WO2017115815A1 - Therapeutic agent for treatment-resistant depression and others - Google Patents

Abstract

The present invention relates to a therapeutic agent, a medicine and a treatment method for treatment-resistant depression, persistent depression and/or recurrent depression, in each of which a compound represented by formula (1') or a pharmaceutically acceptable salt thereof is used as an active ingredient. A compound represented by formula (1') or a pharmaceutically acceptable salt thereof can be useful for the treatment of treatment-resistant depression, persistent depression and/or recurrent depression.

Description

Drugs for treatment-resistant depression, etc.

The present invention relates to a therapeutic agent for treatment-resistant depression, persistent depression, or recurrent depression. Specifically, treatment-resistant depression, persistent depression and / or recurrent depression comprising a compound represented by the following formula (1 ′) or a pharmaceutically acceptable salt thereof as an active ingredient The present invention relates to therapeutic agents, medicines and therapeutic methods.

Mood disorder is a general term that includes the bipolar disorder, related disorder group, and depressive disorder group described in Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5). Depression (DSM-5) / major depressive disorder is classified into one group of depressive disorder, with a lifetime prevalence of more than 10%, one of the most common mental disorders. The main symptoms are strong depression, motivation, decreased interest or joy, psychomotor disorder (irritability or cessation of mental activity), decreased appetite, insomnia, etc., significantly reducing the patient's quality of life (Quality of Life) .

Depression (DSM-5) / major depressive disorder is divided into single episodes and repeated episodes. Single episodes include those in which symptoms are not improved in a short time by commonly used antidepressants. Repeated episodes are also referred to as recurrent or recurrent depression because they recur even after symptoms have improved once with commonly used antidepressants. Furthermore, in the persistent depressive disorder group, which is one of the depressive disorder groups, even if a commonly used antidepressant drug is used, the treatment takes a long time (for example, 2 years or more), so it is also called persistent depression. Thus, the above-mentioned depression whose symptoms are not sufficiently improved even by using general drug therapy for depression is called treatment-resistant depression.

Specifically, in the pharmacotherapy for depression, if an improvement in symptoms is not observed by administering an antidepressant drug in an appropriate amount and duration, switching to another antidepressant drug is still treated. It is said that only about half of the patients are effective. As described above, a treatment-resistant depression is defined as one in which moderate symptoms or more persist even when at least two types of antidepressants are used in a sufficient amount and for a period (Non-patent Document 1).

Also, nearly 20% of patients with depression are considered to have a chronic course of more than 2 years. Thus, persistent depression is defined when the depression phase lasts about 2 years or more. In addition, there is a report that depression has a high recurrence rate, and even if it recovers from a depression episode, nearly 80% will recur within 10 years. Thus, a single episode of depression has only one depression phase, whereas those that repeat the depression phase are defined as recurrent or recurrent depression. Persistent depression and recurrent or recurrent depression are also called intractable depression because they do not lead to remission with general antidepressant treatment, and are included in treatment-resistant depression (Non-patent Document 1) .

Treatment-resistant depression, persistent depression, and / or recurrent depression differ from major depression in that general antidepressant medication does not lead to remission. In the treatment of depression, a method of changing the type of antidepressant (switching method) and a method of adding a drug that enhances the action to the antidepressant being used (enhancement method) are used. The noradrenergic and specific serotonergic antidepressants (NaSSA) mirtazapine and mianserin are often used in switching and potentiation methods. In addition, atypical antipsychotics that are schizophrenia drugs are often used in augmentation methods.

The therapeutic effects of mirtazapine and mianserin have been reported to have shown efficacy in several randomized controlled trials, while some clinical trials have shown an improvement trend, so they are reliable and sufficient. However, further improvement is required in terms of medicinal strength. In addition, although atypical antipsychotic drugs are widely recognized to be effective in the enhancement method, various side effects such as akathisia and weight gain are problematic (Non-patent Documents 4 and 5). In other words, in the drug treatment of treatment-resistant depression, persistent depression and / or repetitive depression, reliable efficacy and avoidance of side effects are unmet needs.

In recent years, cognitive impairment in addition to depressive symptoms is considered as one of the core symptoms of depression. It is known that cognitive dysfunction in depressed patients is widely recognized not only in patients exhibiting depressive symptoms but also in patients with remission of depressive symptoms (Non-patent Document 6). Furthermore, it has been reported that cognitive dysfunction affects the treatment responsiveness to antidepressants, and the effect of antidepressants is lower in patients with more severe cognitive dysfunction (Non-patent Document 7). It has also been reported that the ability to perform daily activities of depressed patients is restored by improving cognitive function (Non-Patent Documents 8 and 9). Therefore, a drug having a cognitive function improving action is expected to be useful for all treatments for depression including treatment-resistant depression, persistent depression, or recurrent depression.

Patent Document 1 discloses an N-acyl cyclic amine derivative useful as a therapeutic agent for schizophrenia and the like.

JP 2013-75894 A

An object of the present invention is to provide a therapeutic agent and a therapeutic method for treating treatment-resistant depression, persistent depression, or repetitive depression.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that the compound represented by the following formula (1 ′) or a pharmaceutically acceptable salt thereof (hereinafter referred to as “the present compound”). Has been found useful for the treatment of treatment-resistant depression, persistent depression and / or recurrent depression, and has led to the completion of the present invention.
Specifically, mirtazapine and mianserin (NaSSA: the main pharmacological actions are serotonin 5-HT _2A receptor and adrenergic α _2A receptor, which are currently used for the treatment of treatment-resistant depression, persistent depression or recurrent depression And pharmacological profiles of atypical antipsychotic drugs (the main pharmacological action is dopamine D ₂ receptor and serotonin 5-HT _2A receptor antagonism), and the compound of the present invention is the dopamine D ₂ described above. It was confirmed that the compound of the present invention has a significant antagonism for any of the three receptors, the receptor, serotonin 5-HT _2A receptor and adrenaline α _2A receptor. It has been found that it can have a therapeutic effect on sexual depression and / or recurrent depression.

That is, the present invention includes the following aspects.
[Claim 1]
Formula (1 ′):

[Where:
Ar is heteroaryl (the heteroaryl is C _1-3 alkyl optionally substituted with 1 to 3 halogens, C _1-3 alkoxy optionally substituted with 1 to 3 halogens, halogen And optionally substituted with 1 to 3 substituents of the same or different types selected from the group consisting of cyano,
V represents nitrogen or CH;
W represents a single bond or C (O) (W represents a single bond when V is nitrogen, and a single bond or C (O) when V is CH);
Y is phenyl (the phenyl may be substituted with 1 to 3 halogens of the same or different type), heteroaryl (the heteroaryl is substituted with 1 to 3 halogens of the same or different type) Or a 4 to 7-membered saturated heterocyclic ring (which may be substituted with 1 to 3 halogens of the same or different types),
R ^1a , R ^1b and R ^1c are the same or different and are each hydrogen, halogen, hydroxy, C _1-3 alkyl (the group may be substituted with hydroxy or C _1-3 alkoxy), or C _1-3 alkoxy (the group may be substituted with hydroxy or C _1-3 alkoxy)]
A therapeutic agent for treatment-resistant depression, persistent depression and / or recurrent depression, comprising a compound represented by the formula: or a pharmaceutically acceptable salt thereof.

[Section 2]
The compound represented by the formula (1 ′) is represented by the formula (1):

[Where:
Ar is heteroaryl (the heteroaryl may be substituted with 1 to 3 substituents of the same or different types selected from the group consisting of C _1-3 alkyl, C _1-3 alkoxy and halogen) Represents
V represents nitrogen or CH;
W represents a single bond or C (O) (W represents a single bond when V is nitrogen, and a single bond or C (O) when V is CH);
Y is phenyl (the phenyl may be substituted with 1 to 3 halogens of the same or different type), heteroaryl (the heteroaryl is substituted with 1 to 3 halogens of the same or different type) Or a 4- to 7-membered saturated heterocycle (the saturated heterocycle may be substituted with 1 to 3 halogens of the same or different types)]
The therapeutic agent of claim | item 1 which is a compound represented by these.

