Pharmaceutical applications of (s) - norketamine and salts thereof

Abstract

To provide a new compound having long-lasting therapeutic effects on diseases showing depressive symptoms.SOLUTION: The present invention provides a pharmaceutical composition for preventing and / or treating depressive symptoms, which is a drug for preventing and / or treating depressive symptoms comprising (S) - norketamine or a pharmacologically acceptable salt thereof, wherein the pharmaceutical composition contains (S) - norketamine or a pharmacologically acceptable salt thereof in an amount effective for alleviating depressive symptoms and does not substantially contain (R) - norketamine. Also provided is a method for the prevention and / or treatment of depressive symptoms comprising administering said medicament or composition, the use of said medicament or composition in the prevention and / or treatment of depressive symptoms, and the use of (S) - norketamine in the manufacture of a medicament or composition for the prevention and / or treatment of depressive symptoms.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical agent for preventing and / or treating a psychiatric disorder, preferably a disorder exhibiting depressive symptoms. More specifically, the present invention relates to an antidepressant comprising (S)-norketamine, an optical isomer of norketamine (N-desmethylketamine), a prodrug of (S)-norketamine, or a pharmacologically acceptable salt thereof, and a pharmaceutical composition for preventing and / or treating a disorder exhibiting depressive symptoms, comprising (S)-norketamine, a prodrug of (S)-norketamine, or a pharmacologically acceptable salt thereof. This application claims priority from Japanese Patent Application No. 2016-210749, which is incorporated herein by reference. [Background technology]

[0002] With changes in social lifestyles and an aging society, the incidence of various mental and neurological disorders is on the rise overall. For example, the incidence rates of major mental disorders, such as depression and schizophrenia, are high, posing a significant challenge in terms of medical economics. Obsessive-compulsive disorder (OCD), an anxiety disorder characterized by obsessive thoughts and compulsive behaviors, is essential for the treatment of mental disorders such as depression, schizophrenia, and anxiety disorders. Drug therapy is essential for the treatment of these disorders, including antidepressants (e.g., tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors) and antipsychotics (e.g., phenothiazines, butyrophenones, benzamides, iminodibenzyl compounds, thiepins, indoles, and serotonin-dopamine receptor blockers). However, while these drugs are effective in clinical settings for some patients and for some symptoms, there are also known patients who are ineffective, so-called treatment-resistant patients, and the development of new therapeutic agents is urgently needed. It is difficult to say that existing drugs are sufficiently effective in treating these mental illnesses, and in reality, there are almost no effective preventive or therapeutic methods available.

[0003] One of the major problems in the treatment of depression is the limited effectiveness of antidepressants and their supplemental therapy. Current antidepressants take several weeks or more to become effective, and there are treatment-resistant patients who do not respond to these antidepressants. As a result, it is said that only 50% of depressed patients achieve remission. Furthermore, if the dose of antidepressants is increased in an attempt to achieve remission, patients suffer from numerous side effects. Furthermore, depression is one of the causes of suicide.

[0004] Recent research has shown that impaired glutamate transmission, particularly glutamate neurotransmission via N-methyl-D-aspartate (hereinafter referred to as NMDA) receptors, is associated with the pathophysiology of mood disorders such as depression and bipolar disorder, and a growing body of evidence suggests that NMDA receptors play a key role in both neurobiology and the treatment of major depressive disorder (hereinafter referred to as MDD) (Non-Patent Document 1).

[0005] It has been reported that ketamine, an NMDA receptor antagonist, exhibits rapid and potent antidepressant effects in patients with treatment-resistant MDD and depressive symptoms associated with treatment-resistant bipolar disorder (Non-Patent Documents 2-4).Ketamine has also been reported to be effective in treating treatment-resistant obsessive-compulsive disorder and treatment-resistant posttraumatic stress disorder (PTSD) (Non-Patent Documents 5-7).

[0006] Currently, ketamine is one of the drugs attracting attention for the treatment of patients with treatment-resistant MDD, treatment-resistant depressive symptoms of bipolar disorder, treatment-resistant obsessive-compulsive disorder, treatment-resistant PTSD, and autism spectrum disorder (Non-patent documents 4-9).

[0007] Ketamine was developed as an anesthetic in 1962 and began clinical use in 1965. However, due to problems with psychiatric symptoms such as hallucinations and delusions, as well as dependency, it was designated as a narcotic drug. Therefore, in clinical settings, it has been used as an anesthetic and for the treatment of chronic pain.

[0008] The clinical antidepressant effect of ketamine has been reported to last for a short period of 1-2 days, beginning several hours after a single administration, while other reports suggest that it may last for more than 2 weeks (Non-Patent Documents 2, 3, 8).Ketamine also has a side effect known as psychosis-inducing activity, and it has been reported that the antidepressant effect of ketamine does not appear until the side effect has disappeared (Non-Patent Documents 2, 3).

[0009] Ketamine is a racemic mixture containing equal amounts of the optical isomers (R)-ketamine and (S)-ketamine. The present inventors have disclosed that (R)-ketamine or a pharmaceutically acceptable salt thereof has a rapid-acting, long-lasting antidepressant effect with fewer side effects observed with (S)-ketamine, and is therefore effective in the prevention and / or treatment of psychiatric disorders exhibiting depressive symptoms (Patent Documents 1 and 2 and Non-Patent Documents 10 and 11).

[0010] Norketamine is a major metabolite of ketamine and has been reported to have an affinity for NMDA receptors approximately 6.8 times lower than that of ketamine (Non-Patent Document 12). Like ketamine, norketamine is also known to have optical isomers, which are called (R)-norketamine and (S)-norketamine.

[0011] Furthermore, it has been reported that norketamine exhibits antidepressant activity, although its activity is weaker than that of ketamine (Non-Patent Document 13). [Prior art documents] [Patent documents]

[0012] [Patent Document 1] JP 2015-078181 A. [Patent Document 2] International Publication No. 2015 / 037248 Brochure. [Patent Document 3] U.S. Patent No. 6,040,479. [Non-patent literature]

[0013] [Non-Patent Document 1] Hashimoto K (2009) Emerging role of glutamatein the pathophysiology of major depressive disorder. Brain Res. Rev. 61:105-23. [Non-patent document 2] Berman RM, Cappiello A, An and A, Oren DA, Henninger GR, Charney DS, Krystal JH (2000) Antidepressant effects of ketaminein depressed patients. Biol. Psychiatry 47:351-4. [Non-patent document 3] Zarate CA, Jr, Singh JB, Carlson PJ, BrutscheNE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK (2006) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.Arch. Gen. Psychiatry 63:856-64. [Non-patent document 4] Diazgranados N , Ibrahim L , Brutsche NE , Newberg A , Kronstein P , Khalife S , Kammerer WA , Quezado Z , Luckenbaugh DA , Salvadore G , Machado-Vieira R , Manji HK , Zarate CA Jr . (2010) A randomizedadd-on trial of an N-methyl-D-aspartate antagonist in treatment-resistantbipolar depression. Arch. Gen. Psychiatry 67:793–802.

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Non-Patent Document 12

Non-Patent Document 13

Non-Patent Document 14

[0014] Ketamine, an NMDA receptor antagonist, has been reported to have rapid antidepressant effects in patients with treatment-resistant depression. However, ketamine is classified as a narcotic drug due to its psychiatric symptoms, such as hallucinations and delusions, as well as side effects such as dependency, making its clinical application difficult.

[0015] An object of the present invention is to provide a novel compound having a long-lasting therapeutic effect on diseases exhibiting depressive symptoms. [Means for solving the problem]

[0016] In the course of intensive research to solve the above problems, the present inventors focused on norketamine, a major metabolite of ketamine, an NMDA receptor antagonist, which had not previously been used in research into the antidepressant effects of ketamine.

[0017] Glutamate neurotransmission via NMDA receptors is thought to be involved in depression, and ketamine has been reported to have rapid antidepressant effects in patients with treatment-resistant depression. Furthermore, it is generally understood that both the analgesic and psychotic effects of ketamine are primarily mediated by blockade of NMDA receptors.

[0018] On the other hand, norketamine, the main metabolite of ketamine, has a lower NMDA receptor affinity than ketamine, so no one has shown any interest in its pharmacological effects as an antidepressant. Furthermore, because norketamine has a lower NMDA receptor affinity, its psychotic effects are expected to be weaker than those of ketamine.

[0019] In a study using a mouse model exhibiting depression-like symptoms, the present inventors found that norketamine exhibits stronger antidepressant effects than ketamine. Meanwhile, the side effects observed with ketamine administration, such as increased locomotion and impaired prepulse inhibition, were weaker with norketamine administration than with ketamine. Norketamine's affinity for NMDA receptors is lower than that of ketamine, suggesting that it has fewer psychotic side effects and is less likely to lead to drug dependence.

[0020] Additionally, in a social defeat stress model of depression, (S)-norketamine exhibited antidepressant effects, whereas (R)-norketamine did not. Furthermore, the antidepressant effects of (S)-norketamine were stronger than those of (R)-norketamine. Furthermore, (S)-norketamine did not induce hyperlocomotion, impaired prepulse inhibition, or rewarding effects. Furthermore, norketamine and (S)-norketamine are not designated as narcotics, making them easier to use in clinical settings than ketamine, which is designated as a narcotic. The present invention was achieved based on these findings.

