JPH11279156A - Indazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide the subject novel compound that has specific substituents in the 1- and the 3-positions in the indazole skeleton and shows excellent calmodulin inhibitory action and anti-hypoxia action and is useful as a treating agent for cerebrovascular disorder. SOLUTION: This compound is represented by formula I R<1> , R<2> , R<4> and R<5> are each H, a halogen, an alkyl or an alkoxyl; R<3> is a (substituted) aryl, a (substituted) heterocyclic group, -NR<6> R<7> [R<6> and R<7> are each H, a (substituted) alkyl or the like],-OR<8> (R<8> is an alkyl or a heterocyclic group) or the like; m is 2-6; n is 1-6}, typically 1-[2-[4-(3-chloro-2-methylphenyl)-1- piperazinyl]ethyl]-3-[(N-ethyl)-N-(n-propylaminomethyl)]-5,6-dimethoxy -1H- indazole. The compound of formula I is obtained, for example, by reaction of a compound of formula II (X is a halogen) with an amine derivative of the formula: HNR<6> R<7> and an alcohol derivative of the formula: HOR<8> in the presence of a base.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel indazole derivative which has a calmodulin inhibitory action and is useful as a therapeutic agent for cardiovascular diseases and diseases of the brain region.

[0002]

2. Description of the Related Art Cerebral vascular disorders are caused by so-called cerebral ischemia, which is caused by stenosis of blood vessels or vascular occlusion caused by cerebral thrombus or cerebral embolism, and cerebral blood flow falls below a certain threshold (Kirino et al., Brain). Res., 377: 3.
44-347, 1982). There are various theories about the process from the occurrence of disorders such as ischemia in cerebral nerve cells to the death of nerve cells. Recently, glutamate is released during ischemia, and the glutamate is a glutamate receptor such as NMDA or AMPA / KA. In order to promote intracellular calcium influx by binding to, and to inhibit intracellular calcium outflow due to calcium-ATPase malfunction, it has become clear that intracellular calcium concentration increases, leading to nerve cell death ( Siesjoe et al., J. Cereb.
BloodFlow Metab. , 9: 127, 19
89).

Further, activation of calmodulin, a calcium-binding protein, by cerebral ischemia (Grotta)
J. et al. Cereb. Blood Floe Meta
b. , 9: 805-812, 1989) and that the activity of calmodulin-dependent kinase is altered (Churn).
Et al., Stroke, 21: 1715-1723, 199.
0), a calmodulin inhibitor calmidazolium (Fischer et al., Biochemistry, 2).
6: 8024, 1987) and W-7 (Hidaka
Et al., Proc. Natl. Acad. Sci. US
A. , 78, 4354, 1981) suppresses neuronal cell death due to NMDA and hypoxia / glucose (Dawson et al., J. Neurosci., 13: 2).
651-2661, and Sun et al., NeuroRepo
rt, 8: 415-418) and inhibitors of calmodulin-dependent enzymes inhibit NMDA-induced neuronal death and cerebrovascular disorders (Dawson et al., Proc. Natl.
Acad. , Sci. , 90: 9808-9812:
Sharkey et al., Nature, 371: 336-3.
39: Ide et al., Neurosci. Lett. , 20
4: 157-160: Hajimohammadre
za et al. Neurosci. , 15: 4093-4.
101: Nagafuji et al., Neurosci. L
ett. , 147: 159-162: Buisson.
J. et al. Neurochem. , 61: 690-69.
6) has been reported.

It has also been shown that the degradation of calmodulin-binding cytoskeletal protein, fodrin, is enhanced in cerebral ischemic injury (Seubert et al., Brain R).
es. , 492: 366-370, 1989). Calmodulin binds to fodrin and regulates the degradation of fodrin by calcium-dependent proteases (calpains) (Harris et al., J. Biol. Che.
m. 264: 17401-17408, 1989) and calmodulin inhibitors have been reported to inhibit the degradation of fodrin (Seubert et al., Synapse,
1: 20-24, 1987).

[0005] At present, as a treatment for brain diseases, methods such as suppression of cerebral nerve cell death, maintenance and regulation of blood flow in the brain, and suppression of ischemic cerebral edema are known. Various antagonists to the NMDA receptor have been considered as drugs that suppress necrosis of brain nerve cells.

[0006] However, these drugs often have side effects such as clouding of consciousness and abnormal brain waves, and there is no report that they have been used effectively clinically. In recent years, calcium antagonists such as nimodipine have been used clinically for the purpose of maintaining and regulating blood flow in the brain.However, treatment with these drugs can be used in combination with drugs that suppress nerve cell death and brain edema. It is considered to be more effective. Treatment of intracranial pressure due to cerebral neoplasms, trauma, and cerebral edema due to cerebral ischemia include large doses of steroid hormones and methods using osmotic pressure with glyceol and mannitol. There is nothing to be satisfied.

On the other hand, excessive activation of calmodulin caused by an increase in intracellular calcium ions at the time of cerebral injury is suppressed by a calmodulin inhibitor, thereby showing a cerebral protective effect (Japanese Patent Laid-Open No. 5-122933).
Certain piperazine derivatives have a calmodulin inhibitory effect (Arzneim. Forsch., 37
(4): 498-502), that certain indazole derivatives have a central nervous activity such as anxiolytic activity and anticonvulsant activity (US Pat. No. 3,362,956), and that another indazole derivative has a calmodulin inhibitory effect. It is also known to have a brain protective effect (Japanese Patent Laid-Open No.
280838).

[0008]

The severity of cerebrovascular disease correlates with the time of ischemia, and mild ischemia does not cause any damage, but if ischemia is prolonged, organic damage to the brain may occur. give. In such a state, even if blood flow is restored, cerebral ischemic injury cannot be relieved. Such an idea was clarified from the fact that experimental animals were loaded with transient cerebral ischemia and hippocampal neurons were necrotic (delayed neuronal death) several days later. This disorder is a permanent structural change because mature neurons do not divide and regenerate, and the prognosis is strongly affected as a sequela of cerebrovascular disorder.If such late neuronal death can be suppressed, cerebrovascular It is extremely useful as an agent for treating disorders and as an agent for improving sequelae.

Based on the above idea, certain indazole derivatives inhibit excessive activation of calmodulin caused by an increase in intracellular calcium ions during brain injury, and inhibit neuronal cell death. It was shown that a protective action was observed (Japanese Patent Laid-Open No. 5-122933).

However, these compounds are not always sufficient to separate the cerebral protective action from the side effects such as the central inhibitory action. Therefore, a compound having a strong calmodulin inhibitory action and having few side effects such as a central inhibitory action is considered to be more useful as a therapeutic drug for diseases of the brain region.

An object of the present inventors is to provide a compound having a small side effect such as a central inhibitory effect, showing a strong calmodulin inhibitory effect and having an excellent anti-hypoxia effect and other cerebral protective effects. That is.

[0012]

Means for Solving the Problems The present inventors have intensively studied the synthesis of indazole derivatives, and have found that the compound represented by the following general formula (I) has excellent calmodulin inhibitory activity and anti-hypoxia activity, It was found to be useful, and the present invention was completed.

The present invention relates to the following (1) to (8). (1) That is, the present invention provides the following general formula (I)

[0014]

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[Wherein R ¹ , R ² , R ⁴ and R ⁵ are each independently a hydrogen atom, a halogen atom, an alkyl group or an alkoxyl group, and R ³ has a substituent An aryl group, a heterocyclic group which may have a substituent, a group -NR ⁶ R ⁷ wherein R ⁶ and R ⁷ are the same or different and are a hydrogen atom, an alkyl group which may have a substituent , An alkoxyl group, an alkoxyalkyl group, an aryl group, an aralkyl group, or a saturated or unsaturated heterocyclic group formed by R ⁶ and R ⁷ together with an adjacent nitrogen atom (one or two oxygen atoms). And a heterocyclic group containing an atom or a nitrogen atom), and these groups may have a substituent. A group —OR ⁸ (where R ⁸ is an alkyl group or a saturated or unsaturated heterocyclic group, and these groups may have a substituent), a group —SR ⁹ (where R ⁹ is An alkyl group or a saturated or unsaturated heterocyclic group, which may have a substituent.) Or a bicyclic heterocyclic group containing one or two nitrogen atoms,
m is an integer of 2 to 6, and n is an integer of 1 to 6. A salt thereof, a hydrate thereof, or an optically active form thereof.

(2) In the present invention, R ³ is a group represented by —NR ⁶
R ⁷ , wherein the saturated or unsaturated heterocyclic group formed by the group —NR ⁶ R ⁷ is a 1-piperidinyl group, a morpholino group, a thiomorpholino group, a 1-pyrrolidinyl group,
1-imidazolyl group, 1-piperazinyl group, 1-
A tetrahydroquinolyl group, or a phthaloyl group,
These groups may further have a substituent, represented by the formula (I)
Or a salt thereof, a hydrate thereof, or an optically active form thereof.

(3) In the present invention, m is 2 and n is
Is 1, the compound according to the formula (I), the compound according to the above (2), a salt thereof, a hydrate thereof, or an optically active form thereof.

(4) Further, according to the present invention, R ¹ and R ² are
A compound according to formula (I), which is a chloro group or a methyl group,
The present invention relates to the compounds described in the above (2) and (3), salts thereof, hydrates thereof, and optically active forms thereof.

[0019] (5) Further, the present invention is R ⁴ and R ^5,
A compound according to formula (I), which is a methoxyl group;
To (4), salts thereof, hydrates thereof,
Or an optically active substance thereof.

(6) In the present invention, the substituent R ³ is selected from the group consisting of: 1. an N-ethyl-N- (n-propylamino) group; 2. N- (3-methoxypropyl) -N-pentylamino group; 3. an N, N-bis (2-ethoxyethyl) amino group; 4. N-cyclohexyl-N-ethylamino group, N-benzyl-N- (2-hydroxyethyl) amino group, 6.3,3-dimethyl-1-piperidinyl group, 7.3-hydroxy-1-piperidinyl group, 8.1,2,3,4-tetrahydro 10. quinolin-1-yl group, 9.4-phenyl-1-piperazinyl group, 10.4-piperidinyloxy group, 13. piperidino group, 12.4-alkyl-1-piperazinyl group, 13.2- (imidazol-4-yl) ethyl group, or 14. The present invention relates to a compound according to formula (I), which is a morpholino group, a compound according to the above (2) to (6), a salt thereof, a hydrate thereof, or an optically active form thereof.

