Ketamine derivatives and their use in the treatment of psychiatric disorders

Abstract

The application discloses a ketamine derivative and application thereof in treatment of mental diseases, and belongs to the technical field of medicines.The compound or the pharmaceutical composition thereof can obviously improve the expression amount of nerve cell BDNF, promote neurite growth, inhibit NMDA receptor signal and treat acute and chronic anti-depression, and has improved oral bioavailability relative to ketamine, and can be used for treating mental diseases such as depression.

Description

[0001] This application claims priority to Chinese Patent Application No. 202510123525.2, filed with the State Intellectual Property Office of China on January 26, 2025, entitled "Ketamine Derivatives and Their Use in the Treatment of Mental Illnesses", and declares that the entire contents of the earlier application are incorporated by reference. Technical Field

[0002] This application falls within the field of life sciences and biomedicine, specifically relating to ketamine derivatives and their use in the treatment of mental disorders. Background Technology

[0003] Mental illness refers to diseases characterized by varying degrees of impairment in cognitive, emotional, volitional, and behavioral activities due to brain dysfunction caused by various biological, psychological, and social environmental factors. These include depression, bipolar disorder, schizophrenia, and anxiety disorders. Mental illnesses primarily affect a patient's psychological state and cognitive function, resulting in extremely high rates of disability and death, and imposing a significant psychological and economic burden on patients' families and society.

[0004] Depression is an affective (mood) disorder caused by various factors, also known as depressive disorder. It is characterized by low mood, slowed thinking, cognitive impairment, and reduced willpower. Many patients also experience physical symptoms, and in severe cases, it can lead to suicide. With changes in the modern living environment and increasing work pressure, the incidence of depression is rising year by year. Traditional antidepressants mostly act on the monoaminergic nervous system, requiring continuous use for weeks or even months to become effective, and are ineffective in treating one-third of patients with treatment-resistant depression. In related technologies, for example, Chinese invention patent document CN115190815B states that approximately one-third of patients with major depressive disorder (MDD) fail to achieve symptom relief even after multiple rounds of treatment with several known classes of antidepressants, including selective serotonin reuptake inhibitors (SSRIs). As a result, the high prevalence, low cure rate, high relapse rate, and high disability rate of depression have become a serious mental illness that endangers human physical and mental health, causing a huge mental and economic burden on society and families. In particular, for treatment-resistant depression (TRD), new and more effective drug therapies for depression are needed.

[0005] Ketamine's primary use is as a dissociative anesthetic. In recent years, its secondary use as a rapid-acting antidepressant has garnered significant attention due to its robust antidepressant effects in patients with TRD (Transient Depression). The antidepressant effect can last for days or weeks after a single dose. Importantly, the S-enantiomer of ketamine (S-ket) has recently been approved by the U.S. Food and Drug Administration (FDA) for the treatment of depression. Ketamine's primary molecular target is the N-methyl-D-aspartate receptor (NMDAR), and researchers believe that inhibition of this target is one of the key molecular mechanisms underlying ketamine's antidepressant effects.

[0006] However, drugs like ketamine and S-ket also have problems such as being addictive and easily abused. Therefore, in clinical practice, these drugs must be used under the supervision of medical institutions, which greatly limits their application in the treatment of depression.

[0007] The antidepressant effects of the R enantiomer of ketamine and its metabolite (2R,6R)-hydroxynorketamine have been investigated in the prior art. In rodent models, the R enantiomer of ketamine (R-ket) has a more potent and longer-lasting antidepressant effect than the S-ket (Transl Psychiatry (2015) 5, e632; doi:10.1038 / tp.2015.136). Similarly, the prior art reports that the ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) also has an antidepressant effect in rodent models, with a bioavailability of approximately 50% (J Psychopharmacol. 2019 January ; 33(1): 12–24. doi:10.1177 / 0269881118812095). Therefore, both R-ket and HNK have certain antidepressant effects, and it is claimed that both can avoid the anesthetic effect of ketamine, thereby further preventing drug abuse. However, their effects in animal models have not yet been effectively verified in human trials. Considering that S-ket has an affinity for NMDA receptors that is about four times that of R-ket (Transl Psychiatry (2015) 5, e632; doi:10.1038 / tp.2015.136), while HNK does not bind to or inhibit NMDA receptors (Nature 533 (7604): 481–486. doi:10.1038 / nature17998), this means that at the same dose, the blocking effect of R-ket and HNK on NMDA receptors is weak, which may be one of the important reasons for their poor efficacy in human clinical trials.

[0008] Ketamine, a novel antidepressant with rapid onset of action, can significantly improve negative symptoms such as depressed mood and low self-esteem within hours of a single subanesthetic dose, and even reduce suicidal ideation, particularly effective for treatment-resistant depression. However, ketamine causes side effects such as dissociative hallucinations and carries the risk of abuse as a recreational drug, greatly limiting its clinical application. Furthermore, ketamine has poor oral bioavailability, which also hinders its clinical efficacy. Therefore, developing novel compound drugs for treating depression and other mental illnesses with fewer side effects, rapid onset of action, or high oral bioavailability has been a focus of research worldwide. Summary of the Invention

[0009] The problem to be solved

[0010] The present invention provides, at least in part, novel ketamine derivatives with significantly improved oral bioavailability compared to ketamine, including compositions of single enantiomers or optical isomers of the novel ketamine derivatives or mixtures thereof.

[0011] The primary objective of this invention is to provide a novel class of ketamine derivatives that have the effects of increasing the expression of BDNF in nerve cells, promoting neurite growth, inhibiting NMDA receptor signaling, and providing acute and chronic antidepressant effects.

[0012] A second objective of this invention is to provide a mixture of isomers of the novel ketamine derivative described above, which has the effects of increasing the expression of BDNF in nerve cells, promoting neurite growth, inhibiting NMDA receptor signaling, and having acute and chronic antidepressant effects.

[0013] A third objective of this invention is to provide a pharmaceutical composition containing the above-mentioned novel ketamine derivative, which has the effects of increasing the expression level of BDNF in nerve cells, promoting neurite growth, inhibiting NMDA receptor signaling, and having acute and chronic antidepressant effects.

[0014] The fourth objective of this invention is to provide the use of the above-mentioned novel ketamine derivatives or pharmaceutical compositions for the prevention, treatment or improvement of mental illness. The administration, especially oral administration, of an effective amount of the novel ketamine derivatives can improve various mouse models of depression and can increase the expression of BDNF in nerve cells, promote neurite growth, and inhibit NMDA receptor signaling in different cell lines, thereby achieving the purpose of preventing, treating or improving the development of depression.

[0015] Based on the above objectives, the core problem that this invention aims to solve is: to address the issue of unsatisfactory or inconvenient effects of existing drug treatments.

[0016] Technical solution

[0017] The role and mechanism of brain-derived neurotrophic factor (BDNF) and its receptors in mental illnesses are currently a hot topic in neuroscience research. BDNF is a growth factor widely distributed in the central nervous system, playing a crucial role in neuronal growth, survival, and synaptic plasticity. In mental illnesses, especially depression and schizophrenia, the expression level and functional state of BDNF are closely related to the development and progression of the disease. In depression, BDNF levels are typically low, which may be related to impaired neuroplasticity. Treatment with antidepressants can improve depressive symptoms by increasing BDNF levels. The antidepressant mechanisms of BDNF may include promoting neurogenesis, enhancing synaptic plasticity, affecting neurotransmission, and antioxidant effects. Furthermore, BDNF gene polymorphisms, such as the Val66Met site, are also associated with susceptibility to depression, treatment efficacy, and cognitive function. In schizophrenia, abnormalities in the BDNF signaling pathway may lead to abnormalities in neurodevelopment and neuroplasticity. Studies have found decreased BDNF concentrations in the brains of patients with schizophrenia, which may be related to the development and progression of the disease. Furthermore, upstream regulatory mechanisms of BDNF, such as microRNA124-3p, are also associated with cognitive impairment in schizophrenia. The role of the BDNF-TrkB signaling system in the pathogenesis and treatment of schizophrenia has also attracted attention, with the binding of BDNF to its receptor, tyrosine receptor kinase B (TrkB), playing a crucial role in regulating neuronal plasticity. The correlation between BDNF and its downstream pathways and the development of GABAergic neurons is also a key research focus. GABAergic neurons regulate neural activity and maintain the normal function of neural circuits by releasing the inhibitory neurotransmitter GABA. BDNF and its downstream signaling pathways play important roles in the development, differentiation, synapse formation, and maturation of GABAergic neurons. BDNF precursors (pro-BDNF) and mature BDNF (mBDNF) play opposite roles in regulating apoptosis; pro-BDNF participates in apoptosis by binding to specific receptors, while mBDNF promotes neuronal survival and synaptic plasticity by binding to TrkB receptors. In summary, BDNF and its receptors play multifaceted roles and mechanisms in mental illnesses, involving aspects such as neuroplasticity, neuroprotection, and cell survival. Increasing BDNF levels is an important means of treating mental illnesses.

[0018] Based on this, this application provides a novel ketamine derivative that has the effects of increasing the expression of BDNF in nerve cells, promoting neurite growth, inhibiting NMDA receptor signaling, and having acute and chronic antidepressant effects.

[0019] 1. Novel ketamine derivative compounds

[0020] The first aspect of this invention provides a compound or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer, or prodrug or mixture thereof, wherein the structure of the compound is shown in Formula I below:

[0021]

[0022] Formula I;

[0023] in,

[0024] R1 and R2 are each independently selected from H, deuterium, C1-C10 alkyl, C1-C10 haloalkyl, and -R4-O-R5; wherein R4 is a C1-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or

[0025] R1 and R2 together with the nitrogen atom to which they are attached form a C3-C6 cyclic heteroalkyl ring; the ring is optionally substituted by one or more straight-chain or branched C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms;

[0026] R3 is one or more substituents at any substituted position on the benzene ring, each independently selected from H, deuterium, OH, halogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, CN, CF3, OCF3, NO2;

[0027] n is an integer selected from 1 to 4. For example, n is 1, 2, 3, or 4.

[0028] According to any embodiment of the first aspect of the present invention, a compound or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer or a prodrug or a mixture thereof, wherein in the compound of formula I, R1 is H and R2 is H.

[0029] As a preferred embodiment of the first aspect of the invention, a compound or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer, or prodrug or mixture thereof is provided, said compound having the structure shown in Formula II:

[0030]

[0031] Formula II.

[0032] As a preferred embodiment of the first aspect of the invention, a compound or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer, or prodrug thereof or a mixture thereof is provided, said compound being of formula II-a:

[0033]

[0034] Formula II-a.

[0035] Preferably, in some embodiments, the optical purity of the compound is >5%, >25%, >50%, >75%, >90%, >95%, >97%, >98%, or >99%.

[0036] In addition to the traditional NMDA receptor drug action mechanism for mental illnesses such as depression, this invention incorporates BDNF levels into the drug activity evaluation criteria, thereby discovering a novel ketamine derivative with multifunctional and multi-target effects.

[0037] This application provides a novel class of ketamine derivatives, compounds within the general formula range of Formula I, particularly compounds of Formula II, Formula II-a, or their pharmaceutically acceptable salts, esters, hydrates, solvates, tautomers, optical isomers, or their prodrugs or mixtures thereof, which maintain the inhibitory effect of ketamine on NMDA receptor signaling, preserve and optimize the activity of ketamine in increasing BDNF levels, and further improve the bioavailability of oral administration. Oral administration also shows significant antidepressant effects in animal models.

[0038] Cellular experiments have shown that compounds within the general formula range of Formula I, especially compounds of Formula II and Formula II-a, can increase the expression of BDNF in nerve cells, promote neurite growth, inhibit NMDA receptor signaling, and have acute and chronic antidepressant effects.

[0039] Animal experiments further demonstrated that, in an acute stress model, intraperitoneal injection / oral administration of compounds of formula I, particularly compounds of formula II, II-a, or pharmaceutically acceptable salts thereof, of the ketamine derivatives of the present invention exhibited acute antidepressant effects, suggesting a possible rapid onset of action. Oral experiments showed that the compounds of the present invention had enhanced acute antidepressant effects compared to the positive control drug fluoxetine. Pharmacokinetic experiments showed that the compounds of the present invention, particularly compounds of formula II-a, achieved oral bioavailability of over 85% after intravenous injection (5 mg / kg body weight) and oral administration (5 mg / kg body weight), while the oral bioavailability of ketamine reported in the literature was only around 20%. Therefore, the compounds of formula I, particularly compounds of formula II, II-a, or pharmaceutically acceptable salts thereof, of the ketamine derivatives of the present invention have significantly improved oral bioavailability compared to the traditional positive control drug ketamine, thus improving ease of use and safety.

