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Preparation method and application of tacrine-sinapic acid heterozygote

A technology of sinapinic acid and tacrine, which is applied to medical preparations with non-active ingredients, medical preparations containing active ingredients, drug combinations, etc., can solve problems such as limiting clinical application, and achieve strong inhibitory effect and obvious anti-oxidation activity, significant in vitro neuroprotective activity

Active Publication Date: 2018-02-02
天津海润家和创新医药研究有限责任公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, its clinical application is limited due to severe hepatotoxicity

Method used

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  • Preparation method and application of tacrine-sinapic acid heterozygote
  • Preparation method and application of tacrine-sinapic acid heterozygote
  • Preparation method and application of tacrine-sinapic acid heterozygote

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Embodiment 1

[0045] The synthesis of embodiment 1 intermediate 1

[0046] Weigh anthranilic acid (50.0g, 364mmol) and dissolve it in 100ml of toluene, add (45.3ml, 437mmol) cyclohexanone, reflux at 110.6°C for 2h, and remove about 6.8ml of water. The mixture was cooled to room temperature, and needle-like crystals precipitated out, which were further cooled to 0°C, filtered, and washed with toluene (50 mL) and ethanol (50 mL). Collect filter cake, dry in vacuum oven, obtain intermediate 1 white crystal 53.2g, yield 67% (synthetic route sees figure 1 , see the characterization map figure 2 ).

Embodiment 2

[0047] The synthesis of embodiment 2 intermediate 2

[0048] Intermediate 1 (67.0 g, 309 mmol) and phosphorus oxychloride (120 ml, 1.29 mol) were successively added into the three-necked flask, and the mixture was refluxed at 85° C. for 2 h. After cooling to room temperature, cold 54% KOH aqueous solution (540 g, 1000 ml) was added dropwise and stirred rapidly. After the addition was completed, a precipitate (yellow solid) was precipitated, and the pH of the supernatant was 10±1. Then add CH 2 Cl 2 (1500ml) to dissolve the solid and wash with CH 2 Cl 2 (3×1000ml) extract the aqueous layer, combine the organic phase, anhydrous MgSO 4 Dry, filter, reclaim solvent, obtain intermediate 2 yellow solid 60.0g, yield 90% (synthetic route sees image 3 ).

Embodiment 3

[0049] The synthesis of embodiment 3 aminotacrine

[0050] Intermediate 2 (30.0 g, 0.14 mol), hexamethylenediamine (54 ml, 0.42 mol) and 1.5 g KI were sequentially added to the three-necked flask, dissolved in 200 ml of n-pentanol, and refluxed at 140° C. for 18 h. The reaction solution was cooled to 0°C, the pH was adjusted to 1.0 with 6M hydrochloric acid, and the layers were separated. The aqueous layer was adjusted to pH 10.0 with cold KOH solution, extracted with dichloromethane (3×200ml), the organic phases were combined, washed three times with saturated NaCl solution, anhydrous NaCl 2 SO 4 Dry, filter and evaporate to dryness under reduced pressure. Purified by column chromatography (eluent: dichloromethane:methanol=50:1-10:1-5:1, 10ml triethylamine / 1000ml) to obtain 36.3g of aminotacrine light yellow oily liquid with a yield of 88% % (synthetic route sees Figure 4 , see the characterization map Figure 5-6 ).

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Abstract

The invention discloses a tacrine-sinapic acid heterozygote, a medicinal composition containing the tacrine-sinapic acid heterozygote, and a preparation method and application thereof. The tacrine-sinapic acid heterozygote has the following structure: the formula is as shown in the description. Experiments prove that the tacrine-sinapic acid heterozygote has high inhibitory activity on acetylcholin esterase (AChE) and butyrylcholine esterase (BuChE), has acetylcholin esterase inhibition capability which is 15 times that of tacrine, has strong inhibition effect on amyloid protein (Abeta) self-aggregation, has remarkable anti-oxidation activity, does not have remarkable in-vitro neurocytotoxicity and in-vivo acute hepatotoxicity, shows remarkable in-vitro nerve cell protective activity, andcan be applied to treatment on Alzheimer's disease.

Description

technical field [0001] The invention belongs to the field of organic synthesis and medicine, and in particular relates to a tacrine-sinapinic acid hybrid for treating Alzheimer's disease, a pharmaceutical composition containing the tacrine-sinapinic acid hybrid, a preparation method and an application thereof , especially relates to the preparation of tacrine-sinapinic acid hybrid by reacting aminotacrine with sinapinic acid, and the application of the tacrine-sinapinic acid hybrid in the preparation of anti-Alzheimer drugs. Background technique [0002] Tacrine is the first drug approved by the FDA for the treatment of Alzheimer's disease (AD), which belongs to the first generation of acetylcholinesterase inhibitors. However, its clinical application is limited due to severe liver toxicity. Studies have confirmed that the hepatotoxicity of tacrine is closely related to its free primary amino groups. Current studies mostly use molecular fragments with different functions to...

Claims

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Application Information

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IPC IPC(8): C07D219/12A61K31/473A61K31/192A61K47/55A61P25/28
CPCA61K31/192A61K31/473C07D219/12A61K2300/00
Inventor 刘天军李国梁洪阁
Owner 天津海润家和创新医药研究有限责任公司
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