Application of (s)-norketamine and salt therof as pharmaceutical

Abstract

Provided are: a pharmaceutical for preventing and / or treating symptoms of depression, the pharmaceutical comprising (S)-norketamine or a pharmacologically acceptable salt thereof; a pharmaceutical composition for preventing and / or treating symptoms of depression, the composition containing (S)-norketamine or a pharmacologically acceptable salt thereof in an amount effective for alleviating symptoms of depression, and containing substantially no (R)-norketamine; a method for preventing and / or treating symptoms of depression, the method including administering the pharmaceutical or composition; and a use for (S)-norketamine in producing a pharmaceutical for preventing and / or treating symptoms of depression or a composition for preventing and / or treating symptoms of depression.

Description

Pharmaceutical applications of (S)-norketamine and its salts

[0001] The present invention relates to a pharmaceutical for the prevention and / or treatment of mental disorders, preferably depressive disorders. More specifically, the present invention relates to an antidepressant comprising an optical isomer of norketamine (N-desmethylketamine), (S)-norketamine, a prodrug of (S)-norketamine, or a pharmacoagulably acceptable salt thereof, and to a pharmaceutical composition for the prevention and / or treatment of depressive disorders containing (S)-norketamine, a prodrug of (S)-norketamine, or a pharmacoagulably acceptable salt thereof. This application claims priority to Japanese Patent Application No. 2016-210749, as incorporated herein by reference.

[0002] Due to changes in social lifestyles and the aging of society, various diseases, including mental and neurological disorders, are generally on the rise. For example, depression and schizophrenia, which are representative mental illnesses, have high incidence rates and pose a significant problem from a healthcare economics perspective. Obsessive-compulsive disorder (OCD) is another type of anxiety disorder consisting of obsessive thoughts and compulsive behaviors. Drug therapy is essential for treating mental illnesses such as depression, schizophrenia, and anxiety disorders, and antidepressants (tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors, etc.) and antipsychotics (phenothiazine compounds, butyrophenone compounds, benzamide compounds, iminodibenzyl compounds, thiepine compounds, indole compounds, and serotonin-dopamine receptor blockers, etc.) are administered. However, while these drugs used in clinical practice are effective for some patients and some symptoms, it is known that there are also patients for whom these drugs are ineffective, so-called treatment-resistant patients, and the development of new therapeutic drugs is urgently needed. Existing medications are not considered sufficiently effective in treating these mental illnesses, and in reality, there are very few effective preventative or therapeutic methods available.

[0003] One of the major problems in treating depression is the limitations of antidepressants and their augmentative therapies. Current antidepressants take several weeks or more to show effects, and there are treatment-resistant patients who do not respond to these medications. As a result, it is said that only about 50% of depressed patients achieve remission. Furthermore, increasing the dosage of antidepressants in an attempt to achieve remission leads to numerous side effects for patients. Moreover, depression is one of the causes of suicide.

[0004] Recent research has provided increasing evidence suggesting that impaired glutamate transmission, particularly glutamate neurotransmission mediated by N-methyl-D-aspartate (NMDA) receptors, is involved in the pathophysiology of mood disorders such as depression and bipolar disorder, and that it plays a major role in neurobiology and in the treatment of major depressive disorder (MDD) (Non-Patent Literature 1).

[0005] Ketamine, an NMDA receptor antagonist, has been reported to exhibit rapid and potent antidepressant effects in patients with treatment-resistant MDD and depressive symptoms of treatment-resistant bipolar disorder (Non-Patent Literature 2-4). Ketamine has also been reported to be effective in treatment-resistant obsessive-compulsive disorder and treatment-resistant post-traumatic stress disorder (PTSD) (Non-Patent Literature 5-7).

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

[0007] Ketamine is a compound developed in 1962 as an anesthetic, and clinical use began in 1965. However, it has been classified as a narcotic due to problems with psychiatric symptoms such as hallucinations and delusions, as well as its addictive potential. For this reason, it has been used in clinical practice as an anesthetic and for the treatment of chronic pain.

[0008] While some reports indicate that the clinical antidepressant effect of ketamine lasts for a short period of time, from a few hours after a single dose to one or two days, others suggest it may last for more than two weeks (Non-Patent Documents 2, 3, 8). Furthermore, ketamine has a side effect of inducing psychotic symptoms, and it has been reported that the antidepressant effect of ketamine did not manifest until this side effect 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 inventors have disclosed that (R)-ketamine or a pharmaceutically acceptable salt thereof has a rapid and long-lasting antidepressant effect and fewer side effects than (S)-ketamine, and is therefore effective in preventing and / or treating mental disorders exhibiting depressive symptoms (Patent Documents 1, 2 and Non-Patent Documents 10, 11).

[0010] Norketamine is the main metabolite of ketamine, and it has been reported that its affinity for the NMDA receptor is approximately 6.8 times lower than that of ketamine (Non-Patent Literature 12). Like ketamine, norketamine is known to have optical isomers, which are called (R)-norketamine and (S)-norketamine.

[0011] Furthermore, norketamine has been reported to exhibit antidepressant effects, albeit weaker than ketamine (Non-Patent Document 13).

[0012] Japanese Patent Publication No. 2015-078181. International Publication No. 2015 / 037248. U.S. Patent No. 6040479.

[0013] Hashimoto K (2009) Emerging role of glutamatein the pathophysiology of major depressive disorder. Brain Res. Rev. 61:105-23.Berman RM, Cappiello A, An and A, Oren DA,Heninger GR, Charney DS, Krystal JH (2000) Antidepressant effects of ketaminein depressed patients. Biol. Psychiatry 47:351-4.Zarate CA, Jr, Singh JB, Carlson PJ, BrutscheNE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK (2006) A randomized trial ofan N-methyl-D-aspartate antagonist in treatment-resistant major depression.Arch. Gen. Psychiatry 63:856-64.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.Bloch MH, Wasylink S, Landeros-WeisenbergerA, Panza KE, Billingslea E, Leckman JF, Krystal JH, Bhagwagar Z, Sanacora G,Pittenger C (2012) Effects of ketamine in treatment-refractoryobsessive-compulsive disorder. Biol. Psychiatry 72(11):964-970.Rodriguez CI, Kegeles LS, Levinson A, FengT, Marcus SM, Vermes D, Flood P, Simpson HB (2013) Randomized ControlledCrossover Trial of Ketamine in Obsessive-Compulsive Disorder: Proof-of-Concept.Neuropsychopharmacology 38(12):2475-2483.Feder A, Parides MK, Murrough JW, Perez AM,Morgan JE, Saxena S, Kirkwood K, Aan Het Rot M, Lapidus KA, Wan LB, IosifescuD, Charney DS (2014) Efficacy of intravenous ketamine for treatment of chronicposttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry71:681-688.Krystal JH, Sanacora G, Duman RS (2013)Rapid-acting glutamatergic antidepressants: the path to ketamine and beyond.Biol. Psychiatry 73:1133-41.Wink LK, O'Melia AM, Shaffer RC, Pedapati E,Friedmann K, Schaefer T, Erickson CA (2014) Intranasal ketamine treatment in anadult with autism spectrum disorder. J. Clin. Psychiatry 75(8):835-836.Zhang JC, Li SX, Hashimoto K (2014)R(-)-Ketamine shows greater potency and longer lasting antidepressant effectsthan S(+)-ketamine. Pharmacol. Biochem. Behav.116: 137-141.Yang C, Shirayama Y, Zhang JC, Ren Q, YaoW, Ma M, Dong C, Hashimoto K (2015) R-Ketamine: a rapid-onset and sustainedantidepressant without psychotomimetic side effects. Transl. Psychiatry 5:e632.Ebert B, Mikkelsen S, Thorkildsen C,Bordbjerg FM (1997) Norketamine, the main metabolite of ketamine, is anon-competitive NMDA receptor antagonist in the rat cortex and spinal cord. Eur.J. Pharmacology 333:99-104.Sarat K, Siwek A, Staroxicz G, Librowski T,Nowak G, Drabik U, Gajdosz R, Popik P (2015) Antidepressant-like effects ofketamine, norketamine and dehydronorketamine in forced swim test: Role ofactivity at NMDA receptor.Neuropharmacology 99:301-307.Ma M, Ren Q, Zhang JC, Hashimoto K (2014)Effects of brilliant blue G on serum levels of tumor necrosis factor-alpha anddepression-like behaviors in mice after administration of lipopolysaccharide.Clin. Psychopharmacol. Neurosci. 12:31-36.Zhang JC, Wu J, Fujita Y, Yao W, Ren Q, YangC, Li SX, Shirayama Y, Hashimoto K (2015) Antidepressant effects of TrkBligands on depression-like behavior and dendritic changes in the hippocampusand nucleus accumbens after inflammation. Int. J. Neuropsychopharmacol. 18:pyu077.Yao W, Zhang JC, Dong C, Zhuang C, Hirota S,Inanaga K, Hashimoto K (2015) Effects of amycenone on serum levels of tumornecrosis factor-alpha and depression-like behaviors in mice afteradministration of lipopolysaccharide. Pharmacol. Biochem. Behav. 136:7-12.Biermann M, Zheng G, Hojahmat M, MoskalevNV, Crooks PA (2015) Asymmetric synthesis of (S)- and (R)-norketamine viaSharpless asymmetric dihydroxylation / Ritteramination sequence.Tetrahedron Letters 56:2608-2610. Rautio J, Kumpulainen H, Heimbach T, Oliyai R, Oh D, Jarvinen T, Savolainen J (2008) Prodrugs: design and clinical applications. Nat. Rev. Drug Discov. 7(3):255-270. Simplicio AL, Clancy JM, Gilmer (2008) Prodrugs for amines. Molecules 13:519-547. [[ID=]1]

[0014] It has been reported that ketamine, an NMDA receptor antagonist, exhibits an immediate antidepressant effect in patients with treatment-resistant depression. However, ketamine has problems such as mental symptoms such as hallucinations and delusions and side effects such as dependence, and is designated as a drug, so it is difficult to be clinically applied.

