Ammonium manganese derivatives, their synthesis methods and applications

Abstract

This invention belongs to the technical field of drug synthesis, specifically relating to memantine derivatives, their synthetic methods, and applications. The memantine derivatives include intermediate structural formulas I, II, and III, as well as a general structural formula. The linker is a substituted or unsubstituted C6-C10 aryl group, R1 is hydrogen or a C1-C6 alkyl group, and R2 is hydrogen, a C1-C6 alkyl group, or a nitrogen-containing or nitrogen-free structural fragment, or the overall structure of R1 and R2 is an N-substituted heterocyclopentyl or heterocyclohexyl group. The memantine derivatives provided by this invention improve drug activity by combining the memantine group with the OAB-14 partial structure, thereby altering the core structure. This invention also provides a synthetic method for the obtained compounds used in the treatment of Alzheimer's disease and Parkinson's disease.

Description

Technical Field

[0001] This invention belongs to the technical field of drug synthesis, specifically relating to memantine derivatives, their synthesis methods, and applications. Background Technology

[0002] Alzheimer's disease and Parkinson's disease are neurodegenerative diseases that severely impact the quality of life of the elderly, and currently there is no cure. Memantine is a moderate-affinity N-methyl-D-aspartate (NMDA) receptor antagonist, widely used as an excitatory amino acid receptor antagonist in the treatment of moderate to severe Alzheimer's disease. Its mechanism of action involves antagonizing NMDA receptors, regulating pathological glutamate neurotransmitter transmission, thereby improving memory processes and producing neuroprotective effects. Clinical studies have shown that memantine not only significantly improves cognitive and behavioral abilities in AD patients but also exhibits good tolerability. Furthermore, studies have found that memantine can directly stimulate dopamine receptors and promote dopamine release, and therefore it is also used to treat Parkinson's syndrome. Particularly in the treatment of Parkinson's disease, memantine hydrochloride combined with conventional therapy has shown significant efficacy, but its widespread application is limited due to insufficient relevant clinical research data.

[0003] The chemical name of memantine hydrochloride is 1-amino-3,5-dimethyladamantaneamine hydrochloride, and its structural formula is [insert structural formula here]. .

[0004] OAB-14 has the chemical name 4-(3-(2-aminoethyl)ureido)-N-(1,1,4,4,5,5,8,8-octamethyl-1,2,3,4,5,6,7,8-octahydroanthracene-9-yl)benzamide, and its structural formula is: Preclinical studies have confirmed that OAB-14 exhibits significant neuroprotective activity and cognitive function improvement, and its mechanism of action may transcend traditional single-target strategies, providing new possibilities for the treatment of Alzheimer's disease.

[0005] Although both memantine and OAB-14 have shown therapeutic potential, no studies have yet combined the structural advantages of memantine with those of OAB-14 to develop novel derivatives with synergistic or enhancing effects. Summary of the Invention

[0006] The technical problem this invention aims to solve is to overcome the aforementioned deficiencies in the prior art and provide a memantine derivative by combining the memantine group with a portion of the OAB-14 structural group, thereby altering the core structure and improving drug activity. This invention also provides a method for its synthesis. The memantine derivative synthesized by this invention can be used for the synergistic treatment of Parkinson's disease and Alzheimer's disease, enhancing its drug development potential.

[0007] The derivatives of methimazole described in this invention include intermediate structural formula I. Intermediate structure formula II Intermediate structure formula III and structural formula The linker is a substituted or unsubstituted C6-C10 aryl group, R1 is hydrogen or a C1-C6 alkyl group, and R2 is hydrogen, a C1-C6 alkyl group, or a nitrogen-containing or nitrogen-free structural segment, or the overall structure of R1 and R2 is an N-substituted heterocyclic pentyl or heterocyclic hexyl group. The preferred structure of the linker is... The substituted groups described in Linker are one or more of the following: C1-C6 alkyl, halogen, amino, nitro, mercapto, sulfide, sulfone, sulfoxide, and oxoalkyl.

[0008] Preferably, the NR1R2 structure is as follows: , , .

[0009] Preferably, the NR1R2 structure is as follows:

[0010] .

[0011] The memantine derivatives of the present invention are: N-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)-4-ureobenzamide, N-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)-4-(3-methylurea)benzamide, N-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)-4-(3-ethylurea)benzamide, N-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)-4-(3-(2-hydroxyethyl)urea)benzamide, N-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)-4-(3- (3-hydroxypropyl)urea)benzamide, N-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)-4-(3-(4-hydroxybutyl)urea)benzamide, 4-(3-(2-(diethylamine)ethyl)urea)-N-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)benzamide, 4-(3-(3-(diethyl)propyl)urea)-N-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)benzamide, N-((1)-3-(2-(diethylamine)ethyl)urea ...1)-3-(2-(diethylamine)ethyl)urea)benzamide, N-(1)-3-(2-(diethylamine)ethyl)urea)benzamide, N-(1)-3-(2-(diethylamine)ethyl)urea)benzamide, N-(1)-3-(2-(diethylamine)ethyl)urea)benzamide, N-(1)-3-(2-(diethylamine)ethyl)urea)benzamide, N-( r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)-4-(3-propylurea)benzamide, 4-(3,3-diethylurea)-N-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)benzamide, N-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)-4-(3,3-dimethylurea)benzamide, N-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)-4-(3-phenylurea)benzamide, N-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)-4-(3-(2-morpholinylethyl)urea)benzamide Formamide, N-(4-(((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)carbamoyl)phenyl)tetrahydrothiazolyl-3-carboxamide, N-(4-(((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)carbamoyl)phenyl)pyrrolidine-1-carboxamide, 4-(3-cyclohexylurea)-N-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)benzamide, N-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)benzamide, N-((1r,3R,5S,7r)-3,5-Dimethyladamantane-1-yl)-4-(3-(3-(4-methylpiperazin-1-yl)propyl)urea)benzamide, N-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)-4-(3-(2-(piperidin-1-yl)ethyl)urea)benzamide, N-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)-4-(3-(3-propylmorpholine)urea)benzamide, N-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)-4-(3-(3-(pyrrolidine-1-yl)propyl)urea)benzamide, N-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl) -4-(3-(3-(dimethylamine)propyl)urea)benzamide, N-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)-4-(3-(2-(4-methylpiperazin-1-yl)ethyl)urea)benzamide, N-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)-4-(3-(2-(pyrrolidine-1-yl)ethyl)urea)benzamide, N-(4-(((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)carbamoyl)phenyl)morpholine-4-carboxamide, 4-(3-cyclopropylurea)-N-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)benzamide.

[0012] The method for synthesizing the memantine derivative includes the following steps: adding p-nitrobenzoyl chloride to memantine hydrochloride, reacting in a solvent at 0-10°C under nitrogen protection, then adding a mixture of triethylamine and solvent, and continuing the reaction at room temperature. The resulting reaction solution is then post-treated to obtain intermediate structural formula I, namely memantine-OAB-1.

[0013] The obtained memantine-OAB-1 was mixed with palladium on carbon and an organic solvent and reacted. After post-treatment, the reaction solution was used to obtain intermediate structure II, namely memantine-OAB-2.

[0014] Phenyl chloroformate, potassium carbonate, and an organic solvent were added to the obtained memantine-OAB-2, and the mixture was refluxed. After post-treatment, intermediate structure III, namely memantine-OAB-3, was obtained.

[0015] An amino-substituted raw material, triethylamine, and solvent were added to the obtained memantine-OAB-3, and the mixture was refluxed. After post-treatment, the memantine-OAB- derivative was obtained.

[0016] The amino-substituted raw materials are ammonia, methylamine, ethylamine, ethanolamine, 3-aminopropanol, 4-aminobutanol, N,N-diethylethylenediamine, 3-diethylaminopropylamine, N,N-dimethylethylenediamine, n-propylamine, diethylamine, aniline, 4-(2-aminoethyl)morpholine, pyrrolidine, cyclohexylamine, 3-(piperidin-1-yl)propyl-1-amine, 1-(3-aminopropyl)-4-methylpiperazine, 1-(2-aminoethyl)piperidine, N-(3-aminopropyl)morpholine, 1-(3-aminopropyl)pyrrolidine, 3-dimethylaminopropylamine, 1-(2-aminoethyl)pyrrolidine, 4-methyl-1-piperazine ethylamine, morpholine, or cyclopropylamine.

[0017] Applications of the aforementioned memantine derivatives: They are used in the preparation of drugs for treating Alzheimer's disease and Parkinson's disease.

[0018] The synthetic route of the compounds of this invention is as follows, wherein the linker is benzoyl, the starting material is memantine hydrochloride, and the memantine-OAB derivative is obtained through acylation, reduction, acylation, and substitution reactions. The synthetic route is as follows:

[0019] .

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] (1) This invention creatively designs and synthesizes a series of novel memantine derivatives. Through a designable linker, the adamantane structural unit of memantine and the benzamide urea structural unit of OAB-14 are covalently integrated into a molecule to form a novel chemical entity.

[0022] (2) This invention optimizes the lead compound through systematic structural modification. By changing the properties of the linker and the structural fragment of the R3 site, the lipid-water partition coefficient, molecular rigidity, and interaction with the target site of the target compound can be finely adjusted.

[0023] (3) This invention provides a simple, mild, high-yield, and widely applicable synthetic method. This synthetic route uses readily available memantine hydrochloride as a starting material and, through efficient and classic reaction steps such as acylation, reduction, reacylation, and nucleophilic substitution, can rapidly and efficiently construct a library of target derivatives. The reagents and solvents used in this method are conventional, and the reaction conditions are easy to control. Attached Figure Description

[0024] Figure 1 The HPLC chromatogram of Amethyst-OAB-1 in Example 1 is shown below.

[0025] Figure 2 The HPLC chromatogram of Amethyst-OAB-2 in Example 2 is shown below.

[0026] Figure 3 The HPLC chromatogram of Amethyst-OAB-3 in Example 3 is shown below.

[0027] Figure 4 The HPLC chromatogram of Amethyst-OAB-4 in Example 4 is shown below.

[0028] Figure 5 The HPLC chromatogram of Amethyst-OAB-6 in Example 5 is shown below.

[0029] Figure 6 The HPLC chromatogram of Amethyst-OAB-7 in Example 6 is shown below.

[0030] Figure 7 The HPLC chromatogram of Amethyst-OAB-8 in Example 7 is shown below.

[0031] Figure 8 The HPLC chromatogram of Amethyst-OAB-9 in Example 8 is shown below.

[0032] Figure 9 The HPLC chromatogram of Amethyst-OAB-10 in Example 9 is shown below.

[0033] Figure 10 The HPLC chromatogram of Amethyst-OAB-11 in Example 10 is shown below.

[0034] Figure 11 The HPLC chromatogram of Amethyst-OAB-12 in Example 11 is shown below.

[0035] Figure 12 The HPLC chromatogram of Amethyst-OAB-13 in Example 12 is shown below.

[0036] Figure 13 The HPLC chromatogram of Amethyst-OAB-15 in Example 13 is shown below.

[0037] Figure 14 The HPLC chromatogram of Amethyst-OAB-16 in Example 14 is shown below.

[0038] Figure 15 The HPLC chromatogram of Amethyst-OAB-17 in Example 15 is shown below.

[0039] Figure 16 The HPLC chromatogram of Amethyst-OAB-18 in Example 16 is shown below.

[0040] Figure 17 The HPLC chromatogram of Amethyst-OAB-19 in Example 17 is shown below.

[0041] Figure 18 The HPLC chromatogram of Amethyst-OAB-20 in Example 18 is shown below.

[0042] Figure 19 The HPLC chromatogram of Amethyst-OAB-21 in Example 19 is shown below.

[0043] Figure 20 The HPLC chromatogram of Amethyst-OAB-22 in Example 20 is shown below.

[0044] Figure 21 The HPLC chromatogram of Amethyst-OAB-23 in Example 21 is shown below.

[0045] Figure 22 The HPLC chromatogram of Amethyst-OAB-24 in Example 22 is shown below.

[0046] Figure 23 The HPLC chromatogram of Amethyst-OAB-25 in Example 23 is shown below.

[0047] Figure 24 The HPLC chromatogram of Amethyst-OAB-26 in Example 24 is shown below.

[0048] Figure 25 The HPLC chromatogram of Amethyst-OAB-27 in Example 25 is shown below.

[0049] Figure 26 The HPLC chromatogram of Amethyst-OAB-28 in Example 26 is shown below.

[0050] Figure 27 The HPLC chromatogram of Amethyst-OAB-29 in Example 27 is shown below.

[0051] Figure 28 The HPLC chromatogram of Amethyst-OAB-30 in Example 28 is shown below.

[0052] Figure 29 The HPLC chromatogram of Amethyst-OAB-34 in Example 29 is shown below.

[0053] Figure 30 The HPLC chromatogram of Amethyst-OAB-35 in Example 30 is shown below.

