Beta-substituted befa-aminoethyl. phosphonates compound

A technology of diethyl ethyl phosphonate and compounds, applied in the field of substituted aminoethyl phosphonate compositions, can solve the problems of not being able to reduce plasma Lp concentration, failing to meet

Inactive Publication Date: 2004-08-04
ILEX PRODUCTS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

No effective therapy exists to lower Lp(a) because cholesterol-lowering drugs such as HMGCoA reductase inhibitors do not reduce plasma Lp(a) concentrations
The only compound capable of reducing Lp(a) concentrations is niacin, but it must be used in high doses to be active, which is associated with unacceptable side effects
Therefore, the need for a therapeutic drug that effectively reduces high levels of Lp(a) has not been met

Method used

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  • Beta-substituted befa-aminoethyl. phosphonates compound
  • Beta-substituted befa-aminoethyl. phosphonates compound
  • Beta-substituted befa-aminoethyl. phosphonates compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0094] Example 1 β-(3,5-dimethoxy-4-hydroxyphenyl)-β-[N-(3-pyridyl)-amino]-ethylphosphonic acid diethyl ester

[0095]

[0096] Add imidazole (14.8g, 217.6mmol) in portions to the stirred syringaldehyde (12.0g, 65.83mmol) and tert-butyldimethylsilyl chloride (14.9g, 98.9mmol) in 80ml of N, N-dimethyl The mixture in formamide (DMF) was continuously stirred at room temperature for 3 hours. The mixture was poured into water kept at 0°C, and 25% ammonium hydroxide solution was added thereto until the pH reached 7. The aqueous phase was extracted with dichloromethane and the organic phase was dried over magnesium sulfate. Evaporation of the solvent gave an oil which was purified by column chromatography (silica gel, eluent: CH 2 Cl 2 ). 16.4 g (84%) of the pure fraction were obtained as a solid, mp = 74-76°C.

[0097] 10.6g (35.8mmol) of 4-(tert-butyldimethylsilyloxy)-3,5-dimethoxybenzaldehyde, 3.36g (35.8mmol) of 3-aminopyridine and a catalytic amount of p-toluenesulfonate...

Embodiment 2

[0113] β-(4-Hydroxy-3-methoxy-5-methylphenyl)-β-[N-(3-pyridyl)-amino]-ethylphosphonic acid diethyl ester

[0114]

[0115] With 35.0g (0.21mol) 4-hydroxyl-3-methoxy-5-methylbenzaldehyde (mp=98-100 ℃), 19.8g (0.21mmol) 3-aminopyridine and catalytic amount of p-toluenesulfonic acid (about 10 mg) of the mixture was dissolved in 150 ml of toluene in a flask connected to a Dean-Stark apparatus and refluxed for 6 hours. Quantitative formation of the Schiff base is indicated by the formation of an equivalent amount of water. The toluene solution was evaporated to dryness to give 51 g (100%) of the crude imine. To this material and a DMF solution (300 ml) of tert-butyldimethylsilyl chloride (47.6 g, 0.32 mol) was added imidazole (28.7 g, 0.42 mol) in three portions, and the resulting mixture was stirred at room temperature for 6 hours . The mixture was poured into ice water, neutralized with 25% ammonia solution and finally with CH 2 Cl 2 extraction. dry (MgSO 4 ) organic ph...

Embodiment 3

[0132] β-(4-Hydroxy-3-methoxy-5-methylphenyl)-β-[N-(3-(2,6-dimethyl)pyridyl))-amino]-ethylphosphonic acid Dimethyl ester

[0133]

[0134] A mixture of 4-hydroxy-3-methoxy-5-methylbenzaldehyde (15.0 g, 90.4 mmol), 3-amino-2,6-lutidine (11.0 g, 90.36 mmol) and 5 mg TsOH was dissolved Reflux for 7 hours in 150 ml of toluene in a flask connected to a Dean-Stark apparatus. Toluene was evaporated to dryness to give 24.4 g (100%) of an orange oil which was used directly in the next step. To a solution of this material (24.4g, 90.4mmol) and tert-butyldimethylsilyl chloride (20.4g, 135.6mmol) in DMF (150ml) was added imidazole (12.3g, 180.7mmol) and the resulting mixture was dissolved in Stir at room temperature for 6 hours. Pour the mixture into ice water, neutralize with 25% ammonia solution, and finally 2 Cl 2 extraction. Evaporation of the dry solvent gave the crude Tbs-protected imine as a brown oil (28 g, 81%).

[0135] To 120 ml of anhydrous THF was added n-butyllithi...

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PUM

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Abstract

The present invention relates to novel beta -substituted- beta -aminoethylphosphonate derivatives and their uses for lowering plasma levels of apo(a), Lp(a), apo B, apo B associated lipoproteins (low density lipoproteins and very low density lipoproteins) and for lowering plasma levels of total cholesterol.

Description

field of invention [0001] The present invention relates to substituted aminoethylphosphonate compositions and their use in therapy. More particularly, the present invention relates to novel β-substituted-β-aminoethylphosphonate derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, for example in reducing plasma apo(a) and apo(a)-related lipoprotein (lipoprotein(a), or "Lp(a)") levels, decreased plasma apo B and apo B-related lipoprotein (low-density lipoprotein and very low-density lipoprotein lipoprotein) levels and use in lowering plasma total cholesterol levels. Background of the invention [0002] Lp(a) is an LDL-like lipoprotein in which the major lipoprotein apo B-100 is covalently linked to the rare glycoprotein apoprotein(a). The covalent association of apo(a) and apo B to form Lp(a) is a secondary event independent of plasma apo B concentration. Due to its structural similarity to plasminogen, apo(a) i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61K31/675A61P3/06A61P7/02A61P9/00A61P9/08A61P9/10A61P43/00C07F9/58
CPCC07F9/588A61P3/06A61P7/02A61P9/00A61P9/08A61P9/10A61P43/00C07F9/58
Inventor H·T·范L·M·阮V·V·迪普R·阿佐莱E·J·尼索尔C·L·本特岑R·J·伊费
Owner ILEX PRODUCTS INC
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