[0021] That is, the present invention comprises the following. 1. A drug for preventing and / or treating depressive symptoms, comprising (S)-norketamine, a prodrug of (S)-norketamine, or a pharmacologically acceptable salt thereof. 2. A drug for preventing and / or treating depressive symptoms according to the preceding item 1, wherein the depressive symptoms are depressive symptoms in depression, depressive symptoms in obsessive-compulsive disorder, depressive symptoms in post-traumatic stress disorder (PTSD), or depressive symptoms in autism spectrum disorder. 3. A drug for preventing and / or treating depressive symptoms according to the preceding item 1 or 2, wherein the pharmacologically acceptable salt of (S)-norketamine is (S)-norketamine hydrochloride. 4. A drug for the prevention and / or treatment of depressive symptoms according to the preceding item 1 or 2, wherein the prodrug of (S)-norketamine is a compound represented by the following formula (VI), formula (VII), formula (XIII), or formula (XIV), or a pharmacologically acceptable salt or hydrochloride thereof, wherein in said formula, R is an alkyl group, an alkoxy group, an aryl group, or an aralkyl group, and R1 and R2 are each independently an alkyl group, an alkoxy group, an aryl group, or an aralkyl group. [ka] [ka] [ka] [ka] 5. A pharmaceutical composition for the prevention and / or treatment of depressive symptoms, comprising (S)-norketamine, a prodrug of (S)-norketamine, or a pharmacologically acceptable salt thereof in an amount effective for alleviating depressive symptoms, and substantially free of (R)-norketamine or a pharmacologically acceptable salt thereof. 6. The pharmaceutical composition for preventing and / or treating depressive symptoms according to the preceding item 5, wherein the depressive symptoms are depressive symptoms in depression, depressive symptoms in obsessive-compulsive disorder, depressive symptoms in PTSD, or depressive symptoms in autism spectrum disorder. 7. The pharmaceutical composition for preventing and / or treating depressive symptoms according to the preceding item 5 or 6, wherein the pharmacologically acceptable salt of (S)-norketamine is (S)-norketamine hydrochloride. 8. A pharmaceutical composition for the prevention and / or treatment of depressive symptoms according to the preceding item 5 or 6, wherein the prodrug of (S)-norketamine is a compound represented by the following formula (VI), formula (VII), formula (XIII) or formula (XIV), or a pharmacologically acceptable salt or hydrochloride thereof, wherein in the formula, R is an alkyl group, an alkoxy group, an aryl group, or an aralkyl group, and R1 and R2 are each independently an alkyl group, an alkoxy group, an aryl group, or an aralkyl group. [ka] [ka] [ka] [ka] 9. A method for preventing and / or treating depressive symptoms, comprising administering to a patient in need of such prevention and / or treatment an amount of (S)-norketamine, a prodrug of (S)-norketamine, or a pharmacologically acceptable salt thereof effective for alleviating depressive symptoms. 10. The method for preventing and / or treating depressive symptoms according to the preceding paragraph 9, wherein the depressive symptoms are depressive symptoms in depression, depressive symptoms in obsessive-compulsive disorder, depressive symptoms in PTSD, or depressive symptoms in autism spectrum disorder. 11. The method for preventing and / or treating depressive symptoms according to the preceding item 9 or 10, wherein the pharmacologically acceptable salt of (S)-norketamine is (S)-norketamine hydrochloride. 12. A method for preventing and / or treating depressive symptoms according to the preceding item 9 or 10, wherein the prodrug of (S)-norketamine is a compound represented by the following formula (VI), formula (VII), formula (XIII) or formula (XIV), or a pharmacologically acceptable salt or hydrochloride thereof, wherein in the formula, R is an alkyl group, an alkoxy group, an aryl group, or an aralkyl group, and R1 and R2 are each independently an alkyl group, an alkoxy group, an aryl group, or an aralkyl group. [ka] [ka] [ka] [ka] 13. Use of (S)-norketamine, a prodrug of (S)-norketamine, or a pharmacologically acceptable salt thereof in the manufacture of a pharmaceutical composition for the prevention and / or treatment of depressive symptoms. 14. The use according to the preceding paragraph 13, wherein the depressive symptoms are depressive symptoms in depression, depressive symptoms in obsessive-compulsive disorder, depressive symptoms in PTSD, or depressive symptoms in autism spectrum disorder. 15. The method according to the preceding item 13 or 14, wherein the pharmacologically acceptable salt of (S)-norketamine is (S)-norketamine hydrochloride. 16. The use according to the preceding item 13 or 14, wherein the prodrug of (S)-norketamine is any one compound selected from the compounds represented by the following formulas (III) to (XIV) or a pharmacologically acceptable salt or hydrochloride thereof, wherein in the formula, R is an alkyl group, an alkoxy group, an aryl group, or an aralkyl group, and R1 and R2 are each independently an alkyl group, an alkoxy group, an aryl group, or an aralkyl group: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] 17. (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl(S)-(1-(2-chlorophenyl)-2-oxocyclohexyl)carbamate. 18. 1-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)carbamoyl)oxy)ethylisobutyrate {1-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)carbamoyl)oxy)ethylisobutyrate}. 19. A drug for the prevention and / or treatment of depressive symptoms comprising (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-(S)-(1-(2-chlorophenyl)-2-oxocyclohexyl)carbamic acid or 1-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)carbamoyl)oxy)ethyl isobutyric acid. 20. (S)-norketamine, a prodrug of (S)-norketamine, or a pharmacologically acceptable salt thereof for the prevention and / or treatment of depressive symptoms. 21. (S)-norketamine, a prodrug of (S)-norketamine, or a pharmacologically acceptable salt thereof for the prevention and / or treatment of depressive symptoms, which is a compound represented by the following formula (VI), (VII), (XIII), or (XIV), wherein R is an alkyl group, an alkoxy group, an aryl group, or an aralkyl group, and R1 and R2 are each independently an alkyl group, an alkoxy group, an aryl group, or an aralkyl group. [Effects of the Invention]

[0022] Norketamine, particularly its optical isomer (S)-norketamine, has long-lasting antidepressant effects with few side effects, making it effective for the prevention and / or treatment of psychiatric disorders characterized by depressive symptoms. Therefore, a drug comprising (S)-norketamine or a pharmacologically acceptable salt thereof, as well as a pharmaceutical composition containing (S)-norketamine or a pharmacologically acceptable salt thereof but substantially free of (R)-norketamine or a pharmacologically acceptable salt thereof, are useful as novel pharmaceuticals in the field of the prevention and / or treatment of psychiatric disorders characterized by depressive symptoms. [Brief explanation of the drawings]

