Novel use of pynegabine in preparation of drugs against psychiatric disorders

Abstract

Provided in the present invention is a novel use of Pynegabine as represented by formula (I) in the preparation of drugs for treating or preventing psychiatric disorders such as depression and schizophrenia. The present invention shows that Pynegabine can exhibit a significant antidepressant effect in an acute forced swimming mouse model and a chronic social defeat stress mouse model; additionally, Pynegabine also has a significant alleviation effect on both positive and negative symptoms in an MK-801-induced mouse model of schizophrenia. The present invention shows good development and application prospects.

Description

New Uses of Pinegabine in the Preparation of Antipsychotic Drugs Technical Field

[0001] This invention belongs to the pharmaceutical field and relates to a novel use of pengabin in the preparation of antipsychotic drugs. Background Technology

[0002] Mental illness refers to brain dysfunction that impairs cognitive, emotional, and behavioral activities to varying degrees, affecting approximately 970 million people worldwide and causing a significant social, economic, and medical burden. Depression and schizophrenia are the two most common mental illnesses, characterized by high incidence, high relapse rate, and high disability rate.

[0003] As a mood disorder, depression affects over 330 million people of all ages worldwide. Its clinical manifestations are diverse, primarily including prolonged low mood, anhedonia, social avoidance, and changes in sleep and appetite. Depression can occur alone or overlap with symptoms of other neuropsychiatric disorders such as anxiety, schizophrenia, bipolar disorder, and sleep disorders. Based on severity, it can be classified as mild, moderate, or severe. Major depressive disorder (MDD) is the most common and extreme form of depression and a leading cause of disability and suicide.

[0004] Currently, there are several hypotheses regarding the pathogenesis of depression, including those related to monoamine neurotransmitters, neuroplasticity, neurotrophic factors, endocrine regulation, and neuroimmune regulation. Antidepressants developed based on these hypotheses mainly include: first-generation monoamine oxidase inhibitors and tricyclic antidepressants; second-generation serotonin reuptake inhibitors (SRIs), serotonin / norepinephrine reuptake inhibitors (SNRs), and norepinephrine / dopamine reuptake inhibitors; and the latest third-generation fast-acting antidepressants such as esketamine (S-ketamine) (an ionotropic glutamate receptor N-methyl-D-aspartate antagonist) and brinolone (a gamma-aminobutyric acid A receptor positive allosteric modulator). Drug therapy is the most important treatment for depression besides psychotherapy. However, the above-mentioned traditional antidepressants have poor clinical efficacy and are accompanied by disadvantages such as slow onset of action, high relapse rate, and poor prognosis. Newer generation antidepressants such as S-ketamine have adverse reactions such as addiction and central nervous system side effects, limiting their clinical use. Currently, approximately 30% of patients with depression, i.e., those with treatment-resistant depression, do not respond to existing medications. Therefore, the development of diversified antidepressants with different mechanisms of action than those mentioned above is of great significance for increasing drug response rates and improving patient prognosis.

[0005] Schizophrenia is another serious chronic mental illness with a lifetime prevalence of nearly 1% worldwide. Its typical characteristics include a lifelong pattern of acute psychotic episodes coupled with long-term maladaptive psychosis and decreased life expectancy. The main clinical manifestations of schizophrenia include: positive symptoms such as delusions, hallucinations, disorganized thinking, and loss of control of speech and behavior, which occur in almost all schizophrenia patients but may alleviate over time; negative symptoms such as lack of motivation, social withdrawal, and anhedonia, which occur in about two-thirds of patients; and a third core symptom, cognitive deficits, which usually precede the positive and negative symptoms and often remain stable like the negative symptoms or worsen over time.

[0006] To date, the etiology of schizophrenia remains incompletely understood, with genetics likely playing a major role. Treatment remains primarily medication-based, including: first-generation typical antipsychotics such as chlorpromazine (a dopamine receptor antagonist), which alleviate positive symptoms but often cause extrapyramidal side effects; second-generation atypical antipsychotics such as olanzapine and risperidone, which have multiple receptor activities including dopamine and serotonin, which can simultaneously alleviate the three core symptoms but may cause metabolic and cardiovascular adverse reactions due to off-target effects; and third-generation atypical antipsychotics such as ibuprofen (a multi-target drug). Although third-generation drugs have improved in efficacy and safety, and typical and atypical antipsychotics can complement each other, the overall efficacy, especially for negative symptoms, remains unsatisfactory, characterized by significant adverse drug reactions, low drug response, poor adherence, and poor prognosis, with approximately 20-30% of patients exhibiting treatment resistance. Currently, antipsychotic drugs under clinical development not only target dopamine and serotonin receptor pathways, but also include those acting on glutamatergic, muscarinic acetylcholine receptors, nicotinic acetylcholine receptors, TAAR1 agonists, and PDE10A inhibitors. Drugs targeting new targets or employing new mechanisms may provide new medication options and personalized treatment plans for drug-resistant schizophrenia patients.

[0007] In summary, there is an urgent need in this field to develop a new class of drugs for treating mental illnesses with better efficacy and safety. Summary of the Invention

[0008] The purpose of this invention is to provide a new class of drugs for treating mental illnesses with better efficacy and safety.

[0009] In a first aspect of the invention, the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of mental illness is provided;

[0010] In another preferred embodiment, the mental illness is selected from the group consisting of depression, schizophrenia, or a combination thereof.

[0011] In another preferred embodiment, the mental illness is depression.

[0012] In another preferred embodiment, the depression is selected from the group consisting of: single-episode depressive disorder, recurrent depressive disorder, mood disorder, mixed depressive and anxiety disorder, premenstrual mood disorder, other specific depressive disorder, undefined depressive disorder, or a combination thereof.

[0013] In another preferred embodiment, the depression is major depressive disorder.

[0014] In another preferred embodiment, the mental illness is schizophrenia.

[0015] In another preferred embodiment, the symptoms of schizophrenia include one or more of positive symptoms, negative symptoms, and cognitive deficits.

[0016] In another preferred embodiment, the positive symptoms include one or more of delusions, hallucinations, confused thinking, and loss of control over speech and behavior.

[0017] In another preferred embodiment, the negative symptoms include one or more of the following: lack of motivation, social withdrawal, anhedonia, emotional dullness, poverty of speech, and apathy.

[0018] In another preferred embodiment, the dosage form of the drug is selected from the group consisting of oral dosage forms, injectable dosage forms, inhaled dosage forms, transdermal absorption dosage forms, or combinations thereof.