(7) The present invention provides the following a. From So.
Or a salt thereof, an optically active form thereof, or a hydrate thereof. 1- [2- [4- (3-Chloro-2-methylphenyl) -1-piperazinyl] ethyl] -3-[(N-ethyl-N- (n-propylaminomethyl)]-5,6-dimethoxy- 1H-indazole dihydrochloride, i. 1- [2- [4- (3-chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-3- [N- (3-methoxy Propyl) -N-pentylaminomethyl] -1H-indazole dihydrochloride, C. 1- [2- [4- (3-chloro-2-methylphenyl) -1-piperazinyl] ethyl] -3- [N, N-bis (2-ethoxyethyl) aminomethyl] -5,6-dimethoxy-1H-indazole dihydrochloride, E.3- (N-cyclohexyl-N-ethylaminomethyl) -1- [2- [4- (3-chloro-2-methyl Phenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-1H-indazole dihydrochloride, o.3- [N-benzyl-N- (2-hydroxyethyl) aminomethyl] -1- [2- [ 4- (3-chloro-
2-methylphenyl) -1-piperazinyl] ethyl]-
5,6-dimethoxy-1H-indazole dihydrochloride; 1- [2- [4- (3-Chloro-2-methylphenyl) -1-piperazinyl] ethyl] -3-homopiperidinomethyl-5,6-dimethoxy-1H-indazole
Dihydrochloride, g. 1- [2- [4- (3-Chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-3- [1- (3,3-dimethylpiperidinyl) methyl]- 1H-indazole dihydrochloride; 1- [2- [4- (3-chloro-2-methylphenyl) -1-piperazinyl] ethyl] -3- [1- (3-
Hydroxypyperidino) methyl] -5,6-dimethoxy-1H-indazole dihydrochloride; 1- [2- [4- (3-Chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-3-morpholinomethyl-1H-indazole dihydrochloride; 1- [2- [4- (3-Chloro-2-methylphenyl) -1-piperazinyl] ethyl] -3- (1,2,
3,4-tetrahydroquinolin-1-ylmethyl)-
5,6-dimethoxy-1H-indazole dihydrochloride; 1- [2- [4- (3-Chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-3- (4-phenyl-1-piperazinylmethyl)-
1H-indazole dihydrochloride; 1- [2- [4- (3-Chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-3- (4-piperidinyloxymethyl) -1H-indazole dihydrochloride , S. 1- [2- [4- (3-chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-3-piperidinomethyl-1H-indazole dihydrochloride; 1- [2- [4- (3-Chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-3-[(4-methylpiperazin-1-yl) methyl] -1H- Indazole trihydrochloride, or so. 1- [2- [4- (3-Chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-3-[(imidazol-4-yl) ethyl] -1H
-Indazole dihydrochloride,

(8) The present invention also relates to a compound represented by the formula (I), a compound according to the above (1) to (7), a salt thereof, a hydrate thereof or an optically active form thereof. Or a calmodulin inhibitor or a cerebral protective agent.

[0023]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention relates to an indazole skeleton.
A compound group having specific substituents at the 3- and 3-positions and having characteristics as a novel indazole derivative is provided. Hereinafter, the substituents of the compound according to the present invention will be described.

In the compound of the present invention, the alkyl group includes
Straight and branched ones are included. Formula (I)

[0025]

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In the compound represented by the formula, R ¹ , R ² ,
R ⁴ and R ⁵ each independently represent a hydrogen atom, a halogen atom, an alkyl group, and an alkoxyl group.

The "alkyl group" has 1 to 3 carbon atoms. Examples of such an alkyl group include a methyl group, an ethyl group, an n-propyl group, and an isopropyl group, and among them, a methyl group is particularly preferable.

The "alkoxyl group" has 1 to 3 carbon atoms, and examples thereof include a methoxyl group, an ethoxyl group, an n-propoxyl group and an isopropoxyl group. However, among these, a methoxyl group is preferable.

Examples of the halogen atom include atoms such as chlorine, bromine and fluorine, and chlorine is preferred.

In the general formula (I), R ¹ and R ² each independently represent a hydrogen atom, a halogen atom, an alkyl group or an alkoxyl group, and the substituent is preferably a halogen atom or an alkyl group. A substituent selected from the groups.

A more preferred example of R ¹ and R ² is a substituent selected from a halogen atom and an alkyl group (C1 to C3) one by one. More preferably, the halogen atom is a chlorine atom and the alkyl group is a chlorine atom. In the case of a methyl group,
Particularly preferred is a case where the substituent formed by R ¹ and R ² is a 3-chloro-2-methyl group.

In the general formula (I), R ⁴ and R ⁵ are preferably those in which both R ⁴ and R ⁵ are alkoxyl groups (C1 to C3), more preferably R ⁴ and R 5.
^The substituent formed by ⁵ is a dimethoxyl group,
Particularly preferred is the case of a 5,6-dimethoxyl group.

M represents an integer of from 2 to 6, and particularly preferably m is 2. Further, n means an integer of 1 to 6, and particularly preferred is a case where n is 1.

Among the above substituents, a particularly preferred combination is that the substituent consisting of R ¹ and R ² is a 3-chloro-2-methyl group, and the substituent consisting of R ⁴ and R ⁵ is 5,6- It is a dimethoxyl group.

Next, R ³ in the general formula (I) will be described. R ³ may have a substituent.
Group, a heterocyclic group which may have a substituent, a group -N
Examples include R ⁶ R ⁷ , group —OR ⁸ , group —SR ⁹ , and a bicyclic heterocyclic group containing one or two nitrogen atoms.

Next, each of the following will be described. The "aryl group which may have a substituent" is described. Examples of the aryl group include a phenyl group and a naphthyl group. Among them, a preferable one is a phenyl group.

Examples of the substituent bonded to the aryl group include an alkyl group, a halogen atom and an alkoxyl group.

"Heterocyclic group which may have a substituent"
Will be described. Examples of the heterocyclic group of the heterocyclic group in which R ³ may have a substituent include a furyl group, a thienyl group,
Examples of the group include an imidazolyl group, a pyridyl group, a pyrimidyl group, a benzothienyl group, a benzofuranyl group, an indolyl group, a quinolyl group, and an isoquinolyl group. Of these, an imidazolyl group is preferable. As a substituent bonded to these heterocyclic groups, an alkyl group (C1 to
3), halogen atom and alkoxyl group (C1-3)
Can be mentioned.

Now, -NR ⁶ R ⁷ will be described. Here, R ⁶ and R ⁷ are the same or different and a. A hydrogen atom, b.
An alkyl group which may have a substituent, c. An alkoxyl group which may have a substituent, d. An alkoxyalkyl group, e. An aryl group which may have a substituent, f.
Means an aralkyl group which may have a substituent,
Or g. R ⁶ and R ⁷ together with an adjacent nitrogen atom mean a saturated or unsaturated heterocyclic group which may have a substituent. Here, b. Is a compound having carbon number (C1-8), preferably carbon number (C1-5). Also, c. Is an alkoxyl group having a carbon number (C1-3), preferably a methoxyl group. D. The alkoxyalkyl group of (C) has a carbon number (C
3 to 8), preferably a group having carbon number (C4). E. The aryl group is a phenyl group or a naphthyl group, and is preferably a phenyl group. F. With regard to the aralkyl group of the above, the "aryl group" constituting the aralkyl group may be a phenyl group or a naphthyl group, and specific examples thereof include a diphenylmethyl group, a trityl group, a benzyl group, a phenethyl group, and a phenylpropyl group. And a naphthylmethyl group. A preferred example is a benzyl group.

G. Examples of the saturated or unsaturated heterocyclic group in which R ⁶ and R ⁷ may have a substituent together with an adjacent nitrogen atom include a heterocyclic group containing one or two oxygen atoms or nitrogen atoms. Can be mentioned.

Examples of the saturated or unsaturated heterocyclic group formed by the group -NR ⁶ R ⁷ include a 1-pyrrolidinyl group, a 1-piperidinyl group, a 1-homopiperazinyl group, a morpholino group, a thiomorpholino group, 1-tetrahydroquinolyl group, phthaloyl group, 1-imidazolyl group (these heterocycles are a hydroxyl group, an alkyl group (C1-3), an alkoxyl group (C1-3), a halogen atom, an aryl group, an aralkyl group or an aromatic heterocyclic group. (The ring group may be substituted.)
And the like.

Here, as an example of the heterocyclic ring having a substituent,
1- (3,3-dimethylpiperidinyl) group, 1- (3-
(Hydroxypiperidinyl) group, 1- [4- (2-hydroxyethyl) piperazinyl] group, 1- (4-phenylpiperazinyl) group, 1- (4-dimethylaminopiperidinyl) group, 1- ( 4-methylpiperazinyl) group, 1- [4
-(2-pyridyl) piperazinyl] group and the like.

The group -OR ⁸ will be described. Where R
⁸ represents a saturated or unsaturated heterocyclic ring or an alkyl group. This heterocyclic group or alkyl group may further have a substituent bonded thereto. Examples of the substituent bonded to the heterocyclic group include a hydroxyl group, an alkyl group, a hydroxyalkyl group, an alkoxycarbonyl group, an alkylsulfonyl group, an aryl group, and an arylsulfonyl group. As a substituent bonded to the alkyl group, a hydroxyl group,
Or a halogen atom.

Representative examples of such “heterocycle” in R ⁸ include: a. A 4- [1- (2-hydroxyethyl) piperidinyl] group, b. A 4- (1-ethylpiperidinyl) group, c. A 4- (1-tert-butoxycarbonylpiperidinyl) group, d. A 4- (1-methanesulfonylpiperidinyl) group, e. Examples thereof include a 4-piperidinyl group.

The alkyl moiety in the alkyl group, hydroxyalkyl group, alkoxycarbonyl group, alkylsulfonyl group, which is mentioned as a substituent bonded to the heterocyclic group, has a linear or branched structure and has 1 carbon atom. ~ 8.

The group -SR ⁹ will be described. here,
R ⁹ represents an alkyl group which may have a substituent (C 1 to
It means 3) or a saturated or unsaturated heterocyclic group which may have a substituent, but preferably the latter group.

Further, when R ⁹ is a saturated or unsaturated heterocyclic ring, examples thereof include a 2-imidazolyl group, a 2-thiazolyl group, a 2-pyrimidyl group and a 2-pyridyl group. And 2-pyridyl groups.

Examples of the substituent bonded thereto include an alkyl group (C1-3) and a halogen atom.

To summarize the above description, a preferred structure for R ³ is the case of the group —NR ⁶ R ⁷ . An N-ethyl-N- (n-propylamino) group; An N- (3-methoxypropyl) -N-pentylamino group, c. N, N-
A bis (2-ethoxyethyl) amino group; An N-cyclohexyl-N-ethylamino group; N-benzyl-N
A-(2-hydroxyethyl) amino group; 3,3-dimethylpiperidinyl group; A 3-hydroxypiperidinyl group; 1,2,3,4-tetrahydroquinoline-1
-Yl group; A 1- (4-phenylpiperazinyl) group,
K. 4-piperidinyloxy group, sa. Piperidino group,
Shi. 4-hydroxyethyl-1-piperazinyl group;
1- [4-82-hydroxyethyl) piperazinyl
Group, c. 1- [4- (2-pyridyl) piperazinyl group], so. And a 1- (4-methylpiperazinyl) group.

The salt of the compound (I) of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt, but a hydrochloride is particularly preferred.

The compound (I) of the present invention has 1 or 2
Since the above-mentioned asymmetric carbon can be present, various isomers exist, and both the racemic form and the optically active form are included. The compound (I) of the present invention may exist in the form of a solvate such as a hydrate.

