Iridoid derivatives and use thereof in the prevention and treatment of nervous system diseases

Abstract

The application relates to the technical field of pharmaceutical chemistry, in particular to an iridoid derivative and application thereof in prevention and treatment of nervous system diseases. The derivative is a compound as shown in a structural formula I, or a pharmaceutically acceptable salt, a stereoisomer, a solvate, a hydrate and an isotopically labeled compound thereof. The iridoid derivative has good neuroprotective activity, can improve the survival rate of nerve cells, reduce nerve cell damage and improve depressive behavior, and has a good application prospect in the prevention and / or treatment of nervous system diseases, in particular depression, neurodegenerative diseases and nerve injury.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and in particular to iridoid derivatives and their application in drugs for the prevention and treatment of nervous system diseases. Background Technology

[0002] Neurological disorders or injuries, such as depression and neurodegenerative diseases, are often accompanied by nerve cell damage, neurological dysfunction, and poor prognosis. Current intervention methods still have certain limitations, making the development of novel active compounds with good neuroprotective effects of great significance.

[0003] Loganin is an iridoid compound derived from plants of the genus Cornus in the family Cornaceae, possessing a characteristic cyclopentane-type iridoid skeleton structure. Existing technologies have established extraction, separation, and raw material preparation methods for loganin (CN 106831910 A), providing a material basis for its pharmacological activity research and structural modification.

[0004] Current research on loganin in the field of nervous system-related areas still mainly focuses on the parent compound or its application in specific injury models. Summary of the Invention

[0005] This invention covers the following technical solutions: This invention relates to the field of biomedical technology, specifically to an iridoid derivative, its pharmaceutical composition, and its pharmaceutical uses.

[0006] This invention provides an iridoid derivative, wherein the derivative is a compound with the structural formula shown in Formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, or isotopically labeled compound thereof;

[0007] Where n = 0, 1, 2, 3 or 4; R1 can be hydrogen, amino, hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -S(O)2-C1-C6 alkyl, -C(O)2-C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, or C6-C 10 aryl, 5- to 12-membered heteroaryl, or -O-C1-C6 alkyl-5- to 12-membered heteroaryl; wherein the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 10The aryl, 5- to 12-membered heteroaryl and -O-C1-C6 alkyl-5- to 12-membered heteroaryl groups are optionally substituted by 1 to 3 substituents independently selected from halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 alkoxy groups; R2 is hydrogen, C1-C 18 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl, C6-C 10 Aryl-C1-C6 alkyl or glycosyl; wherein, except for hydrogen and glycosyl, the remaining groups are optionally substituted by 1 to 3 substituents independently selected from halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 alkoxy.

[0008] Another aspect of the present invention relates to a pharmaceutical composition comprising the above-mentioned iridoid derivatives and a pharmaceutically acceptable carrier.

[0009] The present invention also provides the use of the iridoid derivatives in the preparation of medicaments for the prevention and / or treatment of nervous system diseases.

[0010] The iridoid derivatives described in this invention have good neuroprotective activity, can improve nerve cell survival rate, reduce nerve cell damage, and improve depressive-like behavior. They have good application prospects in the prevention and / or treatment of nervous system diseases, especially depression, neurodegenerative diseases, and nerve damage. Attached Figure Description

[0011] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0012] Figure 1 Representative compounds demonstrate the protective effect of corticosterone-induced HT22 cell protection.

[0013] Figure 2 Effects of compound 27 on the expression of Sigma-1R protein and BDNF in CORT-induced HT22-damaged cells.

[0014] Figure 3 Compound 27 improves depressive-like behavior in a CORT-induced mouse model of depression. Detailed Implementation

[0015] The embodiments of the present invention will now be described in detail. The following examples are only used to explain the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. After reading this specification, those skilled in the art can make various modifications, substitutions or variations to the technical solutions of the present invention without departing from the concept and technical principles of the present invention, and all such modifications, substitutions or variations should fall within the scope of protection of the present invention.

[0016] Unless otherwise stated, the technical and scientific terms used herein shall have the meanings commonly understood by one of ordinary skill in the art. Unless otherwise specified, the experimental methods described herein shall be performed under standard experimental conditions, in accordance with relevant laboratory manuals, or as recommended by the manufacturers of reagents or instruments, or using other equivalent methods known in the art.

[0017] The terms "comprising," "including," and "containing" as used herein are open-ended expressions, and unless explicitly specified, they do not exclude the presence of other components, steps, or structures not explicitly listed. The terms "preferred," "optional," and "optional" as used herein are only for illustrating some embodiments and do not constitute a limitation on the scope of protection of this invention.

[0018] Unless otherwise specified, the numerical ranges mentioned in this article include any integers, fractions, decimals, and their upper and lower limits within that range.

[0019] Unless otherwise specified, the singular expressions such as "a," "a kind," and "the" used in this article also include the plural forms; "multiple" usually refers to two or more.

[0020] The term “and / or” as used in this document refers to any one or any combination of the relevant objects.

[0021] Where there is no contradiction, the technical features of the various embodiments and examples in this specification can be combined with each other. Any conventional adjustments, substitutions, or equivalent modifications made by those skilled in the art based on the content of this specification should be considered part of the disclosure herein.

[0022] In this invention, "cyclopentadiene derivatives" refers to derivatives obtained by structurally modifying the corresponding functional groups or side chains of cyclopentadiene compounds as the parent nucleus. Unless otherwise stated, the cyclopentadiene derivatives include pharmaceutically acceptable salts, stereoisomers, solvates, hydrates, and isotopically labeled compounds.

[0023] In this document, "pharmaceutically acceptable salt" refers to a salt formed by the compound of this invention with a pharmaceutically acceptable acid or base, while maintaining the biological and pharmacological activity of the iridoid derivatives of this invention. This salt is suitable for animal, especially mammalian, and more particularly human administration. Exemplary pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochlorides, hydrobroms, sulfates, nitrates, phosphates, methanesulfonates, ethanesulfonates, p-toluenesulfonates, acetates, lactates, citrates, malates, tartrates, fumarates, maleates, succinates, and benzoates. In some embodiments, the pharmaceutically acceptable alkali metal salt or organic base salt includes, but is not limited to, sodium salts, potassium salts, calcium salts, magnesium salts, ammonium salts, triethylamine salts, diisopropylamine salts, diethanolamine salts, and triethanolamine salts.

[0024] In this article, "stereoisomers" refers to compounds with the same molecular composition and linkage sequence but different spatial arrangements, including but not limited to optical isomers, enantiomers, diastereomers, racemates and mixtures thereof, as well as cis isomers, trans isomers, and E / Z isomers. The iridoid ether derivatives described in this invention include all possible stereoisomers and mixtures thereof in any proportion.

[0025] In this document, "solvent" refers to an associative compound formed by the compound of the present invention and one or more solvent molecules through non-covalent interactions. Exemplary solvents include, but are not limited to, methanol, ethanol, isopropanol, acetonitrile, acetone, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, and combinations thereof.

[0026] In this article, "hydrate" refers to a solvate formed by the compound of the present invention and water molecules, including monohydrate, dihydrate, polyhydrate, and aqueous forms without a fixed stoichiometric ratio.

[0027] In this document, "isotope-labeled compound" refers to a compound formed by replacing one or more atoms of the compound with their corresponding isotopes. Exemplary isotopes include, but are not limited to, ²H, ³H, ¹¹C, ¹³C, ¹³H ...H, ¹³H, ¹³ 4 C、¹ 5 N、¹ 7 O、¹ 8 O、¹ 8 F、³¹P、³²P、³ 5 S and ³ 6 Cl, etc. The isotope-labeled compounds can be used for pharmacokinetic studies, tissue distribution studies, metabolic studies, receptor binding studies, in vivo tracing, and medical imaging.

[0028] In this document, "alkyl" refers to a straight-chain or branched saturated hydrocarbon group containing a specified number of carbon atoms. The alkyl group can be C1-C2. 18Alkyl, C1-C6 alkyl, C1-C4 alkyl, or C1-C3 alkyl. Among them, C1-C6 alkyl, C1-C4 alkyl, or C1-C3 alkyl. 18 Alkyl groups refer to straight-chain or branched saturated hydrocarbon groups containing 1 to 18 carbon atoms; C1-C6 alkyl, C1-C4 alkyl, and C1-C3 alkyl groups are C1-C6, C1-C4, and C1-C3 alkyl groups, respectively. 18 The corresponding sub-range of alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecanyl, and octadecyl.

[0029] In this article, "alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon group containing a specified number of carbon atoms and at least one carbon-carbon double bond. C2-C6 alkenyl in this article refers to alkenyl groups containing 2 to 6 carbon atoms, including but not limited to vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, pentenyl, and hexenyl.

[0030] In this article, "alkynyl" refers to a straight-chain or branched hydrocarbon group containing a specified number of carbon atoms and at least one carbon-carbon triple bond. The C2-C6 alkynyl group in this article refers to an alkynyl group containing 2 to 6 carbon atoms, including but not limited to ethynyl, propynyl, 2-butynyl, 3-butynyl, pentynyl, and hexynyl.

[0031] In this document, "alkoxy group" refers to the group formed by the above-mentioned alkyl group being connected to the parent structure through an oxygen atom. The alkoxy group can be C1-C6 alkoxy or C1-C3 alkoxy, wherein C1-C3 alkoxy is a sub-range of C1-C6 alkoxy. C1-C6 alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, pentoxy, and hexoxy.

[0032] In this article, "halogens" include fluorine, chlorine, bromine, and iodine.

[0033] In this document, "haloalkyl" refers to a group formed by replacing one or more hydrogen atoms in the aforementioned alkyl group with one or more identical or different halogen atoms. The haloalkyl group can be C1-C6 or C1-C3 haloalkyl, wherein C1-C3 haloalkyl is a subrange of C1-C6 haloalkyl. C1-C6 haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl, and 2,2,2-trifluoroethyl.

[0034] In this article, "amino" refers to the -NH2 group.

[0035] In this article, "mono(C1-C6 alkyl)amino" refers to a group formed by replacing one hydrogen atom of an amino group with a C1-C6 alkyl group; "mono(C1-C3 alkyl)amino" is its sub-range, including but not limited to methylamino, ethylamino, n-propylamino and isopropylamino.

[0036] In this article, "di(C1-C6 alkyl)amino" refers to a group formed by replacing two hydrogen atoms in an amino group with the same or different C1-C6 alkyl groups; "di(C1-C3 alkyl)amino" is its sub-range, including but not limited to dimethylamino, diethylamino, methylethylamino, di-n-propylamino, and diisopropylamino.

[0037] In this article, "hydroxyl group" refers to the -OH group.

[0038] In this article, "cyano" refers to the -CN group.

[0039] In this document, "cycloalkyl" refers to a saturated monocyclic or polycyclic alicyclic group having a specified number of carbon atoms. The cycloalkyl group can be C3-C8 or C3-C6 cycloalkyl, wherein C3-C6 cycloalkyl is a subrange of C3-C8 cycloalkyl. C3-C8 cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0040] In this article, "aryl" refers to an aromatic carbocyclic group, which can be monocyclic or fused-ring aryl. The C6-C group in this article... 10 Aryl refers to a monocyclic or fused-ring aromatic group containing 6 to 10 ring carbon atoms, including but not limited to phenyl, naphthyl, and indene. The aryl group may optionally be substituted by one or more substituents.

[0041] In this document, "heterocyclic group" refers to a non-aromatic cyclic group containing one or more heteroatoms, including N, O, and / or S. The 3- to 8-membered heterocyclic group refers to a non-aromatic cyclic group containing 3 to 8 ring atoms, of which 1 to 3 heteroatoms are independently selected from N, O, and S. The heterocyclic group can be a monocyclic, fused-ring, spirocyclic, or bridged ring structure, including but not limited to azirropropyl, azirrobutyl, pyrrolyl, piperidinyl, piperazine, morpholinyl, tetrahydrofuranyl, and tetrahydrothiopheneyl. The 5- to 6-membered nitrogen-containing heterocyclic group refers to a heterocyclic group containing 5 or 6 ring atoms and at least one nitrogen atom, including but not limited to pyrrolyl, piperidinyl, piperazine, and morpholinyl.

[0042] In this document, "heteroaryl" refers to an aromatic cyclic group containing one or more heteroatoms, including N, O, and / or S. The 5- to 12-membered heteroaryl in this document refers to a heterocyclic group containing 5 to 12 ring atoms and exhibiting aromaticity, wherein 1 to 3 heteroatoms are independently selected from N, O, and S. The heteroaryl can be a monocyclic, fused-ring, or fused-heterocyclic structure, including but not limited to furanyl, thiopheneyl, pyrroleyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, purineyl, and acridineyl.

[0043] In this article, "C1-C6 alkoxy-C1-C6 alkyl" refers to a group formed by replacing one hydrogen atom of a C1-C6 alkyl group with a C1-C6 alkoxy group, which is connected to the parent structure through the C1-C6 alkyl group, including but not limited to methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl and 3-methoxypropyl.

