Memantine derivatives, processes for their preparation and use in the manufacture of medicaments for the treatment of diseases mediated by soluble epoxide hydrolase

Abstract

This invention relates to the field of pharmaceutical technology, providing memantine derivatives, their preparation methods, and their application in the preparation of drugs for treating soluble cyclooxygenase-mediated diseases. The memantine derivatives provided by this invention have typical urea or amide structures. The urea and amide structures serve as the primary pharmacophores of sEH (hydrophobic epoxide hemoglobin). The memantine moiety, as a hydrophobic segment, interacts with the receptor hydrophobically. Molecular docking shows that the memantine moiety, as a hydrophobic segment, interacts with the receptor hydrophobically, particularly when both R1 and R2 are methyl groups, which enhances the van der Waals forces. Therefore, the memantine derivatives provided by this invention exhibit high inhibitory activity against human (HsEH) and murine sEH (MsEH), and can be used as sEH inhibitors in the preparation of drugs for treating soluble cyclooxygenase-mediated diseases, showing broad application prospects.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to memantine derivatives, their preparation methods, and their use in the preparation of medicaments for treating soluble epoxide enzyme-mediated diseases. Background Technology

[0002] In mammals, arachidonic acid is a polyunsaturated fatty acid metabolized by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYPs). The COX and LOX pathways primarily lead to the production of pro-inflammatory lipid mediators, such as prostaglandins and leukotrienes, and are drug-targeting (Toxicol. 2014, 114, 83-91.). In contrast, CYP450 enzymes act on long-chain polyunsaturated fatty acids to form EpFAs via epoxidation of double bonds (Biochimica Et Biophysica Acta, 2011, 1814(1): 210-222), a process with high selectivity. Based on the position of the epoxidation double bond, EpFAs are classified into: epoxidized eicosatrienoic acids (EETs), epoxidized eicosatraenoic acids (EEQs), and epoxidized eicosapentaenoic acids (EDPs) (Journal of Lipid Research, 2010, 51(12): 3481-3490.). All types of EpFA can be hydrolyzed by sEH into diols, especially the diols formed by the hydrolysis of EETs have the lowest activity (Neuron, 2007, 55(3):353-364.).

[0003] sEH is a member of the α / β hydrolase family. Studies have found that in mammals, sEH is a homodimer composed of two 60kD subunits arranged in an antiparallel manner, each subunit possessing C-terminal hydrolase and N-terminal phosphatase properties. The C-terminal domain exhibits typical α / β hydrolase characteristics, capable of hydrolyzing epoxides by adding water to a three-membered ethylene oxide ring. The N-terminal domain possesses phosphatase activity and can hydrolyze lipid phosphates, but its specific biological function in mammals remains unclear. sEH is a group of functionally similar enzyme systems, divided into eight different subtypes, including mammalian, plant, and microsomal peroxidases (Biochimie, 2013, 95(1):91-95.), with the mammalian subtype being the most important. In mammals, sEH is widely distributed throughout the body, with the highest activity in the liver, kidneys, intestines, and vascular system.

[0004] Inflammation is a complex biological protective response to harmful stimuli such as pathogens, damaged cells, and irritants, involving immune cells, blood vessels, and molecular mediators. However, excessive inflammatory responses can lead to bodily damage. Chronic inflammation is associated with many diseases, such as Alzheimer's disease, arthritis, and cancer.

[0005] Acute pancreatitis (AP) is an inflammatory disease associated with damage and necrosis of the pancreatic exocrine tissue. It has a rapid onset, severe course, and generally poor prognosis, with an incidence rate of 10%–20% (Nat. Rev. Gastro. Hepat. 2019, 16, 175-184. Lancer. Gastroenterol. 2016, 1, 45-55.). In recent years, the incidence of AP has been rising, with a mortality rate as high as 30% (Pathol. Res Pract. 2019, 215, 106-114.). This disease can cause varying degrees of damage to vital organs such as the lungs, kidneys, liver, and heart. In severe cases, it can lead to systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), and even death in the early stages of the disease. Currently, there is no specific treatment (Gastroenterology. 2013, 144, 1252-1261. N. Engl. J. Med. 2016, 375, 1972-1981. Pancreas. 2017, 46, 482-488.). Studies have shown that inflammatory cytokines play a crucial role in acute pancreatitis (AP), and the progression of AP is driven by an inflammatory cascade, which is initiated by the activation of Toll-like receptors (TLRs)-nuclear factor B (NF-κB) and the production of cytokines by acinar cells (Int. J. Inflam. 2012, 360685-360695). More recently, studies have shown that EPHX2 knockout mice exhibit reduced arginine-induced AP, which is attributed to the effective anti-inflammatory properties of EET and reduced endoplasmic reticulum (ER) stress, suggesting that SEH inhibitors may be pharmacologically effective in treating AP (Mol. Pharmacol. 2015, 88, 281-290. J. Med. Chem. 2020, 63, 9237-9257).

[0006] Given the importance of sEH inhibitors and EpFAs in the occurrence and development of inflammation and pain, as well as their protective effects on multiple organs such as the heart, kidneys, and brain, inhibiting sEH activity can increase and stabilize the levels of EpFAs in the body, such as EETs, thereby exerting analgesic, anti-inflammatory, and multi-organ protective effects. Therefore, the development of novel and highly effective sEH inhibitors is urgent and necessary for the treatment of pain. Summary of the Invention

[0007] In view of this, the present invention provides memantine derivatives, methods for their preparation, and their application in the preparation of medicaments for treating soluble cyclooxygenase-mediated diseases. The memantine derivatives provided by the present invention exhibit high inhibitory activity against human sEH (HsEH) and mouse sEH (MsEH), with few side effects, and can be used as sEH inhibitors in the preparation of medicaments for treating soluble cyclooxygenase-mediated diseases.

[0008] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0009] A memantine derivative having the structure shown in Formula A:

[0010]

[0011] In formula A, R1 and R2 are independently selected from -H, -OH, -NH2, -SH, -CN, halogen groups, alkyl, alkoxy, aryl or heteroaryl groups;

[0012] R3 is selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted alkoxy groups, and substituted or unsubstituted heterocyclic groups;

[0013] D is selected from -CH2- or -NH-.

