Lumepirone derivative as well as preparation method and application thereof

Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to a rumepirone long-acting ester derivative or salt thereof, a preparation method thereof, a pharmaceutical composition thereof and an application of the rumepirone long-acting ester derivative or salt thereof. The derivative of the lumepirone long-acting ester is shown as a formula I, wherein n is an integer from 4 to 14. The invention further relates to a preparation method of the compound shown in the formula I and application of a pharmaceutical preparation of the compound in preparation of drugs for treating mood disorders, sleep disorders, psychotic disorders, excitement and agonism, mental movement states including excitement disorders, behavioral disorders and / or cognitive disorders. The compound provided by the invention has a remarkable long-acting characteristic and ideal pharmaceutical technical properties.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to a lumepirozol derivative or its salt, its preparation method, its pharmaceutical composition, and its uses. Background Technology

[0002] Schizophrenia is a common chronic and severe mental illness with an unknown etiology. 64% of patients can control their condition with medication, significantly reducing the relapse rate; therefore, drug therapy is currently the first-line treatment for schizophrenia. Most second-generation antipsychotics have advantages in safety and tolerability, but they carry greater risks related to metabolic syndrome, especially with more effective medications. Furthermore, current schizophrenia treatments primarily improve positive symptoms; no drugs have yet been approved for treatment of negative symptoms and cognitive impairment. This unmet clinical need continues to drive new drug development.

[0003] Both first- and second-generation antipsychotics have long-acting formulations, primarily used to improve patient adherence. Recent evidence supports that initiating long-acting medication during the acute phase and early initiation can improve long-term patient outcomes. First-generation long-acting antipsychotics include fluphenazine decanoate and haloperidol decanoate; second-generation long-acting antipsychotics currently available in China include risperidone, paliperidone, and aripiprazole in long-acting formulations.

[0004] Lumateperone, first developed by Bristol-Myers Squibb, was exclusively licensed to Intra-Cellular Therapies, Inc. (ITCI) in 2005. It is a pioneering drug for the treatment of schizophrenia and was approved by the FDA on December 23, 2019, for the treatment of schizophrenia in adults. As a novel atypical antipsychotic, lumateperone simultaneously regulates the serotonin (5-HT), dopamine (DA), and glutamate neurotransmitter pathways. 2A This drug is a receptor antagonist and a 5-HT reuptake inhibitor; it is a DA receptor phosphoprotein regulator (DPPM), a partial agonist of the presynaptic D2 receptor, and an antagonist of the postsynaptic D2 receptor; it can also indirectly regulate glutamate receptor activity. This drug is safe and effective, with few extrapyramidal adverse reactions, a low incidence of metabolic abnormalities and weight gain, and good tolerability. The basic properties of this product are shown in Table 1. Table 1. Basic properties of rumepiride mesylate

[0005] The following are existing technologies for rumepiride analogues and derivatives: US20250302739 contains a long-acting injectable drug complex containing a biodegradable polymer for drug delivery. WO2025111568 Lumepiride and its analogues, as 5-HT2A or 5-HT2A / D2 receptor modulators, are used to treat mental illnesses and their symptoms caused by viral, bacterial, or autoimmune encephalitis. CN119707972 Preparation and application of lumepirozone derivatives (N-derived products). Composition and preparation method of long-acting and sustained-release rumepiride (WO2024183538) WO2024173901 Lumepiride and its derivatives are used to regulate the nervous system. WO2024083026 Lumepiride drug composition and its long-acting microsphere sustained-release formulation and preparation method CN115554237 A Long-acting injection and preparation method of rumepiride in situ gel and its application WO2019178484 A new approach to the acute treatment of depression and / or anxiety (deuterated derivatives). WO2017117514 Deuterated lumepirozoline WO2022073470 Heterocyclic substituted γ-carbonic anhydride as a 5-HT2A receptor antagonist and its preparation, pharmaceutical composition and application in the treatment of neuropsychiatric disorders (oxygenation).

[0006] Currently, one of the main causes of relapse in existing antipsychotic medication practices is patients' inability to adhere to their regular medication regimen. Clinical trials have confirmed that existing long-acting injectable antipsychotics significantly reduce hospitalization and treatment interruption rates compared to oral antipsychotics, making them an important treatment method for preventing relapse. Regular injections eliminate the worry of forgetting daily doses, reducing daily burden. Furthermore, they prevent others from discovering their medication use in daily life and work, effectively protecting privacy. Drug abuse can also be prevented. Currently, second-generation long-acting injectable antipsychotics are used as first-line treatments for the acute and maintenance phases of schizophrenia. Second-generation long-acting injectable antipsychotics on the Chinese market include: risperidone microspheres injected every two weeks, paripedone palmitate injected monthly, and paripedone palmitate injected every three months. The development of long-acting extended-release formulations of rumepiride is still in its early stages.

[0007] Optimizing drug bioavailability has many potential benefits. For patient convenience and improved adherence, reducing dosing frequency is generally considered desirable. By prolonging the drug's release time, the duration of action per dose is expected to be longer. This will then lead to an overall improvement in dosing parameters, such as taking the drug once daily instead of four times daily or once weekly, or even less when daily dosing was previously required. Many drugs are currently administered once daily. However, not all of these drugs have pharmacokinetic properties suitable for an exact 24-hour dosing interval. Prolonging the release period of these drugs would also be beneficial.

[0008] One of the fundamental considerations in drug therapy involves the relationship between blood levels and therapeutic activity. For most drugs, maintaining serum levels between the minimum effective concentration and the potential toxic level is of paramount importance. From a pharmacokinetic perspective, the peaks and troughs of drug blood levels ideally fit within the therapeutic window of serum concentration. For some therapeutic agents, this window is so narrow that dosage formulation becomes crucial.

[0009] The currently approved solid oral dosage forms of rumepiride have the disadvantage of very low bioavailability. The absolute bioavailability of rumepiride capsules in humans is 4.4% [https: / / www.accessdata.fda.gov / drugsatfda_docs / nda / 2019 / 209500Orig1s000AdminCorres.pdf], with a plasma protein binding rate of 97.4% and high lipophilicity at pH 7.4 (LogD 3.38). Non-oral administration routes (e.g., parenteral) have been explored for use in other classes of drugs. However, to date, there are no sustained-release injectable prodrug formulations of rumepiride derivatives.

[0010] A key aspect of prodrug development is extending the duration of action: prodrugs can be designed to prolong or sustain the release of the active drug, resulting in a more durable therapeutic effect and potentially reducing dosing frequency. A significant benefit may be improved patient compliance or acceptance, leading to better medication adherence. Furthermore, medication regimens may be simplified, and the drug burden may be reduced. Despite these advantages, the design and development of prodrugs still require a thorough understanding of the pharmacokinetics, pharmacodynamics, and metabolism of the parent drug. In addition, the chemical structure of the parent drug itself can severely limit the design and feasibility of prodrugs.