[Section 3]
Ar is the following formula (4) or (5):

(The group may be substituted with 1 to 3 substituents of the same or different types selected from the group consisting of C _1-3 alkyl, C _1-3 alkoxy, and halogen). Yes;
Y is phenyl (the phenyl may be substituted with the same or different 1 to 3 halogens), or the following formulas (3) to (9):

Item 3. The therapeutic agent according to Item 1 or 2, wherein the group is any one of the following groups (the group may be substituted with 1 to 3 halogens of the same or different types).

[Claim 4]
Ar is a group represented by the formula (4) (the group is substituted with 1 to 3 substituents of the same or different types selected from the group consisting of C _1-3 alkyl, C _1-3 alkoxy and halogen) The therapeutic agent according to any one of Items 1 to 3, which may be

[Section 5]
The compound represented by the formula (1 ′) is represented by the formula (2 ′):

[Where:
R ¹¹ , R ¹² and R ¹³ are the same or different and each is hydrogen, C _1-3 alkyl optionally substituted with 1 to 3 halogens, or optionally substituted with 1 to 3 halogens C _1-3 represents alkoxy, halogen, or cyano,
V represents nitrogen or CH;
W represents a single bond or C (O) (provided that when V is nitrogen, W represents a single bond, and when V is CH, W represents a single bond or C (O)),
Y represents the following formulas (a-1) to (a-8):

(Wherein R ¹ represents hydrogen or fluorine)
Any one of the groups represented by
R ^1a , R ^1b and R ^1c are the same or different and are each hydrogen, halogen, hydroxy, C _1-3 alkyl (the group may be substituted with hydroxy or C _1-3 alkoxy), or C _1-3 alkoxy (the group may be substituted with hydroxy or C _1-3 alkoxy)]
The therapeutic agent of claim | item 1 which is a compound represented by these.

[Claim 6]
The compound represented by formula (1) is represented by formula (2):

[Where:
R ¹¹ , R ¹² and R ¹³ are the same or different and each represents hydrogen, fluorine, methyl or methoxy;
V represents nitrogen or CH;
W represents a single bond or C (O) (provided that when V is nitrogen, W represents a single bond, and when V is CH, W represents a single bond or C (O)),
Y represents the following formulas (a-1) to (a-5):

(Wherein R ¹ represents hydrogen or fluorine)
Represents any of the groups represented by
The therapeutic agent of claim | item 2 which is a compound represented by these.

[Claim 7]
Item 7. The therapeutic agent according to any one of Items 1 to 6, wherein Y is a group represented by the formula (a-1) or (a-5), R ¹ is fluorine, and V is CH. .

[Section 8]
Item 8. The group according to any one of Items 1 to 7, wherein Y is a group represented by the formula (a-1), R ¹ is fluorine, V is CH, and W is C (O). Therapeutic agent.

[Claim 9]
Item 9. The therapeutic agent according to any one of Items 5 to 8, wherein R ¹² is hydrogen, and R ¹¹ and R ¹³ are the same or different and each is hydrogen, fluorine, or methyl.

[Section 10]
Item 10. The therapeutic agent according to any one of Items 5 to 9, wherein R ¹¹ is fluorine.

[Section 11]
The compound represented by the formula (1 ′) is
[(2S) -2- {2- [4- (4-Fluorobenzoyl) piperidin-1-yl] ethyl} pyrrolidin-1-yl] (6-methyl-1H-indol-2-yl) methanone (Examples) 1),
[(2S) -2- {2- [4- (4-Fluorobenzoyl) piperidin-1-yl] ethyl} pyrrolidin-1-yl] (6-fluoro-1H-indol-2-yl) methanone (Examples) 2),
(3,6-difluoro-1H-indol-2-yl) [(2S) -2- {2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethyl} pyrrolidin-1-yl] methanone ( Example 3),
[(2S) -2- {2- [4- (4-Fluorobenzoyl) piperidin-1-yl] ethyl} pyrrolidin-1-yl] (3-fluoro-1H-indol-2-yl) methanone (Examples) 4),
[(2S) -2- {2- [4- (1H-Indol-3-yl) piperidin-1-yl] ethyl} pyrrolidin-1-yl] (6-methoxy-1H-indol-2-yl) methanone (Example 5),
[(2S) -2- {2- [4- (1H-indazol-3-yl) piperazin-1-yl] ethyl} pyrrolidin-1-yl] (6-methyl-1H-indol-2-yl) methanone (Example 6),
[(2S) -2- {2- [4- (5-Fluoro-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] ethyl} pyrrolidin-1-yl] (6-methyl -1H-indol-2-yl) methanone (Example 7),
[(2S) -2- {2- [4- (6-Fluoro-1,2-benzoxazol-3-yl) piperidin-1-yl] ethyl} pyrrolidin-1-yl] (6-methyl-1H- Indol-2-yl) methanone (Example 8) or [(2S) -2- {2- [4- (6-Fluoro-1,2-benzoxazol-3-yl) piperidin-1-yl] ethyl } Pyrrolidin-1-yl] (3-fluoro-1H-indol-2-yl) methanone (Example 9)
The therapeutic agent of claim | item 1 which is these.
Or
[Section 11 ']
The compound represented by the formula (1 ′) is
[2- {2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethyl} pyrrolidin-1-yl] (6-methyl-1H-indol-2-yl) methanone,
[2- {2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethyl} pyrrolidin-1-yl] (6-fluoro-1H-indol-2-yl) methanone,
(3,6-difluoro-1H-indol-2-yl) [2- {2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethyl} pyrrolidin-1-yl] methanone,
[2- {2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethyl} pyrrolidin-1-yl] (3-fluoro-1H-indol-2-yl) methanone,
[2- {2- [4- (1H-indol-3-yl) piperidin-1-yl] ethyl} pyrrolidin-1-yl] (6-methoxy-1H-indol-2-yl) methanone,
[2- {2- [4- (1H-indazol-3-yl) piperazin-1-yl] ethyl} pyrrolidin-1-yl] (6-methyl-1H-indol-2-yl) methanone,
[2- {2- [4- (5-Fluoro-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] ethyl} pyrrolidin-1-yl] (6-methyl-1H-indole -2-yl) methanone,
[2- {2- [4- (6-Fluoro-1,2-benzoxazol-3-yl) piperidin-1-yl] ethyl} pyrrolidin-1-yl] (6-methyl-1H-indole-2- Yl) methanone, or [2- {2- [4- (6-fluoro-1,2-benzoxazol-3-yl) piperidin-1-yl] ethyl} pyrrolidin-1-yl] (3-fluoro-1H The therapeutic agent according to Item 1, which is -indol-2-yl) methanone.

[Claim 12]
Cognitive function in treatment-resistant depression, persistent depression and / or recurrent depression, comprising the compound according to any one of Items 1 to 11 or 11 ′ or a pharmaceutically acceptable salt thereof Disability treatment.

[Claim 13]
A treatment comprising administering to a patient in need of treatment a therapeutically effective amount of the compound according to any one of items 1 to 11 or 11 ', or a pharmaceutically acceptable salt thereof. A method for treating resistant depression, persistent depression and / or recurrent depression.

[Section 14]
Item 11. The compound according to any one of Items 1 to 11 or 11 ′, or a pharmaceutically acceptable salt thereof, for producing a therapeutic agent for treatment-resistant depression, persistent depression and / or repetitive depression Salt used.

[Section 15]
Item 11. The compound according to any one of Items 1 to 11 or 11 ′, or a pharmaceutically acceptable salt thereof, for use in the treatment of treatment-resistant depression, persistent depression and / or recurrent depression. Salt.

[Section 16]
The compound according to any one of Items 1 to 11 or 11 ′, or a dopamine D ₂ receptor, a serotonin 5-HT _2A receptor and an adrenergic α _2A receptor containing a pharmaceutically acceptable salt thereof. Antagonist.

