Use of a compound for the manufacture of an antidepressant medicament

Abstract

The application provides application of a compound in preparation of an antidepressant drug. The application proves through experiments that the compound with the structural formula as shown in formula (1) can effectively resist depression, and the effect of the compound in resisting depression is accurate and significant. The application provides a brand-new strategy for resisting depression, and has a good application prospect.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to the use of a compound in the preparation of antidepressant drugs. Background Technology

[0002] Depression is a common mental disorder characterized by persistent low mood, loss of interest, cognitive impairment, and a range of physical symptoms. According to the World Health Organization (WHO), depression is a leading cause of disability worldwide, imposing a significant health and economic burden on patients, families, and society.

[0003] Currently, hundreds of millions of patients worldwide suffer from this condition, and the incidence rate is increasing year by year. Current antidepressants still have significant limitations, with extremely low cure rates. Therefore, the development of new antidepressants has become an urgent need in the global mental health field. Summary of the Invention

[0004] In view of this, in order to overcome the shortcomings of the prior art, the present invention is proposed.

[0005] The first aspect of this invention provides the use of compounds or forms thereof with the structural formula shown in formula (1) in the preparation of antidepressant drugs:

[0006]

[0007] Equation (1).

[0008] In some embodiments, R1 is optionally a straight-chain or branched C1-C4 alkyl, a straight-chain or branched C2-C4 alkenyl, a straight-chain or branched C2-C4 alkynyl, a straight-chain or branched C1-C4 alkoxy, a straight-chain or branched C3-C10 cycloalkyl, aryl, heteroaryl, heterocyclic, hydrogen, or halogen.

[0009] In some implementations, the halogen includes, but is not limited to, fluorine, chlorine, bromine, iodine, and astatine.

[0010] In some embodiments, R1 is selected from C1 alkyl groups.

[0011] In other embodiments, R1 is a functional group such as carboxyl, carbonyl (C=O), amino (-NH2), hydroxyl (-OH), cyano (-CN).

[0012] In other embodiments, R1 is a substituent with a functional group as described herein, for example, R1 is -CH2-COOH.

[0013] As used herein, the term “C1-C4 alkyl” generally refers to a saturated hydrocarbon group having 1 to 4 carbon atoms in a straight-chain or branched configuration, including but not limited to methyl, ethyl, n-propyl (also known as propyl or propalkyl), isopropyl, n-butyl (also known as butyl or butalkyl), isobutyl, sec-butyl, tert-butyl, etc.

[0014] As used herein, the term "C2-C4 alkenyl" generally refers to a partially unsaturated hydrocarbon group having 2 to 4 carbon atoms in a straight-chain or branched configuration and having one or more carbon-carbon double bonds therein, including but not limited to ethenyl (also known as vinyl), allyl, propenyl, and butenyl. In some respects, C2-C4 alkenyl includes, but is not limited to, C2-C3 alkenyl and C3-C4 alkenyl.

[0015] As used herein, the term "C2-C4 ynyl" generally refers to a partially unsaturated hydrocarbon group having 2 to 4 carbon atoms in a straight-chain or branched configuration and having one or more carbon-carbon triple bonds therein, including but not limited to ethynyl, propynyl, and butynyl. In some respects, C2-C4 ynyl includes, but is not limited to, C2-C3 ynyl and C3-C4 ynyl.

[0016] As used herein, the term “C1-C4 alkoxy” generally refers to a saturated hydrocarbon group having 1 to 4 carbon atoms in a straight-chain or branched configuration of the following formula: -O-C1-C4 alkyl, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.

[0017] As used herein, the term "C3-C10 cycloalkyl" generally refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic hydrocarbon group, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, 1H-indenyl, indenyl, tetrahydro-naphthyl, etc. In some respects, C3-C10 cycloalkyl includes, but is not limited to, C3-C8 cycloalkyl and C5-C8 cycloalkyl.

[0018] As used herein, the term "aryl" generally refers to a monocyclic, bicyclic, or polycyclic aromatic carbon atom ring structure group, including but not limited to phenyl, naphthyl, anthracene, fluorenyl, azulel, phenanthryl, etc.