[0044] In this article, "C6-C" 10 "Aryl-C1-C6 alkyl" refers to a C1-C6 alkyl group in which one hydrogen atom is bonded to a C6-C6 alkyl group. 10 A group formed by aryl substitution, which is connected to the parent structure through the C1-C6 alkyl group, including but not limited to benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl and naphthylmethyl.

[0045] In this article, "-O-C1-C6 alkyl-5 to 12-membered heteroaryl" refers to a group that is connected to the parent structure by an oxygen atom and has 5 to 12-membered heteroaryl groups connected by a C1-C6 alkyl group, including but not limited to -O-CH2-pyridinyl, -O-CH2CH2-pyridinyl, -O-CH2-pyrimidinyl and -O-CH2CH2-quinolinyl, etc.

[0046] In this article, "-S(O)2-C1-C6 alkyl" refers to sulfonyl alkyl, including but not limited to methanesulfonyl, ethanesulfonyl, and propanesulfonyl.

[0047] In this document, "-C(O)2-C1-C6 alkyl" refers to an acyl substituent containing two carbonyl groups, and its specific structure is as defined in the claims and general formula.

[0048] In this document, "glycosyl" refers to a group formed by removing a hydroxyl group or a corresponding terminal group from a carbohydrate compound, including monosaccharide residues, disaccharide residues, or oligosaccharide residues. The glycosyl group includes, but is not limited to, glucosyl, galactosyl, mannose, ribosyl, arabinose, xylose, lactose, maltose, and sucrose. In some preferred embodiments, the glycosyl group is glucosyl.

[0049] In this article, "optional substitution" means that the corresponding group may not be substituted, or it may be substituted by a specified number of one or more substituents. When multiple substituents are present, the substituents may be the same or different, and each may be independently selected from the substituents listed in the respective definition.

[0050] In this article, "pharmaceutically acceptable" means substances or materials that, within reasonable medical judgment, are suitable for contact with the tissues of subjects such as humans or other mammals without causing excessive toxicity, irritation, allergic reactions or other problems, and have a commensurate benefit / risk ratio.

[0051] In this article, "prevention" refers to interventions conducted on subjects at risk before the onset of a disease, symptom, or pathological condition or before the appearance of obvious clinical symptoms, in order to reduce the likelihood of the disease, symptom, or pathological condition occurring, delay its occurrence, reduce its severity, or decrease the occurrence of its related symptoms and complications.

[0052] In this article, "treatment" refers to intervention on a subject's existing disease, symptom, or pathological state to achieve one or more of the following: cure the disease, alleviate disease symptoms, improve the pathological state, control or delay disease progression, promote functional recovery, improve quality of life, reduce the risk of disease recurrence, and / or reduce the risk of disease-related death.

[0053] In this article, "nervous system diseases" refers to diseases, symptoms, or pathological states involving abnormalities in the structure, function, or physiological activity of the central and / or peripheral nervous systems. These include diseases, symptoms, or pathological states caused or accompanied by factors such as neuronal or glial cell damage, death, or functional abnormalities; neurotransmitter or nerve signal transduction abnormalities; abnormal neural plasticity; neuroinflammation; oxidative stress; ischemia-hypoxia; excitotoxicity; abnormal protein aggregation; neuroimmunological abnormalities; neurodevelopmental abnormalities; neurodegenerative changes; or nerve tissue damage. The term "nervous system diseases" includes, but is not limited to, mental and emotional disorders, neurodegenerative diseases, cerebrovascular diseases, central nervous system injury, peripheral nervous system injury, neuroinflammatory diseases, demyelinating diseases, motor disorders, cognitive impairment, and other diseases accompanied by nerve cell damage or abnormal nerve function.

[0054] In this article, "neurodegenerative diseases" refers to a class of neurological diseases characterized by progressive structural damage, loss of function, or death of neurons and / or glial cells, including but not limited to Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Lewy body dementia, multiple system atrophy, frontotemporal dementia, and spinocerebellar ataxia.

[0055] In this article, "neural injury" refers to structural damage or functional impairment of neurons, glial cells, nerve fibers, or nerve tissue in the central and / or peripheral nervous systems caused by mechanical injury, ischemia-hypoxia, oxidative stress, inflammatory response, excitotoxicity, metabolic abnormalities, drugs or toxic substances, abnormal hormone exposure, or other factors, including but not limited to brain injury, spinal cord injury, peripheral nerve injury, and nerve cell injury.

[0056] This invention relates to an iridoid derivative, said derivative being a compound with the structural formula shown in Formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, or isotopically labeled compound thereof;

[0057] Where n = 0, 1, 2, 3 or 4; R1 can be hydrogen, amino, hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -S(O)2-C1-C6 alkyl, -C(O)2-C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, or C6-C 10 aryl, 5- to 12-membered heteroaryl, or -O-C1-C6 alkyl-5- to 12-membered heteroaryl; wherein the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 10 The aryl, 5- to 12-membered heteroaryl and -O-C1-C6 alkyl-5- to 12-membered heteroaryl groups are optionally substituted by 1 to 3 substituents independently selected from halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 alkoxy groups; R2 is hydrogen, C1-C 18 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl, C6-C 10 Aryl-C1-C6 alkyl or glycosyl; wherein, except for hydrogen and glycosyl, the remaining groups are optionally substituted by 1 to 3 substituents independently selected from halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 alkoxy.

[0058] In some embodiments, R1 is selected from C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic groups, and C6-C6 cycloalkyl. 10 Aryl groups, including C1-C6 alkyl groups, C3-C8 cycloalkyl groups, 3- to 8-membered heterocyclic groups, and C6-C6 cycloalkyl groups. 10The aryl group may be optionally substituted by one or two substituents independently selected from halogens, amino groups, mono(C1-C6 alkyl)amino groups, di(C1-C6 alkyl)amino groups, hydroxyl groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, and C1-C6 alkoxy groups.

[0059] In some embodiments, R1 is selected from C1-C4 alkyl, C3-C6 cycloalkyl, 5- to 6-membered nitrogen-containing heterocyclic group and phenyl; wherein the C1-C4 alkyl, C3-C6 cycloalkyl, 5- to 6-membered nitrogen-containing heterocyclic group and phenyl are optionally substituted by 1 to 2 substituents independently selected from fluorine, chlorine, bromine, amino, mono(C1-C3 alkyl)amino, di(C1-C3 alkyl)amino, C1-C3 alkyl, C1-C3 haloalkyl and C1-C3 alkoxy.

[0060] In some embodiments, R1 is an optionally substituted phenyl group, which is optionally substituted by one or two substituents independently selected from fluorine, chlorine, bromine, C1-C3 alkyl, C1-C3 haloalkyl and C1-C3 alkoxy groups.

[0061] In some embodiments, the glycosyl group is a monosaccharide residue, a disaccharide residue, or an oligosaccharide residue.

[0062] In some embodiments, the glycosyl group is selected from glucose, galactosyl, mannose, ribosyl, arabinose, xylose, lactose, maltose, and sucrose.

[0063] In some preferred embodiments, the glycosyl group is a glucose group.

[0064] In some embodiments, the iridoid derivative is selected from any one of compounds 1 to 33:

[0065] The present invention also relates to a pharmaceutical composition comprising the iridoid derivatives described above, and a pharmaceutically acceptable carrier.

[0066] In some embodiments, the pharmaceutical composition comprises 0.1% to 99.5% by weight of the as-described iridoid derivative as an active ingredient, preferably 0.5% to 99.5% by weight, more preferably 1% to 50% by weight, for example 1% by weight, 1.5% by weight, 2% by weight, 5% by weight, 10% by weight, 15% by weight, 20% by weight, 25% by weight, 30% by weight, or 50% by weight of the active ingredient. The remainder of the pharmaceutical composition is a pharmaceutically acceptable carrier.

[0067] In some embodiments, the pharmaceutical composition comprises two, three, or more pharmaceutically acceptable carriers. These pharmaceutically acceptable carriers include those conventional in the pharmaceutical field, such as diluents, fillers, binders, disintegrants, lubricants, wetting agents, solubilizers, solvents, colorants, fragrances, absorption enhancers, surfactants, and adsorbents. Examples include, but are not limited to, starch, pregelatinized starch, sodium carboxymethyl starch, powdered sugar, lactose, calcium phosphate, magnesium stearate, talc, micronized silica gel, dextrin, cellulose and its derivatives, such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, etc., as well as microcrystalline cellulose, mannitol, sorbitol, polysorbate 80, polyethylene glycol, water, water for injection, physiological saline, glucose solution, etc. The pharmaceutical composition may also contain various other commonly used additives, such as preservatives, emulsifiers, suspending agents, and flavoring agents.

[0068] The pharmaceutical composition can be prepared into any pharmaceutically acceptable dosage form using any conventional techniques in the art. In some embodiments, the pharmaceutical composition can be prepared into an oral formulation, an injectable formulation, a topical formulation, a nasal formulation, or other dosage forms suitable for drug administration.

[0069] In some embodiments, the oral formulation includes, but is not limited to, tablets, capsules, granules, powders, pills, oral solutions, oral suspensions, and oral emulsions.

[0070] In some embodiments, the injectable formulation includes, but is not limited to, injection solutions, sterile powders, lyophilized powder injections, injection suspensions, and injection emulsions.

[0071] In some embodiments, the topical administration formulation includes, but is not limited to, ointments, creams, gels, patches, and sprays.

[0072] In some embodiments, the nasal delivery formulation includes, but is not limited to, nasal drops, nasal sprays, nasal gels, and nasal powders.

[0073] In some embodiments, the pharmaceutical composition may also be formulated as a sustained-release formulation, a controlled-release formulation, a targeted formulation, a liposome formulation, a lipid nanoparticle formulation, a polymer nanoparticle formulation, a micelle formulation, or other nanoformulations. The wording of the above pharmaceutical compositions, carriers, and dosage forms is consistent with related documents.

[0074] The present invention also provides the use of the above-mentioned iridoid derivatives in the preparation of medicaments for the prevention and / or treatment of nervous system diseases.

[0075] In some embodiments, the neurological disorder includes one or more of depression, neurodegenerative diseases, and nerve damage.

[0076] In some embodiments, the depression includes, but is not limited to, major depressive disorder, persistent depressive disorder, recurrent depressive disorder, depressive episodes in bipolar disorder, seasonal affective disorder, postpartum depression, perimenopausal depression, geriatric depression, secondary depression, and depression accompanied by anxiety symptoms or other mental symptoms.

[0077] In some embodiments, the neurodegenerative diseases include, but are not limited to, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Lewy body dementia, multiple system atrophy, frontotemporal dementia, and spinocerebellar ataxia.

[0078] In some embodiments, the nerve injury includes, but is not limited to, brain injury, spinal cord injury, peripheral nerve injury, and nerve cell or nerve tissue damage caused by ischemia-hypoxia, oxidative stress, inflammatory response, excitotoxicity, metabolic abnormalities, drugs or toxic substances.

[0079] In some embodiments, the iridoid derivatives of the present invention can improve nerve cell survival, reduce nerve cell damage, maintain or improve nerve cell function, improve neural plasticity, and improve depressive-like behavior, among one or more of these effects. In some embodiments, in vitro nerve cell damage models can be used to evaluate the neuroprotective effects of the iridoid derivatives of the present invention. These in vitro nerve cell damage models include, but are not limited to, corticosterone-induced nerve cell damage models, oxygen-glucose deprivation / reoxygenation damage models, hydrogen peroxide-induced oxidative stress damage models, glutamate-induced excitotoxicity damage models, lipopolysaccharide-induced inflammatory damage models, and other commonly used nerve cell or glial cell damage models.

[0080] The aforementioned in vitro neuronal cell injury model can be used to reflect ischemia-hypoxia, oxidative stress, excitotoxicity, abnormal immune activation, neuroinflammation, abnormal neuroplasticity, and other related pathological processes in nervous system diseases. The neuroprotective effects of the iridoid derivatives can be evaluated by detecting cell viability, lactate dehydrogenase release level, apoptosis rate, mitochondrial functional status, oxidative stress level, inflammatory factor level, neurotrophic factor expression level, or other related biological indicators.

[0081] In some embodiments, animal depression models can be used to evaluate the in vivo efficacy of the iridoid derivatives of this invention. These animal depression models include, but are not limited to, models of chronic unpredictable mild stress, social frustration stress, learned helplessness, olfactory bulb resection, corticosterone-induced models, and other animal models that can reflect depressive-like behaviors, changes in neural plasticity, or related pathophysiological processes. In some embodiments, the ameliorative effect of the iridoid derivatives of this invention on depressive-like behaviors can be evaluated through behavioral tests. These behavioral tests include, but are not limited to, tail suspension test, forced swimming test, sucrose preference test, open field test, novelty inhibition feeding test, and other commonly used methods for evaluating depressive-like behaviors in the art. In some embodiments, the preventive and / or therapeutic effects of the iridoid derivatives of this invention on neurological diseases can also be evaluated through histopathological observation of the hippocampus, prefrontal cortex, or other relevant brain regions, detection of neurogenesis levels, detection of synaptic-related protein expression, detection of neurotrophic factor expression, detection of neurotransmitter levels, detection of inflammatory factor levels, or changes in other relevant biological indicators.