[0014] Preferably, R1 and R2 are independently selected from -H, -OH, -NH2, -SH, -CN, -F, -Cl, -Br, C1-C6 alkyl, C1-C10 alkoxy, phenoxy, or benzyloxy.

[0015] Preferably, R1 and R2 are independently selected from methyl, ethyl, propyl, butyl, pentyl, isobutyl, isopropyl, isopentyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, cyclopentoxy, cyclohexyloxy, phenoxy, or benzyloxy.

[0016] Preferably, R3 is selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, and substituted or unsubstituted C3-C6 heterocyclic groups.

[0017] Preferably, the substituents on the substituted alkyl group are selected from -F, -Cl, -Br, -OH, -NH2, -NHCH3 or -N(CH3)2;

[0018] The substituted alkoxy group and the substituents on the substituted heterocyclic group are independently selected from -F, -Cl, -Br, -OH, -NH2, -NHCH3, -N(CH3)2 or C1 to C6 alkyl groups.

[0019] Preferably, the ammonium nitrate derivative has any one of the structures shown in A-101 to A-106:

[0020]

[0021] This invention also provides a method for preparing the ammonium nitrate derivative described above. When D is -CH2-, the preparation method includes the following steps:

[0022] (1) Mix the compound with the structure shown in Formula 1, the compound with the structure shown in Formula 2, an organic base, a condensing agent and an organic solvent to carry out a first acylation reaction to obtain the compound with the structure shown in Formula a.

[0023]

[0024] (2) The compound with the structure shown in formula a, an acidic reagent and an organic solvent are mixed and subjected to a first deprotection reaction to obtain the compound with the structure shown in formula b;

[0025]

[0026] (3) In the presence of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and N,N-diisopropylethylamine, the compound with the structure shown in Formula b and the compound with the structure shown in Formula 3 are subjected to a second acylation reaction to obtain a memantine derivative having the structure shown in Formula A.

[0027] R3-COOH formula 3;

[0028] When D is -NH-, the preparation method includes the following steps:

[0029] (i) A third acylation reaction is carried out by mixing the compound with the structure shown in Formula 1, solid phosgene, organic base and organic solvent to obtain an intermediate compound with the structure shown in Formula e.

[0030]

[0031] (ii) The intermediate compound, the compound with the structure shown in Formula 4, an organic base and an organic solvent are mixed and subjected to a nucleophilic substitution reaction to obtain the compound with the structure shown in Formula c;

[0032]

[0033] (iii) The compound with the structure shown in formula c, an acidic reagent, and an organic solvent are mixed to carry out a second deprotection reaction to obtain the compound with the structure shown in formula d;

[0034]

[0035] (iv) In the presence of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and N,N-diisopropylethylamine, the compounds with the structure shown in Formula d and the compounds with the structure shown in Formula 3 were subjected to a fourth acylation reaction to obtain a memantine derivative having the structure shown in Formula A.

[0036] Preferably, in step (1), the organic base is one or more of triethylamine, pyridine, and N,N-diisopropylethylamine; the condensing agent is one or more of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and N,N'-dicyclohexylcarbodiimide.

[0037] In steps (2) and (iii), the acidic reagent is independently a methanol solution of hydrogen chloride, an ethyl acetate solution of hydrogen chloride, or trifluoroacetic acid.

[0038] In step (i), the organic base is triethylamine;

[0039] In step (ii), the organic base is triethylamine.

[0040] The present invention also provides the use of the memantine derivatives described in the above-described scheme or the memantine derivatives prepared by the preparation method described in the above-described scheme in the preparation of drugs for treating soluble cyclooxide enzyme-mediated diseases.

[0041] Preferably, the diseases mediated by the soluble cyclooxygenase include inflammatory diseases, pain, cardiovascular diseases, neurodegenerative diseases, diabetes, diabetic complications, renal failure, chronic obstructive pulmonary disease, or pulmonary hypertension.

[0042] This invention provides a memantine derivative, specifically a memantine urea derivative (when D is -NH-) or a memantine amide derivative (when D is -CH2-). The memantine derivative provided by this invention has a typical urea structure and an amide as the primary pharmacophore of sEH. The memantine moiety, acting as a hydrophobic segment, interacts hydrophobically with the receptor. Molecular docking shows that the memantine moiety, as a hydrophobic segment, interacts hydrophobically with the receptor, particularly when R1 and R2 are both methyl (i.e., 3,5-dimethyl substituted), which enhances the van der Waals forces. Therefore, the memantine urea and amide derivatives provided by this invention exhibit high inhibitory activity against human HsEH and murine sEH (MsEH), and can be used as sEH inhibitors in the preparation of drugs for treating soluble cyclooxidase-mediated diseases. Attached Figure Description

[0043] Figure 1 Synthetic route diagram of the ammonium nitrate derivative when D is -CH2-;

[0044] Figure 2 Synthetic route diagram of the ammonium nitrate derivative when D is -NH-;

[0045] Figure 3 Representative H&E stained sections of the pancreas from mice in the control group, model group, celecoxib group, ulinastatin group, and A-105 group;

[0046] Figure 4 The results of the evaluation of (A) edema, (B) inflammatory cells (monocytes and polymorphonuclear cells), (C) parenchymal atrophy and (D) total score (edema, mononuclear cells, polymorphonuclear cells and parenchymal atrophy) of the pancreas in mice in the control group, model group, celecoxib group, ulinastatin group and A-105 group are as follows. Detailed Implementation

[0047] This invention provides a memantine derivative having the structure shown in Formula A:

[0048]

[0049] In formula A, R1 and R2 are independently selected from -H, -OH, -NH2, -SH, -CN, halogen groups, alkyl, alkoxy, aryl or heteroaryl groups;

[0050] R3 is selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted alkoxy groups, and substituted or unsubstituted heterocyclic groups;

[0051] D is selected from -CH2- or -NH-.