[0054] Figure 31 Example 1: Memantine-OAB-1 1 H NMR spectrum;

[0055] Figure 32 Example 1: Memantine-OAB-1 13 C NMR spectrum;

[0056] Figure 33 Example 1: COSY spectrum of methimazole-OAB-1;

[0057] Figure 34Example 1: DEPT135 spectrum of Amanita muscaria-OAB-1;

[0058] Figure 35 Example 1: HMBC spectrum of Amanita muscaria-OAB-1;

[0059] Figure 36 Example 1: HSQC spectrum of Amethyst-OAB-1;

[0060] Figure 37 Example 1: High-resolution mass spectrum of methimazole-OAB-1;

[0061] Figure 38 Example 2: Memantine-OAB-2 1 HNMR spectrum;

[0062] Figure 39 Example 2: Memantine-OAB-2 13 CNMR spectrum;

[0063] Figure 40 Example 2: COSY spectrum of methimazole-OAB-2;

[0064] Figure 41 Example 2: DEPT135 spectrum of Amanita muscaria-OAB-2;

[0065] Figure 42 Example 2: HMBC spectrum of Amanita muscaria-OAB-2;

[0066] Figure 43 Example 2: HSQC spectrum of Amanita muscaria-OAB-2;

[0067] Figure 44 Example 2: High-resolution mass spectrum of methimazole-OAB-2;

[0068] Figure 45 Example 3: Memantine-OAB-3 1 HNMR spectrum;

[0069] Figure 46 Example 3: Memantine-OAB-3 13 CNMR spectrum;

[0070] Figure 47 Example 3: COSY spectrum of methimazole-OAB-3;

[0071] Figure 48 Example 3: DEPT135 spectrum of Amanita muscaria-OAB-3;

[0072] Figure 49 Example 3: HMBC spectrum of Amanita muscaria-OAB-3;

[0073] Figure 50 Example 3: HSQC spectrum of Amethyst-OAB-3;

[0074] Figure 51 Example 3: High-resolution mass spectrum of methimazole-OAB-3;

[0075] Figure 52 Example 4: Memantine-OAB-4 1 HNMR spectrum;

[0076] Figure 53 Example 4: Memantine-OAB-4 13 CNMR spectrum;

[0077] Figure 54 Example 4: COSY spectrum of methimazole-OAB-4;

[0078] Figure 55 Example 4: DEPT135 spectrum of Amanita muscaria-OAB-4;

[0079] Figure 56 Example 4: HMBC spectrum of Amanita muscaria-OAB-4;

[0080] Figure 57 Example 4: HSQC spectrum of Amethyst-OAB-4;

[0081] Figure 58 Example 4: High-resolution mass spectrum of methimazole-OAB-4;

[0082] Figure 59 Example 5: Amaminol-OAB-6 1 HNMR spectrum;

[0083] Figure 60 Example 5: Amaminol-OAB-6 13 CNMR spectrum;

[0084] Figure 61 Example 5: COSY spectrum of Amanita-OAB-6;

[0085] Figure 62 Example 5: DEPT135 spectrum of Amanita muscaria-OAB-6;

[0086] Figure 63 Example 5: HMBC spectrum of Amanita muscaria-OAB-6;

[0087] Figure 64 Example 5: HSQC spectrum of Amethyst-OAB-6;

[0088] Figure 65Example 5: High-resolution mass spectrum of methimazole-OAB-6;

[0089] Figure 66 Example 6: Memantine-OAB-7 1 H NMR spectrum;

[0090] Figure 67 Example 6: Memantine-OAB-7 13 CNMR spectrum;

[0091] Figure 68 Example 6: COSY spectrum of Amanita-OAB-7;

[0092] Figure 69 Example 6: DEPT135 spectrum of Amanita muscaria-OAB-7;

[0093] Figure 70 Example 6: HMBC spectrum of Amanita muscaria-OAB-7;

[0094] Figure 71 Example 6: HSQC spectrum of Amanita muscaria-OAB-7;

[0095] Figure 72 Example 6: High-resolution mass spectrum of Amethyst-OAB-7;

[0096] Figure 73 Example 7: Memantine-OAB-8 1 HNMR spectrum;

[0097] Figure 74 Example 7: Memantine-OAB-8 13 CNMR spectrum;

[0098] Figure 75 Example 7: COSY spectrum of Amethyst-OAB-8;

[0099] Figure 76 Example 7: DEPT135 spectrum of Amanita muscaria-OAB-8;

[0100] Figure 77 Example 7: HMBC spectrum of Amethyst-OAB-8;

[0101] Figure 78 Example 7: HSQC spectrum of Amethyst-OAB-8;

[0102] Figure 79 Example 7: High-resolution mass spectrum of Amanita muscaria-OAB-8;

[0103] Figure 80 Example 8: Amethyst-OAB-9 1 HNMR spectrum;

[0104] Figure 81 Example 8: Amethyst-OAB-9 13 CNMR spectrum;

[0105] Figure 82 Example 8: COSY spectrum of Amanita-OAB-9;

[0106] Figure 83 Example 8: DEPT135 spectrum of Amanita muscaria-OAB-9;

[0107] Figure 84 Example 8: HMBC spectrum of Amethyst-OAB-9;

[0108] Figure 85 Example 8: HSQC spectrum of Amethyst-OAB-9;

[0109] Figure 86 Example 8: High-resolution mass spectrum of methimazole-OAB-9;

[0110] Figure 87 Example 9: Amamin-OAB-10 1 HNMR spectrum;

[0111] Figure 88 Example 9: Amamin-OAB-10 13 CNMR spectrum;

[0112] Figure 89 Example 9: COSY spectrum of Amanita muscaria-OAB-10;

[0113] Figure 90 Example 9: DEPT135 spectrum of Amanita muscaria-OAB-10;

[0114] Figure 91 Example 9: HMBC spectrum of Amanita muscaria-OAB-10;

[0115] Figure 92 Example 9: HSQC spectrum of Amethyst-OAB-10;

[0116] Figure 93 Example 9: High-resolution mass spectrum of Amethyst-OAB-10;

[0117] Figure 94 Example 10: Amamin-OAB-11 1 HNMR spectrum;

[0118] Figure 95 Example 10: Amamin-OAB-11 13 CNMR spectrum;

[0119] Figure 96 Example 10: COSY spectrum of Amanita muscaria-OAB-11;

[0120] Figure 97 Example 10: DEPT135 spectrum of Amanita muscaria-OAB-11;

[0121] Figure 98 Example 10: HMBC spectrum of Amanita muscaria-OAB-11;

[0122] Figure 99 Example 10: HSQC spectrum of Amethyst-OAB-11;

[0123] Figure 100 Example 10: High-resolution mass spectrum of Amethyst-OAB-11;

[0124] Figure 101 Example 11: Memantine-OAB-12 1 HNMR spectrum;

[0125] Figure 102 Example 11: Memantine-OAB-12 13 CNMR spectrum;

[0126] Figure 103 Example 11: COSY spectrum of Amanita muscaria-OAB-12;

[0127] Figure 104 Example 11: DEPT135 spectrum of Amanita muscaria-OAB-12;

[0128] Figure 105 Example 11: HMBC spectrum of Amanita muscaria-OAB-12;

[0129] Figure 106 Example 11: HSQC spectrum of Amanita muscaria-OAB-12;

[0130] Figure 107 Example 11: High-resolution mass spectrum of Amanita murine-OAB-12;

[0131] Figure 108 Example 12: Amamin-OAB-13 1 HNMR spectrum;

[0132] Figure 109 Example 12: Amamin-OAB-13 13 CNMR spectrum;

[0133] Figure 110 Example 12: COSY spectrum of Amanita melanin-OAB-13;

[0134] Figure 111 Example 12: DEPT135 spectrum of Amanita muscaria-OAB-13;

[0135] Figure 112 Example 12: HMBC spectrum of Amanita muscaria-OAB-13;

[0136] Figure 113 Example 12: HSQC spectrum of Amanita muscaria-OAB-13;

[0137] Figure 114 Example 12: High-resolution mass spectrum of Amanita muscaria-OAB-13;

[0138] Figure 115 Example 13: Amamin-OAB-15 1 HNMR spectrum;

[0139] Figure 116 Example 13: Amamin-OAB-15 13 CNMR spectrum;

[0140] Figure 117 Example 13: COSY spectrum of Amaton-OAB-15;

[0141] Figure 118 Example 13: DEPT135 spectrum of Amanita muscaria-OAB-15;

[0142] Figure 119 Example 13: HMBC spectrum of Amaton-OAB-15;

[0143] Figure 120 Example 13: HSQC spectrum of Amethyst-OAB-15;

[0144] Figure 121 Example 13: High-resolution mass spectrum of Amanita muscaria-OAB-15;

[0145] Figure 122 Example 14: Amaton-OAB-16 1 HNMR spectrum;

[0146] Figure 123 Example 14: Amaton-OAB-16 13 CNMR spectrum;

[0147] Figure 124 Example 14: COSY spectrum of Amanita-OAB-16;

[0148] Figure 125 Example 14: DEPT135 spectrum of Amanita muscaria-OAB-16;

[0149] Figure 126Example 14: HMBC spectrum of Amanita muscaria-OAB-16;

[0150] Figure 127 Example 14: HSQC spectrum of Amanita muscaria-OAB-16;

[0151] Figure 128 Example 14: High-resolution mass spectrum of Amanita murine-OAB-16;

[0152] Figure 129 Example 15: Amamin-OAB-17 1 HNMR spectrum;

[0153] Figure 130 Example 15: Amamin-OAB-17 13 CNMR spectrum;

[0154] Figure 131 Example 15: COSY spectrum of Amanita-OAB-17;

[0155] Figure 132 Example 15: DEPT135 spectrum of Amanita muscaria-OAB-17;

[0156] Figure 133 Example 15: HMBC spectrum of Amanita muscaria-OAB-17;

[0157] Figure 134 Example 15: HSQC spectrum of Amethyst-OAB-17;

[0158] Figure 135 Example 15: High-resolution mass spectrum of Amanita muscaria-OAB-17;

[0159] Figure 136 Example 16: Amamin-OAB-18 1 HNMR spectrum;

[0160] Figure 137 Example 16: Amamin-OAB-18 13 CNMR spectrum;

[0161] Figure 138 Example 16: COSY spectrum of Amanita-OAB-18;

[0162] Figure 139 Example 16: DEPT135 spectrum of Amanita muscaria-OAB-18;

[0163] Figure 140 Example 16: HMBC spectrum of Amanita muscaria-OAB-18;

[0164] Figure 141Example 16: HSQC spectrum of Amanita muscaria-OAB-18;

[0165] Figure 142 Example 16: High-resolution mass spectrum of Amanita muscaria-OAB-18;

[0166] Figure 143 Example 17: Amaton-OAB-19 1 HNMR spectrum;

[0167] Figure 144 Example 17: Amaton-OAB-19 13 CNMR spectrum;

[0168] Figure 145 Example 17: COSY spectrum of Amanita-OAB-19;

[0169] Figure 146 Example 17: DEPT135 spectrum of Amanita muscaria-OAB-19;

[0170] Figure 147 Example 17: HMBC spectrum of Amanita muscaria-OAB-19;

[0171] Figure 148 Example 17: HSQC spectrum of Amanita muscaria-OAB-19;

[0172] Figure 149 Example 17: High-resolution mass spectrum of Amanita murine-OAB-19;

[0173] Figure 150 Example 18: Amamin-OAB-20 1 HNMR spectrum;

[0174] Figure 151 Example 18: Amamin-OAB-20 13 CNMR spectrum;

[0175] Figure 152 Example 18: COSY spectrum of Amaton-OAB-20;

[0176] Figure 153 Example 18: DEPT135 spectrum of Amanita muscaria-OAB-20;

[0177] Figure 154 Example 18: HMBC spectrum of Amanita muscaria-OAB-20;

[0178] Figure 155 Example 18: HSQC spectrum of Amanita muscaria-OAB-20;

[0179] Figure 156Example 18: High-resolution mass spectrum of Amanita muscaria-OAB-20;

[0180] Figure 157 Example 19: Amanita Mucosa-OAB-21 1 HNMR spectrum;

[0181] Figure 158 Example 19: Amanita Mucosa-OAB-21 13 CNMR spectrum;

[0182] Figure 159 Example 19: COSY spectrum of Amanita muscaria-OAB-21;

[0183] Figure 160 Example 19: DEPT135 spectrum of Amanita muscaria-OAB-21;

[0184] Figure 161 Example 19: HMBC spectrum of Amanita muscaria-OAB-21;

[0185] Figure 162 Example 19: HSQC spectrum of Amanita muscaria-OAB-21;

[0186] Figure 163 Example 19: High-resolution mass spectrum of Amanita muscaria-OAB-21;

[0187] Figure 164 Example 20: Amethyst-OAB-22 1 HNMR spectrum;

[0188] Figure 165 Example 20: Amethyst-OAB-22 13 CNMR spectrum;

[0189] Figure 166 Example 20: COSY spectrum of Amethyst-OAB-22;

[0190] Figure 167 Example 20: DEPT135 spectrum of Amanita muscaria-OAB-22;

[0191] Figure 168 Example 20: HMBC spectrum of Amethyst-OAB-22;

[0192] Figure 169 Example 20: HSQC spectrum of Amethyst-OAB-22;

[0193] Figure 170 Example 20: High-resolution mass spectrum of Amethyst-OAB-22;

[0194] Figure 171Example 21: Memantine-OAB-23 1 HNMR spectrum;

[0195] Figure 172 Example 21: Memantine-OAB-23 13 CNMR spectrum;

[0196] Figure 173 Example 21: COSY spectrum of Amanita melanin-OAB-23;

[0197] Figure 174 Example 21: DEPT135 spectrum of Amanita muscaria-OAB-23;

[0198] Figure 175 Example 21: HMBC spectrum of Amanita muscaria-OAB-23;

[0199] Figure 176 Example 21: HSQC spectrum of Amanita muscaria-OAB-23;

[0200] Figure 177 Example 21: High-resolution mass spectrum of Amanita murine-OAB-23;

[0201] Figure 178 Example 22: Amanita Mucosa-OAB-24 1 HNMR spectrum;

[0202] Figure 179 Example 22: Amanita Mucosa-OAB-24 13 CNMR spectrum;

[0203] Figure 180 Example 22: COSY spectrum of Amanita-OAB-24;

[0204] Figure 181 Example 22: DEPT135 spectrum of Amanita muscaria-OAB-24;

[0205] Figure 182 Example 22: HMBC spectrum of Amanita muscaria-OAB-24;

[0206] Figure 183 Example 22: HSQC spectrum of Amanita muscaria-OAB-24;

[0207] Figure 184 Example 22: High-resolution mass spectrum of Amanita murine-OAB-24;

[0208] Figure 185 Example 23: Amamin-OAB-25 1 HNMR spectrum;

[0209] Figure 186Example 23: Amamin-OAB-25 13 CNMR spectrum;

[0210] Figure 187 Example 23: COSY spectrum of Amanita-OAB-25;

[0211] Figure 188 Example 23: DEPT135 spectrum of Amanita muscaria-OAB-25;

[0212] Figure 189 Example 23: HMBC spectrum of Amaton-OAB-25;

[0213] Figure 190 Example 23: HSQC spectrum of Amethyst-OAB-25;

[0214] Figure 191 Example 23: High-resolution mass spectrum of Amethyst-OAB-25;

[0215] Figure 192 Example 24: Amaton-OAB-26 1 HNMR spectrum;

[0216] Figure 193 Example 24: Amaton-OAB-26 13 CNMR spectrum;

[0217] Figure 194 Example 24: COSY spectrum of Amanita-OAB-26;

[0218] Figure 195 Example 24: DEPT135 spectrum of Amanita muscaria-OAB-26;

[0219] Figure 196 Example 24: HMBC spectrum of Amanita muscaria-OAB-26;

[0220] Figure 197 Example 24: HSQC spectrum of Amanita muscaria-OAB-26;

[0221] Figure 198 Example 24: High-resolution mass spectrum of Amethyst-OAB-26;

[0222] Figure 199 Example 25: Amamin-OAB-27 1 HNMR spectrum;

[0223] Figure 200 Example 25: Amamin-OAB-27 13 CNMR spectrum;

[0224] Figure 201Example 25: COSY spectrum of Amanita muscaria-OAB-27;

[0225] Figure 202 Example 25: DEPT135 spectrum of Amanita muscaria-OAB-27;

[0226] Figure 203 Example 25: HMBC spectrum of Amanita muscaria-OAB-27;

