[0004] The development of L-type calcium ion channel blockers has improved the pharmacological activity and pharmacokinetic characteristics of calcium ion channel blocker drugs, but the various side effects of long-term medication have not been resolved
Method used
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Examples
Experimental program
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Effect test
Embodiment 1
[0151] Example 1: 3-(1-benzyl-3-methylpyrrolidin-3-yl)5-methyl2,6-dimethyl-4-(3-nitrophenyl)- Preparation of 1,4-dihydropyridine-3,5-dicarboxylate (compound 1) and its hydrochloride
[0152]
[0153] (1) Preparation of 1-benzyl-3-methylpyrrolidin-3-ol
[0154]
[0155] Under stirring at -20°C, 1-benzylpyrrolidone (1.1 g, 6.3 mmol) was dissolved in 4 mL of THF, and the resulting solution was added dropwise to a THF solution of methylmagnesium bromide (13.2 mL, 12.2 mmol) , continue to stir for 3 hours, the reaction is completed, the reaction solution is dropped into ice water, washed with saturated brine, Na 2 SO 4 After drying, separated by column chromatography (silica gel column, petroleumether: ethyl acetate = 20:1 (volume ratio) elution), to obtain 0.7g product 1-benzyl-3-methylpyrrolidin-3-ol , and the yield was 58.1%.
[0156] (2) Preparation of dimethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
[0157]
[0158] Mix 5g of m-n...
Embodiment 2
[0171] Example 2: 3-[1-(3,3-diphenylpropyl)-3-methylpyrrolidin-3-yl]5-methyl 2,6-dimethyl-4-(3- Preparation of nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (compound 2) and its hydrochloride
[0172]
[0173] (1) Preparation of hydrochloride of 3-methylpyrrolidin-3-ol
[0174]
[0175] A solution of tert-butyl 3-carbonylpyrrolidine-1-carboxylate (11.17g, 0.06mol) in THF (45mL) was slowly added to a solution of MeMgI (21.41g, 0.129mol) in ether, and the reaction was stirred at -20°C for 3h. Add a small amount of water to the reaction solution, suction filter, extract the filtrate with dichloromethane, dry the organic layer with anhydroussodiumsulfate, filter, and concentrate the filtrate to obtain 3-hydroxy-3-methyl-pyrrolidine-1- Crude tert-butyl formate.
[0176] The above crude product was dissolved in 20 mL of 1,4-dioxane, HCl gas was introduced into it, stirred overnight, and suction filtered to obtain 1.67 g of the title product as a red solid, with a two...
Embodiment 3
[0188] Example 3: 3-(1-Benzyl-3-methylpyrrolidin-3-yl)5-ethyl 2,6-dimethyl-4-(3-nitrophenyl)- Preparation of 1,4-dihydropyridine-3,5-diester (compound 3)
[0189]
[0190] The experimental procedure is the same as in Example 1, but the reactant methyl acetoacetate in step (2) is replaced by ethyl acetoacetate to obtain compound 3.
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Abstract
The present invention relates to a 1,4-dihydropyridine-3,5-dicarboxylate compound of general compound (I), a process for preparing the same, a use thereof for the manufacture of a medicament for treating and / or preventing kidney injury, cardiovascular diseases and / or endocrine diseases, as well as a pharmaceutical composition and a pharmaceutical formulation containing said compounds, wherein the definitions of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , m, n 1 , n 2 , p and q are the same as those defined in the description.
Description
technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to 1,4-dihydropyridine-3,5-dicarboxylate compounds and their preparation methods and their preparation for treating / or preventing kidney damage, cardiovascular and / or endocrine diseases The pharmaceutical application of the compound, as well as the pharmaceutical composition and pharmaceutical preparation containing the compound. Background technique [0002] Dihydropyridinecalciumion channel blockers are drugs used to treat cardiovascular diseases since the 1970s, which selectively block L-type or / and T-type calciumion channels by binding to protein receptors Medium Ca 2+ Influx, reducing intracellular Ca 2+ Concentration, thereby changing the cardiovascular function, playing a protective role on the heart and cerebrovascular. Dihydropyridinecalcium channel blockers have a high degree of vascular selectivity, clear antihypertensive effect, and a wide range of ap...
Claims
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