WO2022118783A1

WO2022118783A1 - Composition for treating treatment-resistant depression or symptoms of depression requiring urgent care

Info

Publication number: WO2022118783A1
Application number: PCT/JP2021/043568
Authority: WO
Inventors: 昌一島田; 誠近藤; 雪子山本
Original assignee: 国立大学法人大阪大学
Priority date: 2020-12-04
Filing date: 2021-11-29
Publication date: 2022-06-09
Also published as: JPWO2022118783A1

Abstract

[Problem] To provide a drug that can treat treatment-resistant depression, and to provide a drug that can promptly exhibit antidepressant effect and thus early treat symptoms requiring urgent care. [Solution] A serotonin 3 receptor agonist that improves symptoms of treatment-resistant depression. Further, this serotonin 3 receptor agonist promptly improves symptoms of depression and, therefore, is usable in treating a patient with symptoms of depression requiring urgent care. Examples of the serotonin 3 receptor agonist include optionally substituted 4-amino-1-(2-pyridyl)piperidine and a pharmaceutically acceptable salt thereof.

Description

Compositions for treating treatment-resistant depression or symptoms of urgent depression

The present invention relates to the treatment of depression.

The number of patients with depression has been increasing in recent years, and it is said that there are an estimated 300 million people in the world. Symptoms of depression include depressed mood, sleep disorders, loss of interest / joy, loss of appetite, decreased thinking / concentration / decision, sense of worthlessness and self-responsibility, decreased fatigue and energy, suicidal ideation and Suicidal ideation, etc. Treatment of depression is drug therapy centered on selective serotonin reuptake inhibitors (SSRIs), but the remission rate remains at 50% or less. There are many patients with treatment-resistant depression who do not improve sufficiently even with sufficient treatment with existing antidepressants and continue to have moderate or higher symptoms, and there is a need for a therapeutic drug that is effective for treatment-resistant depression. There is.

Currently used depression treatments take a long time to develop a therapeutic effect, and it takes weeks to months to achieve a sufficient effect, during which patients continue to suffer from their own symptoms. The risk of self-harm remains high. There is a demand for a therapeutic drug that rapidly develops antidepressant effects.

Ketamine, which is marketed as an anesthetic in Japan, is known to have antidepressant activity. It is known that it has a rapid effect 2 hours after administration for treatment-resistant depression that does not respond to existing treatments, and that it has an effect of greatly reducing suicidal ideation. However, it is said that there are side effects that form dependence, and that even low therapeutic levels often cause dissociation from reality and out-of-body sensations. The mechanism of action is thought to be NMDA-type glutamate receptor inhibition.

As a serotonin 3 receptor agonist, SR57227A (1- (6-chloropyridin-2-yl) piperidine-4-amine or a hydrochloride thereof) is known (Patent Documents 1 and 2).

The present inventors have found that the serotonin 3 receptor is involved in the antidepressant effect of exercise (Non-Patent Documents 1 and 2). Furthermore, it was found that the serotonin 3 receptor is not involved in the antidepressant effect of SSRI, and that the serotonin 3 receptor agonist SR57227A exhibits an antidepressant effect by a mechanism different from that of SSRI (Non-Patent Document 3). ..

Decipramine, a tricyclic antidepressant, is a relatively selective noradrenaline reuptake inhibitor and exhibits antidepressant effects by a mechanism different from SSRI, but it has antidepressant effects on SSRI treatment-resistant depression. It is known not to show (Non-Patent Document 4).

Japanese Unexamined Patent Publication No. 56-36481 Japanese Unexamined Patent Publication No. 7-145166

It is an object of the present invention to provide a drug capable of treating treatment-resistant depression, and to provide a drug capable of developing antidepressant effect at an early stage and treating an urgent symptom at an early stage.

As a result of conducting research to solve the above-mentioned problems, the present inventors have found that a serotonin 3 receptor (hereinafter, also referred to as "5HT3 receptor") agonist can solve the above-mentioned problems, and completed the present invention. That is, the present invention includes the following aspects.
1. 1. A composition for treating treatment-resistant depression containing a serotonin 3 receptor agonist.
2. 2. The composition according to item 1 above, wherein the treatment-resistant depression is SSRI treatment-resistant depression.
3. 3. The serotonin 3 receptor agonist is based on the following formula (I):

[During the ceremony,
m is an integer from 1 to 4;
R ¹ is a hydrogen atom, a halogen atom, a methyl group optionally substituted with 1 to 3 halogen atoms, a methoxy group optionally substituted with 1 to 3 halogen atoms, and 1 to 3 halogen atoms. An ethoxy group optionally substituted with, a methylthio group optionally substituted with 1 to 3 halogen atoms, and a halogen atom, trifluoromethyl, C _1-3 alkyl, C _1-3 alkoxy, C ₁ -Independently selected from the group consisting of phenoxy groups, which may be substituted with _-3 alkylthio or cyano groups.]
The composition according to the preceding item 1 or 2, which is a compound represented by the above or a pharmaceutically acceptable salt thereof.
4. The composition according to item 3 above, wherein R ¹ is an independently halogen atom.
5. The composition according to item 4 above, wherein the halogen atom is a chlorine atom.
6. A composition comprising a serotonin 3 receptor agonist for treating an urgent symptom in depression.
7. The composition according to item 6 above, wherein the urgent symptom is improved and treated within 14 days from the start of administration.
8. The composition according to item 7 above, wherein within 14 days from the start of administration is within 6 days from the start of administration.
9. The composition according to any one of items 6 to 8 above, wherein the urgent symptom is suicidal ideation.
10. The serotonin 3 receptor agonist is based on the following formula (I):

[During the ceremony,
m is an integer from 1 to 4;
R ¹ is a hydrogen atom, a halogen atom, a methyl group optionally substituted with 1 to 3 halogen atoms, a methoxy group optionally substituted with 1 to 3 halogen atoms, and 1 to 3 halogen atoms. An ethoxy group optionally substituted with, a methylthio group optionally substituted with 1 to 3 halogen atoms, and a halogen atom, trifluoromethyl, C _1-3 alkyl, C _1-3 alkoxy, C ₁ -Independently selected from the group consisting of phenoxy groups, which may be substituted with _-3 alkylthio or cyano groups.]
The composition according to any one of 6 to 9 in the preceding paragraph, which is a compound represented by (1) or a pharmaceutically acceptable salt thereof.
11. The composition according to item 10, wherein R ¹ is an independently halogen atom.
12. 11. The composition according to item 11, wherein the halogen atom is a chlorine atom.
13. A method for screening a compound for treating refractory depression or a compound for treating an urgent symptom in depression, which comprises a step of measuring serotonin 3 receptor agonist activity.
14. A method of treating treatment-resistant depression comprising administering a serotonin 3 receptor agonist to a subject in need thereof.
15. A method for treating treatment-resistant depression comprising administering a composition containing a serotonin 3 receptor agonist to a subject in need thereof.
16. A method of treating urgent symptoms in depression comprising administering a serotonin 3 receptor agonist to a subject in need thereof.
17. A method for treating an urgent symptom in depression comprising administering a composition containing a serotonin 3 receptor agonist to a subject in need thereof.
18. Use of serotonin 3 receptor agonists for the preparation of compositions for treating treatment-resistant depression.
19. Use of serotonin 3 receptor agonists for the preparation of compositions for treating urgent symptoms in depression.

