Use of STING agonists in depression or anxiety disorders

Abstract

The present invention relates to the use of STING agonists in depression or anxiety disorders. Specifically, the compound disclosed by the invention is described in the specification, and the compound disclosed by the invention has an excellent prevention and / or treatment effect on depression and / or anxiety disorder.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to the use of STING agonists in depression or anxiety disorders. Background Art

[0002] Depression and anxiety disorders are the two most common mental disorders in modern society. They often exist in the form of comorbidity, and each of them affects more than 300 million people worldwide. Especially during the 2019 novel coronavirus epidemic, the number of patients with depression and anxiety disorders increased by about 70 million and 90 million, respectively. So far, the pathogenesis of these diseases is still unclear, which has brought great difficulties to treatment.

[0003] The current first-line clinical drugs for the treatment of depression are monoamine neurotransmitter reuptake inhibitors, such as selective serotonin reuptake inhibitors (SSRIs) represented by fluoxetine and serotonin and norepinephrine reuptake inhibitors (SNRIs) represented by venlafaxine. These first-generation antidepressants are also the first-line clinical drugs for anxiety disorders. However, these drugs can only improve the mental symptoms of about 30% of the patient population (about 30%), and there are problems such as slow onset (4-6 weeks or longer), severe side effects, and high relapse after treatment. Second-generation antidepressants represented by ketamine have serious safety issues, including addiction, strong hallucinations, and cognitive dysfunction. At present, this type of drug is not used as a first-line clinical drug, and is only used for patients with strong suicidal intentions or stubborn and refractory patients, and must be strictly supervised and regulated during use.

[0004] Therefore, it is urgent to develop new precision treatments and anti-depression and anxiety disorder drugs that are suitable for more patients. Summary of the invention

[0005] The object of the present invention is to provide a use of a compound in preparing a medicament for preventing and / or treating depression and / or anxiety disorders.

[0006] In a first aspect of the present invention, there is provided a use of a compound, or an isomer, prodrug, solvate, hydrate or a pharmaceutically acceptable salt thereof, for preparing a medicament for preventing and / or treating depression and / or anxiety disorders;

[0007] The compound is selected from the following group: a compound of formula I, a compound of formula II, and a compound of formula III;

[0008]

[0009] In the compound represented by formula I,

[0010] X is selected from the group consisting of C(O), CF2;

[0011] Y is selected from the following group: OR a 、NHR b 、N(R b )2;

[0012] R1 and R4 are independently selected from the following groups: hydrogen, halogen;

[0013] R2 and R3 are independently deuterium-substituted or unsubstituted C1-C4 alkyl;

[0014] R5 and R6 are independently selected from the following groups: hydrogen, halogen, C1-C4 alkyl;

[0015] R a Selected from the group consisting of hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted amino, wherein the substitution refers to substitution by 1-4 substituents selected from the group consisting of deuterium, C1-C4 alkyl, C6-C10 aryl, C6-C10 aryl-(C1-C4 alkylene);

[0016] R b Each occurrence is independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C4 alkyl, hydroxy, substituted or unsubstituted C1-C4 alkoxy, wherein the substitution refers to substitution by 1-4 substituents selected from the group consisting of hydrogen, deuterium, halogen, C1-C4 alkyl, C6-C10 aryl;

[0017] In the compound represented by formula II,

[0018] W is selected from the group consisting of CH2, NH, O;

[0019] n1 is selected from the following group: 0, 1, 2, 3;

[0020] n2 is selected from the following group: 0, 1, 2, 3;

[0021] Ring C is selected from the following groups: substituted or unsubstituted: 5, 6 or 7-membered monocyclic heterocycloalkyl containing 1 or 2 N, 7, 8, 9 or 10-membered spirocyclic heterocycloalkyl containing 2 N, 8, 9 or 10-membered polycyclic heterocycloalkyl containing 2 N, 7 or 8-membered bridged heterocycloalkyl containing 2 N, wherein the substitution refers to 1, 2, 3 or 4 R 1-1 replace;

[0022] R 1-1 Each is independently selected from the following group: C1-C6 alkyl, halogen, hydroxy, -COOH, -(C=O)-O-C1-C6 alkyl, -(C=O)-C1-C6 alkyl, -NH-C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl;

[0023] Alternatively, two R attached to the same atom 1-1Together with this atom, it forms a C3-C6 cycloalkyl group or a 4-5 membered heterocycloalkyl group containing 1 O;

[0024] Z is selected from the group consisting of absent, =O, -CH2-NH-(C=O)-;

[0025] X1 is O or NH;

[0026] Y1 is NH;

[0027] R is selected from the following group: H, -(C=O)-O-C1-C6 alkyl,

[0028]

[0029] In another preferred embodiment, R2, R3, R a , R b At least one of them contains deuterium.

[0030] In another preferred embodiment,

[0031] X is C(O);

[0032] Y is selected from the following group: OR a 、NHR b 、N(R b )2;

[0033] R1 and R4 are independently selected from the following groups: hydrogen, halogen;

[0034] R2 and R3 are independently deuterium-substituted or unsubstituted C1-C4 alkyl;

[0035] R5 and R6 are independently selected from the following groups: hydrogen, halogen, C1-C4 alkyl;

[0036] R a Selected from the group consisting of hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted amino, wherein the substitution refers to substitution by 1-4 substituents selected from the group consisting of deuterium, C1-C4 alkyl, C6-C10 aryl, C6-C10 aryl-(C1-C4 alkylene);

[0037] R b Each occurrence is independently selected from the following group: hydrogen, substituted or unsubstituted C1-C4 alkyl, hydroxyl, substituted or unsubstituted C1-C4 alkoxy, and the substitution refers to substitution by 1-4 substituents selected from the following group: hydrogen, deuterium, halogen, C1-C4 alkyl, C6-C10 aryl.

[0038] In another preferred embodiment,

[0039] X is C(O);

[0040] Y is selected from the following group: OR a 、NHR b 、N(R b )2;

[0041] R1 and R4 are independently selected from the following groups: hydrogen, halogen;

[0042] R2 and R3 are independently deuterium-substituted or unsubstituted C1-C4 alkyl;

[0043] R5 and R6 are independently selected from the following groups: hydrogen, halogen, C1-C4 alkyl;

[0044] R a Selected from the group consisting of hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted amino, wherein the substitution refers to substitution by 1-4 substituents selected from the group consisting of C1-C4 alkyl, C6-C10 aryl, C6-C10 aryl-(C1-C4 alkylene);

[0045] R b Each occurrence is independently selected from the following group: hydrogen, substituted or unsubstituted C1-C4 alkyl, hydroxyl, substituted or unsubstituted C1-C4 alkoxy, and the substitution refers to substitution by 1-4 substituents selected from the following group: hydrogen, halogen, C1-C4 alkyl, C6-C10 aryl.

