JPH0733744A - Imidazole derivative and its salt - Google Patents

Abstract

PURPOSE:To obtain a new imidazole derivative comprising a piperazinyl imidazole derivative, having a psychotropic action and a circulatory organ- controlling action, and useful as an active ingredient for psychotropic medicines and circulatory organ disease-treating medicines. CONSTITUTION:The object imidazole derivative of formula I [(n) is 2-6; V is H, halogen; R<1> is H, lower alkyl, (substituted) phenyl, etc.; W is group of formula II (R<6> is H, halogen, lower alkyl, phenyl, etc.), etc.]. The compound of formula I is obtained by treating 3-chloro-1H-indazole, etc., with sodium hydride in dimethyl formamide, reacting the product with 1,4-dibromobutane at 60 deg.C for 4hrs, reacting the reactional product having a 4-bromobutyl group introduced at the 1-position with 1-(1-toluenesulfonyl-1H-indazol-3-yl)-1-piperazine which is prepared by the reaction of piperazine with 3-chloro-1-toluenesulfonyl-1H- indazole in dimethylformamide in the presence of potassium carbonate, and subsequently removing the protecting group.

Description

Detailed Description of the Invention

BACKGROUND OF THE INVENTION

TECHNICAL FIELD The present invention relates to a compound having a psychotropic action and a circulatory system-regulating action, and a psychotropic drug or a circulatory system therapeutic drug containing at least one of these compounds as an active ingredient. It is a thing.

[0002]

2. Description of the Related Art Among the indazole derivatives bound to piperazine, those having an imide structure are disclosed in Japanese Patent Laid-Open No. 3-1.
67175, JP-A-5-17440, U.S. Pat. No. 4
956368, U.S. Pat. No. 4,957,916 and D
E-3247530 discloses a compound having a thiazolidinyl group in U.S. Pat. No. 5,041,445, and EP-40 relates to a compound bonded to a phenyl group through an oxygen atom.
No. 2644, and compounds relating to a heterocycle bonded via a carbon atom are disclosed in EP-378255.

[Outline of Invention]

The present inventors have found that certain indazole derivatives have a strong psychotropic effect and a high affinity for receptors related to the circulatory system. Was completed.

The object of the present invention is therefore to provide compounds which have a psychotropic or circulatory action.

Another object of the present invention is to provide a psychotropic drug or a remedy for cardiovascular disease, which comprises the above derivative.

[0006]

The compounds according to the invention are
A compound represented by the following general formula (I) and a pharmacologically acceptable salt thereof.

[0007]

[Chemical 5] (In the above formula, n represents an integer of 2 to 6, V represents a hydrogen atom or a halogen atom, and R ¹ represents a hydrogen atom, a lower alkyl group, an acyl group or an optionally substituted phenyl group. And W represents any of the following groups (i) to (xvii)

[0008]

[Chemical 6]

[Chemical 7] (In the above groups, m represents an integer of 0 to 4, a solid line with a dotted line represents a single bond or a double bond, A represents CH,
Represents C or N, B represents CH, C, N, S or a bond, D represents CH, C or N, E represents CH,
Represents C, N or a bond, and Z represents the following groups (a) to (c)
Represents either

[0009]

[Chemical 8] R ² , R ³ , R ⁴ and R ⁵ may be the same or different and each is a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, a hydroxy group, a cyano group, a lower alkylcarbonyl group, a lower group. Represents an alkoxy group, an amino group, or an acyl group, or R ² and R ³ and / or R ⁴ and R ⁵ or R ³ and R
⁴ may form, together with the carbon atom or nitrogen atom to which they are bonded, a 5 to 7 membered saturated or unsaturated ring or heterocyclic ring, R ⁶ is a hydrogen atom, a halogen atom, or a substituted ring. Optionally lower alkyl group, optionally substituted phenyl group, hydroxy group, cyano group, lower alkylcarbonyl group, lower alkoxy group, amino group,
Or represents an acyl group, R ⁷ represents a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, a hydroxy group, a cyano group, a lower alkoxy group, an amino group or an acyl group, and in the group (v), R 7 ² and R ⁷ may form a 5 to 7 membered saturated or unsaturated ring together with the indole ring to which they are bonded)) The compound represented by the general formula (I) is It has psychotropic or circulatory effects. Therefore, the present invention can provide a psychotropic drug or a cardiovascular disease therapeutic drug.

DETAILED DESCRIPTION OF THE INVENTION Compounds of General Formula (I) In the present specification, the term “lower alkyl” or “lower alkoxy” as a group or part of a group means that the group is straight chain or branched. It means an alkyl or alkoxy group having 1 to 6, preferably 1 to 4 carbon atoms in the branched chain. The halogen atom means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. In the general formula (I), n is 2
Represents an integer of 6 and preferably represents an integer of 3 to 5.

V represents a hydrogen atom or a halogen atom, preferably a hydrogen atom.

Furthermore, R ¹ represents a hydrogen atom, a lower alkyl group, an acyl group or an optionally substituted phenyl group, preferably a hydrogen atom or a lower alkyl group.

In the general formula (I), W is the group (i)
~ Represents a group represented by (xvii). Among these R
Preferred examples of the lower alkyl group represented by ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ include methyl, ethyl, isopropyl, cyclopropylmethyl and butyl. One or more hydrogen atoms of this alkyl group may be substituted, and preferable examples of the substituent include a halogen atom, an amino group, an acylamino group, a hydroxyl group and a lower alkoxy group, and a substituted alkyl group is preferable. Examples include methyl, trifluoromethyl, monofluoromethyl.

One or more hydrogen atoms of the phenyl group represented by R ¹ and R ⁶ may be substituted, and preferred examples of the substituent include lower alkoxy, nitro, cyano, acylamino, halogen atom and the like. Examples of preferred phenyl groups include chlorophenyl, bromphenyl, fluorophenyl, trifluorophenyl and methoxyphenyl.

Preferred examples of the lower alkylcarbonyl group represented by R ² , R ³ , R ⁴ , R ⁵ and R ⁶ include acetyl and propionyl, or preferred examples of the lower alkoxy group represented by these are methoxy. , Ethoxy, and isopropyloxy.

As the preferred group (i), A represents CH or N, B represents CH, C, N or a bond, and D represents C.
Represents H, C or N, E represents CH, C, N or a bond, and when two ... Simultaneously exist, each represents a single bond or a double bond, and R ² , R ³ and R ⁴ And R
⁵ are the same or different and each represents a hydrogen atom, a halogen atom or a lower alkyl group (preferably a C _1-4 alkyl group, particularly preferably a methyl group), or
R ² and R ³ and / or R ⁴ and R ⁵ or R
³ and R ⁴ together with the carbon or nitrogen atom to which they are attached form a 5 to 7 membered saturated or unsaturated ring or saturated heterocycle, particularly preferably when they are combined-( CH _{2) 4} - or -CH = CH-CH
The thing which represents = CH- is mentioned.

As the preferred group (ii), m represents an integer of 0 to 4, preferably 2, and A and B are C at the same time.
Represents H or C, R ² and R ³ together with the carbon atom to which they are attached form a 5 to 7 membered saturated or unsaturated ring, particularly preferably when they are attached,-(C
H ₂ ) ₄ -or -CH = CH-CH = CH.

Preferred group (iii) is ^{one in} which R ¹ represents a hydrogen atom or a lower alkyl group (preferably a C _1-4 alkyl group, particularly preferably a methyl group) acyl group (preferably acetyl, propionyl). To be

Preferred group (iv) is one in which R ⁶ represents a hydrogen atom or a halogen atom (particularly preferably a chlorine atom).

As the preferred group (v), all of ... Represent a single bond or a double bond, R ² , R ³ and R ⁷ represent a hydrogen atom, or R ³ represents a hydrogen atom or a lower alkyl group. (Preferably a C _1-4 alkyl group, particularly preferably a methyl group), and R ² and R ⁷ together with the indole ring to which they are bonded form a 5-7 membered saturated or unsaturated ring. Formed, particularly preferably-(CH ₂ ).
_3- is included.

As the preferred group (vii), m represents an integer of 0 to 2, preferably 0, all ... represent a single bond or a double bond, and Z represents a group (a) or (b). The thing which represents is mentioned.

As preferred group (viii), R ² and R ³ are the same or different and each represents a hydrogen atom or a lower alkyl group, or R ² and R ³ are the same as the carbon atom to which they are bonded. To form a 5- to 7-membered saturated or unsaturated ring, particularly preferably ... represents a double bond, and R ² and R ³ are bonded to each other to -CH = CH-
The thing which represents CH = CH- is mentioned.

Preferred groups (ix) are R ² and R
³ are the same or different and each represent a hydrogen atom or a lower alkyl group, or R ² and R ³ together with the carbon atom to which they are bonded form a 5-7 membered saturated or unsaturated ring. However, particularly preferably, ... Represents a single bond, and R ² and R ³ are bonded to each other to represent — (CH ₂ ) ₄ —.

Preferred groups (x), groups (xi) and groups (xii
Examples of i) include those in which R ⁶ represents a hydrogen atom.

Preferred groups (xii) include those in which R ² represents a hydrogen atom or a methyl group and R ⁶ represents a hydrogen atom or a methyl group.

The preferred group (xiv) and group (xv) include those in which R ⁶ represents a hydrogen atom.

[0027] Preferred groups (xvi), represents all ...... single bond, R6 is hydrogen atom or low paper alkyl group (preferably C _1-4 alkyl groups, particularly preferably methyl group) include those representing the To be

Preferred groups (xvii) include all ...
Is a single bond or a double bond.

In the case where A or B represents N and the bond between AB is a double bond, R ² or R ³ does not exist, and D or E represents N. When the bond between DEs is a double bond, R ⁴ or R ⁵ is absent, respectively. Further, when B represents S or a bond, R ³ is absent, and when E represents a bond, R ⁵ is absent.

