Benzamide derivatives, their preparation method and their application in medicine

A technology of phenyl and compound, applied in its preparation method and pharmaceutical composition containing the derivative, in the field of novel benzamide derivatives, which can solve the problem of FGF23 expression reduction and other problems

Active Publication Date: 2020-11-17
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Loss of Npt2b in the small intestine also resulted in reduced FGF23 expression

Method used

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  • Benzamide derivatives, their preparation method and their application in medicine
  • Benzamide derivatives, their preparation method and their application in medicine
  • Benzamide derivatives, their preparation method and their application in medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0188] N 1 -Methyl-N 1 -(2-morpholine ethyl)-N 3 -(3-(4-Phenylethylphenylcarbamoyl)-5,6,7,8-tetrahydronaphthalen-2-yl)isophthalamide

[0189]

[0190] first step

[0191] 3-Amino-5,6,7,8-tetrahydronaphthalene-2-carbonyl chloride

[0192] Dissolve 3-amino-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid 1a (65 mg, 0.34 mmol, prepared by the method disclosed in the patent application "WO2012065963") in 3 mL of thionyl chloride, and heat up to 70°C, and stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title product 3-amino-5,6,7,8-tetrahydronaphthalene-2-carbonyl chloride 1b (71 mg, yellow oil). The product was directly subjected to the next reaction without purification.

[0193] second step

[0194] 3-Amino-N-(4-phenethylphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide

[0195] The crude 3-amino-5,6,7,8-tetrahydronaphthalene-2-formyl chloride 1b (71 mg, 0.34 mmol) was dissolved in 6 mL of dichloromethane, and 4-ph...

Embodiment 2

[0203] 4-(4-(3-(3-(Methyl(2-morpholineethyl)carbamoyl)benzamido)-5,6,7,8-tetrahydronaphthalene-2-carboxamido) Phenylethyl) methyl benzoate

[0204]

[0205]

[0206] first step

[0207] Methyl 4-(4-(3-amino-5,6,7,8-tetralin-2-carboxamido)phenethyl)benzoate

[0208] Crude 3-amino-5,6,7,8-tetrahydronaphthalene-2-carbonyl chloride 1b (110 mg, 0.52 mmol) was dissolved in 6 mL of dichloromethane and 4-(4-aminophenethyl)benzoic acid was added Methyl ester 2a (127mg, 0.47mmol, prepared by the method disclosed in the patent application "WO2013062065") and triethylamine (159mg, 1.57mmol) were stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title product 4-(4-(3-amino-5,6,7,8-tetrahydronaphthalene-2-methanol Acylamino)phenethyl)methylbenzoate 2b (98 mg, pale yellow solid), yield: 48%.

[0209] MS m / z(ESI):429.4[M+1]

[0210] second s...

Embodiment 3

[0216] 4-(3-(4-(3-(3-(Methyl(2-morpholineethyl)carbamoyl)benzamido)-5,6,7,8-tetrahydronaphthalene-2-methanol Acylamino)phenyl)propyl)methylbenzoate

[0217]

[0218] first step

[0219] Methyl 4-(3-(4-(3-amino-5,6,7,8-tetrahydronaphthalene-2-carboxamido)phenyl)propyl)benzoate

[0220] The crude 3-amino-5,6,7,8-tetrahydronaphthalene-2-formyl chloride 1b (110 mg, 0.52 mmol) was dissolved in 6 mL of dichloromethane, and 4-(3-(4-aminophenyl) Propyl) methyl benzoate 3a (127mg, 0.47mmol, prepared by the method disclosed in the patent application "WO2013062065") and triethylamine (160mg, 1.57mmol), stirred and reacted for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title product 4-(3-(4-(3-amino-5,6,7,8-tetrahydronaphthalene- 2-Formylamino)phenyl)propyl)methylbenzoate 3b (60 mg, pale yellow solid), yield: 28.7%.

[0221] MS m / z(ESI):443.4[M...

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Abstract

The invention relates to a benzamide derivative as well as a preparation method and medicinal application thereof. Specifically, the invention relates to a benzamide derivative shown by a general formula (I), a preparation method thereof and a pharmaceutical composition containing the benzamide derivative, and an application of the benzamide derivative as a therapeutic agent and particularly as an intestinal 2B-type sodium phosphate cotransporter (Npt2b) inhibitor and an application thereof in preparing a medicine for treating and / or preventing hyperphosphatemia, wherein the definition of each substituent in the general formula (I) is the same as that in the specification.

Description

technical field [0001] The present invention relates to a class of novel benzamide derivatives, a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as an inhibitor of intestinal 2B sodium phosphate cotransporter (Npt2b) and Use in the preparation of medicines for treating and / or preventing diseases or conditions such as hyperphosphatemia. Background technique [0002] Inorganic phosphate (Pi) is an essential component of bone minerals. About 80% of the adult phosphate is in the extracellular matrix (such as bone and tooth) outside the mine, 18% is in the cells, and 2% is in the extracellular fluid. . Under normal physiological conditions, excess phosphate is taken up by the small intestine, and phosphate homeostasis is regulated by the excretion and reabsorption of the kidneys. Too much or too little phosphate in the body can lead to dysfunction of the body and cause disease: if it is too low,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D295/13C07D231/40C07C237/48A61K31/5375A61K31/5377A61P3/12A61P13/12A61P5/16A61P9/00
CPCC07C237/48C07D231/40C07D295/13
Inventor 应永铖陈刚杨方龙
Owner JIANGSU HENGRUI MEDICINE CO LTD
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