WO2014192865A1

WO2014192865A1 - Phenylpiperazine derivative

Info

Publication number: WO2014192865A1
Application number: PCT/JP2014/064254
Authority: WO
Inventors: 英史吉永; 拓士中川; 龍永田; 森　泰生
Original assignee: 大日本住友製薬株式会社; 国立大学法人京都大学
Priority date: 2013-05-30
Filing date: 2014-05-29
Publication date: 2014-12-04

Abstract

The present invention relates to a therapeutic agent for neurodegenerative diseases and mental diseases, which comprises, as an active ingredient, a compound represented by formula (1) [wherein Z¹ represents a halogen atom, an alkyl group or the like; R¹¹ to R²⁵ independently represent a hydrogen atom, a halogen atom, an alkyl group or the like; and X² represents a halogen atom], a pharmaceutically acceptable salt of the compound or the like.

Description

Phenyl piperazine derivatives

The present invention relates to phenylpiperazine derivatives and salts thereof which activate TRPC3 or TRPC6 channels and exhibit brain-derived nerve growth factor (BDNF) -like action, and therapeutic agents for neurodegenerative diseases and psychiatric disorders containing the compounds as active ingredients.

Neurotrophic factors such as nerve growth factor (NGF), brain-derived nerve growth factor (BDNF), and neurotrophin 3 (NT3) are constitutively produced mainly in the central nervous system and develop neuronal cells ( Plays an important role in differentiation and survival. These neurotrophic factors are activated by binding to specific receptor tyrosine kinases such as TrkA, TrkB, and TrkC. Among them, when BDNF signal is activated, Alzheimer's disease, Huntington's disease, Parkinson's disease, Rett syndrome, traumatic brain injury, neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), senile dementia, depression, It is considered that a therapeutic effect is obtained in mental disorders such as bipolar disorder and schizophrenia (see, for example, Non-Patent Document 1).
However, BDNF itself has a very low usefulness as a therapeutic agent for neurodegenerative diseases and mental disorders because it has a short blood half-life of 1 minute or less and poor migration to the brain when administered peripherally. Therefore, discovery of a low molecular weight compound that exhibits a BDNF-like drug effect by peripheral administration is awaited.
As a low molecular compound having the same effect as BDNF (BDNF-mimic low-molecular compound), a 7,8-dihydroflavone derivative that directly activates the TrkB receptor (see, for example, Non-Patent Document 2), LM22 Compounds (for example, see Non-Patent Document 3) are known. However, these have not been developed as therapeutic agents.
On the other hand, it is known that BDNF and TRPC3 or TRPC6 channels are coupled to generate a BDNF signal (see, for example, Non-Patent Documents 4 and 5). That is, theoretically, a low molecular weight compound that directly activates these channels has the same effect as BDNF, and can be a therapeutic agent for the above-mentioned neurodegenerative diseases and psychiatric diseases. It has been reported that Hyperforin, which is considered to be an active ingredient in St. John's Wort, a European folklore drug, exhibits a neurotrophic factor-like effect by activating TRPC6 channel. However (see, for example, Non-Patent Document 6), there are few reports of other small molecule compounds that activate TRPC3 or TRPC6 channel and exhibit BDNF-like action.

It is known that the compounds shown in [Table 1] below have an NADH-dependent enoyl-ACP reductase inhibitory action (see Non-Patent Document 7). However, there is no description or suggestion that the compound activates the TRPC channel. There is no description suggesting an association between the compound and neurodegenerative diseases and psychiatric diseases.

Further, it is known that a compound represented by the following formula activates an N-formyl peptide receptor (see Non-Patent Document 8). However, there is no description or suggestion that the compound activates the TRPC channel. There is no description suggesting an association between the compound and neurodegenerative diseases and psychiatric diseases.

An object of the present invention is to search for peripherally administrable compounds having a BDNF-like action, and to provide a therapeutic agent for neurodegenerative diseases and a psychiatric disease, which comprises the compound as an active ingredient.

As a result of intensive studies, the present inventors have found that a compound represented by the following formula (1) and a pharmaceutically acceptable salt thereof (hereinafter sometimes abbreviated as “the compound of the present invention”). The inventors have found that the TRPC3 or TRPC6 channel is directly activated and exhibits a BDNF-like action, thereby completing the invention.

That is, the present invention is as follows.
[1] Formula (1):

[Wherein Z ¹ represents a halogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 alkyloxy group, or a C _1-6 haloalkyloxy group;
R ¹¹ , R ¹³ , R ¹⁴ , and R ¹⁵ are the same or different and each represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 alkyloxy group, or C _{1 Represents a -6} haloalkyloxy group;
Provided that R ¹¹ , R ¹³ , R ¹⁴ and R ¹⁵ are not simultaneously hydrogen atoms or simultaneously not halogen atoms;
R ²¹ , R ²³ , R ²⁴ , and R ²⁵ are a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 alkyloxy group, a C _1-6 haloalkyloxy group, _{Represents a} C _1-6 alkylsulfonyl group or a cyano group;
X ² represents a halogen atom], or a pharmaceutically acceptable salt thereof.
However, the following compounds are excluded.

In addition to the compounds removed above, compounds known at the time of this application are further excluded.

[2] Formula (1):

[Where:
Z ¹ represents a halogen atom, a C _1-6 alkyl group, or a C _1-6 haloalkyl group;
R ¹¹ , R ¹³ , and R ¹⁵ are the same or different and each represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 alkyloxy group, or a C _1-6 haloalkyl. Represents an oxy group;
R ¹⁴ represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _2-6 haloalkyl group, a C _1-6 alkyloxy group, or a C _1-6 haloalkyloxy group;
Provided that R ¹¹ , R ¹³ , R ¹⁴ and R ¹⁵ are not simultaneously hydrogen atoms or simultaneously not halogen atoms;
R ²¹ represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 alkyloxy group, a C _1-6 haloalkyloxy group, a C _1-6 alkylsulfonyl group, or a cyano Represents a group;
X ² represents a fluorine atom, a chlorine atom, or a bromine atom;
R ²⁴ represents a hydrogen atom, a C _1-6 alkyl group, a C _2-6 haloalkyl group, a C _1-6 alkyloxy group, a C _1-6 haloalkyloxy group, a C _1-6 alkylsulfonyl group, or a cyano group. ;
R ²³ and R ²⁵ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _2-6 alkyloxy group, a C _1-6 haloalkyloxy group, or a C _1-6 Represents an alkylsulfonyl group or a cyano group;
put it here,
(1) When Z ¹ is a methyl group, R ¹¹ is a hydrogen atom, a halogen atom, a C _2-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 alkyloxy group, or a C _1-6 R ¹³ is a hydrogen atom, a fluorine atom, a bromine atom, a C _2-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 alkyloxy group, or a C _1-6 haloalkyloxy group. Yes;
(2) When X ² is a chlorine atom and R ²¹ , R ²³ , R ²⁴ and R ²⁵ are all hydrogen atoms, Z ¹ is a fluorine atom, a bromine atom, a C _1-6 alkyl group, or A C _1-6 haloalkyl group;
(3) When Z ¹ is a chlorine atom, X ² is a fluorine atom, and R ²¹ , R ²³ , R ²⁴ and R ²⁵ are all hydrogen atoms, R ¹¹ , R ¹³ and R ¹⁵ are A hydrogen atom, a halogen atom, a C _2-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 alkyloxy group, or a C _1-6 haloalkyloxy group, which are the same or different. Or a pharmaceutically acceptable salt thereof.

[3] The compound according to [1] or [2], wherein R ¹¹ and R ¹³ are both hydrogen atoms, or a pharmaceutically acceptable salt thereof.

[4] The compound according to any one of [1] to [3], wherein R ¹⁴ and R ¹⁵ are a halogen atom, a C _1-6 alkyl group, or a C _1-6 alkyloxy group, or a compound thereof A pharmaceutically acceptable salt.

[5] R ¹¹ , R ¹³ , and R ¹⁴ are all hydrogen atoms, and R ¹⁵ is a halogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 alkyloxy group, or The compound according to [1] or [2], which is C _1-6 haloalkyloxy, or a pharmaceutically acceptable salt thereof.

[6] R ¹¹ , R ¹³ , and R ¹⁵ are all hydrogen atoms, and R ¹⁴ is a halogen atom, a C _1-6 alkyl group, a C _2-6 haloalkyl group, a C _1-6 alkyloxy group, or The compound according to [1] or [2], which is C _1-6 haloalkyloxy, or a pharmaceutically acceptable salt thereof.

[7] The compound according to any one of [1] to [6], wherein R ²¹ , R ²³ , R ²⁴ and R ²⁵ are all hydrogen atoms, or a pharmaceutically acceptable salt thereof.

