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Compound for treatment of metabolic diseases, preparation method and application thereof

Active Publication Date: 2020-10-30
XI AN BIOCARE PHARMA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Ursodeoxycholic acid (UDCA) is the most commonly used drug for cholestasis in clinical practice. It is a steroidal compound and an analogue of cholic acid. Stone formation, but UDCA has poor activating effect on bile acid nuclear receptor FXR, so it has limitations in the treatment of cholestasis, and some patients with cholestasis are not sensitive to UDCA

Method used

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  • Compound for treatment of metabolic diseases, preparation method and application thereof
  • Compound for treatment of metabolic diseases, preparation method and application thereof
  • Compound for treatment of metabolic diseases, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0098] Synthesis of embodiment 1 compound 1 (i.e. compound 1-H)

[0099] 1. Synthesis of Compound 2

[0100]

[0101] Add 300mL tetrahydrofuran to a 1000mL round bottom flask, then add 30g chenodeoxycholic acid (shown in formula a) (76.42mmol), and add 3mL perchloric acid, and add 100mL formic acid under stirring at room temperature. The temperature was controlled at 50°C and the reaction was stirred for 15 hours, then concentrated under reduced pressure to remove the solvent. The residue was diluted with 4 L of water, the solid was collected by filtration, and 2 L of dichloromethane was added to dissolve the solid. Anhydrous sodium sulfate was added to dry the solution, filtered and concentrated under reduced pressure. The crude product was slurried by adding 4 L of petroleum ether, and the white solid was collected by filtration to obtain 32.8 g of compound 2 with a yield of 98%.

[0102] 2. Synthesis of compound 3

[0103]

[0104] Under the protection of argon, a...

Embodiment 2

[0170] The synthesis of embodiment 2 compound 2-0

[0171] 1. Synthesis of compound 2-1

[0172]

[0173] A certain volume of anhydrous diethyl ether was added into the there-necked flask, then phenol (1000g, 1.0eq) and triethylamine (1070g, 1.0eq) were added, and phosphorus oxychloride (1600g, 1.0eq) was added dropwise with stirring at 0°C. Under the protection of nitrogen, react for 3h. It was then allowed to warm naturally to room temperature overnight. After the reaction, the triethylamine salt was quickly filtered off, and the filtrate was collected, concentrated, and dried to obtain 800 g of oily product 2-1, which was directly used in the next reaction without further purification.

[0174] 2. Synthesis of compound PH-MIK-001-21

[0175]

[0176]A certain volume of anhydrous dichloromethane 20L was added to the three-necked flask, and then triethylamine (770g, 2.0eq.) was added. The reaction system was placed at -78°C, and compound 2-1 (800g, 1.0 eq) A solutio...

Embodiment 3

[0222] 1. Synthesis of compound PH-MIK-001-22

[0223]

[0224] A certain volume of anhydrous dichloromethane 20L was added to the three-necked flask, and then triethylamine (770g, 2.0eq.) was added. The reaction system was placed at -78°C, and compound 2-1 (according to Example Prepared by the preparation method in 2, 800g, 1.0eq.) solution dissolved in anhydrous dichloromethane and (S)-3-(chloroamino)-1-isopropoxybutan-2-one (631g, 1.0eq.), reacted for 2h after the dropwise addition, and then allowed it to return to room temperature naturally and overnight. The solvent was removed, the residue was washed with ethyl acetate, and then filtered, and the filtrate was concentrated and dried to obtain compound PH-MIK-001-22 (760 g), which was directly used in the next reaction.

[0225] 2. Synthesis of compound 3-1

[0226]

[0227] The crude product 2-13 (120g, 1.0eq.) and N-methylimidazole (126g, 8.0eq.) were added to anhydrous tetrahydrofuran, and the compound PH-MIK- ...

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Abstract

The present invention provides a compound for the treatment of metabolic diseases, which has a structure represented by formula (I) or formula (II), or its racemate, stereoisomer, geometric isomer, tautomer , solvates, hydrates, metabolites, pharmaceutically acceptable salts or prodrugs thereof. The compound provided by the invention is an activator of FXR and / or TGR5 receptors, which has the activity of activating FXR and / or TGR5 receptors, and can be used for preparing medicines for treating chronic liver diseases, metabolic diseases or portal hypertension.

Description

[0001] This application claims the priority of the Chinese patent application submitted to the China Patent Office on December 19, 2017, with the application number 201711371702.0, and the title of the invention is "a compound for the treatment of metabolic diseases and its preparation method and application". The entire contents are incorporated by reference in this application. technical field [0002] The invention relates to the technical field of medicinal chemistry, in particular to a compound used for the treatment of metabolic diseases and its preparation method and application. Background technique [0003] Bile acids have a variety of physiological functions, not only play an important role in the absorption, transport and distribution of fat and fat-soluble vitamins, but also act as a signaling molecule to activate nuclear receptors and then regulate the metabolism of bile acids and cholesterol. The enterohepatic circulation of bile acids is an important regulator...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J43/00C07J41/00A61K31/685A61K31/664A61P1/16A61P3/00A61P9/12A61P1/00A61P3/06
CPCA61K31/575A61K31/58A61K31/664A61K31/685A61P1/16A61P9/12A61P1/00A61P3/00A61P3/06C07F9/242C07F9/657181C07F9/65742C07J9/00C07J9/005C07J41/0094C07J51/00C07F9/222
Inventor 付国琴丁伟尹博杨超王翠芹豆勇王瑞玲
Owner XI AN BIOCARE PHARMA LTD
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