Ketamine derivative and use thereof in treatment of mental illnesses

Abstract

The present application discloses a ketamine derivative and a use thereof in the treatment of mental illnesses. The structural formula of the ketamine derivative is as shown in formula I. The ketamine derivative or pharmaceutical composition thereof provided by the present invention significantly increases an expression level of BDNF in nerve cells, facilitates neurite outgrowth, inhibits NMDA receptor signals, and exhibits a therapeutic effect against acute and chronic depression. Compared with ketamine, the ketamine derivative or pharmaceutical composition thereof provided by the present invention has improved oral bioavailability and can be used in the treatment of mental illnesses such as depression.

Description

Ketamine derivatives and their use in the treatment of mental illness Technical Field

[0001] 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

[0002] 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.

[0003] 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. Depression affects more than 300 million people worldwide, with nearly 800,000 suicides annually. 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, such as CN115190815B, 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.

[0004] 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.

[0005] 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.

[0006] The antidepressant effects of the R enantiomer of ketamine and the ketamine metabolite (2R,6R)-hydroxynorketamine have also been studied in the prior art. In rodent models, the R enantiomer of ketamine (R-ket) has a more effective and longer-lasting antidepressant effect than 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 about 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.

[0007] 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

[0008] 1. The problem to be solved

[0009] This 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 derivative or mixtures thereof. Furthermore, the novel ketamine derivatives of this invention have fewer side effects, and / or, the ketamine derivatives of this invention have a rapid onset of action.

[0010] 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.

[0011] The second objective of this invention is to provide isomers of the above-mentioned novel ketamine derivatives, which have 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.

[0012] 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.

[0013] 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 illnesses. The administration, particularly oral administration, of an effective amount of the novel ketamine derivatives can improve mental illnesses, such as various types 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.

[0014] 2. Technical Solution

[0015] 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 Va166Met 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 precursor (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.

[0016] 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.

[0017] [1. Novel ketamine derivative compounds]

[0018] The first aspect of this invention provides a compound of formula I or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer, or prodrug thereof or a mixture thereof:

[0019] in,

[0020] 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

[0021] 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;

[0022] 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, halogenated C1-C10 alkyl (e.g., CF3), halogenated C1-C10 alkoxy (e.g., OCF3), NO2;

[0023] n is an integer selected from 1 to 4. For example, n is 1, 2, 3 or 4.

[0024] 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 and R2 are each independently selected from H, deuterium, C1-C6 alkyl and C1-C6 haloalkyl, preferably H, deuterium and C1-C4 alkyl; more preferably, R1 is H and R2 is H.

[0025] Preferably, R3 is selected from H, deuterium, C1-C10 alkyl, C1-C10 alkoxy, halogenated C1-C10 alkyl and halogenated C1-C10 alkoxy, more preferably H, deuterium, C1-C10 alkyl or C1-C10 alkoxy, and even more preferably H or deuterium.

[0026] In some embodiments, the present invention provides compounds represented by formulas Ia, Ib, Ic, and Id, or pharmaceutically acceptable salts, esters, hydrates, solvates, tautomers, or prodrugs or mixtures thereof:

[0027] In equations Ia, Ib, Ic, and Id, R1, R2, R3, and n are as described in any embodiment of this document.

[0028] As a preferred embodiment of the first aspect of the invention, a compound of Formula II or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer, or prodrug thereof or a mixture thereof is provided:

[0029] As a preferred embodiment of the first aspect of the present invention, compounds of formulas II-a, II-b, II-c, II-d, or pharmaceutically acceptable salts, esters, hydrates, solvates, tautomers, optical isomers, or prodrugs or mixtures thereof are provided:

[0030] In some embodiments, the present invention provides a mixture of any two, any three, or all four of formulas II-a, II-b, II-c, and II-d in any proportion.

[0031] Preferably, in some embodiments, the optical purity of the compound is >5%, >25%, >50%, >75%, >90%, >95%, >97%, >98%, or >99%.

[0032] 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.

[0033] This application provides compounds within the general formula range of Formula I, particularly compounds of Formula II, or pharmaceutically acceptable salts, esters, hydrates, solvates, tautomers, optical isomers (especially compounds of Formula II-a, II-b, II-c, and II-d), or 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.

[0034] Cellular experiments have shown that compounds within the general formula range of Formula I, especially compounds of Formula II, Formula II-a, Formula II-b, Formula II-c, and Formula II-d, have 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.

[0035] Animal experiments further demonstrated that, in an acute stress model, intraperitoneal injection or oral administration of compounds within the general formula range of Formula I of the present invention, particularly compounds of Formula II, II-a, II-b, II-c, II-d, or their pharmaceutically acceptable salts, exhibited acute antidepressant effects and suggested 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% 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 only around 20%. Therefore, the compounds within the general formula range of Formula I of the present invention, particularly compounds of Formula II, II-a, II-b, II-c, II-d, or their pharmaceutically acceptable salts, have significantly improved oral bioavailability compared to the traditional positive control drug ketamine, thus improving ease of use and safety.

[0036] In a mouse model of oral corticosterone-induced depression, intraperitoneal or oral administration of compounds within the general formula range of Formula I of the present invention, particularly compounds of Formula II, II-a, II-b, II-c, II-d, or pharmaceutically acceptable salts thereof, exhibited rapidly onset antidepressant effects and, in intraperitoneal injection experiments, enhanced antidepressant effects relative to ketamine.

[0037] In a mouse model of chronic unpredictable stress, intraperitoneal injection of compounds of formula I, particularly compounds of formula II, II-a, II-b, II-c, II-d, or pharmaceutically acceptable salts thereof, of the present invention has a rapidly acting antidepressant effect.

[0038] As a preferred embodiment of the first aspect of the present 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, and heptanoate. Propylene salts, 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.

[0039] As described herein, when the compound of Formula I, the compound of Formula II, or the compound of Formula II-a, II-b, II-c, II-d 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 the compound of Formula II. For example, when the compound of Formula I, the compound of Formula II, or the compound of Formula II-a, II-b, II-c, II-d has an optical isomer, the optical isomer separated from the racemic mixture is also included within the scope of the compound of Formula I, the compound of Formula II, or the compound of Formula II-a, II-b, II-c, II-d. These isomers can be obtained as individual products by synthetic or separation methods (e.g., concentration, solvent extraction, column chromatography, recrystallization, etc.).

[0040] The compounds represented by Formula I, Formula II, or Formulas II-a, II-b, II-c, and II-d 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.

[0041] The compounds represented by Formula I, Formula II, Formula II-a, Formula II-b, Formula II-c, and Formula II-d 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.

[0042] The compounds represented by Formula I, Formula II, Formula II-a, Formula II-b, Formula II-c, and Formula II-d 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 or II-b.

[0043] Isotopes can be used (e.g.) 2 H, 3 H, 14 Compounds of formula I, II, II-a, II-b, II-c, and II-d are designated as such.

[0044] 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, Formula II-a, Formula II-b, Formula II-c, and Formula II-d.

[0045] As described herein, a "prodrug," also known as a prodrug, may be a compound that itself has weak or no activity, but which, after administration, is converted under physiological conditions (e.g., through metabolism, solvation, or other means) into the biologically active form of the compound represented by formula I, formula II, formula II-a, formula II-b, formula II-c, or formula II-d. In one case, a prodrug refers to a prodrug that, upon metabolism in vivo, produces the compound represented by formula I, formula II, formula II-a, formula II-b, formula II-c, or formula II-d.

[0046] In this document, C1-C10 alkyl groups include straight-chain or branched C1-C10 alkyl groups, preferably straight-chain or branched C1-C6 alkyl groups, and more preferably straight-chain or branched C1-C4 alkyl groups. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, etc.

[0047] In this article, C1-C10 alkylene refers to divalent C1-C10 alkyl groups, such as methylene (-CH2-) and ethylene (-CH2CH2-).

[0048] In this document, C1-C10 haloalkyl refers to a C1-C10 alkyl group substituted with one or more (e.g., 1, 2, 3, 4, 5, 6 or more) halogens, including but not limited to F, Cl, Br and I. Exemplary C1-C10 haloalkyl groups include, but are not limited to, C1-C6 haloalkyl and C1-C4 haloalkyl, such as -CH2Cl, -CHCl2, etc.

[0049] In this document, C3-C6 cyclic heteroalkyl refers to a saturated cyclic group having 3-6 ring atoms, with one or more heteroatoms among the ring atoms, which may be selected from O, S, and N. Exemplary C3-C6 cyclic heteroalkyl includes, but is not limited to, oxetane, azirane, piperazine, pyrrolidinyl, piperidinyl, etc.

