Levetiracetam derivative as well as synthesis method and application thereof
By binding levoracil to levoracil via a fluoroboron dipyrrole derivative, the problem of fluorescent substances affecting the efficacy of levoracil in existing technologies has been solved. This approach enhances the sensitivity of drug analysis and elucidates the drug mechanism, providing structural diversity and support for drug development.
Patent Information
- Application Number
- CN202510963571.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-07-14
- Publication Date
- 2025-10-31
AI Technical Summary
There is a lack of fluorescent substances that can bind to zolactam in the current technology, and existing fluorescent substances can easily affect the drug's properties when they bind to zolactam, making it difficult to achieve effective binding without affecting the drug's properties.
A chlorofluoroboron dipyrrole levoraracetam derivative is used to combine chlorofluoroboron dipyrrole with levoraracetam via an aromatic nucleophilic substitution reaction, forming a brightly colored derivative for drug delivery and efficacy monitoring.
It retains the antiepileptic properties of zolactam, provides structural diversity, improves the sensitivity and selectivity of drug analysis, reveals the drug's mechanism of action and pharmacokinetic properties, and supports drug development and quality control.
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Figure CN120865259A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical science, specifically to a levetiracetam derivative, its synthesis method, and its application. Background Technology
[0002] Zolazetam is a pyrrolidone derivative primarily used to treat epilepsy, and its synthesis and post-modification have attracted considerable attention. Current research suggests that zolactam may exert its antiepileptic effect by selectively inhibiting the hypersynchronous nature and propagation of epileptiform bursts, but its specific mechanism remains unclear. Existing methods for elucidating drug mechanisms of action and pharmacokinetic properties involve covalently binding or physically adsorbing fluorescent substances to drug molecules, enabling them to emit fluorescent signals under specific conditions. This facilitates drug tracking, localization, and quantitative analysis.
[0003] There are two main methods for preparing derivatives: direct labeling and linker labeling. Direct labeling involves directly binding the fluorescent substance to the drug, while linker labeling involves adding a linker between the drug and the fluorescent substance to adjust the binding affinity and selectivity. Currently, there are no derivatives or derivatives thereof that bind to levoraracetam. Furthermore, many fluorescent substances are readily available on the market. Therefore, how to bind these fluorescent substances to levoraracetam without affecting its pharmacological properties is a pressing problem that needs to be solved. Summary of the Invention
[0004] The purpose of this invention is to provide a levetiracetam derivative, its synthesis method, and its application, so as to solve the technical problem of how to modify levetiracetam in the prior art.
[0005] To solve the above-mentioned technical problems, the present invention specifically provides the following technical solution: This invention provides a levetiracetam derivative, wherein the levetiracetam derivative is a fluoroboron dipyrrole levetiracetam derivative; The structural formula of the fluoroboron dipyrrole levoracetam derivative is shown in formula (I): The fluoroboron dipyrrole levoracetam derivative contains R. 1 R 2 Two substituents; Wherein, the R 1 is -C6H5, -(4-Me)C6H4, -(4-Cl)C6H5, -(4-Br)C6H4, -(4-F)C6H4, -(3-F)C6H4, -(3-Br)C6H4, C4-C 10 Any one of straight-chain or branched alkyl groups; The R2 It is any one of -H, -Cl, -OCH3, -OCH2CH3, -OC6H5, -O(4-OMe-C6H4), -O(4-Me-C6H4), -O(4-ClC6H4), -O(4-BrC6H4), -O(4-CF3C6H4), -C6H5, -(4-Me)C6H4, -(4-Cl)C6H5, -(4-Br)C6H4, -(4-F)C6H4, CH(CO2CH3)2, and CH(CO2CH2CH3)2.
[0006] This invention provides the application of levetiracetam derivatives in the preparation of antiepileptic products.
[0007] This invention provides an application of levetiracetam derivatives in drug delivery studies and efficacy monitoring.