[0019] In another preferred embodiment, the dosage form of the drug is selected from the group consisting of: oral liquid, injection, sublingual tablet, tablet, capsule, pill, aerosol, granule, powder, suppository, sustained-release preparation, controlled-release preparation, nano-preparation, syrup, and transdermal absorption preparation.

[0020] In another preferred embodiment, the oral dosage form includes tablets, capsules, films, and / or granules.

[0021] In another preferred embodiment, the oral dosage form is a sustained-release dosage form or a non-sustained-release dosage form.

[0022] In another preferred embodiment, the medicament comprises 0.001-99 wt% (preferably 1-80 wt%) of a compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutical composition.

[0023] In another preferred embodiment, the dosage of the compound of formula (I) is 0.01 to 20 mg / kg body weight.

[0024] In another preferred embodiment, the application frequency is 1, 2, 3 or 4 times per day.

[0025] In another preferred embodiment, the total daily dose of the application is 0.04 to 2 mg / kg body weight.

[0026] In another preferred embodiment, when the mental illness is depression, the dosage of the compound of formula (I) is 0.04 to 2 mg / kg body weight.

[0027] In another preferred embodiment, when the mental illness is schizophrenia, the dosage of the compound of formula (I) is 0.04 to 2 mg / kg body weight.

[0028] In another preferred embodiment, the dosage refers to a human dosage.

[0029] In a second aspect of the invention, a pharmaceutical composition for treating or preventing mental illness is provided, comprising:

[0030] (a) A compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0031] and

[0032] (b) Pharmaceutically acceptable carriers.

[0033] In another preferred embodiment, the pharmaceutical composition further includes another medicament for treating or preventing mental illness.

[0034] In another preferred embodiment, the other drug for treating or preventing mental illness is selected from: antidepressants, antipsychotics, or combinations thereof.

[0035] In another preferred embodiment, the antidepressant is selected from the group consisting of: tricyclic and tetracyclic antidepressants, monoamine oxidase inhibitors, serotonin reuptake inhibitors, serotonin / norepinephrine reuptake inhibitors, norepinephrine / dopamine reuptake inhibitors, serotonin / dopamine activity modulators, drugs acting on serotonin receptors, drugs acting on glutamate receptors, drugs acting on γ-aminobutyric acid receptors, α2-adrenergic receptor antagonists, and melatonin agonists.

[0036] In another preferred embodiment, the antidepressant includes imipramine, amitriptyline, nortriptyline, protriptyline, doxepin, maprotiline, mianserin, amoxapine, lofepramine, amic acid, tianeptine, phenelzine, cyclophosphamide, toloxacin, maclobemide, fluvoxamine, fluoxetine, citalopram hydrobromide, sertraline, paroxetine, escitalopram, venlafaxine, duloxetine, venlafaxine, levamisole, antsofaxine, trazodone, mirtazapine, naphazodone, tandospirone citrate, reboxetine mesylate, quetiapine fumarate, vilazorone, vortioxetine, olanzapine, aripiprazole, epipiperazole, bupropion, sprotiline, agomelatine, esketamine, brinolone, and zuranolone.

[0037] In another preferred embodiment, the antipsychotic drug is selected from the group consisting of: dopamine receptor antagonists, dopamine D4 / 5-hydroxytryptamine receptor 2 antagonists, dopamine D2 / 5-hydroxytryptamine receptor 2A antagonists, dopamine D2 / D3 antagonists, and other serotonergic modulators.

[0038] In another preferred embodiment, the antipsychotic drug includes chlorpromazine, prochlorazine, chlorprothiazine, chlorprothiazine, flupentixol, tevothiazol, benziridone, sulpiride, pirimicarb, capiprapamine, sulpiride, verapapride, bromipride, remopride, amisulpride, clozapine, risperidone, olanzapine, quetiapine fumarate, ziprasidone, perropirone, bromelain, asenapine maleate, palapirone, ipraridone, lurasidone hydrochloride, cariprazine, aripiprazole, ipipiride, and rumepiride.

[0039] In another preferred embodiment, the mental illness is as defined above.

[0040] In a third aspect of the invention, a medicine box is provided, comprising:

[0041] (i) A drug containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as its active ingredient.

[0042] and

[0043] (ii) Instructions for use.

[0044] In another preferred embodiment, the specification states that the active ingredient is an active ingredient used to treat or prevent mental illness.

[0045] In another preferred embodiment, the specification also states that the dosage of the active ingredient is 0.01 to 20 mg / kg body weight.

[0046] In another preferred embodiment, the specification also states that the active ingredient is applied 1, 2, 3 or 4 times per day.

[0047] In another preferred embodiment, the specification also states that the total daily dose of the active ingredient is 0.04 to 2 mg / kg body weight.

[0048] In another preferred embodiment, the specification also states that when the mental illness is depression, the dosage of the active ingredient is 0.04–2 mg / kg body weight.

[0049] In another preferred embodiment, the specification also states that when the mental illness is schizophrenia, the dosage of the active ingredient is 0.04–2 mg / kg body weight.

[0050] In another preferred embodiment, the specification also states that the dosage refers to a human dosage.

[0051] In another preferred embodiment, the medicine box further includes: another medicine for treating or preventing mental illness.

[0052] In another preferred embodiment, the medicine box is used for the prevention or treatment of mental illness.

[0053] In another preferred embodiment, the other drug for treating or preventing mental illness and the mental illness are as defined above.

[0054] In a fourth aspect of the invention, a method for preventing or treating mental illness is provided, comprising the step of administering a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need;

[0055] In another preferred embodiment, the object includes: a human being, or a non-human mammal.

[0056] In another preferred embodiment, the non-human mammals include primates or rodents (such as mice, rats, etc.).

[0057] In another preferred embodiment, the method further includes administering a safe and effective amount of another drug used to treat or prevent mental illness.

[0058] In another preferred embodiment, the other drug for treating or preventing mental illness and the mental illness are as defined above.

[0059] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0060] Figure 1 shows the antidepressant effect of piengabine in the forced swimming test in mice. Data are expressed as mean ± standard error, with 8–10 animals per group. (a) Effect of a single gavage administration of piengabine on the time to stillness during forced swimming in mice, analyzed using a one-way ANOVA with Dunnett post-hoc multiple comparisons, compared with the solvent control group. * p<0.05, *** p<0.001; (b) The effect of a single gavage administration of piengabine on the number of forced swimming stillnesses in mice was analyzed using a one-way ANOVA with Dunnett post-hoc multiple comparisons, compared with the solvent control group. * p<0.05, *** p<0.001.