Particularly preferred examples of compounds according to the present invention are 1- [4- [4- (1H-indazol-3-yl) -1-piperazinyl] butyl] -3-chloro-1H.
-Indazole, 5- [4- [4- (1H-indazol-3-yl) -1-piperazinyl] butyl] -5H-
Phenanthridin-6-one, 2- [4- [4- (1H
-Indazol-3-yl) -1-piperazinyl] butyl] -2H-phthalazin-1-one, 1- [4- [4-
(1H-indazol-3-yl) -1-piperazinyl] butoxy] phthalazine, 3- [4- [4- (1H-
Indazol-3-yl) -1-piperazinyl] butoxy] -4,4a, 5,6,7,8-hexahydrocinnoline, 2- [4- [4- (1H-indazol-3-yl) -1 -Piperazinyl] butyl] -isoindoline-
1-one, 1- [4- [4- (1H-indazole-3
-Yl) -1-Piperazinyl] butyl] -1H-quinoxalin-2-one, 2- [4- [4- (1H-indazol-3-yl) -1-piperazinyl] butoxy] quinoxaline, Cis-2- [ 4- [4- (1H-indazol-3-yl) -1-piperazinyl] butyl] perhydroisoindole-1,3-dione, 9- [4- [4
-(1H-indazol-3-yl) -1-piperazinyl] butyl] -carbazole, Cis-2- [4- [4
-(1H-Indazol-3-yl) -1-piperazinyl] propyl] perhydroisoindole-1,3-dione, Cis-2- [4- [4- (1H-indazol-3-yl) -1- Piperazinyl] pentyl] perhydroisoindole-1,3-dione, 1- [4- [4-
(1H-Indazol-3-yl) -1-piperazinyl] butyl] perhydroindol-2-one, 2-
[4- [4- (1H-indazol-3-yl) -1-
Piperazinyl] butyl] perhydropyrido [1,2-
a] Pyrazin-3-one, 1- [4- [4- (1H-indazol-3-yl) -1-piperazinyl] butyl]
-3,4,5,6,7,8-Hexahydro-1H-quinolin-2-one, 3- [4- [4- (1H-indazol-3-yl) -1-piperazinyl] butyl] -3H-
1,2,3-benzotriazin-4-one, 5- [4-
[4- (1H-indazol-3-yl) -1-piperazinyl] butyl] -1,2,3,4,7,8,9,10
-Octahydro-5H-phenanthridin-6-one,
3- [4- [4- (1H-indazol-3-yl)-
1-Piperazinyl] butyl] -2-methyl-3H-quinazolin-4-one, 1- [4- [4- (1H-indazol-3-yl) -1-piperazinyl] propyl]-
3,4,5,6,7,8-Hexahydro-1H-quinolin-2-one, 1- [4- [4- (1H-indazol-3-yl) -1-piperazinyl] butyl] -perkidroquinoline -2-one, 2- [4- [4- (1H-indazol-3-yl) -1-piperazinyl] butyl]-
3,4-dimethyl-5,6,7,8-tetrahydro-2
H-isoquinolin-1-one, 1- [4- [4- (1H
-Indazol-3-yl) -1-piperazinyl] butyl] -2a, 3,4,5-tetrahydrobenzo [cd]
-1H-Indol-2-one, 1- [4- [4- (1
H-indazol-3-yl) -1-piperazinyl] butyl] -1H-1,2,3-benzotriazole, 2-
[4- [4- (1H-indazol-3-yl) -1-
Piperazinyl] butyl] -2H-1,2,3-benzotriazole, 2- [4- [4- (1H-indazole-
3-yl) -1-piperazinyl] butyl] -isoindoline-1,3-dione, 1- [4- [4- (1H-indazol-3-yl) -1-piperazinyl] butyl] perhydro-3-methyl Benzimidazol-2-one,
3- [4- [4- (1H-indazol-3-yl)-
1-Piperazinyl] ethyl] -6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one, and Cis-2- [4- [4-
(1-Methyl-1H-indazol-3-yl) -1-
Piperazinyl] butyl] perhydroisoindole-
1,3-dione and the like can be mentioned.

The compound of the present invention can be a salt thereof. Such salts include medically acceptable non-toxic salts. Examples thereof include hydrohalides such as hydrochlorides, inorganic acid salts such as sulfates, organic acid salts such as succinic acid, citric acid, fumaric acid and maleic acid, and amino acid salts such as glycine and phenylalanine. To be

Preparation of Compounds of General Formula (I) The compounds according to the present invention can be prepared by the methods a) and b) shown below.

A) The compound of the general formula (I) according to the present invention has the following general formula (III): Hal- (CH ₂ ) _n- W (III) (wherein W and n are the above-mentioned general formula (III) I) has the same meaning as defined in I), Hal represents a halogen atom) and a compound represented by the following general formula (IV):

[0034]

[Chemical 9] 20 to 110 in the presence of an acid scavenger and optionally a small amount of potassium iodide in a solvent that does not participate in the reaction (for example, anhydrous acetonitrile, dimethylformamide or tetrahydrofuran).
It can be obtained by reacting at a reaction temperature of C, preferably 40 to 80 C for 2 to 24 hours, usually 2 to 6 hours. Examples of the acid scavenger used in the above reaction include alkali carbonates such as potassium carbonate and sodium bicarbonate, and organic amines such as triethylamine.

The compound of the general formula (III) can be produced according to the following reaction scheme according to the method described in Japanese Patent Application No. 08651101. That is,

[0036]

[Chemical 10] (In the above formula, W and n have the same meanings as defined in the general formula (I), and Hal represents the general formula (III).
B) and a compound of the general formula (I) has the following general formula (v):

[0037]

[Chemical 11] (In the above formula, T represents an amino-group protecting group (for example, a sulfonyl group such as benzenesulfonyl, toluenesulfonyl, or an acyl group such as acetyl);
Is a compound represented by the general formula (III) and a compound represented by the general formula (III) in a solvent that does not participate in the reaction (for example, anhydrous acetonitrile, dimethylformamide or tetrahydrofuran) and a small amount of an acid scavenger and optionally a small amount. After the reaction is carried out in the presence of potassium iodide at a reaction temperature of 20 to 110 ° C., preferably 40 to 80 ° C. for 2 to 24 hours, usually 2 to 6 hours, the protecting group T is converted by a suitable method. It can be obtained by deprotection. Deprotection can be carried out by dissolving the compound in, for example, hydrous alcohol, and reacting it with a base such as sodium hydroxide. In addition, the compound in which R ¹ represents a lower alkyl group in the general formula (I) can be obtained by substituting by a known method such that an alkyl halide and a base act.

Use of Compound / Pharmaceutical Composition The compound represented by the general formula (I) according to the present invention has an anti-methamphetamine action, and is further considered to be an important mechanism of antipsychotic action. D2 receptor and depression・ High affinity with 5HT receptors, which are said to be associated with psychiatric / neurological disorders of the central nervous system including schizophrenia such as anxiety. Therefore, the compounds and pharmaceutically acceptable salts according to the present invention can be used as psychotropic drugs. In addition, in this specification, a psychotropic drug shall include an anti-schizophrenia drug, an anxiolytic drug, and an antidepressant drug.

Further, the compound represented by the general formula (I) according to the present invention is adrenaline-α1 which regulates the circulatory system.
High affinity with the receptor. Therefore, the compound and the pharmaceutically acceptable salt according to the present invention can be used as a therapeutic drug for cardiovascular diseases involving not only the adrenergic nervous system but also the dopamine nervous system and the serotonin nervous system.

A pharmaceutical composition containing the present invention as an active ingredient can be administered to humans or non-humans by any of oral and parenteral (eg, intravenous, intramuscular, subcutaneous, rectal, transdermal) routes of administration. Can be administered to any animal. Therefore, the pharmaceutical composition containing the compound according to the present invention as an active ingredient is made into a suitable dosage form depending on the administration route.

Specifically, oral preparations include tablets, capsules, powders, granules, syrups, etc., and parenteral preparations include injections such as intravenous injection and intramuscular injection, rectal administration preparations, Examples include oily suppositories and aqueous suppositories.

These various preparations can be produced by a conventional method using commonly used excipients, disintegrating agents, binders, lubricants, coloring agents and the like. As an excipient,
For example, lactose, glucose, corn starch, sorbit,
Crystalline cellulose and the like, disintegrators such as starch, sodium alginate, gelatin powder, calcium carbonate, calcium citrate, dextrin and the like, as the binder such as dimethyl cellulose, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, acacia gum, Gelatin, hydroxypropyl cellulose, polyvinylpyrrolidone, etc., as the lubricant, for example, talc, magnesium stearate,
Examples thereof include polyethylene glycol and hydrogenated vegetable oil.

If necessary, the above injection may be a buffer,
It can be manufactured by adding a pH adjuster, a stabilizer and the like.

The content of the compound according to the present invention in the pharmaceutical composition varies depending on its dosage form, but is usually 0.
It is about 5 to 50% by weight, preferably about 0.5 to 20% by weight.

The dose is appropriately determined depending on the individual case in consideration of the patient's age, body weight, sex, difference in disease, degree of symptoms, etc., but usually 1 to 1000 m per adult per day.
g, preferably 5-500 mg, which is administered once or several times a day.

[0046]

EXAMPLES The present invention will be described in more detail by the following examples, but the present invention is not limited to these examples.

Example 1 1- [4- [4- (1H-a
Danazol-3-yl) -1-piperazinyl] butyl]
-3-Chloro-1H-indazole (a) 1- (4-bromobutyl) -3-chloro-1H-
Indazole 3-chloro-1H-indazole 1.29 g (7.9 m
(mol) in 16 ml of dimethylformamide,
0.32 g of 0% sodium hydride was added, and the mixture was stirred at 60 ° C for 30
Stir for minutes. After cooling to room temperature, 12.8 g of 1,4-dibromobutane was added thereto, and the mixture was stirred at 60 ° C. for 4 hours. Chloroform was added to the reaction solution, then the insoluble material was filtered and concentrated under reduced pressure. The residue was dissolved in chloroform, washed with water and then concentrated. The obtained residue was purified by silica gel chromatography to obtain 1.97 g of the title compound.

¹ H NMR (CDCl ₃ ) δ 1.8
6 (2H, m, CH ₂ ), 2.08 (2H, m, C
H ₂ ), 3.38 (2H, t, J = 6.6 Hz, CH ₂
Br), 4.36 (2H, t, J = 6.8Hz, NCH)
₂ ), 7.20 (1H, m, Ar), 7.43 (2H,
m, Ar), 7.66 (1H, m, Ar); MW 28
7.60 (C ₁₁ H ₁₂ N ₂ ClBr); mass spectrum
EIMS m / z 288 (M + 1) ⁺ , 286 (M-
1) ⁺ ; mp 260 ° C.

(B) 3-chloro-1-toluenesulfoni
Lu-1H-indazole 3-chloro-1H-indazole 4.0 g (26.2 m
(mol) was dissolved in 50 ml of methylene chloride, 3.8 g (31.4 mmol) of dimethylaminopyridine and 6.0 g (31.4 mmol) of toluenesulfonyl chloride were added, and the mixture was stirred at room temperature for 12 hours. Chloroform and water were added to the reaction solution to separate it. The organic layer was dried and concentrated under reduced pressure, and the obtained residue was crystallized from methanol to give the title compound (8.0 g). ¹ H NMR (CDCl ₃ ) δ
_{2.37 (3H, s, CH 3} ), 7.27 (2H, m,
Ar), 7.40 (1H, m, Ar), 7.64 (2
H, m, Ar), 7.87 (2H, m, Ar), 8.2
0 (1H, m, Ar); MW 306.79 (C ₁₄ H ₁₁
N ₂ SO ₂ Cl); mass spectrum EIMS m / z
306 (M) ⁺ . mp 128-130 ° C

(C) 1- (1-toluenesulfonyl-1
H-indazol-3-yl) -1-piperazine The compound obtained in the above (b) 4.0 g (13.0 mmo
1) and 5.6 g (65.0 mmol) of piperazine were placed in a sealed tube and heated at 130 ° C. for 6 hours. Chloroform and water were added to the reaction mixture and the layers were separated, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 1.6 g of the title compound.

¹ H NMR (CDCl ₃ ) δ 1.7
2 (1H, br s, NH), 2.32 (3H, s, C
_{H 3), 3.01 (4H,} m, piperazine CH _2),
3.45 (4H, m, piperazine CH _2), 7.15
(2H, m, Ar), 7.24 (1H, t, J = 7.0)
Hz, Ar), 7.48 (1H, m, Ar), 7.62
(1H, d, J = 8.2Hz, Ar), 7.72 (2
H, m, Ar), 8.17 (1H, d, J = 8.6H
z, Ar); MW 356.49 (C ₁₈ H ₂₀ N ₄ S
O ₂ ); mass spectrum EIMS, m / z 356
(M) ⁺ ; mp 121-124 ° C.