[8] Formula (4):

[Where:
Z ¹ and R ¹⁵ are the same or different and each represents a halogen atom or a C _1-6 alkyl group;
X ² represents a fluorine atom or a chlorine atom;
Wherein, when Z ¹ is a chlorine atom and R ¹⁵ is a methyl group, X ² is a chlorine atom], or a pharmaceutically acceptable salt thereof, Salt.

[9] The compound or a pharmaceutically acceptable salt thereof according to [8], wherein Z ¹ and R ¹⁵ are the same or different and are a methyl group, a fluorine atom, or a chlorine atom.

[10] The compound according to any one of [1] to [9], wherein X ² is a fluorine atom, or a pharmaceutically acceptable salt thereof.

[11] Formula (5):

[Where:
Z ¹ represents a halogen atom or a C _1-6 alkyl group;
R ¹³ and R ¹⁴ are the same or different and each represents a hydrogen atom or a halogen atom;
Provided that R ¹³ and R ¹⁴ are not simultaneously hydrogen atoms;
Here, when R ¹³ is a chlorine atom, Z ¹ is a halogen atom or a C _2-6 alkyl group], or a pharmaceutically acceptable compound thereof Acceptable salt.

[12] (4- (5-Chloro-2-methylphenyl) piperazin-1-yl) (2,3-difluorophenyl) methanone [Example 1]
(4- (5-Chloro-2-methylphenyl) piperazin-1-yl) (3-fluoro-4-methylphenyl) methanone [Example 2]
(4- (5-Chloro-2-methylphenyl) piperazin-1-yl) (3-fluoro-5-methylphenyl) methanone [Example 3]
(4- (5-Chloro-2-methylphenyl) piperazin-1-yl) (5-fluoro-2-methylphenyl) methanone [Example 4]
(4- (5-Chloro-2-methylphenyl) piperazin-1-yl) (3-fluoro-2-methylphenyl) methanone [Example 5]
(4- (5-Chloro-2-methylphenyl) piperazin-1-yl) (3-fluoro-5-methoxyphenyl) methanone [Example 6],
(4- (5-Chloro-2-methylphenyl) piperazin-1-yl) (3-fluoro-2-methoxyphenyl) methanone [Example 7]
4- (4- (5-chloro-2-methylphenyl) piperazine-1-carbonyl) -2-fluorobenzonitrile [Example 8],
3- (4- (5-Chloro-2-methylphenyl) piperazine-1-carbonyl) -5-fluorobenzonitrile [Example 9],
(4- (5-Chloro-2-methylphenyl) piperazin-1-yl) (5-fluoro-2- (methylsulfonyl) phenyl) methanone [Example 10],
(4- (2,5-dimethylphenyl) piperazin-1-yl) (3-fluorophenyl) methanone [Example 11],
(4- (2,5-dichlorophenyl) piperazin-1-yl) (3-fluorophenyl) methanone [Example 12],
(4- (5-Fluoro-2-methylphenyl) piperazin-1-yl) (3-fluorophenyl) methanone [Example 13],
(4- (2,5-difluorophenyl) piperazin-1-yl) (3-fluorophenyl) methanone [Example 14],
(4- (5-Chloro-2-methoxyphenyl) piperazin-1-yl) (3-fluorophenyl) methanone [Example 15],
(4- (3,4-difluorophenyl) piperazin-1-yl) (3-fluorophenyl) methanone [Example 16],
(4- (3,5-dichlorophenyl) piperazin-1-yl) (3-fluorophenyl) methanone [Example 17],
(3-Chlorophenyl) (4- (2,5-dimethylphenyl) piperazin-1-yl) methanone [Example 18],
(4- (5-Chloro-2-methylphenyl) piperazin-1-yl) (5-fluoro-2-methoxyphenyl) methanone [Example 32]
(4- (5-Chloro-2-methoxyphenyl) piperazin-1-yl) (3-fluorophenyl) methanone [Example 33],
(4- (2,3-dichlorophenyl) piperazin-1-yl) (3-fluorophenyl) methanone [Example 34],
(4- (3,4-Dichlorophenyl) piperazin-1-yl) (3-fluorophenyl) methanone [Example 35] or (4- (5-Chloro-2-methylphenyl) piperazin-1-yl) ( 3-Chlorophenyl) methanone [Example 36], or a pharmaceutically acceptable salt thereof.

[13] (4- (2,5-Dimethylphenyl) piperazin-1-yl) (3-fluorophenyl) methanone [Example 11]
(4- (2,5-dichlorophenyl) piperazin-1-yl) (3-fluorophenyl) methanone [Example 12],
(4- (2,5-difluorophenyl) piperazin-1-yl) (3-fluorophenyl) methanone [Example 14],
(4- (3,4-difluorophenyl) piperazin-1-yl) (3-fluorophenyl) methanone [Example 16],
(4- (3,5-dichlorophenyl) piperazin-1-yl) (3-fluorophenyl) methanone [Example 17],
(4- (3,4-Dichlorophenyl) piperazin-1-yl) (3-fluorophenyl) methanone [Example 35] or (4- (5-Chloro-2-methylphenyl) piperazin-1-yl) ( 3-Chlorophenyl) methanone [Example 36], or a pharmaceutically acceptable salt thereof.

[14] Formula (2):

[Where:
Z ³ represents a halogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 alkyloxy group, or a C _1-6 haloalkyloxy group;
R ³² , R ³³ , R ³⁴ , and R ³⁵ are the same or different and each represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 alkyloxy group, or C _{1 Represents a -6} haloalkyloxy group;
R ^a represents a hydrogen atom or a C _1-6 alkyl group;
Q is an adamantyl group, a C _3-7 cycloalkyl group (the group is the same or different 1 to 4 selected from the group consisting of a halogen atom, C _1-6 alkyl, and C _1-6 alkyloxy) Optionally substituted with a group) or the following formula (3):

(Wherein R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , and R ⁴⁵ are the same or different and are a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _{1-6, or} Represents an alkyloxy group or a C _1-6 haloalkyloxy group);
put it here,
(1) When R ³² , R ³³ , R ³⁴ , and R ³⁵ are all hydrogen atoms, Z ³ represents a C _2-6 alkyl group, a C _1-6 haloalkyl group, or a C _1-6 haloalkyloxy. A group;
(2) When Z ³ is a methyl group, R ³⁴ represents a hydrogen atom, a C _2-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 alkyloxy group, or a C _1-6 haloalkyloxy group. R ³² , R ³³ , and R ³⁵ are the same or different and each represents a hydrogen atom, a halogen atom, a C _2-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 alkyloxy group, or C _{1 A -6} haloalkyloxy group], or a pharmaceutically acceptable salt thereof.
However, the following compounds are excluded.

[15] Formula (2):

(Wherein R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , and R ⁴⁵ are the same or different and are a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _{1-6, or} Represents an alkyloxy group or a C _1-6 haloalkyloxy group);
put it here,
(1) When R ³² , R ³³ , R ³⁴ , and R ³⁵ are all hydrogen atoms, Z ³ represents a C _2-6 alkyl group, a C _1-6 haloalkyl group, or a C _1-6 haloalkyloxy. A group;
(2) When Z ³ is a methyl group, R ³⁴ represents a hydrogen atom, a C _2-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 alkyloxy group, or a C _1-6 haloalkyloxy group. R ³² , R ³³ , and R ³⁵ are the same or different and each represents a hydrogen atom, a halogen atom, a C _2-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 alkyloxy group, or C _{1 A -6} haloalkyloxy group;
(3) When Z ³ is a methyl group and R ³² is a chlorine atom, R ⁴¹ is a halogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 alkyloxy group, Or a C _1-6 haloalkyloxy group, and R ⁴⁴ is a hydrogen atom, a fluorine atom, a bromine atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 alkyloxy group, or a C _{1- 6} haloalkyloxy groups;
(4) When Z ³ is a fluorine atom and R ³³ is a fluorine atom, R ⁴³ is a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _2-6 alkyl An oxy group or a C _1-6 haloalkyloxy group;
(5) When Z ³ is a chlorine atom and R ³⁴ is a chlorine atom, R ⁴³ is a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _2-6 alkyl An oxy group or a C _1-6 haloalkyloxy group).

[16] The compound according to [14] or [15], or a pharmaceutically acceptable salt thereof, wherein R ³³ , R ³⁴ , and R ³⁵ are all hydrogen atoms.

[17] The structure according to any one of [14] to [16], wherein Z ³ and R ³² are the same or different and are a halogen atom, a C _1-6 alkyl group, or a C _1-6 haloalkyl group A compound, or a pharmaceutically acceptable salt thereof.

[18] The compound according to [17] or a pharmaceutically acceptable salt thereof, wherein Z ³ is a C _1-6 alkyl group or a C _1-6 haloalkyl group, and R ³² is a halogen atom.

[19] The compound or a pharmaceutically acceptable salt thereof according to [17], wherein Z ³ is a halogen atom, and R ³² is a halogen atom or a C _1-6 alkyl group.

[20] The compound according to any one of [14] to [18], wherein Z ³ is a C _1-4 haloalkyl group, or a pharmaceutically acceptable salt thereof.