[0040] In a mouse model of oral corticosterone-induced depression, intraperitoneal / oral administration of compounds of the ketamine derivatives of the present invention within the general formula range of Formula I, particularly compounds of Formula II, Formula II-a, or pharmaceutically acceptable salts thereof, demonstrated rapidly onset antidepressant effects and, in intraperitoneal injection experiments, enhanced antidepressant effects relative to ketamine.

[0041] In a mouse model of chronic unpredictable stress, intraperitoneal injection of compounds of the ketamine derivatives of the present invention within the general formula range of Formula I, particularly compounds of Formula II, Formula II-a, or pharmaceutically acceptable salts thereof, has a rapidly onset antidepressant effect.

[0042] As a preferred embodiment of the first aspect of the invention, a compound or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer, or prodrug or mixture thereof is provided, wherein the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, pyrosulfate, bisulfite, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, bromate (such as hydrobromide), iodate (such as hydroiodate), acetate, propionate, decanoate, octanoate, acrylate, formate, isobutyrate, hexanoate, heptanoate, etc. Acrylates, oxalates, malonates, succinates, octanoates, sebacic acid salts, fumarates, maleates, butyn-1,4-diacidates, hexyn-1,6-diacidates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates. Hydrochlorides are preferred.

[0043] As described herein, when the compound of Formula I, Formula II, or Formula II-a has isomers, such as optical isomers, stereoisomers, positional isomers, rotational isomers, etc., any isomers and mixtures of isomers are included within the scope of the compound of Formula I or Formula II. For example, when the compound of Formula I, Formula II, or Formula II-a has an optical isomer, the optical isomer separated from the racemic mixture is also included within the scope of the compound of Formula I, Formula II, or Formula II-a. These isomers can be obtained as individual products by synthetic or separation methods (e.g., concentration, solvent extraction, column chromatography, recrystallization, etc.).

[0044] The compounds represented by Formula I, Formula II, or Formula II-a may be in crystalline or amorphous form. When the compound is crystalline, both single crystals and crystalline mixtures are included within the scope of the compound. Crystals may be prepared according to crystallization methods known in the art.

[0045] The compounds represented by Formula I, Formula II, and Formula II-a can be pharmaceutically acceptable cocrystals or cocrystal salts. In this document, a cocrystal or cocrystal salt refers to a crystalline substance composed of two or more specific solids, each possessing different physical properties (e.g., structure, melting point, heat of fusion, etc.) at room temperature. Cocrystals and cocrystal salts can be prepared using co-crystallization methods known in the art.

[0046] The compounds represented by Formula I, Formula II, and Formula II-a can be solvates (e.g., hydrates, etc.) or non-solvents, both of which are included in the scope of the compounds represented by Formula I or Formula II-a.

[0047] Isotopes can be used (e.g.) 2 H, 3 H, 14 Compounds of formula I, formula II, and formula II-a are represented by C, etc.

[0048] Deuterated compounds (of which) 1 H has been transformed 2 H(D) is also included in the range of compounds shown in Formula I, Formula II, and Formula II-a.

[0049] As described herein, "prodrugs," also known as prodrug precursors, are compounds that may have weak or no activity on their own, but which, after administration, are converted under physiological conditions (e.g., through metabolism, solvation, or other means) into the biologically active form of the compound represented by Formula I or Formula II. In one case, a prodrug is a prodrug that, upon metabolism in vivo, produces the compound represented by Formula I, Formula II, or Formula II-a.

[0050] 2. Pharmaceutical Composition

[0051] A second aspect of the present invention provides a pharmaceutical composition comprising a compound of formula I, formula II, formula II-a, or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer, or a prodrug or mixture thereof as described in any of the first aspects of the present invention, and a pharmaceutically acceptable carrier or diluent.

[0052] A pharmaceutical composition refers to a composition in which the active ingredient is a compound or a pharmaceutically acceptable equivalent (a pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer, optical isomer or prodrug or mixture thereof) described in any embodiment of the first aspect of the present invention, and which contains one or more pharmaceutically acceptable carriers or diluents.

[0053] The term "pharmaceutically acceptable carrier or diluent" as used in this invention refers to excipients, additives, or solvents commonly used in pharmaceutical preparations, including but not limited to lactose, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid, lower alkyl ethers of cellulose, corn starch, potato starch, gums, fatty acids, fatty acid amines, glyceryl monostearate or glyceryl distearate, phospholipids, olive oil, peanut oil, syrups, colorants, flavoring agents, preservatives, water, ethanol, propanol, physiological saline, and glucose solution.

[0054] As a preferred second aspect of the invention, a pharmaceutical composition is provided comprising a compound of formula II-a or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer or prodrug or mixture thereof, and a pharmaceutically acceptable carrier or diluent.

[0055]

[0056] Formula II-a.

[0057] According to any embodiment of the second aspect of the present invention, the pharmaceutical composition is in a single-dose form, wherein the single-dose form contains 0.03 mg to 500 mg of the compound or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer or prodrug or mixture thereof, and a pharmaceutically acceptable carrier or diluent.

[0058] According to any embodiment of the second aspect of the present invention, the compound or its pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer, optical isomer or prodrug or mixture thereof is administered as a single dose selected from any of the following numerical ranges: 0.03-400 mg, 0.03-300 mg, 0.05-280 mg, 0.08-250 mg, 0.1-220 mg, 0.15-200 mg, 0.2-180 mg, 0.25-150 mg, 0.3-100 mg, 0.35-80 mg, 0.4-50 mg, 0.45-30 mg, 0.5-20 mg, 0.8-20 mg, 1-20 mg, 1.5-20 mg, 2-10 mg, 2-8 mg, 2-6 mg, 2.5-5 mg, 2.5-4 mg.

[0059] Satisfactory results are obtained when administered in a single dose as described above. It is preferable to administer the dose 1, 2, or 3 times daily, or in a sustained-release form. This dosage regimen can be adjusted to provide the best therapeutic response. For example, due to the urgency of the treatment condition, several separate doses may be administered daily, or the dose may be reduced proportionally.

[0060] As stated herein, “single dose” as used herein refers to a dose of medicine suitable for a single administration to a subject.

[0061] According to any embodiment of the second aspect of the present invention, the compound or its pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer, optical isomer or prodrug or mixture thereof is administered at a dose selected from any of the following numerical ranges: 0.01-20 mg / Kg, 0.01-10 mg / Kg, 0.01-5 mg / Kg, 0.01-4 mg / Kg, 0.01-3 mg / Kg, 0.01-2 mg / Kg, 0.01-1 mg / Kg, 0.01-0.5 mg / Kg, 0.01-0.2 mg / Kg, 0.01-0.1 mg / Kg.

[0062] Satisfactory results are obtained when administered in a single dose as described above. It is preferable to administer the dose 1, 2, or 3 times daily, or in a sustained-release form. This dosage regimen can be adjusted to provide the best therapeutic response. For example, due to the urgency of the treatment condition, several separate doses may be administered daily, or the dose may be reduced proportionally.

[0063] According to any embodiment of the second aspect of the present invention, the pharmaceutical composition thereof, wherein the compound thereof or a pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer, optical isomer or prodrug or mixture thereof is administered to a mammal, particularly a human, at a dose of 0.02 to 20 mg / kg / day / person.

[0064] Preferably, the medication is administered to the patient at a dose of 0.05~5 mg / kg / day / person.

[0065] Preferably, the medication is administered to the patient at a dose of 0.2 to 2 mg / kg / day / person.

[0066] When administered within the above dosage range, the pharmaceutical composition did not exhibit any toxic side effects.

[0067] According to any embodiment of the second aspect of the present invention, the pharmaceutical composition wherein the compound or its pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer or its prodrug or mixture thereof comprises 1 to 99 wt% of the compound or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer or a prodrug or mixture thereof.

[0068] According to any embodiment of the second aspect of the present invention, the drug loading concentration of the compound or its pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer, optical isomer or prodrug or mixture thereof in the drug composition is 0.01 to 10 mg / mL.

[0069] The pharmaceutical composition according to any embodiment of the second aspect of the present invention further includes an agent selected from at least one of the following: other antidepressant therapeutic agents.

[0070] According to any embodiment of the second aspect of the present invention, the other antidepressant includes any one, two or more of ketamine, fluoxetine, sertraline, citalopram, paroxetine, fluvoxamine, duloxetine, venlafaxine, amitriptyline, doxepin hydrochloride, or amitriptyline hydrochloride.

[0071] There are no restrictions on the timing of administration of the above-mentioned combination drugs. The compounds of the present invention, or their pharmaceutically acceptable salts, esters, hydrates, solvates, or tautomers, optical isomers, or their prodrugs, mixtures, or pharmaceutical compositions thereof, and the combined drugs may be administered simultaneously or at different times. The dosage of the combination drugs may be based on clinical dosage and may be appropriately determined according to the patient, route of administration, disease, combination, etc. The above-mentioned combination drugs may be a combination of two or more of them in suitable proportions.

[0072] Examples of the above-mentioned administration modes include the following: (1) administering a single formulation obtained by simultaneously processing the compound or pharmaceutical composition of the present invention and a combination drug; (2) administering two formulations of the compound or pharmaceutical composition of the present invention and a combination drug prepared separately via the same route of administration; (3) administering two formulations of the compound or pharmaceutical composition of the present invention and a combination drug prepared separately via the same route of administration in an alternating manner; (4) administering two formulations of the compound or pharmaceutical composition of the present invention and a combination drug prepared separately via different routes of administration; (5) administering two formulations of the compound or pharmaceutical composition of the present invention and a combination drug prepared separately via different routes of administration in an alternating manner (e.g., administering in the order of the compound or pharmaceutical composition of the present invention and the combination drug, or in the reverse order), etc.

[0073] According to any embodiment of the second aspect of the present invention, the dosage form of the pharmaceutical composition is selected from one or more of powder, granule, tablet, pill, capsule, sustained-release, controlled-release, injection, infusion or suspension.

[0074] 3. Medicine box

[0075] A third aspect of the present invention provides a medicine box comprising one or more single-dose units of any of the compounds described in the first aspect of the present invention, or a pharmaceutically acceptable salt, ester, hydrate, solvate, or tautomer, optical isomer, or prodrug or mixture thereof, or a pharmaceutical composition comprising one or more single-dose units of any of the compounds described in the second aspect of the present invention, and instructions for use in treating a disease.

[0076] 4. Indications

[0077] The fourth aspect of this invention provides the use of a compound of Formula I or a pharmaceutically acceptable salt, ester, hydrate, solvate, or tautomer, optical isomer, or prodrug thereof or a mixture thereof for the preparation of a medicament for the prevention or treatment of mental illness.

[0078]

[0079] Formula I;

[0080] in,

[0081] R1 and R2 are each independently selected from H, deuterium, C1-C10 alkyl, C1-C10 haloalkyl, and -R4-O-R5; wherein R4 is a C1-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or

[0082] R1 and R2 together with the nitrogen atom to which they are attached form a C3-C6 cyclic heteroalkyl ring; the ring is optionally substituted by one or more straight-chain or branched C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms;

[0083] R3 is one or more substituents at any substituted position on the benzene ring, each independently selected from H, deuterium, OH, halogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, CN, CF3, OCF3, NO2;

[0084] n is an integer selected from 1 to 4.

[0085] As used in this article, “mental illness” refers to depression, obsessive-compulsive disorder, bulimia nervosa, schizophrenia, mood disorders, substance use disorders, stroke, Parkinson’s disease (PD), dementia (AD), and depressive disorders associated with epilepsy.

[0086] According to any embodiment of the fourth aspect of the present invention, in the compound represented by Formula I, R1 is H and R2 is H.

[0087] As a preferred fourth aspect of the invention, the use of a compound of Formula II or a pharmaceutically acceptable salt, ester, hydrate, solvate, or tautomer, optical isomer, or prodrug or mixture thereof for the preparation of a medicament for the prevention or treatment of mental illness is provided.

[0088]

[0089] Formula II.