(D) 1- [4- [4- (1-toluene
Ruphonyl-1H-indazol-3-yl) -1-pipet
Razinyl] butyl] -3-chloro-1H-indazole 0.71 g (2.0 mmo of the compound obtained in the above (c)
l) was dissolved in 4.0 ml of dimethylformamide, 0.33 g (2.4 mmol) of potassium carbonate and 0.58 g (2.0 mmol) of the compound obtained in the above (a) were added, and the mixture was stirred at room temperature for 12 hours. did. After filtering the insoluble matter and concentrating under reduced pressure, chloroform and water were added to separate the layers,
The organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound 0.4
2 g was obtained.

¹ H NMR (CDCl ₃ ) δ 1.5
3 (2H, m, CH ₂ ), 1.98 (2H, m, C
_{H 2), 2.38 (2H,} t, J = 7.4Hz, piperazine _{-CH 2), 2.51 (4H,} t, J = 5.0H
z, piperazine CH ₂ ), 3.47 (4H, t, J =
5.0 Hz, piperazine CH ₂ ) 4.36 (2H,
_{t, J = 7.1Hz, -NCH 2} ), 7.14 (2H,
d, J = 8.0 Hz, Ar), 7.20 (2H, m, A
r), 7.39 (1H, t, J = 7.2Hz, Ar),
7.43 (1H, m, Ar), 7.48 (1H, t, J
= 7.8 Hz, Ar), 7.59 (1H, d, J = 8.
2Hz, Ar), 7.67 (1H, d, J = 8.2H
z, Ar), 7.71 (2H, d, J = 8.5Hz, A
r), 8.16 (1H, d, J = 8.5 Hz, Ar);
_{MW 563.18 (C 29 H 31 N} 6 SOCl); Mass spectrum EIMS, m / z 562 (M -1) +.

(E) 1- [4- [4- (1-H-inder
Zol-3-yl) -1-piperazinyl] butyl] -3
-Chloro -1H-indazole 0.42 g (0.8 mmo) of the compound obtained in the above (d)
l) is dissolved in a mixed solution of 10 ml of dioxane, 10 ml of methanol and 10 ml of 5N sodium hydroxide,
The mixture was stirred at room temperature for 12 hours. After neutralizing with dilute hydrochloric acid, chloroform and water were added to the mixture for liquid separation, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 0.18 g of the title compound.

¹ H NMR (CDCl ₃ ) δ 1.5
7 (2H, m, CH ₂ ), 2.00 (2H, m, C
_{H 2), 2.44 (2H,} t, J = 7.4Hz, piperazine _{-CH 2), 2.62 (4H,} t, J = 5.0H
z, piperazine CH ₂ ), 3.46 (4H, t, J =
5.0 Hz, piperazine CH ₂ ) 4.36 (2H,
_{t, J = 7.1Hz, -NCH 2} ), 7.04 (1H,
m, Ar), 7.18 (1H, t, J = 7.1Hz, A
r), 7.31 (2H, m, Ar), 7.40 (2H,
m, Ar), 7.66 (1H, d, J = 8.0 Hz, A
r), 7.70 (1H, d, J = 8.4 Hz, Ar),
9.12 (1H, br s, NH); MW 408.9
8 (C ₂₂ H ₂₅ N ₆ Cl); mass spectrum EIMS,
m / z 408 (M) ⁺ .

This oily substance was dissolved in dioxane to obtain 4N
Dioxane-hydrochloric acid was added and the resulting precipitate was collected to obtain the desired hydrochloride as a white powder.

Hydrochloride: Mass spectrum EIMS, m
/ Z 408 (M-HCl) ⁺ ; mp 180-182.
° C.

The following Examples 2-8 were synthesized in the same manner as in (d) and (e) of Example 1.

Example 2 5- [4- [4- (1H-in
Dazol-3-yl) -1-piperazinyl] butyl]-
5H-phenanthridinon-6-one (a) 5- [4- [4- (1-toluenesulfonyl-1
H-indazol-3-yl) -1-piperazinyl] bu
Cyl] -5H-phenanthridin-6-one The compound obtained in (c) above (Example 1) and 5- (4-
It was synthesized from bromobutyl) -5H-phenanthridin-6-one in the same manner as in Example 1 (d).

¹ H NMR (CDCl ₃ ) δ 1.7
4 (2H, m, CH ₂ ), 1.86 (2H, m, C
H ₂ ), 2.31 (3H, s, CH ₃ ), 2.49 (2
H, t, J = 7.2Hz, piperazine _N-CH 2),
2.60 (4H, t, J = 5.0Hz, piperazine C
H ₂ ), 3.52 (4H, t, J = 5.0 Hz, piperazine CH ₂ ), 4.45 (2H, t, J = 7.7 Hz,
NCH ₂ ), 7.15 (2H, d, J = 8.2 Hz, A
r), 7.24 (1H, t, J = 7.6Hz, Ar),
7.32 (1H, t, J = 7.2Hz, Ar), 7.4
9 (1H, t, J = 7.8Hz, Ar), 7.52 (2
H, m, Ar), 7.61 (2H, t, J = 7.1H
z, Ar), 7.71 (2H, d, J = 8.2Hz, A
r), 7.77 (1H, t, J = 7.7Hz, Ar),
8.17 (1H, d, J = 8.5Hz, Ar), 8.3
0 (2H, t, J = 8.2Hz, Ar), 8.55 (1
H, d, J = 7.9 Hz, Ar); MW 605.82
_{(C 35 H 35 N 5 SO} 3); mass spectrum EIMS,
M / z 605 (M) ⁺ .

(B) 5- [4- [4- (1H-indazo
Ol-3-yl) -1-piperazinyl] butyl] -5H
-Phenanthridin-6-one was synthesized from the compound obtained in (a) above in the same manner as in Example 1 (e).

¹ H NMR (CDCl ₃ ) δ 1.8
2 (2H, m, CH ₂ ), 1.92 (2H, m, C
_{H 2), 2.59 (2H,} t, J = 7.1Hz, piperazine _{N-CH 2), 2.75 (} 4H, t, J = 4.8H
z, piperazine CH ₂ ), 3.56 (4H, t, J =
4.8 Hz, piperazine CH _2), 4.50 (2H,
t, J = 7.8 Hz, NCH ₂ ), 7.08 (1H,
m, Ar), 7.32 (1H, m, Ar), 7.35
(2H, d, J = 4.2Hz, Ar), 7.57 (2
H, d, J = 3.8 Hz, Ar), 7.61 (1H,
t, J = 7.8 Hz, Ar), 7.77 (2H, m, A
r), 8.32 (2H, t, J = 8.2Hz, Ar),
8.60 (1H, d, J = 8.0 Hz, Ar), 9.4
1 (1H, br s, NH); MW 451.62 (C
₂₈ H ₂₉ N ₅ O); mass spectrum EIMS, m / z
451 (M) ⁺ .

Hydrochloride: Mass spectrum EIMS,
m / z 451 (M-HCl) ^<+> ; mp 162-16.
4 ° C.

Example 3 2- [4- [4- (1H-a
Danazol-3-yl) -1-piperazinyl] butyl]
-2H-phthalazin-1-one (a) 2- [4- [4- (1-toluenesulfonyl-1
H-indazol-3-yl) -1-piperazinyl]
Butyl] -2H-phthalazin-1-one as in Example 1 (d) from the compound obtained in Example 1 (c) above and 2- (4-bromobutyl)-(2H) -phthalazin-1-one. Was synthesized by the method.

¹ H NMR (CDCl ₃ ) δ 1.7
2 (2H, m, CH ₂ ), 1.83 (2H, m, C
H ₂ ), 2.32 (3H, s, CH ₃ ), 2.50 (2
H, t, J = 7.2 Hz, CH ₂ ) 2.62 (4H,
t, J = 4.6 Hz, piperazine CH ₂ ), 3.54
(4H, t, J = 4.6 Hz, piperazine CH ₂ ),
4.30 (2H, t, J = 7.8Hz, NCH 2),
7.15 (2H, d, J = 8.8Hz, Ar), 7.2
4 (1H, m, Ar), 7.35 (1H, m, Ar),
7.47 (2H, m, Ar), 7.58 (2H, m, A
r), 7.72 (2H, d, J = 8.4 Hz, Ar),
7.89 (1H, dd, J = 1.5, 8.0Hz, A
r), 8.16 (1H, d, J = 8.4 Hz, Ar),
8.30 (1H, s, Ar); MW 556.75 (C
₃₀ H ₃₂ N ₆ O ₃ S); mass spectrum EIMS, m
/ Z 556 (M) ⁺ .

(B) 2- [4- [4- (1H-indazo
Ol-3-yl) -1-piperazinyl] butyl] -2H
-Phthalazin-1-one was synthesized from the compound obtained in (a) above in the same manner as in Example 1 (e).

¹ H NMR (CDCl ₃ ) δ 2.4
9 (2H, t, J = 7.6Hz, piperazine N-CH
₂ ), 2.67 (4H, t, J = 4.9 Hz, piperazine CH ₂ ), 3.55 (4H, t, J = 4.9 Hz, piperazine CH ₂ ), 4.29 (2H, t, J) = 7.2
Hz, NCH ₂ ), 7.35 (1H, t, J = 7.6H
z, Ar), 7.46 (1H, t, J = 7.0Hz, A
r), 7.70 (1H, m, Ar), 7.79 (3H,
m, Ar), 7.90 (1H, d, J = 8.2Hz, A
r), 8.17 (1H, s, Ar), 8.43 (1H,
m, Ar); MW 419.60 (C ₂₃ H ₂₅ N ₅ O
S); mass spectrum EIMS, m / z 419
(M) ⁺ .

Hydrochloride: Mass spectrum EIMS,
m / z 420 (M + 1-HCl) ⁺ ; mp 237
-239 ° C.

Example 4 1- [4- [4- (1H-a
Danazol-3-yl) -1-piperazinyl] butoki
Ci] phthalazine (a) 1- [4- [4- (1-toluenesulfonyl-1
H-indazol-3-yl) -1-piperazinyl]
Butoxy] phthalazine was synthesized from the compound obtained in Example 1 (c) and 1- (4-bromobutoxy) phthalazine in the same manner as in Example 1 (d).

¹ H NMR (CDCl ₃ ) δ (pp
m): 1.63 (2H, m, CH ₂ ), 1.93 (2
_{H, m, CH 2),} 2.46 (2H, t, J = 7.5H
z, piperazine _{N-CH 2), 2.58 (} 4H, t, J
= 4.9 Hz, piperazine CH ₂ ), 3.51 (4H,
t, J = 4.9 Hz, piperazine CH ₂ ), 4.30
(2H, t, J = 7.2Hz , O-CH 2), 7.16
(2H, d, J = 8.6Hz, Ar), 7.25 (1
H, t, J = 7.6 Hz, Ar), 7.50 (1H,
t, J = 7.9 Hz, Ar), 7.63 (1H, d, J
= 8.3 Hz, Ar), 7.73 (3H, m, Ar),
7.80 (2H, m, Ar), 8.18 (2H, m, A)
r), 8.46 (1H, d, J = 7.7 Hz, Ar);
_{MW 556.75 (C 30 H 31 N} 6 O 3 S); Mass spectrum EIMS, m / z 556 (M ) +.

(B) 1- [4- [4- (1H-indazo
Ol-3-yl) -1-piperazinyl] butoxy] lid
Radine was synthesized from the compound obtained in (a) above in the same manner as in Example 1 (e).