[0008] This invention provides a method for synthesizing levetiracetam derivatives, comprising the following steps: Chlorofluoroboron dipyrrole, levoraracetam, and phase transfer catalyst were sequentially placed into a solvent, mixed thoroughly, and reacted at 30 °C for 12 h to obtain the fluoroboron dipyrrole levoraracetam derivative. The structural formula of zolactam is shown in formula (B): ; The structural formula of the chlorofluoroboron dipyrrole is shown in formula (A); ; In equation (A), R 1 is -C6H5, -(4-Me)C6H4, -(4-Cl)C6H5, -(4-Br)C6H4, -(4-F)C6H4, -(3-F)C6H4, -(3-Br)C6H4, C4-C 10 Any one of straight-chain or branched alkyl groups, wherein R 2 It is any one of -H, -Cl, -OCH3, -OCH2CH3, -OC6H5, -O(4-OMe-C6H4), -O(4-Me-C6H4), -O(4-ClC6H4), -O(4-BrC6H4), -O(4-CF3C6H4), -C6H5, -(4-Me)C6H4, -(4-Cl)C6H5, -(4-Br)C6H4, -(4-F)C6H4, CH(CO2CH3)2, and CH(CO2CH2CH3)2.
[0009] As a preferred embodiment of the present invention, the molar ratio of the chlorofluoroboron dipyrrole to the levoracet and the phase transfer catalyst is 1:1.2:0.1, based on the amount of reactants added.
[0010] As a preferred embodiment of the present invention, the phase transfer catalyst is (1S,2S,4S,5R)-1-benzyl-2-((R)-hydroxy(6-methoxyquinoline-4-yl)methyl)-5-vinylquinine-1-onium chloride.
[0011] As a preferred embodiment of the present invention, the solvent is a mixed solution of 1,4-dioxane and dichloromethane.
[0012] As a preferred embodiment of the present invention, the molar ratio of 1,4-dioxane to dichloromethane is 7:3, based on the amount of reactants added.
[0013] Compared with the prior art, the present invention has the following advantages: The levetiracetam derivative provided by this invention is a fluoroboron dipyrrole levetiracetam derivative, which not only retains the characteristic of levetiracetam in treating epilepsy and provides richer structural diversity for the further application of this type of compound, but also has a bright color, which can provide favorable conditions for subsequent studies to improve the sensitivity and selectivity of drug analysis, and can also be used in the fields of revealing the mechanism of action and pharmacokinetic characteristics of drugs. This invention relates to a one-step method for preparing fluoroboron dipyrrole levoraracetam compounds by using phase transfer catalysis to achieve an aromatic nucleophilic substitution reaction with levoraracetam. The prepared fluoroboron dipyrrole levoraracetam compounds can have their structure derived by changing the substituents, thereby regulating their biological activity. Attached Figure Description
[0014] To more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are merely exemplary, and those skilled in the art can derive other embodiments based on the provided drawings without creative effort.
[0015] Figure 1 This provides a schematic diagram of the treatment and testing of epileptic mice in Example 1, which serves as a verification example for the present invention. Figure 2 This invention provides a statistical graph illustrating the effect of LEV on KA-induced epileptic symptoms in mice, as shown in Example 1. Figure 3The statistical graph shows the effect of LEV on KA-induced epileptic symptoms in mice, as shown in Example 1, which serves as a verification of the invention. Detailed Implementation
[0016] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.
[0017] This invention provides a levetiracetam derivative, which is a fluoroboron dipyrrole levetiracetam derivative.
[0018] The structural formula of the fluoroboron dipyrrole levoracetam derivative is shown in formula (I): The fluoroboron dipyrrole levoracetam derivative contains R. 1 R 2 Two substituents.
[0019] R 1 R 2 Each can be independently represented as Cl, OCH3, OCH2CH3, -OC6H5, -O(4-OMe-C6H4), -O(4-Me-C6H4), -O(4-ClC6H4), -O(4-BrC6H4), -O(4-CF3C6H4), aromatic substituents, CH(CO2CH3)2, CH(CO2CH2CH3)2, C4-C 10 One of the straight-chain or branched alkyl groups.
