adamantane derivatives, their synthesis methods and applications

Abstract

This invention belongs to the technical field of drug synthesis, specifically relating to adamantane derivatives, their synthetic methods, and applications. The adamantane derivatives described in this invention include intermediate structural formulas I, II, and III, as well as structures with the following general formula: Linker is a substituted or unsubstituted C6-C10 aryl group; R1 is hydrogen or a C1-C6 alkyl group; R2 is hydrogen, a C1-C6 alkyl group, or a nitrogen-containing or nitrogen-free structural fragment; or the overall structure of R1R2 is an N-substituted heterocyclopentyl or heterocyclohexyl group. The adamantane derivatives provided by this invention combine the adamantane structure with a portion of the OAB-14 group, altering the core structure and thus improving drug activity. This invention also provides a synthetic method for these derivatives. Through cellular activity studies, the resulting compounds are screened, demonstrating potential synergistic effects in the prevention of influenza and the treatment of Alzheimer's disease.

Description

Technical Field

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

[0002] Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by senile plaques formed by the deposition of β-amyloid (Aβ) protein, neurofibrillary tangles caused by hyperphosphorylation of tau protein, and the resulting neuronal loss and synaptic dysfunction. Currently, the number of AD patients worldwide is large and continues to grow, but clinical treatments are limited, mainly focusing on cholinesterase inhibitors and NMDA receptor antagonists. These drugs can only alleviate some symptoms and cannot effectively stop or reverse the disease progression. Therefore, developing drugs with novel mechanisms of action that can fundamentally intervene in the pathological process of AD is an urgent research need.

[0003] OAB-14 is a novel and promising candidate compound for treating Alzheimer's disease. Its chemical name is 4-(3-(2-aminoethyl)ureo)-N-(1,1,4,4,5,5,8,8-octamethyl-1,2,3,4,5,6,7,8-octahydroanthracene-9-yl)benzamide. The structural formula of OAB-14 is as follows: Preclinical studies have shown that OAB-14 exhibits significant neuroprotective activity and cognitive function improvement, and its mechanism of action may transcend traditional single-target approaches, offering new possibilities for AD treatment. However, new drug development often faces challenges such as poor pharmacokinetic properties, low bioavailability, or potential toxic side effects. Therefore, structural optimization of lead compounds is a crucial step in drug development.

[0004] On the other hand, adamantane Amantadine is a classic drug that has been on the market for many years, with its unique adamantane structure at its core. Initially used as an antiviral drug, it specifically inhibits the ion channel function of the M2 protein of influenza A virus. Subsequently, its effects on the central nervous system were discovered; it can promote the release of dopamine in the striatum and directly stimulate dopamine receptors, while also possessing a mild anticholinergic effect. Therefore, it is widely used to treat Parkinson's disease and Parkinson's syndrome. Summary of the Invention

[0005] The technical problem this invention aims to solve is to overcome the aforementioned deficiencies in the prior art by providing an adamantane derivative that combines the adamantane structure with certain groups of the OAB-14 structure, thereby altering the core structure and improving drug activity. This invention also provides a method for its synthesis. Its use in the preparation of synergistic therapeutic drugs for the prevention of influenza and the treatment of Alzheimer's disease enhances its drug development potential.

[0006] The adamantane derivatives of this invention include intermediates with structural formula I. Intermediate structure formula II Intermediate structure formula III and the general structural formula is 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.

[0007] Preferably, the NR1R2 structure is as follows: , .

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

[0009] .

[0010] The adamantane derivatives of the present invention are: N-((3s,5s,7s)-adamantane-1-yl)-4-nitrobenzamide, N-((3s,5s,7s)-adamantane-1-yl)-4-aminobenzamide, phenyl(4-((3S,5S,7S)-adamantane-1-yl)carbamoyl)phenyl)carbamate, N-((3s,5s,7s)-p-xylyl)-4-(3-methyluryl)aniline, N-((3s,5s,7s)-p-xylyl)-4-(3-ethyluryl)aniline, N-((3s,5s,7s)-p-xylyl)-4-(3-(2-hydroxyethyl)uryl)benzamide ...3s,5s,7s)-p-xylyl)-4-(3-(2-hydroxyethyl)uryl)benzamide, N-(3s,5s,7s)-p-xylyl)-4-(3-(2-hydroxyethyl)uryl)-4-(3-(3s,5s,7s)-p-xylyl)-4-(3-(2-hydroxyethyl)uryl)-4-(3-(3s,5s,7s)-p-xylyl)-4-( phenyl)-4-(3-(3-hydroxypropyl)uryl)benzamide, N-((3s,5s,7s)-p-xylyl)-4-(3-(4-hydroxybutyl)uryl)benzamide, N-((3s,5s,7s)-p-xylyl)-4-(3-(2-(diethylamino)ethyl)ureo)benzamide, N-((3s,5s,7s)-p-xylyl)-4-(3-(3-(diethylamino)propyl)ureo)benzamide, N-((3s,5s,7s)-p-xylyl)-4-(3-propylureo)benzamide, N-((3s,5s,7s)-p-xylyl)-4-(3,3-diethylureo)benzamide, N-((3s,5s,7s)-p-xylyl)-4-(3,3-diethylureo)benzamide, N-((3s,5s,7s) 7s)-p-xylyl)-4-(3,3-dimethylurea)aniline, N-((3s,5s,7s)-p-xylyl-1-yl)-4-(3-phenyluryl)aniline, N-((3s,5s,7s)-p-xylyl)-4-(3-(2-morpholinoethyl)urea)benzamide, N-(4-(((3s,5s,7s)-p-xylyl)carbamoyl)phenyl)pyrrolidine-1-carboxylic acid ester, N-((3s,5s,7s)-p-xylyl)-4-(3-(3-(piperidin-1-yl)propyl)urea)benzamide, N-((3s,5s,7s)-p-xylyl)-4-(3-(3-(4-methylpiperazin-1-yl)propyl)uryl)benzamide Formamide, N-((3s,5s,7s)-p-xylyl)-4-(3-(2-(piperidin-1-yl)ethyl)ureoyl)benzamide, N-((3s,5s,7s)-p-xylyl)-4-(3-(3-piperidinylpropyl)ureoyl)benzamide, N-((3s,5s,7s)-p-xylyl)-4-(3-(3-(dimethylamino)propyl)ureoyl)benzamide, N-((3s,5s,7s)-p-xylyl)-4-(3-(2-(4-methylpiperazin-1-yl)ethyl)uryl)aniline, N-((3s,5s,7s)-p-xylyl)-4-(3-(2-aminopropyl)ureoyl)benzamide, N-(4-(((3s,5s,7s)7s)-p-xylyl)carbamoyl)phenyl)morpholine-4-carboxamide or N-((3s,5s,7s)-p-xylyl)-4-(3-cyclopropylurea)aniline.

[0011] The method for synthesizing the adamantane derivative includes the following steps: adding p-nitrobenzoyl chloride to adamantaneamine, reacting in a solvent at 0-10°C under nitrogen protection, then adding a mixture of triethylamine and solvent, continuing the reaction at room temperature, and post-processing the resulting reaction solution to obtain adamantane-OAB-1.

[0012] The obtained adamantane-OAB-1 was reacted with palladium on carbon and an organic solvent. After post-treatment, the reaction solution was used to obtain adamantane-OAB-2.

[0013] Phenyl chloroformate, potassium carbonate, and an organic solvent were added to the obtained adamantane-OAB-2, and the mixture was refluxed. After post-treatment, the reaction solution was used to obtain adamantane-OAB-3.

[0014] An amino-substituted raw material, triethylamine, and a solvent were added to the obtained adamantane-OAB-3, and the mixture was refluxed. After post-treatment, the reaction solution was used to obtain the adamantane-OAB- derivative.

[0015] The amino-substituted raw materials are methylamine, ethylamine, ethanolamine, 3-aminopropanol, 4-aminobutanol, N,N-diethylethylenediamine, 3-diethylaminopropylamine, n-propylamine, diethylamine, dimethylamine, aniline, 4-(2-aminoethyl)morpholine, pyrrolidine, 3-(piperidin-1-yl)propyl-1-amine, 1-(3-aminopropyl)-4-methylpiperazine, 1-(2-aminoethyl)piperidine, N-(3-aminopropyl)morpholine, 3-dimethylaminopropylamine, 4-methyl-1-piperazine ethylamine, 1,2-propanediamine, morpholine, or cyclopropylamine.

[0016] This invention utilizes the combination of the adamantane pharmacophore group and the OAB-14 pharmacophore group, while selecting the amino substituent groups, to obtain a series of new compounds. These new compounds have potential synergistic effects in the prevention of influenza and the treatment of Alzheimer's disease. Through in vitro cell activity studies, adamantane-OAB derivative compounds with better activity were preliminarily screened.

[0017] Applications of the aforementioned adamantane derivatives: They are used in the preparation of drugs for the prevention of influenza and the treatment of Alzheimer's disease. Drugs with synergistic effects in preventing influenza and treating Alzheimer's disease are screened.

[0018] The synthetic route of the compounds of this invention is as follows, wherein the linker is benzoyl, the starting material is adamantane, and the adamantane-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 beneficial effects of the present invention are:

[0021] (1) The adamantane derivatives of the present invention are a novel type of compound constructed by innovatively combining the adamantane structural unit with a clear neuromodulatory activity with the candidate drug OAB-14 with significant neuroprotective and cognitive improvement functions.

[0022] (2) The derivatives of the present invention are modified and optimized through flexible linker arms and diverse R3 groups, which significantly enhances the diversity and tunability of the compound structure.

[0023] (3) The synthesis method provided by this invention has a clear route, is easy to operate, and uses readily available raw materials. It can efficiently and efficiently prepare a series of target derivatives and their pharmaceutically acceptable salts, laying a solid material foundation for subsequent in-depth pharmacological activity screening and preclinical research. Attached Figure Description

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

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

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

[0027] Figure 4 The HPLC spectrum of adamantane-OAB-6 in Example 4 is shown below.

[0028] Figure 5 The HPLC spectrum of adamantane-OAB-7 in Example 5 is shown below.

[0029] Figure 6 The HPLC spectrum of adamantane-OAB-8 in Example 6 is shown below.

[0030] Figure 7 The HPLC spectrum of adamantane-OAB-9 in Example 7 is shown below.

[0031] Figure 8 The HPLC spectrum of adamantane-OAB-10 in Example 8 is shown below.