¹ H NMR (CDCl ₃ ) δ (pp
m): 1.65 (2H, m, CH ₂ ), 1.92 (2
H, m, CH ₂ ), 2.52 (2H, t, J = 7.8H
z, piperazine _{N-CH 2), 2.71 (} 4H, t, J
= 4.9 Hz, piperazine CH ₂ ) 3.42 (4H,
t, J = 4.9 Hz, piperazine CH ₂ ), 4.29
(2H, t, J = 7.1Hz , O-CH 2), 7.02
(1H, m, Ar), 7.30 (2H, m, Ar),
7.81 (1H, m, Ar), 7.89 (3H, m, A
r), 8.36 (2H, m, Ar); MW 402.5
5 (C ₂₃ H ₂₆ N ₆ O); mass spectrum EIMS, m
/ Z 402 (M) ⁺ .

Hydrochloride; Mass spectrum EIMS,
m / z 402 (M-HCl) ⁺ ; mp 210-22
0 ° C.

Example 5 3- [4- [4- (1H-a
Danazol-3-yl) -1-piperazinyl] butoki
Si] -4,4a, 5,6,7,8-hexahydrocinno
Phosphorus (a) 3- [4- [4- (1-toluenesulfonyl-1
H-indazol-3-yl) -1-piperazinyl]
Butoxy] -4,4a, 5,6,7,8-hexahydro
The compound obtained in cinnoline Example 1 (c) and 3- (4-bromobutoxy) 4,4a, 5,6,7,8 similarly synthesized from hexahydro cinnolines Example 1 (d) did.

¹ H NMR (CDCl ₃ ) δ (pp
m): 1.30 (1H, m), 1.47 (2H, m),
1.57 (3H, m), 1.70 (2H, m), 1.8
7 (1H, m), 2.00 (1H, m), 2.20 (2
H, m), 2.54 (1H, m), 2.70 (2H,
_{m), 2.36 (3H, s} , CH 3), 2.44 (2
H, t, J = 7.5 Hz, piperazine NCH ₂ ), 2.
60 (4H, t, J = 4.9Hz, piperazine C
H ₂ ), 3.54 (4H, t, J = 4.9 Hz, piperazine CH ₂ ), 3.77 (2H, t, J = 7.2 Hz,
_{O-CH 2), 7.19 (} 2H, d, J = 8.3Hz,
Ar), 7.27 (1H, t, J = 7.7Hz, A
r), 7.52 (1H, t, J = 7.7Hz, Ar),
7.65 (1H, d, J = 8.1Hz, Ar), 7.7
5 (2H, d, J = 8.3 Hz, Ar), 8.20 (1
H, d, J = 8.1 Hz, Ar); MW 562.81
_{(C 30 H 38 N 6 O} 3 S); mass spectrum EIMS,
m / z 562 (M) ⁺ .

(B) 3- [4- [4- (1H-indazo
Ol-3-yl) -1-piperazinyl] butoxy]-
4,4a, 5,6,7,8-Hexahydrocinnoline was synthesized from the compound obtained in (a) above in the same manner as in Example 1 (e).

¹ H NMR (CDCl ₃ ) δ (pp
m): 2.49 (2H, t, J = 7.4Hz, piperazine CH ₂ ), 2.70 (4H, m, piperazine C
H ₂ ), 3.45 (4H, m, piperazine CH ₂ ),
_{3.75 (2H, m, O-} CH 2), 7.06 (1H,
m, Ar), 7.32 (2H, m, Ar), 7.73
(1H, d, J = 8.2Hz, Ar), 9.48 (1
H, br s, NH); MW 408.61 (C 23 H 32
N ₆ O); mass spectrum EIMS, m / z 408
(M) ⁺ ; mp 85-87 ° C.

Hydrochloride; mass spectrum EIMS, m /
z 408 (M-CH1) ⁺ ; mp 107-110.
° C.

Example 6 2- [4- [4- (1H-a
Danazol-3-yl) -1-piperazinyl] butyl]
Isoindoline-1-one (a) 2- [4- [4- (1-toluenesulfonyl-1
H-indazol-3-yl) -1-piperazinyl] bu
Cyl] isoindoline-1-one from the compound obtained in Example 1 (c) and 2- (4-bromobutyl) -isoindoline-1-one.
It was synthesized in the same manner as (d).

¹ H NMR (CDCl ₃ ) δ (pp
m): 1.53 (2H, m, CH ₂ ), 1.65 (2
_{H, m, CH 2),} 2.27 (3H, s, CH 3),
2.38 (2H, t, J = 7.5 Hz, piperazine N-
CH ₂ ), 2.51 (4H, t, J = 4.9 Hz, piperazine CH ₂ ), 3.44 (4H, t, J = 4.9H
z, piperazine CH ₂ ) 3.62 (2H, t, J =
_{7.1Hz, N-CH 2),} 4.34 (2H, s, CH
₂ ), 7.10 (2H, d, J = 8.6Hz, Ar),
7.19 (1H, t, J = 7.6Hz, Ar), 7.3
9-7.50 (4H, m, Ar), 7.56 (1H,
d, J = 8.0 Hz, Ar), 7.66 (2H, d, J
= 8.3 Hz, Ar), 7.80 (1H, d, J = 7.
2Hz, Ar), 8.11 (1H, d, J = 8.6H
z, Ar); MW 543.75 (C ₃₀ H ₃₃ N ₅ O
₃ S); mass spectrum EIMS, m / z 543
(M) ⁺ .

(B) 2- [4- [4- (1H-indazo
Ol-3-yl) -1-piperazinyl] butyl] isoi
Indolin-1-one was synthesized in the same manner as in Example 1 (e) from the compound obtained in (a) above.

¹ H NMR (CDCl ₃ ) δ (pp
m): 1.63 (2H, m, CH ₂ ), 1.78 (2
H, m, CH ₂ ), 2.52 (2H, t, J = 7.8H
z, piperazine _{N-CH 2), 2.71 (} 4H, t, J
= 4.8 Hz, piperazine CH ₂ ) 3.42 (4H,
t, J = 4.8 Hz, piperazine CH ₂ ), 3.69
(2H, t, J = 7.1Hz , N-CH 2), 4.53
(2H, s, CH ₂ ), 7.02 (1H, m, Ar),
7.23 (1H, d, J = 8.0 Hz, Ar), 7.2
9-7.36 (2H, m, Ar), 7.49 (1H,
m, Ar), 7.58 (1H, m, Ar), 7.71
(1H, dd, J = 1.2, 8.4Hz, Ar), 7.
76 (1H, d, J = 7.6Hz, Ar); MW 38
_{9.55 (C 23 H 27 N 5} O); mass spectrum EI
MS, m / z 389 (M) ⁺ .

Hydrochloride; Mass spectrum EIMS,
m / z 389 (M-HCl) ^<+> ; mp 248-25.
0 ° C.

Example 7 1- [4- [4- (1H-a
Danazol-3-yl) -1-piperazinyl] butyl]
-1H-quinoxalin-2-one (a) 1- [4- [4- (1-toluenesulfonyl-1
H-indazol-3-yl) -1-piperazinyl] bu
Cyl] -1H-quinoxalin-2-one Example 1 was prepared from the compound obtained in Example 1 (c) and 1- (4-bromobutyl) -1H-quinoxalin-2-one.
It was synthesized in the same manner as (d).

¹ H NMR (CDCl ₃ ) δ (pp
m): 1.72 (2H, m, CH ₂ ), 1.83 (2
H, m, CH ₂ ), 2.32 (3H, s, CH ₃ ),
2.50 (2H, t, J = 7.2Hz, CH 2), 2.
62 (4H, t, J = 4.6Hz, piperazine C
H ₂ ), 3.54 (4H, t, J = 4.6 Hz, piperazine CH ₂ ), 4.30 (2H, t, J = 7.8 Hz,
NCH ₂ ), 7.15 (2H, d, J = 8.8Hz, A
r), 7.24 (1H, m, Ar), 7.35 (1H,
m, Ar), 7.47 (2H, m, Ar), 7.58
(2H, m, Ar), 7.72 (2H, d, J = 8.4
Hz, Ar), 7.89 (1H, dd, J = 1.5,
8.0 Hz, Ar), 8.16 (1H, d, J = 8.4)
Hz, Ar), 8.30 (1H, s, Ar); MW 5
_{56.75 (C 30 H 32 N 6} O 3 S); mass spectrum
EIMS, m / z 556 (M) ⁺ .

(B) 1- [4- [4- (1H-indazo
Ol-3-yl) -1-piperazinyl] butyl] -1H
-Quinoxalin-2-one was synthesized in the same manner as in Example 1 (e) from the compound obtained in (a) above.

¹ H NMR (CDCl ₃ ) δ (pp
m): 1.75 (2H, m, CH ₂ ), 1.90 (2
H, m, CH ₂ ), 2.57 (2H, t, J = 7.1H
z, NCH ₂ ), 2.74 (4H, t, J = 4.8H
z, piperazine CH ₂ ), 3.55 (4H, t, J =
4.8 Hz, piperazine CH ₂ ) 4.36 (2H,
_{t, N-CH 2),} 7.10 (1H, m, Ar), 7.
31-7.57 (3H, m, Ar), 7.55 (1H,
d, J = 8.4 Hz, Ar), 7.63 (1H, d, J
= 7.4 Hz, Ar), 7.77 (1H, d, J = 8.
4Hz, Ar), 7.94 (1H, d, J = 8.0H
z, Ar), 8.36 (1H, s, Ar), 9.51
(1H, br s, NH); MW 402.55 (C ₂₃
H ₂₆ N ₆ O); mass spectrum EIMS, m / z
402 (M) ⁺ .

Hydrochloride: Mass spectrum EIMS: m
/ Z 402 (M-HCl) ⁺ ; mp 130-133.
° C.

Example 8 2- [4- [4- (1H-a
Danazol-3-yl) -1-piperazinyl] butoki
Ci] quinoxaline (a) 2- [4- [4- (1-toluenesulfonyl-1
H-indazol-3-yl) -1-piperazinyl] bu
Toxy] quinoxaline was synthesized from the compound obtained in Example 1 (c) and 2- (4-bromobutoxy) -quinoxaline in the same manner as in Example 1 (d).

¹ H NMR (CDCl ₃ ) δ (pp
_{m): 1.75 (2H, m} , CH 2), 1.91 (2
H, m, CH ₂ ), 2.31 (3H, s, CH ₃ ),
2.49 (2H, t, J = 7.6 Hz, NCH ₂ ),
2.61 (4H, t, J = 5.0Hz, piperazine CH
_{2), 3.52 (4H, t} , J = 5.0Hz, piperazine _{CH 2), 4.52 (2H,} t, J = 6.4Hz, O
_{-CH 2), 7.14 (2H,} d, J = 7.9Hz, A
r), 7.23 (1H, m, Ar), 7.49 (1H,
m, Ar), 7.56 (1H, m, Ar), 7.61
(1H, d, J = 7.9 Hz, Ar), 7.67 (1
H, m, Ar), 7.72 (2H, d, J = 8.5H
z, Ar), 7.82 (1H, dd, J = 1.3, 8.
2Hz, Ar), 8.01 (1H, dd, J = 1.5,
8.5 Hz, Ar), 8.17 (1H, d, J = 8.5)
Hz, Ar), 8.46 (1H, s, Ar); MW 5
_{56.75 (C 30 H 32 N 6} O 3 S); Mass spectrum EIMS, m / z 556 (M ) +.

