Tetrahydrobenzothiophene compound

A compound and alkyl technology, applied in the field of medicine, can solve problems such as poor drug compliance and increased serum calcium concentration

Active Publication Date: 2020-06-05
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these drugs have various problems such as poor compliance with medication, constipation, diarrhea and other gastrointestinal symptoms, increased serum calcium concentration, and accumulation of various metals due to the need to administer several grams per day, and the development of new drugs that improve these aspects has been demanded. drug for hyperphosphatemia

Method used

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  • Tetrahydrobenzothiophene compound
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  • Tetrahydrobenzothiophene compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0308] 1-((3-((3-((4-(4-Carboxyphenethyl)phenyl)carbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl )carbamoyl)phenyl)sulfonyl)indoline-5-carboxylic acid

[0309]

[0310] Step 1. 1-((3-((3-((4-(4-(methoxycarbonyl)phenethyl)phenyl)carbamoyl)-4,5,6,7-tetrahydrobenzo[ b] Methyl thiophen-2-yl)carbamoyl)phenyl)sulfonyl)indoline-5-carboxylate

[0311] Methyl indoline-5-carboxylate (177 mg, 1.0 mmol) was dissolved in pyridine (4 mL), 4-(4-(2-(3-(chlorosulfonyl)benzamido)-4 was added , 5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamido)phenethyl)benzoic acid methyl ester (800 mg, 1.26 mmol) was heated to reflux for 18 hours. The reaction solution was diluted with ethyl acetate (80 mL) and washed with 0.1 mol / L hydrochloric acid (10 mL×3). The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / dichloromethane (v / v)=1 / 1) to obtain 491 mg of yellow solid, yield: 63.2%.

[0312] M...

Embodiment 2

[0318] 1-((3-((3-((4-(4-Carboxyphenethyl)phenyl)carboxamide)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl) Formamide)phenyl)sulfonyl)decahydroquinoline-6-carboxylic acid

[0319]

[0320] Step 1. Methyl decahydroquinoline-6-carboxylate

[0321] Quinoline-6-carboxylate tert-methyl ester (2.08g, 11.1mmol) was added to glacial acetic acid (20mL), then platinum dioxide (0.40g, 1.7mmol) was added, and the mixture was reacted at 70°C for 17 hours under a hydrogen atmosphere . Cooled to room temperature, filtered with suction, washed with methanol (15 mL), the filtrate was spin-dried, the residue was dissolved in water (40 mL), adjusted to pH=10 with saturated sodium carbonate, extracted with ethyl acetate (80 mL×3), the organic phase was washed with anhydrous sulfuric acid Dry over sodium, filter, and concentrate the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v)=30 / 1) to obtain 1.60 g of a brown oil, yi...

Embodiment 3

[0331] 4-(4-(2-(3-((1-Acetylhexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)sulfonyl)benzamido)-4 ,5,6,7-Tetrahydrobenzo[b]thiophene-3-carboxamido)phenethyl)benzoic acid

[0332]

[0333] Step 1. 6-((3-((3-((4-(4-(methoxycarbonyl)phenethyl)phenyl)carbamoyl)-4,5,6,7-tetrahydrobenzo[ b]Thien-2-yl)carbamoyl)phenyl)sulfonyl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylic acid tert-butyl ester

[0334] Octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylic acid tert-butyl ester (355 mg, 1.57 mmol) and triethylamine (0.44 mL, 3.2 mmol) were dissolved in dichloromethane (20 ml), Cool to -25°C. Then 4-(4-(2-(3-(chlorosulfonyl)benzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamido)phenethyl was added dropwise yl)methyl benzoate (1.00 g, 1.57 mmol) in dichloromethane (15 mL) was added over 15 minutes. Stir at -25°C for 5 minutes, then move to room temperature and stir for 18 hours. A saturated solution of ammonium chloride (20 mL) was added, the aqueous phase was extracted with dic...

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Abstract

The invention provides a benzothiophene tetrahydride compound which has intestinal tract phosphoric acid transport protein (NPT-IIb) inhibition effects and can be used as an effective component of a hyperphosphatemia treatment agent and / or prevention agent, or its stereisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt , prodrug or pharmaceutical composition.

Description

technical field [0001] The present invention belongs to the field of medicine. An object of the present invention is to provide a compound having an inhibitory effect on intestinal phosphate transporter (NPT-IIb) and serving as an active ingredient of a therapeutic and / or preventive agent for hyperphosphatemia, or a stereoisomer, geometric isomer, Tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs and pharmaceutical compositions thereof. Background technique [0002] Phosphorus is an essential element for sustaining life and plays a very important role in various biological functions. Phosphorus is mainly taken from food as phosphoric acid through the digestive tract, and almost all of it is excreted into the urine, thereby maintaining and regulating the total amount in the body. It is known that during the production of urine, almost all phosphoric acid is filtered by the glomerulus, and only the necessary am...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D409/12C07D471/04C07D487/04C07D409/14C07D471/10A61K31/4025A61K31/437A61K31/407A61K31/435A61K31/498A61K31/4439A61K31/454A61K31/438A61K31/5377A61P13/12A61P3/12A61P19/00
CPCC07D409/12C07D409/14C07D471/04C07D471/10C07D487/04
Inventor 王晓军杨新业周平健阳传文林继华熊绍辉张英俊肖瑛王慧曹生田吴方园欧阳罗
Owner SUNSHINE LAKE PHARM CO LTD
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