[0090] As a preferred fourth aspect of the invention, the use of a compound or a pharmaceutically acceptable salt, ester, hydrate, solvate, or tautomer, optical isomer, or prodrug or mixture thereof for the preparation of a medicament for the prevention or treatment of mental illness is provided, wherein the compound is any one of the compounds represented by Formula II-a or any mixture of two or more thereof:

[0091]

[0092] Formula II-a.

[0093] As a preferred fourth aspect of the invention, the use of a compound of formula II-a or a pharmaceutically acceptable salt, ester, hydrate, solvate, or tautomer, optical isomer, or prodrug or mixture thereof for the preparation of a medicament for the prevention or treatment of mental illness is provided.

[0094]

[0095] Formula II-a.

[0096] Cellular experiments have shown that compounds of formula II-a can increase the expression of BDNF in nerve cells, promote neurite growth, and inhibit NMDA receptor signaling.

[0097] Animal experiments further demonstrated that, in an acute stress model, intraperitoneal injection / oral administration of compound II-a exhibited acute antidepressant effects and suggested a possible rapid onset of action. Oral experiments also showed that the compound of this invention had enhanced acute antidepressant effects compared to the positive control drug fluoxetine. Pharmacokinetic experiments showed that the compound of this invention, particularly compound II-a, achieved an oral bioavailability of over 85% via intravenous injection (5 mg / kg body weight) and oral administration (5 mg / kg body weight), while the oral bioavailability of ketamine reported in the literature was less than 20%. Therefore, the compound II-a of this invention has significantly improved oral bioavailability compared to the traditional positive control drug ketamine, enhancing both convenience and safety.

[0098] In a mouse model of depression induced by oral corticosterone, intraperitoneal / oral administration of compound II-a demonstrated a rapidly onset antidepressant effect, and in the intraperitoneal injection experiment, it enhanced the antidepressant effect compared to ketamine.

[0099] In a mouse model of chronic unpredictable stress, intraperitoneal injection of compound II-a demonstrated a rapidly onset antidepressant effect.

[0100] As a preferred fourth aspect of the invention, the use of a pharmaceutical composition for preparing a medicament for the prevention or treatment of mental illness is provided, said pharmaceutical composition comprising a compound of any one of formula II or II-a, or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer, or prodrug or mixture thereof, and a pharmaceutically acceptable carrier or diluent.

[0101] As a preferred fourth aspect of the invention, the use of a pharmaceutical composition for preparing a medicament for the prevention or treatment of mental illness is provided, the pharmaceutical composition comprising a compound of formula II-a or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer or a prodrug or mixture thereof, and a pharmaceutically acceptable carrier or diluent.

[0102]

[0103] Formula II-a.

[0104] As a preferred embodiment of any of the fourth aspects of the present invention, the mental illness is selected from depression, obsessive-compulsive disorder, bulimia nervosa, schizophrenia, mood disorder, substance use disorder, stroke, Parkinson's disease (PD), dementia (AD), and depressive disorder associated with epilepsy.

[0105] As described in this article, "depression," also known as depressive disorder, is characterized by a significant and persistent low mood and is a major type of mood disorder. Clinically, the low mood is disproportionate to the situation, ranging from sullenness to profound grief, feelings of inferiority and depression, and even pessimism and suicidal ideation or behavior; in some cases, stupor may occur; some patients exhibit significant anxiety and psychomotor agitation; and in severe cases, psychotic symptoms such as hallucinations and delusions may appear. Each episode lasts at least two weeks, and in some cases, even several years. Most cases tend to recur, and most episodes can be relieved, although some may leave residual symptoms or become chronic.

[0106] The depression described in this invention includes depression in the general sense and depression or depressive state caused by psychological or social factors, or depression or depressive state induced by any other physical factors. It can be induced by diseases such as brain injury, cardiovascular and cerebrovascular diseases, cancer, and the use of interferon, anticancer drugs and other therapeutic drugs in cancer treatment; it can be caused by life or social rhythm disorders, chronic sleep disorders, long-term deliberate staying up late, or depression or depressive state caused by chronic physical diseases such as chronic pain, diabetes, liver disease, kidney disease, and neurodegenerative diseases, etc.

[0107] As described in this article, "obsessive-compulsive disorder" refers to a common mental disorder characterized by recurring obsessive thoughts and compulsive behaviors. Patients may know that these behaviors are unnecessary, but they find it difficult to control them, which consumes a lot of time and energy, leading to severe anxiety and impaired social functioning.

[0108] As described in this article, "bulimia nervosa" refers to a mental illness of eating disorder in which patients frequently experience uncontrollable binge eating behaviors, and then often resort to inappropriate compensatory behaviors such as purging and excessive exercise to avoid weight gain.

[0109] As described in this article, "schizophrenia" refers to a chronic and severe mental disorder, often accompanied by abnormalities in perception, thinking, emotion, and behavior, which significantly impairs the patient's social functioning and gradually leads to detachment from reality.

[0110] As described in this article, "mood disorders" refer to a class of mental illnesses characterized by significant and persistent elevated or depressed mood, accompanied by cognitive and behavioral changes, which affect an individual's social functioning and quality of life.

[0111] As described in this article, "substance use disorder" refers to a condition in which an individual experiences a series of physiological, psychological, and social functional problems due to long-term and repeated use of psychoactive substances. These psychoactive substances include alcohol, opioids (heroin, morphine, etc.), marijuana, cocaine, amphetamine stimulants, hallucinogens, and prescription drugs (such as some sedative-hypnotics and analgesics).

[0112] Preferably, the major depressive disorder is treatment-resistant depression.

[0113] Preferably, the depression includes acute depressive episodes of bipolar disorder, mild depression, moderate depression, severe depression, or drug-resistant depression.

[0114] As described in this article, the "acute depressive phase of bipolar disorder" refers to the stage in the course of bipolar disorder in which the patient experiences a sudden and prolonged period of extremely low mood, severe lack of interest and energy, often accompanied by typical depressive symptoms such as slowed thinking, self-blame, and guilt.

[0115] As described in this article, "mild depression" refers to symptoms that are relatively mild. The patient's daily functioning is affected to some extent, but they are still able to maintain basic life, work and social interactions. However, their motivation is reduced, they often feel helpless and sad, lack interest in things they used to enjoy, and may be accompanied by mild changes in appetite and sleep.

[0116] As described in this article, "moderate depression" refers to more pronounced symptoms, including increased low mood and loss of interest, difficulty concentrating, a significant decline in work and study efficiency, obvious sleep disturbances such as difficulty falling asleep or waking up early, decreased or increased appetite, frequent self-blame and guilt, and severe blows to self-confidence.

[0117] As described in this article, "major depression" refers to an extremely severe condition in which the patient's social functioning is almost paralyzed. They may be bedridden, completely avoid social interaction, experience extremely low mood and despair, and may even have suicidal thoughts and behaviors. Physically, they may also experience severe weight changes, intractable insomnia, and other conditions.

[0118] As a preferred fourth aspect of the invention, the use of one or more compounds of Formula II, Formula II-a, or pharmaceutically acceptable salts, esters, hydrates, solvates, or tautomers, optical isomers, or prodrugs or mixtures thereof for the preparation of a medicament for the prevention or treatment of mental illness, wherein the mental illness comprises any one or more of the following characteristics:

[0119] Diseases characterized by abnormal BDNF levels;

[0120] Diseases characterized by abnormal activation of NMDA receptors;

[0121] Diseases characterized by abnormal synaptic plasticity;

[0122] The compound has the following structural formula:

[0123]

[0124] Formula II;

[0125]

[0126] Formula II-a.

[0127] As a preferred aspect of the fourth aspect of the invention, the use of a pharmaceutical composition for preparing a medicament for the prevention or treatment of mental illness is provided, the pharmaceutical composition comprising one or more compounds of formula II, formula II-a or the thereof, a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer or prodrug or mixture thereof, and a pharmaceutically acceptable carrier or diluent.

[0128] The mental illness includes any one or more of the following characteristics:

[0129] Diseases characterized by abnormal BDNF levels;

[0130] Diseases characterized by abnormal activation of NMDA receptors;

[0131] Diseases characterized by abnormal synaptic plasticity;

[0132] The compound has the following structural formula:

[0133]

[0134] Formula II;

[0135]

[0136] Formula II-a.

[0137] According to the use of any pharmaceutical composition of the fourth aspect of the present invention, the single-dose form of the pharmaceutical composition contains between 0.03 mg and 500 mg of the compound or a pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer, optical isomer or prodrug or mixture thereof.

[0138] According to any embodiment of the fourth aspect of the present invention, the compound or its pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer, optical isomer or prodrug or mixture thereof (active ingredient) is administered as a single dose selected from any of the following numerical ranges: 0.03-400 mg, 0.03-300 mg, 0.05-280 mg, 0.08-250 mg, 0.1-220 mg, 0.15-200 mg, 0.2-180 mg, 0.25-150 mg, 0.3-100 mg, 0.35-80 mg, 0.4-50 mg, 0.45-30 mg, 0.5-20 mg, 0.8-20 mg, 1-20 mg, 1.5-20 mg, 2-10 mg, 2-8 mg, 2-6 mg, 2.5-5 mg, 2.5-4 mg.

[0139] Satisfactory results are obtained when administered in a single dose as described above. It is preferable to administer the dose 1, 2, or 3 times daily, or in a sustained-release form. This dosage regimen can be adjusted to provide the best therapeutic response. For example, due to the urgency of the treatment condition, several separate doses may be administered daily, or the dose may be reduced proportionally.

[0140] As stated herein, “single dose” as used herein refers to a dose of medicine suitable for a single administration to a subject.

[0141] According to any embodiment of the fourth aspect of the present invention, the active ingredient is administered at a dose selected from any of the following numerical ranges: 0.01-20 mg / Kg, 0.01-15 mg / Kg, 0.01-10 mg / Kg, 0.01-5 mg / Kg, 0.01-4 mg / Kg, 0.01-3 mg / Kg, 0.01-2 mg / Kg, 0.01-1 mg / Kg, 0.01-0.5 mg / Kg, 0.01-0.2 mg / Kg, 0.01-0.1 mg / Kg.

[0142] Satisfactory results are obtained when administered in a single dose as described above. It is preferable to administer the dose 1, 2, or 3 times daily, or in a sustained-release form. This dosage regimen can be adjusted to provide the best therapeutic response. For example, due to the urgency of the treatment condition, several separate doses may be administered daily, or the dose may be reduced proportionally.

[0143] According to any embodiment of the fourth aspect of the invention, the compound or its pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer, optical isomer or prodrug or mixture thereof is administered to a mammal, particularly a human, at a dose of 0.02 to 20 mg / kg / day / person.

[0144] Preferably, the medication is administered to the patient at a dose of 0.05~5 mg / kg / day / person.

[0145] Preferably, the medication is administered to the patient at a dose of 0.2 to 2 mg / kg / day / person.

[0146] When administered within the above dosage range, the pharmaceutical composition did not exhibit any toxic side effects.

[0147] According to any embodiment of the fourth aspect of the present invention, the mass percentage of the compound or its pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer, optical isomer or its prodrug or mixture thereof in the pharmaceutical composition is 1 to 99 wt%.

[0148] According to any embodiment of the fourth aspect of the present invention, the pharmaceutical composition wherein the mass percentage of the active ingredient in the pharmaceutical composition is selected from any of the following numerical ranges: 1~99wt%, 30~99wt%, 30~95wt%, 30~90wt%, 30~85wt%, 30~80wt%, 30~75wt%, 30~70wt%, 30~65wt%, 30~60wt%, 30~55wt%, 30~50wt%, 40~99wt%, 40~95wt%, 40~90wt%, 40~85wt%, 40~80wt%, 40~75wt%, 40~70wt%, 40~65wt%, 40~60wt%, 40~55wt%, 40~50wt%, 50~99wt%, 50~95wt%, 50~90wt%, 50~85wt%. %, 50~80wt %, 50~75wt %, 50~70wt %, 50~65wt %, 50~60wt %, 50~55wt %, 60~99wt %, 60~95wt %, 60~90wt %, 60~85 wt %, 60~80wt %, 60~75wt %, 60~70wt%, 60~65wt %, 70~99wt %, 70~95wt %, 70~90wt %, 70~85 wt %, 70~80wt %, 70~75wt %, 80~99wt %, 80~95wt %, 80~90wt%, 80~85wt%, 90~99wt%, 90~95wt%.