[0015] An object of the present invention is to provide a new compound having a long-lasting therapeutic effect on diseases showing depressive symptoms.

[0016] In the intensive study to solve the above problems, the present inventors focused on its main metabolite, norketamine, which has not been used in the study of the antidepressant effect of ketamine, an NMDA receptor antagonist.

[0017] It is considered that glutamatergic neurotransmission via the NMDA receptor is involved in depression, and it has been reported that ketamine exhibits an immediate antidepressant effect in patients with treatment-resistant depression. In addition, it is generally understood that both the analgesic action and the psychosis-inducing action of ketamine are mainly mediated by the blockade of the NMDA receptor.

[0018] On the other hand, since the NMDA receptor affinity of norketamine, the main metabolite of ketamine, is lower than that of ketamine, no one has shown interest in the pharmacological action of norketamine as an antidepressant. In addition, due to the low NMDA receptor affinity of norketamine, the psychosis-inducing action of norketamine is expected to be lower than that of ketamine.

[0019] In a study using a model mouse showing depressive-like symptoms, the inventor found that nor ketamine exhibits a stronger antidepressant effect than ketamine. On the other hand, side effects observed upon administration of ketamine, such as hyperlocomotion and prepulse inhibition disorder, were weaker upon administration of nor ketamine compared to ketamine. Since the affinity of nor ketamine for the NMDA receptor is lower compared to ketamine, it is considered that the side effect of inducing psychotic symptoms is less and it is less likely to form drug dependence.

[0020] In addition, in the social defeat stress model of depression, (S)-nor ketamine showed an antidepressant effect, while (R)-nor ketamine did not show an antidepressant effect. Also, the antidepressant effect of (S)-nor ketamine was stronger than that of (R)-nor ketamine. Furthermore, (S)-nor ketamine did not cause hyperlocomotion, prepulse inhibition disorder, or rewarding effects. Also, nor ketamine and (S)-nor ketamine are not designated as narcotics and are easier to use in clinical settings compared to ketamine, which is designated as a narcotic. The present invention was achieved based on these findings.

[0021] That is, the present invention consists of the following: 1. An agent for preventing and / or treating depressive symptoms, comprising (S)-nor ketamine, a prodrug of (S)-nor ketamine, or a pharmaceutically acceptable salt thereof. 2. The agent for preventing and / or treating depressive symptoms according to item 1 above, 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. ........... １ and R ２ (注:原文中“当該式中、Rは、アルキル基、アルコキシ基、アリール基、またはアラルキル基であり、RおよびR”部分翻译时保留了原文的未完成表述状态,因为从提供的英文翻译要求来看,应尽量保持原文格式,这部分内容可能是完整原文录入有误,若有更完整准确的原文信息,可进一步完善翻译。)A prophylactic and / or therapeutic agent for depressive symptoms as described in item 1 or 2 above, wherein each is independently an alkyl group, an alkoxy group, an aryl group, or an aralkyl group. 5. A pharmaceutical composition for the prevention and / or treatment of depressive symptoms, containing an effective amount of (S)-norketamine, a prodrug of (S)-norketamine, or a pharmacologically acceptable salt thereof for the relief of depressive symptoms, and substantially free of (R)-norketamine or a pharmacologically acceptable salt thereof. 6. The pharmaceutical composition for the prevention and / or treatment of depressive symptoms according to 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 the prevention and / or treatment of depressive symptoms according to item 5 or 6, wherein the pharmacologically acceptable salt of (S)-norketamine is (S)-norketamine hydrochloride. 8. (S)-norketamine prodrugs are compounds represented by the following formulas (VI), (VII), (XIII), or (XIV) or pharmaceutically acceptable salts or hydrochlorides thereof, wherein R is an alkyl group, alkoxy group, aryl group, or aralkyl group, １ and R ２ The pharmaceutical composition for the prevention and / or treatment of depressive symptoms according to paragraph 5 or 6, wherein each is independently an alkyl group, an alkoxy group, an aryl group, or an aralkyl group. 9. A method for preventing and / or treating depressive symptoms, comprising administering an amount effective in reducing depressive symptoms of (S)-norketamine, a prodrug of (S)-norketamine, or a pharmacologically acceptable salt thereof to a patient in need of prevention and / or treatment of depressive symptoms. 10. The method for preventing and / or treating depressive symptoms according to item 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 item 9 or 10, wherein the pharmacologically acceptable salt of (S)-norketamine is (S)-norketamine hydrochloride. 12. (S)-norketamine prodrugs are compounds represented by the following formulas (VI), (VII), (XIII), or (XIV) or pharmaceutically acceptable salts or hydrochlorides thereof, wherein R is an alkyl group, alkoxy group, aryl group, or aralkyl group, １ and R ２ The method for preventing and / or treating depressive symptoms according to paragraph 9 or 10, wherein each of the groups is independently an alkyl group, an alkoxy group, an aryl group, or an aralkyl group. 13. Use of (S)-norketamine, a prodrug of (S)-norketamine, or a pharmacoagulably acceptable salt thereof in the manufacture of a pharmaceutical composition for the prevention and / or treatment of depressive symptoms. 14. The use according to 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 use according to paragraph 13 or 14, wherein the pharmacoagulably acceptable salt of (S)-norketamine is (S)-norketamine hydrochloride. 16. The prodrug of (S)-norketamine is any one compound selected from the compounds represented by formulas (III) to (XIV) below, or a pharmacoagulably acceptable salt or hydrochloride thereof, wherein R is an alkyl group, an alkoxy group, an aryl group, or an aralkyl group, １ and R ２The use according to paragraph 13 or 14 above, which is each independently an alkyl group, an alkoxy group, an aryl group, or an aralkyl group 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)ethyl isobutyrate. 19. A medicament for preventing and / or treating depressive symptoms, comprising (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. 20. (S)-Norketamine, a prodrug of (S)-norketamine or a pharmacologically acceptable salt thereof, for preventing and / or treating depressive symptoms. 21. A compound represented by formula (VI), formula (VII), formula (XIII) or formula (XIV) described below, wherein R is an alkyl group, an alkoxy group, an aryl group, or an aralkyl group, R １ and R ２ are each independently an alkyl group, an alkoxy group, an aryl group, or an aralkyl group, being (S)-norketamine, a prodrug of (S)-norketamine or a pharmacologically acceptable salt thereof, for preventing and / or treating depressive symptoms.

[0022] Norketamine, and in particular its optical isomer (S)-norketamine, has long-lasting antidepressant effects and few side effects, making it effective for the prevention and / or treatment of mental disorders exhibiting depressive symptoms. Therefore, pharmaceuticals comprising (S)-norketamine or pharmacologically acceptable salts thereof, and pharmaceutical compositions containing (S)-norketamine or pharmacologically acceptable salts but substantially free of (R)-norketamine or pharmacologically acceptable salts thereof, are useful as novel pharmaceuticals in the field of prevention and / or treatment of mental disorders exhibiting depressive symptoms.