[0020] Preferably, the R 1 is -C6H5, -(4-Me)C6H4, -(4-Cl)C6H5, -(4-Br)C6H4, -(4-F)C6H4, -(3-F)C6H4, -(3-Br)C6H4, C4-C 10 Any one of straight-chain or branched alkyl groups; The R 2 It is any one of -H, -Cl, -OCH3, -OCH2CH3, -OC6H5, -O(4-OMe-C6H4), -O(4-Me-C6H4), -O(4-ClC6H4), -O(4-BrC6H4), -O(4-CF3C6H4), -C6H5, -(4-Me)C6H4, -(4-Cl)C6H5, -(4-Br)C6H4, -(4-F)C6H4, CH(CO2CH3)2, and CH(CO2CH2CH3)2.
[0021] Fluoroborodipyrrole compounds possess excellent photophysical properties. The aforementioned fluoroborodipyrrole-levetiracetam derivatives, obtained by linking the skeleton of these compounds with levetiracetam-like compounds, not only retain the epilepsy-treating properties of levetiracetam and potentially provide richer structural diversity for the further application of these compounds, but also exhibit vibrant colors. These colors can enhance the sensitivity and selectivity of drug analysis, reveal the drug's mechanism of action and pharmacokinetic characteristics, and provide strong support for innovative drug development, drug quality control, and rational clinical drug use.
[0022] This fluoroboron dipyrrole levoracetam derivative can be applied to various aspects of drug development, in vivo drug process research, drug efficacy monitoring, and targeted drug delivery. For example, the derivative can be used to monitor the distribution, metabolism, and excretion of drugs in the body, understand drug mechanisms and target distribution, and potentially provide new insights into related drug metabolism and mechanisms.
[0023] For example, the different efficacy of fluoroboron dipyrrole zolactam derivatives with different substituents provides a new direction for the development of epilepsy drugs.
[0024] This invention further provides a method for synthesizing levetiracetam derivatives. The following steps are required: Chlorofluoroboron dipyrrole, levoraracetam, and phase transfer catalyst were sequentially placed into a solvent, mixed thoroughly, and reacted at 30 °C for 12 h to obtain the fluoroboron dipyrrole levoraracetam derivative. The structural formula of zolactam is shown in formula (B): ; The structural formula of the chlorofluoroboron dipyrrole is shown in formula (A); ; In equation (A), R 1 is -C6H5, -(4-Me)C6H4, -(4-Cl)C6H5, -(4-Br)C6H4, -(4-F)C6H4, -(3-F)C6H4, -(3-Br)C6H4, C4-C 10 Any one of straight-chain or branched alkyl groups, wherein R 2It is any one of -H, -Cl, -OCH3, -OCH2CH3, -OC6H5, -O(4-OMe-C6H4), -O(4-Me-C6H4), -O(4-ClC6H4), -O(4-BrC6H4), -O(4-CF3C6H4), -C6H5, -(4-Me)C6H4, -(4-Cl)C6H5, -(4-Br)C6H4, -(4-F)C6H4, CH(CO2CH3)2, and CH(CO2CH2CH3)2.
[0025] This invention relates to a one-step method for preparing fluoroboron dipyrrole levoraracetam compounds by using phase transfer catalysis to achieve an aromatic nucleophilic substitution reaction with levoraracetam. The prepared fluoroboron dipyrrole levoraracetam compounds can be derivatized by changing the substituents, and their biological activity may be regulated.
[0026] Preferably, the molar ratio of the chlorofluoroboron dipyrrole to the levoracetam and the phase transfer catalyst is 1:1.2:0.1.
[0027] Preferably, the phase transfer catalyst is (1S,2S,4S,5R)-1-benzyl-2-((R)-hydroxy(6-methoxyquinoline-4-yl)methyl)-5-vinylquinine-1-onium chloride.
[0028] Preferably, the solvent is a mixed solution of 1,4-dioxane and dichloromethane.
[0029] Preferably, the molar ratio of 1,4-dioxane to dichloromethane is 7:3.