[0227] Figure 204 Example 25: HSQC spectrum of Amanita murine-OAB-27;

[0228] Figure 205 Example 25: High-resolution mass spectrum of Amanita murine-OAB-27;

[0229] Figure 206 Example 26: Amamin-OAB-28 1 HNMR spectrum;

[0230] Figure 207 Example 26: Amamin-OAB-28 13 CNMR spectrum;

[0231] Figure 208 Example 26: COSY spectrum of Amanita melanin-OAB-28;

[0232] Figure 209 Example 26: DEPT135 spectrum of Amanita muscaria-OAB-28;

[0233] Figure 210 Example 26: HMBC spectrum of Amaton-OAB-28;

[0234] Figure 211 Example 26: HSQC spectrum of Amanita muscaria-OAB-28;

[0235] Figure 212 Example 26: High-resolution mass spectrum of Amanita muscaria-OAB-28;

[0236] Figure 213 Example 27: Amaton-OAB-29 1 HNMR spectrum;

[0237] Figure 214 Example 27: Amaton-OAB-29 13 CNMR spectrum;

[0238] Figure 215 Example 27: COSY spectrum of Amanita muscaria-OAB-29;

[0239] Figure 216Example 27: DEPT135 spectrum of Amanita muscaria-OAB-29;

[0240] Figure 217 Example 27: HMBC spectrum of Amanita muscaria-OAB-29;

[0241] Figure 218 Example 27: HSQC spectrum of Amanita muscaria-OAB-29;

[0242] Figure 219 Example 27: High-resolution mass spectrum of Amanita murine-OAB-29;

[0243] Figure 220 Example 28: Amamin-OAB-30 1 HNMR spectrum;

[0244] Figure 221 Example 28: Amamin-OAB-30 13 CNMR spectrum;

[0245] Figure 222 Example 28: COSY spectrum of Amethyst-OAB-30;

[0246] Figure 223 Example 28: DEPT135 spectrum of Amanita muscaria-OAB-30;

[0247] Figure 224 Example 28: HMBC spectrum of Amanita muscaria-OAB-30;

[0248] Figure 225 Example 28: HSQC spectrum of Amaton-OAB-30;

[0249] Figure 226 Example 28: High-resolution mass spectrum of Amethyst-OAB-30;

[0250] Figure 227 Example 29: Amaton-OAB-34 1 HNMR spectrum;

[0251] Figure 228 Example 29: Amaton-OAB-34 13 CNMR spectrum;

[0252] Figure 229 Example 29: COSY spectrum of Amanita-OAB-34;

[0253] Figure 230 Example 29: DEPT135 spectrum of Amanita muscaria-OAB-34;

[0254] Figure 231Example 29: HMBC spectrum of Amanita muscaria-OAB-34;

[0255] Figure 232 Example 29: HSQC spectrum of Amanita-OAB-34;

[0256] Figure 233 Example 29: High-resolution mass spectrum of Amethyst-OAB-35;

[0257] Figure 234 Example 30: Amamin-OAB-35 1 HNMR spectrum;

[0258] Figure 235 Example 30: Amamin-OAB-35 13 CNMR spectrum;

[0259] Figure 236 Example 30: COSY spectrum of Amethyst-OAB-35;

[0260] Figure 237 Example 30: DEPT135 spectrum of Amethyst-OAB-35;

[0261] Figure 238 Example 30: HMBC spectrum of Amethyst-OAB-35;

[0262] Figure 239 Example 30: HSQC spectrum of Amethyst-OAB-35;

[0263] Figure 240 Example 30: High-resolution mass spectrum of Amethyst-OAB-35. Detailed Implementation

[0264] The present invention will be further described below with reference to specific embodiments. Unless otherwise specified, the raw materials used in the following embodiments are all commercially available analytical grade. The room temperature refers to 20~25℃.

[0265] Memantine Hydrochloride: Shanghai Huyuan Pharmaceutical Co., Ltd., content 100.0%, batch number 2002004462.

[0266] p-Nitrobenzoyl chloride: Shandong Kaisheng New Materials Co., Ltd., content 99%, batch number DX22308-10-66.

[0267] Palladium on carbon: Shaanxi Kaida Chemical Co., Ltd., water content 60%, palladium content 10%, batch number 102M191211.

[0268] Phenyl chloroformate: Xinyi Yongcheng Chemical, content 99%, batch number 202005006.

[0269] The ice bath cooling described below to 0~10℃ (5~10℃) will not be recorded separately; it is sufficient to detect that the temperature has dropped to this range. Furthermore, the naming of the adamantane derivatives in each of the following examples (e.g., Ammanite-OAB-1) is entirely our own designation, and the numbers following them have no special meaning.

[0270] Regarding the high-resolution mass spectra of the adamantaneamine derivatives prepared in Examples 1 to 30, as follows: Figure 37 , 44 As shown in Figures 51, 58, 65, 72, 79, 86, 93, 100, 107, 114, 121, 128, 135, 142, 149, 156, 163, 170, 177, 184, 191, 198, 205, 212, 219, 226, 233, and 240, the upper part of the figure is a particle flow diagram, and the lower part is a bar graph.

[0271] Example 1

[0272] N -((1 r ,3 R 5 S 7 r Preparation of 3,5-dimethyladamantane-1-yl)-4-nitrobenzamide (Memantine-OAB-1):

[0273]

[0274] Ammonium Sildenafil-OAB-1, 328.41

[0275] Add 215.8 g (1 mol) of memantine hydrochloride, 213.2 g (1.15 mol) of p-nitrobenzoyl chloride, and 1500 mL of dichloromethane to a 1000 mL three-necked flask. Under nitrogen protection, cool in an ice bath to 0–10 °C. Then, add a mixture of 253 g (0.25 mol) of triethylamine and 250 mL of dichloromethane dropwise, controlling the addition to be completed within 1 hour. Stir overnight at room temperature. Determine the reaction endpoint using a 5:1 (volume ratio) petroleum ether:ethyl acetate TLC. Pour the reaction solution into a 5000 mL separatory funnel. In a liquid funnel, 1000 mL of DCM and 2000 mL of water were added, and the pH was adjusted to 2 (80 mL) with 10% HCl. The mixture was allowed to separate into layers, and then washed with 1000 mL each of saturated NaHCO3 and saturated NaCl. The organic layer was collected in an Erlenmeyer flask, dried with anhydrous MgSO4 for 1 h, filtered, and then rotary evaporated to dryness. The solution was then slurried with a 5:1 (v / v) mixture of petroleum ether and ethyl acetate for 0.5 h, filtered, and dried at 50 °C for 6 h to obtain 290.5 g of yellow needle-like crystals (HPLC 99.85%). Figure 1 As shown in Table 1, the chromatographic peak results show a yield of 88.46%.

[0276] Table 1 Chromatographic Peak Results

[0277]

[0278] (1) Nuclear magnetic resonance detection

[0279] Instrument model: Bruker NEO400M nuclear magnetic resonance spectrometer; Test conditions: DMSO- d 6; 298K; Test items: 1 H, 13 C, Dept135, COSY, HSQC, HMBC, detection spectra as follows Figures 31-36 As shown in Table 2, the test results are as follows.

[0280] Table 2 Detection Results

[0281]

[0282] (2) Mass spectrometry detection

[0283] Instrument: Waters, 2695; Mass spectrometer: QDA; Solvent: Methanol; Ionization method: ESI (+); Detection results are shown in Table 3, and the detection spectra are as follows. Figure 37 As shown.

[0284] Table 3 Mass spectrometry detection results

[0285]

[0286] Example 2

[0287] 4-Amino- N -((1 r ,3 R 5 S 7 r Preparation of 3,5-dimethyladamantane-1-yl)benzamide (Memantine-OAB-2):

[0288]

[0289] Ammonium Manganese OAB-2, 298.43

[0290] 80 g of the memantine-OAB-1 prepared in Example 1 was added to a 1000 mL autoclave, along with 32 g of 10 wt% palladium on carbon, and then 300 mL of LDM. The mixture was purged with hydrogen three times. After reacting at 30 °C and 3 kg pressure for 2 hours, hydrogen consumption ceased significantly. The reaction was complete by TLC after 16 hours. The palladium on carbon was recovered by filtration, and the filtrate was rotary evaporated to obtain 71.04 g of a white solid (HPLC 99.70%). Figure 2 As shown in Table 4, the chromatographic peak results show a yield of 97.43%.

[0291] Table 4 Chromatographic Peak Results

[0292]

[0293] (1) Nuclear magnetic resonance detection

[0294] Instrument model: Bruker NEO400M nuclear magnetic resonance spectrometer; Test conditions: DMSO- d 6; 298K; Test items: 1 H, 13 C, Dept135, COSY, HSQC, HMBC, detection spectra as follows Figures 38-43 As shown in Table 5, the test results are as follows.

[0295] Table 5 Test Results

[0296]

[0297] (2) Mass spectrometry detection

[0298] Instrument: Waters, 2695; Mass spectrometer: QDA; Solvent: Methanol; Ionization method: ESI (+); Detection results are shown in Table 6, and the detection spectra are as follows. Figure 44 As shown.

[0299] Table 6 Mass spectrometry detection results

[0300]

[0301] Example 3

[0302] Phenyl(4-(((1)) r ,3 R 5 S 7 r Preparation of 3,5-dimethyladamantane-1-yl)carbamoyl)phenyl)carbamate (memantine-OAB-3):

[0303]

[0304] Ammonium Manganese OAB-3, 418.54

[0305] 80 g of the memantine-OAB-2 prepared in Example 2 was added to a 100 mL four-necked flask, along with 95 g of phenyl chloroformate, 92.6 g of potassium carbonate, and 1500 mL of LDM. The mixture was refluxed overnight. After 20 h, the reaction was confirmed by TLC. 500 mL of purified water was added, and stirring was continued for 0.5 h. The mixture was then filtered, washed with 300 mL of water and 100 mL of dichloromethane, and dried at 60 °C overnight to obtain 91.81 g of an off-white solid (HPLC 99.12%). Figure 3As shown in Table 7, the chromatographic peak results show a yield of 81.35%.

[0306] Table 7 Chromatographic Peak Results

[0307]

[0308] (1) Nuclear magnetic resonance detection

[0309] Instrument model: Bruker NEO400M nuclear magnetic resonance spectrometer; Test conditions: DMSO- d 6; 298K; Test items: 1 H, 13 C, Dept135, COSY, HSQC, HMBC, detection spectra as follows Figures 45-50 As shown in Table 8, the test results are as follows.

[0310] Table 8 Test Results

[0311]

[0312] (2) Mass spectrometry detection

[0313] Instrument: Waters, 2695; Mass spectrometer: QDA; Solvent: Methanol; Ionization method: ESI (+); Detection results are shown in Table 9, and the detection spectra are as follows. Figure 51 As shown.

[0314] Table 9 Mass Spectrometry Detection Results

[0315]

[0316] Example 4

[0317] N -((1 r ,3 R 5 S 7 r Preparation of 3,5-dimethyladamantane-1-yl)-4-ureobenzamide (memantine-OAB-4):

[0318]

[0319] Memantine-OAB-4, 341.46

[0320] 3 g of memantine-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 7.94 g of ammonia, 2.32 g of triethylamine, and 50 mL of LDM. The mixture was heated to reflux and incubated for 8 hours. TLC showed no complete reaction, so the mixture was kept under reflux overnight. After overnight incubation, TLC confirmed the reaction was complete. The mixture was then cooled to 5-10 °C in an ice bath and allowed to crystallize for another 2 hours. After filtration, the crystals were dried under vacuum at 60 °C for 6 hours to obtain 2.20 g of memantine-OAB-4. HPLC accuracy was 99.92%. Figure 4 As shown in Table 10, the chromatographic peak results show a yield of 89.88%.

[0321] Table 10 Chromatographic Peak Results

[0322]

[0323] (1) Nuclear magnetic resonance detection

[0324] Instrument model: Bruker NEO400M nuclear magnetic resonance spectrometer; Test conditions: DMSO- d 6; 298K; Test items: 1 H, 13 C, Dept135, COSY, HSQC, HMBC, detection spectra as follows Figures 52-57 As shown in Table 11, the test results are as follows.

[0325] Table 11 Test Results

[0326]

[0327] (2) Mass spectrometry detection

[0328] Instrument: Waters, 2695; Mass spectrometer: QDA; Solvent: Methanol; Ionization method: ESI (+); Detection results are shown in Table 12, and the detection spectra are as follows. Figure 58 As shown.

[0329] Table 12 Mass Spectrometry Detection Results

[0330]

[0331] Example 5

[0332] N -((1 r ,3 R 5 S 7 r Preparation of 3,5-dimethyladamantane-1-yl)-4-(3-methylurea)benzamide (memantine-OAB-6):

[0333]

[0334] Memantine-OAB-6, 355.48

[0335] 5 g of the memantine-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 10 mL of 40 wt% methylamine aqueous solution, 3.86 g of triethylamine, and 50 mL of LDM. The mixture was heated to reflux and allowed to react for 5 hours. After TLC monitoring, the reaction was complete. The mixture was then cooled to 5–10 °C in an ice bath and allowed to continue cooling to allow crystallization for 2 hours. The crystals were filtered and dried at 60 °C and 0.08 MPa for 6 hours to obtain 3.81 g of a white solid. HPLC purity: 99.75%. Figure 5 As shown in Table 13, the chromatographic peak results show a yield of 89.72%.

[0336] Table 13 Chromatographic Peak Results

[0337]

[0338] (1) Nuclear magnetic resonance detection

[0339] Instrument model: Bruker NEO400M nuclear magnetic resonance spectrometer; Test conditions: DMSO- d 6; 298K; Test items: 1 H, 13 C, Dept135, COSY, HSQC, HMBC, detection spectra as follows Figures 59-64 As shown in Table 14, the test results are as follows.

[0340] Table 14 Test Results

[0341]

[0342] (2) Mass spectrometry detection

[0343] Instrument: Waters, 2695; Mass spectrometer: QDA; Solvent: Methanol; Ionization method: ESI (+); Detection results are shown in Table 15, and the detection spectra are as follows. Figure 65 As shown.

[0344] Table 15 Mass Spectrometry Detection Results

[0345]

[0346] Example 6

[0347] N -((1 r ,3 R 5 S 7 r Preparation of 3,5-dimethyladamantane-1-yl)-4-(3-ethylurea)benzamide (Memantine-OAB-7):

[0348]

[0349] Memantine-OAB-7, 369.51

[0350] 5 g of the memantine-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 10 mL of 40 wt% ethylamine aqueous solution, 3.86 g of triethylamine, and 50 mL of LCM. The mixture was heated to reflux and reacted under TLC for 5 hours. After the reaction was complete, the mixture was cooled to 5-10 °C in an ice bath and allowed to crystallize for another 2 hours. The crystals were then filtered, and the filter cake was dried at 60 °C and 0.08 MPa for 6 hours to obtain 4.28 g of a white solid. The HPLC accuracy was 99.84%. Figure 6 As shown in Table 16, the chromatographic peak results show a yield of 96.96%.

