Tetrahydrofuran compound as well as pharmaceutical composition and application thereof

Abstract

The invention discloses a tetrahydrofuran compound, or an enantiomer, a raceme or a mixture form of the tetrahydrofuran compound, or pharmaceutically acceptable salt, a deuterated substance, a solvate, a hydrate and a metabolite of the tetrahydrofuran compound, and a pharmaceutical composition and application of the tetrahydrofuran compound. The tetrahydrofuran compound provided by the invention has good excitation activity on a Sigma-1 receptor and an M-type acetylcholine receptor, and has a good treatment effect on central nervous system diseases.

Description

Technical Field

[0001] This invention belongs to the field of innovative medicinal chemistry and relates to a tetrahydrofuran compound, its pharmaceutical composition, and its applications. Background Technology

[0002] Sigma-1 receptor is a receptor located on the mitochondrial-associated endoplasmic reticulum membrane that forms Ca2+ with the molecular chaperone BiP / GRP78. 2+ A sensitive chaperone complex; under the action of specific activators, the Sigma-1 receptor dissociates from BiP and translocates to other cellular sites, regulating the inositol 1,4,5-triphosphate (IP3) receptor, N -Methyl-D-aspartic acid ( N σ-1 receptors, including 3-methyl-D-aspartate (NMDA) receptors, dopamine receptors, and sodium, potassium, and calcium ion channels, influence the cellular tricarboxylic acid cycle (TCA) and ATP production, regulate oxidative stress and mitochondrial function, and regulate the secretion of various neurotransmitters. σ-1 receptors are involved in neuroprotection, neuroinflammation, neurotransmission, and neuroplasticity, and are functionally closely related to higher brain functions such as memory, cognition, emotion, pain, and neurodegeneration. Multiple cell and animal model studies have shown that the loss of Sigma-1 receptor expression or activity is associated with the development of central neurodegenerative diseases, while Sigma-1 receptor activation can improve the progression of diseases such as Alzheimer's disease, Parkinson's syndrome, stroke, tardive dyskinesia, Huntington's disease, depression, Rett syndrome, and amyotrophic lateral sclerosis. In Alzheimer's disease, Sigma-1 receptor agonists can reduce Aβ toxicity, protect neurons, inhibit Aβ-induced excessive phosphorylation of Tau protein, maintain neuronal skeletal protein stability, inhibit neurofibrillary tangles formation, and maintain neuronal function; they can also increase hippocampal acetylcholine and glutamate neurotransmitter levels, alleviate Aβ-induced dysfunction of the cholinergic and glutamatergic neuronal signaling systems, and improve cognitive impairment. Therefore, Sigma-1 receptors are an effective target for the prevention and treatment of central nervous system diseases.

[0003] Muscarinic (M) acetylcholine receptors are G protein-coupled receptors widely distributed on the cell membranes of effector cells innervated by postganglionic parasympathetic fibers. Five subtypes of M receptors have been identified to date (M1, M2, M3, M4, and M5). Among them, the M1 receptor is highly expressed in the hippocampus and cortical regions and has shown cognitive-enhancing effects in preclinical animal studies, thus being widely considered a key receptor mediating cognitive function and a potential therapeutic target for Alzheimer's disease. Many ortho-muscarinic agonists utilizing the natural acetylcholine binding site have entered clinical trials and shown promising efficacy, such as the M1 / M4 agonist xanthipone and the M1 agonist GSK1034702, which can improve patients' cognitive and behavioral impairments, as well as immediate and delayed memory, respectively. However, these trials have been discontinued due to adverse gastrointestinal and cardiovascular reactions in patients. Blarcamesine (ANAVEX2-73) is a Sigma-1 / M1 acetylcholine receptor agonist that has completed phase IIa and IIb / III clinical trials for the treatment of AD.

[0004] .

[0005] Deuterated drugs are those in which some or all of the hydrogen atoms in a drug molecule have been replaced with deuterium. Because deuterium has a shape and volume similar to hydrogen in drug molecules, deuterated drugs generally retain the original drug's biological activity and selectivity. Since CD bonds are more stable than CH bonds, introducing deuterium into drug molecules improves their metabolic stability, prolongs their half-life, and enhances their pharmacokinetic properties. Since 2000, deuteration strategies have been widely used in drug research.

[0006] Based on the above-mentioned prior art, the present invention provides a series of deuterated compounds that can act on both Sigma-1 receptor and M1 acetylcholine receptor. These compounds are expected to retain dual-target agonistic activity and optimize pharmacokinetic properties through deuteration modification, thus providing new drug options for the treatment of central nervous system diseases. Summary of the Invention

[0007] The present invention provides a tetrahydrofuran compound or its enantiomers, diastereomers, racemates or mixtures thereof, or its pharmaceutically acceptable salts, deuterates, solvates, hydrates or metabolites, selected from any of the following structures; .