[0032] Figure 9 The HPLC spectrum of adamantane-OAB-11 in Example 9 is shown below.

[0033] Figure 10The HPLC spectrum of adamantane-OAB-12 in Example 10 is shown below.

[0034] Figure 11 The HPLC spectrum of adamantane-OAB-15 in Example 11 is shown below.

[0035] Figure 12 The HPLC spectrum of adamantane-OAB-16 in Example 12 is shown below.

[0036] Figure 13 The HPLC spectrum of adamantane-OAB-17 in Example 13 is shown below.

[0037] Figure 14 The HPLC spectrum of adamantane-OAB-18 in Example 14 is shown below.

[0038] Figure 15 The HPLC spectrum of adamantane-OAB-19 in Example 15 is shown below.

[0039] Figure 16 The HPLC spectrum of adamantane-OAB-21 in Example 16 is shown below.

[0040] Figure 17 The HPLC spectrum of adamantane-OAB-23 in Example 17 is shown below.

[0041] Figure 18 The HPLC spectrum of adamantane-OAB-24 in Example 18 is shown below.

[0042] Figure 19 The HPLC spectrum of adamantane-OAB-25 in Example 19 is shown below.

[0043] Figure 20 The HPLC spectrum of adamantane-OAB-26 in Example 20 is shown below.

[0044] Figure 21 The HPLC spectrum of adamantane-OAB-28 in Example 21 is shown below.

[0045] Figure 22 The HPLC spectrum of adamantane-OAB-29 in Example 22 is shown below.

[0046] Figure 23 The HPLC spectrum of adamantane-OAB-33 in Example 23 is shown below.

[0047] Figure 24 The HPLC spectrum of adamantane-OAB-34 in Example 24 is shown below.

[0048] Figure 25 The HPLC spectrum of adamantane-OAB-35 in Example 25 is shown below.

[0049] Figure 26 Example 1: 1H NMR spectrum of adamantane-OAB-1;

[0050] Figure 27 Example 1: 13CNMR spectrum of adamantane-OAB-1;

[0051] Figure 28 Example 1: COSY spectrum of adamantane-OAB-1;

[0052] Figure 29 Example 1: DEPT135 spectrum of adamantane-OAB-1;

[0053] Figure 30 Example 1: HMBC spectrum of adamantane-OAB-1;

[0054] Figure 31 Example 1: HSQC spectrum of adamantane-OAB-1;

[0055] Figure 32 Example 1: High-resolution mass spectrum of adamantane-OAB-1;

[0056] Figure 33 Example 2: 1H NMR spectrum of adamantane-OAB-2;

[0057] Figure 34 Example 2: 13CNMR spectrum of adamantane-OAB-2;

[0058] Figure 35 Example 2: COSY spectrum of adamantane-OAB-2;

[0059] Figure 36 Example 2: DEPT135 spectrum of adamantane-OAB-2;

[0060] Figure 37 Example 2: HMBC spectrum of adamantane-OAB-2;

[0061] Figure 38 Example 2: HSQC spectrum of adamantane-OAB-2;

[0062] Figure 39 Example 2: High-resolution mass spectrum of adamantane-OAB-2;

[0063] Figure 40 Example 3: 1H NMR spectrum of adamantane-OAB-3;

[0064] Figure 41 Example 3: 13CNMR spectrum of adamantane-OAB-3;

[0065] Figure 42Example 3: COSY spectrum of adamantane-OAB-3;

[0066] Figure 43 Example 3: DEPT135 spectrum of adamantane-OAB-3;

[0067] Figure 44 Example 3: HMBC spectrum of adamantane-OAB-3;

[0068] Figure 45 Example 3: HSQC spectrum of adamantane-OAB-3;

[0069] Figure 46 Example 3: High-resolution mass spectrum of adamantane-OAB-3;

[0070] Figure 47 Example 4: 1H NMR spectrum of adamantane-OAB-6;

[0071] Figure 48 Example 4: 13CNMR spectrum of adamantane-OAB-6;

[0072] Figure 49 Example 4: COSY spectrum of adamantane-OAB-6;

[0073] Figure 50 Example 4: DEPT135 spectrum of adamantane-OAB-6;

[0074] Figure 51 Example 4: HMBC spectrum of adamantane-OAB-6;

[0075] Figure 52 Example 4: HSQC spectrum of adamantane-OAB-6;

[0076] Figure 53 Example 4: High-resolution mass spectrum of adamantane-OAB-6;

[0077] Figure 54 Example 5: 1H NMR spectrum of adamantane-OAB-7;

[0078] Figure 55 Example 5: 13CNMR spectrum of adamantane-OAB-7;

[0079] Figure 56 Example 5: COSY spectrum of adamantane-OAB-7;

[0080] Figure 57 Example 5: DEPT135 spectrum of adamantane-OAB-7;

[0081] Figure 58 Example 5: HMBC spectrum of adamantane-OAB-7;

[0082] Figure 59 Example 5: HSQC spectrum of adamantane-OAB-7;

[0083] Figure 60 Example 5: High-resolution mass spectrum of adamantane-OAB-7;

[0084] Figure 61 Example 6: 1H NMR spectrum of adamantane-OAB-8;

[0085] Figure 62 Example 6: 13CNMR spectrum of adamantane-OAB-8;

[0086] Figure 63 Example 6: COSY spectrum of adamantane-OAB-8;

[0087] Figure 64 Example 6: DEPT135 spectrum of adamantane-OAB-8;

[0088] Figure 65 Example 6: HMBC spectrum of adamantane-OAB-8;

[0089] Figure 66 Example 6: HSQC spectrum of adamantane-OAB-8;

[0090] Figure 67 Example 6: High-resolution mass spectrum of adamantane-OAB-8;

[0091] Figure 68 Example 7: 1H NMR spectrum of adamantane-OAB-9;

[0092] Figure 69 Example 7: 13CNMR spectrum of adamantane-OAB-9;

[0093] Figure 70 Example 7: COSY spectrum of adamantane-OAB-9;

[0094] Figure 71 Example 7: DEPT135 spectrum of adamantane-OAB-9;

[0095] Figure 72 Example 7: HMBC spectrum of adamantane-OAB-9;

[0096] Figure 73 Example 7: HSQC spectrum of adamantane-OAB-9;

[0097] Figure 74 Example 7: High-resolution mass spectrum of adamantane-OAB-9;

[0098] Figure 75 Example 8: 1H NMR spectrum of adamantane-OAB-10;

[0099] Figure 76 Example 8: 13CNMR spectrum of adamantane-OAB-10;

[0100] Figure 77 Example 8: COSY spectrum of adamantane-OAB-10;

[0101] Figure 78 Example 8: DEPT135 spectrum of adamantane-OAB-10;

[0102] Figure 79 Example 8: HMBC spectrum of adamantane-OAB-10;

[0103] Figure 80 Example 8: HSQC spectrum of adamantane-OAB-10;

[0104] Figure 81 Example 8: High-resolution mass spectrum of adamantane-OAB-10;

[0105] Figure 82 Example 9: 1H NMR spectrum of adamantane-OAB-11;

[0106] Figure 83 Example 9: 13CNMR spectrum of adamantane-OAB-11;

[0107] Figure 84 Example 9: COSY spectrum of adamantane-OAB-11;

[0108] Figure 85 Example 9: DEPT135 spectrum of adamantane-OAB-11;

[0109] Figure 86 Example 9: HMBC spectrum of adamantane-OAB-11;

[0110] Figure 87 Example 9: HSQC spectrum of adamantane-OAB-11;

[0111] Figure 88 Example 9: High-resolution mass spectrum of adamantane-OAB-11;

[0112] Figure 89 Example 10: 1H NMR spectrum of adamantane-OAB-12;

[0113] Figure 90 Example 10: 13CNMR spectrum of adamantane-OAB-12;

[0114] Figure 91 Example 10: COSY spectrum of adamantane-OAB-12;

[0115] Figure 92 Example 10: DEPT135 spectrum of adamantane-OAB-12;

[0116] Figure 93 Example 10: HMBC spectrum of adamantane-OAB-12;

[0117] Figure 94 Example 10: HSQC spectrum of adamantane-OAB-12;

[0118] Figure 95 Example 10: High-resolution mass spectrum of adamantane-OAB-12;

[0119] Figure 96 Example 11: 1H NMR spectrum of adamantane-OAB-15;

[0120] Figure 97 Example 11: 13CNMR spectrum of adamantane-OAB-15;

[0121] Figure 98 Example 11: COSY spectrum of adamantane-OAB-15;

[0122] Figure 99 Example 11: DEPT135 spectrum of adamantane-OAB-15;

[0123] Figure 100 Example 11: HMBC spectrum of adamantane-OAB-15;

[0124] Figure 101 Example 11: HSQC spectrum of adamantane-OAB-15;

[0125] Figure 102 Example 11: High-resolution mass spectrum of adamantane-OAB-15;

[0126] Figure 103 Example 12: 1H NMR spectrum of adamantane-OAB-16;

[0127] Figure 104 Example 12: 13CNMR spectrum of adamantane-OAB-16;

[0128] Figure 105 Example 12: COSY spectrum of adamantane-OAB-16;

[0129] Figure 106 Example 12: DEPT135 spectrum of adamantane-OAB-16;

[0130] Figure 107 Example 12: HMBC spectrum of adamantane-OAB-16;

[0131] Figure 108 Example 12: HSQC spectrum of adamantane-OAB-16;

[0132] Figure 109 Example 12: High-resolution mass spectrum of adamantane-OAB-16;

[0133] Figure 110 Example 13: 1H NMR spectrum of adamantane-OAB-17;

[0134] Figure 111 Example 13: 13CNMR spectrum of adamantane-OAB-17;

[0135] Figure 112 Example 13: COSY spectrum of adamantane-OAB-17;

[0136] Figure 113 Example 13: DEPT135 spectrum of adamantane-OAB-17;

[0137] Figure 114 Example 13: HMBC spectrum of adamantane-OAB-17;

[0138] Figure 115 Example 13: HSQC spectrum of adamantane-OAB-17;

[0139] Figure 116 Example 13: High-resolution mass spectrum of adamantane-OAB-17;

[0140] Figure 117 Example 14: 1H NMR spectrum of adamantane-OAB-18;

[0141] Figure 118 Example 14: 13CNMR spectrum of adamantane-OAB-18;