[0082] The present invention also provides a method for preventing and / or treating neurological diseases, comprising administering to a subject in need a preventive and / or therapeutically effective amount of the above-mentioned iridoid derivative or the above-mentioned pharmaceutical composition.

[0083] In some implementations, the prevention includes one or more of the following: reducing the risk of developing a neurological disorder, delaying the onset of a neurological disorder, reducing the severity of a neurological disorder, and reducing the occurrence of symptoms or complications related to a neurological disorder.

[0084] In some implementations, the treatment includes one or more of the following: curing the disease, relieving disease symptoms, improving pathological conditions, controlling or delaying disease progression, promoting neurological function recovery, improving the patient's quality of life, reducing the risk of disease recurrence, and / or reducing the risk of disease-related death.

[0085] In some embodiments, the neurological disorder includes one or more of depression, neurodegenerative diseases, and nerve damage.

[0086] The iridoid derivatives or pharmaceutical compositions of the present invention can be administered to subjects via any route of administration, including, for example, oral, intravenous, intraperitoneal, intramuscular, topical, transdermal, ocular, nasal, inhalation, subcutaneous, oral, sublingual, rectal, etc.

[0087] In some preferred embodiments, the administration method is oral administration, intravenous injection, intraperitoneal injection, or nasal administration.

[0088] The effective amount of the iridoid derivatives of the present invention depends on a variety of factors, including but not limited to: the specific compound to be administered; the species, size, age and general health of the mammal; the severity of the disease; the individual patient’s response; the route of administration; the bioavailability characteristics of the administered formulation; the selected dosage regimen; and the use of other concomitant medications, which can usually be determined by the attending physician based on routine practice.

[0089] Generally, the effective dose is typically in the range of about 0.001 to about 100 mg / kg body weight / day, preferably about 0.01 to about 50 mg / kg body weight / day. In some cases, dose levels below the lower limit of the above range may be sufficient, while in other cases, a larger dose may be required without causing any harmful side effects, where such a larger dose is usually divided into several smaller doses to be administered throughout the day.

[0090] In some embodiments, the iridoid derivative is administered once or more daily, or every other day.

[0091] In some embodiments, the iridoid derivatives may be administered alone or in combination with one or more other drugs used for the prevention and / or treatment of nervous system diseases.

[0092] In some embodiments, the other drugs for the prevention and / or treatment of nervous system diseases include, but are not limited to, antidepressants, anxiolytics, antipsychotics, mood stabilizers, sedative-hypnotics, neuroprotective agents, anti-inflammatory drugs, antioxidants, cholinesterase inhibitors, N-methyl-D-aspartate receptor antagonists, dopaminergic drugs, neurotrophic factors or their analogues, and other drugs that can prevent, treat or improve nervous system diseases.

[0093] In some embodiments, the combined application includes simultaneous application, sequential application, or intermittent application.

[0094] In some embodiments, the subject is a mammal. In some embodiments, the mammal includes a human, monkey, dog, cat, cow, sheep, pig, rabbit, rat, mouse, or guinea pig. In some preferred embodiments, the subject is a primate, preferably a human.

[0095] The embodiments of the present invention will be described in detail below with reference to the examples. It should be understood that these embodiments are only used to illustrate the technical content of the present invention and are not intended to limit the scope of protection of the present invention. Unless otherwise specified, the specific experimental conditions in the following embodiments are given priority reference to the guidelines provided in this specification, or may be carried out according to generally accepted experimental manuals or conventional experimental conditions, or other experimental methods known in the art, or according to the conditions recommended by the relevant reagent or instrument manufacturers. In specific embodiments, unless otherwise specified, minor deviations within the weighing accuracy range are allowed for the measurement parameters involving raw material components; reasonable deviations due to instrument detection accuracy or operational accuracy are also allowed for parameters such as temperature and time.

[0096] Example 1. Synthesis of Compound 1 (General Synthesis Method A)

[0097] Loganin (0.26 mmol) was placed in an 8 mL reaction vial, and 2 mL of purified water was added. The mixture was stirred to dissolve the 0.26 mmol KOH and stirred at 60 °C for 2 h. The reaction was monitored by TLC (developing solvent: DCM / MeOH = 5 / 1). After the reaction was complete, dilute hydrochloric acid was added to adjust the pH of the reaction solution to 6-7. The crude extract was then concentrated. The crude extract was purified by rapid silica gel column chromatography (DCM / MeOH = 6 / 1), concentrated, and dried to obtain the target product, Loganin acid (80 mg, 89.3%).

[0098] Loganin acid (0.13 mmol) was placed in an 8 mL reaction vial, and 1 mL of acetonitrile was added. The mixture was stirred to dissolve the 0.13 mmol loganin acid. EDCI (0.40 mmol), HOBT (0.16 mmol), and TEA (0.27 mmol) were then added to the reaction system. The mixture was stirred at 0 °C for 10 min, and the reaction was monitored by TLC (evolving solvent: DCM / MeOH = 5 / 1). After the loganin acid had completely reacted, reactant R-1 (0.13 mmol) was added. The reaction was monitored by TLC again, and after the reaction was complete, two volumes of water were added to quench the reaction mixture. The crude extract was then concentrated. The crude extract was purified by rapid silica gel column chromatography, concentrated under reduced pressure, and freeze-dried to obtain compound 1, a white solid powder (18.1 mg, 33.8%, purity 98%).

[0099] 1 H NMR (400 MHz, CD3OD) d 7.01 (d, J = 1.3 Hz, 1H), 5.25 (d, J= 4.2 Hz, 1H), 4.64 (d, J = 7.9 Hz, 1H), 4.06 (td, J = 5.0, 1.8 Hz, 1H), 3.89 (dd, J = 12.0,1.6 Hz, 1H), 3.70 - 3.63 (m, 1H), 3.28 (d, J = 1.8 Hz, 1H), 3.25 - 3.18 (m,2H), 3.14 (t, J = 7.5 Hz, 1H), 2.12 (ddd, J = 13.9, 7.9, 1.9 Hz, 1H), 2.04 (td, J =9.1, 4.2 Hz, 1H), 1.89 (ddd, J = 9.7, 7.1, 4.9 Hz, 1H), 1.61 (ddd, J = 13.9, 7.0,5.1 Hz, 1H), 1.13 (t, J = 7.2 Hz, 3H), 1.09 (d, J = 6.9 Hz, 3H). 13 C NMR (100 MHz, CD3OD) d 170.26, 146.19, 117.44, 99.85, 96.99, 78.33, 77.97, 74.98, 74.76,71.59, 62.74, 46.68, 41.88, 41.77, 35.30, 31.93, 15.00, 13.35.HR-ESI-MS m / z calcd for C 18 H 29 NO9[M+HCOO] - : 448.1819, found: 448.1821. Example 2. Synthesis of Compound 2

[0100] Compound 2 was prepared as a white solid powder (27.5 mg, 49.6%, purity 98%) using loganin and compound R-2 respectively, according to the general synthesis method A described in Example 1. 1 H NMR (400 MHz, CDCl3) d7.02 (s, 1H), 5.26 (d, J = 4.2 Hz, 1H), 4.65 (d, J = 7.8 Hz, 1H), 4.07 (td, J = 5.2, 1.9 Hz,1H), 3.89 (dd, 1H), 3.70 - 3.64 (m, 1H), 3.37 (d, J = 9.9 Hz, 1H), 3.22 (td, J =8.5, 7.7, 4.4 Hz, 2H), 3.19 - 3.11 (m, 2H), 2.13 (ddd, J = 13.9, 7.9, 1.9 Hz,1H), 2.05 (td, J = 9.1, 4.2 Hz, 1H), 1.90 (ddd, J = 9.7, 7.0, 4.9 Hz, 1H), 1.62(ddd, J = 13.8, 7.0, 5.1 Hz, 1H), 1.54 (p, J = 7.3 Hz, 2H), 1.10 (d, J = 6.8 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3) d 170.41, 146.11, 117.48,99.82, 96.98, 78.31, 77.94, 74.97, 74.75, 71.58, 62.73, 46.67, 42.24, 41.86,41.79, 31.94, 23.76, 13.36, 11.76.HR-ESI-MS m / z calcd for C 19 H 31 NO9[M+HCOO] - :462.1969, found: 462.1979. Example 3. Synthesis of Compound 3

[0101] Compound 3 was prepared as a white solid powder (20.8 mg, 36.3%, purity 98%) using loganin and compound R-3 respectively, according to the general synthesis method A described in Example 1.1 H NMR (400 MHz, CDCl3) d 7.00 (s, 1H), 5.26 (d, J = 4.2 Hz, 1H), 4.64 (d, J = 7.8 Hz, 1H), 4.06 (td, 1H), 3.89 (dd,1H), 3.71 - 3.58 (m, 1H), 3.26 - 3.16 (m, 2H), 3.19 - 3.10 (m, 2H), 2.11(ddd, J = 15.2, 8.5, 2.3 Hz, 1H), 2.07 - 1.99 (m, 1H), 1.94 - 1.84 (m, 1H), 1.66 - 1.56 (m, 1H), 1.54 - 1.46 (m, 2H), 1.39 - 1.33 (m, 2H), 1.09 (d, J = 6.8Hz, 3H), 0.94 (t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, CDCl3) d 170.39, 146.08,117.50, 99.82, 96.95, 78.33, 77.96, 74.98, 74.77, 71.59, 62.75, 46.68, 41.86,41.78, 40.22, 32.72, 31.94, 21.16, 14.13, 13.34. HR-ESI-MS m / z calcd forC 20 H 33 NO9[M+HCOO] - : 476.2132, found: 476.2134. Example 4. Synthesis of Compound 4

[0102] Compound 4 was prepared as a white solid powder (38.9 mg, 68.2%, purity 98%) using loganin and compound R-4 respectively, according to the general synthesis method A described in Example 1. 1 H NMR (400 MHz, CD3OD) d 7.04 (d, J =1.3 Hz, 1H), 5.26 (d, J= 4.2 Hz, 1H), 4.65 (d, J = 7.9 Hz, 1H), 4.07 (td, J = 5.0, 1.8 Hz, 1H), 3.90 (dd, J = 12.0, 1.7 Hz, 1H), 3.71 - 3.65 (m, 1H), 3.15 - 3.00(m, 2H), 2.13 (ddd, J = 13.9, 7.9, 1.9 Hz, 1H), 2.06 (td, J = 9.2, 4.2 Hz, 1H), 1.90 (ddd, J = 9.6, 7.0, 4.9 Hz, 1H), 1.64 (ddd, J = 13.9, 7.0, 5.1 Hz, 1H), 1.10(d, J = 6.9 Hz, 3H), 0.48 (dd, J = 8.1, 1.7 Hz, 2H), 0.22 (dd, J = 4.7, 1.5 Hz, 2H). 13 C NMR (100 MHz, CD3OD) d 169.93, 146.22, 117.40, 99.83, 96.98, 78.30,77.93, 74.96, 74.74, 71.57, 62.72, 46.67, 45.02, 41.86, 41.77, 31.94, 13.36,11.71, 3.83, 3.77. HR-ESI-MS m / z calcd for C 20 H 31 NO9[M+HCOO] - : 474.1975, found:474.1976. Example 5. Synthesis of Compound 5

[0103] Compound 5 was prepared as a white solid powder (9.0 mg, 18.5%, purity 98%) using loganin and compound R-5 respectively, according to the general synthesis method A described in Example 1. 1 H NMR (500 MHz, CD3OD) d 6.97 (s, OH), 5.25 (d,J = 4.2 Hz, 1H), 4.64 (d, J = 7.9 Hz, 1H), 4.06 (td, J = 5.1, 2.0 Hz, 1H), 3.89 (dd, J = 11.9, 1.7 Hz, 1H), 3.71 (dt, J = 11.0, 3.9 Hz, 1H), 3.69 -3.63 (m, 1H), 3.41 - 3.34 (m, 1H), 3.30 - 3.26 (m, 1H), 3.24 - 3.12 (m, 2H),2.16 - 1.98 (m, 2H), 1.94 - 1.86 (m, 2H), 1.77 (dt, J = 12.9, 3.8 Hz, 2H), 1.68- 1.57 (m, 2H), 1.40 - 1.32 (m, 3H), 1.27 - 1.20 (m, 3H), 1.09 (d, J = 6.9 Hz, 3H). 13 C NMR (125 MHz, CD3OD) d 169.68, 145.91, 117.65, 99.84, 96.96, 78.35,77.98, 75.00, 74.79, 71.62, 62.76, 49.94, 46.72, 41.84, 41.67, 33.86, 33.78,32.00, 26.65, 26.35, 13.34. HR-ESI-MS m / z calcd for C 22 H 35 NO9[M+HCOO] - : 502.2282, found: 502.2294. Example 6. Synthesis of Compound 6

