FXR regulator with spirane structure

A technology of stereoisomers and compounds, applied in the field of medicinal chemistry, can solve problems such as differential nuclear receptor selectivity

Inactive Publication Date: 2018-12-21
SCINNOHUB PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Steroid agonists usually have poor nuclear receptor selectivity because they contain a common steroidal mother nucleus, so researchers have turned their research focus to non-steroidal agonists. Although progress has been made, it is still Huge room for improvement

Method used

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  • FXR regulator with spirane structure
  • FXR regulator with spirane structure
  • FXR regulator with spirane structure

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Example 1: 4-(3-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy)-1-oxa-8 -Azaspiro[4.5]decane-8-yl)benzoic acid

[0061] The synthesis steps are as follows:

[0062]

[0063] Step 1: Preparation of (E)-2-(trifluoromethyl)benzaldehyde oxime:

[0064]

[0065] NH at -5℃ 2 A solution of OH·HCl (8.0 g, 115 mmol) in water (15 mL) was slowly dropped into a solution of NaOH (4.8 g, 120 mmol) in water (15 mL). After stirring for 15 min, a solution of 2-(trifluoromethyl)benzaldehyde (17.4 g, 100 mmol) in ethanol (15 mL) was slowly added dropwise and the system was kept at -5°C. The reaction system became turbid, and the stirring was continued until the system became clear, and the system was slowly warmed to room temperature. After reacting at room temperature for 1 hour, TLC monitored the consumption of raw materials. The reaction system was diluted with water, extracted with EA three times, the organic layers were combined, washed with saturated brine, and anhy...

Embodiment 2

[0092] Example 2: 2-(3-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy)-1-oxa-8 -Azaspiro[4.5]decane-8-yl)benzo[d]thiazole-6-carboxylic acid

[0093] The synthesis steps are as follows:

[0094]

[0095] Step 1: Preparation of 2-aminobenzo[d]thiazole-6-carboxylic acid methyl ester

[0096]

[0097] Bromine (3.10g, 19.85mmol) was dissolved in acetic acid (18mL) and slowly added dropwise to methyl 4-aminobenzoate (3.00g, 19.85mmol), KSCN (6.89g, 70.86mmol) in acetic acid (67mL) In the solution, react overnight at room temperature. Quench with water, use saturated Na 2 CO 3 Adjust the pH of the solution to 9. Extract three times with EA, wash with saturated brine, anhydrous Na 2 SO 4 After drying and concentration, the crude product was passed through column chromatography (PE / EA=3 / 1) to obtain the target compound (3.30 g, yield: 80%) as a white solid.

[0098] Step 2: Preparation of 2-aminobenzo[d]thiazole-6-carboxylic acid methyl ester

[0099]

[0100] Under the p...

Embodiment 3

[0109] Example 3: 6-(3-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy)-1-oxa-8 -Azaspiro[4.5]decane-8-yl) nicotinic acid

[0110] The synthesis steps are as follows:

[0111]

[0112] Step 1: 6-(3-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy)-1-oxa-8- Preparation of azaspiro[4.5]decane-8-yl) nicotinic acid ethyl ester

[0113]

[0114] Will K 2 CO 3 (124mg, 0.9mmol), 3-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy)-1-oxa-8 -Azaspiro[4.5]decane (211 mg, 0.5 mmol) and ethyl 6-fluoronicotinate (118 mg, 0.7 mmol) were dispersed in DMF (6 mL), and reacted at 100°C under nitrogen protection for 3.5 hours. After cooling, the reaction system was poured into water, EA was added for extraction three times, the organic layers were combined, washed with water and saturated brine, anhydrous Na 2 SO 4 The crude product obtained after drying and concentration was separated and purified by a thin-layer preparation plate (PE / EA=3 / 1) to...

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PUM

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Abstract

The invention provides a new compound which has certain agonist activity on a Farnesoid X receptor (FXR) and is used for treating FXR mediated diseases and / or symptoms such as liver disease and gastrointestinal disease. (The formula is shown in the description.).

Description

Technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a compound and its use. Background technique [0002] The full name of FXR is the farnesoid derivative X receptor, a member of the nuclear receptor superfamily. It is a bioreceptor for bile acid receptor and bile acid synthesis, and bile acid is its natural ligand. As a multifunctional transcription factor, it plays an important role by regulating multiple target genes and is an important target for the development of drugs for the treatment of dyslipidemia and anti-fatty liver. In terms of mechanism of action, FXR can regulate the gene expression of cholesterol 7α hydroxylase, and CYP7A1 is the rate-limiting enzyme of bile acid biosynthesis. In addition, it can also enhance the secretion of fibroblast factor 19, which is an inhibitory regulator of bile acids in the bile. FXR can also regulate liver gluconeogenesis and glycogen decomposition, control glucose metabolism, control th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/107A61P9/00A61P9/10A61P3/06A61P1/16A61P1/00A61P13/12A61P3/00A61P35/00A61P25/00A61P3/10A61P3/04A61K31/438A61K31/444
CPCA61P1/00A61P1/16A61P3/00A61P3/04A61P3/06A61P3/10A61P9/00A61P9/10A61P13/12A61P25/00A61P35/00C07D491/107
Inventor 黄浩喜李劲思刘冠锋陈垌珲任俊峰易守兵李英富苏忠海
Owner SCINNOHUB PHARM CO LTD
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