[0142] Figure 119 Example 14: COSY spectrum of adamantane-OAB-18;

[0143] Figure 120 Example 14: DEPT135 spectrum of adamantane-OAB-18;

[0144] Figure 121 Example 14: HMBC spectrum of adamantane-OAB-18;

[0145] Figure 122 Example 14: HSQC spectrum of adamantane-OAB-18;

[0146] Figure 123 Example 14: High-resolution mass spectrum of adamantane-OAB-18;

[0147] Figure 124 Example 15: 1H NMR spectrum of adamantane-OAB-19;

[0148] Figure 125 Example 15: 13CNMR spectrum of adamantane-OAB-19;

[0149] Figure 126 Example 15: COSY spectrum of adamantane-OAB-19;

[0150] Figure 127 Example 15: DEPT135 spectrum of adamantane-OAB-19;

[0151] Figure 128 Example 15: HMBC spectrum of adamantane-OAB-19;

[0152] Figure 129 Example 15: HSQC spectrum of adamantane-OAB-19;

[0153] Figure 130 Example 15: High-resolution mass spectrum of adamantane-OAB-19;

[0154] Figure 131 Example 16: 1H NMR spectrum of adamantane-OAB-21;

[0155] Figure 132 Example 16: 13CNMR spectrum of adamantane-OAB-21;

[0156] Figure 133 Example 16: COSY spectrum of adamantane-OAB-21;

[0157] Figure 134 Example 16: DEPT135 spectrum of adamantane-OAB-21;

[0158] Figure 135 Example 16: HMBC spectrum of adamantane-OAB-21;

[0159] Figure 136 Example 16: HSQC spectrum of adamantane-OAB-21;

[0160] Figure 137 Example 16: High-resolution mass spectrum of adamantane-OAB-21;

[0161] Figure 138 Example 17: 1H NMR spectrum of adamantane-OAB-23;

[0162] Figure 139 Example 17: 13CNMR spectrum of adamantane-OAB-23;

[0163] Figure 140 Example 17: COSY spectrum of adamantane-OAB-23;

[0164] Figure 141 Example 17: DEPT135 spectrum of adamantane-OAB-23;

[0165] Figure 142 Example 17: HMBC spectrum of adamantane-OAB-23;

[0166] Figure 143 Example 17: HSQC spectrum of adamantane-OAB-23;

[0167] Figure 144 Example 17: High-resolution mass spectrum of adamantane-OAB-23;

[0168] Figure 145 Example 18: 1H NMR spectrum of adamantane-OAB-24;

[0169] Figure 146 Example 18: 13CNMR spectrum of adamantane-OAB-24;

[0170] Figure 147 Example 18: COSY spectrum of adamantane-OAB-24;

[0171] Figure 148 Example 18: DEPT135 spectrum of adamantane-OAB-24;

[0172] Figure 149 Example 18: HMBC spectrum of adamantane-OAB-24;

[0173] Figure 150 Example 18: HSQC spectrum of adamantane-OAB-24;

[0174] Figure 151 Example 18: High-resolution mass spectrum of adamantane-OAB-24;

[0175] Figure 152 Example 19: 1H NMR spectrum of adamantane-OAB-25;

[0176] Figure 153 Example 19: 13CNMR spectrum of adamantane-OAB-25;

[0177] Figure 154Example 19: COSY spectrum of adamantane-OAB-25;

[0178] Figure 155 Example 19: DEPT135 spectrum of adamantane-OAB-25;

[0179] Figure 156 Example 19: HMBC spectrum of adamantane-OAB-25;

[0180] Figure 157 Example 19: HSQC spectrum of adamantane-OAB-25;

[0181] Figure 158 Example 19: High-resolution mass spectrum of adamantane-OAB-25;

[0182] Figure 159 Example 20: 1H NMR spectrum of adamantane-OAB-26;

[0183] Figure 160 Example 20: 13CNMR spectrum of adamantane-OAB-26;

[0184] Figure 161 Example 20: COSY spectrum of adamantane-OAB-26;

[0185] Figure 162 Example 20: DEPT135 spectrum of adamantane-OAB-26;

[0186] Figure 163 Example 20: HMBC spectrum of adamantane-OAB-26;

[0187] Figure 164 Example 20: HSQC spectrum of adamantane-OAB-26;

[0188] Figure 165 Example 20: High-resolution mass spectrum of adamantane-OAB-26;

[0189] Figure 166 Example 21: 1H NMR spectrum of adamantane-OAB-28;

[0190] Figure 167 Example 21: 13CNMR spectrum of adamantane-OAB-28;

[0191] Figure 168 Example 21: COSY spectrum of adamantane-OAB-28;

[0192] Figure 169 Example 21: DEPT135 spectrum of adamantane-OAB-28;

[0193] Figure 170 Example 21: HMBC spectrum of adamantane-OAB-28;

[0194] Figure 171 Example 21: HSQC spectrum of adamantane-OAB-28;

[0195] Figure 172 Example 21: High-resolution mass spectrum of adamantane-OAB-28;

[0196] Figure 173 Example 22: 1H NMR spectrum of adamantane-OAB-29;

[0197] Figure 174 Example 22: 13CNMR spectrum of adamantane-OAB-29;

[0198] Figure 175 Example 22: COSY spectrum of adamantane-OAB-29;

[0199] Figure 176 Example 22: DEPT135 spectrum of adamantane-OAB-29;

[0200] Figure 177 Example 22: HMBC spectrum of adamantane-OAB-29;

[0201] Figure 178 Example 22: HSQC spectrum of adamantane-OAB-29;

[0202] Figure 179 Example 22: High-resolution mass spectrum of adamantane-OAB-29;

[0203] Figure 180 Example 23: 1H NMR spectrum of adamantane-OAB-33;

[0204] Figure 181 Example 23: 13CNMR spectrum of adamantane-OAB-33;

[0205] Figure 182 Example 23: COSY spectrum of adamantane-OAB-33;

[0206] Figure 183 Example 23: DEPT135 spectrum of adamantane-OAB-33;

[0207] Figure 184 Example 23: HMBC spectrum of adamantane-OAB-33;

[0208] Figure 185 Example 23: HSQC spectrum of adamantane-OAB-33;

[0209] Figure 186 Example 23: High-resolution mass spectrum of adamantane-OAB-33;

[0210] Figure 187 Example 24: 1H NMR spectrum of adamantane-OAB-34;

[0211] Figure 188 Example 24: 13CNMR spectrum of adamantane-OAB-34;

[0212] Figure 189 Example 24: COSY spectrum of adamantane-OAB-34;

[0213] Figure 190 Example 24: DEPT135 spectrum of adamantane-OAB-34;

[0214] Figure 191 Example 24: HMBC spectrum of adamantane-OAB-34;

[0215] Figure 192 Example 24: HSQC spectrum of adamantane-OAB-34;

[0216] Figure 193 Example 24: High-resolution mass spectrum of adamantane-OAB-34;

[0217] Figure 194 Example 25: 1H NMR spectrum of adamantane-OAB-35;

[0218] Figure 195 Example 25: 13CNMR spectrum of adamantane-OAB-35;

[0219] Figure 196 Example 25: COSY spectrum of adamantane-OAB-35;

[0220] Figure 197 Example 25: DEPT135 spectrum of adamantane-OAB-35;

[0221] Figure 198 Example 25: HMBC spectrum of adamantane-OAB-35;

[0222] Figure 199 Example 25: HSQC spectrum of adamantane-OAB-35;

[0223] Figure 200 Example 25 High-resolution mass spectrum of adamantane-OAB-35. Detailed Implementation

[0224] 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℃.

[0225] The sources of the raw materials used in the examples are as follows:

[0226] Amantadine: Bid Pharmaceutical, content 97%, batch number EKX873.

[0227] p-Nitrobenzoyl chloride: Shandong Kaisheng New Materials Co., Ltd., content 99%, batch number DX22308-10-66.

[0228] Palladium on carbon: Shaanxi Kaida Chemical Co., Ltd., water content 60%, palladium content 10%, batch number 102M191211.

[0229] Phenyl chloroformate: Xinyi Yongcheng Chemical, content 99%, batch number 202005006.

[0230] The ice bath cooling to 5~10°C described below 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., adamantane-OAB-1) is entirely our own designation, and the numbers following them have no special meaning.

[0231] Regarding the high-resolution mass spectra of the adamantane derivatives prepared in Examples 1 to 25, as follows: Figure 32 , 39 As shown in Figures 46, 53, 60, 67, 74, 81, 88, 95, 102, 109, 116, 123, 130, 137, 144, 151, 158, 165, 172, 179, 186, 193, and 200, the upper part of the figure is a particle flow diagram, and the lower part is a bar graph.

[0232] Example 1

[0233] N Preparation of -((3s,5s,7s)-adamantaneamine-1-yl)-4-nitrobenzamide (adamantane-OAB-1):

[0234]

[0235] Adamantane-OAB-1,300.15

[0236] Add 151.2 g (1 mol) of adamantane to a 5000 mL three-necked flask, along with 213 g (1.15 mol) of p-nitrobenzoyl chloride and 1500 mL of dichloromethane. Cool the flask to 0–10 °C in an ice bath under nitrogen protection. Then, add a mixture of 253 g (2.5 mol) of triethylamine and 250 mL of dichloromethane (DCM) dropwise, completing the addition within 1 hour. Stir at room temperature for 24 hours. Determine the reaction endpoint using a 5:1 (volume ratio) petroleum ether:ethyl acetate TLC test. Pour the reaction mixture into a 5000 mL separatory funnel and add DC... Mix 1000 mL of M and 2000 mL of water, adjust the pH to 2 (80 mL) with 10% HCl, separate the layers, and wash with 1000 mL each of saturated NaHCO3 and saturated NaCl. Collect the organic layer in an Erlenmeyer flask, add anhydrous MgSO4 and dry for 1 h. Filter the solution and evaporate to dryness. Pulverize with a 5:1 (1000 mL: 200 mL) mixture of petroleum ether and ethyl acetate for 0.5 h, filter, and dry at 50 °C for 6 h to obtain 236.72 g of a light yellow solid. HPLC analysis showed a purity of 99.98%. HPLC results are as follows: Figure 1 As shown in Table 1, the chromatographic peak results show that the yield was calculated to be 78.81%.