[21] The compound according to any one of [14] to [20], wherein Q is a group represented by the formula (3), or a pharmaceutically acceptable salt thereof.

[22] The compound according to any one of [14] to [21], wherein R ⁴³ , R ⁴⁴ and R ⁴⁵ are all hydrogen atoms, or a pharmaceutically acceptable salt thereof.

[23] Formula (6):

[Where:
Z ³ represents a halogen atom, a C _1-6 alkyl group, or a C _1-6 haloalkyl group;
R ³² represents a hydrogen atom, a halogen atom, or a C _1-6 alkyl group;
Q is an adamantyl group, a C _3-7 cycloalkyl group (the group is the same or different 1 to 4 selected from the group consisting of a halogen atom, C _1-6 alkyl, and C _1-6 alkyloxy) Which may be substituted with a group), or the following formula (7):

Wherein R ⁴¹ represents a halogen atom, a C _1-6 alkyloxy group, or a C _1-6 haloalkyloxy group;
put it here,
(1) when R ³² is a hydrogen atom, Z ³ is a C _1-6 haloalkyl group;
(2) When Z ³ is a methyl group, R ³² is a halogen atom or a C _2-6 alkyl group]. The compound according to any one of [14] to [20] Or a pharmaceutically acceptable salt thereof.

[24] The compound according to [23] or a pharmaceutically acceptable salt thereof, wherein Q is a group represented by the formula (7).

[25] The compound according to any one of [14] to [16] and [21] to [24], wherein Z ³ is a C _1-6 haloalkyl group, and R ³² is a hydrogen atom, or a pharmaceutical product thereof Top acceptable salt.

[26] The structure described in any one of [14] to [17] and [21] to [24], wherein Z ³ and R ³² are the same or different and are a halogen atom or a C _1-6 alkyl group Or a pharmaceutically acceptable salt thereof.

[27] The compound according to any one of [14] to [26], wherein R ⁴¹ is a C _1-6 alkyloxy group, or a pharmaceutically acceptable salt thereof.

[28] Q is an adamantyl group or a C _3-7 cycloalkyl group (the group is the same or different 1 selected from the group consisting of a halogen atom, C _1-6 alkyl, and C _1-6 alkyloxy) The compound according to any one of [14] to [20] and [23], or a pharmaceutically acceptable salt thereof, which may be substituted with up to 4 groups.

[29] The compound according to [28], wherein Q is a C _3-7 cycloalkyl group, or a pharmaceutically acceptable salt thereof.

[30] 2- (4- (2-Chloro-3-methylphenyl) piperazin-1-yl) -N- (2-ethoxyphenyl) acetamide [Example 19]
2- (4- (3-Chloro-2-methylphenyl) piperazin-1-yl) -N- (2-ethoxyphenyl) acetamide [Example 20],
N- (2-ethoxyphenyl) -2- (4- (2-fluoro-3-methylphenyl) piperazin-1-yl) acetamide [Example 21],
N- (2-ethoxyphenyl) -2- (4- (3-fluoro-2-methylphenyl) piperazin-1-yl) acetamide [Example 22],
2- (4- (2,3-dichlorophenyl) piperazin-1-yl) -N- (2-ethoxyphenyl) acetamide [Example 23],
N- (2-ethoxyphenyl) -2- (4- (2- (trifluoromethyl) phenyl) piperazin-1-yl) acetamide [Example 24],
2- (4- (2,4-dichlorophenyl) piperazin-1-yl) -N- (2-ethoxyphenyl) acetamide [Example 25],
2- (4- (2-Fluoro-3-methylphenyl) piperazin-1-yl) -N- (2- (trifluoromethoxy) phenyl) acetamide [Example 26],
N- (2-chlorophenyl) -2- (4- (2-fluoro-3-methylphenyl) piperazin-1-yl) acetamide [Example 27],
N- (5-chloro-2-methoxyphenyl) -2- (4- (2-fluoro-3-methylphenyl) piperazin-1-yl) acetamide [Example 28],
N- (3,4-dimethylphenyl) -2- (4- (2-fluoro-3-methylphenyl) piperazin-1-yl) acetamide [Example 29],
N-cycloheptyl-2- (4- (2-fluoro-3-methylphenyl) piperazin-1-yl) acetamide [Example 30],
N-cyclohexyl-N-methyl-2- (4- (2-fluoro-3-methylphenyl) piperazin-1-yl) acetamide [Example 31],
2- (4- (3,4-difluorophenyl) piperazin-1-yl) -N- (2-ethoxyphenyl) acetamide [Example 40],
2- (4- (3,5-dichlorophenyl) piperazin-1-yl) -N- (2-ethoxyphenyl) acetamide [Example 41] or 2- (4- (2,4-difluorophenyl) piperazine- 1-yl) -N- (2-ethoxyphenyl) acetamide [Example 42], or a pharmaceutically acceptable salt thereof.

[31] 2- (4- (2-Chloro-3-methylphenyl) piperazin-1-yl) -N- (2-ethoxyphenyl) acetamide [Example 19]
2- (4- (3-Chloro-2-methylphenyl) piperazin-1-yl) -N- (2-ethoxyphenyl) acetamide [Example 20],
N- (2-ethoxyphenyl) -2- (4- (2-fluoro-3-methylphenyl) piperazin-1-yl) acetamide [Example 21],
N- (2-ethoxyphenyl) -2- (4- (3-fluoro-2-methylphenyl) piperazin-1-yl) acetamide [Example 22] or N- (2-ethoxyphenyl) -2- ( 4- (2- (trifluoromethyl) phenyl) piperazin-1-yl) acetamide [Example 24], or a pharmaceutically acceptable salt thereof.

[32] A therapeutic agent for neurodegenerative disease or psychiatric disease, comprising as an active ingredient the compound according to any one of [1] to [31] above or a pharmaceutically acceptable salt thereof.

[33] Formula (1):

[Wherein Z ¹ represents a halogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 alkyloxy group, or a C _1-6 haloalkyloxy group;
R ¹¹ , R ¹³ , R ¹⁴ , and R ¹⁵ are the same or different and each represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 alkyloxy group, or C _{1 Represents a -6} haloalkyloxy group;
R ²¹ , R ²³ , R ²⁴ , and R ²⁵ are a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 alkyloxy group, a C _1-6 haloalkyloxy group, _{Represents a} C _1-6 alkylsulfonyl group or a cyano group;
X ² represents a halogen atom], or a therapeutic agent for neurodegenerative disease or psychiatric disease, comprising as an active ingredient a compound represented by the formula: or a pharmaceutically acceptable salt thereof.

[34] Formula (2):

Wherein R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ and R ⁴⁵ are the same or different and are a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, C _{A 1-6} alkyloxy group or a group represented by C _1-6 haloalkyloxy group), or a pharmaceutically acceptable salt thereof as an active ingredient, A remedy for mental illness.

[35] A neurodegeneration characterized by administering a therapeutically effective amount of the compound according to any one of [1] to [31] above or a pharmaceutically acceptable salt thereof to a mammal in need of treatment. A method of treating a disease or psychiatric disorder.

[36] A neurodegenerative disease or psychiatric disease characterized by administering a therapeutically effective amount of the compound according to [33] or [34] above or a pharmaceutically acceptable salt thereof to a mammal in need of treatment. How to treat the disease.

[37] The compound according to any one of the above [1] to [31] or a pharmaceutically acceptable salt thereof for use in the treatment of a neurodegenerative disease or a mental disorder.

[38] The compound according to [33] or [34], or a pharmaceutically acceptable salt thereof, for use in the treatment of a neurodegenerative disease or a mental illness.

[39] Use of the compound according to any one of [1] to [31] above or a pharmaceutically acceptable salt thereof in the manufacture of a therapeutic agent for neurodegenerative disease or psychiatric disorder.

[40] Use of the compound according to [33] or [34] above or a pharmaceutically acceptable salt thereof in the manufacture of a therapeutic agent for neurodegenerative disease or psychiatric disorder.

In the above formula (1) or formula (2)

In Z ³ , R ³² to R ³⁵ , preferably 4 or less, or 3 or less, more preferably 2 or less, and hydrogen other than the substituent is hydrogen.

The compound of the present invention directly activates TRPC3 or TRPC6 channel, which is known as a source of BDNF signal, and has the same neurite outgrowth action as BDNF. Therefore, it prevents neurodegenerative diseases and mental disorders. And / or useful for treatment.

Shows the results of Test Example 2 of the compounds represented by formula (1) and formula (2), and the results of no addition of compounds and BDNF as controls. The micrograph which observed the neurite extension effect | action after compound administration in the primary cultured rat hippocampal nerve cell is shown. By administration, enhancement of the neurite extension effect similar to that of BDNF was observed. These show the results of Test Example 2 for the compounds represented by formula (1) and formula (2). The micrograph which observed the neurite extension effect | action after compound administration in the primary cultured rat hippocampal nerve cell is shown. By administration, enhancement of the neurite extension effect similar to that of BDNF was observed.