[0046] In another preferred embodiment,

[0047] X is CF2;

[0048] Y is selected from the following group: OR a 、NHR b 、N(R b )2;

[0049] R1 and R4 are independently selected from the following groups: hydrogen, halogen;

[0050] R2 and R3 are independently deuterium-substituted or unsubstituted C1-C4 alkyl;

[0051] R5 and R6 are independently selected from the following groups: hydrogen, halogen, C1-C4 alkyl;

[0052] R a Selected from the group consisting of hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted amino, wherein the substitution refers to substitution by 1-4 substituents selected from the group consisting of deuterium, C1-C4 alkyl, C6-C10 aryl, C6-C10 aryl-(C1-C4 alkylene);

[0053] R bEach occurrence is independently selected from the following group: hydrogen, substituted or unsubstituted C1-C4 alkyl, hydroxyl, substituted or unsubstituted C1-C4 alkoxy, and the substitution refers to substitution by 1-4 substituents selected from the following group: hydrogen, deuterium, halogen, C1-C4 alkyl, C6-C10 aryl.

[0054] In another preferred embodiment,

[0055] X is CF2;

[0056] Y is selected from the following group: OR a 、NHR b 、N(R b )2;

[0057] R1 and R4 are independently selected from the following groups: hydrogen, halogen;

[0058] R2 and R3 are independently deuterium-substituted or unsubstituted C1-C4 alkyl;

[0059] R5 and R6 are independently selected from the following groups: hydrogen, halogen, C1-C4 alkyl;

[0060] R a Selected from the group consisting of hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted amino, wherein the substitution refers to substitution by 1-4 substituents selected from the group consisting of C1-C4 alkyl, C6-C10 aryl, C6-C10 aryl-(C1-C4 alkylene);

[0061] R b Each occurrence is independently selected from the following group: hydrogen, substituted or unsubstituted C1-C4 alkyl, hydroxyl, substituted or unsubstituted C1-C4 alkoxy, and the substitution refers to substitution by 1-4 substituents selected from the following group: hydrogen, halogen, C1-C4 alkyl, C6-C10 aryl.

[0062] In another preferred embodiment, R1 and R4 are independently selected from the following group: hydrogen and halogen.

[0063] In another preferred embodiment, R2 and R3 are each independently an unsubstituted C1-C4 alkyl group.

[0064] In another preferred embodiment, R2 and R3 are independently one or more deuterated or perdeuterated C1-C4 alkyl groups.

[0065] In another preferred embodiment, R2 and R3 are independently one or more deuterated or fully deuterated groups selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl and tert-butyl.

[0066] In another preferred embodiment, R2 and R3 are independently selected from the following group: perdeuterated methyl, perdeuterated ethyl, perdeuterated propyl, perdeuterated isopropyl, perdeuterated butyl, and perdeuterated tert-butyl.

[0067] In another preferred embodiment, R2 and R3 are both perdeuterated methyl groups.

[0068] In another preferred embodiment, R5 and R6 are independently selected from the following groups: hydrogen and C1-C4 alkyl.

[0069] In another preferred embodiment, R a Selected from the group consisting of hydrogen, substituted or unsubstituted amino, wherein the substitution refers to substitution by 1 to 4 substituents selected from the group consisting of deuterium, C1-C4 alkyl.

[0070] In another preferred embodiment, R b Each occurrence is independently selected from the following group: hydrogen, substituted or unsubstituted C1-C4 alkyl, hydroxyl, substituted or unsubstituted C1-C4 alkoxy, and the substitution refers to substitution by 1-4 substituents selected from the following group: deuterium, C1-C4 alkyl, C6-C10 aryl.

[0071] In another preferred embodiment, R a It is not deuterated.

[0072] In another preferred embodiment, R b It is not deuterated.

[0073] In another preferred embodiment, W is O.

[0074] In another preferred embodiment, n1 is 1.

[0075] In another preferred embodiment, n2 is 1.

[0076] In another preferred embodiment, the 5-, 6- or 7-membered monocyclic heterocycloalkyl group containing 1 or 2 N atoms is selected from the following group:

[0077] In another preferred embodiment, the 7-, 8-, 9- or 10-membered spirocyclic heterocycloalkyl group containing 2 N atoms is selected from the following group:

[0078]

[0079] In another preferred embodiment, the 8-, 9- or 10-membered heterocycloalkyl group containing 2 N is

[0080] In another preferred embodiment, the 7- or 8-membered bridged heterocycloalkyl group containing 2 N atoms is selected from the following group:

[0081] In another preferred embodiment, R is selected from the following group: H, -(C=O)-O-tert-butyl,

[0082]

[0083] In another preferred embodiment, the compound represented by formula I is selected from the following group:

[0084]

[0085]

[0086]

[0087] The compound represented by formula II is selected from the following group:

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094] In another preferred embodiment, the drug is used to shorten the immobility time of patients with depression and / or anxiety disorders.

[0095] In another preferred embodiment, the drug is used to increase the sucrose preference level of patients with depression and / or anxiety disorders.

[0096] In another preferred embodiment, the drug is used to reduce the degree of anhedonia in patients with depression and / or anxiety disorders.

[0097] In another preferred embodiment, the drug is used to reduce the level of despair in patients with depression and / or anxiety disorders.

[0098] In another preferred embodiment, the drug is used to enhance the degree of resistance behavior in patients with depression and / or anxiety disorders in difficult situations.

[0099] In another preferred embodiment, the drug is used to reduce the anxiety level of patients with depression and / or anxiety disorders.

[0100] In another preferred embodiment, the drug is used to enhance the resistance of patients with depression and / or anxiety disorders to fight against the "exploration-avoidance" conflict behavior, thereby increasing the probability of them choosing exploratory behavior.

[0101] In another preferred embodiment, the drug has no effect on the blood-brain barrier.

[0102] In another preferred embodiment, the drug does not penetrate the blood-brain barrier.

[0103] In another preferred embodiment, the drug is used for one or more purposes selected from the following group:

[0104] 1) Improve behavioral despair in patients with depression and / or anxiety disorders;

[0105] 2) Improve anhedonia in patients with depression and / or anxiety disorders;

[0106] 3) Improve anxiety levels in patients with depression and / or anxiety disorders.

[0107] In another preferred embodiment, the drug is administered before modeling of depression and / or anxiety disorders.

[0108] In another preferred embodiment, the drug is administered after modeling of depression and / or anxiety disorders.

[0109] In another preferred embodiment, the depression and / or anxiety disorder is depression and / or anxiety disorder associated with the peripheral monocyte / macrophage STING pathway.

[0110] In another preferred embodiment, the depression and / or anxiety disorder is depression and / or anxiety disorder with low expression of STING.

[0111] In another preferred embodiment, the depression and / or anxiety disorder is depression and / or anxiety disorder with low expression of CXCL10.

[0112] In another preferred embodiment, the dosage of the drug is 3-30 mg / kg, preferably 5-20 mg / kg, and more preferably 7-15 mg / kg.

[0113] In another preferred embodiment, the dosage of the drug is 1 μg / 10-14g.

[0114] In another preferred embodiment, the depression and / or anxiety disorder is modeled by LPS induction.

[0115] In another preferred embodiment, the depression and / or anxiety disorder is induced by a chronic restraint stress model.