[0052] In this invention, when D is -CH2-, the memantine derivative is a memantine amide derivative, and when D is -NH-, the memantine derivative is a memantine urea derivative.

[0053] In this invention, R1 and R2 are preferably independently selected from -H, -OH, -NH2, -SH, -CN, -F, -Cl, -Br, C1-C6 alkyl, C1-C10 alkoxy, phenoxy, or benzyloxy; further, R1 and R2 are independently selected from methyl, ethyl, propyl, butyl, pentyl, isobutyl, isopropyl, isopentyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, cyclopentoxy, cyclohexyloxy, phenoxy, or benzyloxy; in specific embodiments of this invention, R1 and R2 are further preferably C1-C3 alkyl, and most preferably methyl.

[0054] In this invention, R3 is preferably selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, and substituted or unsubstituted C3-C6 heterocyclic groups; the substituents on the substituted alkyl groups are independently selected from -F, -Cl, -Br, -OH, -NH2, -NHCH3, or -N(CH3)2; the substituents on the substituted alkoxy groups and the substituted heterocyclic groups are independently selected from -F, -Cl, -Br, -OH, -NH2, -NHCH3, -N(CH3)2, or C1-C6 alkyl groups. In specific embodiments of this invention, R3 is preferably a C1-C4 alkyl group, specifically preferably ethyl, 2-methylpropyl, (R)-2-methylpropyl, or (S)-2-methylpropyl.

[0055] In this invention, the ammonium nitrate derivative preferably has any one of the structures shown in A-101 to A-106:

[0056]

[0057] In this invention, the chemical names of the compounds with structures shown in formulas A-101 to A-106 are, in order: N-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)-2-(1-propionylpiperidin-4-yl)acetamide, N-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)-2-(1-(2-methylbutyryl)piperidin-4-yl)acetamide, 1-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)-3-(1- Propionylpiperidin-4-yl)urea, 1-((1r,3R,5S,7R)-3,5-dimethyladamantane-1-yl)-3-(1-(S)-2-methylbutyryl)piperidin-4-yl)urea, 1-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)-3-(1-(2-methylbutyryl)piperidin-4-yl)urea, 1-((1r,3R,5S,7R)-3,5-dimethyladamantane-1-yl)-3-(1-(R)-2-methylbutyryl)piperidin-4-yl)urea.

[0058] The present invention also provides a method for preparing the memantine derivatives described in the above scheme, including methods for preparing memantine amide derivatives and memantine urea derivatives, which will be described in detail below.

[0059] In this invention, when D is -CH2-, the preparation method includes the following steps:

[0060] (1) Mix the compound with the structure shown in Formula 1, the compound with the structure shown in Formula 2, an organic base, a condensing agent and an organic solvent to carry out a first acylation reaction to obtain the compound with the structure shown in Formula a.

[0061]

[0062]

[0063] (2) The compound with the structure shown in formula a, an acidic reagent and an organic solvent are mixed and subjected to a first deprotection reaction to obtain the compound with the structure shown in formula b;

[0064]

[0065] (3) In the presence of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and N,N-diisopropylethylamine, the compound with the structure shown in Formula b and the compound with the structure shown in Formula 3 were subjected to a second acylation reaction to obtain a memantine derivative having the structure shown in Formula A.

[0066] R3-COOH (Formula 3)

[0067] In Equations 1, a, and b, the types of R1 and R2 are the same as in Equation A, and the types of R3 in Equation 3 are the same as in Equation A.

[0068] Figure 1 The synthetic route of the micranioline derivative when D is -CH2- is shown below, in conjunction with... Figure 1 Please provide a detailed explanation.

[0069] In this invention, a compound with the structure shown in Formula 1, a compound with the structure shown in Formula 2, an organic base, a condensing agent, and an organic solvent are mixed and subjected to a first acylation reaction to obtain a compound with the structure shown in Formula a. In this invention, the molar ratio of the compound with the structure shown in Formula 1, the compound with the structure shown in Formula 2, the organic base, and the condensing agent is preferably (1.0–1.5):1:(2–4):(1.2–2), more preferably 1.2:1:3:1.5; the organic base preferably includes one or more of triethylamine, pyridine, and N,N-diisopropylethylamine, more preferably N,N-diisopropylethylamine (DIEA); the condensing agent preferably includes 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate. One or more of (HATU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and N,N'-dicyclohexylcarbodiimide, more preferably 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; the organic solvent for the first acylation reaction preferably includes one or more of dichloromethane, trichloromethane, and tetrahydrofuran, more preferably tetrahydrofuran; the present invention does not have special requirements for the amount of organic solvent used in each step, as long as it can ensure the smooth progress of the reaction, and will not be elaborated further. In the present invention, the temperature of the first acylation reaction is preferably 10-30°C, more preferably 25°C, and the time is preferably 30-60 min, more preferably 30 min.

[0070] In a specific embodiment of the present invention, it is preferable to first dissolve the compound with the structure shown in Formula 2 in an organic solvent, then add a condensing agent and an organic base, stir for 60 min, and then add the compound with the structure shown in Formula 1 dropwise to carry out the reaction.

[0071] After the first acylation reaction, the present invention preferably mixes the obtained reaction solution with water, then adds dichloromethane for extraction to obtain an organic layer. The organic layer is then washed sequentially with hydrochloric acid, saturated sodium carbonate solution, water, and saturated brine. The washed organic phase is then concentrated under reduced pressure to remove the solvent, yielding a compound with the structure shown in formula a.

[0072] After obtaining the compound with the structure shown in Formula a, the present invention mixes the compound with the structure shown in Formula a, an acidic reagent, and an organic solvent to carry out a first deprotection reaction to obtain the compound with the structure shown in Formula b. In the present invention, the molar ratio of the compound with the structure shown in Formula a to the acidic reagent is preferably 1:(3-10), more preferably 1:5; the acidic reagent is preferably a methanol solution of hydrogen chloride, an ethyl acetate solution of hydrogen chloride, or trifluoroacetic acid, more preferably trifluoroacetic acid. When the acidic reagent is a methanol solution of hydrogen chloride or an ethyl acetate solution of hydrogen chloride, the molar amount of the acidic reagent is calculated based on the molar amount of hydrogen chloride; the organic solvent for the first deprotection reaction preferably includes one or more of acetonitrile, dichloromethane, and tetrahydrofuran, more preferably dichloromethane; in the present invention, the temperature of the first deprotection reaction is preferably -20 to 50°C, more preferably 30°C, and the time is preferably 2 to 8 hours, more preferably 3 hours.