[0008] This invention provides the use of tetrahydrofuran compounds or their enantiomers, racemates or mixtures thereof, or pharmaceutically acceptable salts, deuterated derivatives, solvates, hydrates or metabolites thereof in the preparation of Sigma-1 receptor ligands and / or M-type acetylcholine receptor ligands.

[0009] This invention provides the use of a tetrahydrofuran compound or its enantiomers, racemates or mixtures thereof, or pharmaceutically acceptable salts, deuterated derivatives, solvates, hydrates or metabolites thereof in the preparation of a medicament for treating the modulation of Sigma-1 receptors and / or M-type acetylcholine receptors.

[0010] This invention provides the use of a tetrahydrofuran compound or its enantiomers, racemates or mixtures thereof, or its pharmaceutically acceptable salts, deuterated derivatives, solvates, hydrates or metabolites in the preparation of a medicament for the prevention and / or treatment of diseases of the central nervous system.

[0011] In some implementations, the central nervous system disease is selected from Alzheimer's disease, Parkinson's syndrome, stroke, depression, Rett syndrome, tardive dyskinesia, Huntington's disease, amyotrophic lateral sclerosis, or pain.

[0012] More preferably, the central nervous system disease is Alzheimer's disease.

[0013] In some embodiments, the central nervous system disease is a central nervous system disease associated with abnormalities of Sigma-1 receptors and / or M-type acetylcholine receptors.

[0014] More preferably, the central nervous system disease associated with abnormalities of Sigma-1 receptors and / or M-type acetylcholine receptors is selected from Alzheimer's disease, Parkinson's syndrome, stroke, depression, Rett syndrome, tardive dyskinesia, Huntington's disease, amyotrophic lateral sclerosis, or pain.

[0015] More preferably, the central nervous system disease associated with abnormalities of Sigma-1 receptors and / or M-type acetylcholine receptors is selected from central nervous system diseases such as Alzheimer's disease.

[0016] The present invention provides a pharmaceutical composition comprising the tetrahydrofuran compound, or its enantiomers, racemates, or mixtures thereof, or its pharmaceutically acceptable salts, deuterates, solvates, hydrates, metabolites, and pharmaceutically acceptable carriers or excipients.

[0017] In the pharmaceutical composition described herein, the amount of the drug or its enantiomer, racemate or mixture thereof, or its pharmaceutically acceptable salt, deuterated product, solvate, hydrate or metabolite is a therapeutically effective amount.

[0018] This invention provides the use of the pharmaceutical composition in the preparation of Sigma-1 receptor ligands and / or M-type acetylcholine receptor ligands.

[0019] This invention provides the use of the pharmaceutical composition in the preparation of a medicament for modulating Sigma-1 receptors and / or M-type acetylcholine receptors.

[0020] This invention provides the use of a pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of diseases of the central nervous system.

[0021] In some implementations, the central nervous system disease is selected from Alzheimer's disease, Parkinson's syndrome, stroke, depression, Rett syndrome, tardive dyskinesia, Huntington's disease, amyotrophic lateral sclerosis, or pain.

[0022] More preferably, the central nervous system disease is Alzheimer's disease.

[0023] In some embodiments, the central nervous system disease is a central nervous system disease associated with abnormalities of Sigma-1 receptors and / or M-type acetylcholine receptors.

[0024] More preferably, the central nervous system disease associated with abnormalities of Sigma-1 receptors and / or M-type acetylcholine receptors is selected from Alzheimer's disease, Parkinson's syndrome, stroke, depression, Rett syndrome, tardive dyskinesia, Huntington's disease, amyotrophic lateral sclerosis, or pain.

[0025] More preferably, the central nervous system disease associated with abnormalities of Sigma-1 receptors and / or M-type acetylcholine receptors is selected from central nervous system diseases such as Alzheimer's disease.

[0026] The pharmaceutical excipients described herein may be those widely used in the pharmaceutical manufacturing field. Excipients primarily serve to provide a safe, stable, and functional pharmaceutical composition, and may also provide methods for enabling the active ingredient to dissolve at a desired rate after administration to a subject, or to promote the effective absorption of the active ingredient after administration to a subject. The pharmaceutical excipients may be inert fillers, or provide a function such as stabilizing the overall pH of the composition or preventing the degradation of the active ingredient. The pharmaceutical excipients may include one or more of the following: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesion agents, flow aids, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[0027] The pharmaceutical compositions of the present invention can be prepared using any method known to those skilled in the art, based on the disclosure. For example, conventional mixing, dissolving, granulation, emulsification, grinding, encapsulation, embedding, or lyophilization processes.

[0028] The pharmaceutical compositions of this invention can be administered in any form, including by injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical, or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular) administration. The pharmaceutical compositions of this invention can also be controlled-release or delayed-release dosage forms (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, tablets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations. Examples of parenteral formulations include, but are not limited to, solutions for injection, dry formulations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic preparations; aerosols, such as nasal sprays or inhalers; liquid dosage forms suitable for parenteral administration; suppositories; and tablets.