[0011] Therefore, given the advantages of long-acting formulations, the need to develop long-acting parenteral formulations of rumepiride remains unmet. Summary of the Invention

[0012] This invention selectively modifies the structure of rumepiride to prepare a prodrug with long-acting properties. This type of drug is formulated into a preparation suitable for intramuscular, subcutaneous, or intravenous injection. After intramuscular, subcutaneous, or intravenous injection, a drug reservoir is formed in the body, from which the drug is slowly, continuously, and stably released and converted into rumepiride, thereby exerting a long-acting effect. This invention is achieved using the following technical solution: The purpose of this invention is to overcome the shortcomings of the prior art and provide a compound or pharmaceutically acceptable salt represented by Formula I: , Where n is an integer from 4 to 14.

[0013] The present invention also provides that the pharmaceutically acceptable salt of the compound represented by Formula I is a compound represented by Formula II: , Where n is an integer from 4 to 14. X is a monoprotic inorganic acid, diprotic inorganic acid, triprotic inorganic acid, or organic acid. Suitable addition salts include acetates, para-aminobenzoates, ascorbic acid salts, aspartate salts, benzenesulfonates, benzoates, bicarbonates, dimethylene salicylate, bisulfates, tartrates, borates, calcium edetate, camphor sulfonate, carbonates, clavulanates, citrates, cyclohexylaminosulfonate, edetate, ethanedisulfonate, propionate lauryl sulfate, ethanesulfonate, ethanedisulfonate, ethanesulfonate, formate, fumarate, gluconate, gluconate, glutamate, glycolate, glycolyl-p-aminophenylarsethanoate, hexylresorcinate, heparin, hydrobromide, hydrochloride, dihydrochloride, hydrogen fumarate, hydrogen phosphate, and hydroiodide. Hydromaleate, hydrosuccinate, hydroxynaphthyl carboxylate, hydroxyethyl sulfonate, itaconic acid, lactate, lacturonate, laurate, malate, maleate, mandelate, methanesulfonate, methyl sulfate, monopotassium maleate, mucilage, naphthalene sulfonate, nitrate, N-methylglucosamine salt, oxalate, oxaloacetate, pyruvate (bishydroxynaphthyl acidate), palmitate, palmitate, pantothenate, phosphate / bisphosphate, pyruvate, polygalacturonate, propionate, glycodiacidate, salicylate, stearate, basic acetate, succinate, sulfate, tannate, tartrate, chlorothenate, toluenesulfonate, triethyliodide, trifluoroacetate, and valerate.

[0014] In a preferred embodiment of the present invention, the compound represented by Formula I is selected from any of the following compounds:

[0015] In another aspect of the present invention, a method for preparing the compound represented by Formula I or a salt thereof is provided, comprising the following steps: The compound of formula I was prepared by reacting lumepirozol with acyl chloride in a reaction solvent and with a basic acid-binding agent, as shown in the following reaction formula: , Where R is a straight-chain or branched alkyl group corresponding to the structure of Formula I.

[0016] Furthermore, in the preparation method provided by the present invention, the reaction solvent is selected from one or more combinations of n-pentane, n-hexane, n-heptane, cyclohexane, petroleum ether, toluene, xylene, dimethyl ether, diethyl ether, isopropyl ether, tetrahydrofuran, methyl acetate, ethyl acetate, dichloromethane, dichloroethane, and chloroform, preferably tetrahydrofuran; the acid-binding agent is selected from lithium diisopropylamino, n-butyllithium, phenyllithium, methyllithium, and lithium tert-butoxide, preferably lithium diisopropylamino.

[0017] In some preferred embodiments of the present invention, the preparation method further includes further purification of the product.

[0018] The purity and structure of the product prepared by this invention were confirmed by chromatographic spectroscopy analysis, and the chromatographic analysis conditions are shown in Table 2: Table 2 Chromatographic conditions for YPK-030

[0019] The typical chromatograms and spectra are shown in the attached figure.

[0020] According to the present invention, compounds of Formula I or salts thereof can be formulated into various pharmaceutical preparations to provide a prolonged therapeutic effect. In this regard, compounds of Formula I or salts thereof can be mixed with a selected oil carrier to form a parenteral formulation, such that the release rate of the target drug, i.e., lumepirox, may be slowed down at the time of administration due to factors such as increased solubility of the target drug in oil. Therefore, longer dosing intervals can be set due to the prolonged duration of action of the target drug.

[0021] Gelders reported in International Clinical Psychopharmacology, (1986) Vol. 1, 1-11, and CN Hinko et al. reported in Neuropharmacology, (1988) Vol. 27, 475-483, that the controlled-release formulation of haloperidol decyl ester in injectable oils (such as sesame oil or soybean oil) prolongs its antipsychotic effect, making it possible to extend the dosing interval from 2-4 times per day to 1-2 times per month.

[0022] TR Norman reported the preparation of fluphenazine decyl ester from fluphenazine in International Clinical Psychopharmacology, (1987) Vol. 2, 299-305. CN Hinko reported the preparation of lactoferrate in Neuropharmacology (1988), Vol. 27, 475-483. CL Broekkamp reported the preparation of nicotinylmorphine ester from morphine in the Journal of Pharmacy and Pharmacology (1988) Vol. 40, 434-437. JV Joshi et al. reported a prodrug of testosterone enanthate in Steroids, (1989) Vol. 53, 751-761, with a dosing interval of up to two months.

[0023] However, due to unknown factors in nature, the target drug may sometimes be released rapidly from the oil base. For example, it has been found that intramuscularly injected testosterone suspensions release testosterone rapidly (T Tanaka (1974), Chemical & Pharmaceutical Bulletin, Vol. 22, pp. 1275-1284). HAC Titulaer reported the addition of artemisinin to parenteral oils to form various dosage forms for intramuscular, intravenous, oral, or rectal administration. However, the drug is rapidly released from these dosage forms (Journal of Pharmacy and Pharmacology (1990), Vol. 42, pp. 810-813). Z. Zuidema et al. reported in the International Journal of Pharmaceutics (1994), Vol. 105, pp. 189-207 that the release rate and extent of parenteral administration dosage forms are highly unstable and variable.

[0024] Based on the above studies, dosage forms containing drug compositions suspended or dissolved in an oil carrier will certainly not exhibit a longer duration of therapeutic effect. In view of this, any attempt to extend the duration of action of rumepiride generally requires consideration of the physical solubility, stability, and release rate of the target drug from the carrier in order to obtain a long-acting dosage form.

[0025] The applicant provides a pharmaceutical composition comprising a compound of formula I or a salt thereof and a pharmaceutically acceptable carrier.

[0026] Suitable oil carriers for use in this invention are injectable formulations, including, for example, vegetable oils, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil (early peanut oil), poppy seed oil, tea seed oil, and soybean oil, and combinations thereof. Furthermore, the compositions according to this invention may optionally include pharmaceutically acceptable excipients commonly used in the manufacture of pharmaceuticals. The use of such excipients will be apparent to those skilled in the art. Preferably, if present, the excipients may be selected from benzyl alcohol, benzyl benzoate, or combinations thereof. The formulated compositions are intended for intramuscular, intradermal, or subcutaneous injection.

[0027] The compounds described in this invention, or their salts or pharmaceutically acceptable salts, are intended for use in the preparation of remedies for mood disorders, sleep disorders, psychotic disorders, agitation and excitement, including psychomotor states of agitation disorders, behavioral disorders (including autistic behaviors), and / or cognitive impairments. Mood disorders are selected from major depressive disorder, atypical depression, melancholic depression, psychotic depression, depression unless otherwise specified, postpartum depression, dysphoric disorder, depressive mood regulation disorder, and seasonal affective disorder.