(B) 2- [4- [4- (1H-indazo
Ol-3-yl) -1-piperazinyl] butoxy] quino
Xaline was synthesized from the compound obtained in (a) above in the same manner as in Example 1 (e).

¹ H NMR (CDCl ₃ ) δ (pp
m): 1.76 (2H, m, CH ₂ ), 1.92 (2
H, m, CH ₂ ), 2.54 (2H, t, J = 7.6H
z, NCH ₂ ), 2.71 (4H, t, J = 4.9H
z, piperazine CH ₂ ), 3.50 (4H, t, J =
4.9 Hz, piperazine _CH 2), 4.53 (2H,
_{t, J = 6.5Hz, O-} CH 2), 7.05 (1H,
m, Ar), 7.32 (2H, d, J = 3.5Hz, A
r), 7.56 (1H, m, Ar), 7.66 (1H,
m, Ar), 7.72 (1H, d, J = 8.2Hz, A
r), 7.82 (1H, dd, J = 1.2, 8.2H
z, Ar), 8.01 (1H, dd, J = 1.2, 8.
2Hz, Ar), 8.47 (1H, s, Ar), 9.2
7 (1H, br s, NH); MW 402.55 (C
₂₃ H ₂₆ N ₆ O); mass spectrum EIMS, m /
z 402 (M) ⁺ .

Hydrochloride: Mass spectrum EIMS: m
/ Z 402 (M-HCl) ⁺ ; mp 177-180.
° C.

Example 9 Cis-2- [4- [4-
(1H-indazol-3-yl) -1-piperazini
Lu] butyl] perhydroisoindole-1,3-dio
Down (a) 1- (1H- indazol-3-yl) piperazine
The compound obtained in emissions Example 1 (c) 6.1g (17mmo
l) was dissolved in 30 ml of methanol, 2.3 g (41 mmol) of potassium hydroxide was added, and the mixture was stirred at room temperature for 12 hours. After neutralization with 5N hydrochloric acid, chloroform and water were added to the mixture for liquid separation, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 2.1 g of the title compound.

¹ H NMR (CDCl ₃ ) δ (pp
m): 2.93 (4H, t , J = 4.7Hz, piperazine _{CH 2), 3.26 (4H,} t, J = 4.7Hz, piperazine _{CH 2), 6.95 (1H,} t, J = 7.4H
z, Ar), 7.26 (1H, dd, J = 6.6, 6.
0Hz, Ar), 7.34 (1H, d, J = 8.2H)
z, Ar), 7.72 (1H, d, J = 8.2Hz, A
r), 11.96 (1H, br s, NH); MW 2
02.29 (C ₁₁ H ₁₄ N ₄ ); mass spectrum EIM
S, m / z 202 (M) ⁺ .

(B) Cis-2- [4- [4- (1H-
Indazol-3-yl) -1-piperazinyl] buty
[ L ] perhydroisoindole-1,3-dione 0.26 g (1.3 mmo) of the compound obtained in the above (a)
l) was dissolved in 4 ml of dimethylformamide, 0.22 g of potassium carbonate and 0.50 g of Cis-2- (4-bromobutyl) perhydroisoindole-1,3-dione were added, and the mixture was stirred at 60 ° C. for 12 hours. After filtering the insoluble matter,
The solvent was evaporated under reduced pressure, chloroform and water were added to the mixture for liquid separation, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 0.42 g of the title compound.

¹ H NMR (CDCl ₃ ) δ (pp
m): 1.54-1.85 (12H, m , CH 2),
2.44 (2H, t, J = 7.4Hz, piperazine N-
_{CH 2), 2.66 (4H,} t, J = 5.1Hz, piperazine _{CH 2), 2.85 (2H,} m, CH), 3.4
7 (4H, t, J = 5.1 Hz, piperazine CH ₂ ),
3.53 (2H, t, J = 7.2Hz, N-CH 2),
7.05 (1H, m, Ar), 7.33 (2H, m, A)
r), 7.72 (1H, d, J = 8.2Hz, Ar),
9.17 (1H, brs, NH); MW 409.5
_{9 (C 23 H 31 N 5} O 2); Mass spectrum EIMS,
m / z 409 (M) ⁺ .

This oily substance was dissolved in dioxane to obtain 4N
Dioxane-hydrochloric acid was added and the resulting precipitate was collected by filtration to obtain the desired hydrochloride as a white powder.

Hydrochloride: Mass spectrum EIMS, m
/ Z 409 (M-HCl) ⁺ ; mp 121-124.
° C.

The following Examples 10 to 26 were synthesized in the same manner as in Example 9 (b).

Example 10 9- [4- [4- (1H-
Indazol-3-yl) -1-piperazinyl] buty
L] carbazole was synthesized from the compound obtained in Example 9 (a) and 9- (4-bromobutyl) carbazole in the same manner as in Example 9 (b).

¹ H NMR (CDCl ₃ ) δ (pp
m): 1.65 (2H, m, CH ₂ ), 1.96 (2
_{H, m, CH 2),} 2.44 (2H, t, J = 7.4H
z, NCH ₂ ), 2.61 (4H, t, J = 4.9H
z, piperazine CH ₂ ), 3.45 (4H, t, J =
4.9 Hz, piperazine CH ₂ ) 4.36 (2H,
t, J = 7.2 Hz, CH ₂ N), 7.04 (1H,
m, Ar), 7.23 (2H, m, Ar), 7.32
(2H, m, Ar), 7.45 (4H, m, Ar),
7.70 (1H, d, J = 8.2Hz, Ar), 8.1
0 (2H, m, Ar), 9.15 (1H, br s, N)
H); MW 423.61 (C ₂₃ H ₂₉ N ₅ ); mass spectrum EIMS, m / z 423 (M-HC
l) ⁺ ; mp 127-129 ° C.

Hydrochloride: Mass spectrum EIMS, m
/ Z 423 (M-HCl) ⁺ ; mp 127-129.
° C.

Example 11 Cis-2- [4- [4-
(1H-indazol-3-yl) -1-piperazini
]] Propyl] perhydroisoindole-1,3-di
On the compound obtained in Example 9 (a) and Cis-2- (3-
Bromopropyl) perhydroisoindole-1,3-
It was synthesized from dione in the same manner as in Example 9 (b).

¹ H NMR (CDCl ₃ ) δ (pp
_{m): 1.40-1.50 (4H, m} , CH 2), 1.
_{70-1.80 (2H, m, CH 2} ), 1.80-1.
90 (4H, m, CH ₂ ), 2.48 (2H, t, J =
7.3 Hz, piperazine _{N-CH 2), 2.68 (} 4
H, br s, piperazine CH ₂ ), 2.85 (1H,
m, CH), 3.48 (4H, br s, piperazine C
H ₂ ), 3.58 (2H, t, J = 7.3 Hz, NC)
H ₂ ), 7.05 (1H, m, Ar), 7.33 (2
H, m, Ar), 7.70 (1H, d, J = 8.0H
z, Ar), 9.23 (1H, br s, NH); MW
_{395.56 (C 22 H 29 N 5} O 2); Mass spectrum EIMS, m / z 395 (M ) +.

Hydrochloride: Mass spectrum EIMS,
m / z 395 (M-HCl) ^<+> ; mp 115-11.
7 ° C.

Example 12 Cis-2- [4- [4-
(1H-indazol-3-yl) -1-piperazini
L] Pentyl] perhydroisoindole-1,3-di
On the compound obtained in Example 9 (a) and Cis-2- (5-
Bromopentyl) perhydroisoindole-1,3-
It was synthesized from dione in the same manner as in Example 9 (b).

¹ H NMR (CDCl ₃ ) δ (pp
_{m): 1.30-1.45 (6H, m} , CH 2), 1.
_{50-1.60 (4H, m, CH 2} ), 1.65-1.
_{75 (2H, m, CH 2} ), 1.80-1.90 (2
H, m, Ar), 2.39 (2H, t, J = 7.6H
z, piperazine _{N-CH 2), 2.65 (} 4H, m, piperazine _{CH 2), 2.80 (2H,} m, CH), 3.
46 (2H, t, J = 7.4Hz, N-CH 2), 7.
03 (1H, m, Ar), 7.29 (2H, m, A)
r), 7.68 (1H, d, J = 8.0 Hz, Ar),
9.23 (1H, brs, NH); MW 423.6
2 (C ₂₄ H ₃₃ N ₅ O ₂ ); mass spectrum EIMS,
m / z 423 (M) ⁺ .

Hydrochloride: Mass spectrum EIMS, m
/ Z 423 (M-HCl) ⁺ ; mp 112-115.
° C.

Example 13 1- [4- [4- (1H-
Indazol-3-yl) -1-piperazinyl] buty
Lu] perhydro-indol-2-one Example 9 from the compound obtained in Example 9 (a) and 1- (bromobutyl) perhydroindol-2-one
It was synthesized in the same manner as in (b).

¹ H NMR (CDCl ₃ ) δ (pp
m): 1.30-1.80 (12H, m , CH 2),
2.15 (1H, m, CH), 2.30 (2H, m, C
_{H 2), 2.44 (2H,} t, J = 7.0Hz, piperazine _{N-CH 2), 2.66 (} 4H, t, J = 4.8H
z, piperazine CH ₂ ), 2.94 (1H, m, C
H), 3.48 (4H, t , J = 4.8Hz, piperazine _{CH 2), 3.55 (1H,} m, N-CH 2), 3.
_{66 (1H, m, N-} CH 2), 7.05 (1H, m,
Ar), 7.72 (1H, d, J = 8.2Hz, A
r), 9.16 (1H, brs, NH); MW 39
_{5.61 (C 23 H 33 N 5} O); mass spectrum EIM
S, m / z 395 (M) ⁺ .

Hydrochloride; Mass spectrum EIMS, m
/ Z 395 (M-HCl) ⁺ ; mp 209-212.
° C.

Example 14 2- [4- [4- (1H-
Indazol-3-yl) -1-piperazinyl] buty
Lu] perhydro-pyrido [1,2-a] pyrazine-3-
On The compound obtained in Example 9 (a) and 2- (bromobutyl) perhydropyrido (1,2-a) pyrazin-3-one were synthesized in the same manner as in Example 9 (b).

¹ H NMR (CDCl ₃ ) δ (pp
_{m): 1.30 (2H, m} , CH 2), 1.5-1.6
5 (6H, m, CH ₂ ), 1.70 (2H, m, C
H ₂ ), 1.80 (2H, m, CH ₂ ), 1.95 (1
H, m), 2.25 (1H, m), 2.45 (2H,
t, J = 7.0Hz, piperazine _N-CH 2), 2.6
7 (4H, t, J = 4.9 Hz, piperazine CH ₂ ),
2.80-2.95 (2H, m), 3.05-3.20
(2H, m), 3.30-3.50 (2H, m), 3.
47 (4H, t, J = 4.8Hz, piperazine C
H ₂ ), 7.05 (1H, m, Ar), 7.33 (2
H, m), 7.72 (1H, d, J = 8.2Hz, A
r), 9.26 (1H, br s, NH); MW 41
_{0.63 (C 23 H 34 N 6} O); mass spectrum EIM
S, m / z 410 (M) ⁺ .

Hydrochloride: Mass spectrum EIMS,
m / z 410 (M-HCl) ⁺ ; mp 167-17.
0 ° C.

