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Phenothiazine derivative as well as preparation method and application thereof

A technology of phenothiazine derivatives and derivatives, applied in the field of biomedicine, to achieve the effects of good selectivity, good affinity, and good water solubility

Inactive Publication Date: 2018-06-22
GUANGDONG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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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  • Phenothiazine derivative as well as preparation method and application thereof
  • Phenothiazine derivative as well as preparation method and application thereof
  • Phenothiazine derivative as well as preparation method and application thereof

Examples

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preparation example Construction

[0042] The invention provides a preparation method of phenothiazine derivatives, comprising:

[0043]The thiophenealdehyde compound is condensed with cyanoacetic acid or derivatives thereof to obtain a compound of formula (I); the thiophenealdehyde compound has a structure shown in formula (III) or formula (IV); the cyanoacetic acid Or its derivative is selected from the one in cyanoacetic acid, methyl cyanoacetate, ethyl cyanoacetate and the compound of formula (V) structure;

[0044]

[0045] or

[0046] The thiophene aldehyde compound is subjected to condensation reaction with the compound of the formula (VI) to obtain the compound of the formula (II);

[0047]

[0048] The preparation method of the compound of formula (I) structure provided by the invention is specifically:

[0049] The thiophene aldehyde compound is condensed with cyanoacetic acid or its derivatives to obtain the compound with the structure of formula (I).

[0050] Wherein, the thiophene aldehyde...

Embodiment 1

[0088] Embodiment 1 Synthesis of 10-methylphenothiazine 1

[0089] Weigh NaH (60% purity, 0.5g, 12.55mmol) and slowly add it into a 50mL round bottom bottle with DMF (10mL) in an ice-water bath, then add methyl iodide (0.65g, 5.52mmol) and compound phenothiazine (1g , 5.0mmol), transferred to room temperature and stirred for 2h, TLC monitored the reaction, added water, extracted with DCM (50mL x 3), dried over magnesium sulfate and then concentrated to dryness, separated by silica gel column to obtain product 1 (1.0g), white solid , melting point: 96°C, yield 93.9%.

[0090] 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).

Embodiment 2

[0091] Example 2 Synthesis of 10-methyl-10H-phenothiazine-3-formaldehyde 2

[0092]In an ice-water bath at 0°C, slowly drop phosphorus oxychloride (1.98g, 1.18mL, 12.9mmol) into a 25mL round-bottomed bottle containing dry DMF (856mg, 11.73mmol), stir for 0.5h, then add Compound 1 (500 mg, 2.34 mmol) in 5 mL DCM, the reaction was warmed to reflux for 7 h. 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 2 (298mg) was obtained by silica gel column separation, a yellow solid, melting point: 106°C, yield 54%.

[0093] 1 H NMR (400MHz, CDCl 3 )δ9.78(s,1H),7.64(dd,J=8.7,2.0Hz,1H),7.59(d,J=2.0Hz,1H),7.17(td,J=7.8,1.6Hz,1H), 7.11(dd, J=7.8,1.6Hz,1H),6.97(t,J=7.5Hz,1H),6.85(d,J=7.5Hz,1H),6.82(d,J=7.5Hz,1H), 3.41(s,3H).

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Abstract

The invention provides a phenothiazine derivative. The phenothiazine derivative has a structure shown as a formula (I) or a formula (II), wherein in the formula (I), R[1] is selected from one or moreof H, CH3, C2H5, the formula shown in the description and the formula shown in the description; n is an integer and is 1 or 2; in the formula (II), R[1] is selected from one or more of the formula shown in the description and the formula shown in the description. The phenothiazine derivative with the specific structure, provided by the invention, has relatively good water solubility, high sensitivity, good selectivity, good light stability and high bioavailability, and has very good affinity with Abeta1-42 aggregates. Therefore, the phenothiazine derivative provided by the invention not only can be used as a fluorescent molecular probe applied to imaging of Abeta protein plaques, but also can be used for early diagnosis of Alzheimer's disease.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to a phenothiazine derivative, its preparation method and application. Background technique [0002] Alzheimer's disease (AD) is a malignant neurodegenerative disorder that affects nearly 50% of people over the age of 85. Less than 5% of cases are due to genetic disorders, and more than 95% are sporadic cases. According to statistics, there are currently more than 5.6 million patients in China, and it is showing a trend of rapid growth 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 impact on the economy, which has attracted widespread attention. [0003] AD is a multifactorial disease, which is mainly induced by aging, genetic and environmental factors. The currently recognized pathogenesis of AD based on mo...

Claims

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Application Information

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IPC IPC(8): C07D279/22C07D417/14C07D417/06A61K31/5415A61P25/28A61K49/00
CPCA61K49/0021C07D279/22C07D417/06C07D417/14
Inventor 陈惠雄鄢龙家张万正黎永良杜志云
Owner GUANGDONG UNIV OF TECH
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