[Section 17]
Item 12. The compound according to any one of Items 1 to 11 or 11 ′, or a pharmaceutical preparation thereof, for producing an antagonist of dopamine D ₂ receptor, serotonin 5-HT _2A receptor and adrenergic α _2A receptor Use of chemically acceptable salts.

[Section 18]
Item 11. The compound according to any one of Items 1 to 11 or 11 ′ or a pharmaceutical preparation thereof for use as an antagonist of dopamine D ₂ receptor, serotonin 5-HT _2A receptor and adrenergic α _2A receptor Acceptable salt.

[Section 19]
A compound according to any one of Items 1 to 11 or 11 ′, or a pharmaceutically acceptable salt thereof, and a dopamine D ₂ receptor, a serotonin 5-HT _2A receptor and an adrenergic α _2A receptor A therapeutic agent for treatment-resistant depression, persistent depression, or repetitive depression having an antagonistic action.

[Section 20]
A therapeutic agent for treatment-resistant depression, persistent depression, or recurrent depression comprising a compound having an antagonistic action of dopamine D ₂ receptor, serotonin 5-HT _2A receptor and adrenergic α _2A receptor as an active ingredient.

The compound of the present invention has a significant antagonistic action on any of the dopamine D ₂ receptor, serotonin 5-HT _2A receptor and adrenaline α _2A receptor, and has a significant cognitive function improving action. Thus, it may be effective in treating treatment-resistant depression, persistent depression and / or recurrent depression. In addition, the compound of the present invention has a low binding affinity to receptors (for example, adrenaline α _1D , histamine H ₁ , muscarin M _1, etc.) that are considered to be involved in the development of side effects of conventional drugs for treating schizophrenia. Thus, according to the present invention, high therapeutic effects similar to those of the enhancement method described above can be expected, and oversedation, weight gain, hyperglycemia, sleepiness, and cognitive function expressed by existing antidepressants and antipsychotics Side effects such as disability and dry mouth can be significantly reduced.

The present invention is described in further detail below.
In the present specification, the number of substituents in the group defined as “optionally substituted” is not particularly limited as long as substitution is possible, and is one or more. In addition, unless otherwise specified, the description of each group also applies when the group is a part of another group or a substituent.

In the present specification, examples of the “halogen” include fluorine, chlorine, bromine, and iodine. Preferably, fluorine is used.

“C _1-3 alkyl” includes, for example, linear or branched alkyl having 1 to 3 carbon atoms. Preferably, methyl is used.

“C _1-3 alkoxy” includes, for example, linear or branched alkoxy having 1 to 3 carbon atoms. Preferably, methoxy is mentioned.

The “heteroaryl” includes, for example, a 5- to 10-membered monocyclic or polycyclic heteroaryl, and the heteroaryl is one or more heteroatoms selected from nitrogen, sulfur or oxygen, the same or different. (For example, 1-2). Specific examples of “heteroaryl” include, for example, groups represented by the following formulae.

The bond across the ring in the above formula means that the group is bonded at a substitutable position in the group. For example, the following formula

In addition to 2-benzofuryl or 3-benzofuryl, 4-, 5-, 6- or 7-benzofuryl may be used.

Examples of the “heteroaryl” in Y include groups represented by the formula (3), (4), (5), (6), (8) or (9). Preferably, the group represented by Formula (4), (5) or (6) is mentioned, More preferably, the group represented by Formula (6) is mentioned. Here, the groups represented by the formulas (3), (4), (5), (6), (8) and (9) may be substituted with 1 to 3 halogens of the same or different types. Good.

As another embodiment of “heteroaryl” in Y, for example, the following formulas (a-2), (a-3), (a-5), (a-6), (a-7) or (a- And a group represented by 8).

(Wherein R ¹ represents hydrogen or fluorine)
Preferred is a group of the formula (a-2), (a-3) or (a-5), and more preferred is a group of the formula (a-5).

Examples of the “heteroaryl” in Ar include a group represented by the formula (4) or (5). Preferably, the group represented by Formula (4) is mentioned. Here, the groups represented by the formulas (4) and (5) may be substituted with 1 to 3 halogens optionally substituted with C _1-3 alkyl and 1 to 3 halogens. It may be substituted with the same or different 1 to 3 substituents selected from the group consisting of C _1-3 alkoxy, halogen, and cyano.

Another embodiment of “heteroaryl” in Ar includes, for example, a group represented by the following formula (a-9).

(Wherein R ¹¹ , R ¹² and R ¹³ are the same or different and each is hydrogen, C _1-3 alkyl which may be substituted with 1 to 3 halogens, or 1 to 3 halogens. Optionally represents C _1-3 alkoxy, halogen, or cyano)
Here, Preferably, R <^11> , R < ¹² > and R < ¹³ > are the same or different, and are hydrogen, fluorine, methyl, or methoxy. More preferably, R ¹² is hydrogen, and R ¹¹ and R ¹³ are the same or different and are hydrogen, fluorine, or methyl. More preferably, R ¹¹ is fluorine, R ¹² is hydrogen, and R ¹³ is hydrogen, fluorine, or methyl.

Examples of the “saturated heterocycle” include a 4- to 7-membered saturated heterocycle containing 1 to 2 nitrogen atoms. In the ring, the nitrogen constituting the ring is a bond of the “ring”. Specific examples include pyrrolidine.

The “saturated heterocycle” includes those in which a saturated heterocycle and a benzene ring form a condensed ring. Specific examples include groups represented below.

(Wherein R ¹ represents hydrogen or fluorine)

The compound represented by the formula (1 ′) can be produced according to the production method and Examples described in Patent Document 1.

The pharmaceutically acceptable salt of the compound represented by the formula (1 ′) is a pharmaceutically acceptable salt in the case of the compound of the formula (1 ′) having a group capable of forming an acid addition salt in the structure. It means an acceptable acid addition salt. Specific examples of acid addition salts include hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate, phosphate and other inorganic acid salts, oxalate, malonate, maleate Acid, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate Organic acid salts such as, and amino acid salts such as glutamate and aspartate.

Preferred are hydrochloride, hydrobromide, sulfate, acetate, fumarate, maleate, oxalate, methanesulfonate, benzenesulfonate, or p-toluenesulfonate. .

Since the compound represented by the formula (1 ′) or a pharmaceutically acceptable salt thereof may exist in the form of a hydrate and / or solvate, these hydrate and / or solvent A solvate is also included in the compound represented by the formula (1 ′) of the present invention or a pharmaceutically acceptable salt thereof.

The compound represented by the formula (1 ′) or a pharmaceutically acceptable salt thereof has a stereoisomer, a tautomer and / or an optical isomer. The compound represented by the formula (1 ′) or a pharmaceutically acceptable salt thereof includes a mixture of these isomers and an isolated isomer. In addition, a deuterium converter obtained by converting any one or two or more ¹ H of the compound represented by the formula (1 ′) into ² H (D) is also converted into the compound represented by the formula (1 ′). Is included.

In the present specification, the formula (1 ′):

The compound represented by includes both of the following isomers:

In the present specification, the formula (2 ′):

The compound represented by includes both of the following isomers:

As used herein, “therapeutically effective amount” means an amount of a drug or pharmaceutical agent that elicits a biological or pharmaceutical response required by a researcher or physician in a tissue, system, animal or human.
As used herein, “treatment” includes any treatment of a disease (eg, improvement of symptoms, reduction of symptoms, suppression of progression of symptoms, etc.).