[0149] According to the use of any pharmaceutical composition of the fourth aspect of the present invention, the drug loading concentration of the compound in the pharmaceutical composition or its pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer, optical isomer or prodrug or mixture thereof is 0.01 to 10 mg / mL.

[0150] As a preferred embodiment of any of the fourth aspects of the present invention, the concentration (drug loading concentration) of the active ingredient in the pharmaceutical composition is selected from any of the following numerical ranges: 0.01-10 mg / mL, 0.01-8 mg / mL, 0.01-5 mg / mL, 0.01-3 mg / mL, 0.01-2 mg / mL, 0.01-1 mg / mL, 0.1-10 mg / mL, 0.1-8 mg / mL, 0.1-5 mg / mL, 0.1-3 mg / mL, 0.1-2 mg / mL, 0.1-1 mg / mL, 1-10 mg / mL, 1-8 mg / mL, 1-5 mg / mL, 1-3 mg / mL, 1-2 mg / mL, 2-10 mg / mL, 2-8 mg / mL, 2-5 mg / mL, 2-3 mg / mL, 4-10 mg / mL, 4-8 mg / mL, 4-5 mg / mL, 6-10 mg / mL, 6-8 mg / mL, 6-8 mg / mL, 6-8 mg / mL, 6-10 ... mg / mL, 8-10 mg / mL.

[0151] According to the use of any pharmaceutical composition of the fourth aspect of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or diluent.

[0152] According to the use of any pharmaceutical composition of the fourth aspect of the present invention, the dosage form of the pharmaceutical composition is selected from one or more of powder, granule, tablet, pill, capsule, sustained-release, controlled-release, injection, infusion or suspension.

[0153] The optical isomers described in this invention refer to compounds with the same molecular formula and structural formula but different optical rotation properties. A preferred embodiment of the optical isomers described in this invention is an enantiomer, which refers to a pair of compounds with the same physicochemical properties, molecular formula, and structural formula but mirror-symmetric.

[0154] The term "prevention" as used herein refers to administering the compounds or pharmaceutical compositions of the present invention to a subject before the onset of the disease or symptoms, in order to avoid the occurrence of the disease or symptoms or to reduce the risk of the occurrence of the disease or symptoms.

[0155] The “reduction in the risk of disease or symptoms” described herein refers to a subject’s lower likelihood of developing a disease or symptom than an equivalent control individual, for example, a subject given the compound or pharmaceutical composition of the present invention while the control did not receive treatment or medication.

[0156] As used herein, the term "treatment" refers to the relief of symptoms or complications by suppressing, alleviating, or eradicating a disease state or its symptoms, to delaying disease progression, and / or to curing or eliminating the disease. Patients wishing to be treated are preferably mammals, particularly humans.

[0157] As described herein, the term "therapeutic and / or preventative effective amount" for the pharmaceutical compositions of the present invention refers to an amount sufficient to cure, alleviate, or partially prevent the clinical manifestations of a given disease and its complications in a therapeutic intervention including administration of the composition. An amount sufficient to achieve the above is defined as a "therapeutic and / or preventative effective amount." The effective amount for each purpose will depend on the severity of the disease or lesion and the subject's weight and general condition. However, it should be recognized that the total daily dosage of the pharmaceutical compositions of the present invention must be determined by the attending physician within the bounds of reliable medical judgment. For any specific patient, the specific therapeutically effective dose level must be determined based on a number of factors, including the disorder being treated and its severity; the activity of the specific pharmaceutical composition used; the specific pharmaceutical composition used; the patient's age, weight, general health condition, sex, and diet; the timing, route of administration, and excretion rate of the specific pharmaceutical composition used; the duration of treatment; other drugs used in combination with or concurrently with the pharmaceutical composition used; and similar factors known in the medical field. For example, it is practiced in the art to start the dose of the pharmaceutical composition below the level required to obtain the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.

[0158] The term “treatment of disease” refers to reducing the frequency or severity of at least one symptom or sign of a disease or condition experienced by a subject.

[0159] The term "pharmaceutically acceptable salt" refers to an acidic or basic salt of the compounds of the present invention, which has the desired pharmaceutical activity and is not biologically or otherwise undesirable.

[0160] definition

[0161] As used herein, the term "solvent" refers to a compound that carries solvent molecules, such as a hydrate.

[0162] In this invention, the term "comprising" or "containing" indicates that various ingredients may be used together in the composition of this invention. Therefore, the terms "consistent with..." and "composed of..." are included in the term "comprising" or "containing".

[0163] In this invention, a "pharmaceuticalally acceptable" ingredient is a substance that is suitable for humans and / or animals without excessive adverse side effects (such as toxicity, irritation, and allergic reactions), i.e., has a reasonable benefit / risk ratio.

[0164] The actual dosage level and route of administration of the active ingredient (compound of formula I, compound of formula II, compound of formula II-a, or a pharmaceutically acceptable salt, ester, hydrate, solvate, or tautomer, optical isomer, or prodrug or mixture thereof) in the pharmaceutical composition of the present invention can be modified so that the resulting amount of active ingredient can effectively achieve the desired therapeutic response in a specific patient. The dosage level must be selected based on the activity of the specific active ingredient, the route of administration, the severity of the condition being treated, and the condition and medical history of the patient to be treated. However, it is the practice in the art to start the dosage of the active ingredient below the level required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0165] Beneficial effects

[0166] Compared with the prior art, the advantages of this application are as follows:

[0167] (1) Existing ketamine drugs have poor oral bioavailability when treating depression. The present invention discovers a new ketamine derivative, compounds within the general formula range of Formula I, especially compounds of Formula II, Formula II-a, or pharmaceutically acceptable salts thereof, which have improved oral bioavailability relative to ketamine. Cell experiments show that the compounds of the present invention have the effects of increasing the expression of BDNF in nerve cells, promoting neurite growth, inhibiting NMDA receptor signaling, and acute and chronic antidepressant effects.

[0168] (2) Animal experiments further demonstrate that, in an acute stress model, intraperitoneal injection / oral administration of compounds of the ketamine derivatives of the present invention within the general formula range of Formula I, especially compounds of Formula II, Formula II-a, or pharmaceutically acceptable salts thereof, has an acute antidepressant effect and suggests a possible rapid onset of action. Oral experiments show that the compounds of the present invention have an enhanced acute antidepressant effect compared to the positive drug fluoxetine. Pharmacokinetic experiments show that the compounds of the present invention, especially compounds of Formula II-a, have an oral bioavailability of over 85% via intravenous injection (5 mg / kg body weight) and oral administration (5 mg / kg body weight), while the oral bioavailability of ketamine reported in the literature is only around 20%. Therefore, it can be seen that the compounds of the ketamine derivatives of the present invention within the general formula range of Formula I, especially compounds of Formula II, Formula II-a, or pharmaceutically acceptable salts thereof, have enhanced oral bioavailability compared to the traditional positive drug ketamine, thus improving the convenience and safety of use.

[0169] (3) Animal experiments further demonstrate that, in a mouse model of oral corticosterone depression, intraperitoneal injection of compounds of the ketamine derivatives of the present invention within the general formula range of Formula I, especially compounds of Formula II, Formula II-a, or pharmaceutically acceptable salts thereof, has a rapidly onset antidepressant effect and an enhanced antidepressant effect relative to ketamine.

[0170] (4) Animal experiments have further demonstrated that oral administration of compounds of the ketamine derivatives of the present invention within the general formula range of Formula I, especially compounds of Formula II, Formula II-a, or pharmaceutically acceptable salts thereof, in mice with oral corticosterone depression has a rapid onset of antidepressant effect and has an enhanced antidepressant effect relative to ketamine.

[0171] (5) Animal experiments have further demonstrated that intraperitoneal injection of compounds of the ketamine derivatives of the present invention within the general formula range of Formula I, especially compounds of Formula II, Formula II-a, or pharmaceutically acceptable salts thereof, in a mouse model of chronic unpredictable stress has a rapid onset of antidepressant effect. Attached Figure Description

[0172] Figure 1 This describes the effect of the novel ketamine derivative EW705 (1 μM, 3 μM, 10 μM) in Example 1 on BDNF levels in neural stem cells.

[0173] Figure 2 This describes the effect of the novel ketamine derivative EW705 (1 μM, 3 μM, 10 μM) on BDNF levels in glial cells in Example 2.

[0174] Figure 3 The effects of novel ketamine derivatives EW705 (1 μM, 3 μM, 10 μM) on neurite growth in Example 3; and the effects of EW706 (1 μM, 3 μM, 10 μM) on neurite growth.

[0175] Figure 4 This refers to the inhibitory effect of the novel ketamine derivative EW705 (10 μM) and ketamine (10 μM) on NMDA receptor signaling in Example 4.

[0176] Figure 5 The acute antidepressant effects of the novel ketamine derivatives EW705 and EW706 in Example 5;

[0177] Figure 6 This refers to the antidepressant effect of intraperitoneal injection of a novel ketamine derivative in a corticosterone-induced depression animal model as shown in Example 6.

[0178] Figure 7 This refers to the antidepressant effect of the novel ketamine derivative administered orally in an animal model of corticosterone depression, as described in Example 7.

[0179] Figure 8 This refers to the antidepressant effect of the novel ketamine derivative in Example 8 on a chronic unpredictable stress model;

[0180] Figure 9 It is the preparation of EW705 in Example 1. 1 H NMR spectrum;

[0181] Figure 10 It is the preparation of EW705 in Example 1. 13 C NMR spectrum;

[0182] Figure 11 It is the EW705 prepared in Example 1. 19 F NMR spectrum;

[0183] Figure 12 It is the preparation of EW706 in Example 2. 1 H NMR spectrum;

[0184] Figure 13 It is the preparation of EW706 in Example 2. 13 C NMR spectrum;

[0185] Figure 14 It is the preparation of EW706 in Example 2. 19 F NMR spectrum. Detailed Implementation

[0186] The present application will be further described below with reference to specific embodiments.

[0187] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains; the term “and / or” as used herein includes any and all combinations of one or more of the associated listed items.

[0188] As used herein, the term “about” is used to provide for the flexibility and imprecision associated with a given term, measure, or value. Those skilled in the art can readily determine the degree of flexibility for a particular variable.

[0189] Concentration, amount, and other numerical data may be presented in range format herein. It should be understood that such range format is used solely for convenience and brevity and should be flexibly interpreted to include not only the values ​​explicitly stated as the limits of the range, but also all individual values ​​or subranges encompassed within the range, as if each value and subrange were explicitly stated. For example, a range of values ​​from about 1 to about 4.5 should be interpreted to include not only the explicitly stated limits of 1 to 4.5, but also individual numbers (such as 2, 3, 4) and subranges (such as 1 to 3, 2 to 4, etc.). The same principle applies to ranges that describe only a single value, such as "less than about 4.5," which should be interpreted to include all the values ​​and ranges described above. Furthermore, this interpretation should apply regardless of the breadth of the range or characteristic described.

[0190] Unless otherwise specified in the examples, the procedures should be performed under standard conditions or conditions recommended by the manufacturer. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0191] Ketamine is a racemic mixture of R and S configurations in a 1:1 ratio.

[0192] Fluoxetine was purchased from Ticare.

[0193]

[0194] The hydrochloride salt (EW705) of the compound shown in Formula II-a was provided by Shanghai Dongxi Zhihui Biomedical Co., Ltd., with an optical purity of ≥99%. For cell experiments, the required concentration was prepared using cell culture medium; for animal experiments, the required concentration was prepared using physiological saline.

[0195] EW706:

[0196]

[0197] Provided by Shanghai Dongxi Zhihui Biomedical Co., Ltd., with an optical purity of ≥99%. Cell experiments require preparation of cell culture medium to the required concentration, while animal experiments require preparation of physiological saline to the required concentration.

[0198] The present invention will be further described below with reference to specific embodiments. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer.