[0019] As used herein, the term "heteroaryl" generally refers to a monocyclic, bicyclic, or polycyclic aromatic carbon ring structural group in which one or more carbon atom ring members are replaced by one or more heteroatoms (e.g., O, S, or N atoms) where structural stability allows, including but not limited to furanyl, thiophene, pyrrole, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, 1,3-thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridylylpyrazine. Azinyl, triazinyl, indoleyl, indazoleyl, indoleazinyl, isoindoleyl, benzofuranyl, benzothiophenyl, benzimidazolyl, 1,3-benzothiazolyl, 1,3-benzooxazolyl, purineyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, 1,3-diazinyl, 1,2-diazinyl, 1,2-diazolyl, 1,4-diazanaphthyl, acridineyl, furano[3,2-b]pyridyl, furano[3,2-c]pyridyl, furano[2,3-c]pyridyl pyridyl, 6H-thieno[2,3-b]pyrrolyl, thieno[3,2-c]pyridyl, thieno[2,3-d]pyrimidinyl, 1H-pyrrol[2,3-b]pyridyl, 1H-pyrrol[2,3-c]pyridyl, 1H-pyrrol[3,2-b]pyridyl, pyrrol[1,2-a]pyrazinyl, pyrrol[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrazinyl, imidazo[1,2- [a]pyridyl, 3H-imidazo[4,5-b]pyridyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,2,4]triazolo[1,5-a]pyridyl, [1,2,4]triazolo[4,3-a]pyridyl, etc.

[0020] In some respects, the nomenclature of heteroaryl groups may differ. For example, in non-limiting instances, furanyl may also be called furyl, thienyl may also be called thiophenyl, pyridinyl may also be called pyridyl, benzothienyl may also be called benzothiophenyl, and 1,3-benzoxazolyl may also be called 1,3-benzooxazolyl.

[0021] In some other respects, the term heteroaryl may also include other regioisomers, for example, in non-limiting examples, wherein the term pyrrole may also include 2H-pyrrole, 3H-pyrrole, etc., the term pyrazolyl may also include 1H-pyrazolyl, etc., the term imidazolyl may also include 1H-imidazolyl, etc., the term triazolyl may also include H-1,2,3-triazolyl, etc., the term oxadiazolyl may also include 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, etc., the term tetrazolyl may also include 1H-tetrazolyl, 2H-tetrazolyl, etc., the term indole may also include 1H-indoleyl, etc., the term indazole may also include 1H-indazole, 2H-indazole, etc., the term benzimidazolyl may also include 1H-benzimidazolyl, and the term purine may also include 9H-purine, etc.

[0022] As used herein, the term "heterocyclic group" generally refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic carbon ring structural group in which one or more carbon atom ring members are replaced by heteroatoms such as O, S, or N atoms, where structural stability allows. This includes, but is not limited to, ethylene oxide, oxacyclobutane, azacyclobutane, tetrahydrofuranyl, pyrrolinyl, pyrrolylalkyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, isoxazolinyl, isoxazolinyl, isothiazolinyl, isothiazolinyl, isothiazolinyl, oxazolinyl, thiazolinyl, thiazolinyl, triazolinyl, triazolinyl, oxadiazolinyl, oxadiazolinyl, thiadiazolinyl, thiadiazolinyl, tetrazolinyl, tetrazolinyl, pyranyl, dihydro-2H-pyranyl, thiazolin ... thiazolinyl, thiazolinyl, thiazolinyl, thiazolinyl, thiazolinyl, thiazolinyl, thiazolinyl, thiazolinyl, thiazolinyl, pyranyl, di 1,3-dioxyl, 1,2,5,6-tetrahydropyridyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,4-diazacycloheptyl, 1,3-benzodioxane-pentenyl, 1,4-benzodioxyl, 2,3-dihydro-1,4-benzodioxin, hexahydropyrrolo[3,4-b] Pyrrolo-(1H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4b]pyrrolo-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrolo-(1H)-yl, hexahydropyrrolo[3,4-b]pyrrolo(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrolo-(2H)-yl (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrolo-(2H)-yl, hexahydropyrrolo[3,4-c]pyrrolo-(1H)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrolo(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-c]pyrrolo-(1H)-yl, octahydro-5H- Pyrrolo[3,2-c]pyridyl, octahydro-6H-pyrrolo[3,4-b]pyridyl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridyl, (4aS,7aS)octahydro-6H-pyrrolo[3,4-b]pyridyl, hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (7R,8aS)- Hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl Azine-(1H)-yl, hexahydropyrrolo[1,2-a]pyrazin-(2H)-one, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl, (1R,5S)-3-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl, (1R,5S)-8azabicyclo[3.2.1] Octyl, 8-azabicyclo[3.2.1] Oct-2-enyl, (1R,5S)-8-azabicyclo[3.2.1] Oct-2-enyl, 9-azabicyclo[3.3.1] Nonyl, (1R,5S)-9-azabicyclo[3.3.1] Nonyl, 2,5-diazabicyclo[2.2.1] Heptyl, (1S,4S)-2,5-diazabicyclo[2.2.1] Heptyl, 2,5-diazabicyclo[2.2.2] Octyl 3,8-diazabicyclo[3.2.1]octyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octyl, 1,4-diazabicyclo[3.2.2]nonyl, azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl, 5,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl, 6,9-diazaspiro[4.5]decyl, etc. Where the available valence allows, the heterocyclic group may optionally be substituted on the carbon or nitrogen ring member by the substituents described herein.