[0023] [Figure 1A] Figure 1 illustrates the experimental design for investigating the antidepressant effect of norketamine. The experiment was conducted using 8-week-old male C57BL / 6 mice (purchased from CLEA Japan) intraperitoneally administered 0.5 mg / kg of lipopolysaccharide (hereinafter referred to as LPS) (hereinafter referred to as LPS-treated mice) as an inflammatory model of depression. 23 hours after LPS administration, saline (10 ml / kg) or norketamine (5, 10, or 20 mg / kg) was intraperitoneally administered. One hour later, a locomotor activity test (hereinafter sometimes abbreviated as LMT) was performed, 3 hours later, a tail suspension test (hereinafter sometimes abbreviated as TST) was performed, and 5 hours later, a forced swimming test (hereinafter sometimes abbreviated as FST) was performed. (Example 1) [Figure 1B]This figure explains the results of a spontaneous motor activity test examining the amount of spontaneous motor activity after norketamine administration. There was no difference in spontaneous motor activity between normal mice (Normal), LPS-treated mice administered with saline, and LPS-treated mice administered with norketamine (5, 10, or 20 mg / kg). The vertical axis of the figure indicates spontaneous motor activity (counts / 60 minutes). (Example 1) [Figure 1C] This figure explains the results of examining the antidepressant effect of norketamine in a tail suspension test. A significant increase in immobility time was observed in LPS-treated mice administered with saline compared to control mice. Norketamine dose-dependently reduced the increased immobility time in LPS-treated mice. The vertical axis of the figure represents immobility time (seconds) in the TST. (Example 1) [Figure 1D] This figure explains the results of examining the antidepressant effect of norketamine in a forced swimming test. A significant increase in immobility time was observed in LPS-treated mice administered with saline compared to control mice. Norketamine dose-dependently reduced the increased immobility time in LPS-treated mice. The vertical axis of the figure represents immobility time (seconds) in the FST. (Example 1) [Figure 2A] FIG. 1 illustrates the experimental design for a comparative study of the antidepressant effects of ketamine and norketamine. Eight-week-old male C57 / BL6 mice (purchased from CLEA Japan) were intraperitoneally administered 0.5 mg / kg of LPS, and 23 hours after LPS administration, saline (10 ml / kg), ketamine (10 mg / kg), or norketamine (10 mg / kg) was intraperitoneally administered. LMT was performed 1 hour after administration, TST 3 hours later, and FST 5 hours later. (Example 2) [Figure 2B] This figure illustrates the results of a comparative study of spontaneous motor activity after administration of ketamine and norketamine. There was no difference in spontaneous motor activity between normal mice, LPS-treated mice administered with saline, and LPS-treated mice administered with ketamine (10 mg / kg) and norketamine (10 mg / kg). The vertical axis of the figure indicates spontaneous motor activity (counts / 60 minutes). (Example 2) [Figure 2C]This figure explains the experimental design for comparing the antidepressant effects of ketamine and norketamine using the TST. A significant increase in immobility time was observed in LPS-treated mice administered with saline compared to control mice. Both ketamine and norketamine significantly reduced the increased immobility time in LPS-treated mice. The antidepressant effect of norketamine was significantly stronger than that of ketamine. The vertical axis of the figure indicates immobility time (seconds) in the TST. (Example 2) [Figure 2D] This figure explains the experimental design for comparing the antidepressant effects of ketamine and norketamine in the FST. A significant increase in immobility time was observed in LPS-treated mice administered with saline compared to control mice. Both ketamine and norketamine significantly reduced the increased immobility time in LPS-treated mice. The antidepressant effect of norketamine was significantly stronger than that of ketamine. The vertical axis of the figure indicates the immobility time (seconds) in the FST. (Example 2) [Figure 3A] The results of a comparative study of the side effects of ketamine and norketamine based on their activity to increase locomotion, one of the evaluation methods for side effects, are shown below. Mice administered ketamine (10 mg / kg) and norketamine (20 mg / kg) showed a significant increase in locomotion 10 minutes after drug administration compared with normal mice administered saline. On the other hand, administration of 5 mg / kg and 10 mg / kg of norketamine did not affect locomotion. The vertical axis of the figure indicates spontaneous locomotion (counts / 10 minutes). (Example 3) [Figure 3B] The side effects of ketamine and norketamine were compared based on changes in prepulse (PP) inhibition, one of the evaluation methods for side effects. Administration of ketamine (10 mg / kg) resulted in impaired prepulse inhibition at prepulse stimuli of 77 dB and 81 dB (Figure 3B). On the other hand, administration of norketamine at 20 mg / kg significantly impaired prepulse inhibition at 81 dB, but administration of 5 mg / kg or 10 mg / kg did not. The vertical axis of the figure represents prepulse inhibition (%). (Example 3) [Figure 4A]This figure shows the antidepressant effects of (S)- and (R)-norketamine in social defeat stress mice. In the figure, S-NK and R-NK represent social defeat stress mice administered with (S)-norketamine (10 mg / kg) and (R)-norketamine (10 mg / kg), respectively. Saline represents a social defeat stress mouse group administered with saline (10 ml / kg). Control represents a normal mouse group administered with saline. In the figure, LMT represents locomotor activity test, TST represents tail suspension test, FST represents forced swimming test, and SPT represents 1% sucrose preference test. (Example 4) [Figure 4B] This figure shows the results of LMT analysis of the antidepressant effects of (S)- and (R)-norketamine in social defeat stress mice one day after administration. In the figure, S-NK and R-NK represent social defeat stress mouse groups administered with (S)-norketamine and (R)-norketamine, respectively; Saline represents a social defeat stress mouse group administered with saline; and Control represents a normal mouse group administered with saline. The vertical axis of the figure represents spontaneous movement activity (counts / 60 minutes). (Example 4) [Figure 4C] This figure shows the results of examining the antidepressant effects of (S)- and (R)-norketamine in social defeat stress mice using the TST one day after administration. In the figure, S-NK and R-NK represent social defeat stress mouse groups administered with (S)-norketamine and (R)-norketamine, respectively; Saline represents a social defeat stress mouse group administered with saline; and Control represents a normal mouse group administered with saline. The vertical axis of the figure represents immobility time (seconds) in the TST. (Example 4) [Figure 4D] This figure shows the results of examining the antidepressant effects of (S)- and (R)-norketamine in social defeat stress mice using the FST two days after administration. In the figure, S-NK and R-NK represent social defeat stress mouse groups administered with (S)-norketamine and (R)-norketamine, respectively; Saline represents a social defeat stress mouse group administered with saline; and Control represents a normal mouse group administered with saline. The vertical axis of the figure represents the immobility time (seconds) in the FST. (Example 4) [Figure 4E] This figure shows the results of examining the antidepressant effects of (S)- and (R)-norketamine in social defeat stress mice using a 1% sucrose preference test 7 days after administration. In the figure, S-NK and R-NK represent social defeat stress mouse groups administered with (S)-norketamine and (R)-norketamine, respectively; Saline represents a social defeat stress mouse group administered with saline; and Control represents a normal mouse group administered with saline. The vertical axis of the figure represents sucrose preference (%). (Example 4) [Figure 4F] 1 shows the results of examining the effects of (S)- and (R)-norketamine on spine density in brain regions of social defeat stress mice 8 days after administration (Example 4). [Figure 4G] The results of a comparative study of the side effects of (S)-norketamine and (S)-ketamine based on their activity to increase locomotion, which is one of the evaluation methods for side effects, are shown in the figure. In the figure, S-norket, S-ket, and saline represent groups administered with (S)-norketamine, (S)-ketamine, and saline, respectively. The vertical axis of the figure represents spontaneous locomotion (counts / 10 minutes). (Example 4) [Figure 4H] This figure shows the results of a comparison of the side effects of (S)-norketamine and (S)-ketamine in a prepulse inhibition test, which is one of the methods for evaluating side effects. In the figure, Saline, S-ket, and S-norket represent groups administered with saline, (S)-ketamine, and (S)-norketamine, respectively. Furthermore, each bar represents, from left to right, groups administered with saline, (S)-ketamine 10 mg / kg, (S)-norketamine 5 mg / kg, (S)-norketamine 10 mg / kg, and (S)-norketamine 20 mg / kg. The vertical axis of the figure represents prepulse inhibition (%). (Example 4) [Figure 4I]This figure shows the results of comparing the side effects of (S)-norketamine and (S)-ketamine in a place preference test (CPP test), which is one of the methods for evaluating side effects. In the figure, S-norket, S-ket, and saline represent groups administered with (S)-norketamine (20 mg / kg), (S)-ketamine (20 mg / kg), and saline (10 ml / kg), respectively. The vertical axis of the figure represents the CPP score. (Example 4) [Figure 5] Synthesis scheme of (S)-norketamine derivatives (Example 5) [Figure 6A] This figure shows the antidepressant effect of an (S)-norketamine derivative in socially defeated mice. In the figure, "Vehicle" refers to the vehicle (0.5% carboxymethylcellulose (CMC) 10 ml / kg, 0.4% DMSO), and "Compound 1" refers to the (S)-norketamine derivative (30 mg / kg). "PO" refers to oral administration. "LMT" refers to the spontaneous motor activity test, and "SPT" refers to the 1% sucrose preference test. The vertical axis of the figure indicates spontaneous motor activity (counts / 60 minutes). (Example 7) [Figure 6B] This figure shows the results of an LMT study of the spontaneous motor activity 1 hour after oral administration of an (S)-norketamine derivative to assess the antidepressant effect in socially defeated mice. In the figure, "Vehicle" represents the vehicle (0.5% carboxymethylcellulose (CMC) 10 ml / kg, 0.4% DMSO), and "Compound 1" represents the (S)-norketamine derivative (30 mg / kg). "Control" represents a group of normal mice administered with the vehicle. The vertical axis of the figure represents spontaneous motor activity (counts / 60 minutes). (Example 7) [Figure 6C] This figure shows the results of a 1% sucrose preference test conducted to examine the antidepressant effect of an (S)-norketamine derivative in socially defeated mice, examining sucrose preference 3 and 7 days after oral administration. Control indicates a group of normal mice administered with the vehicle. The vertical axis of the figure indicates sucrose preference (%). (Example 7) DETAILED DESCRIPTION OF THE INVENTION

[0024] The present invention relates to a pharmaceutical agent for preventing and / or treating depressive symptoms, comprising (S)-norketamine, an optical isomer of norketamine, a prodrug of (S)-norketamine, or a pharmacologically acceptable salt thereof. The present invention also relates to a pharmaceutical composition for preventing and / or treating depressive symptoms, comprising (S)-norketamine, a prodrug of (S)-norketamine, or a pharmacologically acceptable salt thereof in an amount effective for alleviating depressive symptoms.

[0025] In the present invention, we demonstrated that norketamine, a major metabolite of ketamine, has a stronger antidepressant effect than ketamine using an inflammatory animal model of depression. This animal model was created based on the finding that depression-like behavior is observed in mice administered LPS in adulthood (Non-Patent Documents 14-16).

[0026] Furthermore, in the present invention, it was revealed that (S)-norketamine, a major metabolite of (S)-ketamine, exhibits antidepressant effects in a social defeat stress model, and that the antidepressant effects are still observed 7 days after administration. Furthermore, it was revealed that when a prodrug of (S)-norketamine was administered to the same model, the antidepressant effects were also observed, and that the antidepressant effects are still observed 7 days after administration.

[0027] A single dose of norketamine demonstrated a stronger antidepressant effect than ketamine in a mouse model of inflammatory depression induced by LPS administration (see Examples 1 and 2). (S)-norketamine demonstrated a strong antidepressant effect in a social defeat stress model, with the antidepressant effect confirmed even 7 days after administration (see Example 4). Furthermore, when a prodrug of (S)-norketamine was administered to the same model, a strong antidepressant effect was also demonstrated, with the antidepressant effect confirmed even 7 days after administration (see Example 7). Meanwhile, significant changes were observed in the locomotor activity increase and prepulse inhibition impairment, which are used to evaluate side effects, with ketamine administration, whereas norketamine and (S)-norketamine showed weak side effects (see Examples 3 and 4). Furthermore, norketamine, (S)-norketamine, and (R)-norketamine have lower NMDA receptor affinity than ketamine (Non-Patent Document 12), and are thought to have fewer side effects, such as psychotic symptom induction, and therefore may be more promising and safer antidepressants than ketamine. In fact, ketamine is designated as a narcotic, but norketamine is not.

[0028] Like ketamine, norketamine is known to exist as optical isomers, designated (R)-norketamine and (S)-norketamine. Ketamine is a racemic mixture containing equal amounts of (R)-ketamine and (S)-ketamine. The present inventors have disclosed that (R)-ketamine or a pharmacologically acceptable salt thereof is effective in preventing and / or treating psychiatric disorders exhibiting depressive symptoms because it has rapid and long-lasting antidepressant effects that are statistically significantly higher than those of (S)-ketamine and has fewer side effects than those observed with (S)-ketamine (Patent Documents 1 and 2 and Non-Patent Documents 10 and 11). However, among norketamine's optical isomers, it has been revealed that (S)-norketamine is primarily responsible for the high antidepressant effect and low side effects, in contrast to the optical isomers of ketamine.

[0029] (S)-Norketamine or a pharmacologically acceptable salt thereof can be used as an antidepressant to treat and / or prevent depression, loss of motivation, anxiety and associated depressive symptoms such as insomnia and loss of appetite, and suicidal thoughts.