[0073] After the first deprotection reaction is completed, the present invention preferably concentrates the resulting reaction solution under reduced pressure to obtain a compound with the structure shown in formula b.

[0074] After obtaining the compound with the structure shown in Formula b, the present invention further describes a second acylation reaction in the presence of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIEA) to obtain a memantine derivative having the structure shown in Formula A. In this invention, the molar ratio of the compound with the structure shown in Formula b to the compound with the structure shown in Formula 3 is preferably 1:(1.5-2.0), more preferably 1:2; the compound with the structure shown in Formula 3 is specifically preferably propionic acid, 2-methylbutyric acid, (R)-2-methylbutyric acid, or (S)-2-methylbutyric acid; the molar ratio of the compound with the structure shown in Formula b, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, and N,N-diisopropylethylamine is preferably 1:(1.2-1.7):(2-3), more preferably 1:1.2:2.4. In this invention, the temperature of the second acylation reaction is preferably 25-35°C, more preferably 30°C; the time is preferably 1-3 h, more preferably 2 h; the organic solvent for the second acylation reaction is preferably dichloromethane.

[0075] In a specific embodiment of the present invention, it is preferable to first dissolve the compound with the structure shown in Formula 3 in an organic solvent, then add HATU and DIEA, and then react with a solution of the compound with the structure shown in Formula b.

[0076] After the second acylation reaction is completed, the present invention preferably mixes the obtained reaction solution with water and then extracts it with dichloromethane to obtain an organic layer; the organic layer is then washed sequentially with hydrochloric acid, saturated sodium carbonate solution, water, and saturated brine; the washed organic phase is concentrated under reduced pressure to obtain a crude product; the crude product is subjected to silica gel column chromatography to obtain the memantine derivative; the concentration of hydrochloric acid used for the hydrochloric acid washing is preferably 1 mol / L; the eluent used for the silica gel column chromatography is preferably a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate in the mixed solvent is preferably 1:1.

[0077] In this invention, when D is -NH-, the preparation method includes the following steps:

[0078] (i) The compound with the structure shown in Formula 1, solid phosgene, organic base and organic solvent are mixed and subjected to a third acylation reaction to obtain an intermediate compound; the structural formula of the intermediate compound is shown in Formula e.

[0079]

[0080] (ii) The intermediate compound, the compound with the structure shown in Formula 4, an organic base and an organic solvent are mixed and subjected to a nucleophilic substitution reaction to obtain the compound with the structure shown in Formula c;

[0081]

[0082] (iii) The compound with the structure shown in formula c, an acidic reagent, and an organic solvent are mixed to carry out a second deprotection reaction to obtain the compound with the structure shown in formula d;

[0083]

[0084] (iv) In the presence of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and N,N-diisopropylethylamine, the compounds with the structure shown in Formula d and the compounds with the structure shown in Formula 3 were subjected to a fourth acylation reaction to obtain the memantine derivative having the structure shown in A.

[0085] Figure 2 The synthetic route of the micranioline derivative when D is -NH- is shown below, in conjunction with... Figure 2 Please provide a detailed explanation.

[0086] This invention involves mixing a compound with the structure shown in Formula 1, solid phosgene, an organic base, and an organic solvent to undergo a third acylation reaction to obtain an intermediate compound. In this invention, the molar ratio of the compound with the structure shown in Formula 1 to solid phosgene is preferably 1:(0.3–0.5), more preferably 1:0.5; the organic base is preferably triethylamine; the organic solvent for the third acylation reaction is preferably dichloromethane; the temperature of the third acylation reaction is preferably -78–25°C, and the time is preferably 30–60 min, more preferably 30 min.

[0087] In a specific embodiment of the present invention, it is preferable to first mix solid phosgene and dry dichloromethane, cool the mixture to -78°C, and then add dropwise the compound with the structure shown in Formula 1 and a dichloromethane solution of triethylamine. After the addition is complete, the mixture is stirred at room temperature to react.

[0088] After the third acylation reaction is completed, the present invention preferably concentrates the obtained reaction solution under reduced pressure to obtain an intermediate compound; the temperature of the reduced pressure concentration is preferably 40°C.

[0089] After obtaining the intermediate compound, the present invention mixes the intermediate compound, the compound with the structure shown in Formula 4, an organic base, and an organic solvent to carry out a nucleophilic substitution reaction to obtain the compound with the structure shown in Formula c. In the present invention, the molar ratio of the intermediate compound and the compound with the structure shown in Formula 4 is preferably (0.8-1.0):1; the organic base is preferably triethylamine, and the molar ratio of the compound with the structure shown in Formula 4 and the organic base is preferably 1:(4-6), more preferably 1:6; the temperature of the nucleophilic substitution reaction is preferably -10 to 30°C, more preferably 25°C, and the time is preferably 30 to 60 min, more preferably 30 min.

[0090] In a specific embodiment of the present invention, it is preferable to dissolve the intermediate compound and the compound with the structure shown in Formula 4 in dichloromethane, and then add the resulting dichloromethane solution with the structure shown in Formula 4 dropwise to the dichloromethane solution of the intermediate compound to carry out the reaction.

[0091] After the nucleophilic substitution reaction is completed, the present invention preferably mixes the resulting reaction solution with water, then adds ethyl acetate for extraction, and then dries the resulting organic phase and sequentially filters and concentrates it to obtain the compound with the structure shown in formula c.

[0092] After obtaining the compound with the structure shown in formula c, the present invention mixes the compound with the structure shown in formula c, an acidic reagent, and an organic solvent to carry out a second deprotection reaction to obtain the compound with the structure shown in formula d. In the present invention, the reaction conditions and post-treatment methods used in the second deprotection reaction are preferably the same as those used in the first deprotection reaction in step (2), except that the compound with the structure shown in formula a is replaced with the compound with the structure shown in formula c, which will not be described in detail here.