[0061] Figure 2 shows the effects of pengabin and XEN1101 on the depressive susceptibility phenotype in a mouse model of chronic social frustration stress. Data are expressed as mean ± standard error, with 8–18 animals per group. (ab) Effects of continuous intraperitoneal injection of pengabin and XEN1101 for 8 days on social interaction and sucrose preference in depressed mice in a chronic social frustration stress model. Unpaired t-tests and one-way ANOVA with Fisher's LSD test were used for analysis. Compared with the solvent control group, * p<0.05, ** p<0.01, *** p<0.001; (cf) The effects of continuous intraperitoneal injection of piengabine and XEN1101 for 12 days on social interaction, sucrose preference, and sucrose splashing in depressed mice in a chronic social frustration stress model were analyzed using unpaired t-tests and one-way ANOVA with Fisher's LSD test. * p<0.05, ** p<0.01, *** p<0.001, **** p<0.0001.

[0062] Figure 3 shows the effects of piongabin and XEN1101 on MK-801-induced hyperactivity in mice. Data are expressed as mean ± standard error, with 8–10 animals per group. (a) Effects of a single gavage administration of piongabin and XEN1101 on open field distance over time in MK-801-induced hyperactivity in mice, analyzed using a two-way repeated measures ANOVA with Bonferroni post-hoc multiple comparisons, compared to the solvent control group. **** p<0.0001; (b) Effects of single gavage administration of piengabine and XEN1101 on the total open field distance of MK-801-induced hyperactive mice, using unpaired t-tests and one-way ANOVA with Dunnett post-hoc multiple comparisons, compared with the solvent control group, *p<0.05, ** p<0.01, **** p<0.0001.

[0063] Figure 4 shows the effects of piongabin and XEN1101 on MK-801-induced social withdrawal behavior in mice. Data are expressed as mean ± standard error, with 7–11 animals per group. (a) Effects of a single gavage administration of piongabin and XEN1101 on the duration of intimate interaction during the social phase in MK-801-induced social withdrawal mice, analyzed using a two-way ANOVA with Bonferroni post-hoc multiple comparisons, compared with the solvent control group. * p<0.05, ** p<0.01, *** p<0.001, **** p<0.0001; (b) Effects of single gavage administration of piengabine and XEN1101 on the social index of MK-801-induced social withdrawal mice, analyzed by unpaired t-test and one-way ANOVA with Fisher's LSD test, compared with the solvent control group, ** p<0.01; (c) Effects of single gavage administration of piengabine and XEN1101 on the intimate interaction time during the novelty phase of MK-801-induced social withdrawal mice, using a two-way Bonferroni post-hoc multiple comparison analysis, compared with the solvent control group, * p<0.05; (d) The effect of a single gavage administration of piengabine and XEN1101 on the novelty index of MK-801-induced social withdrawal mice was analyzed using unpaired t-tests and one-way ANOVA with Fisher's LSD test. Compared with the solvent control group, * p<0.05, ** p<0.01. Detailed Implementation

[0064] Through extensive and in-depth research, the inventors unexpectedly discovered that piengabine (i.e., compound (I)) with a unique structure (such as an alkynyl group) exhibits excellent therapeutic and preventative effects in multiple animal models of mental illness. In particular, compared to other compounds targeting the same target (such as retigabine and XEN1101), the compound of this application demonstrates comparable or even superior antidepressant and antipsychotic effects in the same models at significantly lower dosages, making it suitable for developing drugs for treating mental illnesses. Furthermore, piengabine possesses a higher safety profile and safety window, making it highly suitable for developing antipsychotic drugs that typically require long-term administration. Based on these findings, the inventors completed this invention.

[0065] the term

[0066] In this invention, unless otherwise specified, the abbreviations have the conventional meanings understood by those skilled in the art.

[0067] Active ingredients

[0068] As used in this invention, the terms “compound of the invention,” “pyngabine,” “compound of formula (I),” and “compound of formula (I)” are used interchangeably to refer to the compound represented by formula (I) (i.e., methyl 4-(N,N-p-fluorobenzyl-propargyl)amino-2,6-dimethylanilinecarbamate), and the term also includes various crystal forms of compounds of formula (I), pharmaceutically acceptable salts, etc.

[0069] The term "pharmaceutically acceptable salt" refers to a salt formed by the compound of the present invention with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include both inorganic and organic salts. A preferred class of salts are those formed by the compound of the present invention with an acid. Suitable acids for salt formation include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

[0070] Piangabine is a small molecule compound currently being developed in China for the treatment of epilepsy. Its Chinese patents (ZL201110328036.9 and ZL201410175315.X) and PCT patents (WO2013060097 and WO2015165352) have been published regarding its role as a KCNQ potassium channel agonist, its preparation method, and its uses. The entire contents of these patents are hereby incorporated by reference.

[0071] The purpose of this invention is to provide new uses for piengabine in the preparation of antipsychotic drugs. One specific purpose is to provide new uses for piengabine or pharmaceutically acceptable salts thereof in the preparation of antidepressant drugs. Another purpose is to provide new uses for piengabine or pharmaceutically acceptable salts thereof in the preparation of antischizophrenia drugs.

[0072] In some aspects, the use of pengabin in the preparation of medicaments for the treatment and / or prevention of depression is provided. Preferably, the depression is a single-episode depressive disorder, recurrent depressive disorder, mood disorder, mixed depression and anxiety disorder, premenstrual mood disorder, other specific depressive disorders, or undefined depressive disorder. Preferably, the depression treated and / or prevented by pengabin is major depressive disorder.

[0073] In some aspects, the use of piengabine in the preparation of medicaments for the treatment and / or prevention of schizophrenia is provided. Preferably, the symptoms of said schizophrenia are positive symptoms, negative symptoms, and cognitive deficits. Preferably, piengabine treats and / or prevents the improvement of positive symptoms in patients with schizophrenia. Preferably, piengabine treats and / or prevents the improvement of negative symptoms in patients with schizophrenia.

[0074] In some aspects, a class of pharmaceutical compositions is provided, wherein the active ingredient comprises piengabine or a pharmaceutically acceptable salt thereof and excipients or derivatives thereof. Preferably, the pharmaceutical composition is used in the preparation of medicaments for the treatment and / or prevention of mental illnesses. Preferably, the mental illnesses treated and / or prevented by the pharmaceutical composition are depression and schizophrenia.