[0050] In this document, C2-C10 alkenyl refers to a straight-chain or branched hydrocarbon group having one or more carbon-carbon double bonds, preferably having 2-6 carbon atoms, more preferably 2-4. Exemplary C2-C10 alkenyl groups include, but are not limited to, vinyl, propenyl, etc.

[0051] In this document, C2-C10 alkynyl refers to a straight-chain or branched hydrocarbon group having one or more carbon-carbon triple bonds, preferably having 2-6 carbon atoms, more preferably 2-4. Exemplary C2-C10 alkenyl groups include, but are not limited to, ethynyl and propynyl.

[0052] In this document, C1-C10 alkoxy refers to the RO- group, where R is a C1-10 alkyl group as defined in any embodiment of this document.

[0053] In this article, halogenated C1-C10 alkoxy groups refer to C1-C10 alkoxy groups that have been substituted with halogens, such as halogenated C1-C6 alkoxy groups, halogenated C1-C4 alkoxy groups, etc.

[0054] 2. Pharmaceutical Composition

[0055] A second aspect of the present invention provides a pharmaceutical composition comprising any of the compounds of formula I, formula II, formula II-a, formula II-b, formula II-c, formula II-d, or pharmaceutically acceptable salts, esters, hydrates, solvates, tautomers, optical isomers, or prodrugs or mixtures thereof as described in the first aspect of the present invention, and a pharmaceutically acceptable carrier or diluent.

[0056] 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 a mixture thereof) as described in any embodiment of the first aspect of the present invention, and is combined with one or more pharmaceutically acceptable carriers or diluents. In some embodiments, the pharmaceutical composition comprises the active ingredient and a pharmaceutically acceptable carrier; or, the pharmaceutical composition comprises the active ingredient and a pharmaceutically acceptable diluent.

[0057] 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.

[0058] 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.

[0059] As a preferred second aspect of the invention, a pharmaceutical composition is provided comprising a compound of formula II-b or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer or prodrug or mixture thereof, and a pharmaceutically acceptable carrier or diluent.

[0060] As a preferred second aspect of the invention, a pharmaceutical composition is provided comprising a compound of formula II-c or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer or prodrug or mixture thereof, and a pharmaceutically acceptable carrier or diluent.

[0061] As a preferred second aspect of the invention, a pharmaceutical composition is provided comprising a compound of formula II-d or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer or prodrug or mixture thereof, and a pharmaceutically acceptable carrier or diluent.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] As stated herein, “single dose” as used herein refers to a dose of medicine suitable for a single administration to a subject.

[0066] 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. The unit "Kg" refers to the subject's body weight.

[0067] 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.

[0068] 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.

[0069] Preferably, the medication is administered to the patient at a dose of 0.05–5 mg / kg / day / person.

[0070] Preferably, the medication is administered to the patient at a dose of 0.2–2 mg / kg / day / person.

[0071] When administered within the above dosage range, the pharmaceutical composition did not exhibit any toxic side effects.

[0072] 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 prodrug or mixture thereof comprises 1 to 99 wt% by mass.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] The pharmaceutical compositions according to the present invention can also be widely used as food and beverage compositions. Specifically, in addition to various foods such as breads, cakes, noodles, pastries, jellies, frozen foods, ice cream, dairy products, beverages, soups, and edible oils, examples include fruit juices, carbonated beverages, tea-based beverages, sports drinks, milk beverages, alcoholic beverages, and soft drinks. Furthermore, food and beverage compositions also include functional foods, nutritional functional foods, foods for specific health purposes, foods for special purposes, foods for the elderly, foods for patients, and health supplements. These are not particularly limited in form and can be oral formulations of the aforementioned pharmaceuticals and quasi-drugs. It should be noted that these can be compositions formed by adding the preventive agents and / or therapeutic agents of the present invention to existing food and beverage compositions during or after preparation; the timing and method of addition are not particularly limited.

[0080] [Medicine box]

[0081] 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.

[0082]

Indications

[0083] 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.

[0084] in,

[0085] 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

[0086] 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;

[0087] 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, deuterated C1-C10 alkyl (e.g., CF3), deuterated C1-C10 alkoxy (e.g., OCF3), NO2;

[0088] n is an integer selected from 1 to 4.

[0089] In some embodiments, the compound of formula I is formula Ia, Ib, Ic and Id as described in any of the embodiments herein.

[0090] 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.

[0091] 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.

[0092] In some implementations, Formula I is defined as described in any of the embodiments herein.

[0093] 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.

[0094] 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, II-b, II-c, II-d, or any mixture of two or more thereof:

[0095] 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.

[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 oral corticosterone-induced depression, intraperitoneal / oral administration of compound II-a demonstrated a rapidly acting 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 exhibited a rapidly onset antidepressant effect.

[0100] As a preferred fourth aspect of the invention, the use of a compound of formula II-b 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.

[0101] As a preferred fourth aspect of the invention, the use of a compound of formula II-c 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.

[0102] As a preferred fourth aspect of the invention, the use of a compound of formula II-d 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.

[0103] Cellular experiments have shown that compounds of formula II-d promote neurite growth.

[0104] 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, II-a, II-b, II-c, II-d or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer or prodrug or mixture thereof, and a pharmaceutically acceptable carrier or diluent.

[0105] 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 prodrug or mixture thereof, and a pharmaceutically acceptable carrier or diluent.

[0106] 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-b or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer or prodrug or mixture thereof, and a pharmaceutically acceptable carrier or diluent;

[0107] 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-c or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer or prodrug or mixture thereof, and a pharmaceutically acceptable carrier or diluent.

[0108] 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-d or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer or prodrug or mixture thereof, and a pharmaceutically acceptable carrier or diluent.

[0109] 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.

[0110] As a preferred embodiment of any of the fourth aspects of the present invention, the mental illness is depression.

[0111] 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 have residual symptoms or become chronic.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] As described in this article, "mood disorder" refers to a type of mental illness 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.

[0117] 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-hypnotic drugs and analgesics).

[0118] Preferably, the major depressive disorder is treatment-resistant depression.

[0119] Preferably, the depression includes acute depressive episodes of bipolar disorder, mild depression, moderate depression, severe depression, or drug-resistant depression.

[0120] 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.

[0121] 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, and they have little interest in things they used to enjoy. They may also experience mild changes in appetite and sleep.

[0122] 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.

[0123] As described in this article, "major depression" refers to an extremely severe condition in which the patient's social functioning is almost paralyzed. The patient may be bedridden, completely avoid social interaction, experience extremely low mood and despair, and may even have suicidal thoughts and behaviors. Physical symptoms may also include severe weight changes and intractable insomnia.

[0124] As a preferred fourth aspect of the invention, the use of one or more compounds of formula I (including formulas Ia, Ib, Ic, and Id), formula II, II-a, II-b, II-c, or II-d, or their 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, said mental illness including any one or more of the following characteristics: a disease characterized by abnormal BDNF levels, a disease characterized by abnormal activation of NMDA receptors, or a disease characterized by abnormal synaptic plasticity.

[0125] As a preferred embodiment of the fourth aspect of the present invention, the present invention provides the use of a pharmaceutical composition for preparing a medicament for the prevention or treatment of mental illness, said pharmaceutical composition comprising one or more compounds of formula I (including formulas Ia, Ib, Ic and Id), formula II, II-a, II-b, II-c or II-d, or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer or prodrug or mixture thereof, and a pharmaceutically acceptable carrier or diluent; said mental illness includes any one or more of the following characteristics: a disease characterized by abnormal BDNF levels, a disease characterized by abnormal activation of NMDA receptors, or a disease characterized by abnormal synaptic plasticity.

[0126] The fourth aspect of this invention also provides the use of the compounds described in the first aspect of this invention, or pharmaceutically acceptable salts, esters, hydrates, solvates, tautomers, optical isomers, or prodrugs or mixtures thereof, or the pharmaceutical compositions described in the second aspect of this invention, in (preferably in vitro) increasing the expression of BDNF in nerve cells, promoting neurite growth, and / or inhibiting NMDA receptor signaling. Preferably, the nerve cells are neural stem cells or glial cells.

[0127] In this document, the compounds represented by one or more of Formula I (including Formulas Ia, Ib, Ic, and Id), Formula II, Formula II-a, Formula II-b, Formula II-c, or Formula II-d, or their pharmaceutically acceptable salts, esters, hydrates, solvates, tautomers, optical isomers, or prodrugs or mixtures thereof, or the pharmaceutical compositions thereof, can be used to increase the plasma concentration of the active ingredient, improve bioavailability, and / or cross the blood-brain barrier. The active ingredient in the pharmaceutical composition is defined as described in any embodiment herein.