[0093] After obtaining the compound with the structure shown in formula d, the present invention performs a fourth acylation reaction on the compound with the structure shown in formula d and the compound with the structure shown in formula 3 in the presence of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and N,N-diisopropylethylamine to obtain a memantine derivative having the structure shown in formula A. In the present invention, the reaction conditions and post-processing methods used in the fourth acylation reaction are preferably consistent with the reaction conditions and post-processing methods of the second acylation reaction in step (3), only the compound with the structure shown in formula b is replaced with the compound with the structure shown in formula d, which will not be described again here.

[0094] This invention also provides the use of the memantine derivatives described in the above-described schemes or the memantine derivatives prepared by the preparation methods described in the above-described schemes in the preparation of medicaments for treating soluble cyclooxygenase-mediated diseases. In this invention, the soluble cyclooxygenase-mediated diseases preferably include inflammatory diseases, pain, cardiovascular diseases, neurodegenerative diseases, diabetes, diabetic complications, renal failure, chronic obstructive pulmonary disease, or pulmonary hypertension; the inflammatory diseases preferably include acute pancreatitis, rheumatoid arthritis, or chronic nephritis.

[0095] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0096] Example 1 Synthesis of tert-butyl 4-(2-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)amino)-2-oxoethyl)piperidine-1-carboxylate (a compound with the structure shown in Formula a)

[0097] 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (2.0 g, 8.23 ​​mmol) and dry dichloromethane (20 mL) were added to a single-necked flask. After the 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid dissolved, HATU (3.76 g, 9.88 mmol) and DIEA (2.55 g, 19.76 mmol) were added. The mixture was stirred for 30 min until the solution turned pale yellow. Memantine (1.77 g, 9.88 mmol) was then added dropwise. After 30 min, the TLC reaction was complete, and the reaction was stopped. Water (10 mL) was added, and the mixture was extracted with DCM (15 mL × 2). The organic layers were combined, washed once with 1N hydrochloric acid (20 mL), once with saturated sodium carbonate (20 mL), once with water (20 mL), and once with saturated brine (20 mL). The organic phase was concentrated under reduced pressure to obtain 2.99 g of a pale yellow oil, with a yield of 90%.

[0098] Example 2 Synthesis of N-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)-2-(piperidin-4-yl)acetamide (a compound with the structure shown in formula b)

[0099] Add 2.99 g (7.41 mmol) of 4-(2-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)amino)-2-oxoethyl)piperidine-1-carboxylic acid tert-butyl ester to a single-necked flask, dissolved in dry dichloromethane (5 mL), and add 2.5 mL of TFA dropwise. After reacting at 25 °C for 3 h, the reaction was completed by TLC. The mixture was concentrated under reduced pressure to remove trifluoroacetic acid and directly added to the next step.

[0100] Example 3 N-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)-2-(1-propionylpiperidin-4-yl)acetamide (A-101)

[0101] Add propionic acid (0.12 g, 1.64 mmol) and dry dichloromethane (10 mL) to a single-necked flask. After dissolution, add HATU (0.75 g, 1.97 mmol) and stir for 15 min. Add DIEA (0.51 g, 3.94 mmol) dropwise and stir for 30 min. Add a mixture of N-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)-2-(piperidin-4-yl)acetamide (0.5 g, 1.64 mmol) and dry dichloromethane (5 mL) dropwise. After 2 h, the TLC reaction is complete, and the reaction is stopped. Add water (10 mL), extract with DCM (10 mL × 2), combine organic layers, wash once with 1 mol / L hydrochloric acid (10 mL), once with saturated sodium carbonate (10 mL), once with water (10 mL), and once with saturated saline (10 mL). Concentrate the organic phase under reduced pressure to obtain 0.6 g of a pale yellow oily substance. Pack a column with 5x silica gel, mix with 1.2x silica gel, and use eluent (EA:PE = 1:1). Column chromatography yields a white solid, A-101, with a yield of 0.23 g and a yield of 40.0%, mp 123-126℃. 1 . H NMR (400MHz, CDCl3): δ (ppm) 5.20 (s, 1H), 4.61 (br, 1H), 3.84 (br, 1H), 3.00 (br, 1H), 2.56 (br, 1H), 2.33 (q, J = 7.5Hz, 2H), 2. 07-2.00(m,3H),1.82(d,J=2.5Hz,2H),1.76(br,2H),1.67-1.60(m,4H),1.39-1.36(m,2H),1.20-1.12(m,7H),0.85(s,6H). 13 C NMR (100MHz, CDCl3): δ172.12,170.59,53.68,50.07,47.66,45.60,44.41,42.64,41.89,40.25,33.62,32.38,31.82,30.11,30.04,26.08,9.63.

[0102] Example 4 N-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)-2-(1-(2-methylbutyryl)piperidin-4-yl)acetamide (A-102)

[0103] Following the method described in Example 3, using 2-methylbutyric acid as a raw material, a white solid, namely A-102, was obtained with a yield of 0.25 g and a recovery rate of 41.0%, at mp 60-62℃. 1HNMR (400MHz, CDCl3): δ (ppm) 5.20 (s, 1H), 4.65 (br, 1H), 3.95 (br, 1H), 3.00 (br, 1H), 2.65-2.57 (m, 2H), 2.15-2.12 (m, 1H), 2.07-2.01 (m, 3H),1.91(s,2H),1.82(d,J=2.5Hz,2H),1.79(br,1H),1.64(s,1H),1.43-1.36(m,3H),1.30-1.25(m,2H),1.19-1.15(m,2H),0.85(s,6H). 13 C NMR (100MHz, CDCl3): δ174.84,170.71,53.73,50.58,47.66,45.72,44.45,42.65,42.1 0,40.25,36.94,33.79,32.88,32.40,32.08,30.12,30.07,29.72,27.07,17.33,12.01.