Representative examples of the compounds according to the present invention include: 1- [2- [4- (3-Chloro-2-methylphenyl) -1-piperazinyl] ethyl] -3-[(N-ethyl-N- (n-propylaminomethyl)]-5,6-dimethoxy- 1H-indazole dihydrochloride (I-1), i. 1- [2- [4- (3-Chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-3- [N -(3-methoxypropyl) -N-pentylaminomethyl] -1H-indazole dihydrochloride (I
-6), c. 1- [2- [4- (3-Chloro-2-methylphenyl) -1-piperazinyl] ethyl] -3- [N, N-bis (2-ethoxyethyl) aminomethyl] -5,6-dimethoxy- 1H-indazole dihydrochloride (I-7), d. 3- (N-cyclohexyl-N-ethylaminomethyl) -1- [2- [4- (3-chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-1H-indazole 2 Hydrochloride (I-8), e. 3- [N-benzyl-N- (2-hydroxyethyl) aminomethyl] -1- [2- [4- (3-chloro-
2-methylphenyl) -1-piperazinyl] ethyl]-
5,6-dimethoxy-1H-indazole dihydrochloride (I-11); 1- [2- [4- (3-Chloro-2-methylphenyl) -1-piperazinyl] ethyl] -3-homopiperidinomethyl-5,6-dimethoxy-1H-indazole
Dihydrochloride (I-12), g. 1- [2- [4- (3-Chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-3- [1- (3,3-dimethylpiperidinyl) methyl]- 1H-indazole dihydrochloride (I-13); 1- [2- [4- (3-chloro-2-methylphenyl) -1-piperazinyl] ethyl] -3- [1- (3-
Hydroxypiperidino) methyl] -5,6-dimethoxy-1H-indazole dihydrochloride (I-14); 1- [2- [4- (3-chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-3-morpholinomethyl-1H-indazole dihydrochloride (I-15); . 1- [2- [4- (3-Chloro-2-methylphenyl) -1-piperazinyl] ethyl] -3- (1,2,
3,4-tetrahydroquinolin-1-ylmethyl)-
5,6-dimethoxy-1H-indazole dihydrochloride (I-16); 1- [2- [4- (3-Chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-3- (4-phenyl-1-piperazinylmethyl)-
1H-indazole dihydrochloride (I-18); 1- [2- [4- (3-Chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-3- (4-piperidinyloxymethyl) -1H-indazole dihydrochloride (I-22); 1- [2- [4- (3-chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-3-piperidinomethyl-1H-indazole dihydrochloride (I-27); 1- [2- [4- (3-Chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-3-[(4-methylpiperazin-1-yl) methyl] -1H- Indazole trihydrochloride (I-28); 1- [2- [4- (3-Chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-3-[(imidazol-4-yl) ethyl] -1H
-Indazole dihydrochloride (I-33). And the like.

[0053]

[Production method] The production method of the compound of the present invention will be described.
Among the compounds of the present invention, those having an asymmetric carbon in the molecule may be finally optically resolved using a known technique, or a synthetic intermediate may be optically resolved by a known technique, or a known technique may be used. By introducing an asymmetric carbon into the intermediate using the compound, an optically active substance can be produced.

Hereinafter, a method for producing a racemate will be described. The compound of the present invention can be produced, for example, by any of the following methods A to G.

[Method A] comprises the following reaction steps.

[0056]

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[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ , R ⁷ , R ⁸ , R ⁹ , m and n have the same meaning as described above, and X represents a halogen atom. As the halogen atom represented by X, a chlorine atom and a bromine atom are particularly preferable.

That is, the compound (II) is substituted with an amine derivative (II
I), alcohol derivative (IV) or thiol derivative (V)
The compound (I) of the present invention can be produced by reacting

The reaction is carried out, for example, with ethanol or N, N
-Compound (II) and amine derivative (III), alcohol derivative (IV) or thiol derivative (V) in a solvent such as dimethylformamide at 0 to 100 ° C, preferably at room temperature to 70 ° C.
When these reactions are performed, a base such as potassium carbonate or sodium hydride is appropriately used. [Method B] The method B includes the following steps.

[0060]

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[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
m and n are as defined above. The compound represented by formula (I) can be produced by reacting compound (VI) with phthalimide (VII).

That is, this reaction is carried out by adding diethyl azodicarboxylate and triphenylphosphine to a mixture of compound (VI) and compound (VII) at 0 to 70 ° C., preferably at room temperature, in an inert solvent such as tetrahydrofuran. Compound (I) can be synthesized.

[Method C] The method C comprises the following reaction steps.

[0064]

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[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
m and n have the same meaning as described above; R ¹⁰ represents a phenyl group which may have a substituent; and an unsaturated heterocyclic group which may have a substituent, and j is an integer of 0 to 4. The compound (I) can be produced by subjecting the compound (VIII) to a catalytic reduction reaction in a solvent such as ethanol in the presence of a catalyst such as palladium hydroxide-carbon or the like at room temperature in a hydrogen atmosphere at 1 atm. it can. This reaction can be carried out under heated and pressurized conditions, and other catalysts generally used for catalytic reduction reactions are also useful.

[Method D] Method D comprises the following reaction steps. In the formula (I), when an N-trityl group or an N-tertiary-butoxycarbonyl group is present in R ³ , the compound may be used in the absence of a solvent or in a suitable solvent in the range of 0 to 5;
The corresponding amino derivative can be prepared by treatment at 0 ° C., preferably at room temperature, with an acid, for example aqueous hydrochloric acid or trifluoroacetic acid.

[Method E] will be described. In the production by the method E, in (I), the compound in which R ³ is an amino group is obtained by converting the compound in which R ³ is a phthaloyl group to chloroform,
This is a method of producing by reacting with hydrazine hydrate in dichloromethane, ethanol, methanol or a mixed solvent thereof at 0 to 50 ° C., preferably at room temperature.

[Method F] Next, the method F will be described. F
In the method, when a primary amine or a secondary amine is present in R ³ in the formula (I), the compound is reacted with a halogen in the presence of a base such as potassium carbonate in a solvent such as N, N-dimethylformamide. By reacting with an alkyl halide, the corresponding N-alkyl derivative can be produced. Preferred as the halogen atom of the alkyl halide used in this reaction are a chlorine atom, a bromine atom and an iodine atom.

Further, the above primary amine or secondary amine is reacted with a sulfonyl chloride derivative in an inert solvent such as dichloromethane in the presence of a base, for example, pyridine at 0 to 50 ° C., preferably 0 ° C. to room temperature. Sulfonamide derivatives can be produced.

[G Method] Next, the G method will be described.
In the method G, the hydrochloride of the compound represented by the formula (I) is produced by dissolving the compound obtained by the reaction in an alcohol such as ethanol, adding an aqueous hydrochloric acid solution, and distilling off the solvent under reduced pressure. Is the way.

The raw materials used in the above methods A, B and C will be described. First, methods for producing compound (II) and compound (VI) used in method A and method B will be described.
The methods A and B are the following reactions.

[0072]

Embedded image

[Wherein R ¹ , R ² , R ⁴ , R ⁵ , X,
m and n have the same meaning as described above, R ¹¹ represents an alkyl group excluding a tertiary butyl group, and q represents an integer from 0 to 5. ].

Next, the synthesis of the starting compound (VIII) used in the method C will be described. Starting compound (VI) is obtained by treating compound (X) with a reducing agent, for example, sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al) at 0 to 60 ° C., preferably at room temperature, in a solvent such as tetrahydrofuran. After reducing the ester group by isolating the compound (IX) with a compound such as dimethyl sulfoxide in a solvent such as dimethyl sulfoxide in the presence of a base such as lithium methoxide at room temperature to 100 ° C., preferably without isolation. It can be produced by reacting at 40 to 60 ° C. In the reduction reaction in the present synthesis, lithium aluminum hydride and the like are also useful as a reducing agent in addition to Red-Al.

Compound (II) can be produced by reacting compound (VI) with thionyl chloride in an inert solvent such as methylene chloride at a temperature from room temperature to reflux. In this reaction, the compound (II) is obtained as a hydrochloride, and a free base can be obtained by treating this with an aqueous alkali solution, for example, a saturated aqueous sodium hydrogen carbonate solution.

Next, a method for producing the starting compound (VIII) used in the method C will be described. Furthermore,

[0077]

Embedded image

[Wherein R ¹ , R ² , R ⁴ , R ⁵ , X,
m, n and j have the same meaning as described above, R ¹² represents an alkyl group excluding a tertiary butyl group, and Ph ₃ P represents a triphenylphosphine residue. ], (X) to (XI), (XI
(VIII) can be synthesized via (I), (XIII), (XIV) and (XVI).

The steps will be described below in order. Compound
(XI) is produced by reacting compound (X) with trityl chloride in a solvent such as N, N-dimethylformamide in the presence of a base such as potassium carbonate at room temperature to 100 ° C, preferably 40 to 60 ° C. be able to. As the base used in the reaction, pyridine, sodium hydride or a mixture thereof is also useful.

Compound (XII) is prepared by converting compound (XI) into a reducing agent such as bis (2-methoxyethoxy) aluminum sodium (Red-Al) at 0 to 50 ° C., preferably at room temperature, in a solvent such as toluene or tetrahydrofuran. )
And can be produced by reduction. As the reducing agent used in the reaction, other reducing agents capable of reducing an ester group are also useful.

Compound (XIII) can be prepared by adding compound (XII) to a mixture of oxalyl chloride and dimethyl sulfoxide in a solvent such as methylene chloride at -78 to 50 ° C, preferably -78 ° C.
It can be produced by reacting at a temperature of from 0 ° C. to room temperature, and further reacting a base, for example, triethylamine. In the reaction for synthesizing compound (XIII) from compound (XII), other oxidation reactions that do not affect the trityl group are also useful.

Compound (XIV) can be obtained by removing compound (XIII) from the trityl group by heating to reflux with a hydrochloric acid aqueous solution, for example, 4N hydrochloric acid in a solvent such as dioxane, and then subjecting the product to a base such as methylene chloride. For example, it can be produced by reacting with benzoyl chloride in the presence of triethylamine at 0 to 50 ° C, preferably at 0 ° C to room temperature.

Compound (XVI) was obtained by reacting compound (XV) with a base such as potassium-bis (trimethylsilyl) amide in a solvent such as tetrahydrofuran at -78 to -30 ° C, preferably -78 to -70 ° C. Thereafter, the compound (XIV) can be further produced by reacting the compound (XIV) at -78 to 0 ° C. The compound (XV) used in this reaction is
It can be produced by heating a mixture of triphenylphosphine and an alkyl halide derivative in a solvent such as toluene.

Compound (VIII) is prepared by heating compound (XVI) in a solvent such as tetrahydrofuran with an aqueous alkali hydroxide solution to remove the benzoyl group, and then subjecting the product to a base such as lithium methoxyl in a solvent such as dimethyl sulfoxide. In the presence of a compound (IX) at room temperature to 100 ° C, preferably 50 to 70 ° C.

Reference Examples and Examples are shown below. In the nuclear magnetic resonance (NMR) spectrum, s is a singlet, d is a doublet, t is a triplet, m is a multiplet, and br
s means a wide singlet.

[0086]

EXAMPLES Reference Example 1 1- [2- [4- (3-chloro-2-methylphenyl)]
-1-piperazinyl] ethyl] -3-hydroxymethyl-5,6-dimethoxy-1H-indazole (VI-1:

Ethyl 5,6-dimethoxy-1H-indazole-3-carboxylate (2.50 g) was suspended in tetrahydrofuran (20 ml), and 3.4M bis (2-methoxyethoxy) aluminum sodium hydride (3.4 M) was stirred at room temperature. (Red-Al) toluene solution (6.0 ml) was added, and the mixture was stirred at the same temperature for 2 hours. Ethyl acetate was added to the reaction solution to decompose excess Red-Al, and then the solvent was distilled off under reduced pressure. The residue was dissolved in dimethyl sulfoxide (20 ml), and lithium methoxide (1.0 g) was added with stirring at room temperature, followed by stirring at 50 ° C. for 15 minutes. This is 1- (2
A solution of (-chloroethyl) -4- (3-chloro-2-methylphenyl) piperazine (5.7 g) in dimethyl sulfoxide (20 ml) was added, and the mixture was stirred at 50 ° C for 2 hours. The reaction solution was poured into water, and the precipitate was collected by filtration. This was dissolved in chloroform and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography using chloroform-methanol as an eluent to obtain Compound VI-1 (2.5 g).

