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Benzimidazole derivative and use as angiotensin ii antagonist

A benzimidazole and biphenyl technology, applied in the field of new benzimidazole derivatives, can solve the problems of compound synthesis and separation unknown, reduce absorbability, reduce compound solubility, etc., and achieve excellent preventive or therapeutic effects

Inactive Publication Date: 2011-06-29
TAKEDA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it is often unpredictable whether a compound can be crystallized, and it is unknown whether the compound can actually be synthesized and isolated
On the other hand, crystallization usually reduces the solubility of the compound, which often consequently reduces oral absorbability

Method used

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  • Benzimidazole derivative and use as angiotensin ii antagonist
  • Benzimidazole derivative and use as angiotensin ii antagonist
  • Benzimidazole derivative and use as angiotensin ii antagonist

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0196] 2-cyclopropyl-1-{[2'-(5-oxo-4,5-dihydro-1,2,4- Oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid [(5-methyl-2-oxo-1,3-dioxolane En-4-yl)methyl]ester

[0197]

[0198] The compound (4.20 g) obtained in Reference Example 3 was dissolved in THF (42 ml), triethylamine (1.42 ml) and 2,4,6-trichlorobenzoyl chloride (1.52 ml) were added, and the mixture was stirred 12 hours. Insoluble materials were removed by filtration, and the filtrate was concentrated. The residue was dissolved in dichloromethane (42ml), medoxomil alcohol (1.45g) and DMAP (1.36g) were added, and the mixture was stirred for 12 hours. The reaction mixture was diluted with chloroform, washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated brine. The organic layer was dried over magnesium sulfate and concentrated to give the title compound (3.08 g, 59%).

[0199] 1H NMR (300MHz, DMSO-d 6 )δppm 0.97-1.10(m, 4H), 2.14(s, 3H), 2.1...

Embodiment 2

[0201] 3-{4'-[(2-cyclopropyl-7-{[(5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy]carbonyl }-1H-benzimidazol-1-yl)methyl]biphenyl-2-yl}-1,2,4- Oxadiazole-5-potassium salt

[0202]

[0203] The compound obtained in Example 1 (1.00 g) was dissolved in acetone (20 ml), potassium 2-ethylhexanoate (0.323 g) was added, and the mixture was stirred for 4 hours and 30 minutes. Precipitated crystals were collected by filtration to obtain the title compound (0.581 g, 54%).

[0204] 1H NMR (300MHz, DMSO-d 6 )δppm 1.08(d, 4H, J=6.2Hz), 2.15(s, 3H), 2.25-2.34(m, 1H), 5.09(s, 2H), 5.84(s, 2H), 6.82(d, 2H, J=8.3Hz), 7.18-7.28(m, 4H), 7.29-7.42(m, 2H), 7.45-7.50(m, 1H), 7.53(dd, 1H, J=7.5, 1.1Hz), 7.80(dd , 1H, J=7.9, 1.1Hz).

Embodiment 3

[0206] 2-cyclopropyl-1-{[2'-(5-oxo-4,5-dihydro-1,2,4- Oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid [(5-methyl-2-oxo-1,3-dioxolane Crystals of en-4-yl)methyl]ester

[0207] The compound obtained in Example 1 was recrystallized from acetonitrile to obtain solvate crystals containing acetonitrile. It was dried at 100° C. overnight under reduced pressure to obtain Form A crystals, which were thermally stable and practical. The obtained crystals had the powder X-ray crystal diffraction pattern shown in Fig. 1 and diffraction angles approximately as described below.

[0208] Table 1

[0209]

[0210]

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PUM

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Abstract

The present invention provides (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-cyclopropyl-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate represented by the formula: which has superior properties as a pharmaceutical agent, a salt thereof, a crystal thereof, a pharmaceutical agent containing the compound, and the like.

Description

technical field [0001] The present invention relates to novel benzimidazole derivatives having excellent properties as medicaments, a process for their preparation and their use. More specifically, the present invention relates to a prodrug of a benzimidazole derivative having a specific structure, a preparation method thereof, a use thereof, etc., which exhibit excellent pharmacological effects (such as stable and sustained hypotensive effect, insulin sensitizing activity, etc.) and excellent properties (such as crystallinity, stability, etc.), and it is used as a drug for the prevention or treatment of circulatory system diseases such as hypertension, heart disease (cardiac hypertrophy, heart failure, myocardial infarction, etc.), nephritis , stroke, etc. and metabolic diseases such as diabetes. Background technique [0002] Angiotensin II causes vasoconstriction and increases blood pressure via angiotensin II receptors on cell membranes. Therefore, angiotensin II recept...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61P3/10A61K31/4245C07D413/10
Inventor 黑板孝信小岛真身伴淳子
Owner TAKEDA PHARMA CO LTD
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