[0199] Preparation Example 1

[0200] Synthesis of EW705 hydrochloride (hydrochloride of compound II-a)

[0201]

[0202] EW705;

[0203]

[0204] 1. Preparation of intermediate M1

[0205]

[0206] In a 1 L double-necked round-bottom flask, the starting material SM (44.07 g, 393 mmol, 1.0 eq.) was placed in a container, and methanol (400 mL) was added and stirred to disperse the mixture. Sulfuric acid (42 mL, 786 mmol, 2.0 eq.) was then added, followed by reflux and reaction for 16 h. The reaction endpoint was determined by TLC (EA / PE = 30%, Rf = 0.4). The reaction mixture was cooled to 0 °C, and the pH was adjusted to 6-7 with 2 M NaOH solution. Extraction was performed with EA (4 × 500 mL), and the organic phase was washed with saturated NaHCO3 solution (500 mL). The organic phase was separated, dried, and concentrated. The crude product was chromatographically analyzed using a 100-200 mesh silica gel column with 20-30% EA / PE as eluent to obtain compound M1 (27.00 g, pale yellow liquid, yield 54%).

[0207] Spectral data:

[0208] HRMS (ESI-TOF) m / z Calculated. For C7H 11 O2 + [M+H] + =127.0754, found: 127.0752.

[0209] 2. Preparation of intermediate M2

[0210]

[0211] In a 1 L three-necked round-bottom flask, add starting material M1 (25.10 g, 198 mmol, 1.0 eq.) and anhydrous DCM (600 mL). Stir to disperse and cool to -78 °C. Add Br2 (20 mL, 396 mmol, 2.0 eq.) and stir at -78 °C for 2 h. Determine the reaction endpoint by TLC (EA / PE=30%, M1 Rf=0.25). Add triethylamine (55 mL, 396 mmol, 2.0 eq.) at -78 °C and determine the endpoint by TLC (EA / PE=30%, Rf=0.6). Allow the reaction to cool naturally to -20 °C and let stand overnight. Filter and concentrate the filtrate. The crude product was subjected to chromatography on a 100-200 mesh silica gel column with 10% EA / PE as eluent to separate compound M2 (26.70 g, pale yellow liquid, yield 66%).

[0212] Spectral data:

[0213] 1 H NMR (500 MHz, Chloroform- d ) δ 3.75 (s, 3H), 2.90 (dt, J = 15.7, 6.0Hz, 2H), 2.57 - 2.48 (m, 2H), 2.06 - 1.94 (m, 2H).

[0214] 13 C NMR (126 MHz, Chloroform- d )δ 192.14, 151.06, 135.33, 59.84, 38.38,35.86, 22.67.

[0215] HRMS (ESI-TOF) m / z Calculated. For C7H 10 BrO2 + [M+H] + 204.9859, found: 204.9857.

[0216] 3. Preparation of intermediate M3

[0217]

[0218] Compound M2 (4.38 g, 21.4 mmol, 1 eq.) was added to a dry three-necked flask (250 mL), dissolved in THF (70 mL), and then 2-chlorophenylboronic acid (4.34 g, 27.8 mmol, 1.3 eq.), triphenylphosphine (560.5 mg, 2.14 mmol, 0.1 eq.), palladium acetate (245.5 mg, 1.1 mmol, 0.05 eq.), and potassium carbonate aqueous solution (40 mL, 11.8 g, 85.44 mmol, 4 eq.) were added under an argon atmosphere. The atmosphere was then replaced with argon again, and the reaction was carried out at 50 °C (internal temperature) for 6 h. TLC analysis showed that the reaction proceeded completely. The extract was concentrated until most of the THF was evaporated, extracted with ethyl acetate (2 × 300 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to column chromatography (100-200 mesh, mobile phase 10%-20% EA / PE) to give a pale yellow oily compound M3 (2.80 g, yield: 55%, Rf = 0.37 (20% EA / PE)).

[0219] 1 H NMR δ 7.51 – 7.38 (m, 1H), 7.28 (p, J = 4.8 Hz, 2H), 7.22 – 7.12 (m,1H), 3.67 – 3.33 (m, 3H), 2.61 (dd, J = 11.3, 5.8 Hz, 4H), 2.13 (d, J = 5.7 Hz, 2H).

[0220] 13 C NMR (126 MHz, Chloroform- d ) δ 195.58, 149.23, 143.53, 137.14,131.58, 129.69, 129.21, 129.08, 126.82, 59.94, 38.99, 31.08, 22.64.

[0221] HRMS (ESI-TOF) m / z Calculated. For C 13 H 14 ClO2 + [M+H] + 237.0677, found: 237.0696.

[0222] 4. Preparation of intermediate M4

[0223]

[0224] Fill a 200 mL dry round-bottom flask with argon gas, and add anhydrous THF (40 mL) sequentially at room temperature. R )-Me-CBS ((R)-1-methyl-3,3-diphenyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazolborane, 4 mL, 1 M in Toluene, 4 mmol, 0.4 eq.) and BH3THF (2 mL, 1 M in THF, 0.2 eq.). Then, an anhydrous THF solution (20 mL) of M3 (2.40 g, 10 mmol, 1.0 eq.) was added dropwise over 30 min. BH3THF (6 mL, 1 M in THF, 0.6 eq.) was slowly added to the solution over 30 min, and the resulting mixture was stirred at room temperature for 1 h. The reaction proceeded completely as detected by TLC. The reaction was then quenched with MeOH (10 mL) and concentrated. Dissolve in EA (100 mL), wash once with 1 M NaOH, extract with EA (100 mL) in aqueous solution, combine organic phases, concentrate, and purify the crude product by silica gel column chromatography (100-200 mesh, mobile phase 20%-30% EA / PE elution) to obtain M4 (1.95 g, yield: 80%), a white solid.

[0225] 1 H NMR (500 MHz, Chloroform- d (500 MHz, Chloroform- d ) δ 7.38 (dd, J =7.8, 1.6 Hz, 1H), 7.25 – 7.13 (m, 3H), 4.42 (s, 1H), 3.40 (s, 3H), 2.52 –2.20 (m, 2H), 2.16 (s, 1H), 1.93 (s, 2H), 1.82 (dt, J = 13.2, 6.4 Hz, 1H), 1.69(dt, J = 13.2, 5.2 Hz, 1H).

[0226] 13 C NMR (126 MHz, Chloroform- d) (126 MHz, CDCl3) δ 139.25, 129.61,128.31, 126.81, 119.78, 31.84, 30.59.

[0227] HRMS (ESI-TOF) m / z Calculated. For C 13 H 19 NClO2 + [M+NH4] + : 256.1099, found:256.1125.

[0228] 5. Preparation of intermediate M5

[0229]

[0230] In a 50 mL round-bottom flask dried in an oven, M4 (328.3 mg, 1.38 mmol, 1 eq.) was dissolved in 16 mL of anhydrous DCM solution. Argon gas was purged, and trichloroacetyl isocyanate (0.52 g, 2.75 mmol, 2 eq.) was added at 0 °C. The reaction was carried out at 0 °C for 15 min, then the temperature was raised to 20 °C and the reaction was carried out for another 15 min. After the reaction was completed by TLC monitoring, the reaction solution was concentrated. Methanol was added to the residue (16 mL of unreacted trichloroacetyl isocyanate was quenched by the reaction with methanol), followed by the addition of 8 mL of potassium carbonate (1.52 g, 11 mmol, 8 eq.) aqueous solution. Argon gas was purged, and the reaction was carried out at 20 °C for 2 h. Extraction was performed with ethyl acetate (3 × 30 mL), and the solution was dried over sodium sulfate and concentrated to dryness. The residue was purified by column chromatography (100-200 mesh silica gel, elution with 3% MeOH / DCM) to give a off-white solid M5 (0.38 g, yield: 98%). Rf = 0.2, 30% ethyl acetate / petroleum ether).

[0231] 1 H NMR (500 MHz, Chloroform- d ) δ 7.38 (dd, J = 7.7, 1.6 Hz, 1H), 7.26 –6.97 (m, 3H), 5.51 (s, 1H), 4.75 (s, 3H), 3.37 (s, 3H), 2.06 (ddd, J = 11.5,5.9, 2.9 Hz, 1H), 1.82 – 1.74 (m, 1H), 1.72 (q, J= 4.5 Hz, 1H).

[0232] 13 C NMR (126 MHz, Chloroform- d ) δ 156.49, 138.88, 129.46, 128.21,126.68, 61.13, 29.96, 29.76, 29.25, 18.20, 14.52.

[0233] HRMS (ESI-TOF) m / z Calculated. For C 14 H 16 ClNO3 + [M+Na] + 304.0711, found: 304.0743.

[0234] 6. Preparation of intermediate M6

[0235]

[0236] In a 500 mL three-necked round-bottom flask, starter M5 (9.50 g, 33.7 mmol, 1 eq.) was added, followed by anhydrous DCM (150 mL). The mixture was purged with argon three times, cooled to 0 °C, and then redistilled triethylamine (TEA) (14 mL, 101 mmol, 3.0 eq.) and redistilled trifluoroacetic anhydride (TFAA) (7 mL, 59.58 mmol, 1.5 eq.) were added. The reaction endpoint was determined by TLC (EA / PE = 20%, Rf = 0.9) (approximately 2 h). After the reaction was complete, the mixture was quenched in 200 mL of ice water. The organic phase was separated, and the aqueous phase was extracted with DCM (2 × 100 mL), dried, and concentrated. The crude product was subjected to chromatography on a 100-200 mesh alkaline silica gel column with 1 / 1000 triethylamine as the column wettant and 1% EA / PE as the eluent. Compound M6 (4.50 g, yellow oil, yield: 51%) was isolated. The product is unstable under acidic conditions and was purified using an alkaline column.

[0237] 1H NMR (500 MHz, Chloroform-d) δ 7.61 (dd, J = 7.8, 1.8 Hz, 1H), 7.28– 7.20 (m, 1H), 7.22 – 7.18 (m, 1H), 7.13 (td, J = 7.6, 1.8 Hz, 1H), 4.84 (t,J = 4.1 Hz, 1H), 2.39 – 2.27 (m, 1H), 2.19 (td, J = 5.2, 2.4 Hz, 2H), 1.85 –1.77 (m, 1H), 1.71 (dt, J = 6.7, 4.8 Hz, 1H), 1.61 (dt, J = 9.1, 4.1 Hz, 1H).

[0238] 13 C NMR (126 MHz, Chloroform- d ) δ 154.33, 139.94, 131.33, 131.22,129.33, 128.67, 126.75, 97.38, 65.70, 54.65, 37.54, 23.31, 19.40.

[0239] HRMS (ESI-TOF) m / z Calculated. For C 14 H 15 ClNO2 + [M+H] + 264.0786, found: 264.0784.

[0240] 7. Preparation of intermediate M7

[0241]

[0242] In a 500 mL three-necked round-bottom flask, starting material M6 (1.99 g, 7.55 mmol, 1.0 eq.) was added, followed by anhydrous THF (75 mL). The mixture was purged with argon three times, cooled to 0 °C, and then potassium trimethylsilanolate (TMSOK) (1.95 g, 15.2 mmol, 2.0 eq.) was added. The mixture was allowed to react at room temperature for 0.5 h. The reaction endpoint was determined by TLC (EA / PE = 20%, Rf = 0.1). The solution was then added to 50 mL of saturated NaCl solution, followed by the addition of EA (100 mL). The organic phase was separated, and the aqueous phase was extracted with EA (1 × 50 mL), dried, and concentrated. The crude product was purified by chromatography on a 100-200 mesh silica gel column with 3% MeOH / DCM as eluent to obtain compound M7 (1.38 g, pale yellow oil, yield: 77%).

[0243] HRMS (ESI-TOF) m / z Calculated. For C 13 H 17 ClNO + [M+H] + 238.0993, found: 238.0995.

[0244] 8. ( S,S Preparation of )-FNK hydrochloride (EW705 hydrochloride)

[0245]

[0246] Add starting material M7 (1.38 g, 5.8 mmol, 1.0 eq.) to a 100 mL three-necked round-bottom flask. Add acetonitrile:water = 1:1 (20 mL), purge with argon three times, and cool to 0 °C. Dissolve the selective fluoride reagent (select fluro) (CAS No: 140681-55-6, 15.34 g, 42.6 mmol, 1.1 eq.) in acetonitrile (10 mL) and slowly add it. Maintain the reaction temperature at 0 °C for 20 min, then return to room temperature and react for 18 h. Determine the reaction endpoint by TLC (EA / PE = 40%, Rf = 0.2). Note that M8 will be formed; continue stirring to convert it to the target product. Neutralize the reaction with saturated sodium carbonate solution to a pH between 9 and 10, add sodium chloride to saturate the solution, and extract with ethyl acetate (3 × 50 mL). Dry and concentrate with sodium sulfate. The crude product was chromatographically separated using a 100-200 mesh silica gel column with 10-100% EA / PE as eluent to obtain the compound ( S,S )-FNK (yellow oily substance, 1.00 g) and byproducts (0.56 g, white solid).

