Compound with HMG-CoA reductase inhibitory activity, pharmaceutical composition and application thereof
A compound and reductase technology, applied in the field of biomedicine, can solve the problems of high price, drug resistance and efficacy, and achieve the effects of strong activity, overcoming drug resistance, and simple structure
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Embodiment 1
[0034](1) Synthesis of the compound of formula II:
[0035]
[0036]In the formula, N is an integer of 1 to 3, and when N = 1, the structure of the compound is as shown in Formula II-1, and the structure of the compound is as shown in formula II-2, when n = 3 when n = 3 As shown in the following formula II-3:
[0037]
[0038]The compounds of formula II-1 are sesame phenol, commercialized, and purchased directly. The compounds of formula II-2 and formula II-3 were disclosed in conventional literature [Nippon Kagaku Kaishi (1977), (6), 925-7; JP 52133984], 1,2,4-benzene and 1, 2-dichloroethane or 1,3-dichloropropane reaction was prepared, and the specific reaction method was as follows.
[0039]Preparation of the compound of formula II-3: 1,2.4-phenyl phenol 12.6 g, 1,3-dichloropropane 11.3 g, sodium hydroxide 8.8 g and DMSO 63G reaction bottle, under stirring conditions, heated to 120 The reaction was reacted at -130 ° C for 6 hours, then cooled to room temperature, and then the pH of the concentr...
Embodiment 2
[0066]Example 2: COMPD1-9 inhibits human HMG-COA reductase activity test
[0067]NADPH, human HMG-CoA reductase, HMGRH detection kit and positive control simvastatin and dimethyl sulfoxide were purchased from US Sigma.
[0068]Specific experiments were carried out in accordance with the reagent specification: HMG-COA was 0.13 mm, HMGRH 1 μL, and the test sample was mixed with 50 mM pH = 7.5 tris-HCl buffer to 100 μL. After incubation at 37 ° C for 15 minutes, NADPH was added to 0.13 mm, and 10 minutes were detected continuously. The NADPH oxidation absorption value was measured at a wavelength of 340 nm by a spectrophotometer, and the activity of HMG-COA reductase activity was calculated according to the activity of the absorption value, and the desired sample concentration was calculated. The different sample experiment should be at least 6 times and do not add 2 times. Each unit enzyme activity is defined as the amount of enzyme required to catalyze 1 mmol NADPH oxidation per minute. Th...
Embodiment 3
[0072]Example 3: Lipcharin Experiment
[0073]The selection represents Compound COMPD 1, COMPD5, and COMPD9 for lipid-lowering tests in mice. Both the animal room, laboratory and experiments are carried out in GLP standards.
[0074]The drug is configured as follows:
[0075]Tyloxapol: A solution of 80 mg / mL was prepared by saline;
[0076]Simvastatin: A solution of 2 mg / ml was prepared by saline;
[0077]Try: A solution of 1 mg / ml, 2 mg / ml and 5 mg / ml of saline.
[0078]test:
[0079]Healthy male ICR mice, weight 18-22g, freely eating drinking water, randomly divided into blank group, model group, statin group and trial group. Each drug in the test group is divided into three dosage groups, a total of 12 groups, and 8 animals per group. Three doses of the test group were 5 mg / kg, 10 mg / kg and 25 mg / kg, and the dose of Tatin was 10 mg / kg. The administration is IP, the administration volume is 100 μL. The blank group was given a biological saline, the model group gave Tyloxapol, and the...
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