[0023] This figure illustrates the study design for investigating the antidepressant effect of norketamine. The study was conducted using 8-week-old male C57BL / 6 mice (purchased from CLEA Japan) that were intraperitoneally administered lipopolysaccharide (hereinafter abbreviated as LPS) at a dose of 0.5 mg / kg (hereinafter referred to as LPS-treated mice) as an inflammatory model of depression. 23 hours after LPS administration, physiological saline (10 ml / kg) or norketamine (5, 10, or 20 mg / kg) was administered intraperitoneally. One hour later, a spontaneous movement test (hereinafter sometimes abbreviated as LMT) was performed, three hours later, a tail suspension test (hereinafter sometimes abbreviated as TST) was performed, and five hours later, a forced swim test (hereinafter sometimes abbreviated as FST) was performed. (Example 1) This figure illustrates the results of examining the amount of spontaneous movement after norketamine administration using the spontaneous movement test. There was no difference in spontaneous kinetic energy among normal mice, LPS-treated mice administered with physiological saline, and LPS-treated mice administered with norketamine (5, 10, or 20 mg / kg). The vertical axis of the figure shows spontaneous kinetic energy (counts / 60 minutes). (Example 1) This figure illustrates the results of investigating the antidepressant effect of norketamine in a tail suspension test. LPS-treated mice administered with physiological saline showed a significant increase in immobility time compared to normal mice. Norketamine dose-dependently reduced the increased immobility time in LPS-treated mice. The vertical axis of the figure shows immobility time (seconds) in the TST. (Example 1) This figure illustrates the results of investigating the antidepressant effect of norketamine in a forced swim test. LPS-treated mice administered with physiological saline showed a significant increase in immobility time compared to normal mice. Norketamine dose-dependently reduced the increased immobility time in LPS-treated mice. The vertical axis of the figure shows immobility time (seconds) in the FST. (Example 1) This diagram illustrates the test plan for comparing 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, physiological saline (10 ml / kg), ketamine (10 mg / kg), or norketamine (10 mg / kg) were administered intraperitoneally. LMT was performed 1 hour after administration, TST 3 hours later, and FST 5 hours later.(Example 2) This figure illustrates the results of a comparative study of spontaneous motility after administration of ketamine and norketamine, respectively. There was no difference in spontaneous motility among normal mice, LPS-treated mice administered with physiological saline, and LPS-treated mice administered with ketamine (10 mg / kg) and norketamine (10 mg / kg), respectively. The vertical axis of the figure shows spontaneous motility (counts / 60 minutes). (Example 2) This figure illustrates the test plan for a comparative study of the antidepressant effects of ketamine and norketamine using TST. LPS-treated mice administered with physiological saline showed a significant increase in immobility time compared to normal 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 shows immobility time (seconds) in TST. (Example 2) This figure illustrates the test plan for a comparative study of the antidepressant effects of ketamine and norketamine using FST. LPS-treated mice administered with physiological saline showed a significant increase in immobility time compared to normal 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 shows immobility time (seconds) in FST. (Example 2) The side effects of ketamine and norketamine were compared using the exercise-enhancing effect, one of the side effect evaluation systems, and the results are shown. In mice administered with ketamine (10 mg / kg) and norketamine (20 mg / kg), a significant increase in exercise volume was observed 10 minutes after drug administration compared to normal mice administered with physiological saline. On the other hand, administration of norketamine at doses of 5 mg / kg and 10 mg / kg did not affect exercise volume. The vertical axis of the figure shows spontaneous movement (counts / 10 minutes). (Example 3) The side effects of ketamine and norketamine were compared using changes in prepulse (PP) stimulation inhibition, one of the side effect evaluation systems. The administration of ketamine (10 mg / kg) resulted in impaired prepulse inhibition at prepulse stimulation levels of 77 dB and 81 dB (Figure 3B).On the other hand, norketamine administration at 20 mg / kg significantly caused prepulse inhibition impairment at a prepulse stimulation of 81 dB, but administration at 5 mg / kg or 10 mg / kg did not cause prepulse inhibition impairment. The vertical axis of the figure shows prepulse inhibition (%). (Example 3) 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 the social defeat stress mouse groups administered with (S)-norketamine (10 mg / kg) and (R)-norketamine (10 mg / kg), respectively, Saline represents the social defeat stress mouse group administered with physiological saline (10 ml / kg), and Control represents the normal mouse group administered with physiological saline. In the figure, LMT means spontaneous exercise test, TST means tail suspension test, FST means forced swimming test, and SPT means 1% sucrose palatability test. (Example 4) This figure shows the results of examining the antidepressant effects of (S)- and (R)-norketamine in social defeat stress mice one day after administration using LMT. In the figure, S-NK and R-NK represent the social defeat stress mouse groups administered with (S)-norketamine and (R)-norketamine, respectively, Saline represents the social defeat stress mouse group administered with physiological saline, and Control represents the normal mouse group administered with physiological saline. The vertical axis of the figure shows spontaneous movement (counts / 60 minutes). (Example 4) This figure shows the results of examining the antidepressant effects of (S)- and (R)-norketamine in social defeat stress mice one day after administration using TST. In the figure, S-NK and R-NK represent the social defeat stress mouse groups administered with (S)-norketamine and (R)-norketamine, respectively, Saline represents the social defeat stress mouse group administered with physiological saline, and Control represents the normal mouse group administered with physiological saline. The vertical axis of the figure shows the immobility time (seconds) in TST. (Example 4) This figure shows the results of examining the antidepressant effects of (S)- and (R)-norketamine in social defeat stress mice using FST two days after administration. In the figure, S-NK and R-NK represent the social defeat stress mouse groups administered with (S)-norketamine and (R)-norketamine, respectively, Saline represents the social defeat stress mouse group administered with physiological saline, and Control represents the normal mouse group administered with physiological saline.The vertical axis of the figure shows the immobility time (seconds) in FST. (Example 4) This figure shows the results of examining the antidepressant effect of (S)- and (R)-norketamine in social defeat stress mice using a 1% sucrose palatability test 7 days after administration. In the figure, S-NK and R-NK represent the social defeat stress mouse groups administered with (S)-norketamine and (R)-norketamine, respectively, Saline represents the social defeat stress mouse group administered with physiological saline, and Control represents the normal mouse group administered with physiological saline. The vertical axis of the figure shows sucrose palatability (%). (Example 4) This figure shows the results of examining the effect of (S)- and (R)-norketamine on spine density in brain regions of social defeat stress mice 8 days after administration. (Example 4) This shows the results of comparing the side effects of (S)-norketamine and (S)-ketamine using the exercise-enhancing effect, one of the side effect evaluation systems. In the figure, S-norket, S-ket, and Saline represent the groups administered (S)-norketamine, (S)-ketamine, and physiological saline, respectively. The vertical axis of the figure shows spontaneous movement (counts / 10 minutes). (Example 4) This figure shows the results of comparing the side effects of (S)-norketamine and (S)-ketamine using the prepulse suppression test, one of the side effect evaluation systems. In the figure, Saline, S-ket, and S-norket represent the groups administered physiological saline, (S)-ketamine, and (S)-norketamine, respectively. Also, each bar from left to right represents the groups administered physiological 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 shows prepulse suppression (%). (Example 4) This figure shows the results of comparing the side effects of (S)-norketamine and (S)-ketamine using the CPP test, one of the side effect evaluation systems. In the figure, S-norket, S-ket, and Saline are the groups administered (S)-norketamine (20 mg / kg), (S)-ketamine (20 mg / kg), and physiological saline (10 ml / kg), respectively. The vertical axis of the figure shows the CPP score. (Example 4) Synthesis scheme of (S)-norketamine derivative.(Example 5) This figure shows the antidepressant effect of (S)-norketamine derivatives in socially defeated mice. In the figure, Vehicle represents the medium (0.5% carboxymethylcellulose (CMC) 10 ml / kg, 0.4% DMSO), and Compound 1 represents the (S)-norketamine derivative (30 mg / kg). PO means oral administration. LMT means spontaneous movement test, and SPT means 1% sucrose palatability test. The vertical axis of the figure shows spontaneous movement (counts / 60 minutes). (Example 7) This figure shows the results of examining the amount of spontaneous movement one hour after oral administration of (S)-norketamine derivatives in socially defeated mice using the LMT. In the figure, Vehicle represents the medium (0.5% carboxymethylcellulose (CMC) 10 ml / kg, 0.4% DMSO), and Compound 1 represents the (S)-norketamine derivative (30 mg / kg). Control represents the normal mouse group administered the medium. The vertical axis of the figure represents spontaneous movement (counts / 60 minutes). (Example 7) This figure shows the results of a 1% sucrose preference test conducted 3 and 7 days after oral administration to examine the antidepressant effect of the (S)-norketamine derivative in socially defeated mice. Control represents the normal mouse group administered the medium. The vertical axis of the figure represents sucrose preference (%). (Example 7).

[0024] The present invention relates to a preventive and / or therapeutic agent for depressive symptoms comprising the optical isomer (S)-norketamine, a prodrug of (S)-norketamine, or a pharmacoagulably acceptable salt thereof. The present invention also relates to a pharmaceutical composition for the preventive and / or therapeutic of depressive symptoms containing an effective amount of (S)-norketamine, a prodrug of (S)-norketamine, or a pharmacoagulably acceptable salt thereof for the alleviation of depressive symptoms.

[0025] In this invention, we demonstrated that norketamine, the main metabolite of ketamine, has a stronger antidepressant effect than ketamine, using an animal model of depression with inflammation. This animal model was created based on the inventors' finding that mice administered LPS in adulthood exhibit depressive-like behavior (Non-Patent Documents 14-16).