Example 15 1- [4- [4- (1H-
Indazol-3-yl) -1-piperazinyl] buty
]]-3,4,5,6,7,8-Hexahydro-1H-
Quinolin-2-one From the compound obtained in Example 9 (a) and 1- (4-bromobutyl) 3,4,5,6,7,8-hexahydroquinolin-2-one to Example 9 (b ) Was synthesized.

¹ H NMR (CDCl ₃ ) δ (pp
m): 1.57 (6H, m, CH ₂ ), 1.70 (2
H, m, CH ₂ ), 2.06 (4H, m, CH ₂ ),
2.16 (2H, br m, CH ₂ ), 2.45 (4
H, m, CH ₂ ), 2.66 (4H, t, J = 4.9H
z, piperazine CH ₂ ), 3.48 (4H, t, J =
4.9 Hz, piperazine CH ₂ ) 3.61 (4H,
_{t, J = 6.7Hz, N-} CH 2), 7.50 (1H,
m, Ar), 7.50 (1H, m, Ar), 7.32
(2H, d, J = 3.3Hz, Ar), 7.71 (1
H, d, J = 7.2 Hz, Ar), 9.50 (1 H, b
r s, NH); MW 407.54 (C ₂₄ H ₃₃ N
₅ O); mass spectrum EIMS, m / z 407
(M) ⁺ .

Hydrochloride: Mass spectrum EIMS,
m / z 407 (M-HCl) ⁺ ; 148-149 ° C.
dec. .

Example 16 3- [4- [4- (1H-
Indazol-3-yl) -1-piperazinyl] buty
]]-3H-1,2,3-benzotriazin-4-one The compound obtained in Example 9 (a) and 3- (4-bromobutyl) -3H-1,2,3-benzotriazin-4- From the on state, synthesis was performed in the same manner as in Example 9 (b).

¹ H NMR (CDCl ₃ ) δ (pp
m): 1.68 (2H, m, CH ₂ ), 2.01 (2
H, m, CH ₂ ), 2.51 (2H, t, J = 7.4H
z, piperazine NCH ₂ ) 2.68 (4H, t, J =
4.7 Hz, piperazine CH ₂ ) 3.47 (4H,
t, J = 4.7 Hz, piperazine CH ₂ ), 4.54
(2H, t, J = 7.2Hz , N-CH 2), 7.06
(1H, m, Ar), 7.33 (2H, m, Ar),
7.71 (1H, d, J = 8.2 Hz, Ar), 7.8
0 (1H, m, Ar), 7.95 (1H, m, Ar),
8.16 (1H, m, Ar), 8.37 (1H, m, A)
r), 9.10 (1H, br s, NH); MW40
3.47 (C ₂₂ H ₂₅ N ₇ O); mass spectrum EIM
S, m / z 403 (M) ⁺ ; mp 148-14
9 ° C.

Hydrochloride: Mass spectrum EIMS, m
/ Z 403 (M-HCl) ⁺ ; 235 ° C. dec. .

Example 17 5- [4- [4- (1H-
Indazol-3-yl) -1-piperazinyl] buty
]]-1,2,3,4,7,8,9,10-octahydr
Ro-5H-phenanthridin-6-one The compound obtained in Example 9 (a) and 5- (4-bromobutyl) -1,2,3,4,7,8,9,10-octahydro-5H It was synthesized from -phenanthridin-6-one in the same manner as in Example 9 (b).

¹ H NMR (CDCl ₃ ) δ (pp
m): 1.65-1.78 (10H, m , CH 2),
_{1.80 (2H, m, CH 2} ), 2.40 (4H, m,
CH ₂ ), 2.49 (2H, br t, J = 7.2H
_{z, CH 2), 2.55 (} 2H, br, CH 2), 2.
68 (6H, m, CH ₂ ), 3.48 (4H, br
t, J = 4.9 Hz, piperazine CH ₂ ), 4.05
(2H, t, J = 8.6 Hz, CH ₂ ), 7.06 (1
H, ddd, J = 3.6, 4.4, 8.0 Hz, A
r), 7.34 (2H, dd, J = 3.6, 4.4H
z, Ar), 7.72 (1H, d, J = 8.0 Hz, A
r), 9.14 (1H, br s, NH); MW 45
9.61 (C ₂₈ H ₃₇ N ₅ O); mass spectrum EIM
S, m / z 459 (M) ^<+> ; mp 253-25.
4 ° C.

Hydrochloride; mass spectrum EIMS, m /
z 459 (M-HCl) ⁺ ; 245 ° C dec. .

Example 18 3- [4- [4- (1H-
Indazol-3-yl) -1-piperazinyl] buty
]]-2-Methyl-3H-quinazolin-4-one Example 9 (a) with 3- (4-bromobutyl) -2-methyl-3H-quinazolin-4-one It was synthesized in the same manner as in (b).

¹ H NMR (CDCl ₃ ) δ (pp
m): 1.70 (2H, m, CH ₂ ), 1.82 (2
H, m, CH ₂ ), 2.51 (2H, t, J = 7.2H
z, CH ₂ ), 2.68 (3H, s, CH ₃ ), 2.6
9 (4H, t, J = 5.0 Hz, piperazine CH ₂ ),
3.49 (4H, t, J = 5.0Hz, piperazine CH
₂ ), 4.15 (2H, t, J = 7.3Hz, N-CH
₂ ), 7.06 (1H, m, Ar), 7.33 (2H,
d, J = 3.8 Hz, Ar), 7.44 (1H, t, J
= 7.3 Hz, Ar), 7.60 (1H, d, J = 7.
3Hz, Ar), 7.72 (1H, m, Ar), 8.2
5 (1H, d, J = 8.0 Hz, Ar), 9.16 (1
H, br s, NH); MW 416.51 (C ₂₄ H ₂₈
N ₆ O); mass spectrum EIMS, m / z 41
6 (M) ⁺ .

Hydrochloride; mass spectrum EIMS, m
/ Z 416 (M-HCl) ^<+> .

Example 19 1- [4- [4- (1H-
Indazol-3-yl) -1-piperazinyl] propyi
]]-3,4,5,6,7,8-Hexahydro-1H-
Quinolin-2-one Compound obtained in Example 9 (a) and 1- (3-bromopropyl) -3,4,5,6,7,8-hexahydro-1
It was synthesized in the same manner as in Example 9 (b) from H-quinolin-2-one.

¹ H NMR (CDCl ₃ ) δ (pp
m): 1.59 (2H, m, CH ₂ ), 1.73 (4
H, m, CH ₂ ), 2.07 (4H, m, CH ₂ ),
_{2.19 (2H, m, CH 2} ), 2.45 (4H, d
d, J = 6.9, 7.8 Hz, CH ₂ ) 2.67 (4
H, t, J = 4.8 Hz, piperazine CH ₂ ), 3.4
8 (4H, t, J = 4.8 Hz, piperazine CH ₂ ),
3.65 (2H, t, J = 7.2Hz, N-CH 2),
7.05 (1H, m, Ar), 7.32 (2H, dd,
J = 3.4, 4.5 Hz, Ar), 7.71 (1H,
d, J = 8.0 Hz, Ar), 9.29 (1H, br
s, NH); MW 393.51 ( C 20 H 31 N 5 O);
Mass spectrum EIMS, m / z 393
(M) ⁺ .

Hydrochloride; mass spectrum EIMS, m /
z 393 (M-HCl) ^<+> .

Example 20 1- [4- [4- (1H-
Indazol-3-yl) -1-piperazinyl] buty
[ L ] perhydroquinolin-2-one Example 9 from the compound obtained in Example 9 (a) and 1- (bromobutyl) perhydroquinolin-2-one
It was synthesized in the same manner as in (b).

¹ H NMR (CDCl ₃ ) δ (pp
m): 1.25 (1H, m, CH), 1.42 (4H,
m, CH ₂ ), 1.60 (5H, m), 1.75 (2
_{H, m, CH 2),} 1.92 (1H, m), 2.09
(2H, m, CH ₂ ), 2.45 (4H, m, C
H ₂ ), 2.69 (4H, br t, J = 4.4 Hz,
Piperazine CH ₂ ), 2.87 (1H, m), 3.22
(1, m), 3.50 (4H, t, J = 4.4Hz, piperazine CH ₂ ), 3.82 (1H, m), 7.07
(1H, m, Ar), 7.33 (2H, m, Ar),
7.71 (1H, d, J = 8.1Hz, Ar), 9.3
5 (1H, br s, NH); MW 409.55 (C
₂₄ H ₃₅ N ₅ O); mass spectrum EIMS, m / z
409 (M) ⁺ .

Hydrochloride; mass spectrum EIMS, m
/ Z 409 (M-HCl) ⁺ ; 120 ° C. dec. .

Example 21 2- [4- [4- (1H-
Indazol-3-yl) -1-piperazinyl] buty
]]-3,4-Dimethyl-5,6,7,8-tetrahydr
B-2H-isoquinolin-1-one The compound obtained in Example 9 (a) and 2- (4-bromobutyl) -3,4-dimethyl-5,6,7,8-tetrahydro-2H-isoquinoline-1. -ON and Example 9
It was synthesized in the same manner as in (b).

¹ H NMR (CDCl ₃ ) δ (pp
_{m): 1.72 (8H, m} , CH 2), 1.98 (3
H, s, CH ₃ ), 2.35 (3H, s, CH ₃ ),
_{2.48 (4H, m, CH 2} ), 2.56 (2H, b
r, CH ₂ ), 2.67 (4H, t, J = 4.7 Hz,
Piperazine CH ₂ ), 3.48 (4H, t, J = 4.7)
Hz, piperazine CH ₂ ), 4.13 (2H, br, N
_{-CH 2), 7.07 (1H,} m, Ar), 7.33
(2H, m, Ar), 7.72 (1H, d, J = 8.3)
Hz, Ar), 9.26 (1H, br s, NH); M
_{W 433.57 (C 26 H 35 N} 5 O); Mass spectrum EIMS, m / z 433 (M ) +.

Hydrochloride; mass spectrum EIMS, m
/ Z 433 (M-HCl) ⁺ ; mp 148-150.
° C.

Example 22 1- [4- [4- (1H-
Indazol-3-yl) -1-piperazinyl] buty
]]-2a, 3,4,5-tetrahydrobenzo [ab]
-1H-Indol-2-one The compound obtained in Example 9 (a) and 1- (4-bromobutyl) -2a, 3,4,5-tetrahydrobenzo [c
d] -1H-Indol-2-one from Example 9
It was synthesized in the same manner as in (b).

¹ H NMR (CDCl ₃ ) δ (pp
m): 1.11 (1H, m), 1.36 (2H, m, C
H ₂ ), 1.47 (2H, m, CH ₂ ), 1.85 (4
H, m, CH ₂ ), 2.13 (2H, m, CH ₂ ),
_{2.34 (2H, m, CH 2} ), 2.61 (4H, br
m, piperazine CH ₂ ), 2.65 (1H, m),
2.85 (1H, m), 3.45 (4H, br m, piperazine CH ₂ ), 6.67 (1H, d, J = 7.6H
z, Ar), 6.80 (1H, d, J = 7.6Hz, A
r), 7.04 (1H, m, Ar), 7.11 (1H,
t, J = 7.6 Hz, Ar), 7.32 (2H, d, J)
= 3.8 Hz, Ar), 7.69 (1H, d, J = 8.
4Hz, Ar), 7.89 (1H, br), 9.26
(1H, br s, NH); MW 428.53 (C ₂₆
H ₃₀ N ₅ O); mass spectrum EIMS, m / z
429 (M + 1) ⁺ .