[0247] Preparation of hydrochloride: The crude oily product was dispersed in approximately 100 mL of diethyl ether. 10 mL of 10% HCl / Et₂O was added under stirring at 0 °C, resulting in the precipitation of a white solid. The solid was filtered, washed with Et₂O (2 × 50 mL), collected, and dried under an oil pump. HPLC: 99.2%. The solution was dissolved in 20 mL of purified water and lyophilized (white solid, 1.00 g, yield 71%).

[0248] The characterization spectrum of EW705 is attached. Figure 9-11 As shown.

[0249] 1 H NMR (500 MHz, Methanol- d 4) δ 7.91 – 7.89 (m, 1H), 7.64 – 7.58 (m,3H), 5.16 (ddd, J = 48.9, 1.6, 7.1 Hz, 1H), 3.28 – 3.24 (m, 1H), 2.52 – 2.47(m, 1H), 2.03 – 1.96 (m, 2H), 1.88 (dtd, J = 13.2, 11.6, 4.2 Hz, 1H), 1.79(dddd, J = 15.5, 11.8, 3.7, 2.0 Hz, 1H).

[0250] 13 C NMR (126 MHz, Methanol- d 4) δ 203.58 (d, J = 15.6 Hz), 135.33,133.87, 133.18, 131.58, 131.18, 129.96, 92.01 (d, J = 193.9 Hz), 68.46, 38.13,36.95 (d, J = 19.0 Hz), 19.06 (d, J = 11.5 Hz).

[0251] 19 F NMR (471 MHz, Methanol- d 4) δ -192.32.

[0252] HRMS (ESI-TOF) m / z Calculated. For C12 H 14 FNClO + [M+H] + 242.0743, found: 242.0747.

[0253] Optical rotation: [α] D 20 +96.6 (c=1, H2O, hydrochloride).

[0254] Preparation Example 2

[0255] Synthesis method of EW706 hydrochloride

[0256]

[0257] EW706

[0258] Preparation route:

[0259]

[0260] 1. Preparation of intermediate M1

[0261] See Preparation Example 1 for the preparation of intermediate M1.

[0262] 2. Preparation of intermediate M2

[0263] See Preparation Example 1 for the preparation of intermediate M2.

[0264] 3. Preparation of intermediate M3

[0265] See Preparation Example 1 for the preparation of intermediate M3.

[0266] 4. Preparation of intermediate M4

[0267]

[0268] Experimental Procedure: 250 mL of dry THF was added to a 500 mL three-necked round-bottom flask. Argon gas was purged three times. The reaction temperature was lowered to 0 °C. Then, BH3 / THF (0.8 M, 19 mL, 15.1 mmol, 0.2 eq.) was added. At 0 °C, (S)-Me-CBS (SM2, (S)-1-methyl-3,3-diphenyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazolborane, CAS No.: 112022-81-8; 0.8 M, 30.5 mL, 30.3 mmol, 0.4 eq.) was added. The system became colorless and clear. Then, M3 (17.90 g, 75.6 mmol, 1.0 eq.) dissolved in 130 mL of dry THF was slowly added to the reaction mixture. The addition time exceeded 3 h. The reaction was then cooled to 0 °C. Add BH3 / THF (0.8 M, 77 mL, 60.5 mmol, 0.8 eq.) at 0 °C. The system becomes clear and brownish-yellow. Maintain the reaction temperature at 0 °C for 1 h. Determine the reaction endpoint by TLC (EA / PE = 20%, Rf = 0.3). Quench the reaction with 100 mL MeOH at 0 °C, evaporate to dryness, dissolve in 200 mL EA, wash once with 300 mL 1 M NaOH, separate the organic phase, extract with EA (2 × 150 mL) in aqueous solution, combine the organic phases, dry and concentrate. Analyze the crude product onto a 100-200 mesh silica gel column with 10% EA / PE as eluent to obtain compound M4 (14.67 g, yellow liquid, yield 81%).

[0269] HRMS (ESI-MS): Calculated. For C 13 H 15 ClO2[M+NH4] + =256.1116 found : 256.1116.

[0270] 5. Preparation of intermediate M5

[0271]

[0272] Experimental procedure: Add raw material M4 (14.70 g, 61.6 mmol, 1.0 eq.) to a 1 L three-necked round-bottom flask, add anhydrous DCM (615 mL), cool to 0 °C, and then add trichloroacetyl isocyanate (14.7 mL, 123 mmol, 2.0 eq.). Determine the reaction endpoint by TLC (EA / PE=30%, Rf=0.6), and evaporate the solvent DCM to obtain a yellow oil. MeOH (250 mL) was added at 0 °C to quench the reaction. Potassium carbonate (68.57 g, 493 mmol, 8.0 eq.) was dissolved in 200 mL of water and added. Argon gas was purged three times. The reaction was allowed to proceed at room temperature for 2 h. The reaction endpoint was determined by TLC (EA / PE = 30%, Rf = 0.2). The solvent MeOH was evaporated to dryness, and 500 mL of water was added. The mixture was extracted with EA (3 × 150 mL), dried, and concentrated. The crude product was chromatographically analyzed on a 100-200 mesh silica gel column with 20% EA / PE as eluent to obtain compound M5 (15.88 g, grayish-white solid, yield 91%).

[0273] 1 H NMR: (500 MHz, Chloroform- d ) δ 7.39 (dd, J = 7.7, 1.6 Hz, 1H), 7.29 -7.15 (m, 3H), 5.52 (s, 1H), 3.38 (s, 3H), 2.07 (ddt, J = 13.7, 5.8, 3.1 Hz,3H), 1.90 (s, 1H), 1.84 - 1.76 (m, 1H), 1.73 (tq, J = 8.1, 3.4 Hz, 1H).

[0274] 13 C NMR: (126 MHz, CDCl3) δ 156.55, 138.88, 130.43, 129.46, 128.22, 126.68, 77.29, 77.04, 76.78, 52.33, 29.96, 29.76, 18.20.

[0275] HRMS (ESI-MS): Calculated. For C 14 H 16 ClNO3[M+Na] + =304.0726 found : 304.0726.

[0276] 6. Preparation of intermediate M6

[0277]

[0278] Experimental Procedure: In a 500 mL three-necked round-bottom flask, add starting material M5 (15.50 g, 55.0 mmol, 1.0 eq.), anhydrous DCM (150 mL), purge with argon three times, cool to 0 °C, add redistilled TEA (23 mL, 165 mmol, 3.0 eq.), and then redistilled TFAA (11.5 mL, 82.5 mmol, 1.5 eq.). Maintain the reaction temperature at 0 °C for 2 h. Determine the reaction endpoint by TLC (EA / PE = 20%, Rf = 0.9). After the reaction is complete, quench the mixture in ice water (200 mL), separate the organic phase, extract the aqueous phase with DCM (2 × 100 mL), dry, and concentrate. The crude product was subjected to chromatography on a 100-200 mesh alkaline silica gel column with 1 / 1000 triethylamine as the column lubricant and 1% EA / PE as the eluent. Compound M6 (12.61 g, a light yellow oily substance, yield 87%) was obtained.

[0279] 1 H NMR: (500 MHz, Chloroform- d ) δ 7.68 (dd, J = 7.9, 1.8 Hz, 1H), 7.35 -7.16 (m, 3H), 4.91 (dd, J = 4.9, 3.5 Hz, 1H), 3.53 (s, 3H), 2.41 (ddd, J = 13.7,12.2, 3.3 Hz, 1H), 2.31 - 2.19 (m, 2H), 1.93 - 1.64 (m, 3H).

[0280] 13 C NMR: (126 MHz, CDCl3) δ 154.33, 139.93, 131.33, 131.22, 129.33,128.67, 126.75, 97.37, 77.28, 77.02, 76.77, 65.70, 54.66, 37.54, 23.31,19.40, -2.15.

[0281] 7. Preparation of intermediate M7

[0282]

[0283] Experimental Procedure: In a 500 mL three-necked round-bottom flask, add starting material M6 (12.30 g, 46.6 mmol, 1.0 eq.), anhydrous THF (235 mL), purge with argon three times, cool to 0 °C, add TMSOK (11.83 g, 91.9 mmol, 2.0 eq.), and return to room temperature for 1.5 h. Determine the reaction endpoint by TLC (EA / PE = 20%, Rf = 0.1). Pour into 200 mL of saturated NaCl solution, add EA (300 mL), separate the organic phase, extract the aqueous phase with EA (100 mL), and concentrate after drying. Analyze the crude product using a 100-200 mesh silica gel column with 3% MeOH / DCM as eluent to obtain compound M7 (9.59 g, pale yellow oil, yield 88%).

[0284] 1 H NMR: (500 MHz, Chloroform- d ) δ 7.57 (dd, J = 7.9, 1.8 Hz, 1H), 7.32(dd, J = 7.8, 1.5 Hz, 1H), 7.21 (td, J = 7.5, 1.5 Hz, 1H), 7.16 (td, J = 7.5, 1.8Hz, 1H), 4.82 (t, J = 4.0 Hz, 1H), 3.52 (s, 3H), 2.49 (ddd, J = 13.0, 9.5, 3.1Hz, 1H), 2.20 (tdd, J = 5.7, 4.0, 1.2 Hz, 4H), 1.76 (ddd, J = 13.4, 8.6, 3.0 Hz,1H), 1.64 (ddtd, J = 12.7, 9.3, 6.3, 3.0 Hz, 1H), 1.43 (ddt, J = 16.4, 8.6, 4.4Hz, 1H).

[0285] 13C NMR: (126 MHz, CDCl3) δ 157.18, 143.42, 132.20, 131.48, 130.02, 127.88, 126.36, 95.74, 77.29, 77.04, 76.79, 67.99, 58.64, 54.29, 36.55,23.84, 19.44.

[0286] HRMS (ESI-MS): Calculated. For C 14 H 16 ClNO3[M+H] + =238.1008 found : 238.1008.

[0287] 7. Preparation of DP (EW706)

[0288]

[0289] Experimental Procedure: In a 500 mL three-necked round-bottom flask, add starting material M7 (9.21 g, 38.7 mmol, 1.0 eq.), then add acetonitrile:water = 1:1 (150 mL). Replace with argon gas three times, cool to 0 °C, and slowly add selectedfluro (15.34 g, 42.6 mmol, 1.1 eq.) dissolved in acetonitrile (50 mL). Maintain the reaction temperature at 0 °C for 20 min, then allow to return to room temperature for 18 h. Determine the reaction endpoint by TLC (EA / PE = 40%, Rf = 0.2). Neutralize the reaction with saturated sodium carbonate solution to a pH between 9 and 10, then extract with saturated ethyl acetate (3 × 120 mL) using sodium chloride, and concentrate by drying with sodium sulfate. Separate the crude product using a 100-200 mesh silica gel column with 10-50% EA / PE eluent to obtain compound DP (yellow oil, 7.84 g).

[0290] Preparation of hydrochloride by DP: Approximately 100 mL of diethyl ether was added to disperse the crude oily product. 10% HCl / Et₂O (50 mL) was added under stirring at 0 °C, resulting in the precipitation of a white solid. The solid was filtered, washed with Et₂O (2 × 50 mL), collected, and dried under an oil pump. HPLC: 99.2%. The solution was dissolved in 70 mL of purified water and lyophilized (white solid, 7.46 g, yield 81%).

[0291] The characterization spectrum of EW706 is attached. Figure 12-14 As shown.

[0292] 1H NMR: (500 MHz, Methanol-d4): δ 7.91 (dd, J = 7.4, 2.2 Hz, 1H),7.64- 7.58 (m, 3H),5.17 (ddd, J = 48.9, 11.6, 7.1 Hz, 1H),3.29 - 3.24 (m, 1H),2.50 (dtd, J = 9.2, 5.4, 4.4, 2.5 Hz, 1H),2.00 (td, J = 14.3, 3.6 Hz, 2H),1.90 - 1.76 (m, 2H).