[0237] Table 1 Chromatographic Peak Results

[0238]

[0239] (1) Nuclear magnetic resonance detection

[0240] Instrument model: Bruker NEO400M nuclear magnetic resonance; Test conditions: DMSO- d 6; 298K; Test items: 1 H, 13 C, Dept135, COSY, HSQC, HMBC, detection spectra as follows Figures 26-31 As shown in Table 2, the test results are as follows.

[0241] Table 2 Test Results

[0242]

[0243] (2) Mass spectrometry detection

[0244] 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 32 As shown.

[0245] Table 3 Mass Spectrometry Results

[0246]

[0247] Example 2

[0248] N Preparation of -((3s,5s,7s)-adamantaneamine-1-yl)-4-aminobenzamide (adamantane-OAB-2):

[0249]

[0250] Adamantane-OAB-2,270.38

[0251] 120 g of adamantane-OAB-1 prepared in Example 1, 48 g of 10% palladium on carbon, and 450 mL of LDC were added to a 1000 mL autoclave. The mixture was purged with hydrogen six times, heated to 50°C, pressurized to 5 kg, and maintained at this temperature for 24 hours. TLC analysis showed that the reaction was incomplete, so the mixture was refluxed overnight. The mixture was then filtered and concentrated. The palladium on carbon and solvent were changed, and the reflux process was repeated. After 24 hours, TLC analysis showed the reaction was complete. The mixture was then filtered, concentrated, and vacuum dried at 60°C for 6 hours to obtain 86.23 g of adamantane-OAB-2. HPLC analysis showed a purity of 98.90%. HPLC results are as follows: Figure 2 As shown in Table 4, the chromatographic peak results show that the yield was calculated to be 78.89%.

[0252] Table 4 Chromatographic Peak Results

[0253]

[0254] (1) Nuclear magnetic resonance detection

[0255] 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 33-38 As shown in Table 5, the test results are as follows.

[0256] Table 5 Test Results

[0257]

[0258] (2) Mass spectrometry detection

[0259] 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 39 As shown.

[0260] Table 6 Mass Spectrometry Results

[0261]

[0262] Example 3

[0263] Preparation of phenyl(4-(((3S,5S,7S)-adamantaneamine-1-yl)carbamoyl)phenyl)carbamate (adamantane-OAB-3):

[0264]

[0265] Adamantane-OAB-3,390.19

[0266] Add 80g of adamantane-OAB-2 prepared in Example 2 to a 3000mL four-necked flask, along with 105g of phenyl chloroformate and 102g of potassium carbonate, then add 1500mL of DCM. Reflux overnight. TLC analysis showed incomplete reaction. Add 18g of phenyl chloroformate and 20g of anhydrous potassium carbonate, and continue reflux for 24 hours. TLC analysis showed complete reaction. Add 500mL of purified water, continue stirring for 0.5 hours, filter, wash with 300mL of water and 100mL of dichloromethane, and dry at 60℃ overnight to obtain 108.58g of off-white solid adamantane-OAB-3. HPLC purity was 96.70%. HPLC results are as follows: Figure 3 As shown in Table 7, the chromatographic peak results show that the yield was calculated to be 90.88%.

[0267] Table 7 Chromatographic Peak Results

[0268]

[0269] (1) Nuclear magnetic resonance detection

[0270] 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 40-45 As shown in Table 8, the test results are as follows.

[0271] Table 8 Test Results

[0272]

[0273] (2) Mass spectrometry detection

[0274] 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 46 As shown.

[0275] Table 9 Mass Spectrometry Results

[0276]

[0277] Example 4

[0278] N Preparation of -((3s,5s,7s)-p-xylyl)-4-(3-methyluryl)aniline (adamantane-OAB-6):

[0279]

[0280] Adamantane-OAB-6,327.19

[0281] 5 g of adamantane-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 11 mL of 40% methylamine aqueous solution, 4.25 g of triethylamine, and 50 mL of LCM. The mixture was heated to reflux. After 2 hours, the reaction was complete under TLC monitoring. The mixture was cooled to 5-10 °C in an ice bath and allowed to crystallize for another 2 hours. After filtration, the crystals were dried at 60 °C and 0.08 MPa for 6 hours to obtain 3.35 g of an off-white solid. The purity was 99.60% as determined by HPLC. Figure 4 As shown in Table 10, the chromatographic peak results are presented, and the yield was calculated to be 79.58%.

[0282] Table 10 Chromatographic Peak Results

[0283]

[0284] (1) Nuclear magnetic resonance detection

[0285] 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 47-52 As shown in Table 11, the test results are as follows.

[0286] Table 11 Test Results

[0287]

[0288] (2) Mass spectrometry detection

[0289] 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 53 As shown.

[0290] Table 12 Mass Spectrometry Results

[0291]

[0292] Example 5

[0293] N Preparation of -((3s,5s,7s)-p-xylyl)-4-(3-ethyluryl)aniline (adamantane-OAB-7):

[0294]

[0295] Adamantane-OAB-7,341.46

[0296] 5 g of adamantane-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 11 mL of 40% ethylamine aqueous solution, 4.25 g of triethylamine, and 50 mL of LCM. The mixture was then heated to reflux. After 5 h, the reaction was monitored by TLC until complete. The mixture was then cooled to 5-10 °C in an ice bath and allowed to continue cooling to allow crystallization for 2 h. The crystals were filtered, and the filter cake was dried at 60 °C and 0.08 MPa for 6 h to obtain 3.25 g of a white solid. The purity was determined to be 99.44% by HPLC. HPLC results are as follows: Figure 5 As shown in Table 13, the chromatographic peak results show that the yield was calculated to be 73.92%.

[0297] Table 13 Chromatographic Peak Results

[0298]

[0299] (1) Nuclear magnetic resonance detection

[0300] 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 54-59 As shown in Table 14, the test results are as follows.

[0301] Table 14 Test Results

[0302]

[0303] (2) Mass spectrometry detection

[0304] 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 60 As shown.

[0305] Table 15 Mass Spectrometry Results

[0306]

[0307] Example 6

[0308] N Preparation of -((3s,5s,7s)-p-xylyl)-4-(3-(2-hydroxyethyl)uryl)benzamide (adamantane-OAB-8):

[0309]

[0310] Adamantane-OAB-8,357.21

[0311] 5 g of adamantane-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 2 g of ethanolamine, 4.25 g of triethylamine, and 30 mL of LDM. The mixture was heated to reflux and reacted under TLC for 5 hours until 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 at 60 °C and 0.08 MPa for 6 hours to obtain 3.98 g of a white solid. HPLC analysis showed a purity of 96.68%. HPLC results are as follows: Figure 6 As shown in Table 16, the chromatographic peak results show that the yield was calculated to be 84.07%.

[0312] Table 16 Chromatographic Peak Results

[0313]

[0314] (1) Nuclear magnetic resonance detection

[0315] 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 61-66 As shown in Table 17, the test results are as follows.

[0316] Table 17 Test Results

[0317]

[0318] (2) Mass spectrometry detection

[0319] 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 67 As shown.

[0320] Table 18 Mass Spectrometry Results

[0321]

[0322] Example 7

[0323] NPreparation of -((3s,5s,7s)-p-xylyl)-4-(3-(3-hydroxypropyl)uryl)benzamide (adamantane-OAB-9):

[0324]

[0325] Adamantane-OAB-9,371.22

[0326] 5 g of adamantane-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 4.52 g of 3-aminopropanol and 3.88 g of triethylamine, followed by 50 mL of LDM. The mixture was heated to reflux and reacted under TLC for 4 hours 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 4.38 g of a white solid with a purity of 98.45% as determined by HPLC. HPLC results are as follows: Figure 7 As shown in Table 19, the chromatographic peak results show that the yield was calculated to be 90.65%.

[0327] Table 19 Chromatographic Peak Results

[0328]

[0329] (1) Nuclear magnetic resonance detection

[0330] 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 68-73 As shown in Table 20, the test results are as follows.

[0331] Table 20 Test Results

[0332]

[0333] (2) Mass spectrometry detection

[0334] 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 74 As shown.

[0335] Table 21 Mass Spectrometry Results

[0336]

[0337] Example 8

[0338] NPreparation of -((3s,5s,7s)-p-xylyl)-4-(3-(4-hydroxybutyl)uryl)benzamide (adamantane-OAB-10):

[0339]

[0340] Adamantane-OAB-10,385.24

[0341] 5 g of adamantane-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 5.85 g of 4-aminobutanol and 4.24 g of triethylamine, followed by 50 mL of LCM. The mixture was heated to reflux and, after 2.5 h, was monitored by TLC. Once the reaction was complete, the mixture was cooled to 5-10 °C in an ice bath and allowed to crystallize for another 2 h. The crystals were then filtered, washed with 10 mL of dichloromethane, and dried at 60 °C and 0.08 MPa for 6 h to obtain 4.59 g of an off-white solid. The purity was determined to be 98.35% by HPLC. HPLC results are as follows: Figure 8 As shown in Table 22, the chromatographic peak results show that the yield was calculated to be 91.45%.

[0342] Table 22 Chromatographic Peak Results

[0343]

[0344] (1) Nuclear magnetic resonance detection

[0345] 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 75-80 As shown in Table 23, the test results are as follows.

[0346] Table 23 Test Results

[0347]

[0348] (2) Mass spectrometry detection

[0349] 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 81 As shown.

[0350] Table 24 Mass Spectrometry Results

[0351]

[0352] Example 9

[0353] NPreparation of -((3s,5s,7s)-p-xylyl)-4-(3-(2-(diethylamino)ethyl)ureo)benzamide (adamantane-OAB-11):

[0354]

[0355] Adamantane-OAB-11,412.28

[0356] 5 g of adamantane-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 2.2 g of N,N-diethylethylenediamine and 2.64 g of triethylamine, followed by 30 mL of LDM. The mixture was heated to reflux and allowed to react for 2 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 4.49 g of a white solid. HPLC analysis showed a purity of 97.28%. HPLC results are as follows: Figure 9 As shown in Table 25, the chromatographic peak results show that the yield was calculated to be 77.41%.

[0357] Table 25 Chromatographic Peak Results

[0358]

[0359] (1) Nuclear magnetic resonance detection

[0360] 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 82-87 As shown in Table 26, the test results are as follows.

[0361] Table 26 Test Results

[0362]

[0363] (3) Mass spectrometry detection

[0364] 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 88 As shown.

