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Novel fxr (nr1h4) binding and activity modulating compounds

A technology of compounds and solvates, applied in the field of compounds of agonists or modulators, which can solve problems such as low levels

Active Publication Date: 2014-04-02
GILEAD SCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

NR without LBD constitutively activates transcription, but at lower levels

Method used

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  • Novel fxr (nr1h4) binding and activity modulating compounds
  • Novel fxr (nr1h4) binding and activity modulating compounds
  • Novel fxr (nr1h4) binding and activity modulating compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0129] Example 1: 3-((1s , 3s)-3-(2-chloro-4-((5-cyclopropyl-3-(2 , 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -3- Methyl hydroxycyclobutyl)benzoate (1)

[0130]

[0131] Step 1: 4-((4-Bromo-3-chlorophenoxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)-isoxazole (1a)

[0132] To (5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methanol (13g, 45.8mmol) in CH 2 Cl 2 SOCl was added dropwise to a solution in (DCM) (200 mL) 2 (40 mL, 336 mmol). The resulting mixture was stirred at room temperature for 24 hours, and the solvent was removed under reduced pressure. The residue was dissolved in N,N-dimethylformamide (DMF) (200 mL), and to this solution was added 4-bromo-3-chlorophenol (9.7 g, 47 mmol), K 2 CO 3(40g, 290mmol) and NaI (12g, 80mmol). The mixture was stirred at 60 °C overnight, then cooled to room temperature, diluted with water (1000 mL) and extracted with ethyl acetate (EA) (500 mL×3). The organic phases were combined, washed with brine (500 mL...

Embodiment 2

[0139] Example 2: 3-((1s,3s)-3-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) Methoxy)phenyl)-3- Hydroxycyclobutyl)benzoic acid (2)

[0140]

[0141] Compound 1 (1.7 g, 2.84 mmol) was dissolved in THF (100 mL) at room temperature. A solution of LiOH (285 mg, 4.2 equiv) in water (20 mL) was added and the solution was stirred and warmed to 35 °C for three days. After this time, THF was removed under reduced pressure. The remaining aqueous solution was diluted with water (25 mL) and washed with Et 2 O (2x50 mL) washes. The aqueous layer was then transferred to a round bottom flask and acidified to pH 6 using 1N HCl. The formed white precipitate was filtered off, and dried under reduced pressure at 50° C. to obtain the title compound 2 (1.3 g, 78%, passed 1 Single isomer by H-NMR and LC-MS) as a white solid. 1H NMR (400MHz, CD3OD) δ: 7.98 (s, 1H), 7.86 (d, J=7.6Hz, 1H), 7.58-7.46 (m, 5H), 7.41 (t, J=7.6Hz, 1H), 6.91 (d, J=2.4Hz, 1H), 6.80 (dd, J=8.8...

preparation Embodiment 3

[0154]

[0155] Step 1: Methyl 3-(3-hydroxyazetidin-1-yl)benzoate (3a)

[0156] To a solution of methyl 3-iodobenzoate (4.5 g, 17.2 mmol) in DMSO (30 mL) was added 3-azetidin-3-ol hydrochloride (1.3 g, 11.8 mmol), Cs 2 CO 3 (9.5g, 29.2mmol), CuI (446mg, 2.3mmol) and L-proline (540mg, 4.7mmol), and the mixture was heated at 90°C for 18 hours under an argon atmosphere. The solution was diluted with EA and water, then the organic layer was washed three times with brine, concentrated under reduced pressure, and purified with CC (PE / EA=2:1) ​​to give compound 3a (1.6 g, 66%) as a yellow solid.

[0157] Step 2: Methyl 3-(3-oxoazetidin-1-yl)benzoate (3)

[0158]To a solution of compound 3a (1.60 g, 7.7 mmol) in dry DCM (30 mL) was added Dess-Martin periodinane (6.5 g, 15.4 mmol) at 0 °C and incubated under N 2 The mixture was stirred at room temperature under atmosphere for 2 hours. The mixture was quenched with saturated sodium bicarbonate solution and diluted with EA. T...

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Abstract

The present invention relates to compounds which bind to the NR1H4 receptor (FXR) and act as agonists of FXR. The invention further relates to the use of the compounds for the preparation of a medicament for the treatment of diseases and / or conditions through binding of the nuclear receptor by the compounds and to a process for the synthesis of the compounds (1). Z is selected from (a), (b), (c) or (d).

Description

technical field [0001] The present invention relates to compounds that bind to the NR1H4 receptor (FXR) and act as agonists or modulators of FXR. The present invention further relates to the use of said compounds for the treatment and / or prevention of diseases and / or disorders by binding said compounds to said nuclear receptors. Background technique [0002] Multicellular organisms rely on advanced information transmission mechanisms between the cellular and humoral compartments. The transmitted information can be highly complex and can result in changes in genetic programs involved in cell differentiation, proliferation or replication. The signals, or hormones, are usually low molecular weight molecules such as peptides, fatty acids or cholesterol derivatives. [0003] Many of these signals exert their effects by ultimately altering the transcription of specific genes. A well-studied group of proteins that regulate cellular responses to various signals is the family of t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P1/16A61P3/10A61P35/00A61K31/42C07D261/08C07D413/12C07D413/14
CPCC07D413/14C07D261/08C07D413/12A61K31/42A61K31/422A61K31/4439A61P1/00A61P1/04A61P1/16A61P13/12A61P29/00A61P3/00A61P3/04A61P35/00A61P3/06A61P7/02A61P9/10A61P3/10A61K31/435A61K31/495
Inventor 奥拉夫·金策尔克里斯托弗·斯蒂内克克洛·克伦默泽
Owner GILEAD SCI INC
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