The present invention is described in further detail below. In the present specification, the number of carbons in the definition of “substituent” may be expressed as “C _1-6 ”, for example. Specifically, the expression “C _1-6 alkyl” is synonymous with an alkyl group having 1 to 6 carbon atoms.

In this specification, the term “group” means a monovalent group. For example, “alkyl group” means a monovalent saturated hydrocarbon group. In addition, in the description of substituents in this specification, the term “group” may be omitted.
In addition, unless otherwise specified, the description of each group also applies when the group is a part of another group or a substituent.

“Halogen atom” includes fluorine atom, chlorine atom, bromine atom or iodine atom. Preferably a fluorine atom or a chlorine atom is mentioned.

“C _1-6 alkyl group” means a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Preferred is a “C _1-4 alkyl group”. Specific examples of “C _1-6 alkyl group” include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl and isohexyl. 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.

“C _1-6 haloalkyl group” means a C _1-6 alkyl group substituted with one or more independently selected halogens. Preferably, it is a “C _1-4 haloalkyl group”. Specific examples of “C _1-6 haloalkyl group” include, for example, mono-, di- or tri-fluoromethyl; mono-, di- or tri-chloromethyl; mono-, di-, tri-, tetra- or Penta-fluoroethyl; mono-, di-, tri-, tetra- or penta-chloroethyl; and 1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl and the like. Exemplary haloalkyl groups include trifluoromethyl and difluoromethyl.

“C _3-7 cycloalkyl group” means a 3- to 7-membered monocyclic saturated hydrocarbon group. Preferred is “C _3-6 cycloalkyl group”. Specific examples of “C _3-7 cycloalkyl group” include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

The “C _1-6 alkyl” part of the “C _1-6 alkyloxy group” has the same _{meaning as} the above “C _1-6 alkyl”. Preferred is a “C _1-4 alkyloxy group”. Specific examples of “C _1-6 alkyloxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

The “C _1-6 haloalkyl” part of the “C _1-6 haloalkyloxy group” has the same meaning as the above “C _1-6 alkyl”. A “C _1-4 haloalkyloxy group” is preferable. Specific examples of “C _1-6 haloalkyloxy group” include, for example, mono-, di- or tri-fluoromethoxy; mono-, di- or tri-chloromethoxy; mono-, di-, tri-, tetra- Or penta-fluoroethoxy; mono-, di-, tri-, tetra- or penta-chloroethoxy and the like. Exemplary haloalkyl groups include trifluoromethoxy and difluoromethoxy.

The “C _1-6 alkyl” part of the “C _1-6 alkylsulfonyl group” has the same meaning as the above “C _1-6 alkyl”. Preferably, it is “C _1-4 alkylsulfonyl group”. Specific examples of “C _1-6 alkylsulfonyl group” include, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, pentylsulfonyl, isobutylsulfonyl, butylsulfonyl and the like.

Examples of the pharmaceutically acceptable salt of the compound represented by formula (1) or formula (2) include salts with inorganic acids or organic acids. Specific examples of the salt with an inorganic acid include hydrochloride, hydrobromide, nitrate, sulfate, phosphate and the like. Specific examples of salts with organic acids include, for example, formate, acetate, trifluoroacetate, propionate, lactate, tartrate, oxalate, ascorbate, fumarate, maleate, Examples thereof include citrate, malonate, methanesulfonate, benzenesulfonate, and p-toluenesulfonate. The compounds of the present invention may take the form of solvates such as hydrates.

Since the compound represented by the formula (1) or the formula (2) may exist in the form of a hydrate and / or a solvate, a solvate such as a hydrate or an ethanol solvate thereof. Are also included in the compounds of the present invention. Further, the compounds of the present invention include all forms of crystal forms.

The compounds of the present invention may have at least one asymmetric carbon atom. Accordingly, the compounds of the present invention include not only racemic isomers of the compounds represented by formula (1) or formula (2) but also optically active isomers of these compounds. When the compound represented by formula (1) or formula (2) has two or more asymmetric carbon atoms, stereoisomerism may occur. Therefore, this invention compound also includes the stereoisomer of these compounds, its mixture, and the isolated thing.
Further, a deuterium converter obtained by converting any one or two or more ¹ H of the compounds represented by formula (1) or formula (2) into ² H (D) is also represented by formula (1) or formula (2). ).

The present invention includes a prodrug range of the compound of the present invention or a pharmaceutically acceptable salt thereof. In general, such prodrugs are functional derivatives of the compounds of the present invention that can be readily converted into the required compound in vivo.

Hereinafter, the production method of the compound of the present invention will be described with examples, but the present invention is not limited to this example. These reactions are merely examples, and based on the knowledge of those skilled in organic synthesis, they can also be produced by appropriately combining known raw material compounds with conventional methods or production methods based thereon.

The compound represented by the production process formula (1) can be produced, for example, by the production process A or B shown below. In addition, the compound used with the following manufacturing method may form the salt in the range which does not interfere with reaction.

[Production method A]

(In the formula, R ¹¹ , Z ¹ , R ¹³ , R ¹⁴ , R ¹⁵ , R ²¹ , X ² , R ²³ , R ²⁴ , and R ²⁵ are as defined above in [1].)

[Process 1]
Compound (1) is obtained by performing a condensation reaction between compound (II) and the corresponding carboxylic acid or the like. This reaction can be performed according to a conventional method. For example, this reaction can be achieved by reacting compound (II) with various carboxylic acids in the presence of a condensing agent or the like in a suitable solvent or in the absence of a solvent. The starting compound (II) is synthesized by a method according to a known method (for example, Bioorganic & Medicinal Chemistry Letters 18, 2008, 3513-3516, Organic Process Research & Development 10, 2006, 762-769, Bioorganic & Medicinal Chemistry Letters 14, 2004, 4417-4423).

Specific examples of the condensing agent include N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide monohydrochloride, N, N′-carbonyldiimidazole, dimethylaminosulfonic acid chloride, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, benzotriazol-1-yl-oxytris (pyrrolidino) phosphonium-hexafluorophosphate, O- (1H-7-aza-1-benzotriazolyl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate and the like.
These condensing agents can be used alone or in combination with condensing aids such as N-hydroxysuccinimide and N-hydroxybenzotriazole.

Specific examples of the solvent include, for example, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane; aromatic hydrocarbons such as benzene and toluene; ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran (THF) and 1,4-dioxane. Examples of the solvent include: aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; basic solvents such as pyridine; or a mixed solvent thereof.

The reaction temperature varies depending on the raw material compound and reagent used, but is usually −20 to 200 ° C., preferably 0 to 100 ° C.

Compound (1) can also be produced by reacting the corresponding acid chloride or acid anhydride and the like with compound (II) in the presence of a base or the like in an appropriate solvent or without solvent.

Specific examples of the base include, for example, inorganic bases such as potassium carbonate, sodium carbonate and cesium carbonate; organic bases such as triethylamine and diisopropylethylamine.

[Production method B]

(In the formula, R ¹¹ , Z ¹ , R ¹³ , R ¹⁴ , R ¹⁵ , R ²¹ , X ² , R ²³ , R ²⁴ , and R ²⁵ are as defined in the above [1]. P is a hydrogen atom or (Amino-protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl, etc.)

[Step 2-1]
Corresponding benzoic acid, acid chloride or acid anhydride and compound (III) can be reacted in the same manner as in step 1 to produce compound (IV). These starting materials are commercially available, or are produced by a known method or a method according to a known method.

[Step 2-2]
When P is an amino-protecting group, compound (V) can be produced by deprotecting compound (IV). This reaction can be performed by a method according to a known method (see, for example, T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wieley & Sons, New York, 1999).

[Step 2-3]
The compound (1) is produced by reacting the compound (V) with various aryl halides in an appropriate solvent or in the absence of a solvent in the presence of a transition metal catalyst and a base as necessary. Can do. This reaction can be performed by a method according to a known method (for example, Beilstein Journal of Organic Chemistry 7, 2011, 59-74, Tetrahedron 62, 2006, 9010-9016, Accounts of Chemical Research 41, 2008, 1534 -1544, Chemical Science 2, 2011, 27-50).

The compound represented by the formula (2) can be produced, for example, by the production method C or D shown below. In addition, the compound used by the following manufacturing method may form the salt in the range which does not interfere with reaction.

[Production Method C]

(In the formula, Z ³ , R ³² , R ³³ , R ³⁴ , R ³⁵ , R ^a , and Q are as defined in [2] above. X represents a chlorine atom or a bromine atom. A represents OH. Represents a chlorine atom or a bromine atom.)

[Step 3-1]
Compound (VIII) can be produced by reacting compound (VI) with compound (VII) in the same manner as in Step 1. These starting materials are commercially available, or are produced by a known method or a method according to a known method.