[0116] In another preferred embodiment, the administration method of the drug is selected from the following group: subcutaneous injection, intracerebroventricular injection, and oral administration.

[0117] The second aspect of the present invention provides a use of CXCL10 for preparing a medicament for preventing and / or treating depression and / or anxiety disorders.

[0118] In another preferred embodiment, the depression and / or anxiety disorder is depression and / or anxiety disorder with low expression of CXCL10.

[0119] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0120] Figure 1 Subcutaneous administration of D166 alleviated the depression and anxiety-like behaviors of LPS model mice. (a) Results of tail suspension test, (b) results of forced swimming test, (c) results of sucrose preference test, (d) results of elevated plus maze test, and (e) results of fatigue rotarod test.

[0121] Figure 2 Intracerebroventricular administration of D166 alleviated the depression and anxiety-like behaviors of LPS model mice. (a) Results of tail suspension test, (b) results of forced swimming test, (c) results of sucrose preference test, (d) results of elevated plus maze test, and (e) results of open field test.

[0122] Figure 3 Subcutaneous administration of D166 before chronic restraint stress modeling alleviated the depression and anxiety-like behaviors of model mice. (a) Results of tail suspension test, (b) results of forced swimming test, (c) results of sucrose preference test, (d) results of elevated plus maze test, and (e) results of open field test.

[0123] Figure 4 Intracerebral administration of D166 before chronic restraint stress modeling alleviated depression and anxiety-like behaviors in model mice. (a) Results of tail suspension test, (b) results of forced swimming test, (c) results of sucrose preference test, (d) results of elevated plus maze test, and (e) results of open field test.

[0124] Figure 5 Subcutaneous administration of D166 in the late stage of chronic restraint stress modeling alleviated the depression and anxiety-like behaviors of model mice. The efficacy of D166 was superior to fluoxetine (FLX) and venlafaxine (VEN). (a) Results of tail suspension test, (b) results of forced swimming test, (c) results of sucrose preference test, (d) results of elevated plus maze, and (e) results of open field test.

[0125] Figure 6 Oral administration of D166 in the late stage of chronic restraint stress modeling alleviated the depression and anxiety-like behaviors of model mice. The efficacy of D166 is better than fluoxetine (FLX). (a) Results of tail suspension test, (b) results of forced swimming test, (c) results of sucrose preference test, (d) results of elevated plus maze test, and (e) results of open field test.

[0126] Figure 7 Subcutaneous administration of MCB-23-208 in the late stage of chronic restraint stress modeling alleviated the depression and anxiety-like behaviors of model mice. (a) Results of tail suspension test, (b) results of forced swimming test, (c) results of sucrose preference test, (d) results of elevated plus maze, and (e) results of open field test.

[0127] Figure 8 Subcutaneous administration of DMXAA in the late stage of chronic restraint stress modeling alleviated the depression and anxiety-like behaviors of model mice. (a) Results of tail suspension test, (b) results of forced swimming test, (c) results of sucrose preference test, (d) results of elevated plus maze, and (e) results of open field test.

[0128] Fig. 9 The effective dose of D166 and the administration method and frequency did not cause pathological damage to the heart, liver, spleen, lung and kidney of mice. Representative results of immunohistochemical HE staining of paraffin sections of the heart, liver, spleen, lung and kidney of mice.

[0129] Fig.10 .The content of D166 in plasma, prefrontal cortex, hippocampus and whole brain tissue changed at different time points after subcutaneous administration.

[0130] Fig.11 .D166 protects the integrity of the blood-brain barrier in mice with chronic restraint stress. Serum albumin infiltration was detected in the brains of mice with chronic restraint stress (as indicated by the black arrows), but no serum albumin infiltration was observed in the brains of model mice after subcutaneous administration of D166. Representative results of immunofluorescence double staining of frozen sections of mouse brain tissue.

[0131] Fig.12 Central microglial cell STING knockout mice showed moderate depressive-like behavior, and the depressive-like behavior of knockout mice tended to be alleviated after administration of D166. (a) Results of tail suspension test, (b) results of forced swimming test, (c) results of sucrose preference test, (d) results of elevated plus maze, and (e) results of open field test.

[0132] Fig.13 Peripheral monocyte / macrophage STING knockout mice showed obvious depression and anxiety-like behaviors, and the depressive-like behaviors of knockout mice were not improved after administration of D166. (a) Results of tail suspension test, (b) results of forced swimming test, (c) results of sucrose preference test, (d) results of elevated plus maze, and (e) results of open field test.

[0133] Fig.14 Peripheral administration of CXCL10 alleviated the depressive-like behavior of chronic restraint stress mice. (a) Results of tail suspension test, (b) results of forced swimming test, (c) results of sucrose preference test, and (d) results of open field test.

[0134] Fig.15 CXCL10 blocking peptide induced depressive-like behavior in mice, but D166 could not reverse the depressive-like behavior induced by CXCL10 blocking peptide in mice. (a) Results of forced swimming test, (b) Results of sucrose preference test. DETAILED DESCRIPTION

[0135] After long-term and in-depth research, the inventors unexpectedly discovered that the compounds of the present invention have excellent effects on preventing and / or treating depression and / or anxiety disorders. Specifically, the compounds of the present invention can significantly improve the depression and / or anxiety symptoms of the research subjects when administered before modeling, that is, they have the effect of preventing the occurrence and development of depression and / or anxiety; the compounds of the present invention can also significantly improve the depression and / or anxiety symptoms of the research subjects when administered after modeling, that is, they have the effect of treating the development of depression and / or anxiety. Further mechanism studies have shown that peripheral administration of the compounds of the present invention mainly exerts antidepressant-like behavior by inducing CXCL10, a downstream molecule of STING. On this basis, the inventors completed the present invention.

[0136] the term

[0137] In the present invention, unless otherwise specified, the terms used have the general meanings well known to those skilled in the art.

[0138] In the present invention, the term "halogen" refers to F, Cl, Br or I.

[0139] In the present invention, "C1-C6 alkyl" refers to a straight or branched alkyl group including 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, tert-pentyl, or the like. The term "C1-C4 alkyl" has a similar meaning.

[0140] In the present invention, the term "C2-C6 alkenyl" refers to a straight or branched alkenyl group having 2 to 6 carbon atoms and containing one double bond, including but not limited to ethenyl, propenyl, butenyl, isobutenyl, pentenyl and hexenyl.

[0141] In the present invention, the term "C2-C6 alkynyl" refers to a straight or branched alkynyl group having 2 to 6 carbon atoms and containing one triple bond, including but not limited to ethynyl, propynyl, butynyl, isobutynyl, pentynyl and hexynyl.

[0142] In the present invention, the term "C3-C8 cycloalkyl" refers to a cyclic alkyl group having 3 to 8 carbon atoms in the ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

[0143] In the present invention, the term "C1-C6 alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc. Preferably, it is a C1-C4 alkoxy group.

[0144] In the present invention, the term "aromatic ring" or "aryl group" has the same meaning, preferably "C6-C10 aryl group". The term "C6-C10 aryl group" refers to an aromatic ring group having 6-10 carbon atoms without heteroatoms in the ring, such as phenyl, naphthyl, etc.