[0351] Table 16 Chromatographic Peak Results

[0352]

[0353] (1) Nuclear magnetic resonance detection

[0354] Instrument model: Bruker NEO400M nuclear magnetic resonance spectrometer; Test conditions: DMSO- d 6; 298K; Test items: 1 H, 13 C, Dept135, COSY, HSQC, HMBC, detection spectra as follows Figures 66-71 As shown in Table 17, the test results are as follows.

[0355] Table 17 Test Results

[0356]

[0357] (2) Mass spectrometry detection

[0358] Instrument: Waters, 2695; Mass spectrometer: QDA; Solvent: Methanol; Ionization method: ESI (+); Detection results are shown in Table 18, and the detection spectra are as follows. Figure 72 As shown.

[0359] Table 18 Mass Spectrometry Detection Results

[0360]

[0361] Example 7

[0362] N -((1 r ,3 R 5 S 7 r Preparation of 3,5-dimethyladamantane-1-yl)-4-(3-(2-hydroxyethyl)urea)benzamide (Memantine-OAB-8):

[0363]

[0364] Memantine-OAB-8, 385.51

[0365] 5 g of the memantine-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 1.1 g of aqueous ethanolamine solution, 2.42 g of triethylamine, and 30 mL of LDM. The mixture was then heated to reflux. After 5 hours, the reaction was monitored by TLC until complete. The mixture was then cooled to 5-10 °C in an ice bath and allowed to crystallize for another 2 hours. No solid precipitated. The mixture was concentrated, and 20 mL of saturated sodium carbonate was added and stirred for half an hour. The mixture was then filtered, washed with water, and dried at 60 °C and 0.08 MPa for 6 hours to obtain 4.54 g of a white solid. HPLC analysis showed 99.34% purity. Figure 7 As shown in Table 19, the chromatographic peak results show a yield of 98.58%.

[0366] Table 19 Chromatographic Peak Results

[0367]

[0368] (1) Nuclear magnetic resonance detection

[0369] Instrument model: Bruker NEO400M nuclear magnetic resonance spectrometer; Test conditions: DMSO- d 6; 298K; Test items: 1 H, 13 C, Dept135, COSY, HSQC, HMBC, detection spectra as follows Figures 73-78 As shown in Table 20, the test results are as follows.

[0370] Table 20 Test Results

[0371]

[0372] (3) Mass spectrometry detection

[0373] Instrument: Waters, 2695; Mass spectrometer: QDA; Solvent: Methanol; Ionization method: ESI (+); Detection results are shown in Table 21, and the detection spectra are as follows. Figure 79 As shown.

[0374] Table 21 Mass Spectrometry Detection Results

[0375]

[0376] Example 8

[0377] N -((1 r ,3 R 5 S 7r Preparation of 3,5-dimethyladamantane-1-yl)-4-(3-(3-hydroxypropyl)urea)benzamide (Memantine-OAB-9):

[0378]

[0379] Ammonium Sildenafil-OAB-9, 399.54

[0380] 4.19 g of memantine-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 3.76 g of 3-aminopropanol and 3.23 g of triethylamine, followed by 50 mL of LDM. The mixture was heated to reflux and allowed to react for 4 hours. After TLC monitoring, the reaction was complete. The mixture was then cooled to 5–10 °C in an ice bath and allowed to continue cooling for 2 hours to allow crystals to precipitate. The crystals were filtered, washed with 10 mL of dichloromethane, and dried at 60 °C and 0.08 MPa for 6 hours to obtain 2.14 g of a white solid (HPLC 99.62%). Figure 8 As shown in Table 22, the chromatographic peak results show a yield of 53.50%.

[0381] Table 22 Chromatographic Peak Results

[0382]

[0383] (1) Nuclear magnetic resonance detection

[0384] Instrument model: Bruker NEO400M nuclear magnetic resonance spectrometer; Test conditions: DMSO- d 6; 298K; Test items: 1 H, 13 C, Dept135, COSY, HSQC, HMBC, detection spectra as follows Figures 80-85 As shown in Table 23, the test results are as follows.

[0385] Table 23 Test Results

[0386]

[0387] (3) Mass spectrometry detection

[0388] Instrument: Waters, 2695; Mass spectrometer: QDA; Solvent: Methanol; Ionization method: ESI (+); Detection results are shown in Table 24, and the detection spectra are as follows. Figure 86 As shown.

[0389] Table 24 Mass Spectrometry Detection Results

[0390]

[0391] Example 9

[0392] N -((1r ,3 R 5 S 7 r Preparation of 3,5-dimethyladamantane-1-yl)-4-(3-(4-hydroxybutyl)urea)benzamide (Memantine-OAB-10):

[0393]

[0394] Ammonium Sildenafil-OAB-10, 413.56

[0395] 4.19 g of the memantine-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 4.46 g of 4-aminobutanol and 3.23 g of triethylamine. Then, 50 mL of LDM was added, and the mixture was heated to reflux. After 4 hours, the reaction was monitored by TLC until complete. The mixture was then cooled to 5–10 °C in an ice bath and allowed to crystallize for another 2 hours. The crystals were filtered, washed with 10 mL of dichloromethane, and dried at 60 °C and 0.08 MPa for 6 hours to obtain 3.61 g of an off-white solid. HPLC accuracy was 99.92%. Figure 9 As shown in Table 25, the chromatographic peak results show a yield of 87.29%.

[0396] Table 25 Chromatographic Peak Results

[0397]

[0398] (1) Nuclear magnetic resonance detection

[0399] Instrument model: Bruker NEO400M nuclear magnetic resonance spectrometer; Test conditions: DMSO- d 6; 298K; Test items: 1 H, 13 C, Dept135, COSY, HSQC, HMBC, detection spectra as follows Figures 87-92 As shown in Table 26, the test results are as follows.

[0400] Table 26 Test Results

[0401]

[0402] (2) Mass spectrometry detection

[0403] Instrument: Waters, 2695; Mass spectrometer: QDA; Solvent: Methanol; Ionization method: ESI (+); Detection results are shown in Table 27, and the detection spectra are as follows. Figure 93 As shown.

[0404] Table 27 Mass Spectrometry Detection Results

[0405]

[0406] Example 10

[0407] 4-(3-(2-(diethylamine)ethyl)urea)- N -((1 r ,3 R 5 S 7 r Preparation of 3,5-dimethyladamantane-1-yl)benzamide (Memantine-OAB-11):

[0408]

[0409] Memantine-OAB-11, 440.63

[0410] 5 g of the memantine-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 2 g of N,N-diethylethylenediamine and 2.4 g of triethylamine, and then 30 mL of LDM. The mixture was heated to reflux and allowed to react for 3 hours. After TLC monitoring, the reaction was complete. The mixture was then cooled to 5-10 °C in an ice bath and allowed to continue cooling to allow crystallization for 2 hours. The crystals were filtered, washed with 10 mL of dichloromethane, and dried at 60 °C and 0.08 MPa for 6 hours to obtain 3.34 g of an off-white solid. HPLC analysis showed 99.53% purity. Figure 10 As shown in Table 28, the chromatographic peak results are as follows, with a yield of 63.45%.

[0411] Table 28 Chromatographic Peak Results

[0412]

[0413] (1) Nuclear magnetic resonance detection

[0414] Instrument model: Bruker NEO400M nuclear magnetic resonance spectrometer; Test conditions: DMSO- d 6; 298K; Test items: 1 H, 13 C, Dept135, COSY, HSQC, HMBC, detection spectra as follows Figures 94-99 As shown in Table 29, the test results are as follows.

[0415] Table 29 Test Results

[0416]

[0417] (2) Mass spectrometry detection

[0418] Instrument: Waters, 2695; Mass spectrometer: QDA; Solvent: Methanol; Ionization method: ESI (+); Detection results are shown in Table 30, and the detection spectra are as follows. Figure 100 As shown.

[0419] Table 30 Mass Spectrometry Detection Results

[0420]

[0421] Example 11

[0422] 4-(3-(3-(diethyl)propyl)urea)- N -((1 r ,3 R 5 S 7 r Preparation of 3,5-dimethyladamantane-1-yl)benzamide (Memantine-OAB-12):

[0423]

[0424] Ammonium Sildenafil-OAB-12, 454.66

[0425] 5 g of the memantine-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 2.33 g of 3-diethylaminopropylamine and 2.4 g of triethylamine, followed by 30 mL of LDM. The mixture was heated to reflux and reacted under TLC for 4 hours. After the reaction was complete, the mixture was cooled to 5-10 °C in an ice bath and allowed to continue cooling for 2 hours to allow crystallization. No crystals were precipitated. 20 mL of saturated sodium carbonate was added and stirred for 2 hours, but no solid precipitated. The mixture was separated into layers, and the organic phase was concentrated. It was then slurried overnight with 60 mL of a 10:1 (v / v) mixture of petroleum ether and ethyl acetate. The mixture was filtered and dried at 60 °C and 0.08 MPa for 6 hours to obtain 4.62 g of a white solid, which showed 98.94% purity according to HPLC. Figure 11 As shown in Table 31, the chromatographic peak results show a yield of 84.16%.

[0426] Table 31 Chromatographic Peak Results

[0427]

[0428] (1) Nuclear magnetic resonance detection

[0429] Instrument model: Bruker NEO400M nuclear magnetic resonance spectrometer; Test conditions: DMSO- d 6; 298K; Test items: 1 H, 13 C, Dept135, COSY, HSQC, HMBC, detection spectra as follows Figures 101-106 As shown in Table 32, the test results are as follows.

[0430] Table 32 Test Results

[0431]

[0432] (2) Mass spectrometry detection

[0433] Instrument: Waters, 2695; Mass spectrometer: QDA; Solvent: Methanol; Ionization method: ESI (+); Detection results are shown in Table 33, and the detection spectrum is as follows. Figure 107 As shown.

[0434] Table 33 Mass Spectrometry Detection Results

[0435]

[0436] Example 12

[0437] N -((1 r ,3 R 5 S 7 r Preparation of 3,5-dimethyladamantane-1-yl)-4-(3-(2-(dimethylamine)ethyl)urea)benzamide (Memantine-OAB-13):

[0438]

[0439] Memantine-OAB-13, 412.28

[0440] 5 g of the memantine-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 1.58 g of N,N-dimethylethylenediamine and 2.4 g of triethylamine, followed by 30 mL of LDM. The mixture was heated to reflux and reacted under TLC for 4 hours. After the reaction was complete, the mixture was cooled to 5-10 °C in an ice bath and allowed to crystallize for another 2 hours. The crystals were then filtered and dried at 60 °C and 0.08 MPa for 6 hours to obtain 4.22 g of a white solid. HPLC analysis showed a purity of 96.79%. Figure 12 As shown in Table 34, the chromatographic peak results show a yield of 82.87%.

[0441] Table 34 Chromatographic Peak Results

[0442]

[0443] (1) Nuclear magnetic resonance detection

[0444] Instrument model: Bruker NEO400M nuclear magnetic resonance spectrometer; Test conditions: DMSO- d 6; 298K; Test items: 1 H, 13 C, Dept135, COSY, HSQC, HMBC, detection spectra as follows Figures 108-113 As shown in Table 35, the test results are as follows.

[0445] Table 35 Test Results

[0446]

[0447] (2) Mass spectrometry detection

[0448] Instrument: Waters, 2695; Mass spectrometer: QDA; Solvent: Methanol; Ionization method: ESI (+); Detection results are shown in Table 36, and the detection spectrum is as follows. Figure 114 As shown.

[0449] Table 36 Mass Spectrometry Detection Results

[0450]

[0451] Example 13

[0452] N -((1 r ,3 R 5 S 7 r Preparation of 3,5-dimethyladamantane-1-yl)-4-(3-propylurea)benzamide (Memantine-OAB-15):

[0453]

[0454] Memantine-OAB-15, 383.54

[0455] 5 g of the memantine-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 1.06 g of n-propylamine and 2.4 g of triethylamine, followed by 50 mL of LCM. The mixture was heated to reflux and reacted under TLC for 4 hours. After the reaction was complete, the mixture was cooled to 5-10 °C in an ice bath and allowed to crystallize for another 2 hours. The crystals were then filtered and dried at 60 °C for 3 hours to obtain 3.93 g of a white solid. HPLC accuracy was 99.31%. Figure 13 As shown in Table 37, the chromatographic peak results show a yield of 85.18%.

[0456] Table 37 Chromatographic Peak Results

[0457]

[0458] (1) Nuclear magnetic resonance detection

[0459] Instrument model: Bruker NEO400M nuclear magnetic resonance spectrometer; Test conditions: DMSO- d 6; 298K; Test items: 1 H, 13 C, Dept135, COSY, HSQC, HMBC, detection spectra as follows Figures 115-120 As shown in Table 38, the test results are as follows.

[0460] Table 38 Test Results

[0461]

[0462] (2) Mass spectrometry detection

[0463] Instrument: Waters, 2695; Mass spectrometer: QDA; Solvent: Methanol; Ionization method: ESI (+); Detection results are shown in Table 39, and the detection spectrum is as follows. Figure 121 As shown.

[0464] Table 39 Mass Spectrometry Detection Results

[0465]

[0466] Example 14

[0467] 4-(3,3-Diethylurea)- N -((1 r ,3 R 5 S 7 r Preparation of 3,5-dimethyladamantane-1-yl)benzamide (Memantine-OAB-16):

[0468]

[0469] Memantine-OAB-16, 397.56

[0470] 5 g of the memantine-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 1.3 g of diethylamine and 2.4 g of triethylamine, followed by 30 mL of LDM. The mixture was heated to reflux and reacted under TLC for 5 hours. After the reaction was complete, the mixture was cooled to 5-10 °C in an ice bath and allowed to crystallize for another 2 hours. The crystals were then filtered and dried at 60 °C for 3 hours to obtain 3.23 g of a white solid. HPLC accuracy was 99.81%. Figure 14 As shown in Table 40, the chromatographic peak results show a yield of 67.88%.

[0471] Table 40 Chromatographic Peak Results

[0472]

[0473] (1) Nuclear magnetic resonance detection

[0474] Instrument model: Bruker NEO400M nuclear magnetic resonance spectrometer; Test conditions: DMSO- d 6; 298K; Test items: 1 H, 13 C, Dept135, COSY, HSQC, HMBC, detection spectra as follows Figures 122-127 As shown in Table 41, the test results are as follows.