[0030] The pharmaceutical composition of the present invention may be substantially free of (R)-norketamine or a pharmacologically acceptable salt thereof, and such a pharmaceutical composition is preferred. The term "substantially free of (R)-norketamine or a pharmacologically acceptable salt thereof" means that the composition is completely free of (R)-norketamine or a pharmacologically acceptable salt thereof, or that the composition may contain the compound or a pharmacologically acceptable salt thereof in an amount sufficient to prevent the compound from exerting its effects or side effects, or that the composition may contain the compound or a pharmacologically acceptable salt thereof as an impurity unavoidably mixed in during the manufacturing process. For example, the content of (R)-norketamine or a pharmacologically acceptable salt thereof in the pharmaceutical composition may be 2 wt% or less, preferably 1 wt% or less, and more preferably 0.5 wt% or less. For example, the content of (R)-norketamine or a pharmacologically acceptable salt thereof in 100 mg of the pharmaceutical composition may be 2 mg or less, preferably 1 mg or less, and more preferably 0.5 mg or less. Furthermore, for example, per 100 mg of (S)-norketamine in the pharmaceutical composition, the amount of (R)-norketamine may be 2 mg or less, preferably 1 mg or less, and more preferably 0.5 mg or less. Furthermore, the pharmaceutical composition of the present invention may be substantially free of ketamine, (R)-ketamine, (S)-ketamine, or pharmacologically acceptable salts thereof, and such pharmaceutical compositions are preferred. The term "substantially free of ketamine, (R)-ketamine, (S)-ketamine, or pharmacologically acceptable salts thereof" means that such compounds or pharmacologically acceptable salts thereof are completely absent, or that such compounds or pharmacologically acceptable salts thereof may be contained in an amount sufficient to prevent the compounds or pharmacologically acceptable salts from exerting their effects or side effects, or that such compounds or pharmacologically acceptable salts may be contained as impurities unavoidably mixed in during the manufacturing process. For example, the content of such compounds or pharmacologically acceptable salts in the pharmaceutical composition may be 2 wt% or less, preferably 1 wt% or less, and more preferably 0.5 wt% or less. For example, the content of such compounds or pharmacologically acceptable salts in 100 mg of the pharmaceutical composition may be 2 mg or less, preferably 1 mg or less, and more preferably 0.5 mg or less.

[0031] The drugs and pharmaceutical compositions of the present invention are preferably applicable to diseases exhibiting depressive symptoms, such as depression, MDD, and bipolar disorder, which alternates between depressive symptoms and their opposite, manic symptoms. Furthermore, since ketamine has been reported to be effective for treatment-resistant obsessive-compulsive disorder, treatment-resistant PTSD, and autism spectrum disorder (Non-Patent Documents 5-7, 9), the drugs and pharmaceutical compositions of the present invention are also preferably applicable to obsessive-compulsive disorder, PTSD, and autism spectrum disorder. Obsessive-compulsive disorder is a type of anxiety disorder characterized by obsessions and compulsive behaviors. It is believed to be associated with depression, and many cases of depression coexist, exhibiting depressive symptoms in addition to obsessions and compulsive behaviors. Many PTSD patients exhibit depressive symptoms, and antidepressants such as SSRIs are used to treat PTSD, but their therapeutic efficacy is limited. Autism spectrum disorder is a developmental disorder characterized by an inability to maintain normal social relationships, abnormal language use, and threatening behaviors. The scope of the present invention includes a pharmaceutical composition for the prevention and / or treatment of obsessive-compulsive disorder, PTSD, and autism spectrum disorder, which contains (S)-norketamine or a pharmacologically acceptable salt thereof in an amount effective for alleviating the symptoms of obsessive-compulsive disorder, PTSD, and autism spectrum disorder.

[0032] The medicaments and pharmaceutical compositions of the present invention can be administered orally or parenterally. For oral administration, known dosage forms such as tablets, capsules, coated tablets, troches, and liquid preparations such as solutions or suspensions can be used. Parenteral administration can include intravenous, intramuscular, or subcutaneous administration by injection, transmucosal administration such as nasal or oral administration using sprays or aerosols, rectal administration using suppositories, and transdermal administration using patches, liniments, gels, etc. Preferred are oral administration, nasal administration, and intravenous administration by injection.

[0033] (S)-Norketamine is a compound represented by the following formula (I) and can be used in the form of either a free base or a pharmacologically acceptable salt thereof. As the pharmacologically acceptable salt, a pharmacologically acceptable acid addition salt is preferred, and the hydrochloride salt is more preferred.

[0034] [ka]

[0035] (S)-Norketamine can be produced by known methods, for example, using 1-(2-chlorophenyl)-1-cyclohexene as a starting material (Non-Patent Document 17, formula (II) below).

[0036] [ka]

[0037] (S)-norketamine or a pharmacologically acceptable salt thereof can be modified, for example, by substituting a chlorine atom with another halogen atom to produce a derivative, which may result in a compound with a more desirable effect.

[0038] Furthermore, prodrugs of (S)-norketamine or pharmacologically acceptable salts thereof can be synthesized and developed as pharmaceuticals. A prodrug refers to a compound that does not exhibit the intended pharmacological effect itself, or exhibits only a weak effect, but is metabolized to an active metabolite after administration to a living body, thereby exhibiting the desired pharmacological effect. In other words, a prodrug of (S)-norketamine refers to a compound that does not exhibit the intended pharmacological effect itself, or exhibits only a weak effect, but is metabolized to (S)-norketamine after administration to a living body, thereby exhibiting the effect of alleviating depressive symptoms. The design of (S)-norketamine prodrugs can be carried out using publicly reported methods (Non-Patent Documents 18 and 19). The prodrug of (S)-norketamine is not particularly limited as long as it is metabolized to (S)-norketamine in a living body and exhibits the effect of alleviating depressive symptoms. For example, a compound in which a substituent has been introduced into the nitrogen atom of the amino group of (S)-norketamine can be used.Specific examples of prodrugs of (S)-norketamine include N-alkylated (S)-norketamine represented by the following formula (III), N-amide derivatives of (S)-norketamine represented by the following formula (IV), N-carbamate derivatives of (S)-norketamine represented by the following formula (V), N-acyloxyalkyl carbamates of (S)-norketamine represented by the following formula (VI), oxodioxolenylmethyl carbamates of (S)-norketamine represented by the following formula (VII), N-oxodioxolenylmethyl derivatives of (S)-norketamine represented by the following formula (VIII), and N-Mannich base derivatives of (S)-norketamine represented by the following formula (IX). Examples include S-norketamine, phosphoryloxy methyl carbamates of S-norketamine represented by the following formula (X), N-phosphate derivatives of S-norketamine represented by the following formula (XI), and imines of S-norketamine represented by the following formula (XII). In the formulas below containing R, the substituent R is preferably an alkyl group, an alkoxy group, an aryl group, or an aralkyl group, more preferably a lower alkyl group or a lower alkoxy group, and even more preferably a methyl group, an ethyl group, a butyl group, a methoxy group, an ethoxy group, or a butoxy group. In the formulas below containing R1 and R2, the substituents R1 and R2 are each independently preferably an alkyl group, an alkoxy group, an aryl group, or an aralkyl group, more preferably a lower alkyl group or a lower alkoxy group, and even more preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a methoxy group, an ethoxy group, or a butoxy group.Examples of compounds satisfying these R, R1, and R2 include (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-(S)-(1-(2-chlorophenyl)-2-oxocyclohexyl)carbamate} represented by the following formula (XIII) and 1-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)carbamoyl)oxy)ethylisobutyrate} represented by the following formula (XIV). The pharmacologically acceptable salt of the (S)-norketamine prodrug can be used in the form of either the free base or a pharmacologically acceptable salt thereof. As the pharmacologically acceptable salt, a pharmacologically acceptable acid addition salt is preferred, and the hydrochloride salt is more preferred.

[0039] [ka]

[0040] [ka]

[0041] [ka]

[0042] [ka]

[0043] [ka]

[0044] [ka]

[0045] [ka]

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[0048] [ka]

[0049] [ka]

[0050] [ka]

[0051] Furthermore, the compound according to the present invention may be isotopic-labeled, for example, with a stable isotope. 13 C and 2 By using H(D), quantitative measurements of the in vivo kinetics of this compound can be performed.

[0052] In addition to (S)-norketamine, a prodrug of (S)-norketamine, or a pharmacologically acceptable salt thereof, the pharmaceutical composition of the present invention may contain other medicinal ingredients effective against depressive symptoms. In addition to these medicinal ingredients, the composition may also contain appropriate pharmacologically acceptable carriers well known to those skilled in the art, depending on the dosage form, etc. Examples of pharmacologically acceptable carriers include antioxidants, stabilizers, preservatives, flavoring agents, coloring agents, solubilizers, surfactants, emulsifiers, antifoaming agents, viscosity modifiers, gelling agents, absorption enhancers, dispersants, excipients, and pH adjusters.

[0053] When the medicaments and pharmaceutical compositions of the present invention are prepared as injectable formulations, they are preferably in the form of solutions or suspensions. For transmucosal administration, such as nasal or oral administration, they are preferably in the form of powders, drops, or aerosols. For rectal administration, semisolid formulations such as creams or suppositories are preferred. All of these formulations can be prepared by any method known to those skilled in the pharmaceutical arts, such as those described in Remington's Pharmaceutical Sciences (Mack Publishing Company, Easton, PA, 1970). Injectable formulations can contain carriers such as plasma-derived proteins such as albumin, amino acids such as glycine, and sugars such as mannitol. Furthermore, buffers, solubilizers, and isotonicity agents can also be added. When used as aqueous or lyophilized formulations, Tween 2000 can be used to prevent aggregation. (登録商標) 80, Tween (登録商標)It is preferable to add a surfactant such as 20. Furthermore, parenteral dosage forms other than injection preparations may contain distilled water or physiological saline, polyalkylene glycols such as polyethylene glycol, plant-derived oils, hydrogenated naphthalene, etc. For example, preparations for rectal administration such as suppositories contain common excipients such as polyalkylene glycols, petrolatum, and cocoa oil. Vaginal preparations may contain absorption enhancers such as bile salts, ethylenediamine salts, and citrate salts. Preparations for inhalation may be solid and may contain excipients such as lactose, and nasal drops may be water or oil solutions.

[0054] The exact dosage and administration schedule of the drugs and pharmaceutical compositions of the present invention can be adjusted depending on the required amount, treatment method, disease or severity of need, etc. of each individual subject. The dosage can be determined specifically depending on the age, body weight, general health condition, sex, diet, administration time, administration method, excretion rate, drug combination, and the patient's condition, and may also be determined taking other factors into consideration. When the pharmaceutical composition of the present invention is administered to diseases exhibiting depressive symptoms, such as depression, bipolar disorder, and obsessive-compulsive disorder, the active ingredient contained in the pharmaceutical composition preferably contains an amount effective for alleviating the symptoms of each disease, such as depression, bipolar disorder, and obsessive-compulsive disorder, preferably the depressive symptoms of each disease. (S)-norketamine or a pharmacologically acceptable salt thereof has fewer side effects than ketamine and can be used safely. The daily dosage varies depending on the condition and body weight of the patient, the type of compound, the route of administration, and the like. For example, in the case of parenteral administration, the amount of the active ingredient is about 0.01 to 1000 mg / person / day, preferably 0.1 to 500 mg / person / day, 0.1 to 100 mg / person / day, 1.0 to 100 mg / person / day, 10 to 10 The dose is preferably 0 mg / person / day, 100 to 200 mg / person / day, 200 to 300 mg / person / day, 300 to 400 mg / person / day, or 400 to 500 mg / person / day, and in the case of oral administration, the dose is preferably about 0.01 to 500 mg / person / day, and more preferably 0.1 to 100 mg / person / day, 0.1 to 1.0 mg / person / day, 1.0 to 20 mg / person / day, 20 to 40 mg / person / day, 40 to 60 mg / person / day, or 80 to 100 mg / person / day.