[0145] In the present invention, the term "halo" means substituted with halogen.

[0146] In the present invention, the term "deuterated" means substituted with deuterium.

[0147] In the present invention, the term "substituted" refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent. The specific substituent is the substituent described above, or the substituent appearing in each embodiment. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different at each position. It should be understood by those skilled in the art that the combination of substituents contemplated by the present invention is those stable or chemically feasible combinations. The substituents include, for example (but not limited to): halogen, hydroxyl, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic radical, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amino, C1-C6 alkoxy, C1-C10 sulfonyl, etc.

[0148] In the present invention, the term 1-6 means 1, 2, 3, 4, 5 or 6. Other similar terms independently have similar meanings.

[0149] The term "amino" is -NH2.

[0150] It should be understood that when a group is present in multiple different positions of a compound at the same time, its definition at each position is independent of each other and may be the same or different. That is, the term "selected from the following group:" has the same meaning as the term "each independently selected from the following group:".

[0151] Active ingredients

[0152] Currently, the reports on the indications of the compounds of the present invention, or their isomers, prodrugs, solvates, hydrates or pharmaceutically acceptable salts are mainly tumors, and there are no reports in the literature on depression and / or anxiety disorders.

[0153] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention and an acid or base that is suitable for use as a drug. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is a salt formed by a compound of the present invention and an acid. Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0154] Another preferred salt is a salt of the compound of the present invention and a base, such as an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., magnesium salt or calcium salt), an ammonium salt (e.g., lower alkanolammonium salt and other pharmaceutically acceptable amine salts), for example, methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0155] The term "solvate" refers to a complex formed by the coordination of the compound of the present invention with solvent molecules in a specific ratio. "Hydrate" refers to a complex formed by the coordination of the compound of the present invention with water.

[0156] In addition, the compounds of the present invention also include prodrugs of the compounds. The term "prodrug" includes a compound that may be biologically active or inactive, and when taken by an appropriate method, it undergoes metabolism or chemical reactions in the human body and is converted into the compounds of the present invention, or a salt or solution composed of the compounds of the present invention. The prodrugs include (but are not limited to) carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone, sulfoxide, amino compound, carbamate, azo compound, phosphoramide, glucoside, ether, acetal and the like forms of the compounds.

[0157] Indications

[0158] The drug of the present invention can regulate more than 40 kinds of amino acids, neurotransmitters and metabolites in the brain of mice to return to normal levels.

[0159] The present invention adopts different depression and anxiety mouse models, different administration methods and administration times, and adding the compound of the present invention to the drug can significantly alleviate the depression and anxiety-like behaviors of the model mice. Compared with the clinical first-line drugs fluoxetine and venlafaxine, the drug of the present invention has more advantages in administration frequency and dosage.

[0160] It should be understood that, with respect to the administration method of the drug of the present invention, the STING agonist of the present invention can significantly relieve the symptoms of depression and / or anxiety disorders after peripheral administration (such as subcutaneous injection, oral administration, etc.). Therefore, compared with the existing cyclic dinucleotide STING agonists that are administered intracerebrally (or centrally), it has a completely different antidepressant mechanism of action. Even if the existing cyclic dinucleotide antidepressants are administered centrally, their clinical efficacy is very limited considering the influence of nuclease-mediated metabolic instability. In addition, the existing cyclic dinucleotide drugs that must be administered intracerebrally (or centrally) do not show a good depression relief effect after the peripheral administration of the present invention.

[0161] Compared with the prior art, the present invention has the following main advantages:

[0162] (1) The compounds of the present invention have a significant preventive effect on depression and / or anxiety disorders;

[0163] (2) The compounds of the present invention have significant therapeutic effects on depression and / or anxiety disorders;

[0164] (3) The compounds of the present invention have excellent safety when used to prevent and / or treat depression and / or anxiety disorders, and do not cause pathological damage to the heart, liver, spleen, lungs, and kidneys of the subjects;

[0165] (4) The compounds of the present invention do not cross the blood-brain barrier when used to prevent and / or treat depression and / or anxiety disorders, and have good safety;

[0166] (5) The mechanism of action of the present invention is to act peripherally and has a good protective effect on the integrity of the blood-brain barrier;

[0167] (6) The mechanism of action of the present invention is that the STING agonist takes effect by inducing the downstream molecule CXCL10, and has a significant therapeutic effect on depression and / or anxiety disorders;

[0168] (7) The CXCL10 described in the present invention has a significant therapeutic effect on depression and / or anxiety disorders.

[0169] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are generally performed under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or under conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0170] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0171] Example 1 Effects and mechanisms of action of benzothiophene compounds in the treatment of depression and anxiety

[0172] 1. Experimental Animals:

[0173] SPF (specific pathogen-free) C57BL / 6 mice, 6-12 weeks old, male / female, weighing approximately 20-28 g, were purchased from Shanghai Slake Laboratory Animal Co., Ltd. flox / flox Cx3cr1Cre mice) and peripheral monocyte / macrophage conditional knockout mice (Sting flox / flox LysMCre mice) were expressed by Sting flox / flox Cx3cr1-Cre mice and Sting flox / flox The mice were bred with LysM-Cre mice. The experimental mice were raised and managed by the Experimental Animal Center of Shanghai Jiao Tong University. The mice were raised at SPF level. The breeding conditions were stable, with constant temperature and humidity, 12 hours of light and 12 hours of darkness. The mice could drink water and eat freely. No more than 5 mice were raised in each cage.

[0174] 2. Modeling method

[0175] 2.1 Acute depression model:

[0176] Depression and anxiety-like behaviors were induced in mice by intraperitoneal injection of lipopolysaccharide (LPS) at a dose of 0.83 mg / kg. After 24 hours, the mice showed depression and anxiety-like behaviors.

[0177] 2.1 Chronic restraint stress (CRS) model:

[0178] The mice were restrained for 6 hours every day using a mouse fixator for 21 days. Then, classic behavioral experiments were used to detect the mice's despair (tail suspension test and forced swimming test), lack of pleasure (sucrose preference test), anxiety (elevated plus maze test) and autonomous movement ability (open field test).

[0179] 3. Treatment methods:

[0180] 3.1 Experimental treatment methods related to the effects of benzothiophene compounds in acute depression model mice

[0181] 3.1.1 Subcutaneous drug intervention

[0182] Control group: After the mice were adapted to the environment for one week, they were subcutaneously injected with the corresponding drug solvents on the first, fourth and seventh days, and intraperitoneally injected with normal saline on the tenth day. Various behavioral tests were performed 24 hours later.

[0183] Model group: After the mice were adapted to the environment for one week, the corresponding drug solvents were subcutaneously injected on the first, fourth and seventh days, and LPS (dissolved in saline, dose of 0.83 mg / kg) was intraperitoneally injected on the tenth day. Various behavioral tests were performed 24 hours later.

