzyl) -1
-Methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl)-
4- (3,4-difluorobenzyl) -1-methyl-4
H-2,3,4,5,10b-pentaazabenzo [e]
Azulene, 6- (4-chlorophenyl) -1-methyl-
4- (2-trifluoromethylbenzyl) -4H-2,
3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -1-methyl-4-
(4-trifluoromethylbenzyl) -4H-2,3
4,5,10b-pentaazabenzo [e] azulene, 6
-(4-chlorophenyl) -1-methyl-4- (3-trifluoromethylbenzyl) -4H-2,3,4,5
10b-pentaazabenzo [e] azulene, 6- (4-
Chlorophenyl) -1-methyl-4- (4-trifluoromethoxybenzyl) -4H-2,3,4,5,10b
-Pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -1-methyl-4- (3-nitrobenzyl)
-4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 4- (2-chlorobenzyl) -6
(4-chlorophenyl) -1-methyl-4H-2,3,
4,5,10b-pentaazabenzo [e] azulene, 4
-(3-chlorobenzyl) -6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 4- (4-chlorobenzyl) -6 -(4-chlorophenyl) -1-methyl-4
H-2,3,4,5,10b-pentaazabenzo [e]
Azulene, 6- (4-chlorophenyl) -4- (2-cyanobenzyl) -1-methyl-4H-2,3,4,5
10b-pentaazabenzo [e] azulene, 6- (4-
Chlorophenyl) -4- (4-cyanobenzyl) -1-
Methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -4
-(2-methoxybenzyl) -1-methyl-4H-2,
3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -4- (3-methoxybenzyl) -1-methyl-4H-2,3,4,5,10
b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -4- (4-methoxybenzyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene , 6- (4-chlorophenyl) -4-
(2,5-dimethoxybenzyl) -1-methyl-4H-
2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -1-methyl-4-
(3,4,5-trimethoxybenzyl) -4H-2,
3,4,5,10b-pentaazabenzo [e] azulene, 4- (5-acetyl-2-methoxybenzyl) -6
-(4-chlorophenyl) -1-methyl-4H-2,
3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -1-methyl-4-
(3,4-methylenedioxybenzyl) -4H-2,
3,4,5,10b-pentaazabenzo [e] azulene, 4- (2-chloro-4,5-methylenedioxybenzyl) -6- (4-chlorophenyl) -1-methyl-4
H-2,3,4,5,10b-pentaazabenzo [e]
Azulene, 6- (4-chlorophenyl) -4- (2-methoxy-5-nitrobenzyl) -1-methyl-4H-
2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -4- (4-methoxy-3-nitrobenzyl) -1-methyl-4H-2,
3,4,5,10b-pentaazabenzo [e] azulene, 4- (3-chloro-4-methoxybenzyl) -6
(4-chlorophenyl) -1-methyl-4H-2,3,
4,5,10b-pentaazabenzo [e] azulene, 6
-(4-chlorophenyl) -4- (3,5-dichloro-
4-methoxybenzyl) -1-methyl-4H-2,3,
4,5,10b-pentaazabenzo [e] azulene, 6
-(4-chlorophenyl) -1-methyl-4- (2-methylbenzyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -1- Methyl-4- (3-methylbenzyl) -4H
-2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -1-methyl-4
-(4-methylbenzyl) -4H-2,3,4,5,1
0b-pentaazabenzo [e] azulene, 4- (4-t
tert-butylbenzyl) -6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -1-methyl- 4- (naphthalen-1-ylmethyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -1-
Methyl-4- (naphthalen-2-ylmethyl) -4H-
2,3,4,5,10b-pentaazabenzo [e] azulene, 4- (4-benzyloxybenzyl) -6- (4
-Chlorophenyl) -1-methyl-4H-2,3,4
5,10b-pentaazabenzo [e] azulene, 4-benzyl-6- (4-chlorophenyl) -1-methyl-4
H-2,3,4,5,10b-pentaazabenzo [e]
Azulene, 6- (4-chlorophenyl) -1-methyl-
4- (4-phenylbenzyl) -4H-2,3,4
5,10b-pentaazabenzo [e] azulene, 4-