[0128] 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.

[0129] 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.

[0130] 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.

[0131] As stated herein, “single dose” as used herein refers to a dose of medicine suitable for a single administration to a subject.

[0132] 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.

[0133] 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.

[0134] 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.

[0135] Preferably, the medication is administered to the patient at a dose of 0.05–5 mg / kg / day / person.

[0136] Preferably, the medication is administered to the patient at a dose of 0.2–2 mg / kg / day / person.

[0137] When administered within the above dosage range, the pharmaceutical composition did not exhibit any toxic side effects.

[0138] 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 prodrug or mixture thereof in the pharmaceutical composition is 1 to 99 wt%.

[0139] According to any embodiment of the fourth aspect of the present invention, the mass percentage of the active ingredient in the pharmaceutical composition is selected from any of the following numerical ranges: 1–99 wt%, 30–99 wt%, 30–95 wt%, 30–90 wt%, 30–85 wt%, 30–80 wt%, 30–75 wt%, 30–70 wt%, 30–65 wt%, 30–60 wt%, 30–55 wt%, 30–50 wt%, 40–99 wt%, 40–95 wt%, 40–90 wt%, 40–85 wt%, 40–80 wt%, 40–75 wt%, 40–70 wt%, 40–65 wt%, 40–60 wt%, 40–55 wt%, 40–50 wt%. 50~99wt%, 50~95wt%, 50~90wt%, 50~85wt%, 50~80wt%, 50~75wt%, 50~70wt%, 50~6 5wt%, 50~60wt%, 50~55wt%, 60~99wt%, 60~95wt%, 60~90wt%, 60~85wt%, 60~80wt%, 60~75wt%, 60~70wt%, 60~65wt%, 70~99wt%, 70~95wt%, 70~90wt%, 70~85wt%, 70~8 0wt%, 70~75wt%, 80~99wt%, 80~95wt%, 80~90wt%, 80~85wt%, 90~99wt%, 90~95wt%.

[0140] 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 its prodrug or mixture thereof is 0.01 to 10 mg / mL.

[0141] As a preferred embodiment of any aspect of the fourth aspect 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- 3mg / mL, 0.1-2mg / mL, 0.1-1mg / mL, 1-10mg / mL, 1-8mg / mL, 1-5mg / mL, 1-3mg / mL, 1-2mg / mL, 2-10mg / mL , 2-8mg / mL, 2-5mg / mL, 2-3mg / mL, 4-10mg / mL, 4-8mg / mL, 4-5mg / mL, 6-10mg / mL, 6-8mg / mL, 8-10mg / mL.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] 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.

[0147] 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. The patients or subjects to be treated are preferably mammals, particularly humans.

[0148] 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.

[0149] 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.

[0150] 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.

[0151]

method

[0152] A fifth aspect of the invention also provides a method for treating and / or preventing mental illness, the method comprising administering to a subject in need a therapeutically effective or preventatively effective amount of a compound of the first aspect of the invention or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer or a prodrug or a mixture thereof, or a pharmaceutical composition of the second aspect of the invention. In some embodiments, the invention provides a method for increasing the expression level of BDNF in an individual's nerve cells, promoting individual neurite growth, and / or inhibiting individual NMDA receptor signaling, the method comprising administering to a desired individual an effective amount of a compound of the first aspect of the invention or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer or a prodrug or a mixture thereof, or a pharmaceutical composition of the second aspect of the invention. In some embodiments, the individual suffers from or is at risk of suffering from the mental illness described herein.

[0153] In some implementations, mental illness is defined as described in any of the implementations herein, preferably as depression.

[0154] In some implementations, the subjects are patients with mental illnesses, such as patients with depression, corticosteroid depression, or chronic unpredictable stress.

[0155] In some implementations, the administration includes injection (e.g., intraperitoneal injection, intravenous injection) or oral administration.

[0156] [definition]

[0157] As used herein, the term "solvent" refers to a compound that carries solvent molecules, such as a hydrate.

[0158] 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".

[0159] 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.

[0160] The actual dosage level and route of administration of the active ingredient (compound of formula I, compound II, compound II-a, compound II-b, compound II-c, compound II-d, 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 dose of the active ingredient below the level required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. 3. Beneficial effects

[0161] Compared with the prior art, the advantages of this application are as follows:

[0162] (1) Existing ketamine drugs have poor oral bioavailability in the treatment of 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, Formula II-b, Formula II-c, Formula II-d, 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.

[0163] (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, particularly compounds of Formula II, II-a, II-b, II-c, II-d, or pharmaceutically acceptable salts thereof, exhibits acute antidepressant effects and suggests a possible rapid onset of action. Oral experiments also show that the compounds of the present invention have enhanced acute antidepressant effects compared to the positive control drug fluoxetine. Pharmacokinetic experiments show that the compounds of the present invention, particularly compound II-a, achieve 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, the compounds of the ketamine derivatives of the present invention within the general formula range of Formula I, particularly compounds of Formula II, II-a, II-b, II-c, II-d, or pharmaceutically acceptable salts thereof, have enhanced oral bioavailability compared to the traditional positive control drug ketamine, improving ease of use and safety.

[0164] (3) Animal experiments have further demonstrated that, in a mouse model of oral corticosterone-induced 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, Formula II-b, Formula II-c, Formula II-d, or pharmaceutically acceptable salts thereof, has a rapidly onset antidepressant effect and an enhanced antidepressant effect relative to ketamine.

[0165] (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, Formula II-b, Formula II-c, Formula II-d (preferably compounds of Formula II and Formula II-a) or their pharmaceutically acceptable salts, in mice with oral corticosterone-induced depression has a rapid onset of antidepressant effect and has an enhanced antidepressant effect relative to ketamine.

[0166] (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, Formula II-b, Formula II-c, Formula II-d, or pharmaceutically acceptable salts thereof, in a mouse model of chronic unpredictable stress has a rapid onset of antidepressant effect. Attached Figure Description

[0167] Figures 1-3 are the spectra of EW705 hydrochloride in Preparation Example 1.

[0168] Figure 4-6 is the spectrum of EW706 hydrochloride in Preparation Example 2.

[0169] Figure 7 shows the 1H NMR spectrum of the hydrochloride salt of compound II-b prepared in Example 3.

[0170] Figure 8 shows the mass spectrum of the compound of formula II-b obtained in Preparation Example 3.

[0171] Figure 9 shows the 1H NMR spectrum of the hydrochloride salt of the compound of formula II-c obtained in Preparation Example 4.

[0172] Figure 10 shows the mass spectrum of the compound of formula II-c obtained in Preparation Example 4.

[0173] Figure 11 shows the effect of the novel ketamine derivative EW705 hydrochloride (1 μM, 3 μM, 10 μM) on BDNF levels in neural stem cells in Example 1.

[0174] Figure 12 illustrates the effects of novel ketamine derivatives EW706 hydrochloride (1 μM, 3 μM, 10 μM), EW710 hydrochloride (1 μM, 3 μM, 10 μM), and EW711 hydrochloride (1 μM, 3 μM, 10 μM) on BDNF levels in neural stem cells in Example 1.

[0175] Figure 13 shows the effect of the novel ketamine derivative EW705 hydrochloride (1 μM, 3 μM, 10 μM) on BDNF levels in glial cells in Example 2.

[0176] Figure 14 illustrates the effects of novel ketamine derivatives EW706 hydrochloride (1 μM, 3 μM, 10 μM) and EW710 (1 μM, 3 μM, 10 μM) on BDNF levels in glial cells in Example 2.

[0177] Figure 15 shows the effects of novel ketamine derivatives EW705 hydrochloride (1 μM, 3 μM, 10 μM) and EW706 (1 μM, 3 μM, 10 μM) on neurite growth in Example 3.

[0178] Figure 16 shows the inhibitory effect of the novel ketamine derivative EW705 hydrochloride (10 μM) and ketamine (10 μM) on NMDA receptor signaling in Example 4.

[0179] Figure 17 shows the acute antidepressant effect of the novel ketamine derivative in Example 5.

[0180] Figure 18 shows the acute antidepressant effect of the novel ketamine derivative in Example 5.

[0181] Figure 19 shows the antidepressant effect of intraperitoneal injection of a novel ketamine derivative in an animal model of corticosterone depression in Example 6.

[0182] Figure 20 shows the antidepressant effect of the oral administration of the novel ketamine derivative in an animal model of corticosterone depression in Example 7.

[0183] Figure 21 shows the antidepressant effect of the oral administration of the novel ketamine derivative in an animal model of corticosterone depression in Example 7.