¹ H-NMR (ppm, CDCl ₃ ):
2.32 (3H, s), 2.69 (4H, brs),
2.88-2.94 (6H, m), 3.94 (3H,
s), 3.98 (3H, s), 4.45 (2H,
t), 4.99 (2H, s), 6.80 (1H,
s), 6.89-6.92 (1H, m), 7.08-
7.13 (3H, m)

Reference Example 2 1- [2- [4- (3-chloro-2-methylphenyl)]
-1-piperazinyl] ethyl] -3-chloromethyl-
5,6-Dimethoxy-1H-indazole (II-1): Reference compound VI-1 (4.10 g) in chloroform (10
0 ml) solution and thionyl chloride (0.74 m
l) was added, and the mixture was further stirred at room temperature for 3 hours and under reflux with heating for 1 hour. The reaction was cooled to room temperature and poured into saturated aqueous sodium bicarbonate. The two layers were separated, and the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography using ethyl acetate as an eluent, and further powdered with ether to give the compound
II-1 (3.10 g) was obtained.

¹ H-NMR (ppm, CDCl ₃ ):
2.32 (3H, s), 2.68 (4H, brs),
2.88-2.90 (4H, m), 2.94 (2H,
t), 3.96 (3H, s), 3.98 (3H,
s), 4.45 (2H, t), 4.93 (2H,
s), 6.82 ((1H, s), 6.89-6.92)
(1H, m), 7.07-7.10 (3H, m)

Example 1 1- [2- [4- (3-chloro-2-methylphenyl)]
-1-piperazinyl] ethyl] -3-[(N-ethyl-
N- (n-propylaminomethyl)]-5,6-dimethoxy-1H-indazole dihydrochloride (I-1):

Compound II-1 (0.93 g) of Reference Example,
A solution of N-ethylpropylamine (0.26 g) and potassium carbonate (0.69 g) in N, N-dimethylformamide (30 ml) was stirred at 60 ° C. for 8 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography using chloroform-methanol as an eluent, and treated with 1N hydrochloric acid to obtain compound I-1 (0.60 g). Was.

¹ H-NMR (ppm, DMSO-d
₆ ): 0.89 (3H, t), 1.34 (3H, t)
t), 1.79-1.87 (2H, m), 2.29
(3H, s), 2.98-3.66 (14H, m),
3.84 (3H, s), 3.92 (3H, s),
60 (2H, s), 4.99 (2H, m), 7.05
(1H, dd), 7.19-7.24 (2H, m),
7.54 (1H, s), 7.59 (1H, s), 1
1.00 (1H, brs), 11.89 (1H, br)
s)

Example 2 3- [N- (n-butyl) -N-ethylaminomethyl]
-1- [2- [4- (3-Chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-1H-indazole dihydrochloride (I-2):

Compound II-1 (0.23 g) of Reference Example, N
-Butylethylamine (0.08 g) and potassium carbonate (0.21 g) in N, N-dimethylformamide (2
0 ml) solution was stirred at 70 ° C. for 7 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography using chloroform-methanol as an eluent, and treated with 1N hydrochloric acid to obtain compound I-2 (0.10 g). Was.

¹ H-NMR (ppm, DMSO-d
₆ ): 0.89 (3H, t), 1.27-1.35
(5H, m), 1.78 (2H, brs), 2.30
(3H, s), 3.03-3.66 (14H, m),
3.84 (3H, s), 3.92 (3H, m),
61 (2H, s), 4.98 (2H, brs), 7.
05-7.06 (1H, m), 7.19-7.24 (2
H, m), 7.52 (1H, s), 7.56 (1H,
s), 10.85 (1H, brs), 11.78 (1
H, brs)

Example 3 3- [N-tert-butyl-N-ethylaminomethyl]-
1- [2- [4- (3-chloro-2-methylphenyl)
-1-piperazinyl] ethyl] -5,6-dimethoxy-1H-indazole dihydrochloride (I-3): Compound II-1 (0.23 g) of Reference Example, N-tert-butylethylamine (0.08 g) And potassium carbonate (0.21
A solution of g) in N, N-dimethylformamide (20 ml) was stirred at 70 ° C. for 8 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography using chloroform-methanol as an eluent, and further treated with 1N hydrochloric acid to obtain compound I.
-3 (0.15 g) was obtained.

¹ H-NMR (ppm, DMSO-d
₆ ): 1.14 (3H, t), 1.50 (9H,
s), 2.30 (3H, s), 3.22-3.35 and 3.62-3.68 (12H, m), 3.84 (3
H, s), 3.92 (3H, s), 4.56 (1H,
dd), 4.77 (1H, d), 4.98 (2H, b
rs), 7.04-7.06 (1H, m), 7.19.
−7.25 (2H, m), 7.51 (1H, s),
7.54 (1H, s), 9.76 (1H, brs),
11.62 (1H, brs)

Example 4 1- [2- [4- (3-chloro-2-methylphenyl)]
-1-piperazinyl] ethyl] -3- (N-methyl-N
-Methoxyaminomethyl) -5,6-dimethoxy-1H
-Indazole dihydrochloride (I-4):

Compound (II-1) of Reference Example (0.92)
g), a solution of N, O-dimethylhydroxylamine hydrochloride (0.29 g) and potassium carbonate (0.69 g) in N, N-dimethylformamide (20 ml) was added to a solution of 70 g.
Stirred at C for 8 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography using chloroform-methanol as an eluent, and further treated with 1N hydrochloric acid to obtain compound I-4.
(0.70 g).

¹ H-NMR (ppm, DMSO-d
₆ ): 2.28 (3H, s), 2.78 (3H, s)
s), 3.18-3.30 (6H, m), 3.43-
3.64 (4H, m), 3.59 (3H, s),
81 (3H, s), 3.92 (3H, s), 4.40
(2H, s), 4.95 (2H, m), 7.04-
7.06 (1H, m), 7.18-7.23 (2H,
m), 7.33 (1H, s), 7.49 (1H,
s), 11.96 (1H, brs)

Example 5 1- [2- [4- (3-Chloro-2-methylphenyl)]
-1-piperazinyl] ethyl] -3- [N- (2-hydroxyethyl) -N-methylaminomethyl] -5,6-
Dimethoxy-1H-indazole dihydrochloride (I-
5):

Compound II-1 (0.92 g) of Reference Example,
A solution of N-methylethanolamine (0.23 g) and potassium carbonate (0.69 g) in N, N-dimethylformamide (20 ml) was stirred at 70 ° C. for 8 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography using chloroform-methanol as an eluent, and further treated with 1N hydrochloric acid to obtain Compound I-5 (0.62 g). Was.

¹ H-NMR (ppm, DMSO-d
₆ ): 2.29 (3H, s), 2.82 (3H, s)
s), 3.19-3.67 (12H, m), 3.84.
(5H, s), 3.92 (3H, s), 4.65 (2
H, m), 4.99 (2H, m), 5.40 (1H,
brs), 7.05 (1H, dd), 7.18-7.
24 (2H, m), 7.52 (1H, s), 7.57
(1H, s), 10.66 (1H, brs), 11.8
9 (1H, brs)

Example 6 1- [2- [4- (3-chloro-2-methylphenyl)]
-1-piperazinyl] ethyl] -5,6-dimethoxy-
3- [N- (3-methoxypropyl) -N-pentylaminomethyl] -1H-indazole dihydrochloride (I-
6):

Compound (II-1) of Reference Example (0.50
g), N- (3-methoxypropyl) pentylamine (0.21 g) and potassium carbonate (0.29 g) in a solution of N, N-dimethylformamide (20 ml) in 60 ml.
Stirred at C for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography using chloroform-methanol as an eluent, and further treated with 1N hydrochloric acid to obtain compound I-6.
(0.25 g).

¹ H-NMR (ppm, DMSO-d
₆ ): 0.86 (3H, t), 1.22-1.32.
(4H, m), 1.80 (2H, brs), 2.05
-2.10 (2H, m), 2.30 (3H, s),
3.03-3.40 (12H, m), 3.21 (3H,
s), 3.61-3.65 (4H, m), 3.83.
(3H, s), 3.92 (3H, s), 4.62 (2
H, s), 4.98 (2H, brs), 7.04-
7.06 (1H, m), 7.19-7.24 (2H,
m), 7.52 (1H, s), 7.55 (1H,
s), 10.91 (1H, brs), 11.78 (1
H, brs)

Example 7 1- [2- [4- (3-Chloro-2-methylphenyl)]
-1-piperazinyl] ethyl] -3- [N, N-bis (2-ethoxyethyl) aminomethyl] -5,6-dimethoxy-1H-indazole dihydrochloride (I-7):

Compound II-1 (0.50 g) of Reference Example,
A solution of bis (2-ethoxyethyl) amine (0.21 g) and potassium carbonate (0.29 g) in N, N-dimethylformamide (20 ml) was stirred at 60 ° C. for 4 hours.
Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography using chloroform-methanol as an eluent, and treated with 1N hydrochloric acid to obtain compound I-7 (0.25 g). Was.

¹ H-NMR (ppm, DMSO-d
₆ ): 1.13 (6H, t), 2.29 (3H,
s), 3.20-3.43 (10H, m), 3.49.
(4H, q), 3.59-3.67 (4H, m),
3.84 (3H, s), 3.92 (3H, s),
85-3.90 (4H, m), 4.71 (2H, s),
4.98-5.01 (2H, m), 7.04-7.0
6 (1H, m), 7.19-7.24 (2H, m),
7.51 (1H, s), 7.53 (1H, s), 1
0.75 (1H, brs), 11.86 (1H, br)
s)

Example 8 3- (N-cyclohexyl-N-ethylaminomethyl)
-1- [2- [4- (3-Chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-1H-indazole dihydrochloride (I-8):

Compound II-1 (0.92 g) of Reference Example,
A solution of N-ethylcyclohexylamine (0.38 g) and potassium carbonate (0.69 g) in N, N-dimethylformamide (20 ml) was stirred at 70 ° C. for 8.5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography using chloroform-methanol as an eluent, and further treated with 1N hydrochloric acid to obtain compound I-8 (0.35 g). Was.

¹ H-NMR (ppm, DMSO-d
₆ ): 1.05-1.34 (3H, m), 1.57
(3H, brs), 1.79-1.82 (2H, m),
2.13-2.22 (2H, m), 1.32 (3H,
t), 2.30 (3H, s), 3.16-3.79
(13H, m), 3.84 (3H, s), 3.92
(3H, s), 4.55 (1H, dd), 4.67
(1H, dd), 4.99 (2H, brs), 7.0
4 (1H, d), 7.19-7.24 (2H, m),
7.53 (1H, s), 7.57 (1H, s), 1
0.57 (1H, brs), 11.76 (1H, br)
s):

Example 9 1- [2- [4- (3-chloro-2-methylphenyl)]
-1-piperazinyl] ethyl] -5,6-dimethoxy-
3- (N-methyl-N-phenylaminomethyl) -1H
-Indazole dihydrochloride (I-9):

Compound II-1 (0.46 g) of Reference Example,
N, N-dimethylformamide (20 g) of N-methylaniline (0.16 g) and potassium carbonate (0.41 g)
ml) The solution was stirred at 70 ° C. for 9 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography using chloroform-methanol as an eluent, and further treated with 1N hydrochloric acid to obtain a residue.
Compound I-9 (0.35 g) was obtained.