The composition of the present invention can exert an antidepressant effect and improve symptoms in treatment-resistant depression. Treatment-resistant depression occurs relatively commonly in clinical practice, with approximately half of patients not achieving adequate response after treatment with depression medications. Since the composition of the present invention has an antidepressant effect on many patients, it contributes greatly to the care of patients.

The composition of the present invention can improve the symptoms of depression at an early stage. With existing treatments for depression, it takes 3 weeks to several months for the antidepressant effect to appear after the start of administration. The delay in the onset of this antidepressant effect raises a high risk of urgent symptoms such as suicidal behavior. The composition of the present invention capable of rapidly exhibiting antidepressant effect makes a great contribution to the care of patients with urgency. In addition, the composition of the present invention prevents interruption of administration due to early onset of side effects and facilitates treatment of depression.

The composition of the present invention is excellent as a pharmaceutical without side effects such as dependence.

FIG. 1 is a graph showing the results of a tail suspension test in which physiological saline or ketamine (3,10,30 mg / kg) was intraperitoneally administered to wild-type mice (□) and 5HT3 receptor knockout mice (■). Is. Ketamine administration reduced akinesia time in wild-type mice. There was no change in akinesia time in 5HT3 receptor knockout mice. (Wild-type mouse group n = 12.5HT3 receptor knockout mouse group n = 10; ^* p <0.05) FIG. 2 is a graph showing the results of a forced swimming test in which physiological saline or ketamine (3,10,30 mg / kg) was intraperitoneally administered to wild-type mice (□) and 5HT3 receptor knockout mice (■). Is. Ketamine administration reduced akinesia time in wild-type mice. There was no change in akinesia time in 5HT3 receptor knockout mice. (Wild-type mouse group n = 12.5HT3 receptor knockout mouse group n = 10; ^* p <0.05) FIG. 3 shows saline, fluoxetine (Flx, 10 mg / kg) or SR57227A (SR, 5 mg / kg) administered to wild-type mice (□) and 5HT3 receptor knockout mice (■) for 6 days (once / once /). It is a graph which shows the result of having performed the novelty superpressed saline test after day). The vertical axis is the time (seconds) until eating food. In the SSRI fluoxetine-administered group, the time to eat the food was not shortened, but in the SR57227A-administered group, the time to eat the food was shortened. On the other hand, in 5HT3 receptor knockout mice, SR57227A administration did not shorten the time to eat. (N = 10 in each group; ^* p <0.05) FIG. 4 is a graph showing the results of a tail suspension test using treatment-resistant depression model mice. Saline, fluoxetine (Flx, 10 mg / kg), ketamine (Ket, 10 mg / kg), or SR57227A (SR, 5 mg / kg) was intraperitoneally administered, and a tail suspension test was performed 1 hour later. In control mice (□), the immobility time was shortened in the fluoxetine-administered group, the ketamine-administered group, and the SR57227A-administered group. In the treatment-resistant depression model mice (■), the fluoxetine-administered group did not shorten the immobility time, but the ketamine-administered group and the SR57227A-administered group shortened the immobility time. (N = 10 in each group; ^* p <0.05, ^** p <0.01) FIG. 5 is a graph showing the results of a forced swimming test using treatment-resistant depression model mice. Physiological saline, fluoxetine (Flx, 10 mg / kg), ketamine (Ket, 10 mg / kg), or SR57227A (SR, 5 mg / kg) were intraperitoneally administered, and a forced swimming test was performed 1 hour later. In control mice (□), the immobility time was shortened in the fluoxetine-administered group, the ketamine-administered group, and the SR57227A-administered group. In the treatment-resistant depression model mice (■), the fluoxetine-administered group did not shorten the immobility time, but the ketamine-administered group and the SR57227A-administered group shortened the immobility time. (Each group n = 10; ^* p <0.05, ^** p <0.01, ^*** p <0.001)

The serotonin 3 receptor agonist, which is the active ingredient of the composition of the present invention, is a substance that binds to the serotonin 3 receptor and exerts the same action as serotonin, and is not limited thereto.

The present inventors have found that the antidepressant action of ketamine is mediated by the serotonin 3 receptor (Reference Example 1). However, ketamine is known as an antagonist of the NMDA-type glutamate receptor and is not included in the serotonin 3 receptor agonist of the present invention.

As a suitable compound of the serotonin 3 receptor agonist which is the active ingredient of the composition of the present invention, any of the following formulas (I), (II), (III), (IV), (V) or (VI) Examples thereof include the compounds shown or pharmaceutically acceptable salts thereof, or hydrates or solvates thereof.

Unless otherwise specified, each group defined in the substituents of the structural formulas of the compounds of formulas (I), (II), (III), (IV), (V) and (VI) may be freely combined. Can be done.

In the present specification, the number of carbons in the definition of "substituent" may be expressed as, for example, "C _1-3 ", "C _1-6 " and the like. Specifically, the notation "C _1-3 alkyl" is synonymous with a linear or branched alkyl group having 1 to 3 carbon atoms, and the notation "C _1-6 alkyl" has a carbon number of carbons. It is synonymous with 1 to 6 linear or branched alkyl groups.

As used herein, the term "base" means a monovalent group. For example, "alkyl group" means a monovalent saturated hydrocarbon group. In addition, the term "group" may be omitted in the description of the substituent in the present specification. Unless otherwise indicated, the description of each group also applies when the group is part of another group or a substituent.

Examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

In one embodiment, the serotonin 3 receptor agonist which is the active ingredient of the present invention is represented by the following formula (I):

[During the ceremony,
m is an integer from 1 to 4;
R ¹ is a hydrogen atom, a halogen atom, a methyl group optionally substituted with 1 to 3 halogen atoms, a methoxy group optionally substituted with 1 to 3 halogen atoms, and 1 to 3 halogen atoms. An ethoxy group optionally substituted with, a methylthio group optionally substituted with 1 to 3 halogen atoms, and a halogen atom, trifluoromethyl, C _1-3 alkyl, C _1-3 alkoxy, C ₁ -Independently selected from the group consisting of phenoxy groups, which may be substituted with _-3 alkylthio or cyano groups.]
A compound represented by or a pharmaceutically acceptable salt thereof.

m is an integer of 1 to 4, preferably an integer of 1 to 3, more preferably an integer of 1 to 2, and particularly preferably 1.

As the halogen atom in R ¹ , a fluorine atom and a chlorine atom are preferable, and a chlorine atom is particularly preferable.

As the methyl group which may be substituted with 1 to 3 halogen atoms in ^R1 , a methyl group which may be substituted with 1 to 3 fluorine atoms is preferable, and a methyl group and a trifluoromethyl group are particularly preferable. preferable.

As the methoxy group which may be substituted with 1 to 3 halogen atoms in ^R1 , a methoxy group which may be substituted with 1 to 3 fluorine atoms is preferable, and a methoxy group and a trifluoromethoxy group are particularly preferable. preferable.

