A class of glyoxalase I irreversible inhibitors and their preparation methods and uses
A technology based on dichloromethane and dimethylaminopropyl, which is applied in the field of medicine, can solve the problems of poor affinity of irreversible inhibitors and lack of breakthroughs in research and development, and achieve good application prospects, long-lasting drug effects, and good therapeutic effects
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Embodiment 1
[0076] Example 1 Preparation of compound 15 of the present invention
[0077] The synthetic route is as follows:
[0078]
[0079] The specific synthesis process is as follows:
[0080] Preparation of compound 2
[0081] Compound 1 (10.00g, 49.02mmol), potassium carbonate (13.53g, 98.04mmol) and potassium hydroxide (2.75g, 49.02mmol) were dissolved in a mixed solvent of THF (90mL) and water (30mL), under ice bath Stir and add benzyloxycarbonylsuccinimide (18.3 g, 73.53 mmol). After the addition, it was naturally raised to room temperature and reacted for 8 hours. The THF was removed by concentration under reduced pressure, the aqueous layer was extracted with ether, and the layers were separated. The aqueous layer was acidified with citric acid to pH=4, and the precipitate was precipitated and extracted with methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 2 (15.57 g, yield 94%), which was direc...
Embodiment 2
[0110] Example 2 Preparation of compound 15DE of the present invention
[0111]
[0112] Preparation of compound 16
[0113] Under an ice bath, dissolve compound 2 (5g, 14.79mmol) and potassium carbonate (3.06g, 22.19mmol) in DMF (50mL), stir electromagnetically, and add ethyl iodide (3.45g, 22.19mmol) to the reaction flask. ), after the addition, it was naturally warmed to room temperature and reacted for 5 hours. TLC monitored the reaction to be complete. The reaction solution was poured into water (300 mL), extracted with ethyl acetate (300 mL×2), and the organic phases were combined. The organic phase was washed with saturated aqueous sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. After drying the organic solvent, the mixed solvent of ethyl acetate and petroleum ether was stirred and dispersed uniformly, and then filtered to obtain light yellow solid 16 (4.8 g, yield 88%). ESI-MS m / z:389.2(M+Na) + ;
[0114] Prepa...
Embodiment 3
[0132] Example 3. Preparation of glyoxalase I inhibitor freeze-dried powder injection of the present invention
[0133] The preparation process of the glyoxalase I inhibitor freeze-dried powder injection of the present invention includes the following steps:
[0134] 1) Add freeze-dried support agent and cosolvent: adjust the pH value of the drug solution to 4-9, and add half the weight of the freeze-dried support agent mannitol with glyoxalase I inhibitor. The cosolvent is β-hydroxymethyl cyclodextrin for injection, and the added amount is the same amount as the glyoxalase I inhibitor.
[0135] The weight ratio of the glyoxalase I inhibitor and the freeze-dried support agent mannitol is 6:1 to 3:1.
[0136] Lyophilization support agent is selected from one or a mixture of any two of mannitol, xylitol, sorbitol, sodium chloride and dextran; the weight of glyoxalase I inhibitor and β-hydroxymethyl cyclodextrin The ratio is 10:1 to 1:1.
[0137] 2) Pyrogen removal: add 0.1% (W / V) activa...
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