The compound represented by the formula (1 ') or a pharmaceutically acceptable salt thereof can be administered orally or parenterally when they are used as a medicament. That is, it can be administered orally in dosage forms such as commonly used dosage forms such as powders, granules, tablets, capsules, syrups, suspensions, etc., or for example, solutions, emulsions, suspensions thereof. The dosage form can be administered parenterally in the form of an injection. It can also be administered transdermally as a tape or rectally in the form of a suppository. It can also be injected intravesically in the form of a solution. The above-mentioned appropriate dosage form is, for example, a compound represented by the formula (1 ′) or a pharmaceutically acceptable compound thereof in an acceptable ordinary carrier, excipient, binder, stabilizer, diluent. It can manufacture by mix | blending a salt. When used as an injection, for example, an acceptable buffer, solubilizer, and isotonic agent can be added. The dose and frequency of administration vary depending on, for example, the target disease, symptoms, age, body weight, and administration form, but are usually 0.1 to 2000 mg, preferably 1 to 200 mg per day for an adult once or several times (for example, 2-4 times).

As used herein, “treatment-resistant depression” refers to depression that is not ameliorated by commonly used antidepressants. Specifically, even if a sufficient amount and duration of at least two types of antidepressants are used, they are moderate. Depression that persists with the above symptoms.

As used herein, “persistent depression” refers to “sustained depression (mood modulation) disorders described in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5). ”; And“ Persistent Mood (Emotion) Disorder ”(Category No. F34) described in the International Disease Classification 10th Edition (ICD-10).
Specifically, it is a depression that takes a long time to be treated, and it does not lead to remission by general antidepressant treatment, and the depression phase lasts about 2 years or more.

As used herein, “repetitive depression” refers to “repetitive episodes” of “major depressive disorders” described in DSM-5; and “recurrent depressive disorders” described in ICD-10 (classification). Number: F33), also called recurrent depression.
Specifically, it means that after a recovery from a depression episode by general antidepressant therapy, the depression phase recurs repeatedly. More specifically, for example, seasonal depression is applicable.

The compound represented by the formula (1 ′) or a pharmaceutically acceptable salt thereof has a high binding affinity (antagonism) for dopamine D ₂ receptor, serotonin 5-HT _2A receptor and adrenergic α _2A receptor. Action).
Dopamine D ₂ receptor and serotonin 5-HT _2A receptor antagonism is the main pharmacology of atypical antipsychotics used in augmentation in the treatment of treatment-resistant depression, persistent depression and / or recurrent depression It is an action. In addition, serotonin 5-HT _2A receptor and adrenergic α _2A receptor antagonism is also the effect of NaSSA used in switching and augmentation methods in the treatment of treatment-resistant depression, persistent depression and / or recurrent depression. The main pharmacological action.
Therefore, a compound represented by the formula (1 ′) having a pharmacological profile of an atypical antipsychotic drug and NaSSA, or a pharmaceutically acceptable salt thereof, is resistant to treatment-resistant depression, persistent depression and / or Useful for the treatment of recurrent depression.

Adrenergic α ₁ receptor antagonism is thought to be involved in the development of side effects of conventional schizophrenia drugs such as hypersedation and orthostatic hypotension. By deviating from this effect, α ₁ receptor antagonism It is expected to reduce side effects.

Histamine H ₁ receptor antagonism is thought to be involved in the development of side effects of conventional therapeutic agents for schizophrenia such as weight gain, hyperglycemia, sleepiness, and cognitive dysfunction. Mirtazapine, which is NaSSA, and olanzapine, risperidone, which are atypical antipsychotics typically used in the above-mentioned enhancement method, have affinity for the H ₁ receptor (by GP Reynolds, Pharmacology & Therapeutics, 2010, 125, p.169-179; see T. Enomoto, SYNAPSE, 2012, 66, p.483-488, etc., and weight gain has been reported as a side effect (JP Domecq, J Clin Endocrinol Metab) , February, 2015 100 (2), p.363-370 etc.). Therefore, by deviating from this action, reduction of side effects via H ₁ receptor antagonism such as weight gain can be expected.

Muscarinic M ₁ receptors, dry mouth, constipation, believed to be involved with cognitive impairment, such as a conventional antipsychotic drug side effects, and by the divergence of this action, via the M ₁ receptor antagonism Reduction of side effects can be expected.

Adrenaline α _2A receptor antagonism is one of the main pharmacological actions of the antidepressants mirtazapine and mianserin and is considered to play an important role in the improvement of depressive symptoms. In addition, selective adrenergic α _2A receptor antagonists have been reported to increase the release of neurotransmitters dopamine, norepinephrine and acetylcholine in rat frontal cortex (Int J Neuropsychopharmacol. 2010, 13, 1193-1205). ). In addition, donepezil, galantamine, and rivastigmine, which are treatments for Alzheimer's dementia, can increase the amount of acetylcholine in the brain by inhibiting acetylcholinesterase, thereby improving cognitive function or suppressing cognitive deterioration in patients with dementia. Known (pharmacological properties of donepezil hydrochloride (Alicept (registered trademark)), a therapeutic drug for Alzheimer's disease, Journal of Japanese Pharmacology 2000, 115, 45-51). Therefore, the compounds of the present invention also increase brain acetylcholine release based on adrenergic α _2A receptor antagonism and improve cognitive dysfunction in diseases such as treatment-resistant depression, persistent depression or recurrent depression It is expected.

As one of the cognitive function evaluation systems in rodents, a passive avoidance reaction test is widely used. In the animal model of the test, anticholinergic drugs (for example, scopolamine) and NMDA receptor antagonists (MK-801, phencyclidine) are generally used as substances causing cognitive impairment. It is a useful tool for screening cognitive function improving drugs.
There is no animal model that mimics cognitive dysfunction of depression, including treatment-resistant depression, persistent depression, and / or repetitive depression. It is considered possible to find a drug for cognitive dysfunction in Japan.
Since the compound of the present invention showed a remarkable cognitive function improving action in the following Test Examples 12 and 13, it was applied to all treatments for depression including treatment-resistant depression, persistent depression and / or repetitive depression. It is expected to be useful.

Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited thereto. DMSO means dimethyl sulfoxide, and EDTA means ethylenediaminetetraacetic acid.

Production Examples The compounds of Examples 1 to 20 shown in the following table were produced according to the method described in Patent Document 1 (Japanese Patent Laid-Open No. 2013-75894).

The mass of the produced Example compound was measured with a high performance liquid chromatograph mass spectrometer (LC-MS). The measurement conditions of LC-MS are as follows, and the observed mass spectrometry value [MS (m / z)] is represented by MH ⁺ and the retention time is represented by Rt (min).
Detection equipment: ACQUITY (registered trademark) SQ deceter (Waters)
HPLC: ACQUITY UPLC (registered trademark) system
Column: Waters ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm, 2.1 mm × 30 mm)
Moving bed: Liquid A; 0.06% formic acid / H2O
Liquid B: 0.06% formic acid / acetonitrile gradient condition: 0.0-1.3 minutes (linear gradient from B 2% to 96%)
Flow rate: 0.8 mL / min Detection UV: 220 nm and 254 nm
Temperature: 40 ° C

Test example <Test method>
(1) Dopamine D _2L receptor binding test The D _2L receptor binding test was performed as follows, and the human D _2L receptor binding activity of [ ³ H] -spiperone was measured.
50 μL of [ ³ H] -spiperone (final concentration 0.5 nmol / L), 2 μL of test drug DMSO solution or solvent (DMSO) and 148 μL of human D _2L receptor-expressing CHO cell membrane preparation were prepared at 50 mmol / L Tris-HCl. (PH = 7.6) After reacting in a buffer solution, the mixture was allowed to stand at room temperature for 60 minutes, and then quickly put on a glass fiber filter plate (Multiscreen FB, manufactured by Millipore) coated with 0.3% polyhyleneimine (PEI). And filtered under reduced pressure. The filtrate on the glass fiber filter was washed twice with 200 μL of ice-cold 50 mmol / L Tris-HCl (pH = 7.6) and repeatedly filtered under reduced pressure. Then, the glass fiber filter was filtered with 2 mL of Ecocinchi A (National Diagnostics). The product was transferred to a vial containing The radioactivity of the filtrate remaining on the glass fiber filter was measured with a liquid scintillation counter. The radioactivity value measured with a liquid scintillation counter is defined as receptor binding activity. Total binding (TB), non-specific binding (NSB), and specific binding of a test drug (SB) The binding inhibition rate was calculated from
Total binding (TB) = Radioactivity in solvent addition group Non-specific binding (NSB) = Radioactivity in piperone solution addition group Specific binding (SB) = Radioactivity in test compound solution addition group-NSB
Binding inhibition rate (%) = SB / (TB−NSB) × 100
In the formula, non-specific binding was measured in the presence of 10 μmol / L piperone solution, and the [ ³ H] -spiperone binding inhibition rate (%) at 10 nmol / L of the test drug was determined. The larger the value of the binding inhibition rate (%), the higher the binding affinity of the test drug for the human D _2L receptor.