[0023] In some respects, the nomenclature of heterocyclic groups may differ; for example, in non-limiting instances, 1,3-benzodioxacyclopentenyl may also be called benzo[d][1,3]dioxacyclopentenyl, and 2,3-dihydro-1,4-benzodioxinyl may also be called 2,3-dihydrobenzo[b][1,4]dioxinyl.

[0024] In some embodiments, R2 is optionally aryl or heteroaryl. For an explanation of aryl and heteroaryl, see the explanation of aryl and heteroaryl in R1.

[0025] In some preferred embodiments, the aryl group is selected from phenyl, naphthyl, anthraceneyl, fluorenyl, azulel, and phenanthrene.

[0026] In some other preferred embodiments, the heteroaryl group is selected from furanyl, thiophene, pyrrole, pyrazolyl, and imidazolyl. In the most preferred embodiment, the heteroaryl group is selected from furanyl.

[0027] The scope of this invention also includes compounds of formula (1), wherein one or more atoms are substituted with specific isotopes of the corresponding atoms. For example, the invention covers compounds of formula (1) wherein one or more hydrogen atoms (or, for example, all hydrogen atoms) are substituted with deuterium atoms (i.e., 2H; also referred to as "D"). Accordingly, the invention also includes deuterium-rich compounds of formula (1). Naturally occurring hydrogen is an isotopic mixture containing about 99.98 mol% hydrogen-1 (1H) and about 0.0156 mol% deuterium (2H or D). The deuteration content at one or more hydrogen positions in a compound of formula (1) can be increased using deuteration techniques known in the art to which this invention pertains. For example, a compound of formula (1) or a reactant or precursor used to synthesize a compound of formula (1) can be subjected to an H / D exchange reaction using, for example, heavy water (D2O). The deuterium content can be determined, for example, using mass spectrometry or NMR spectroscopy. Unless otherwise specifically stated, it is preferable that compounds of formula (1) are not deuterium-rich. Accordingly, the compound of preferred formula (1) contains naturally occurring hydrogen atoms or 1H hydrogen atoms.

[0028] In some embodiments, the form of the compound includes, but is not limited to, pharmaceutically acceptable salts of the compound, solid forms, all possible stereoisomers, tautomers, or amorphous forms.

[0029] In some embodiments, the form of the compound includes, but is not limited to, one or more of the following: pharmaceutically acceptable salts, solvates, eutectics, amorphous forms, racemic mixtures, enantiomers, diastereomers, stereoisomers, or tautomers.

[0030] In some embodiments, the solvate includes hydrates.

[0031] As used herein, the term "salt" refers to an acidic salt formed with an inorganic and / or organic acid and a basic salt formed with an inorganic and / or organic base. Additionally, when a compound of formula (1) or its form contains both a basic moiety (e.g., but not limited to an amine moiety) and an acidic moiety (e.g., but not limited to a carboxylic acid), an amphoteric ion ("internal salt") may be formed and included in the term "salt" as used herein.

[0032] As used herein, the term “pharmaceutically acceptable salt” means a salt of the compound described herein that is safe and effective (i.e., non-toxic, physiologically acceptable) and biologically active for use in subjects, but other salts are also available. A salt of a compound of formula (1) may be formed, for example, by reacting a compound of formula (1) or its form with a certain amount (e.g., an equivalent) of an acid or base in a medium (e.g., a medium in which the salt is precipitated) or in an aqueous medium, followed by lyophilization.