[0029] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound having specific substituents discovered in this invention with a relatively non-toxic acid or base. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonates or bicarbonates), phosphoric acid (forming phosphates, monohydrogen phosphates, dihydrogen phosphates, sulfuric acid (forming sulfates or bisulfates), hydroiodic acid, phosphorous acid, etc.); and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, etc. Acids such as tartaric acid and methanesulfonic acid; organic acid salts also include salts of amino acids (such as arginine) and salts of organic acids such as glucuronic acid. Certain compounds of the present invention contain both basic and acidic functional groups, thus allowing them to be converted into any base or acid addition salt. Preferably, the salt is contacted with a base or acid in a conventional manner, followed by separation of the parent compound, thereby regenerating the free form of the compound. The free form of the compound differs from its various salt forms in certain physical properties, such as different solubilities in polar solvents.

[0030] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of both. Non-aqueous media such as ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile are generally preferred.

[0031] The term "metabolite" refers to a pharmaceutically active product produced in vivo by the metabolism of the compounds of the present invention or their salts. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, glucuronidation, enzymatic cleavage, etc., of the administered compound. Therefore, the present invention includes metabolites of the compounds of the present invention, including compounds produced by methods that expose the compounds of the present invention to mammals for a sufficient period of time to obtain their metabolites.

[0032] The identification of metabolites is typically performed by preparing a radiolabeled isotope of the compound of the invention, administering it parenterally to an animal, such as a rat, mouse, guinea pig, monkey, or human, at a detectable dose (e.g., greater than about 0.5 mg / kg), allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours), and isolating the metabolites from urine, blood, or other biological samples. These products are readily isolated because they are labeled (others are isolated using antibodies capable of binding to antigenic epitopes present in the metabolites). The metabolite structure is determined in a conventional manner, for example, by MS, LC / MS, or NMR analysis. Typically, the analysis of metabolites is performed using methods known to those skilled in the art for routine drug metabolism studies. The metabolite products can be used for assays of therapeutic doses of the compound of the invention, provided they are not otherwise undetectable in vivo. The compounds of the invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compound may be radiolabeled with radioisotopes, such as tritium ( 3 H), Iodine-125 ( 125 I) or C-14 14 C). All isotopic variations of the compounds of the present invention, regardless of radioactivity, are included within the scope of the present invention.

[0033] The term "enantiomer" refers to stereoisomers that are mirror images of each other and cannot be superimposed. The compounds of this invention can exist as enantiomers and mixtures thereof, and all such stereoisomers and mixtures thereof are included within the scope of this disclosure. Optically active (-)- and (+)- isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. R )-and( S(D)- and (L)- isomers. This disclosure describes an isomer of a compound that can be prepared by asymmetric synthesis or with a chiral auxiliary, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a salt of the diastereomer with a suitable optically active acid or base, followed by diastereomer resolution using conventional methods known in the art to obtain the pure isomer. In the chemical structure of the compound described in this disclosure, the bond " / " indicates an unspecified configuration; that is, if a chiral isomer exists in the chemical structure, the bond " / " can be "...". "or" , or both contain " "or" "Two configurations."

[0034] The positive and progressive effects of this invention are as follows: (1) The compounds of this invention have dual-target effects, that is, they act on both the Sigma-1 receptor and the M1 receptor simultaneously; specifically: the compounds of this invention have a significant affinity for the Sigma-1 receptor, which is superior to or comparable to ANAVEX2-73. The compounds of this invention have a significant affinity for the M1 receptor, which is superior to or comparable to ANAVEX2-73.

[0035] (2) The compounds of the present invention have significantly improved metabolic stability, increased plasma exposure, prolonged half-life, and reduced single-dose dosage.

[0036] (3) The compounds of the present invention have good therapeutic effects on central nervous system diseases such as Alzheimer's disease. Detailed Implementation

[0037] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0038] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention. All reagents and raw materials used in the present invention are commercially available.