[0030] The present invention further provides embodiments illustrating the use of fluoroboron dipyrrole levoracetam derivatives: Example 1 Add the compound with the structure shown in formula (A-1) (33.6 mg, 0.1 mmol), the compound with the structure shown in formula (B-1) (20.4 mg, 0.12 mmol), (1S,2S,4S,5R)-1-benzyl-2-((R)-hydroxy(6-methoxyquinoline-4-yl)methyl)-5-vinylquinine-1-onium chloride (2.7 mg, 10 mol%), and cesium carbonate (65.1 mg, 0.2 mmol) to a 25 mL Shrek reaction tube.
[0031] After the reaction mixture was added with a stir bar, the reaction tube was evacuated and purged with nitrogen. This process was repeated three times. Under nitrogen conditions, 1,4-dioxane (1.4 mL) and dichloromethane (0.6 mL) were added separately. The reaction mixture was heated in a 25°C oil bath for 12 hours and then cooled to room temperature. The reaction mixture was transferred to a 25 mL round-bottom flask, and the solvent was removed by rotary evaporation, yielding a residue. The compound was obtained by column chromatography. The chemical formula of this product is shown in C-1, with a yield of 42.2 mg (91%), and the morphology was a red solid.
[0032] The reaction formula for Example 1 is as follows: Example 2 Add A-2 (35.6 mg, 0.1 mmol), B-1 (20.2 mg, 0.12 mmol), (1S,2S,4S,5R)-1-benzyl-2-((R)-hydroxy(6-methoxyquinoline-4-yl)methyl)-5-vinylquinine-1-onium chloride (2.7 mg, 10 mol%), and cesium carbonate (65.3 mg, 0.2 mmol) to a 25 mL Shrek reaction tube. After adding a stir bar to the reaction mixture, evacuate the reaction tube and purge with nitrogen. Repeat this process three times. Under nitrogen atmosphere, add 1,4-dioxane (1.4 mL) and dichloromethane (0.6 mL), respectively. Heat the reaction mixture in a 25°C oil bath for 12 hours, then cool to room temperature. Transfer the reaction mixture to a 25 mL round-bottom flask and remove the solvent using a rotary evaporator to obtain the residue. The compound was obtained by column chromatography. The chemical formula of the product is shown in C-2. The yield was 44.2 mg, with a yield of 90%, and the product was a red solid.
[0033] The reaction formula for Example 2 is as follows: Example 3 Add A-3 (40.1 mg, 0.1 mmol), B-1 (20.9 mg, 0.12 mmol), (1S,2S,4S,5R)-1-benzyl-2-((R)-hydroxy(6-methoxyquinoline-4-yl)methyl)-5-vinylquinine-1-onium chloride (2.6 mg, 10 mol%), and cesium carbonate (65.7 mg, 0.2 mmol) to a 25 mL Shrek reaction tube. After adding a stir bar to the reaction mixture, evacuate the reaction tube and purge with nitrogen. Repeat this process three times. Under nitrogen atmosphere, add 1,4-dioxane (1.4 mL) and dichloromethane (0.6 mL), respectively. Heat the reaction mixture in a 25°C oil bath for 12 hours, then cool to room temperature. Transfer the reaction mixture to a 25 mL round-bottom flask and remove the solvent using a rotary evaporator to obtain the residue.
[0034] The compound was obtained by column chromatography. The chemical formula of the product is shown in C-3. The yield was 44.7 mg, with a yield of 86%, and the product was a red solid.
[0035] The reaction formula for Example 3 is as follows: Example 4 Add A-4 (41.8 mg, 0.1 mmol), B-1 (20.1 mg, 0.12 mmol), (1S,2S,4S,5R)-1-benzyl-2-((R)-hydroxy(6-methoxyquinoline-4-yl)methyl)-5-vinylquinine-1-onium chloride (2.7 mg, 10 mol%), and cesium carbonate (65.3 mg, 0.2 mmol) to a 25 mL Shrek reaction tube. After adding a stir bar to the reaction mixture, evacuate the reaction tube and purge with nitrogen. Repeat this process three times. Under nitrogen atmosphere, add 1,4-dioxane (1.4 mL) and dichloromethane (0.6 mL), respectively. Heat the reaction mixture in a 25°C oil bath for 12 hours, then cool to room temperature. Transfer the reaction mixture to a 25 mL round-bottom flask and remove the solvent using a rotary evaporator to obtain the residue.