¹ H-NMR (ppm, DMSO-d
₆ ): 2.29 (3H, s), 3.09 (3H,
s), 3.15-3.26 (6H, m), 3.54-
3.56 (4H, m), 3.66 (3H, s), 3.
87 (3H, s), 4.87-4.90 (4H, m),
6.98 (2H, brs), 7.04-7.06 (1
H, m), 7.19-7.30 (6H, m), 7.4
0 (1H, s), 11.76 (1H, brs)

Example 10 3- (N-benzyl-N-methylaminomethyl) -1-
[2- [4- (3-chloro-2-methylphenyl) -1
-Piperazinyl] ethyl] -5,6-dimethoxy-1H
-Indazole dihydrochloride (I-10):

Compound (II-1) of Reference Example (0.46
g), a solution of N-methylbenzylamine (0.18 g) and potassium carbonate (0.41 g) in N, N-dimethylformamide (20 ml) was stirred at 70 ° C. for 5.5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography using chloroform-methanol as an eluent, and further treated with 1 N hydrochloric acid to obtain compound I-10 (0.55 g). Was.

¹ H-NMR (ppm, DMSO-d
₆ ): 2.28 (3H, s), 2.68 (3H, s)
d), 3.20-3.70 (10H, m), 3.83
(3H, s), 3.92 (3H, s), 4.29-
4.33 (1H, m), 4.52-4.55 (1H,
m), 4.59 (2H, s), 5.00 (2H, br)
s), 6.99-7.02 (1H, m), 7.19-
7.22 (2H, m), 7.45-7.46 (3H,
m), 7.52 (2H, brs), 7.72 (2H,
brs), 11.33 (1H, brs), 11.79
(1H, brs).

Example 11 3- [N-benzyl-N- (2-hydroxyethyl) aminomethyl] -1- [2- [4- (3-chloro-2-methylphenyl) -1-piperazinyl] Ethyl] -5,6
-Dimethoxy-1H-indazole dihydrochloride (I-1
1):

Compound II-1 (0.92 g) of Reference Example,
A solution of N-benzylethanolamine (0.45 g) and potassium carbonate (0.69 g) in N, N-dimethylformamide (20 ml) was stirred at 70 ° C. for 8 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified with chloroform-
The product was purified by silica gel column chromatography using methanol as an eluting solvent, and further treated with 1N hydrochloric acid to obtain compound I-11 (0.97 g).

¹ H-NMR (ppm, DMSO-d
₆ ): 2.28 (3H, s), 3.06-3.72.
(14H, m), 3.82 (3H, s), 3.93
(3H, s), 4.40-4.45 (1H, m),
4.60-4.65 (1H, m), 4.65 (2H,
s), 5.01 (2H, brs), 5.40 (1H,
brs), 7.00-7.04 (1H, m), 7.1.
7-7.22 (2H, m), 7.44-7.54 (4
H, m), 7.76 (3H, brs), 11.04
(1H, brs), 11.92 (1H, brs)

Example 12 1- [2- [4- (3-Chloro-2-methylphenyl)]
-1-piperazinyl] ethyl] -3-homopiperidinomethyl-5,6-dimethoxy-1H-indazole dihydrochloride (I-12):

Compound II-1 (0.23 g) of Reference Example,
Hexamethyleneimine (0.07 g) and potassium carbonate (0.21 g) in N, N-dimethylformamide (1
0 ml) solution was stirred at 70 ° C. for 7.5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography using chloroform-methanol as an eluent, and further treated with 1N hydrochloric acid to obtain compound I-12 (0.20 g). Was.

¹ H-NMR (ppm, DMSO-d
₆ ): 1.53-1.99 (8H, m), 2.29
(3H, s), 3.21-3.68 (14H, m),
3.84 (3H, s), 3.92 (3H, s),
6. 60 (2H, s), 4.97 (2H, brs),
04-7.06 (1H, m), 7.19-7.24 (2
H, m), 7.50 (1H, s), 7.59 (1H,
s), 10.84 (1H, brs), 11.69 (1
H, brs)

Example 13 1- [2- [4- (3-chloro-2-methylphenyl)]
-1-piperazinyl] ethyl] -5,6-dimethoxy-
3- [1- (3,3-dimethylpiperidinyl) methyl]
-1H-indazole dihydrochloride (I-13):

To a solution of compound II-1 (0.50 g) in Reference Example in acetonitrile (20 ml) was added 3,3-dimethylpiperidine (2.0 ml) with stirring at room temperature, and the mixture was stirred at the same temperature for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in chloroform, washed with a saturated aqueous solution of sodium hydrogen carbonate and water, and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography using chloroform-methanol as an eluent, and further treated with 1N hydrochloric acid to obtain compound I.
-13 (0.40 g) was obtained.

¹ H-NMR (ppm, DMSO-d
₆ ): 0.89 (3H, s), 1.11 (3H,
s), 1.29 (1H, m), 1.38 (1H,
m), 1.72 (1H, m), 1.92 (1H,
m), 2.29 (3H, s), 2.74-2.92
(2H, m), 3.11-3.52 (8H, m),
3.65 (4H, m), 3.84 (3H, s),
92 (3H, s), 4.59 (1H, m), 4.68
(1H, m), 4.98 (2H, t), 7.04 (1
H, m), 7.20 (2H, m), 7.50 (1H,
s), 7.60 (1H, s)

Example 14 1- [2- [4- (3-Chloro-2-methylphenyl)]
-1-piperazinyl] ethyl] -3- [1- (3-hydroxypiperidino) methyl] -5,6-dimethoxy-1
H-indazole dihydrochloride (I-14):

Compound II-1 of Reference Example (0.92 g), 3
A solution of -hydroxypiperidine hydrochloride (0.41 g) and potassium carbonate (0.69 g) in N, N-dimethylformamide (20 ml) was stirred at 70 ° C for 6 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified with chloroform-
The product was purified by silica gel column chromatography using methanol as an eluting solvent, and further treated with 1 N hydrochloric acid to obtain Compound I-14 (0.35 g).

¹ H-NMR (ppm, DMSO-d
₆ ): 1.19-2.13 (4H, m), 2.29
(3H, s), 2.61-3.80 (16H, m),
3.85 (3H, s), 3.92 (3H, s),
6. 60 (2H, m), 5.00 (2H, brs),
04-7.08 (1H, m), 7.18-7.24 (2
H, m), 7.52-7.54 (2H, m), 9.9
3 and 11.27 (1H, each brs), 11.
77 and 12.00 (1H, each brs)

Example 15 1- [2- [4- (3-Chloro-2-methylphenyl)]
-1-piperazinyl] ethyl] -5,6-dimethoxy-
3-morpholinomethyl-1H-indazole dihydrochloride (I-15):

To a solution of compound II-1 (0.50 g) in Reference Example in acetonitrile (20 ml) was added morpholine (2.0 ml) with stirring at room temperature, and the mixture was stirred at the same temperature for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in chloroform, washed with a saturated aqueous solution of sodium hydrogen carbonate and water, and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography using chloroform-methanol as an eluent, and further treated with 1N hydrochloric acid to obtain compound I-15 (0.4%).
8 g) were obtained.

¹ H-NMR (ppm, DMSO-d
₆ ): 2.29 (3H, s), 3.20-3.44
(8H, m), 3.58-3.68 (4H, m),
3.79-3.95 (4H, m), 3.85 (3H,
s), 3.92 (3H, s), 4.63 (4H, br)
s), 4.98 (2H, m), 7.05 (1H,
m), 7.20 (2H, m), 7.50 (1H,
s), 7.60 (1H, s)

Example 16 1- [2- [4- (3-Chloro-2-methylphenyl)]
-1-piperazinyl] ethyl] -3- (1,2,3,4
-Tetrahydroquinolin-1-ylmethyl) -5,6-
Dimethoxy-1H-indazole dihydrochloride (I-1
6):

Compound II-1 (0.46 g) of Reference Example,
1,2,3,4-tetrahydroquinoline (0.20 g)
And a solution of potassium carbonate (0.41 g) in N, N-dimethylformamide (20 ml) was stirred at 70 ° C. for 7.5 hours. After adding water to the reaction solution and extracting with ethyl acetate,
The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography using chloroform-methanol as an eluent, and further treated with 1N hydrochloric acid to obtain compound I-16 (0.25 g).
I got

¹ H-NMR (ppm, DMSO-d
₆ ): 1.89-1.92 (2H, m), 2.27
(3H, s), 2.67-2.70 (2H, m), 3.
12-3.61 (12H, m), 3.67 (3H,
s), 3.88 (3H, s), 4.75 (2H,
s), 4.91 (2H, m), 6.60 (1H, br)
s), 6.91-7.06 (5H, m), 7.18-
7.23 (2H, m), 7.44 (1H, s), 1
1.84 (1H, brs)

Example 17 1- [2- [4- (3-Chloro-2-methylphenyl)]
-1-piperazinyl] ethyl] -3- [4- (2-hydroxyethyl) -1-piperazinylmethyl] -5,6-
Dimethoxy-1H-indazole trihydrochloride (I-1
7):

Compound of Reference Example II-1 (0.46 g), 1
-A solution of piperazine ethanol (0.19 g) and potassium carbonate (0.69 g) in N, N-dimethylformamide (20 ml) was stirred at 70 ° C for 8 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography using chloroform-methanol as an eluent, and treated with 1N hydrochloric acid to obtain compound I-17 (0.25 g). Was.

¹ H-NMR (ppm, DMSO-d
₆ ): 2.29 (3H, s), 3.21-3.77
(23H, m), 3.85 (3H, s), 3.92
(3H, s), 4.67 (2H, brs), 4.99
(2H, m), 7.05-7.09 (1H, m),
7.19-7.24 (2H, m), 7.52 (1H,
s), 7.62 (1H, brs), 11.40 (1
H, brs), 11.68 (2H, brs)

Example 18 1- [2- [4- (3-Chloro-2-methylphenyl)]
-1-piperazinyl] ethyl] -5,6-dimethoxy-
3- (4-phenyl-1-piperazinylmethyl) -1H
-Indazole dihydrochloride (I-18):

Compound II-1 (0.46 g) of Reference Example, N
-Phenylpiperazine (0.24 g) and potassium carbonate (0.41 g) in N, N-dimethylformamide (2
0 ml) solution was stirred at 70 ° C. for 4 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography using chloroform-methanol as an eluent, and further treated with 1N hydrochloric acid to obtain compound I-18 (0.48 g). Was.

¹ H-NMR (ppm, DMSO-d
₆ ): 2.28 (3H, s), 3.19-3.30
(10H, m), 3.62-3.82 (8H, m),
3.86 (3H, s), 3.92 (3H, s),
5. 71 (2H, s), 5.01 (2H, brs),
85 (1H, t), 6.96 (2H, d), 7.02
−7.06 (1H, m), 7.18-7.26 (4H,
m), 7.53 (1H, s), 7.67 (1H,
s), 11.51 (1H, brs), 11.79 (1
H, brs)

Example 19 1- [2- [4- (3-chloro-2-methylphenyl)]
-1-piperazinyl] ethyl] -5,6-dimethoxy-
3- [4- (2-pyridyl) -1-piperazinylmethyl] -1H-indazole trihydrochloride (I-19):

Compound of Reference Example II-1 (0.46 g), 1
A solution of-(2-pyridyl) piperazine (0.24 g) and potassium carbonate (0.42 g) in N, N-dimethylformamide (20 ml) was stirred at 70 ° C for 8 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified with chloroform-
The product was purified by silica gel column chromatography using methanol as an eluting solvent, and further treated with 1N hydrochloric acid to obtain compound I-19 (0.47 g).