[Step 3-2]
Compound (2) can be produced by reacting compound (VIII) and compound (IX) in an appropriate solvent or in the absence of a solvent in the presence of a base or the like.

Specific examples of the base include, for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, barium carbonate, potassium phosphate and other inorganic bases; sodium tert-butoxide, potassium tert-butoxide and the like And metal alkoxides.

The reaction temperature varies depending on the raw material compound and reagent used, but is usually 0 to 200 ° C., preferably 0 to 150 ° C.

[Production Method D]

(In the formula, Z ³ , R ³² , R ³³ , R ³⁴ , R ³⁵ , R ^a , and Q are as defined in [2] above. X represents a chlorine atom or a bromine atom. P represents hydrogen. Represents an atom or a protecting group for an amino group such as tert-butoxycarbonyl, benzyloxycarbonyl, etc.)

[Step 4-1]
Compound (X) can be produced in the same manner as in Step 3-2 using compound (VIII) and the corresponding piperazine compound. These starting materials are commercially available, or are produced by a known method or a method according to a known method.

[Step 4-2]
When P is an amino-protecting group, compound (XI) can be produced from compound (X) by the same method as in Step 2-2.

[Step 4-3]
Compound (2) can be produced in the same manner as in Step 2-3 using compound (XI) and the corresponding aryl halide.

Examples of a method for purely obtaining an optical isomer of the compound of the present invention include a method using an optically active column and an optical resolution method.

The compound of the present invention directly activated the TRPC6 channel and / or the TRPC3 channel, and exhibited a neurite extension action similar to BDNF in primary cultured rat hippocampal neurons. Accordingly, the compound of the present invention is a neurite extension agent and is expected to have the following pharmacological effects of BDNF: Alzheimer's disease, Huntington's disease, Parkinson's disease, Rett syndrome, traumatic brain injury, spinal cord injury, It is useful as a therapeutic agent for neurodegenerative diseases and mental disorders such as multiple sclerosis, senile dementia, ALS, depression, bipolar disorder, schizophrenia and the like.

As used herein, “therapeutically effective amount” means the amount of a drug or pharmaceutical agent that elicits a biological or pharmaceutical response in a tissue, system, animal or human that is required by a researcher or physician.
The “treatment” used in the present invention includes all treatments of diseases (for example, improvement of symptoms, reduction of symptoms, suppression of progression of symptoms, etc.).

“Peripheral administration” encompasses any route of administration other than the route of administration of the compound of the present invention directly into the central nervous system, eg, intraventricularly or intrathecally. For example, oral administration; nasal administration; sublingual administration; transdermal administration; ophthalmic administration; pulmonary administration; rectal administration; intravitreal administration; intraperitoneal administration; intravenous administration; subcutaneous administration; Administration is by a route selected from the group consisting of a combination of two or more of these administration routes.

When administered orally, it can be administered in a commonly used dosage form. Examples of the oral agent or rectal administration agent include capsules, tablets, pills, powders, cachets, suppositories, and liquids. Examples of injections include sterile solutions or suspensions. Examples of the topical administration agent include creams, ointments, lotions, transdermal agents (ordinary patches, matrix agents) and the like.

The above dosage form is formulated in the usual manner together with pharmaceutically acceptable excipients and additives. Examples of pharmaceutically acceptable excipients and additives include carriers, binders, fragrances, buffers, thickeners, colorants, stabilizers, emulsifiers, dispersants, suspending agents, preservatives, and the like. It is done.

Pharmaceutically acceptable carriers include, for example, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter Etc. Capsules can be formulated by placing the compound of the invention in a pharmaceutically acceptable carrier. The compounds of the invention can be mixed with pharmaceutically acceptable excipients or encapsulated without excipients. Cachets can be produced in the same manner.

Examples of injection solutions include solutions, suspensions, and emulsions. Examples thereof include an aqueous solution and a water-propylene glycol solution. The solution can also be prepared in the form of a solution of polyethylene glycol and / or propylene glycol, which may contain water. Solutions suitable for oral administration can be prepared by adding the compounds of the present invention to water and adding colorants, fragrances, stabilizers, sweeteners, solubilizers, thickeners and the like as necessary. A solution suitable for oral administration can also be produced by adding the compound of the present invention together with a dispersant to water to make it viscous. Examples of the thickener include pharmaceutically acceptable natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, or a known suspending agent.

Examples of the topical administration agent include the above liquid preparations, creams, aerosols, sprays, powders, lotions, ointments and the like. The above topical preparations can be prepared by mixing the compound of the present invention with commonly used pharmaceutically acceptable diluents and carriers. Ointments and creams are obtained, for example, by adding a thickener and / or a gelling agent to an aqueous or oily base. Examples of the base include water, liquid paraffin, vegetable oil (peanut oil, castor oil, etc.) and the like. Examples of the thickener include soft paraffin, aluminum stearate, cetostearyl alcohol, propylene glycol, polyethylene glycol, lanolin, hydrogenated lanolin, beeswax and the like.

Lotions can add one or more pharmaceutically acceptable stabilizers, suspending agents, emulsifying agents, diffusing agents, thickening agents, coloring agents, flavorings, etc. to an aqueous or oily base. .

Powder is formulated with a pharmaceutically acceptable powder base. Examples of the base include talc, lactose, starch and the like. Drops can be formulated with an aqueous or non-aqueous base and one or more pharmaceutically acceptable diffusing agents, suspending agents, solubilizing agents, and the like.

The topical administration agent may contain a preservative such as methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chloride, and a bacterial growth inhibitor, if necessary.

The compound of the present invention or a salt thereof can be administered to a patient suffering from a neurodegenerative disease or a mental illness. In this case, the dose and frequency of administration vary depending on symptoms, age, body weight, dosage form, etc., but when administered orally, it is usually in the range of about 1 to about 500 mg per day for adults, preferably about 5 The range of about 100 mg can be administered in one or several divided doses. In the case of administration as an injection, the range of about 0.1 to about 300 mg, preferably about 1 to about 100 mg can be administered once or divided into several times.

Hereinafter, the present invention will be described more specifically with reference to reference examples, examples and test examples, but the present invention is not limited thereto. In addition, the compound names shown in the following Reference Examples and Examples do not necessarily follow the IUPAC nomenclature. In addition, although abbreviations may be used for simplification of description, these abbreviations have the same meanings as described above.
In the present specification, the following abbreviations may be used.
The following abbreviations are used in the NMR data of Reference Examples and Examples.
Me group: methyl group MeO group: methoxy group EtO group: ethoxy group tert-: tertiary s: singlet
brs: Broad singlet
d: Doublet
t: triplet
q: quartet
dd: double doublet
m: multiplet
J: coupling constant
Hz: Hertz
DMF: N, N-dimethylformamide TFA: trifluoroacetic acid CDCl ₃ : deuterated chloroform CD ₃ OD: deuterated methanol DMSO-d ₆ : deuterated dimethyl sulfoxide

Reference Example 1-1
1- (2,5-dichlorophenyl) piperazine hydrochloride

[Step 1]
1-bromo-2,5-dichlorobenzene (500 mg), tert-butylpiperazine-1-carboxylate (343 mg), sodium tert-butoxide (194 mg), 2,2′-bis (diphenylphosphino) -1,1 '-Binaphthyl (8 mg) and tris (dibenzylideneacetone) dipalladium (0) (4 mg) were added to toluene (10 mL), and the mixture was stirred at 90 ° C. for 12 hours in a nitrogen atmosphere. The reaction mixture was filtered through celite, concentrated under reduced pressure, and purified on a silica gel column to give tert-butyl 4- (2,5-dichlorophenyl) piperazine-1-carboxylate (430 mg).
[Step 2]
The tert-butyl 4- (2,5-dichlorophenyl) piperazine-1-carboxylate (480 mg) obtained in Step 1 was dissolved in 1,4-dioxane (10 mL), and the solution was dissolved in 4 mol / L hydrochloric acid-dioxane solution ( Slowly added to 5 mL). The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to obtain 240 mg of 1- (2,5-dichlorophenyl) piperazine hydrochloride.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.3-7.2 (m, 1H), 7.0-6.9 (m, 2H), 3.3-3.2 (m, 8H)

Reference Examples 1-2 to 1-8
The compounds of Reference Examples 1-2 to 1-8 were synthesized according to the method described in Reference Example 1-1 using the corresponding starting compounds.

Example 1
(4- (5-Chloro-2-methylphenyl) piperazin-1-yl) (2,3-difluorophenyl) methanone

1- (5-chloro-2-methylphenyl) piperazine (150 mg), 1-hydroxybenzotriazole monohydrate (131 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (164 mg), Triethylamine (0.15 mL) was dissolved in DMF (8 mL) and 2,3-difluorobenzoic acid (145 mg) was added. The reaction mixture was stirred at room temperature overnight, water (80 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic layer was concentrated under reduced pressure and purified by reverse phase HPLC to give the title compound (54 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.3-6.9 (m, 6H), 3.99 (m, 2H), 3.51 (m, 2H), 2.99 (m, 2H), 2.89 (m, 2H), 2.28 (s, 3H)

Examples 2-18
The compounds of Examples 2 to 18 were synthesized according to the method described in Example 1, using the corresponding phenylpiperazine derivative and benzoic acid derivative. What has the description of TFA in the chemical structural formula of Table 3 means trifluoroacetate.