[0475] Table 41 Test Results

[0476]

[0477] (2) Mass spectrometry detection

[0478] Instrument: Waters, 2695; Mass spectrometer: QDA; Solvent: Methanol; Ionization method: ESI (+); Detection results are shown in Table 42, and the detection spectrum is as follows. Figure 128 As shown.

[0479] Table 42 Mass Spectrometry Detection Results

[0480]

[0481] Example 15

[0482] N -((1 r ,3 R 5 S 7 r Preparation of 3,5-dimethyladamantane-1-yl)-4-(3,3-dimethylurea)benzamide (Memantine-OAB-17):

[0483]

[0484] Memantine-OAB-17, 369.51

[0485] Add 5 g of the memantine-OAB-3 prepared in Example 3 to a 100 mL four-necked flask, along with 10 mL of 2 mol / L diethylaminetetrahydrofuran solution, 2.4 g of triethylamine, and 30 mL of LDCM. React overnight at room temperature, then cool in an ice bath to 5-10 °C. Continue cooling to allow crystallization for 2 hours, filter, and dry at 60 °C for 3 hours to obtain 3.24 g of a white solid (HPLC 99.86%). Figure 15 As shown in Table 43, the chromatographic peak results are as follows, with a yield of 73.30%.

[0486] Table 43 Chromatographic Peak Results

[0487]

[0488] (2) Nuclear magnetic resonance detection

[0489] Instrument model: Bruker NEO400M nuclear magnetic resonance spectrometer; Test conditions: DMSO- d 6; 298K; Test items: 1 H, 13 C, Dept135, COSY, HSQC, HMBC, detection spectra as follows Figures 129-134 As shown in Table 44, the test results are as follows.

[0490] Table 44 Test Results

[0491]

[0492] (2) Mass spectrometry detection

[0493] Instrument: Waters, 2695; Mass spectrometer: QDA; Solvent: Methanol; Ionization method: ESI (+); Detection results are shown in Table 45, and the detection spectra are as follows. Figure 135 As shown.

[0494] Table 45 Mass Spectrometry Detection Results

[0495]

[0496] Example 16

[0497] N -((1 r ,3 R 5 S 7 r Preparation of 3,5-dimethyladamantane-1-yl)-4-(3-phenylurea)benzamide (Memantine-OAB-18):

[0498]

[0499] Memantine-OAB-18, 417.55

[0500] Add 5g of the memantine-OAB-3 prepared in Example 3 to a 100mL four-necked flask, along with 1.33g of aniline and 2.4g of triethylamine, then add 30mL of LDM. Heat to reflux, and after 4 hours, monitor by TLC. Add another 0.33g of aniline, cool in an ice bath to 5-10°C, and continue cooling to allow crystallization for 2 hours. Filter, and dry at 60°C for 3 hours to obtain 1.62g of a white solid (HPLC 99.81%). Figure 16 As shown in Table 46, the chromatographic peak results show a yield of 32.42%.

[0501] Table 46 Chromatographic Peak Results

[0502]

[0503] (1) Nuclear magnetic resonance detection

[0504] Instrument model: Bruker NEO400M nuclear magnetic resonance spectrometer; Test conditions: DMSO- d 6; 298K; Test items: 1 H, 13 C, Dept135, COSY, HSQC, HMBC, detection spectra as follows Figures 136-141 As shown in Table 47, the test results are as follows.

[0505] Table 47 Test Results

[0506]

[0507] (2) Mass spectrometry detection

[0508] Instrument: Waters, 2695; Mass spectrometer: QDA; Solvent: Methanol; Ionization method: ESI (+); Detection results are shown in Table 48, and the detection spectra are as follows. Figure 142 As shown.

[0509] Table 48 Mass Spectrometry Detection Results

[0510]

[0511] Example 17

[0512] N -((1 r ,3 R 5 S 7 r Preparation of 3,5-dimethyladamantane-1-yl)-4-(3-(2-morpholinylethyl)urea)benzamide (Memantine-OAB-19):

[0513]

[0514] Memantine-OAB-19, 454.54

[0515] 5 g of memantine-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 2.3 g of 4-(2-aminoethyl)morpholine and 2.4 g of triethylamine. Then, 30 mL of LDM was added, and the mixture was heated to reflux. After 4 hours, the reaction was monitored by TLC until complete. The mixture was then cooled to 5-10 °C in an ice bath and allowed to crystallize for another 2 hours. The crystals were filtered and dried at 60 °C for 3 hours to obtain 4.51 g of a white solid. HPLC accuracy was 98.95%. Figure 17 As shown in Table 49, the chromatographic peak results show a yield of 82.17%.

[0516] Table 49 Chromatographic Peak Results

[0517]

[0518] (1) Nuclear magnetic resonance detection

[0519] Instrument model: Bruker NEO400M nuclear magnetic resonance spectrometer; Test conditions: DMSO- d 6; 298K; Test items: 1 H, 13 C, Dept135, COSY, HSQC, HMBC, detection spectra as follows Figures 143-148As shown in Table 50, the test results are as follows.

[0520] Table 50 Test Results

[0521]

[0522] (2) Mass spectrometry detection

[0523] Instrument: Waters, 2695; Mass spectrometer: QDA; Solvent: Methanol; Ionization method: ESI (+); Detection results are shown in Table 51, and the detection spectra are as follows. Figure 149 As shown.

[0524] Table 51 Mass Spectrometry Detection Results

[0525]

[0526] Example 18

[0527] N -(4-(((1 r ,3 R 5 S 7 r Preparation of 3,5-dimethyladamantane-1-yl)carbamoyl)phenyl)tetrahydrothiazole-3-carboxamide (Amantane-OAB-20):

[0528]

[0529] Ammonium Sildenafil-OAB-20, 413.58

[0530] Add 5g of the memantine-OAB-3 prepared in Example 3 to a 100mL four-necked flask, along with 1.6g of tetrahydrothiazole, 2.4g of triethylamine, and 30mL of LDM. Heat to reflux and allow to react for 4 hours. After TLC monitoring, once the reaction is complete, cool to 5-10°C in an ice bath and continue cooling to allow crystallization for 2 hours. Filter and dry at 60°C for 3 hours to obtain 4.10g of a white solid. Add 4g of the above sample to a 100mL four-necked flask, along with 4mL of methanol and 40mL of dichloromethane. Stir at room temperature, cool to 5-10°C in an ice bath, and continue cooling to allow crystallization for 2 hours. Filter and dry at 60°C for 3 hours to obtain 3.5g of a white solid. HPLC accuracy: 97.10%. Figure 18 As shown in Table 52, the chromatographic peak results show a yield of 68.79%.

[0531] Table 52 Chromatographic Peak Results

[0532]

[0533] (1) Nuclear magnetic resonance detection

[0534] Instrument model: Bruker NEO400M nuclear magnetic resonance spectrometer; Test conditions: DMSO- d 6; 298K; Test items: 1 H, 13 C, Dept135, COSY, HSQC, HMBC, detection spectra as follows Figures 150-155 As shown in Table 53, the test results are as follows.

[0535] Table 53 Test Results

[0536]

[0537] (2) Mass spectrometry detection

[0538] Instrument: Waters, 2695; Mass spectrometer: QDA; Solvent: Methanol; Ionization method: ESI (-); Detection results are shown in Table 54, and the detection spectra are as follows. Figure 156 As shown.

[0539] Table 54 Mass Spectrometry Detection Results

[0540]

[0541] Example 19

[0542] N -(4-(((1 r ,3 R 5 S 7 r Preparation of 3,5-dimethyladamantane-1-yl)carbamoyl)phenyl)pyrrolidine-1-carboxamide (Amantane-OAB-21):

[0543]

[0544] Memantine-OAB-21, 395.55

[0545] 5 g of the memantine-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 1.27 g of pyrrolidine and 2.4 g of triethylamine, followed by 30 mL of LDM. The mixture was heated to reflux and reacted under TLC for 4 hours. After the reaction was complete, the mixture was cooled to 5-10 °C in an ice bath and allowed to crystallize for another 2 hours. The crystals were then filtered and dried at 60 °C for 3 hours to obtain 3.49 g of a white solid. HPLC accuracy was 99.93%. Figure 19 As shown in Table 55, the chromatographic peak results show a yield of 73.81%.

[0546] Table 55 Chromatographic Peak Results

[0547]

[0548] (1) Nuclear magnetic resonance detection

[0549] Instrument model: Bruker NEO400M nuclear magnetic resonance spectrometer; Test conditions: DMSO- d 6; 298K; Test items: 1 H, 13 C, Dept135, COSY, HSQC, HMBC, detection spectra as follows Figures 157-162 As shown in Table 56, the test results are as follows.

[0550] Table 56 Test Results

[0551]

[0552] (2) Mass spectrometry detection

[0553] Instrument: Waters, 2695; Mass spectrometer: QDA; Solvent: Methanol; Ionization method: ESI (+); Detection results are shown in Table 57, and the detection spectrum is as follows. Figure 163 As shown.

[0554] Table 57 Mass Spectrometry Detection Results

[0555]

[0556] Example 20

[0557] 4-(3-Cyclohexylurea)- N -((1 r ,3 R 5 S 7 r Preparation of 3,5-dimethyladamantane-1-yl)benzamide (Memantine-OAB-22):

[0558]

[0559] Ammonium Manganese OAB-22, 423.60

[0560] 5 g of the memantine-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 1.78 g of cyclohexylamine and 2.4 g of triethylamine, followed by 30 mL of LDM. The mixture was heated to reflux and reacted under TLC for 4 hours. After the reaction was complete, the mixture was cooled to 5-10 °C in an ice bath and allowed to crystallize for another 2 hours. The crystals were then filtered and dried at 60 °C for 3 hours to obtain 4.22 g of a white solid. HPLC accuracy was 99.52%. Figure 20 As shown in Table 58, the chromatographic peak results show a yield of 82.99%.

[0561] Table 58 Chromatographic Peak Results

[0562]

[0563] (1) Nuclear magnetic resonance detection

[0564] Instrument model: Bruker NEO400M nuclear magnetic resonance spectrometer; Test conditions: DMSO- d 6; 298K; Test items: 1 H, 13 C, Dept135, COSY, HSQC, HMBC, detection spectra as follows Figures 164-169 As shown in Table 59, the test results are as follows.

[0565] Table 59 Test Results

[0566]

[0567] (2) Mass spectrometry detection

[0568] Instrument: Waters, 2695; Mass spectrometer: QDA; Solvent: Methanol; Ionization method: ESI (+); Detection results are shown in Table 60, and the detection spectrum is as follows. Figure 170 As shown.

[0569] Table 60 Mass Spectrometry Detection Results

[0570]

[0571] Example 21

[0572] N -((1 r ,3 R 5 S 7 r Preparation of 3,5-dimethyladamantane-1-yl)-4-(3-(3-(piperidin-1-yl)propyl)urea)benzamide (Memantine-OAB-23):

[0573]

[0574] Mega-King Kong - OAB-23, 466.33

[0575] 5 g of memantine-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 2.55 g of 3-(piperidin-1-yl)propyl-1-amine and 2.4 g of triethylamine. Then, 30 mL of LDM was added, and the mixture was heated to reflux. After 4 hours, the reaction was monitored by TLC. Once complete, the mixture was cooled to 5-10 °C in an ice bath and allowed to crystallize for another 2 hours. 20 mL of saturated sodium carbonate was added for washing, and the mixture was stirred for 2 hours. The organic phase was separated, concentrated, and 30 mL of PE:EA = 10:1 (volume ratio) was added and stirred for 2 hours. The mixture was then filtered and dried at 60 °C for 3 hours to obtain 4.59 g of a white solid. HPLC accuracy was 98.45%. Figure 21As shown in Table 61, the chromatographic peak results show a yield of 81.12%.

[0576] Table 61 Chromatographic Peak Results

[0577]

[0578] (1) Nuclear magnetic resonance detection

[0579] Instrument model: Bruker NEO400M nuclear magnetic resonance spectrometer; Test conditions: DMSO- d 6; 298K; Test items: 1 H, 13 C, Dept135, COSY, HSQC, HMBC, detection spectra as follows Figures 171-176 As shown in Table 62, the test results are as follows.

[0580] Table 62 Test Results

[0581]

[0582] (2) Mass spectrometry detection

[0583] Instrument: Waters, 2695; Mass spectrometer: QDA; Solvent: Methanol; Ionization method: ESI (+); Detection results are shown in Table 63, and the detection spectrum is as follows. Figure 177 As shown.

[0584] Table 63 Mass Spectrometry Detection Results

[0585]

[0586] Example 22

[0587] N -((1 r ,3 R 5 S 7 r Preparation of 3,5-dimethyladamantane-1-yl)-4-(3-(3-(4-methylpiperazin-1-yl)propyl)urea)benzamide (Memantine-OAB-24):

[0588]

[0589] Memantine-OAB-24, 481.69

[0590] 5 g of memantine-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 2.82 g of 1-(3-aminopropyl)-4-methylpiperazine and 2.4 g of triethylamine, followed by 30 mL of LDM. The mixture was heated to reflux. After 4 hours, the reaction was monitored by TLC until complete. The mixture was then cooled to 5-10 °C in an ice bath and allowed to crystallize for another 2 hours. 20 mL of saturated sodium carbonate was added for washing, and the mixture was stirred for 2 hours. The organic phase was separated, concentrated, and 50 mL of PE:EA = 10:1 (volume ratio) was added and stirred for 2 hours. The mixture was then filtered and dried at 60 °C for 3 hours to obtain 4.91 g of a white solid (HPLC 96.43%). Figure 22 As shown in Table 64, the chromatographic peak results show a yield of 85.33%.

[0591] Table 64 Chromatographic Peak Results

[0592]

[0593] (1) Nuclear magnetic resonance detection

[0594] Instrument model: Bruker NEO400M nuclear magnetic resonance spectrometer; Test conditions: DMSO- d 6; 298K; Test items: 1 H, 13 C, Dept135, COSY, HSQC, HMBC, detection spectra as follows Figures 178-183 As shown in Table 65, the test results are as follows.

[0595] Table 65 Test Results

[0596]

[0597] (2) Mass spectrometry detection

[0598] Instrument: Waters, 2695; Mass spectrometer: QDA; Solvent: Methanol; Ionization method: ESI(+); Detection results are shown in Table 66, and the detection spectrum is as follows. Figure 184 As shown.