[0104] Compound 6 was prepared as a white solid powder (11.3 mg, 19.0%, purity 98%) using loganin and compound R-6 respectively, according to the general synthesis method A described in Example 1. 1 H NMR (500 MHz, CD3OD) d 7.13 (d, J =1.3 Hz, 1H), 5.27 (d,J = 4.2 Hz, 1H), 4.64 (d, J = 7.9 Hz, 1H), 4.06 (td, J = 5.0, 1.8 Hz, 1H), 3.89 (dd, J = 12.0, 1.8 Hz, 1H), 3.71 - 3.62 (m, 1H), 3.53 (q, J =6.1 Hz, 2H), 3.36 (d, J = 9.1 Hz, 1H), 3.01 (t, J = 6.2 Hz, 2H), 2.71 (s, 6H), 2.16 (ddd, J = 13.9, 7.9, 1.9 Hz, 1H), 2.05 (td, J = 9.2, 4.3 Hz, 1H), 1.88 (ddd, J = 9.7, 6.1, 3.5 Hz, 1H), 1.62 (ddd, J = 13.9, 7.2, 5.1 Hz, 1H), 1.10 (d, J = 6.9Hz, 3H). 13 C NMR (125 MHz, CD3OD) d 170.91, 147.43, 116.98, 99.87, 97.13, 78.37,78.02, 75.01, 74.79, 71.61, 62.74, 58.89, 46.69, 44.35, 42.00, 41.98, 36.67,31.86, 13.34.HR-ESI-MS m / z calcd for C 20 H 34 N2O9[M+HCOO] - : 491.2241, found:491.2245. Example 7. Synthesis of Compound 7

[0105] Compound 7 was prepared as a white solid powder (29.6 mg, 45.8%, purity 98%) using loganin and compound R-7 respectively, according to the general synthesis method A described in Example 1. 1 H NMR (500 MHz, CD3OD) d7.12 (s, 1H), 5.27 (d, J = 4.2 Hz, 1H), 4.64 (d, J = 7.9 Hz, 1H), 4.06 (td, J = 4.9, 1.8 Hz, 1H), 3.89 (dd, J = 12.0, 1.8 Hz, 1H), 3.66 (dd, J = 11.9, 5.2 Hz, 1H), 3.52 (q, J =6.1 Hz, 2H), 3.37 (t, J = 8.9 Hz, 1H), 3.23 - 3.11 (m, 2H), 3.00 - 2.82 (m,6H), 2.15 (ddd, J = 13.9, 7.9, 1.9 Hz, 1H), 2.05 (td, J = 9.2, 4.2 Hz, 1H), 1.88(ddd, J = 9.6, 7.0, 4.8 Hz, 1H), 1.76 (t, J = 5.8 Hz, 4H), 1.65 - 1.61 (m, 1H), 1.59 (t, J = 6.8 Hz, 2H), 1.09 (d, J = 6.9 Hz, 3H). 13 C NMR (125 MHz, CD3OD) d 170.91, 147.35, 116.94, 99.89, 97.12, 78.36, 78.02, 74.99, 74.79, 71.60,62.74, 58.56, 55.04, 46.67, 41.98, 41.96, 36.49, 31.86, 25.36, 23.78, 13.34.HR-ESI-MS m / z calcd for C 23 H 38 N2O9[M+HCOO] - : 531.2548, found: 531.2560. Example 8. Synthesis of Compound 8

[0106] Compound 8 was prepared as a white solid powder (8.7 mg, yield 28.5%, purity 98%) using loganin and compound R-8 respectively, according to the general synthesis method A described in Example 1. 1 H NMR (400 MHz, CD3OD) d 7.53(d, J = 7.9 Hz, 2H), 7.30 (t, J = 7.9 Hz, 2H), 7.19 (s, 1H), 7.09 (t, J = 7.4 Hz, 1H), 5.31 (d, J = 4.2 Hz, 1H), 4.68 (d, J = 7.8 Hz, 1H), 4.09 (td, J = 5.0, 1.8 Hz, 1H), 3.91 (dd, J = 12.0, 1.6 Hz, 1H), 3.68 (dd, J = 12.1, 5.3 Hz, 1H), 3.41 -3.35 (m, 1H), 3.28 - 3.16 (m, 2H), 2.18 (ddd, J = 14.0, 7.9, 1.9 Hz, 1H), 2.10(td, J = 9.2, 4.2 Hz, 1H), 1.94 (ddd, J = 9.7, 7.1, 5.0 Hz, 1H), 1.70 (ddd, J =13.9, 7.1, 5.1 Hz, 1H), 1.12 (d, J = 6.9 Hz, 3H). 13 C NMR (100 MHz, CD3OD) d 169.01, 147.08, 139.81, 129.70, 125.22, 122.09, 118.28, 99.85, 97.17, 78.39,78.00, 75.03, 74.78, 71.59, 62.76, 46.74, 41.98, 41.92, 32.15, 13.38. HR-ESI-MS m / z calcd for C 22 H 29 NO9[M+HCOO] -: 496.1813, found: 496.1824. Example 9. Synthesis of Compound 9

[0107] Compound 9 was prepared as a white solid powder (15.7 mg, yield 25.4%, purity 98%) using loganin and compound R-9 respectively, according to the general synthesis method A described in Example 1. 1 H NMR (400 MHz, CD3OD) d 7.40(d, J = 8.4 Hz, 2H), 7.16 (d, J = 1.3 Hz, 1H), 7.11 (d, J = 8.4 Hz, 2H), 5.30 (d, J =4.2 Hz, 1H), 4.68 (d, J = 7.9 Hz, 1H), 4.09 (td, J = 5.0, 1.8 Hz, 1H), 3.90 (dd, J = 12.0, 1.7 Hz, 1H), 3.70 - 3.64 (m, 1H), 3.41 - 3.34 (m, 1H), 3.28 - 3.19(m, 2H), 2.30 (s, 3H), 2.21 - 2.13 (m, 1H), 2.09 (td, J = 9.2, 4.2 Hz, 1H), 1.93 (ddd, J = 9.7, 7.0, 4.9 Hz, 1H), 1.69 (ddd, J = 13.9, 7.1, 5.1 Hz, 1H), 1.12(d, J = 6.9 Hz, 3H). 13 C NMR (100 MHz, CD3OD) d 168.94, 146.89, 137.16, 134.98,130.16, 122.21, 118.26, 99.84, 97.14, 78.38, 77.99, 75.03, 74.78, 71.60,62.76, 46.74, 41.96, 41.89, 32.15, 20.91, 13.38. HR-ESI-MS m / z calcd forC23 H 31 NO9[M+HCOO] - : 510.1975, found: 510.1979. Example 10. Synthesis of Compound 10

[0108] Compound 10 was prepared as a white solid powder (22.3 mg, yield 35.8%, purity 98%) using loganin and compound R-10 respectively, according to the general synthesis method A described in Example 1. 1 H NMR (400 MHz, CD3OD) d 7.53(dd, J = 9.1, 4.9 Hz, 2H), 7.19 (d, J = 1.3 Hz, 1H), 7.04 (t, J = 8.8 Hz, 2H), 5.30(d, J = 4.2 Hz, 1H), 4.68 (d, J = 7.9 Hz, 1H), 4.09 (td, J = 5.0, 1.7 Hz, 1H), 3.90(dd, J = 11.9, 1.7 Hz, 1H), 3.71 - 3.64 (m, 1H), 3.26 - 3.16 (m, 2H), 2.18(ddd, J = 13.9, 7.9, 1.9 Hz, 1H), 2.09 (td, J = 9.2, 4.2 Hz, 1H), 1.93 (ddd, J =9.7, 7.0, 4.8 Hz, 1H), 1.69 (ddd, J = 14.0, 7.2, 5.1 Hz, 1H), 1.12 (d, J = 6.9Hz, 3H). 13 C NMR (100 MHz, CD3OD) d168.93, 161.93, 159.53, 147.17, 136.02,135.99, 124.02, 123.95, 118.10, 116.25, 116.03, 99.86, 97.20, 78.39, 78.01,75.02, 74.78, 71.59, 62.76, 46.72, 41.99, 41.93, 32.14, 13.39. HR-ESI-MS m / z calcd for C 22 H 28 FNO9[M+HCOO] - : 514.1725, found: 514.1729. Example 11. Synthesis of Compound 11

[0109] Compound 11 was prepared as a white solid powder (6.1 mg, yield 9.5%, purity 98%) using loganin and compound R-11 respectively, according to the general synthesis method A described in Example 1. 1 H NMR (500 MHz, CD3OD) d 7.42(d, J = 9.0 Hz, 2H), 7.16 (d, J = 1.4 Hz, 1H), 6.87 (d, J = 9.0 Hz, 2H), 5.30 (d, J =4.2 Hz, 1H), 4.67 (d, J = 7.9 Hz, 1H), 4.09 (td, J = 5.1, 1.9 Hz, 1H), 3.90 (dd, J = 11.9, 1.7 Hz, 1H), 3.77 (s, 3H), 3.71 - 3.64 (m, 1H), 2.17 (ddd, J = 13.8,8.0, 2.0 Hz, 1H), 2.09 (td, J = 9.2, 4.2 Hz, 1H), 1.93 (ddd, J = 9.7, 7.1, 4.9Hz, 1H), 1.70 (ddd, J = 13.9, 7.1, 5.1 Hz, 1H), 1.12 (d,J = 6.9 Hz, 3H). 13 C NMR (125 MHz, CD3OD) d 169.28, 156.05, 146.16, 133.35, 124.00, 118.18, 115.42,98.64, 94.94, 78.75, 78.02, 76.00, 74.80, 68.59, 62.30, 55.85, 46.16, 42.45,40.81, 32.56, 12.93, 7.22. HR-ESI-MS m / z calcd for C 23 H 31 NO 10 [M+HCOO] - : 526.1925, found: 526.1931. Example 12. Synthesis of Compound 12

[0110] Compound 12 was prepared as a white solid powder (16.7 mg, yield 27.3%, purity 98%) using loganin and compound R-12 respectively, according to the general synthesis method A described in Example 1. 1 H NMR (400 MHz, CD3OD) d 7.34- 7.26 (m, 4H), 7.25 - 7.20 (m, 1H), 7.08 (s, 1H), 5.27 (d, J = 4.2 Hz, 1H), 4.64 (d, J = 7.9 Hz, 1H), 4.43 (q, 2H), 4.07 (t, 1H), 3.89 (dd, J = 11.9, 1.7 Hz, 1H), 3.66 (dd, J = 11.8, 5.2 Hz, 1H), 3.25 - 3.11 (m, 2H), 2.13 (ddd, J = 13.9,7.9, 1.9 Hz, 1H), 2.06 (td, J = 9.2, 4.2 Hz, 1H), 1.09 (d, J = 6.9 Hz, 3H), 1.90(ddd, J = 9.7, 7.0, 4.9 Hz, 1H), 1.64 (ddd,J = 13.8, 7.1, 5.1 Hz, 1H). 13 C NMR (100 MHz, CD3OD) d 170.36, 146.60, 140.37, 129.49, 128.44, 128.08, 117.35,99.84, 97.02, 78.35, 77.98, 75.00, 74.78, 71.60, 62.76, 46.70, 44.04, 41.92,41.90, 31.98, 13.35. HR-ESI-MS m / z calcd for C 23 H 31 NO9[M+HCOO] - : 510.1969, found:510.1979. Example 13. Synthesis of Compound 13

[0111] Compound 13 was prepared as a white solid powder (10.9 mg, yield 17.0%, purity 98%) using loganin and compound R-13 respectively, according to the general synthesis method A described in Example 1. 1 H NMR (400 MHz, CD3OD) d 7.30(dd, J = 8.5, 5.5 Hz, 2H), 7.08 (s, 1H), 7.03 (t, J = 8.7 Hz, 2H), 5.27 (d, J = 4.1Hz, 1H), 4.64 (d, J = 7.9 Hz, 1H), 4.48 - 4.31 (m, 2H), 4.06 (td, J = 5.0, 1.7Hz, 1H), 3.89 (d, J = 11.1 Hz, 1H), 3.66 (dd, J = 11.9, 5.2 Hz, 1H), 3.21 (d, J =7.7 Hz, 1H), 3.19 - 3.16 (m, 1H), 2.13 (ddd, J = 13.9, 7.9, 1.9 Hz, 1H), 2.06(td, J= 9.2, 4.2 Hz, 1H), 1.92 - 1.86 (m, 1H), 1.63 (ddd, J = 13.8, 7.1, 5.1 Hz,1H), 1.09 (d, J = 6.8 Hz, 3H). 13 C NMR (100 MHz, CD3OD) d 170.32, 164.60, 162.18,146.67, 136.48, 136.45, 130.38, 130.30, 117.31, 116.18, 115.96, 99.84, 97.02,78.36, 77.99, 75.00, 74.77, 71.60, 62.76, 46.69, 43.31, 41.93, 41.90, 31.95,13.34, 9.22. HR-ESI-MS m / z calcd for C 23 H 30 FNO9[M+HCOO] - : 528.1881, found:528.1884. Example 14. Synthesis of Compound 14