(2) Serotonin 5-HT _2A receptor binding test The 5-HT _2A receptor binding test was performed as follows, and the human 5-HT _2A receptor binding activity of [ ³ H] -ketserin was measured.
50 μL of [ ³ H] -ketanserin (final concentration 1 nmol / L), 2 μL of test drug DMSO solution or solvent (DMSO) and 148 μL of human 5-HT _2A receptor-expressing CHO cell membrane preparation were prepared at 50 mmol / L Tris-HCl. (PH = 7.6) After reacting in a buffer solution, the mixture was allowed to stand at 37 ° C. for 15 minutes, and then immediately on a glass fiber filter plate (Multiscreen FB, manufactured by Millipore) coated with 0.05% Brij 35. Added and filtered under reduced pressure. The filtrate on the glass fiber filter was washed twice with 200 μL of ice-cold 50 mmol / L Tris-HCl (pH = 7.6) and repeatedly filtered under reduced pressure. Then, the glass fiber filter was filtered with 2 mL of Ecocinchi A (National Diagnostics). The product was transferred to a vial containing The radioactivity of the filtrate remaining on the glass fiber filter was measured with a liquid scintillation counter. The radioactivity value measured with a liquid scintillation counter is defined as receptor binding activity. Total binding (TB), non-specific binding (NSB), and specific binding of a test drug (SB) The binding inhibition rate was calculated from
Total binding (TB) = Radioactivity in solvent addition group Nonspecific binding (NSB) = Radioactivity in MDL-100907 solution addition group Specific binding (SB) = Radioactivity in test compound solution addition group-NSB
Binding inhibition rate (%) = SB / (TB−NSB) × 100
In the formula, non-specific binding was measured in the presence of 10 μmol / L of MDL-100907, and the inhibition rate (%) of [ ³ H] -ketserin binding at 1 nmol / L or 10 nmol / L of the test drug was determined. The larger the value of the binding inhibition rate (%), the higher the binding affinity of the test drug for the human 5-HT _2A receptor.

(3) Adrenaline α _2A receptor binding test [ ³ H] -Rauwolcine was measured for human α _2A receptor binding activity as follows.
50 μL of [ ³ H] -Rauwolcine (final concentration 2 nmol / L), 2 μL of test drug DMSO solution or solvent (DMSO) and 148 μL of human α _2A receptor-expressing CHO cell membrane preparation were added to 50 mmol / L Tris-HCl (pH = 7.6) After reacting in buffer solution, allowed to stand at room temperature for 60 minutes, and then quickly added onto glass fiber filter plate (Multiscreen FB, manufactured by Millipore) coated with 0.3% polyphenyleneimine (PEI) And filtered under reduced pressure. The filtrate on the glass fiber filter was washed twice with 200 μL of ice-cold buffer [50 mmol / L Tris-HCl (pH = 7.6), 1 mmol / L EDTA] and repeatedly filtered under reduced pressure. It was transferred to a vial containing 2 mL of Ecocinti A (National Diagnostics). The radioactivity of the filtrate remaining on the glass fiber filter was measured with a liquid scintillation counter. The radioactivity value measured with a liquid scintillation counter is defined as receptor binding activity. Total binding (TB), non-specific binding (NSB), and specific binding of a test drug (SB) The binding inhibition rate was calculated from
Total binding (TB) = Radioactivity in solvent addition group Non-specific binding (NSB) = Radioactivity in BRL44408 solution addition group Specific binding (SB) = Radioactivity in test compound solution addition group-NSB
Binding inhibition rate (%) = SB / (TB−NSB) × 100
In the formula, non-specific binding was measured in the presence of 10 μmol / L BRL44408, and the [ ³ H] -Rauwolcine binding inhibition rate at 10 nmol / L of the test drug was determined. It means that the larger the value of the binding inhibition rate (%), the higher the binding affinity of the test drug for the human α _2A receptor.
The results of the binding tests (1) to (3) are shown in the following table. The compounds of Examples 1 to 9 exhibited a high binding inhibitory action on all of the dopamine D ₂ receptor, serotonin 5-HT _2A receptor, and adrenergic α _2A receptor.

(4) Adrenaline α _1D receptor binding test [ ³ H] -prazosin was measured for human α _1D receptor binding activity as follows.
50 μL of [ ³ H] -prazosin (final concentration 0.6 nmol / L), 1 μL of test drug DMSO solution or solvent (DMSO) and 149 μL of human α _1D receptor-expressing CHO cell membrane preparation were prepared at 50 mmol / L Tris- After reacting in HCl (pH = 7.6) buffer, the mixture was allowed to stand at room temperature for 30 minutes, and then coated on a glass fiber filter plate (Multiscreen FB, manufactured by Millipore) coated with 0.3% polyphenyleneimine (PEI). Immediately added and filtered under reduced pressure. The filtrate on the glass fiber filter was washed twice with 200 μL of ice-cold 50 mmol / L Tris-HCl (pH = 7.6), and after repeated filtration under reduced pressure, the glass fiber filter was subjected to 4 mL of Ecocinchi A (National Diagnostics). ). The radioactivity of the filtrate remaining on the glass fiber filter was measured with a liquid scintillation counter. The radioactivity value measured with a liquid scintillation counter is defined as receptor binding activity. Total binding (TB), non-specific binding (NSB), and specific binding of a test drug (SB) The binding inhibition rate was calculated from
Total binding (TB) = Radioactivity in solvent addition group Non-specific binding (NSB) = Radioactivity in prazosin solution addition group Specific binding (SB) = Radioactivity in test compound solution addition group−NSB
Binding inhibition rate (%) = SB / (TB−NSB) × 100
In the formula, nonspecific binding was measured in the presence of 1 μmol / L prazosin, and the [ ³ H] -prazosin binding inhibition rate at 100 nmol / L of the test drug was determined. It means that the larger the value of the binding inhibition rate (%), the higher the binding affinity of the test drug for the human α _1D receptor.

(5) Histamine H ₁ receptor binding test The human H ₁ receptor binding activity of [ ³ H] -pyrilamine was measured as follows.
50 μL of [ ³ H] -pyramine (final concentration 1 nmol / L), 2 μL of test drug DMSO solution or solvent (DMSO) and 148 μL of human H ₁ receptor-expressing CHO cell membrane preparation were added to buffer [50 mmol / L Tris- After reaction in HCl (pH = 7.6), 2 mmol / L MgCl ₂ , 100 mM NaCl], the glass fiber filter plate (Multiscreen FB, coated with 0.3% polyphenylenemine (PEI) after standing at room temperature for 30 minutes and then standing still for 30 minutes. The product was immediately added onto Millipore and filtered under reduced pressure. The filtrate on the glass fiber filter was washed twice with 200 μL of ice-cold buffer [50 mmol / L Tris-HCl (pH = 7.6), 2 mmol / L MgCl ₂ , 675 mmol / L NaCl], and repeated under reduced pressure. After that, the glass fiber filter was transferred to a vial containing 2 mL of Ecocinchi A (National Diagnostics). The radioactivity of the filtrate remaining on the glass fiber filter was measured with a liquid scintillation counter. The radioactivity value measured with a liquid scintillation counter is defined as receptor binding activity. Total binding (TB), non-specific binding (NSB), and specific binding of a test drug (SB) The binding inhibition rate was calculated from
Total binding (TB) = Radioactivity in solvent addition group Non-specific binding (NSB) = Radioactivity in triprolidine solution addition group Specific binding (SB) = Radioactivity in test compound solution addition group-NSB
Binding inhibition rate (%) = SB / (TB−NSB) × 100
In the formula, non-specific binding was measured in the presence of 10 μmol / L triprolidene, and the [ ³ H] -Pyrilamine binding inhibition rate at 100 nmol / L or 1000 nmol / L of the test drug was determined. The larger the value of the binding inhibition rate (%), the higher the binding affinity of the test drug to the human H ₁ receptor.