[0599] Table 66 Mass Spectrometry Detection Results

[0600]

[0601] Example 23

[0602] N -((1 r ,3 R 5 S 7 r Preparation of 3,5-dimethyladamantane-1-yl)-4-(3-(2-(piperidin-1-yl)ethyl)urea)benzamide (Memantine-OAB-25):

[0603]

[0604] Ammonium Sildenafil-OAB-25, 452.64

[0605] 5 g of the memantine-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 2.30 g of 1-(2-aminoethyl)piperidine and 2.4 g of triethylamine. Then, 30 mL of LDM was added, and the mixture was heated to reflux. After 4 hours, the reaction was monitored by TLC until complete. The mixture was then cooled to 5-10 °C in an ice bath and allowed to crystallize for another 2 hours. The crystals were filtered and dried at 60 °C for 3 hours to obtain 3.69 g of a white solid. HPLC accuracy was 99.28%. Figure 23 As shown in Table 67, the chromatographic peak results show a yield of 42.53%.

[0606] Table 67 Chromatographic Peak Results

[0607]

[0608] (1) Nuclear magnetic resonance detection

[0609] Instrument model: Bruker NEO400M nuclear magnetic resonance spectrometer; Test conditions: DMSO- d 6; 298K; Test items: 1 H, 13 C, Dept135, COSY, HSQC, HMBC, detection spectra as follows Figures 185-190 As shown in Table 68, the test results are as follows.

[0610] Table 68 Test Results

[0611]

[0612] (2) Mass spectrometry detection

[0613] Instrument: Waters, 2695; Mass spectrometer: QDA; Solvent: Methanol; Ionization method: ESI (+); Detection results are shown in Table 69, and the detection spectrum is as follows. Figure 191 As shown.

[0614] Table 69 Mass Spectrometry Detection Results

[0615]

[0616] Example 24

[0617] N -((1 r ,3 R 5 S 7 rPreparation of 3,5-dimethyladamantane-1-yl)-4-(3-(3-propylmorpholino)urea)benzamide (Memantine-OAB-26):

[0618]

[0619] Memantine-OAB-26, 468.64

[0620] 5 g of memantine-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 2.58 g of N(3-aminopropyl)morpholine and 2.4 g of triethylamine. Then, 30 mL of LDM was added, and the mixture was heated to reflux. After 4 hours, the reaction was monitored by TLC. Once complete, the mixture was cooled to 5-10 °C in an ice bath and allowed to crystallize for another 2 hours. 20 mL of saturated sodium carbonate was added for washing, and the mixture was stirred for 2 hours. The organic phase was separated, concentrated, and 50 mL of PE:EA = 10:1 (volume ratio) was added and stirred for 2 hours. No crystallization occurred. The mixture was then placed in a refrigerator overnight, and no crystallization occurred. After standing at room temperature for one day, crystallization occurred. The mixture was filtered and dried at 60 °C for 3 hours to obtain 4.00 g of a white solid. HPLC accuracy was 98.81%. Figure 24 As shown in Table 70, the chromatographic peak results are as follows, with a yield of 71.45%.

[0621] Table 70 Chromatographic Peak Results

[0622]

[0623] (1) Nuclear magnetic resonance detection

[0624] Instrument model: Bruker NEO400M nuclear magnetic resonance spectrometer; Test conditions: DMSO- d 6; 298K; Test items: 1 H, 13 C, Dept135, COSY, HSQC, HMBC, detection spectra as follows Figures 192-197 As shown in Table 71, the test results are as follows.

[0625] Table 71 Test Results

[0626]

[0627] (2) Mass spectrometry detection

[0628] Instrument: Waters, 2695; Mass spectrometer: QDA; Solvent: Methanol; Ionization method: ESI (+); Detection results are shown in Table 72, and the detection spectrum is as follows. Figure 198 As shown.

[0629] Table 72 Mass Spectrometry Detection Results

[0630]

[0631] Example 25

[0632] N -((1 r ,3 R 5 S 7 r Preparation of 3,5-dimethyladamantane-1-yl)-4-(3-(3-(pyrrolidone-1-yl)propyl)urea)benzamide (Memantine-OAB-27):

[0633]

[0634] Memantine-OAB-27, 452.64

[0635] 5 g of memantine-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 2.3 g of 1-(3-aminopropyl)pyrrolidine and 2.4 g of triethylamine. Then, 30 mL of LDM was added, and the mixture was heated to reflux. After 4 hours, the reaction was monitored by TLC. Once complete, the mixture was cooled to 5-10°C in an ice bath and allowed to crystallize for another 2 hours. 20 mL of saturated sodium carbonate was added for washing, and the mixture was stirred for 2 hours. The organic phase was separated, concentrated, and 50 mL of a PE:EA mixture (10:1, v / v) was added and stirred for 2 hours. The mixture was allowed to stand at room temperature for one day to crystallize. The crystals were then filtered and dried at 60°C for 3 hours to obtain 4.64 g of a white solid. 40 mL of a 2:1 (v / v) mixture of ethyl acetate and petroleum ether was added, and the mixture was stirred for 2 hours. The mixture was cooled to 5-10°C in an ice bath and allowed to crystallize for another 2 hours. The crystals were then filtered and dried at 60°C for 3 hours to obtain 4.09 g of a white solid. HPLC accuracy was 95.52%. Figure 25 As shown in Table 73, the chromatographic peak results are as follows, with a yield of 72.25%.

[0636] Table 73 Chromatographic Peak Results

[0637]

[0638] (1) Nuclear magnetic resonance detection

[0639] Instrument Model: Bruker NEO400M NMR Spectrometer; Test Conditions: DMSO- d 6; 298K; Test items: 1 H, 13 C, Dept135, COSY, HSQC, HMBC, detection spectra as follows Figures 199-204 As shown in Table 74, the test results are as follows.

[0640] Table 74 Test Results

[0641]

[0642] (2) Mass spectrometry detection

[0643] Instrument: Waters, 2695; Mass spectrometer: QDA; Solvent: Methanol; Ionization method: ESI (+); Detection results are shown in Table 75, and the detection spectrum is as follows. Figure 205 As shown.

[0644] Table 75 Mass Spectrometry Detection Results

[0645]

[0646] Example 26

[0647] N -((1 r ,3 R 5 S 7 r Preparation of 3,5-dimethyladamantane-1-yl)-4-(3-(3-(dimethylamine)propyl)urea)benzamide (Memantine-OAB-28):

[0648]

[0649] Memantine-OAB-28, 426.61

[0650] 5 g of the memantine-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 1.83 g of 3-dimethylaminopropylamine and 2.4 g of triethylamine, followed by 30 mL of LDM. The mixture was heated to reflux and reacted under TLC for 4 hours. After the reaction was complete, the mixture was cooled to 5-10 °C in an ice bath and allowed to crystallize for another 2 hours. The crystals were then filtered and dried at 60 °C for 3 hours to obtain 3.96 g of a white solid. HPLC accuracy was 99.48%. Figure 26 As shown in Table 76, the chromatographic peak results are as follows, with a yield of 77.70%.

[0651] Table 76 Chromatographic Peak Results

[0652]

[0653] (1) Nuclear magnetic resonance detection

[0654] Instrument model: Bruker NEO400M nuclear magnetic resonance spectrometer; Test conditions: DMSO- d 6; 298K; Test items: 1 H, 13 C, Dept135, COSY, HSQC, HMBC, detection spectra as follows Figures 206-211 As shown in Table 77, the test results are as follows.

[0655] Table 77 Test Results

[0656]

[0657] (2) Mass spectrometry detection

[0658] Instrument: Waters, 2695; Mass spectrometer: QDA; Solvent: Methanol; Ionization method: ESI (+); Detection results are shown in Table 78, and the detection spectra are as follows. Figure 212 As shown.

[0659] Table 78 Mass Spectrometry Detection Results

[0660]

[0661] Example 27

[0662] N -((1 r ,3 R 5 S 7 r Preparation of 3,5-dimethyladamantane-1-yl)-4-(3-(2-(4-methylpiperazin-1-yl)ethyl)urea)benzamide (Memantine-OAB-29):

[0663]

[0664] Memantine-OAB-29, 467.66

[0665] 5 g of memantine-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 2.57 g of 4-methyl-1-piperazine ethylamine and 2.4 g of triethylamine. Then, 30 mL of LDM was added, and the mixture was heated to reflux. After 4 hours, the reaction was monitored by TLC. Once complete, the mixture was cooled to 5-10 °C in an ice bath and allowed to continue cooling for 2 hours to allow crystallization. No crystals precipitated. 50 mL of saturated sodium bicarbonate was added and stirred for half an hour, resulting in the precipitation of a solid. The solid was filtered, and the filter cake was washed with 30 mL of a 10:1 (v / v) mixture of petroleum ether and ethyl acetate. The mixture was dried at 60 °C for 3 hours to obtain 5.24 g of a white solid (HPLC 98.93%). Figure 27 As shown in Table 79, the chromatographic peak results show a yield of 92.79%.

[0666] Table 79 Chromatographic Peak Results

[0667]

[0668] (1) Nuclear magnetic resonance detection

[0669] Instrument model: Bruker NEO400M nuclear magnetic resonance spectrometer; Test conditions: DMSO- d 6; 298K; Test items: 1 H, 13 C, Dept135, COSY, HSQC, HMBC, detection spectra as follows Figures 213-218 As shown in Table 80, the test results are as follows.

[0670] Table 80 Test Results

[0671]

[0672] (2) Mass spectrometry detection

[0673] Instrument: Waters, 2695; Mass spectrometer: QDA; Solvent: Methanol; Ionization method: ESI (+); Detection results are shown in Table 81, and the detection spectrum is as follows. Figure 219 As shown.

[0674] Table 81 Mass Spectrometry Detection Results

[0675]

[0676] Example 28

[0677] N -((1 r ,3 R 5 S 7 r Preparation of 3,5-dimethyladamantane-1-yl)-4-(3-(2-(pyrrolidone-1-yl)ethyl)urea)benzamide (Memantine-OAB-30):

[0678]

[0679] Ammonium Sildenafil-OAB-30, 438.61

[0680] Add 5g of memantine-OAB-3 prepared in Example 3 to a 100mL four-necked flask, along with 2.05g of 1-(2-aminoethyl)pyrrolidine and 2.4g of triethylamine, then add 30mL of LDM. Heat to reflux and allow to react for 4 hours. After TLC monitoring, once the reaction is complete, cool to 5-10°C in an ice bath and continue cooling to allow crystallization for 2 hours. The precipitated solid is filtered and dried at 60°C for 3 hours to obtain 4.64g of a white solid. First, homogenize with ethyl acetate for 1 hour, then homogenize with 40mL of a 1:10 (v / v) methanol:dichloromethane mixture for 2 hours. Filter and dry at 60°C for 3 hours to obtain 2.42g of the solid. HPLC 95.46%. Figure 28 As shown in Table 82, the chromatographic peak results are as follows, with a yield of 44.09%.

[0681] Table 82 Chromatographic Peak Results

[0682]

[0683] (1) Nuclear magnetic resonance detection

[0684] Instrument model: Bruker NEO400M nuclear magnetic resonance spectrometer; Test conditions: DMSO- d6; 298K; Test items: 1 H, 13 C, Dept135, COSY, HSQC, HMBC, detection spectra as follows Figures 220-225 As shown in Table 83, the test results are as follows.

[0685] Table 83 Test Results

[0686]

[0687] (2) Mass spectrometry detection

[0688] Instrument: Waters, 2695; Mass spectrometer: QDA; Solvent: Methanol; Ionization method: ESI (+); Detection results are shown in Table 84, and the detection spectrum is as follows. Figure 226 As shown.

[0689] Table 84 Mass Spectrometry Detection Results

[0690]

[0691] Example 29

[0692] N -(4-(((1 r ,3 R 5 S 7 r Preparation of 3,5-dimethyladamantane-1-yl)carbamoyl)phenyl)morpholine-4-carboxamide (Amantane-OAB-34):

[0693]

[0694] Memantine-OAB-34, 411.55

[0695] 5 g of the memantine-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 1.56 g of morpholine and 2.4 g of triethylamine. Then, 30 mL of LDM was added, and the mixture was heated to reflux. After 4 hours, TLC was used to monitor the reaction. Once the reaction was complete, the mixture was cooled in an ice bath for 2 hours to allow crystals to precipitate. The crystals were then filtered and dried at 60 °C for 2 hours to obtain 4.12 g of solid. HPLC accuracy was 99.78%. Figure 29 As shown in Table 85, the chromatographic peak results show a yield of 83.61%.

[0696] Table 85 Chromatographic Peak Results

[0697]

[0698] (1) Nuclear magnetic resonance detection

[0699] Instrument model: Bruker NEO400M nuclear magnetic resonance spectrometer; Test conditions: DMSO-d 6; 298K; Test items: 1 H, 13 C, Dept135, COSY, HSQC, HMBC, detection spectra as follows Figures 227-232 As shown in Table 86, the test results are as follows.

[0700] Table 86 Test Results

[0701]

[0702] (2) Mass spectrometry detection

[0703] Instrument: Waters, 2695; Mass spectrometer: QDA; Solvent: Methanol; Ionization method: ESI (+); Detection results are shown in Table 87, and the detection spectrum is as follows. Figure 233 As shown.

[0704] Table 87 Mass Spectrometry Detection Results

[0705]

[0706] Example 30

[0707] 4-(3-Cyclopropylurea)- N -((1 r ,3 R 5 S 7 r Preparation of 3,5-dimethyladamantane-1-yl)benzamide (Memantine-OAB-35):

[0708]

[0709] Ammonium Sildenafil-OAB-35, 381.52

[0710] 5 g of the memantine-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 1.02 g of cyclopropylamine and 2.4 g of triethylamine, followed by 30 mL of LDM. The mixture was heated to reflux and allowed to react for 4 hours. TLC monitoring showed that the reaction was complete. The mixture was then cooled in an ice bath for 2 hours to allow crystals to precipitate. After filtration and drying at 60 °C for 2 hours, 4.23 g of solid was obtained. HPLC accuracy was 99.79%. Figure 30 As shown in Table 88, the chromatographic peak results are as follows, with a yield of 92.61%.

[0711] Table 88 Chromatographic Peak Results

[0712]

[0713] (1) Nuclear magnetic resonance detection

[0714] Instrument model: Bruker NEO400M nuclear magnetic resonance spectrometer; Test conditions: DMSO- d 6; 298K; Test items: 1 H, 13 C, Dept135, COSY, HSQC, HMBC, detection spectra as follows Figures 234-239 As shown in Table 89, the test results are as follows.

[0715] Table 89 Test Results

[0716]

[0717] (2) Mass spectrometry detection

[0718] Instrument: Waters, 2695; Mass spectrometer: QDA; Solvent: Methanol; Ionization method: ESI (+); Detection results are shown in Table 90, and the detection spectrum is as follows. Figure 240 As shown.

[0719] Table 90 Mass Spectrometry Detection Results

[0720]

[0721] The memantine-OAB compounds prepared in Examples 1 to 30 above were subjected to activity studies.