[0365] Table 27 Mass Spectrometry Results

[0366]

[0367] Example 10

[0368] N Preparation of -((3s,5s,7s)-p-xylyl)-4-(3-(3-(diethylamino)propyl)ureo)benzamide (adamantane-OAB-12):

[0369]

[0370] Adamantane-OAB-12,426.30

[0371] 5 g of adamantane-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 2.56 g of 3-diethylaminopropylamine and 2.64 g of triethylamine, followed by 30 mL of LCM. The mixture was heated to reflux and reacted under TLC for 2.5 h. After the reaction was complete, the mixture was cooled to 5-10 °C in an ice bath and allowed to crystallize for another 2 h. The crystals were then filtered and dried at 60 °C and 0.08 MPa for 6 h to obtain 4.33 g of a white solid. The purity was 95.61% as determined by HPLC. Figure 10 As shown in Table 28, the chromatographic peak results show that the yield was calculated to be 75.79%.

[0372] Table 28 Chromatographic Peak Results

[0373]

[0374] (1) Nuclear magnetic resonance detection

[0375] 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 89-94 As shown in Table 29, the test results are as follows.

[0376] Table 29 Test Results

[0377]

[0378] (2) Mass spectrometry detection

[0379] 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 95 As shown.

[0380] Table 30 Mass Spectrometry Results

[0381]

[0382] Example 11

[0383] N Preparation of -((3s,5s,7s)-p-xylyl)-4-(3-propylureo)benzamide (adamantane-OAB-15):

[0384]

[0385] Adamantane-OAB-15,355.23

[0386] 5 g of adamantane-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 1.17 g of n-propylamine and 2.64 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 4.44 g of a white solid. The purity was determined to be 98.55% by HPLC. HPLC results are as follows: Figure 11 As shown in Table 31, the chromatographic peak results show that the yield was calculated to be 96.13%.

[0387] Table 31 Chromatographic Peak Results

[0388]

[0389] (1) Nuclear magnetic resonance detection

[0390] 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 96-101 As shown in Table 32, the test results are as follows.

[0391] Table 32 Test Results

[0392]

[0393] (2) Mass spectrometry detection

[0394] 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 102 As shown.

[0395] Table 33 Mass Spectrometry Results

[0396]

[0397] Example 12

[0398] NPreparation of -((3s,5s,7s)-p-xylyl)-4-(3,3-diethylureo)benzamide (adamantane-OAB-16):

[0399]

[0400] Adamantane-OAB-16,369.24

[0401] 5 g of adamantane-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 1.43 g of diethylamine and 2.64 g of triethylamine, and then 30 mL of LDM. The mixture was 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. After filtration, the crystals were dried at 60 °C for 3 hours to obtain 4.31 g of a white solid. The purity was determined to be 98.31% by HPLC. HPLC results are as follows: Figure 12 As shown in Table 34, the chromatographic peak results show that the yield was calculated to be 89.55%.

[0402] Table 34 Chromatographic Peak Results

[0403]

[0404] (1) Nuclear magnetic resonance detection

[0405] 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 103-108 As shown in Table 35, the test results are as follows.

[0406] Table 35 Test Results

[0407]

[0408] (2) Mass spectrometry detection

[0409] 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 109 As shown.

[0410] Table 36 Mass Spectrometry Results

[0411]

[0412] Example 13

[0413] NPreparation of -((3s,5s,7s)-p-xylyl)-4-(3,3-dimethylureo)aniline (adamantane-OAB-17):

[0414]

[0415] Adamantane-OAB-17,341.21

[0416] 5 g of adamantane-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 12 mL of 2 mol / L dimethylaminetetrahydrofuran solution, 2.64 g of triethylamine, and 30 mL of LDCM. The mixture was refluxed and, after 1.5 h, the reaction was complete by TLC. The mixture was then cooled to 5-10 °C in an ice bath and allowed to crystallize for another 2 h. After filtration, the crystals were dried at 60 °C for 3 h, yielding 4.23 g of a white solid. HPLC analysis showed a purity of 95.69%. HPLC results are as follows: Figure 13 As shown in Table 37, the chromatographic peak results show that the yield was calculated to be 92.58%.

[0417] Table 37 Chromatographic Peak Results

[0418]

[0419] (1) Nuclear magnetic resonance detection

[0420] 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 110-115 As shown in Table 38, the test results are as follows.

[0421] Table 38 Test Results

[0422]

[0423] (2) Mass spectrometry detection

[0424] 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 116 As shown.

[0425] Table 39 Mass Spectrometry Results

[0426]

[0427] Example 14

[0428] NPreparation of -((3s,5s,7s)-p-xylyl-1-yl)-4-(3-phenyluryl)aniline (adamantane-OAB-18):

[0429]

[0430] Adamantane-OAB-18,389.21

[0431] 5 g of adamantane-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 1.6 g of aniline and 2.64 g of triethylamine. Then, 30 mL of LDM was added, and the mixture was heated to reflux. After 4 hours, TLC was performed under medium control. 0.33 g of aniline was added, and the mixture was cooled in an ice bath to 5–10 °C. Crystallization was continued for 2 hours, followed by filtration and drying at 60 °C for 3 hours to obtain 3.78 g of a white solid. HPLC analysis showed a purity of 97.65%. HPLC results are as follows: Figure 14 As shown in Table 40, the chromatographic peak results are presented, and the yield was calculated to be 74.01%.

[0432] Table 40 Chromatographic Peak Results

[0433]

[0434] (1) Nuclear magnetic resonance detection

[0435] 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 117-122 As shown in Table 41, the test results are as follows.

[0436] Table 41 Test Results

[0437]

[0438] (2) Mass spectrometry detection

[0439] 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 123 As shown.

[0440] Table 42 Mass Spectrometry Results

[0441]

[0442] Example 15

[0443] NPreparation of -((3s,5s,7s)-p-xylyl)-4-(3-(2-morpholinoethyl)ureo)benzamide (adamantane-OAB-19):

[0444]

[0445] Adamantane-OAB-19,426.26

[0446] 5 g of adamantane-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 2.76 g of 4-(2-aminoethyl)morpholine and 2.64 g of triethylamine. Then, 30 mL of LCM 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 5.15 g of a white solid. HPLC analysis showed a purity of 95.86%. HPLC results are as follows: Figure 15 As shown in Table 43, the chromatographic peak results show that the yield was calculated to be 90.38%.

[0447] Table 43 Chromatographic Peak Results

[0448]

[0449] (1) Nuclear magnetic resonance detection

[0450] 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 124-129 As shown in Table 44, the test results are as follows.

[0451] Table 44 Test Results

[0452]

[0453] (2) Mass spectrometry detection

[0454] Instrument: Waters, 2695; Mass spectrometer: QDA; Solvent: Methanol; Ionization method: ESI (+); Detection results are shown in Table 45, and the detection spectrum is as follows. Figure 130 As shown.

[0455] Table 45 Mass Spectrometry Results

[0456]

[0457] Example 16

[0458] NPreparation of -(4-(((3s,5s,7s)-p-xylyl)carbamoyl)phenyl)pyrrolidine-1-carboxylic acid ester (adamantane-OAB-21):

[0459]

[0460] Adamantane-OAB-21,367.23

[0461] 5 g of adamantane-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 1.52 g of pyrrolidine and 2.64 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 analysis showed a purity of 95.13%. HPLC results are as follows: Figure 16 As shown in Table 46, the chromatographic peak results show that the yield was calculated to be 91.18%.

[0462] Table 46 Chromatographic Peak Results

[0463]

[0464] (1) Nuclear magnetic resonance detection

[0465] 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 131-136 As shown in Table 47, the test results are as follows.

[0466] Table 47 Test Results

[0467]

[0468] (2) Mass spectrometry detection

[0469] 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 137 As shown.

[0470] Table 48 Mass Spectrometry Results

[0471]

[0472] Example 17

[0473] NPreparation of -((3s,5s,7s)-p-xylyl)-4-(3-(3-(piperidin-1-yl)propyl)ureo)benzamide (adamantane-OAB-23):

[0474]

[0475] Adamantane-OAB-23,438.30

[0476] 5 g of adamantane-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 3.06 g of 3-(piperidin-1-yl)propyl-1-amine and 2.64 g of triethylamine. Then, 30 mL of LCM 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 continue cooling to allow crystallization for 2 hours. After cooling overnight in a refrigerator, no crystals were observed. The mixture was concentrated and slurried with 30 mL of a 10:1 (v / v) mixture of petroleum ether and ethyl acetate. The slurry was filtered and dried at 60 °C for 3 hours to obtain 5.54 g of a white solid. The purity was 98.45% as determined by HPLC. HPLC results are as follows: Figure 17 As shown in Table 49, the chromatographic peak results show that the yield was calculated to be 95.41%.

[0477] Table 49 Chromatographic Peak Results

[0478]

[0479] (1) Nuclear magnetic resonance detection

[0480] 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 138-143 As shown in Table 50, the test results are as follows.

[0481] Table 50 Test Results

[0482]

[0483] (2) Mass spectrometry detection

[0484] 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 144 As shown.

[0485] Table 51 Mass Spectrometry Results

[0486]

[0487] Example 18

[0488] N Preparation of -((3s,5s,7s)-p-xylyl)-4-(3-(3-(4-methylpiperazin-1-yl)propyl)uryl)benzamide (adamantane-OAB-24):

[0489]

[0490] Adamantane-OAB-24,453.62

[0491] 5 g of adamantane-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 3.38 g of 1-(3-aminopropyl)-4-methylpiperazine and 2.64 g of triethylamine. Then, 30 mL of LDM was added, and the mixture was heated to reflux. After 2 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 continue cooling for 2 hours to allow crystallization. No crystals were observed. The mixture was concentrated, and 30 mL of a 10:1 (v / v) mixture of petroleum ether and ethyl acetate was added and stirred for 2 hours. The mixture was then filtered and dried at 60 °C for 3 hours to obtain 5.70 g of a white solid. HPLC analysis showed a purity of 96.68%. HPLC results are as follows: Figure 18 As shown in Table 52, the chromatographic peak results show that the yield was calculated to be 94.96%.

[0492] Table 52 Chromatographic Peak Results

[0493]

[0494] (1) Nuclear magnetic resonance detection

[0495] 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 145-150 As shown in Table 53, the test results are as follows.

[0496] Table 53 Test Results

[0497]

[0498] (2) Mass spectrometry detection

[0499] Instrument: Waters, 2695; Mass spectrometer: QDA; Solvent: Methanol; Ionization method: ESI (+); Detection results are shown in Table 54, and the detection spectrum is as follows. Figure 151 As shown.