[0184] Figure 22 shows the antidepressant effect of the novel ketamine derivative in Example 8 on a chronic unpredictable stress model.

[0185] Figure 23 shows the preliminary results of the open field test for evaluating whether EW705 hydrochloride has potential neuropsychiatric side effects.

[0186] In the various figures, "705" and "EW705" have the same meaning, both referring to compound EW705 hydrochloride; "706" and "EW706" both refer to compound EW706 hydrochloride; "710" and "EW710" both refer to compound EW710 hydrochloride; and "710" and "EW710" both refer to compound EW711 hydrochloride.

[0187] In the figure, * indicates p < 0.05%, ** indicates p < 0.01%, *** indicates p < 0.001%, and **** indicates p < 0.0001%. Detailed Implementation

[0188] The present application will be further described below with reference to specific embodiments.

[0189] 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.

[0190] 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.

[0191] 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 aforementioned values ​​and ranges. Furthermore, this interpretation should apply regardless of the breadth of the range or characteristic described.

[0192] 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.

[0193] Ketamine is a racemic mixture of R and S configurations in a 1:1 ratio.

[0194] Fluoxetine was purchased from Tichia.

[0195] 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.

[0196] EW706:

[0197] The hydrochloride salt (EW706) of the compound shown in Formula II-d 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.

[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 method of EW705 hydrochloride (hydrochloride of compound II-a)

[0201] 1. Preparation of intermediate M1

[0202] In a 1L double-necked round-bottom flask, the starting material SM (44.07 g, 393 mmol, 1.0 eq.) was placed in the flask, and methanol (400 mL) was added and stirred to disperse the mixture. Sulfuric acid (42 mL, 786 mmol, 2.0 eq.) was then added, and the mixture was heated to reflux and reacted 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). The organic phase was washed with saturated NaHCO3 solution (500 mL), and 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 MI (27.00 g, pale yellow liquid, 54% yield).

[0203] Spectral data:

[0204] HRMS(ESI-TOF)m / z Calcd.For C7H11O2 + [M+H] + =127.0754, found: 127.0752.

[0205] 2. Preparation of intermediate M2

[0206] In a 1L three-necked round-bottom flask, starting material M1 (25.10 g, 198 mmol, 1.0 eq.) was added, followed by anhydrous DCM (600 mL). The mixture was stirred and dispersed, cooled to -78°C, and Br2 (20 mL, 396 mmol, 2.0 eq.) was added. The mixture was then stirred at -78°C for 2 hours. The reaction was confirmed by TLC (EA / PE = 30%, M1 Rf = 0.25) to indicate the absence of starting material. Triethylamine (55 mL, 396 mmol, 2.0 eq.) was added at -78°C, and the reaction endpoint was determined by TLC (EA / PE = 30%, Rf = 0.6). The reaction mixture was allowed to cool naturally to -20°C and allowed to stand overnight. The mixture was filtered, and the filtrate was concentrated. The crude product was purified by chromatographic column chromatography using a 100-200 mesh silica gel column with 10% EA / PE as eluent, yielding compound M2 (26.70 g, pale yellow liquid, 66% yield).

[0207] Spectral data:

[0208] 1 H NMR (500MHz, Chloroform-d) δ3.75 (s, 3H), 2.90 (dt, J=15.7, 6.0Hz, 2H), 2.57-2.48 (m, 2H), 2.06-1.94 (m, 2H).

[0209] 13 C NMR (126MHz, Chloroform-d) δ192.14, 151.06, 135.33, 59.84, 38.38, 35.86, 22.67.

[0210] HRMS(ESI-TOF)m / z Calcd.For C7H 10 BrO2 + [M+H] + 204.9859, found: 204.9857.

[0211] 3. Preparation of intermediate M3

[0212] 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, under an argon atmosphere, 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. The atmosphere was then replaced with argon, 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)).

[0213] 1 H NMR δ7.51-7.38 (m, 1H), 7.28 (p, J=4.8Hz, 2H), 7.22-7.12 (m, 1H), 3.67-3.33 (m, 3H), 2.61 (dd, J=11.3, 5.8Hz, 4H), 2.13 (d, J=5.7Hz, 2H).

[0214] 13 C NMR (126MHz, Chloroform-d) δ195.58, 149.23, 143.53, 137.14, 131.58, 129.69, 129.21, 129.08, 126.82, 59.94, 38.99, 31.08, 22.64.

[0215] HRMS(ESI-TOF) m / z Calcd. For C 13 H 14 ClO2 + [M+H] + 237.0677, found: 237.0696.

[0216] 4. Preparation of intermediate M4

[0217] A 200 mL dry round-bottom flask was filled with argon gas, and anhydrous THF (40 mL), (R)-Me-CBS ((R)-1-methyl-3,3-diphenyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazolylborane, 4 mL, 1 M in Toluene, 4 mmol, 0.4 eq.), and BH3 THF (2 mL, 1 M in THF, 0.2 eq.) were added dropwise over 30 min. Then, a solution of M3 (2.40 g, 10 mmol, 1.0 eq.) in anhydrous THF (20 mL) was added dropwise. BH3 THF (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 was confirmed to be complete 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%), which is a white solid.

[0218] 1 H NMR (500MHz, Chloroform-d) (500MHz, Chloroform-d) δ7.38 (dd, J=7.8, 1.6Hz, 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, 6.4Hz, 1H), 1.69 (dt, J=13.2, 5.2Hz, 1H).

[0219] 13 C NMR (126MHz, Chloroform-d) (126MHz, CDCl3) δ139.25, 129.61, 128.31, 126.81, 119.78.31.84.30.59.

[0220] HRMS(ESI-TOF) m / z Calcd. For C 13 H 19 NClO2 + [M+NH4] + :256.1099, found:256.1125.

[0221] 5. Preparation of intermediate M5

[0222] 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 off-white solid M5 (0.38 g, yield: 98%, Rf = 0.2, 30% ethyl acetate / petroleum ether).

[0223] 1 H NMR (500MHz, Chloroform-d) δ7.38 (dd, J=7.7, 1.6Hz, 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, 2.9Hz, 1H), 1.82-1.74 (m, 1H), 1.72 (q, J=4.5Hz, 1H).

[0224] 13 C NMR (126MHz, Chloroform-d) δ156.49, 138.88, 129.46, 128.21, 126.68, 61.13, 29.96, 29.76, 29.25, 18.20, 14.52.

[0225] HRMS(ESI-TOF) m / z Calcd. For C 14 H 16 ClNO3 + [M+Na] +304.0711, found: 304.0743.

[0226] 6. Preparation of intermediate M6

[0227] In a 500 mL three-necked round-bottom flask, raw material 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 completed, the mixture was quenched in ice water (200 mL), 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.

[0228] 1 H NMR (500MHz, Chloroform-d) δ7.61 (dd, J=7.8, 1.8Hz, 1H), 7.28-7.20 (m, 1H), 7.22-7.18 (m, 1H), 7.13 (td, J=7.6, 1.8Hz, 1H), 4.84 (t, J= 4.1Hz, 1H), 2.39-2.27 (m, 1H), 2.19 (td, J=5.2, 2.4Hz, 2H), 1.85-1.77 (m, 1H), 1.71 (dt, J=6.7, 4.8Hz, 1H), 1.61 (dt, J=9.1, 4.1Hz. 1H).

[0229] 13 C NMR (126MHz, Chloroform-d) δ154.33, 139.94, 131.33, 131.22, 129.33, 128.67, 126.75, 97.38, 65.70, 54.65, 37.54, 23.31, 19.40.

[0230] HRMS(ESI-TOF) m / z Calcd. For C 14 H 15 ClNO2 + [M+H] + 264.0786, found: 264.0784.

[0231] 7. Preparation of intermediate M7

[0232] 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 chromatographically separated using 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%).

[0233] HRMS(ESI-TOF) m / z Calcd. For C 13 H 17 ClNO + [M+H] + 238.0993, found: 238.0995

[0234] 8. Preparation of (S,S)-FNK hydrochloride (EW705 hydrochloride)

[0235] In a 100 mL three-necked round-bottom flask, add starting material M7 (1.38 g, 5.8 mmol, 1.0 eq.) and acetonitrile:water = 1:1 (20 mL). Purge with argon three times, cool to 0 °C, and slowly add a selective fluoride reagent (select fluro) (CAS No: 140681-55-6, 15.34 g, 42.6 mmol, 1.1 eq.) dissolved in acetonitrile (10 mL). Maintain the reaction temperature at 0 °C for 20 min, then allow to cool to room temperature and react for 18 h. Determine the reaction endpoint by TLC (EA / PE = 40%, Rf = 0.2). Note the formation of M8; 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 compound (S,S)-FNK (yellow oil, 1.00 g, i.e. EW705) and byproduct M8 (0.56 g, white solid).