Reference Example 2-1
2-Bromo-N- (2-ethoxyphenyl) acetamide

2-Ethoxyaniline (2.9 g) and triethylamine (3.2 mL) were dissolved in methylene chloride (10 mL), bromoacetyl bromide (6.6 g) was added, and the mixture was stirred at 0 ° C. for 3 hr. Water (15 mL) was added to the reaction solution, the organic layer was taken, and the aqueous layer was extracted with methylene chloride (15 mL × 3). The organic layers were combined and concentrated under reduced pressure, and then purified with a silica gel column to give the title compound (4 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.98 (brs, 1H), 8.34 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.99 (t, J = 8.0 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 4.14 (q, J = 7.2 Hz, 2H), 4.07 (s, 2H), 1.51 (t, J = 7.2 Hz, 3H)

Reference Examples 2-2 to 2-14
Using the corresponding starting compounds, the compounds of Reference Examples 2-2 to 2-14 were synthesized according to the method described in Reference Example 2-1.

Example 19
2- (4- (2-Chloro-3-methylphenyl) piperazin-1-yl) -N- (2-ethoxyphenyl) acetamide

2-Bromo-N- (2-ethoxyphenyl) acetamide (89 mg), 1- (2-chloro-3-methylphenyl) piperazine (60 mg) and potassium carbonate (47 mg) were added to acetonitrile (15 mL), and the mixture was heated to 80 ° C. And stirred for 12 hours. The reaction mixture was added to water (20 mL) and extracted with methylene chloride (15 mL). The organic layer was washed with water (10 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by reverse phase HPLC gave the title compound (39 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 9.90 (brs, 1H), 8.48 (d, J = 8.0 Hz, 1H), 7.2-6.9 (m, 6H), 4.14 (q, J = 7.2 Hz, 2H), 3.27 (s, 2H), 3.02 (m, 4H), 2.84 (brs, 4H), 2.38 (s, 3H), 1.55 (t, J = 7.2 Hz, 3H)

Examples 20-31
The compounds of Examples 20 to 31 were synthesized according to the method described in Example 19 using the corresponding compounds of Reference Examples 2-1 to 2-14 and the corresponding starting compound phenylpiperazine derivative.

Examples 32-36
The compounds of Examples 32-36 were synthesized according to the method described in Example 1 using the corresponding phenylpiperazine derivative and benzoic acid derivative. Those having the notation of TFA in the chemical structural formula of Table 6 mean trifluoroacetate.

Examples 37-51
Using the compounds of Reference Examples 2-1 to 2-3 and 2-8 to 2-14 and the corresponding phenylpiperazine derivatives, the compounds of Examples 37 to 51 were synthesized according to the method described in Example 18. What has the description of TFA in the chemical structural formula of Table 7 means trifluoroacetate.

Test example 1
According to the following test examples, the TRPC channel activation ability of the compounds of the present invention was evaluated.

Membrane potential assay using HEK293 cells transiently expressing TRPC channel TRPC channel expression into HEK293 cells was expressed using lipofection method or virus. In the lipofection method, the expression plasmid was introduced into HEK293 cells using a lipofection reagent and then cultured overnight at 37 ° C. The cells were detached with trypsin, suspended in 10% FBS / DMEM, replated at 4 × 10 ³ cells / 50 μL / well in a 384-well black / clear plate (for cell culture), and cultured overnight. When virus was used, HEK293 cells suspended in 10% FBS / DMEM were infected with the virus, seeded again at 4 × 10 ³ cells / 50 μL / well in a 384 well black / clear plate, and cultured overnight. .
Next, the medium was discarded, and a membrane potential measuring reagent (Molecular) prepared with Tyrode's Buffer (132 mM NaCl, 1 mM KCl, 1 mM CaCl ₂ , 1 mM MgCl ₂ , 5 mM Glucose, 5 mM HEPES (pH 7.4)). Devices, FLIPR membrane potential assay kit BLUE Cat # R8034) was added at 40 μL / well and allowed to stand at 37 ° C. for 1 hour. At FLIPRtetra (Molecular Devices), 10 μL / well of a test compound diluted with Tyrode's Buffer was added, and the fluorescence intensity at that time was measured over time (Ex 515_545, Em 565_625 nm). The maximum fluorescence intensity when carbachol was added was defined as 100%, and the amount of change at 10 μM of the test compound was expressed.

The evaluation results of Test Example 1 are described below.

Test example 2
Neurite outgrowth using primary cultured rat hippocampal neurons Wister rat fetus 19-day-old frozen hippocampus (Sumitomo Bakelite: MBX0402) was used to obtain primary neurons using nerve cell dispersion (Sumitomo Bakelite: MBX0802) . The obtained hippocampus-derived neurons were prepared in a nerve cell culture solution (Sumitomo Bakelite: MBX9501) at 5 × 10 ⁴ cells / well and seeded on a poly-D lysine-coated 8-well chamber slide (BD: 354632). did. Four hours later, after confirming the adhesion of neurons, the cells were replaced with a nerve cell test solution (Sumitomo Bakelite: MBX0701) containing BDNF (50 ng / mL) or a test compound (100 nM), and cultured for 48 hours. The cells after 48 hours of culture were fixed with paraformaldehyde. The neurite extension effect was evaluated by observing with a microscope.
The results of Test Example 2 are shown in FIGS. By adding the test compound, enhancement of the neurite extension effect similar to that of BDNF was observed.

Test example 3
Quantitative evaluation of neurite outgrowth using primary cultured rat hippocampal neurons . The immobilized cells obtained in Test Example 2 were washed with PBS, and then membrane permeabilized with Triton X-100. After washing, the cells were blocked with 1% BSA / PBS, anti-MAP2 antibody was added as a neuronal marker, and the mixture was shaken overnight at 4 ° C. After washing, secondary antibody Alexa Fluor (registered trademark) 488-anti-mouse IgG and Alexa546 (registered trademark) phalloidin staining actin fibers were added and shaken at room temperature for 1 hour. After washing, it was sealed on a slide glass and observed with a confocal laser microscope. For cells in which a MAP2 signal was observed, neurite outgrowth was measured using the actin fiber signal as an index. Neurite outgrowth was assessed by determining the total neurite length per cell.
In the above test, the total length of neurite outgrowth was 152.8 μm in the control group, whereas it was 259.4 μm in the BDNF addition group (T test: P <0.001 vs control), and 195.5 m in the Example compound 36 addition group. (T test: P <0.05 vs control), 236.4 m in the Example compound 47 addition group (T test: P <0.001 vs control), 212.5 m in the Example compound 48 addition group (T test: P <0.01 vs control) Control).
The average length of the longest neurite outgrowth was 51.8 μm in the control group, compared with 68.1 μm in the BDNF addition group (T test: P <0.01 vs control), 49.1 μm in the Example compound 36 addition group, Example It was 65.1 μm in the compound 47 addition group (T test: P <0.05 vs control) and 58.3 μm in the example compound 48 addition group.

The compound of the present invention directly activates the TRPC3 or TRPC6 channel and exhibits a BDNF-like action, and thus is useful for the prevention and / or treatment of neurodegenerative diseases and psychiatric diseases.

Claims

Formula (1):

[Wherein Z 1 represents a halogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkyloxy group, or a C 1-6 haloalkyloxy group;
R 11 , R 13 , R 14 , and R 15 are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkyloxy group, or C 1 Represents a -6 haloalkyloxy group;
Provided that R 11 , R 13 , R 14 and R 15 are not simultaneously hydrogen atoms or simultaneously not halogen atoms;
R 21 , R 23 , R 24 , and R 25 are a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkyloxy group, a C 1-6 haloalkyloxy group, Represents a C 1-6 alkylsulfonyl group or a cyano group;
X 2 represents a halogen atom], or a pharmaceutically acceptable salt thereof.
However, the following compounds are excluded.
Formula (1):