[0500] Table 54 Mass Spectrometry Results

[0501]

[0502] Example 19

[0503] N Preparation of -((3s,5s,7s)-p-xylyl)-4-(3-(2-(piperidin-1-yl)ethyl)ureo)benzamide (adamantane-OAB-25):

[0504]

[0505] Adamantane-OAB-25,424.28

[0506] 5 g of adamantane-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 2.76 g of 1-(2-aminoethyl)piperidine and 2.64 g of triethylamine. Then, 30 mL of LCM was added, and the mixture was heated to reflux. After 4.5 h, 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 h. The crystals were filtered and dried at 60 °C for 3 h to obtain 5.04 g of a white solid. HPLC analysis showed a purity of 96.13%. HPLC results are as follows: Figure 19 As shown in Table 55, the chromatographic peak results are presented, and the yield was calculated to be 89.20%.

[0507] Table 55 Chromatographic Peak Results

[0508]

[0509] (1) Nuclear magnetic resonance detection

[0510] 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 152-157 As shown in Table 56, the test results are as follows.

[0511] Table 56 Test Results

[0512]

[0513] (2) Mass spectrometry detection

[0514] 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 158 As shown.

[0515] Table 57 Mass Spectrometry Results

[0516]

[0517] Example 20

[0518] N Preparation of -((3s,5s,7s)-p-xylyl)-4-(3-(3-piperidinylpropyl)ureo)benzamide (adamantane-OAB-26):

[0519]

[0520] Adamantane-OAB-26,440.59

[0521] 5 g of adamantane-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 3.10 g of N-(3-aminopropyl)morpholine and 2.64 g of triethylamine. Then, 30 mL of LCM was added, and the mixture was heated to reflux. After 3.5 h, 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 h. The crystals were filtered and dried at 60 °C for 3 h to obtain 5.11 g of a white solid. HPLC analysis showed a purity of 97.84%. HPLC results are as follows: Figure 20 As shown in Table 58, the chromatographic peak results show that the yield was calculated to be 88.70%.

[0522] Table 58 Chromatographic Peak Results

[0523]

[0524] (1) Nuclear magnetic resonance detection

[0525] 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 159-164 As shown in Table 59, the test results are as follows.

[0526] Table 59 Test Results

[0527]

[0528] (2) Mass spectrometry detection

[0529] 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 165 As shown.

[0530] Table 60 Mass Spectrometry Results

[0531]

[0532] Example 21

[0533] N Preparation of -((3s,5s,7s)-p-xylyl)-4-(3-(3-(dimethylamino)propyl)ureo)benzamide (adamantane-OAB-28):

[0534]

[0535] Adamantane-OAB-28,398.27

[0536] 5 g of adamantane-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 2.20 g of 3-dimethylaminopropylamine and 2.64 g of triethylamine, followed by 30 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 3.96 g of a white solid. The purity was 99.43% as determined by HPLC. HPLC results are as follows: Figure 21 As shown in Table 61, the chromatographic peak results are presented, and the yield was calculated to be 77.70%.

[0537] Table 61 Chromatographic Peak Results

[0538]

[0539] (1) Nuclear magnetic resonance detection

[0540] 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 166-171 As shown in Table 62, the test results are as follows.

[0541] Table 62 Test Results

[0542]

[0543] (2) Mass spectrometry detection

[0544] 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 172 As shown.

[0545] Table 63 Mass Spectrometry Results

[0546]

[0547] Example 22

[0548] N Preparation of -((3s,5s,7s)-p-xylyl)-4-(3-(2-(4-methylpiperazin-1-yl)ethyl)uryl)aniline (adamantane-OAB-29):

[0549]

[0550] Adamantane-OAB-29,439.29

[0551] 3 g of adamantane-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 crystals to precipitate. No crystals precipitated. 50 mL of a 10:1 (v / v) mixture of petroleum ether and ethyl acetate was added, and the mixture was stirred for half an hour. A solid precipitated, which was filtered and dried at 60 °C for 3 hours to obtain 3.3 g of a white solid. HPLC analysis showed a purity of 95.27%. HPLC results are as follows: Figure 22 As shown in Table 64, the chromatographic peak results show that the yield was calculated to be 96.26%.

[0552] Table 64 Chromatographic Peak Results

[0553]

[0554] (1) Nuclear magnetic resonance detection

[0555] 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 173-178 As shown in Table 65, the test results are as follows.

[0556] Table 65 Test Results

[0557]

[0558] (2) Mass spectrometry detection

[0559] 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 179 As shown.

[0560] Table 66 Mass Spectrometry Results

[0561]

[0562] Example 23

[0563] N Preparation of -((3s,5s,7s)-p-xylyl)-4-(3-(2-aminopropyl)ureo)benzamide (adamantane-OAB-33):

[0564]

[0565] Adamantane-OAB-33,370.24

[0566] 1 g of adamantane-OAB-3 prepared in Example 3 was added to a 100 mL four-necked flask, along with 1.33 g of 1,2-propanediamine and 2.4 g of triethylamine, followed by 30 mL of LCM. The mixture was heated to reflux and allowed to react for 4 hours. TLC monitoring showed the reaction was complete. After the reaction was complete, the mixture was cooled to 5-10°C in an ice bath and allowed to crystallize for 2 hours. The crystals were then filtered and dried at 60°C for 2 hours to obtain 0.66 g of solid. HPLC analysis showed a purity of 95.75%. HPLC results are as follows: Figure 23 As shown in Table 67, the chromatographic peak results are presented, and the yield was calculated to be 59.67%.

[0567] Table 67 Chromatographic Peak Results

[0568]

[0569] (1) Nuclear magnetic resonance detection

[0570] 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 180-185 As shown in Table 68, the test results are as follows.

[0571] Table 68 Test Results

[0572]

[0573] (2) Mass spectrometry detection

[0574] 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 186 As shown.

[0575] Table 69 Mass Spectrometry Results

[0576]

[0577] Example 24

[0578] N Preparation of -(4-(((3s,5s,7s)-p-xylyl)carbamoyl)phenyl)morpholine-4-carboxamide (adamantane-OAB-34):

[0579]

[0580] Adamantane-OAB-34,383.22

[0581] 1 g of adamantane-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 LCM was added, and the mixture was heated to reflux. After 4 hours, TLC was used to monitor the reaction until the reactants had reacted completely. The mixture was then cooled in an ice bath to 5-10 °C and allowed to continue cooling for 2 hours to allow crystallization. The crystals were then filtered and dried at 60 °C for 2 hours to obtain 0.90 g of solid. HPLC analysis showed a purity of 97.44%. HPLC results are as follows: Figure 24 As shown in Table 70, the chromatographic peak results show that the yield was calculated to be 93.40%.

[0582] Table 70 Chromatographic Peak Results

[0583]

[0584] (2) Nuclear magnetic resonance detection

[0585] 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 187-192 As shown in Table 71, the test results are as follows.

[0586] Table 71 Test Results

[0587]

[0588] (3) Mass spectrometry detection

[0589] 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 193 As shown.

[0590] Table 72 Mass Spectrometry Results

[0591]

[0592] Example 25

[0593] N Preparation of -((3s,5s,7s)-p-xylyl)-4-(3-cyclopropylurea)aniline (adamantane-OAB-35):

[0594]

[0595] Adamantane-OAB-35,353.21

[0596] 1 g of adamantane-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 LCM. The mixture was heated to reflux and allowed to react for 4 hours. TLC monitoring showed that the reaction was complete. After the reaction was complete, the mixture was cooled to 5-10 °C in an ice bath and allowed to continue cooling to allow crystallization for 2 hours. The crystals were then filtered and dried at 60 °C for 2 hours to obtain 0.84 g of solid. HPLC analysis showed a purity of 97.74%. HPLC results are as follows: Figure 25 As shown in Table 73, the chromatographic peak results show that the yield was calculated to be 94.87%.

[0597] Table 73 Chromatographic Peak Results

[0598]

[0599] (1) Nuclear magnetic resonance detection

[0600] 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 194-199 As shown in Table 74, the test results are as follows.

[0601] Table 74 Test Results

[0602]

[0603] (2) Mass spectrometry detection

[0604] 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 200 As shown.

[0605] Table 75 Mass Spectrometry Results

[0606]

[0607] The adamantane-OAB compounds prepared in Examples 1 to 25 above were subjected to activity studies.

[0608] Materials and Methods

[0609] 1.1 Experimental System

[0610] 1.1.1 Cells, cell information is shown in Table 76.

[0611] Table 76 Cell Information

[0612]

[0613] 1.1.2 Grouping, as shown in Table 77.

[0614] Table 77 Grouping

[0615]

[0616] 1.2 Compound Information

[0617] 1.2.1 Test substance information, as shown in Table 78.

[0618] Table 78 Test Substance Information

[0619]

[0620] 1.2.2 Solvent information is shown in Table 79.

[0621] Table 79 Solvent Information

[0622]

[0623] 1.3 Information on Reagents, Consumables and Instruments

[0624] 1.3.1 Information on reagents and consumables is shown in Table 80.

[0625] Table 80 Reagent and Consumable Information

[0626]

[0627] 1.3.2 Instrument information, as shown in Table 81.

[0628] Table 81 Instrument Information

[0629]

[0630] 1.4 Compound Preparation

[0631] 1.4.1 Test substance preparation information

[0632] The compounds obtained in Examples 1 to 25 were dissolved in DMSO and sonicated 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.

[0633] 1.4.2 The storage conditions are shown in Table 82.

[0634] Table 82 Storage Conditions

[0635]

[0636] 2. CCK-8 test method

[0637] 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.

[0638] Remove the culture plate to be tested from the incubator (5% CO2, 37℃);

[0639] Use a pipette to add 10 μL of CK-8 reagent to each well, and gently shake the culture plate by hand;

[0640] Place the culture plate in the incubator and incubate for 3 hours;

[0641] Turn on the microplate reader 25 minutes in advance and heat it to 37°C;

[0642] After the culture was completed, the absorbance (OD value) at a wavelength of 450 nm was measured using a microplate reader.

[0643] Detection indicators: assess cell survival rate.

[0644] 3. Data Analysis

[0645] GraphpadPrism 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 GraphpadPrism software.