[0028] The key points of this invention are: This invention discloses novel rumepiride prodrug derivatives formulated into an injection solution using an oil-based carrier. Upon injection, the prodrug cleaves to release rumepiride and a safe and biodegradable component of hexanoic acid, decanoic acid, lauric acid, or palmitic acid. Compared to oral rumepiride formulations, the novel rumepiride prodrugs and formulations described herein represent a breakthrough because they offer higher bioavailability, eliminate the food effect, reduce pill burden, decrease dosing frequency, and provide sustained effective plasma levels of rumepiride, for example, at least one week, typically at least two weeks, and up to ten weeks or longer after administration of the rumepiride prodrug formulation. Furthermore, pharmacokinetic studies of representative rumepiride prodrugs demonstrate that the novel rumepiride laurate formulation is suitable for weekly, monthly, bi-monthly, tri-monthly, or even less frequent dosing, a characteristic that alone represents a significant improvement over currently marketed Caplyta® tablets, which require patients to take a large number of tablets daily (42 mg tablets once daily).

[0029] This disclosure also demonstrates that administration of the compounds of the present invention is generally well tolerated. For example, administration of controlled doses of the compounds of the present invention showed minimal toxicity to Caco-2 cells and hepatocytes, and minimal injection irritation. Furthermore, this disclosure provides novel parenteral formulations of lumepimeperone derivatives that are more suitable for drug development. The compositions and methods described herein address a long-unmet need by providing alternatives to oral formulations that suffer from: 1) low bioavailability (only 4.4%); 2) interactions with ingested food; 3) delivery of highly variable parent drug blood levels, potentially reducing efficacy and increasing side effects; 4) daily dose requirements and high pill burden; and 5) poor patient compliance. Attached Figure Description

[0030] Figure 1 This is the structure of compound I.

[0031] Figure 2 The image shows the HPLC chromatogram of compound I-3, rumepiride lauryl acid.

[0032] Figure 3 The 1H NMR spectrum of compound I-3-lumepiride laurate.

[0033] Figure 4 This is the carbon spectrum of compound I-3 rumeperone lauryl acid.

[0034] Figure 5 LC-MS of compound I-3-rumepiride lauryl acid.

[0035] Figure 6 This is a pharmacokinetic diagram of the compound of this invention in rats.

[0036] Figure 7 This is a diagram showing the cytotoxicity of the compounds in this invention. Detailed Implementation

[0037] The following embodiments can further describe the present invention; however, these embodiments should not be construed as limiting the scope of the present invention.

[0038] Example 1: Preparation of compound I-1 (lumepiride hexanoate).

[0039]

[0040] Material proportions:

[0041] Under nitrogen protection, LDA / THF solution (10 mL, 2.0 eq) was added to a 250 mL three-necked flask, and the temperature was lowered to -30 °C. Lumepiride / THF solution (3.94 g / 25 mL) was added dropwise to the pre-cooled solution. After the addition was complete, the temperature was maintained at -30 °C and the reaction was stirred for 45 min. Hexanoyl chloride (2.03 g, 1.5 eq) was then added dropwise to the reaction mixture. After the addition was complete, the temperature was maintained at -30 °C and the reaction was stirred for 30 min. The temperature was then raised to room temperature and the reaction proceeded for 2 minutes. The reaction was monitored by TLC for 254 nm (PE:EA:triethylamine = 40:10:1) until complete. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, and washed once with water and once with brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by column chromatography (PE:EA:triethylamine = 350:50:10) to obtain 1.5 g of pale yellow product, yield: 30.5%. Samples were sent for 1H NMR and mass spectrometry analysis. 1 H-NMR (400MHz, CDCl3): δ7.38~7.32(m,2H), 7.03~6.96(m,2H), 6.66(t,1H), 6.53(d,1H), 6.41(d,1H), 5.75(t,1H), 3.34~3.23(m,4 H), 2.93~2.80(m,5H), 2.56~2.49(m,4H), 2.38~2.27(m,4H), 2.00~1.93(m,2H), 1.30~1.28(m,4H), 1.27~1.23(m,4H), 0.87(t,3H).

[0042] MS:M+H=492.3.

[0043] Example 2: Preparation of compound I-1 (lumepiride hexanoate).

[0044] Under nitrogen protection, LDA / THF solution (15 mL, 3.0 eq) was added to a 250 mL three-necked flask and cooled to -30 °C. Lumepiride / THF solution (3.94 g / 25 mL) was added dropwise to the pre-cooled solution. After the addition was complete, the temperature was maintained at -30 °C and the mixture was stirred for 45 min. Hexanoyl chloride (2.03 g, 1.5 eq) was added dropwise to the reaction solution. After the addition was complete, the temperature was maintained at -30 °C and the mixture was stirred for 30 min. The temperature was then raised to room temperature and the reaction was carried out for 2 hours. The reaction was monitored by TLC (λ=254 nm, PE:EA:triethylamine=40:10:1) until complete. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The solution was washed once with water and once with brine. The ethyl acetate layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure to dryness. The solution was purified by column chromatography (PE:EA:triethylamine=350:50:10) to obtain 1.7 g of pale yellow product, yield: 34.6%.

[0045] Example 3: Preparation of compound I-1 (lumepiride hexanoate).

[0046] Under nitrogen protection, LDA / THF solution (10 mL, 2.0 eq) was added to a 250 mL three-necked flask and cooled to -30 °C. Lumepiride / THF solution (3.94 g / 25 mL) was added dropwise to the pre-cooled solution. After the addition was complete, the temperature was maintained at -30 °C and the mixture was stirred for 45 min. Hexanoyl chloride (2.71 g, 2.0 eq) was added dropwise to the reaction solution. After the addition was complete, the temperature was maintained at -30 °C and the mixture was stirred for 30 min. The temperature was then raised to room temperature and the reaction was carried out for 2 hours. The reaction was monitored by TLC (λ=254 nm, PE:EA:triethylamine=40:10:1) until complete. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The solution was washed once with water and once with brine. The ethyl acetate layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure to dryness. The solution was purified by column chromatography (PE:EA:triethylamine=350:50:10) to obtain 1.7 g of pale yellow product, yield: 34.6%.

[0047] Example 4: Preparation of compound I-2 (lumepiride decanoate).

[0048]

[0049] Material proportions:

[0050] Under nitrogen protection, LDA / THF solution (10 mL, 2.0 eq) was added to a 250 mL three-necked flask, and the temperature was lowered to -30 °C. Lumepiride / THF solution (3.94 g / 25 mL) was added dropwise to the pre-cooled solution. After the addition was complete, the temperature was maintained at -30 °C and the reaction was stirred for 45 min. Decanoyl chloride (2.85 g, 1.5 eq) was then added dropwise to the reaction solution. After the addition was complete, the temperature was maintained at -30 °C and the reaction was stirred for 30 min. The temperature was then raised to room temperature and the reaction was continued for 2 minutes. The reaction was monitored by TLC for 254 nm (PE:EA:triethylamine = 40:10:1) until complete. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, and washed once with water and once with brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by column chromatography (PE:EA:triethylamine = 350:50:10) to obtain 1.9 g of pale yellow product, yield: 34.7%. Samples were sent for 1H NMR and mass spectrometry analysis. 1H-NMR (400MHz, CDCl3): δ7.39~7.34(m,2H), 7.02~6.97(m,2H), 6.65(t,1H), 6.55(d,1H), 6.42(d,1H), 5.76(t,1H), 3.34~3.23(m,4 H), 2.93~2.80(m,5H), 2.56~2.49(m,4H), 2.38~2.27(m,4H), 2.00~1.93(m,2H), 1.31~1.28(m,4H), 1.28~1.23(m,12H), 0.88(t,3H).