[0293] 13 C NMR: (126 MHz, Methanol-d4) δ 203.59 (d, J = 15.9 Hz), 135.31,133.86, 133.16, 131.61, 131.21, 129.96, 92.02 (d, J = 193.9 Hz), 68.45 (d, J =2.0 Hz), 38.15, 36.96 (d, J = 18.9 Hz), 19.07 (d, J = 11.7 Hz).

[0294] 19 F NMR: (471 MHz, Methanol-d4) δ -192.33.

[0295] HRMS (ESI-MS): Calculated. For C 12 H 13 FClNO[M+H] + =242.0744 found : 242.0744.

[0296] Example 1

[0297] Effects of the novel ketamine derivative EW705 on BDNF levels in neural stem cells:

[0298] Experimental cells: neural stem cells;

[0299] Experimental instrument: Bio-Rad electrophoresis apparatus, serial number: 042BR10743;

[0300] Experimental methods: After neural stem cell plating and culture, EW705 (1 μM, 3 μM, 10 μM) was added and incubated for 24 h. Afterward, the supernatant was discarded, and an appropriate amount of 1× Loading Buffer was added according to the cell volume for lysis. The cells were heated in a metal bath at 95 °C for 5 min, followed by SDS-PAGE electrophoresis at 80 V for 30 min, 120 V for 1 h, and transfer to a membrane at 400 mA for 2 h. After blocking for 0.5 h, the cells were incubated overnight with primary antibody at 4 °C, washed three times with TBST for 5 min each time, incubated with secondary antibody for 1 h, washed three times with TBST for 5 min each time, and then developed and photographed.

[0301] Experimental conclusions: such as Figure 1 The results showed that 10 μM EW705 could increase the expression level of BDNF in neural stem cells.

[0302] Example 2

[0303] Effects of the novel ketamine derivative EW705 on BDNF levels in glial cells:

[0304] Experimental cells: HA glial cells;

[0305] Experimental instrument: Bio-Rad electrophoresis apparatus, serial number: 042BR10743;

[0306] Experimental methods: After plating HA glial cells, EW705 (1 μM, 3 μM, 10 μM) was added and incubated for 24 h. Afterward, the supernatant was discarded, and an appropriate amount of 1× Loading Buffer was added according to the cell volume for lysis. The cells were heated in a metal bath at 95 °C for 5 min, followed by SDS-PAGE electrophoresis at 80 V for 30 min, then at 120 V for 1 h, and finally transferred to a membrane at 400 mA for 2 h. After blocking for 0.5 h, the cells were incubated overnight with primary antibody at 4 °C, washed three times with TBST for 5 min each time, incubated with secondary antibody for 1 h, washed three times with TBST for 5 min each time, and then developed and photographed.

[0307] Experimental conclusions: such as Figure 2 The results showed that 3 μM EW705 could increase the expression of BDNF in HA glial cells.

[0308] Example 3

[0309] Effects of novel ketamine derivatives EW705 and EW706 on neurite growth:

[0310] Experimental cells: SH-SY5Y;

[0311] Experimental apparatus: IX73 inverted microscope;

[0312] Experimental methods: After SH-SY5Y neural cells were plated and cultured, EW705 (1 μM, 3 μM, 10 μM) and EW706 (1 μM, 3 μM, 10 μM) were added and incubated for 24 hours. After that, the cells were photographed under a microscope and the length of the neurites was analyzed and counted.

[0313] Experimental conclusions: such as Figure 3 The results showed that EW705 and EW706 had similar efficacy, and both 10 μM EW705 and 10 μM EW706 could promote neurite growth.

[0314] Example 4

[0315] Inhibitory effect of novel ketamine derivative EW705 on NMDA receptor signaling:

[0316] Experimental cells: 293T cells;

[0317] Experimental instrument: BioTek Synergy NEO multi-functional microplate analyzer;

[0318] Experimental methods: 293T cells were transfected with NR1 and NR2A expression plasmids for 48 h, stained with 2 μM Fluo-4 AM calcium ion fluorescent probe for 30 min, washed three times with PBS, and then incubated for another 30 min. Ketamine (10 μM) and EW705 (10 μM) were added and incubated for 30 min. After that, 1 mM NMDA was added and calcium flux was detected immediately.

[0319] Experimental conclusions: such as Figure 4 The results showed that both 10 μM ketamine and 10 μM EW705 could significantly inhibit NMDA receptor signaling.

[0320] Example 5

[0321] Acute antidepressant effects of novel ketamine derivatives EW705 and EW706:

[0322] Laboratory animals: 8-week-old male C57BL / 6 rats;

[0323] Experimental apparatus: Cylindrical glass jar;

[0324] Forced swimming test method: Mice were placed individually in a cylindrical glass tank 30 cm high and 20 cm in diameter, with a water depth of 15 cm, ensuring the mice could not escape the tank while their feet and tails did not touch the bottom. The water temperature was 23℃-25℃. A 10-minute pre-swimming exercise was performed the day before the actual experiment. During the actual experiment, video was recorded for 6 minutes after the mice entered the water. Since most mice were very active in the first two minutes, the immobility time for the remaining 4 minutes was calculated (immobility criteria: the mouse stopped struggling in the water, remained still, and exhibited only minor limb movements to maintain balance or float). Each group of mice underwent the test in parallel.

[0325] Experimental methods:

[0326] Figure 5 In the study, 21 eight-week-old male C57BL / 6 mice were used for intraperitoneal injection experiments and were randomly divided into groups using a random number table.

[0327] Negative control group (Vehicle, intraperitoneal injection of physiological saline, 10 mice);

[0328] Intraperitoneal injection of EW705 group (EW705, 10 mg / kg, intraperitoneal injection, 11 mice).

[0329] Figure 5 In the b-group experiment, 16 eight-week-old male C57BL / 6 mice were selected for intraperitoneal injection and randomly divided into groups using a random number table:

[0330] Negative control group (Vehicle, intraperitoneal injection of physiological saline, 8 mice);

[0331] Intraperitoneal injection of EW706 group (EW706, 10 mg / kg, intraperitoneal injection, 8 mice).

[0332] Figure 5 Thirty 8-week-old male C57BL / 6 mice were used in the oral administration experiment and were randomly divided into groups using a random number table.

[0333] Oral negative control group (Veh, water administered by gavage, 10 mice);

[0334] Oral EW705 administration group (EW705, 30 mg / kg, administered by gavage, 10 mice);

[0335] Oral fluoxetine administration group (Fluoxetine, 20 mg / kg, administered by gavage, 10 mice);

[0336] Forced swimming test was performed 30 minutes or 24 hours after the last administration.

[0337] Conclusion: Figure 5The results showed that EW705 had an acute antidepressant effect, while EW706 did not.

[0338] Example 6

[0339] Antidepressant effect of intraperitoneal injection of novel ketamine derivative EW705 in a corticosterone-induced depression animal model:

[0340] Laboratory animals: 8-10 week old C57BL / 6 male rats;

[0341] Experimental equipment: Supporting software: Lab Chart;

[0342] Corticosterone modeling method: The modeling period lasted three weeks. For the first two weeks, mice were fed corticosterone at 25 μg / ml, approximately 5 ml / day per mouse. On days 1 and 2 of the third week, the dosage was halved to 12.5 μg / ml, approximately 5 ml / day per mouse. On days 3 and 4, the dosage was 6.25 μg / ml, approximately 5 ml / day per mouse. From days 5 to 7, the mice were given normal drinking water, approximately 5 ml / day per mouse. Mice not yet modeled were given normal drinking water throughout the three weeks.

[0343] Forced swimming test method: Mice were placed individually in a cylindrical glass tank 30 cm high and 20 cm in diameter, with a water depth of 15 cm, ensuring that the mice could neither escape from the tank nor have their feet and tails touch the bottom. The water temperature was 23-25℃. Videos were recorded of the mice 6 minutes after they entered the water, showing them immobile for the last 4 minutes (criterion for immobility: the mouse stopped struggling in the water, remained still, and exhibited only minor limb movements to maintain balance or float). The experiment was performed in parallel in each group, with 8-9 mice per group.

[0344] Tail suspension test method: The mouse is suspended upside down on a tail suspension test frame about 15 cm above the ground, with tape or clips used to secure the tail about 1 cm from the tip. The mouse struggles to overcome the abnormal position, but after a period of activity, it becomes intermittently still, indicating a state of disappointment. The test time for each group is 6 minutes. Since the mice struggle frequently due to excitement in the first two minutes, the time of stillness in the following 4 minutes is recorded. Each group of mice is operated in parallel, with 8-9 mice in each group.

[0345] Experimental methods: Thirty-three male C57BL / 6 mice aged 8-10 weeks were selected and randomly divided into groups using a random number table.

[0346] Control group (WT, intraperitoneal injection of physiological saline, 8 normal non-model mice);

[0347] Negative control group (Veh, intraperitoneal injection of physiological saline, 8 model mice);

[0348] EW705 administration group (EW705, 10 mg / kg, intraperitoneal injection, 9 model mice); and

[0349] Ketamine administration group (positive control group, Ket, 10 mg / kg, intraperitoneal injection, 8 model mice);

[0350] EW705 and ketamine were administered after modeling. Forced swimming test was performed 30 minutes after administration, and tail suspension test was performed 24 hours after administration.

[0351] Conclusion: Figure 6 The results showed that intraperitoneal injection of EW705 had a rapid onset of antidepressant effect, and the 30 min-FST and 24 h-TST effects were slightly better than those of the ketamine group.

[0352] Example 7

[0353] Antidepressant effect of oral administration of novel ketamine derivative EW705 in an animal model of corticosterone depression:

[0354] Laboratory animals: 8-10 week old C57BL / 6 male rats;

[0355] Experimental apparatus: Cylindrical glass jar;

[0356] The method for establishing the corticosterone model is the same as in Example 6. Each group contains 10-11 mice.

[0357] The forced swimming experiment method is the same as in Example 6.

[0358] Experimental methods: Thirty-one male C57BL / 6 mice aged 8-10 weeks were selected and randomly divided into groups using a random number table.

[0359] Control group (WT, administered water by gavage, 10 normal mice without modeling);

[0360] Negative control group (Vehicles, administered water by gavage, 11 model mice);

[0361] EW705 administration group (EW705, 10 mg / kg, by gavage, 10 model mice).

[0362] EW705 is provided after the molding process is completed.

[0363] Forced swimming tests were conducted 30 minutes and 24 hours after drug administration.

[0364] Conclusion: Figure 7 The results showed that oral EW705 had a rapid-onset antidepressant effect.

[0365] Example 8

[0366] Antidepressant effect of novel ketamine derivative EW705 in a chronic unpredictable stress model.

[0367] Experimental animals: 7-week-old male C57BL / 6 rats;

[0368] Experimental apparatus: Cylindrical glass jar;

[0369] Experimental Methods: Twenty-one 7-week-old male C57BL / 6 mice were selected and divided into:

[0370] Control group (WT, intraperitoneal injection of physiological saline, 8 normal non-model mice);

[0371] Negative control group (Vehicles, 7 mice that underwent modeling and were injected intraperitoneally with saline);

[0372] EW705 administration group (EW705, 10 mg / kg, intraperitoneal injection, 6 model mice).

[0373] The modeling group was stimulated according to the stress treatment sequence in Table 1, which was randomly generated using a random number table method. The stimulation lasted for 10 weeks. After the stimulation was completed, the phenotype was tested by tail suspension. If the depressive symptoms were not obvious, the modeling time could be extended.

[0374] After the modeling was completed, EW705 was administered (once), and a forced swimming experiment was conducted 24 hours after administration.

[0375] Table 1. Different stress treatments were applied to the model mice.

[0376]

[0377] Conclusion: Figure 8 The results showed that EW705 had a significant antidepressant effect in a chronic unpredictable stress model.

[0378] Example 9

[0379] Experimental animals: C57BL / 6 mice;

[0380] Dosage: 5 mg / kg body weight;

[0381] Experimental method: Plasma concentration test method;

[0382] Pharmacokinetic Experiment

[0383] Experimental animals: C57BL / 6J mice, male, purchased from Shanghai Lingchang Biotechnology Co., Ltd.

[0384] Administration: 2-3 male C57BL / 6J mice were administered EW705 via intravenous administration at a concentration of 1 mg / ml orally at a concentration of 0.5 mg / kg orally after fasting overnight.