[0033] Pharmaceutically acceptable salts include one or more salts containing acidic or basic groups present in the compounds described herein. Specific aspects of acid addition salts include, but are not limited to, acetates, ascorbic acid salts, benzoates, benzenesulfonates, hydrogen sulfates, hydrogen tartrates, borates, bromides, butyrates, chlorides, citrates, camphorates, camphor sulfonates, ethanesulfonates, formates, fumarates, gentianates, gluconates, glucuronates, glutamates, iodides, isonicotinates, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, dihydroxynaphthalate, pantothenates, phosphates, propionates, sucroseates, salicylates, succinates, sulfates, tartrates, thiocyanates, toluenesulfonate (also known as tosylate), trifluoroacetates, etc. Some specific aspects of acid addition salts include chlorides, bromides, or dichlorides.

[0034] Suitable base addition salts include, but are not limited to, aluminum salts, ammonium salts, calcium salts, lithium salts, magnesium salts, potassium salts, sodium salts, and zinc salts.

[0035] All such acid and base addition salts are intended to be included within the pharmaceutically acceptable range of salts as described herein. Furthermore, for the purposes of this specification, all such acid and base addition salts are considered equivalent to the free form of the respective compound.

[0036] As used herein, the term "solvent" means the physical bond between a compound described herein and one or more solvent molecules. This physical bond involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, a solvate can be separated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. As used herein, "solvent" includes both a solution phase and a separable solvate. Non-limiting examples of suitable solvates include ethanolides, methanolides, etc.

[0037] As used in this article, the term "hydrate" refers to a solvation in which the solvent molecules are water.

[0038] "Eutectic" refers to a crystal structure containing at least two different compounds that are solids in their pure form under ambient conditions. Eutectic is made of neutral molecular species, and all species remain neutral after crystallization; furthermore, typically and preferably, eutectic is a homogeneous crystalline material in which two or more building compounds are present in a defined stoichiometric ratio.

[0039] The compounds of formula (1) may be amorphous or exist in one or more different crystalline states (polymorphs), which may have different macroscopic properties (such as stability) or exhibit different biological properties (such as activity). The present invention relates to the amorphous and crystalline forms of compounds of formula (1), mixtures of compounds of formula (1) in different crystalline states, and their amorphous or crystalline salts.

[0040] In some embodiments, the compounds described herein may contain one or more chiral centers and thus may exist as a racemic mixture (R / S) or substantially pure enantiomers and diastereomers.

[0041] In some implementations, the chiral center is introduced via R1.

[0042] Compounds of formula (1) or in other forms may contain asymmetric or chiral centers and thus exist in different stereoisomers. This specification is intended to include all stereoisomers of compounds of formula (1) and mixtures thereof.

[0043] Compounds of formula (1) and their forms may further exist in tautomer forms. All such tautomer forms are considered and intended to be included within the scope of compounds of formula (1) or their forms as described herein.

[0044] In addition, this specification includes all geometric and positional isomers. The terms “salt,” “solvent,” etc., are intended to apply equally to the enantiomers, stereoisomers, or tautomers of the compounds described herein.

[0045] In some preferred embodiments, the compounds described herein do not contain a chiral center.

[0046] As used in this invention, the term "depression" is a general term for a class of diseases characterized primarily by low mood or emotional state, accompanied by varying degrees of cognitive and behavioral changes. Psychotic symptoms may be present, such as hallucinations and delusions. These diseases often recur, with complete remission during remission periods, and some patients have residual symptoms.

[0047] In some implementations, the depression includes, but is not limited to, major depressive disorder, unipolar depression, treatment-resistant depression, resistant depression, anxiety depression, bipolar depression, and dysphoric mood.

[0048] In this invention, “antidepressant” means: (i) preventing a subject who may be susceptible to a disease, disorder and / or condition but has not yet been diagnosed with the disease, disorder and / or condition from developing the disease, disorder or condition; (ii) inhibiting the disease, disorder or condition, i.e. preventing its development; and / or (iii) alleviating the disease, disorder or condition, i.e., causing the disease, disorder and / or condition to subside.

[0049] A second aspect of the present invention provides an antidepressant pharmaceutical composition comprising a compound or a form thereof having the structural formula shown in formula (1), and a pharmaceutically acceptable carrier and / or excipient thereof.

[0050] In some embodiments, the form of the compound includes, but is not limited to, one or more of the following: pharmaceutically acceptable salts, solvates, eutectics, amorphous forms, racemic mixtures, enantiomers, diastereomers, stereoisomers, or tautomers.