¹ H-NMR (ppm, DMSO-d
₆ ): 2.28 (3H, s), 3.19-3.69
(16H, m), 3.85 (3H, s), 3.91
(3H, s), 4.49 (2H, m), 4.68 (2
H, s), 4.98 (2H, brs), 6.90-
6.93 (1H, m), 7.03 (1H, d), 7.
19-7.23 (3H, m), 7.51 (1H, s),
7.63 (1H, s), 7.89 (1H, brs),
8.06 (1H, d), 11.70 (1H, br)
s), 11.85 (1H, brs)

Example 20 1- [2- [4- (3-Chloro-2-methylphenyl)]
-1-piperazinyl] ethyl] -5,6-dimethoxy-
3- (2-Pyridylthiomethyl) -1-piperazinylmethyl] -1H-indazole dihydrochloride (I-20):

Compound II-1 (0.92 g) of Reference Example was added to an ethanol solution of 2-mercaptopyridine (0.33 g) and potassium carbonate (0.69 g), and the mixture was stirred at room temperature overnight. After the solvent was distilled off, the residue was partitioned between ethyl acetate and water. After separating two layers, the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography using chloroform-methanol as an eluent, and further treated with 1 N hydrochloric acid to obtain compound I-20 (1.10 g). Was.

1H-NMR (ppm, DMSO-d
₆ ): 2.28 (3H, s), 3.12-3.28
(6H, m), 3.55-3.60 (4H, m),
3.73 (3H, s), 3.89 (3H, s),
76 (2H, s), 4.89 (2H, m), 7.04
−7.06 (1H, m), 7.18-7.25 (4H,
m), 7.44 (1H, s), 7.49 (1H,
d), 7.77 (1H, m), 8.55 (1H,
d), 11.77 (1H, brs)

Example 21 3- (N-tert-butoxycarbonyl-4-piperidinyloxymethyl) -1- [2- [4- (3-chloro-2
-Methylphenyl) -1-piperazinyl] ethyl]-
5,6-dimethoxy-1H-indazole (I-2
1):

To a solution of N-tert-butoxycarbonyl-4-hydroxypiperidine (1.05 g) in N, N-dimethylformamide (20 ml) was added sodium hydride (60% oil, 0.24 g) under ice-cooling and stirring. The mixture was stirred at room temperature for 1 hour. To this reaction solution was added a solution of the compound of Reference Example II-1 (1.4 g) in N, N-dimethylformamide (20 ml) under ice cooling and stirring, and the mixture was further stirred at room temperature for 5 hours. Ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography using chloroform-methanol as an eluting solvent, to obtain compound I-21.
(1.90 g) was obtained.

¹ H-NMR (ppm, CDCl ₃ ):
1.44 (9H, s), 1.61 (2H, m), 1.
84 (2H, m), 2.32 (3H, s), 2.69
(2H, brs), 2.88-3.08 (8H, brs)
m), 3.60 (1H, m), 3.84 (4H,
m), 3.93 (3H, s), 3.98 (3H,
s), 4.45 (2H, t), 4.87 (2H,
s), 6.80 (1H, s), 6.89-6.92
(1H, m), 7.08-7.09 (2H, m),
7.14 (1H, s)

Example 22 1- [2- [4- (3-Chloro-2-methylphenyl)]
-1-piperazinyl] ethyl] -5,6-dimethoxy-
3- (4-Piperidinyloxymethyl) -1H-indazole dihydrochloride (I-22):

Trifluoroacetic acid (20 ml) was added to a dichloromethane (100 ml) solution of the compound I-21 (1.90 g) of the example under ice cooling and stirring, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform, washed with a saturated aqueous solution of sodium hydrogen carbonate, water and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was dissolved in ethanol (20 ml), 1N hydrochloric acid (5 ml) was added, and the solvent was distilled off to obtain Compound I-22 (0.85 g).

¹ H-NMR (ppm, DMSO-d
₆ ): 1.79 (2H, brs), 1.98-2.0
3 (2H, m), 2.29 (3H, s), 2.96
(2H, brs), 3.12-3.47 (8H, m),
3.58-3.62 (4H, m), 3.73-3.7
6 (1H, m), 3.80 (3H, s), 3.91
(3H, s), 4.78 (2H, s), 4.89-
4.92 (2H, m), 7.06 (1H, dd),
7.16-7.24 (3H, m), 7.48 ((1
H, s), 9.00 (2H, brs), 11.88
(1H, brs)

Example 23 1- [2- [4- (3-Chloro-2-methylphenyl)]
-1-piperazinyl] ethyl] -3- [1- (2-hydroxyethyl) -4-piperidinyloxymethyl]-
5,6-Dimethoxy-1H-indazole dihydrochloride (I-23):

To a solution of the compound I-22 of the example (0.30 g) and triethylamine (0.7 ml) in dichloromethane (20 ml) was added 2-bromoethanol (0.07 ml).
l) was added and the mixture was stirred at room temperature for 3 days. The reaction solution was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography using chloroform-methanol as an eluting solvent, and further treated with 1N hydrochloric acid to obtain compound I-23 (0.20 g).

¹ H-NMR (ppm, DMSO-d
₆ ): 1.78-2.17 (4H, m), 2.29
(3H, s), 3.00-3.74 (19H, m),
3.81 (3H, s), 3.90 (3H, s),
79 (2H, s), 4.88 (2H, s), 5.40
(1H, brs), 7.07 (1H, d), 7.16
−7.24 (3H, m), 7.43 (1H, s),
9.80 (1H, brs), 11.40 (1H, br)
s)

Example 24 1- [2- [4- (3-Chloro-2-methylphenyl)]
-1-piperazinyl] ethyl] -3- (1-ethyl-4
-Piperidinyloxymethyl) -5,6-dimethoxy-
1H-indazole dihydrochloride (I-24):

Ethyl iodide (0.04 ml) was added to a dichloromethane (10 ml) solution of the compound I-22 of the example (0.15 g) and triethylamine (0.14 ml), and the mixture was stirred at room temperature overnight. The reaction solution was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography using chloroform-methanol as an eluent, treated with 1N hydrochloric acid, and further crystallized with ethanol-ethyl acetate-n-hexane. Thereby, compound I-24 (0.10) was obtained.

¹ H-NMR (ppm, DMSO-d
₆ ): 1.22 (3H, t), 1.75-1.81
(1H, m), 1.97-2.04 (2H, m),
2.15 to 2.19 (1H, m), 2.29 (3H,
s), 2.84-3.46 (13H, m), 3.59.
-3.67 (4H, m), 3.81 (3H, s),
3.90 (3H, s), 4.79 (2H, d), 4.
89 (2H, brs), 7.06-7.08 (1H,
m), 7.16-7.24 (3H, m), 7.44-
7.45 (1H, m), 10.32 (1H, brs),
11.64 (1H, brs)

Example 25 4- [1- [2- [4- (3-Chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-1H-indazol-3-yl Methyloxy] piperidine-1-methanesulfonamide hydrochloride (I-2
5):

Methanesulfonyl chloride (0.04 ml) was added to a solution of the compound I-22 of the example (0.27 g) and triethylamine (0.14 ml) in dichloromethane (10 ml) with stirring under ice-cooling, and the mixture was stirred at room temperature for 1 hour. did. The reaction solution was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using chloroform-methanol as an eluent. This was further dissolved in ethanol, 1N hydrochloric acid (1 ml) was added, the solvent was distilled off under reduced pressure, and the residue was powdered with ethanol-ethyl acetate-n-hexane to give compound I-25 (0.20%).
g) was obtained.

¹ H-NMR (ppm, DMSO-d
₆ ): 1.59-1.67 (2H, m), 1.89-
1.94 (2H, m), 2.29 (3H, s), 2.
84 (3H, s), 2.96-3.62 (15H,
m), 3.80 (3H, s), 3.90 (3H,
s), 4.78 (2H, s), 4.89 (2H,
m), 7.05-7.07 (1H, m), 7.17-
7.24 (3H, m), 7.44 (1H, s), 1
1.56 (1H, brs)

Example 26 1- [2- [4- (3-Chloro-2-methylphenyl)]
-1-piperazinyl] ethyl] -3- (imidazole-
1-ylmethyl) -5,6-dimethoxy-1H-indazole dihydrochloride (I-26):

To a solution of the compound of Reference Example II-1 (0.70 g) in dimethyl sulfoxide (20 ml) was added imidazole (0.51 g), and the mixture was stirred at 50 ° C. for 1 hour. The reaction solution was poured into a 10% aqueous potassium carbonate solution, and the precipitated solid was collected by filtration. This was dissolved in chloroform, dried over sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography using chloroform-methanol as an eluting solvent, treated with 1N hydrochloric acid, and further powdered with isopropanol-diisopropyl ether to give compound I-26 (0.75 g). Obtained.

¹ H-NMR (ppm, DMSO-d
₆ ): 2.99 (3H, s), 3.16-3.61
(10H, m), 3.82 (3H, s), 3.90
(3H, s), 4.91 (2H, m), 5.76 (2
H, s), 7.07 (1H, m), 7.20 (2H,
m), 7.47 (1H, s), 7.68 (1H,
s), 7.79 (1H, s), 9.32 (1H, s)

Example 27 1- [2- [4- (3-Chloro-2-methylphenyl)]
-1-piperazinyl] ethyl] -5,6-dimethoxy-
3-Piperidinomethyl-1H-indazole dihydrochloride (I-27):

Compound II-1 (0.30 g) of the reference example was dissolved in acetonitrile (15 ml), piperidine (1.5 ml) was added with stirring at room temperature, and the mixture was further stirred at the same temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform, washed with a 0.1 N aqueous sodium hydroxide solution and water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained oil was treated with hydrochloric acid and crystallized from ethyl acetate to obtain compound I-27 (0.28 g).

¹ H-NMR (ppm, CD ₃ OD):
1.80-1.99 (6H, m), 2.37 (3H,
s), 3.00-3.86 (14H, m), 3.92.
(3H, s), 3.98 (3H, s), 4.63 (2
H, s), 4.94 (2H, t), 7.10 (1H,
m), 7.16 (2H, m), 7.29 (1H,
s), 7.35 (1H, s)

Example 28 1- [2- [4- (3-Chloro-2-methylphenyl)]
-1-piperazinyl] ethyl] -5,6-dimethoxy-
3-[(4-methylpiperazin-1-yl) methyl]-
1H-indazole trihydrochloride (I-28):

Compound II-1 (0.30 g) of Reference Example was dissolved in acetonitrile (15 ml) and stirred at room temperature for N-.
Methylpiperazine (1.5 ml) was added, and the mixture was further stirred at the same temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform, washed with a 0.1 N aqueous sodium hydroxide solution and water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained oil was treated with hydrochloric acid, and then crystallized from ethanol-isopropanol to give Compound I-28
(0.28 g).

¹ H-NMR (ppm, CD ₃ OD):
2.38 (3H, s), 2.99 (3H, s), 3.
50-3.92 (18H, m), 3.93 (3H,
s), 3.98 (3H, s), 4.79 (2H,
s), 4.92 (2H, t), 7.12 (1H,
m), 7.17 (2H, m), 7.28 (1H,
s), 7.43 (1H, s)

Example 29 1- [2- [4- (3-chloro-2-methylphenyl)]
-1-piperazinyl] ethyl] -5,6-dimethoxy-
3-[(4-Dimethylaminopiperidin-1-yl) methyl] -1H-indazole trihydrochloride (I-29):

Compound II-1 (0.30 g) of Reference Example was dissolved in acetonitrile (15 ml), 4-dimethylaminopiperidine (1.5 ml) was added with stirring at room temperature, and the mixture was further stirred at the same temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform, washed with a 0.1 N aqueous sodium hydroxide solution and water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained oil was treated with hydrochloric acid.
Crystallization with isopropanol gave compound I-29 (0.1
3 g) was obtained.

