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Dihydropyridine derivative

A compound, hydrogen atom technology, applied in the field of medicine, can solve the problems of high incidence of ankle edema, slow onset of action, and long duration of action

Active Publication Date: 2012-03-14
XUANZHU BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It has a stronger coronary artery expansion effect, a longer plasma half-life, and a longer duration of action. Its representative drug is benidipine (benidipine), which has low bioavailability and large fluctuations in peak plasma concentration. The main side effects Response is peripheral vasodilation causing ankle edema
The third generation is a long-acting blocker, which binds slowly and firmly to receptors or tissue components, and has a slow onset and long-lasting effect. The representative drug is amlodipine. However, the incidence of ankle edema caused by peripheral vasodilation is relatively low high
With the development of L-type calcium ion channel blockers, pharmacological activity and pharmacokinetic characteristics have been improved, but various side effects of long-term medication have not been resolved

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0146] Example 1 3-(2-Benzyl octahydrocyclopentyl[c]pyrrol-5-yl)5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4 - Preparation of dihydropyridine-3,5-dicarboxylate (compound 1)

[0147]

[0148] (1) Preparation of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate methyl ester

[0149]

[0150] Mix m-nitrobenzaldehyde 5g (0.033mol), methyl acetoacetate 8mL (0.072mol), ethanol 10mL, ammonium bicarbonate 4g (0.05mol), water 4mL, stir at 55-60°C until there are no bubbles (about 1 hour), and then continued to reflux for 1-2 hours, cooled, filtered with suction, and dried to obtain 8.1 g of a yellow solid with a yield of 70.9%.

[0151] (2) Preparation of 5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid

[0152]

[0153] Mix 3.5 g (0.01 mol) of methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate with 150 mL of methanol, and stir Add 9g (0.225mol) NaOH saturated aqueous solution, stir vigorou...

Embodiment 2

[0165] Example 2 3-(2-Dibenzyl octahydrocyclopentyl[c]pyrrol-5-yl)5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1 , 4-dihydropyridine-3, the preparation of 5-dicarboxylate (compound 2)

[0166]

[0167] (1) Preparation of tert-butyl 5-hydroxyhexahydrocyclopentyl[c]pyrrole-2(1H)-carboxylate

[0168]

[0169] Mix 1.125g (5.0mmol) of tert-butyl 5-oxohexahydrocyclopentyl[c]pyrrole-2(1H)-carboxylate, 0.756g (20mmol) of sodium borohydride, and 10mL of methanol, and place in an ice bath The reaction was carried out under low pressure for 3 hours. After the methanol was distilled off under reduced pressure, 20 mL of water was added to the residue, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.135 g of a colorless oil.

[0170] (2) Preparation of tert-butyl 5-acetoxyhexahydrocyclopentyl[c]pyrrole-2(1H)-carboxylate

[0171]

[0172] To 5-hydroxyhexahydrocyclopentyl[c]pyrrole-2(1H)-carboxylic acid tert-butyl ...

Embodiment 3

[0184] Example 3 3-(2-Benzyl octahydrocyclopentyl[c]pyrrol-5-yl)5-methyl 2-((2-aminoethoxy)yl)-4-(2-chlorobenzene base)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate (compound 3)

[0185]

[0186] (1) 3-(2-benzyl octahydrocyclopentyl[c]pyrrol-5-yl)5-methyl 2-((2-azidoethoxy)methyl)-4-(2-chloro Preparation of phenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate

[0187]

[0188] The specific operation refers to (4) in Example 5, and 2-((2-azidoethoxy) methyl)-4-(2-chlorophenyl)-5-(methoxycarbonyl)-6-methyl Base-1,4-dihydropyridine-3-carboxylic acid (preparation method refers to J.Med.Chem.1986,29,1696-1702) 0.208g (0.511mmol), 2-benzyl octahydrocyclopentyl [c ]pyrrol-5-ol (for the preparation method, see (4) in Example 1) 0.094g (0.43mmol) to obtain 103mg of light yellow solid, yield 39.8%.

[0189] (2) 3-(2-Benzyloctahydrocyclopentyl[c]pyrrol-5-yl)5-methyl2-((2-aminoethoxy)methyl)-4-(2-chlorobenzene base)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate

[0190] ...

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Abstract

The invention belongs to the technical field of medicine, particularly relates to a dihydropyridine derivative disclosed in a general formula (I) and clinically-acceptable salt thereof, wherein R1, R2, R3, R4, R5, X or n is defined as in a specification. The invention also relates to a preparation method of the compounds and the application of the compounds in preparing medicines capable of treating hypertension.

Description

1. Technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to dihydropyridine derivatives, pharmaceutically acceptable salts or stereoisomers thereof, preparation methods of these compounds, and the use of these compounds in the preparation of medicines for treating hypertension. 2. Background technology [0002] Dihydropyridine calcium channel blockers are drugs used to treat cardiovascular diseases since the 1970s, which selectively block Ca by binding to protein receptors. 2+ Influx, reducing intracellular Ca 2+ Concentration, thereby changing the cardiovascular function, playing a protective role on the heart and cerebrovascular. Dihydropyridine calcium channel blockers have a high degree of vascular selectivity, clear antihypertensive effect, and a wide range of applications. They are widely used in clinical practice and have become the first choice of antihypertensive drugs. [0003] Most of the listed varieties are L...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07D487/08C07D453/06C07D211/90C07D409/12C07D401/14C07D417/14C07D487/04A61K31/4439A61K31/444A61K31/5377A61K31/496A61P9/12A61P9/04A61P9/10A61P9/00A61P9/06A61P5/00A61P5/40
Inventor 黄振华
Owner XUANZHU BIOPHARMACEUTICAL CO LTD
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