[0646] 4. Experimental Results and Conclusions

[0647] 4.1 CCK-8 Test

[0648] 4.1.1 Effects of different concentrations of ZFQ-II-1 on Aβ 1-42 The effects of inducing AD cell model are shown in Table 83.

[0649] Table 83 Effects of different concentrations of ZFQ-II-1 on Aβ 1-42 Effects of induced AD cell model

[0650]

[0651] In the table: mean plus or minus standard error, n=3; express p <0.01, express p <0.001.

[0652] 4.1.2 Effects of different concentrations of ZFQ-II-2 on Aβ 1-42 The effects of inducing AD cell models are shown in Table 84.

[0653] Table 84 Effects of different concentrations of ZFQ-II-2 on Aβ 1-42 Effects of induced AD cell model

[0654]

[0655] In the table: mean plus or minus standard error, n=3; express p <0.001.

[0656] 4.1.3 Effects of different concentrations of ZFQ-II-3 on Aβ 1-42 The effects of inducing an AD cell model are shown in Table 85.

[0657] Table 85 Effects of different concentrations of ZFQ-II-3 on Aβ 1-42 Effects of induced AD cell model

[0658]

[0659] In the table: mean plus or minus standard error, n=3; express p <0.01, express p <0.001.

[0660] 4.1.4 Effects of different concentrations of ZFQ-II-4 on Aβ 1-42 The effects of inducing AD cell models are shown in Table 86.

[0661] Table 86 Effects of different concentrations of ZFQ-II-4 on Aβ 1-42 Effects of induced AD cell model

[0662]

[0663] In the table: mean plus or minus standard error, n=3; express p <0.001.

[0664] 4.1.5 Effects of different concentrations of ZFQ-II-5 on Aβ 1-42 The effects of inducing AD cell models are shown in Table 87.

[0665] Table 87 Effects of different concentrations of ZFQ-II-5 on Aβ 1-42 Effects of induced AD cell model

[0666]

[0667] In the table: mean plus or minus standard error, n=3; express p <0.05, express p <0.001.

[0668] 4.1.6 Effects of different concentrations of ZFQ-II-6 on Aβ 1-42 The effects of inducing AD cell model are shown in Table 88.

[0669] Table 88 Effects of different concentrations of ZFQ-II-6 on Aβ 1-42 Effects of induced AD cell model

[0670]

[0671] In the table: mean plus or minus standard error, n=3; express p <0.05, express p <0.001.

[0672] 4.1.7 Effects of different concentrations of ZFQ-II-7 on Aβ 1-42 The effects of inducing AD cell model are shown in Table 89.

[0673] Table 89 Effects of different concentrations of ZFQ-II-7 on Aβ 1-42 Effects of induced AD cell model

[0674]

[0675] In the table: mean plus or minus standard error, n=3; express p <0.05, express p <0.001.

[0676] 4.1.8 Effects of different concentrations of ZFQ-II-8 on Aβ 1-42 The effects of inducing AD cell model are shown in Table 90.

[0677] Table 90. Effects of different concentrations of ZFQ-II-8 on Aβ 1-42 Effects of induced AD cell model

[0678]

[0679] In the table: mean plus or minus standard error, n=3; express p <0.01, express p <0.001.

[0680] 4.1.9 Effects of different concentrations of ZFQ-II-9 on Aβ 1-42 The effects of inducing AD cell model are shown in Table 91.

[0681] Table 91 Effects of different concentrations of ZFQ-II-9 on Aβ 1-42 Effects of induced AD cell model

[0682]

[0683] In the table: mean plus or minus standard error, n=3; express p <0.001.

[0684] 4.1.10 Effects of different concentrations of ZFQ-II-10 on Aβ 1-42 The effects of inducing AD cell model are shown in Table 92.

[0685] Table 92 Effects of different concentrations of ZFQ-II-10 on Aβ 1-42 Effects of induced AD cell model

[0686]

[0687] In the table: mean plus or minus standard error, n=3; express p <0.01, express p <0.001.

[0688] 4.1.11 Effects of different concentrations of ZFQ-II-11 on Aβ 1-42 The effects of inducing AD cell model are shown in Table 93.

[0689] Table 93 Effects of different concentrations of ZFQ-II-11 on Aβ 1-42 Effects of induced AD cell model

[0690]

[0691] In the table: mean plus or minus standard error, n=3; express p <0.01, express p <0.001.

[0692] 4.1.12 Effects of different concentrations of ZFQ-II-12 on Aβ 1-42 The effects of inducing AD cell models are shown in Table 94.

[0693] Table 94 Effects of different concentrations of ZFQ-II-12 on Aβ 1-42 Effects of induced AD cell model

[0694]

[0695] In the table: mean plus or minus standard error, n=3; express p <0.001.

[0696] 4.1.13 Effects of different concentrations of ZFQ-II-13 on Aβ 1-42 The effects of inducing AD cell models are shown in Table 95.

[0697] Table 95. Effects of different concentrations of ZFQ-II-13 on Aβ 1-42 Effects of induced AD cell model

[0698]

[0699] In the table: mean plus or minus standard error, n=3; express p <0.001.

[0700] 4.1.14 Effects of different concentrations of ZFQ-II-14 on Aβ 1-42 The effects of inducing AD cell models are shown in Table 96.

[0701] Table 96. Effects of different concentrations of ZFQ-II-14 on Aβ 1-42 Effects of induced AD cell model

[0702]

[0703] In the table: mean plus or minus standard error, n=3; express p <0.001.

[0704] 4.1.15 Effects of different concentrations of ZFQ-II-15 on Aβ 1-42 The effects of inducing AD cell models are shown in Table 97.

[0705] Table 97 Effects of different concentrations of ZFQ-II-15 on Aβ 1-42 Effects of induced AD cell model

[0706]

[0707] In the table: mean plus or minus standard error, n=3; express p <0.001.

[0708] 4.1.16 Effects of different concentrations of ZFQ-II-16 on Aβ 1-42 The effects of inducing AD cell model are shown in Table 98.

[0709] Table 98. Effects of different concentrations of ZFQ-II-16 on Aβ 1-42 Effects of induced AD cell model

[0710]

[0711] In the table: mean plus or minus standard error, n=3; p <0.05, express p <0.01, express p <0.001.

[0712] 4.1.17 Effects of different concentrations of ZFQ-II-17 on Aβ 1-42 The effects of inducing AD cell model are shown in Table 99.

[0713] Table 99 Effects of different concentrations of ZFQ-II-17 on Aβ 1-42 Effects of induced AD cell model

[0714]

[0715] In the table: mean plus or minus standard error, n=3; express p <0.001.

[0716] 4.1.18 Effects of different concentrations of ZFQ-II-18 on Aβ 1-42 The effects of inducing AD cell models are shown in Table 100.

[0717] Table 100 Effects of different concentrations of ZFQ-II-18 on Aβ 1-42 Effects of induced AD cell model

[0718]

[0719] In the table: mean plus or minus standard error, n=3; express p <0.001.

[0720] 4.1.19 Effects of different concentrations of ZFQ-II-19 on Aβ 1-42 The effects of inducing AD cell models are shown in Table 101.

[0721] Table 101 Effects of different concentrations of ZFQ-II-19 on Aβ 1-42 Effects of induced AD cell model

[0722]

[0723] In the table: mean plus or minus standard error, n=3; express p <0.001.

[0724] 4.1.20 Effects of different concentrations of ZFQ-II-20 on Aβ1-42 The effects of inducing AD cell models are shown in Table 102.

[0725] Table 102 Effects of different concentrations of ZFQ-II-20 on Aβ 1-42 Effects of induced AD cell model

[0726]

[0727] In the table: mean plus or minus standard error, n=3; express p <0.001.

[0728] 4.1.21 Effects of different concentrations of ZFQ-II-21 on Aβ 1-42 The effects of inducing AD cell models are shown in Table 103.

[0729] Table 103 Effects of different concentrations of ZFQ-II-21 on Aβ 1-42 Effects of induced AD cell model

[0730]

[0731] In the table: mean plus or minus standard error, n=3; express p <0.01, express p <0.001.

[0732] 4.1.22 Effects of different concentrations of ZFQ-II-22 on Aβ 1-42 The effects of inducing AD cell models are shown in Table 104.

[0733] Table 104 Effects of different concentrations of ZFQ-II-22 on Aβ 1-42 Effects of induced AD cell model

[0734]

[0735] In the table: mean plus or minus standard error, n=3; express p <0.05, express p <0.001.

[0736] 4.1.23 Effects of different concentrations of ZFQ-II-23 on Aβ 1-42The effects of inducing AD cell models are shown in Table 105.

[0737] Table 105 Effects of different concentrations of ZFQ-II-23 on Aβ 1-42 Effects of induced AD cell model

[0738]

[0739] In the table: mean plus or minus standard error, n=3; express p <0.001.

[0740] 4.1.24 Effects of different concentrations of ZFQ-II-24 on Aβ 1-42 The effects of inducing an AD cell model are shown in Table 106.

[0741] Table 106 Effects of different concentrations of ZFQ-II-24 on Aβ 1-42 Effects of induced AD cell model

[0742]

[0743] In the table: mean plus or minus standard error, n=3; express p <0.01, express p <0.001.

[0744] 4.1.25 Effects of different concentrations of ZFQ-II-25 on Aβ 1-42 The effects of inducing an AD cell model are shown in Table 107.

[0745] Table 107 Effects of different concentrations of ZFQ-II-25 on Aβ 1-42 Effects of induced AD cell model

[0746]

[0747] In the table: mean plus or minus standard error, n=3; express p <0.01, express p <0.001.

[0748] The above activity assays demonstrated the construction of Aβ in SH-SY5Y cells. 1-42In an induced Alzheimer's disease (AD) cell model, the protective activity of 25 adamantane-OAB derivative compounds (ZFQ-II 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 three categories. The specific conclusions are as follows:

[0749] I. The compound exhibits dose-dependent activity (its activity changes with concentration in a clear and predictable manner, making its efficacy highly predictable).

[0750] 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.

[0751] (i) The compound exhibits a positive dose-dependent effect (activity gradually increases with increasing concentration).

[0752] ZFQ-Ⅱ-3: No protective effect at a concentration of 0.1 μmol / L (45.510±2.323%). p <0.01, lower than the model group), with extremely significant effect at a concentration of 1 μmol / L (71.943±2.754%). p <0.001), and the activity was further enhanced at a concentration of 10 μmol / L (73.630±2.026%). p <0.001), showing a clear trend of increased concentration-enhanced activity.