As the ethoxy group which may be substituted with 1 to 3 halogen atoms in ^R1 , the ethoxy group which may be substituted with 1 to 3 fluorine atoms is preferable, and the ethoxy group and 2,2,2- A trifluoroethoxy group is particularly preferred.

As the methylthio group which may be substituted with 1 to 3 halogen atoms in ^R1 , a methylthio group which may be substituted with 1 to 3 fluorine atoms is preferable, and a methylthio group and a trifluoromethylthio group are particularly preferable. preferable.

R ¹ can be a phenoxy group optionally substituted with a halogen atom, trifluoromethyl, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkyl thio or a cyano group. "C _1-3 Alkoxy", "C _1-3 Alkoxy" and "C _1-3 Alkoxy" are residues of saturated aliphatic hydrocarbons having 1, 2 or 3 carbon atoms (methyl, ethyl, propyl, isopropyl, etc.). )including.

In one preferred embodiment, each R ¹ is an independent halogen atom, more preferably each R ¹ is a chlorine atom.

In one preferred embodiment, m is 1. In a more preferred embodiment, R ¹ is a halogen atom and m is 1.

In a preferred embodiment, the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is the following formula (I'):

[In the formula, R ¹ has the same meaning as described above]
A compound represented by or a pharmaceutically acceptable salt thereof.

In a more preferred embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is the following formula:

(Compound name: 1- (6-chloropyridin-2-yl) piperidine-4-amine; hereinafter also referred to as "Compound A") or a pharmaceutically acceptable salt thereof. Particularly preferred is SR57227A (Compound A or its hydrochloride).

In another embodiment, the serotonin 3 receptor agonist which is the active ingredient of the present invention has the following formula (II) :.

[During the ceremony,
n is an integer from 1 to 4;
^R2 is a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a methyl group which may be substituted with 1 to 3 halogen atoms, a methoxy group which may be substituted with 1 to 3 halogen atoms, and a methoxy group. Each is independently selected from the group consisting of methylthio groups that may be substituted with 1 to 3 halogen atoms]
A compound represented by or a pharmaceutically acceptable salt thereof.

n is an integer of 1 to 4, preferably an integer of 1 to 3, more preferably an integer of 1 to 2, and particularly preferably 1.

As the halogen atom in ^R2 , a fluorine atom and a chlorine atom are preferable, and a chlorine atom is particularly preferable.

As the methyl group which may be substituted with 1 to 3 halogen atoms in ^R2 , a methyl group which may be substituted with 1 to 3 fluorine atoms is preferable, and a methyl group and a trifluoromethyl group are particularly preferable. preferable.

As the methoxy group which may be substituted with 1 to 3 halogen atoms in ^R2 , a methoxy group which may be substituted with 1 to 3 fluorine atoms is preferable, and a methoxy group and a trifluoromethoxy group are particularly preferable. preferable.

As the methylthio group which may be substituted with 1 to 3 halogen atoms in ^R2 , a methylthio group which may be substituted with 1 to 3 fluorine atoms is preferable, and a methylthio group and a trifluoromethylthio group are particularly preferable. preferable.

In one embodiment, R ² is an independent hydrogen or halogen atom, preferably R ² is an independent hydrogen or chlorine atom, respectively.

In another embodiment, n is 1. In another embodiment, R ² is a hydrogen atom or a halogen atom and n is 1.

In another embodiment, the compound represented by the formula (II) or a pharmaceutically acceptable salt thereof is the following formula (II'):

[In the formula, R ² has the same meaning as described above]
A compound represented by or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, the compound of formula (II) or a pharmaceutically acceptable salt thereof is the following formula:

(Compound name: m-chlorophenylbiguanide; hereinafter also referred to as "Compound B") or a pharmaceutically acceptable salt thereof, and particularly preferably a hydrochloride of Compound B.

(Compound name: 1-phenylbiguanide; hereinafter also referred to as "Compound C") or a pharmaceutically acceptable salt thereof, and particularly preferably a hydrochloride of Compound C.

In another embodiment, the serotonin 3 receptor agonist which is the active ingredient of the present invention has the following formula (III) :.

[During the ceremony,
o is an integer from 1 to 4;
R ³ is a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a methyl group which may be substituted with 1 to 3 halogen atoms, a methoxy group which may be substituted with 1 to 3 halogen atoms, and a methoxy group. Each is independently selected from the group consisting of methylthio groups which may be substituted with 1 to 3 halogen atoms;
^R4 is selected from the group consisting of a hydrogen atom and a methyl group optionally substituted with 1 to 3 halogen atoms]
A compound represented by or a pharmaceutically acceptable salt thereof.

o is an integer of 1 to 4, preferably an integer of 1 to 3, more preferably an integer of 1 to 2, and particularly preferably 1.

As the halogen atom in R3 ^, a fluorine atom and a chlorine atom are preferable, and a chlorine atom is particularly preferable.

As the methyl group which may be substituted with 1 to ³ halogen atoms in R3, a methyl group which may be substituted with 1 to 3 fluorine atoms is preferable, and a methyl group and a trifluoromethyl group are particularly preferable. preferable.

As the methoxy group which may be substituted with 1 to ³ halogen atoms in R3, a methoxy group which may be substituted with 1 to 3 fluorine atoms is preferable, and a methoxy group and a trifluoromethoxy group are particularly preferable. preferable.

As the methylthio group which may be substituted with 1 to ³ halogen atoms in R3, a methylthio group which may be substituted with 1 to 3 fluorine atoms is preferable, and a methylthio group and a trifluoromethylthio group are particularly preferable. preferable.

As the methyl group which may be substituted with 1 to 3 halogen atoms in ^R4 , a methyl group which may be substituted with 1 to 3 fluorine atoms is preferable, and a methyl group is particularly preferable.

In one embodiment, R ³ is independently a hydrogen or halogen atom, preferably R ³ is independently a hydrogen or chlorine atom, respectively.

In another embodiment, ^R4 is a hydrogen atom or a methyl group.

In another embodiment, o is 1. In another embodiment, R ³ is a hydrogen atom or a halogen atom, R ⁴ is a hydrogen atom or a methyl group, and o is 1.

In another embodiment, the compound represented by the formula (III) or a pharmaceutically acceptable salt thereof is the following formula (III'):

[In the formula, R ⁴ has the same meaning as described above]
A compound represented by or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, the compound represented by formula (III) or a pharmaceutically acceptable salt thereof is the following formula:

(Compound name: N-methylkipadin; hereinafter also referred to as "Compound D") or a pharmaceutically acceptable salt thereof, and particularly preferably a dimaleate of Compound D.

(Compound name: quipazine; hereinafter also referred to as "Compound E") or a pharmaceutically acceptable salt thereof, and particularly preferably a dimaleate of Compound E.

In another embodiment, the serotonin 3 receptor agonist which is the active ingredient of the present invention has the following formula (IV) :.

[During the ceremony,
p is an integer from 1 to 4;
R ⁵ and R ⁶ are hydrogen atom, halogen atom, hydroxy group, cyano group, methyl group which may be substituted with 1 to 3 halogen atoms, and methoxy which may be substituted with 1 to 3 halogen atoms. Each is independently selected from the group consisting of a group and a methylthio group optionally substituted with 1 to 3 halogen atoms;
^R7 is selected from the group consisting of a hydrogen atom and a methyl group optionally substituted with 1 to 3 halogen atoms]
A compound represented by or a pharmaceutically acceptable salt thereof.

p is an integer of 1 to 4, preferably an integer of 1 to 3, more preferably an integer of 1 to 2, and particularly preferably 1.

