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Fluorine-containing isoxazole compounds as well as preparation method and pharmaceutical composition of compounds and application of compounds or pharmaceutical composition

The technology of a compound, isoxazole, applied in the field of medicinal chemistry and pharmacotherapeutics, can solve the problems of limiting widespread use, itching, lowering high-density lipoprotein cholesterol, etc.

Active Publication Date: 2019-11-15
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, although obeticholic acid played a positive role in reducing liver fibrosis, it increased low-density lipoprotein cholesterol (LDL) and lowered high-density lipoprotein cholesterol (HDL), suggesting that the drug may increase heart disease. The risk of vascular disease, but also cause side effects such as itching in the patient's body, which limits its widespread use to a certain extent
[0006]Therefore, in the face of the unmet clinical needs of NASH, it is urgent to develop innovative NASH therapeutic drugs targeting at new targets of NASH, to fill the market gap and meet the clinical drug demand

Method used

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  • Fluorine-containing isoxazole compounds as well as preparation method and pharmaceutical composition of compounds and application of compounds or pharmaceutical composition
  • Fluorine-containing isoxazole compounds as well as preparation method and pharmaceutical composition of compounds and application of compounds or pharmaceutical composition
  • Fluorine-containing isoxazole compounds as well as preparation method and pharmaceutical composition of compounds and application of compounds or pharmaceutical composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0159] Example 1 4-(4-(((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)methyl)-4-fluoropiperidine- 1-yl) Preparation of benzoic acid (FL1)

[0160]

[0161] 1.1 Synthesis of 2,6-dichloro-benzaldehyde oxime

[0162]

[0163] Hydroxylamine hydrochloride (67.6g, 0.943mol) was dissolved in 100mL of water, and sodium hydroxide 3N (314mL, 9.43mol) was added dropwise with stirring at 0°C. 2,6-Dichlorobenzaldehyde (150g, 0.857mol) was added to ethanol (300mL ) after dissolving, drop into the above-mentioned mixed solution, then heat up to 90°C and stir overnight. Monitor the reaction with thin-layer chromatography (TLC), cool to room temperature after the reaction, concentrate in vacuo to 10% solution, a large amount of solids are precipitated, and the solids are obtained by suction filtration , and dried to obtain 162 g of white solid with a yield of 98%. ESI-MS m / z: 190 (M+1).

[0164] 1.2 2,6-Dichloro-benzaldehyde chloro-oxime

[0165]

[0166] 2,6-Dichloro-...

Embodiment 2

[0194] Example 2 4-(4-(((3-(2-chloro-6-fluorophenyl)-5-cyclopropylisoxazol-4-yl)methoxy)methyl)-4-fluoropiperidine -1-yl) Preparation of benzoic acid (FL2)

[0195] Replace 2,6-dichlorobenzaldehyde with 2-chloro-6-fluorobenzaldehyde, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 1 to obtain the product FL2. 1 H NMR (400MHz, DMSO-d 6 )δ12.28(s,1H),7.77(d,J=8.9Hz,2H),7.62(td,J=8.3,6.2Hz,1H),7.51(d,J=8.1Hz,1H),7.41( t,J=8.7Hz,1H),6.95(d,J=9.0Hz,2H),4.35(s,2H),3.61(d,J=13.2Hz,2H),3.39(s,2H),3.03( t,J=10.8Hz,2H),2.37-2.30(m,1H),1.70-1.35(m,4H),1.19-1.04(m,4H).LRMS(EI)m / z 504(M + ).

Embodiment 3

[0196]Example 3 6-(4-(((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)methyl)-4-fluoropiperidine- Preparation of 1-yl)-1-ethyl-1H-indole-3-carboxylic acid (FL3)

[0197] Replace 4-iodo-ethyl benzoate with 6-bromo-1-ethyl-1H-indole-3-carboxylic acid methyl ester, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 1 to obtain the product FL3. 1 H NMR (400MHz, DMSO-d 6 )δ11.81(s,1H),7.89(s,1H),7.82(d,J=8.7Hz,1H),7.64(d,J=7.5Hz,2H),7.57(dd,J=9.1,6.9 Hz, 1H), 7.01-6.91(m, 2H), 4.35(s, 2H), 4.21(q, J=7.0Hz, 2H), 3.50-3.36(m, 4H), 2.90(t, J=12.3Hz ,2H),2.44-2.30(m,1H),1.78-1.47(m,4H),1.37(t,J=7.2Hz,3H),1.20-1.06(m,4H).; LRMS(EI)m / z587(M + ).

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Abstract

The invention relates to fluorine-containing isoxazole compounds as well as a preparation method and a pharmaceutical composition of the compounds and an application of the compounds or the pharmaceutical composition. In particular, the invention discloses the compounds represented by a general formula I or enantiomers of the compounds or diastereomers of the compounds, or pharmaceutically acceptable salts of the compounds, or a mixture of the compounds, the enantiomers, the diastereomers and the pharmaceutically acceptable salts. The invention also discloses an application of the compounds asa targeting FXR small-molecular agonist. The agonist provided by the invention can be used for treating FXR mediated diseases.

Description

technical field [0001] The present invention relates to the fields of medicinal chemistry and pharmacotherapeutics, in particular to a class of fluorine-containing isoxazole compounds, a preparation method thereof, a pharmaceutical composition containing such compounds and as an FXR agonist, especially prepared for the treatment of non-alcoholic Use of drugs for fatty liver disease and liver fibrosis. Background technique [0002] Nonalcoholic fatty liver disease (NAFLD) refers to a clinicopathological syndrome characterized by excessive fat deposition in liver cells caused by alcohol and other definite liver damage factors, and is an acquired metabolic stress disorder. Liver damage is closely related to insulin resistance and genetic susceptibility. In developed countries, the prevalence of NAFLD in people with risk factors increases by about 2% per year, and the onset tends to be younger. In addition to directly causing decompensated cirrhosis, hepatocellular carcinoma, ...

Claims

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Application Information

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IPC IPC(8): C07D413/12C07D413/14C07D417/14C07D471/04C07D519/00C07D451/04A61K31/4523A61K31/454A61K31/4535A61K31/4545A61K31/46A61K31/437A61P1/16A61P3/06
CPCC07D413/12C07D413/14C07D417/14C07D471/04C07D519/00C07D451/04A61P1/16A61P3/06A61K31/437A61K31/4523A61K31/4535A61K31/454A61K31/4545A61K31/46
Inventor 柳红李佳周宇臧奕李亚洲孙丹丹李俊友茹弘博高立信蒋华良陈凯先
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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