[0051] In some embodiments, the pharmaceutical composition may optionally comprise one or more pharmaceutically acceptable carriers and / or excipients, such as, but not limited to, excipients, diluents, fillers, disintegrants, lubricants, binders, colorants, pigments, stabilizers, preservatives, antioxidants and / or solubility enhancers, or any combination thereof. Specifically, the pharmaceutical composition may contain one or more solubility enhancers, such as, for example, poly(ethylene glycol), including poly(ethylene glycol), ethylene glycol, propylene glycol, nonionic surfactants, tyloxapol, polysorbate 80, polyethylene glycol-15-hydroxystearate, phospholipids, lecithin, myristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearate phosphatidylcholine, cyclodextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-γ-cyclodextrin, hydroxypropyl... γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, sulfonyl ether-β-cyclodextrin, sulfonyl ether-γ-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, disaccharosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriose-β-cyclodextrin, maltotriose-γ-cyclodextrin, disaccharosyl-β-cyclodextrin, methyl-β-cyclodextrin, carboxyl alkyl sulfides, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, vinyl acetate copolymer, vinylpyrrolidone, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, or any combination thereof.

[0052] In some implementations, the compound or its form represented by formula (1) is administered in a therapeutically effective amount.

[0053] As used herein, the term “effective amount” is equivalent to “therapeutic effective amount” and means an amount of a compound of formula (1) or a pharmaceutically acceptable salt, solvate, hydrate, eutectic, racemic, enantiomer, diastereomer, stereoisomer, or tautomer thereof, which achieves a target plasma concentration that is effective in treating or ameliorating depression as described herein and thus produces the desired therapeutic, ameliorating, inhibitory, or preventative effect in a subject in need. In one aspect, an effective amount may be the amount required to treat depression in a subject or patient (more specifically, a human).

[0054] As used herein, the term "subject" refers to an animal or any living organism that has sensory and motor abilities and requires oxygen and organic food. Non-limiting examples include rodents (e.g., guinea pigs, hamsters, rats, mice), canines (e.g., dogs), cats (e.g., cats), pigs (e.g., pigs), equines (e.g., horses), non-human primates (e.g., monkeys, apes, baboons, gorillas, chimpanzees, orangutans), or humans. In a preferred embodiment, the subject is selected from humans.

[0055] In some implementations, the effective dose for a given subject can be determined through routine testing, which can be performed by a clinician or practitioner in the field based on factors relevant to the subject. Dosage and administration can be adjusted to provide adequate levels of the drug or maintain the desired effect. Factors considered may include, but are not limited to, genetic screening, severity of the disease state, disease progression, the subject's overall health status, race, age, weight, sex, diet, timing and frequency of administration, drug combination, response sensitivity, experience with other therapies, and tolerance / responsiveness to the therapy.

[0056] In some implementations, the dosage to achieve an effective target plasma concentration may be once daily (once within a 24-hour period), twice daily (once within a 12-hour period), three times daily (once within an 8-hour period), or four times daily (once within a 6-hour period).

[0057] In some implementation schemes, the dosage required to achieve the effective target plasma concentration can be administered for one, two, three, or even more days.

[0058] For any compound, the effective amount can initially be estimated in cell culture assays or in relevant animal models (e.g., mice, guinea pigs, chimpanzees, marmosets, or tamarins). Relevant animal models can also be used to determine appropriate concentration ranges and routes of administration. This information can then be used to determine the effective dose and route of administration to humans. Therapeutic efficacy and toxicity can be determined in cell cultures or laboratory animals using standard pharmaceutical procedures, such as EDTA. 50(Dose effective for 50% of the population) and LD 50 (The dose that would be lethal to 50% of the population). The dose ratio between therapeutic and toxic effects is the therapeutic index, which can be expressed as the ratio LD50. 50 / ED 50 In some respects, the effective dose achieves a high therapeutic index. More specifically, the dose is within a range of circulating concentrations that include an ED50 with little or no toxicity. The dose can vary within this range depending on the dosage form used, patient sensitivity, and route of administration.

[0059] The compounds or their forms or pharmaceutical compositions described herein can be administered to subjects using any pharmaceutical dosage form known in the art. Non-limiting examples include non-gastrointestinal dosage forms and gastrointestinal dosage forms.

[0060] In some preferred embodiments, the pharmaceutical composition is selected from non-gastrointestinal dosage forms.

