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Compounds for modulating FXR

A technology of compounds, compositions, applied in the fields of medicinal chemistry, pharmacology and medicine

Pending Publication Date: 2022-02-01
NANJING RUIJIE PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Although progress has been made in the development of novel FXR agonists, there is still much room for improvement

Method used

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  • Compounds for modulating FXR
  • Compounds for modulating FXR
  • Compounds for modulating FXR

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0259] 6-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)ethyl)piperazin-1-yl)-1-methyl -1H-indole-3-carboxylic acid (I1)

[0260]

[0261]Step 1: Synthesis 4:

[0262]

[0263] Add K to a solution of compound 3 (31 g, 122.0 mmol) in acetonitrile (ACN, 300 mL) at room temperature 2 CO 3 (33.7 g, 244.0 mmol), followed by the addition of iodomethane (MeI) (43.3 g, 305.0 mmol). The reaction mixture was stirred overnight then concentrated. The residue was diluted with water, extracted with ethyl acrylate (EA), and the organic layers were combined, washed with brine, dried, concentrated and purified by silica gel column (heptane / EA=5:1) to give the desired product, compound 4 (12.1 g, white solid, 15% overall yield over three steps). LCMS: (ESI-MS): [M+H] + =268.0,270.0; 1 H NMR (400MHz, DMSO) δppm: 8.15(s,1H), 7.92(d, J=8.8Hz,1H), 8.84(s,1H), 7.38(s,1H), 3.85(s,3H), 3.80 (s,3H).

[0264] Step 2: Synthesis 5:

[0265]

[0266] Under nitrogen, compound 4 ...

Embodiment 2

[0298] 6-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-acetyl)ethyl)piperazin-1-yl)-1-methanol Amyl-1H-indole-3-carboxylic acid (I2)

[0299]

[0300] Step 1: Synthesis of 16:

[0301]

[0302] To a solution of compound 11 (460 mg, 1.62 mmol) in DCM (10 mL) was added triphenylphosphine (PPh3, 637 mg, 2.43 mmol). Then, CBr was added dropwise to the mixture 4 (805mg, 2.43mmol), and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated and purified by silica gel column (heptane / EA=10:1) to obtain the desired product, compound 16 (360 mg, white solid, yield 64%). LCMS: (ESI-MS): [M+H]+=347.9; 1H NMR (300MHz, CDCl 3 ) δppm: 7.47-7.37 (m, 3H), 4.24 (s, 2H), 2.17-2.12 (m, 1H), 1.32-1.29 (m, 2H), 1.24-1.20 (m, 2H).

[0303] Step 2: Synthesis of 17:

[0304]

[0305] To a solution of compound 16 (320 mg, 0.92 mmol) in THF (5 mL) was added TBAF 1M / THF (1.84 mL, 1.84 mmol). Trimethylcyanosilane (TMSCN, 18...

Embodiment 3

[0316] 6-(4-(2-(3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl)ethyl)piperazin-1-yl)-1-methyl -1H-indole-3-carboxylic acid (I3)

[0317]

[0318] Step 1: Synthesis of 22

[0319]

[0320] According to the synthetic steps of 10, compound 21 was obtained. 1 H NMR (400MHz, DMSO-d6) δppm: 7.73-7.58 (m, 3H), 3.93-3.81 (m, 1H), 3.69 (s, 3H), 1.43 (d, J=6.8Hz, 6H).

[0321] Step 2: Synthesis 22:

[0322]

[0323] To a solution of compound 21 (6.0 g, 22 mmol) in THF (40 mL) was added lithium aluminum hydride (LAH) (88 mL, 88 mmol, 1 M in THF) at 0 °C. The reaction was stirred at room temperature for 2 hours, then 100 mL of 1N aqueous NaOH was added. The formed precipitate was filtered through celite and all solvent was removed in vacuo. The residue was purified by flash chromatography (PE:EA=1:2) to give product 22 (2.11 g white solid, yield: 33.5%). 1HNMR (400MHz, DMSO-d6): δppm: 7.71-7.51(m, 3H), 4.96-4.91(m, 1H), 4.22(d, J=4.8Hz, 2H), 3.41-3.35(m, 1H), 1.31 (d, J=6...

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Abstract

The invention relates to compounds of Formula (I), a stereoisomer, enantiomer or a pharmaceutically acceptable salt thereof, wherein groups are as defined herein; and their pharmaceutical compositions, which have good effect of modulating the activity of Farnesoid X receptors (FXR).

Description

technical field [0001] The present invention relates to the fields of medicinal chemistry, pharmacology and medicine. In particular, the present invention relates to novel compounds useful for modulating the activity of farnesoid X receptors (FXRs). Background technique [0002] Farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily and is mainly expressed in the liver, kidney and intestine (see, for example, Seol et al. (1995) Mol. Endocrinol. (" Molecular Endocrinology) 9:72-85 and Forman et al. (1995) Cell 81:687-693). It functions as a heterodimer with the retinoid X receptor (RXR) and binds to response elements in target gene promoters in order to regulate gene transcription. The FXR-RXR heterodimer binds with the highest affinity to the inverted repeat-1 (IR-1) response element, where the consensus receptor-binding hexamer is separated by one nucleotide. FXR forms part of a related process because it is activated by bile acids, the end pr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/12C07D413/14A61K31/422A61P3/00A61P1/16
CPCC07D413/12C07D413/14A61P3/00A61P1/16A61K45/06C07D487/08C07D261/08C07D417/14C07D471/08
Inventor 张军波朱曙灏齐晓昕
Owner NANJING RUIJIE PHARMATECH CO LTD
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