[0236] 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%).

[0237] 1 H NMR (500MHz, Methanol-d4) δ7.91-7.89 (m, 1H), 7.64-7.58 (m, 3H), 5.16 (ddd, J = 48.9, 1.6, 7.1Hz, 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, 4.2Hz, 1H), 1.79 (dddd, J=15.5, 11.8, 3.7, 2.0Hz, 1H).

[0238] 13 C NMR (126MHz, Methanol-d4) δ203.58 (d, J=15.6Hz), 135.33, 133.87, 133.18, 131.58, 131.1 8, 129.96, 92.01 (d, J = 193.9Hz), 68.46, 38.13, 36.95 (d, J = 19.0Hz), 19.06 (d, J = 11.5Hz).

[0239] 19 F NMR(471MHz, Methanol-d4)δ-192.32.

[0240] HRMS(ESI-TOF) m / z Calcd. For C 12 H 14 FNClO + : [M+H]+242.0743, found: 242.0747.

[0241] Optical rotation: [α]D 20 +96.6 (c=1, H2O, hydrochloride).

[0242] The characterization spectrum of EW705 is shown in Figures 1-3.

[0243] Preparation Example 2

[0244] Synthetic method of EW706 hydrochloride (hydrochloride of compound II-d)

[0245] Preparation route:

[0246] 1. Preparation of intermediate M1

[0247] See Preparation Example 1 for the preparation of intermediate M1.

[0248] 2. Preparation of intermediate M2

[0249] See Preparation Example 1 for the preparation of intermediate M2.

[0250] 3. Preparation of intermediate M3

[0251] See Preparation Example 1 for the preparation of intermediate M3.

[0252] 4. Preparation of intermediate M4

[0253] Experimental procedure: Add 250 mL of dry THF to a 500 mL three-necked round-bottom flask, purge with argon three times, cool the reaction to 0 °C, then add BH3 / THF (0.8 M, 19 mL, 15.1 mmol, 0.2 eq.), and at 0 °C add (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.) were added to the reaction mixture, resulting in a colorless and clear system. Then, M3 (17.90 g, 75.6 mmol, 1.0 eq.) was dissolved in 130 mL of dry THF and slowly added to the reaction mixture over a period exceeding 3 hours. Next, BH3 / THF (0.8 M, 77 mL, 60.5 mmol, 0.8 eq.) was added at 0 °C, resulting in a clear, brownish-yellow system. The reaction was maintained at 0 °C for 1 hour, and the endpoint was determined by TLC (EA / PE = 20%, Rf = 0.3). The reaction was quenched by adding 100 mL of MeOH at 0 °C, and the mixture was directly evaporated to dryness. 200 mL of EA was added to dissolve the organic phase, and the mixture was washed once with 300 mL of 1 M NaOH. The organic phase was separated, extracted with EA (2 × 150 mL) in aqueous solution, and the organic phases were combined, dried, and concentrated. The crude product was subjected to chromatography on a 100-200 mesh silica gel column with 10% EA / PE as eluent to separate compound M4 (14.67 g, yellow liquid, yield 81%).

[0254] HRMS (ESI-MS): Calcd.For C 13 H 15 ClO2[M+NH4] + =256.1116 found: 256.1116.

[0255] 5. Preparation of intermediate M5

[0256] Experimental Procedure: In a 1L three-necked round-bottom flask, add raw material M4 (14.70 g, 61.6 mmol, 1.0 eq.) and anhydrous DCM (615 mL). Cool to 0°C, then add trichloroacetyl isocyanate (14.7 mL, 123 mmol, 2.0 eq.). Determine the reaction endpoint by TLC (EA / PE = 30%, Rf = 0.6). Recycle the solvent DCM to obtain a yellow oil. Add MeOH (250 mL) at 0°C to quench the reaction. Dissolve potassium carbonate (68.57 g, 493 mmol, 8.0 eq.) in 200 mL of water and add it to the mixture. Replace the argon atmosphere three times. Transfer to room temperature and react for 2 hours. Determine the reaction endpoint by TLC (EA / PE = 30%, Rf = 0.2). Recycle the solvent MeOH to 500 mL of water, extract with EA (3 × 150 mL), dry, and concentrate. The crude product was purified by chromatography 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%).

[0257] 1 H NMR: (500MHz, Chloroform-d) δ7.39 (dd, J=7.7, 1.6Hz, 1H), 7.29-7.15 (m, 3H), 5.52 (s, 1H), 3.38 (s, 3H), 2.07 (ddt, J=13.7, 5.8, 3.1Hz, 3H), 1.90 (s, 1H), 1.84-1.76 (m, 1H), 1.73 (tq, J=8.1, 3.4Hz, 1H).

[0258] 13 C NMR: (126MHz, CDCl3) δ156.55, 138.88, 130.43, 129.46, 128.22, 126.68, 77.29, 77.04, 76.78, 52.33, 29.96, 29.76, 18.20.

[0259] HRMS (ESI-MS): Calcd.For C 14 H 16 ClNO3[M+Na] + =304.0726found: 304.0726.

[0260] 6. Preparation of intermediate M6

[0261] 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 at 0 °C for 2 h. Determine the reaction endpoint by TLC (EA / PE = 20%, Rf = 0.9). After the reaction is complete, quench with 200 mL of ice water, 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, pale yellow oil, yield 87%) was obtained.

[0262] 1 H NMR: (500MHz, Chloroform-d) δ7.68 (dd, J=7.9, 1.8Hz, 1H), 7.35-7.16 (m, 3H), 4.91 (dd, J=4.9, 3. 5Hz, 1H), 3.53 (s, 3H), 2.41 (ddd, J = 13.7, 12.2, 3.3Hz, 1H), 2.31-2.19 (m, 2H), 1.93-1.64 (m, 3H).

[0263] 13 C NMR: (126MHz, CDCl3) δ154.33, 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.

[0264] 7. Preparation of intermediate M7

[0265] 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 react at 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%).

[0266] 1 H NMR: (500MHz, Chloroform-d) δ7.57 (dd, J=7.9, 1.8Hz, 1H), 7.32 (dd, J=7.8, 1.5Hz, 1H), 7. 21 (td, J=7.5, 1.5Hz, 1H), 7.16 (td, J=7.5, 1.8Hz, 1H), 4.82 (t, J=4.0Hz, 1H), 3.52 (s, 3H), 2 .49 (ddd, J=13.0, 9.5, 3.1Hz, 1H), 2.20 (tdd, J=5.7, 4.0, 1.2Hz, 4H), 1.76 (ddd, J=13.4, 8. 6, 3.0Hz, 1H), 1.64 (ddtd, J=12.7, 9.3, 6.3, 3.0Hz, 1H), 1.43 (ddt, J=16.4, 8.6, 4.4Hz, 1H).

[0267] 13 C NMR: (126MHz, CDCl3) δ157.18, 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.

[0268] HRMS (ESI-MS): Calcd.For C 14 H 16 ClNO3[M+H] + =238.1008 found: 238.1008.

[0269] 7. Preparation of DP (EW706)

[0270] 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 in a 1:1 ratio (150 mL). Replace the acetonitrile atmosphere with argon 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 the temperature to rise 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, i.e., EW706).

[0271] Preparation of hydrochloride: The crude oily product was dispersed in approximately 100 mL of diethyl ether. 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%).

[0272] 1 H NMR: (500MHz, Methanol-d4): δ7.91 (dd, J=7.4, 2.2Hz, 1H), 7.64-7.58 (m, 3H), 5.17 (ddd, J=48.9, 11.6, 7.1Hz, 1H), 3.29-3.24 (m, 1H), 2.50 (dtd, J=9.2, 5.4, 4.4, 2.5Hz, 1H), 2.00 (td, J=14.3, 3.6Hz, 2H), 1.90-1.76 (m, 2H).

[0273] 13 C NMR: (126MHz, Methanol-d4) δ203.59 (d, J=15.9Hz), 135.31, 133.86, 133.16, 131.61, 131.21, 129 .96, 92.02 (d, J = 193.9Hz), 68.45 (d, J = 2.0Hz), 38.15, 36.96 (d, J = 18.9Hz), 19.07 (d, J = 11.7Hz).

[0274] 19 F NMR: (471MHz, Methanol-d4)δ-192.33.