[0061] In some implementations, the compound of formula (1) or its form, or the above-described pharmaceutical composition, may be administered to the subject via any convenient route of administration (whether systemic / peripheral or at the site of desired action).

[0062] In some embodiments, the compound or its form or pharmaceutical composition may be administered orally in the form of tablets, capsules, ovules, elixirs, solutions or suspensions for rapid, delayed, modified, sustained, pulsatile or controlled release applications, and these forms may contain flavoring or coloring agents.

[0063] In some embodiments, the tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, and glycine; disintegrants such as starch (preferably corn, potato, or cassava starch), sodium carboxymethyl starch, croscarmellose sodium, and certain complex silicates; and granulating binders such as polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sucrose, gelatin, and gum arabic. Additionally, lubricants such as magnesium stearate, stearic acid, glyceryl docosinate, and talc may be included. Similar types of solid compositions may also be used as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, cellulose, or high molecular weight polyethylene glycol. For aqueous suspensions and / or elixirs, the agent may be combined with various sweeteners or flavorings, colorants or dyes, emulsifiers and / or suspending agents, and diluents (such as water, ethanol, propylene glycol, and glycerin) and combinations thereof.

[0064] If administered parenterally, examples of such administration include one or more of the following: intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracardiac, intramuscular, or subcutaneous administration of the compound or pharmaceutical composition, and / or administration via infusion techniques. For parenterally administration, the compound is preferably used in the form of a sterile aqueous solution, which may contain other substances, such as sufficient salt or glucose, to make the solution isotonic with blood. If necessary, the aqueous solution should be appropriately buffered (preferably to a pH of 3 to 9). The preparation of suitable parenteral formulations under sterile conditions can be readily accomplished using standard pharmaceutical techniques known to those skilled in the art to which this invention pertains.

[0065] Alternatively, the compound or its form, or the pharmaceutical composition, may be administered as a suppository or vaginal suppository, or topically as a gel, hydrogel, lotion, solution, cream, ointment, or powder. The compounds of the present invention may also be administered dermally or transdermally, for example, through the use of a skin patch.

[0066] In some embodiments, the compound or its form, or a pharmaceutical composition, may also be administered via a sustained-release system. Suitable examples of sustained-release compositions include semi-permeable polymer matrices in the form of molded articles, such as films or microcapsules. Sustained-release matrices include, for example, polylactide, copolymers of L-glutamic acid and γ-ethyl-L-glutamic acid, poly(2-hydroxyethyl methacrylate), ethylene vinyl acetate, or poly-D-(-)-3-hydroxybutyric acid. Sustained-release pharmaceutical compositions also include compounds encapsulated in liposomes. Liposomes containing compounds of the present invention may be prepared by methods known in the art to which the invention pertains.

[0067] In some embodiments, the compound or its form, or pharmaceutical composition, may also be administered via the pulmonary, rectal, or ocular routes. For ophthalmic use, these compounds or their forms, or pharmaceutical compositions, may be formulated as micronized suspensions in isotonic, pH-adjusted, sterile saline, or preferably as solutions in isotonic, pH-adjusted, sterile saline, optionally in combination with a preservative (such as benzalkonium chloride). Alternatively, these compounds or their forms, or pharmaceutical compositions, may be formulated as ointments, such as petrolatum.

[0068] In some embodiments, it is also envisioned to prepare dry powder formulations of compounds of formula (1) or their forms or pharmaceutical compositions for pulmonary administration (particularly inhalation). Such dry powders can be prepared by spray drying under conditions that produce substantially amorphous, glassy, ​​or substantially crystalline bioactive powders.

[0069] In some embodiments, for topical application to the skin, the compound or its form, or pharmaceutical composition, may be formulated as a suitable ointment containing an active compound suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsified wax, and water. Alternatively, these compounds or pharmaceutical compositions may be formulated as a suitable lotion or cream suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, dehydrated sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, hexadecyl ester wax, 2-octyldodecyl alcohol, benzyl alcohol, and water.

[0070] In some embodiments, the compounds of formula (1) may be used in combination with other therapeutic agents (e.g., a second therapeutic agent), particularly including other antidepressant drugs. When the compounds of the present invention are used in combination with a second therapeutic agent active against the same disease, the dosage of each compound may differ from the dosage when the compound is used alone. The combination of the compounds of the present invention with a second therapeutic agent may include the administration of the second therapeutic agent and the compounds of the present invention simultaneously / concurrently or sequentially / separately.