[0104] Example 5 Synthesis of tert-butyl 4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)ureo)piperidine-1-carboxylate (a compound with the structure shown in formula c)

[0105] Add solid phosgene (1.66 g, 5.58 mmol) and dry DCM (30 mL) to a three-necked flask. Cool the hydrazine to below -78 °C and add a solution of memantine (2.0 g, 11.15 mmol) and triethylamine (6.77 g, 66.9 mmol) in dry dichloromethane (50 mL) dropwise. After the addition is complete, move the mixture to room temperature and stir for 0.5 h. Then stop the reaction and concentrate the resulting reaction solution to dryness under reduced pressure. Add dry DCM (10 mL) to the residue (i.e., the intermediate compound) to dissolve it, and obtain an isocyanate solution for later use.

[0106] 223 g (11.15 mmol) of 4-aminopiperidine-1-carboxylic acid tert-butyl ester, 6.77 g (66.9 mmol), and 25 mL of dry dichloromethane were added to a three-necked flask. The above isocyanate solution was added dropwise, and the reaction was allowed to proceed at room temperature for 0.5 h. TLC showed that the reaction was complete. The reaction solution was poured into water (20 mL), extracted with DCM (20 mL × 2), and then washed successively with 1 mol / L HCl (30 mL × 2), water (30 mL × 2), saturated brine (30 mL), and dried over anhydrous sodium sulfate. The solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 3.6 g of a pale yellow oil, with a yield of 80.0%.

[0107] Example 6 Synthesis of 1-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)-3-(piperidin-4-yl)urea (a compound with the structure shown in formula d)

[0108] Following the method described in Example 2, using tert-butyl 4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)ureo)piperidine-1-carboxylate (3.6 g, 8.88 mmol) as the starting material, the yield was 2.44 g, with a yield of 90.0%.

[0109] Example 7 1-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)-3-(1-propionylpiperidin-4-yl)urea (A-103)

[0110] Following the method described in Example 3, propionic acid (0.12 g, 1.64 mmol) and 1-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)-3-(piperidin-4-yl)urea (0.50 g, 1.64 mmol) were used as raw materials to obtain a white solid, namely A-103, with a yield of 0.23 g and a recovery rate of 39.0%, at mp 188-189 °C. 1 HNMR (400MHz, CDCl3): δ (ppm) 4.48 (d, J = 12.7Hz, 2H), 3.81-3.74 (m, 2H), 3.10 (t ,J=12.2Hz,1H),2.73(t,J=11.8Hz,1H),2.38-2.31(m,2H),2.13-2.12(m,1H),2. 06-2.04(m,1H),1.89-1.87(m,1H),1.78(d,J=2.6Hz,2H),1.60(s,4H),1.37-1. 34(m,2H),1.29-1.22(m,2H),1.19-1.15(m,1H),1.15-1.12(m,5H),0.84(s,6H). 13 C NMR (100MHz, CDCl3): δ172.41,156.56,52.64,50.68,48.50,46.91,44.50,42.76,41.04,40.94,32.86,32.51,32.43,30.23,30.13,26.56,9.65.

[0111] Example 8 Synthesis of 1-((1r,3R,5S,7R)-3,5-dimethyladamantane-1-yl)-3-(1-(S)-2-methylbutyryl)piperidin-4-yl)urea (A-104)

[0112] Following the method described in Example 3, using (s)-2-methylbutyric acid (0.17 g, 1.64 mmol) and 1-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)-3-(piperidin-4-yl)urea (0.50 g, 1.64 mmol) as raw materials, a white solid, namely A-104, was obtained with a yield of 0.4026 g and a yield of 640.0%, at mp 82-85 °C. 1 H NMR (400MHz, CDCl3): δ (ppm) 4.73-4.48 (m, 3H), 3.90-3.79 (m, 2H), 3.16-3.09 (m, 1H),2.77-2.71(m,1H),2.67-2.58(m,1H),2.13-2.06(m,2H),1.87(br,1H),1.78- 1.77(m,2H),1.72-1.57(m,5H),1.45-1.34(m,3H),1.29-1.26(m,2H),1.24-1.17 (m,2H),1.14-1.13(m,2H),1.08(d,J=6.8Hz,3H),0.90-0.87(m,3H),0.84(s,6H). 13 C NMR (100MHz, CDCl3): δ175.23,156.83,52.47,50.70,48.53,46.80,46.70,44.58,44.50,42.7 8,41.10,41.05,36.94,32.72,32.57,32.40,30.23,30.15,27.18,27.00,17.33,12.05,11.84.

[0113] Example 9 1-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)-3-(1-(2-methylbutyryl)piperidin-4-yl)urea (A-105)

[0114] Following the method described in Example 3, using 2-methylbutyric acid (0.17 g, 1.64 mmol) and 1-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)-3-(piperidin-4-yl)urea (0.50 g, 1.64 mmol) as raw materials, a white solid, namely A-105, was obtained with a yield of 0.24 g and a yield of 38.0%, at mp 82-85 °C. 1H NMR (400MHz, CDCl3): δ (ppm) 4.73-4.48 (m, 3H), 3.90-3.79 (m, 2H), 3.16-3.09 (m, 1H),2.77-2.71(m,1H),2.67-2.58(m,1H),2.13-2.06(m,2H),1.87(br,1H),1.78- 1.77(m,2H),1.72-1.57(m,5H),1.45-1.34(m,3H),1.29-1.26(m,2H),1.24-1.17 (m,2H),1.14-1.13(m,2H),1.08(d,J=6.8Hz,3H),0.90-0.87(m,3H),0.84(s,6H). 13 C NMR (100MHz, CDCl3): δ175.23,156.83,52.47,50.70,48.53,46.80,46.70,44.58,44.50,42.7 8,41.10,41.05,36.94,32.72,32.57,32.40,30.23,30.15,27.18,27.00,17.33,12.05,11.84.