[0112] Compound 14 was prepared as a white solid powder (39.1 mg, yield 58.9%, purity 98%) using loganin and compound R-14 respectively, according to the general synthesis method A described in Example 1. 1 H NMR (400 MHz, CD3OD) d 7.29(q, J = 8.6 Hz, 4H), 7.08 (d, J = 1.3 Hz, 1H), 5.28 (d, J = 4.1 Hz, 1H), 4.64 (d, J =7.9 Hz, 1H), 4.48 - 4.33 (m, 2H), 4.06 (td, J = 5.0, 1.8 Hz, 1H), 3.89 (dd, J =12.0, 1.7 Hz, 1H), 3.69 - 3.63 (m, 1H), 3.23 - 3.14 (m, 2H), 2.13 (ddd, J=13.9, 7.9, 1.9 Hz, 1H), 2.06 (dt, J = 9.0, 4.6 Hz, 1H), 1.89 (ddd, J = 9.7, 7.0,4.8 Hz, 1H), 1.63 (ddd, J = 13.9, 7.1, 5.1 Hz, 1H), 1.09 (d, J = 6.9 Hz, 3H). 13 CNMR (100 MHz, CD3OD) d 170.37, 146.74, 139.33, 133.80, 130.06, 129.52, 117.30,99.84, 97.01, 78.37, 78.00, 75.00, 74.77, 71.61, 62.76, 46.70, 43.35, 41.96,41.91, 31.94, 13.33. HR-ESI-MS m / z calcd for C 23 H 30 ClNO9[M+HCOO] - : 544.1586, found: 544.1593. Example 15. Synthesis of Compound 15

[0113] Compound 15 was prepared as a white solid powder (13.6 mg, yield 18.8%, purity 98%) using loganin and compound R-15 respectively, according to the general synthesis method A described in Example 1. 1 H NMR (400 MHz, CD3OD) d 7.46(d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 1.2 Hz, 1H), 5.28 (d, J =4.1 Hz, 1H), 4.64 (d, J = 7.9 Hz, 1H), 4.46 - 4.31 (m, 2H), 4.06 (td, J = 5.0, 1.8 Hz, 1H), 3.89 (dd, J= 12.0, 1.7 Hz, 1H), 3.66 (ddd, J = 11.9, 4.4, 1.8 Hz,1H), 3.38 (d, J = 8.7 Hz, 1H), 3.23 - 3.13 (m, 2H), 2.13 (ddd, J = 13.9, 7.9, 1.9Hz, 1H), 2.06 (td, J = 9.1, 4.1 Hz, 1H), 1.89 (ddd, J = 9.6, 7.0, 4.8 Hz, 1H),1.63 (ddd, J = 13.8, 7.1, 5.1 Hz, 1H), 1.09 (d, J = 6.9 Hz, 3H). 13 C NMR (100 MHz, CD3OD) d 170.37, 146.75, 139.81, 132.53, 130.40, 121.70, 117.28, 99.83, 97.01,78.36, 77.99, 75.00, 74.77, 71.60, 62.76, 46.70, 43.39, 41.95, 41.90, 31.93,13.33. HR-ESI-MS m / z calcd for C 23 H 30 BrNO9[M+HCOO] - : 588.1080, found: 588.1088. Example 16. Synthesis of Compound 16

[0114] Compound 16 was prepared as a white solid powder (51.1 mg, yield 72.1%, purity 98%) using loganin and compound R-16 respectively, according to the general synthesis method A described in Example 1. 1 H NMR (400 MHz, CD3OD) d 7.62(d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 1.2 Hz, 1H), 5.29 (d, J=4.1 Hz, 1H), 4.65 (d, J = 7.9 Hz, 1H), 4.58 - 4.42 (m, 2H), 4.07 (td, J = 5.0, 1.8 Hz, 1H), 3.89 (dd, J = 11.9, 1.7 Hz, 1H), 3.70 - 3.63 (m, 1H), 3.20 (dd, J =9.1, 7.8 Hz, 2H), 2.15 (ddd, J = 13.9, 7.9, 2.0 Hz, 1H), 2.07 (td, J = 9.2, 4.2Hz, 1H), 1.90 (ddd, J = 9.6, 7.0, 4.8 Hz, 1H), 1.65 (ddd, J = 13.9, 7.1, 5.1 Hz,1H), 1.10 (d, J = 6.9 Hz, 3H). 13 C NMR (100 MHz, CD3OD) d 170.47, 146.88, 145.15,130.40, 130.08, 128.88, 127.11, 126.37, 126.33, 124.42, 117.26, 99.84, 97.03,78.37, 78.01, 75.02, 74.78, 71.61, 62.76, 46.71, 43.59, 42.00, 41.92, 31.94,13.33. HR-ESI-MS m / z calcd for C 24 H 30 F3NO9[M+HCOO] - : 578.1849, found: 578.1853. Example 17. Synthesis of Compound 17

[0115] Compound 17 was prepared as a white solid powder (16.0 mg, 24.3%) using loganin and compound R-17 respectively, according to the general synthesis method A described in Example 1. 1 H NMR (400 MHz, DMSO- d 6) d 7.16 (d,J = 8.6Hz, 2H), 7.07 (d, J = 1.4 Hz, 1H), 6.86 (d, J = 8.6 Hz, 2H), 5.04 (d, J = 5.0 Hz, 1H), 4.48 (d, J = 7.9 Hz, 1H), 4.31 - 4.14 (m, 2H), 3.88 (t, J = 3.9 Hz, 1H), 3.72 (s, 3H), 3.66 (dd, J = 11.8, 2.0 Hz, 1H), 3.42 (dd, J = 11.8, 6.3 Hz, 1H), 3.17 - 3.09 (m, 2H), 3.08 - 2.99 (m, 2H), 2.95 (d, J = 8.9 Hz, 1H), 2.04 (dd, J =12.5, 8.6 Hz, 1H), 1.83 (td, J = 8.7, 5.0 Hz, 1H), 1.76 - 1.69 (m, 1H), 1.38(ddd, J = 13.4, 8.2, 5.1 Hz, 1H), 0.98 (d, J = 6.9 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6) d 166.33, 158.07, 144.53, 132.02, 128.40, 116.01, 113.61, 98.51, 95.65,77.21, 76.68, 73.06, 72.03, 69.97, 61.02, 55.05, 45.57, 44.96, 41.39, 40.53,30.75, 13.56. HR-ESI-MS m / z calcd for C 24 H 33 NO 10 [M+HCOO] - : 540.2081, found:540.2084. Example 18. Synthesis of Compound 18

[0116] Compound 18 was prepared as a white solid powder (16.0 mg, yield 23.6%, purity 98%) using loganin and compound R-18 respectively, according to the general synthesis method A described in Example 1. 1 H NMR (400 MHz, CD3OD) d 7.06(d, J = 1.3 Hz, 1H), 6.92 - 6.82 (m, 3H), 5.27 (d, J = 4.1 Hz, 1H), 4.64 (d, J =7.9 Hz, 1H), 4.45 - 4.27 (m, 2H), 4.06 (td, J = 5.0, 1.9 Hz, 1H), 3.89 (dd, J =12.0, 1.8 Hz, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.69 - 3.62 (m, 1H), 3.23 -3.16 (m, 2H), 2.12 (ddd, J = 13.9, 7.9, 1.9 Hz, 1H), 2.06 (td, J = 9.2, 4.2 Hz, 1H), 1.89 (ddd, J = 9.6, 7.0, 4.9 Hz, 1H), 1.64 (ddd, J = 13.8, 7.0, 5.2 Hz, 1H),1.09 (d, J = 6.9 Hz, 3H). 13 C NMR (100 MHz, CD3OD) d 170.29, 150.49, 149.63,146.51, 133.26, 121.03, 117.38, 112.93, 112.55, 99.83, 96.98, 78.34, 77.97,74.97, 74.76, 71.59, 62.75, 56.51, 56.42, 46.69, 43.77, 41.90, 41.86, 31.96,13.34. EHR-ESI-MS m / z calcd for C 25 H 35 NO 11 [M+HCOO] -: 570.2187, found: 570.2199. Example 19. Synthesis of Compound 19

[0117] Compound 19 was prepared as a white solid powder (17.0 mg, yield 26.7%, purity 98%) using loganin and compound R-19 respectively, according to the general synthesis method A described in Example 1. 1 H NMR (400 MHz, CD3OD) d 7.28(dd, J = 8.0, 6.8 Hz, 2H), 7.23 (d, J = 1.7 Hz, 1H), 7.22 - 7.15 (m, 2H), 6.97(d, J = 1.3 Hz, 1H), 5.24 (d, J = 4.2 Hz, 1H), 4.64 (d, J = 7.9 Hz, 1H), 4.03 (td, J = 5.0, 1.9 Hz, 1H), 3.89 (dd, J = 12.0, 1.6 Hz, 1H), 3.69 - 3.63 (m, 1H), 3.51(dt, J = 13.4, 7.2 Hz, 1H), 3.44 - 3.36 (m, 2H), 3.20 (dd, J = 9.1, 7.9 Hz, 1H), 3.11 (q, J = 8.5, 7.9 Hz, 1H), 2.82 (td, J = 7.3, 1.9 Hz, 2H), 2.07 - 1.98 (m,2H), 1.86 (ddd, J = 9.6, 7.0, 4.9 Hz, 1H), 1.54 (ddd, J = 13.9, 7.1, 5.2 Hz, 1H),1.08 (d, J = 6.9 Hz, 3H). 13 C NMR (100 MHz, CD3OD) d170.41, 146.27, 140.61,129.89, 129.50, 127.34, 117.41, 99.86, 97.01, 78.34, 77.98, 74.97, 74.78,71.60, 62.76, 46.67, 42.14, 41.86, 41.75, 36.56, 31.92, 13.34. HR-ESI-MS m / z calcd for C 24 H 33 NO9[M+HCOO] - : 524.2132, found: 524.2134. Example 20. Synthesis of Compound 20

[0118] Compound 20 was prepared as a white solid powder (12.6 mg, yield 19.1%, purity 98%) using loganin and compound R-20 respectively, according to the general synthesis method A described in Example 1. 1 H NMR (400 MHz, CD3OD) d 7.23(dd, J = 8.5, 5.6 Hz, 2H), 7.01 (t, J = 8.8 Hz, 2H), 6.97 (s, 1H), 5.24 (d, J = 4.2Hz, 1H), 4.64 (d, J = 7.9 Hz, 1H), 4.03 (td, J = 5.1, 1.8 Hz, 1H), 3.89 (dd, J =11.9, 1.6 Hz, 1H), 3.66 (dd, J = 11.9, 5.3 Hz, 1H), 3.55 - 3.44 (m, 1H), 3.43 -3.37 (m, 1H), 3.24 - 3.17 (m, 1H), 3.12 (q, J = 7.8 Hz, 1H), 2.81 (td, J = 7.2, 2.1 Hz, 2H), 2.03 (dt, J = 8.9, 5.2 Hz, 2H), 1.91 - 1.82 (m, 1H), 1.53 (ddd, J=14.0, 7.1, 5.2 Hz, 1H), 1.08 (d, J = 6.8 Hz, 3H). 13 C NMR (100 MHz, CD3OD) d 170.41, 164.23, 161.82, 146.32, 136.57, 136.54, 131.59, 131.51, 117.39,116.15, 115.94, 99.85, 97.02, 78.34, 77.98, 74.95, 74.77, 71.60, 62.75,46.67, 42.08, 41.86, 41.76, 35.69, 31.92, 13.35. HR-ESI-MS m / z calcd forC 24 H 32 FNO9[M+HCOO] - : 542.2032, found: 542.2040. Example 21. Synthesis of Compound 21

[0119] Compound 21 was prepared as a white solid powder (9.7 mg, yield 18.5%, purity 98%) using loganin and compound R-21 respectively, according to the general synthesis method A described in Example 1. 1 H NMR (400 MHz, CD3OD) d 7.28(d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 1.2 Hz, 1H), 5.24 (d, J =4.2 Hz, 1H), 4.64 (d, J = 7.9 Hz, 1H), 4.03 (td, J = 5.0, 1.9 Hz, 1H), 3.89 (dd, J = 11.9, 1.8 Hz, 1H), 3.69 - 3.63 (m, 1H), 3.50 (dt, J = 13.9, 7.1 Hz, 1H), 3.43- 3.35 (m, 2H), 3.23 - 3.18 (m, 1H), 3.11 (q, J= 7.2 Hz, 1H), 2.81 (td, J = 7.1,2.0 Hz, 2H), 2.07 - 1.99 (m, 2H), 1.86 (dtd, J = 9.5, 5.8, 4.8, 2.3 Hz, 1H),1.52 (ddd, J = 13.9, 7.1, 5.2 Hz, 1H), 1.08 (d, J = 6.8 Hz, 3H). 13 C NMR (100 MHz, CD3OD) d 170.42, 146.34, 139.44, 133.14, 131.53, 129.51, 117.36, 99.85, 97.02,78.34, 77.98, 74.96, 74.77, 71.59, 62.75, 46.65, 41.86, 41.84, 41.76, 35.83,31.91, 13.35. HR-ESI-MS m / z calcd for C 24 H 32 ClNO9[M+HCOO] - : 558.1742, found:558.1758. Example 22. Synthesis of Compound 22