[0071] In some embodiments, the other antidepressant drugs include, but are not limited to, one or more of the following: tricyclic and tetracyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), serotonin and norepinephrine reuptake inhibitors (SRIs), serotonin-balanced antidepressants, norepinephrine and dopamine reuptake inhibitors (NROIs), selective norepinephrine reuptake inhibitors (NROIs), and norepinephrine and specific serotonergic antidepressants.

[0072] In some implementations, the tricyclic and tetracyclic antidepressants include, but are not limited to, amitriptyline, doxepin, clomipramine, imipramine, maprotiline, and mianserin.

[0073] In some implementations, the selective serotonin reuptake inhibitors include, but are not limited to, fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, and escitalopram.

[0074] In some embodiments, the monoamine oxidase inhibitor includes, but is not limited to, moclobemide.

[0075] In some implementations, the serotonin and norepinephrine reuptake inhibitors include, but are not limited to, venlafaxine and duloxetine.

[0076] In some implementations, the 5-hydroxytryptamine-balancing antidepressant includes, but is not limited to, trazodone.

[0077] In some implementations, the norepinephrine and dopamine reuptake inhibitors include, but are not limited to, bupropion.

[0078] In some implementations, the selective norepinephrine reuptake inhibitor includes, but is not limited to, reboxetine.

[0079] In some implementations, the norepinephrine and specific serotonergic antidepressants include, but are not limited to, mirtazapine.

[0080] A third aspect of the present invention provides a method for treating depression, the method comprising administering a therapeutically effective amount of a compound having the structural formula as shown in formula (1) or a form thereof, or a pharmaceutical composition as described in the second aspect of the present invention.

[0081] In some embodiments, the form of the compound includes, but is not limited to, one or more of the following: pharmaceutically acceptable salts, solvates, eutectics, amorphous forms, racemic mixtures, enantiomers, diastereomers, stereoisomers, or tautomers.

[0082] The advantages and beneficial effects of this invention are as follows:

[0083] This invention provides the application of a compound in the preparation of antidepressant drugs. Experiments demonstrate that the compound with the structural formula shown in formula (1) is effective in treating depression, exhibiting definite and significant therapeutic effects. This invention provides a novel strategy for treating depression and has promising application prospects. Attached Figure Description

[0084] Figure 1 Structural information of compounds with the structure of formula (1);

[0085] Figure 2 Purity information for compounds with the structure of formula (1);

[0086] Figure 3 The results of the sugar water preference experiment are shown in the figure.

[0087] Figure 4 The image shows the results of the tail suspension experiment;

[0088] Figure 5 The image shows the results of the forced swimming experiment. Detailed Implementation

[0089] The present invention will be further described below with reference to embodiments. The following description is merely a preferred embodiment of the present invention and is not intended to limit the invention in any other way. Any person skilled in the art may make equivalent modifications to the disclosed technical content to create equivalent embodiments. Any simple modifications or equivalent changes made to the following embodiments based on the technical essence of the present invention without departing from the scope of the invention are all within the protection scope of the present invention.

[0090] Example

[0091] I. Experimental Materials

[0092] 1. Mice

[0093] Mouse source: Spaford (Beijing) Biotechnology Co., Ltd.;

[0094] Mouse type: C57BL / 6J male;

[0095] Mice age: 8 weeks.

[0096] 2. Instruments

[0097] Restraint device: 50 mL centrifuge tubes with 0.5 cm diameter ventilation holes drilled in the tube walls to ensure unobstructed breathing for the animals. Clean the restraint tubes daily.

[0098] Stereo positioning device: Shenzhen Ruiward Life Science Co., Ltd.;

[0099] Microinfusion pump: Shenzhen Ruiwode Life Science Co., Ltd.

[0100] 3. Reagents

[0101] Physiological sodium chloride solution: Shijiazhuang No. 4 Pharmaceutical Co., Ltd. (National Drug Approval Number H20066533);

[0102] DMSO: Beijing Solarbio Science & Technology Co., Ltd. (Catalog No.: D8371 Cell Grade);

[0103] Solutol: Jiafashi (Shanghai) Trading Co., Ltd.

[0104] Compounds with the structure of formula (1): structural information as follows Figure 1 As shown, the purity information is as follows: Figure 2 As shown;

[0105] Dental cement: NISSIN, a dental resin adhesive.