[0075] In this invention, the dosage form of the drug, drug composition, or drug preparation is not particularly limited, including oral liquid, injection, sublingual tablet, tablet, capsule, pill, aerosol, granule, powder, suppository, sustained-release agent, controlled-release agent, nano-formulation, syrup, and transdermal absorption preparation.

[0076] In this invention, the drug, drug composition, or drug preparation is administered via one or more of the following methods: oral administration, sublingual administration, subcutaneous injection, intramuscular injection, intravenous injection, spray administration, skin application, intralesional or intracerebral delivery, or implantation.

[0077] In the above applications, the dosage of paengabin administered to subjects is usually 0.5-1000 mg per administration, preferably 2-100 mg. The specific dosage is determined by a combination of factors, including the patient's gender, age, weight, condition, and tolerance, and a skilled clinician selects the appropriate prescription based on actual needs.

[0078] In some implementations, when pinegabine is used to treat or prevent mental illnesses as described above, the required dose (total daily dose or frequency of administration) is less than that of retigabine and XEN1101.

[0079] In some implementations, when pengabin is used to treat or prevent mental illnesses as described above, the probability or severity of side effects is less than that of retigabine and XEN1101.

[0080] Pharmaceutical Compositions and Administration

[0081] Because the compounds of the present invention exhibit excellent antipsychotic effects (such as antidepressant or antischizophrenic) in animal models, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, and pharmaceutical compositions or drugs containing the compounds of the present invention as the main active ingredient can be used to treat, prevent, and / or alleviate mental illnesses (such as depression and schizophrenia). In some embodiments, the depression is a single-episode depressive disorder, recurrent depressive disorder, mood disorder, mixed depression and anxiety disorder, premenstrual mood disorder, other specific depressive disorder, undefined depressive disorder, or a combination of the above. In other embodiments, the depression is major depressive disorder. In some embodiments, the symptoms of schizophrenia include positive symptoms, negative symptoms, and cognitive deficits. In other embodiments, the schizophrenia includes one or more symptoms selected from the group consisting of: (1) positive symptoms such as delusions, hallucinations, disorganized thinking, and loss of control of speech; (2) negative symptoms such as lack of motivation, social withdrawal, anhedonia, emotional blunting, poverty of speech, and apathy; and (3) cognitive deficits.

[0082] The pharmaceutical compositions, drugs, or formulations of the present invention comprise, within a safe and effective range, a compound of the present invention (compound of formula I) or a pharmacologically or pharmaceutically acceptable salt thereof. The pharmaceutical compositions of the present invention may also include other drugs for treating mental illnesses (such as antidepressants or antipsychotics). The pharmaceutical compositions of the present invention may also include pharmacologically or pharmaceutically acceptable excipients or carriers.

[0083] "Safe and effective dose" means that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 0.5-1000 mg of the compound of the present invention per dose, more preferably, 2-100 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0084] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0085] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention, and they can be administered to the desired subjects (such as humans and non-human mammals) in a conventional manner. Representative administration methods include (but are not limited to): oral, injection (such as intravenous, intramuscular, or subcutaneous), and inhalation (such as nebulized inhalation).

[0086] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain a buffer. Solid dosage forms such as tablets, sugar pills, capsules, pills, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound in such a composition may be delayed in a portion of the digestive tract (i.e., a sustained-release formulation). Examples of encapsulating components that may be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0087] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0088] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0089] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0090] Compositions for injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0091] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0092] When using the pharmaceutical composition of the present invention, a safe and effective amount of the drug is administered to mammals (such as humans or non-human mammals), wherein the safe and effective amount is generally at least about 10 micrograms per kilogram of body weight, and in most cases does not exceed about 20 milligrams per kilogram of body weight (daily). Preferably, the dose is about 10 micrograms per kilogram of body weight to about 10 milligrams per kilogram of body weight, more preferably, 0.04 to 2 mg / kg of body weight, and most preferably, 0.1 to 0.5 mg / kg of body weight. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skill of a skilled physician.

[0093] The main advantages of this invention include:

[0094] (a) The compounds of the present invention have been verified in animal models to have significantly improved antidepressant and antischizophrenic effects.

[0095] (b) The compounds of the present invention have been shown by examples to have significantly improved safety.

[0096] Specifically, this invention evaluated the antidepressant and antischizophrenic effects of piengabine using a mouse forced swimming model, a chronic social frustration stress model, and an MK-801-induced hyperactivity and social withdrawal model. Administration methods included oral prophylactic administration and multiple intraperitoneal injections for therapeutic administration. Simultaneously, the acute neurotoxicity of intraperitoneal administration of piengabine was assessed using a rotarod test. Results showed that piengabine had antidepressant effects in both acute and chronic models of depression, and also significantly improved positive and negative symptom behaviors in a mouse model of schizophrenia. Its efficacy was superior to that of retigabine and XEN1101, which target the same drug. Furthermore, piengabine exhibited weaker acute neurotoxicity in the mouse rotarod test than XEN1101, indicating a longer safety window and suggesting promising potential for the treatment and / or prevention of mental illnesses.

[0097] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions, such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0098] Example 1: Forced Swimming Experiment in Mice

[0099] The forced swimming test is a behavioral despair model that simulates human behavior and is often used as a primary screening method for antidepressants. This study used the forced swimming test in mice to detect the antidepressant effect of a single oral dose of piengabine.

[0100] Laboratory animals: Male ICR mice, weighing 20-22g at the time of testing, purchased from Shanghai Shengchang Biotechnology Co., Ltd., animal qualification certificate number 20210002006466. Five animals were housed per cage in a standard SPF-grade room with free access to food and water. Testing was conducted after 3 days of environmental acclimatization. The testing procedure was approved by the Institutional Animal Care and Use Committee (IACUC) of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, IACUC approval number 2023-02-GZB-16.

[0101] Preparation of compounds and reagents: Piangabine and retigabine were synthesized in-house according to methods published in the prior art, with purities (HPLC) of 99.49% and 99.57%, respectively; the reference drug imipramine was purchased from MedChemExpress (MCE), USA, with a purity (LCMS) of 99.90%. The formulations of the solvents for pimgabine, retigabine, and the reference solvent were 0.5% sodium carboxymethyl cellulose (CMC-Na) aqueous solution, while the solvent for imipramine was physiological saline. All percentages are volume percentages. The compounds were freshly prepared on the day of administration.