[0275] HRMS (ESI-MS): Calcd.For C 12 H 13 FClNO[M+H] + =242.0744 found:242.0744.

[0276] The characterization spectrum of EW706 is shown in Figure 4-6.

[0277] Preparation Example 3 (Synthesis of Formula II-b, i.e., EW711)

[0278] M7 was prepared using the same method as in Preparation Example 2.

[0279] Preparation of product DP (EW711):

[0280] In a 500 mL three-necked round-bottom flask, starting material M7 (9.21 g, 38.7 mmol, 1.0 eq.) was added, followed by acetonitrile:water in a 1:1 ratio (150 mL). The mixture was purged with argon three times, cooled to 0 °C, and a selective fluorine reagent (CasNo: 140681-55-6, 15.34 g, 42.6 mmol, 1.1 eq.) dissolved in acetonitrile (50 mL) was slowly added to the reaction mixture. The reaction was maintained at 0 °C for 20 min, then allowed to cool to room temperature for 20 h. The reaction endpoint was determined by TLC (EA / PE = 40%, DP Rf = 0.2). The pH of the reaction mixture was adjusted to between 9 and 10 using saturated sodium carbonate solution, saturated with sodium chloride, extracted with ethyl acetate (3 × 120 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was chromatographically separated using a 100-200 mesh silica gel column with 10-50% EA / PE as eluent. The diastereomers (R, S)-configuration compounds (EW711, 0.7 g, white solid) were separated.

[0281] Preparation of hydrochloride: The (R,S)-configured compound (0.7 g, 2.9 mmol) obtained above was dissolved in methanol (20 mL), concentrated to 5 mL, and a white solid precipitated. This was filtered, washed with cold methanol, and dried to obtain the product (0.35 g, 99.3% purity). The remaining filtrate was directly separated using a C18 column: eluted with 60% to 85% methanol, and the eluents were combined and concentrated until a white solid precipitated. The white solid was extracted with dichloromethane (3 × 20 mL), and the organic phase was dried with sodium sulfate solid and concentrated to obtain a white solid (0.2 g, 99% purity). The purified solid (0.5 g) was suspended in 10 mL of diethyl ether / dichloromethane (2:1), and HCl / diethyl ether solution (approximately 3-4 M, 4 mL) was added. The mixture was stirred at room temperature for 2 h, and a white solid precipitated. This solid was filtered, redissolved in water (5 mL), and lyophilized to obtain 0.45 g of solid, which was EW711 hydrochloride.

[0282] 1 H NMR (600MHz, Deuterium Oxide) δ7.95-7.76 (m, 1H), 7.64-7.30 (m, 3H), 5.25 (ddd, J=50.4, 3.9, 1.5Hz, 1H), 3.31 (dq, J=14.2, 2.9Hz, 1H), 2.39 (dddd, J=13.2, 11.0, 6.2, 2.9Hz, 1H), 2.09 (td, J=13.7, 3.8Hz, 1H), 2.06-1.90 (m, 2H), 1.85 (dq, J=13.9, 3.5Hz, 1H).

[0283] 13 C NMR (151MHz, Deuterium Oxide) δ204.83, 204.69, 134.14, 132.23, 130.95, 129.64, 128.45, 128.20, 95.46, 94.24, 67.89, 37.80, 34.98, 34.84, 16.23.

[0284] 19 F NMR (565MHz, Deuterium Oxide) δ-189.90.

[0285] HRMS (ESI-MS): Calcd.For C 12 H 13 FClNO[M+H]+=242.0744 found: 242.0731.

[0286] Figure 7 shows the 1H NMR spectrum of the hydrochloride salt of compound II-b. Figure 8 shows the mass spectrum of compound II-b.

[0287] Preparation Example 4 (Synthesis of Formula II-c, i.e., EW710)

[0288] M7 was prepared using the same method as in Preparation Example 1.

[0289] Preparation of product DP (EW710):

[0290] Selectfluro (7.11 g, 19.9 mmol, 1.1 eq.) was added to a 500 mL three-necked round-bottom flask, followed by acetonitrile:water in a 1:1 ratio (120 mL). The mixture was purged with argon three times, cooled to 0 °C, and the starting material M7 (4.30 g, 18.1 mmol, 1.0 eq.) was dissolved in acetonitrile (30 mL) and added to the reaction mixture. The reaction was maintained at 0 °C for 20 min, then allowed to return to room temperature for 25 h. The reaction endpoint was determined by TLC (EA / PE = 40%, DP Rf = 0.4). The pH of the reaction mixture was adjusted to 9-10 with saturated sodium carbonate solution, saturated with sodium chloride, extracted with ethyl acetate (3 × 100 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was chromatographically separated using a 100-200 mesh silica gel column with 10-50% EA / PE as eluent to obtain compound DP (yellow oil, 569.3 mg, i.e., EW710). DP was prepared by reverse column chromatography, lyophilized, and analyzed by HPLC, with a purity of 96.6%. Further purification: the solid was added to an aqueous solution of NaHCO3, extracted with DCM (3 × 50 mL), dried, concentrated, purified with 100-200 silica gel, eluted with 30% EA / PE, and the fraction was collected and evaporated to dryness. A small amount of Et2O was added to dissolve the solid, followed by the addition of 5 mL of HCl / Et2O. The mixture was stirred for 10 min, filtered, and the solid was collected to obtain EW710 hydrochloride.

[0291] 1 H NMR: 1 H NMR (500MHz, Methanol-d4) δ7.74 (dd, J=7.7, 1.7Hz, 1H), 7.49-7.26 (m, 3H), 5.63-5.40 (m, 1H) , 2.72 (ddd, J=14.4, 10.4, 3.9Hz, 1H), 2.41-2.25 (m, 1H), 2.21-2.03 (m, 2H), 2.00-1.81 (m, 2H).

[0292] 13 C NMR: 13 C NMR (126MHz, MeOD) δ204.68, 133.11, 132.97, 130.35, 129.13, 127.53, 126.89, 92.11, 90.62, 66.20, 48.11, 47.94, 47.77, 47.60, 47.43, 47.26, 47.09, 38.26, 33.21, 33.06, 18.05.17.97.

[0293] HRMS (ESI-MS): Calcd.For C 12 H 13 FClNO[M+H]+ =241.0670 found: 242.0743.

[0294] Figure 9 shows the 1H NMR spectrum of the hydrochloride salt of compound II-c. Figure 10 shows the mass spectrum of compound II-c.

[0295] Example 1

[0296] Effects of novel ketamine derivatives EW705, EW706, EW710, and EW711 on BDNF levels in neural stem cells:

[0297] Experimental cells: neural stem cells;

[0298] Experimental instrument: Bio-Rad electrophoresis apparatus, serial number: 042BR10743;

[0299] Experimental methods: After neural stem cell plating and culture, ketamine derivatives (1 μM, 3 μM, 10 μM) were added and incubated for 24 h. The supernatant was discarded, and lysis was performed by adding an appropriate amount of 1× Loading Buffer according to the cell volume. The cells were heated in a metal bath at 95°C for 5 min, followed by SDS-PAGE electrophoresis at 80V for 30 min, then at 120V for 1 h, and finally transferred to a membrane at 400mA for 2 h. After blocking for 0.5 h, the cells were incubated overnight at 4°C with primary antibody, 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.

[0300] Experimental conclusion: The results are shown in Figures 11 and 12. The ketamine derivative of the present invention can increase the expression level of BDNF in neural stem cells.

[0301] Example 2

[0302] Effects of novel ketamine derivatives EW705, EW706, and EW710 on BDNF levels in glial cells:

[0303] Experimental cells: HA glial cells;

[0304] Experimental instrument: Bio-Rad electrophoresis apparatus, serial number: 042BR10743;

[0305] Experimental methods: After plating HA glial cells, ketamine derivatives (1 μM, 3 μM, 10 μM) were added and incubated for 24 h. The supernatant was discarded, and lysis was performed by adding an appropriate amount of 1× Loading Buffer according to the cell volume. The cells were heated in a metal bath at 95°C for 5 min, followed by SDS-PAGE electrophoresis at 80V for 30 min, then at 120V for 1 h, and finally transferred to a membrane at 400mA for 2 h. After blocking for 0.5 h, the cells were incubated overnight at 4°C with primary antibody, 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.

[0306] Experimental conclusion: The results are shown in Figures 13 and 14. EW705, EW706 and EW710 can increase the expression level of BDNF in HA glial cells.