[0055] The present invention further relates to a method comprising administering the agent or pharmaceutical composition according to the present invention to a patient in need of prevention and / or treatment of depressive symptoms. The present invention also relates to a method for preventing and / or treating depressive symptoms, comprising administering to a subject the agent according to the present invention in an amount effective for alleviating depressive symptoms. The present invention further relates to a method for preventing and / or treating depressive symptoms, comprising administering to a subject the pharmaceutical composition according to the present invention in an amount effective for alleviating depressive symptoms. The subject to which the composition is administered may be a human or mammal diagnosed with depressive symptoms, or a human or mammal in need of relief from depressive symptoms.

[0056] The present invention also relates to the use of (S)-norketamine, a prodrug of (S)-norketamine, or a pharmacologically acceptable salt thereof in the manufacture of a pharmaceutical composition for the prevention and / or treatment of depressive symptoms.

[0057] The present invention also relates to (S)-norketamine, a prodrug of (S)-norketamine, or a pharmacologically acceptable salt thereof for use in the prevention and / or treatment of depressive symptoms.

[0058] The present invention will be described in more detail in the following examples, but the present invention is not limited to these examples. Various modifications are possible within the scope of the technical concept of the present invention. All tests were conducted with the permission of the Chiba University Animal Experiment Committee. [Example]

[0059] Using an inflammatory animal model of depression (Non-Patent Documents 14-16), the antidepressant effect of norketamine, a major metabolite of ketamine, on depressive-like behavior in the model animals was examined.

[0060] 1. Materials and Methods Norketamine hydrochloride was purchased from Tocris Biosciences (Bristol, UK). Saline was used as a drug negative control.

[0061] An inflammatory animal model of depression was established by administering lipopolysaccharide (LPS) to adult mice. Depressive-like behavior was observed in LPS-treated mice, suggesting that this mouse model could serve as a novel animal model of depression. This mouse model was developed by the present inventors and their collaborators and has been reported in several papers (Non-Patent Documents 14-16). This mouse model showed increased immobility time compared with control mice in both the tail suspension test (TST) and the forced swimming test (FST), behavioral tests used as indicators for screening antidepressants. On the other hand, there was no difference in spontaneous locomotion between LPS-treated and control mice in the locomotion test (LMT), an indicator of motor function. These results suggest that LPS administration induces depressive-like behavior in this mouse model.

[0062] The antidepressant effects of norketamine were examined in adult mice using behavioral tests: the LMT, TST, and FST. The administration schedules for LPS and norketamine are shown in Figure 1A. Both the TST and FST were performed after norketamine administration. The TST was performed as follows: First, mice were removed from their cages, and a small piece of adhesive tape was attached approximately 2 cm from the tip of their tails. Small holes were made in the tape, and each mouse was hung on a hook. The immobility time of each mouse was recorded for 10 minutes. Only mice that remained completely motionless and unresisting were considered immobile. The immobility time increased in depressed states. The FST was performed as follows: First, a mouse was placed in a cylinder (23 cm diameter, 31 cm height) filled to 15 cm with water and maintained at 23 ± 1°C. Mice were tested in an automated forced-swimming apparatus using a SCANET MV-40 (Melquest Co., Ltd., Toyama, Japan). Immobility time was calculated as the total time minus the active time using the apparatus's analysis software. Cumulative immobility time was recorded for 6 min during the test period. LMT was performed as follows: First, mice were placed in an experimental cage (length × width × height: 560 × 560 × 330 mm). Spontaneous locomotor activity of the mice was counted using a SCANET MV-40, and cumulative movement was recorded for 60 min. The cage was washed between tests. Immobility time increased in a depressed state.

[0063] Statistical analysis was performed by one-way ANOVA followed by the least significant difference (LSD) test. Data are presented as mean ± standard error (n = 8-12 mice / group). Significant differences compared with the saline-administered LPS-treated mice group were not observed. * p<0.05, ** p<0.01, *** Significant differences compared to the LPS-treated mice group administered ketamine are indicated by p<0.001. # p<0.05, ## p<0.01.

[0064] 2.Results In the LMT, there was no difference in locomotor activity among normal mice, LPS-treated mice administered saline, or LPS-treated mice administered norketamine (5, 10, or 20 mg / kg) (Fig. 1B), confirming that these treatments did not affect motor function.

[0065] On the other hand, in the TST and FST, LPS-treated mice administered saline showed a significant increase in immobility time compared with control mice.Norketamine dose-dependently reduced the increased immobility time in LPS-treated mice (Figures 1C and 1D).

[0066] These results demonstrate that norketamine exerts an antidepressant effect in LPS-treated mice. That is, the antidepressant effect of norketamine was confirmed in both the TST and FST. [Example]

[0067] The antidepressant effects of norketamine were compared with those of ketamine. Specifically, using inflammatory animal models of depression (Non-Patent Documents 14-16), the antidepressant effects of ketamine and norketamine on depressive-like behavior in these model animals were examined.

[0068] 1. Materials and Methods Norketamine hydrochloride was purchased from Tocris Biosciences (Bristol, UK). Ketamine hydrochloride (Ketalar (登録商標) ) was purchased from Daiichi Sankyo Co., Ltd. (Tokyo, Japan). Physiological saline was used as a negative control for the drug.

[0069] As in Example 1, an inflammatory animal model of depression was created by administering lipopolysaccharide (hereinafter abbreviated as LPS) to mice at adulthood.

[0070] The antidepressant effects of ketamine and norketamine were examined in adult mice using behavioral tests, the LMT, TST, and FST, in a manner similar to that described in Example 1. The administration schedules for LPS, ketamine, and norketamine are shown in Figure 2A. Statistical analysis was also performed in a manner similar to that described in Example 1.

[0071] 2.Results In the LMT, there was no difference in locomotor activity among normal mice, LPS-treated mice administered saline, and LPS-treated mice administered ketamine (10 mg / kg) or norketamine (10 mg / kg) (Fig. 2B), confirming that these treatments did not affect motor function.

[0072] On the other hand, in the TST and FST, LPS-treated mice administered saline showed a significant increase in immobility time compared to control mice. Both ketamine and norketamine significantly reduced the increased immobility time in LPS-treated mice (Figures 2C and 2D). The antidepressant effect of norketamine was significantly stronger than that of ketamine (Figures 2C and 2D).

[0073] These results demonstrate that ketamine and norketamine at a dose of 10 mg / kg exhibit antidepressant effects in LPS-treated mice. Notably, the antidepressant effect of norketamine was significantly stronger than that of ketamine. These results suggest that norketamine has a stronger antidepressant effect than ketamine. Because norketamine has weaker affinity for NMDA receptors than ketamine, we suggest that the antidepressant effect of norketamine may involve factors other than NMDA receptor blockade. [Example]

[0074] A comparative study of the side effects of ketamine and norketamine was conducted using the locomotor activity enhancement test and the prepulse inhibition test, which are used to evaluate side effects.

[0075] 1. Materials and Methods The effects of ketamine and norketamine on mouse locomotion were examined using a SCANET MV-40 (Melquest Co., Ltd., Toyama, Japan). Specifically, measurements were taken for a total of 180 minutes, from 60 minutes before administration to 120 minutes after administration, and locomotion was calculated every 10 minutes. Statistical analysis of locomotion results was performed using repeated one-way ANOVA followed by the least significant difference (LSD) test. Data are presented as mean ± standard error (n = 7 or 8 mice per group). Significant differences compared to the saline-administered group were calculated. ** p<0.05, *** Significant differences compared to the ketamine (10 mg / kg) group are indicated by p<0.001. ## p<0.01.

[0076] The prepulse inhibition test was performed using a startle response apparatus (SR-LAB, San Diego Instruments, San Diego, CA, USA). Specifically, mice were habituated to a 65-dB background noise in the apparatus, and then presented with a 69, 73, 77, or 81 decibel (dB) sound stimulus (prepulse stimulus) for more than 20 ms, followed 100 ms later by a 120-dB sound stimulus (pulse stimulus). The startle response to the pulse stimulus was recorded. The startle response to the pulse stimulus without the prepulse stimulus was also recorded. PPI was calculated from the obtained data according to the following formula: PPI (%) = [1-(pPx / P120] × 100. In this formula, PPI stands for prepulse inhibition, pPx indicates the maximum startle intensity in response to a pulse stimulus when a prepulse stimulus is administered, and P120 indicates the average maximum startle intensity when a pulse stimulus is administered without a prepulse stimulus. Analysis of the results regarding prepulse inhibition was performed using Wilks' lambda, a multivariate analysis of variance, followed by a least significant difference test (LSD test). Data are expressed as mean ± standard error (n = 10-12 mice / group). Significant differences compared to the saline-administered group were determined. * p<0.05, *** p<0.001.

[0077] 2.Results Locomotion measurements revealed that mice treated with ketamine (10 mg / kg) showed a significant increase in locomotion compared with control mice treated with saline 10 min after drug administration. Norketamine (20 mg / kg) also showed a significant increase in locomotion compared with control mice treated with saline 10 min after drug administration. Locomotion after 10 min after administration of norketamine (20 mg / kg) was significantly lower than that of mice treated with ketamine (10 mg / kg). The increased locomotion after ketamine and norketamine administration was transient, returning to normal levels 20 min after drug administration. Administration of 5 mg / kg and 10 mg / kg of norketamine did not affect locomotion (Figure 3A).

