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2H-thiazolo [3, 2-b]-1, 2, 4-triazine-3, 7-diketone derivative and application thereof

A 2-b, thiazolo technology, applied in the field of medicine, can solve problems such as drug resistance or pharmacokinetic defects

Active Publication Date: 2020-12-08
SHIJIAZHUANG UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004]Existing acetylcholinesterase inhibitors such as tacrine, stigmine, galantamine, etc., still have drug resistance or pharmacokinetic defects

Method used

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  • 2H-thiazolo [3, 2-b]-1, 2, 4-triazine-3, 7-diketone derivative and application thereof
  • 2H-thiazolo [3, 2-b]-1, 2, 4-triazine-3, 7-diketone derivative and application thereof
  • 2H-thiazolo [3, 2-b]-1, 2, 4-triazine-3, 7-diketone derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Preparation of 3,4-dihydro-6-benzyl-3-thio-1,2,4-triazin-5(2H)-one

[0018] Add 0.1 mol of benzaldehyde, 0.13 mol of acetylglycine, 0.12 mol of anhydrous sodium acetate and 50 g of acetic anhydride into a 100 mL three-neck flask in sequence, control the temperature at 90°C, stir for 5 h, and cool to room temperature, the solution becomes into a solid, suction filtered, and the filter cake was washed with cold water to obtain 2-methyl-4-benzylidene oxazolone with a yield of 100%.

[0019] Add 0.1 mol of 2-methyl-4-benzylidene oxazolone, 150 mL of water, and 170 mL of acetone into a round-bottomed flask in sequence, heat to reflux and stir for 12 h, and monitor the completion of the reaction by TLC, cool to room temperature, and precipitate Suction filter a lot of solids, rinse the filter cake with cold water and a small amount of acetone, and dry to obtain α-acetylamino-β-phenylacrylic acid with a yield of 90%.

[0020] Add 0.1 mol of α-acetamido-β-phenylacrylic acid, 2...

Embodiment 2

[0023] Preparation of (E)-6-benzyl-2-benzylidene-2H-thiazolo[3,2-b]-1,2,4-triazine-3,7-dione (L1)

[0024] Add 1mmol of 3,4-dihydro-6-benzyl-3-thioxo-1,2,4-triazin-5(2H)-one, 1mmol of bromoacetonitrile, 1mmol of benzaldehyde, and 5mL of ice vinegar into the round bottom flask , after reflux reaction for 10 h, neutralize with ammonia water for cooling, filter with suction, and recrystallize the solid with absolute ethanol, the yield is 68%. Mp: 180-182℃; ESI-MS (m / z): 347.7 (M+H)+, 369.6 (M+Na)+, 718.3(2M+Na)+; 1H NMR (600 MHz, DMSO) δ 8.25 13C NMR (151 MHz, DMSO ) δ165.49, 159.90, 154.19, 138.48, 136.04, 132.96, 132.22, 131.25, 130.14, 129.67, 128.89, 127.28, 117.48, 36.95.

Embodiment 3

[0026] (E)-6-Benzyl-2-(4-methoxybenzylidene)-2H-thiazolo[3,2-b]-1,2,4-triazine-3,7-dione Preparation of (L2)

[0027] The benzaldehyde was replaced with p-methoxybenzaldehyde, and the synthetic method was referred to Example 2, and the yield was 60%. Mp: 190-193℃; ESI-MS (m / z): 400.3 (M+Na)+; 1H NMR (600 MHz, DMSO) δ 8.20 (s, 1H), 7.75 (d, J= 9 Hz, 2H ), 7.36- 7.21 (m, 5H), 7.17 (d, J = 9 Hz, 2H), 4.01 (s, 2H), 3.86(s, 3H); 13C NMR (151 MHz, DMSO) δ 165.37, 162.63, 159.96, 154.21, 138.70, 136.10, 133.71, 129.67, 128.87, 127.25, 125.51, 115.79, 113.80, 56.21, 36.86.

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Abstract

The invention discloses a 2Hthiazolo [3, 2b] 1, 2, 4triazine 3, 7diketone derivative as shown in a general formula I or pharmaceutically acceptable hydrate and salt thereof, the 2Hthiazolo [3, 2b] 1,2, 4triazine 3, 7diketone derivative comprises stereoisomers or tautomers thereof, and R1 and R2 in the general formula I can be optionally selected from one, two or three independently selected fromhydrogen, alkyl, alkoxy, halogen, hydroxyl, acetyl, propionyl, nitro or trifluoromethyl. The 1, 2, 4-triazine 3, 7diketone derivative has an obvious inhibiting effect on acetylcholin esterase, and isused for enhancing the memory of a patient suffering from dementia and Alzheimer's disease. The invention also relates to a preparation method of the compound and the application of the compound in preparation of drugs for treating Alzheimer's disease.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to 2H-thiazolo[3,2-b]-1,2,4-triazine-3,7-dione derivatives and their preparation methods and as acetylcholinesterase inhibitors , an application for improving memory in patients with dementia and Alzheimer's disease. Background technique [0002] Alzheimer's disease is associated with the degeneration of cholinergic neurons in the basal forebrain. As a result of said degeneration, patients suffering from this disease exhibit marked attenuations in acetylcholine synthesis, choline acetyltransferase activity, acetylcholinesterase activity, and choline absorption. [0003] Acetylcholinesterase inhibitors are known to be effective in increasing cholinergic activity and thus may be used to improve memory in Alzheimer's disease patients. By inhibiting acetylcholinesterase, the compound increases levels of the neurotransmitter acetylcholine in the brain, thereby enhancing memory. [00...

Claims

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Application Information

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IPC IPC(8): C07D513/04A61P25/28A61K31/53
CPCC07D513/04A61P25/28
Inventor 刘斯婕赵星王欣肖霄张彬
Owner SHIJIAZHUANG UNIVERSITY
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