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Thienocycloalkyl or thienoheterocyclic derivatives, preparation method and application in medicine

A technology of heterocyclyl and alkyl groups, which is applied to thienocycloalkyl or thienoheterocyclyl derivatives, their preparation and their application in medicine, and can solve the problems of reduced expression of FGF23 and the like

Active Publication Date: 2019-03-08
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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  • Thienocycloalkyl or thienoheterocyclic derivatives, preparation method and application in medicine
  • Thienocycloalkyl or thienoheterocyclic derivatives, preparation method and application in medicine
  • Thienocycloalkyl or thienoheterocyclic derivatives, preparation method and application in medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0189] 4-(3-(4-(2-(3-(Methyl(2-morpholineethyl)carbamoyl)benzamido)-4,5,6,7-tetrahydrobenzo[b] Thiophene-3-carboxamido)phenyl)propyl)benzoic acid

[0190]

[0191]

[0192] first step

[0193]4-(3-(4-(2-(3-(Methyl(2-morpholineethyl)carbamoyl)benzamido)-4,5,6,7-tetrahydrobenzo[b] Thiophene-3-carboxamido)phenyl)propyl)methyl benzoate

[0194] Methyl 4-(3-(4-(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamido)phenyl)propyl)benzoate 1a (149mg , 0.33mmol, prepared by the method disclosed in the patent application "WO2011136269") was dissolved in 5mL of dichloromethane, triethylamine (101mg, 1mmol) was added, and then 5mL of 3-(methyl(2-morpholine ethyl )carbamoyl)benzoyl chloride 1b (124mg, 0.40mmol, prepared by the method disclosed in the patent application "WO2012006477") in dichloromethane, stirred for 3 hours. Add 20mL of water, extract with dichloromethane (50mL×3), combine the organic phases, wash with water (50mL×1), saturated sodium chloride solution (50mL×...

Embodiment 2

[0203] 4-(4-(2-(3-(3-methyl-3-(2-morpholine ethyl)ureido)benzamido)-4,5,6,7-tetrahydrobenzo[b ]thiophene-3-carboxamido)phenethyl)benzoic acid

[0204]

[0205] first step

[0206] 3-(3-Methyl-3-(2-morpholineethyl)ureido)benzoyl chloride

[0207] Dissolve 3-(3-methyl-3-(2-morpholineethyl)ureido)benzoic acid 2a (150 mg, 0.50 mmol, prepared by the method disclosed in the patent application "WO2012054110") in 60 mL of dichloromethane , cooled to 0°C, added thionyl chloride (177 mg, 1.50 mmol), heated to reflux, and stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title product 3-(3-methyl-3-(2-morpholineethyl)ureido)benzoyl chloride 2b (163 mg, white solid), and the product was directly carried to the next step without purification reaction.

[0208] second step

[0209] 4-(4-(2-(3-(3-methyl-3-(2-morpholine ethyl)ureido)benzamido)-4,5,6,7-tetrahydrobenzo[b ]thiophene-3-carboxamido)phenethyl)methyl benzoate

[0210] Me...

Embodiment 3

[0219] 4-(3-(4-(2-(3-(Methyl(2-morpholine ethyl)carbamoyl)benzamido)-6-((tetrahydro-2H-pyran-4-yl )methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamido)phenyl)propyl)benzoic acid

[0220]

[0221] first step

[0222] 2-amino-3-(4-(3-(4-(methoxycarbonyl)phenyl)propyl)anilinocarbonyl)-4,5-dihydrothieno[2,3-c]pyridine-6 (7H)-tert-butyl formate

[0223]Sulfur (71 mg, 2.23 mmol) was dissolved in 20 mL of ethanol, and methyl 4-(3-(4-(2-cyanoacetamido)phenyl)propyl)benzoate 3a (750 mg, 2.23 mmol, Prepared by the method disclosed in the patent application "WO2013062065"), tert-butyl 4-carbonylpiperidine-1-carboxylate (443mg, 4.97mmol) and morpholine (213mg, 2.45mmol), heated to 90°C, and stirred for reaction 12 hours. Add 60mL of saturated sodium chloride solution, extract with ethyl acetate (50mL×3), combine the organic phases, wash with saturated sodium chloride solution (50mL×1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced p...

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Abstract

The present invention relates to thienocycloalkyl or thienoheterocyclic derivatives, a preparation method thereof and use thereof in medicine. In particular, the present invention relates to thienocycloalkyl or thienoheterocyclic derivatives shown by the general formula (I), a preparation method thereof and a pharmaceutical composition containing the derivatives, and the use thereof as a therapeutic agent, especially as the intestinal type 2B sodium phosphate cotransporter (Npt2b) inhibitor and use thereof in the preparation of drugs for the treatment and / or prevention of hyperphosphatemia, wherein the definitions of the substituents in the general formula (I) are the same as defined in the description.

Description

technical field [0001] The present invention relates to a class of novel thienocycloalkyl or thienoheterocyclyl derivatives, their preparation methods and pharmaceutical compositions containing the derivatives, and their use as therapeutic agents, especially as intestinal 2B sodium phosphate cotransporter Uses of (Npt2b) inhibitors and uses 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 an...

Claims

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Application Information

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IPC IPC(8): C07D333/70C07D495/04A61K31/5377A61K31/496A61P13/12A61P9/00A61P5/16A61P3/12A61P7/00
CPCA61K31/496A61K31/5377C07D333/70C07D495/04
Inventor 应永铖杨方龙王伟民李言华陈刚董庆孙飘扬
Owner JIANGSU HENGRUI MEDICINE CO LTD
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