[0036] The compound was obtained by column chromatography. The chemical formula of the product is shown in C-4. The yield was 49.5 mg, with a yield of 90%, and the product was a red solid.
[0037] The reaction formula for Example 4 is as follows: Example 5 Add A-5 (37.9 mg, 0.1 mmol), B-1 (21.1 mg, 0.12 mmol), (1S,2S,4S,5R)-1-benzyl-2-((R)-hydroxy(6-methoxyquinoline-4-yl)methyl)-5-vinylquinine-1-onium chloride (2.9 mg, 10 mol%), and cesium carbonate (65.1 mg, 0.2 mmol) to a 25 mL Shrek reaction tube. After adding a stir bar to the reaction mixture, evacuate the reaction tube and purge with nitrogen. Repeat this process three times. Under nitrogen atmosphere, add 1,4-dioxane (1.4 mL) and dichloromethane (0.6 mL), respectively. Heat the reaction mixture in a 25°C oil bath for 12 hours, then cool to room temperature. Transfer the reaction mixture to a 25 mL round-bottom flask and remove the solvent using a rotary evaporator to obtain the residue.
[0038] The compound was obtained by column chromatography. The chemical formula of the product is shown in C-5. The yield was 38.9 mg, with a yield of 87%, and the product was a red solid.
[0039] The reaction formula for Example 5 is as follows: Example 6 Add A-6 (41.9 mg, 0.1 mmol), B-1 (20.5 mg, 0.12 mmol), (1S,2S,4S,5R)-1-benzyl-2-((R)-hydroxy(6-methoxyquinoline-4-yl)methyl)-5-vinylquinine-1-onium chloride (2.6 mg, 10 mol%), and cesium carbonate (65.8 mg, 0.2 mmol) to a 25 mL Shrek reaction tube. After adding a stir bar to the reaction mixture, evacuate the reaction tube and purge with nitrogen. Repeat this process three times. Under nitrogen atmosphere, add 1,4-dioxane (1.4 mL) and dichloromethane (0.6 mL), respectively. Heat the reaction mixture in a 25°C oil bath for 12 hours, then cool to room temperature. Transfer the reaction mixture to a 25 mL round-bottom flask and remove the solvent using a rotary evaporator to obtain the residue.
[0040] The compound was obtained by column chromatography. The chemical formula of the product is shown in C-6. The yield was 42.5 mg, with a yield of 78%, and the product was a red solid.
[0041] The reaction formula for Example 6 is as follows: Example 7 Add A-4 (41.8 mg, 0.1 mmol), B-1 (20.1 mg, 0.12 mmol), (1S,2S,4S,5R)-1-benzyl-2-((R)-hydroxy(6-methoxyquinoline-4-yl)methyl)-5-vinylquinine-1-onium chloride (2.7 mg, 10 mol%), and cesium carbonate (65.3 mg, 0.2 mmol) to a 25 mL Shrek reaction tube. After adding a stir bar to the reaction mixture, evacuate the reaction tube and purge with nitrogen. Repeat this process three times. Under nitrogen atmosphere, add 1,4-dioxane (1.4 mL) and dichloromethane (0.6 mL), respectively. Heat the reaction mixture in a 25°C oil bath for 12 hours, then cool to room temperature. Transfer the reaction mixture to a 25 mL round-bottom flask and remove the solvent using a rotary evaporator to obtain the residue.
[0042] The compound was obtained by column chromatography. The chemical formula of the product is shown in C-4. The yield was 49.5 mg, with a yield of 90%, and the product was a red solid.