[0184] Benzothiophene compound (D166) intervention + model group: After the mice were adapted to the environment for one week, D166 was subcutaneously injected on the first, fourth and seventh days, with a drug dose of 7.5 mg / kg or 15 mg / kg. LPS (dissolved in saline, dose of 0.83 mg / kg) was intraperitoneally injected on the tenth day, and various behavioral tests were performed 24 hours later.

[0185] 3.1.2 Intraventricular Drug Intervention

[0186] Control group: After the mice were adapted to the environment for one week, they were given the corresponding drug solvent by intracerebroventricular injection. On the fourth day after the injection, normal saline was injected intraperitoneally, and various behavioral tests were performed 24 hours later.

[0187] Model group: After the mice were adapted to the environment for one week, they were given the corresponding drug solvent by intracerebroventricular injection. On the fourth day after the injection, LPS (dissolved in saline, dose of 0.83 mg / kg) was injected intraperitoneally, and various behavioral tests were performed 24 hours later.

[0188] Benzothiophene compound (D166) intervention + model group: After the mice were adapted to the environment for one week, D166 was administered to the mice by intracerebroventricular injection. The dosage was 1 μg each in the left and right lateral ventricles. On the fourth day after administration, LPS (dissolved in saline, the dosage was 0.83 mg / kg) was injected intraperitoneally, and various behavioral tests were performed 24 hours later.

[0189] 3.2 Experimental methods related to the effects of benzothiophene compounds in the chronic restraint stress-induced depression model

[0190] 3.2.1 Subcutaneous administration of drugs for intervention before modeling

[0191] Control group: After the mice were adapted to the environment for one week, the corresponding drug solvents were subcutaneously administered to the mice on the first, fourth and seventh days and they were raised normally for 21 days.

[0192] Model group: After the mice adapted to the environment for one week, the corresponding drug solvents were subcutaneously administered to the mice on the first, fourth and seventh days, and then the mice were restrained in a mouse fixator for 6 hours every day for 21 days.

[0193] Benzothiophene compound (D166) intervention + model group: After the mice adapted to the environment for one week, D166 was subcutaneously administered on the first, fourth and seventh days at a dose of 15 mg / kg. After that, a mouse fixator was used to restrict the movement of the mice for 6 hours every day for 21 days.

[0194] All groups were subjected to various behavioral tests on the 22nd day.

[0195] 3.2.2 Drug intervention in the lateral ventricle before modeling

[0196] Control group: After the mice were adapted to the environment for one week, the corresponding drug solvent was injected into the left and right lateral ventricles. After the wound was sutured, the mice recovered for five days and then were fed normally for 21 days.

[0197] Modeling group: After the mice adapted to the environment for one week, the corresponding drug solvent was injected into the left and right lateral ventricles. After the wound was sutured, the mice recovered for five days, and then the mice were restrained for 6 hours every day with a mouse fixator for 21 days.

[0198] Benzothiophene compound (D166) intervention + model group: After the mice adapted to the environment for one week, 1 μg of D166 was injected into the left and right lateral ventricles. After the wound was sutured, the mice recovered for five days, and then the mice were restrained for 6 hours every day for 21 days.

[0199] All groups were subjected to various behavioral tests on the 22nd day.

[0200] 3.2.3 Subcutaneous drug intervention in the late stage of modeling (using positive control drugs fluoxetine and venlafaxine)

[0201] Control group: After the mice adapted to the environment for one week, they were subcutaneously injected with the corresponding drug solvents on the 15th, 18th and 21st days.

[0202] Model group: After the mice adapted to the environment for one week, they were restrained for 6 hours every day for 21 days, and the corresponding drug solvents were subcutaneously injected on the 15th, 18th and 21st days.

[0203] Model + benzothiophene compound (D166) intervention group: After the mice adapted to the environment for one week, they were restrained for 6 hours every day using a mouse fixator for 21 days. D166 was subcutaneously administered on the 15th, 18th, and 21st days at a dose of 7.5 mg / kg or 15 mg / kg.

[0204] Model + fluoxetine (FLX) intervention group 1: After the mice adapted to the environment for one week, they were restrained for 6 hours every day using a mouse fixer for 21 days. From the eighth day to the twenty-first day, FLX was intraperitoneally administered once a day at a dose of 20 mg / kg.

[0205] Model + fluoxetine (FLX) intervention group 2: After the mice adapted to the environment for one week, they were restrained for 6 hours every day using a mouse fixer for 21 days. On the 15th, 18th, and 21st days, FLX was intraperitoneally administered at a dose of 20 mg / kg.

[0206] Model + venlafaxine (VEN) intervention group 1: After the mice adapted to the environment for one week, they were restrained for 6 hours a day using a mouse fixer for 21 days. VEN was intraperitoneally administered starting on the 15th day, once a day for 7 days at a dose of 10 mg / kg.

[0207] Model + venlafaxine (VEN) intervention group 2: After the mice adapted to the environment for one week, they were restrained for 6 hours every day using a mouse fixer for 21 days. VEN was subcutaneously administered on the 15th, 18th, and 21st days at a dose of 20 mg / kg.

[0208] All groups were subjected to various behavioral tests on the 22nd day.

[0209] 3.2.4 Oral administration of drugs for intervention in the late stage of modeling (using positive control drug fluoxetine)

[0210] Control group: After the mice adapted to the environment for one week, they were orally administered the corresponding drug solvents on the 15th, 18th and 21st days.

[0211] Model group: After the mice adapted to the environment for one week, they were restrained in a mouse immobilizer for 6 hours every day for 21 days. On the 15th, 18th and 21st days, they were orally administered with the corresponding drug solvents.

[0212] Model + benzothiophene compound (D166) intervention group: After the mice adapted to the environment for one week, they were restrained for 6 hours every day using a mouse fixator for 21 days. On the 15th, 18th, and 21st days, D166 was orally administered at doses of 1, 6, and 12 mg / kg, respectively.

[0213] Model + fluoxetine (FLX) intervention group: After the mice adapted to the environment for one week, they were restrained for 6 hours every day using a mouse fixer for 21 days. On the 15th, 18th, and 21st days, FLX was orally administered at a dose of 12 mg / kg.

[0214] All groups were subjected to various behavioral tests on the 22nd day.

[0215] 3.2.5 Drug intervention in two STING conditional knockout mice

[0216] Control group: Sting flox / flox The mice were subcutaneously administered the corresponding drug solvents on the first, fourth and seventh days.

[0217] Sting flox / flox Cx3cr1Cre mice and Sting flox / flox LysMCre mice were subcutaneously administered the corresponding drug solvents on the first, fourth, and seventh days.

[0218] Sting group + benzothiophene compound (D166) intervention group: flox / flox Cx3cr1Cre mice and Sting flox / flox LysMCre mice were subcutaneously administered D166 on days 1, 4, and 7 at a dose of 15 mg / kg.

[0219] All groups were subjected to various behavioral tests on the eighth day.

[0220] 3.3 Experimental treatment methods related to the role of CXC motif chemokine 10 (CXCL10) in alleviating depression / anxiety behavior in depressed mice

[0221] 3.3.1 Experimental methods related to the role of C-XC motif chemokine 10 (CXCL10) in the chronic restraint stress depression model mouse

[0222] Control group: After the mice adapted to the environment for one week, they were subcutaneously injected with the corresponding drug solvents on the 15th, 18th and 21st days.