[0026] Furthermore, in this invention, we have demonstrated that (S)-norketamine, the main metabolite of (S)-ketamine, exhibits an antidepressant effect in a social defeat stress model, and that this antidepressant effect is still observed 7 days after administration. Moreover, we have demonstrated that an antidepressant effect is also observed when a prodrug of (S)-norketamine is administered to the same model, and that this antidepressant effect is still observed 7 days after administration.

[0027] Norketamine, with a single dose, showed a stronger antidepressant effect than ketamine in an LPS-induced inflammatory depression model mouse (see Examples 1 and 2). (S)-norketamine showed a strong antidepressant effect in a social defeat stress model, and the antidepressant effect was confirmed even after 7 days of administration (see Example 4). Furthermore, when a prodrug of (S)-norketamine was administered to the same model, a strong antidepressant effect was also shown, and the antidepressant effect was confirmed even after 7 days of administration (see Example 7). On the other hand, in the evaluation system for side effects, such as increased exercise activity and impaired prepulse inhibition, significant changes were observed with ketamine administration, but such side effects were weaker with norketamine and (S)-norketamine (see Examples 3 and 4). Furthermore, norketamine, (S)-norketamine, and (R)-norketamine have lower NMDA receptor affinity compared to ketamine (Non-Patent Literature 12), and are thought to have fewer side effects such as psychotic symptom induction, making them potentially more promising and safer antidepressants compared to ketamine. In fact, ketamine is classified as a narcotic, but norketamine is not.

[0028] Norketamine, like ketamine, is known to have optical isomers, which are referred to as (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 pharmacopositically acceptable salt thereof is effective in preventing and / or treating mental disorders exhibiting depressive symptoms because it is fast-acting and long-lasting, has a statistically significant higher antidepressant effect compared to (S)-ketamine, and has fewer side effects than (S)-ketamine (Patent Documents 1, 2 and Non-Patent Documents 10, 11). However, in the case of norketamine optical isomers, it has become clear that, contrary to the optical isomers of ketamine, (S)-norketamine is primarily responsible for the high antidepressant effect and low side effects.

[0029] (S)-norketamine, or any pharmacologically acceptable salt thereof, may be used as an antidepressant to treat and / or prevent depressive symptoms such as mood depression, decreased motivation, anxiety and associated insomnia, loss of appetite, and suicidal ideation.

[0030] The pharmaceutical composition according to 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 it does not contain (R)-norketamine or a pharmacologically acceptable salt thereof at all, or that it may contain the compound or a pharmacologically acceptable salt thereof in an amount that does not cause any effects or side effects, or that it may contain it as an impurity that is inevitably introduced during its manufacture. 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. Also, 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, the amount of (R)-norketamine in the pharmaceutical composition may be 2 mg or less, preferably 1 mg or less, and more preferably 0.5 mg or less, per 100 mg of (S)-norketamine. Furthermore, the pharmaceutical composition according to the present invention may be substantially free of ketamine, (R)-ketamine, or (S)-ketamine, or their pharmaceutically acceptable salts, and such a pharmaceutical composition is preferred. The term "substantially free of ketamine, (R)-ketamine, or (S)-ketamine, or their pharmaceutically acceptable salts" means that such compounds or their pharmaceutically acceptable salts are not included at all, or that the compounds or their pharmaceutically acceptable salts may be included in an amount that does not cause any effects or side effects, or that they may be included as impurities that are inevitably introduced during the manufacturing process. For example, the content of the compounds or their pharmaceutically 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 the compound or a pharmaceutically acceptable salt 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 according to the present invention can be preferably applied to diseases exhibiting depressive symptoms, such as depression, MDD, and bipolar disorder characterized by recurrent depressive symptoms and 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 according to the present invention can also be preferably applied to obsessive-compulsive disorder, PTSD, and autism spectrum disorder. Obsessive-compulsive disorder is a type of anxiety disorder characterized by obsessive thoughts and compulsive behaviors, and is thought to be related to depression. There are a great many cases where depression co-occurs, and in addition to obsessive thoughts and compulsive behaviors, depressive symptoms are also present. Many patients with PTSD exhibit depressive symptoms, and in fact, antidepressants such as SSRIs are used as treatments for PTSD, but their therapeutic effect is weak. Autism spectrum disorder is a developmental disorder characterized by an inability to maintain normal social relationships, abnormal language use, and behaviors such as compulsive behavior. The scope of the present invention includes pharmaceutical compositions for the prevention and / or treatment of obsessive-compulsive disorder, PTSD, and autism spectrum disorder, containing an amount of (S)-norketamine or a pharmacologically acceptable salt thereof effective in alleviating the symptoms of obsessive-compulsive disorder, PTSD, and autism spectrum disorder.

[0032] The drugs and pharmaceutical compositions according to the present invention can be administered orally or parenterally. For oral administration, known dosage forms such as tablets, capsules, coated tablets, lozenges, solutions, or suspensions can be used. Parenteral administration can be administered intravenously, intramuscularly, or subcutaneously by injection; administered via mucous membranes such as the nasal cavity or oral cavity using sprays or aerosols; administered rectally using suppositories; or administered transdermally using patches, liniments, or gels. Preferably, oral administration, nasal administration, or intravenous administration by injection can be used.

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

[0034]

[0035] (S)-norketamine can be produced by known methods. For example, it can be produced using 1-(2-chlorophenyl)-1-cyclohexene as a raw material (Non-Patent Document 17, Formula (II) below).

[0036]

[0037] (S)-norketamine or its pharmacoposly acceptable salts can be modified, for example by substituting a chlorine molecule of a substituent with another halogen molecule, to produce derivatives that may yield compounds with more desirable effects.

[0038] Furthermore, (S)-norketamine prodrugs or pharmacologically acceptable salts thereof can be synthesized and developed as pharmaceuticals. A prodrug is a compound that does not exert the desired pharmacological effect itself, or has a weak effect, but after administration to the body, is metabolized in the body to become an active metabolite and exerts the desired pharmacological effect. In other words, a (S)-norketamine prodrug is a compound that does not exert the desired pharmacological effect itself, or has a weak effect, but after administration to the body, is metabolized in the body to become (S)-norketamine and exhibits an effect of reducing depressive symptoms. The design of (S)-norketamine prodrugs can be carried out using known and reported methods (Non-Patent Documents 18, 19). A (S)-norketamine prodrug is not particularly limited as long as it is a compound that is metabolized in the body to become (S)-norketamine and exhibits an effect of reducing depressive symptoms, but for example, a compound in which a substituent is introduced to the nitrogen atom of the amino group of (S)-norketamine can be exemplified.Specifically, as prodrugs of (S)-norketamine, the following are N-alkyl derivatives represented by formula (III) below (N-alkylated (S)-norketamine), N-amide derivatives represented by formula (IV) below (N-amides of (S)-norketamine), N-carbamate derivatives represented by formula (V) below (N-carbamates of S-norketamine), N-acyloxyalkylcarbamate derivatives represented by formula (VI) below (N-acyloxyalkylcarbamates of (S)-norketamine), and oxodioxolenylmethylcarbamate derivatives represented by formula (VII) below ( (S)-norketamine), N-oxodioxolenylmethyl derivatives of (S)-norketamine represented by formula (VIII) below, N-mannich base derivatives of S-norketamine represented by formula (IX) below, phospholoriloxymethyl carbamate derivatives of S-norketamine represented by formula (X) below, N-phosphate derivatives of S-norketamine represented by formula (XI) below, and imine derivatives of (XII) below Examples include S-norketamine. In the formulas below that include 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. R in the formulas below. １ and R ２ In a formula including substituent R １ and R ２Each of these R, R is 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. １ and R ２ Examples of compounds that satisfy the following conditions include (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-(S)-(1-(2-chlorophenyl)-2-oxocyclohexyl)carbamate, represented by formula (XIII) below, and 1-((((S)-1-(2-chlorophenyl)-2-oxocyclohexyl)carbamoyl)oxy)ethylisobutyrate, represented by formula (XIV) below. Pharmacologically acceptable salts of (S)-norketamine prodrugs can be used in both free base and pharmacologically acceptable salt forms. The pharmacologically acceptable salt is preferably an addition salt of a pharmacologically acceptable acid, and more preferably a hydrochloride salt.

[0039]

[0040]

[0041]

[0042]

[0043]

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051] Furthermore, isotope labeling is applied to the compound according to the present invention, for example, to a stable isotope. １３ C or ２ By performing the procedure using H(D), quantitative measurements of the in vivo dynamics of this compound can be carried out.

[0052] The pharmaceutical composition according to the present invention may contain (S)-norketamine, a prodrug of (S)-norketamine, or a pharmacokinetically acceptable salt thereof, in addition to other pharmacoactive ingredients effective against depressive symptoms. Furthermore, in addition to these pharmacoactive ingredients, it may contain, as appropriate, a suitable pharmacokinetically acceptable carrier well known to those skilled in the art, depending on the dosage form, etc. Examples of pharmacokinetically acceptable carriers include antioxidants, stabilizers, preservatives, flavoring agents, colorants, solvents, solubilizers, surfactants, emulsifiers, defoaming agents, viscosity modifiers, gelling agents, absorption enhancers, dispersants, excipients, and pH adjusters.