[0039] Example 1: Synthesis of compounds (+)-1 and (-)-1: ; Step 1: Synthesis of compounds 1-3 Sodium hydride (3.29 g, 82.32 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL). Compound 1-2 (16.33 mL, 82.32 mmol) was slowly added under nitrogen protection at 0 °C, and the mixture was stirred at this temperature for another half hour. Then, compound 1-1 (5 g, 27.44 mmol) was added. The reaction was allowed to proceed overnight under reflux. After the reaction was complete as monitored by TLC, water was slowly added to the reaction mixture at 0 °C to quench the reaction. The mixture was extracted with water and ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 1-3 (70%, 4.58 g). MS (ESI, m / z): 253 (M + +1). 1 H NMR (300 MHz, Chloroform- d ) δ 7.43 – 7.32 (m, 8H), 7.27 – 7.18 (m, 2H), 6.39 (s, 1H), 4.08(q, J = 7.1 Hz, 2H), 1.14 (t, J = 7.1 Hz, 3H). Step 2: Synthesis of compounds 1-4 Compounds 1-3 (1 g, 3.96 mmol) were dissolved in acetic acid (35 mL), followed by the addition of manganese acetate dihydrate (3.19 g, 11.89 mmol) and acetic anhydride (6 mL). The reaction mixture was refluxed under nitrogen protection for 2 hours. Water (150 mL) was then added to the reaction mixture, and the precipitated solid was filtered. The solid was dissolved in EA solution, filtered again, and the filtrate was concentrated and subjected to rapid column chromatography to obtain compounds 1-4 (57%, 700 mg). MS (ESI, m / z): 311 (M + +1). 1 H NMR (400 MHz, Chloroform- d ) δ 7.62 (d, J = 7.7 Hz, 2H), 7.46 – 7.18 (m, 8H), 4.18 (dd, J =8.2, 3.6 Hz, 1H), 3.76 (m, 2H), 3.02 (dd, J = 17.5, 3.6 Hz, 1H), 2.71 (dd, J = 17.5, 8.2 Hz, 1H), 0.89 (t, J = 7.2 Hz, 3H). Step 3: Synthesis of compounds 1-5 At 0 °C, lithium aluminum hydride (0.6 g, 15.79 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), followed by the slow addition of a tetrahydrofuran (15 mL) solution of compounds 1-4 (0.7 g, 2.26 mmol). The mixture was refluxed overnight under a nitrogen atmosphere. The reaction solution was cooled to room temperature, and then 0.6 mL of water, followed by 0.6 mL of 5 M sodium hydroxide solution, and then 1.8 mL of water was added. The mixture was stirred at room temperature for 10 minutes, followed by drying with anhydrous sodium sulfate. The reaction solution was filtered, and the filtrate was evaporated to dryness. Column chromatography was used to purify compounds 1-5 (75%, 460 mg). MS (ESI, m / z): 273 (M + +1). 1 H NMR (400 MHz, Chloroform- d ) δ 7.55 (m, 4H), 7.29 (m, 4H), 7.22 – 7.12 (m, 2H), 4.57 (d, J = 2.8 Hz,1H), 3.94 – 3.72 (m, 4H), 2.80 (m, 2H), 2.03 – 1.93 (m, 1H), 1.72 (m, 1H),1.60 (s, 1H). Step 4: Synthesis of compounds 1-6 Compounds 1-5 (3.5 g, 12.85 mmol) were dissolved in anhydrous DCM (80 mL), and anhydrous p-toluenesulfonic acid (0.5 g, 2.9 mmol) was added to the reaction solution. The reaction solution was then heated under reflux for 5 h. After the reaction was complete as monitored by TLC, the reaction was stopped, cooled to room temperature, and the reaction solution was diluted with DCM. The mixture was washed with saturated sodium carbonate solution, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compounds 1-6 (2.4 g, 73%). MS (ESI, m / z): 255 (M + +1). 1 H NMR (400 MHz, Chloroform- d ) δ 7.58 – 7.51 (m, 2H), 7.41 – 7.31 (m, 4H), 7.30 – 7.16 (m, 4H), 4.16 (m, 1H), 3.76 (m, 1H), 3.50 (m, 1H), 3.35 (m, 1H), 3.24 – 3.17 (m, 1H), 2.12 – 1.98 (m, 2H), 1.26 (t, J = 5.9 Hz, 1H). Step 5: Synthesis of compounds 1-7 Compounds 1-6 (2.4 g, 9.44 mmol) were dissolved in anhydrous DCM (40 mL). At -10 °C, 2,6-dimethylpyridine (1.65 mL, 14.15 mmol) and trifluoromethanesulfonic anhydride (2.38 mL, 14.15 mmol) were slowly added dropwise to the solution. The reaction was carried out at this temperature for 1 hour. After the reaction was completed by TLC monitoring, the reaction solution was concentrated at low temperature, ether was added, the mixture was rapidly washed with ice water, dried, and concentrated again at low temperature before proceeding to the next step. MS (ESI, m / z): 387 (M + +1). Step Six: Synthesis of Compounds 1-8 Compounds 1-7 (3.65 g, 9.45 mmol) were dissolved in anhydrous THF (10 mL). A methylamine THF solution (2 M, 48 mL, 94.5 mmol) was then added to the reaction system at 0 °C. The reaction was allowed to proceed for 3 hours at room temperature. The reaction was monitored by TLC until complete. The reaction was quenched with saturated ammonium chloride solution, extracted with water and EA, dried, and purified by column chromatography to obtain compounds 1-8 (1.30 g, 50%). MS (ESI, m / z): 268 (M + +1). 1 H NMR (400 MHz, Chloroform- d ) δ 7.52 (d, J =7.7 Hz, 2H), 7.41 (d, J = 7.7 Hz, 2H), 7.33 (m, 4H), 7.25 (t, J = 7.8 Hz, 2H), 4.20 (m, 1H), 3.81 (m, 1H), 3.50 (m, 1H), 2.81 (m, 1H), 2.59 (s, 4H), 2.13 (tt, J = 12.3, 6.1 Hz, 2H), 1.00 – 0.87 (m, 1H). Step 7: Synthesis of Compound 1 Compounds 1-8 (3 g, 11.22 mmol) were dissolved in anhydrous THF (30 mL), and sodium hydride (540 mg, 13.46 mmol) was added at 0 °C. The reaction was then carried out at this temperature for 10 min, followed by the addition of deuterated iodomethane (1.07 mL, 16.83 mmol), and the reaction was carried out at room temperature for 2 h. The reaction was monitored by TLC to indicate completion. The reaction was quenched by the addition of saturated ammonium chloride solution, followed by extraction with EA and water, drying, and purification by column chromatography to give compound 1 (2.3 g, 72%). MS (ESI, m / z): 285 (M + +1). 1 H NMR (400MHz, Chloroform- d ) δ 7.57 – 7.49 (m, 2H), 7.36 – 7.27 (m, 4H), 7.26 – 7.19 (m, 3H), 7.18 – 7.13 (m, 1H), 4.19 (m, 1H), 3.83 (td, J = 8.2, 6.8 Hz, 1H), 3.12 (m, 1H), 2.22 (s, 3H), 2.15 – 1.97 (m, 4H). Step 8: Synthesis of compounds (+)-1 and (-)-1 Compound 1 (1.36 g, 4.72 mmol) was dissolved in 95% ethanol, and then added at room temperature. R - Mandelic acid (0.36 g, 2.36 mmol) was reacted at this temperature for 1 hour. The solvent was then evaporated under vacuum, and the resulting residue was dissolved in water (1.7 mL) and ethanol (0.4 mL), heated, and stirred at room temperature for 30 minutes. Toluene was then added, and the solvent was evaporated under vacuum. Azeotropic distillation of water and ethanol with toluene was repeated twice to give a white solid, which was recrystallized from isopropanol / ethyl ether and filtered. A white crystalline product was given, which was R-mandelic acid salt of compound (+)-1 (54%, 550 mg).

