Heterocyclic derivatives

A technology of derivatives and heterocycles, applied in drug combinations, metabolic diseases, cardiovascular system diseases, etc., can solve problems such as no established correlation

Inactive Publication Date: 2006-01-25
NIPPON SHINYAKU CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although it has been discussed many times before that the blood triglyceride level may be an important risk factor for atherosclerosis, a clear correlation has not been established

Method used

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  • Heterocyclic derivatives
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Examples

Experimental program
Comparison scheme
Effect test

reference example 1

[0267] (4-Chlorobutyl)diethylmalonate

[0268] In 458 ml of dry tetrahydrofuran (THF), 13.4 g of 60% sodium hydride was added, and 160.6 g of diethyl malonate was added dropwise with ice-cooling and stirring. After dropping, stir for 15 minutes, then add 57.3 g of 1-bromo-4-chlorobutane, and stir at room temperature for 50 hours. The reaction solution was poured into ice water, neutralized with dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was distilled under reduced pressure to obtain 26.8 g of the title compound as a colorless oil.

[0269] Boiling point 127~130℃(5mmHg)

[0270] The following compounds were produced in the same manner as in Reference Example 1.

[0271] (3-Chloropropyl)diethylmalonate

[0272] Diethyl (5-chloropentyl)malonate

reference example 2

[0274] Diethyl (5-hexenyl)malonate

[0275] In 120 ml of dry tetrahydrofuran (THF), 4.9 g of 60% sodium hydride was added, and 29.5 g of diethyl malonate was added dropwise with ice-cooling and stirring. After the dropwise addition, stir for 15 minutes, then add 10 g of 6-bromo-1-hexane, and heat to reflux for 21 hours. The reaction solution was cooled, poured into ice water, neutralized with dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane:ethyl acetate=20:1) to obtain 14.5 g of the title compound as a yellow oil.

[0276] 1 H-NMR (CDCl 3 )δ: 1.23~1.47(10H, m), 1.84~2.11(4H, m), 3.28~3.37(1H, m), 4.14~4.25(4H, m), 4.91~5.05(2H, m), 5.69~ 5.90 (1H, m)

reference example 3

[0278] 6-Chloro-2-hydroxymethyl-1-hexanol

[0279] In 214 ml of dry diethyl ether, 8 g of lithium aluminum hydride was added, and a solution of 26.7 g of 4-chlorobutyldiethylmalonate / 53 ml of diethyl ether was added dropwise with ice-cooling and stirring. Stir at room temperature for 1 hour, then cool in ice water, and add 173 ml tetrahydrofuran / 14.7 ml water dropwise. Next, 14.7 ml of 1N sodium hydroxide and 35 ml of water were added, stirred for 15 minutes, then filtered to remove insoluble matter, and the filtrate was concentrated to obtain 18.2 g of the title compound as a colorless oil.

[0280] 1 H-NMR (CDCl 3 )δ: 1.22~1.38(2H, m), 1.42~1.58(2H, m), 1.68~1.88(3H, m), 2.36~2.44(2H, m), 3.55(2H, t), 3.61~3.72( 2H, m), 3.77~3.88 (2H, m)

[0281] The following compounds were produced in the same manner as in Reference Examples.

[0282] 5-Chloro-2-hydroxymethyl-1-hexanol,

[0283] 7-Chloro-2-hydroxymethyl-1-heptanol,

[0284] 2-Hydroxymethyl-7-octen-1-ol

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Abstract

The present invention provides a preventive or therapeutic agent for hyperlipidemia, comprising as an active ingredient a heterocyclic compound of the formula Ä1Ü or a pharmaceutically acceptable salt thereof: R<1>-Het-D-E wherein: R<1> is optionally substituted aryl or aromatic heterocyclic group, Het is a divalent aromatic heterocyclic group, D is alkylene, alkenylene, alkynylene, or the like, and E is carboxy, or the like, and novel compounds among the heterocyclic compounds of the formula Ä1Ü above, which has blood triglyceride lowering effect, LDL-C lowering effect, and blood glucose lowering effect and blood insulin lowering effect, or HDL-C increasing effect or atherogenic index lowering effect all together, and hence is useful in the prevention or treatment of hyperlipidemia, arteriosclerosis, diabetes mellitus, hypertension, obesity, and the like.

Description

technical field [0001] The present invention relates to novel heterocyclic derivatives (heterocyclic compounds) or pharmaceutically acceptable salts thereof. [0002] The compound of the present invention has the effect of lowering blood triglycerides and lowering low-density lipoprotein cholesterol (hereinafter referred to as LDL-C), and also has the effect of lowering blood sugar and blood insulin, or has the effect of increasing hyperlipidemia The effect of high-density lipoprotein cholesterol (hereinafter referred to as HDL-C) or the reduction of arteriosclerosis index [the ratio of non-high-density lipoprotein cholesterol to HDL-C, calculated by (total cholesterol value-HDL-C value) / HDL-C value ], it is useful in the prevention or treatment of coronary artery disease, cerebral infarction, hyperlipidemia, arteriosclerosis or diabetes. Background technique [0003] Insulin resistance syndrome complicated with abnormal glucose and lipid metabolism and hypertension is attr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D263/32C07D413/06C07D413/04C07D413/14C07D417/06C07D413/12C07D405/06C07D277/30A61K31/421A61K31/422A61K31/4439A61K31/427A61K31/4178A61K31/426A61P3/06A61P3/10A61P9/10A61P9/12A61P3/04C07D277/24
CPCC07D405/06C07D263/32C07D277/24C07D413/04A61K31/421C07D413/14A61K31/422A61K31/427C07D413/12A61K31/4439A61K31/426C07D413/06A61K31/4178A61P3/10A61P3/04A61P3/06A61P9/10A61P9/12
Inventor 桑原健誌青木富义
Owner NIPPON SHINYAKU CO LTD
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