[0051] MS:M+H=548.3.

[0052] Example 5: Preparation of compound I-2 (lumepiride decanoate).

[0053] Under nitrogen protection, LDA / THF solution (15 mL, 3.0 eq) was added to a 250 mL three-necked flask and cooled to -30 °C. Lumepiride / THF solution (3.94 g / 25 mL) was added dropwise to the pre-cooled solution. After the addition was complete, the temperature was maintained at -30 °C and the mixture was stirred for 45 min. Decanoyl chloride (2.85 g, 1.5 eq) was added dropwise to the reaction solution. After the addition was complete, the temperature was maintained at -30 °C and the mixture was stirred for 30 min. The temperature was then raised to room temperature and the reaction was carried out for 2 hours. The reaction was monitored by TLC (λ=254 nm, PE:EA:triethylamine=40:10:1) until complete. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The solution was washed once with water and once with brine. The ethyl acetate layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure to dryness. The solution was purified by column chromatography (PE:EA:triethylamine=350:50:10) to obtain 2.1 g of pale yellow product, yield: 38.3%.

[0054] Example 6: Preparation of compound I-2 (lumepiride decanoate).

[0055] Under nitrogen protection, LDA / THF solution (15 mL, 2.0 eq) was added to a 250 mL three-necked flask and cooled to -30 °C. Lumepiride / THF solution (3.94 g / 25 mL) was added dropwise to the pre-cooled solution. After the addition was complete, the temperature was maintained at -30 °C and the mixture was stirred for 45 min. Decanoyl chloride (3.80 g, 2.0 eq) was added dropwise to the reaction solution. After the addition was complete, the temperature was maintained at -30 °C and the mixture was stirred for 30 min. The temperature was then raised to room temperature and the reaction was carried out for 2 hours. The reaction was monitored by TLC (λ=254 nm, PE:EA:triethylamine=40:10:1) until complete. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The solution was washed once with water and once with brine. The ethyl acetate layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure to dryness. The solution was purified by column chromatography (PE:EA:triethylamine=350:50:10) to obtain 2.0 g of pale yellow product, yield: 36.5%.

[0056] Example 7: Preparation of compound I-3 (lumepiride lauryl acid).

[0057]

[0058] Material proportions:

[0059] Under nitrogen protection, LDA / THF solution (10 mL, 2.0 eq) was added to a 250 mL three-necked flask, and the temperature was lowered to -30 °C. Lumepiride / THF solution (3.94 g / 25 mL) was added dropwise to the pre-cooled solution. After the addition was complete, the temperature was maintained at -30 °C and the reaction was stirred for 45 min. Dodecyl chloride (3.29 g, 1.5 eq) was then added dropwise to the reaction solution. After the addition was complete, the temperature was maintained at -30 °C and the reaction was stirred for 30 min. The temperature was then raised to room temperature and the reaction was continued for 2 minutes. The reaction was monitored by TLC for hours (λ=254nm, PE:EA:triethylamine=40:10:1) until complete. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, washed once with water and once with brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by column chromatography (PE:EA:triethylamine=350:50:10) to obtain 1.7g of pale yellow product, yield: 29.5%. Samples were sent for 1H NMR and mass spectrometry analysis. 1H-NMR (400MHz, CDCl3): δ7.37~7.33(m,2H), 7.03~6.97(m,2H), 6.65(t,1H), 6.52(d,1H), 6.41(d,1H), 5.74(t,1H), 3.33~3.21(m,4 H), 2.92~2.81(m,5H), 2.55~2.47(m,4H), 2.37~2.27(m,4H), 2.00~1.93(m,2H), 1.35~1.32(m,4H), 1.27~1.23(m,16H), 0.88(t,3H).

[0060] MS:M+H=576.2.

[0061] Example 8: Preparation of compound I-3 (lumepiride lauryl acid).

[0062] Under nitrogen protection, LDA / THF solution (15 mL, 3.0 eq) was added to a 250 mL three-necked flask and cooled to -30 °C. Lumepiride / THF solution (3.94 g / 25 mL) was added dropwise to the pre-cooled solution. After the addition was complete, the temperature was maintained at -30 °C and the mixture was stirred for 45 min. Dodecyl chloride (3.29 g, 1.5 eq) was added dropwise to the reaction solution. After the addition was complete, the temperature was maintained at -30 °C and the mixture was stirred for 30 min. The temperature was then raised to room temperature and the reaction was carried out for 2 hours. The reaction was monitored by TLC (λ=254 nm, PE:EA:triethylamine=40:10:1) until complete. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The solution was washed once with water and once with brine. The ethyl acetate layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure to dryness. The solution was purified by column chromatography (PE:EA:triethylamine=350:50:10) to obtain 1.9 g of pale yellow product, yield: 33.0%.

[0063] Example 9: Preparation of compound I-3 (lumepiride lauryl acid).

[0064] Under nitrogen protection, LDA / THF solution (10 mL, 2.0 eq) was added to a 250 mL three-necked flask and cooled to -30 °C. Lumepiride / THF solution (3.94 g / 25 mL) was added dropwise to the pre-cooled solution. After the addition was complete, the temperature was maintained at -30 °C and the mixture was stirred for 45 min. Dodecyl chloride (4.39 g, 2.0 eq) was added dropwise to the reaction solution. After the addition was complete, the temperature was maintained at -30 °C and the mixture was stirred for 30 min. The temperature was then raised to room temperature and the reaction was carried out for 2 hours. The reaction was monitored by TLC (λ=254 nm, PE:EA:triethylamine=40:10:1) until complete. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The solution was washed once with water and once with brine. The ethyl acetate layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure to dryness. The solution was purified by column chromatography (PE:EA:triethylamine=350:50:10) to obtain 1.8 g of pale yellow product, yield: 31.3%.

[0065] Example 10: Preparation of compound I-4 (lumepiride palmitate).