[0053] When preparing the drugs and pharmaceutical compositions according to the present invention as injectable formulations, the form of a solution or suspension is preferred. For transmucosal administration, such as to the nasal cavity or oral cavity, the form of a powder, drop, or aerosol formulation is preferred. For rectal administration, the form of a semi-solid formulation, such as a cream or suppository, is preferred. All of these formulations can be prepared by any method known to those skilled in the art of pharmaceutical technology, such as as described in, for example, Remington's Pharmaceutical Sciences (Mac Publishing Company, Easton, PA, 1970). The injectable formulations may contain, for example, plasma-derived proteins such as albumin, amino acids such as glycine, and sugars such as mannitol as carriers, and may also contain buffers, solubilizers, and isotonic agents. When used as a water-soluble or lyophilized formulation, Tween is used to prevent aggregation. （登録商標） 80. Tween （登録商標）It is preferable to add surfactants such as 20. Furthermore, parenteral dosage forms other than injectable formulations may contain distilled water or physiological saline solution, polyalkylene glycosides such as polyethylene glycosides, plant-derived oils, and hydrogenated naphthalene. For example, rectal administration formulations such as suppositories contain polyalkylene glycosides, petrolatum, and cocoa oil as common excipients. Vaginal formulations may contain absorption enhancers such as bile salts, ethylenediamine salts, and citrates. Inhalation formulations may be solid and may contain lactose as an excipient, for example, and nasal drops may be water or oil solutions.

[0054] The precise dosage and administration plan of the drugs and pharmaceutical compositions according to the present invention can be adjusted depending on the required amount for each individual treatment target, the method of treatment, the degree of the disease or need, etc. Specifically, the dosage can be determined according to age, weight, general health status, sex, diet, administration time, method of administration, excretion rate, combination of drugs, and the patient's medical condition, and may also be determined by considering other factors. When administering the pharmaceutical composition according to the present invention to diseases exhibiting depressive symptoms such as depression, bipolar disorder, and obsessive-compulsive disorder, it is preferable that the active ingredient contained in the pharmaceutical composition contains an amount effective in alleviating the symptoms of each disease, preferably the depressive symptoms of each disease. (S)-norketamine or its pharmacologically acceptable salts can be used safely because they have fewer side effects than ketamine. The daily dose varies depending on the patient's condition, weight, type of compound, and route of administration, but for example, in the case of parenteral administration, the amount of active ingredient is approximately 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 It is administered at doses of 0 mg / person / day, 100-200 mg / person / day, 200-300 mg / person / day, 300-400 mg / person / day, or 400-500 mg / person / day. When administered orally, it is preferable to administer approximately 0.01-500 mg / person / day, preferably 0.1-100 mg / person / day, 0.1-1.0 mg / person / day, 1.0-20 mg / person / day, 20-40 mg / person / day, 40-60 mg / person / day, or 80-100 mg / person / day.

[0055] The present invention further relates to a method comprising administering the above-described agent or pharmaceutical composition according to the present invention to a patient who requires the prevention and / or treatment of depressive symptoms. The present invention also relates to a method for preventing and / or treating depressive symptoms, comprising administering the above-described agent according to the present invention to a subject 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 the above-described pharmaceutical composition according to the present invention to a subject in an amount effective for alleviating depressive symptoms. The subject of administration may be a human or mammal diagnosed with depressive symptoms, or a human or mammal requiring alleviation of depressive symptoms.

[0056] The present invention also relates to the use of (S)-norketamine, (S)-norketamine prodrugs, or pharmacoagulably acceptable salts thereof in the manufacture of pharmaceutical compositions for the prevention and / or treatment of depressive symptoms.

[0057] The present invention also relates to (S)-norketamine, (S)-norketamine prodrugs, or pharmacoagulated salts thereof for the prevention and / or treatment of depressive symptoms.

[0058] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples. Furthermore, various modifications are possible without departing from the technical spirit of the present invention. All tests were conducted with the permission of the Animal Experiment Committee of Chiba University.

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

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

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

[0062] The antidepressant effects of norketamine were investigated using behavioral tests (LMT, TST, and FST) in adult mice. The administration schedules for LPS and norketamine are shown in Figure 1A. Both TST and FST were performed after norketamine administration. The TST was performed as follows: First, the 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 piece, and each mouse was suspended from a hook. The immobility time of each mouse was recorded for 10 minutes. Immobility was defined only when the mouse was completely still and unresponsive. Immobility time increased in the depressed state. The FST was performed as follows: First, a cylinder (diameter: 23 cm, height: 31 cm) was filled with water to 15 cm and maintained at 23 ± 1°C, and a mouse was placed in each cylinder. Mice were tested in an automated forced-swimming apparatus using a SCANET MV-40 (Melquest Co., Ltd., Toyama, Japan). Idle time was calculated using the apparatus's analysis software as the total time minus the active time. Cumulative idle time was recorded over a 6-minute period during the test. The LMT was performed as follows: First, the mice were placed in an experimental cage (length × width × height: 560 × 560 × 330 mm). The mice's spontaneous motor activity was counted using the SCANET MV-40, and cumulative motor activity was recorded for 60 minutes. The cage was cleaned between tests. Idle time increases in a depressed state.

[0063] Statistical analysis was performed using one-way ANOVA followed by a minimum significance test (LSD test). Data are expressed as mean ± standard error (n = 8-12 mice / group). The significant difference compared to the LPS-treated mouse group administered with physiological saline was: ＊ p < 0.05, ＊＊ p < 0.01, ＊＊＊ The p-value < 0.001 indicates a significant difference compared to the LPS-treated mouse group administered ketamine. ＃ p < 0.05, ＃＃ This is shown by p < 0.01.

[0064] 2. Results In LMT, there was no difference in spontaneous motility among normal mice, LPS-treated mice administered with physiological saline, and LPS-treated mice administered with norketamine (5, 10, or 20 mg / kg) (Figure 1B). Therefore, it was confirmed that these treatments do not affect motor function.

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

[0066] The results above clearly show that norketamine exhibits antidepressant effects in mice administered with LPS. Specifically, the antidepressant effect of norketamine was observed in both TST and FST mice.

[0067] The antidepressant effects of norketamine were compared with those of ketamine. Specifically, an inflammatory animal model of depression (Non-Patent Literature 14-16) was used to examine the antidepressant effects of ketamine and norketamine on depressive-like behavior in the model animals.

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

[0069] An inflammatory animal model of depression was created by administering lipopolysaccharide (hereinafter abbreviated as LPS) to adult mice, similar to the method used in Example 1.

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

[0071] 2. Results In LMT, there was no difference in spontaneous motility among normal mice, LPS-treated mice administered with physiological saline, and LPS-treated mice administered with ketamine (10 mg / kg) or norketamine (10 mg / kg) (Figure 2B). Therefore, it was confirmed that these treatments do not affect motor function.

[0072] On the other hand, in TST and FST, LPS-treated mice administered with physiological saline showed a significant increase in immobility time compared to normal 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] The results above clearly show that ketamine and norketamine at a dose of 10 mg / kg exhibit antidepressant effects in LPS-administered mice. Notably, the antidepressant effect of norketamine was significantly stronger than that of ketamine. This result indicates that norketamine has a stronger antidepressant effect than ketamine. Since norketamine has a weaker affinity for NMDA receptors compared to ketamine, we believe that factors other than NMDA receptor blocking action are involved in the antidepressant effect of norketamine.

[0074] A comparative study of the side effects of ketamine and norketamine was conducted using the exercise-enhancing effect test and the prepulse suppression test, which are side effect evaluation systems.

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

[0076] The pre-pulse suppression test was conducted using a startle response device (SR-LAB, San Diego Instruments, San Diego, CA, USA). Specifically, mice were trained by playing a 65-decibel sound as background noise inside the device, and then given sound stimuli (pre-pulse stimuli) of 69, 73, 77, or 81 decibels (dB) for a period of more than 20 milliseconds. After 100 milliseconds, they were presented with a 120 dB sound stimulus (pulse stimulus), and their startle response to the pulse stimulus was recorded. The startle response when the pulse stimulus was applied without the pre-pulse stimulus was also recorded. Then, from the obtained data, PPI was calculated according to the following formula: PPI (%) = [1 - (pPx / P120)] × 100. In this formula, PPI represents prepulse suppression, pPx represents the maximum startle intensity in response to pulse stimulation when prepulse stimulation is applied, and P120 represents the average maximum startle intensity when pulse stimulation is applied without prepulse stimulation. The results regarding prepulse suppression were analyzed using Wilkes' lambda multivariate analysis of variance, followed by a least significant difference (LSD) test. Data are expressed as mean ± standard error (n = 10⁻¹² mice / group). The significant difference compared to the group administered physiological saline was calculated. ＊ p < 0.05, ＊＊＊ This is shown by p < 0.001.

