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Benzoxazepine compounds, their production and use

a technology of benzoxazepine and compound, applied in the direction of biocide, drug composition, cardiovascular disorder, etc., can solve the problem of feared undesirable side effects and achieve the effect of excellent lipid-level lowering activity

Inactive Publication Date: 2004-04-15
TAKEDA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention relates to a new compound, called a 4,1-benzoxazepine compound, which has specific chemical structure and is found to have excellent lipid-level lowering activity. This compound has a unique structure that includes specific substituents at certain positions in its molecule. The invention also includes methods for synthesizing this new compound and its use in reducing lipid levels in humans. The technical effect of this invention is the discovery of a new compound with specific chemical structure that has excellent lipid-level lowering activity.

Problems solved by technology

However, when HMG-CoA reductase is inhibited, not only the biosynthesis of cholesterol but the biosynthesis of some other components such as ubiquinone, dolichol and heme A, which are necessary for the living body, is also inhibited, so that occurrences of undesirable side effects to be caused thereby are feared.

Method used

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  • Benzoxazepine compounds, their production and use
  • Benzoxazepine compounds, their production and use
  • Benzoxazepine compounds, their production and use

Examples

Experimental program
Comparison scheme
Effect test

working example 1

[0248] Methyl ester of N-[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neope-ntyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidine-4-carb-oxylic acid 16

[0249] To a solution of (3R,5S)-7-chloro-5-(2,3-dim thoxyphenyl)-1-n opentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin -3-acetic acid (0.5 g) and 0.25 g of piperidine-4-carboxylic acid methyl ester hydrochloride in dimethylformamide (10 ml) were added, at room temperature, diethylcyanophosphonate (0.28 g) and triethylamine (0.38 ml), and the mixture was stirred for one hour. To the mixture were added water (100 ml) and ethyl acetate (100 ml). The organic layer was washed with 1N HCl and a saturated aqueous solution of sodium hydrogencarbonate, followed by drying over an hydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica-gel column chromatography (eluents: hexane: ethyl acetate =1:1 (v / v) to afford 0.62 g of a colorless crystalline product, m.p. 124-126.degree. C.

[0250] Element...

working example 2

[0253] By substantially the same procedure as in Example 1, compounds shown in [Table 1] were obtained.

1TABLE 1 17 Compound No. Y m.p. (.degree. C.) 2-1 18 159-160 2-2 19 110-112 2-3 20 200-202 2-4 21 123-125 2-5 22 196-198 2-6 23 169-171 2-7 24 256-258 2-8 25 175-177 2-9 26 86-89 2-10 27 154-155 2-11 28 141-142 2-12 29 146-148 2-13 30 111-113 2-14 31 125-127 2-15 32 180-180.5 2-16 33 195-197 2-17 34 203-204 2-18 35 132-134 2-19 36 197-200 2-20 37 165-166 2-21 38 142-145 2-22 39 209-210 2-23 40 123-125 2-24 41 96-98 2-25 42 107-108 2-26 43 142-144 2-27 44 216-218 2-28 45 132-134 2-29 46 amorphous solid 2-30 47 amorphous solid 2-31 48 amorphous solid 2-32 49 104-106 2-33 50 115-116 2-34 51 103-105 2-35 52 193-195 2-36 53 126-128 2-37 54 124-127 2-38 55 150-151

working example 3

[0254] N-[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3-,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidine-4-carboxylic acid 56

[0255] The compound (0.5 g) obtained in Example 1 was dissolved in a mixture of 1N aqueous solution of sodium hydroxide (4 ml), methanol (10 ml) and tetrahydrofuran (5 ml). The solution was stirred for one hour at room temperature, to which were added 1N HCl (50 ml) and ethyl acetate (100 ml). The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was recrystallized from hexane-diethyl ether to afford 0.47 g of colorless crystals, m.p. 145-147.degree. C.

[0256] Elemental analysis for C.sub.30H.sub.37ClN.sub.2O.sub.7.0.3H.sub.2O-:

[0257] Calcd.: C, 62.29; H, 6.55; N, 4.84

[0258] Found: C, 62.20; H, 6.65; N, 4.83

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Abstract

This invention provides new benzoxazepine compounds represented by the formula: [wherein R stands for a lower alkyl group optionally substituted with a hydroxyl group, X stands for an optionally substituted carbamoyl group or an optionally substituted heterocyclic group having a deprotonatable hydrogen atom, R1 stands for a lower alkyl group and W stands for a halogen atom] having activities of lowering chlesterol-level and lowering trigluceride-level, and being useful for prophylaxis and therapy of hyperlipidemia.

Description

[0001] This invention relates to a benzoxazepine compound having an activity of lowering cholesterol-level and an activity of lowering triglyceride-level and useful for prophylaxis and therapy of hyperlipemia.[0002] Abnormal increase of concentrations of lipids in plasma is called "hyperlipidemia" or "hyperlipemia". Serum lipids include cholesterol (cholesterol ester, free cholesterol), phospholipid (lecithin, sphingomyelin, etc.), triglyceride (neutral fat), free fatty acid and other sterols. Increase of cholesterol and triglyceride is especially taken up as a problem from the clinical viewpoint [cf. Common Disease Series No.19 Koskhikessho (hyperlipemia) compiled by Haruo Nakamura, published by Nankodo].[0003] Therefore, adequate control of lipid concentration in blood is remarkably important for the prophylaxis or therapy of various diseases related to arteriosclerosis typically exemplified by ischemic heart disease and cerebral infarction. And, hypertriglyceridemia is considered...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61P9/10C07D267/14C07D413/06C07D413/12C07D413/14C07D491/10C07D521/00C07F9/6527C07F9/6558
CPCC07D231/12C07D233/56C07D249/08C07D267/14C07D281/10C07F9/65583C07D413/12C07D413/14C07D491/10C07F9/6527C07D413/06A61P9/10
Inventor YUKIMASA, HIDEFUMISUGIYAMA, YASUOTOZAWA, RYUICHI
Owner TAKEDA PHARMA CO LTD
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