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Novel phenothiazine derivative and preparation method and application thereof

A phenothiazine derivative, phenothiazine technology, applied in the field of biomedicine, to achieve good inhibitory effect and strong inhibitory effect

Inactive Publication Date: 2016-10-26
GUANGDONG UNIV OF TECH
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  • Abstract
  • Description
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Problems solved by technology

But currently, near-infrared fluorescence (NIRF) imaging probes for amyloid-beta plaques in Alzheimer's disease are still in the preclinical research stage

Method used

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  • Novel phenothiazine derivative and preparation method and application thereof
  • Novel phenothiazine derivative and preparation method and application thereof
  • Novel phenothiazine derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Embodiment 1: synthetic 10-methyl-10H-phenothiazine-3-formaldehyde 2a

[0040] Weigh NaH (60% purity, 1.0g, 25.1mmol) and slowly add it into a 50mL round bottom bottle with DMF (10mL) in an ice-water bath, then add methyl iodide (1.3g, 11.04mmol) and compound phenothiazine (2g , 10.0mmol), transferred to room temperature and stirred for 2h. After the reaction was monitored by TLC, water was added, extracted with DCM (50mL x 3), dried over magnesium sulfate and then concentrated to dryness. The product 1a (2.1g) was obtained by silica gel column separation as a white solid , melting point: 96°C, yield 97%.

[0041] 1 H NMR (400MHz, (CD 3 ) 2 CO)δ7.21(td, J=8.0,1.5Hz,2H),7.21(d,J=2.0Hz,1H),7.14(d,J=1.5Hz,1H),6.96-6.93(m,4H) ,3.39(s,3H).

[0042] In an ice-water bath at 0°C, slowly drop phosphorus oxychloride (1.98g, 1.18mL, 12.9mmol) into a 25mL round-bottom bottle with dry DMF (904L, 11.73mmol), stir for 0.5h, then add Compound 1a (500 mg, 2.34 mmol) in 5 mL DCM, t...

Embodiment 2

[0044] Embodiment 2: synthetic 8-chloro-10-methyl-10H-phenothiazine-3-formaldehyde 2b

[0045] Referring to the first step of the operation process in Example 1, the product 1b was isolated as a white solid, melting point: 75°C, yield 97%;

[0046] 1 H NMR (400MHz, CDCl 3 )δ7.16(td, J=7.8,1.3Hz,1H),7.12(dd,J=7.8,1.3Hz,1H),6.99(d,J=8.5Hz,1H),6.94(t,J=7.5 Hz,1H),6.88(dd,J=8.5,2.0Hz,1H),6.78(d,J=8.5Hz,1H),6.73(d,J=2.0Hz,1H),3.29(s,3H).

[0047] Referring to the second step operation process of Example 1, the product 2b was isolated as a yellow solid, melting point: 160° C., yield 38%.

[0048] 1 H NMR (400MHz, CDCl 3 )δ7.16(td, J=7.8,1.4Hz,1H),7.11(dd,J=7.8,1.4Hz,1H),7.01(d,J=8.2Hz,1H),6.93(td,J=7.6 ,1.4Hz,1H),6.88(dd,J=8.2,2.0Hz,1H),6.8(d,J=8.2Hz,1H),6.75(d,J=2.0Hz,1H),3.35(s,3H ).

Embodiment 3

[0049] Embodiment 3: synthetic 8-(dimethylamino)-10-methyl-10H-phenothiazine-3-formaldehyde 2c

[0050] Dimethylamine (1.6mL, 3.1mmol, 1.5eq) was added to dioxane (4mL) dissolved in compound 1b (500mg, 2.02mmol, 1eq) followed by the catalyst tris(dibenzylideneacetone)dipalladium (75mg, 0.08mmol, 0.04eq) and the ligand 2-dicyclohexylphosphonium-2,4,6-triisopropylbiphenyl (78mg, 0.16eq, 0.08eq) and cesium carbonate (1.4g, 2eq), Under the protection of argon, the reaction was carried out at 120°C for 7h. After the reaction was monitored by TLC, suction filtration was performed after cooling to room temperature. After the obtained filtrate was concentrated to dryness, the product 1c (260 mg) was separated by column chromatography, a white liquid, and the yield was 50%.

[0051] 1 H NMR (400MHz, CDCl 3 )δ7.16-7.10 (m, 2H), 6.97 (d, J = 8.5, 1H), 6.89 (td, J = 8.0, 1.0Hz, 1H), 6.8 (dd, J = 8.0, 1.0Hz, 1H) ,6.33(dd,J=8.0,2.5Hz,1H),6.21(d,J=2.5,1H),3.36(s,3H),2.92(s,6H).

[0052]...

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Abstract

The invention discloses a novel phenothiazine derivative and a preparation method and application thereof, and belongs to the technical field of biological medicines. The invention particularly discloses a compound of a structural general formula I and salts, applicable in pharmacy, of the compound, and the compound and the salts can be used as near-infrared fluorescent molecular probes. The invention further provides a preparation method of the molecular probes and application of the molecular probes. Fluorescent molecules are novel in structure, good in sensitivity and selectivity and good in light stability. The molecules and Abeta(1-42) aggregates have good affinity, and meanwhile auto-polymerization of beta-amyloid protein can be well inhibited. Therefore, the probes can be applied to imaging of Abeta amyloid plaque and can be used for treating the Alzheimer's disease.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, in particular to a novel phenothiazine derivative and its preparation method and application. Background technique [0002] Alzheimer's disease (AD) is a malignant neurodegenerative disease, the cause of which is still unknown, and there is no specific drug or method to cure it. AD is characterized by a gradual reduction in cognitive functions such as memory, thinking, comprehension, calculation, language, learning ability, and judgment, and is diagnosed as dementia when the reduction is sufficient to affect an individual's activities of daily living. According to statistics, there are currently more than 5.6 million patients in China, and it is showing a rapid growth trend with the aging of the population. AD not only seriously endangers the health of the elderly, but also brings a heavy mental burden to the family members of the patients, a huge health crisis for the society, and a huge im...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/06C09K11/06A61K31/5415A61K49/00A61P25/28
CPCA61K49/0021C07D417/06C09K11/06C09K2211/1037
Inventor 陈惠雄帕斯卡·道郭启辉叶飞飞
Owner GUANGDONG UNIV OF TECH
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