[0753] ZFQ-Ⅱ-4: 0.1μmol / L (42.770±1.451%, p <0.001 (lower than the model group) and 1 μmol / L (51.620±1.556%, no statistical difference) concentration were ineffective, while 10 μmol / L concentration was extremely significantly effective (69.203±2.000%). p <0.001), consistent with the characteristics of activity enhancement dependent on medium to high concentrations.

[0754] ZFQ-Ⅱ-20: No significant activity at concentrations of 0.1 μmol / L and 1 μmol / L, but potent at a concentration of 10 μmol / L (68.180±1.191%). p <0.001), showing a clear trend of increased specificity at high concentrations, with significant dose dependence.

[0755] ZFQ-Ⅱ-21: The activity gradually increased at concentrations of 0.1 μmol / L and 1 μmol / L, and reached a significant protective level (68.940±3.196%) at a concentration of 10 μmol / L.p <0.01), and the trend of increased concentration is consistent with the increase in activity.

[0756] ZFQ-Ⅱ-24: No significant activity at a concentration of 0.1 μmol / L, but significant effect at a concentration of 1 μmol / L (63.117±1.752%). p <0.01%, and at a concentration of 10 μmol / L, the activity further increased to its peak (73.863±2.126%). p <0.001), with a clear positive dose-dependent characteristic.

[0757] 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).

[0758] These compounds do not exhibit a clear positive or negative dose-activity 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.

[0759] (a) Low to medium concentration of effective compounds

[0760] ZFQ-Ⅱ-5: Significantly effective only at a concentration of 1 μmol / L (59.227±1.029%). 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.

[0761] ZFQ-Ⅱ-6: Significantly effective at a low concentration of only 0.1 μmol / L (61.130±3.126%). p <0.05), the activity did not reach a significant level at concentrations of 1 μmol / L and 10 μmol / L, indicating that it was specifically effective at low concentrations.

[0762] ZFQ-Ⅱ-10: The activity was optimal at a low concentration of 0.1 μmol / L (75.240±1.071%). p <0.01), the activity decreased at concentrations of 1 μmol / L and 10 μmol / L with no statistically significant difference, indicating that the low concentration was specifically effective.

[0763] ZFQ-Ⅱ-16: 1μmol / L (67.470±2.065%, p <0.05) and 10 μmol / L (70.360±0.744%) p It showed significant efficacy at concentrations <0.01, with no statistically significant difference at 0.1 μmol / L. The activity gradually increased at medium and high concentrations, but there was no typical dose dependence.

[0764] ZFQ-Ⅱ-22: Significantly effective at a concentration of only 0.1 μmol / L (66.620±6.384%). p <0.05), the activity decreased to a level with no statistical difference at concentrations of 1 μmol / L and 10 μmol / L, indicating that it is specifically effective at low concentrations.

[0765] ZFQ-II-22: Significantly effective at a concentration of only 1 μmol / L (65.077±3.662%). p <0.05%, no activity at 0.1 μmol / L concentration, and decreased cell viability at 10 μmol / L concentration (36.810±3.149%). p <0.01), with specific efficacy at medium concentrations.

[0766] ZFQ-II-23: Significantly effective at a concentration of only 1 μmol / L (66.417±3.098%). p <0.05%, no activity at 0.1 μmol / L concentration, and cell viability drops sharply at 10 μmol / L concentration (4.373±0.519%). p <0.001), with specific efficacy at medium concentrations.

[0767] (ii) Medium to high concentration of effective compounds

[0768] ZFQ-Ⅱ-1: Significantly effective only at high concentrations of 10 μmol / L (76.623 ± 0.435%). p <0.01), no protective effect at concentrations of 0.1 μmol / L and 1 μmol / L, but specific and effective at high concentrations.

[0769] ZFQ-Ⅱ-23 showed significant activity at concentrations of 1 μmol / L (76.943±13.442%) and 10 μmol / L (75.900±12.014%), but without dose dependence. It was effective and showed stable activity at medium and high concentrations.

[0770] (iii) Compounds that are effective at all concentrations but not dose-dependent

[0771] ZFQ-Ⅱ-7: Significant toxicity at a concentration of 0.1 μmol / L (41.183±0.558%). p <0.001), 1μmol / L (49.210±3.429%, p At concentrations <0.05, the levels were still lower than in the model group, and there was no statistically significant difference at a concentration of 10 μmol / L. It showed no protective effect and significant toxicity at low concentrations.

[0772] ZFQ-Ⅱ-8: 0.1μmol / L (43.993±1.850%, p<0.001) and 1 μmol / L (45.283±2.514%) p Significant toxicity at concentrations <0.01, no statistically significant difference at 10 μmol / L concentration, and no protective activity.

[0773] ZFQ-Ⅱ-9: Cell viability at all tested concentrations (0.1 μmol / L: 61.737±4.866%, 1 μmol / L: 60.343±1.352%, 10 μmol / L: 62.327±5.093%) was not significantly better than that of the model group, indicating no clear protective effect.

[0774] ZFQ-Ⅱ-11: 0.1μmol / L (75.883±2.658%, p <0.001), 1μmol / L (73.420±0.709%, p <0.001), 10μmol / L (71.277±2.545%, p It was significantly effective at concentrations of <0.01, and the activity decreased slightly with increasing concentration but remained stable overall, showing no dose dependence.

[0775] ZFQ-Ⅱ-12: Cell viability at each concentration (0.1 μmol / L: 56.703±1.393%, 1 μmol / L: 56.270±3.439%, 10 μmol / L: 53.967±1.135%) was not significantly different from that in the model group, and did not show any anti-AD cell damage activity.

[0776] III. Compounds with no clear protective effect or containing potential toxicity

[0777] 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.

[0778] ZFQ-Ⅱ-2: Cell viability at all tested concentrations (0.1 μmol / L: 47.257±2.637%, 1 μmol / L: 49.687±5.950%, 10 μmol / L: 66.337±6.588%) did not reach statistical significance compared with the model group, indicating no clear protective effect.

[0779] ZFQ-Ⅱ-13: The cell viability at concentrations of 0.1 μmol / L (63.883±2.285%), 1 μmol / L (62.600±0.697%), and 10 μmol / L (63.777±1.657%) was higher than that in the model group, but the difference was not statistically significant, and there was no clear protective effect.

[0780] ZFQ-Ⅱ-14: Cell viability at each concentration (0.1 μmol / L: 64.847±2.248%, 1 μmol / L: 63.620±1.105%, 10 μmol / L: 54.893±4.338%) was not significantly different from that in the model group, and showed no protective activity.

[0781] ZFQ-Ⅱ-15: Cell viability at all tested concentrations (0.1 μmol / L: 64.363±0.894%, 1 μmol / L: 63.563±1.627%, 10 μmol / L: 63.190±1.066%) did not reach statistical significance, indicating no clear protective effect.

[0782] ZFQ-Ⅱ-17: Cell viability at each concentration (0.1 μmol / L: 50.723±4.107%, 1 μmol / L: 53.453±5.571%, 10 μmol / L: 56.820±4.714%) was not significantly different from that in the model group, and it did not show anti-AD activity.

[0783] ZFQ-Ⅱ-18: Cell viability at all tested concentrations (0.1 μmol / L: 60.890±3.817%, 1 μmol / L: 60.620±2.965%, 10 μmol / L: 54.470±3.291%) was not significantly better than that of the model group, and had no protective effect.

[0784] ZFQ-Ⅱ-19: Cell viability at each concentration (0.1 μmol / L: 50.093±1.351%, 1 μmol / L: 56.723±3.619%, 10 μmol / L: 59.660±2.184%) was not significantly different from that of the model group, and it did not show anti-AD activity.

[0785] ZFQ-Ⅱ-25: Cell viability at all tested concentrations (0.1 μmol / L: 58.717±2.932%, 1 μmol / L: 60.807±2.877%, 10 μmol / L: 66.320±1.447%) did not reach statistical significance, indicating no clear protective effect.

[0786] In summary, the dose-dependent compounds include ZFQ-Ⅱ-3, ZFQ-Ⅱ-4, ZFQ-Ⅱ-20, ZFQ-Ⅱ-21, and ZFQ-Ⅱ-24; the non-dose-dependent compounds effective at low to medium concentrations include ZFQ-Ⅱ-1, ZFQ-Ⅱ-5, ZFQ-Ⅱ-6, ZFQ-Ⅱ-10, ZFQ-Ⅱ-11, ZFQ-Ⅱ-16, and ZFQ-Ⅱ-24. Compounds ZFQ-II-22 and ZFQ-II-23 did not show significant protective effects overall. These compounds were ZFQ-II-2, ZFQ-II-7, ZFQ-II-8, ZFQ-II-9, ZFQ-II-12, ZFQ-II-13, ZFQ-II-14, ZFQ-II-15, ZFQ-II-17, ZFQ-II-18, ZFQ-II-19, and ZFQ-II-25.

[0787] ZFQ-II-11 exhibited highly significant and stable protective effects at all three concentrations, making it the most promising compound in the II series.

Claims

1. An adamantane derivative, characterized in that: The structural formula is , , , , , , , .

2. A method for synthesizing the adamantane derivative according to claim 1, characterized in that: The process includes the following steps: Under nitrogen protection, p-nitrobenzoyl chloride is added to adamantane and reacted in a solvent at 0-10°C. Then, a mixture of triethylamine and solvent is added, and the reaction continues at room temperature. The resulting reaction solution is post-treated to obtain intermediate with structural formula I. The obtained intermediate structure I was reacted with palladium on carbon and an organic solvent. After post-treatment, the reaction solution was used to obtain intermediate structure II. Phenyl chloroformate, potassium carbonate, and an organic solvent were added to the obtained intermediate structural formula II, and the mixture was refluxed. After post-treatment, the reaction solution was used to obtain intermediate structural formula III. An amino-substituted raw material, triethylamine, and a solvent were added to the obtained intermediate structural formula III, and the mixture was refluxed. After post-treatment, the reaction solution was used to obtain the adamantane-OAB- derivative. The amino-substituted raw materials are 3-diethylaminopropylamine, n-propylamine, pyrrolidine, N-(3-aminopropyl)morpholine, 3-dimethylaminopropylamine, 4-methyl-1-piperazineethylamine, 1,2-propanediamine, and morpholine.

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

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