[0078] In the prepulse inhibition test, ketamine (10 mg / kg) impaired prepulse inhibition at prepulse stimuli of 77 dB and 81 dB (Fig. 3B). On the other hand, norketamine at 20 mg / kg significantly impaired prepulse inhibition at 81 dB, but administration of 5 mg / kg or 10 mg / kg did not (Fig. 3B).

[0079] As mentioned above, in terms of side effects, ketamine administration causes side effects such as increased locomotion, impaired prepulse inhibition, and dependence, whereas norketamine administration was found to cause less increased locomotion and impaired prepulse inhibition compared to ketamine. In other words, norketamine is a safer drug than ketamine. [Example]

[0080] Using a social defeat stress model of depression (Non-Patent Document 11), we investigated the antidepressant effects of (S)- and (R)-norketamine on depressive-like behavior in this model animal. We also investigated the side effects of (S)-norketamine.

[0081] 1. Materials and Methods (S)- and (R)-norketamine hydrochloride were prepared by optical resolution of norketamine. The purity of these isomers was confirmed by high performance liquid chromatography (CHIRALPAK) (登録商標) IA, column size: 250 × 4.6 mm, mobile phase: n-hexane / dichloromethane / diethylamine (75 / 25 / 0.1), Daicel Corporation, Tokyo, Japan). (S)-Ketamine, used as a control in the investigation of side effects, was prepared by a previously reported method (Patent Documents 1-3).

[0082] A social defeat stress model of depression was established by exposing male C57BL / 6 mice to male ICR mice (large, aggressive mice) for 10 consecutive days, a process known as "social defeat stress." Mice exposed to social defeat stress exhibited depressive-like behavior. Specifically, the social defeat stress model exhibited increased immobility time in both the TST and FST. Furthermore, a significant decrease in the rate of drinking sucrose water in the 1% sucrose preference test (SPT) suggested the induction of depressive-like behavior. However, there was no difference in locomotor activity between social defeat stress mice and control mice in the LMT.

[0083] The depression model animals were created and administered with drugs as described below (Figure 4A). Male C57BL / 6 mice (7 weeks old, Japan SLC Co., Ltd., Hamamatsu, Japan) and ICR mice (9 weeks old, Japan SLC Co., Ltd., Hamamatsu, Japan) were used. Mice were allowed free access to water and food. Social defeat stress was performed by cohabiting one C57 / B6 mouse with one ICR mouse for 10 days. On day 11, a social interaction test was performed, and mice exhibiting depressive symptoms were selected and used for the following behavioral evaluation. Control mice were intraperitoneally administered vehicle (10 ml / kg saline), and mice exhibiting depressive symptoms were intraperitoneally administered (S)- or (R)-norketamine (10 mg / kg) or vehicle (10 ml / kg saline).

[0084] To evaluate the antidepressant effects of the drugs, behavioral tests, including the TST, FST, LMT, and SPT, were performed (Figure 4A). The LMT and TST were performed on the day of administration, and the FST was performed the day after administration. The SPT was performed 7 days after administration. The TST was performed as follows: First, mice were removed from their cages, and a small piece of adhesive tape was attached approximately 2 cm from the tip of their tails. A small hole was made in the tape, and each mouse was hung on a hook. The immobility time of each mouse was recorded for 10 minutes. Mice were considered immobile only when they remained completely still and unresisting. The immobility time increased in depressed states. The FST was performed as follows: First, a mouse was placed in a cylinder (23 cm diameter, 31 cm height) filled with water to a depth of 15 cm and maintained at 23 ± 1°C. Mice were tested in an automated forced swimming apparatus using a SCANET MV-40 (Melquest Co., Ltd., Toyama, Japan). Immobility time was calculated using the analysis software of the device as the total time minus the active time. Cumulative immobility time was recorded for 6 min during the test period. LMT was performed as follows: First, mice were placed in an experimental cage (length × width × height: 560 × 560 × 330 mm). Spontaneous locomotor activity was counted using a SCANETMV-40, and cumulative movement was recorded for 60 min. The cage was washed between tests. Depression increased immobility time. SPT was performed by measuring the rate of sucrose consumption after providing normal drinking water and 1% sucrose solution ad libitum. Depression reduces sucrose consumption, a rewarding response. Eight days after administration of (S)- or (R)-norketamine, mice were decapitated, and brains were rapidly removed and Golgi stained. Spine density was quantitatively assessed using a Keyence microscope (BZ-9000, Osaka, Japan).

[0085] The side effects of (S)-norketamine were evaluated using normal mice in a locomotor activity test, a prepulse inhibition test, and a conditioned place preference test (CPP). (S)-Ketamine was used as a control for the evaluation of side effects. The locomotor activity test was performed by examining the effects of (S)-norketamine and (S)-ketamine on mouse locomotion using a SCANET MV-40 (Melquest Co., Ltd., Toyama, Japan). Measurements were taken over a 180-minute period, from 60 minutes before administration to 120 minutes after administration. Locomotion was calculated as the amount of locomotion every 10 minutes. The prepulse inhibition test was performed using a startle response apparatus (SR-LAB, San Diego Instruments, San Diego, CA, USA). The place preference test was performed using a place preference test apparatus (Brain Science Idea Co., Ltd., Osaka, Japan).

[0086] Statistical analysis of the results of the social defeat stress model was performed by one-way analysis of variance followed by the least significant difference test. Data are presented as mean ± standard error (n = 8 or 9 mice / group). * p<0.05, ** p<0.01, *** p<0.001 indicates a significant difference compared with the group of social defeat stress mice administered saline. # p<0.05, ## P<0.01 indicates a significant difference compared with the group of social defeat stress mice administered (R)-norketamine.

[0087] Statistical analysis of the Golgi staining results was performed by repeated one-way analysis of variance followed by least significant difference test. Data are presented as mean ± standard error (n = 6 mice / group). ** p<0.01, *** p<0.001 indicates a significant difference compared with the group of social defeat stress mice administered saline. # p<0.05, ###P<0.001 indicates a significant difference compared with the social defeat stress mice group administered (R)-norketamine.

[0088] Statistical analysis of the locomotion results was performed by one-way repeated measures analysis of variance followed by least significant difference test. Data are presented as mean ± standard error (n = 10 to 12 mice / group). ** p<0.01, *** p<0.001 indicates a significant difference compared with the group administered physiological saline.

[0089] Analysis of prepulse inhibition results was performed by multivariate analysis of variance (MANOVA) followed by least significant difference tests. Data are presented as mean ± standard error (n = 8 or 9 mice / group). ** p<0.01 indicates a significant difference compared with the group administered with saline.

[0090] The results of the place preference test were analyzed by one-way analysis of variance followed by the least significant difference test. Data are presented as mean ± standard error (n = 7 or 9 mice / group). * p<0.05, ** p<0.01 indicates a significant difference compared with the group administered with saline.

[0091] 2.Results First, social defeat stress mice showed significantly increased immobility time in the TST and FST compared with control mice, and significantly decreased sucrose preference in the SPT, whereas there was no difference in locomotor activity between social defeat stress mice and control mice in the LMT.

[0092] In the LMT performed after administration of either norketamine isomer, there was no difference in locomotor activity among normal mice, saline-treated social defeat stress mice, and (S)- or (R)-norketamine-treated social defeat stress mice (Fig. 4B), confirming that these treatments did not affect motor function.

[0093] In the TST performed after administration of both norketamine isomers, a significant increase in immobility time was observed in social defeat stress mice administered saline compared to control mice. (S)-norketamine significantly reduced the increased immobility time in the TST in social defeat stress mice, whereas (R)-norketamine did not exhibit any antidepressant effect (Figure 4C). (S)-norketamine exhibited a significantly stronger antidepressant effect than (R)-norketamine (Figure 4C).

[0094] In the FST, social defeat stress mice administered both norketamine isomers showed a significant increase in immobility time compared to normal mice. (S)-norketamine significantly reduced the increased immobility time in the TST in social defeat stress mice, whereas (R)-norketamine did not exhibit antidepressant effects (Figure 4D). (S)-norketamine exhibited significantly greater antidepressant effects than (R)-norketamine (Figure 4D).

[0095] In the SPT performed 7 days after administration of both norketamine isomers, reduced sucrose consumption preference was observed in saline-treated social defeat stress mice compared to control mice. (S)-norketamine significantly restored the reduced sucrose consumption preference in social defeat stress mice 7 days after administration, but (R)-norketamine did not. This difference between (S)-norketamine and (R)-norketamine was statistically significant (Figure 4E).

[0096] Golgi staining performed 8 days after administration of both norketamine isomers revealed significantly decreased spine density in the frontal cortex (prelimbic region), hippocampal CA3 region, and hippocampal dentate gyrus of social defeat stress mice treated with saline compared with control mice. (S)-norketamine significantly increased the decreased spine density in social defeat stress mice 8 days after administration, whereas (R)-norketamine did not improve the density (Figure 4F). On the other hand, spine density in the hippocampal CA1 region of social defeat stress mice remained unchanged. Furthermore, spine density in the nucleus accumbens (core and shell regions) of social defeat stress mice increased, but was unaffected by (S)-norketamine or (R)-norketamine administration.

[0097] Next, in a locomotion-enhancing test to examine side effects, mice administered (S)-ketamine (10 mg / kg) showed a significant increase in locomotion 10 and 20 minutes after administration compared to control mice administered saline. The increase in locomotion induced by (S)-ketamine (10 mg / kg) was transient, returning to normal levels 30 minutes after administration. In contrast, administration of (S)-norketamine (5, 10, or 20 mg / kg) had no effect on locomotion (Figure 4G).

[0098] In the prepulse inhibition test after (S)-ketamine and (S)-norketamine administration, (S)-ketamine (10 mg / kg) caused a prepulse inhibition impairment (Figure 4H), whereas (S)-norketamine (5, 10, or 20 mg / kg) did not (Figure 4H).

[0099] In the place preference test after (S)-ketamine and (S)-norketamine administration, (S)-ketamine (20 mg / kg) significantly increased the CPP score, indicating dependence (Figure 4I), whereas (S)-norketamine (20 mg / kg) did not increase the CPP score (Figure 4I).