[0120] Compound 22 was prepared as a white solid powder (11.7 mg, yield 17.5%, purity 98%) using loganin and compound R-22 respectively, according to the general synthesis method A described in Example 1. 1 H NMR (400 MHz, CD3OD) d 7.43(d, J = 8.3 Hz, 2H), 7.15 (d, J = 8.3 Hz, 2H), 6.97 (d, J = 1.3 Hz, 1H), 5.24 (d, J =4.2 Hz, 1H), 4.64 (d, J = 7.9 Hz, 1H), 4.03 (td, J = 5.0, 1.8 Hz, 1H), 3.89 (dd, J= 12.1, 1.6 Hz, 1H), 3.66 (dd, J = 11.9, 5.3 Hz, 1H), 3.50 (dt, J = 14.0, 7.1 Hz,1H), 3.43 - 3.35 (m, 2H), 3.20 (dd, J = 9.2, 7.9 Hz, 1H), 3.11 (q, J = 7.2 Hz, 1H), 2.80 (td, J = 7.1, 2.0 Hz, 2H), 2.06 - 2.00 (m, 2H), 1.86 (ddd, J = 9.6,7.1, 4.9 Hz, 1H), 1.52 (ddd, J = 13.9, 7.1, 5.1 Hz, 1H), 1.08 (d, J = 6.8 Hz, 3H). 13 C NMR (100 MHz, CD3OD) d 170.41, 146.35, 139.92, 132.53, 131.92, 121.03,117.36, 99.84, 97.02, 78.33, 77.98, 74.96, 74.77, 71.59, 62.75, 46.64, 41.87,41.76, 35.89, 31.91, 13.35. HR-ESI-MS m / z calcd for C 24 H 32 BrNO9[M+HCOO] - :602.1237, found: 602.1254. Example 23. Synthesis of Compound 23

[0121] Compound 23 was prepared as a white solid powder (13.0 mg, yield 18.6%, purity 98%) using loganin and compound R-23 respectively, according to the general synthesis method A described in Example 1. 1 H NMR (400 MHz, CD3OD) d 7.13(d, J = 8.6 Hz, 2H), 6.96 (d, J = 1.3 Hz, 1H), 6.84 (d,J = 8.6 Hz, 2H), 5.24 (d, J =4.2 Hz, 1H), 4.64 (d, J = 7.9 Hz, 1H), 4.03 (td, J = 5.0, 1.9 Hz, 1H), 3.89 (dd, J = 12.0, 1.7 Hz, 1H), 3.76 (s, 3H), 3.69 - 3.64 (m, 1H), 3.51 - 3.43 (m, 1H), 3.40 - 3.36 (m, 1H), 3.20 (dd, J = 9.1, 7.9 Hz, 1H), 3.15 - 3.08 (m, 1H), 2.76(td, J = 7.2, 2.0 Hz, 2H), 2.06 - 1.99 (m, 2H), 1.87 (dddd, J = 11.9, 9.6, 6.0,2.9 Hz, 1H), 1.54 (ddd, J = 13.9, 7.0, 5.2 Hz, 1H), 1.08 (d, J = 6.9 Hz, 3H). 13 CNMR (100 MHz, CD3OD) d 170.39, 159.75, 146.23, 132.52, 130.81, 117.43, 114.92,99.85, 96.98, 78.34, 77.98, 74.97, 74.77, 71.59, 62.75, 55.66, 46.67, 42.30,41.84, 41.73, 35.66, 31.91, 13.33. HR-ESI-MS m / z calcd for C 25 H 35 NO 10 [M+HCOO] - :554.2238, found: 554.2251. Example 24. Synthesis of Compound 24

[0122] Compound 24 was prepared as a white solid powder (35.7 mg, yield 49.8%, purity 98%) using loganin and compound R-24 respectively, according to the general synthesis method A described in Example 1. 1 H NMR (400 MHz, CDCl3) d 6.99(d, J = 1.3 Hz, 1H), 6.92 - 6.85 (m, 2H), 6.77 (dd, J = 8.1, 2.0 Hz, 1H), 5.24(d, J = 4.3 Hz, 1H), 4.64 (d, J = 7.9 Hz, 1H), 4.03 (td, J = 5.0, 1.8 Hz, 1H), 3.90(dd, J = 11.7, 1.6 Hz, 1H), 3.84 (d, J = 6.7 Hz, 3H), 3.81 (d, J = 4.4 Hz, 3H),3.70 - 3.64 (m, 1H), 3.54 - 3.45 (m, 1H), 3.24 - 3.20 (m, 1H), 3.19 - 3.08(m, 2H), 2.77 (t, J = 7.2 Hz, 2H), 2.03 (ddd, J = 13.0, 7.8, 3.2 Hz, 2H), 1.87(ddd, J = 9.6, 7.0, 4.9 Hz, 1H), 1.57 - 1.48 (m, 1H), 1.09 (d, J = 6.9 Hz, 3H). 13 CNMR (100 MHz, CDCl3) d 170.32, 150.36, 149.00, 146.28, 133.54, 122.25, 117.38,113.81, 113.18, 99.84, 97.02, 78.31, 77.94, 74.93, 74.75, 71.58, 62.72,56.56, 56.45, 46.63, 42.16, 41.86, 41.74, 36.09, 31.92, 13.36. HR-ESI-MS m / z calcd for C26 H 37 NO 11 [M+HCOO] - : 584.2343, found: 584.2347. Example 25. Synthesis of Compound 25

[0123] Compound 25 was prepared as a white solid powder (20.8 mg, yield 36.3%, purity 98%) using loganin and compound R-25 respectively, according to the general synthesis method A described in Example 1. 1 H NMR (400 MHz, CDCl3) d 7.00 (s, 1H), 5.26 (d, J = 4.2 Hz, 1H), 4.64 (d, J = 7.8 Hz, 1H), 4.06 (td, 1H), 3.89(dd, 1H), 3.71 - 3.58 (m, 1H), 3.26 - 3.16 (m, 2H), 3.19 - 3.10 (m, 2H), 2.11(ddd, J = 15.2, 8.5, 2.3 Hz, 1H), 2.07 - 1.99 (m, 1H), 1.94 - 1.84 (m, 1H), 1.66 - 1.56 (m, 1H), 1.54 - 1.46 (m, 2H), 1.39 - 1.33 (m, 2H), 1.09 (d, J = 6.8Hz, 3H), 0.94 (t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, CDCl3) d 170.39, 146.08,117.50, 99.82, 96.95, 78.33, 77.96, 74.98, 74.77, 71.59, 62.75, 46.68, 41.86,41.78, 40.22, 32.72, 31.94, 21.16, 14.13, 13.34. HR-ESI-MS m / z calcd forC 20 H 33 NO9[M+HCOO] - : 476.2132, found: 476.2134. Example 26. Synthesis of Compound 26 (General Synthetic Method B)

[0124] Loganetin (2.66 mmol) was placed in a 20 mL reaction flask and dissolved in 5 mL of purified water to obtain a clear solution. Snail enzyme (500.0 mg) was added to the reaction system, turning the solution reddish-brown. The mixture was stirred at room temperature for 12 h. The reaction was monitored by TLC. Once the reaction was complete, 2 volumes of acetonitrile were added to the reaction solution, and the mixture was stirred to denature and precipitate the enzyme. The solution was filtered, and the filtrate was collected to obtain a pale yellow clear solution. This solution was extracted three times with ethyl acetate, and the organic phases were combined. The solution was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered, concentrated under reduced pressure, and freeze-dried to obtain the target product, loganetin (B-1).

[0125] Loganin aglycone (2.31 mmol) was placed in a 20 mL reaction flask and dissolved in 1.8 mL of tetrahydrofuran to obtain a clear solution. Methanol (18.48 mmol) was added to the reaction system under nitrogen protection and stirred at 0 °C for 10 min. Then, boron trifluoride diethyl ether (2.31 mmol) was added, and the mixture was slowly brought to room temperature and stirred overnight. The reaction was monitored by TLC. After the reaction was complete, NaHCO3 was added to adjust the pH of the reaction solution to 7. Ethyl acetate was added for extraction three times. The organic phases were combined, washed once with saturated NaCl solution, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was separated by P-TLC using ethyl acetate:petroleum ether = 1:1 as the developing solvent. The final product, B-2, was obtained by vacuum distillation and freeze-drying.

[0126] B-2 (2.06 mmol) was placed in a 20 mL reaction flask, and 5 mL of purified water and 0.5 mL of tetrahydrofuran were added. The mixture was stirred to dissolve the B-2. KOH (8.2 mmol) was then added to the reaction system, and the mixture was stirred at room temperature for 12 h. The reaction was monitored by TLC. Once the reaction was complete, dilute hydrochloric acid was added to adjust the pH of the reaction solution to a weakly acidic state. The mixture was extracted three times with 5 times the amount of ethyl acetate. The organic phases were combined, washed once with saturated NaCl solution, and then concentrated under reduced pressure after dehydration with anhydrous Na2SO4. Finally, the solution was freeze-dried to obtain the target product B-3.

[0127] B-3 (0.13 mmol) was placed in an 8 mL reaction vial, and 1 mL of acetonitrile was added. The mixture was stirred to dissolve the B-3. EDCI (0.39 mmol), HOBT (0.16 mmol), and TEA (0.26 mmol) were then added to the reaction system. The mixture was stirred at 0 °C for 10 min, and the reaction was monitored by TLC. Once B-3 had completely reacted, reactant R-26 (0.13 mmol) was added, and the mixture was allowed to react at a suitable temperature. The reaction was monitored by TLC. Once the reaction was complete, the mixture was quenched with 2 times its volume of water, and extracted three times with 5 times its volume of ethyl acetate. The organic phases were combined. The crude product was separated by P-TLC using ethyl acetate:petroleum ether = 1:1 as the developing solvent. After vacuum distillation and freeze-drying, compound 26 was obtained.

[0128] White solid powder (21.5 mg, yield 57.8%, purity 98%). 1 H NMR (400 MHz, CDCl3) d 7.19(d, J = 1.2 Hz, 1H), 5.52 (t, J = 5.7 Hz, 1H), 4.58 (d, J = 4.1 Hz, 1H), 4.12 (t, J =4.6 Hz, 1H), 3.46 (s, 3H), 3.34 (dt, J = 13.4, 6.7 Hz, 1H), 3.29 - 3.18 (m,1H), 3.06 (q, J = 8.1 Hz, 1H), 2.16 (ddd, J = 14.0, 7.9, 1.4 Hz, 1H), 2.07 (td, J =9.3, 4.2 Hz, 1H), 1.83 (ddd, J = 9.8, 7.0, 4.5 Hz, 1H), 1.64 (ddd, J = 13.9, 7.5,4.8 Hz, 1H), 1.53 - 1.44 (m, 2H), 1.34 (q, J = 7.5 Hz, 2H), 1.10 (d, J = 6.9 Hz, 3H), 0.92 (t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, CDCl3) d167.21, 146.46, 114.92,101.19, 74.58, 56.65, 45.58, 41.72, 40.89, 39.37, 31.91, 30.93, 20.28, 13.90,12.93. HR-ESI-MS m / z calcd for C 15 H 25 NO4[M+HCOO] - : 328.1754, found: 328.1771. Example 27. Synthesis of Compound 27

[0129] Compound 27 was prepared as a white solid powder (18.9 mg, yield 46.5%, purity 98%) using loganin and compound R-27 respectively, according to the general synthesis method B described in Example 26. 1 H NMR (400 MHz, CDCl3) d 7.18 (d, J = 1.2 Hz, 1H), 5.33 (d, J = 8.1 Hz, 1H), 4.60 (d, J = 3.9 Hz, 1H), 4.11(d, J = 4.8 Hz, 1H), 3.89 - 3.78 (m, 1H), 3.46 (s, 3H), 3.04 (q, J = 8.0 Hz, 1H),2.19 - 2.05 (m, 2H), 1.94 - 1.88 (m, 2H), 1.82 (ddd, J = 9.9, 7.1, 4.4 Hz, 1H),1.67 (qd, J = 8.9, 5.5 Hz, 3H), 1.58 (t, J = 4.0 Hz, 1H), 1.43 - 1.31 (m, 2H), 1.21 - 1.11 (m, 3H), 1.10 (d, J = 6.9 Hz, 3H). 13 C NMR (100 MHz, CDCl3) d166.22,146.30, 115.02, 101.02, 74.62, 56.62, 48.10, 45.56, 41.66, 40.80, 33.35,33.32, 30.78, 25.69, 24.95, 12.85. HR-ESI-MS m / z calcd for C 17 H 27 NO4[M+HCOO] - :354.1911, found: 354.1924. Example 28. Synthesis of Compound 28