Hydrochloride; mass spectrum EIMS, m /
z 428 (M-HCl) ^<+> .

Example 23 1- [4- [4- (1H-
Indazol-3-yl) -1-piperazinyl] buty
]]-1H-1,2,3-Benzotriazole The compound obtained in Example 9 (a) and 1- (4-bromobutyl) -1H-1,2,3-benzotriazole were used in Example 9 (b ) Was synthesized.

¹ H NMR (CDCl ₃ ) δ (pp
m): 1.62 (2H, m, CH ₂ ), 2.11 (2
_{H, m, CH 2),} 2.46 (2H, t, J = 7.2H
z, piperazine NCH ₂ ), 2.62 (4H, t, J =
5.0 Hz, piperazine CH ₂ ) 3.45 (4H,
t, J = 5.0 Hz, piperazine CH ₂ ), 4.71
(2H, t, J = 7.0Hz , N-CH 2), 7.05
(1H, m, Ar), 7.33 (2H, d, J = 3.4)
Hz, Ar), 7.37 (1H, t, J = 7.6Hz,
Ar), 7.49 (1H, m, Ar), 7.55 (1
H, m, Ar), 7.70 (1H, m, Ar), 8.0
7 (1H, m, Ar), 9.21 (1H, br s, N)
H); MW 375.46 (C ₂₁ H ₂₅ N ₇ ); mass spectrum EIMS, m / z 375 (M) ⁺ ; mp
102-103 ° C.

Hydrochloride; mass spectrum EIMS, m
/ Z 403 (M-HCl) ⁺ ; 165 ° C. dec. .

Example 24 2- [4- [4- (1H-
Indazol-3-yl) -1-piperazinyl] buty
]]-2H-1,2,3-Benzotriazole The compound obtained in Example 9 (a) and 2- (4-bromobutyl) -2H-1,2,3-benzotriazole are used in Example 9 (b). ) Was synthesized.

¹ H NMR (CDCl ₃ ) δ (pp
m): 1.61 (2H, m, CH ₂ ), 2.20 (2
H, m, CH ₂ ) 2.48 (2H, t, J = 6.9H
z, piperazine NCH ₂ ) 2.65 (4H, t, J =
5.0 Hz, piperazine CH ₂ ) 3.46 (4H,
t, J = 5.0 Hz, piperazine CH ₂ ), 4.79
(2H, t, J = 6.9Hz , N-CH 2), 7.05
(1H, m, Ar), 7.33 (2H, d, J = 3.4)
Hz, Ar), 7.38 (2H, m, Ar), 7.70
(1H, d, J = 7.6Hz, Ar), 7.87 (1
H, m, Ar), 9.21 (1H, br s, NH);
MW 375.46 (C ₂₁ H ₂₅ N ₇ ); mass spectrum EIMS, m / z 375 (M) ⁺ ; mp 12
6-127 ° C.

Hydrochloride; Mass spectrum EIMS, m
/ Z 375 (M-HCl) ^<+> .

Example 25 2- [4- [4- (1H-
Indazol-3-yl) -1-piperazinyl] buty
[L] isoindoline-1,3-dione from the compound obtained in Example 9 (a) and 2- (4-bromobutyl) isoindoline-1,3-dione.
It was synthesized in the same manner as in (b).

¹ H NMR (CDCl ₃ ) δ (pp
m): 1.72 (2H, m, CH ₂ ), 1.85 (2
_{H, m, CH 2),} 2.47 (2H, t, J = 7.7H
z, piperazine _{N-CH 2), 2.67 (} 4H, t, J
= 4.7 Hz, piperazine _{N-CH 2), 3.48 (} 4
H, t, J = 4.7 Hz, piperazine CH ₂ ), 3.7
4 (2H, t, J = 7.1Hz, N-CH 2), 7.1
6 (1H, m, Ar), 7.33 (2H, d, J = 4.
0Hz, Ar), 7.72 (3H, m, Ar), 7.8
4 (2H, m, Ar), 9.19 (1H, br s, N)
_{H); MW 403.53 (C 23} H 25 N 5 O 2); Mass spectrum EIMS, m / z 403 (M ) +.

Hydrochloride; Mass spectrum EIMS, m
/ Z 403 (M-HCl) ⁺ ; mp 227-229.
° C.

Example 26 1- [4- [4- (1H-
Indazol-3-yl) -1-piperazinyl] buty
Lu] perhydro-3-methylbenzimidazole-2-
On Compound obtained in Example 9 (a) and 1- (4-bromobutyl) perhydro-3-methylbenzimidazole-2
Was synthesized in the same manner as in Example 9 (b).

¹ H NMR (CDCl ₃ ) δ (pp
_{m): 1.25-60 (8H, m} , CH 2), 1.65
_{-1.80 (4H, m, CH 2} ), 2.43 (2H,
m, piperazine _{N-CH 2), 2.66 (} 4H, t, J
= 4.9 Hz, piperazine _CH 2), 2.70 (3H,
_{s, CH 3), 2.95 (} 1H, m, CH), 3.28
(1H, m, CH), 3.40-3.50 (6H, m,
CH ₂ ), 7.03 (1H, m, Ar), 7.32 (2
H, m, Ar), 7.71 (1H, d, J = 8.2H
z, Ar), 9.64 (1H, br s, NH); MW
_{410.63 (C 23 H 34 N 6} O); mass spectrum
EIMS, m / z 410 (M) ⁺ .

Hydrochloride; Mass spectrum EIMS, m
/ Z 410 (M-HCl) ⁺ ; mp 120-122.
° C.

Example 27 3- [4- [4- (1H-
Indazol-3-yl) -1-piperazinyl] eth
]]-6,7,8,9-Tetrahydro-2-methyl-4
H-pyrido [1,2-a] pyrimidin-4-one The compound obtained in Example 9 (a) and 3- (2-chloroethyl) -6,7,8,9-tetrahydro-2-methyl-
It was synthesized from 4H-pyrido [1,2-a] pyrimidin-4-one in the same manner as in Example 9 (b).

¹ H NMR (CDCl ₃ ) δ (pp
m): 1.88 (2H, m, CH ₂ ), 1.96 (2
H, m, CH ₂ ), 2.32 (3H, s, CH ₃ ),
_{2.57 (2H, m, CH 2} ), 2.79 (2H, m,
CH ₂ ), 2.80 (4H, t, J = 3.6Hz, CH
₂ ) 2.86 (2H, t, J = 6.4Hz, C
H ₂ ), 3.50 (4H, t, J = 3.6Hz, C
H ₂ ), 3.93 (2H, t, J = 6.4 Hz, C
H ₂ ), 7.06 (1H, ddd, J = 8.3, 3.
8, 3.8 Hz, Ar), 7.33 (1Hx2, d, J
= 3.8 Hz, Ar), 7.72 (1H, d, J = 8.
3 Hz, Ar); MW 392 (C ₂₂ H ₂₈ N ₆ O); mass spectrum EIMS, m / z 392 (M) ⁺ .

Hydrochloride; mass spectrum EIMS, m
/ Z 392 (M-HCl) ^<+> .

Example 28 Cis-2- [4- [4-
(1-Methyl-1H-indazol-3-yl) -1-
Piperazinyl] butyl] perhydroisoindole-
1,3-dione 0.42 g of the free compound obtained in Example 9 (b)
(1.0 mmol) was dissolved in 10 ml of tetrahydrofuran, 43 mg of sodium hydride was added, and the mixture was stirred for 1 hour at room temperature. 67 μl of methyl iodide was added to the reaction solution,
The mixture was stirred at room temperature for 12 hours. Chloroform and water were added to the reaction solution, the layers were separated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol (95: 5)) to give 0.19 g of the title compound as an oil.

¹ H NMR (CDCl ₃ ) δ (pp
_{m): 1.40-1.65 (8H, m} , CH 2), 1.
_{70-1.80 (2H, m, CH 2} ), 1.80-1.
90 (2H, m, CH ₂ ), 2.44 (2H, t, J =
7.3 Hz, piperazine _{N-CH 2), 2.65 (} 4
H, t, J = 4.8 Hz, piperazine CH ₂ ), 2.8
5 (2H, m, CH), 3.45 (4H, t, J = 4.
8 Hz, piperazine CH ₂ ), 3.52 (2H, t, J
_{= 7.3Hz, N-CH 2)} , 3.88 (3H, s, N
CH ₃ ), 7.00 (1H, t, J = 7.6Hz, A
r), 7.22 (1H, d, J = 8.8Hz, Ar),
7.32 (1H, t, J = 7.6Hz, Ar), 7.6
9 (1H, d, J = 8.0 Hz, Ar); MW 42
_{3.62 (C 24 H 33 N 5} O 2); Mass spectrum EI
MS, m / z 423 (M) ⁺ .

Hydrochloride: Mass spectrum EIMS,
m / z 423 (M-HCl) ^<+> ; mp 134-13.
7 ° C.

The structures of the above compounds are shown in Table 1.

[0159]

[Table 1]

[0160]

[Table 2]

[0161]

[Table 3]

[0162]

[Table 4]

[0163]

[Table 5]

Pharmacological test (1) Antipsychotic effect The antipsychotic effect of the compound according to the present invention was evaluated using the inhibitory effect on methamphetamine-induced hyperlocomotion in mice as an index. 25-35g ddY
Male mice of each strain were used and the number of mice was 3 to 6 per group. Methamphetamine 2 mg / kg was subcutaneously administered to mice, and 15 minutes later, the compound according to the present invention was intraperitoneally administered. After another 15 minutes, the mouse was used for measuring the amount of exercise (Muromachi Kikai, ANIMEX
It was placed in a transparent acrylic box (30 cm in height and width) installed on AUTOMK-110), and the momentum was measured for 30 minutes. The effects of haloperidol and chlorpromazine as comparative drugs were also evaluated. The results are as shown in Table 2.

(2) Extrapyramidal Action The extrapyramidal action of the compounds of the present invention was evaluated using the catalepsy inducing action, which is a typical pharmacological evaluation method, as an index. Using male ddY mice weighing 25 to 35 g, 1
The group consisted of 3 to 6 animals. The compound according to the present invention was intraperitoneally administered, and 20, 30, and 40 minutes later, the presence or absence of catalepsy was determined. The presence or absence of catalepsy was judged to be positive for catalepsy when a mouse whose forelimbs were forcibly hung on a horizontal iron rod having a diameter of 1 mm horizontally placed at a height of 3 cm showed the unnatural state for 30 seconds or longer. The effects of haloperidol and chlorpromazine as comparative drugs were also evaluated. The results are shown in Table 3.

(3) Binding Affinity with Various Receptors (a) Dopamine-D2 Receptor Using the rat brain striatal P2 fraction, the affinity of the compound of the present invention for the D2 receptor was evaluated. The rat brain striatum was homogenized in 10 volumes of 0.32 M sucrose, and the supernatant obtained by centrifugation at 900 xg for 10 minutes was further centrifuged at 11,500 xg for 20 minutes. Incubation buffer (50 mM
Tris, 120 mM NaCl, 5 mM KCl, 1
mM MgCl ₂ , 1 mM CaCl ₂ , pH 7.4)
Was added, and the mixture was further centrifuged at 39,900 × g for 20 minutes, and the obtained precipitate was used as a P2 fraction. This was incubated for 30 minutes at 37 ° C. in 20 volumes of buffer containing 0.1 nM [ ³ H] spiperone and each concentration of the compound according to the invention. After the reaction, they were collected by Whatman GF / B glass filter, and the amount of bound [ ³ H] spiperone was measured by a liquid scintillation counter. The specific binding amount of [ ³ H] spiperone to the D2 receptor was determined from the following formula, and the IC ₅₀ value was calculated from the inhibition curve to determine the Ki value. Specific binding amount = total binding amount−nonspecific binding amount ^* (* binding amount in the presence of * 10 ⁻⁵ M sulpiride) The results are shown in Table 4.