[0043] The reaction formula for Example 7 is as follows: Example 8 Add A-8 (37.6 mg, 0.1 mmol), B-1 (21.8 mg, 0.12 mmol), (1S,2S,4S,5R)-1-benzyl-2-((R)-hydroxy(6-methoxyquinoline-4-yl)methyl)-5-vinylquinine-1-onium chloride (2.8 mg, 10 mol%), and cesium carbonate (65.5 mg, 0.2 mmol) to a 25 mL Shrek reaction tube. After adding a stir bar to the reaction mixture, evacuate the reaction tube and purge with nitrogen. Repeat this process three times. Under nitrogen atmosphere, add 1,4-dioxane (1.4 mL) and dichloromethane (0.6 mL), respectively. Heat the reaction mixture in a 25°C oil bath for 12 hours, then cool to room temperature. Transfer the reaction mixture to a 25 mL round-bottom flask and remove the solvent using a rotary evaporator to obtain the residue.
[0044] The compound was obtained by column chromatography. The chemical formula of the product is shown in C-8. The yield was 40.9 mg, with a yield of 93%, and the product was a red solid.
[0045] The reaction formula for Example 8 is as follows: Example 9 Add A-9 (32.6 mg, 0.1 mmol), B-1 (20.8 mg, 0.12 mmol), (1S,2S,4S,5R)-1-benzyl-2-((R)-hydroxy(6-methoxyquinoline-4-yl)methyl)-5-vinylquinine-1-onium chloride (2.5 mg, 10 mol%), and cesium carbonate (65.0 mg, 0.2 mmol) to a 25 mL Shrek reaction tube. After adding a stir bar to the reaction mixture, evacuate the reaction tube and purge with nitrogen. Repeat this process three times. Under nitrogen atmosphere, add 1,4-dioxane (1.4 mL) and dichloromethane (0.6 mL), respectively. Heat the reaction mixture in a 25°C oil bath for 12 hours, then cool to room temperature. Transfer the reaction mixture to a 25 mL round-bottom flask and remove the solvent using a rotary evaporator to obtain the residue.
[0046] The compound was obtained by column chromatography. The chemical formula of the product is shown in C-9. The yield was 28.9 mg, the yield was 76%, and the product was a red solid.
[0047] The reaction formula for Example 9 is as follows: Example 10 Add A-10 (32.9 mg, 0.1 mmol), B-1 (20.3 mg, 0.12 mmol), (1S,2S,4S,5R)-1-benzyl-2-((R)-hydroxy(6-methoxyquinoline-4-yl)methyl)-5-vinylquinine-1-onium chloride (2.7 mg, 10 mol%), and cesium carbonate (65.2 mg, 0.2 mmol) to a 25 mL Shrek reaction tube. After adding a stir bar to the reaction mixture, evacuate the reaction tube and purge with nitrogen. Repeat this process three times. Under nitrogen atmosphere, add 1,4-dioxane (1.4 mL) and dichloromethane (0.6 mL), respectively. Heat the reaction mixture in a 25°C oil bath for 12 hours, then cool to room temperature. Transfer the reaction mixture to a 25 mL round-bottom flask and remove the solvent using a rotary evaporator to obtain the residue.
[0048] The compound was obtained by column chromatography. The chemical formula of the product is shown in C-10. The yield was 26.7 mg, the yield was 67%, and the product was a red solid.
[0049] The reaction formula for Example 10 is as follows: Example 11 Add A-11 (33.7 mg, 0.1 mmol), B-1 (20.9 mg, 0.12 mmol), (1S,2S,4S,5R)-1-benzyl-2-((R)-hydroxy(6-methoxyquinoline-4-yl)methyl)-5-vinylquinine-1-onium chloride (2.6 mg, 10 mol%), and cesium carbonate (65.9 mg, 0.2 mmol) to a 25 mL Shrek reaction tube. After adding a stir bar to the reaction mixture, evacuate the reaction tube and purge with nitrogen. Repeat this process three times. Under nitrogen atmosphere, add 1,4-dioxane (1.4 mL) and dichloromethane (0.6 mL), respectively. Heat the reaction mixture in a 25°C oil bath for 12 hours, then cool to room temperature. Transfer the reaction mixture to a 25 mL round-bottom flask and remove the solvent using a rotary evaporator to obtain the residue.
[0050] The compound was obtained by column chromatography. The chemical formula of the product is shown in C-11. The yield was 29.2 mg, the yield was 76%, and the product was a red solid.