(4-chlorophenoxymethyl) -6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,10b
-Pentazabenzo [e] azulene, 6- (4-chlorophenyl) -1-methyl-4- (pyridin-2-ylmethyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulene , 6- (4-chlorophenyl) -1
-Methyl-4- (pyridin-3-ylmethyl) -4H-
2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -4- [2- (indol-3-yl) ethyl] -1-methyl-4H-2,
3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -4- (2-methyl-
1,3-thiazol-4-ylmethyl) -1-methyl-
4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -4-
(5-chlorothiophen-2-ylmethyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -1-methyl-4- ( 3,5-dimethylisoxazole-4-
Ylmethyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -1-methyl-4-phenethyl-4H-2,3,
4,5,10b-pentaazabenzo [e] azulene, 6
-(4-chlorophenyl) -1-methyl-4- (3-phenylpropyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -4- (3,3-diphenylpropyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -4-
Cyclopropylmethyl-1-methyl-4H-2,3,
4,5,10b-pentaazabenzo [e] azulene, 6
-(4-chlorophenyl) -4-cyclohexylmethyl-1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -4- (2-cyclohexyl Ethyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -1-methyl-4- (3-phenyl-2-propenyl) -4H-
2,3,4,5,10b-pentaazabenzo [e] azulene, 4-allyl-6- (4-chlorophenyl) -1-
Methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -1
-Methyl-4- (2-methyl-2-propenyl) -4H
-2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -4- (2-chloro-2-propenyl) -1-methyl-4H-2,3,
4,5,10b-pentaazabenzo [e] azulene, 4
-(2-bromo-2-propenyl) -6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,10
b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -4- (2,3-dichloro-2-propenyl) -1-methyl-4H-2,3,4,5,10b-pentaaza Benzo [e] azulene, 6- (4-chlorophenyl) -4- (3,4-dibenzyloxybenzyl)-
1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 4-benzyloxymethyl-
6- (4-chlorophenyl) -1-methyl-4H-2,
3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -1-methyl-4-
(3-phenoxypropyl) -4H-2,3,4,5
10b-pentaazabenzo [e] azulene, 6- (4-
Chlorophenyl) -4- (3,3-dichloro-2-propenyl) -1-methyl-4H-2,3,4,5,10b
-Pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -4- (4-methoxy-3-methylbenzyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [ e] azulene, 6- (4-chlorophenyl) -1-methyl-4- (pyridin-4-ylmethyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4 -Chlorophenyl) -1-
Methyl-4- (4-methylsulfonylbenzyl) -4H
-2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -1-methyl-4
-(4-nitrobenzyl) -4H-2,3,4,5,1
0b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -4- (2,6-dichloropyridine-4
-Ylmethyl) -1-methyl-4H-2,3,4,5
10b-pentaazabenzo [e] azulene, 6- (4-
Chlorophenyl) -4- (2,2,2-trifluoroethyl) -1-methyl-4H-2,3,4,5,10b-
Pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -4- (3,5-dinitrobenzyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene 8-chloro-1-methyl-6-phenyl-4- (pyridin-4-ylmethyl) -4H-2,
3,4,5,10b-pentaazabenzo [e] azulene, 8-chloro-1-methyl-6-phenyl-4- (pyridin-3-ylmethyl) -4H-2,3,4,5,1
0b-pentaazabenzo [e] azulene, 1-methyl-
6-phenyl-4- (pyridin-3-ylmethyl) -4