[0077] 2. Results: In the measurement of exercise levels, mice administered ketamine (10 mg / kg) showed a significant increase in exercise level 10 minutes after drug administration compared with normal mice administered physiological saline. Mice administered norketamine (20 mg / kg) also showed a significant increase in exercise level 10 minutes after drug administration compared with normal mice administered physiological saline. Furthermore, the exercise level 10 minutes after norketamine (20 mg / kg) administration was significantly lower than that of mice administered ketamine (10 mg / kg). The increased exercise level after ketamine and norketamine administration was transient, returning to normal levels 20 minutes after drug administration. On the other hand, administration of norketamine at doses of 5 mg / kg and 10 mg / kg did not affect exercise level (Figure 3A).

[0078] In the prepulse suppression test, administration of ketamine (10 mg / kg) caused prepulse suppression impairment at prepulse stimuli of 77 dB and 81 dB (Figure 3B). On the other hand, norketamine, administered at 20 mg / kg, significantly caused prepulse suppression impairment at a prepulse stimuli of 81 dB, but did not cause prepulse suppression impairment at doses of 5 mg / kg or 10 mg / kg (Figure 3B).

[0079] As described above, from the perspective of side effects, ketamine administration causes side effects such as increased motility, impaired prepulse inhibition, and dependence. However, it was found that norketamine administration causes less increased motility and impaired prepulse inhibition compared to ketamine. In other words, norketamine is a safer drug compared to ketamine.

[0080] Using a social defeat stress model of depression (Non-Patent Literature 11), the antidepressant effects of (S)- and (R)-norketamine on depressive-like behavior in the model animals were investigated. The side effects of (S)-norketamine were also examined.

[0081] 1. Materials and Methods (S)- and (R)-norketamine hydrochloride were prepared from norketamine by optical resolution. The purity of these isomers was determined by high-performance liquid chromatography (CHIRALPAK). （登録商標）Confirmation was made using 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 study of side effects, was prepared by the previously reported method (Patent Documents 1-3).

[0082] A social defeat stress model for depression was created, following a previously reported study (Non-Patent Literature 11), by subjecting C57BL / 6 male mice to a stress called "social defeat stress" by exposing them to ICR male mice (large, aggressive mice) for 10 consecutive days. Mice subjected to social defeat stress exhibited depressive-like behavior. Specifically, the social defeat stress model showed an increase in immobility time in both TST and FST. Furthermore, in the 1% sucrose preference test (SPT), the proportion of mice drinking sucrose water decreased significantly, suggesting that depressive-like behavior was induced. On the other hand, in LMT, there was no difference in spontaneous motility between social defeat stress mice and normal mice.

[0083] The creation of the above-mentioned depression model animals and the administration of drugs were carried out specifically as described below (Figure 4A). Male C57BL / 6 mice (7 weeks old, Nippon SLC Co., Ltd., Hamamatsu, Japan) and ICR mice (9 weeks old, Nippon SLC Co., Ltd., Hamamatsu, Japan) were used. The mice were given free access to water and feed. Social defeat stress was performed by housing one C57 / B6 mouse and one ICR mouse together for 10 days. On day 11, a social interaction test was conducted, and mice exhibiting depressive symptoms were selected and used for the following behavioral evaluation. Control mice were administered the medium (10 ml / kg of physiological saline), and mice exhibiting depressive symptoms were administered (S)- or (R)-norketamine (10 mg / kg) or the medium (10 ml / kg of physiological saline) intraperitoneally.

[0084] The antidepressant effects of the drug were investigated using behavioral tests such as TST, FST, LMT, and SPT (Figure 4A). LMT and TST were performed on the day of administration, FST was performed the day after administration, and SPT was performed 7 days after administration. The TST was performed as follows: First, the 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 piece, and each mouse was suspended from a hook. The immobility time of each mouse was recorded for 10 minutes. Immobility was defined only when the mouse was completely still and unresponsive. Immobility time increased in the depressed state. The FST was performed as follows: First, a cylinder (diameter: 23 cm, height: 31 cm) was filled with water to 15 cm and maintained at 23 ± 1°C, and a mouse was placed in each cylinder. The mice were tested in an automatic forced swimming apparatus using SCANET MV-40 (Melquest Co., Ltd., Toyama, Japan). Immobility time was calculated using the device's analysis software as the total time minus the activity time. Cumulative immobility time was recorded over a 6-minute period during the test. LMT was performed as follows: First, mice were placed in experimental cages (length × width × height: 560 × 560 × 330 mm). Spontaneous motor activity of the mice was counted using SCANETMV-40, and cumulative movement was recorded for 60 minutes. The cage was cleaned between tests. Immobility time increases in a depressed state. SPT was performed by providing regular drinking water and a 1% sucrose solution for free intake and measuring the proportion of sucrose solution consumption. In a depressed state, the consumption of sucrose solution, which is a reward response, is reduced. Eight days after administration of (S)- or (R)-norketamine, mice were decapitated, their brains were quickly removed, and Golgi staining was performed. Spine density was observed and quantitatively evaluated using a Keyence microscope (BZ-9000, Osaka, Japan).

[0085] The side effects of (S)-norketamine were investigated using normal mice by comparing the effects of the exercise-enhancing effect test, the prepulse suppression test, and the conditioned place preference test (CPP), which are evaluation systems for side effects. In the side effect investigation, (S)-ketamine was used as a control for comparison. The exercise-enhancing effect test was conducted by testing the effect of (S)-norketamine and (S)-ketamine on the exercise volume of mice using SCANET MV-40 (Melquest Co., Ltd., Toyama, Japan). Measurements were taken for a total of 180 minutes, from 60 minutes before administration to 120 minutes after administration. Exercise volume was calculated as 10-minute intervals. The prepulse suppression test was conducted using a startle reaction device (SR-LAB, San Diego Instruments, San Diego, CA, USA). Furthermore, location preference tests were conducted using a location preference testing device (Brenscience Idea Co., Ltd., Osaka, Japan).

[0086] Statistical analysis of the results of the social defeat stress model was performed using one-way ANOVA followed by a minimum significance test. Data are expressed as mean ± standard error (n = 8 or 9 mice / group). ＊ p < 0.05, ＊＊ p < 0.01, ＊＊＊ p < 0.001 indicates a statistically significant difference compared to the group of mice subjected to social defeat stress and administered physiological saline. ＃ p < 0.05, ＃＃ A P < 0.01 indicates a statistically significant difference compared to the group of mice subjected to social defeat stress by (R)-norketamine.

[0087] Statistical analysis of the Golgi staining results was performed using repeated one-way ANOVA followed by a minimum significance test. Data are expressed as mean ± standard error (n = 6 mice / group). ＊＊ p < 0.01, ＊＊＊ A p < 0.001 indicates a statistically significant difference compared to the group of mice subjected to social defeat stress and administered physiological saline. ＃ p < 0.05, ＃＃＃ A P < 0.001 indicates a statistically significant difference compared to the group of mice subjected to social defeat stress by (R)-norketamine.

[0088] Statistical analysis of the kinetic energy results was performed using repeated one-way ANOVA followed by a minimum significance test. Data are expressed as mean ± standard error (n = 10 to 12 mice / group). ＊＊ p < 0.01, ＊＊＊ A p < 0.001 indicates a statistically significant difference compared to the group administered physiological saline.

[0089] The results regarding prepulse suppression were analyzed using multivariate analysis of variance (MANOVA) followed by a minimum significance test. Data are expressed as mean ± standard error (n = 8 or 9 mice / group). ＊＊ A p < 0.01 indicates a statistically significant difference compared to the group administered physiological saline.

[0090] The results of the location preference test were analyzed using one-way ANOVA followed by a minimum significance test. Data are expressed as mean ± standard error (n = 7 or 9 mice / group). ＊ p < 0.05, ＊＊ A p < 0.01 indicates a statistically significant difference compared to the group administered physiological saline.

[0091] 2. Results First, compared to normal mice, social defeat stress mice showed a significant increase in immobility time in TST and FST, and a significant decrease in sucrose consumption preference in SPT. On the other hand, there was no difference in spontaneous motility between social defeat stress mice and normal mice in LMT.

[0092] In LMTs conducted after administration of both norketamine isomers, there was no difference in spontaneous motility among normal mice, social defeat stress mice administered with physiological saline, and social defeat stress mice administered with (S)- or (R)-norketamine (Figure 4B). Therefore, it was confirmed that these treatments do not affect motor function.

[0093] In TSTs conducted after administration of both norketamine isomers, social defeat stress mice administered with physiological saline showed a significant increase in immobility time compared to normal mice. (S)-norketamine significantly reduced the increased immobility time in TST in social defeat stress mice, while (R)-norketamine did not show an antidepressant effect (Figure 4C). (S)-norketamine showed a significantly higher antidepressant effect compared to (R)-norketamine (Figure 4C).