[0307] Example 3

[0308] Effects of novel ketamine derivatives EW705 and EW706 on neurite growth:

[0309] Experimental cells: SH-SY5Y;

[0310] Experimental apparatus: IX73 inverted microscope;

[0311] Experimental methods: After SH-SY5Y neural cells were plated and cultured, EW705 (1μM, 3μM, 10μM) and EW706 (1μM, 3μM, 10μM) were added and incubated for 24 hours. After that, microscopic images were taken and the length of neurites was analyzed and counted.

[0312] Experimental conclusion: As shown in Figure 15, both EW705 and EW706 can promote neurite growth.

[0313] Example 4

[0314] Inhibitory effect of novel ketamine derivative EW705 on NMDA receptor signaling:

[0315] Experimental cells: 293T cells;

[0316] Experimental instrument: BioTek Synergy NEO multi-functional microplate analyzer;

[0317] Experimental methods: 293T cells were transfected with NR1 and NR2A expression plasmids for 48 h, stained with 2 μM Fluo-4AM 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. 1 mM NMDA was added and calcium flux was detected immediately.

[0318] Experimental conclusion: As shown in Figure 16, the results show that both 10 μM ketamine and 10 μM MEW705 can significantly inhibit NMDA receptor signaling.

[0319] Example 5

[0320] Acute antidepressant effects of novel ketamine derivatives EW705, EW706, EW710, and EW711:

[0321] Laboratory animals: 8-week-old male C57BL / 6 rats;

[0322] Experimental apparatus: Cylindrical glass jar;

[0323] 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.

[0324] Experiment 1:

[0325] Twenty-one 8-week-old male C57BL / 6 mice were selected for the intraperitoneal injection experiment and randomly divided into two groups using a random number table: a negative control group (Veh, intraperitoneal injection of physiological saline, 10 mice) and an EW705 administration group (EW705, 10 mg / kg, intraperitoneal injection, 11 mice). Forced swimming tests were performed 30 min and 24 h after administration.

[0326] The results are shown in Figure 17(a). The results indicate that EW705 has an acute antidepressant effect.

[0327] Experiment 2:

[0328] Sixteen 8-week-old male C57BL / 6 mice were selected for the intraperitoneal injection experiment and randomly divided into two groups using a random number table: a negative control group (Veh, intraperitoneal injection of physiological saline, 8 mice) and an EW706 administration group (EW705, 10 mg / kg, intraperitoneal injection, 8 mice). Forced swimming tests were performed 30 min and 24 h after administration.

[0329] The results are shown in Figure 17(b). The results indicate that EW706 has no acute antidepressant effect.

[0330] Experiment 3:

[0331] Thirty 8-week-old male C57BL / 6 mice were selected for the oral administration experiment and randomly divided into three groups using a random number table: a negative control group (Veh, administered via gavage, 10 mice), an EW705 administration group (EW705, 30 mg / kg, administered via gavage, 10 mice), and a fluoxetine administration group (Fluoxetine, 20 mg / kg, administered via gavage, 10 mice). Forced swimming tests were performed 30 minutes and 24 hours after administration.

[0332] The results are shown in Figure 17(c). The results indicate that EW705 has an acute antidepressant effect.

[0333] Experiment 4: Twenty-four 8-week-old male C57BL / 6 mice were selected for intraperitoneal injection experiments and randomly divided into four groups using a random number table: a negative control group (Veh, intraperitoneal injection of physiological saline, 8 mice), an EW705 administration group (705, 10 mg / kg, intraperitoneal injection, 8 mice), an EW710 administration group (710, 10 mg / kg, intraperitoneal injection, 8 mice), and an EW711 administration group (711, 10 mg / kg, intraperitoneal injection, 8 mice). Forced swimming experiments were performed at 30 min, 24 h, and 7 days after administration.

[0334] The results are shown in Figure 18. The results indicate that EW705 has an acute, rapid, and long-lasting antidepressant effect. On day 7, EW710 and EW711 also showed antidepressant effects.

[0335] Example 6

[0336] Antidepressant effect of intraperitoneal injection of novel ketamine derivative EW705 in a corticosterone-induced depression animal model:

[0337] Laboratory animals: 8-10 week old C57BL / 6 male rats;

[0338] Experimental apparatus: lab chart;

[0339] 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.

[0340] 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 made only minor limb movements to maintain balance or float). The experiment was performed in parallel in each group, with 8-9 mice per group.

[0341] 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, showing a state of frustration. 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 on in parallel, with 8-9 mice in each group.

[0342] Experimental methods: Thirty-three male C57BL / 6 mice aged 8-10 weeks were selected and randomly divided into groups using a random number table.

[0343] Control group (WT, intraperitoneal injection of physiological saline, 8 normal non-model mice);

[0344] Negative control group (Vehicles, intraperitoneal injection of saline, 8 model mice);

[0345] EW705 administration group (EW705, 10 mg / kg, intraperitoneal injection, 9 model mice); and

[0346] Ketamine administration group (positive control group, Ket, 10 mg / kg, intraperitoneal injection, 8 model mice);

[0347] 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.

[0348] Conclusion: The results are shown in Figure 19. The results show that intraperitoneal injection of EW705 has a rapid onset of antidepressant effect, and the 30-min-FST and 24-h-TST effects are superior to those of the ketamine group.

[0349] Example 7

[0350] Antidepressant effects of oral administration of novel ketamine derivatives EW705, EW706, EW710, and EW711 in an animal model of corticosterone-induced depression:

[0351] Laboratory animals: 8-10 week old C57BL / 6 male rats;

[0352] Experimental apparatus: Cylindrical glass jar;

[0353] The method for establishing the corticosterone model is the same as in Example 6. Each group contains 10-11 mice.

[0354] The forced swimming experiment method is the same as in Example 6.

[0355] Experiment 1:

[0356] Thirty-one male C57BL / 6 mice aged 8-10 weeks were randomly divided into three groups using a random number table: a control group (WT, administered water by gavage, 10 normal mice without modeling); a negative control group (Vehicle, administered water by gavage, 11 mice with modeling); and an EW705 treatment group (EW705, 30 mg / kg, administered by gavage, 10 mice with modeling). EW705 was administered after modeling was completed. Forced swimming tests were performed at 30 min and 24 h after administration.

[0357] The results are shown in Figure 20. The results indicate that oral EW705 has a rapidly onset antidepressant effect.

[0358] Experiment 2:

[0359] Sixty male C57BL / 6 mice aged 8-10 weeks were randomly divided into the following groups using a random number table: control group (WT, water administered by gavage, 10 normal mice without modeling); negative control group (Vehicle administered by gavage, 10 mice with modeling); EW705 treatment group (705, 30 mg / kg, administered by gavage, 10 mice with modeling); EW706 treatment group (710, 30 mg / kg, administered by gavage, 10 mice with modeling); EW710 treatment group (710, 30 mg / kg, administered by gavage, 10 mice with modeling); and EW711 treatment group (711, 30 mg / kg, administered by gavage, 10 mice with modeling). Each ketamine derivative was administered after modeling. Forced swimming tests were performed at 30 min, 24 h, 7 days, and 14 days after administration.

[0360] The results are shown in Figure 21. The results indicate that oral EW705 has a rapid-onset antidepressant effect; EW705 also exhibits a significant long-lasting antidepressant effect. EW710 and EW711 also showed antidepressant effects.

[0361] Example 8

[0362] Antidepressant effect of novel ketamine derivative EW705 in a chronic unpredictable stress model.

[0363] Experimental animals: 7-week-old male C57BL / 6 rats;

[0364] Experimental apparatus: Cylindrical glass jar;

[0365] Experimental methods: Twenty-one 7-week-old male C57BL / 6 mice were selected and divided into:

[0366] Control group (WT, intraperitoneal injection of physiological saline, 8 normal non-model mice);

[0367] Negative control group (Vehicles, 7 mice that underwent modeling and were injected intraperitoneally with saline);

[0368] EW705 administration group (EW705, 10 mg / kg, intraperitoneal injection, 6 model mice).

[0369] 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.

[0370] After the modeling was completed, EW705 was administered once, and a forced swimming test was conducted 24 hours after administration.

[0371] Table 1: Different stress treatments applied to model mice

[0372] Conclusion: The results are shown in Figure 22. The results indicate that EW705 has a significant antidepressant effect in a chronic unpredictable stress model.

[0373] Example 9

[0374] Experimental animals: C57BL / 6 mice;

[0375] Dosage: 5 mg / kg body weight;

[0376] Experimental method: Plasma concentration test method;

[0377] Pharmacokinetic Experiment

[0378] Experimental animals: C57BL / 6J mice, male, purchased from Shanghai Lingchang Biotechnology Co., Ltd.

[0379] 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.

[0380] 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.

[0381] 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.