¹ H-NMR (ppm, CD ₃ OD):
2.30-2.37 (4H, m), 2.38 (3H,
s), 2.89 (6H, s), 3.00-3.90.
(15H, m), 3.94 (3H, s), 3.98
(3H, s), 4.72 (2H, s), 4.92 (2
H, t), 7.11 (1H, m), 7.16 (2H,
m), 7.28 (1H, s), 7.40 (1H, s)

Example 30 1- [2- [4- (3-chloro-2-methylphenyl)]
-1-piperazinyl] ethyl] -3- (N-phthaloylaminomethyl) -5,6-dimethoxy-1H-indazole (I-30):

Compound VI-1 (2.80 g) of Reference Example,
Phthalimide (1.10 g) and triphenylphosphine (2.50 g) in tetrahydrofuran (50 m
l) A solution of diethyl azodicarboxylate (1.70 g) in tetrahydrofuran (10 ml) was added to the solution while stirring at room temperature, and the mixture was stirred at the same temperature for 6.5 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography using chloroform-methanol as an eluent to obtain Compound I-30 (2.40 g).

¹ H-NMR (ppm, CDCl ₃ ):
2.30 (3H, s), 2.63-2.66 (4H,
m), 2.84-2.92 (6H, m), 3.95
(3H, s), 3.96 (3H, s), 4.45 (2
H, t), 5.16 (2H, s), 6.76 (1H,
s), 6.86-6.91 (1H, m), 7.07-
6.08 (2H, m), 7.31 (1H, s), 7.
64-7.67 (2H, m), 7.82-7.85 (2
H, m)

Example 31 3-Aminomethyl-1- [2- [4- (3-chloro-2)
-Methylphenyl) -1-piperazinyl] ethyl]-
5,6-dimethoxy-1H-indazole (I-3
1):

Compound I-30 of the example (2.40 g) was added to ethanol (50 ml) and chloroform (30 ml).
1) The mixture was dissolved in the mixed solution of 1), hydrazine monohydrate (0.8 ml) was added under stirring at room temperature, and the mixture was stirred overnight at the same temperature. After evaporating the solvent under reduced pressure, chloroform was added to the residue and insoluble materials were removed by filtration. The solvent of the filtrate was distilled off, and the residue was purified by silica gel column chromatography using chloroform-methanol as an eluent to give Compound I-
31 (0.60 g) was obtained.

¹ H-NMR (ppm, CDCl ₃ ):
1.89 (2H, brs), 2.32 (3H, s),
2.70 (4H, brs), 2.89-2.95 (6
H, m), 3.94 (3H, s), 3.98 (3H,
s), 4.17 (2H, s), 4.44 (2H,
t), 6.80 (1H, s), 6.90-6.92
(1H, m), 7.06-7.09 (3H, m)

Example 32 N- [1- [2- [4- (3-Chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-1H-indazol-3-ylmethyl ] Methanesulfonamide hydrochloride (I-32):

Compound I-31 of the Example (0.60 g) and pyridine (0.11 ml) in dichloromethane (50
methanesulfonyl chloride (0.11 ml) was added to the solution under ice-cooling and stirring, and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using chloroform-methanol as an eluting solvent. This was dissolved in ethanol (20 ml), 1N hydrochloric acid (3 ml) was added, and the pressure was reduced. To dryness. The residue was ethanol-ethyl acetate-n-
Crystallized from hexane, compound I-32 (0.30 g)
I got

¹ H-NMR (ppm, DMSO-d
₆ ): 2.29 (3H, s), 2.85 (3H, s)
s), 3.19-3.31 (6H, m), 3.57-
3.60 (4H, m), 3.80 (3H, s),
91 (3H, s), 4.43 (2H, s), 4.91
(2H, m), 7.05-7.07 (1H, m),
7.18-7.24 (2H, m), 7.35 (1H,
s), 7.46 (1H, s), 7.70 (1H, br)
s), 11.85 (1H, brs)

The method up to obtaining the starting compound (VIII) is described below.

[0187]

Embedded image

The compound can be synthesized by the steps shown below. Hereinafter, each step will be described in detail in Reference Examples 3 to 9.

Reference Example 3 Ethyl 5,6-dimethoxy-1-trityl-1H-indazole-3-carboxylate (XI-1): Ethyl 5,6-dimethoxy-1H-indazole-3-carboxylate (10 .
0g), trityl chloride (16.7 g) and potassium carbonate (12.1 g) in N, N-dimethylformamide (200 ml) were stirred at 50 ° C. overnight. The solvent was distilled off under reduced pressure, chloroform was added to the residue, and the insoluble matter was removed by filtration. After concentrating the filtrate, the precipitated crystals were collected by filtration to give Compound XI-1.
(13.7 g) was obtained.

¹ H-NMR (ppm, CDCl ₃ ):
1.42 (3H, t), 3.34 (3H, s), 3.
94 (3H, s), 4.42 (2H, q), 5.67
(1H, s), 7.17-7.30 (15H, m),
7.56 (1H, s)

Reference Example 4 3-Hydroxymethyl-5,6-dimethoxy-1-trityl-1H-indazole (XII-1):

The compound XI-1 (12.0 g) of Reference Example 1 was dissolved in toluene (200 ml), and stirred at room temperature with a 65% sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al) toluene solution (Red-Al). 20 ml) and stirred at the same temperature for 1.5 hours. After a small amount of a saturated aqueous solution of sodium sulfate was added to the reaction solution, sodium sulfate and chloroform (300 ml) were added, and the mixture was stirred for 30 minutes.
After removing the solid by filtration, the solvent of the filtrate was distilled off, and the residue was crystallized from chloroform-n-hexane to give compound XI.
I-1 (10.4 g) was obtained.

¹ H-NMR (ppm, CDCl ₃ ):
3.35 (3H, s), 3.90 (3H, s), 4.
94 (2H, d), 5.65 (1H, s), 7.06
(1H, s), 7.18-7.28 (15H, m)

Reference Example 5 3-Formyl-5,6-dimethoxy-1-trityl-1
H-indazole (XIII-1): Ogilzyl chloride (1 m) was added to dichloromethane (100 ml) under an argon atmosphere.
After adding l), dimethyl sulfoxide (1.7 ml) was added thereto while cooling and stirring at -78 ° C, and the mixture was stirred at the same temperature for 5 minutes. To this, a suspension of compound XII-1 (4.50 g) of the reference example in dichloromethane (50 ml) was added dropwise, and the mixture was stirred at the same temperature for 30 minutes, then, triethylamine (7.0 ml) was added, and the mixture was further stirred for 30 minutes. After the temperature of the reaction solution was raised to room temperature, a small amount of water was added. Next, the organic layer was washed with water and dried over sodium sulfate. After distilling off the solvent under reduced pressure,
The residue was crystallized from chloroform-n-hexane to give compound XIII-1 (4.10 g).

¹ H-NMR (ppm, CDCl ₃ ):
3.34 (3H, s), 3.94 (3H, s), 5.
72 (1H, s), 7.15-7.30 (15H,
m), 7.62 (1H, s), 10.09 (1H,
s):

Reference Example 6 1-benzoyl-3-formyl-5,6-dimethoxy-
1H-indazole (XIV-1): Compound XIII-1 of Reference Example
(3.50 g) was heated under reflux in a mixed solvent of dioxane (70 ml) and 4N hydrochloric acid (70 ml) for 1.5 hours. After the solvent was distilled off under reduced pressure, chloroform was added to the residue for crystallization to obtain white crystals (0.84 g). The crystals (0.62 g) and triethylamine (1.25 m
l) was dissolved in dichloromethane (25 ml), benzoyl chloride (0.39 ml) was added under ice cooling and stirring, and the mixture was stirred at the same temperature for 15 minutes. A small amount of water was added to the reaction solution, which was further diluted with chloroform (100 ml), washed with water,
Dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was crystallized from chloroform-n-hexane to obtain compound XIV-1 (0.50 g).

¹ H-NMR (ppm, CDCl ₃ ):
4.02 (3H, s), 4.06 (3H, s), 7.
56 (2H, m), 7.67 (2H, m), 7.04
(1H, s), 8.13 (2H, d), 10.23
(1H, s)

Reference Example 7 [(1-Tritylimidazol-4-yl) methyl] triphenylphosphonium chloride (XV-1): triphenylphosphine (3.14 g) and 4-chloromethyl-1- Trityl imidazole (4.30 g) was dissolved in toluene (35 ml) and heated under reflux overnight. After allowing the reaction mixture to cool, the precipitated crystals were collected by filtration and subjected to compound XV-1 (4.16).
g) was obtained.

¹ H-NMR (ppm, CDCl ₃ ):
5.23 (1H, d), 6.89-7.82 (32
H, m)

Reference Example 8 1-Benzoyl-5,6-dimethoxy-3-[(1-tritylimidazol-4-yl) ethenyl] -1H-indazole (XVI-1): Compound XV-1 of Reference Example 0.93g)
Was suspended in tetrahydrofuran (20 ml), and potassium-bis (trimethylsilyl) amide (0.5 M toluene solution 3 m) was cooled and stirred at −78 ° C. in an argon atmosphere.
l) was added and the mixture was stirred at the same temperature for 1 hour. The compound XIV-1 (0.31 g) of Reference Example was added thereto, and the mixture was further stirred for 30 minutes, and then heated to 0 ° C. over about 1 hour. After a small amount of water was added to the reaction solution, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography using n-hexane-ethyl acetate as an eluting solvent, and further crystallized from n-hexane-ethyl acetate to give compound XVI-1
(0.28 g).

¹ H-NMR (ppm, CDCl ₃ ):
4.00 (3H, s), 4.06 (3H, s), 7.
01 (1H, s), 7.14-7.59 (22H,
m), 8.13 (3H, m)

Reference Example 9 1- [2- [4- (3-chloro-2-methylphenyl)]
-1-piperazinyl] ethyl] -5,6-dimethoxy-
3-[(1-Tritylimidazol-1-yl) ethenyl] -1H-indazole (VIII-1):

Compound XVI-1 (0.26 g) of Reference Example was dissolved in a mixture of tetrahydrofuran (4 ml) and a 1N aqueous solution of sodium hydroxide (2 ml), and the mixture was heated under reflux for 30 minutes. After evaporating the solvent under reduced pressure, the residue was dissolved in chloroform, washed with 0.1 N aqueous sodium hydroxide and water, and dried over sodium sulfate. After evaporating the solvent under reduced pressure, lithium methoxide (0.07 g) and dimethyl sulfoxide (10 ml) were added to the residue,
For 30 minutes. 1- (2-chloroethyl)
-4- (3-Chloro-2-methylphenyl) piperazine (0.18 g) was added, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was poured into ice water (100 ml), and the precipitate was collected by filtration. This was dissolved in chloroform and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography using chloroform-methanol as an eluent to obtain Compound VIII-1 (0.30 g).

¹ H-NMR (ppm, CDCl ₃ ):
2.31 (3H, s), 2.68-2.98 (10
H, m), 3.94 (3H, s), 3.97 (3H,
s), 4.45 (2H, m), 6.79 (1H,
s), 6.92 (2H, m), 7.07 (2H,
m), 7.16-7.51 (19H, m)

Next, using the compound VIII synthesized through the steps of Reference Examples 3 to 9, one of the compounds of the present invention (1-33) represented by the formula (I) was obtained. Obtainable. The method is described below in Example 33.

Example 33 1- [2- [4- (3-Chloro-2-methylphenyl)]
-1-piperazinyl] ethyl] -5,6-dimethoxy-
3- [2- (imidazol-4-yl) ethyl] -1H
-Indazole dihydrochloride (I-33):

Compound VIII-1 (0.30 g) of Reference Example was dissolved in ethanol (20 ml), palladium hydroxide-carbon (0.10 g) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere of 1 atm for 3 days. . The reaction solution was filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography using chloroform-methanol as an eluent, and the obtained oil was treated with hydrochloric acid and crystallized from ethyl acetate to obtain compound I-33 (0.03 g). .

