A kind of medicine for preventing or treating fxr-mediated disease and its preparation method and application

Abstract

The invention relates to a medicine for preventing or treating FXR-mediated diseases, and a preparation method and an application of the medicine. The medicine for preventing or treating FXR-mediated diseases has a structure shown in a formula I(I) in the specification, wherein R is CO(O)R' or P(O)(OH)2; and R' is C1-C6 alkyl. According to the compound provided by the invention, the half-life period is significantly prolonged; and the oral bioavailability is obviously improved.

Description

technical field

[0001] The present invention relates to a medicine for preventing or treating FXR-mediated diseases, its preparation method and application. Background technique

[0002] Farnesoid X receptor (FXR) is a member of the orphan nuclear receptor family. It was first cloned and discovered in rat liver cDNA library by Forman et al. in 1995. It is named because its transcriptional activity can be enhanced by supraphysiological concentrations of farnesoid. 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 the nature of the endogenous FXR ligand un...

Examples

Embodiment 1

[0042] The preparation of the compound shown in embodiment 1 formula (III)

[0043]

[0044] To a solution of compound 1 (2.5 g, 6.4 mmol) in methanol (60 mL) was added p-TsOH.H 2 O(p-toluenesulfonic acid monohydrate) (0.12 g, 0.64 mmol). The resulting mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in EtOAc (ethyl acetate) (150 mL). NaHCO 3 (saturated, 100mL), water (50mL) and brine (50mL) washed twice, the organic layer was washed with Na 2 SO 4 Dried and evaporated under reduced pressure to obtain product 2 as a white solid (2.5 g, 96%).

[0045] 1 H NMR (400MHz, CDCl 3):δ3.66(s,3H),3.60(m,1H),2.85(dd,J=12.4,6.0Hz,1H),2.47-2.30(m,2H),2.28-2.20(m,2H), 2.05-1.60(m,10H),1.50-1.09(m,14H),0.92(d,3H),0.65(m,J=6.4Hz,3H).

[0046] To a solution of diisopropylamine (5.2 mL, 39.5 mmol) in dry tetrahydrofuran (30 mL) was added dropwise a solution of n-butyllithium (15.8 mL, 2.5M in n-he...

Embodiment 2

[0049] The preparation of embodiment 2 compound A

[0050]

[0051] To a solution of compound (III) (83 mg, 0.2 mmol) in MeOH (10 mL) was added TsOH (p-toluenesulfonic acid) (5.1 mg, 0.03 mmol). The mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in EtOAc (20ml), washed with saturated aqueous sodium bicarbonate (2x10ml), water (10ml) and brine (10ml). The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluted with DCM / MeOH (dichloromethane / methanol)=100:1 to 80:1) to obtain compound A as a white solid (42 mg, 50%).

[0052] 1 H NMR (400MHz, CDCl 3 ):3.70(s,1H),3.66(s,3H),3.43-3.37(m,1H),2.39-2.31(m,1H),2.26-2.18(m,1H),1.00(td,J=14.0 ,3.2Hz,1H),0.93-0.388(m,9H),0.66(s,3H).LC-MS: m / z 869.7[2M+H] + ,452.3[M+H 2 O] + .

Embodiment 3

[0053] The preparation of embodiment 3 compound B

[0054]

[0055] To a solution of compound (III) (83 mg, 0.2 mmol) in EtOH (10 mL) was added TsOH (5.1 mg, 0.03 mmol). The mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure, the residue was dissolved in EtOAc (20ml), washed with saturated aqueous sodium bicarbonate (2 x 10ml), water (10ml) and brine (10ml). The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluted with DCM / MeOH=100:1 to 80:1) to obtain compound B as a white solid (30 mg, 36%).

[0056] 1 H NMR (400MHz, CDCl 3 ):4.12(q,J=7.2Hz,2H),3.70(s,1H),3.43-3.35(m,1H),2.38-2.30(m,1H),2.26-2.18(m,1H),0.95- 0.86(m,12H),0.66(s,3H).LC-MS: m / z 897.7[2M+H] + ,466.4[M+H 2 O] + .

technical field

[0001] The present invention relates to a medicine for preventing or treating FXR-mediated diseases, its preparation method and application. Background technique

[0002] Farnesoid X receptor (FXR) is a member of the orphan nuclear receptor family. It was first cloned and discovered in rat liver cDNA library by Forman et al. in 1995. It is named because its transcriptional activity can be enhanced by supraphysiological concentrations of farnesoid. 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 the nature of the endogenous FXR ligand un...

Examples

Embodiment 1

[0042] The preparation of the compound shown in embodiment 1 formula (III)

[0043]

[0044] To a solution of compound 1 (2.5 g, 6.4 mmol) in methanol (60 mL) was added p-TsOH.H 2 O(p-toluenesulfonic acid monohydrate) (0.12 g, 0.64 mmol). The resulting mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in EtOAc (ethyl acetate) (150 mL). NaHCO 3 (saturated, 100mL), water (50mL) and brine (50mL) washed twice, the organic layer was washed with Na 2 SO 4 Dried and evaporated under reduced pressure to obtain product 2 as a white solid (2.5 g, 96%).

[0045] 1 H NMR (400MHz, CDCl 3):δ3.66(s,3H),3.60(m,1H),2.85(dd,J=12.4,6.0Hz,1H),2.47-2.30(m,2H),2.28-2.20(m,2H), 2.05-1.60(m,10H),1.50-1.09(m,14H),0.92(d,3H),0.65(m,J=6.4Hz,3H).

[0046] To a solution of diisopropylamine (5.2 mL, 39.5 mmol) in dry tetrahydrofuran (30 mL) was added dropwise a solution of n-butyllithium (15.8 mL, 2.5M in n-he...

Embodiment 2

[0049] The preparation of embodiment 2 compound A

[0050]

[0051] To a solution of compound (III) (83 mg, 0.2 mmol) in MeOH (10 mL) was added TsOH (p-toluenesulfonic acid) (5.1 mg, 0.03 mmol). The mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in EtOAc (20ml), washed with saturated aqueous sodium bicarbonate (2x10ml), water (10ml) and brine (10ml). The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluted with DCM / MeOH (dichloromethane / methanol)=100:1 to 80:1) to obtain compound A as a white solid (42 mg, 50%).

[0052] 1 H NMR (400MHz, CDCl 3 ):3.70(s,1H),3.66(s,3H),3.43-3.37(m,1H),2.39-2.31(m,1H),2.26-2.18(m,1H),1.00(td,J=14.0 ,3.2Hz,1H),0.93-0.388(m,9H),0.66(s,3H).LC-MS: m / z 869.7[2M+H] + ,452.3[M+H 2 O] + .

Embodiment 3

[0053] The preparation of embodiment 3 compound B

[0054]

[0055] To a solution of compound (III) (83 mg, 0.2 mmol) in EtOH (10 mL) was added TsOH (5.1 mg, 0.03 mmol). The mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure, the residue was dissolved in EtOAc (20ml), washed with saturated aqueous sodium bicarbonate (2 x 10ml), water (10ml) and brine (10ml). The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluted with DCM / MeOH=100:1 to 80:1) to obtain compound B as a white solid (30 mg, 36%).

[0056] 1 H NMR (400MHz, CDCl 3 ):4.12(q,J=7.2Hz,2H),3.70(s,1H),3.43-3.35(m,1H),2.38-2.30(m,1H),2.26-2.18(m,1H),0.95- 0.86(m,12H),0.66(s,3H).LC-MS: m / z 897.7[2M+H] + ,466.4[M+H 2 O] + .

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