[0051] The reaction formula for Example 11 is as follows: Example 12 Add A-12 (39.7 mg, 0.1 mmol), B-1 (20.9 mg, 0.12 mmol), (1S,2S,4S,5R)-1-benzyl-2-((R)-hydroxy(6-methoxyquinoline-4-yl)methyl)-5-vinylquinine-1-onium chloride (2.7 mg, 10 mol%), and cesium carbonate (65.2 mg, 0.2 mmol) to a 25 mL Shrek reaction tube. After adding a stir bar to the reaction mixture, evacuate the reaction tube and purge with nitrogen. Repeat this process three times. Under nitrogen atmosphere, add 1,4-dioxane (1.4 mL) and dichloromethane (0.6 mL), respectively. Heat the reaction mixture in a 25°C oil bath for 12 hours, then cool to room temperature. Transfer the reaction mixture to a 25 mL round-bottom flask and remove the solvent using a rotary evaporator to obtain the residue.
[0052] The compound was obtained by column chromatography. The chemical formula of the product is shown in C-12. The yield was 39.2 mg, the yield was 78%, and the product was a red solid.
[0053] The reaction formula for Example 12 is as follows: Example 13 Add A-13 (40.3 mg, 0.1 mmol), B-1 (20.7 mg, 0.12 mmol), (1S,2S,4S,5R)-1-benzyl-2-((R)-hydroxy(6-methoxyquinoline-4-yl)methyl)-5-vinylquinine-1-onium chloride (2.6 mg, 10 mol%), and cesium carbonate (65.3 mg, 0.2 mmol) to a 25 mL Shrek reaction tube. After adding a stir bar to the reaction mixture, evacuate the reaction tube and purge with nitrogen. Repeat this process three times. Under nitrogen atmosphere, add 1,4-dioxane (1.4 mL) and dichloromethane (0.6 mL), respectively. Heat the reaction mixture in a 25°C oil bath for 12 hours, then cool to room temperature. Transfer the reaction mixture to a 25 mL round-bottom flask and remove the solvent using a rotary evaporator to obtain the residue.
[0054] The compound was obtained by column chromatography. The chemical formula of the product is shown in C-13. The yield was 42.5 mg, the yield was 81%, and the product was a red solid.
[0055] The reaction formula for Example 13 is as follows: The performance of Example 1 was tested as follows: (1) Test Example 1: The pharmaceutical properties of the embodiments were tested. Establishment of a kaempferol-induced mouse model of epilepsy: Male C57 / BL6 mice (7-8 weeks old, 22 ± 2 g) were weighed and pretreated with levetiracetam derivative (600 mg / kg, ip) 1 hour before modeling. Acute seizures were induced by injection of kaempferol (24 mg / kg, ip; HY-N2309, MedChemExpress).
[0056] The modified Racine scale (Racine scale: 1. Freezing behavior; 2. Rigid posture, tail held high; 3. Continuous head shaking and wagging of front paws; 4. Standing, falling, and jumping; 5. Continuous standing and jumping; 6. Loss of posture, generalized convulsions, or death. A Racine score greater than 4 is considered a successful induction of epilepsy) was used to assess the modeling effect and the efficacy of drug treatment.
[0057] Racine scores are shown in Table 1: Table 1 A schematic diagram of the treatment and testing of epileptic mice in Example 1 is shown below. Figure 1 As shown.
[0058] The results of drug administration to mice are shown in the table below. Figure 2 and Figure 3 As shown, Figure 2 To investigate the effect of LEV on KA-induced epileptic symptoms in mice, behavioral epileptic seizures were assessed using the Racine scale (n=10) during the acute phase. Data were analyzed using univariate ANCOVA and are presented as mean ± standard error. Figure 3 To investigate the effect of LEV on KA-induced epileptic symptoms in mice, the percentage of grade 4–6 seizures (n=10) was recorded during the acute phase using the Racine scale.
[0059] Statistical analysis showed that, compared with the control group, the intervention group had lower lacin scores and reduced seizure severity after using this compound. This indicates that the compound has a significant anti-epileptic effect.