[0223] Model group: After the mice adapted to the environment for one week, they were restrained for 6 hours every day for 21 days, and the corresponding drug solvents were subcutaneously injected on the 15th, 18th and 21st days.

[0224] Model + benzothiophene compound (D166) intervention group: After the mice adapted to the environment for one week, they were restrained for 6 hours every day using a mouse fixator for 21 days, and D166 was subcutaneously administered on the 15th, 18th, and 21st days at a dose of 15 mg / kg.

[0225] Model + CXC motif chemokine 10 (CXCL10) intervention group: After the mice adapted to the environment for one week, they were restrained for 6 hours every day using a mouse fixator for 21 days. On the 15th, 18th, and 21st days, CXCL10 was administered through the tail vein at a dose of 1 ng per mouse.

[0226] All groups were subjected to various behavioral tests on the 22nd day.

[0227] 3.3.2 Effects of benzothiophene compounds (D166) in chronic restraint stress-induced depression model after administration of CXCL10 blocking peptide Related experimental treatment methods

[0228] Control group: After the mice were adapted to the environment for one week, the corresponding solvent of CXCL10 blocking peptide was injected into the tail vein, and the corresponding solvent of D166 was subcutaneously administered 1 hour later.

[0229] CXCL10 blocking peptide intervention group: After the mice adapted to the environment for one week, CXCL10 blocking peptide was injected into the tail vein at a dose of 60 μg per mouse.

[0230] CXCL10 blocking peptide intervention + benzothiophene compound (D166) group: After the mice adapted to the environment for one week, CXCL10 blocking peptide was injected into the tail vein at a dose of 60 μg per mouse. One hour later, D166 was subcutaneously administered at a dose of 15 mg / kg.

[0231] All groups underwent behavioral experiments 2-4 hours after drug intervention.

[0232] 3.4 Drug safety evaluation in mice

[0233] Control group: After the mice adapted to the environment for one week, they were subcutaneously injected with the corresponding drug solvent once every three days for three times.

[0234] Benzothiophene compound (D166) intervention group: After the mice adapted to the environment for one week, D166 was injected subcutaneously once every three days for three times, with the dosages of 1, 7.5, and 15 mg / kg respectively.

[0235] All groups were subjected to various behavioral experiments on the second day after the last injection. After the behavioral experiments, the heart, liver, spleen, lung and kidney were taken for paraffin section HE staining to observe the effects of the drugs on the heart, liver, spleen, lung and kidney.

[0236] 3.5 Drug pharmacokinetic testing in mice

[0237] The benzothiophene compound D166 (15 mg / kg) was administered subcutaneously to mice. Blood was drawn from the mice's orbits at 5 min, 30 min, 2 h, and 8 h to collect plasma. The mice were then perfused by heart to obtain the prefrontal cortex, hippocampus, and entire brain tissue. The drug levels in plasma, prefrontal cortex, hippocampus, and the entire brain were detected using chromatography / mass spectrometry.

[0238] 3.6 Testing of Drug Protection on Blood-brain Barrier

[0239] The brain tissues of mice in the control group, chronic restraint stress model group and chronic restraint stress model group subcutaneously administered with benzothiophene compound D166 (15 mg / kg) were selected, and frozen sections were prepared. Double immunofluorescence staining experiments were performed using serum albumin antibodies and blood-brain barrier endothelial cell marker CD31 antibodies to observe the protective effect of the drug on the integrity of the blood-brain barrier.

[0240] 4 Mouse behavioral experiments

[0241] 4.1 Tail suspension test (TST)

[0242] Animals were suspended at least 80 cm above the floor under acoustic and visual isolation by tape placed approximately 1 cm from the tip of the tail. The total TST duration was 6 min, with the last 4 min of immobility recorded; mice were considered immobile only when passively suspended and motionless.

[0243] 4.2 Forced swimming test (FST)

[0244] Each mouse was placed individually in a 4000 mL glass beaker containing 3000 mL of warm water (temperature 25 ± 1 °C). The total FST duration was 6 min, and the last 4 min of immobility was recorded; mice were considered immobile only when they were motionless or floating or had only small movements required to keep their heads above the water.

[0245] 4.3 Sucrose preference test (SPT)

[0246] The experiment was conducted using 2% fresh sucrose solution and normal drinking water. The mice were adapted to the sucrose solution for 12 hours, then deprived of water and food for 12 hours. The mice were divided into individual cages, and each cage was given a bottle of sucrose solution and a bottle of normal drinking water. After 12 hours, the consumption of sucrose solution and drinking water was weighed to calculate the sucrose preference level of the mice. Sucrose preference = 2% fresh sucrose solution consumption / (2% fresh sucrose solution consumption + drinking water consumption).

[0247] 4.4 Elevated plus-maze test (EPM)

[0248] One week before the experiment, stroke the experimental mice for 1-5 minutes every day to eliminate the mice's fear of the experimenter. Place the mouse in the central area of ​​the maze with its head facing the open arm, and make sure that each mouse is placed in the same position thereafter. At the same time, turn on the monitor to record the number of times the mouse enters the open and closed arms within 5 minutes. During the experiment, the experimenter needs to be 1 meter away from the maze. After the experiment, put the mouse back in the breeding cage, and wipe the maze with 75% alcohol to eliminate the impact of animal odor on subsequent mice. Percentage of open arm entries = open arm entries / (open arm entries + closed arm entries).

[0249] 4.5 Open field test (OFT)

[0250] The mice were placed in the central area of ​​the experimental box, and the monitor was turned on to record the total distance the mice moved in the box within 5 minutes. After the experiment, the mice were returned to the cage, and the maze was cleaned with 75% alcohol to eliminate the influence of animal odor on subsequent mice.

[0251] 4.6 Fatigue Rotarod Test

[0252] Place the mouse on the rotating rod of the instrument and set the rotating rod speed to increase from 2rpm to 50rpm within 5min. The instrument will automatically record the movement time of the mouse on the rotating rod. Each mouse will undergo adaptive training once, and then undergo three rotating rod experiments, each experiment lasting 5 minutes, with an interval of at least 30 minutes between experiments.

[0253] 5 Experimental evaluation indicators

[0254] 5.1 Mouse behavioral experimental indicators

[0255] 5.1.1 The forced swimming test and tail suspension test are the most commonly used experimental methods to detect depressive-like behaviors in rodents, and are mainly used to assess the degree of despair in mice. Normal mice will actively swim or struggle for a long time when they are in an environment where they cannot escape (water tank or hanging state). If the mouse is in a depressed state, it will be in a state of immobility and despair for a long time after the initial swimming or struggling. We reflect the degree of despair of the mouse by recording the time the mouse is immobile for a certain period of time.