[0102] The structure of retigabin is as follows:

[0103] Forced swimming test: Animals in the oral administration group were fasted for 8 hours before administration. Before the experiment, animals were administered the control solvent, pirengabin at doses of 1 mg / kg and 3 mg / kg, and the control drug retigabine at dose of 30 mg / kg via oral gavage (po), and the traditional antidepressant imipramine at dose of 30 mg / kg via intraperitoneal injection (ip), with an administration volume of 20 ml / kg. Forced swimming was tested 60 minutes after oral administration and 30 minutes after intraperitoneal administration. Mice were placed in a 25 cm high transparent glass cylinder with a water level of approximately 10 cm and a water temperature maintained between 23 and 25°C. The entire 6-minute swimming experiment was video-recorded using the ANYmaze video analysis system, and the subsequent 4-minute stillness time and number of stillnesses were recorded.

[0104] Statistical analysis: Data processing and graphing were performed using GraphPad Prism 8.0.2 software. Data are expressed as mean ± standard error. One-way ANOVA was used to compare the data with the solvent control group, and p < 0.05 was considered statistically significant.

[0105] Experimental Results: The results are shown in Figure 1. Compared with the solvent control group, intraperitoneal injection of the antidepressant imipramine at a dose of 30 mg / kg significantly reduced the resting time and number of resting episodes in forced swimming mice (P = 0.0003; P = 0.0019); while oral administration of 30 mg / kg retigabine had no effect on the resting time and number of resting episodes in mice (P = 0.8792; P = 0.5388); when piengabine was administered orally at doses of 1 mg / kg and 3 mg / kg, the 3 mg / kg dose significantly shortened the resting time and number of resting episodes in forced swimming mice (P = 0.0442; P = 0.0455). These results indicate that piengabine has a dose-dependent antidepressant effect in the acute forced swimming model in mice.

[0106] Example 2 Evaluation of a mouse model of chronic social frustration stress

[0107] Social stress is one of the most critical factors in the pathogenesis of depression in humans. The chronic social defeat stress (CSDS) model, exhibiting two subtypes—susceptibility and resilience—effectively mimics different individual responses to stress and is frequently used in studies of depression-related mechanisms and the evaluation of antidepressants. Research has found that compared to mice with a CSDS-prone depression phenotype, stress-resilient mice showed upregulated Kv7.3 expression in the ventral tegmental area (VTA), and viral Kv7.3 expression in the VTA reversed the depressive susceptibility phenotype and its hyperexcitability in this model. Therefore, this study used a chronic social defeat stress model in depressed-susceptible mice to evaluate the antidepressant effect of piengabine administered via multiple intraperitoneal injections.

[0108] Laboratory animals: 7-8 week old male C57BL / 6J mice and retired male CD1 mice were purchased from Shanghai Shengchang Biotechnology Co., Ltd. and Beijing Huafukang Biotechnology Co., Ltd., respectively. The first batch animal qualification certificate numbers were 20210002007535, 20210002007592, and NO.110322241101083553, respectively. The second batch animal qualification certificate numbers were 20210002008517 and NO.110322241102290371, respectively. Animals were housed in a standard SPF-grade room with free access to food and water. Five C57BL / 6J mice were housed per cage, and CD1 mice were housed individually. After acclimatization, the animals underwent screening for aggressive mice, construction of a chronic social frustration stress model, and drug evaluation. All animal procedures were approved by the IACUC, approval number 2024-03-GZB-19.

[0109] Preparation of compounds and reagents: Piangabine, Retigabine, and XEN1101 were synthesized in-house according to methods published in the prior art, with purities (HPLC) of 99.13%, 99.57%, and 98.82%, respectively. The control drug, S-ketamine (esketamine hydrochloride injection, specification 2ml:50mg / vial, national drug approval number H20193336), was purchased from Shanghai Pharmaceuticals Holding Co., Ltd. The solvent formulations for Piangabine, Retigabine, XEN1101, and the control were all 5% dimethyl sulfoxide (DMSO) / 95% 1% Tween-80 (prepared with physiological saline). S-ketamine injection was diluted with physiological saline. All percentages are volume percentages. All compounds were freshly prepared on the day of administration.

[0110] The structure of XEN1101 is as follows:

[0111] Establishment of the CSDS model and evaluation of compounds: First, aggressive CD1 mice were individually housed to develop territorial awareness. After one week, C57BL / 6J mice were used for selection. Different C57BL / 6J mice were placed in the CD1 mouse cages for 5 minutes daily, and the attack latency of the CD1 mice was recorded. This process was repeated for three consecutive days to select qualified CD1 attack mice. Then, the C57BL / 6J mice were placed in different CD1 attack mouse cages (separated by a perforated transparent plate) daily for 10 days of social frustration stress. During each stress test, the mice were attacked on the CD1 mouse side for 5-10 minutes before being placed on the other side for 24 hours of isolation. The blank control group consisted of CD1 mice replaced with another C57BL / 6J mouse, with all other procedures the same. All animals maintained normal food and water intake during the stress period. Twenty-four hours after the last stress test, social interaction tests were performed on the stressed mice to identify depressive susceptibility and resilience phenotypes.

[0112] Susceptible mice selected through screening were randomly assigned to groups for compound evaluation. In the first batch of experiments, the blank control group and the control solvent group received intraperitoneal injections once daily, while the pengabin and XEN1101 dosage groups received intraperitoneal injections of 0.3 mg / kg once daily for 8 consecutive days. Social interaction and sucrose preference tests were then performed. The control drug, S-ketamine, was administered intraperitoneally at a dose of 20 mg / kg once 24 hours prior to the tests. In the second batch of experiments, the blank control group and the control solvent group received intraperitoneal injections once daily, while the pengabin 0.1 and 0.5 mg / kg, XEN1101 0.5 mg / kg, and retigabine 1 mg / kg dosage groups received intraperitoneal injections once daily for 12 consecutive days. Social interaction, sucrose preference, and sucrose splash tests were then performed. All drug administration volumes were 20 ml / kg.

[0113] Social interaction test: Used to detect whether animals exhibit social avoidance behavior. The ANYmaze video tracking system was used to record the time mice spent in the social interaction area and the time spent in the corner area under conditions of presence of aggressive mice (targeted) and absence of aggressive mice (no target), with each test lasting 2.5 minutes. The social interaction ratio (SI ratio) was further calculated based on the social interaction time: SI ratio = Social interaction time (with target) / Social interaction time (without target). Mice with chronic social frustration stress had an SI value less than 1, indicating a susceptible phenotype; mice with an SI value greater than 1 were considered to have a resilient phenotype.