[0040] The R-mandelate of compound (+)-1 (550 mg, 2.55 mmol) was dissolved in water (5 mL), and a 10% sodium hydroxide aqueous solution (5 mL) and diethyl ether (15 mL) were added at 0 °C. The reaction was carried out at room temperature for half an hour, followed by separation of the two phases. The organic phase was washed with saturated brine, dried, and concentrated to give the target compound (+)-1 (95%, 340 mg). MS (ESI, m / z): 285 (M + +1). Following the same method described above, replacing R-mandelic acid with S-mandelic acid yields the target compound (-)-1. MS (ESI, m / z): 285 (M + +1).

[0041] Example 2, Synthesis of Compounds 2, (+)-2 and (-)-2: ; Steps one through six: Synthesis of compound 2; Steps one through six are the same as steps one through six in Example 1, except that the corresponding starting materials are replaced to obtain compound 2. MS (ESI, m / z): 298 (M + +1). 1 H NMR (400 MHz, Chloroform- d ) δ 4.19 (m, 1H), 3.83 (td, J = 8.2, 6.8 Hz, 1H), 3.12 (m, 1H), 2.15 – 1.97 (m, 4H). Step 7: Synthesis of compounds (+)-2 and (-)-2 Referring to step eight in Example 1, compounds (+)-2 and (-)-2 can be obtained simply by replacing the corresponding starting materials. MS (ESI, m / z): 298 (M + +1).

[0042] Example 3, synthesis of compounds 3, (+)-3 and (-)-3: ; Step 1-Step 2: Synthesis of Compound 3 Starting from intermediates 2-7 in Example 2, and referring to steps six and seven in Example 1, compound 3 can be obtained. MS (ESI, m / z): 295 (M + +1). 1 H NMR (400 MHz, Chloroform- d ) δ 4.19 (m, 1H), 3.83 (td, J = 8.2, 6.8 Hz, 1H), 3.12 (m, 1H), 2.23 (s, 3H), 2.15 – 1.97 (m, 4H). Step 3: Synthesis of compounds (+)-3 and (-)-3 Following step eight in Example 1, compounds (+)-3 and (-)-3 were obtained. MS (ESI, m / z): 295 (M + +1).

[0043] Example 4, Synthesis of compounds 4, (+)-4 and (-)-4: ; Steps 1-6: Synthesis of Compound 4 Steps one through six are the same as steps one through six in Example 1, except that the corresponding starting materials are replaced to obtain compound 4. MS (ESI, m / z): 293 (M + +1). 1 H NMR (400 MHz, Chloroform- d ) δ 7.52 (m,1H), 7.36 – 7.27 (m, 2H), 7.24 – 7.17 (m, 2H), 4.19 (m, 1H), 3.83 (td, J =8.2, 6.8 Hz, 1H), 3.12 (m, 1H), 2.15 – 1.97 (m, 4H). Step 7: Synthesis of compounds (+)-4 and (-)-4 Referring to step eight in Example 1, compounds (+)-4 and (-)-4 can be obtained simply by replacing the corresponding starting materials. MS (ESI, m / z): 293 (M + +1).