[0115] Example 10 Synthesis of 1-((1r,3R,5S,7R)-3,5-dimethyladamantane-1-yl)-3-(1-(R)-2-methylbutyryl)piperidin-4-yl)urea (A-106)

[0116] Following the method described in Example 3, using (R)-2-methylbutyric acid (0.17 g, 1.64 mmol) and 1-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)-3-(piperidin-4-yl)urea (0.50 g, 1.64 mmol) as raw materials, a white solid, namely A-106, was obtained with a yield of 0.26 g and a recovery rate of 40.0%, mp 149-150 °C. mp 82-85 °C. 1HNMR (400MHz, CDCl3): δ (ppm) 4.73-4.48 (m, 3H), 3.90-3.79 (m, 2H), 3.16-3.09 (m ,1H),2.77-2.71(m,1H),2.67-2.58(m,1H),2.13-2.06(m,2H),1.87(br,1H),1.78 -1.77(m,2H),1.72-1.57(m,5H),1.45-1.34(m,3H),1.29-1.26(m,2H),1.24-1.17 (m,2H),1.14-1.13(m,2H),1.08(d,J=6.8Hz,3H),0.90-0.87(m,3H),0.84(s,6H). 13 C NMR (100MHz, CDCl3): δ175.23,156.83,52.47,50.70,48.53,46.80,46.70,44.58,44.50,42.7 8,41.10,41.05,36.94,32.72,32.57,32.40,30.23,30.15,27.18,27.00,17.33,12.05,11.84.

[0117] Test case

[0118] 1. Inhibitory activity test

[0119] Detection Principle: The specific substrate (3-phenyl-oxy)-cyanoacetate-(6-methoxy-naphth-2-yl)methyl ester, i.e., PHOME, is itself non-fluorescent. However, under the action of sEH enzyme, it is hydrolyzed to produce the product 6-methoxy-2-naphthaldehyde. 6-methoxy-2-naphthaldehyde can emit fluorescence at a wavelength of 465 nm when excited by light at 330 nm. The intensity of the detected fluorescence signal is inversely proportional to the strength of the inhibitory effect on sEH enzyme. Based on the above principle, the inhibition rate of samples at different concentrations was calculated compared with the positive control group. The IC50 of the compound was calculated using SPSS 20 software based on the inhibition rate and concentration. 50 value.

[0120] 2. Preparation of reagents and drugs

[0121] 25mM Tris-HCl buffer (pH=7.4, containing 0.1mg / mL BSA): Take 12.5mL of 1M Tris-HCl buffer, add 5mg BSA, dilute with purified water and adjust the pH to 7.4 with hydrochloric acid, and bring the volume to 500mL.

[0122] PHOME solution: Dissolve 0.79 mg of PHOME in 106 μL of DMSO to obtain a 20 mM PHOME solution. Dilute to 1 / 3 mM with Tris-HCl buffer before use.

[0123] sEH solution: The sEH (5 mg / mL) stock solution was stored at -80°C and diluted to 4 μg / mL with 25 mM Tris-HCl buffer before use.

[0124] The sample powder to be tested is dissolved in DMSO to prepare a 20mM solution, stored at -20℃ for later use, and diluted with Tris-HCl buffer to the corresponding concentration before use.

[0125] 3. Experimental Grouping

[0126] Experimental design: solvent group, 100% activity group (A), inhibitor group (B), positive control group (C), as shown in Table 1.

[0127] Table 1 Experimental Grouping

[0128] hole buffer solution DMSO Inhibitors sEH Substrate Solvent group 168μL 2μL — — 30μL 100% Vitality Group (A) 148μL 2μL — 20μL 30μL Inhibitor group (B) 148μL — 2μL 20μL 30μL Positive control group (C) 148μL — 2μL 20μL 30μL

[0129] 4. Experimental Procedure

[0130] (a) Add 148 μL / well of Tris-HCl buffer to a 96-well black microplate;

[0131] (b) Add 2 μL of the test sample solution, replace the solvent group and the 100% activity group with an equal volume of DMSO, and add the lead compound t-TUCB to the positive control group;

[0132] (c) The inhibitor group had a total of 5 concentrations, with final concentrations of 10 nM, 5 nM, 2.5 nM, 1.25 nM and 0.625 nM, respectively;

[0133] (d) Add 20 μL of s-EH solution (final concentration of 400 ng / mL), and replace the solvent group with an equal volume of Tris-HCl buffer;

[0134] (e) Add 30 μL of PHOME substrate to start the reaction (final concentration 50 μM) and incubate at 37 °C for 10 min;

[0135] (f) ELISA reader detects fluorescence signal data, with an excitation wavelength of 330 nm and an emission wavelength of 465 nm.

[0136] 5. Data Analysis

[0137] Each sample was prepared in triplicate, and the mean of the three replicates was the fluorescence value (F) of the analyte. The inhibition rate % was calculated as [(AF - BF) / AF] × 100, where AF is the fluorescence value of the 100% activity group and BF is the fluorescence value of the inhibitor group. The IC50 of the compound was calculated using SPSS 20 software based on the inhibition rate and concentration. 50 value.

[0138] Table 2 shows the inhibitory activities of the A-101 to A-106 series compounds on human sEH (HsEH) and mouse sEH (MsEH).

[0139] Table 2 shows the inhibitory activities of compounds in the A-101 to A-106 series against human sEH (HsEH) and murine sEH (MsEH).

[0140]

[0141] As can be seen from the data in Table 2, the IC50 values ​​of compounds A-101 to A-106 provided by this invention for HsEH are... 50 The values ​​are between 259.4 nM and 0.5 nM, exhibiting good inhibitory effects. The compounds A-101 to A-106 provided by this invention have IC50 values ​​for MsEH. 50 Values ​​between 66.0 nM and 0.74 nM also showed good inhibitory effects. Experimental results showed that the inhibitory activity of A-103, A-104, A-105, and A-106 against HsEH was similar to that of the positive control drug t-TUCB, indicating very good development prospects.

[0142] 6. Study on the effect of compound A-105 on L-arginine-induced acute pancreatitis model in mice

[0143] All mice used in the pharmacological experiments were female (20-22g) from Kunming, provided by Liaoning Changsheng Biotechnology Co., Ltd. (Liaoning, China), license number: SCXK(Liaoning)2015-0001. Mice were housed under controlled environmental conditions: temperature 22-24℃, relative humidity 50-60%, natural diurnal rhythm, free access to water and food, and were acclimatized for one week. The experiments were approved by the Animal Management and Use Committee of Shenyang Pharmaceutical University and complied with the relevant ethical guidelines for experimental animal research.