As the halogen atom in ^R5 and ^R6 , a fluorine atom and a chlorine atom are preferable, and a chlorine atom is particularly preferable.

As the methyl group which may be substituted with 1 to 3 halogen atoms in R ⁵ and R ⁶ , the methyl group which may be substituted with 1 to 3 fluorine atoms is preferable, and the methyl group and trifluoromethyl are preferable. Groups are particularly preferred.

As the methoxy group which may be substituted with 1 to 3 halogen atoms in R ⁵ and R ⁶ , the methoxy group which may be substituted with 1 to 3 fluorine atoms is preferable, and the methoxy group and trifluoromethoxy are preferable. Groups are particularly preferred.

As the methylthio group which may be substituted with ¹ to ³ halogen atoms in R5 and R6, a methylthio group which may be substituted with 1 to 3 fluorine atoms is preferable, and a methylthio group and a trifluoromethylthio group are preferable. Groups are particularly preferred.

As the methyl group which may be substituted with 1 to 3 halogen atoms in ^R7 , a methyl group which may be substituted with 1 to 3 fluorine atoms is preferable, and a methyl group is particularly preferable.

In one embodiment, R ⁵ is independently selected from the group consisting of hydrogen atom, halogen atom, hydroxy group, and cyano group, preferably each R ⁵ is a hydroxy group.

In another embodiment, R ⁶ is selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, and a methyl group optionally substituted with 1 to 3 halogen atoms, preferably a methyl group. be.

In another embodiment, R ⁷ is a hydrogen atom or a methyl group, preferably a hydrogen atom.

In another embodiment, p is 1. In another embodiment, R ⁵ is selected from the group consisting of a halogen atom, a hydroxy group, and a cyano group, and R ⁶ is a methyl that may be substituted with a hydrogen atom, a halogen atom, and 1 to 3 halogen atoms. Selected from the group consisting of groups, R ⁷ is a hydrogen atom or a methyl group and p is 1.

In another embodiment, the compound represented by the formula (IV) or a pharmaceutically acceptable salt thereof is the following formula (IV'):.

[In the formula, R ⁵ , R ⁶ and R ⁷ have the same meaning as described above]
A compound represented by or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, the compound of formula (IV) or a pharmaceutically acceptable salt thereof is the following formula:

(Compound name: 2-methyl-5-hydroxytryptamine; hereinafter also referred to as "Compound F") or a pharmaceutically acceptable salt thereof, and particularly preferably a hydrochloride of Compound F.

In another embodiment, the serotonin 3 receptor agonist which is the active ingredient of the present invention has the following formula (V) :.

[During the ceremony,
q is an integer from 1 to 4;
R ⁸ and R ⁹ are hydrogen atom, halogen atom, hydroxy group, cyano group, methyl group which may be substituted with 1 to 3 halogen atoms, and methoxy which may be substituted with 1 to 3 halogen atoms. Each is independently selected from the group consisting of a group and a methylthio group optionally substituted with 1 to 3 halogen atoms;
R ¹⁰ is selected from the group consisting of a hydrogen atom and a methyl group optionally substituted with 1 to 3 halogen atoms]
A compound represented by or a pharmaceutically acceptable salt thereof.

q is an integer of 1 to 4, preferably an integer of 1 to 3, more preferably an integer of 1 to 2, and particularly preferably 1.

As the halogen atom in R ⁸ and R ⁹ , a fluorine atom and a chlorine atom are preferable, and a chlorine atom is particularly preferable.

As the methyl group which may be substituted with 1 to 3 halogen atoms in R ⁸ and R ⁹ , the methyl group which may be substituted with 1 to 3 fluorine atoms is preferable, and the methyl group and trifluoromethyl are preferable. Groups are particularly preferred.

As the methoxy group which may be substituted with 1 to 3 halogen atoms in R ⁸ and R ⁹ , the methoxy group which may be substituted with 1 to 3 fluorine atoms is preferable, and the methoxy group and trifluoromethoxy are preferable. Groups are particularly preferred.

As the methylthio group which may be substituted with 1 to 3 halogen atoms in R ⁸ and R ⁹ , the methyl thio group which may be substituted with 1 to 3 fluorine atoms is preferable, and the methyl thio group and trifluoromethyl thio are preferable. Groups are particularly preferred.

As the methyl group which may be substituted with 1 to ³ halogen atoms in R10, a methyl group which may be substituted with 1 to 3 fluorine atoms is preferable, and a methyl group is particularly preferable.

In one embodiment, R ⁸ is independently selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxy group, and a cyano group, preferably each R ⁸ is a hydrogen atom.

In another embodiment, R ⁹ is selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, and a methyl group optionally substituted with 1 to 3 halogen atoms, preferably a hydrogen atom. be.

In another embodiment, R ¹⁰ is a hydrogen atom or a methyl group, preferably a methyl group.

In another embodiment, q is 1. In another embodiment, R ⁸ is a hydrogen atom or a hydroxy group, R ⁹ is a hydrogen atom or a methyl group, R ¹⁰ is a hydrogen atom or a methyl group, and q is 1.

In another embodiment, the compound represented by the formula (V) or a pharmaceutically acceptable salt thereof is the following formula (V'):

[In the formula, R ⁸ , R ⁹ , and R ¹⁰ have the same meaning as described above]
A compound represented by or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, the compound represented by the formula (V) or a pharmaceutically acceptable salt thereof is the following formula:

Compound represented by (RS56812; compound name: (R) -N- (1-azabicyclo [2.2.2] octo-3-yl) -2- (1-methyl-1H-indole-3-yl)- 2- (1-Methyl-1H-indole-3-yl) -2-oxoacetamide; hereinafter also referred to as "Compound G") or a pharmaceutically acceptable salt thereof, particularly preferably a hydrochloride of Compound G. be.

In another embodiment, the serotonin 3 receptor agonist which is the active ingredient of the present invention has the following formula (VI) :.

[In the formula, Q is the following formulas (a) to (c):

(In the formula, R ¹¹ represents a hydrogen atom or a C _1-6 alkyl group;
Do R ¹² and R ¹³ represent the same or different hydrogen atoms, or C _1-6 alkyl groups;
Alternatively, they may be combined with the carbon atoms to which they are attached to form a 3- to 8-membered cycloalkane;
Do R ¹⁴ and R ¹⁵ represent the same or different hydrogen atoms, or C _1-6 alkyl groups;
Alternatively, they may be combined with the nitrogen atom to which they bind to form a 3- to 8-membered cyclic amine;
n represents 0, 1, 2, 3, 4, or 5;
Here, when R ¹⁴ and R ¹⁵ are both hydrogen atoms, R ¹² represents a group represented by any one of (C _2-6 alkyl groups)].
A compound represented by or a pharmaceutically acceptable salt thereof.

Preferably, Q is a group represented by the formula (a) or (b). More preferably, Q is a group represented by the formula (a).

Preferably, n is 1, 2, or 3.