[0044] Example 5, synthesis of compounds 5, (+)-5 and (-)-5: ; Step 1-Step 2: Synthesis of Compound 5 Starting from intermediates 4-7 in Example 4, and referring to steps six and seven in Example 1, compound 5 can be obtained. MS (ESI, m / z): 290 (M + +1). 1 H NMR (400 MHz, Chloroform- d ) δ 7.52 (m, 1H), 7.36 – 7.27 (m, 2H), 7.24 – 7.17 (m, 2H), 4.19 (m, 1H), 3.83 (td, J= 8.2,6.8 Hz, 1H), 3.12 (m, 1H), 2.24 (s, 3H), 2.15 – 1.97 (m, 4H). Step 3: Synthesis of compounds (+)-5 and (-)-5 Following step eight in Example 1, compounds (+)-5 and (-)-5 were obtained. MS (ESI, m / z): 290 (M + +1).

[0045] Example 6, Synthesis of compounds 6, (+)-6 and (-)-6: ; Step 1: Synthesis of intermediate 6-2 In an argon-filled glove box, DMSO (10 mL) was added to a sealed tube containing Pd2(dba)3 (183 mg, 0.2 mmol), t-Bu3P (120 mg, 0.6 mmol), DCOONa (1.38 g, 20 mmol), and 6-1 (2.62 g, 10 mmol). The reaction was carried out overnight at 80 °C. After the reaction was complete, saturated NH4Cl solution was added to quench the reaction. The mixture was extracted with water and EA, dried, concentrated, and purified by column chromatography to give compound 6-2 (1.14 g, 62%). MS (ESI, m / z): 185 (M + +1). Steps two through seven: Synthesis of compound 6 Following steps one through seven of Example 1, compound 6 can be obtained simply by replacing the corresponding starting materials. MS (ESI, m / z): 290 (M + +1). 1 H NMR (400 MHz, Chloroform- d ) δ 7.36 – 7.27 (m, 4H), 7.26 – 7.19 (m, 3H), 7.18 – 7.13 (m, 1H), 4.19 (m, 1H), 3.83 (td, J = 8.2,6.8 Hz, 1H), 3.12 (m, 1H), 2.15 – 1.97 (m, 4H). Step 8: Synthesis of compounds (+)-6 and (-)-6 Following step eight in Example 1, compounds (+)-6 and (-)-6 were obtained. MS (ESI, m / z): 287 (M + +1).

[0046] Example 7, Synthesis of compounds 7, (+)-7 and (-)-7: ; Step 1: Synthesis of Compound 7 Starting from intermediates 6-7 in Example 6, and referring to step six in Example 1, compound 7 can be obtained by simply replacing the corresponding starting materials. MS (ESI, m / z): 287 (M++1). 1H NMR (400 MHz, Chloroform-d) δ 7.36 – 7.27 (m, 4H), 7.26 – 7.19 (m, 3H), 7.18 – 7.13 (m, 1H), 4.19 (m, 1H), 3.83 (td, J = 8.2, 6.8 Hz, 1H), 3.12 (m, 1H), 2.22 (s, 3H), 2.15 – 1.97 (m, 4H). Step 2: Synthesis of compounds (+)-7 and (-)-7 Following step eight in Example 1, compounds (+)-7 and (-)-7 were obtained. MS (ESI, m / z): 290 (M + +1).

[0047] Example 8, Sigma-1 receptor radioligand affinity experiment: Sigma-1 receptor-rich cell membranes were collected from HEK-293 cells transfected with human Sigma-1 receptor for […]. 3H]-di-o-toluidine (DTG) was used as the radioligand. Cell membranes and the radioligand were added to binding buffer (50 mM TRIS-HCl, pH 7.4, 120 mM NaCl, 5 mM KCl, 2 mM CaCl2, 1 mM MgCl2). Complete binding (buffer + cell membrane + radioligand), non-specific binding (1 μM haloperidol + cell membrane + radioligand), and test (different concentrations of the compound of this invention + cell membrane + radioligand) were established. ANAVEX2-73 was used as the positive control. The reaction system was incubated at 37°C for 120 minutes, and the reaction was terminated by adding cold buffer. After the reaction, the mixture contained receptor-bound radioligands and unbound free radioligands. A filter was soaked with 0.1% polyethyleneimine (PEI). The reaction mixture was transferred to a filter plate. The receptor-membrane protein complex bound to the radioligand, due to its large molecular weight, was retained on the filter membrane, while the free radioligands were filtered out. Wash with cold buffer, dry the filter membrane, and place the dried filter membrane in scintillation solution. Measure using a microplate scintillation counter. Calculate the inhibition rate: %inhibition = 100 - 100 * (sample signal value - nonspecific binding signal value) / (summary and confidence score - nonspecific binding signal value), and calculate the Ki value using Graphpad Prim software. The affinity of the compounds of this invention for the Sigma-1 receptor is shown in Table 1. As shown in Table 1, the compounds of this invention have significant affinity for the Sigma-1 receptor, which is superior to or comparable to ANAVEX2-73.