H-2,3,4,5,10b-pentaazabenzo [e]
Azulene, 1-methyl-6-phenyl-4- (pyridin-4-ylmethyl) -4H-2,3,4,5,10b-
Pentaazabenzo [e] azulene, 1,9-dimethyl-
6-phenyl-4- (pyridin-3-ylmethyl) -4
H-2,3,4,5,10b-pentaazabenzo [e]
Azulene, 1,9-dimethyl-6-phenyl-4- (pyridin-4-ylmethyl) -4H-2,3,4,5,1
0b-pentaazabenzo [e] azulene, 4- (3-cyanobenzyl) -1,9-dimethyl-6-phenyl-4
H-2,3,4,5,10b-pentaazabenzo [e]
Azulene, 1-methyl-8-nitro-6-phenyl-4
-(Pyridin-3-ylmethyl) -4H-2,3,4
5,10b-pentaazabenzo [e] azulene, 1-methyl-8-nitro-6-phenyl-4- (pyridine-4
-Ylmethyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 1-methyl-6- (4-
Methylphenyl) -4- (pyridin-4-ylmethyl)
-4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 4- (3-cyanobenzyl) -1-methyl-6- (4-methylphenyl) -4H-2,3
4,5,10b-pentaazabenzo [e] azulene, 8
-Chloro-6- (2-chlorophenyl) -1-methyl-
4- (pyridin-3-ylmethyl) -4H-2,3,
4,5,10b-pentaazabenzo [e] azulene, 8
-Chloro-6- (2-chlorophenyl) -1-methyl-
4- (pyridin-4-ylmethyl) -4H-2,3,
4,5,10b-pentaazabenzo [e] azulene, 4
-(4-chlorophenyl) -2,3,9-trimethyl-
6- (pyridin-3-ylmethyl) -6H-5,6,
7,8,9a-pentaazathieno [2,3-e] azulene, 4- (4-chlorophenyl) -2,3,9-trimethyl-6- (pyridin-4-ylmethyl) -6H-5
6,7,8,9a-pentaazathieno [2,3-e] azulene, 4- (4-chlorophenyl) -2-ethyl-9
-Methyl-6- (pyridin-3-ylmethyl) -6H-
5,6,7,8,9a-pentaazathieno [2,3-
e] Azulene, 4- (4-chlorophenyl) -2-ethyl-9-methyl-6- (pyridin-4-ylmethyl)-
6H-5,6,7,8,9a-pentaazathieno [2,
3-e] azulene, 2,9-dimethyl-4-phenyl-
6- (pyridin-3-ylmethyl) -6H-5,6,
7,8,9a-pentaazathieno [2,3-e] azulene, 2,9-dimethyl-4-phenyl-6- (pyridin-4-ylmethyl) -6H-5,6,7,8,9a-pentaazathieno [ 2,3-e] azulene, 2,3,9-
Trimethyl-4-phenyl-6- (pyridin-3-ylmethyl) -6H-5,6,7,8,9a-pentaazathieno [2,3-e] azulene, 2,3,9-trimethyl-4-phenyl- 6- (pyridin-4-ylmethyl)-
6H-5,6,7,8,9a-pentaazathieno [2,
3-e] azulene, 2-ethyl-9-methyl-4-phenyl-6- (pyridin-3-ylmethyl) -6H-5,
6,7,8,9a-pentaazathieno [2,3-e] azulene, 2-ethyl-9-methyl-4-phenyl-6
(Pyridin-4-ylmethyl) -6H-5,6,7,
8,9a-pentaazathieno [2,3-e] azulene,
4- (4-methoxyphenyl) -2,3,9-trimethyl-6- (pyridin-3-ylmethyl) -6H-5
6,7,8,9a-pentaazathieno [2,3-e] azulene, 4- (4-methoxyphenyl) -2,3,9-
Trimethyl-6- (pyridin-4-ylmethyl) -6H
-5,6,7,8,9a-pentaazathieno [2,3-
e] azulene, 6- (4-chlorophenyl) -1-methyl-4- (2-nitrobenzyl) -4H-2,3,4
5,10b-pentaazabenzo [e] azulene, 6-
(4-chlorophenyl) -4-ethoxycarbonylmethyl-1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene, [6- (4-chlorophenyl) -1-methyl-4H -2,3,4,5,10b-
Pentaazabenzo [e] azulen-4-yl] acetic acid, 6
-(4-chlorophenyl) -1-methyl-4-phenylcarbamoylmethyl-4H-2,3,4,5,10b-
Pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -1-methyl-4- (4-methylphenylcarbamoylmethyl) -4H-2,3,4,5,10b-pentaazabenzo [e] azulene , 6- (4-chlorophenyl) -4- (2-methoxyphenylcarbamoylmethyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl ) -4- (2,5-Dimethoxyphenylcarbamoylmethyl) -1-methyl-4H-2,3,4,5,10
b-pentaazabenzo [e] azulene, 4- (4-chloro-2,5-dimethoxyphenylcarbamoylmethyl)
-6- (4-chlorophenyl) -1-methyl-4H-
2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -1-methyl-4-
(Naphthalen-1-ylcarbamoylmethyl) -4H-
