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Fluorinated bile acid derivatives

A compound, cholane technology, applied in the field of compounds for the treatment of liver diseases, compounds for the treatment of diseases such as non-alcoholic steatohepatitis and primary cholangitis, selective agonists

Active Publication Date: 2021-05-07
NZP UK LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] One of the problems with the bile acid analogs described in the prior art is that, in addition to their activity as FXR agonists, they are also modulators of the G protein-coupled receptor TGR5

Method used

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  • Fluorinated bile acid derivatives
  • Fluorinated bile acid derivatives
  • Fluorinated bile acid derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0329] Example 1 - 3α-hydroxy-4β-fluoro-6α-ethyl-7α-hydroxy-5β-cholane with a sulfonylurea-substituted side chain Synthesis of acid analogs

[0330] A. 6α-Ethyl-3α, 7α-dihydroxy-5β-cholan-24-oic acid methyl ester

[0331]

[0332] To a solution of OCA (23.5 g, 55.87 mmol) in MeOH (540 mL) was added p-toluenesulfonic acid (1.02 mg, 5.59 mmol, ~0.1 equiv) at RT and sonicated at 30 °C for 3 h. Upon completion, the reaction mixture was concentrated in vacuo. The residue was dissolved in chloroform (500 mL), washed with saturated NaHCO 3 (500mL), H 2 O (500 mL) and brine (500 mL), washed with MgSO 4 Dry, filter, and concentrate in vacuo to afford the title compound as a white solid in quantitative yield. The resulting solid was used without further purification.

[0333] 1 H NMR (400MHz, CDCl 3): δ3.70(1H, s), 3.67(3H, s,), 3.44-3.37(1H, m), 2.40-2.32(1H, m), 2.26-2.18(1H, m), 1.96(1H, dt, J=12.0, 2.6Hz), 1.92-1.76 (6H, m), 1.69-1.59 (3H, m), 1.58-1.12 (14H, m), 1.00...

Embodiment 2

[0482] Example 2 - Alternative Synthesis of Compounds with Sulfonylurea-Substituted Side Chains

[0483] The following methods are exemplified for 4β-fluoro derivatives, but can also be used for 2β-fluorinated, 4,4-difluorinated or 2,4-difluorinated compounds.

[0484] A. 6α-Ethyl-4β-fluoro-7α-trimethylsilyloxy-3-oxo-5β-cholane-24-oic acid methyl ester

[0485]

[0486] To a stirred, precooled solution of diisopropylamine (0.78 mL, 5.54 mmol, ~12 equiv) in dry THF (6.9 mL) was added n-BuLi in hexane dropwise at -78 °C under argon atmosphere solution (1.44 mL, 2.31 mmol, ~5.0 equiv) over 0.25 h. After the addition, trimethylsilyl chloride (0.29 mL, 2.31 mmol, ~5.0 equiv) was added and stirred for 1 h. 6α-Ethyl-7α-hydroxy-3-oxo-5β-cholan-24-oic acid methyl ester (200 mg, 0.46 mmol) from Example 1 Step B was then added in dry THF (3 mL) and triethylamine ( 1.16 mL, 8.32 mmol, ~18 equiv). After the addition, the reaction system was gradually warmed to -20 °C and stirred f...

Embodiment 3

[0519] Example 3 - Synthesis of compounds with sulfonamide-substituted side chains

[0520] The procedure below exemplifies 4β-fluoro derivatives, but can also be used with 2β-fluorinated, 4,4-difluorinated or 2,4-difluorinated compounds. Steps A and B are as described in Example 2.

[0521] C. 6α-Ethyl-4β-fluoro-7α-trimethylsilyloxy-3α-hydroxy-5β-cholanic acid

[0522]

[0523] 6α-Ethyl-4β-fluoro-7α-trimethylsilyloxy-3α-hydroxy-5β-cholan-24-oic acid methyl ester (162.3 mg) from Step B was dissolved in IPA ( 1.6mL). 0.5M NaOH (1.6 mL) was added and the reaction was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure to -half the volume, then water (5 mL) was added and the 2 SO 4 The solution was neutralized and diluted with EtOAc (10 mL). with 2M H 2 SO 4The mixture was acidified to pH 1, the phases were separated and the aqueous phase was extracted with EtOAc (10 mL). The combined extracts were washed with water (3 mL) and brine ...

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Abstract

Compounds of general formula (I): wherein R2a, R2b, R3a, R3b, R5, Y and R7 are as defined herein are selective agonists at the FXR receptor and are useful for the treatment or prevention of diseases and conditions including nonalcoholic steatohepatitis (NASH); primary biliary cirrhosis; primary sclerosing cholangitis; biliary atresia; cholestatic liver disease; hepatitis C infection; alcoholic liver disease; fibrosis; or liver damage arising from fibrosis.

Description

[0001] field of invention [0002] The present invention relates to compounds which are derivatives of bile acids and which can be used in the treatment of liver diseases. In particular, the present invention relates to compounds that are selective agonists of the Farnesoid X receptor and are thus useful in the treatment of diseases such as non-alcoholic steatohepatitis (NASH) and primary cholangitis. The invention also relates to pharmaceutical compositions comprising the compounds of the invention. [0003] Background of the invention [0004] Nonalcoholic fatty liver disease (NAFLD) is one of the leading causes of chronic liver disease worldwide and is rapidly becoming a major indication for liver transplantation (Bellentani, 2017). NAFLD describes a spectrum of physiological conditions ranging from simple accumulation of lipids in the liver (sebaceous disease) to nonalcoholic steatohepatitis (NASH), characterized by lobular inflammation and hepatocellular damage (Haas, Fra...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J41/00A61K31/575A61P1/16C07J9/00C07J11/00C07J51/00C07J71/00
CPCC07J9/005C07J71/001C07J41/0055C07J51/00C07J41/0061C07J11/00A61P1/16A61K31/575A61K31/64
Inventor A·C·韦茅斯-威尔逊G·帕克B·J·P·林克劳D·基德-辛克莱K·A·沃森
Owner NZP UK LTD
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