[0066]

[0067] Material proportions:

[0068] Under nitrogen protection, LDA / THF solution (10 mL, 2.0 eq) was added to a 250 mL three-necked flask, and the temperature was lowered to -30 °C. Lumepiride / THF solution (3.94 g / 25 mL) was added dropwise to the pre-cooled solution. After the addition was complete, the temperature was maintained at -30 °C and the reaction was stirred for 45 min. Palmitoyl chloride (4.13 g, 1.5 eq) was then added dropwise to the reaction solution. After the addition was complete, the temperature was maintained at -30 °C and the reaction was stirred for 30 min. The temperature was then raised to room temperature and the reaction was continued for 2 minutes. The reaction was monitored by TLC for 254 nm (PE:EA:triethylamine = 40:10:1) until complete. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, and washed once with water and once with brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by column chromatography (PE:EA:triethylamine = 350:50:10) to obtain 2.3 g of pale yellow product, yield: 36.4%. Samples were sent for 1H NMR and mass spectrometry analysis. 1H-NMR (400MHz, CDCl3): δ7.37~7.32(m,2H), 7.00~6.96(m,2H), 6.64(t,1H), 6.53(d,1H), 6.41(d,1H), 5.73(t,1H), 3.35~3.26(m,4 H), 2.94~2.80(m,5H), 2.57~2.48(m,4H), 2.38~2.29(m,4H), 2.00~1.94(m,2H), 1.30~1.27(m,4H), 1.28~1.24(m,24H), 0.88(t,3H).

[0069] MS:M+H=632.5.

[0070] Example 11: Preparation of compound I-4 (lumepiride palmitate).

[0071] Under nitrogen protection, LDA / THF solution (15 mL, 3.0 eq) was added to a 250 mL three-necked flask and cooled to -30 °C. Lumepiride / THF solution (3.94 g / 25 mL) was added dropwise to the pre-cooled solution. After the addition was complete, the temperature was maintained at -30 °C and the mixture was stirred for 45 min. Palmitoyl chloride (4.13 g, 1.5 eq) was added dropwise to the reaction solution. After the addition was complete, the temperature was maintained at -30 °C and the mixture was stirred for 30 min. The temperature was then raised to room temperature and the reaction was carried out for 2 hours. The reaction was monitored by TLC (λ=254 nm, PE:EA:triethylamine=40:10:1) until complete. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The solution was washed once with water and once with brine. The ethyl acetate layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure to dryness. The solution was purified by column chromatography (PE:EA:triethylamine=350:50:10) to obtain 2.6 g of pale yellow product, with a yield of 41.1%.

[0072] Example 12: Preparation of compound I-4 (lumepiride palmitate).

[0073] Under nitrogen protection, LDA / THF solution (10 mL, 2.0 eq) was added to a 250 mL three-necked flask and cooled to -30 °C. Lumepiride / THF solution (3.94 g / 25 mL) was added dropwise to the pre-cooled solution. After the addition was complete, the temperature was maintained at -30 °C and the mixture was stirred for 45 min. Palmitoyl chloride (5.51 g, 2.0 eq) was added dropwise to the reaction solution. After the addition was complete, the temperature was maintained at -30 °C and the mixture was stirred for 30 min. The temperature was then raised to room temperature and the reaction was carried out for 2 hours. The reaction was monitored by TLC (λ=254 nm, PE:EA:triethylamine=40:10:1) until complete. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The solution was washed once with water and once with brine. The ethyl acetate layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure to dryness. The solution was purified by column chromatography (PE:EA:triethylamine=350:50:10) to obtain 2.4 g of pale yellow product, yield: 38.0%.

[0074] The following is a typical spectral analysis of a representative compound (using compound I-3 (rumepiride lauryl acid) as an example):

[0075] 1 H-NMR (400MHz, CDCl3): δ7.37~7.33(m,2H), 7.03~6.97(m,2H), 6.65(t,1H), 6.52(d,1H), 6.41(d,1H), 5.74(t,1H), 3.33~3.21(m,4 H), 2.92~2.81(m,5H), 2.55~2.47(m,4H), 2.37~2.27(m,4H), 2.00~1.93(m,2H), 1.35~1.32(m,4H), 1.27~1.23(m,16H), 0.88(t,3H).

[0076] Table 3. 1H NMR spectroscopy results of the products

[0077] 13 C-NMR (100MHz, CDCl3): δ171.59, 163.62, 161.97, 137.43, 135.23, 130.9 8, 126.56, 126.50, 121.02, 115.56, 115.42, 112.61, 109.32, 67.00, 64.0 3, 50.45, 49.89, 48.40, 45.78, 44.38, 37.43, 34.33, 34.10, 31.88, 29.58 ,29.45,29.32,29.30,29.23,29.18,24.97,24.92,24.79,22.66,14.09.

[0078] Table 4. Nuclear magnetic resonance carbon spectrum detection results of the products

[0079] MS:M+H=576.2.

[0080] Example 13: Preparation of a typical injection solution for animal testing according to the present invention.

[0081] Prescription 1: , Note: All concentrations above are calculated as 210 mg / vial of rumepiride.

[0082] 2. Preparation method: Dissolve compounds I-1 to I-4 in a specific ratio of benzyl benzoate and sesame oil according to the prescribed dosage, and gently shake to ensure complete dissolution. Fill 1 ml ampoules and sterilize at 121°C for 15 minutes.

[0083] Example 14: Stability Test The compounds of this invention may be used as active pharmaceutical ingredients (APIs) in the preparation of injectable solutions; therefore, storage is crucial. Impurities may be introduced or generated during storage, affecting the use of the API. Therefore, the stability of the API of this invention is investigated. Following the ICH guideline "Stability Testing of New APIs and Formulations," influencing factor tests were conducted.

[0084] 1. Test conditions: The high humidity test of this product was conducted at 25℃±2℃, RH: 75%±5%, and high temperature (60℃) with the inner and outer packaging removed for 30 days. The light exposure (total illuminance not less than 1.2×106Lux·hr) was also conducted with the inner and outer packaging removed.

[0085] 2. Sampling and testing: High temperature samples were taken at 5, 10 and 30 days; high humidity samples were taken at 5 and 10 days; and light conditions samples were taken at 5 and 11 days.

[0086] 3. Observation results: See Table 5 below: Table 5. Factors affecting the stability of compounds (stability test) , Conclusion: As shown in the table, the active pharmaceutical ingredient of the present invention is relatively stable under the relevant conditions and no obvious impurities are generated. Therefore, after the active pharmaceutical ingredient is prepared, it can be stored at room temperature.

[0087] The following comparative test cases (lumepiridone acetate, lumepiridone propionate, and lumepiridone docosinate) were further tested using the same test method described above, and the test results are shown in the table below.

[0088] Table 6 Comparative Examples of Stability Tests

[0089] Judging from the results, lumateperone acetate and lumateperone propionate are very sensitive to light and unstable, and lumateperone behenate is very unstable to heat.

[0090] Example 15: Pharmacokinetic Study in Rats.

[0091] 1 Test System 1.1 Information on Experimental Animals License number for the use of experimental animals in this institution: SYXK (Anhui) 2024-014; Level: SPF; Gender and number of animals used in the experiment: male, 18; Body weight range at the time of animal purchase: 180 - 220 g; Sources of experimental animals, production license numbers, animal certificate numbers and the units issuing the animal certificates are recorded in the original materials. Method of handling experimental animals: After the experiment, the animals are euthanized with CO2.