2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -1-methyl-4-
(Pyridin-3-ylcarbamoylmethyl) -4H-
2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -4- (cyclohexylcarbamoylmethyl) -1-methyl-4H-2,
3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -1-methyl-4-n
-Propylcarbamoylmethyl-4H-2,3,4
5,10b-pentaazabenzo [e] azulene, 4-bromoacetyl-6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 6 -(4-chlorophenyl) -4-
(2-methoxyphenylaminoacetyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -1-methyl-4-phenylaminoacetyl -4H-2,3
4,5,10b-pentaazabenzo [e] azulene, 6
-(4-chlorophenyl) -1-methyl-4- (4-methylphenylaminoacetyl) -4H-2,3,4
5,10b-pentaazabenzo [e] azulene, 6-
(4-Chlorophenyl) -4- (3-fluorophenylaminoacetyl) -1-methyl-4H-2,3,4
5,10b-pentaazabenzo [e] azulene, 6-
(4-chlorophenyl) -4- (2,5-dimethoxyphenylaminoacetyl) -1-methyl-4H-2,3
4,5,10b-pentaazabenzo [e] azulene, 6
-(4-chlorophenyl) -1-methyl-4-phenylthioacetyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -1-methyl-4 -Phenylacetyl-4H-2,
3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -1-methyl-4-phenyloxalyl-4H-2,3,4,5,10b-pentaazabenzo [ e] azulene, 6- (4-chlorophenyl) -4-ethoxymethyl-1-methyl-4H-2,
3,4,5,10b-pentaazabenzo [e] azulene, [6- (4-chlorophenyl) -1-methyl-4H
-2,3,4,5,10b-pentaazabenzo [e] azulen-4-ylmethyl] -phenyl-amine, 4-benzylcarbamoyl-6- (4-chlorophenyl) -1
-Methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl)-
1-methyl-4- (3-methylphenylcarbamoyl)
-4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -4-
(4-hydroxybenzyl) -1-methyl-4H-2,
3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -4- (3,4-dihydroxybenzyl) -1-methyl-4H-2,3,4
5,10b-pentaazabenzo [e] azulene, 6-
(4-chlorophenyl) -4- (4-ethoxybenzyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -1-methyl -4- (4-methylsulfonylphenyl) hydroxymethyl-4H-2,3,4,5,10
b-pentaazabenzo [e] azulene, 4- (4-aminobenzyl) -6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene , 6- (4-chlorophenyl) -4-
(4-formylaminobenzyl) -1-methyl-4H-
2,3,4,5,10b-pentaazabenzo [e] azulene, 4- (4-acetylaminobenzyl) -6- (4
-Chlorophenyl) -1-methyl-4H-2,3,4
5,10b-pentaazabenzo [e] azulene, 6-
(4-Chlorophenyl) -4- (4-methylsulfonylaminobenzyl) -1-methyl-4H-2,3,4
5,10b-pentaazabenzo [e] azulene, 4-
[4-bis (methylsulfonyl) aminobenzyl] -6
-(4-chlorophenyl) -4H-2,3,4,5,1
0b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -4- (4-dimethylaminobenzyl)
-1-Methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -4- (2-hydroxy-2-phenylethyl)-
1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl)
-4- (2-oxo-2-phenylethyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -1-methyl- 4- [3-phenyl-2- (tetrahydropyran-2-yloxy) propyl] -4H-2,3,4
5,10b-pentaazabenzo [e] azulene, 6-
(4-Chlorophenyl) -4- [2- (2-methoxyphenyl) -2- (tetrahydropyran-2-yloxy) ethyl] -1-methyl-4H-2,3,4,5,1
0b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -4- (2-hydroxy-3-phenylpropyl) -1-methyl-4H-2,3,4,5,10
b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -4- (2-oxo-3-phenylpropyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [E] Azulene, 6- (4-chlorophenyl) -4- [2- (4-chlorophenyl) -2-oxoethyl] -1-methyl-4H-2,3,4,5,10