[0100] These results demonstrate that a 10 mg / kg dose of (S)-norketamine, but not (R)-norketamine, exhibited antidepressant effects in social defeat stress mice. Notably, the antidepressant effects of (S)-norketamine were significantly stronger than those of (R)-norketamine in the SPT, TST, and FST. These results suggest that (S)-norketamine has a longer-lasting antidepressant effect than (R)-norketamine. Both isomers of ketamine and their metabolites are known to be rapidly cleared from the body. (S)-norketamine exhibited antidepressant effects even though it is believed to be absent from the body 7 days after a single administration. Therefore, the difference in the effects of the two isomers of norketamine 7 days after administration is not due to differences in pharmacokinetics.

[0101] Furthermore, in terms of side effects, administration of (S)-ketamine was associated with increased locomotor activity, impaired prepulse inhibition, and the development of dependence. On the other hand, administration of (S)-norketamine did not result in increased locomotor activity, impaired prepulse inhibition, or the development of dependence. These results indicate that (S)-norketamine is a safer drug than (RS)-ketamine and (S)-ketamine, which are currently in clinical use. [Example]

[0102] The synthesis of (S)-norketamine derivatives was carried out by the following procedure. The synthesis scheme is shown in Figure 5. In the following, compounds (1) to (9) correspond to 1 to 9 in Figure 5.

[0103] 1. Synthesis of Compound (2) Compound (1), i.e., 3.09 g (31.4 mmol) of cyclohexanone and 3.00 g (15.7 mmol) of 1-bromo-2-chlorobenzene, were added to a mixture of 48 mg (0.053 mmol) of Pd2(dba)3, 73 mg (0.13 mmol), 7.61 g (23.3 mmol) of cesium carbonate, and 1,4-dioxane (11 mL) under a nitrogen atmosphere and stirred at 100 °C for 20 hours. After cooling, water and ethyl acetate were added for extraction and separation. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained after concentration under reduced pressure was purified by silica gel chromatography (65 g of neutral SiO2, eluted with a gradient of hexane / ethyl acetate = 20:1 to 10:1) to obtain 1.93 g (9.26 mmol) of compound (2) as a white solid (yield: 59.0%). The synthesis of compound (2) was confirmed by NMR.

[0104] 2. Synthesis of Compound (3) Under a nitrogen atmosphere, 1.90 g (8.23 mmol) of tert-butyl azodicarboxylate, 1.06 g of powdered MS5A, and 0.76 g (0.633 mmol) of (R)-C8-TCYP were added to a dichloromethane solution (6.3 mL) of 1.32 g (6.33 mmol) of compound (2). The mixture was heated and stirred at 45°C for 2 hours in an open system to remove the dichloromethane. The resulting residue was heated at 45°C for 60 hours under a nitrogen atmosphere. After cooling, the residue was purified by silica gel chromatography (56 g of neutral SiO2, hexane / ethyl acetate = 9:1) to obtain 2.50 g (5.70 mmol) of compound (3). (Yield: 90.0%) The synthesis of compound (3) was confirmed by NMR.

[0105] 3. Synthesis of (S)-norketamine Under a nitrogen atmosphere, trifluoroacetic acid (25 mL) was added to a solution of 2.50 g (5.70 mmol) of compound (3) in 49 mL of dichloromethane and stirred at room temperature for 3 hours. Acetone (29 mL) was added to the mixture, which was stirred for 10 minutes and then concentrated under reduced pressure. To the resulting residue, 46 mL of a mixed solvent of acetic acid, THF, and water (3:1:1 v / v / v) was added, followed by 9.12 g (140 mmol) of zinc powder in several portions. The mixture was heated and stirred at room temperature for 30 minutes and then at 60 °C for 4 hours. After cooling, the mixture was diluted with dichloromethane and extracted with saturated aqueous sodium carbonate solution. The aqueous layer was extracted five times with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate. The residue obtained after concentration under reduced pressure was purified by silica gel chromatography (25 g of neutral SiO2, hexane / ethyl acetate = 1:2) to obtain 1.00 g (4.47 mmol) of (S)-norketamine as a white solid (yield: 78.4%). The synthesis of (S)-norketamine was confirmed by NMR. The S-isomer was detected 100% by chiral chromatography, and the R-isomer was not detected. The retention time was consistent with that obtained by optical resolution of the S-isomer using racemic D-tartaric acid [Nature, 533, 481(2016)].

[0106] 4. Synthesis of Compound (5) Under a nitrogen atmosphere, 0.35 g (2.69 mmol) of compound (4) and 0.33 g (3.23 mmol) of triethylamine were dissolved in acetonitrile (7.3 mL) and 0.83 g (3.23 mmol) of N,N'-disuccinimidyl carbonate was added and stirred at room temperature for 3 hours. Dichloromethane (73 mL) and water were added, followed by extraction and separation with 3.23 mL (3.23 mmol) of 1N hydrochloric acid. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and water, and then dried over anhydrous magnesium sulfate. The residue obtained after concentration under reduced pressure was purified by silica gel chromatography (29 g of neutral SiO2, hexane / ethyl acetate = 1:1) to give 0.19 g (0.701 mmol) of compound (5) as a colorless oil (yield: 26.1%). The synthesis of compound (5) was confirmed by NMR.

[0107] 5. Synthesis of (S)-norketamine derivative (1) Under a nitrogen atmosphere, 0.16 g (0.716 mmol) of (S)-norketamine and 0.95 mL of saturated aqueous sodium bicarbonate solution were added to 1.9 mL of acetonitrile solution of 0.19 g (0.701 mmol) of compound (5), and the mixture was stirred overnight at room temperature. Ethyl acetate and water were added to the mixture, and the mixture was extracted and separated. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (11 g of neutral SiO2, hexane / ethyl acetate = 2:1) to obtain 0.16 g (0.422 mmol) of the (S)-norketamine derivative (1) represented by the following formula (XIII) as a colorless resin (yield: 60.2%). The synthesis of the (S)-norketamine derivative (1) was confirmed by NMR.

[0108] [ka]

[0109] 6. Synthesis of compound (7) Under a nitrogen atmosphere, 13.6 g (29.1 mmol) of 15% MeSNa aqueous solution was added dropwise to a mixture of 4.17 g (29.2 mmol) of compound (6), 0.10 g (0.292 mmol) of n-Bu4N HSO4, and 11 mL of dichloromethane over 2 hours. The mixture was stirred at room temperature for an additional hour, and the organic layer was separated. This was washed twice with saturated brine and dried over anhydrous sodium sulfate. The residue obtained after concentration under reduced pressure was distilled (boiling point 173 °C, atmospheric pressure) to give 3.3 g (21.6 mmol) of compound (7) as a colorless oil (yield: 74.2%). The synthesis of compound (7) was confirmed by NMR.

[0110] 7. Synthesis of compound (8) Under a nitrogen atmosphere, a mixture of 3.35 g (21.6 mmol) of compound (7) and 2.85 g (32.3 mmol) of isobutyric acid was added dropwise to a mixture of 2.85 g (32.3 mmol) of isobutyric acid and 4.18 g (32.4 mmol) of diisopropylethylamine. After the addition was complete, the mixture was heated and stirred at 55°C for 16 hours. After cooling, the mixture was diluted with diethyl ether (220 mL), washed four times with water, twice with saturated aqueous sodium bicarbonate, and once with saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained after concentration under reduced pressure was distilled under reduced pressure (boiling point 84-91°C / 6 mmHg) to obtain 4.33 g (21.0 mmol) of compound (8) as a colorless oil (yield: 97.0%). The synthesis of compound (8) was confirmed by NMR.

[0111] 8. Synthesis of compound (9) Under a nitrogen atmosphere, 1.68 g (14.6 mmol) of N-hydroxysuccinimide was added to a solution (35 mL) of 1.52 g (7.38 mmol) of compound (8) in dichloromethane and cooled in an ice bath. 12.3 g (14.6 mmol) of a 9% peracetic acid / acetic acid solution was added dropwise over 10 minutes and stirred at room temperature for 24 hours. The mixture was diluted with diethyl ether (180 mL), washed twice with water, three times with saturated aqueous sodium bicarbonate (until the pH became weakly basic), and once with saturated brine, and then dried over anhydrous magnesium sulfate. The residue obtained after concentration under reduced pressure was purified by silica gel chromatography (40 g neutral SiO2, hexane / ethyl acetate = 3:1) to give 1.20 g (4.40 mmol) of compound (9) as a colorless oil (yield: 59.6%). The synthesis of compound (9) was confirmed by NMR.

[0112] 9. Synthesis of (S)-norketamine derivative (2) Under a nitrogen atmosphere, 0.14 g (0.626 mmol) of (S)-norketamine and 0.85 mL of saturated aqueous sodium bicarbonate solution were added to 1.7 mL of acetonitrile solution of 0.17 g (0.626 mmol) of compound (5), and the mixture was stirred overnight at room temperature. Ethyl acetate and water were added to the mixture, and the mixture was extracted and separated. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (10 g of neutral SiO2, hexane / ethyl acetate = 5:1) to obtain 0.18 g (0.471 mmol) of the (S)-norketamine derivative (2) represented by the following formula (XIV) as a colorless oily diastereomeric mixture (yield: 75.2%). The synthesis of the (S)-norketamine derivative (2) was confirmed by NMR.

[0113] [ka] [Example]

[0114] The pharmacokinetics of (S)-norketamine derivatives was investigated by measuring the blood concentration after administration of the (S)-norketamine derivatives.

[0115] 1. Materials and Methods Male C57 / B6 mice (7-8 weeks old, Japan SLC Co., Ltd., Hamamatsu, Japan) were used. Mice were allowed free access to water and food. (S)-norketamine derivatives ((S)-norketamine derivative (1) or (S)-norketamine derivative (2)) (30 mg / kg) were orally administered in a vehicle (0.5% carboxymethylcellulose (CMC) 10 ml / kg, 0.4% DMSO). After 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours, mice were anesthetized with 5% isoflurane and cardiac blood was collected. The collected blood was placed in a tube containing EDTA and centrifuged to obtain plasma. The plasma was then stored in a polypropylene microtube at -80°C in a freezer. The plasma (S)-norketamine concentration was measured by the following method.