[0092] 1.2 Labeling and Identification Before grouping, white cage cards are uniformly used to identify each cage of animals, and the animals in each cage are further marked by drawing lines on the tail with an oil-based pen. For example, one horizontal line represents 1, two horizontal lines represent 2, three horizontal lines represent 3, four horizontal lines represent 4, and no marking represents 5, which serves as the temporary number of the animal; after grouping, all animals are marked and identified using the body surface staining method. 1.3 Rearing of Experimental Animals Permissible temperature range in the rearing room: 20 - 26 °C, daily temperature difference ≤ 4 °C; Permissible humidity range in the rearing room: 30% - 70%; Number of air changes: At least 15 times of fresh air per hour; Lighting cycle: 12 h light / 12 h dark; Type of cage: PP rat cage (540 × 390 × 210 mm3); Rearing density: Not exceeding 5 animals per cage.

[0093] 1.4 Feed Information Type of feed: Formulated feed for experimental rats; Feeding method: Free intake; Name of bedding: Sterilized corncob bedding; Confirmation tests on the nutritional components of the feed and the pollutant content of the feed and bedding are provided by the supplier with the test report for each batch.

[0094] 1.5 Drinking Water Information Type: Sterilized drinking water; Water supply method: Animals drink water freely through a dedicated water bottle; Water quality detection: The drinking water for animals is detected by a professional testing institution at least once a year to ensure that the pollutant content in the water will not affect the research results, and the water quality test reports are regularly archived in the archives of this institution.

[0095] 1.6 Quarantine and Adaptive Rearing: At least 5 days of quarantine and adaptive rearing, and used after passing the quarantine.

[0096] 1.7 Veterinary Treatment: Veterinarians were available to provide advice on animal management and care throughout the study. If medication was required for sick animals, the veterinarian would provide a treatment recommendation, which would be implemented only after approval by the SD (Student Management Office). No veterinary treatment was provided during the entire study.

[0097] 2 Experimental Design 2.1 Random Grouping This study selected 15 healthy male animals and randomly divided them into 5 groups. Group 1 was administered rumeperone tablet suspension by gavage (fasting for approximately 12 hours before administration, followed by food and free access to water 1 hour after administration). Groups 2-5 were administered the compound of this invention by intramuscular injection. The specific administration regimens are shown in Table 7 below: Table 7 Dosing Regimen

[0098] △ All values ​​are calculated based on rumepiride. Taking formulation 1 as an example, 262 mg / mL × 0.8 = 209 mg / mL (conversion factor: 393.51 / 491.65 = 0.8).

[0099] 2.2 Drug administration related information Route of administration: intramuscular injection (hamstring muscles) and subcutaneous injection (skin of neck and back); Frequency of administration: single dose.

[0100] 2.3 Rationale for the design of the route of administration and dosage According to the information provided by the client, the test product is intended for intramuscular injection in clinical use, therefore intramuscular injection was chosen. For oral administration of rumepiride tablets, gavage was chosen. The recommended clinical dose of rumepiride tablets for diabetic retinopathy is 42 mg once daily (total dose 42 mg / person), which is approximately 0.7 mg / kg in rats based on a daily dose of 42 mg / 60 kg. Based on the maximum permissible intramuscular injection volume in rats, the maximum intramuscular dose of YPK-030 is calculated to be 52.4 mg / kg (equivalent to 42 mg / kg in rumepiride form). Therefore, the dose for this experiment was appropriately increased from the human daily dose converted to a rat dose of 42 mg / kg to investigate relative bioavailability.

[0101] 3. Animal observation, blood sample collection and biological sample analysis 3.1 Clinical observation No obvious abnormalities were observed after administration.

[0102] 3.2 Sample Collection Collection method: Blood is collected from the submandibular vein, approximately 0.15 mL each time.

[0103] Data collection time points: 0h before administration, 15 min, 30 min, 1h, 2h, 4h, 8h, 12h, 24h (1 day), 48h (2 days), 72h (3 days), 168h (7 days), 336h (14 days), 504h (21 days), and 672h (28 days) after administration for each group.

[0104] 3.3 Sample Separation and Preservation Sampling requirements and processing: Blood was collected using EDTA-K2 anticoagulant tubes. After collection, the blood was centrifuged at 1500g for 15 minutes under yellow light, followed by plasma separation. The samples were temporarily frozen at approximately -20℃, and then transferred to the sample room refrigerator for further analysis.

[0105] 3.4 Biological Sample Analysis After sampling, the concentration of lumepiroline in the samples was determined using LC-MS / MS.

[0106] 3.5 Data Processing and Statistical Analysis Data processing of measurement results: The concentration results of all samples were acquired and processed by the analytical instrument itself; pharmacokinetic parameters were calculated using WinNonlin. BLQ samples before reaching Cmax were calculated as zero values, while samples after reaching Cmax were left blank for calculation. After WinNonlin calculation, concentrations and parameters are expressed to three significant figures, and ratios and percentages of parameters are retained to two decimal places. Values ​​in some tables may differ slightly from individually calculated results, but the completeness and continuity of the data are not affected.

[0107] 3.6 Results and Evaluation The pharmacokinetic curves were obtained based on the concentration data at each time point. The pharmacokinetic parameters AUC0-t, Cmax, Tmax, and T1 / 2 were calculated using the non-compartmental model module of Phoenix WinNolin software, and the pharmacokinetic differences among the groups were compared.

[0108] 4 Results For the preparations 1-4 administered by gavage and intramuscular injection respectively, corresponding to compounds I-1-I-4, the blood concentrations of the original drug lumepiroline are detailed in Table 8. It can be seen that the compounds of the present invention can be slowly, continuously, and stably released and converted into lumepiroline in vivo, thereby exerting a long-acting effect. The results show that the present invention achieves a long-acting release effect.

[0109] Table 8. Blood drug concentrations in rats after administration

[0110] Example 16: Toxicity test on Caco-2 cells (30 times the maximum blood drug concentration).

[0111] The MTT assay is a commonly used method for detecting the impact of samples on cell survival and growth. MTT is a yellow dye, its full name being 3-(4,5-dimethylthiazol-2)-2,5-diphenyltetrazolium bromide. The detection principle is that succinate dehydrogenase present in the mitochondria of living cells can reduce MTT to formazan, a water-insoluble, blue-purple crystal that deposits in the cell; dead cells do not have this function. Formazan is dissolved in DMSO solution, and its absorbance is measured using an enzyme-linked immunosorbent assay (ELISA) reader at 490 nm or 570 nm. Within a certain cellular range, the number of viable cells is directly proportional to the amount of formazan formed. Referring to the values ​​of the blank control group, the number of viable cells in the experimental group can be indirectly reflected. The specific experimental steps are as follows: 1) Take Caco-2 cells that are in normal growth state and in the logarithmic growth phase, digest them with trypsin to form a single cell suspension, and adjust the concentration of the Caco-2 cell suspension to 1×104 cells / mL. 2) Spread the cell suspension evenly into a 96 cell culture plate, add 100 μL to each well, and fill the edge wells with 100 μL of PBS buffer. Incubate the plate at 37°C in a 5% CO2 cell culture incubator. 3) After 24 hours of culture, the cell state was observed under a microscope, showing uniform monolayer growth. The old culture medium was carefully aspirated from each well, and different concentrations of rumepiride and its compounds I-1 to I-4, along with the control example compounds, were added to each well. The final concentrations of rumepiride and its compounds I-1 to I-4, along with the control example compounds, in each experimental group were 2.29, 18.28, 73.125, 146.25, 292.5, and 585 μmol / L, respectively. Each concentration group had three replicates. Control wells (containing an equal volume of Caco-2 cell suspension, without drug administration) and zeroing wells (containing no cells, no drug administration, and 100 μL of an equal volume of culture medium) were also included. The cells were then placed in a cell culture incubator for further culture. 4) After culturing for 4 hours, discard the old culture medium, add fresh culture medium, and add 20 μL of MTT solution (5 mg / mL) to each well of the 96-well plate under dark conditions, and incubate in an incubator. 5) After incubating for 4 h, gently remove the 96-well plate from the incubator, carefully aspirate the liquid from each well, add 150 μL of DMSO solution, and shake on a shaker at 37 °C for 10–15 min to completely dissolve the blue-purple crystals. 6) Use an ELISA reader to measure the absorbance (OD) value of each well at a wavelength of 490 nm, and calculate the cell inhibition rate of each experimental group: 7) The results showed that after 4 hours of treatment with rumepiride and its compounds I-1 to I-4 at concentrations of 2.29, 18.28, 73.125, 146.25, 292.5, and 585 μmol / L, the survival rate of Caco-2 cells could still reach over 80%, indicating that the drugs had almost no toxic effect on the cells within this uptake time and concentration range.