[0256] 5.1.2 Rodents have a strong desire for sweets. For normal mice, drinking 2% sucrose will produce a pleasant mood, prompting them to selectively drink too much sucrose solution instead of drinking water. For depressed mice, drinking sugar water cannot make them feel pleasant, so they will not selectively drink too much sucrose solution. By calculating the sucrose preference level of mice, the degree of anhedonia of mice can be analyzed.

[0257] 5.1.3 The elevated plus maze uses the contradictory and conflicting behaviors of animals' exploration of novel environments and fear of high-hanging open arms to examine the anxiety state of animals. The elevated plus maze has a pair of open arms and a pair of closed arms. Rodents tend to move in the closed arms due to their dark preference, but they will move in the open arms out of curiosity and exploration. When faced with novel stimuli, animals have the impulse to explore and fear at the same time, which creates a conflicting behavior between exploration and avoidance, thus generating anxiety.

[0258] 5.1.4 The total distance traveled by mice in the open field test reflects the mice's athletic ability.

[0259] 5.1.5 In the fatigue rotarod test, the motor coordination of mice was measured by recording the time required for the mice to fall.

[0260] 5.2 Evaluation indicators of whether drugs can enter the brain

[0261] The ratio of drug concentration in the brain to that in plasma (B / P): B / P>0.3 indicates that the drug can enter the central nervous system, and B / P<0.1 indicates that the drug cannot enter the central nervous system.

[0262] 5.3 Evaluation indicators of blood-brain barrier integrity

[0263] The expression of serum albumin in the brain was detected. If it was co-localized with the blood-brain barrier endothelial cells and invaded the brain tissue, it was considered that the blood-brain barrier was destroyed and its integrity was impaired.

[0264] 6 Experimental results:

[0265] 6.1 Benzothiophene compounds (D166) significantly improved the depression and anxiety-like behaviors of mice with acute depression model.

[0266] 6.1.1 24 hours after intraperitoneal injection of LPS, mice showed depression and anxiety-like behaviors. In the FST and TST experiments, the immobility time of mice after LPS administration was significantly higher than that of the control group ( Figure 1 a,b). In the SPT experiment, the sucrose preference level of mice after LPS administration was significantly lower than that of the control group ( Figure 1 c) The EPM experiment showed that LPS caused a significant decrease in the frequency of mice entering the open arms ( Figure 1 d), these results indicate that LPS successfully induced depression and anxiety-like behaviors in mice. LPS had no effect on the motor ability of mice ( Figure 1 e).

[0267] 6.1.2 Subcutaneous and intracerebroventricular injection of D166 significantly improved the depression and anxiety-like behaviors of mice induced by LPS. That is, it reversed the increase in immobility time of LPS model mice in FST and TST experiments ( Figure 1 a,b, Figure 2 a,b), the despair level of mice was reduced to a level similar to that of the control group. In the SPT experiment, the mice treated with the drug showed a clear preference for sucrose ( Figure 1 c, Figure 2 c). In the EPM experiment, the drug intervention group significantly reversed the LPS-induced decrease in the frequency of mice entering the open arms ( Figure 1 d, Figure 2 d). There was no significant difference in the total distance traveled by each group of mice in the open field test, which ruled out the influence of the experimental results on the differences in motor ability of mice in different groups ( Figure 2 e).

[0268] 6.2 Benzothiophene compounds (D166) significantly improved the depression and anxiety-like behaviors of mice with chronic depression model, and the effect of improving depressive symptoms was superior to the first-line clinical drugs fluoxetine and venlafaxine in terms of usage frequency and dosage; STING agonist MCB-23-208 significantly improved the depression and anxiety-like behaviors of mice with chronic depression model; STING agonist DMXAA improved the depression and anxiety-like behaviors of mice with chronic depression model.

[0269] 6.2.1 For the chronic restraint stress mouse model, we used various drug administration methods, such as subcutaneous drug intervention before modeling ( Figure 3 ), drug intervention of lateral ventricle before modeling ( Figure 4 ) and subcutaneous drug intervention after modeling ( Figure 5 ), the results showed that D166 could significantly improve the depression and anxiety-like symptoms of the model mice; and for the administration before modeling, it took 21 days for the mice to be depressed after administration, and the behavioral experiment was performed 21 days later. The D166 administration group significantly alleviated the depression and anxiety-like behaviors of the model mice, indicating that the improvement of the depression / anxiety-like symptoms of the model by D166 can last for at least 21 days ( Figure 5 ).

[0270] 6.2.2 We used fluoxetine and venlafaxine, the first-line drugs for depression and anxiety disorders, as positive controls and used the same dosing method (three times subcutaneously, once every two days). Higher doses of fluoxetine and venlafaxine did not significantly alleviate the depressive-like behavior of chronic restraint stressed mice; intraperitoneal injection of higher doses of fluoxetine achieved similar efficacy to D166 in TST and FST experiments, but did not significantly improve the sugar water preference of the model mice; intraperitoneal injection of similar doses of venlafaxine for 7 consecutive days did not improve the depressive-like behavior of the model mice. These results suggest that D166 is superior to fluoxetine and venlafaxine in improving depressive-like symptoms in terms of both dosage and frequency of use ( Figure 5 ). In addition, the improvement of anxiety-like behavior of model mice by D166 was similar to that of fluoxetine and venlafaxine.

[0271] 6.2.3 In addition to subcutaneous administration, we also verified the improvement effect of oral administration of D166 on depression and anxiety-like behaviors in chronic restraint stress mice, and used fluoxetine as a positive control. The results showed that after the chronic restraint stress mice were modeled, the same administration method and dose (oral administration three times, once every two days, 12 mg / kg) were used. D166 had a significant improvement effect on all behavioral experimental indicators of the model mice, while fluoxetine only improved the different times of TST and FST of the model mice, and had no significant improvement on sugar water preference and the frequency of entry into the open arm ( Figure 6 ). This indicates that for oral administration, D166 is more effective than fluoxetine in improving depression and anxiety-like symptoms.

[0272] 6.3 In addition to D166, STING agonists MCB-23-208 and DMXAA can alleviate the depression and anxiety-like behaviors of chronic depression model mice.

[0273] We used STING agonists MCB-23-208 and DMXAA to peripherally administer to chronic restraint stress mice to verify the effects of STING agonists. The results showed that with the same administration method (administration in the late stage of modeling, subcutaneous administration three times, once every two days), MCB-23-208 ( Figure 7 ) and DMXAA( Figure 8 ) can alleviate the depression and anxiety-like behaviors of chronic depression model mice.

[0274] 6.4 Effective dose of benzothiophene compound (D166) did not cause pathological damage to the heart, liver, spleen, lungs and kidneys of mice

[0275] We evaluated the safety of D166 in mice. Different doses of D166 were administered subcutaneously (the same as the subcutaneous administration method for modeling), and immunohistochemistry experiments were performed on the heart, liver, spleen, lung and kidney of mice. The results showed that this administration method and dose did not cause pathological damage to the heart, liver, spleen, lung and kidney of mice ( Fig. 9 ).

[0276] 6.5 Peripherally administered benzothiophene compounds (D166) do not cross the blood-brain barrier

[0277] We evaluated the pharmacokinetics of D166 in mice. The results showed that only a small amount of D166 (pM level, Fig.10 ), and the B / P value is less than 0.3.