[0144] Twenty-four female Kunming mice (weighing 20-22g) were randomly divided into five groups: solvent group, model group (L-Arg), A-105 (5mg / kg) group, A-105 (10mg / kg) group, ulinastatin (5mg / kg) group, and celecoxib (5mg / kg) group. Before the experiment, the mice were fasted for 6-8 hours but given free access to water. Each mouse was weighed and injected intraperitoneally with 20% L-arginine (2g / kg, ip), except for the solvent group. The solvent group received a second injection of 20% L-arginine (2g / kg, ip) one hour later. Fourteen hours after modeling, A-105 (5mg / kg), A-105 (10mg / kg), ulinastatin (5mg / kg), and celecoxib (5mg / kg) were injected intraperitoneally. The solvent group and the model group (L-Arg) received an equal volume of 0.9% saline intraperitoneally. Ten hours after drug treatment, mice in each group were sacrificed, and pancreatic tissue was removed and fixed in 10% formalin for further sectioning. The basic sectioning procedure included: embedding, dewaxing, staining, dehydration, clearing, sealing, and slide scanning.

[0145] Acute pancreatitis (AP) is a potentially life-threatening gastrointestinal disease whose incidence has been increasing over the past few decades. Currently, there are no effective treatments for AP, making the development of a therapeutic drug urgently needed. Given the association between sEH (saturated epithelial hyperplasia) and the pathogenesis of AP, the sEH inhibitor A-105 at doses of 5 mg / kg and 10 mg / kg was evaluated in an L-arginine-induced mouse model of acute pancreatitis and compared with celecoxib (5 mg / kg, ip) and ulinastatin (5 mg / kg).

[0146] First, a histological analysis of the pancreas was performed to determine whether A-105 treatment reduced the severity of L-arginine-induced pancreatitis. Histological results are as follows: Figures 3-4 As shown, Figure 3 Representative H&E stained sections of the pancreas of mice in the control group, model group, celecoxib group, ulinastatin group and A-105 group are shown. (a), (b), (c), (d), (e) and (f) are the control group, model group, celecoxib group, A-105 group (5 mg / kg), ulinastatin group (5 mg / kg) and A-105 group (10 mg / kg), respectively.

[0147] Figure 4 This study evaluated the pancreatic pancreas (A) edema, (B) inflammatory cells (monocytes and polymorphonuclear cells), (C) parenchymal atrophy, and (D) total score (edema, mononuclear cells, polymorphonuclear cells, and parenchymal atrophy) in mice from the control group, model group, celecoxib group, ulinastatin group, and A-105 group (n=4 per group); Significance: *p<0.05, **p<0.01 compared with the control group; Compared with Mod. # p<0.05 and## p<0.01.

[0148] according to Figures 3-4 The results showed that the L-arginine model group (6.67±0.58) exhibited pancreatic damage representative of acute pancreatitis (AP), including edema. Figure 4 A) Inflammatory cell infiltration ( Figure 4 B) and solid atrophy ( Figure 4 (C) In contrast, compounds A-105 at 5 mg / kg (2.75 ± 0.50) and 10 mg / kg (1.67 ± 1.15) both improved L-arginine-induced pancreatic injury in AP. A-105 (10 mg / kg) was more effective than 5 mg / kg, and A-105 at 10 mg / kg (1.67 ± 1.15) was more effective than celecoxib at 5 mg / kg (3.50 ± 2.08) and ulinastatin at 5 mg / kg (2.0 ± 0.82) in reversing pancreatic injury, edema, and neutrophil infiltration.

[0149] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A derivative of memantine, characterized in that, It has the structure shown in Equation A: Formula A; In formula A, R1 and R2 are independently selected from alkyl groups; the alkyl group has 1 to 3 carbon atoms; R3 is selected from 2-methylpropyl, (R)-2-methylpropyl, or (S)-2-methylpropyl; D is selected from -NH-.

2. The derivative of memantine according to claim 1, characterized in that The ammonium sappan derivative has any one of the structures shown in A-104 to A-106: 。 3. The method of preparing the memantine derivative according to any one of claims 1 to 2, characterized in that, Includes the following steps: (i) The compound with the structure shown in Formula 1, solid phosgene, organic base and organic solvent are mixed and subjected to a third acylation reaction to obtain an intermediate compound with the structure shown in Formula e; Formula 1; Formula e; (ii) The intermediate compound, the compound with the structure shown in Formula 4, an organic base and an organic solvent are mixed and subjected to a nucleophilic substitution reaction to obtain the compound with the structure shown in Formula c; Equation 4; Formula c; (iii) The compound with the structure shown in formula c, an acidic reagent, and an organic solvent are mixed to carry out a second deprotection reaction to obtain the compound with the structure shown in formula d; Formula d; (iv) In the presence of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and N,N-diisopropylethylamine, the compound with the structure shown in Formula d and the compound with the structure shown in Formula 3 were subjected to a fourth acylation reaction to obtain a memantine derivative having the structure shown in A. R3-COOH (Formula 3) 4. The production method according to claim 3, characterized by, In step (iii), the acidic reagent is a methanol solution of hydrogen chloride, an ethyl acetate solution of hydrogen chloride, or trifluoroacetic acid. In step (i), the organic base is triethylamine; In step (ii), the organic base is triethylamine.

5. The use of the memantine derivative according to any one of claims 1 to 2 or the memantine derivative prepared by the preparation method according to any one of claims 3 to 4 in the preparation of a medicament for treating soluble cyclooxide enzyme-mediated diseases.

6. Use according to claim 5, characterized in that, The diseases mediated by the soluble cyclooxygenase include inflammatory diseases, pain, cardiovascular diseases, neurodegenerative diseases, diabetes, diabetic complications, renal failure, chronic obstructive pulmonary disease, or pulmonary hypertension.

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