[0112] Example 17: Local safety evaluation 1. In vitro tube hemolytic test 1.1 Test Methods Unless otherwise specified, for injectable preparations intended for non-intravascular administration, the test solution shall be prepared by diluting the clinically used concentration specified in the drug's instructions for use with 0.9% sodium chloride solution at a ratio of 1:3. For injectable preparations intended for intravascular administration, the clinically used concentration of the test substance shall be used as the concentration of the test solution.

[0113] 1.2 Preparation of test sample 1.2.1 Preparation of Red Blood Cell Suspension: 9.8 mL of blood was collected from the heart of a New Zealand rabbit and placed in a beaker. The blood was stirred in the same direction with a fine glass rod to remove fibrinogen, and then transferred to a centrifuge tube. Approximately 10 times the volume of sodium chloride injection solution was added and mixed thoroughly. The mixture was centrifuged at 1500 rpm for 15 min, and the supernatant was removed. The precipitated red blood cells were washed three times with sodium chloride injection solution as described above until the supernatant was colorless and transparent. Finally, the obtained red blood cells were diluted with sodium chloride injection solution at a volume ratio to prepare a 2% red blood cell suspension.

[0114] 1.2.2 Test Number and Method Table 9 Test Numbers and Methods

[0115] Note: All concentrations above are initially prepared as 210 mg / vial of lumepirozoline. For experimental dilution, benzyl benzoate was used to prepare a solution to 0.8 mg / ml.

[0116] First, take seven test tubes and number them sequentially as Experiment 1 to 7. Add 2.5 ml of 2% red blood cell suspension to each tube. Add 2.0 ml of sodium chloride injection to tubes 1-5, 2.5 ml of sodium chloride injection to tube 6, and 2.5 ml of distilled water to tube 7 as a positive control. Add 0.5 ml of 0.8 mg / mL lumepimeron injection and compound I-1-4 injection to tubes 1-5, respectively. Incubate in a water bath at 37℃±0.5℃. Observe every 15 minutes initially, then every hour thereafter, for a total of 3 hours. Visually inspect each tube for hemolysis; the judgment criteria are shown in Table 10.

[0117] Table 10 Criteria for Judging Hemolysis and Agglutination of Erythrocytes

[0118] 1.3 Test Results In tube #7 (positive control), the solution turned clear red after adding distilled water in about 5 minutes, with no red blood cell precipitate at the bottom, indicating hemolysis. In tubes #1-5, the solution was initially turbid after adding the test sample, without a clear red or brownish-red color, indicating no hemolysis at that stage. Over time, the red blood cells in tubes #2-5 began to settle, and all settled after 3 hours. In tube #1, some red blood cells remained in the upper layer after 2 hours, indicating partial hemolysis. Tubes #2-5 showed similar patterns to tube #6, but differed significantly from tube #7. The results are shown in Table 11.

[0119] Table 11 Results of erythrocyte hemolysis

[0120] Note: In the table, "-" indicates no hemolysis, and "+" indicates hemolysis.

[0121] The experimental results show that the compound of the present invention does not cause hemolysis upon injection, while the parent compound has a potential for hemolysis due to lumepirozol injection.

[0122] 2. Stimulation test 1) Muscle stimulation test Healthy female SD rats, weighing 300–350 g, were selected and allowed free access to food and water during the experiment. Following a bilateral comparison method, 0.2 mL (approximately 30 times the dose recommended by the European Medicines Agency) of lumepirolimus injection and the injection of this invention (dilution method and concentration as in the in vitro hemolysis test, 0.8 mg / mL) were injected intramuscularly into the quadriceps femoris muscle of the left hind limb of the rats. The same volume of 0.9% saline was injected intramuscularly into the quadriceps femoris muscle of the right hind limb as a control. The stimulation response scores of the quadriceps femoris muscle were evaluated according to Table 12. The stimulation response scores of the lumepirolimus injection group, the injection of this invention group, and the 0.9% saline injection group were added together to obtain their respective total scores. The final score was obtained by dividing the total score by the number of rats, and the stimulation level was determined according to Table 13. If necessary, oily muscle tissue was collected, fixed in 4% paraformaldehyde solution, and sent to a third-party company for section preparation and pathological examination such as HE staining.

[0123] Table 12 Criteria for Determining the Grade of Muscle Stimulation Response

[0124] Table 13 Average scores and levels of muscle stimulation

[0125] Post-mortem results: 48 hours after administration, the quadriceps femoris muscle injected with 0.9% saline and the quadriceps femoris muscle injected with the injection of the present invention were both rosy in color, elastic to the touch, and showed no obvious abnormalities. However, the muscle at the site of lumepirocin injection showed redness and congestion, with a diameter of about 1 cm, and mild irritation.

[0126] 2) Subcutaneous tissue irritation test Healthy female SD rats, weighing 300–350 g, were selected and allowed free access to food and water during the experiment. Following a bilateral comparison method, rats were placed in a prone position and injected subcutaneously into the left side of the neck with 0.2 mL (approximately 30 times the dose recommended by the European Medicines Agency) of lumepimeperone injection and the injectable formulation of this invention (dilution method and concentration as in the in vitro hemolytic test, 0.8 mg / mL). The same volume of 0.9% saline was injected subcutaneously into the right side of the neck as a control. The inflammatory response at the subcutaneous injection site was scored according to the skin irritation response evaluation criteria. The irritation response scores of the lumepimeperone injection and injectable formulation groups and the 0.9% saline injection group were added together to obtain their respective total scores. The final score was obtained by dividing the total score by the number of rats. The irritant intensity of the subcutaneous injection was evaluated according to the skin irritation intensity standard. If necessary, subcutaneous tissue encapsulated with gel was taken, fixed in 4% paraformaldehyde solution, and sent to a third-party company for section preparation and pathological examination such as HE staining.

[0127] The experimental results showed that, 48 hours after a single subcutaneous injection of lumepimeron injection and the injection of this invention into the neck of the experimental rats, no obvious pathological changes were observed in the subcutaneous tissue of the neck. According to the evaluation criteria, neither caused any irritation to the subcutaneous tissue.