[0060] As demonstrated by the above detection methods, this invention provides a simple and efficient one-pot method for preparing a class of chiral N-benzoyl-3-benzyl-4-carboxylo-benzofuran-5-amine compounds using 3-alkoxybenzaldehyde and dioxazolone derivatives. This one-pot method is simple and highly efficient. Furthermore, biological studies of these compounds have shown that they exhibit significant anti-epileptic effects in mice, demonstrating important potential applications.
[0061] The above embodiments are merely exemplary embodiments of this application and are not intended to limit this application. The scope of protection of this application is defined by the claims. Those skilled in the art can make various modifications or equivalent substitutions to this application within its substance and scope of protection, and such modifications or equivalent substitutions should also be considered to fall within the scope of protection of this application.
Claims
1. A levetiracetam derivative, characterized in that, The levetiracetam derivative is a fluoroboron dipyrrole levetiracetam derivative; The structural formula of the fluoroboron dipyrrole levoracetam derivative is shown in formula (I): The fluoroboron dipyrrole levoracetam derivative contains R. 1 R 2 Two substituents; The R 1 is -C6H5, -(4-Me)C6H4, -(4-Cl)C6H5, -(4-Br)C6H4, -(4-F)C6H4, -(3-F)C6H4, -(3-Br)C6H4, C4-C 10 Any one of straight-chain or branched alkyl groups; The R 2 It is any one of -H, -Cl, -OCH3, -OCH2CH3, -OC6H5, -O(4-OMe-C6H4), -O(4-Me-C6H4), -O(4-ClC6H4), -O(4-BrC6H4), -O(4-CF3C6H4), -C6H5, -(4-Me)C6H4, -(4-Cl)C6H5, -(4-Br)C6H4, -(4-F)C6H4, CH(CO2CH3)2, and CH(CO2CH2CH3)2.
2. The use of a levetiracetam derivative as described in claim 1 in the preparation of an antiepileptic product.
3. The application of a levetiracetam derivative as described in any one of claims 1-2 in the fields of drug delivery and efficacy monitoring.
4. A method for synthesizing a levetiracetam derivative as described in claim 1, characterized in that, Includes the following steps: Chlorofluoroboron dipyrrole, levoracetam, and phase transfer catalyst were sequentially placed into a solvent, mixed thoroughly, and reacted at 30°C for 12 h to obtain the fluoroboron dipyrrole levoracetam derivative. The structural formula of zolactam is shown in formula (B): ； The structural formula of the chlorofluoroboron dipyrrole is shown in formula (A); ； Wherein, in the above formula (A), R 1 is -C6H5, -(4-Me)C6H4, -(4-Cl)C6H5, -(4-Br)C6H4, -(4-F)C6H4, -(3-F)C6H4, -(3-Br)C6H4, C4-C 10 Any one of straight-chain or branched alkyl groups, wherein R 2 It is any one of -H, -Cl, -OCH3, -OCH2CH3, -OC6H5, -O(4-OMe-C6H4), -O(4-Me-C6H4), -O(4-ClC6H4), -O(4-BrC6H4), -O(4-CF3C6H4), -C6H5, -(4-Me)C6H4, -(4-Cl)C6H5, -(4-Br)C6H4, -(4-F)C6H4, CH(CO2CH3)2, and CH(CO2CH2CH3)2.
5. The method for synthesizing a levetiracetam derivative according to claim 4, characterized in that, The molar ratio of the chlorofluoroboron dipyrrole to the levoracet and the phase transfer catalyst, based on the amount of reactants added, is 1:1.2:0.
1.
6. The method for synthesizing a levetiracetam derivative according to claim 4, characterized in that, The phase transfer catalyst is (1S,2S,4S,5R)-1-benzyl-2-((R)-hydroxy(6-methoxyquinoline-4-yl)methyl)-5-vinylquinine-1-onium chloride.
7. The method for synthesizing a levetiracetam derivative according to claim 4, characterized in that, The solvent is a mixed solution of 1,4-dioxane and dichloromethane.
8. The method for synthesizing a levetiracetam derivative according to claim 7, characterized in that, Based on the amount of reactants added, the molar ratio of 1,4-dioxane to dichloromethane is 7:3.