Potassium salt of benzimidazole compound and preparation method therefor, composition and application thereof
The preparation method for the compound, composition and application thereof in preparing an angiotensin II receptor antagonist or application in preparing medicine for preventing and/or treating hypertension, chronic heart failure and diabetic nephropathy. After entering a human body, when releasing azilsartan, the compound releases hydroxyligustrazine or NO at the same time, thus generating a synergistic effect with azilsartan. The compound therefore has stronger and longer blood pressure lowering effect, more obvious and longer lasting heart rate lowering effect and high safety, and achieves ideal protective effect for heart and kidney functions.
1. Compound of formula I:
2. A method for preparing the compound according to claim 1 , comprising:
reacting a compound of formula II with a potassium salt reagent in a solvent to form the compound of formula I,
3. The preparation method according to claim 2 , wherein the solvent is selected from water, ether solvents, ketone solvents, alcohol solvents, ester solvents, aromatic hydrocarbon solvents, alkane solvents, nitrile solvents, and a mixture thereof.
4. The preparation method according to claim 2 , wherein the potassium salt reagent is one or more organic acid potassium salts, one or more inorganic acid potassium salts, or a mixture thereof;
wherein the organic acid potassium salt is selected from potassium biphthalate, potassium acetate, potassium formate, potassium di-tert-butyl phosphate, dipotassium glycyrrhizinate, potassium 2-ethylhexanoate, potassium ethylxanthogenate, potassium sorbate, potassium phthalimide, potassium maleimide, potassium oxalate, potassium olefinate, potassium citrate, potassium malate, potassium gluconate, potassium lactate, potassium tartrate, potassium salicylate, potassium fumarate, potassium stearate, and potassium laurate, and
wherein the inorganic acid potassium salt is selected from potassium nitrate, potassium sulfate, potassium sulfite, potassium bromate, potassium hydrogencarbonate, potassium thiocyanate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and potassium hydrogen phthalate.
5. The preparation method according to claim 4 , further comprising adding the compound of formula II into the solvent to form a first solution; adding the potassium salt into the first solution to form a reaction mixture; and
maintaining a temperature of the reaction mixture between room temperature and a reflux temperature of the solvent.
6. The preparation method according to claim 5 , further comprising: cooling the temperature of the reaction mixture to between about −10° C. to about 10° C.; obtaining the compound of formula I after filtration and drying.
7. The preparation method according to claim 5 , further comprising adding an anti-solvent to the reaction mixture; filtering and drying a solid to obtain the compound of formula I;
wherein the anti-solvent is selected from methyl tetrahydrofuran, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, isopropyl ether, ethyl ether, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, nitroethane, n-hexane, cyclohexane, pentane, n-heptane, benzene, toluene, xylene, and a mixture thereof.
8. A pharmaceutical composition, comprising a therapeutically effective amount of the compound according to claim 1 and a pharmaceutically acceptable carrier.
9. A method for treating hypertension, comprising administering an effective amount of the compound according to claim 1 .
10. The preparation method of claim 2 , wherein the solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, acetone, butyl ketone, methyl ethyl ketone, 4-methyl-2-pentanone, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, t-butyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, nitroethane, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, malononitrile, benzene, toluene, xylene, n-hexane, cyclohexane, pentane, n-heptane, and a mixture thereof.
11. The preparation method of claim 2 , wherein a ratio between a volume of solvent to per gram of the compound of formula II is 5 to 100 ml.
12. The preparation method of claim 4 , wherein a molar ratio between the compound of formula II to K of the potassium salt reagent is about 1:0.3-3.