[0130] Compound 28 was prepared as a white solid powder (16.9 mg, yield 31.8%, purity 98%) using loganin and compound R-28 respectively, according to the general synthesis method B described in Example 26. 1 H NMR (400 MHz, CDCl3) d 7.47 - 7.41 (m, 2H), 7.26 - 7.21 (m, 2H), 7.20 (s, 1H), 7.03 (t, J = 7.4 Hz, 1H), 4.56 (d, J = 4.3 Hz, 1H), 4.09 (dt, J = 4.7, 2.4 Hz, 1H), 3.44 (s, 3H), 3.16(q, J = 8.1 Hz, 1H), 2.20 (ddd, J = 14.0, 7.8, 1.4 Hz, 1H), 2.06 (td, J = 9.3, 4.3Hz, 1H), 1.83 - 1.78 (m, 1H), 1.64 (ddd, J = 13.9, 7.7, 4.8 Hz, 1H), 1.07 (d, J =6.9 Hz, 3H). 13 C NMR (100 MHz, CDCl3) d165.56, 147.50, 138.06, 129.09, 124.34,120.43, 115.47, 101.50, 74.56, 56.80, 45.55, 41.72, 41.00, 31.17, 12.98. HR-ESI-MS m / z calcd for C 17 H 21 NO4[M+HCOO] - : 348.1441, found: 348.1455. Example 29. Synthesis of Compound 29

[0131] Compound 29 was prepared as a white solid powder (20.7 mg, yield 47.3%, purity 98%) using loganin and compound R-29 respectively, according to the general synthesis method B described in Example 26. 1 H NMR (400 MHz, CDCl3) d 7.39 - 7.31 (m, 2H), 7.16 (s, 1H), 6.79 (d, J = 9.0 Hz, 2H), 4.57 (d, J = 4.4 Hz, 1H), 4.10 (t, J = 4.6 Hz, 1H), 3.73 (s, 3H), 3.46 (s, 3H), 3.15 (q, J = 8.1 Hz, 1H), 2.20 (ddd, J = 14.0, 7.8, 1.3 Hz, 1H), 2.06 (td, J = 9.2, 4.4 Hz, 1H), 1.81(ddd, J = 9.6, 7.0, 4.4 Hz, 1H), 1.65 (ddd, J = 13.9, 7.8, 4.8 Hz, 1H), 1.08 (d, J = 6.9 Hz, 3H). 13 C NMR (100 MHz, CDCl3) d165.43, 156.44, 147.21, 130.99, 122.36,115.23, 114.13, 101.41, 74.43, 56.69, 55.51, 45.46, 41.65, 40.93, 31.08,12.93.HR-ESI-MS m / z calcd for C 18 H 23 NO5 [M+HCOO] - : 378.1547, found: 378.1562. Example 30. Synthesis of Compound 30

[0132] Compound 30 was prepared as a white solid powder (13.9 mg, yield 50.0%, purity 98%) using loganin and compound R-30 respectively, according to the general synthesis method B described in Example 26. 1 H NMR (400 MHz, CDCl3) d 7.35 - 7.18 (m, 6H), 5.82 (t, J = 5.7 Hz, 1H), 4.57 (d, J = 4.2 Hz, 1H), 4.55 -4.36 (m, 2H), 4.09 (td, J = 4.7, 1.3 Hz, 1H), 3.45 (s, 3H), 3.05 (q, J = 8.2, 7.6Hz, 1H), 2.19 - 2.10 (m, 1H), 2.05 (td, J = 9.3, 4.2 Hz, 1H), 1.83 - 1.80 (m,1H), 1.63 (ddd, J = 13.9, 7.6, 4.8 Hz, 1H), 1.08 (d, J = 6.9 Hz, 3H). 13 C NMR (100MHz, CDCl3) d 167.21, 146.91, 138.58, 128.85, 127.88, 127.59, 114.77, 101.26,74.59, 56.69, 45.55, 43.73, 41.76, 40.90, 30.90, 12.91.HR-ESI-MS m / zcalcd forC 18 H 23 NO4[M+HCOO] - : 362.1598, found: 362.1612. Example 31. Synthesis of Compound 31

[0133] Compound 31 was prepared as a white solid powder (21.8 mg, yield 49.5%, purity 98%) using loganin and compound R-31 respectively, according to the general synthesis method B described in Example 26. 1 H NMR (400 MHz, CDCl3) d 7.27 - 7.24 (m, 2H), 7.02 (t, J = 8.7 Hz, 2H), 5.96 (t, J = 5.8 Hz, 1H), 4.59 (d, J = 4.3 Hz, 1H), 4.55 - 4.35 (m, 2H), 4.12 (td, J = 4.6, 1.2 Hz, 1H), 3.49 (s,3H), 3.09 (q, J = 7.6 Hz, 1H), 2.17 (ddd, J = 13.9, 7.8, 1.4 Hz, 1H), 2.07 (dt, J =9.2, 4.6 Hz, 1H), 1.84 (ddd, J = 9.5, 6.9, 4.4 Hz, 1H), 1.63 (ddd, J = 13.9, 7.8,4.8 Hz, 1H), 1.12 (d, J = 6.9 Hz, 3H). 13 C NMR (100 MHz, CDCl3) d 167.27, 163.45,161.01, 147.11, 134.47, 134.43, 129.54, 129.46, 115.73, 115.52, 114.61,101.38, 74.52, 56.73, 45.50, 42.94, 41.76, 40.98, 30.96, 12.97. HR-ESI-MS m / z calcd for C18 H 22 FNO4[M+HCOO] - 380.1503, found: 380.1518. Example 32. Synthesis of Compound 32

[0134] Compound 32 was prepared as a white solid powder (21.6 mg, yield 47.3%, purity 98%) using loganin and compound R-32 respectively, according to the general synthesis method B described in Example 26. 1 H NMR (400 MHz, CDCl3) d 7.24 - 7.16 (m, 3H), 6.84 (d, J = 8.7 Hz, 2H), 5.81 (t, J = 5.6 Hz, 1H), 4.57 (d, J = 4.2 Hz, 1H), 4.51 - 4.30 (m, 2H), 4.09 (td, J = 4.7, 1.3 Hz, 1H), 3.78 (s,3H), 3.46 (s, 3H), 3.05 (q, J = 8.1 Hz, 1H), 2.13 (ddd, J = 13.9, 7.8, 1.4 Hz,1H), 2.05 (td, J = 9.3, 4.3 Hz, 1H), 1.81 (ddd, J = 9.7, 7.0, 4.4 Hz, 1H), 1.62(ddd, J = 13.9, 7.6, 4.8 Hz, 1H), 1.09 (d, J = 6.9 Hz, 3H). 13 C NMR (100 MHz, CDCl3) d 167.13, 159.08, 146.81, 130.65, 129.22, 114.80, 114.20, 101.27, 74.53,56.67, 55.41, 45.53, 43.18, 41.73, 40.91, 30.89, 12.93.HR-ESI-MS m / z calcd forC 19 H 25 NO5 [M+HCOO]- : 392.1703, found: 392.1720. Example 33. Synthesis of Compound 33

[0135] Compound 33 was prepared as a white solid powder (18.1 mg, yield 39.9%, purity 98%) using loganin and compound R-33 respectively, according to the general synthesis method B described in Example 26. 1 H NMR (400 MHz, CDCl3) d 7.28 (dd, J = 8.4, 6.3 Hz, 2H), 7.21 - 7.15 (m, 4H), 5.55 (t, J = 5.8 Hz, 1H), 4.57 (d, J = 4.2 Hz, 1H), 4.10 (t, J = 4.7 Hz, 1H), 3.47 (s, 3H), 3.38 (dt, J =13.4, 6.7 Hz, 1H), 3.29 (dt, J = 13.4, 6.6 Hz, 1H), 3.02 (q, J = 8.1 Hz, 1H), 2.65 (t, J = 7.7 Hz, 2H), 2.13 (ddd, J = 14.0, 7.8, 1.3 Hz, 1H), 2.06 (td, J = 9.2,4.2 Hz, 1H), 1.90 - 1.79 (m, 3H), 1.61 (ddd, J = 13.9, 7.6, 4.8 Hz, 1H), 1.10(d, J = 6.9 Hz, 3H). 13 C NMR (100 MHz, CDCl3) d 167.26, 146.52, 141.61, 128.60,128.47, 126.11, 114.85, 101.24, 74.51, 56.66, 45.53, 41.72, 40.90, 39.33,33.54, 31.43, 30.94, 12.96. HR-ESI-MS m / z calcd for C 20H 27 NO4[M+HCOO] - 390.1911, found: 390.1925. Example 34. Injection using compound 27 as active pharmaceutical ingredient Each 1000 vials of injection contains the following components: 2720 g of compound, 20 g of polysorbate 80, 15 g of mannitol, and 5000 mL of water for injection.

[0136] According to the formulation, compound 27, polysorbate 80 and mannitol from Example 2 were added to 4000 mL of water for injection. After stirring and dissolving, water for injection was added to a total volume of 5000 mL. Stirring was continued, and the mixture was sterilized by filtering through a 0.22 μm microporous membrane. The filtrate was aseptically filled into 5 mL ampoules (25 mg / ampoule) at 5 mL per ampoule, sealed, and sterilized.

[0137] Example 35. Tablets using compound 27 as the active pharmaceutical ingredient. Each 1000 tablets contains the following components: 2750 g of compound, 30 g of lactose, 15 g of microcrystalline cellulose, 10 g of sodium carboxymethyl starch, 0.1 g of micronized silica, 0.1 g of magnesium stearate, and 0.3% HPMC as needed.

[0138] Compound 27 from Example, lactose, and a portion of microcrystalline cellulose were micronized in a ratio of 200:100:30. The remaining microcrystalline cellulose, micronized silica gel, and sodium carboxymethyl starch (which had passed through an 80-mesh sieve) were added according to the formula ratio. After mixing evenly, an appropriate amount of 0.3% HPMC solution was added to form a soft mass. The mass was granulated through an 18-mesh sieve and dried at 60°C (the moisture content of the granules was controlled to be around 3%). Magnesium stearate (which had passed through an 80-mesh sieve) was added and mixed evenly with the granules. The granules were then sized through a 16-mesh sieve, compressed into tablets, and packaged.

[0139] Example 36. Evaluation of the neuroprotective activity of the compound against corticosterone-induced HT22 cell damage. To evaluate the bioactivity of the compounds of general formula I of this invention, 31 representative compounds synthesized were preliminarily screened. The protective effect of these compounds on HT22 cells was investigated using a corticosterone-induced HT22 cell model, with the parent compound loganin as a control.

[0140] HT22 cells were cultured in complete medium (90% high-glucose DMEM, 10% FBS, 1% penicillin-streptomycin) in a cell culture incubator at 37°C and 5% CO2. Cells were used for subsequent experiments when they reached 70%–80% confluence.

[0141] HT22 cells in logarithmic growth phase were harvested and their density adjusted to 5 × 10⁻⁶ cells / year. 3Cells were seeded at a density of 100 μL / mL in 96-well plates. After 24 h of culture and cell attachment, the supernatant was discarded. Cells were washed once with PBS. 10 μL of DMEM medium containing the test compounds was added to each experimental group; 100 μL of blank medium was added to the negative control group and the unseeded control group. After 24 h of incubation, 10 μL of CCK-8 reagent was added to each well, and incubation continued for 2 h. The absorbance was measured at 450 nm using a microplate reader to calculate cell viability.

[0142] Figure 1 The results showed that, at a concentration of 40 µM, all derivatives significantly enhanced cell viability in HT22 cells induced by corticosterone. P <0.05, P <0.01, P <0.0001 vs. Model; $ P <0.05, $$ P <0.01, $$$ P <0.001, $$$$ P <0.0001 vs. Loganin). This indicates that the compound's activity is significantly improved after modification at the C4 position.

[0143] The above results demonstrate that the compound of general formula I of this invention can effectively improve CORT-induced HT22 cell damage and has good biological activity, providing a basis for further evaluation of its neuroprotective activities.

[0144] Example 37. Compound 27 improves CORT-induced Sigma-1R / BDNF expression in HT22 cells. To evaluate the antidepressant effect of the compound of general formula I of the present invention, compound 27 prepared in Example 27 was selected as a representative compound and evaluated in vitro using a CORT-induced HT22 cell damage model.

[0145] (1) Cell resuscitation and culture Remove the cryovials of HT22 cells from liquid nitrogen and quickly place them in a 37°C water bath, gently agitating for about 1 minute to thaw rapidly. In a clean bench, transfer the cell suspension to a 15 mL centrifuge tube, add an appropriate amount of DMEM medium, mix gently, and centrifuge at 800 rpm for 5 minutes. Remove the supernatant, wash once with PBS, and resuspend the cells in DMEM complete medium containing 10% FBS. Transfer the cells to a culture dish and incubate at 37°C with 5% CO2.

[0146] (2) Cell passage When cells reach approximately 70%-80% confluence, passage them. Remove the culture medium, gently wash twice with 2 mL PBS, add 2 mL trypsin to cover the cell layer, and incubate at 37°C for approximately 1 minute for digestion. Once the cells begin to loosen under a microscope, immediately add 4 mL DMEM culture medium to stop the digestion. Collect the cell suspension from the culture dish into a centrifuge tube, centrifuge at 800 rpm for 5 min, discard the supernatant, resuspend and wash once with PBS, then add 2 mL of complete culture medium and gently pipette to mix. Seed an appropriate number of cells into new culture dishes according to the cell count and continue culturing.