[0114] Sugar water preference test: Used to detect whether animals experience anhedonia. Animals are housed individually, with two identical water bottles containing drinking water and 1% sucrose solution placed in the cage. Animals are first acclimatized to the sugar water; after 24 hours, the bottle positions are switched for another 24 hours of acclimatization. Then, water is withheld for 24 hours before the sugar water preference test begins. The water bottles containing drinking water and 1% sucrose solution are weighed before and after the 4-hour test. The bottle positions are switched 2 hours in between to prevent positional preference. The sugar water preference rate (%) is calculated as: (Sucrose water consumption / (Drinking water consumption + Sucrose water consumption)) × 100%.

[0115] Sucrose splash test: used to detect animal motivation and self-care behavior. Animals were individually acclimatized to the environment for at least half an hour before the test. During the test, a 10% sucrose solution was sprayed onto the fur on the back of the mice using a spray bottle. The mice's grooming behavior, including licking, scratching, and / or face-washing, was recorded on video. The start time and total grooming time within 5 minutes after sucrose spraying were recorded.

[0116] Statistical analysis: Data processing and graphing were performed using GraphPad Prism 8.0.2 software. Data are expressed as mean ± standard error. Unpaired t-tests were used to compare the model solvent control group with the blank control group, and one-way ANOVA was used to compare the drug-treated group with the solvent control group. p < 0.05 was considered statistically significant.

[0117] Experimental results: The results are shown in Figure 2. When mice with a chronic social frustration stress model were administered the drug via intraperitoneal injection once daily for 8 consecutive days, compared with the blank control group, susceptible mice in the solvent control group had lower social interaction rates and sucrose preference rates (P = 0.0006, P = 0.0212). Compared with the solvent control group, a single intraperitoneal injection of the positive control drug S-ketamine at 20 mg / kg significantly increased the social interaction rate and sucrose preference rate of susceptible mice (P = 0.0074, P = 0.0261). Continuous administration of the control drug XEN1101 at a dose of 0.3 mg / kg for 8 days did not significantly increase the social interaction rate and sucrose preference rate of susceptible mice (P = 0.3647, P = 0.1152). While continuous administration of the same dose of 0.3 mg / kg for 8 days did not increase the social interaction rate of susceptible mice (P = 0.5839), it did have a certain effect on increasing the sucrose preference rate of susceptible mice (P = 0.0615). When the administration period was extended to 12 days, the results showed that, compared with the blank control group, susceptible mice in the solvent control group still had lower social interaction rates and sucrose preference rates (P = 0.0077, P = 0.0176), and longer grooming latency and shorter grooming time in the sucrose splash test (P = 0.0064, P < 0.0001). Continuous administration of the control drug retigabine at a dose of 1 mg / kg for 12 days did not significantly improve the social interaction rate and sucrose preference rate in susceptible mice (P = 0.9496, P = 0.8454), but it significantly shortened the grooming latency and prolonged the grooming time in susceptible mice (P = 0.0031, P = 0.0335). Another control drug, XEN1101, administered at a dose of 0.5 mg / kg for 12 consecutive days, had no effect on the social interaction rate of susceptible mice, but showed a trend of increasing the sugar water preference rate (P = 0.6676, P = 0.0692). This drug also improved the grooming behavior of susceptible mice, that is, shortened the grooming latency and prolonged the grooming time (P = 0.0072, P = 0.0006). Administering 0.1 mg / kg and 0.5 mg / kg of pinenabine for 12 consecutive days showed that the 0.1 mg / kg dose group did not significantly improve the social interaction rate and sucrose preference rate in susceptible mice (P = 0.2013, P = 0.4714), but it significantly improved the grooming behavior of susceptible mice (P = 0.0051, P = 0.0006). The 0.5 mg / kg dose group not only significantly improved the grooming behavior of susceptible mice (P = 0.0006, P < 0.0001), but also significantly improved the social interaction rate and sucrose preference rate of susceptible mice (P = 0.0125, P = 0.0098).The results showed that mice susceptible to chronic social frustration stress exhibited typical depressive-like behaviors, namely significant social failure, anhedonia, and reduced motivation and self-care behaviors. Administration of sufficient doses and duration of piengabine completely reversed the depressive symptoms in susceptible mice, demonstrating a stronger antidepressant effect than retigabine and XEN1101. Furthermore, because the compounds of this application showed significant alleviating effects on core symptoms such as anhedonia in this chronic social frustration stress model, the compounds of this application possess therapeutic potential for major depressive disorder.

[0118] Example 3 Evaluation of the MK-801-induced hyperactive mouse model

[0119] MK-801 is a selective and non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist. Administration of different doses of MK-801 can induce typical positive, negative, and cognitive impairment symptoms of schizophrenia in animals, and this model is currently one of the widely used pharmacological models in schizophrenia research. This study used an acute administration of MK-801 at a dose of 0.3 mg / kg to induce a hyperactive mouse model to detect the effect of a single oral dose of piengabine.

[0120] Experimental animals: Male C57BL / 6J mice, weighing 22-26g at the time of testing, purchased from Shanghai Shengchang Biotechnology Co., Ltd., with animal qualification certificate numbers 20210002008973 and 20210002009582. Five animals were housed per cage in a standard SPF-grade room with free access to food and water. The testing procedure was approved by IACUC under the same approval number as in Example 2.

[0121] Preparation of compounds and reagents: Piangabine and XEN1101 were sourced from the same sources as in Example 2; the control drug, chlorpromazine hydrochloride, was purchased from MCE Pharmaceuticals, USA, with a purity (LCMS) of 99.90%; dizopine maleate (MK-801) was purchased from MCE Pharmaceuticals, USA, with a purity (HPLC) of 99.9%. The solvents for MK-801 and chlorpromazine hydrochloride were physiological saline. The solvent formulations for pyengabine, XEN1101, and the control were all 0.5% CMC-Na aqueous solution. All percentages are volume percentages. Compounds and reagents were freshly prepared on the day of administration.

[0122] Spontaneous Activity Test: Animals in the oral administration group were fasted for 8 hours before administration. Prior to the experiment, animals were administered the control solvent, pyrenegade 1 mg / kg and 3 mg / kg, and XEN1101 3 mg / kg and 8 mg / kg orally via gavage, and the antipsychotic drug chlorpromazine 0.5 mg / kg via intraperitoneal injection (administration volume 20 ml / kg). Spontaneous activity in an open field (40 cm x 40 cm) was tested for 1 hour using the ANYmaze video tracking system 30 minutes after oral administration and 15 minutes after intraperitoneal administration. The change in animal movement distance over time and the total movement distance over 1 hour were recorded.

