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Pyridine derivative and preparation method and application thereof

A compound and hydrate technology, applied in the field of pyridine derivatives and its preparation, can solve problems such as unsatisfactory effects and difficult synthesis of Tau protein tracers

Inactive Publication Date: 2020-12-01
WEST CHINA HOSPITAL SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, the currently known Tau protein tracers are difficult to synthesize and their effects cannot meet clinical needs.

Method used

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  • Pyridine derivative and preparation method and application thereof
  • Pyridine derivative and preparation method and application thereof
  • Pyridine derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Embodiment 1, the synthesis of compound 5 of the present invention

[0061] (1) Synthetic compound 3:

[0062]

[0063] Compound 1 (22.0g, 143.66mmol) and compound 2 (10.35g, 143.66mmol) were dissolved in glacial acetic acid, refluxed for 5 hours, after the reaction was monitored by TLC, the solvent was spin-dried, washed with water, extracted with EA (ethyl acetate) , the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated, and then subjected to silica gel column chromatography to obtain compound 3 (23 g, yield 85%). MS(ESI)m / z:190.1[M+H] + .

[0064] (2) Synthetic compound 5:

[0065]

[0066] Methyl trioctyl ammonium chloride (Aliquat336, 64mg, 0.159mmol) was dissolved in 5M sodium hydroxide solution, compound 3 (150.00mg, 0.797mmol), 5-dimethylaminothiophene-2-formaldehyde (compound 4, 123mg, 0.797mmol), reflux at 110°C, after TLC monitors the reaction is complete, adjust the pH to 7, wash with water, extract with DCM, take the or...

Embodiment 2

[0067] Embodiment 2, the synthesis of compound 6 of the present invention

[0068]

[0069] A solution of compound 5 (30 mg) and the phase transfer catalyst kryptofix (5 mg) in DMF (1.5 mL) was added to a solution containing dry [ 18 F] fluoride (this embodiment is K[ 18 F]) in a microwave reaction tube, and the reaction mixture was heated at 140°C (65W) for 4 minutes. After cooling below 50°C, the reaction mixture was washed with H 2 0 (1 mL), mixed, and injected onto a semi-preparative HPLC column. The resulting product was purified using a Zorbax Eclipse XDB-C-18 liquid chromatography column, 5 μm, 9.4×250 mm (Agilent) at a flow rate of 5 mL / min. The mobile phase used was 50% to 80% acetonitrile solution, and the solvent in this solution was 10 mM NaH 2 P0 4 aqueous solution for 15 minutes. The resulting radioactive fraction was collected, concentrated under reduced pressure, diluted with 0.9% saline solution (3 mL) and transferred to a sterile container to obtain ...

Embodiment 3

[0071] Embodiment 3, the synthesis of compound 7~11 of the present invention

[0072] According to the synthetic route of the above-mentioned general formula compound 5a, adopt the same method as in Example 1, the compound 4 in Replace with the corresponding R 6 group to prepare compounds 7-11 of the present invention, the structures and characterizations of which are shown in Table 1.

[0073] Table 1 Structure and characterization data of compounds 7-11 of the present invention

[0074]

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Abstract

The invention relates to a pyridine derivative and a preparation method and application thereof. Specifically, the invention provides a compound shown as a formula I, or a pharmaceutically acceptablesalt, or a hydrate, or a solvate, or a conformational isomer, or a crystal form, or an isotope replacement form thereof, and a preparation method and application thereof. Experimental results show that the pyridine compound is labeled by radionuclide and can be used as a Tau protein tracer agent for identifying neurofibrillar entanglement (NFTs) formed by abnormal aggregation of over-phosphorylated Tau protein in the brain, and can be used for diagnosing neurofibrillar entanglement related diseases, can also be used for monitoring the progress of the diseases in the treatment process, provideshigher and more accurate diagnosis and tracking for patients with the neurofibrillar entanglement related diseases or potential patients, and has a good application prospect in clinical diagnosis.

Description

technical field [0001] The invention belongs to the field of material processing, and in particular relates to a pyridine derivative and its preparation method and application. Background technique [0002] Alzheimer's disease (AD), also known as senile dementia, is the most common chronic neurodegenerative disease causing dementia in the elderly. The number of AD patients in my country has reached 6 million. With the aging of the global population, the incidence rate will show a significant upward trend. Therefore, clarifying the pathogenesis of AD and finding effective treatment methods to prevent and delay the occurrence and development of AD have not only become a key topic of medical research at home and abroad, but also have strategic significance for the long-term economic development of various countries. The current research targets on Alzheimer's disease mainly focus on the aggregation of β-amyloid protein and neurofibrillary tangles (NFTs) formed by the abnormal ...

Claims

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Application Information

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IPC IPC(8): C07D409/06C07D405/06C07D401/06C07D241/42A61K51/04A61K49/22A61K49/00
CPCA61K49/0002A61K49/22A61K51/0459C07D241/42C07D401/06C07D405/06C07D409/06A61K49/00A61K51/00A61K51/04
Inventor 况伟宏李进谢永美田蓉吴小艾张霓
Owner WEST CHINA HOSPITAL SICHUAN UNIV
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