(6) Muscarinic M ₁ receptor binding test [ ³ H] -QNB was assayed for human H ₁ receptor binding activity as follows.
50 μL of [ ³ H] -quinidine benzilate (QNB) (final concentration 0.5 nmol / L), 2 μL of test drug DMSO solution or solvent (DMSO) and 148 μL of human M ₁ receptor-expressing CHO cell membrane preparation After reacting in a buffer solution, the mixture was allowed to stand at room temperature for 60 minutes, and then quickly added onto a glass fiber filter plate (Multiscreen FB, manufactured by Millipore) coated with 0.5% polyphenyleneimine (PEI) and filtered under reduced pressure. The filtrate on the glass fiber filter was washed twice with 200 μL of ice-cold buffer [50 mmol / L Tris-HCl (pH = 7.6), 150 mmol / L NaCl] and filtered under reduced pressure. It was transferred to a vial containing 2 mL of Ecocinti A (National Diagnostics). The radioactivity of the filtrate remaining on the glass fiber filter was measured with a liquid scintillation counter. The radioactivity value measured with a liquid scintillation counter is defined as receptor binding activity. Total binding (TB), non-specific binding (NSB), and specific binding of a test drug (SB) The binding inhibition rate was calculated from
Total binding (TB) = Radioactivity in the solvent addition group Non-specific binding (NSB) = Radioactivity in the oxotremorine solution addition group Specific binding (SB) = Radioactivity in the test compound solution addition group−NSB
Binding inhibition rate (%) = SB / (TB−NSB) × 100
In the formula, total binding is measured, non-specific binding is measured in the presence of 100 μmol / L oxtremoline, specific binding is measured, and the [ ³ H] -QNB binding inhibition rate at 1000 nmol / L of the test drug is determined. It was. Binding affinity value is too large test drug human M ₁ receptor binding inhibition rate (%) means a high.
The results of the binding tests (4) to (6) are shown in the following table.

(7) Efficacy evaluation based on Montgomery-Asberg Depression Rating Scale (MADRS) or Hamilton Depression Rating Scale (HAM-D) The compound represented by formula (1 ′) or a pharmaceutically It can be seen that acceptable salts are useful for the treatment of treatment-resistant depression, persistent depression or recurrent depression.

”The treatment will be conducted on adult patients who have been diagnosed with major depression and who are inadequately responsive to adequate amounts of commonly used antidepressants. Montgomery-Asberg Depression Rating Scale (MADRS) total score of 20 or more patients is selected as a selection criterion. Even if the selection criteria are met, various substance dependences (nicotine, drugs, etc.) have been diagnosed. Patients with bipolar disorder, schizophrenia, schizophrenic emotional disorder or a history of depression episodes with psychotic symptoms, patients with delirium or dementia are excluded. Subjects are randomly assigned to placebo and test compound groups and administered continuously for 4-12 weeks. Evaluation of depressive symptoms on MADRS or Hamilton Depression Rating Scale (HAM-D) before and after the start of administration, the score is lower than before administration, and statistics at the test compound group rather than the placebo administration group at the final evaluation When the score improves significantly, it is judged that the treatment-resistant depression was effective.

(8) Dopamine D ₂ receptor in vivo binding test Male Sprague-Dawley rats (232-250 g; n = 4-6 / group) were administered with vehicle (0.5% methylcellulose) or 1 mL / kg of the test drug. Orally. Sixty minutes after oral administration, ³ H-racropride (60 μCi / ml) was administered at 1 mL / kg via the tail vein, and brain and blood were collected 30 minutes after the administration of ³ H-racropride. The removed brain was immediately frozen and stored at −80 ° C. until the tissue was fractionated. Blood was fractionated by centrifugation and the resulting plasma samples were stored at −80 ° C. until analysis was performed.
A 20 μm coronal brain slice was prepared from a rat brain using Leica CM1900 cryostat, and a striatum slice was used as a region of interest and a cerebellar slice was used as a reference region. A slide glass sample was prepared from these sections and imaged with a Biospace β-imager (Biospace Inc) to obtain image data of the sample. Image data was quantified with β-vision plus software (Biospace Inc), and the radioactivity per 1 mm ² was calculated.
The signal / noise (S: N) ratio was calculated by the ratio between the striatum and the cerebellum, and the receptor occupancy (% RO) was calculated by the following formula.
% RO = 100 × [(average S: NVehicle) −S: NTreaction] / [(average S: NVehicle) −1]
Vehicle: 0.5% methylcellulose
Treatment: Each test drug The brain concentration and plasma concentration of the test drug were analyzed by LC / MS, the brain concentration was calculated as ng / g, and the plasma concentration was calculated as ng / mL and converted to nmol / L. The RO50 value (50% occupancy) of the dose, brain concentration and blood concentration was calculated using the dose-response curve of Graphpad Prism (version 5.04).

(9) Serotonin 5-HT _2A receptor in vivo binding experiment Male Sprague-Dawley rats (232-255 g; n = 4-6 / group) were administered vehicle (0.5% methylcellulose) or the test drug at 1 mL / kg. Orally administered in liquid volume. 60 minutes after oral administration, ³ H-MDL100907 (100 μCi / ml) was administered at 1 mL / kg via the tail vein, and brain and blood were collected 30 minutes after administration of ³ H-MDL100907. The removed brain was immediately frozen and stored at −80 ° C. until the tissue was fractionated. Blood was fractionated by centrifugation and the resulting plasma samples were stored at −80 ° C. until analysis was performed.
A 20 μm coronal brain section was prepared from a rat brain using Leica CM1900 cryostat, and a striatum and cerebral cortex section were used as a region of interest, and a cerebellar section was used as a reference region. A slide glass sample was prepared from these sections and imaged with a Biospace β-imager (Biospace Inc) to obtain image data of the sample. Image data was quantified with Biospace's β-vision plus software, and the radioactivity per 1 mm ² was calculated. The signal / noise (S: N) ratio was calculated by the ratio of striatum and cerebral cortex to cerebellum, and receptor occupancy (% RO) was calculated from the following equation.
% RO = 100 × [(average S: NVehicle) −S: NTreaction] / [(average S: NVehicle) −1]
Vehicle: 0.5% methylcellulose
Treatment: Each test drug The brain concentration and plasma concentration of the test drug were analyzed by LC / MS, the brain concentration was calculated as ng / g, and the plasma concentration was calculated as ng / mL and converted to nmol / L. The RO50 value (50% occupancy) of the dose, brain concentration and blood concentration was calculated using the dose-response curve of Graphpad Prism (version 5.04).