[0094] In FSTs conducted after administration of both norketamine isomers, social defeat stress mice administered with physiological saline showed a significant increase in immobility time compared to normal mice. (S)-norketamine significantly reduced the increased immobility time in TSTs in social defeat stress mice, while (R)-norketamine did not show an antidepressant effect (Figure 4D). (S)-norketamine showed a significantly higher antidepressant effect compared to (R)-norketamine (Figure 4D).

[0095] In SPT (Stress Test) conducted 7 days after administration of both norketamine isomers, social defeat stress mice administered with physiological saline showed a decreased preference for sucrose consumption compared to normal mice. (S)-norketamine significantly restored the decreased preference for sucrose consumption in social defeat stress mice 7 days after administration, while (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 a significant decrease in spine density in the frontal cortex (prelimbic region), hippocampal CA3 region, and hippocampal dentate gyrus of socially defeated stress mice administered with physiological saline compared to normal mice. (S)-norketamine significantly increased the decreased spine density in socially defeated stress mice 8 days after administration, while (R)-norketamine did not show any improvement (Figure 4F). On the other hand, the spine density in the hippocampal CA1 region of socially defeated stress mice remained unchanged. Furthermore, the spine density in the nucleus accumbens (core region and shell region) of socially defeated stress mice increased, but was not affected by administration of (S)-norketamine and (R)-norketamine.

[0097] Next, in an exercise-enhancing study to examine side effects, mice administered (S)-ketamine (10 mg / kg) showed a significant increase in exercise volume 10 and 20 minutes after administration compared to normal mice administered with physiological saline. The increase in exercise volume with (S)-ketamine (10 mg / kg) was transient and returned to normal levels 30 minutes after administration. On the other hand, administration of (S)-norketamine (5, 10, 20 mg / kg) had no effect on exercise volume (Figure 4G).

[0098] In prepulse suppression tests following administration of (S)-ketamine and (S)-norketamine, administration of (S)-ketamine (10 mg / kg) resulted in impaired prepulse suppression (Figure 4H). On the other hand, administration of (S)-norketamine (5, 10, 20 mg / kg) did not cause impaired prepulse suppression (Figure 4H).

[0099] In a location preference test following administration of (S)-ketamine and (S)-norketamine, administration of (S)-ketamine (20 mg / kg) significantly increased CPP scores and induced dependence (Figure 4I). On the other hand, administration of (S)-norketamine (20 mg / kg) did not increase CPP scores (Figure 4I).

[0100] The results above clearly show that (S)-norketamine at a dose of 10 mg / kg exhibits an antidepressant effect in social defeat stress mice, while (R)-norketamine does not. Notably, in SPT, TST, and FST, the antidepressant effect of (S)-norketamine was significantly stronger than that of (R)-norketamine. This result indicates that (S)-norketamine has a longer-lasting antidepressant effect than (R)-norketamine. Ketamine and both isomers of its metabolites are known to be rapidly cleared in the body. Despite the fact that (S)-norketamine is thought to be absent from the body 7 days after a single administration, an antidepressant effect was observed. From this, we believe that the difference in the effects of the two isomers of norketamine 7 days after administration is not due to differences in pharmacokinetics.

[0101] Furthermore, from the perspective of side effects, administration of (S)-ketamine resulted in increased physical activity, impaired prepulse inhibition, and dependence formation. On the other hand, administration of (S)-norketamine did not result in increased physical activity, impaired prepulse inhibition, or dependence formation. Based on these results, (S)-norketamine is a safer drug compared to (RS)-ketamine and (S)-ketamine, which are currently used clinically.

[0102] The (S)-norketamine derivative was synthesized according to 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): Under a nitrogen atmosphere, compound (1), namely cyclohexanone 3.09 g (31.4 mmol) and 1-bromo-2-chlorobenzene 3.00 g (15.7 mmol), was added to a mixture of Pd2(dba)3 48 mg (0.053 mmol), Xantphos 73 mg (0.13 mmol), cesium carbonate 7.61 g (23.3 mmol), and 1,4-dioxane (11 mL) and heated 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 layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel chromatography (65 g neutral SiO₂). ２ Compound (2) was eluted (using a hexane / ethyl acetate gradient from 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, 1.32 g (6.33 mmol) of Compound (2) was dissolved in a dichloromethane solution (6.3 mL). 1.90 g (8.23 mmol) of tert-butyl azodicarboxylic acid, 1.06 g of MS5A powder, and 0.76 g (0.633 mmol) of (R)-C8-TCYP were added, and 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 neutral SiO₂). ２ Compound (3) was obtained in 2.50 g (5.70 mmol) by diluting with hexane / ethyl acetate (9:1). (Yield: 90.0%) The synthesis of compound (3) was confirmed by NMR.

[0105] 3. Synthesis of (S)-norketamine: Under a nitrogen atmosphere, 2.50 g (5.70 mmol) of compound (3) was added to a 49 mL dichloromethane solution and trifluoroacetic acid (25 mL) was added. The mixture was stirred at room temperature for 3 hours. Acetone (29 mL) was added to the mixture and stirred for 10 minutes, then concentrated under reduced pressure. To the resulting residue, 46 mL (3:1:1 v / v / v) of a mixed solvent of acetic acid-THF-water was added, followed by 9.12 g (140 mmol) of zinc powder in several additions. 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 by adding saturated sodium carbonate aqueous solution. The aqueous layer was extracted five times with dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel chromatography (25 g neutral SiO ２ (S)-norketamine was obtained as a white solid of 1.00 g (4.47 mmol) by dissolving (S)-norketamine in a hexane / ethyl acetate ratio of 1:2 (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 the optical resolution of the S-isomer of the racemic mixture with 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 mixed in an acetonitrile solution (7.3 mL). 0.83 g (3.23 mmol) of N,N'-disuccinimidyl carbonate was added, and the mixture was stirred at room temperature for 3 hours. 73 mL of dichloromethane and water were added, and then 3.23 mL (3.23 mmol) of 1N hydrochloric acid was added for extraction and liquid-liquid separation. The organic layer was washed in the order of water, saturated sodium bicarbonate aqueous solution, and water, and dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel chromatography (29 g neutral SiO₂). ２ Compound (5) was dissolved in hexane / ethyl acetate (1:1) to obtain 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, 0.19 g (0.701 mmol) of compound (5) was added to acetonitrile solution (1.9 mL), to which 0.16 g (0.716 mmol) of (S)-norketamine and saturated sodium bicarbonate aqueous solution (0.95 mL) were added, and the mixture was stirred overnight at room temperature. Ethyl acetate and water were added to the mixture, and the extract was separated. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by concentration under reduced pressure was purified by silica gel chromatography (11 g neutral SiO ２ By dissolving hexane / ethyl acetate in a 2:1 ratio, 0.16 g (0.422 mmol) of the (S)-norketamine derivative (1), represented by the following formula (XIII), was obtained as a colorless resin. (Yield: 60.2%) The synthesis of the (S)-norketamine derivative (1) was confirmed by NMR.

[0108]

[0109] 6. Synthesis of Compound (7) Under a nitrogen atmosphere, 13.6 g (29.1 mmol) of a 15% MeSNa aqueous solution was added dropwise over 2 hours 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. The mixture was then stirred at room temperature for 1 hour, and the organic layer was separated. This was washed twice with saturated brine and dried over anhydrous sodium sulfate. The residue was concentrated under reduced pressure and distilled (boiling point 173°C, atmospheric pressure) to obtain 3.35 g (21.6 mmol) of Compound (7) as a colorless oil. (Yield: 74.2%) Synthesis of Compound (7) was confirmed by NMR.

[0110] 7. Synthesis of Compound (8) Under a nitrogen atmosphere, a mixture of 2.85 g (32.3 mmol) of isobutyric acid and 4.18 g (32.4 mmol) of diisopropylethylamine was dropwise added to a mixture of 3.35 g (21.6 mmol) of compound (7) and 2.85 g (32.3 mmol) of isobutyric acid. After the dropwise addition was complete, the mixture was heated and stirred at 55°C for 16 hours. After the mixture cooled, it was diluted with diethyl ether (220 mL), washed four times with water, twice with saturated sodium bicarbonate aqueous solution, and once with saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was subjected to vacuum distillation (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, 1.52 g (7.38 mmol) of compound (8) was added to a 35 mL solution of dichloromethane, to which 1.68 g (14.6 mmol) of N-hydroxysuccinimide was added and cooled in an ice bath. 12.3 g (14.6 mmol) of 9% peracetic acid / acetic acid solution was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 24 hours. The mixture was diluted with diethyl ether (180 mL), washed twice with water, three times with saturated sodium bicarbonate aqueous solution (until the pH became weakly basic), and once with saturated saline solution, and dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel chromatography (40 g neutral SiO2). ２ Compound (9) was dissolved in hexane / ethyl acetate in a 3:1 ratio to obtain 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, 0.17 g (0.626 mmol) of compound (5) was added to acetonitrile solution (1.7 mL), to which 0.14 g (0.626 mmol) of (S)-norketamine and saturated sodium bicarbonate aqueous solution (0.85 mL) were added, and the mixture was stirred overnight at room temperature. Ethyl acetate and water were added to the mixture, and the extract was separated. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by concentrating under reduced pressure was purified by silica gel chromatography (10 g neutral SiO ２By dissolving the (S)-norketamine derivative (2), represented by the following formula (XIV), in a ratio of 5:1 (hexane / ethyl acetate), 0.18 g (0.471 mmol) was obtained as a colorless oily substance in a diastereomer mixture. (Yield: 75.2%) The synthesis of (S)-norketamine derivative (2) was confirmed by NMR.

