Mutual prodrugs of amlodipine and atorvastatin

A technology of atorvastatin and amlodipine, which is applied in the field of treating patients with cardiac risk symptoms, and the compound of formula I can solve problems such as inability to normalize cardiovascular mortality

Inactive Publication Date: 2002-06-05
PFIZER PRODS ETAT DE CONNECTICUT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, hypertension intervention trials have been unable to fully normalize cardiovascular mortality attributable to coronary heart disease

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0109] 4-(2-chloro-phenyl)-2-(2-[(5-{7-[2-(4-fluoro-phenyl)-5-isopropyl-3-phenyl-4-phenyl Carbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoyloxymethyl}-2-oxo-[1,3]dioxol-4-ylmethyl)-amino ]-ethoxymethyl}-6-methyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-ethyl ester 5-methyl ester

[0110] At 5°C, a solution of 4,5-bis(bromomethyl)-1,3-dioxol-2-one (10g, 36.8mmol) in ethyl acetate (10ml) was added dropwise to Atorval In a mixture of statin (7.45g, 12.9mmol), potassium bicarbonate (3g) and sodium iodide (0.05g) in ethyl acetate (60ml) and N,N-dimethylformamide (20ml), the mixture was stirred at room temperature The mixture was left for 8 hours. Cold water (30ml) was added with stirring and the organic phase was separated, washed with 5% aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to produce atorvastatin 5-bromomethyl-2-oxo-1,3-dioxol-4-yl)methyl ...

Embodiment 2

[0112] 4-(2-Chloro-phenyl)-2-(2-{7-[2-(4-fluoro-phenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl- Pyrrol-1-yl]-3,5-dihydroxy-heptanoyloxymethoxycarbonylamino}-ethoxymethyl)-6-methyl-1,4-dihydro-pyridine-3,5-dicarboxy Acid 3-ethyl ester 5-methyl ester

[0113] Chloromethyl chloroformate (2.85g, 22mmol) was added to a solution of amlodipine (10.5g, 20mmol) and pyridine (1.6g) in 300ml of chloroform, which was cooled in an ice bath. The reaction mixture was stirred at room temperature for 16 hours, washed with water, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The residue was dissolved in a solution of calcium salt of atorvastatin (10.75 g, 0.018 mol) in dimethylformamide (50 ml), and the reaction mixture was heated at 80°C for 20 hours. Dimethylformamide was removed in vacuo and the residue was triturated with chloroform-hexane to produce the title compound of Example 2.

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PUM

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Abstract

This invention relates to mutual prodrugs of amlodipine and atorvastatin and to pharmaceutical compositions thereof. This invention also relates to methods of treating angina pectoris, atherosclerosis, and hypertension and hyperlipidemia in a mammal using those prodrugs and compositions. This invention also relates to methods of managing cardiac risk in a mammal, including humans, presenting with symptoms of cardiac risk by administering those prodrugs and compositions.

Description

[0001] The present invention relates to the common prodrug of amlodipine (amlodipine) and atorvastatin (atorvastatin), its pharmaceutically acceptable acid addition salt, its pharmaceutical composition and use this prodrug and composition to treat patient Patients with angina pectoris, atherosclerosis, combined hypertension and hyperlipidemia, and methods of treating patients (including humans) presenting symptoms of cardiac danger. Background of the invention [0002] The conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate is an early and rate-limiting step in the cholesterol biosynthetic pathway. This step is catalyzed by HMG-CoA reductase. Inhibins inhibit HMG-CoA reductase from catalyzing this conversion. Therefore, statins are effective lipid-lowering agents. [0003] Atorvastatin calcium disclosed in U.S. Patent No. 5,273,995 (which is incorporated herein by reference) is currently available as Lipitor  sales, and has...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61KA61K31/40A61K31/4025A61K31/44A61K31/4422A61K31/4439A61K47/48A61PA61P3/06A61P9/10A61P9/12C07DC07D401/12C07D401/14C07D405/12C07D405/14
CPCC07D401/12C07D405/14A61K47/481A61K47/55A61P3/06A61P9/10A61P9/12
Inventor G·常E·S·哈玛纳卡J·L·拉玛缇那
Owner PFIZER PRODS ETAT DE CONNECTICUT
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