(10) Adrenaline α _2A receptor ex vivo binding experiment Male Sprague-Dawley rats (200-250 g; n = 4-6 / group) were administered with vehicle (0.5% methylcellulose) or test drug at 2 mL / kg. The brain and blood were collected 90 minutes after oral administration. The removed brain was immediately frozen and stored at −80 ° C. until the tissue was fractionated. The blood was fractionated by centrifugation and the resulting plasma sample was stored at -80 ° C.
A 20 μm coronal brain section was prepared from the rat brain using Leica CM3050S cryostat, and a slide glass sample was prepared from the region including the septum and cerebral cortex (bregma 1.18 / 0.26).
The slide glass preparation was bound at 4 ° C. for 30 minutes in a binding buffer solution (50 mM Tris-HCl, pH 7.5, 1 mM MgCl ₂ , 1 g / L ascorbic acid, 20 nM ARC339, 20 nM WAY100635) containing 1 nM [ ³ H] RX821002. Reacted. After the reaction, the reaction was washed twice with ice-cold binding buffer, then washed with ice-cold deionized water and allowed to air dry. After drying, the sample was imaged with β-imager 2000 (Biospace) to obtain image data.
The image data was quantified with β-vision plus software from Biospace, and the radioactivity per 1 mm ² was calculated.
Receptor occupancy (% RO) was calculated from the following formula.
% RO = 100x [Average vehicle-Average treatment] / Average vehicle
Vehicle: 0.5% methylcellulose
Treatment: Each test drug The brain concentration and plasma concentration of the test drug were analyzed by LC / MS, the brain concentration was calculated as ng / g, and the plasma concentration was calculated as ng / mL and converted to nmol / L. The RO50 value (50% occupancy) of the dose, brain concentration and blood concentration was calculated using the graph-pad Prism (version 5.0) dose response curve.

(11) Measurement of acetylcholine and glutamate release in the brain using rat microdialysis method Sprague-Dawley male rats of 8-10 weeks old were used. Microinjection cannula (Eicom) in rat hippocampus (AP-5.2 mm, L + 5.0 mm, V-3.9 mm) and cerebral cortex (AP + 3.2 mm, L-0.5 mm, V-1.4 mm) under isoflurane anesthesia Corp.). After 5 days, a microdialysis probe (0.22 mm od, 3 mm membrane length with 50,000 Da cut-off, Eicom CX-I, Eicom Corp.) was inserted from the cannula, and artificial cerebrospinal fluid was added 1 Perfusion was performed at a flow rate of 5 μl / min. From 2 hours after the start of perfusion, the perfusate was collected every 30 minutes, and acetylcholine in the perfusate was collected by high performance liquid chromatography-electrochemical detector (HTEC-500 (Eicom Corp.), CMA / 200 Refrigerated Microsampler (CMA Microdialysis). ), Glutamic acid was measured by a high performance liquid chromatography-fluorescence detector (L-7480 (Merck / Hitachi), CMA / 200 Refrigerated Microsampler (CMA Microdialysis)). Vehicle (0.5% sodium carboxymethylose) or test drug was orally administered at a dose of 5 mL / kg, and the perfusate was collected up to 240 minutes after administration. The release amount after administration was calculated with the release amount of acetylcholine or glutamic acid immediately before administration of vehicle or test drug (0 minutes) as 100%.

(12) Evaluation of Test Drug for Scopolamine-Induced Memory Learning Disorder in Rat Passive Avoidance Response Test 7-week-old Wistar male rats were used (n = 6-8 / group). The test drug was suspended in 0.5% methylcellulose (MC), and the anticholinergic scopolamine hydrobromide (Wako Pure Chemicals 198-07971) was dissolved in physiological saline. Rats were intraperitoneally administered test drug suspended in 0.5% MC, or 0.5% MC as its control, 30 minutes prior to training in the passive avoidance reaction task, and simultaneously dissolved in saline Scopolamine 0.5 mg / kg, or physiological saline as a control drug, was intraperitoneally administered. In all cases, the dose was 5 mL / kg. Using a device composed of a light / dark test box, a sliding door that partitions the light / dark test box and a shock generator as an experimental device (manufactured by Ohara Medical Industry Co., Ltd., PA-2030A, PA-3001A), a passive avoidance reaction test was performed as follows. Was carried out as follows.
That is, on the first day of the experiment, after administration of the test drug and scopolamine, the rat was placed in the light box of the experimental apparatus with the back facing the dark box side, and 10 seconds later, the sliding door provided at the boundary of the light-dark box was opened. When the rat entered the dark box according to the behavior, the sliding door was quickly closed, and after 3 seconds from entering the dark box, an electric shock of 0.3-0.5 mA for 3 seconds was applied. The time from when the slide door was opened to when the rat entered the dark box was measured as a step-through latency. For animals that did not enter the darkroom for more than 300 seconds, the training was terminated and excluded from the following test as training failure.
On the second day of the experiment, the test was conducted about 24 hours after the training. The operation during the test was performed in the same manner as in the above training except that no electric shock was given. The moving latency at the time of the test was measured up to 300 seconds, and those exceeding 300 seconds were set to 300 seconds. As for the improvement rate of each test drug for scopolamine-induced memory learning disorder, the value of the movement latency at the time of the test was used, the vehicle group (the group administered with only 0.5% MC and saline alone), 100%, (0.5% MC only and scopolamine administration group) was taken as 0% and calculated according to the following formula.
Improvement rate (%) = 100 × [average treatment-average scopolamine] / [average vehicle-average scopolamine]
Vehicle: 0.5% MC alone and saline alone group Scopolamine: 0.5% MC alone and scopolamine administration group Treatment: Each test drug and scopolamine administration group The test results are shown in the table below.

(13) Evaluation of Test Drug for MK-801-induced Memory Learning Disorder in Rat Passive Avoidance Response Test 7-week-old Wistar male rats were used (n = 6-8 / group). The test drug was suspended in 0.5% methylcellulose (MC), and the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 hydrogen maleate (SIGMA-ALDRICH M-107) was dissolved in physiological saline. . The test drug suspended in 0.5% MC, or 0.5% MC as its control, was administered intraperitoneally 30-60 minutes before training in the passive avoidance reaction task, and dissolved in physiological saline. Rats were subcutaneously administered 801 0.05 mg / kg, or saline as its control, 30 minutes before training and testing. In all cases, the dose was 5 mL / kg. Using a device composed of a light / dark test box, a sliding door that partitions the light / dark test box and a shock generator as an experimental device (manufactured by Ohara Medical Industry Co., Ltd., PA-2030A, PA-3001A), a passive avoidance reaction test was performed as follows. Was carried out as follows.
That is, on the first day of the experiment, after administration of the test drug and MK-801, the rat was placed in the light box of the experimental apparatus with the back facing the dark box side, and 10 seconds later, the slide door provided at the boundary of the light-dark box was opened. . When the rat entered the dark box according to the behavior, the sliding door was quickly closed, and after 3 seconds from entering the dark box, an electric shock of 0.3-0.5 mA for 3 seconds was applied. The time from when the slide door was opened to when the rat entered the dark box was measured as a step-through latency. For animals that did not enter the darkroom for more than 300 seconds, the training was terminated and excluded from the following test as training failure.
On the second day of the experiment, the test was conducted about 24 hours after the training. Thirty minutes before the test, subcutaneous administration of MK-801 or physiological saline as its solvent was performed. The operation during the test was performed in the same manner as during the training except that no electric shock was given. The moving latency at the time of the test was measured up to 300 seconds, and those exceeding 300 seconds were set to 300 seconds. For the improvement rate of each test drug for MK-801-induced memory learning disorder, the value of the migration latency at the time of the test was used, and the vehicle group (group receiving only 0.5% MC and saline alone) was 100%. The MK-801 group (0.5% MC alone and MK-801 administration group) was taken as 0%, and the calculation was performed according to the following formula.
Improvement rate (%) = 100 × [average treatment-average MK-801] / [average vehicle-average MK-801]
Vehicle: Group MK-801 administered with 0.5% MC alone and saline alone MK-801: 0.5% MC alone and MK-801 administration group Treatment: Each test drug and MK-801 administration group The test results are shown in the table below. To express.

The compound represented by the formula (1 ′) or a pharmaceutically acceptable salt thereof exhibits high effectiveness as a therapeutic drug for treatment-resistant depression, persistent depression and / or repetitive depression, It is possible to reduce the risk of side effects seen with conventional schizophrenia drugs.