[0048] Table 1. Affinity test results of the compounds of the present invention to the Sigma-1 receptor. .

[0049] Example 9, M1 receptor radioligand affinity experiment: M1 receptor-rich cell membranes were collected from HEK-293 cells transfected with human M1 receptor and analyzed with Scopolamine Methyl Chloride, [N-methyl- 3 H]- as a radioligand. The procedure is similar to the Sigma-1 receptor radioligand affinity experiment in Example 8, only the non-specific binding group is changed to: pirenzepine + cell membrane + radioligand. The affinity test results of the compounds of this invention for the M1 receptor are shown in Table 2. As shown in Table 2, the compounds of this invention have significant affinity for the M1 receptor, which is superior to or comparable to ANAVEX2-73.

[0050] Table 2. Affinity test results of the compounds of the present invention to the M1 receptor. .

[0051] Example 10, Liver microsomal stability experiment: After constructing a 200 μL NADPH generating system, the compound of this invention and the positive control ANAVEX2-73 (final concentration 1 μM) were added to the system, followed by 5 μL of liver microsomal enzyme. The mixture was then incubated at 37°C. Samples were collected at five time points between 0 min and 60 min. After the reaction was complete, 400 μL of ice-cold methanol containing an internal standard was added to terminate the reaction. The mixture was centrifuged, and the supernatant was collected. The percentage of residue at each time point was determined using LC-MS / MS. The natural logarithm of the percentage of residue at each time point was linearly regressed against time to calculate the slope k. The in vitro half-life T... 1 / 2 = -0.693 / k. Clearance in liver microsomes (CL) = 0.693 / T 1 / 2 × Incubation solution (mL) / liver microsomes (mg). The half-life and clearance rate of the compounds of the present invention in human liver microsomes are shown in Table 3. As shown in Table 3, compared with ANAVEX2-73, the compounds of the present invention have significantly enhanced metabolic stability in liver microsomes and a significantly prolonged half-life.

[0052] Table 3. Results of metabolic clearance and half-life tests of the compounds of this invention in human liver microparticles. .

[0053] Example 11, In vitro anti-Aβ 1-42 Toxicity activity testing: Human neuroblastoma SH-SY5Y cells were cultured in DMEM medium containing 10% fetal bovine serum and 5% penicillin / streptomycin. Cells were seeded in 96-well plates (5 × 10³ cells / well) and cultured overnight in a 5% CO2, 37 °C incubator. The compounds of this invention and the positive control ANAVEX2-73 (all compounds at a final concentration of 2 μM) were added to the 96-well plates for pre-incubation for 2 h. Then, 25 μM Aβ was added to the medium. 1-42 The cells were cultured for another 24 hours. Cells were then collected, and 10 µL of pre-prepared CCK-8 solution was added. After culturing for another 1-4 hours, the absorbance was measured at 450 nM to calculate the effect of the compound on cell viability. The experimental results are shown in Table 4. Compared with the blank control, the compound of this invention showed a significant effect on Aβ... 1-42 The induced neurotoxicity has a significant protective effect and is significantly superior to ANAVEX2-73.

[0054] Table 4. Effects of the compounds of this invention on Aβ 1-42Results of assay for protective effect against induced cytotoxicity .

[0055] Example 12, Evaluation of pharmacokinetic properties in rats: Male SD rats were selected, and the compound of this invention, ANAVEX2-7, was administered orally (10 mg / kg) or intravenously (1 mg / kg). Blood samples were continuously collected from the fundus venous plexus at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 10 h, and 24 h after administration and placed in EP tubes containing heparin. After centrifugation, the supernatant plasma was collected for LC-MS / MS analysis. Based on the obtained blood drug concentration-time data, the pharmacokinetic parameters were calculated using WinNonlin software, and the oral bioavailability was calculated.

[0056] As shown in Table 2, all rats tolerated the drug well after administration, and no abnormalities were observed. The compounds of this invention have high exposure levels, long half-lives, good oral bioavailability, and favorable pharmacokinetic properties.

[0057] .

[0058] Example 13, compound in Aβ 25-35 Efficacy evaluation in induced Alzheimer's disease models: By injecting (ICV) Aβ into the lateral ventricle of ICR mice 25-35 A protein was used to induce an Alzheimer's disease (AD) model, with saline injection serving as the sham-operated group. Aβ 25-35 From day 7 to day 28 after protein injection, the compound of the present invention was administered by gavage once a day (10 mg / kg once a day), the positive control compound ANAVEX2-73 was administered by gavage once a day (10 mg / kg once a day), and the positive control compound ANAVEX2-73 was administered by intraperitoneal injection once a day (3 mg / kg once a day). The water maze test and behavioral test were performed from day 20 to day 28.