¹ H-NMR (ppm, CD ₃ OD):
2.31 (3H, s), 3.30-3.84 (16
H, m), 3.87 (3H, s), 3.98 (3H,
s), 4.85 (2H, m), 7.01-7.21.
(5H, m), 7.32 (1H, s), 8.79 (1
H, s)

[Test Example] Measurement of calmodulin-dependent phosphodiesterase activity: Phosphodiesterase activity was measured by the method of Thompson and Appleman (Biochemistry 10, p311-316, 1971).
I went based on. 50 mM Tris-HCl (Tris-HCl buffer) (pH 7.5), 0.025 unit / ml calmodulin-dependent phosphodiesterase, 1.25 unit / ml calmodulin,
6.25 mM magnesium chloride, 0.125 mM calcium chloride or 1.25 mM EGTA (ethylene glycol bis (β-aminoethyl ether) -N, N, N ', N'-tetraacetic acid), 0.12
30 kBq / ml as a substrate in 400 ml of a reaction solution containing 5 mg / ml BSA and a sample solution (final concentration 3 or 5 μM, 5% dimethyl sulfoxide) dissolved in dimethyl sulfoxide
100 ml of [ ³ H] -cGMP solution was added, and the mixture was incubated at 30 ° C. for 10 minutes to perform a decomposition reaction from cGMP to 5′-GMP.
After heating for 1 minute in boiling water to stop the reaction, add 1 mg / ml
50 ml of an aqueous solution of snake venom (phosphodiesterase I type V from Bothrops atrox) was added, and the mixture was incubated at 30 ° C. for 10 minutes to decompose 5′-GMP to guanosine. Anion exchange resin AG1-X8 200-400 suspension (resin: methanol
(1: 5 weight / volume) was added and left in ice water for 15 minutes. Unreacted [ ³ H] -cGM by centrifuging at 4 ° C, 500g for 20 minutes
After removing P, 500 ml of the supernatant was sampled, and the radioactivity was measured with a liquid scintillation counter. Measurement of calmodulin-dependent phosphodiesterase activity
The difference between the radioactivity in the presence of Ca ²⁺ and the radioactivity in the presence of EGTA was taken. The activity of the solvent control (in the presence of 5% dimethyl sulfoxide) was defined as 100%, and the activity of each sample was converted to%.

The inhibition rate of the calmodulin-dependent phosphodiesterase activity at a concentration of 5 μM of the compound of the example is shown below (the inhibition rate of the compound (I-22) of Example 22 at a concentration of 3 μM) is shown below.

[0211]

[Table 1] (Note) The treatment concentration of compound (I-11) is 3 μM. The control compound of No. 15 was 3- [2- [4- (3-chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-1- (4-imidazolylmethyl ) -1H-indazole (the compound of Example 23 of that publication described in JP-A-7-097364).

[0212]

EFFECT OF THE INVENTION The indazole derivative represented by the formula (I) and a salt thereof show a potent calmodulin inhibitory activity and an excellent cerebral protective effect by oral and parenteral administration at a dose that does not show side effects such as central inhibitory activity. showed that. Therefore, the compounds of the present invention are useful for treating cerebrovascular disorders (cerebral infarction, cerebral embolism, transient ischemic attack, cerebral thrombosis) and cerebral degenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's chorea, etc.) Poisoning, gas poisoning, traumatic brain disease and illnesses based on it (spontaneous depression, depression, memory impairment, etc.)
Can be a preventive or therapeutic drug for

When the indazole derivative represented by the formula (I) is used in combination with another drug, an additive and synergistic effect can be expected for the prevention and treatment of various diseases.

For example, drugs for improving cerebral circulation (such as cinepazide maleate), drugs for improving brain metabolism (such as idebenone and indeloxazine), psychotropic drugs (such as timiperone, imipramine, and diazepam), drugs for lowering intracranial pressure (such as glyceol), Antihypertensives, vasodilators (such as trapidil), antipyretic analgesics and anti-inflammatory agents,
Anti-inflammatory steroids, antiplatelet drugs (ticlopidine, etc.),
Anticoagulants (haparin, etc.), fibrinolytics (tissue plasminogen activator, etc.), diuretics, antihyperlipidemic drugs (probucol, etc.), peptic ulcer treatment, blood substitute,
Agents for liver disease, anti-neoplastic agents and the like.

 ──────────────────────────────────────────────────続 き Continuing from the front page (72) Inventor Kenjiro Yamamoto 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo Inside the Tokyo Research and Development Center, Daiichi Pharmaceutical Co., Ltd.

Claims (12)

[Claims] (1) The following general formula (I): [Wherein R ¹ , R ² , R ⁴ and R ⁵ are each independently
R ³ is a hydrogen atom, a halogen atom, an alkyl group, or an alkoxyl group; 1. an aryl group which may have a substituent; 2. a heterocyclic group which may have a substituent; A group —NR ⁶ R ⁷ wherein R ⁶ and R ⁷ are the same or different and are a hydrogen atom, an alkyl group which may have a substituent, an alkoxyl group, an alkoxyalkyl group, an aryl group, an aralkyl group, or ⁶ and R ⁷ are saturated or unsaturated heterocyclic groups (including heterocyclic groups containing one or two oxygen atoms or nitrogen atoms) formed together with adjacent nitrogen atoms, and these groups May have a substituent. ], 4. 4. a group —OR ⁸ (where R ⁸ is an alkyl group or a saturated or unsaturated heterocyclic ring, and these groups may have a substituent); 5. a group -SR ⁹ (where R ⁹ is an alkyl group or a saturated or unsaturated heterocyclic group, and these groups may have a substituent); or A bicyclic heterocyclic group containing one or two nitrogen atoms, m is an integer of 2 to 6, and n is an integer of 1 to 6. Or a salt, hydrate or optically active form thereof. 2. A compound according to claim 1, wherein R ³ is a group —NR ⁶ R ⁷ ,
The saturated or unsaturated heterocyclic group formed by R ⁶ R ⁷ is
1-piperidinyl group, morpholino group, thiomorpholino group, 1-pyrrolidinyl group, 1-imidazolyl group, 1-piperazinyl group, 1-tetrahydroquinolyl group, or phthaloyl group, and these groups further have a substituent. The compound according to claim 1, a salt thereof, a hydrate, or an optically active form thereof. 3. R ³ is a group —NR ⁶ R ⁷ , wherein R ⁶ and R ⁷ are the same or different and each represent a hydrogen atom, an alkyl group,
The compound according to claim 1, which is an alkoxyl group, an aryl group, an aralkyl group, or an alkoxyalkyl group, and these groups may further have a substituent. Activator. 4. R ³ is a group —OR ⁸ , wherein R ⁸ is an alkyl group which may have a substituent or a saturated or unsaturated heterocyclic ring, and these groups further have a substituent. 2. The compound according to claim 1, which may have a salt, a hydrate, or an optically active form thereof. 5. The method according to claim 1, wherein R ³ is a group —SR ⁹ , wherein R ⁹ is an alkyl group or a saturated or unsaturated heterocyclic ring, and these groups may further have a substituent. Compounds, salts, hydrates, or optically active forms thereof. 6. The substituent R ³ is: 1. an N-ethyl-N- (n-propylamino) group; 2. N- (3-methoxypropyl) -N-pentylamino group; 3. an N, N-bis (2-ethoxyethyl) amino group; 4. N-cyclohexyl-N-ethylamino group, N-benzyl-N- (2-hydroxyethyl) amino group, 6.3,3-dimethyl-1-piperidinyl group, 7.3-hydroxy-1-piperidinyl group, 8.1,2,3,4-tetrahydro 10. quinolin-1-yl group, 9.4-phenyl-1-piperazinyl group, 10.4-piperidinyloxy group, 13. piperidino group, 12.4-alkyl-1-piperazinyl group, 13.2- (imidazol-4-yl) ethyl group, or 14. The compound according to claim 1, which is a morpholino group, a salt, a hydrate, or an optically active form thereof. 7. The compound according to any one of claims 1 to 6, wherein m is 2 and n is 1, a salt thereof, a hydrate or an optically active form thereof. 8. The compound according to any one of claims 1 to 7, wherein R ¹ and R ² are a chloro group or a methyl group, a salt thereof, a hydrate thereof, or an optically active form thereof. 9. The compound according to any one of claims 1 to 8, wherein R ⁴ and R ⁵ are a methoxyl group, a salt thereof,
Hydrates or optically active forms thereof. 10. A compound represented by the formula (1): From So. A compound selected from the group consisting of: an optically active form thereof, or a hydrate thereof: a. 1- [2- [4- (3-Chloro-2-methylphenyl) -1-piperazinyl] ethyl] -3-[(N-ethyl-N- (n-propylaminomethyl)]-5,6-dimethoxy- 1H-indazole dihydrochloride, i. 1- [2- [4- (3-chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-3- [N- (3-methoxy Propyl) -N-pentylaminomethyl] -1H-indazole dihydrochloride, C. 1- [2- [4- (3-chloro-2-methylphenyl) -1-piperazinyl] ethyl] -3- [N, N-bis (2-ethoxyethyl) aminomethyl] -5,6-dimethoxy-1H-indazole dihydrochloride, E.3- (N-cyclohexyl-N-ethylaminomethyl) -1- [2- [4- (3-chloro-2-methyl Phenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-1H-indazole dihydrochloride, o.3- [N-benzyl-N- (2-hydroxyethyl) aminomethyl] -1- [2- [ 4- (3-chloro-
2-methylphenyl) -1-piperazinyl] ethyl]-
5,6-dimethoxy-1H-indazole dihydrochloride; 1- [2- [4- (3-Chloro-2-methylphenyl) -1-piperazinyl] ethyl] -3-homopiperidinomethyl-5,6-dimethoxy-1H-indazole
Dihydrochloride, g. 1- [2- [4- (3-Chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-3- [1- (3,3-dimethylpiperidinyl) methyl]- 1H-indazole dihydrochloride; 1- [2- [4- (3-chloro-2-methylphenyl) -1-piperazinyl] ethyl] -3- [1- (3-
Hydroxypyperidino) methyl] -5,6-dimethoxy-1H-indazole dihydrochloride; 1- [2- [4- (3-Chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-3-morpholinomethyl-1H-indazole dihydrochloride; 1- [2- [4- (3-Chloro-2-methylphenyl) -1-piperazinyl] ethyl] -3- (1,2,
3,4-tetrahydroquinolin-1-ylmethyl)-
5,6-dimethoxy-1H-indazole dihydrochloride; 1- [2- [4- (3-Chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-3- (4-phenyl-1-piperazinylmethyl)-
1H-indazole dihydrochloride; 1- [2- [4- (3-Chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-3- (4-piperidinyloxymethyl) -1H-indazole dihydrochloride , S. 1- [2- [4- (3-chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-3-piperidinomethyl-1H-indazole dihydrochloride; 1- [2- [4- (3-Chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-3-[(4-methylpiperazin-1-yl) methyl] -1H- Indazole trihydrochloride, or so. 1- [2- [4- (3-Chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-3-[(imidazol-4-yl) ethyl] -1H
-Indazole dihydrochloride. 11. A pharmaceutical comprising the compound according to any one of claims 1 to 10, a salt thereof, a hydrate or an optically active form thereof as an active ingredient. 12. A calmodulin inhibitor comprising the compound according to any one of claims 1 to 10, a salt thereof, a hydrate, or an optically active form thereof as an active ingredient.