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FXR agonist and preparation method and application thereof

A NR10R11, selected technology, applied in antiviral agents, pharmaceutical formulations, medical preparations containing active ingredients, etc.

Inactive Publication Date: 2017-08-01
SHANGHAI HANSOH BIOMEDICAL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there is no typical FXR binding response sequence in the promoter sequence of major FXR-regulated genes such as cholesterol 7α hydroxylase (CYP7α1). (LRH-1) forms an inhibitory complex, thereby blocking the transcription of CYP7α1 and other LRH-1 target genes

Method used

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  • FXR agonist and preparation method and application thereof
  • FXR agonist and preparation method and application thereof
  • FXR agonist and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0247] Example 1 3-(3-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)phenyl)- 3-Hydroxycyclobutyl)benzoic acid (1)

[0248]

[0249] Step 1: Dissolve compound 1-a (468mg, 1.45mmol) in dry THF (6mL), stir under nitrogen atmosphere, add n-butyl lithium (1.6M, 1.0mL) dropwise at -70~-78°C ). Stir at this temperature for 45 min after the addition. Then a solution of compound I-4 (270 mg, 1.32 mmol) in dry THF (0.5 mL) was added dropwise. Stir at this temperature for 1 h after addition. Warm to room temperature slowly, and wash with saturated NH 4 Quenched with Cl (5 mL) and extracted with ethyl acetate. The organic phase was dried, concentrated, and separated by column chromatography (PE / EA, EA: 0-15%) to obtain compound 1-b (246 mg, yield: 42%).

[0250] LC-MS:t R =3.825min,[M-OH] + = 429.1;

[0251] 1 HNMR (400MHz, CDCl 3 )δ7.97(s,1H),7.88(d,J=7.7Hz,1H),7.48(dd,J=16.4,8.1Hz,2H),7.39(t,J=7.7Hz,1H),6.96( d,J=2.5Hz,1H),6.78(dd,J=8.5,2.5Hz,1...

Embodiment 2

[0260] Example 2 3-(3-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)-2-methoxyphenyl) -3-Hydroxycyclobutyl)benzoic acid (2)

[0261]

[0262] The first step: the synthesis of compound 2-a refers to the preparation method of the first step to the third step of Example 1.

[0263] LC-MS:t R =3.465min,[M-OH] + = 592.0;

[0264] 1 HNMR (400MHz, CDCl 3 )δ7.98-7.93(m,1H),7.89-7.84(m,1H),7.53-7.44(m,1H),7.41-7.35(m,3H),7.33-7.27(m,2H),6.48- 6.35(m,2H),4.92(s,2H),3.91(s,3H),3.85(s,3H),3.05-2.89(m,3H),2.54-2.47(m,2H),2.34-2.25( m,1H), 1.33-1.26(m,2H), 0.98-0.92(m,2H).

[0265] Second step: Compound 2-a (30 mg, 0.05 mmol) was dissolved in THF / MeOH (1 mL, 1:1). Aqueous NaOH (1.0M, 1 mL) was added. The reaction solution was stirred overnight at 60 °C. After cooling, it was acidified to pH=5 with 3N HCl, then extracted twice with ethyl acetate. The organic phase was dried, concentrated, and purified by PTLC to obtain compound 2 (3.0 mg);

[0266] LC-MS:t ...

Embodiment 3

[0268] Example 3 3-(3-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isothiazol-4-yl)methoxy)-2-methylphenyl) -3-Hydroxycyclobutyl)benzoic acid (3)

[0269]

[0270] The first step: the synthesis of compound 3-a refers to the preparation method of the first step to the third step of Example 1.

[0271] LC-MS:t R =3.514min,[M+H] + = 594.1.

[0272] Step 2: Dissolve compound 3-a (8mg, 0.013mmol) in tetrahydrofuran (1mL), add aqueous sodium hydroxide solution (1mL, 1N), and react at 60°C for 4h. After the reaction is complete, add dilute hydrochloric acid to acidify to weak acidity, and extract with ethyl acetate. The organic phase was dried, concentrated, and separated by PTLC to obtain compound 3 (4 mg, 53%).

[0273] LC-MS:t R =3.2min,[M-OH] + =580.0,582.1;

[0274] 1 HNMR (400MHz, CDCl 3 )δ7.95(s,1H),7.87(d,J=7.8Hz,1H),7.48-7.44(m,1H),7.35(d,J=7.7Hz,1H),7.33-7.28(m,3H ),7.25-7.21(m,1H),6.65(d,J=2.5Hz,1H),6.58(dd,J=8.5,2.7Hz,1H),4.85(s,2H),3.16-3.05(m, 2H),3.01-2.89(m...

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Abstract

The invention discloses a FXR agonist and a preparation method and application thereof, and particularly relates to compounds with a structure shown in a formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof. The FXR agonist has the advantages that the series of compounds can be used for treating FXR-mediated diseases, such as cardiovascular disease, atherosclerosis, arteriosclerosis, hypercholesterolemia, hyperlipidemia chronic hepatitis disease, chronic liver disease, gastrointestinal disease, nephrosis, metabolic disease, cancers (such as colorectal cancer) and nerve signs (such as stroke); the broad medical application is realized, and a new generation of FXR regulator is expected to develop. The formula (I) is shown in the description.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and specifically relates to a 3-(2,6-dichlorophenyl)isothiazole / isoxazole series compound with FXR agonistic activity and a preparation method and application thereof. Background technique [0002] Farnesoid derivative X receptor (FXR) is a member of the hormone nuclear receptor superfamily, which is mainly expressed in the liver, small intestine, kidney and adrenal gland, and less expressed in adipose tissue and heart. Farnesol was originally thought to be its ligand, hence the name. When the FXR ligand binds directly to the ligand-binding domain (LBD) at the carboxy-terminal of FXR, the spatial conformation of the nuclear receptor changes and forms a heterodimer with the retinoid receptor (RXR), and finally binds to the target gene specific FXR DNA response elements are combined to regulate the transcription of target genes, participate in the regulation of sugar and lipid metabolism, and are imp...

Claims

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Application Information

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IPC IPC(8): C07D275/02C07D417/12C07D261/08C07D413/12C07D417/14C07D413/14A61K31/425A61K31/427A61K31/4439A61K31/42A61K31/422A61K31/428A61K31/4709A61K31/4245A61P9/00A61P9/10A61P3/06A61P1/16A61P1/00A61P13/12A61P3/00A61P35/00A61P25/00A61P37/00A61P3/10A61P31/12A61P3/04A61P37/06
CPCC07D261/08C07D275/02C07D413/12C07D413/14C07D417/12C07D417/14
Inventor 何剑林包如迪李元念
Owner SHANGHAI HANSOH BIOMEDICAL
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