[0722] Materials and Methods

[0723] 1.1 Experimental System

[0724] 1.1.1 Cells. Cell information is shown in Table 91.

[0725] Table 91 Cell Information

[0726]

[0727] 1.12 Grouping, as shown in Table 92.

[0728] Table 92 Grouping

[0729]

[0730] 1.2 Compound Information

[0731] 1.2.1 Test substance information, as shown in Table 93.

[0732] Table 93 Test Substance Information

[0733]

[0734] 1.2.2 Solvent information is shown in Table 94.

[0735] Table 94 Solvent Information

[0736]

[0737] 1.3 Information on Reagents, Consumables and Instruments

[0738] 1.3.1 Information on reagents and consumables is shown in Table 95.

[0739] Table 95 Reagent and Consumable Information

[0740]

[0741] 1.3.2 Instrument information, as shown in Table 96.

[0742] Table 96 Instrument Information

[0743]

[0744] 1.4 Compound Preparation

[0745] 1.4.1 Test substance preparation information

[0746] The compounds obtained in Examples 1 to 30 were dissolved in DMSO and ultrasonically disrupted under ice bath conditions to prepare a 10 mmol / L stock solution, which was stored at -20°C in the dark. Before use, the stock solution was diluted with DMSO to 10 mmol / L, 1 mmol / L, and 0.1 mmol / L, respectively. The 10 mmol / L, 1 mmol / L, and 0.1 mmol / L solutions were then diluted 1000-fold with culture medium and incubated with cells.

[0747] 1.4.2 The storage conditions are shown in Table 97.

[0748] Table 97 Storage Conditions

[0749]

[0750] 2. CCK-8 test method

[0751] SH-SY5Y cells were seeded in 96-well plates. After culturing, the corresponding concentration of drug was added to each well. After 2 hours, pre-prepared Aβ1-42 oligomers were added, and the cells were cultured for 24 hours.

[0752] Remove the culture plate to be tested from the incubator (5% CO2, 37℃);

[0753] Use a pipette to add 10 μL of CCK-8 reagent to each well, and gently shake the culture plate by hand;

[0754] Place the culture plate in the incubator and incubate for 3 hours;

[0755] Turn on the microplate reader 25 minutes in advance and heat it to 37°C;

[0756] After the culture was completed, the absorbance (OD value) at a wavelength of 450 nm was measured using a microplate reader.

[0757] Detection indicators: assess cell survival rate.

[0758] 3. Data Analysis

[0759] Graphpad Prism software was used to perform between-group statistical analysis on the data coefficients. Quantitative data were expressed as mean plus or minus standard error. One-way ANOVA was used to compare differences, and graphs were generated using Graphpad Prism software.

[0760] 4. Experimental Results and Conclusions

[0761] 4.1 CCK-8 Test

[0762] 4.1.1 Effects of different concentrations of ZFQ-I-1 on Aβ 1-42 The effects of inducing AD cell model are shown in Table 98.

[0763] Table 98 Effects of different concentrations of ZFQ-I-1 on Aβ 1-42 Effects of induced AD cell model

[0764]

[0765] In the table: mean plus or minus standard error, n=3; * indicates p <0.05, ** indicates p<0.01, *** indicates p <0.001.

[0766] 4.1.2 Effects of different concentrations of ZFQ-I-2 on Aβ 1-42 The effects of inducing AD cell model are shown in Table 99.

[0767] Table 99 Effects of different concentrations of ZFQ-I-2 on Aβ 1-42 Effects of induced AD cell models

[0768]

[0769] In the table: mean plus or minus standard error, n=3; * indicates p <0.05, ** indicates p <0.01, *** indicates p <0.001.

[0770] 4.1.3 Effects of different concentrations of ZFQ-I-3 on Aβ 1-42The effects of inducing AD cell models are shown in Table 100.

[0771] Table 100 Effects of different concentrations of ZFQ-I-3 on Aβ 1-42 Effects of induced AD cell models

[0772]

[0773] In the table: mean plus or minus standard error, n=3; * indicates p <0.05, ** indicates p <0.01, *** indicates p <0.001.

[0774] 4.1.4 Effects of different concentrations of ZFQ-I-4 on Aβ 1-42 The effects of inducing AD cell models are shown in Table 101.

[0775] Table 101 Effects of different concentrations of ZFQ-I-4 on Aβ 1-42 Effects of induced AD cell models

[0776]

[0777] In the table: mean plus or minus standard error, n=3; * indicates p<0.05, ** indicates p<0.01, *** indicates p<0.001.

[0778] 4.1.5 Effects of different concentrations of ZFQ-I-5 on Aβ 1-42 The effects of inducing AD cell models are shown in Table 102.

[0779] Table 102 Effects of different concentrations of ZFQ-I-5 on Aβ 1-42 Effects of induced AD cell models

[0780]

[0781] In the table: mean plus or minus standard error, n=3; * indicates p<0.05, *** indicates p<0.001.

[0782] 4.1.6 Effects of different concentrations of ZFQ-I-6 on Aβ 1-42 The effects of inducing AD cell models are shown in Table 103.

[0783] Table 103 Effects of different concentrations of ZFQ-I-6 on Aβ 1-42 Effects of induced AD cell models

[0784]

[0785] In the table: mean plus or minus standard error, n=3; ** indicates p<0.01, *** indicates p<0.001.

[0786] 4.1.7 Effects of different concentrations of ZFQ-I-7 on Aβ 1-42 The effects of inducing an AD cell model are shown in Table 104.

[0787] Table 104 Effects of different concentrations of ZFQ-I-7 on Aβ 1-42 Effects of induced AD cell models

[0788]

[0789] In the table: mean plus or minus standard error, n=3; *** indicates p<0.001.

[0790] 4.1.8 Effects of different concentrations of ZFQ-I-8 on Aβ 1-42 The effects of inducing AD cell models are shown in Table 105.

[0791] Table 105 Effects of different concentrations of ZFQ-I-8 on Aβ 1-42 Effects of induced AD cell models

[0792]

[0793] In the table: mean plus or minus standard error, n=3; ** indicates p<0.01, *** indicates p<0.001.

[0794] 4.1.9 Effects of different concentrations of ZFQ-I-9 on Aβ 1-42 The effects of inducing AD cell models are shown in Table 106.

[0795] Table 106 Effects of different concentrations of ZFQ-I-9 on Aβ 1-42 Effects of induced AD cell models

[0796]

[0797] In the table: mean plus or minus standard error, n=3; * indicates p<0.05, *** indicates p<0.001.

[0798] 4.1.10 Effects of different concentrations of ZFQ-I-10 on Aβ 1-42 The effects of inducing AD cell models are shown in Table 107.

[0799] Table 107 Effects of different concentrations of ZFQ-I-10 on Aβ 1-42 Effects of induced AD cell models

[0800]

[0801] In the table: mean plus or minus standard error, n=3; * indicates p<0.05, *** indicates p<0.001.

[0802] 4.1.11 Effects of different concentrations of ZFQ-I-11 on Aβ 1-42 Effects of induced AD cell models

[0803] Table 108 Effects of different concentrations of ZFQ-I-11 on Aβ 1-42 Effects of induced AD cell models

[0804]

[0805] In the table: mean plus or minus standard error, n=3; * indicates p<0.05, *** indicates p<0.001.

[0806] 4.1.12 Effects of different concentrations of ZFQ-I-12 on Aβ 1-42 The effects of inducing AD cell model are shown in Table 109.

[0807] Table 109 Effects of different concentrations of ZFQ-I-12 on Aβ 1-42 Effects of induced AD cell models

[0808]

[0809] In the table: mean plus or minus standard error, n=3; * indicates p<0.05, *** indicates p<0.001.

[0810] 4.1.13 Effects of different concentrations of ZFQ-I-13 on Aβ 1-42 The effects of inducing AD cell model are shown in Table 110.

[0811] Table 110 Effects of different concentrations of ZFQ-I-13 on Aβ 1-42 Effects of induced AD cell models

[0812]

[0813] In the table: mean plus or minus standard error, n=3; ** indicates p<0.01, *** indicates p<0.001.

[0814] 4.1.14 Effects of different concentrations of ZFQ-I-14 on Aβ 1-42 The effects of inducing AD cell model are shown in Table 111.

[0815] Table 111 Effects of different concentrations of ZFQ-I-14 on Aβ 1-42 Effects of induced AD cell models

[0816]

[0817] In the table: mean plus or minus standard error, n=3; * indicates p<0.05, ** indicates p<0.01, *** indicates p<0.001.

[0818] 4.1.15 Effects of different concentrations of ZFQ-I-15 on Aβ 1-42 The effects of inducing AD cell model are shown in Table 112.

[0819] Table 112 Effects of different concentrations of ZFQ-I-15 on Aβ 1-42 Effects of induced AD cell models

[0820]

[0821] In the table: mean plus or minus standard error, n=3; *** indicates p<0.001.

[0822] 4.1.16 Effects of different concentrations of ZFQ-I-16 on Aβ 1-42 The effects of inducing AD cell models are shown in Table 113.

[0823] Table 113 Effects of different concentrations of ZFQ-I-16 on Aβ 1-42 Effects of induced AD cell models

[0824]

[0825] In the table: mean plus or minus standard error, n=3; *** indicates p<0.001.

[0826] 4.1.17 Effects of different concentrations of ZFQ-I-17 on Aβ 1-42 The effects of inducing AD cell models are shown in Table 114.

[0827] Table 114 Effects of different concentrations of ZFQ-I-17 on Aβ 1-42 Effects of induced AD cell models

[0828]

[0829] In the table: mean plus or minus standard error, n=3; ** indicates p<0.01, *** indicates p<0.001.

[0830] 4.1.18 Effects of different concentrations of ZFQ-I-18 on Aβ 1-42 The effects of inducing AD cell models are shown in Table 115.

[0831] Table 115 Effects of different concentrations of ZFQ-I-18 on Aβ 1-42 Effects of induced AD cell models

[0832]

[0833] In the table: mean plus or minus standard error, n=3; *** indicates p<0.001.

[0834] 4.1.19 Effects of different concentrations of ZFQ-I-19 on Aβ 1-42 The effects of inducing AD cell models are shown in Table 116.

[0835] Table 116 Effects of different concentrations of ZFQ-I-19 on Aβ 1-42 Effects of induced AD cell models

[0836]

[0837] In the table: mean plus or minus standard error, n=3; *** indicates p<0.001.

[0838] 4.1.20 Effects of different concentrations of ZFQ-I-20 on Aβ 1-42 The effects of inducing AD cell models are shown in Table 117.

[0839] Table 117 Effects of different concentrations of ZFQ-I-20 on Aβ 1-42 Effects of induced AD cell models

[0840]

[0841] In the table: mean plus or minus standard error, n=3; *** indicates p<0.001.

[0842] 4.1.21 Effects of different concentrations of ZFQ-I-21 on Aβ 1-42 The effects of inducing AD cell models are shown in Table 118.

[0843] Table 118 Effects of different concentrations of ZFQ-I-21 on Aβ 1-42 Effects of induced AD cell models

[0844]

[0845] In the table: mean plus or minus standard error, n=3; *** indicates p<0.001.

[0846] 4.1.22 Effects of different concentrations of ZFQ-I-22 on Aβ 1-42 The effects of inducing AD cell models are shown in Table 119.

[0847] Table 119 Effects of different concentrations of ZFQ-I-22 on Aβ 1-42 Effects of induced AD cell models

[0848]

[0849] In the table: mean plus or minus standard error, n=3; *** indicates p<0.001.

[0850] 4.1.23 Effects of different concentrations of ZFQ-I-23 on Aβ 1-42 The effects of inducing AD cell model are shown in Table 120.

[0851] Table 120 Effects of different concentrations of ZFQ-I-23 on Aβ 1-42 Effects of induced AD cell models

[0852]

[0853] In the table: mean plus or minus standard error, n=3; * indicates p <0.05, *** indicates p<0.001.

[0854] 4.1.24 Effects of different concentrations of ZFQ-I-24 on Aβ 1-42 The effects of inducing AD cell model are shown in Table 121.

[0855] Table 121 Effects of different concentrations of ZFQ-I-24 on Aβ 1-42 Effects of induced AD cell models

[0856]

[0857] In the table: mean plus or minus standard error, n=3;** p <0.01, *** indicates p<0.001.

[0858] 4.1.25 Effects of different concentrations of ZFQ-I-25 on Aβ 1-42 The effects of inducing AD cell model are shown in Table 122.

[0859] Table 122 Effects of different concentrations of ZFQ-I-25 on Aβ 1-42 Effects of induced AD cell models

[0860]

[0861] In the table: mean plus or minus standard error, n=3; *** indicates p<0.001.

[0862] 4.1.26 Effects of different concentrations of ZFQ-I-26 on Aβ 1-42 The effects of inducing AD cell models are shown in Table 123.

[0863] Table 123 Effects of different concentrations of ZFQ-I-26 on Aβ 1-42 Effects of induced AD cell models

[0864]

[0865] In the table: mean plus or minus standard error, n=3; *** indicates p<0.001.

[0866] 4.1.27 Effects of different concentrations of ZFQ-I-27 on Aβ 1-42 The effects of inducing AD cell models are shown in Table 124.

[0867] Table 124 Effects of different concentrations of ZFQ-I-27 on Aβ 1-42 Effects of induced AD cell models

[0868]

[0869] In the table: mean plus or minus standard error, n=3; *** indicates p<0.001.

[0870] 4.1.28 Effects of different concentrations of ZFQ-I-28 on Aβ 1-42 The effects of inducing AD cell models are shown in Table 125.

[0871] Table 125 Effects of different concentrations of ZFQ-I-28 on Aβ 1-42 Effects of induced AD cell models

[0872]

[0873] In the table: mean plus or minus standard error, n=3; *** indicates p<0.001.

[0874] 4.1.29 Effects of different concentrations of ZFQ-I-29 on Aβ 1-42 The effects of inducing AD cell models are shown in Table 126.

[0875] Table 126 Effects of different concentrations of ZFQ-I-29 on Aβ 1-42 Effects of induced AD cell models

[0876]

[0877] In the table: mean plus or minus standard error, n=3; ** indicates p<0.01, *** indicates p<0.001.

[0878] 4.1.30 Effects of different concentrations of ZFQ-I-30 on Aβ 1-42 The effects of inducing AD cell models are shown in Table 127.

[0879] Table 127 Effects of different concentrations of ZFQ-I-30 on Aβ 1-42 Effects of induced AD cell models

[0880]

[0881] In the table: mean plus or minus standard error, n=3; *** indicates p<0.001.

