Heterocyclic farnesoid X receptor modifier

A technology of derivatives and compounds, applied in the field of isotope derivatives, can solve the problem of no non-steroidal FXR agonists

Inactive Publication Date: 2016-11-23
SHANGHAI DE NOVO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although there has been some progress in the development of new FXR agonists, there is currently no non-steroidal FXR agonist on the market, so there is still a lot of room for development

Method used

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  • Heterocyclic farnesoid X receptor modifier
  • Heterocyclic farnesoid X receptor modifier
  • Heterocyclic farnesoid X receptor modifier

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0126] Compound preparation:

[0127] Intermediate 1:

[0128]

[0129]

[0130] Step 1: Under ice-bath condition, in the water (16.5mL) solution of hydroxylamine hydrochloride (22.5g, 362mmol), add dropwise sodium hydroxide aqueous solution (25g, 629mmol, be dissolved in 105mL water), stir under ice-bath for 30 minutes, will The above solution was added to a solution of 2,6-dichlorobenzaldehyde in ethanol (250 mL), and the reaction system was heated to 90° C. and stirred overnight. Cool to room temperature, concentrate under reduced pressure to obtain a crude product, recrystallize the crude product with ethanol / water (1:10), filter, and dry to obtain (E)-2,6-dichlorobenzaldehyde oxime (1-2) (50g, yield Yield 92%) is a white solid.

[0131] Step 2: Slowly add N-chlorosuccinimide (36 g , 268mmol, solution in 140mL of N,N-dimethylformamide), the dropwise addition was completed, the reaction system was stirred at 40°C for 1 hour, then diluted with ethyl acetate, the org...

Embodiment 1

[0146]

[0147] Step 1: Compound I-1-1

[0148] Methyl p-benzoate (11.7 mg, 0.065 mmol), HATU (25 mg, 0.065 mmol) and compound 2-2 (32 mg, 0.065 mmol) were dissolved in N,N-dimethylformamide (1 mL), in Add N,N-diisopropylethylamine (21mg, 0.16mmol) while cooling in an ice bath, react at room temperature and stir overnight, add water (2mL) to quench the reaction, and extract the aqueous phase with ethyl acetate (3mL×3), The organic phases were combined, washed successively with saturated ammonium chloride, water, saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated and purified with a thin-layer silica gel plate (2% methanol in dichloromethane solution). Compound I-1-1 (16 mg, yield: 44%) was an oily product.

[0149] m / z: [M+H] + 555.1;

[0150] Step 2: Compound I-1A

[0151] Compound I-1-1 (16 mg, 0.029 mmol) was dissolved in methanol (2 mL), lithium hydroxide (3 mg, 0.059 mmol) was dissolved in 1 mL of water ...

Embodiment 2

[0160]

[0161] Step 1: Compound I-2-1

[0162] Dissolve Intermediate 2-2 (32mg, 0.065mmol), triethylamine (16mg, 016mmol), 3-ethoxycarbonylphenylisocyanate (12.4mg, 0.065mmol) in dichloromethane (1mL), and stir at room temperature for 1 After 2 hours, the organic solvent was spin-dried, and the obtained crude product was purified by a thin-layer silica gel plate (2% methanol in dichloromethane solution) to obtain compound I-2-1 (30 mg, yield: 79%) as a pale yellow oil.

[0163] m / z: [M+H] + 583.2;

[0164] Step 2: Compound I-2A

[0165] Compound I-2-1 (30 mg, 0.05 mmol) was dissolved in methanol (2 mL), lithium hydroxide (11 mg, 0.25 mmol) was dissolved in 1 mL of water and added dropwise to the above solution, stirred at room temperature overnight, and the methanol was distilled off under reduced pressure , the aqueous phase was adjusted to a pH value approximately equal to 3 with 2N hydrochloric acid diluent, extracted with ethyl acetate (3mL×3), the organic phase was...

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PUM

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Abstract

The invention relates to a preparation method of a heterocyclic compound and a composition with components the same as those of the heterocyclic compound and application of the heterocyclic compound as a farnesoid X receptor active modifier. The modifier is the heterocyclic compound shown as the formula I or salt acceptable pharmaceutically or a predrug or a solvent compound or a polycrystal or an isomer or a stable isotope derivative. The compound can be used for treating or preventing related diseases mediated by FXR, and the related diseases are caused by saccharide or lipid or bile metabolic disturbance. The formula I is shown in the specification.

Description

technical field [0001] The present invention relates to a class of heterocyclic farnesoid derivative X receptor modulator, its isomer, prodrug or pharmaceutically acceptable salt, stable isotope derivative, its pharmaceutical composition, preparation method and application. Background technique [0002] Nuclear receptors (Nuclear Receptors, NRs) are a ligand-dependent transcription factor superfamily that activate and regulate the transcription of target genes through endogenous or exogenous ligand substances. play an important role. [0003] Farnesoid X Receptor (FXR) is a member of the orphan nuclear receptor family. It was first cloned and discovered in rat liver cDNA by Forman et al. in 1995. Named after ester enhancement. FXR plays an important regulatory role in glucose metabolism, lipid metabolism and bile balance. [0004] FXR is involved in the process of glucose metabolism in the body, but its mechanism is not very clear. FXR is controversial in regulating PEPC...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/12C07D401/12C07D401/14C07D417/14C07D413/14A61K31/439A61K31/4192A61K31/444A61K31/4439A61K31/428A61K31/506A61P1/16A61P3/10A61P9/10A61P1/00A61P9/00A61P3/06A61P3/00
Inventor 孔诺尔曼祥龙高大新
Owner SHANGHAI DE NOVO PHARMA
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