[0147] (3) Cell drug administration: Cells in good condition and in the logarithmic growth phase were selected for the experiment. Sterile drug solutions of different concentrations were prepared according to the group design. Before drug administration, the drug was mixed with the culture medium, the original culture medium was aspirated, and the cells were gently rinsed once with pre-warmed PBS to remove residual metabolites. Then, drug-containing culture medium was added for intervention. After treatment, the cells were returned to the 37°C incubator for continued culture. Cell morphology changes were observed regularly and the effect of the drug on cell growth was recorded.

[0148] (4) Dosing regimen HT22 cells were evenly seeded in 6-well plates (1×10⁻⁶ cells per well). 5 Cells were incubated for 24 h, followed by drug administration: ① Control group: DMEM; ② Model group: CORT (200 μM) + DMEM; ③ 27 group: CORT (200 μM) + 27 (40 μM) + DMEM; ④ 27 + BD-1047 group: CORT (200 μM) + 27 (40 μM) + BD-1047 (10 μM) + DMEM. After 24 h of incubation following drug administration, cells were collected for protein extraction and concentration determination.

[0149] (5) Protein extraction and concentration determination The test sample was diluted 10-fold with PBS. Simultaneously, standards were prepared at concentration gradients of 2000–31.25 μg / mL using a 5 mg / mL BSA standard stock solution, with a PBS blank control included. Using a 96-well plate, 200 μL of BCA working solution (Solution A:Solution B) prepared at a 50:1 ratio was added to each well. After incubation at 37°C for 15–30 minutes, absorbance was measured at 562 nm using a microplate reader. A linear regression standard curve was plotted using the standards (R²>0.99), and the original protein concentration of the sample was calculated based on the regression equation.

[0150] (6) Western blotting of proteins SDS-PAGE separating and stacking gels were prepared according to the molecular weight of the target protein. After denaturation of the protein sample by heating at 100℃ for 3 minutes, the loading volume was calculated according to the quantitative results. Electrophoresis was performed at a constant voltage of 80 V followed by 120 V to the bromophenol-landa gel bottom. Subsequently, the sample was transferred to a methanol-activated PVDF membrane at a constant current of 400 mA. The transferred membrane was blocked with 5% BSA at room temperature for 1 hour, incubated overnight at 4℃ with primary antibody, washed with TBST, incubated with secondary antibody at room temperature for 1 hour, and washed again. Finally, the sample was developed in the dark with an equal volume of ECL chemiluminescent solution, and chemiluminescence images were acquired in an imager. The grayscale of the bands was analyzed using ImageJ software, and the relative expression level was reflected by the grayscale ratio of the target protein to the internal reference protein.

[0151] (7) Experimental results Compared with the control group, CORT-induced damage significantly decreased the expression levels of Sigma-1R, BDNF, and pro-BDNF in the model group cells. Compared with the model group, the expression level of Sigma-1R in the compound 27 treatment group was significantly increased, suggesting that 27 can effectively reverse CORT-induced downregulation of Sigma-1R expression. The investigation of downstream effector molecules showed that, compared with the model group, 27 also significantly increased the expression of mature BDNF and its precursor protein pro-BDNF. Furthermore, the upregulation effect of 27 on Sigma-1R, BDNF, and pro-BDNF protein expression was significantly weakened after combined application of the Sigma-1R protein-specific antagonist BD-1047, and there was no statistically significant difference in protein expression between the 27 combined with BD-1047 group and the model group.

[0152] The results showed that compound 27 significantly reversed the CORT-induced decrease in Sigma-1R expression levels in HT22 cells and regulated the expression of downstream proteins BDNF and pro-BDNF, indicating that it plays a role in regulating the Sigma-1R / BDNF signaling axis. This effect was inhibited by the Sigma-1R protein-specific antagonist BD-1047, suggesting that compound 27 exerts its neuroprotective effect by regulating downstream BDNF through Sigma-1R protein-mediated activation of this signaling pathway.

[0153] Example 38. Effect of compound 27 on improving CORT-induced depressive-like behavior in mice. To evaluate the antidepressant effect of the compound of general formula I of the present invention, compound 27 prepared in Example 27 was selected as a representative compound, and its in vivo efficacy was evaluated using a CORT-induced chronic depression mouse model.

[0154] (1) Establishment of a depression model After two days of acclimatization, mice were intraperitoneally injected daily with CORT (40 mg / kg) to establish a depression model for 21 consecutive days. Control mice were injected with an equal volume of saline. On day 14 of CORT modeling, tail suspension and open field tests were performed to confirm the successful establishment of the depression model.

[0155] (2) Experimental grouping and dosing regimen ① Control group: Mice were not given CORT modeling and were given an equal volume of physiological saline daily; ② Model group: CORT modeling (40 mg / kg) + an equal volume of physiological saline; ③ Positive drug group (Fluoxetine): CORT modeling (40 mg / kg) + fluoxetine (10 mg / kg); ④ Low-dose group: CORT modeling (40 mg / kg) + 27 (0.3 mg / kg); ⑤ Medium-dose group: CORT modeling (40 mg / kg) + 27 (1 mg / kg); ⑥ High-dose group: CORT modeling (40 mg / kg) + 27 (3 mg / kg). Mice in each group were administered CORT solution or physiological saline via intraperitoneal injection daily for 14 consecutive days. The establishment of the model was confirmed by tail suspension and open field tests. From day 15 onwards, each treatment group received, concurrently with CORT, appropriate doses of normal saline, fluoxetine, 27, or loganin via gavage, once daily until day 21. After administration, sucrose preference test, open field test, and tail suspension test were performed sequentially.

[0156] (3) Behavioral indicators Sugar water preference experiment: Two mice were housed in one cage, with two bottles of water containing 1% sucrose solution in each cage, allowing free access to water. After 24 hours, one bottle was replaced with pure water, and the mice continued free access to water for 12 hours. The positions of the two bottles were then swapped, and free access to water continued for another 12 hours to eliminate positional preference. After the adaptation period, water was withheld for 12 hours. Each mouse was then given a pre-weighed bottle of 1% sucrose solution and a bottle of pure water, allowing free access to water for 12 hours. The positions of the two bottles were then swapped, and free access to water continued for another 12 hours. After the test, the bottles were removed and weighed again, and the sugar water preference rate was calculated.

[0157] Tail suspension test: Secure the mouse's tail (approximately 1-2 cm from the tip) to the horizontal bar of the tail suspension box with tape, suspending the mouse upside down with its head about 5-10 cm above the bottom of the box. Each mouse is tested for 6 minutes, with the first 2 minutes for acclimatization, and the cumulative immobility time recorded in the following 4 minutes. Judgment criteria: The mouse is considered immobile when it stops struggling, its body is vertically suspended, and it remains motionless. The experiment is conducted in a quiet environment with soft lighting, and the excrement in the box is cleaned after each mouse's test.

[0158] The open-field apparatus consisted of a square, open box (50 cm × 50 cm × 40 cm), with the bottom divided into 25 equal-sized squares (10 cm × 10 cm). Mice were removed from their cages and gently placed in the center square of the open field, while the camera system recorded the activity. After acclimatization for 2 minutes, the mice's activity was recorded over a 4-minute period. After each mouse's test, excrement was cleaned from the open box, and the box was wiped with 75% ethanol to remove any odor residue. Observation indicators: (4) Experimental results Sugar water preference rate: such as Figure 3 As shown in Figure A, compared with the blank control group, the sucrose preference rate in the model group mice was significantly reduced (P<0.0001), indicating that CORT-induced anhedonia was successfully induced, and the mice exhibited significant anhedonia. Compared with the model group, the 1 mg / kg dose group of compound 27 showed the best improvement effect, and the 0.3 mg / kg and 3 mg / kg dose groups of 27 also showed a certain improvement trend. This result indicates that compound 27 can effectively improve the anhedonia state induced by CORT, and even at low doses, it shows better effects than classic antidepressants.

[0159] Tail remaining stationary for a period of time: such as Figure 3 As shown in Figure B, the immobility time of the model group mice was significantly prolonged compared with the blank control group (P<0.01), indicating that the model group mice were in a depressive-like state. Compared with the model group, fluoxetine (10 mg / kg) and each dose group of compound 27 (0.3, 1, 3 mg / kg) significantly shortened the immobility time (P<0.01 or P<0.001), with 27 (1 mg / kg and 3 mg / kg) showing the most significant effects, indicating the antidepressant potential of compound 27. This is consistent with the results of the sucrose preference experiment, indicating that compound 27 has a significant ameliorative effect on depressive-like behavior.

[0160] Number of squares traversed and number of foot lifts: such as Figure 3As shown in Figures C and D, compared with the blank control group, the number of squares crossed and the number of paw lifts in the model group mice were significantly reduced, suggesting that CORT-induced depression model mice exhibited decreased spontaneous activity. Compared with the model group, all 27 dosage groups (0.3, 1, and 3 mg / kg) increased the number of squares crossed and the number of paw lifts to varying degrees, with the 1 mg / kg dosage group of compound 27 showing the most significant effect (P<0.0001), and its effect was close to that of the positive control fluoxetine. The results indicate that compound 27 can improve the CORT-induced decrease in spontaneous activity in mice, suggesting that it has a certain antidepressant-like effect.

[0161] The above results indicate that compound 27 exhibits good antidepressant effects in a CORT-induced chronic depression model, thus demonstrating its application value in the preparation of neuroprotective drugs for the prevention and / or treatment of depression.

[0162] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of protection of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the scope of protection of the present invention. The scope of protection of the present invention should be determined by the appended claims, and the specification and drawings can be used to interpret the content of the claims.

Claims

1. A cyclopentadiene derivative, characterized in that, The derivative is a compound with the structural formula shown in Formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, or isotopically labeled compound thereof. Where n = 0, 1, 2, 3 or 4; R1 can be hydrogen, amino, hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -S(O)2-C1-C6 alkyl, -C(O)2-C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, or C6-C 10 aryl, 5- to 12-membered heteroaryl, or -O-C1-C6 alkyl-5- to 12-membered heteroaryl; wherein the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 10 The aryl, 5- to 12-membered heteroaryl and -O-C1-C6 alkyl-5- to 12-membered heteroaryl groups are optionally substituted by 1 to 3 substituents independently selected from halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 alkoxy groups; R2 is hydrogen, C1-C 18 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl, C6-C 10 Aryl-C1-C6 alkyl or glycosyl; wherein, except for hydrogen and glycosyl, the remaining groups are optionally substituted by 1 to 3 substituents independently selected from halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 alkoxy.

2. The iridoid derivative according to claim 1, characterized in that, R1 is selected from C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic groups, and C6-C6 alkyl groups. 10 Aryl groups, including C1-C6 alkyl groups, C3-C8 cycloalkyl groups, 3- to 8-membered heterocyclic groups, and C6-C6 cycloalkyl groups. 10 The aryl group may be optionally substituted by one or two substituents independently selected from halogens, amino groups, mono(C1-C6 alkyl)amino groups, di(C1-C6 alkyl)amino groups, hydroxyl groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, and C1-C6 alkoxy groups.

3. The iridoid derivative according to claim 2, characterized in that, R1 is selected from C1-C4 alkyl, C3-C6 cycloalkyl, 5- to 6-membered nitrogen-containing heterocyclic group and phenyl; wherein the C1-C4 alkyl, C3-C6 cycloalkyl, 5- to 6-membered nitrogen-containing heterocyclic group and phenyl are optionally substituted by 1 to 2 substituents independently selected from fluorine, chlorine, bromine, amino, mono(C1-C3 alkyl)amino, di(C1-C3 alkyl)amino, C1-C3 alkyl, C1-C3 haloalkyl and C1-C3 alkoxy.

4. The iridoid derivative according to claim 3, characterized in that, R1 is an optionally substituted phenyl group, which is optionally substituted by one or two substituents independently selected from fluorine, chlorine, bromine, C1-C3 alkyl, C1-C3 haloalkyl and C1-C3 alkoxy groups.

5. The iridoid derivative according to claim 1, characterized in that, R2 is a C1-C6 alkyl or glycosyl group; wherein the C1-C6 alkyl group is optionally substituted by one or two substituents independently selected from halogens, hydroxyl groups, amino groups, C1-C3 alkoxy groups and C1-C3 haloalkyl groups.

6. The iridoid derivative according to claim 5, characterized in that, The glycosyl group is a monosaccharide residue, a disaccharide residue, or an oligosaccharide residue; Optionally, the glycosyl group is selected from glucose, galactosyl, mannose, ribosyl, arabinose, xylose, lactose, maltose, and sucrose; preferably glucose.

7. The iridoid derivative according to any one of claims 1 to 6, characterized in that, The iridoid derivatives are selected from any one of compounds 1 to 33:

8. A pharmaceutical composition, characterized in that, It comprises the iridoid derivatives according to any one of claims 1 to 7, and a pharmaceutically acceptable carrier.

9. The use of the iridoid derivatives according to any one of claims 1 to 7 in the preparation of medicaments for the prevention and / or treatment of nervous system diseases.

10. The application according to claim 9, characterized in that, The neurological disorders include one or more of depression, neurodegenerative diseases, and nerve damage.

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