b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -1-methyl-4- [2- (4-methylphenyl) -2-oxoethyl] -4H-2,3,4,
5,10b-pentaazabenzo [e] azulene, 6-
(4-chlorophenyl) -4- [2- (2-methoxyphenyl) -2-oxoethyl] -1-methyl-4H-
2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -4- [2- (2,
5-dimethoxyphenyl) -2-oxoethyl] -1-
Methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -4
-[3- (2-methoxyphenyl) -2-oxopropyl] -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene, 6- (4-chlorophenyl) -4 -[3- (2,5-dimethoxyphenyl)-
2-oxopropyl] -1-methyl-4H-2,3,
4,5,10b-pentaazabenzo [e] azulene, 4
-Benzyl-6- (4-chlorophenyl) -1-methyl-4H-2,3,4,5,10b-pentaazabenzo [e] azulene and 6- (4-chlorophenyl) -4
-(4-methoxybenzyl) -4H-3,4,5,10
The therapeutic agent for osteoporosis according to claim 1, which comprises a triazepine compound selected from the group consisting of b-tetraazabenzo [e] azulene or a pharmaceutically acceptable salt thereof as an active ingredient. 8. A compound of the general formula [I ′] [Wherein, R ¹ represents an optionally substituted aryl group or an optionally substituted heteroaryl group; R ² represents a hydrogen atom,
R ⁴ represents a hydrogen atom or a halogen atom, or R ² and R ⁴ together form a carbonyl group together with the carbon atom to which they are attached; R ³ represents a lower alkoxy group, cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl ^{group, -CR 5 = CR 6 R 7} (R 5, R 6 and R ⁷
Is the same or different and is a hydrogen atom, a halogen atom, a lower alkyl group or an optionally substituted aryl group. ), −
OR ¹⁸ (R ¹⁸ is an optionally substituted aryl group), (Where R ⁸ is a hydrogen atom, a lower alkyl group, a cycloalkyl group, an optionally substituted aryl group, an aralkyl group or an optionally substituted heteroaryl group, and R ⁹ and R ¹⁰ are the same or different. Hydrogen atom, lower alkyl group,
It is a lower alkoxy group, a hydroxyl group, a halogen atom, a nitro group or an amino group, and R ²⁰ is an optionally substituted aryl group, an aralkyl group or an optionally substituted heteroaryl group. ) Or -XY ｛where X is-(CH ₂ )
_m- (m is an integer of 1 to 4), -CO-, -C
OCH ₂ —, —NH—, —NHCH ₂ —, —CH ₂ NH
_{-, - CH 2 NHCO -,} - OCH 2 -, - (CH 2)
_n O-(n is an integer of 1 to 4.) or -CH ₂ S
And Y is a halogen atom, a cycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group. And ring A is a ring selected from the following: ｛Wherein, R ¹¹ and R ¹² are the same or different and each represent a hydrogen atom,
Halogen atom, lower alkyl group (the lower alkyl group is
Halogen atom, lower alkoxy group, nitro group, amino group, amino group substituted with lower alkyl group, cyclic amino group, hydroxyl group, acyloxy group, cyano group, carbamoyl group, carbamoyl group substituted with lower alkyl group, cyclic amino It may be substituted by a carbonyl group, a carboxy group, a lower alkoxycarbonyl group or an aralkyloxycarbonyl group. ), Lower alkenyl group, aralkyl group, aralkyl group substituted with alkyl group, lower alkoxy group, nitro