Preferably, R ¹² is a hydrogen atom. Preferably, R ¹³ is a hydrogen atom or a C _1-6 alkyl group. More preferably, R ¹² is a hydrogen atom and R ¹³ is a hydrogen atom or a C _1-6 alkyl group.

Preferably, R ¹⁴ is a hydrogen atom or a C _1-6 alkyl group. Preferably, R ¹⁵ is a C _1-6 alkyl group. More preferably, R ¹⁴ is a hydrogen atom or a C _1-6 alkyl group and R ¹⁵ is a C _1-6 alkyl group.

Preferably, R ¹¹ is a hydrogen atom. Preferably, R ¹¹ and R ¹² are hydrogen atoms. Preferably, R ¹¹ is a hydrogen atom and R ¹³ is a hydrogen atom or a C _1-6 alkyl group. More preferably, R ¹¹ and R ¹² are hydrogen atoms and R ¹³ is a hydrogen atom or a C _1-6 alkyl group.

Preferably, R ¹¹ is a hydrogen atom and R ¹⁴ is a hydrogen atom or a C _1-6 alkyl group. Preferably, R ¹¹ is a hydrogen atom and R ¹⁵ is a C _1-6 alkyl group. More preferably, R ¹¹ is a hydrogen atom, R ¹⁴ is a hydrogen atom or a C _1-6 alkyl group, and R ¹⁵ is a C _1-6 alkyl group.

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

Examples of the "cycloalkane" in which R ¹² and R ¹³ "may form a 3- to 8-membered cycloalkane together with the carbon atom to which they are bonded" include cyclopropane and cyclobutane. , Cyclopentane, Cyclohexane, Cycloheptane, Cyclooctane and the like.

Specific examples of Q in the case where R ¹² and R ¹³ "may form a 3- to 8-membered cycloalkane together with the carbon atom to which they are bonded" are represented by the following formula. The basis etc. can be mentioned.

"3- to 8-membered cyclic amine" means a 3- to 8-membered saturated or unsaturated cyclic amine. Examples of the "cyclic amine" in which R ¹⁴ and R ¹⁵ "may be combined with the nitrogen atom to which they bind to form a 3- to 8-membered cyclic amine" include aziridine, azetidine, and the like. Examples thereof include pyrrolidine, piperidine, azepane and azocane.

Specific examples of Q in the case where R ¹⁴ and R ¹⁵ "may form a 3- to 8-membered cyclic amine together with the nitrogen atom to which they are bonded" are represented by the following formula. The basis etc. can be mentioned.

Group represented by formula (a):

Examples thereof include 2-aziridinyl group, 3-azetidinyl group, 3-pyrrolidinyl group, 3-piperidinyl group and the like. Preferably, it is a 3-azetidinyl group, a 3-pyrrolidinyl group, or a 3-piperidinyl group.

Group represented by formula (b):

Examples thereof include aziridine-2-ylmethyl group, azetidine-2-ylmethyl group, pyrrolidine-2-ylmethyl group, piperidine-2-ylmethyl group and the like. It is preferably a pyrrolidine-2-ylmethyl group.

In a preferred embodiment, the compound represented by the formula (VI) or a pharmaceutically acceptable salt thereof is the following formula:

(Compound name: (2-aminophenyl) (azetidine-3-yl) methanone; hereinafter also referred to as "Compound H") or a pharmaceutically acceptable salt thereof.

(Compound name: 1- (2-aminophenyl) -3- (methylamino) propan-1-one; hereinafter also referred to as "Compound I") or a pharmaceutically acceptable salt thereof. Particularly preferred is the hydrochloride salt of compound I.

(Compound name: (2-aminophenyl) (pyrrolidin-3-yl) methanone; hereinafter also referred to as "Compound J") or a pharmaceutically acceptable salt thereof. Particularly preferred is the hydrochloride salt of compound J.

(Compound name: (2-aminophenyl) (piperidine-3-yl) methanone; hereinafter also referred to as "Compound K") or a pharmaceutically acceptable salt thereof.

(Compound name: 1- (2-aminophenyl) -2- (pyrrolidin-2-yl) etanone; hereinafter also referred to as "Compound L") or a pharmaceutically acceptable salt thereof. Particularly preferred is the hydrochloride salt of compound L.

(Compound name: 1- (2-aminophenyl) -3- (methylamino) butane-1-one; hereinafter also referred to as "Compound M") or a pharmaceutically acceptable salt thereof.

(Compound name: 3-amino-1- (2-aminophenyl) butane-1-one; hereinafter also referred to as "Compound N") or a pharmaceutically acceptable salt thereof.

(Compound name: (-)-(2-aminophenyl) (pyrrolidin-3-yl) metanone; hereinafter also referred to as "Compound O") or a pharmaceutically acceptable salt thereof. Particularly preferred is the hydrochloride salt of compound O.

(Compound name: (+)-(2-aminophenyl) (pyrrolidin-3-yl) metanone; hereinafter also referred to as "Compound P") or a pharmaceutically acceptable salt thereof. Particularly preferred is the hydrochloride salt of compound P.

In one embodiment, the serotonin 3 receptor agonist that is the active ingredient of the invention is represented by any of the formulas (I), (II), (III), (IV), (V) or (VI). A compound or a pharmaceutically acceptable salt thereof. In another embodiment, the serotonin 3 receptor agonist which is the active ingredient of the present invention is a compound represented by any one of the formulas (I), (II), (IV), (V) or (VI) or a pharmaceutical agent thereof. It is an acceptable salt. In another embodiment, the serotonin 3 receptor agonist which is the active ingredient of the present invention is one of the formulas (I'), (II'), (III'), (IV'), or (V'). The compound shown or a pharmaceutically acceptable salt thereof. In another embodiment, the serotonin 3 receptor agonist that is the active ingredient of the present invention is a compound represented by any of the formulas (I'), (II'), (IV'), or (V') or a compound thereof. It is a pharmaceutically acceptable salt. In another embodiment, the serotonin 3 receptor agonist, which is the active ingredient of the present invention, is compound A, B, C, D, E, F, G, H, I, J, K, L, M, N, O. Alternatively, it is P or a pharmaceutically acceptable salt thereof. In another embodiment, the serotonin 3 receptor agonist which is the active ingredient of the present invention is compound A, B, C, F, G, H, I, J, K, L, M, N, O or P or a compound thereof. It is a pharmaceutically acceptable salt.

In a preferred embodiment, the serotonin 3 receptor agonist which is the active ingredient of the present invention is a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof. In a more preferred embodiment, the serotonin 3 receptor agonist which is the active ingredient of the present invention is a compound represented by the formula (I') or a pharmaceutically acceptable salt thereof. In a more preferred embodiment, the serotonin 3 receptor agonist which is the active ingredient of the present invention is Compound A or a pharmaceutically acceptable salt thereof.

The active ingredient of the present invention, a serotonin 3 receptor agonist, for example, a compound represented by any of the formulas (I), (II), (III), (IV), (V) or (VI) is in free form. However, it can also be present in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts include, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, formate, acetate, propionate, fumarate, etc. Succinate, malonate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, maleate, dimaleate, lactate, malate, tartrate , Citrate, pamoate and acid addition salts such as trifluoroacetate; metal salts such as lithium salt, potassium salt, calcium salt, magnesium salt, sodium salt, zinc salt, and aluminum salt; as well as ammonium salt, diethanolamine. Examples thereof include salts, ethylenediamine salts, triethanolamine salts, and base-added salts such as triethylamine salts.

