Guanidino Benzoate Compounds

A guanidinobenzoyl compound technology, applied in the field of guanidinobenzoate compounds, can solve the problems of low compliance, low practice of low-protein diet therapy, and high cost

Active Publication Date: 2018-05-29
TAKEDA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

On the other hand, low-protein diet therapy has the problem of long-term strict practice because of the need for professional knowledge, high cost, and low compliance with meals such as taste.

Method used

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  • Guanidino Benzoate Compounds
  • Guanidino Benzoate Compounds
  • Guanidino Benzoate Compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0194] Hereinafter, the production method of the compound of formula (I) is demonstrated in more detail based on an Example. It should be noted that the present invention is not limited to the compounds described in the following examples. In addition, the production methods of the raw material compounds are shown in the production examples. In addition, the production method of the compound of formula (I) is not limited to the production method of the specific examples shown below, and the compound of formula (I) can also be produced by a combination of these production methods or by a method obvious to those skilled in the art .

[0195] In addition, the following abbreviations may be used in Examples, Production Examples, and Tables described below.

manufacture example 1

[0199] tert-butyl 4-methylthiophene-2-carboxylate (12.0g), N-bromosuccinimide (10.8g), 2,2'-azobisisobutyronitrile (496mg) and carbon tetrachloride (119 mL) was stirred at 90°C for 1 hour. Then N-bromosuccinimide (1.08 g) was added and stirred at 90°C for 1 hour. The reaction suspension was cooled to room temperature, then the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 4-(bromomethyl)thiophene-2-carboxylate (16.3 g).

[0200] To a solution of 4-(bromomethyl)thiophene-2-carboxylic acid tert-butyl ester (9.90 g) in N,N-dimethylformamide (100 mL) was added glycine tert-butyl ester hydrochloride (18.0 g) and triethyl amine (19.9 mL), and stirred at 60°C for 15 hours. The reaction suspension was cooled to room temperature, then sodium triacetoxyborohydride (22.7 g) was added, and stirred at room temperature for 5 hours. Water...

manufacture example 2

[0202] To a solution of 6-hydroxy-2-naphthoic acid (220mg) in N,N-dimethylformamide (3.30mL) was added 4-{[(2-tert-butoxy-2-oxoethyl)amino] Methyl}thiophene-2-carboxylic acid tert-butyl ester (383mg), O-(7-azobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (489 mg) and N,N-diisopropylethylamine (500 μL), and stirred at room temperature for 20 hours. Then O-(7-azobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (222 mg) and N,N-diisopropylethyl amine (200 μL) and stirred at room temperature for 6 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 4-{[(2-tert-butoxy-2-oxoethyl)(6-hydroxy-2-naphthoyl)amino] Methyl}thiophene-2-carb...

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Abstract

The present invention provides a compound useful as a prophylactic and / or therapeutic agent for nephropathy. The inventors of the present invention conducted research on compounds having trypsin inhibitory activity, confirmed that guanidinobenzoate compounds have trypsin inhibitory activity, and completed the present invention. The guanidine benzoate compound of the present invention can be used as a preventive and / or therapeutic agent for renal disease (for example, chronic kidney disease, acute glomerulonephritis, acute kidney injury, etc.) Use as a prophylactic and / or therapeutic agent for diseases in which proteases are involved (for example, chronic pancreatitis, reflux esophagitis, hepatic encephalopathy, influenza, etc.).

Description

technical field [0001] The present invention relates to a guanidinobenzoate compound useful as an active ingredient of a pharmaceutical composition, for example, a pharmaceutical composition for treating kidney disease. Background technique [0002] Low-protein diet therapy for various kidney diseases (eg, chronic kidney disease, acute glomerulonephritis, acute kidney injury, etc.) has been practiced since ancient times. Although the mechanism of its effect has not yet been fully elucidated, it is believed that by inhibiting protein intake from food sources, (1) nitrogen compounds from protein are reduced to reduce the burden on glomeruli, and (2) the production of uremic toxins that cause kidney damage is inhibited. (3) inhibit the accumulation of phosphorus and potassium, (4) inhibit the production of acid, etc. So far, clinical trials have confirmed the effect of low-protein diet therapy on delaying the progression of nephropathy ((a) "The New England Journal of Medicine...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C279/18A61K31/24A61K31/343A61K31/381A61K31/472A61P13/12C07D217/26C07D307/80C07D333/40C07D333/68C07D333/70
CPCA61K31/24A61K31/343A61K31/381A61K31/472C07D217/26C07C279/18C07D333/40C07D333/68C07D307/81C07C2602/08C07C2602/10C07D333/70C07D333/24A61P13/00A61P13/12
Inventor 藤安次郎浅野亨山木晋金子统小池由佳今泉智祯浦野泰治佐藤知兴笹村智司
Owner TAKEDA PHARMA CO LTD
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