group, amino group, amino group substituted with lower alkyl group, cyclic amino group, hydroxyl group, acyloxy group, cyano group, A carbamoyl group, a carbamoyl group substituted with a lower alkyl group, a cyclic aminocarbonyl group, a carboxy group, a lower alkoxycarbonyl group or an aralkyloxycarbonyl group, R ¹³ and R ¹⁴ are the same or different and are a hydrogen atom, a halogen atom, Lower alkyl group, lower alkenyl group, lower alkynyl group, haloalkyl group,
Lower alkoxy group, nitro group, amino group, amino group substituted with lower alkyl group, cyclic amino group, hydroxyl group, acyloxy group, cyano group, carbamoyl group, carbamoyl group substituted with lower alkyl group, cyclic aminocarbonyl group, A carboxy group, a lower alkoxycarbonyl group, an aralkyloxycarbonyl group, a cycloalkyl group or a lower alkylcarbonyl group. Represents｝; (Where R ¹⁵ is a lower alkyl group and R ¹⁹ is a hydrogen atom or a lower alkyl group). Or a pharmaceutically acceptable salt thereof. 9. Ring A is ^{(R 11, R 12, R} 13 and R ¹⁴ are as defined in claim 8.) Triazepine compound or a pharmaceutically acceptable salt thereof according to claim 8, wherein a. (10) (R ¹⁵ is a lower alkyl group.) Triazepine compound or a pharmaceutically acceptable salt thereof according to claim 9, wherein a. 11. The triazepine compound or a pharmaceutically acceptable salt thereof according to claim 10, wherein R ¹ is an optionally substituted aryl group. 12. The triazepine compound or a pharmaceutically acceptable salt thereof according to claim 11, wherein R ¹ is an optionally substituted phenyl group. 13. The triazepine compound according to claim 12, wherein R ² and R ⁴ are both hydrogen atoms, or a pharmaceutically acceptable salt thereof. 14. The triazepine compound or a pharmaceutically acceptable salt thereof according to claim 13, wherein R ³ is a pyridyl group or an optionally substituted phenyl group. 15. A triazepine compound selected from the group consisting of the compounds according to claim 7, or a pharmaceutically acceptable salt thereof. 16. A compound of the general formula [I ′] (Wherein, R ¹ , R ² , R ³ , R ⁴ , ring A and Is as described in claim 8. A) a pharmaceutical composition comprising a triazepine compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 17. In the general formula [I ′], ring A is ^{(R 11, R 12, R} 13 and R ¹⁴ are as defined in claim 8.) The pharmaceutical composition of claim 16 wherein the. 18. A compound represented by the general formula [I ′]: (R ¹⁵ is a lower alkyl group.) A is 17. The pharmaceutical composition according. 19. The pharmaceutical composition according to claim 18, wherein R ¹ in the general formula [I ′] is an optionally substituted aryl group. 20. The pharmaceutical composition according to claim 19, wherein R ¹ in the general formula [I ′] is an optionally substituted phenyl group. 21. The compound of the formula [I ′], wherein R ² and R ⁴
21. The pharmaceutical composition according to claim 20, wherein both are hydrogen atoms. 22. In the general formula [I ′], R ³ is a pyridyl group or an optionally substituted phenyl group.