[0059] (1) Water Maze Experiment: The pool is 120cm in diameter and 50cm high. Divide the pool into four quadrants according to the four cardinal directions (north, south, east, and west). The platform is 10cm in diameter and 14cm high, and can be placed in the center of any quadrant. The temperature inside the pool is maintained at 22±2℃, and the depth is approximately 30cm when full. Before the experiment, add titanium dioxide white dye to the pool and stir until the water turns milky white. This experiment consists of three stages.

[0060] ① The first stage is the platform visibility period, during which the platform must be above the water surface, and the cycle lasts for two days. Each mouse is trained four times a day, with the platform placed in different locations for the first two and last two training sessions. The mice are placed on either side of the quadrant opposite the platform. The mice freely explore in the water for 90 seconds. If they do not find the platform within 90 seconds, they are guided to the platform and allowed to stay there for 15 seconds.

[0061] ②The second stage is the platform hiding period, where the platform needs to be about 1 cm below the water surface, and the cycle is five days. Each mouse is trained 4 times a day, with the platform location fixed. The mouse explores freely in the water for 90 seconds, and the time it takes to find the platform is recorded. If the mouse does not find the platform after 90 seconds, it is guided to the platform and allowed to stay on it for 15 seconds.

[0062] ③ The third stage is the platform-free exploration period, during which the platform is removed and the cycle is one day. Each mouse is trained once, placed at the midpoint of the edge of the opposite quadrant of the platform, and allowed to explore freely in the water for 90 seconds. The number of times the mouse crosses the platform and the time spent in the platform area are recorded.

[0063] The water maze test assesses the learning and memory abilities of mice. As shown in Table 5, during the hiding plateau phase, the time required for mice in the compound administration group to find the platform (escape latency) was significantly shorter than that in the model group and the solvent group, and superior to that in the ANAVEX2-73 intraperitoneal injection group. During the platform-free exploration phase, the number of times mice crossed the platform and the percentage of time spent in the platform quadrant relative to the total measurement time were significantly higher in the compound administration group than in the model group and the solvent group, and superior to that in the ANAVEX2-73 administration group. There was no significant difference between the ANAVEX2-73 oral administration group and the model group, indicating that oral administration of ANAVEX2-73 does not improve Aβ protein-induced learning and memory impairment. A t-test was used for significance analysis between the two groups. **** p <0.0001, *** p <0.001, ** p <0.01, ns (no significant difference) represents the treatment group vs. the model group; #### p <0.0001 represents the model group vs. the sham surgery group.

[0064] Table 5. Compounds of the present invention in Aβ 25-35 Behavioral evaluation results in induced Alzheimer's disease model .

[0065] a Escape incubation period: The time it takes for a mouse to find the platform after 5 days of training following its hiding place.b After the platform was removed, the number of times the mice crossed the platform and the percentage of the total measurement time spent in the platform quadrant were recorded.

Claims

1. A tetrahydrofuran compound, or its enantiomers, racemates, mixtures thereof, or pharmaceutically acceptable salts, deuterates, solvates, hydrates, or metabolites, selected from any of the following structures: 。 2. A pharmaceutical composition, characterized in that, The pharmaceutical composition contains a therapeutically effective amount of a tetrahydrofuran compound as described in claim 1, or its enantiomer, racemate, or mixture thereof, or a pharmaceutically acceptable salt, deuterated derivative, solvate, hydrate, or metabolite thereof, and a pharmaceutically acceptable carrier or excipient.

3. Use of a tetrahydrofuran compound as claimed in claim 1, or its enantiomers, racemates, mixtures thereof, or pharmaceutically acceptable salts, deuterates, solvates, hydrates, metabolites thereof, or a pharmaceutical composition as claimed in claim 2, in the preparation of Sigma-1 receptor ligands and / or M-type acetylcholine receptor ligands.

4. Use of a tetrahydrofuran compound as claimed in claim 1, or its enantiomers, racemates, mixtures thereof, or pharmaceutically acceptable salts, deuterates, solvates, hydrates, metabolites thereof, or a pharmaceutical composition as claimed in claim 2, in the preparation of a medicament for modulating Sigma-1 receptors and / or M-type acetylcholine receptors.

5. Use of a tetrahydrofuran compound as claimed in claim 1, or its enantiomers, racemates, or mixtures thereof, or its pharmaceutically acceptable salts, deuterates, solvates, hydrates, metabolites, or a pharmaceutical composition as claimed in claim 2, in the preparation of a medicament for the prevention and / or treatment of diseases of the central nervous system.

6. The use according to claim 5, characterized in that, The central nervous system disease mentioned is a central nervous system disease associated with abnormalities of Sigma-1 receptors and / or M-type acetylcholine receptors.

7. The use according to claim 6, characterized in that, The central nervous system diseases mentioned are selected from any one or more of Alzheimer's disease, Parkinson's syndrome, stroke, depression, Rett syndrome, tardive dyskinesia, Huntington's disease, amyotrophic lateral sclerosis, or pain.

8. The use according to claim 7, characterized in that, The central nervous system disease mentioned is Alzheimer's disease.

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