[0113]

[0114] The pharmacokinetics of (S)-norketamine derivatives were investigated by measuring their blood concentrations after administration.

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

[0116] As a 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 sample, blank sample, and QC (quality control) sample. After stirring for 10 seconds, I.S. (internal standard) solution (Norketamine-D) was added. ４ 100 μL of (10 ng / mL) was added. For the blank sample, acetonitrile:methanol = 9:1 was added. The mixture was stirred for 30 seconds and centrifuged at room temperature, 16000 x g, for 3 minutes. 80 μL of the supernatant was transferred to a new μtube and 100 μL of 0.001 mol / L ammonium bicarbonate was added. The mixture was stirred for 10 seconds and centrifuged at room temperature, 16000 x g, for 2 minutes. The (S)-norketamine concentration was 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 × 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 washing 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 Ionspray 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. The results of the concentration measurement are shown in Table 1.

[0119]

[0120] In Table 1, "compound1" represents (S)-norketamine derivative (1), and "compound2" represents (S)-norketamine derivative (2). From the results in Table 1, (S)-norketamine derivative (1) showed a slower elimination of (S)-norketamine from the blood than (S)-norketamine derivative (2), indicating that it remained in the blood as (S)-norketamine for a longer period. Therefore, (S)-norketamine derivative (1) was selected for the following pharmacological experiments.

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

[0122] 1. Materials and Methods A social defeat stress model for depression was created in accordance with previously reported information (Non-Patent Literature 11) by subjecting C57BL / 6 male mice to a stress called "social defeat stress" by exposing them to ICR male mice (large, aggressive mice) for 10 consecutive days. Mice subjected to social defeat stress exhibited depressive-like behavior. Specifically, in the 1% sucrose preference test (SPT), the proportion of mice drinking sucrose water in the social defeat stress model was significantly reduced, suggesting that depressive-like behavior (anhedonia) was induced. On the other hand, there was no difference in spontaneous motility between social defeat stress mice and normal mice.

[0123] The creation of the above-mentioned depression model animals and the administration of drugs were carried out specifically as described below (Figure 6A). Male C57BL / 6 mice (7 weeks old, SLC Japan Co., Ltd., Hamamatsu, Japan) and ICR mice (9 weeks old, SLC Japan Co., Ltd., Hamamatsu, Japan) were used. The mice were given free access to water and feed. Social defeat stress was performed by housing one C57BL / 6 mouse and one ICR mouse together for 10 days. On the 11th day, a social interaction test was conducted, and mice exhibiting depressive symptoms were selected and used for the following behavioral evaluation. Control mice were orally administered the medium (0.5% carboxymethylcellulose (CMC) 10 ml / kg, 0.4% DMSO), while mice exhibiting depressive symptoms were orally administered either (S)-norketamine derivative (Compound 1) (30 mg / kg) or the medium (0.5% carboxymethylcellulose (CMC) 10 ml / kg, 0.4% DMSO).

[0124] The antidepressant effects of the drug were investigated using behavioral tests such as LMT and SPT (Figure 6A). The LMT was performed one hour after administration, and the SPT was performed two and six days after administration. The SPT was conducted by providing participants with regular drinking water and a 1% sucrose solution and allowing them to freely consume either. The proportion of sucrose solution consumption was measured. In a depressive state, the consumption of sucrose solution, which is a reward response, decreases.

[0125] Statistical analysis was performed using one-way ANOVA followed by a minimum significance test (LSD test). Data are expressed as mean ± standard error (n = 9-11 mice / group). The significant difference compared to the group of mice exhibiting depressive symptoms that received oral administration of (S)-norketamine derivative (1) was: ＊＊＊ This is shown by p < 0.001.

[0126] 2. Results: There was no difference in exercise levels among the three groups one hour after oral administration (Figure 6B). In 1% sucrose preference tests three and seven days after administration, the group exhibiting depressive symptoms consumed significantly less sucrose solution, but the group administered compound I showed significant improvement (Figure 6C). These results indicate that compound I exhibits an antidepressant effect in a social defeat stress model.

[0127] As described above, the agents and pharmaceutical compositions for the prevention and / or treatment of depressive symptoms according to the present invention have a rapid and long-lasting antidepressant effect, and also have few side effects such as psychotic symptom induction and drug dependence, making them useful as novel pharmaceuticals in the field of prevention and / or treatment of mental illnesses exhibiting depressive symptoms.

Claims

1. A medicament for preventing and / or treating depressive symptoms, comprising (S)-norketamine, a prodrug of (S)-norketamine, or a pharmaceutically acceptable salt thereof.

2. The medicament for preventing and / or treating depressive symptoms according to claim 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. The medicament for preventing and / or treating depressive symptoms according to claim 1 or 2, wherein the pharmaceutically acceptable salt of (S)-norketamine is (S)-norketamine hydrochloride.

4. The prodrug of (S)-norketamine is a compound represented by the following formula (VI), formula (VII), formula (XIII) or formula (XIV), or a pharmaceutically acceptable salt or hydrochloride thereof, wherein R is an alkyl group, an alkoxy group, an aryl group, or an aralkyl group, and R １ and R ２ are each independently an alkyl group, an alkoxy group, an aryl group, or an aralkyl group. The medicament for preventing and / or treating depressive symptoms according to claim 1 or 2.

5. A pharmaceutical composition for preventing and / or treating depressive symptoms, containing (S)-norketamine, a prodrug of (S)-norketamine, or a pharmaceutically acceptable salt thereof in an amount effective for reducing depressive symptoms, and substantially free of (R)-norketamine or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical composition for preventing and / or treating depressive symptoms according to claim 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 claim 5 or 6, wherein the pharmaceutically acceptable salt of (S)-norketamine is (S)-norketamine hydrochloride.

8. The prodrug of (S)-norketamine is a compound represented by the following formula (VI), formula (VII), formula (XIII) or formula (XIV), or a pharmaceutically acceptable salt or hydrochloride thereof, wherein R is an alkyl group, an alkoxy group, an aryl group, or an aralkyl group, and R １ and R ２ are each independently an alkyl group, an alkoxy group, an aryl group, or an aralkyl group. The pharmaceutical composition for preventing and / or treating depressive symptoms according to claim 5 or 6.

9. A method for preventing and / or treating depressive symptoms, comprising administering to a patient in need of prevention and / or treatment of depressive symptoms an effective amount of (S)-norketamine, a prodrug of (S)-norketamine, or a pharmaceutically acceptable salt thereof.

10. The method for preventing and / or treating depressive symptoms according to claim 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 claim 9 or 10, wherein the pharmaceutically acceptable salt of (S)-norketamine is (S)-norketamine hydrochloride.

12. The prodrug of (S)-norketamine is a compound represented by the following formula (VI), formula (VII), formula (XIII) or formula (XIV), or a pharmaceutically acceptable salt or hydrochloride thereof, wherein R is an alkyl group, an alkoxy group, an aryl group, or an aralkyl group, and R １ and R ２ are each independently an alkyl group, an alkoxy group, an aryl group, or an aralkyl group. The method for preventing and / or treating depressive symptoms according to claim 9 or 10.

13. Use of (S)-norketamine, a prodrug of (S)-norketamine, or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for preventing and / or treating depressive symptoms.

14. The use according to claim 13, wherein the depressive symptom is a depressive symptom in depression, a depressive symptom in obsessive-compulsive disorder, a depressive symptom in PTSD, or a depressive symptom in autism spectrum disorder.

15. The use according to claim 13 or 14, wherein the pharmacologically acceptable salt of (S)-norketamine is (S)-norketamine hydrochloride.

16. The prodrug of (S)-norketamine is any one compound selected from the compounds represented by the following formula (III) to formula (XIV) or a pharmacologically acceptable salt or hydrochloride thereof, wherein R is an alkyl group, an alkoxy group, an aryl group, or an aralkyl group, and R １ and R ２ are each independently an alkyl group, an alkoxy group, an aryl group, or an aralkyl group. The use according to claim 13 or 14:

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)ethyl isobutyrate.

19. A medicament for preventing and / or treating depressive symptoms, comprising (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.

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