(B) Serotonin-5HT2 Receptor The affinity of the compound of the present invention for the rat cerebral cortex 5HT2 receptor was evaluated as follows. A P2 fraction was prepared by the same method as in (1) above. This was mixed with 50 mM Tris / HCl buffer (pH 7.4) containing 1 nM [ ³ H] ketanserin and each concentration of the compound of the present invention.
And incubated at 37 ° C for 15 minutes. After the reaction
The amount of bound [ ³ H] ketanserin was measured. The amount of non-specific binding was measured in the presence of 10 μM ketanserin, and the Ki value was determined by the same method as above. The results are as shown in Table 5.

(C) Adrenergic-α1 Receptor The affinity of the compound of the present invention for the α1 receptor of rat cerebral cortex membrane fraction was evaluated as follows. Rat cerebral cortex added 10 times 0.25M sucrose 10 mM
Homogenized in Tris / HCl buffer (pH 7.4) and centrifuged at 40,000 xg for 30 minutes. 20 times amount of 50 mM Tris / HC in the obtained sediment
l buffer solution (pH 7.4) was added to obtain a membrane fraction sample.
This was incubated for 45 minutes at 25 ° C. in a buffer containing 0.2 nM [ ³ H] prazosin and each concentration of the compound according to the invention. After the reaction, the amount of bound [ ³ H] prazosin was measured. The amount of non-specific binding was measured in the presence of 10 μM prazosin, and the Ki value was determined by the same method as above. The results are shown in Table 6.

(4) Evaluation Results As is clear from these results, haloperidol and chlorpromazine, which were evaluated as comparative drugs, have anti-methamphetamine action, that is, antipsychotic action.
At the same time, it can be seen that the catalepsy inducing action, that is, the extrapyramidal system action is strong.

On the other hand, it is clear that the compound according to the present invention has an antipsychotic effect similar to the comparative drug, and has an extremely weak extrapyramidal effect. Therefore, it can be said that the compound according to the present invention is a drug having a wide safety margin as an antipsychotic drug.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI Technical display location C07D 417/12 231 471/04 120 (72) Inventor Yuko Kashima Master of Kohoku Ward, Yokohama City, Kanagawa Prefecture 760 Okamachi Meiji Seika Co., Ltd. Pharmaceutical Research Laboratory (72) Inventor Yoshimasa Fukuda 760 Shishiokacho, Kohoku Ward, Yokohama City, Kanagawa Meiji Seika Chemical Research Institute

Claims (11)

[Claims] 1. A compound represented by the following general formula (I) and a pharmacologically acceptable salt thereof. [Chemical 1] (In the above formula, n represents an integer of 2 to 6, V represents a hydrogen atom or a halogen atom, and R ¹ represents a hydrogen atom, a lower alkyl group, an acyl group or an optionally substituted phenyl group. And W represents any of the following groups (i) to (xvii): [Chemical 3] (In the above groups, m represents an integer of 0 to 4, ... represents a single bond or a double bond, A represents CH, C or N, B represents CH, C, N, S or Represents a bond, D represents CH, C or N, E represents CH, C, N or a bond, Z represents any of the following groups (a) to (c), and R ² , R ³ , R ⁴ and R ⁵ may be the same or different and each is a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, a hydroxy group, a cyano group, a lower alkylcarbonyl group, a lower group. Represents an alkoxy group, an amino group, or an acyl group, or R ² and R ³ and / or R ⁴ and R ⁵
Alternatively, R ³ and R ⁴ may form, together with the carbon atom or nitrogen atom to which they are bonded, a 5 to 7 membered saturated or unsaturated ring or heterocycle, and R ⁶ is a hydrogen atom, A halogen atom, an optionally substituted lower alkyl group, an optionally substituted phenyl group, a hydroxy group, a cyano group, a lower alkylcarbonyl group, a lower alkoxy group, an amino group, or an acyl group, and R ⁷ is hydrogen An atom, a halogen atom, or an optionally substituted lower alkyl group, wherein in the group (v), R ² and R ⁷ together with the indole ring to which they are bonded are saturated or unsaturated with 5 to 7 members. May form a saturated ring)) 2. W represents a group (i) (wherein A represents CH, C or N, B represents CH, C, N or a bond, D represents CH, C or N, E represents CH, C, N or a bond, and when two ... Are present at the same time, each represents a single bond or a double bond, and R ² , R ³ , R ⁴ and R ⁵ are the same or Differently,
Each represents a hydrogen atom, a halogen atom or a lower alkyl group, or R ² and R ³ and / or R ⁴ and R ⁵
Or R ³ and R ⁴ together with the carbon or nitrogen atom to which they are attached form a 5 to 7 membered saturated or unsaturated ring or saturated heterocycle). The compound according to 1, and a pharmaceutically acceptable salt thereof. 3. W is a group (i) (wherein A represents CH or N, B represents CH, C, N or a bond, D represents CH, C or N, and E represents , CH, C, N or a bond, and when two ... Simultaneously represent a single bond or a double bond, R ² , R ³ , R ⁴ and R ⁵ are the same or different. ,
Represents a hydrogen atom or a methyl group, respectively, or R ² and R ³ and / or R ⁴ and R ⁵
Or R ³ and R ⁴ are taken together when they are — (C
H ₂ ) ₄ -or -CH = CH-CH = CH- represents)
The compound according to claim 1, which is represented by: and a pharmaceutically acceptable salt thereof. 4. W is a group (ii) (wherein m represents an integer of 0 to 4, A and B simultaneously represent CH or C, and R ² and R ³ are carbons to which they are bonded. And a pharmaceutically acceptable salt thereof together with the atom to form a 5-7 membered saturated or unsaturated ring. 5. The compound according to claim 1, wherein W represents a group (iii) (wherein R ¹ represents a hydrogen atom, a lower alkyl group or an acyl group), and a pharmaceutically acceptable salt thereof. . 6. W is a group (v) (wherein ... Represents a single bond or a double bond, and R ² , R ³ and R ⁷ are the same or different and each represents a hydrogen atom or a lower alkyl group). Or R ³ represents a hydrogen atom or a lower alkyl group, and R 3
² and R ⁷ together with the indole ring to which they are attached form a 5-7 membered saturated or unsaturated ring), and a pharmaceutically acceptable compound. That salt that will be. 7. The method according to claim 1, wherein W is represented by a group (vii) (wherein m represents an integer of 0 to 2 and all ... represent a single bond or a double bond). Compounds and pharmaceutically acceptable salts thereof. 8. W is a group (viii) or group (ix) (wherein R ² and R ³ are the same or different and each represents a hydrogen atom or a lower alkyl group, or R ² and R ³ are Represents a 5-7 membered saturated or unsaturated ring together with the carbon atom to which it is attached), and a pharmaceutically acceptable salt thereof. 9. 1- [4- [4- (1H-indazole-
3-yl) -1-piperazinyl] butyl] -3-chloro-1H-indazole, 5- [4- [4- (1H-indazol-3-yl)-
1-Piperazinyl] butyl] -5H-phenanthridin-6-one, 2- [4- [4- (1H-indazol-3-yl)-
1-Piperazinyl] butyl] -2H-phthalazine-1-
On, 1- [4- [4- (1H-indazol-3-yl)-
1-piperazinyl] butoxy] phthalazine, 3- [4- [4- (1H-indazol-3-yl)-
1-Piperazinyl] butoxy] -4,4a, 5,6
7,8-Hexahydrocinnoline, 2- [4- [4- (1H-indazol-3-yl)-
1-Piperazinyl] butyl] -isoindoline-1-one, 1- [4- [4- (1H-indazol-3-yl)-
1-Piperazinyl] butyl] -1H-quinoxaline-2
-One, 2- [4- [4- (1H-indazol-3-yl)-
1-piperazinyl] butoxy] quinoxaline, Cis-2- [4- [4- (1H-indazole-3-
Yl) -1-Piperazinyl] butyl] perhydroisoindole-1,3-dione, 9- [4- [4- (1H-indazol-3-yl)-
1-piperazinyl] butyl] -carbazole, Cis-2- [4- [4- (1H-indazole-3-
Yl) -1-piperazinyl] propyl] perhydroisoindole-1,3-dione, Cis-2- [4- [4- (1H-indazole-3-
Yl) -1-Piperazinyl] pentyl] perhydroisoindole-1,3-dione, 1- [4- [4- (1H-indazol-3-yl)-
1-Piperazinyl] butyl] perhydroindole-2
-One, 2- [4- [4- (1H-indazol-3-yl)-
1-Piperazinyl] butyl] perhydropyrido [1,2
-A] pyrazin-3-one, 1- [4- [4- (1H-indazol-3-yl)-
1-Piperazinyl] butyl] -3,4,5,6,7,8
-Hexahydro-1H-quinolin-2-one, 3- [4- [4- (1H-indazol-3-yl)-
1-Piperazinyl] butyl] -3H-1,2,3-benzotriazin-4-one, 5- [4- [4- (1H-indazol-3-yl)-
1-piperazinyl] butyl] -1,2,3,4,7,
8,9,10-octahydro-5H-phenanthridin-6-one, 3- [4- [4- (1H-indazol-3-yl)-
1-Piperazinyl] butyl] -2-methyl-3H-quinazolin-4-one, 1- [4- [4- (1H-indazol-3-yl)-
1-piperazinyl] propyl] -3,4,5,6,7,
8-hexahydro-1H-quinolin-2-one, 1- [4- [4- (1H-indazol-3-yl)-
1-Piperazinyl] butyl] -perhydroquinoline-2
-One, 2- [4- [4- (1H-indazol-3-yl)-
1-Piperazinyl] butyl] -3,4-dimethyl-5,
6,7,8-Tetrahydro-2H-isoquinoline-1-
On, 1- [4- [4- (1H-indazol-3-yl)-
1-Piperazinyl] butyl] -2a, 3,4,5-tetrahydrobenzo [cd] -1H-indol-2-one, 1- [4- [4- (1H-indazol-3-yl)-
1-Piperazinyl] butyl] -1H-1,2,3-benzotriazole, 2- [4- [4- (1H-indazol-3-yl)-
1-Piperazinyl] butyl] -2H-1,2,3-benzotriazole, 2- [4- [4- (1H-indazol-3-yl)-
1-Piperazinyl] butyl] -isoindoline-1,3
-Dione, 1- [4- [4- (1H-indazol-3-yl)-
1-piperazinyl] butyl] perhydro-3-methylbenzimidazol-2-one, 3- [4- [4- (1H-indazol-3-yl)-
1-piperazinyl] ethyl] -6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one, and Cis-2- [4- [4- ( Compounds and pharmacology according to any one of claims 1 to 8, selected from 1-methyl-1H-indazol-3-yl) -1-piperazinyl] butyl] perhydroisoindole-1,3-dione. Acceptable salt. 10. A psychotropic drug comprising at least one compound of the general formula (I) according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof as an active ingredient. . 11. A circulatory system comprising at least one compound of the general formula (I) according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof as an active ingredient. Disease remedy.