Obeticholic acid salts and pharmaceutical composition thereof

A technology of obeticholic acid salt and obeticholic acid potassium salt, which is applied in the field of medicinal chemistry and can solve problems such as poor stability of obeticholic acid

Pending Publication Date: 2017-09-22
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it has been found through research that the crystal form of obeticholic acid has the problem of poor stability

Method used

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  • Obeticholic acid salts and pharmaceutical composition thereof
  • Obeticholic acid salts and pharmaceutical composition thereof
  • Obeticholic acid salts and pharmaceutical composition thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] Embodiment 1 obeticholic acid sodium salt

[0081] Preparation method one

[0082] Add obeticholic acid (2.0 g, 4.75 mmol) into methanol (20.0 mL, 10 times the amount v / w), and stir until dissolved; add purified water (4 mL, 2 times the amount v / w) and sodium hydroxide ( 0.19g, 4.75mmol); stirred at 10-30°C for 1h, concentrated to dryness under reduced pressure at 40°C to obtain an oily substance; added acetonitrile (20.0mL, 10 times the amount v / w) into the reaction flask containing the above solid, stirred After dispersion, beat for 1 hour; filter with suction, wash the filter cake once with acetonitrile (4.0 mL, 2 times the amount v / w), and dry under reduced pressure at 65-75°C for 8 hours. 2.0 g of white solid was obtained, yield: 95%.

[0083] Preparation method two

[0084] Sodium hydroxide (0.38g, 9.51mmol) was added to purified water (20mL, 5 times the amount v / w), and obeticholic acid (4.0g, 9.51mmol) was slowly added, stirred until dissolved, and the insolu...

Embodiment 2

[0086] Embodiment 2 obeticholic acid potassium salt

[0087]Add obeticholic acid (2.0 g, 4.75 mmol) into methanol (20.0 mL, 10 times the amount v / w), and stir until dissolved; add purified water (4 mL, 2 times the amount v / w) and potassium hydroxide ( 0.27g, 4.75mmol); Stir at 10~30°C for 1h, concentrate to dryness under reduced pressure at 40°C to obtain foam or oil; add acetonitrile (20.0mL, 10 times the amount v / w) into the reaction flask containing the above solid , after stirring and dispersing, beat for 1 h; filter with suction, wash the filter cake once with acetonitrile (4.0 mL, 2 times the amount v / w), and dry under reduced pressure at 65-75°C for 8 h. 2.04 g of white solid was obtained, yield: 94%.

[0088] Elemental analysis: Ret.Time=6.11min, Height=74.09μS, Area=17.61μS*min.

Embodiment 3

[0089] Embodiment 3 Obeticholic acid magnesium salt

[0090] Preparation method one

[0091] Add sodium hydroxide (0.19g, 4.75mmol) into purified water (20mL, 10 times the amount v / w), slowly add obeticholic acid (2.0g, 4.75mmol), stir until dissolved, and filter out insoluble matter; Magnesium sulfate heptahydrate (0.58g, 2.38mmol) was added to purified water (5mL, 2.5 times the amount v / w), stirred until dissolved; the magnesium salt solution was dropped into the obeticholic acid sodium salt solution, and stirred after the dropping was completed After 1h, filter with suction, wash the filter cake twice with purified water (20mL×2, 10 times the amount v / w), and dry under reduced pressure at 65-75°C for 8h. 1.96 g of white solid was obtained, yield: 95%.

[0092] Preparation method two

[0093] Add triethylamine (0.66mL, 4.75mmol), acetone (2mL, 1 times v / w), purified water (8mL, 4 times v / w) into the reaction flask, slowly add obeticholic acid (2.0g , 4.75mmol), stirred u...

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Abstract

The invention belongs to the field of medicine chemistry and relates to obeticholic acid salts and a pharmaceutical composition thereof. Particularly, obeticholic acid salts includes obeticholic acid sodium salt, obeticholic acid potassium salt, obeticholic acid magnesium salt, obeticholic acid calcium salt and obeticholic acid ammonium salt. The invention further relates to a preparing method of obeticholic acid sodium salt, obeticholic acid potassium salt, obeticholic acid magnesium salt, obeticholic acid calcium salt and obeticholic acid ammonium salt, a pharmaceutical composition including the salts and medical application of the salts. The obeticholic acid salts have the advantages of being high in purity, stability and solubility property, show a good pharmacokinetics property and are suitable for being prepared into medicine products for use.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to obeticholic acid salt and a pharmaceutical composition thereof. Background technique [0002] Farnesoid X Receptor (FXR) was originally an orphan nuclear receptor (Orphan Nuclear Receptors), which was first identified from a mouse liver cDNA library (B.M Forman et al., Cell. 81:687-693 (1995)) , which are members of the family of ligand-activated transcription factor nuclear receptors, including receptors for steroids, retinoids, and thyroid hormones (D. J. Mangelsdorf et al., Cell. 83:841-850 (1995)). [0003] WO02072598 discloses obeticholic acid (Obeticholic Acid), which is a chenodeoxycholic acid derivative, the chemical name is 6-ethylchenodeoxycholic acid, the CAS number is 459789-99-2, and the structural formula is as follows Shown: [0004] [0005] Obeticholic acid is an FXR agonist that can effectively control the level of bile acids, reduce the need ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J9/00A61K31/575A61P9/00A61P1/16A61P3/06A61P43/00
CPCC07J9/005
Inventor 程兴栋李其德张爱明陈超高策刘世鹏赵丹李洋周金幸江竹莲吴刚左沛东夏春光张喜全王善春
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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