Fluoropyrrolopyrimidine compounds and their preparation methods and applications

A technology of fluoropyrrolopyrimidine and pyrrolopyrimidine, which is applied in the field of preparation of positron emission imaging agents, can solve problems such as unclear detailed etiology, and achieve the effect of benefiting radiation protection

Active Publication Date: 2021-06-25
XIAMEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Despite efforts to study the pathogenesis of PD, the detailed etiology remains unclear and effective treatments have not been approved to prevent, cure, or slow the progression of PD

Method used

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  • Fluoropyrrolopyrimidine compounds and their preparation methods and applications
  • Fluoropyrrolopyrimidine compounds and their preparation methods and applications
  • Fluoropyrrolopyrimidine compounds and their preparation methods and applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] This embodiment provides a 19 F-substituted fluoropyrrolopyrimidine compounds, which can be used for LRRK2 positron emission imaging, the preparation process and specific steps are as follows:

[0060]

[0061] Synthetic steps of compound 1:

[0062] A solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.96g, 7mmol) dissolved in tetrahydrofuran (50ml) was cooled to 0°C and washed with sodium hydride (60% in oil, 0.308g, 7.7mmol) was added in three portions. After stirring the reaction mixture at 0 °C for 1 h, 2-(trimethylsilyl)ethoxymethyl chloride (1.28 g, 7.6 mmol) was added dropwise, and the reaction mixture was warmed to room temperature and stirred for 4 h. The reaction was quenched with saturated aqueous sodium chloride (10m). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (eluent, 10:1 petroleum ether / ethyl acetate), the product is a white solid, and the yield is about 55%.

[0063] Com...

Embodiment 2

[0087] This embodiment provides a 18 F-labeled fluoropyrrolopyrimidine compounds, the preparation method of which is as follows:

[0088]

[0089] The compound 3 prepared in Example 1 is used as a raw material to carry out the following steps:

[0090] [ 18 F]4 synthetic steps:

[0091] After 1 mg of compound 3 was dissolved in 200 μL DMSO, it was added to a dry [ 18 F] In the F-reaction bottle, press the cap, react at 150°C for 20 minutes to realize the labeling reaction, and obtain [ 18 F]4.

[0092] compound [ 18 F] 4 and compound 4 were co-injected into HPLC, suggesting that compound 3 was successfully labeled.

[0093] [ 18 Synthetic steps of F]5:

[0094] Will[ 18 F] After 4C18 column solid-phase extraction, rinse with 2 mL of dichloromethane, blow dry with nitrogen, add dichloromethane (200 μL) to dissolve, slowly add trifluoroacetic acid (200 μL) dropwise at 40 ° C and shake the cap for 5 min. The pH value of the reaction mixture was adjusted to neutral wi...

Embodiment 3

[0097] This embodiment provides a method for LRRK2 positron emission imaging 19 F-substituted pyrrolopyrimidine compounds, the preparation process and specific steps are as follows:

[0098]

[0099] Synthetic steps of compound 1:

[0100] A solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.96g, 7mmol) dissolved in tetrahydrofuran (50ml) was cooled to 0°C and washed with sodium hydride (60% in oil, 0.308g, 7.7mmol) was added in three portions. After stirring the reaction mixture at 0 °C for 1 h, 2-(trimethylsilyl)ethoxymethyl chloride (1.28 g, 7.6 mmol) was added dropwise, and the reaction mixture was warmed to room temperature and stirred for 4 h. The reaction was quenched with saturated aqueous sodium chloride (10m). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (eluent, 10:1 petroleum ether / ethyl acetate), the product is a white solid, and the yield is about 55%.

[0101] Compound 1 NMR result...

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Abstract

The present invention relates to a fluoropyrrolopyrimidine compound and its preparation method and application. The fluoropyrrolopyrimidine compound has the structure shown in formula I. The present invention uses pyrrolopyrimidine compounds as 18 F-labeled precursors, a positron tracer of LRRK2 prepared by a nucleophilic substitution reaction, can accurately reflect differences in LRRK2 expression levels in LRRK2 wild-type transgenic mice and G2019S mutant transgenic mice without significant bone uptake , indicating that the compound has high specificity and sensitivity, is stable in vivo, is not easy to defluorinate, and can be quickly cleared through metabolic organs. The fluoropyrrolopyrimidine compounds provided by the invention can be used for PET imaging of LRRK2, and are of great significance for the research of neurodegenerative diseases.

Description

technical field [0001] The invention relates to the synthesis and labeling of a fluoropyrrolopyrimidine compound, in particular to the application of the compound as an LRRK2 positron tracer in the preparation of a positron emission imaging agent. Background technique [0002] Parkinson's disease (PD) is one of the most common neurodegenerative diseases of the central nervous system (CNS), affecting one in every 1000 people, and hereditary Parkinson's disease accounts for 5-10% of all patients. Despite efforts to study the pathogenesis of PD, the detailed etiology remains unclear, and no effective treatments have been approved to prevent, cure, or slow the progression of PD. [0003] Over the past few decades, the leucine-rich repeat kinase 2 (LRRK2) gene has been identified to be associated with hereditary Parkinson's disease, and in vitro studies have shown that Parkinson's disease-associated mutations result in LRRK2 kinase Increased activity and decreased rate of GTP hy...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61K51/04A61K103/00
CPCA61K51/0459C07D487/04
Inventor 李子婧陈雪媛张运明牟钊彪潘晓东谢芳张秋阳苏融
Owner XIAMEN UNIV
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