[0882] The above activity assays demonstrated the construction of Aβ in SH-SY5Y cells. 1-42 In an induced Alzheimer's disease (AD) cell model, the protective activity of 30 memantine-OAB derivative compounds (ZFQ-Ⅰ series) at three concentrations (0.1 μmol / L, 1 μmol / L, and 10 μmol / L) against AD model cells was systematically evaluated using the CCK-8 assay. Based on statistical analysis and dose-response characteristics, all tested compounds were classified into the following three categories. The specific conclusions are as follows:

[0883] I. The compound exhibits dose-dependent activity (its activity changes with concentration in a clear and predictable manner, making its efficacy highly predictable).

[0884] The cytoprotective activity of these compounds shows a significant and regular correlation with the administered concentration, exhibiting a gradual increase in activity with increasing concentration or a typical concentration-dependent characteristic of "effective at low and medium concentrations and inhibited at high concentrations," with outstanding pharmacodynamic stability and predictability.

[0885] (i) The compound exhibits a positive dose-dependent effect (activity gradually increases with increasing concentration).

[0886] ZFQ-Ⅰ-17 showed significant efficacy at a concentration of 0.1 μmol / L (71.990±3.574%). p <0.01%, stable activity at a concentration of 1 μmol / L (72.400±3.053%). p <0.01%, and at a concentration of 10 μmol / L, the activity further increased to its peak (76.847±1.486%). p <0.001), showing a clear trend of increased activity with increasing concentration, and a significant dose-dependent effect.

[0887] (ii) Dose-dependent compounds that are effective at low to medium concentrations and inhibited at high concentrations

[0888] ZFQ-Ⅰ-23: Significantly effective at a concentration of 0.1 μmol / L (67.467±2.033%). p <0.05%, activity decreased at 1 μmol / L concentration (63.147±2.600%, no statistical difference), and cell viability plummeted to 33.120±3.248% at 10 μmol / L concentration. p <0.001), exhibiting a dose-dependent characteristic of being effective at low concentrations and strongly inhibitory at high concentrations.

[0889] II. Compounds that are not dose-dependent but are effective at low to medium or medium to high concentrations (with stable activity but atypical concentration-effect relationships).

[0890] These compounds do not exhibit a clear dose-activity positive or negative correlation, but they consistently show significant cytoprotective effects in the low-to-medium concentration range or the medium-to-high concentration range, with a wide activity coverage and certain development potential.

[0891] (a) Low to medium concentration of effective compounds

[0892] ZFQ-Ⅰ-1: 0.1μmol / L (71.913±1.902%, p <0.01) and 1 μmol / L (68.977±4.554%) p The activity was significant at concentrations <0.01%, and decreased slightly at a concentration of 10 μmol / L (66.713±3.201%). p <0.05), with better activity at low and medium concentrations, and no dose dependence.

[0893] ZFQ-Ⅰ-2: The optimal activity was observed at a concentration of 0.1 μmol / L (73.720 ± 3.480%). p <0.01%, activity decreased at 1 μmol / L concentration (65.133±4.298%, no statistical difference), and significantly increased again at 10 μmol / L concentration (71.537±4.934%). p <0.05), the concentration effect fluctuates, but it shows a protective effect at low and medium concentrations.

[0894] ZFQ-Ⅰ-9: Significantly effective only at a concentration of 1 μmol / L (64.637±1.440%). p <0.05), the activity was not different from the model group at concentrations of 0.1 μmol / L and 10 μmol / L, and it was specifically effective at medium concentrations.

[0895] ZFQ-Ⅰ-11: Significantly effective at a concentration of 1 μmol / L (64.403 ± 0.789%). p <0.05), the activity was not significant at concentrations of 0.1 μmol / L and 10 μmol / L, but the activity was prominent at medium concentrations.

[0896] (ii) Medium to high concentration of effective compounds

[0897] ZFQ-Ⅰ-7: Extremely effective at all three tested concentrations ( p<0.001), 0.1μmol / L (75.187±1.952%), 1μmol / L (77.997±1.683%), 10μmol / L (74.003±2.320%) showed small activity fluctuations, sustained and stable efficacy at medium and high concentrations, and no dose dependence.

[0898] ZFQ-Ⅰ-8: 0.1μmol / L (89.590±6.717%, p <0.001), 1μmol / L (80.863±3.029%, p <0.01), 10μmol / L (76.807±0.868%, p It is significantly effective at concentrations of <0.01, with optimal activity at low concentrations but still maintaining strong efficacy at medium and high concentrations, and there is no dose dependence.

[0899] ZFQ-Ⅰ-12: At a medium concentration of 1 μmol / L, it showed a highly significant effect (78.573±1.816%). p <0.001), no protective effect at 0.1 μmol / L concentration, and toxicity at 10 μmol / L concentration (36.887±3.048%). p <0.05), medium concentration, specific and potent.

[0900] (iii) Compounds that are effective at all concentrations but not dose-dependent

[0901] ZFQ-Ⅰ-3: 0.1μmol / L (81.100±4.694%, p <0.001), 1μmol / L (80.723±5.232%, p <0.01), 10μmol / L (83.133±2.963%, p The activity was highly significant at concentrations of <0.001, and its activity was close to that of the normal control group. The activity was stable across the entire concentration range, but there was no dose-dependent difference.

[0902] ZFQ-Ⅰ-13: Significantly effective at all three tested concentrations ( p <0.01 or p The activity was stable at concentrations of <0.001 μmol / L, 0.1 μmol / L (73.230±3.079%), 1 μmol / L (75.750±0.830%), and 10 μmol / L (71.003±2.417%), with no significant dose-dependent fluctuations, and it could effectively protect cells across the entire concentration range.

[0903] ZFQ-Ⅰ-18: Extremely effective at all three tested concentrations ( p<0.001), 0.1 μmol / L (78.710±1.983%), 1 μmol / L (83.257±2.424%), 10 μmol / L (74.107±1.961%). The activity was optimal at the 1 μmol / L concentration, but there was no significant dose-dependent fluctuation overall, and the protective effect was stable across the entire concentration range.

[0904] ZFQ-Ⅰ-19: 0.1μmol / L (70.543±2.452%, p <0.001), 1μmol / L (74.727±1.941%, p <0.001), 10μmol / L (74.570±2.340%, p It is potent and effective at concentrations of <0.001, and the activity increases slightly with increasing concentration but there is no significant difference. It is not dose-dependent.

[0905] ZFQ-Ⅰ-24: 0.1μmol / L (76.213±2.043%, p The activity was optimal at a concentration of <0.001%, and at 1 μmol / L (71.467±1.960%). p <0.001) and 10 μmol / L (66.240±1.762%) p At concentrations <0.01, the activity decreased slightly but remained significant. It effectively protected cells across the entire concentration range and was not dose-dependent.

[0906] III. Compounds that offer no clear protection or contain potential toxicity.

[0907] These compounds did not exhibit clear cell-protective activity against AD at all tested concentrations, and some compounds even showed lower cell viability than the model group, indicating potential cytotoxicity.

[0908] ZFQ-Ⅰ-4: 0.1μmol / L (26.660±0.924%, p <0.01) and 1 μmol / L (32.980±1.066%) p At a concentration of <0.05%, cell survival was significantly lower than that in the model group, showing clear toxicity. At a concentration of 10 μmol / L, cell survival only recovered to 60.767±4.440% (no statistical difference), with no protective effect.

[0909] ZFQ-Ⅰ-5: 0.1μmol / L (25.147±0.527%, p <0.001) and 1 μmol / L (24.700±2.442%) pThe toxicity was significant at concentrations <0.001%, and only recovered to 35.090±0.718% at a concentration of 10 μmol / L. p <0.05), indicating no effective protection.

[0910] ZFQ-Ⅰ-6: 0.1μmol / L (26.730±2.885%, p <0.01) and 1 μmol / L (31.703±2.491%) p At concentrations <0.01, the toxicity was significant, but at a concentration of 10 μmol / L, it recovered to 43.450±0.942% (no statistical difference), showing no protective activity.

[0911] ZFQ-Ⅰ-10: 0.1μmol / L (39.930±2.012%, p <0.05), 1μmol / L (41.920±0.312%, p <0.05), 10μmol / L (28.337±1.116%, p Cell survival rates at concentrations <0.001 were significantly lower than in the model group, and toxicity increased with increasing concentration, with no protective effect.

[0912] ZFQ-Ⅰ-14: 0.1μmol / L (47.333±2.773%, p <0.05) and 10 μmol / L (39.017±4.337%) p Significant toxicity at concentrations <0.01%, with only slight activity at 1 μmol / L concentration (71.237±0.356%). p Although the concentration of the substance was less than 0.01%, its overall toxicity was significant, and it did not provide any obvious protective effect.

[0913] ZFQ-Ⅰ-15: Cell viability at all tested concentrations (0.1 μmol / L: 67.250±6.863%, 1 μmol / L: 60.457±4.496%, 10 μmol / L: 57.647±2.197%) did not reach statistical significance compared with the model group, indicating no clear protective effect.

[0914] ZFQ-Ⅰ-16: Extremely toxic at a concentration of 10 μmol / L (28.000±2.518%). p <0.001), and at concentrations of 0.1 μmol / L and 1 μmol / L, the activity was no different from that of the model group, indicating significant potential toxicity.

[0915] ZFQ-Ⅰ-20: Cell viability at all tested concentrations (0.1 μmol / L: 52.713±1.477%, 1 μmol / L: 62.947±4.809%, 10 μmol / L: 51.370±3.367%) did not reach statistical significance compared with the model group, indicating no clear protective effect.

[0916] ZFQ-Ⅰ-21: Cell viability at each concentration (0.1 μmol / L: 52.043±3.203%, 1 μmol / L: 59.950±2.537%, 10 μmol / L: 60.927±2.784%) was not significantly different from that in the model group, and it did not show any anti-AD cell damage activity.

[0917] ZFQ-Ⅰ-22: Cell viability at all tested concentrations (0.1 μmol / L: 56.590±3.851%, 1 μmol / L: 55.243±4.568%, 10 μmol / L: 52.970±4.333%) was not significantly better than that of the model group, indicating no protective activity.

[0918] ZFQ-Ⅰ-25: Cell viability at all tested concentrations (0.1 μmol / L: 52.833±3.073%, 1 μmol / L: 56.590±4.103%, 10 μmol / L: 56.647±2.001%) did not reach statistical significance compared with the model group, indicating no clear protective effect.

[0919] ZFQ-Ⅰ-26: Cell viability at each concentration (0.1 μmol / L: 51.363±2.646%, 1 μmol / L: 56.643±6.908%, 10 μmol / L: 68.680±1.153%) did not reach statistical significance, indicating no protective activity.

[0920] ZFQ-Ⅰ-27: Cell viability at all tested concentrations (0.1 μmol / L: 51.307±1.112%, 1 μmol / L: 60.840±4.096%, 10 μmol / L: 53.867±2.563%) was not significantly better than that of the model group, indicating no protective activity.

[0921] ZFQ-Ⅰ-28: Cell viability at each concentration (0.1 μmol / L: 55.883±3.763%, 1 μmol / L: 55.393±1.554%, 10 μmol / L: 58.933±2.963%) was not significantly different from that in the model group, and it did not show any anti-AD cell damage activity.

[0922] ZFQ-Ⅰ-29: No significant activity was observed at concentrations of 0.1 μmol / L and 1 μmol / L. The cell viability at a concentration of 10 μmol / L (68.900±1.628%) did not reach statistical significance, indicating no clear protective effect.

[0923] ZFQ-Ⅰ-30: Cell viability at all tested concentrations (0.1 μmol / L: 58.550±3.976%, 1 μmol / L: 51.250±1.280%, 10 μmol / L: 50.437±5.551%) was not significantly better than that of the model group, indicating no protective activity.

[0924] In summary, the dose-dependent compounds are ZFQ-Ⅰ-17 and ZFQ-Ⅰ-23, while the non-dose-dependent compounds effective at low to medium concentrations are ZFQ-Ⅰ-1, ZFQ-Ⅰ-2, ZFQ-Ⅰ-3, ZFQ-Ⅰ-7, ZFQ-Ⅰ-8, ZFQ-Ⅰ-9, ZFQ-Ⅰ-11, ZFQ-Ⅰ-12, ZFQ-Ⅰ-13, ZFQ-Ⅰ-18, ZFQ-Ⅰ-19, and ZFQ-Ⅰ-24. The compounds that did not show significant protective effects in vivo were ZFQ-Ⅰ-4, ZFQ-Ⅰ-5, ZFQ-Ⅰ-6, ZFQ-Ⅰ-10, ZFQ-Ⅰ-14, ZFQ-Ⅰ-15, ZFQ-Ⅰ-16, ZFQ-Ⅰ-20, ZFQ-Ⅰ-21, ZFQ-Ⅰ-22, ZFQ-Ⅰ-25, ZFQ-Ⅰ-26, ZFQ-Ⅰ-27, ZFQ-Ⅰ-28, ZFQ-Ⅰ-29, and ZFQ-Ⅰ-30.

[0925] Among them, ZFQ-Ⅰ-3, ZFQ-Ⅰ-7, ZFQ-Ⅰ-8, ZFQ-Ⅰ-13, ZFQ-Ⅰ-18, ZFQ-Ⅰ-19, and ZFQ-Ⅰ-24 all showed extremely significant protective effects at the three test concentrations, with stable activity and no obvious toxicity, making them the core advantageous candidates of the I series.

Claims

1. A memantine derivative, characterized in that: Structural formula is , , , , , , , .

2. A method for synthesizing the amantadine derivative according to claim 1, characterized in that: The method comprises the following steps: adding p-nitrobenzoyl chloride into memantine hydrochloride, reacting at 0-10 DEG C in a solvent under nitrogen protection, then adding a mixture of triethylamine and a solvent, continuing to react at room temperature, and carrying out post-treatment on the obtained reaction solution to obtain an intermediate of structural formula I The obtained intermediate of structural formula I is mixed with palladium-carbon and an organic solvent to react, and the reaction solution is subjected to post-treatment to obtain an intermediate of structural formula II Phenyl chloroformate, potassium carbonate and an organic solvent are added into the obtained intermediate of structural formula II to react under reflux, and the reaction solution is subjected to post-treatment to obtain an intermediate of structural formula III An amino-substituted base material, triethylamine and a solvent are added into the obtained intermediate of structural formula III to react under reflux, and the reaction solution is subjected to post-treatment to obtain a memantine derivative The amino-substituted raw materials are ethanolamine, 3-aminopropanol, N,N-dimethylethylenediamine, n-propylamine, 4-(2-aminoethyl)morpholine, tetrahydrothiazole, pyrrolidine, and N-(3-aminopropyl)morpholine.

3. An application of the ammonium nitrate derivative according to claim 1, characterized in that: It is used in the preparation of drugs for treating Alzheimer's disease and Parkinson's disease.

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