[0385] Blood collection: Blood was collected from the inferior vena cava or heart of each animal (approximately 0.1 mL at each time point). The collected blood was placed in pre-cooled EDTA-K2 tubes and kept on ice until centrifugation.

[0386] Plasma preparation: Blood samples were centrifuged at approximately 4°C and 3,200 g for 10 minutes to prepare plasma. Plasma was collected separately and transferred to pre-labeled 96-well plates or polypropylene tubes, rapidly frozen with dry ice, and stored at -60°C or below until LC-MS / MS analysis.

[0387] Sample processing and testing:

[0388] 1) Add 200 μL of acetonitrile or methanol containing internal standard (100 ng / mL) to 5 μL of plasma sample for precipitation, then vortex mix at 800 rpm for 10 minutes, and centrifuge at 4°C and 3220 × g for 15 minutes.

[0389] 2) Take 50 µL of the supernatant solution after treatment in 1) and transfer it to a clean 96-well plate. Centrifuge at 4°C and 3220×g for 5 minutes. Then inject the supernatant directly for LC-MS / MS analysis.

[0390] Analysis and detection were performed using an LC-MS / MS-DS_TQ7500 instrument.

[0391] The bioavailability of the novel ketamine derivative EW705 is shown in Table 2 below.

[0392] Table 2 Bioavailability of C57BL / 6 mice (5 mg / kg body weight)

[0393]

[0394] Experimental conclusion: Oral administration of EW705 resulted in excellent plasma concentrations, with a peak value of 3282 ng / ml and an oral bioavailability of 86.7%.

[0395] Example 10

[0396] Experimental animals: C57BL / 6J mice.

[0397] Dosage: Two male C57BL / 6J mice were administered the drug at a dose of 10 mL / kg after fasting overnight. The drug was dissolved in physiological saline.

[0398] Experimental method: Blood brain concentration test method.

[0399] Sample collection:

[0400] (1) Blood collection: Blood was collected from the inferior vena cava or heart of each animal (approximately 0.1 mL at each time point). The collected blood was placed in pre-cooled EDTA-K2 tubes and placed on ice until centrifugation.

[0401] Plasma preparation: Blood samples were centrifuged at approximately 4°C and 3,200 g for 10 minutes to prepare plasma. Plasma was collected separately and transferred to pre-labeled 96-well plates or polypropylene tubes, rapidly frozen with dry ice, and stored at -60°C or below until LC-MS / MS analysis.

[0402] (2) Brain tissue collection: After perfusion with physiological saline, the brain was rinsed with physiological saline and placed on soft absorbent paper to drain all remaining fluid. The brain was then weighed and transferred to pre-labeled test tubes and homogenized with (PBS*1) at a ratio of 1:3 (1 gram of tissue to 3 ml of buffer) under ice-cold conditions. After final homogenization, all homogenates were stored in a freezer at approximately -80°C until LC-MS / MS analysis was performed.

[0403] Sample processing and testing:

[0404] 1) Add 20uL of plasma sample to 400uL of acetonitrile or methanol containing internal standard (100ng / mL) for precipitation, then vortex mix at 800 rpm for 10 minutes, and centrifuge at 4°C and 3220×g for 15 minutes.

[0405] 2) Add 400 μL of acetonitrile or methanol containing internal standard (100 ng / mL) to 40 μL of brain homogenate sample for precipitation, then vortex mix at 800 rpm for 10 minutes, and centrifuge at 4°C and 3220×g for 15 minutes.

[0406] 3) Take 50 µL of the supernatant solution after treatment 1) or 2) and transfer it to a clean 96-well plate. Centrifuge at 4°C and 3220×g for 5 minutes. Then inject the supernatant directly for LC-MS / MS analysis.

[0407] Analysis and detection were performed using an LC-MS / MS_CT_Triple Quad 6500 plus instrument.

[0408] As shown in Tables 3 and 4, EW705 could be detected in the brain within 5 minutes after intraperitoneal injection of 10 mg / kg body weight and oral administration of 30 mg / kg body weight, indicating that compound EW705 can rapidly cross the blood-brain barrier and enter the mouse brain.

[0409]

Claims

1. A compound represented by formula II-a or a pharmaceutically acceptable salt thereof: Formula II-a.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The pharmaceutically acceptable salts are selected from hydrochlorides, sulfates, pyrosulfates, bisulfites, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, bromates, iodates, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propynylates, oxalates, malonates, succinates, octanoates, sebacic acid salts, fumarates, maleates, butyn-1,4-dicitates, hexyn-1,6-dicitates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

3. A pharmaceutical composition, characterized in that, It comprises a compound represented by formula II-a or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier: Formula II-a.

4. The pharmaceutical composition according to claim 3, characterized in that, The pharmaceutical composition is in a single-dose form, wherein the content of the compound represented by formula II-a or its pharmaceutically acceptable salt in the single-dose form is between 0.03 mg and 500 mg.

5. The pharmaceutical composition according to claim 3, characterized in that, The mass percentage of the compound represented by formula II-a or its pharmaceutically acceptable salt in the pharmaceutical composition is 1 to 99 wt%.

6. The pharmaceutical composition according to claim 3, characterized in that, The drug loading concentration of the compound represented by formula II-a or its pharmaceutically acceptable salt in the pharmaceutical composition is 0.01~10 mg / mL.

7. The pharmaceutical composition according to claim 3, characterized in that, It also includes other antidepressants.

8. The pharmaceutical composition according to claim 7, characterized in that, The other antidepressants include any one or more of ketamine, fluoxetine, sertraline, citalopram, paroxetine, fluvoxamine, duloxetine, venlafaxine, amitriptyline, or doxepin hydrochloride.

9. The pharmaceutical composition according to any one of claims 3 to 8, characterized in that, The pharmaceutical composition contains a pharmaceutically acceptable diluent.

10. The pharmaceutical composition according to any one of claims 3 to 8, characterized in that, The dosage form of the pharmaceutical composition is selected from one or more of the following: powder, tablet, pill, capsule, and suspension.

11. The pharmaceutical composition according to any one of claims 3 to 8, characterized in that, The dosage form of the pharmaceutical composition is a sustained-release formulation.

12. The pharmaceutical composition according to any one of claims 3 to 8, characterized in that, The dosage form of the pharmaceutical composition is a controlled-release formulation.

13. The pharmaceutical composition according to any one of claims 3 to 8, characterized in that, The dosage form of the pharmaceutical composition is selected from injections and infusions.

14. The pharmaceutical composition according to any one of claims 3 to 8, characterized in that, The dosage form of the pharmaceutical composition is a powder.

15. A medicine box comprising: (1) one or more single-dose units of the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, or one or more single-dose units of the pharmaceutical composition of any one of claims 3 to 14, and (2) instructions for their use in treating a disease.

16. The use of a compound represented by formula II-a or a pharmaceutically acceptable salt thereof in the preparation of a drug for the prevention or treatment of depression: Formula II-a.

17. The use according to claim 16, characterized in that, The depression mentioned includes major depressive disorder, persistent depressive disorder, premenstrual anxiety disorder, or a combination thereof.

18. The use according to claim 16, characterized in that, The depression includes seasonal affective disorder, postpartum depression, situational depression, anhedonia, melancholy, midlife depression, geriatric depression, depression caused by a identifiable stressor, or a combination thereof.

19. The use according to claim 17, characterized in that, The major depressive disorder mentioned above includes treatment-resistant depression.

20. The use according to any one of claims 16 to 19, characterized in that, The single-dose form of the drug contains between 0.03 mg and 500 mg of a compound represented by Formula II-a or a pharmaceutically acceptable salt thereof.

21. The use according to any one of claims 16 to 19, characterized in that, The drug has a drug loading concentration of 0.01 to 10 mg / mL for the compound represented by formula II-a or its pharmaceutically acceptable salt.

22. The use according to any one of claims 16 to 19, characterized in that, The dosage form of the drug is selected from one or more of the following: powder, granule, tablet, pill, capsule, and suspension.

23. The use according to any one of claims 16 to 19, characterized in that, The drug is a sustained-release formulation.

24. The use according to any one of claims 16 to 19, characterized in that, The drug is a controlled-release formulation.

25. The use according to any one of claims 16 to 19, characterized in that, The drug is in the form of an injection or an infusion.

26. Use of a pharmaceutical composition for the preparation of a medicament for the prevention or treatment of depression, said pharmaceutical composition comprising a compound represented by formula II-a or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; Formula II-a.

27. The use according to claim 26, characterized in that, The depression mentioned includes major depressive disorder, persistent depressive disorder, premenstrual anxiety disorder, or a combination thereof.

28. The use according to claim 26, characterized in that, The depression includes seasonal affective disorder, postpartum depression, situational depression, anhedonia, melancholy, midlife depression, geriatric depression, depression caused by a identifiable stressor, or a combination thereof.

29. The use according to claim 27, characterized in that, The major depressive disorder mentioned above includes treatment-resistant depression.

30. The use according to claim 26, characterized in that, The pharmaceutical composition contains a pharmaceutically acceptable diluent.

31. The use according to any one of claims 26 to 30, characterized in that, The single-dose form of the drug contains between 0.03 mg and 500 mg of a compound represented by Formula II-a or a pharmaceutically acceptable salt thereof.

32. The use according to any one of claims 26 to 30, characterized in that, The drug has a drug loading concentration of 0.01 to 10 mg / mL for the compound represented by formula II-a or its pharmaceutically acceptable salt.

33. The use according to any one of claims 26 to 30, characterized in that, The dosage form of the drug is selected from one or more of the following: powder, granule, tablet, pill, capsule, and suspension.

34. The use according to any one of claims 26 to 30, characterized in that, The drug is a sustained-release formulation.

35. The use according to any one of claims 26 to 30, characterized in that, The drug is a controlled-release formulation.

36. The use according to any one of claims 26 to 30, characterized in that, The drug is in the form of an injection or an infusion.

37. The use of a compound represented by formula II-a or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of mental illness, wherein the mental illness comprises any one or more of the following characteristics: Diseases characterized by abnormal BDNF levels; Diseases characterized by abnormal activation of NMDA receptors; Diseases characterized by abnormal synaptic plasticity; The structural formula of the compound represented by formula II-a is as follows: Formula II-a.

38. The use according to claim 37, characterized in that, The single-dose form of the drug contains between 0.03 mg and 500 mg of a compound represented by Formula II-a or a pharmaceutically acceptable salt thereof.

39. The use according to claim 37 or 38, characterized in that, The drug has a drug loading concentration of 0.01 to 10 mg / mL for the compound represented by formula II-a or its pharmaceutically acceptable salt.

40. The use according to claim 37 or 38, characterized in that, The dosage form of the drug is selected from one or more of the following: powder, granule, tablet, pill, capsule, and suspension.

41. The use according to claim 37 or 38, characterized in that, The drug is a sustained-release formulation.

42. The use according to claim 37 or 38, characterized in that, The drug is a controlled-release formulation.

43. The use according to claim 37 or 38, characterized in that, The drug is in the form of an injection or an infusion.

44. Use of a pharmaceutical composition for the preparation of a medicament for the prevention or treatment of mental illness, said pharmaceutical composition comprising a compound represented by formula II-a or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; The mental illness includes any one or more of the following characteristics: Diseases characterized by abnormal BDNF levels; Diseases characterized by abnormal activation of NMDA receptors; Diseases characterized by abnormal synaptic plasticity; The structural formula of the compound represented by formula II-a is as follows: Formula II-a.

45. The use according to claim 44, characterized in that, The single-dose form of the drug contains between 0.03 mg and 500 mg of a compound represented by Formula II-a or a pharmaceutically acceptable salt thereof.

46. ​​The use according to claim 44, characterized in that, The drug has a drug loading concentration of 0.01 to 10 mg / mL for the compound represented by formula II-a or its pharmaceutically acceptable salt.

47. The use according to claim 44, characterized in that, The pharmaceutical composition contains a pharmaceutically acceptable diluent.

48. The use according to any one of claims 44 to 47, characterized in that, The dosage form of the drug is selected from one or more of the following: powder, granule, tablet, pill, capsule or suspension.

49. The use according to any one of claims 44 to 47, characterized in that, The drug is a sustained-release formulation.

50. The use according to any one of claims 44 to 47, characterized in that, The drug is a controlled-release formulation.

51. The use according to any one of claims 44 to 47, characterized in that, The drug is in the form of an injection or an infusion.

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