COMT inhibitor comprising terminal olefinic bond and hydrazide structure and application of COMT inhibitor
A technology of hydrazine hydrate and cyclopentadiene, which can be used in the fields of nervous system diseases, organic chemistry, drug combination, etc., and can solve problems such as limited applications
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Embodiment 1
[0020] Example 1 Synthesis of Compound I-1
[0021]
[0022] Step 1. Synthesis of compound VI-1
[0023] Compound II (1.32g, 20mmol) was dissolved in 20mL DMSO, stirred at room temperature, KOH solid (2.24g, 40mmol) was added, and stirring was continued for 1 hour at room temperature. Then MeI (III-1,2.84g, 20mmol) was added, and stirring was continued overnight at room temperature. Then tert-butyl bromoacetate V (3.90 g, 20 mmol) was added, and stirring was continued for 12 hours. TLC detection revealed that the reaction was complete. The reaction mixture was carefully poured into 200mL ice water, stirred, and 50mL×3CH 2 Cl 2 After extraction, the extract phases were combined, washed with 100 mL of 5% brine, and dried over anhydrous sodium sulfate. The desiccant was removed by suction filtration, the filtrate was evaporated to dryness on a rotary evaporator, and the residue was purified by silica gel column chromatography to obtain compound VI-I, 2.99 g (combined yield 77%). ES...
Embodiment 2
[0028] Example 2 Synthesis of Compound I-2
[0029]
[0030] Step 1. Synthesis of compound VI-2
[0031] Compound II (1.32g, 20mmol) was dissolved in 20mL DMSO, stirred at room temperature, KOH solid (2.24g, 40mmol) was added, and stirring was continued for 1 hour at room temperature. Then add III-2 (2.42g, 20mmol), continue to stir at room temperature overnight. Then, V (3.90 g, 20 mmol) was added, and stirring was continued for 12 hours. TLC detection revealed that the reaction was complete. The reaction mixture was carefully poured into 200mL ice water, stirred, and 50mL×3CH 2 Cl 2 After extraction, the extracts were combined, washed with 100 mL of 5% brine, and dried over anhydrous sodium sulfate. The desiccant was removed by suction filtration, the filtrate was evaporated to dryness on a rotary evaporator, and the residue was purified by silica gel column chromatography to obtain compound VI-2. ESI-MS, m / z=221([M+H] + ).
[0032] Step 2. Synthesis of compound VII-2
[0033] ...
Embodiment 3
[0036] Example 3 Compound Inhibition of COMT Analysis in Vitro
[0037] The COMT inhibitory activity of the compound of the present invention is determined by the experimental method described below. The fluorescence analysis is based on the substrate (6,7-dihydroxycoumarin) being methylated by COMT to generate a highly fluorescent product (7-hydroxy-6-methoxycoumarin). The reaction requires the presence of magnesium ions and a methyl donor [in this case S-adenosylmethionine (SAM)]. A stock solution of 10 mM compound in DMSO was used to prepare a 10-point 3-fold dilution series and 1 μL of the appropriate dilution was placed in the assay wells (black 96-well round bottom polystyrene plates from Costar; catalog number 3792). Dilute the recombinase in assay buffer (100mM Na 2 HPO 4 pH 7.4, 1 mM DTT, 0.005% Tween-20) and 35 μL was added to the analysis well containing 1 μL of compound. The pre-incubation of COMT enzyme and compound was performed at room temperature for 2 hours....
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