[0106] II. Experimental Methods

[0107] 1. Compound preparation:

[0108] The compound was dissolved in 5% DMSO / 10% Solutol / 85% physiological saline to a concentration of 2 mg / mL and stored at -80°C.

[0109] 2. Animal experiments:

[0110] (1) Modeling of Chronic Restraint Stress (CRS)

[0111] Eight-week-old male C57BL / 6J mice were acclimatized for one week with a 12h / 12h light / dark cycle and free access to food and water. The mice were stroked daily for three days prior to the experiment to reduce operational stress.

[0112] Mice were placed headfirst into a restraint tube, the cap tightened to prevent escape, and restrained for 6 hours daily before being returned to their original cages for individual rearing. This restraint was repeated for 21 consecutive days to obtain a mouse model of depression. The group that did not undergo chronic restraint stress served as the blank control group (Control group).

[0113] (2) Administration

[0114] Immediately after restraint, a ventricular cannulation experiment was performed. The deeply anesthetized mice were fixed on a stereotaxic apparatus, and the drug delivery cannula was implanted into the lateral ventricle (AP=-0.22, ML=-1.0, DV=-2.23) and secured with dental cement. Drug administration was administered 7 days after the mice recovered.

[0115] Mice that had undergone chronic restraint stress modeling were randomly divided into a saline group (CRS group) and a drug-treated group. During drug administration, the mice were allowed free movement in their original cages. A syringe was connected to the administration tube; the drug-treated group received 2.82 μL of the compound at a concentration of 2 mg / mL, while the saline group received an equal volume of saline. The injection was stopped for 5 minutes after administration. Drug administration was repeated for 3 consecutive days.

[0116] (3) Behavioral evaluation was conducted on the second day after the administration of the drug.

[0117] (3.1) Preference for sugary drinks

[0118] Mice were provided with two identical water bottles and allowed to acclimatize for two days. On the first day, both bottles contained water. On the second day, both bottles contained a 1% sucrose solution. On the third day, after a 12-hour fast, one bottle contained the 1% sucrose solution, and the other contained regular drinking water. The mice were allowed free access to both liquids. After 6 hours, the positions of the water and sucrose solution were switched to eliminate the influence of positional preference. The bottles were weighed before and after the sucrose preference experiment, and the consumption of sucrose solution and water was recorded. The sucrose preference rate was calculated by dividing the consumption of sucrose solution by the total consumption of sucrose solution and water.

[0119] (3.2) Tail Suspension Experiment

[0120] Two hours prior to the experiment, mice were placed in the laboratory for pre-acclimatization. The tails of the mice were suspended 20 cm above the table using medical tape and clips for 6 minutes. Mouse behavior was recorded on video, and the immobility time during the last 4 minutes of the experiment was automatically analyzed using Smart 3.0 software (Panlab, Spain).

[0121] (3.3) Forced swimming experiment

[0122] Mice were placed in the laboratory for pre-acclimatization two hours prior to the test. During the test, the mice were placed in a glass beaker (14 cm in diameter, 19 cm in height) filled with water at a temperature of 18-21°C. The total test duration was 6 minutes. The mice's behavior was recorded, and then the immobility time in the last 4 minutes was automatically analyzed using Smart 3.0 software (Panlab, Spain).

[0123] III. Experimental Results

[0124] Experimental results are as follows Figures 3-5 As shown.

[0125] Figure 3 The results showed that, compared with the control group, the CRS group showed a decreased preference for sucrose water; while the drug-treated group showed an increased preference for sucrose water compared with the CRS group, which means that the compound can effectively fight depression.

[0126] Figure 4 The results showed that, compared with the control group, the immobility time of the CRS group was prolonged; while compared with the CRS group, the immobility time of the treated mice was shortened, indicating that the compound can effectively fight depression.

[0127] Figure 5 The results showed that, compared with the control group, the immobility time of the CRS group was prolonged; while compared with the CRS group, the immobility time of the treated mice was shortened, indicating that the compound can effectively fight depression.

[0128] The above description of the embodiments is only for understanding the method and core ideas of the present invention. It should be noted that those skilled in the art can make various improvements and modifications to the present invention without departing from the principles of the invention, and these improvements and modifications will also fall within the protection scope of the claims of the present invention.

Claims

1. The use of compounds with the following structural formula or pharmaceutically acceptable salts thereof in the preparation of antidepressant drugs: 。

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