The pharmaceutical composition according to any one of the preceding claims. 23. A pharmaceutical composition comprising a triazepine compound selected from the group consisting of the compounds according to claim 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 24. A compound of the general formula [II ′] (Wherein R ¹ , R ² , R ³ , R ⁴ and ring A are as defined in claim 8) or a salt thereof. 25. Ring A is (R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are as defined in claim 8), R ¹ is a phenyl group which may be substituted, and R ² and R ⁴ are both hydrogen atoms Claim 24
Or a salt thereof. 26. 5- (4-chlorophenyl) -3-
(3,4-dimethoxybenzyl) -1,3-dihydrobenzo [e] [1,2,4] triazepine-2-thione,
3- (4-methoxybenzyl) -5-phenyl-1,3
-Dihydrobenzo [e] [1,2,4] triazepine-
2-thione, 5- (4-chlorophenyl) -3- (4-
Methoxybenzyl) -1,3-dihydrobenzo [e]
[1,2,4] triazepine-2-thione, 7-chloro-3- (4-methoxybenzyl) -5-phenyl-1,
3-dihydrobenzo [e] [1,2,4] triazepine-2-thione, 3- (4-methoxybenzyl) -7-nitro-5-phenyl-1,3-dihydrobenzo [e]
[1,2,4] triazepine-2-thione, 3- (4-
Methoxybenzyl) -5- (4-methylphenyl)-
1,3-dihydrobenzo [e] [1,2,4] triazepine-2-thione, 7-chloro-5- (2-chlorophenyl) -3- (4-methoxybenzyl) -1,3-dihydrobenzo [ e] [1,2,4] triazepine-2-thione, 5- (4-chlorophenyl) -3- (pyridine-
3-ylmethyl) -1,3-dihydrobenzo [e]
[1,2,4] triazepine-2-thione, 4- (4-
Chlorophenyl) -6- (4-methoxybenzyl)-
2,3-dimethyl-6,8-dihydro-1-thia-5
6,8-triaza-azulene-7-thione, 4- (4-
(Chlorophenyl) -2-ethyl-6- (4-methoxybenzyl) -6,8-dihydro-1-thia-5,6,8-
Triaza-azulene-7-thione, 6- (4-methoxybenzyl) -2-methyl-4-phenyl-6,8-dihydro-1-thia-5,6,8-triaza-azulene-7
-Thion, 6- (4-methoxybenzyl) -2,3-dimethyl-4-phenyl-6,8-dihydro-1-thia-
5,6,8-triaza-azulene-7-thione, 2-ethyl-6- (4-methoxybenzyl) -4-phenyl-
6,8-dihydro-1-thia-5,6,8-triaza-
Azulene-7-thione, 6- (4-methoxybenzyl)
-4- (4-methoxyphenyl) -2,3-dimethyl-
6,8-dihydro-1-thia-5,6,8-triaza-
Azulene-7-thione, 4- (2-chlorophenyl)-
2,3-dimethyl-6- (pyridin-4-ylmethyl)
-6,8-Dihydro-1-thia-5,6,8-triaza-azulene-7-thione, 3- (4-methoxybenzyl) -8-methyl-5-phenyl-1,3-dihydrobenzo [e ] [1,2,4] triazepine-2-thione,
And 3-benzyl-5- (4-chlorophenyl) -1,
The triazepinethione compound or a salt thereof according to claim 25, which is selected from the group consisting of 3-dihydrobenzo [e] [1,2,4] triazepine-2-thione. 27. The general formula [III '] (Wherein R ¹ , R ² , R ³ , R ⁴ and ring A are as described in claim 8, and R ¹⁶ represents a lower alkyl group) or a salt thereof. 28. The ring A is (R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are as defined in claim 8), R ¹ is a phenyl group which may be substituted, and R ² and R ⁴ are both hydrogen atoms Claim 27
