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Pyrazine compounds and their use in medicine

A compound and drug technology, applied in the field of new small molecule fluorescent compounds, to achieve the effect of good brain penetration and enhanced fluorescence intensity

Active Publication Date: 2018-07-27
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are few research reports on fluorescent compounds targeting Aβ plaques or neurofibrillary tangles at home and abroad, and it is still in its infancy.

Method used

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  • Pyrazine compounds and their use in medicine
  • Pyrazine compounds and their use in medicine
  • Pyrazine compounds and their use in medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Embodiment one: the synthesis of the compound shown in formula (I)

[0027] The synthetic route of the compound represented by the formula (I) of the present invention is as follows: figure 1 shown.

[0028] Synthetic PB-1

[0029]

[0030] Dissolve 2-methylpyrazine (282.3 mg, 3 mmol) and 4-N,N dimethylaminocinnamaldehyde (175.4 mg, 1 mmol) in 20 mL of dry tetrahydrofuran, add potassium tert-butoxide (448.8 mg, 4 mmol ), heated to reflux at 80°C for 2 hours, and the solvent was removed by rotary evaporation; 20 mL of water was added to precipitate a solid, and after suction filtration, the resulting solid was separated by column chromatography to obtain 105.8 mg of PB-1, with a yield of 42.1%. The structure is as follows: 1 H-NMR (400 MHz, CDCl 3 ): δ 8.50 (s, 1H), 8.47 (s, 1H), 8.30(s, 1H), 7.51 (dt, J = 36.4, 18.2 Hz, 1H), 7.38 (d, J = 8.5 Hz, 2H), 6.83 (d, J = 7.0 Hz, 1H),6.81 (d, J = 4.1 Hz, 1H), 6.70 (d, J = 7.7 Hz, 1H), 6.61 (s,1H), 6.58 (s, 1H), 3.00 (...

Embodiment 2

[0031] Embodiment two: the synthesis of the compound shown in formula (II)

[0032] The synthetic route of the compound represented by the formula (II) of the present invention is as follows: figure 1 shown.

[0033] Synthetic QB-1

[0034]

[0035] Dissolve 2-methylquinoxaline (288 mg, 2 mmol) and 4-N,N dimethylaminocinnamaldehyde (175.4 mg, 1 mmol) in 15 mL of sodium hydroxide solution (5mol / L), add Aliquat 336 (43 mg, 0.1 mmol), heated to reflux at 100°C for 10 hours, cooled, filtered, and the resulting solid was separated by column chromatography to obtain 91.0 mg of QB-1, with a yield of 30.2%. The structure is as follows: 1 H-NMR (400 MHz, CDCl 3 ): δ 8.90 (s, 1H), 8.03-7.99 (m, 1H), 7.73-7.63 (m, 4H),7.40 (d, 2H, J = 8.8 Hz), 6.89 (d, 2H, J = 8.0 Hz ), 6.81 (d, 1H, J = 15.6Hz), 6.70 (d, 2H, J = 8.8 Hz), 3.02 (s, 6H).

Embodiment 3

[0036] Embodiment three: the mensuration of optical parameter

[0037] 1. Determination of maximum absorption wavelength and molar absorption coefficient

[0038] Using dichloromethane as solvent, prepare compounds with a certain concentration gradient, such as 1, 5, 10, 20, and 25 μM solutions, scan the ultraviolet absorption spectrum with a UV-visible spectrophotometer, and record the maximum absorption wavelength (λ abs ) and absorbance, and calculate the molar absorption coefficient ε (M -1 cm -1 ). The maximum absorption wavelengths and molar absorption coefficients of some compounds in the examples of the present invention are shown in Table 1.

[0039] 2. Determination of fluorescence excitation wavelength and fluorescence emission wavelength

[0040] The compounds of the present invention have good fluorescence properties. In order to investigate the fluorescence properties of the compounds of the present invention, the specific implementation steps are: accurate...

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Abstract

Disclosed in the present invention are a compound for performing fluorescent marking on β-amyloid plaques and / or neurofibrillary tangles, a preparation method therefor and applications thereof, a method for performing fluorescent marking on on Aβ plaques on brain slices of a transgenic mouse, a method for performing fluorescent marking on neurofibrillary tangles of brain slices of an AD patient, a pharmaceutical composition, and a synchronous detection method for Aβ plaques and neurofibrillary tangles in the transgenic mouse and a human body tissue. The present invention provides a small-molecular fluorescent compound having no charges. An electron donating group and an electron withdrawing group in the structure form a conjugated structure of donating electrons and withdrawing electrons, and a conjugated system of π-π* transition is increased by means of carbon-carbon double bonds, so that fluorescence generated by molecules of the compound moves to a long-wave direction (bioluminescence interference is reduced), and the structure wholly satisfies the affinity of Aβ plaques or neurofibrillary tangles.

Description

technical field [0001] The present invention relates to the field of specific molecular recognition diagnostic reagents, more specifically, to a class of novel small-molecule fluorescent compounds with high affinity to β-amyloid plaques and neurofibrillary tangles, and the preparation of such compounds for detection Or use in imaging agents for imaging beta-amyloid deposition diseases or neurofibrillary tangle diseases. Background technique [0002] Alzheimer's Disease (AD) is a progressive and fatal neurodegenerative disease. At present, my country has entered an aging society ahead of schedule, and about 6 million people suffer from AD, ranking first in the world, and the number of patients is increasing at a rate of more than 300,000 per year. The prevalence rate of people over 65 years old in my country is 7.2%, and AD patients are becoming younger. AD has become the fourth leading cause of death among the elderly after heart disease, cancer and stroke. AD not only se...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D241/12C07D241/42A61K49/00A61K49/04A61K49/06A61K49/22
CPCA61K49/00A61K49/04A61K49/06A61K49/22C07D241/12C07D241/42
Inventor 程妍
Owner SICHUAN UNIV
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