[0116] For the calibration curve sample, 10 μL of STD (standard) solution was added to 20 μL of mouse plasma. Acetonitrile / water (1:1, v / v) was added to the samples, blank samples, and QC (quality control) samples. After stirring for 10 seconds, 100 μL of an internal standard (IS) solution (Norketamine-D4: 10 ng / mL) was added. A blank sample was prepared by adding acetonitrile:methanol (9:1). The mixture was stirred for 30 seconds and centrifuged at 16,000 xg for 3 minutes at room temperature. 80 μL of the supernatant was transferred to a new μ-tube, and 100 μL of 0.001 mol / L ammonium bicarbonate was added. The mixture was stirred for 10 seconds and centrifuged at room temperature, 16,000 xg, for 2 minutes. (S)-norketamine concentrations were measured by HPLC.

[0117] The measurement conditions are as follows. ○LC conditions High-performance liquid chromatograph: LC-20A system (Shimadzu Corporation) Analytical column: CHIRALPAK AS-3R, 3 µm, 4.6 mm x 100 mm, DAICEL Column temperature: 25°C Mobile phase: 0.001 mol / L ammonium bicarbonate / acetonitrile (54:46, v / v) Flow rate: 1.0 mL / min Autosampler cleaning solution: 0.001 mol / L ammonium bicarbonate / acetonitrile (54:46, v / v) Autosampler temperature: 4°C MS / MS conditions Tandem Mass Spectrometer:API5000 AB Sciex Pte. Ltd. API interface:Turbo Spray(ESI) Heated gas temperature: 650°C Ion spray voltage: 5500 V Nebulizer gas setting (GS1):60 psi, air Heated gas setting (GS2): 80 psi, air Curtain gas setting:20 psi, nitrogen Collision gas setting:4, nitrogen Ionization mode: MRM mode, positive ion detection mode Monitored ions and collision energy: S-Norketamine: m / z 224.1 to m / z 125.1 IS (Norketamine-D4): m / z 228.2 to m / z 129.1

[0118] 2.Results The concentration measurement results are shown in Table 1.

[0119] [Table 1]

[0120] In Table 1, "compound 1" represents (S)-norketamine derivative (1), and "compound 2" represents (S)-norketamine derivative (2). The results in Table 1 show that (S)-norketamine derivative (1) loses its blood concentration more slowly than (S)-norketamine derivative (2), indicating that it remains in the blood as (S)-norketamine for a longer period. Therefore, (S)-norketamine derivative (1) was selected for the following pharmacological experiments. [Example]

[0121] Using a social defeat stress model of depression (Non-Patent Document 11), the antidepressant effect of (S)-norketamine derivative (1) on depressive-like behavior in the model animals was examined.

[0122] 1. Materials and Methods A social defeat stress model of depression was established by exposing male C57BL / 6 mice to male ICR mice (large, aggressive mice) for 10 consecutive days, a process known as "social defeat stress," as previously reported (Non-Patent Document 11). Mice exposed to social defeat stress exhibited depressive-like behavior. Specifically, the social defeat stress model showed a significant decrease in the rate of drinking sucrose water in the 1% sucrose preference test (SPT), suggesting that depressive-like behavior (anhedonia) was induced. However, there was no difference in locomotor activity between social defeat stress-exposed mice and control mice.

[0123] The depression model animals were created and administered with drugs as described below (Figure 6A). Male C57BL / 6 mice (7 weeks old, Japan SLC Co., Ltd., Hamamatsu, Japan) and ICR mice (9 weeks old, Japan SLC Co., Ltd., Hamamatsu, Japan) were used. Mice were allowed free access to water and food. Social defeat stress was performed by cohabiting one C57BL / 6 mouse with one ICR mouse for 10 days. On day 11, a social interaction test was performed, and mice exhibiting depression were selected and used for the following behavioral evaluation. Control mice were orally administered vehicle (0.5% carboxymethylcellulose (CMC) 10 ml / kg, 0.4% DMSO), while depressed mice were orally administered (S)-norketamine derivative (Compound 1) (30 mg / kg) or vehicle (0.5% carboxymethylcellulose (CMC) 10 ml / kg, 0.4% DMSO).

[0124] To examine the antidepressant effects of the drugs, behavioral tests such as the LMT and SPT were performed (Figure 6A). The LMT was performed 1 hour after administration, and the SPT was performed 2 and 6 days after administration. The SPT was performed by providing normal drinking water and a 1% sucrose solution ad libitum and measuring the rate of sucrose solution consumption. In a depressed state, consumption of sucrose solution, a reward response, is reduced.

[0125] Statistical analysis was performed by one-way ANOVA followed by the least significant difference test (LSD test). Data are expressed as mean ± standard error (n = 9-11 mice / group). Significant differences compared to the group in which mice exhibiting depressive symptoms were orally administered (S)-norketamine derivative (1) were *** p<0.001.

[0126] 2.Results There was no difference in the amount of activity one hour after oral administration among the three groups (Figure 6B). In a 1% sucrose preference test 3 and 7 days after administration, the group exhibiting depressive symptoms showed significantly lower consumption of sucrose solution, while the group administered Compound I showed a significant improvement (Figure 6C). These results indicated that Compound I has an antidepressant effect in the social defeat stress model. [Industrial Applicability]

[0127] As explained above, the drug and pharmaceutical composition for preventing and / or treating depressive symptoms according to the present invention have a rapid-acting and long-lasting antidepressant effect and have few side effects such as psychotic symptom-inducing effects and drug dependence, and are therefore useful as novel pharmaceuticals in the field of the prevention and / or treatment of mental disorders presenting with depressive symptoms.

[0128] The present invention includes the following. 1. A pharmaceutical composition for the prevention and / or treatment of depressive symptoms, comprising (S)-norketamine or a pharmacologically acceptable salt thereof, and substantially free of (R)-norketamine or a pharmacologically acceptable salt thereof. 2. The pharmaceutical composition according to the preceding item 1, wherein the depressive symptoms are depressive symptoms in depression, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), or autism spectrum disorder. 3. The pharmaceutical composition according to the preceding item 1 or 2, wherein the pharmacologically acceptable salt of (S)-norketamine is (S)-norketamine hydrochloride. 4. The pharmaceutical composition according to any one of the preceding items 1 to 3, which contains a pharmacologically acceptable carrier. 5. The pharmaceutical composition according to any one of the preceding items 1 to 4, wherein the composition is administered in an amount effective for alleviating depressive symptoms. 6. The pharmaceutical composition according to any one of items 1 to 5 above, wherein the composition is parenterally administered at a daily dose of about 0.01 to about 1,000 milligrams per day (mg / person / day), about 0.1 to about 500 mg / person / day, about 0.1 to 100 mg / person / day, about 1.0 to about 100 mg / person / day, about 10 to about 100 mg / person / day, about 100 to about 200 mg / person / day, about 200 to about 300 mg / person / day, about 300 to about 400 mg / person / day, or about 400 to about 500 mg / person / day. 7. The pharmaceutical composition according to any one of items 1 to 5 above, wherein the composition is orally administered at a daily dose of about 0.01 to about 500 mg / person / day, about 0.1 to about 100 mg / person / day, about 0.1 to about 1.0 mg / person / day, about 1.0 to about 20 mg / person / day, about 20 to about 40 mg / person / day, about 40 to about 60 mg / person / day, or about 80 to about 100 mg / person / day. 8. The pharmaceutical composition according to any one of the preceding items 1 to 7, wherein the composition is administered orally, transdermally, transmucosally, subcutaneously, by inhalation, or intravenously. 9. (S)—An agent for preventing and / or treating depressive symptoms, consisting essentially of norketamine or a pharmacologically acceptable salt thereof. 10. The agent according to the preceding item 9, wherein the depressive symptoms are depressive symptoms in depression, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), or autism spectrum disorder. 11. The agent according to the preceding item 9 or 10, wherein the composition is administered in an amount effective for alleviating depressive symptoms. 12. An agent for preventing and / or treating depressive symptoms, wherein the prodrug of (S)-norketamine essentially consists of a compound represented by the following formula (XIII) or formula (XIV) or a pharmacologically acceptable salt thereof. [ka] [ka] 13. The agent according to the preceding item 12, wherein the depressive symptoms are depressive symptoms in depression, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), or autism spectrum disorder. 14. The agent according to the preceding item 12 or 13, wherein the agent is administered in an amount effective for alleviating depressive symptoms. 15. (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl-(S)-(1-(2-chlorophenyl)-2-oxocyclohexyl)carbamate. 16. 1-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)carbamoyl)oxy)ethyl isobutyrate. 17. A preventive and / or therapeutic agent for depressive symptoms containing (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-(S)-(1-(2-chlorophenyl)-2-oxocyclohexyl)carbamate or 1-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)carbamoyl)oxy)ethyl isobutyrate.

Claims

1. A pharmaceutical composition for the prevention and / or treatment of depressive symptoms, comprising a prodrug of (S)-norketamine or a pharmacologically acceptable salt thereof, wherein the prodrug of (S)-norketamine is selected from the group consisting of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-(S)-(1-(2-chlorophenyl)-2-oxocyclohexyl)carbamate and 1-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)carbamoyl)oxy)ethyl isobutyrate.

2. 2. The pharmaceutical composition according to claim 1, wherein the depressive symptoms are depressive symptoms in depression, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), or autism spectrum disorder.

3. The pharmaceutical composition according to claim 1 or 2, which comprises a pharmacologically acceptable carrier.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the composition is administered in an amount effective to reduce symptoms of depression.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the composition is administered orally, transdermally, transmucosally, subcutaneously, by inhalation, or intravenously.

6. An agent for preventing and / or treating depressive symptoms, consisting essentially of a prodrug of (S)-norketamine or a pharmacologically acceptable salt thereof, wherein the prodrug of (S)-norketamine is selected from the group consisting of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-(S)-(1-(2-chlorophenyl)-2-oxocyclohexyl)carbamate and 1-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)carbamoyl)oxy)ethyl isobutyrate.

7. The agent according to claim 6, wherein the depressive symptoms are depressive symptoms in depression, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), or autism spectrum disorder.

8. The agent according to claim 6 or 7, wherein the composition is administered in an amount effective to reduce depressive symptoms.

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