[0128] Example 18: Experimental study on in vitro cytotoxicity of normal human hepatocytes.

[0129] 1. Experimental Materials 1.1 Cells: LO2 cells, a human hepatitis cell line 1.2 Drug: Compound of Example 11 of this invention, HPLC purity 99.54% 1.3 Reagents and Instruments: Modified RPMI-1640 culture medium, penicillin-streptomycin solution, 0.25% trypsin-EDTA, fetal bovine serum, MTT, dimethyl sulfoxide, CO-150 carbon monoxide incubator, SW-CJ-2F medical clean bench, CKX-41-32 inverted microscope, CU600 electric thermostatic water bath, RT-2100C enzyme-linked immunosorbent assay (ELISA) analyzer. 2 Experimental Methods 2.1 Reagent Preparation 2.1.1 Preparation of MTT: Weigh 0.25g of MTT using a precision balance and place it in a 50mL volumetric flask. Add an appropriate amount of PBS, incubate in a 50-60℃ water bath, and shake well to dissolve completely. Add PBS to the mark to prepare a 5mg / kg solution. Filter the solution through a 0.22μm microporous membrane for sterilization, aliquot, and store in a refrigerator at 4℃ protected from light.

[0130] 2.1.2 Preparation of cell cryopreservation solution: Mix 20% serum, 10% DMSO and 70% 1640 medium evenly and store at -20℃.

[0131] 2.1.3 A stock solution of the drug was prepared using DMSO, with typical compounds I-1 and I-4 of this invention as representative compounds. The stock solution was then diluted with culture medium to the concentration of the drug to be used. The final concentration of DMSO was controlled to be ≤0.1%.

[0132] 2.2 LO2 cell culture: Normal human LO2 cells were placed in a 25cm² culture medium. 2 Add approximately 4–5 mL of RPMI-1640 culture medium containing 10% FBS to cell culture flasks and incubate at 37°C in a 5% CO2 saturated humidity cell culture incubator. Change the culture medium every 2 days and observe cell growth daily. Once cells reach 80% confluence, passage or cryopreserve them. Use cells from passages 5–7 for formal experiments.

[0133] 2.3 Grouping and Dosing Experiments: The experiment was divided into a normal cell control group and different concentrations of the drug group of the present invention, based on the preliminary experimental results. The concentrations were 10.0, 100, 200, 1000, 2000, and 10000 μmol / L.

[0134] 2.4 Hepatocyte MTT assay: Logarithmic growth phase LO2 cells were prepared into a cell suspension of 5.0 × 10³ cells / mL and seeded into 96-well plates. A normal control group and different concentrations (10.0, 100, 200, 1000, 2000, and 10000 μmol / L) of the compound of the present invention were set up. After 24 h of culture, the culture medium was aspirated, and the cells were washed 2–3 times with PBS. Different concentrations of the compound of the present invention were added, with 8 replicates per concentration. The plates were incubated at 37°C in a 5% CO₂ incubator. After 24, 48, and 72 h of culture, MTT solution was added at each time point, and the plates were incubated in the dark for 4 h. After 4 h, the supernatant was aspirated, and 150 L DMSO was added to each well to dissolve the thiazolyl blue crystals. The plates were gently shaken to ensure uniform dissolution. The absorbance of each well was measured at 490 nm using a microplate reader. The absorbance value of each well directly reflects the number of cells. The experiment was repeated three times. The cell viability rate was calculated as follows: Cell viability rate (%) = Absorbance of each group (OD490) × 100 / Absorbance of the control group (OD490).

[0135] 2.5 Statistical Analysis All data are expressed as mean ± standard deviation and were processed using SPSS 17.0 statistical software. t-tests were performed for statistical analysis; paired t-tests were used for self-comparisons, and unpaired t-tests were used for inter-group comparisons. The significance level was P < 0.05.

[0136] 3 Experimental Results Table 14 In vitro cytotoxicity assay of normal human hepatocytes

[0137] Conclusion: After 72 h of administration, the OD values ​​of cells in each group showed an increasing trend at different concentrations of the present invention, but the growth rate decreased, indicating that the cells were still in the growth stage and the growth rate was somewhat inhibited. The typical representative compounds I-1 and I-4, at different concentrations, showed no inhibitory effect on cells. Compared with the normal group, the cell survival rate was greater than 90%. Within the range of 10.0, 100, 200, 1000, 2000, and 10000 μmol / L, there was almost no inhibition of cell growth and no cytotoxicity.

[0138] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. The compound represented by Formula I or a pharmaceutically acceptable salt: ， Where n is an integer from 4 to 14.

2. The compound of formula I as claimed in claim 1, characterized in that, The pharmaceutically acceptable salt of the compound shown in Formula I is the compound shown in Formula II: ， Wherein n is as described in claim 1; X is a monobasic inorganic acid, a dibasic inorganic acid, a ternary inorganic acid, or an organic acid.

3. The compound of formula I as claimed in claim 1, characterized in that, The compound represented by Formula I is any of the following compounds: 。 4. A method for preparing the compound represented by Formula I according to claim 1 or a salt thereof, characterized in that: Includes the following steps: The compound of formula I was prepared by reacting lumepirozol with acyl chloride in a reaction solvent and with an acid-binding agent, as shown in the following reaction formula: ， Where R is C 4-14 Alkyl groups that are straight-chain or branched.

5. The method for preparing the compound of formula I or its salt according to claim 4, characterized in that: The reaction solvent is selected from one or more of n-pentane, n-hexane, n-heptane, cyclohexane, petroleum ether, toluene, xylene, dimethyl ether, diethyl ether, isopropyl ether, tetrahydrofuran, methyl acetate, ethyl acetate, dichloromethane, dichloroethane, and chloroform, preferably tetrahydrofuran; the acid-binding agent is selected from diisopropylaminolithium, n-butyllithium, phenyllithium, methyllithium, and tert-butoxide lithium, preferably diisopropylaminolithium.

6. A pharmaceutical composition comprising the compound of any one of claims 1 to 2 or a salt thereof, and a pharmaceutically acceptable carrier thereof.

7. The pharmaceutical composition of claim 6, formulated for intramuscular, intradermal, or subcutaneous injection.

8. The pharmaceutical composition of claim 7, wherein the pharmaceutically acceptable oil is selected from vegetable oils, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, peanut oil, poppy seed oil, tea seed oil, and soybean oil, and the other pharmaceutically acceptable solvent, if present, comprises benzyl alcohol, benzyl benzoate, or a combination thereof.

9. Use of the compound of any one of claims 1 or 2 or a salt thereof, or the pharmaceutical composition of any one of claims 6-8, in the preparation of a medicament for treating mood disorders, sleep disorders, psychotic disorders, excitement and agitation, including psychomotor states of excitement disorders, behavioral disorders, autistic behaviors, and / or cognitive impairments.

10. The mood disorder according to claim 9 includes major depressive disorder, atypical depression, melancholic depression, psychotic depression, depression unless otherwise stated, postpartum depression, dysphoric disorder, depressive mood regulation disorder, and seasonal affective disorder.

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