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Ursodeoxycholic acid compound for preventing or treating FXR (farnesol X receptor)-mediated disease

A compound, cholanoic acid technology, applied in the field of medicine, can solve problems such as increasing energy consumption

Active Publication Date: 2016-10-12
SHENZHEN TARGETRX INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

While the activation of this membrane receptor in macrophages reduces the production of pro-inflammatory cytokines, the stimulation of TGR5 by bile acids in adipocytes and muscle cells increases energy consumption

Method used

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  • Ursodeoxycholic acid compound for preventing or treating FXR (farnesol X receptor)-mediated disease
  • Ursodeoxycholic acid compound for preventing or treating FXR (farnesol X receptor)-mediated disease
  • Ursodeoxycholic acid compound for preventing or treating FXR (farnesol X receptor)-mediated disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Example 1 Preparation of 3α, 7α-di-hydroxy-7-d-6β-ethyl-5β-cholanic acid (compound 7)

[0062]

[0063] Concrete synthetic steps are as follows:

[0064]

[0065]

[0066] Step 1: Synthesis of methyl α-hydroxy-7-keto-5β-cholanate (compound 2).

[0067] Two drops of concentrated sulfuric acid were added dropwise to 3α-hydroxy-7-keto-5β-cholanic acid (5.00 g, 12.80 mmol) in methanol, and reflux reaction (65oC) for 3 hrs. Concentrate under reduced pressure to remove methanol, concentrate liquid column chromatography to obtain 4.60 g colorless solid (compound 2), yield: 88.3%.

[0068] LC-MS(APCI):m / z=405.3[M+1] + .

[0069] Step 2: Synthesis of methyl α-7α-di-trimethylsilyloxy-5β-cholanate (compound 3).

[0070] At -78°C, trimethylchlorosilane (7.15 mL, 57.0 mmol) was added dropwise to a solution of lithium diisopropylamide (LDA 2M, 34.2 mL, 68.4 mmol) in anhydrous tetrahydrofuran (70 mL), and stirred for 30 minutes. Then a mixture of 3α-hydroxy-7-keto-5β-ch...

Embodiment 2

[0083] Example 2 Preparation of 3α, 7α-di-hydroxy-6β-(ethyl-1-d)-5β-cholanic acid (compound 10)

[0084]

[0085] Concrete synthetic steps are as follows:

[0086]

[0087] Step 1: Synthesis of methyl 3α-hydroxy-6β-(ethyl-1-d)-6-d-7-keto-5β-cholanate (compound 8).

[0088] Pd / C (10%, 55% in D 2 2, 60 mg) was added to 3α-hydroxy-6-ethylidene-7-keto-5β-cholanoic acid methyl ester (600 mg, 1.39 mmol) in anhydrous tetrahydrofuran and deuterated methanol (20 mL, 1:1 v / v ) in a mixed solvent. The air was replaced by deuterium gas, and the reaction was stirred overnight under deuterium gas. Filtrate with celite, concentrate under reduced pressure, and purify by column chromatography to obtain 420 mg of light yellow oil, yield: 70.0%.

[0089] LC-MS(APCI):m / z=435.3[M+1] + .

[0090] Step 2: Synthesis of 3α-hydroxy-6β-(ethyl-1-d)-7-keto-5β-cholanic acid (Compound 9).

[0091] Sodium hydroxide (120mg, 2.90mmol) was added to 3α-hydroxy-6β-(ethyl-1-d)-6-d-7-keto-5β-cholanoi...

Embodiment 3

[0096] Example 3 Preparation of 3α, 7α-di-hydroxy-6β-ethyl-6-d-5β-cholanic acid (compound 12)

[0097]

[0098] Concrete synthetic steps are as follows:

[0099]

[0100] Step 1: Synthesis of 3α-hydroxy-6β-ethyl-6-d-7-keto-5β-cholanic acid (Compound 11).

[0101] Sodium deuterated oxide (120 mg, 2.90 mmol) was added to methyl 3α-hydroxy-6β-ethyl-7-keto-5β-cholanate (420 mg, 0.97 mmol) in deuterated methanol and heavy water (20 mL, 1: 1v / v) in a mixed solvent, the reaction was stirred overnight, methanol was removed under reduced pressure, diluted with water (20mL), acidified with 2N HCl, extracted with ethyl acetate (50mL x 3), the organic layer was washed with saturated brine, anhydrous Na2SO4 dried. The organic layer was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 280 mg of white solid, yield: 68.8%.

[0102] LC-MS(APCI):m / z=418.1[M-1] - .

[0103] Step 3: Synthesis of 3α,7α-di-hydroxy-6β-(ethyl-1-d)-5...

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Abstract

The invention relates to an ursodeoxycholic acid compound for preventing or treating an FXR (farnesol X receptor)-mediated disease. Specially, the invention discloses the ursodeoxycholic acid compound shown in formula (I) and a drug combination containing the compound or the crystalline pharmaceutically-acceptably salt of the compound, a produg, tautomer, stereisomer, enantiomer, aquo-complex or solvate. The compound can serve as FXR stimulant and then is applicable to preparation of drugs for treating FXR related diseases such as fatty liver.

Description

technical field [0001] The invention belongs to the field of medicine. Specifically, the present invention relates to a cholanic acid compound for preventing or treating FXR-mediated diseases, its pharmaceutical composition and use. Background technique [0002] Farnesoid X receptor (FXR) is a member of the orphan nuclear receptor family. It was first discovered by Forman et al. in 1995. It is named because its transcriptional activity can be enhanced by farnesoid at supraphysiological concentrations. Northern and in situ analysis revealed that FXR is abundantly expressed in the lung, intestine, kidney, and adrenal gland. FXR forms a heterodimer with 9-cis retinoic acid receptor (RXR) and binds to DNA. The FXR / RXR heterodimer binds preferentially to a component consisting of binuclear receptor half-sites sharing the AG(G / T)TCA, which form inverted repeats and separate single nucleosides (IR-1 motif). However, these compounds fail to activate mouse and human FXR, making th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J9/00C07B59/00A61K31/575A61P35/00A61P1/16A61P1/00A61P13/12A61P9/00A61P3/00A61P3/04A61P3/10
CPCA61K31/575C07B59/00C07J9/00C07J9/005C07B59/007C07B2200/05
Inventor 王义汉任兴业
Owner SHENZHEN TARGETRX INC
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