[0123] Statistical analysis: Data processing and graphing were performed using GraphPad Prism 8.0.2 software. Data are expressed as mean ± standard error. The changes in movement distance over time for each group were analyzed using two-way repeated measures ANOVA. Differences in total movement distance were analyzed using unpaired t-tests and one-way ANOVA. p < 0.05 was considered statistically significant.

[0124] Experimental Results: The results are shown in Figure 3. When MK-801 was administered intraperitoneally at a dose of 0.3 mg / kg, from 15 minutes after administration until 1 hour later, the animals exhibited consistently active spontaneous movement. Both the time-varying distance and the total distance moved were significantly increased compared to the blank control group (P<0.0001; P<0.0001). Intraperitoneal injection of 0.5 mg / kg of the positive control drug chlorpromazine 15 minutes prior to administration significantly reduced MK-801-induced hyperactivity, as evidenced by a significant reduction in both time-varying distance and total distance compared to the solvent control group (P<0.0001; P=0.0180). Oral administration of the control drug XEN1101 (3 mg / kg and 8 mg / kg doses) 30 minutes prior to administration significantly inhibited MK-801-induced hyperactivity at the 8 mg / kg dose (P<0.0001; P=0.0080), while the 3 mg / kg dose had no effect (P=0.9997; P=0.9999). Similarly, oral administration of 1 mg / kg and 3 mg / kg of paengabine 30 minutes prior to administration significantly inhibited MK-801-induced hyperactivity at both dose levels (P<0.0001, P=0.0465; P<0.0001, P=0.0030). The results showed that piengabin significantly inhibited the hyperactivity induced by MK-801 in mice, and its efficacy was stronger than that of the control drug XEN1101.

[0125] Example 4 Evaluation of the MK-801-induced social withdrawal mouse model

[0126] This study used an acute administration of MK-801 at a dose of 0.1 mg / kg to induce a social withdrawal mouse model in order to test the effect of a single oral administration of pengabin.

[0127] Experimental animals: Male C57BL / 6J mice, weighing 22-24g at the time of testing, purchased from Shanghai Shengchang Biotechnology Co., Ltd., with animal qualification certificate numbers 20210002009582 and 20210002009816. Animal husbandry and IACUC approval numbers are the same as in Example 3.

[0128] Compound and reagent preparation: The sources and preparation methods of piengabin, XEN1101, and MK-801 were the same as in Example 3. The positive control drug risperidone was purchased from MCE Pharmaceuticals, USA, with a purity (LCMS) of 99.92%, and the solvent formulation was 5% DMSO / 5% Tween-80 / 90% physiological saline. The control solvent formulation was 0.5% CMC-Na aqueous solution. All percentages are volume percentages. All compounds were freshly prepared on the day of administration.

[0129] The three-chamber social test: This method is currently widely used to assess social interaction behavior in rodents. The test is conducted in a rectangular plexiglass box (60 cm x 40 cm x 20 cm, divided into three chambers by two partitions with small doors). Animals in the oral administration group were fasted for 8 hours before administration. Before the test, animals were administered the control solvent, pirengabine 1 and 3 mg / kg, and the control drug XEN1101 3 and 8 mg / kg orally via gavage, respectively. Then, they were administered MK-801 0.1 mg / kg intraperitoneally. Another positive control group received risperidone 0.05 mg / kg intraperitoneally 15 minutes before MK-801 administration. The blank control group received only saline. The administration volume was 20 ml / kg for all tests. Animals were placed in the test chamber 10 minutes after MK-801 administration. The test was conducted in three phases: adaptation, socialization, and novelty. In the adaptation phase, empty wire cages were placed in both left and right chambers. In the socialization phase, a new mouse of the same sex and age (S1) was placed in one cage on one side. In the novelty phase, another new mouse of the same sex and age (S2) was placed on the other side. For each phase, mice were first placed in the middle chamber and then allowed to freely explore all chambers for 10 minutes. The activity time of the mice in both chambers and their interaction time with the cages were recorded using the ANYmaze video tracking system. The Social Index (SI) for the socialization phase and the Novel Index (NI) for the novelty phase were calculated: SI = (Interaction time with new mouse S1) / (Interaction time with new mouse S1 + Interaction time with the empty cage); NI = (Interaction time with new mouse S2) / (Interaction time with new mouse S2 + Interaction time with new mouse S1).

[0130] Statistical analysis: Data processing and graphing were performed using GraphPad Prism 8.0.2 software. Data are expressed as mean ± standard error. Intimate interaction time was analyzed using two-way ANOVA, while social index and novelty index were analyzed using unpaired t-test and one-way ANOVA. p < 0.05 was considered statistically significant.

[0131] Experimental Results: The results are shown in Figure 4. During the social phase, the interaction time between the blank control group mice and the unfamiliar mouse S1 was significantly longer than their interaction time with the empty wire cage (P = 0.0002), while there was no significant difference in the interaction time between the solvent control group mice and the unfamiliar mouse S1 and the empty wire cage (P = 0.9266). During the social novelty phase, there was no significant difference in the interaction time between the blank control group mice and the unfamiliar mouse S1 (P > 0.9999), while the interaction time between the solvent control group mice and the unfamiliar mouse S2 was significantly shorter than their interaction time with the unfamiliar mouse S1 (P = 0.0402). Comparison of the social index and novelty index revealed that both were significantly lower in the solvent control group than in the blank control group (P = 0.0023, P = 0.0005). These results indicate that acute administration of 0.1 mg / kg MK-801 can induce social withdrawal behavior in animals. Fifteen minutes before administration of MK-801, 0.05 mg / kg of the antipsychotic drug risperidone was administered via intraperitoneal injection. Three out of ten mice experienced sedation as a side effect, meaning they did not engage in any spontaneous exploration activities and were therefore excluded from the statistical analysis. Further analysis revealed that risperidone significantly increased the time of close interaction between the model mice and the unfamiliar mouse S1 during the social phase (P = 0.0021), but did not significantly decrease the time of close interaction between the model mice and the unfamiliar mouse S2 (P = 0.7102). It significantly increased the social index and novelty index (P = 0.0037, P = 0.0084), thus improving social withdrawal in mice. Another control drug, XEN1101, was administered orally at doses of 3 and 8 mg / kg. One mouse in the high-dose group was sedated and was not included in the statistical analysis. The results showed that the 8 mg / kg dose significantly increased the time of close interaction with the unfamiliar mouse S1 during the social phase of the model mice (P<0.0001) but did not decrease the time of close interaction with the unfamiliar mouse S2 (P>0.9999). It also significantly improved the social index and novelty index of the animals (P=0.0057, P=0.0468), while the 3 mg / kg dose group had no significant changes in the above indicators. Oral administration of 1 mg / kg and 3 mg / kg of paengabine significantly increased the time spent in close interaction with stranger mice S1 during the social phase of the model mice (P = 0.0442, P < 0.0001) but did not decrease the time spent in close interaction with stranger mice S2 (P > 0.9999, P > 0.9999). The 1 mg / kg dose showed a trend of increasing both the social index and the novelty index (P = 0.0721, P = 0.1771), while the 3 mg / kg dose significantly increased both of these indicators (P = 0.0102, P = 0.0258). These results indicate that paengabine significantly improves MK-801-induced social withdrawal behavior in mice, and its efficacy is superior to the control drug XEN1101.