[0278] 6.6 Peripheral administration of benzothiophene compounds (D166) to protect blood-brain barrier integrity

[0279] The results of immunofluorescence experiments showed that the blood-brain barrier of mice in the chronic restraint stress model group was damaged, and peripheral serum albumin infiltrated into the brain. However, after peripheral administration of D166, no serum albumin infiltration was observed in the mouse brain ( Fig.11 ). The results showed that peripheral administration of D166 protected the integrity of the blood-brain barrier of model mice.

[0280] 6.7 The peripheral monocyte / macrophage STING pathway is involved in the occurrence and development of depression (depression and anxiety-like behaviors in mice with acute depression model induced by benzothiophene compounds (D166))

[0281] To explore the role of STING in the progression of depressive pathology and the mechanism of action of STING agonists, we used central microglia STING knockout and peripheral monocyte / macrophage STING knockout mice for verification. The results showed that compared with microglia bar knockout mice, peripheral monocyte / macrophage STING knockout mice showed more obvious depressive symptoms; and after administration of D166, there was a trend to alleviate the depressive-like symptoms of microglia bar knockout mice, but it could not alleviate the depression and anxiety-like behaviors of monocyte / macrophage STING bar knockout mice ( Fig.12 , 13). These results suggest that the peripheral monocyte / macrophage STING pathway plays a more important role in the pathological progression of depression.

[0282] 6.8STING exerts antidepressant effects by inducing CXCL10

[0283] In order to further study whether the mechanism of benzothiophene compounds (D166) in exerting antidepressant effects is through inducing the production of downstream molecules CXCL10, we administered CXCL10 to CRS model mice for intervention. The experimental results showed that the administration of CXCL10 effectively alleviated the depressive-like behavior of mice induced by chronic restraint stress ( Fig.14 ), and its effect is similar to that of D166; in addition, administration of CXCL10 blocking peptide to mice can induce depressive-like behavior in mice; and after administration of blocking peptide, D166 intervention cannot reverse the depressive-like behavior of mice induced by CXCL10 blocking peptide ( Fig.15 ). These results suggest that benzothiophene compounds (D166) exert their antidepressant effects mainly through CXCL10.

[0284] illustrate:

[0285] 1) Benzothiophene compound D166 is compound S1 of the present invention. The preparation of compound S1 refers to Preparation Example 1 of patent application with publication number CN115772154A.

[0286] 2) Compound MCB-23-208, i.e., compound SA5 of the present invention, has a preparation reference application number of 2023102301712, an application date of March 10, 2023, and an invention name of "A class of nitrogen-oxyalkyl chain-substituted benzimidazole dimers, preparation methods and uses thereof" in Preparation Example 3 of the patent application.

[0287] 3) Compound DMXAA is the compound represented by formula III.

[0288] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A use of a compound, or an isomer, prodrug, solvate, hydrate or a pharmaceutically acceptable salt thereof, characterized in that: for the preparation of a medicament for the prevention and / or treatment of depression and / or anxiety disorders; The compound is selected from the following group: a compound of formula I, a compound of formula II, and a compound of formula III; In the compound represented by formula I, X is selected from the group consisting of C(O), CF2; Y is selected from the following group: OR a 、NHR b 、N(R b )2; R1 and R4 are independently selected from the following groups: hydrogen, halogen; R2 and R3 are independently deuterium-substituted or unsubstituted C1-C4 alkyl; R5 and R6 are independently selected from the following groups: hydrogen, halogen, C1-C4 alkyl; R a Selected from the group consisting of hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted amino, wherein the substitution refers to substitution by 1-4 substituents selected from the group consisting of deuterium, C1-C4 alkyl, C6-C10 aryl, C6-C10 aryl-(C1-C4 alkylene); R b Each occurrence is independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C4 alkyl, hydroxy, substituted or unsubstituted C1-C4 alkoxy, wherein the substitution refers to substitution by 1-4 substituents selected from the group consisting of hydrogen, deuterium, halogen, C1-C4 alkyl, C6-C10 aryl; In the compound represented by formula II, W is selected from the group consisting of CH2, NH, O; n1 is selected from the following group: 0, 1, 2, 3; n2 is selected from the following group: 0, 1, 2, 3; Ring C is selected from the following groups: substituted or unsubstituted: 5, 6 or 7-membered monocyclic heterocycloalkyl containing 1 or 2 N, 7, 8, 9 or 10-membered spirocyclic heterocycloalkyl containing 2 N, 8, 9 or 10-membered polycyclic heterocycloalkyl containing 2 N, 7 or 8-membered bridged heterocycloalkyl containing 2 N, wherein the substitution refers to 1, 2, 3 or 4 R 1-1 replace; R 1-1 Each is independently selected from the following group: C1-C6 alkyl, halogen, hydroxy, -COOH, -(C=O)-O-C1-C6 alkyl, -(C=O)-C1-C6 alkyl, -NH-C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl; Alternatively, two R attached to the same atom 1-1 Together with this atom, it forms a C3-C6 cycloalkyl group or a 4-5 membered heterocycloalkyl group containing 1 O; Z is selected from the group consisting of absent, =O, -CH2-NH-(C=O)-; X1 is O or NH; Y1 is NH; R is selected from the following group: H, -(C=O)-O-C1-C6 alkyl, 2. The use according to claim 1, characterized in that The compound represented by formula I is selected from the following group: The compound represented by formula II is selected from the following group:

3. The use according to claim 1, characterized in that The drug is used for one or more purposes selected from the following group: 1) Used to shorten the immobility time of patients with depression and / or anxiety disorders; 2) for increasing sucrose preference in patients with depression and / or anxiety disorders; 3) Used to reduce the level of hopelessness in patients with depression and / or anxiety disorders; 4) Used to reduce anxiety levels in patients with depression and / or anxiety disorders.

4. The use according to claim 1, characterized in that The drug is used for one or more purposes selected from the following group: 1) Improve behavioral despair in patients with depression and / or anxiety disorders; 2) Improve anhedonia in patients with depression and / or anxiety disorders; 3) Improve anxiety levels in patients with depression and / or anxiety disorders.

5. The use according to claim 1, characterized in that The drug is administered before modeling of depression and / or anxiety disorders; and / or The drug is administered after the depression and / or anxiety disorder disease modeling.

6. The use according to claim 1, characterized in that The depression and / or anxiety disorder is a depression and / or anxiety disorder associated with the peripheral monocyte / macrophage STING pathway.

7. The use according to claim 1, characterized in that The depression and / or anxiety disorder is a depression and / or anxiety disorder with low STING expression.

8. The use according to claim 1, characterized in that The administration method of the drug is selected from the following group: subcutaneous injection, intracerebroventricular injection, and oral administration.

9. A use of CXCL10, characterized in that: Used for preparing a medicament for preventing and / or treating depression and / or anxiety disorders.

10. The use according to claim 9, characterized in that The depression and / or anxiety disorder is depression and / or anxiety disorder with low expression of CXCL10.

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