The active ingredient of the present invention is a cellotonin 3 receptor agonist, for example, a compound represented by any one of the formulas (I), (II), (III), (IV), (V) or (VI) or a pharmaceutically thereof. The acceptable salt includes any of its intramolecular salts and additives, their solvates or hydrates, co-crystals and the like.

The active ingredient of the present invention, a serotonin 3 receptor agonist, for example, a compound represented by any of the formulas (I), (II), (III), (IV), (V) or (VI) is contained in the molecule. When having an asymmetric carbon atom, it may exist as a plurality of stereoisomers (that is, diastereomeric isomers, optical isomers) based on the asymmetric carbon atom, and the active ingredient of the present invention is any of these. Includes any one stereoisomer and mixtures thereof.

In addition, the active ingredient of the present invention, a serotonin 3 receptor agonist, for example, a compound represented by any one of the formulas (I), (II), (III), (IV), (V) or (VI) is geometric. The isomers may include cis and trans isomers, and may also include isomers based on axial asymmetry if the molecule has axial asymmetry, any one of these isomers or isomers thereof. Includes any mixture.

The active ingredient of the present invention is a serotonin 3 receptor agonist, for example, a compound represented by any one of the formulas (I), (II), (III), (IV), (V) or (VI) is an isotope ( For example, it includes compounds labeled with ^2H , ^3H , ^13C , ^14C , ^15N , ^18F , ^32P , ^35S , ^125I , etc.) and deuterium converters.

The invention also includes prodrugs of the compounds of the invention or pharmaceutically acceptable salts thereof. The prodrug is a functional derivative of the compound of the invention that can be easily converted into the required compound in vivo.

The present application administers a cellotonin 3 receptor agonist, an invention relating to a composition for treating a treatment-resistant depression containing a serotonin 3 receptor agonist and for treating an urgent symptom in depression. The present invention includes an invention relating to a method for treating those symptoms, an invention relating to the use of a serotonin 3 receptor agonist for preparing a composition for treating those symptoms, and the like. Descriptions and embodiments of the invention according to the present specification relating to a composition for treating treatment-resistant depression containing a serotonin 3 receptor agonist and for treating an urgent symptom in depression are described. Descriptions and embodiments of all these inventions.

Symptoms of depression include depressed mood, sleep disorders, loss of interest, loss of joy, loss of appetite, poor thinking, poor concentration, poor determination, worthlessness, suicidal ideation, fatigue, Includes depression, suicidal ideation, and suicide attempts. ICD (International Statistical Classification of Diseases and Related Health Problems) and DSM (Diagnostic and Statistical Manual of Mental Disorders) have come to be used as diagnostic criteria for depression. Depression in the present specification refers to the depressive state (for example, anxiety disorder) exhibited in the diseases included in the mood (emotion) disorder of the ICD10 classification, the neurotic disorder, the stress-related disorder, and the somatic symptom disorder. Includes accompanying depression). It also includes depression associated with other illnesses (eg, depression associated with cancer).

As used herein, the treatment of depression or the treatment of depression symptoms includes at least one improvement, alleviation, exacerbation suppression, recurrence suppression, etc. of depression symptoms.

The composition containing the serotonin 3 receptor agonist of the present invention has an antidepressant effect on treatment-resistant depression and can treat the symptoms of depression. The treatment-resistant depression as used herein is a depression in which the symptoms do not improve even if appropriate treatment with an existing therapeutic agent for depression is performed. Existing therapeutic agents for depression include therapeutic agents such as SSRIs (selective serotonin reuptake inhibitors), SNRIs (serotonin noradrenaline reuptake inhibitors) and tricyclic antidepressants.

The composition of the present invention is preferably capable of providing antidepressant effects on SSRI (selective serotonin reuptake inhibitor) treatment-resistant depression and ameliorating symptoms. The most widely used antidepressant drug in the United States is the SSRI fluoxetine. Examples of SSRIs used in Japan include fluvoxamine, paroxetine, sertraline, and escitalopram. In addition, the composition of the present invention can preferably bring about an antidepressant effect on tricyclic antidepressant treatment-resistant depression and improve symptoms. Examples of the tricyclic antidepressant include desipramine, imipramine, amoxapine, nortriptyline, amitriptyline and the like.

The composition containing the serotonin 3 receptor agonist of the present invention can be used for the treatment of urgent symptoms of depression. Early symptom improvement is required for all patients, but it is important to promptly improve urgent symptoms. Symptoms with urgency include suicidal ideation, slight weakness in eating, and severe frustration that significantly impairs life. In particular, the compositions of the present invention are suitable for the treatment of suicidal ideation symptoms. Suicidal ideation in the present specification includes symptoms such as wanting to commit suicide, wanting to die, strongly imagining death, and attempting suicide (suicide attempt).

The suicidal ideation patient who can be treated with the composition of the present invention may be a patient who has expressed suicidal ideation or a patient who is objectively determined to have suicidal ideation. For clinical evaluation of suicidal ideation, SSI (Scale for Suicidal Ideation) or the like is used. SSI is a scale in which the scores of 19 questions are totaled and the minimum score is 0 and the maximum score is 38. The higher the score, the more serious the symptom. The current SSI score (SSI-C) and the maximum (worst value) (SSI-W) of the patient's SSI score from the past to the present are used for clinical evaluation. Suicidal ideation symptoms herein can be symptoms with an SSI-C score of 1 or higher. Symptoms with higher urgency may be SSI-C of 2 or more, 4 or more, 6 or more, 8 or more, 10 or more, 12 or more, 14 or more, 15 or more, 16 or more. The possibility of suicide can be evaluated by the SSI-C score, but since the score changes according to changes in the mind and feelings, the maximum value (worst value) of the patient's SSI score from the past to the present (SSI-W). More strongly correlates with committing suicide. Specifically, in past reports, a suicide rate of about 6 times higher when the current SSI score (SSI-C) is 2 or more than when it is less than 2. On the other hand, when the maximum value (SSI-W) of the SSI score from the past to the present is 16 or more, the suicide rate increases about 14 times compared to the case where it is less than 16 (Beck AT et al. Suicide Life Threat Behav. 1999). Spring; 29 (1): 1-9). Symptoms with high urgency have a maximum SSI score (SSI-W) of 2 or more, 4 or more, 6 or more, 8 or more, 10 or more, 12 or more, 14 or more, 15 or more, 16 or more. , 17 or more.

By administering the composition containing the serotonin 3 receptor agonist of the present invention, the symptoms of depression can be treated at an early stage. The composition containing the serotonin 3 receptor agonist of the present invention can improve the symptoms of depression within 14 days from the start of administration. Preferably, it can be improved within 7 days. More preferably, it can be improved within 6 days. The time for the therapeutic effect (improving effect) of the symptoms of depression to appear from the administration of the composition of the present invention is 5 days, 4 days, 3 days, 2 days, 1 day, 12 hours, 6 hours, and 2 hours. , Or can be one hour. Currently used depressive drugs have a long time to develop a therapeutic effect, and it takes weeks to months to achieve a sufficient effect, but side effects appear early, so a depressive drug. Many patients discontinue their administration. The composition of the present invention that develops a therapeutic effect at an early stage prevents interruption of administration due to the early onset of side effects and facilitates the treatment of depression.

