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Sulphonylaminocarbonyl derivatives, and pharmaceutical compositions and use thereof

A technology of compounds and hydrates, which can be used in drug combinations, steroids, pharmaceutical formulations, etc., and can solve the problems of lack of drugs and listing.

Inactive Publication Date: 2016-11-09
SHANGHAI DE NOVO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the research on these two targets is still in-depth, but there are no drugs targeting these two targets on the market, so there is still a lot of room for development

Method used

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  • Sulphonylaminocarbonyl derivatives, and pharmaceutical compositions and use thereof
  • Sulphonylaminocarbonyl derivatives, and pharmaceutical compositions and use thereof
  • Sulphonylaminocarbonyl derivatives, and pharmaceutical compositions and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0138] Embodiment 1: the synthesis of compound 1.7

[0139]

[0140] Step 1: Preparation of compound 1.1

[0141] Add chenodeoxycholic acid (190g, 0.474mol), sodium bromide (2.5g, 0.024mol), tetrabutylammonium bromide (0.5g, 1.55mmol), methanol (616mL) in a 5L four-neck round bottom flask , acetic acid (200 mL), water (49 mL), and tetrahydrofuran (1330 mL). The reaction solution was stirred at room temperature for 15 minutes until the solution was clear, and cooled to 0°C. Sodium hypochlorite (~5%, 756g, 0.531mol) was slowly added dropwise to the reaction system, and the internal temperature was controlled at 1-2°C (exothermic). After the dropwise addition, the stirring was continued for 30 minutes, and the temperature was slowly raised to 5°C. Stir at this temperature for 3 hours until the starting material disappears by TLC. The reaction was quenched by adding saturated sodium bisulfite (3.3%, 83 g, 0.0135 mol) until the starch potassium iodide was free of peroxide. W...

Embodiment 2

[0165] Embodiment 2: the synthesis of compound 2.5

[0166]

[0167] Step 1: Synthesis of Compound 2.1

[0168] Compound 1.7 (10g, 24mmol) and 4-dimethylaminopyridine (DMAP) (300mg, 2.4mmol) were dissolved in a mixed solution of acetic anhydride (50mL) and toluene (100mL), and the reaction system was reacted at 110°C for 2 Cool to room temperature one day later, remove the solvent by rotary evaporation under reduced pressure, dissolve the residue in ethyl acetate (200mL), wash the organic phase with cold water (3×50mL) and saturated brine (100mL), separate the organic phase and wash with anhydrous sodium sulfate After drying and concentration, the residue was purified by Flash column chromatography (ethyl acetate / petroleum ether=0-50%) to obtain compound 2.1 (10.4 g, yield: 86%) as a white solid.

[0169] m / z: [M-H] – 503

[0170] Step 2: Synthesis of compound 2.2

[0171] Under ice-bath conditions, dissolve compound 2.1 (1.0 g, 2.0 mmol) in dry tetrahydrofuran (30 mL),...

Embodiment 3

[0182] Embodiment 3: the synthesis of compound 3.2

[0183]

[0184] Step 1: Synthesis of Compound 3.1

[0185] Under ice-bath conditions, compound 2.1 (3.65g, 7.24mmol) was added to trifluoroacetic acid (6.6mL) and trifluoroacetic anhydride (11.4g, 54.3mmol), stirred until dissolved, and sodium nitrite (1.5 g, 21.7mmol), the addition was completed, and the reaction system was stirred under ice bath for 1 hour, and then stirred at 40°C for 2 hours. The reaction system was neutralized with saturated aqueous sodium bicarbonate solution, then extracted with ethyl acetate (3×50 mL), the organic phases were combined, washed with saturated brine, the organic phase was separated and dried with anhydrous sodium sulfate, concentrated, and the residue After purification by Flash column chromatography (ethyl acetate / petroleum ether=0-20%), compound 3.1 (2.4 g, yield: 70%) was obtained as a pale yellow oil.

[0186] 1 H NMR (400MHz, CDCl 3 ):δ5.11(s,1H),4.54-4.62(m,1H),2.22-2.38(m,...

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PUM

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Abstract

The invention relates to preparation methods of sulphonylaminocarbonyl derivatives and compositions containing the same component and a use of the sulphonylaminocarbonyl derivatives as FXR and / or TGR5 agonists; the agonists are the sulphonylaminocarbonyl derivatives represented by the formula I, or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, polymorphs, isomers, and stable isotope derivatives thereof. The compounds can be used for treatment of diseases and symptoms mediated by FXR and / or TGR5 and other therapeutic fields, wherein the diseases and symptoms include primary biliary cirrhosis, nonalcoholic fatty liver, portal hypertension, bile acid diarrhea and cholestasis, type II diabetes and obesity.

Description

technical field [0001] The present invention relates to a sulfonylaminocarbonyl derivative and its isomer, prodrug or pharmaceutically acceptable salt, stable isotope derivative, its pharmaceutical composition, preparation method and application containing the same component composition. Background technique [0002] The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily and belongs to one of the transcription factors activated by ligands. This family includes steroid receptors, retinol receptors, and thyroid hormone receptors . FXR is widely present in the liver, intestines, kidneys, adrenal glands, and other tissues where bile acids are present. Cholic acid or its taurine or glycine amide conjugates are known endogenous ligands of FXR, including chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), they can Binds to and activates FXR receptors at physiological concentrations. FXR plays an important regulatory role ...

Claims

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Application Information

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IPC IPC(8): C07J41/00C07J43/00A61K31/58A61K31/575A61P1/16A61P9/10A61P3/04A61P3/10A61P13/12A61P1/00A61P9/12A61P3/00A61P3/06
CPCC07J41/0066C07J43/003A61K45/06A61P1/00A61P1/16A61P3/00A61P3/04A61P3/06A61P3/10A61P9/00A61P9/10A61P9/12A61P13/12C07J9/00C07J9/005C07J31/006C07J41/0055C07J41/0061C07J41/0088C07J41/0094C07J51/00
Inventor 利群高大新
Owner SHANGHAI DE NOVO PHARMA
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