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

[0015] Through intensive investigations from the above viewpoints, the present inventors synthesized, for the first time, a 4,1-benzoxazepine compound with the characteristic feature having specific substituents at 1-, 3-, 5- and 7-positions, and found that this compound has unexpectedly excellent lipid-level lowering activity based on the specific chemical structure, thus accomplishing the present invention.
[0231] The compound represented by the formula (I) or a salt thereof in the present invention [hereinafter sometimes called the compound of the formula (I) or the compound (I)] is low in toxicity, has a squalene synthetase inhibiting activity and an activity of lowering the level of triglyceride, and, has an excellent activity of lowering the level of lipids, and is useful for the prophylaxis or therapy of hyperlipemia such as hypercholesteremia and hypertriglycerolemia of mammals (e.g. mouse, rat, rabbit, dog, cat, cow, pig and man), and also useful for the prophylaxis or therapy of renal diseases such as n phritis and nephropathy, arteriosclerosis, ischemic diseases, myocardial infarction, angina pectoris, aneurysm, cerebral arteriosclerosis, peripheral arteriosclerosis, thrombosis, diabetes mellitus (e.g. insulin resistant diabetes), pancreatic disorders and re-stenosis after percutaneous transluminal coronary angioplasty (PTCA).
[0240] Another possible use of the compound of the general formula (I) of this invention is to inhibit the formation of thrombus. In view of the fact that the triglyceride level in blood is an positive correlation with th blood coagulation factor VII and intake of .omega.-3 type fatty acid serves to lower the triglyceride level and, at the same time, the coagulation is inhibited, it has been considered that hypertriglycemia would promote the formation of thrombus. Since VLDL (very low density lipoprotein) of the patients suffering from hyperlipemia increased more strongly the secretion of plasminogen activator inhibitor from vascular endothelial cells than that of the patients suffering from normal lipemia, it is considered that triglyceride (hereinafter TG) acts to lower the fibrinolytic activity. Therefore, taking the TG lowering action, the compound of the general formula (I) can be effectively used for the prophylaxis and therapy of the formation of thrombus. The compound (I) can be administered singly or in combination with any of the following exemplary known therapeutic agents, preferably orally.

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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