The composition of the present invention that develops a therapeutic effect at an early stage can treat the urgent symptoms of depression at an early stage. Preferably, the symptoms of urgent depression are ameliorated and treated within 14 days of the start of administration. Preferably, the symptoms of urgent depression can be ameliorated within 7 days. More preferably, the symptoms of urgent depression can be ameliorated within 6 days. The time for the therapeutic effect (improvement effect) of the urgent depressive symptom to appear from the administration of the composition of the present invention is 5 days, 4 days, 3 days, 2 days, 1 day, 12 hours, 6 hours. It can be hours, 2 hours, or 1 hour.

The composition of the present invention may contain two or more serotonin 3 receptor agonists as an active ingredient. The composition of the present invention may contain a therapeutic agent for depression other than the serotonin 3 receptor agonist. In addition, the composition of the present invention may contain a drug other than the therapeutic agent for depression.

The composition of the present invention may be used in combination with other therapeutic agents for depression. The other therapeutic agent for depression is a therapeutic agent for depression other than the serotonin 3 receptor agonist. Other therapeutic agents for depression include, for example, therapeutic agents such as SSRIs, SNRIs and tricyclic antidepressants. Examples of SSRIs include fluoxetine, fluvoxamine, paroxetine, sertraline, and escitalopram.

The composition of the present invention can obtain an excellent antidepressant effect when used in combination with other therapeutic agents for depression.

When administered in combination with other therapeutic agents for depression, the administration start timing of the composition of the present invention is not particularly limited. For example, the composition of the present invention can be started before the antidepressant effect of another depressive therapeutic agent used in combination is exhibited. Since existing therapeutic agents for depression such as SSRI take about 3 weeks to develop antidepressant effect, early administration of the composition of the present invention is suitable for patients who require early improvement of symptoms. The composition of the present invention can be started before the start of administration of another therapeutic agent for depression. The composition of the present invention can be started at the same time as other therapeutic agents for depression. The composition of the present invention can be started after the start of administration of another depressive therapeutic agent and before the anti-depressive effect of the depressive therapeutic agent is exhibited. Administration of the composition of the present invention can be started after the start of administration of another therapeutic agent for depression and when sufficient improvement in the symptoms of depression is not observed.

The composition of the present invention can include a serotonin 3 receptor agonist which is an active ingredient and a pharmaceutically acceptable carrier.

Such carriers include excipients (eg, sugar derivatives such as mannitol, sorbitol; starch derivatives such as corn starch, potato starch; or cellulose derivatives such as crystalline cellulose), lubricants (eg, stearic acid). Metallic acid salts such as magnesium; or talc etc.), binders (eg hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or polyvinylpyrrolidone, etc.), disintegrants (eg, cellulose derivatives such as carboxymethyl cellulose, carboxymethyl cellulose calcium, etc.), Water, preservatives (eg, paraoxybenzoic acid esters such as methylparaben, propylparaben; or alcohols such as chlorobutanol, benzyl alcohol, etc.), pH adjusters (eg, inorganic acids such as hydrochloric acid, sulfuric acid or phosphate, acetic acid). , Organic acids such as starch, starch or cellulose, or salts thereof, etc.), and commonly used pharmaceutical carriers such as diluents (eg, water for injection, etc.), alone or in admixture of two or more. Can be blended. The composition of the present invention contains a liquid preparation in which the active ingredient is dissolved in water.

The serotonin 3 receptor agonist, which is the active ingredient of the present invention, is mixed with the above-mentioned carrier as necessary, and then used as a tablet, a granule, a capsule, a powder, a solution, a suspension, an emulsion, or the like. It can be orally administered in a dosage form, or parenterally in a dosage form such as a suppository, an injection, an intravenous drip, a transdermal agent, a transmucosal agent, or an inhalant.

The serotonin 3 receptor agonist, which is the active ingredient of the present invention, is formulated into the above-mentioned dosage form and then administered to a subject in need thereof, for example, a human or an animal, preferably a human.

The dose and frequency of administration of the serotonin 3 receptor agonist of the present invention may be appropriately changed depending on the conditions such as the severity of symptoms, the age, weight, sex of the patient, the type of drug, the dosage form, and the route of administration. When administered to humans, the active ingredient is, for example parenterally, subcutaneously, intravenously, intraperitoneally, intramuscularly, intrarectally, etc., preferably about 0.01-10 mg / kg body weight per dose. Is about 0.1-5 mg / kg body weight, particularly preferably about 0.3-3 mg / kg body weight, and orally about 0.01-100 mg / kg body weight, preferably about 0.1-50 mg / kg body weight. , Particularly preferably about 1-30 mg / kg body weight. The number of administrations may be once or a plurality of times per day, for example, 1 to 3 times, 1 to 2 times, or once per day.

The serotonin 3 receptor agonist of the present invention can be produced according to a known method. For example, the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof can be produced by the method described in Patent Document 1 or 2. Further, the compounds H, I, J, K, L, M, N, O or P can be produced by the method described in International Publication WO2016 / 027757. Commercially available compounds A, B, C, D, E, F, or G can also be used.

Furthermore, the present invention relates to a method for screening a compound for treating treatment-resistant depression or a compound for treating urgent symptoms in depression, which comprises a step of measuring serotonin 3 receptor agonist activity.

The screening method of the present invention comprises, for example, measuring the serotonin 3 receptor agonist activity for a compound library.

The compound library may be known or unknown. Known compound libraries include compound libraries (eg, RESTWICK) that collect compounds that have already been approved by a food product (eg, US Food and Drug Administration (FDA)) or a drug (eg, European Pharmaceutical Review Board (EMEA)). CHEMICAL libraries) (which is a collection of compounds whose patents have expired), and compound libraries of compounds that have not yet been approved for foods or pharmaceuticals.

In addition, as a method for measuring serotonin 3 receptor agonist activity, the cDNA of 5HT3A receptor or 5HT3AB receptor, which is a subunit of serotonin 3 receptor, is expressed in cells (such as egg mother cells and HEK293 cells of African turkey). A method of measuring the current flowing into the cell electrophysiologically (Nakamura Y et al. Biochem Biophyss Res Commun. 415 (2) (2011) 416-20) or fluoreceptor pivot Examples thereof include a method of measuring the current flowing into the cell by measuring the intensity (Lumisis S et al. Neurophysiology 73 (2013) 241-246). In either method or the like, the serotonin 3 receptor agonist activity can be measured by examining the response obtained by administering the compound to cells.

The screening method of the present invention may further include a step of selecting compounds based on the measured serotonin 3 receptor agonist activity.

Since the compound obtained by the screening method of the present invention has serotonin 3 receptor agonist activity, it can be used for treating refractory depression or for treating urgent symptoms in depression.

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.