Claims (20)

1. Formula (1 ′):
   

   

   [Where:
   Ar is heteroaryl (the heteroaryl is C _1-3 alkyl optionally substituted with 1 to 3 halogens, C _1-3 alkoxy optionally substituted with 1 to 3 halogens, halogen And optionally substituted with 1 to 3 substituents of the same or different types selected from the group consisting of cyano,
   V represents nitrogen or CH;
   W represents a single bond or C (O) (W represents a single bond when V is nitrogen, and a single bond or C (O) when V is CH);
   Y is phenyl (the phenyl may be substituted with 1 to 3 halogens of the same or different type), heteroaryl (the heteroaryl is substituted with 1 to 3 halogens of the same or different type) Or a 4 to 7-membered saturated heterocyclic ring (which may be substituted with 1 to 3 halogens of the same or different types),
   R ^1a , R ^1b and R ^1c are the same or different and are each hydrogen, halogen, hydroxy, C _1-3 alkyl (the group may be substituted with hydroxy or C _1-3 alkoxy), or C _1-3 alkoxy (the group may be substituted with hydroxy or C _1-3 alkoxy)]
   A therapeutic agent for treatment-resistant depression, persistent depression and / or recurrent depression, comprising a compound represented by the formula: or a pharmaceutically acceptable salt thereof.
2. The compound represented by the formula (1 ′) is represented by the formula (1):
   

   

   [Where:
   Ar is heteroaryl (the heteroaryl may be substituted with 1 to 3 substituents of the same or different types selected from the group consisting of C _1-3 alkyl, C _1-3 alkoxy and halogen) Represents
   V represents nitrogen or CH;
   W represents a single bond or C (O) (W represents a single bond when V is nitrogen, and a single bond or C (O) when V is CH);
   Y is phenyl (the phenyl may be substituted with 1 to 3 halogens of the same or different type), heteroaryl (the heteroaryl is substituted with 1 to 3 halogens of the same or different type) Or a 4- to 7-membered saturated heterocycle (the saturated heterocycle may be substituted with 1 to 3 halogens of the same or different types)]
   The therapeutic agent of Claim 1 which is a compound represented by these.
3. Ar is the following formula (4) or (5):
   

   

   (The group may be substituted with 1 to 3 substituents of the same or different types selected from the group consisting of C _1-3 alkyl, C _1-3 alkoxy, and halogen). Yes;
   Y is phenyl (the phenyl may be substituted with the same or different 1 to 3 halogens), or the following formulas (3) to (9):
   

   

   The therapeutic agent according to claim 1 or 2, wherein the group is any one of the following groups (the group may be substituted with 1 to 3 halogens of the same or different types).
4. Ar is a group represented by the formula (4) (the group is substituted with 1 to 3 substituents of the same or different types selected from the group consisting of C _1-3 alkyl, C _1-3 alkoxy and halogen) The therapeutic agent according to any one of claims 1 to 3, which may be
5. The compound represented by the formula (1 ′) is represented by the formula (2 ′):
   

   

   [Where:
   R ¹¹ , R ¹² and R ¹³ are the same or different and each is hydrogen, C _1-3 alkyl optionally substituted with 1 to 3 halogens, or optionally substituted with 1 to 3 halogens C _1-3 represents alkoxy, halogen, or cyano,
   V represents nitrogen or CH;
   W represents a single bond or C (O) (provided that when V is nitrogen, W represents a single bond, and when V is CH, W represents a single bond or C (O)),
   Y represents the following formulas (a-1) to (a-8):
   

   

   (Wherein R ¹ represents hydrogen or fluorine)
   Any one of the groups represented by
   R ^1a , R ^1b and R ^1c are the same or different and are each hydrogen, halogen, hydroxy, C _1-3 alkyl (the group may be substituted with hydroxy or C _1-3 alkoxy), or C _1-3 alkoxy (the group may be substituted with hydroxy or C _1-3 alkoxy)]
   The therapeutic agent of Claim 1 which is a compound represented by these.
6. The compound represented by formula (1) is represented by formula (2):
   

   

   [Where:
   R ¹¹ , R ¹² and R ¹³ are the same or different and each represents hydrogen, fluorine, methyl or methoxy;
   V represents nitrogen or CH;
   W represents a single bond or C (O) (provided that when V is nitrogen, W represents a single bond, and when V is CH, W represents a single bond or C (O)),
   Y represents the following formulas (a-1) to (a-5):
   

   

   (Wherein R ¹ represents hydrogen or fluorine)
   Represents any of the groups represented by
   The therapeutic agent of Claim 2 which is a compound represented by these.
7. The treatment according to any one of claims 1 to 6, wherein Y is a group represented by the formula (a-1) or (a-5), R ¹ is fluorine, and V is CH. Agent.
8. 8. Y is a group represented by formula (a-1), R ¹ is fluorine, V is CH, and W is C (O). The therapeutic agent described.
9. The therapeutic agent according to any one of claims 5 to 8, wherein R ¹² is hydrogen, and R ¹¹ and R ¹³ are the same or different and each is hydrogen, fluorine, or methyl.
10. The therapeutic agent according to any one of claims 5 to 9, wherein R ¹¹ is fluorine.
11. The compound represented by the formula (1 ′) is
    [2- {2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethyl} pyrrolidin-1-yl] (6-methyl-1H-indol-2-yl) methanone,
    [2- {2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethyl} pyrrolidin-1-yl] (6-fluoro-1H-indol-2-yl) methanone,
    (3,6-difluoro-1H-indol-2-yl) [2- {2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethyl} pyrrolidin-1-yl] methanone,
    [2- {2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethyl} pyrrolidin-1-yl] (3-fluoro-1H-indol-2-yl) methanone,
    [2- {2- [4- (1H-indol-3-yl) piperidin-1-yl] ethyl} pyrrolidin-1-yl] (6-methoxy-1H-indol-2-yl) methanone,
    [2- {2- [4- (1H-indazol-3-yl) piperazin-1-yl] ethyl} pyrrolidin-1-yl] (6-methyl-1H-indol-2-yl) methanone,
    [2- {2- [4- (5-Fluoro-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] ethyl} pyrrolidin-1-yl] (6-methyl-1H-indole -2-yl) methanone,
    [2- {2- [4- (6-Fluoro-1,2-benzoxazol-3-yl) piperidin-1-yl] ethyl} pyrrolidin-1-yl] (6-methyl-1H-indole-2- Yl) methanone, or [2- {2- [4- (6-fluoro-1,2-benzoxazol-3-yl) piperidin-1-yl] ethyl} pyrrolidin-1-yl] (3-fluoro-1H The therapeutic agent according to claim 1, which is -indol-2-yl) methanone.
12. Cognitive dysfunction in treatment-resistant depression, persistent depression and / or recurrent depression, comprising the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof. Therapeutic agent.
13. A therapeutic resistance comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof. A method of treating depression, persistent depression and / or recurrent depression.
14. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable product thereof, for producing a therapeutic agent for treatment-resistant depression, persistent depression and / or recurrent depression Use of salt.
15. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, for use in the treatment of treatment-resistant depression, persistent depression and / or recurrent depression .
16. An antagonistic action of dopamine D ₂ receptor, serotonin 5-HT _2A receptor and adrenergic α _2A receptor containing the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof medicine.
17. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof for producing an antagonist of dopamine D ₂ receptor, serotonin 5-HT _2A receptor and adrenergic α _2A receptor. Use of acceptable salt.
18. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, for use as an antagonist of dopamine D ₂ receptor, serotonin 5-HT _2A receptor and adrenergic α _2A receptor. Acceptable salt.
19. An antagonist of dopamine D ₂ receptor, serotonin 5-HT _2A receptor and adrenergic α _2A receptor, comprising the compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof. A therapeutic agent for treatment-resistant depression, persistent depression or recurrent depression having an action.
20. A therapeutic agent for treatment-resistant depression, persistent depression, or recurrent depression comprising a compound having an antagonistic action of dopamine D ₂ receptor, serotonin 5-HT _2A receptor and adrenergic α _2A receptor as an active ingredient.