[0382] Sample processing and testing:

[0383] 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℃ and 3220×g for 15 minutes.

[0384] 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.

[0385] Analysis and detection were performed using an LC-MS / MS-DS_TQ7500 instrument.

[0386] The bioavailability of the novel ketamine derivative EW705 is shown in Table 2 below.

[0387] Table 2: Bioavailability of C57BL / 6 mice (5 mg / kg body weight)

[0388] "*" indicates N / A

[0389] Experimental conclusion:

[0390] Oral administration of EW705 resulted in excellent plasma concentrations, with a peak concentration of 3282 ng / ml and an oral bioavailability of 86.7%.

[0391] Example 10

[0392] Experimental animals: C57BL / 6J mice.

[0393] 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.

[0394] Experimental method: Blood brain concentration test method.

[0395] Sample collection:

[0396] (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 kept on ice until centrifugation.

[0397] 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.

[0398] (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 (1×1) 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.

[0399] Sample processing and testing:

[0400] 1) Add 20 μL of plasma sample to 400 μL of acetonitrile or methanol containing internal standard (100 ng / mL) for precipitation, then vortex mix at 800 rpm for 10 minutes, and centrifuge at 4℃ and 3220×g for 15 minutes.

[0401] 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℃ and 3220×g for 15 minutes.

[0402] 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℃ and 3220×g for 5 minutes. Then inject the supernatant directly for LC-MS / MS analysis.

[0403] Analysis and detection were performed using an LC-MS / MS_CT_Triple Quad 6500plus instrument.

[0404] 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.

[0405] Table 3: Blood brain concentrations of EW705 (10 mg / kg) after intraperitoneal injection (n=2)

[0406] Table 4: Blood brain concentrations of EW705 (30 mg / kg) after gavage (n = 2)

[0407] Example 11

[0408] This embodiment uses an open field test to preliminarily evaluate whether EW705 has potential neuropsychiatric side effects.

[0409] Laboratory animals: 8-10 week old C57BL / 6 male rats;

[0410] Experimental apparatus: Noldus

[0411] Experimental Methods: Ten male C57BL / 6 mice aged 8-10 weeks were randomly divided into two groups using a random number table: a ketamine group (10 mg / kg intraperitoneally, 5 mice) and an EW705 group (10 mg / kg intraperitoneally, 5 mice). Two hours before the experiment, the animals were placed in the acclimatization room. During the experiment, the animals were placed in a plastic box (40 cm long x 40 cm wide x 40 cm high) and video was recorded. The experiment lasted 45 minutes and was conducted in a quiet environment. The mice were injected with the drug 30 minutes after being placed in the box. After each experiment, the bottom and inner walls of the open box were wiped with 70% alcohol to prevent residual odors from the previous experiment from interfering with the next experiment. The video was analyzed using animal spontaneous activity analysis software (Noldus) to determine the total distance traveled by the animals.

[0412] The results are shown in Figure 23. In Figure 23, the upper left image shows the movement trajectory of the mice given Ket, and the upper right image shows the movement trajectory of the mice given EW705. The lower image shows the movement distance of the mice.

[0413] The results showed no difference between the ketamine group and the EW705 group before administration. Shortly after intraperitoneal injection of 10 mg / kg, the ketamine group showed a highly significant increase in spontaneous activity, demonstrating the excitatory effect of ketamine. In contrast, 10 mg / kg of EW705 did not increase spontaneous activity in mice, indicating that EW705 did not cause excessive excitement or induce any neurological side effects.

Claims

a compound of the following formula I or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer, or prodrug thereof or mixtures thereof: in, 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 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; 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, halo-C1-C10 alkyl, halo-C1-C10 alkoxy, and NO2; n is an integer selected from 1 to 4. The compound according to claim 1, or its pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer, or prodrug or mixture thereof, is characterized in that: R1 and R2 are each independently selected from H, deuterium, C1-C6 alkyl, and C1-C6 haloalkyl, preferably H, deuterium, and C1-C4 alkyl; preferably, R1 is H and R2 is H; and / or R3 is selected from H, deuterium, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy, preferably H, deuterium, C1-C4 alkyl or C1-C4 alkoxy, more preferably H or deuterium. The compound or its pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer, or prodrug thereof or mixture thereof according to claim 1 or 2, characterized in that, The compounds are compounds of the following formulae I-a, I-b, I-c and I-d: In each formula, R1, R2, R3 and n are as defined in claim 1 or 2. The compound or its pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer, or prodrug thereof or mixture thereof according to claim 1, characterized in that, The compound is a compound of the following formula II: Preferably, the compound is any one of formulae II-a, II-b, II-c, II-d or a mixture of any of them: The compound or its pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer, or prodrug thereof or mixture thereof according to any one of claims 1-4, 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. A pharmaceutical composition comprising: (1) The compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer or prodrug or mixture thereof; (2) A pharmaceutically acceptable carrier or diluent; and (3) Other optional antidepressants. The pharmaceutical composition according to claim 6 is characterized in that: 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. and / or The pharmaceutical composition comprises, by mass percentage, 1–99 wt% of the compound or its pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer, or prodrug or mixture thereof; and / or The drug loading concentration 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 0.01–10 mg / mL; and / or The other antidepressants include any one, two or more of ketamine, fluoxetine, sertraline, citalopram, paroxetine, fluvoxamine, duloxetine, venlafaxine, amitriptyline or doxepin hydrochloride. The pharmaceutical composition according to any one of claims 6 to 7, characterized in that The dosage form of the pharmaceutical composition is selected from one or more of the following: powder, granule, tablet, pill, capsule, sustained-release, controlled-release, injection, infusion, or suspension. A medicine box comprising one or more single-dose units of a compound according to any one of claims 1 to 5, 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 according to any one of claims 6 to 8, and instructions for use in treating a disease. Use of the compound of formula I according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, ester, hydrate, solvate, or tautomer, optical isomer, or prodrug or mixture thereof, or the pharmaceutical composition according to any one of claims 6 to 8, in the preparation of a medicament for the prevention or treatment of mental illness. Use according to claim 10, characterized in that, The mental illnesses mentioned are selected from 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; Preferably, the depression includes major depressive disorder, persistent depressive disorder, seasonal affective disorder, postpartum depression, premenstrual anxiety disorder, situational depression, anhedonia, melancholy, midlife depression, geriatric depression, depression caused by a identifiable stressor, treatment-resistant depression, or a combination thereof. Preferably, the major depressive disorder includes treatment-resistant depression. The use according to claim 10 or 11 is characterized in that: The single-dose form of the drug contains 0.03 mg to 500 mg of the compound or its pharmaceutically acceptable salt, ester, hydrate, solvate, or tautomer, optical isomer, or prodrug or mixture thereof; and / or The drug contains a drug loading concentration of 0.01–10 mg / mL for the compound or its pharmaceutically acceptable salt, ester, hydrate, solvate, or tautomer, optical isomer, or its prodrug or mixture thereof; and / or The drug also contains a pharmaceutically acceptable carrier or diluent; and / or The dosage form of the drug is selected from one or more of the following: powder, granule, tablet, pill, capsule, sustained-release, controlled-release, injection, infusion, or suspension. Use of the compound of formula I according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, ester, hydrate, solvate, or tautomer, optical isomer, or prodrug or mixture thereof, or the pharmaceutical composition according to any one of claims 6 to 8, in the preparation of a medicament for the prevention or treatment of mental illness, wherein, The mental illness includes any one or more of the following characteristics: Abnormal BDNF levels; Aberrant activation of NMDA receptors; and Abnormal synaptic plasticity. The use according to claim 13 is characterized in that: The single-dose form of the drug contains 0.03 mg to 500 mg of the compound or its pharmaceutically acceptable salt, ester, hydrate, solvate, or tautomer, optical isomer, or prodrug or mixture thereof; and / or The drug contains a drug loading concentration of 0.01–10 mg / mL for the compound or its pharmaceutically acceptable salt, ester, hydrate, solvate, or tautomer, optical isomer, or its prodrug or mixture thereof; and / or The drug also contains a pharmaceutically acceptable carrier or diluent; and / or The dosage form of the drug is selected from one or more of the following: powder, granule, tablet, pill, capsule, sustained-release, controlled-release, injection, infusion, or suspension. The use of any compound of claims 1 to 5 or a pharmaceutically acceptable salt, ester, hydrate, solvate, tautomer, optical isomer or prodrug or mixture thereof, or the pharmaceutical composition of any one of claims 6 to 8, in the preparation of a medicament for increasing BDNF expression in nerve cells, promoting synaptic growth and / or inhibiting NMDA receptor signaling.

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