[Where:
Z 1 represents a halogen atom, a C 1-6 alkyl group, or a C 1-6 haloalkyl group;
R 11 , R 13 , and R 15 are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkyloxy group, or a C 1-6 haloalkyl. Represents an oxy group;
R 14 represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 2-6 haloalkyl group, a C 1-6 alkyloxy group, or a C 1-6 haloalkyloxy group;
Provided that R 11 , R 13 , R 14 and R 15 are not simultaneously hydrogen atoms or simultaneously not halogen atoms;
R 21 represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkyloxy group, a C 1-6 haloalkyloxy group, a C 1-6 alkylsulfonyl group, or a cyano Represents a group;
X 2 represents a fluorine atom, a chlorine atom, or a bromine atom;
R 24 represents a hydrogen atom, a C 1-6 alkyl group, a C 2-6 haloalkyl group, a C 1-6 alkyloxy group, a C 1-6 haloalkyloxy group, a C 1-6 alkylsulfonyl group, or a cyano group. ;
R 23 and R 25 are the same or different and each represents a hydrogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 2-6 alkyloxy group, a C 1-6 haloalkyloxy group, or a C 1-6 Represents an alkylsulfonyl group or a cyano group;
put it here,
(1) When Z 1 is a methyl group, R 11 is a hydrogen atom, a halogen atom, a C 2-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkyloxy group, or a C 1-6 R 13 is a hydrogen atom, a fluorine atom, a bromine atom, a C 2-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkyloxy group, or a C 1-6 haloalkyloxy group. Yes;
(2) When X 2 is a chlorine atom and R 21 , R 23 , R 24 and R 25 are all hydrogen atoms, Z 1 is a fluorine atom, a bromine atom, a C 1-6 alkyl group, or A C 1-6 haloalkyl group;
(3) When Z 1 is a chlorine atom, X 2 is a fluorine atom, and R 21 , R 23 , R 24 and R 25 are all hydrogen atoms, R 11 , R 13 and R 15 are A hydrogen atom, a halogen atom, a C 2-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkyloxy group, or a C 1-6 haloalkyloxy group, which are the same or different. Or a pharmaceutically acceptable salt thereof.
The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 11 and R 13 are both hydrogen atoms.
The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 14 and R 15 are a halogen atom, a C 1-6 alkyl group, or a C 1-6 alkyloxy group. salt.
R 11 , R 13 , and R 14 are all hydrogen atoms, and R 15 is a halogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkyloxy group, or a C 1- The compound according to claim 1 or 2, which is 6 haloalkyloxy, or a pharmaceutically acceptable salt thereof.
R 11 , R 13 , and R 15 are all hydrogen atoms, and R 14 is a halogen atom, a C 1-6 alkyl group, a C 2-6 haloalkyl group, a C 1-6 alkyloxy group, or a C 1- The compound according to claim 1 or 2, which is 6 haloalkyloxy, or a pharmaceutically acceptable salt thereof.
The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 21 , R 23 , R 24 and R 25 are all hydrogen atoms.
Formula (4):

[Where:
Z 1 and R 15 are the same or different and each represents a halogen atom or a C 1-6 alkyl group;
X 2 represents a fluorine atom or a chlorine atom;
Here, when Z 1 is a chlorine atom and R 15 is a methyl group, X 2 is a chlorine atom], or a pharmaceutically acceptable compound thereof. salt.
The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein Z 1 and R 15 are the same or different and are a methyl group, a fluorine atom, or a chlorine atom.
The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein X 2 is a fluorine atom.
Formula (5):

[Where:
Z 1 represents a halogen atom or a C 1-6 alkyl group;
R 13 and R 14 are the same or different and each represents a hydrogen atom or a halogen atom;
Provided that R 13 and R 14 are not simultaneously hydrogen atoms;
Here, when R 13 is a chlorine atom, Z 1 is a halogen atom or a C 2-6 alkyl group], or a pharmaceutically acceptable salt thereof. Salt.
(4- (5-chloro-2-methylphenyl) piperazin-1-yl) (2,3-difluorophenyl) methanone,
(4- (5-chloro-2-methylphenyl) piperazin-1-yl) (3-fluoro-4-methylphenyl) methanone,
(4- (5-chloro-2-methylphenyl) piperazin-1-yl) (3-fluoro-5-methylphenyl) methanone,
(4- (5-chloro-2-methylphenyl) piperazin-1-yl) (5-fluoro-2-methylphenyl) methanone,
(4- (5-chloro-2-methylphenyl) piperazin-1-yl) (3-fluoro-2-methylphenyl) methanone,
(4- (5-chloro-2-methylphenyl) piperazin-1-yl) (3-fluoro-5-methoxyphenyl) methanone,
(4- (5-chloro-2-methylphenyl) piperazin-1-yl) (3-fluoro-2-methoxyphenyl) methanone,
4- (4- (5-chloro-2-methylphenyl) piperazine-1-carbonyl) -2-fluorobenzonitrile,
3- (4- (5-chloro-2-methylphenyl) piperazine-1-carbonyl) -5-fluorobenzonitrile,
(4- (5-chloro-2-methylphenyl) piperazin-1-yl) (5-fluoro-2- (methylsulfonyl) phenyl) methanone,
(4- (2,5-dimethylphenyl) piperazin-1-yl) (3-fluorophenyl) methanone,
(4- (2,5-dichlorophenyl) piperazin-1-yl) (3-fluorophenyl) methanone,
(4- (5-fluoro-2-methylphenyl) piperazin-1-yl) (3-fluorophenyl) methanone,
(4- (2,5-difluorophenyl) piperazin-1-yl) (3-fluorophenyl) methanone,
(4- (5-chloro-2-methoxyphenyl) piperazin-1-yl) (3-fluorophenyl) methanone,
(4- (3,4-difluorophenyl) piperazin-1-yl) (3-fluorophenyl) methanone,
(4- (3,5-dichlorophenyl) piperazin-1-yl) (3-fluorophenyl) methanone,
(3-chlorophenyl) (4- (2,5-dimethylphenyl) piperazin-1-yl) methanone,
(4- (5-chloro-2-methylphenyl) piperazin-1-yl) (5-fluoro-2-methoxyphenyl) methanone,
(4- (5-chloro-2-methoxyphenyl) piperazin-1-yl) (3-fluorophenyl) methanone,
(4- (2,3-dichlorophenyl) piperazin-1-yl) (3-fluorophenyl) methanone,
(4- (3,4-Dichlorophenyl) piperazin-1-yl) (3-fluorophenyl) methanone or (4- (5-chloro-2-methylphenyl) piperazin-1-yl) (3-chlorophenyl) methanone Or a pharmaceutically acceptable salt thereof.
(4- (2,5-dimethylphenyl) piperazin-1-yl) (3-fluorophenyl) methanone,
(4- (2,5-dichlorophenyl) piperazin-1-yl) (3-fluorophenyl) methanone,
(4- (2,5-difluorophenyl) piperazin-1-yl) (3-fluorophenyl) methanone,
(4- (3,4-difluorophenyl) piperazin-1-yl) (3-fluorophenyl) methanone,
(4- (3,5-dichlorophenyl) piperazin-1-yl) (3-fluorophenyl) methanone,
(4- (3,4-Dichlorophenyl) piperazin-1-yl) (3-fluorophenyl) methanone or (4- (5-chloro-2-methylphenyl) piperazin-1-yl) (3-chlorophenyl) methanone Or a pharmaceutically acceptable salt thereof.
Formula (2):

[Where:
Z 3 represents a halogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkyloxy group, or a C 1-6 haloalkyloxy group;
R 32 , R 33 , R 34 , and R 35 are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkyloxy group, or C 1 Represents a -6 haloalkyloxy group;
R a represents a hydrogen atom or a C 1-6 alkyl group;
Q is an adamantyl group, a C 3-7 cycloalkyl group (the group is the same or different 1 to 4 selected from the group consisting of a halogen atom, C 1-6 alkyl, and C 1-6 alkyloxy) Optionally substituted with a group) or the following formula (3):

(Wherein R 41 , R 42 , R 43 , R 44 , and R 45 are the same or different and are a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6, or Represents an alkyloxy group or a C 1-6 haloalkyloxy group);
put it here,
(1) When R 32 , R 33 , R 34 , and R 35 are all hydrogen atoms, Z 3 represents a C 2-6 alkyl group, a C 1-6 haloalkyl group, or a C 1-6 haloalkyloxy. A group;
(2) When Z 3 is a methyl group, R 34 represents a hydrogen atom, a C 2-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkyloxy group, or a C 1-6 haloalkyloxy group. R 32 , R 33 , and R 35 are the same or different and each represents a hydrogen atom, a halogen atom, a C 2-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkyloxy group, or C 1 A -6 haloalkyloxy group], or a pharmaceutically acceptable salt thereof.
However, the following compounds are excluded.
Formula (2):

[Where:
Z 3 represents a halogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkyloxy group, or a C 1-6 haloalkyloxy group;
R 32 , R 33 , R 34 , and R 35 are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkyloxy group, or C 1 Represents a -6 haloalkyloxy group;
R a represents a hydrogen atom or a C 1-6 alkyl group;
Q is an adamantyl group, a C 3-7 cycloalkyl group (the group is the same or different 1 to 4 selected from the group consisting of a halogen atom, C 1-6 alkyl, and C 1-6 alkyloxy) Optionally substituted with a group) or the following formula (3):