<Example 1>
SR57227A (TOCRIS, hydrochloride of compound A) was dissolved in physiological saline to prepare an injectable preparation (0.5 mg / ml).

The agents used in the following reference and test examples are SR57227A (TOCRIS), fluoxetine (Sigma) and ketamine (Daiichi Sankyo).

<Reference example 1>
Analysis of the mechanism of antidepressant action of ketamine Wild-type mice (B6J) (SLC) of 7-11 week old males and 5HT3 receptor knockout mice (Jackson Laboratory) were obtained. Intraperitoneal administration of saline or ketamine (3,10,30 mg / kg) was performed 1 hour later, and a behavioral test (tail suspension test and forced swimming test) was performed (wild-type mouse group n = 12.5HT3 receptor). Knockout mouse group n = 10).
A. The tail suspension test mouse was hung upside down from the tail, and the time of immobility for 6 minutes was measured. The results are shown in FIG.
B. Forced swimming test Mice were placed in a cylindrical container containing water, and the time of immobility for 4 minutes was measured. The results are shown in FIG.

As a result of the tail suspension test and the forced swimming test, it was shown that the immobility time was shortened in each group of wild-type mice treated with ketamine, and that ketamine exhibited antidepressant effect, but each group of 5HT3 receptor knockout mice treated with ketamine. There was no change in immobility time, and ketamine did not exhibit antidepressant effect. It was clarified that the antidepressant effect of ketamine is mediated by the 5HT3 receptor because the antidepressant effect of ketamine is not expressed in 5HT3 receptor knockout mice.

<Test Example 1>
Examination of immediate effect of antidepressant effect We obtained 8-11 week old male wild-type mice (B6J) and 5HT3 receptor knockout mice. Saline, fluoxetine (10 mg / kg) or SR57227A (5 mg / kg) was intraperitoneally administered for 6 days (once / day) (n = 10 in each group). On the 6th day, the animals were fasted, and on the 7th day, a novelty superpressed feeding test (NSF test) was performed. The NSF test is a test used to determine the effect of chronic administration of antidepressants. When animals such as mice are placed in a novel environment, it takes a long time to feed, but chronic administration of antidepressants shortens this time. Specifically, a mouse was placed in a box of 50 cm × 50 cm, and the time until eating food was measured. The results are shown in FIG. The 6-day administration did not shorten the time to eat in the SSRI fluoxetine-administered group, whereas the SR57227A-administered group shortened the time to eat. On the other hand, in 5HT3 receptor knockout mice, SR57227A administration did not shorten the time to eat. After 6 days of administration, fluoxetine did not develop antidepressant effects, whereas SR57227A did. SR57227A did not exhibit antidepressant effects in 5HT3 receptor knockout mice. From the above, it was clarified that the antidepressant effect of SR57227A is expressed via the 5HT3 receptor and has an immediate effect, and that SR57227A can improve the symptoms of depression at an early stage.

<Test Example 2>
Examination Using Treatment-Resistant Depression Model Mice Wild-type mice (BKS. Cg-m + / m +) and type 2 diabetic (leptin receptor deficient) mice (BKS. Cg- + db / + db) Was obtained from Nippon Charles River Co., Ltd. Wild-type mice were used as controls. Saline, fluoxetine (Flx, 10 mg / kg), ketamine (Ket, 10 mg / kg), or SR57227A (SR, 5 mg / kg) was administered intraperitoneally, and one hour later, a behavioral test (tail suspension test and forced swimming test) ) (N = 10 in each group). Type 2 diabetic (leptin receptor deficient) mice (db / db) are used as model mice for treatment-resistant depression, and the literature (Transl Psychiatry 4, e486, 2014) states that the mice are treated with fluoxetine. And is described as resistant to desipramine treatment.

A. The tail suspension test mouse was hung upside down from the tail, and the time of immobility for 6 minutes was measured. The results are shown in FIG.
B. Forced swimming test Mice were placed in a cylindrical container containing water, and the time of immobility for 4 minutes was measured. The results are shown in FIG.

As a result of the tail suspension test and the forced swimming test, the immobility time was shortened in the control mice in the fluoxetine-administered group, the ketamine-administered group, and the SR57227A-administered group. In control mice, fluoxetine, ketamine, and SR57227A all exhibited antidepressant effects.

In the treatment-resistant depression model mice, the fluoxetine-administered group did not shorten the immobility time, but the ketamine-administered group and the SR57227A-administered group shortened the immobility time. In treatment-resistant depression model mice, fluoxetine did not exhibit antidepressant effects, but ketamine and SR57227A did. It was revealed that SR57227A exerts an antidepressant effect on treatment-resistant depression via the 5HT3 receptor and exerts a therapeutic effect on treatment-resistant depression.

The present invention contributes to the treatment of depression.

Claims

A composition for treating treatment-resistant depression containing a serotonin 3 receptor agonist.
The composition according to claim 1, wherein the treatment-resistant depression is SSRI treatment-resistant depression.
The serotonin 3 receptor agonist is based on the following formula (I):

[During the ceremony,
m is an integer from 1 to 4;
R 1 is a hydrogen atom, a halogen atom, a methyl group optionally substituted with 1 to 3 halogen atoms, a methoxy group optionally substituted with 1 to 3 halogen atoms, and 1 to 3 halogen atoms. An ethoxy group optionally substituted with, a methylthio group optionally substituted with 1 to 3 halogen atoms, and a halogen atom, trifluoromethyl, C 1-3 alkyl, C 1-3 alkoxy, C 1 -Independently selected from the group consisting of phenoxy groups, which may be substituted with an alkylthio or cyano group.]
The composition according to claim 1 or 2, which is a compound represented by the above or a pharmaceutically acceptable salt thereof.
The composition according to claim 3, wherein R 1 is an independently halogen atom.
The composition according to claim 4, wherein the halogen atom is a chlorine atom.
A composition comprising a serotonin 3 receptor agonist for treating an urgent symptom in depression.
The composition according to claim 6, wherein the urgent symptom is improved and treated within 14 days from the start of administration.
The composition according to claim 7, wherein within 14 days from the start of administration is within 6 days from the start of administration.
The composition according to any one of claims 6 to 8, wherein the urgent symptom is suicidal ideation.
The serotonin 3 receptor agonist is based on the following formula (I):

[During the ceremony,
m is an integer from 1 to 4;
R 1 is a hydrogen atom, a halogen atom, a methyl group optionally substituted with 1 to 3 halogen atoms, a methoxy group optionally substituted with 1 to 3 halogen atoms, and 1 to 3 halogen atoms. An ethoxy group optionally substituted with, a methylthio group optionally substituted with 1 to 3 halogen atoms, and a halogen atom, trifluoromethyl, C 1-3 alkyl, C 1-3 alkoxy, C 1 -Independently selected from the group consisting of phenoxy groups, which may be substituted with an alkylthio or cyano group.]
The composition according to any one of claims 6 to 9, which is a compound represented by the above or a pharmaceutically acceptable salt thereof.
The composition according to claim 10, wherein R 1 is an independently halogen atom.
The composition according to claim 11, wherein the halogen atom is a chlorine atom.
A method for screening a compound for treating refractory depression or a compound for treating an urgent symptom in depression, which comprises a step of measuring serotonin 3 receptor agonist activity.