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3-fluoropyridine heterocyclic compound and application thereof

A technology of heterocyclic compound, fluoropyridine, applied in the field of medicine

Active Publication Date: 2017-10-24
SUZHOU YUNXUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Dysregulation of Wnt signaling also contributes to the development of diabetic retinopathy by inducing retinal inflammation, vascular leakage, and neovascularization

Method used

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  • 3-fluoropyridine heterocyclic compound and application thereof
  • 3-fluoropyridine heterocyclic compound and application thereof
  • 3-fluoropyridine heterocyclic compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0114] This example provides a 3-fluoropyridine heterocyclic compound and its synthesis method.

[0115] (1) Heterocyclic compound B1, which is synthesized by the following method:

[0116]

[0117] 1) Synthesis of Intermediate B1-2:

[0118] Add 20 mL of anhydrous tetrahydrofuran to a 50 mL two-neck flask, protect with nitrogen, cool to -78°C, add 2.5N LDA tetrahydrofuran solution (4.4 mL, 11 mmol), and slowly add B1-1 (1.15 g, 10 mmol). Stir at -78°C for 1 h, then slowly add triisopropyl borate (2.82 g, 15 mmol). After adding, stir at -78°C for 1.5h, then slowly rise to room temperature. 5 mL of 2N aqueous sodium hydroxide solution was added, and stirred for 10 minutes. Separate the layers, adjust the pH of the aqueous phase to 5, and extract three times with ethyl acetate. The organic phases were combined, washed once with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a white so...

Embodiment 2

[0126] This embodiment provides a 3-fluoropyridine heterocyclic compound B2, which is synthesized by the following method:

[0127]

[0128] 1) Synthesis of intermediate B2-2:

[0129] Dissolve compound B2-1 (5g, 34.3mmol) in acetonitrile (100mL), add NBS (18.3g, 103mmol) and benzoyl peroxide (829mg, 3.43mmol), reflux overnight, cool to room temperature, add water (200mL ), extracted with ethyl acetate (200mL×3), the organic phase was washed with saturated brine (300mL×3), dried over anhydrous sodium sulfate, filtered off sodium sulfate, spin-dried the solvent, and the residue was purified by column chromatography (petroleum ether :ethyl acetate=100:1), a yellow oil (7.45g, 97%) was obtained. 1 HNMR (400MHz, CDCl 3) δ 8.23 ​​(d, J = 1.2 Hz, 1H), 7.56-7.53 (m, 1H), 4.45 (s, 2H).

[0130] 2) Synthesis of Intermediate B2-3:

[0131] Intermediate B2-2 (7.45g, 33.1mmol) was dissolved in DMF (50mL), NaN was added under ice-cooling 3 (8.61g, 132mmol), stirred overnight at 50°...

Embodiment 3

[0139] This embodiment provides a 3-fluoropyridine heterocyclic compound B3, which is synthesized by the following method:

[0140]

[0141] 1) Synthesis of Intermediate B3-2:

[0142] Dissolve compound B3-1 (5g, 25.4mmol) in acetonitrile (100mL), add NBS (6.8g, 38mmol) and benzoyl peroxide (100mg, 0.41mmol), reflux overnight, and then add benzoyl peroxide (50mg, 0.21mmol), and then refluxed for 12h. Cool to room temperature, concentrate and evaporate the solvent, and the residue is purified by column chromatography (petroleum ether: ethyl acetate = 100:1-50:1) to obtain a solid (4.3 g, 61%).

[0143] 2) Synthesis of Intermediate B3-3:

[0144] Intermediate B3-2 (2.3g, 8.2mmol) was dissolved in DMSO (40mL), NaN was added under ice bath 3 (637mg, 9.8mmol), stirred at room temperature for 30 minutes, added water (100mL), extracted with ethyl acetate (100mL×3), washed the organic phase with saturated brine (50mL×3), dried over anhydrous sodium sulfate, filtered off Sodium ...

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Abstract

The invention provides a 3-fluoropyridine heterocyclic compound. The 3-fluoropyridine heterocyclic compound and pharmacologically acceptable salts thereof have structures as shown in a formula I, and the formula I is described in the description. The invention also provides a pharmaceutical composition, which is prepared from effective treatment dose of the 3-fluoropyridine heterocyclic compound and a pharmacologically acceptable carrier thereof. The invention also provides application of the 3-fluoropyridine heterocyclic compound in preparation of medicines for treating or preventing an abnormal Wnt signaling pathway. The 3-fluoropyridine heterocyclic compound provided by the invention can effectively antagonize the Wnt signaling pathway, thus being used for treating or preventing diseases caused by disorder of the Wnt signaling pathway.

Description

technical field [0001] The invention relates to a 3-fluoropyridine heterocyclic compound and its application, belonging to the technical field of medicine. Background technique [0002] The earliest discovery of the Wnt signaling pathway came from the study of oncogenic viruses and the developmental mechanism of Drosophila. The Wnt gene was discovered in 1982 and was initially identified as a preferential integration site for mouse mammary tumor virus. This gene can transmit proliferation and differentiation information between cells. It is an oncogene and was named Int gene at that time ( Mouse Int-1 and Int-3). It was later found that it belongs to the same orthologous gene as the wingless gene of Drosophila, so the combination of the two was named Wnt gene. [0003] So far, 19 members of the Wnt gene family have been discovered and cloned, and the signal transduction pathway mediated by the Wnt gene is called the Wnt signaling pathway. The Wnt pathway is a very conserv...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D413/14C07D471/04C07D487/04A61K31/4709A61K31/502A61K31/444A61K31/519A61K31/541A61P35/00A61P35/02A61P7/06A61P7/00A61P11/00A61P1/16A61P13/12A61P9/10A61P3/10A61P33/06A61P33/12A61P33/00
CPCC07D401/14C07D413/14C07D471/04C07D487/04Y02A50/30
Inventor 张小虎
Owner SUZHOU YUNXUAN PHARMA
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