(Wherein R 41 , R 42 , R 43 , R 44 , and R 45 are the same or different and are a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6, or Represents an alkyloxy group or a C 1-6 haloalkyloxy group);
put it here,
(1) When R 32 , R 33 , R 34 , and R 35 are all hydrogen atoms, Z 3 represents a C 2-6 alkyl group, a C 1-6 haloalkyl group, or a C 1-6 haloalkyloxy. A group;
(2) When Z 3 is a methyl group, R 34 represents a hydrogen atom, a C 2-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkyloxy group, or a C 1-6 haloalkyloxy group. R 32 , R 33 , and R 35 are the same or different and each represents a hydrogen atom, a halogen atom, a C 2-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkyloxy group, or C 1 A -6 haloalkyloxy group;
(3) When Z 3 is a methyl group and R 32 is a chlorine atom, R 41 is a halogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkyloxy group, Or a C 1-6 haloalkyloxy group, and R 44 is a hydrogen atom, a fluorine atom, a bromine atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkyloxy group, or a C 1- 6 haloalkyloxy groups;
(4) When Z 3 is a fluorine atom and R 33 is a fluorine atom, R 43 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 2-6 alkyl An oxy group or a C 1-6 haloalkyloxy group;
(5) When Z 3 is a chlorine atom and R 34 is a chlorine atom, R 43 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 2-6 alkyl An oxy group or a C 1-6 haloalkyloxy group).
The compound according to claim 14 or 15, or a pharmaceutically acceptable salt thereof, wherein all of R 33 , R 34 , and R 35 are hydrogen atoms.
Z 3 and R 32 are the same or different and each is a halogen atom, a C 1-6 alkyl group, or a C 1-6 haloalkyl group, or a compound thereof, or a pharmaceutical product thereof Top acceptable salt.
The compound according to claim 17, or a pharmaceutically acceptable salt thereof, wherein Z 3 is a C 1-6 alkyl group or a C 1-6 haloalkyl group, and R 32 is a halogen atom.
The compound according to claim 17, or a pharmaceutically acceptable salt thereof, wherein Z 3 is a halogen atom, and R 32 is a halogen atom or a C 1-6 alkyl group.
The compound according to any one of claims 14 to 18, or a pharmaceutically acceptable salt thereof, wherein Z 3 is a C 1-4 haloalkyl group.
The compound according to any one of claims 14 to 20, or a pharmaceutically acceptable salt thereof, wherein Q is a group represented by the formula (3).
The compound according to any one of claims 14 to 21, or a pharmaceutically acceptable salt thereof, wherein R 43 , R 44 and R 45 are all hydrogen atoms.
Formula (6):

[Where:
Z 3 represents a halogen atom, a C 1-6 alkyl group, or a C 1-6 haloalkyl group;
R 32 represents a hydrogen atom, a halogen atom, or a C 1-6 alkyl group;
Q is an adamantyl group, a C 3-7 cycloalkyl group (the group is the same or different 1 to 4 selected from the group consisting of a halogen atom, C 1-6 alkyl, and C 1-6 alkyloxy) Which may be substituted with a group), or the following formula (7):

Wherein R 41 represents a halogen atom, a C 1-6 alkyloxy group, or a C 1-6 haloalkyloxy group;
put it here,
(1) when R 32 is a hydrogen atom, Z 3 is a C 1-6 haloalkyl group;
(2) When Z 3 is a methyl group, R 32 is a halogen atom or a C 2-6 alkyl group], or a compound according to any one of claims 14 to 20, Its pharmaceutically acceptable salt.
24. The compound according to claim 23, or a pharmaceutically acceptable salt thereof, wherein Q is a group represented by the formula (7).
The compound according to any one of claims 14 to 16 and 21 to 24, or a pharmaceutically acceptable salt thereof, wherein Z 3 is a C 1-6 haloalkyl group, and R 32 is a hydrogen atom.
The compound according to any one of claims 14 to 17 and 21 to 24, or a pharmaceutically acceptable salt thereof, wherein Z 3 and R 32 are the same or different and are a halogen atom or a C 1-6 alkyl group. Salt.
The compound according to any one of claims 14 to 26, or a pharmaceutically acceptable salt thereof, wherein R 41 is a C 1-6 alkyloxy group.
Q is an adamantyl group or a C 3-7 cycloalkyl group (the group is 1 to 4 of the same or different groups selected from the group consisting of a halogen atom, C 1-6 alkyl, and C 1-6 alkyloxy) The compound according to any one of claims 14 to 20 and 23, or a pharmaceutically acceptable salt thereof.
29. The compound according to claim 28, or a pharmaceutically acceptable salt thereof, wherein Q is a C3-7 cycloalkyl group.
2- (4- (2-chloro-3-methylphenyl) piperazin-1-yl) -N- (2-ethoxyphenyl) acetamide,
2- (4- (3-chloro-2-methylphenyl) piperazin-1-yl) -N- (2-ethoxyphenyl) acetamide,
N- (2-ethoxyphenyl) -2- (4- (2-fluoro-3-methylphenyl) piperazin-1-yl) acetamide,
N- (2-ethoxyphenyl) -2- (4- (3-fluoro-2-methylphenyl) piperazin-1-yl) acetamide,
2- (4- (2,3-dichlorophenyl) piperazin-1-yl) -N- (2-ethoxyphenyl) acetamide,
N- (2-ethoxyphenyl) -2- (4- (2- (trifluoromethyl) phenyl) piperazin-1-yl) acetamide,
2- (4- (2,4-dichlorophenyl) piperazin-1-yl) -N- (2-ethoxyphenyl) acetamide,
2- (4- (2-fluoro-3-methylphenyl) piperazin-1-yl) -N- (2- (trifluoromethoxy) phenyl) acetamide,
N- (2-chlorophenyl) -2- (4- (2-fluoro-3-methylphenyl) piperazin-1-yl) acetamide,
N- (5-chloro-2-methoxyphenyl) -2- (4- (2-fluoro-3-methylphenyl) piperazin-1-yl) acetamide,
N- (3,4-dimethylphenyl) -2- (4- (2-fluoro-3-methylphenyl) piperazin-1-yl) acetamide,
N-cycloheptyl-2- (4- (2-fluoro-3-methylphenyl) piperazin-1-yl) acetamide,
N-cyclohexyl-N-methyl-2- (4- (2-fluoro-3-methylphenyl) piperazin-1-yl) acetamide,
2- (4- (3,4-difluorophenyl) piperazin-1-yl) -N- (2-ethoxyphenyl) acetamide,
2- (4- (3,5-dichlorophenyl) piperazin-1-yl) -N- (2-ethoxyphenyl) acetamide or 2- (4- (2,4-difluorophenyl) piperazin-1-yl)- N- (2-ethoxyphenyl) acetamide or a pharmaceutically acceptable salt thereof.
2- (4- (2-chloro-3-methylphenyl) piperazin-1-yl) -N- (2-ethoxyphenyl) acetamide,
2- (4- (3-chloro-2-methylphenyl) piperazin-1-yl) -N- (2-ethoxyphenyl) acetamide,
N- (2-ethoxyphenyl) -2- (4- (2-fluoro-3-methylphenyl) piperazin-1-yl) acetamide,
N- (2-ethoxyphenyl) -2- (4- (3-fluoro-2-methylphenyl) piperazin-1-yl) acetamide or N- (2-ethoxyphenyl) -2- (4- (2- (Trifluoromethyl) phenyl) piperazin-1-yl) acetamide, or a pharmaceutically acceptable salt thereof.
A therapeutic agent for a neurodegenerative disease or a mental illness comprising the compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof as an active ingredient.
Formula (1):

[Wherein Z 1 represents a halogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkyloxy group, or a C 1-6 haloalkyloxy group;
R 11 , R 13 , R 14 , and R 15 are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkyloxy group, or C 1 Represents a -6 haloalkyloxy group;
R 21 , R 23 , R 24 , and R 25 are a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkyloxy group, a C 1-6 haloalkyloxy group, Represents a C 1-6 alkylsulfonyl group or a cyano group;
X 2 represents a halogen atom], or a therapeutic agent for neurodegenerative disease or psychiatric disease, comprising as an active ingredient a compound represented by the formula: or a pharmaceutically acceptable salt thereof.
Formula (2):

[Where:
Z 3 represents a halogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkyloxy group, or a C 1-6 haloalkyloxy group;
R 32 , R 33 , R 34 , and R 35 are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkyloxy group, or C 1 Represents a -6 haloalkyloxy group;
R a represents a hydrogen atom or a C 1-6 alkyl group;
Q is an adamantyl group, a C 3-7 cycloalkyl group (the group is the same or different 1 to 4 selected from the group consisting of a halogen atom, C 1-6 alkyl, and C 1-6 alkyloxy) Optionally substituted with a group) or the following formula (3):

Wherein R 41 , R 42 , R 43 , R 44 and R 45 are the same or different and are a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, C A 1-6 alkyloxy group or a group represented by C 1-6 haloalkyloxy group), or a pharmaceutically acceptable salt thereof as an active ingredient, A remedy for mental illness.