[0132] Example 5: Mouse rotarod test

[0133] The rotarod test is used to assess the balance and motor coordination of animals and is one of the commonly used detection methods for evaluating acute neurotoxicity. In this study, the mouse rotarod test was used to evaluate the behavioral tolerance of pengabin and XEN1101.

[0134] Experimental animals: Male C57BL / 6J mice, weighing 22-26g at the time of testing, purchased from Shanghai Shengchang Biotechnology Co., Ltd., animal qualification certificate number 20210002007282. Animal husbandry and IACUC approval number are the same as in Example 3.

[0135] Compound and reagent preparation: The sources and preparation methods of pimgabine and XEN1101 are the same as in Example 2. The control solvent was formulated as a 5% DMSO / 95% (1% Tween-80) solution. All percentages are volume percentages. The compounds were freshly prepared before administration.

[0136] Rotary test: The diameter of the rotundum used was 3 cm, and the rotation speed was set to 6 rpm. Animals were administered the control solvent, pirengabine (1–20 mg / kg), and the control drug XEN1101 (1–10 mg / kg) via intraperitoneal injection (ip), respectively, at a volume of 20 ml / kg. The rotundum test was performed 30 minutes after administration. If an animal fell off the rotundum three times consecutively within a 1-minute test time, it was considered that the animal's balance and motor coordination were impaired, and the number of animals with motor impairment was recorded.

[0137] Statistical analysis: Data processing and statistical analysis were performed using GraphPad Prism 8.0.2 and SPSS 16.0 software. Data were expressed as the ratio of the number of animals with impaired motor function to the total number of test animals, thus obtaining the ratio of animals with impaired motor function. The median neurotoxic dose (TD) of the drug was calculated using a nonlinear regression curve. 50 The corresponding 95% confidence interval (95% CI) was used to compare the values ​​with the control solvent group. Fisher's exact test was used, and p < 0.05 indicated a significant difference.

[0138] Experimental Results: The results of the rotundus test are shown in Table 1. In the solvent control group, none of the animals fell off the rotundus. However, in the groups receiving intraperitoneal injections of different doses of piengabin and the control drug XEN1101, the proportion of animals with impaired movement increased with increasing dosage. The minimum intraperitoneal injection doses of piengabin and XEN1101 that caused animals to fall off the rotundus were 5 mg / kg (3 / 11) and 3 mg / kg (3 / 10), respectively. Further calculations of the TD (Total Displacement) values ​​for both drugs were performed. 50The dosages were 6.5 (6.1-7.1) mg / kg and 4.2 (3.5-5.3) mg / kg, respectively. The results showed that, under intraperitoneal administration, piengabine caused less motor impairment in mice than the control drug XEN1101. Based on previously disclosed oral and intraperitoneal administration results for piengabine and XEN1101, oral administration would provide better safety than intraperitoneal administration. Combining the efficacy results from intraperitoneal and oral administration, it is indicated that the safety window of piengabine is significantly longer than that of the control drug XEN1101.

[0139] Table 1. Results of piengabin and control drug XEN1101 in mouse rotarod assay

[0140] Compared with the solvent control group, Fisher's exact test showed *p<0.05, **p<0.01.

[0141] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of mental illness.

2. The use as described in claim 1, characterized in that, The mental illnesses mentioned are selected from the following group: depression, schizophrenia, or a combination thereof.

3. The use as described in claim 1, characterized in that, The mental illness mentioned is depression.

4. The use as described in claim 2 or 3, characterized in that, The depression referred to is selected from the following group: single-episode depressive disorder, recurrent depressive disorder, mood disorder, mixed depressive and anxiety disorder, premenstrual mood disorder, other specific depressive disorder, undefined depressive disorder, or a combination thereof.

5. The use as described in claim 2 or 3, characterized in that, The depression mentioned is severe depression.

6. The use as described in claim 2, characterized in that, The mental illness mentioned is schizophrenia.

7. The use as described in claim 2 or 6, characterized in that, The symptoms of schizophrenia include one or more of the following: positive symptoms, negative symptoms, and cognitive deficits.

8. The use as described in claim 7, characterized in that, The positive symptoms include one or more of the following: delusions, hallucinations, confusion, and loss of control over speech and behavior; and / or, The negative symptoms include one or more of the following: lack of motivation, social withdrawal, anhedonia, emotional dullness, poverty of speech, and apathy.

9. The use as described in any one of claims 1, 2, 3 or 6, characterized in that, The dosage form of the drug is selected from the following group: oral dosage form, injection dosage form, inhalation dosage form, transdermal absorption dosage form, or a combination thereof.

10. The use as described in claim 1, characterized in that, The drug comprises 0.001-99 wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the total weight of the pharmaceutical composition.

11. The use as described in claim 1, characterized in that, The dosage of the compound of formula (I) is 0.01–20 mg / kg body weight; and / or, The application frequency is 1, 2, 3, or 4 times per day; and / or, The total daily dose of the application is 0.04–2 mg / kg body weight.

12. A pharmaceutical composition for treating or preventing mental illness, characterized in that, include: (a) A compound of formula (I) or a pharmaceutically acceptable salt thereof. and (b) Pharmaceutically acceptable carriers.

13. A medicine box, characterized in that, include: (i) A drug containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as its active ingredient. and (ii) Instructions for use.

14. A method for preventing or treating a mental illness, comprising the steps of: administering to a subject a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof;

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