Or an alkylthiotriazepine compound or a salt thereof. 29. 5- (4-chlorophenyl) -3-
(3,4-dimethoxybenzyl) -2-methylthio-3
H-benzo [e] [1,2,4] triazepine, 3-
(4-methoxybenzyl) -2-methylthio-5-phenyl-3H-benzo [e] [1,2,4] triazepine, 7-chloro-3- (4-methoxybenzyl) -2-
Methylthio-5-phenyl-3H-benzo [e] [1,
2,4] triazepine, 3- (4-methoxybenzyl)
-8-methyl-2-methylthio-5-phenyl-3H-
Benzo [e] [1,2,4] triazepine, 3- (4-
Methoxybenzyl) -7-nitro-2-methylthio-5
-Phenyl-3H-benzo [e] [1,2,4] triazepine, 3- (4-methoxybenzyl) -5- (4-methylphenyl) -2-methylthio-3H-benzo [e]
[1,2,4] triazepine, 7-chloro-5- (2-
Chlorophenyl) -3- (4-methoxybenzyl) -2
-Methylthio-3H-benzo [e] [1,2,4] triazepine, 5- (4-chlorophenyl) -2-methylthio-3- (pyridin-3-ylmethyl) -3H-benzo [e] [1,2 , 4] Triazepine, 4- (4-chlorophenyl) -6- (4-methoxybenzyl) -2,3-
Dimethyl-7-methylthio-6H-1-thia-5,6,
8-triazaazulene, 4- (4-chlorophenyl)-
2-ethyl-6- (4-methoxybenzyl) -7-methylthio-6H-1-thia-5,6,8-triazaazulene, 6- (4-methoxybenzyl) -2-methyl-7-
Methylthio-4-phenyl-6H-1-thia-5,6,
8-triazaazulene, 6- (4-methoxybenzyl)
-2,3-dimethyl-7-methylthio-4-phenyl-
6H-1-thia-5,6,8-triazaazulene, 2-
Ethyl-6- (4-methoxybenzyl) -7-methylthio-4-phenyl-6H-1-thia-5,6,8-triazaazulene, 6- (4-methoxybenzyl) -4-
(4-methoxyphenyl) -2,3-dimethyl-7-methylthio-6H-1-thia-5,6,8-triazaazulene, 4- (2-chlorophenyl) -2,3-dimethyl-7-methylthio -6- (pyridin-4-ylmethyl)
-6H-1-thia-5,6,8-triazaazulene and 5- (4-chlorophenyl) -3- (4-methoxybenzyl) -2-methylthio-3H-benzo [e] [1,
2,4] selected from the group consisting of triazepines.
8. The alkylthiotriazepine compound or a salt thereof according to item 8. 30. A compound of the general formula [IV '] (Wherein R ¹ , R ² , R ³ , R ⁴ , R ¹⁵ and ring A are as defined in claim 8), or a salt thereof. 31. When the ring A is (R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are as defined in claim 8), R ¹ is a phenyl group which may be substituted, and R ² and R ⁴ are both hydrogen atoms Claim 30
And / or a salt thereof. 32. N '-[5- (4-chlorophenyl) -3- (3,4-dimethoxybenzyl) -3H-benzo [e] [1,2,4] triazepin-2-yl] hydrazide acetate; N '-[3- (4-methoxybenzyl) acetate
-5-phenyl-3H-benzo [e] [1,2,4] triazepin-2-yl] hydrazide and acetic acid N'-
The acyl according to claim 31, wherein the acyl is selected from the group consisting of [3- (4-methoxybenzyl) -8-methyl-5-phenyl-3H-benzo [e] [1,2,4] triazepin-2-yl] hydrazide. A hydrazotriazepine compound or a salt thereof.