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Thiazolotriazole-6-acetamide derivatives and their application

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

Active Publication Date: 2019-05-10
SHIJIAZHUANG POLEE PHARMA CO LTD
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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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  • Thiazolotriazole-6-acetamide derivatives and their application
  • Thiazolotriazole-6-acetamide derivatives and their application
  • Thiazolotriazole-6-acetamide derivatives and their application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Preparation of 2-{2-(4-chlorophenyl)thiazolo[3,2-b][1,2,4]triazol-6-yl}acetic acid

[0018] Add 0.1 mol of thiosemicarbazide and 100 mL of dichloromethane into a 250 mL three-necked flask, stir in an ice-water bath to dissolve, and then add 0.13 mol of pyridine. Slowly add 0.13 mol of 4-chlorobenzoyl chloride dropwise at 0-5°C, the dropwise addition is completed in 20 minutes, react at 15°C for 2 hours, and end the reaction. A large amount of white solid appeared in the system and was filtered. Dissolve the obtained white solid in 80 mL of 5% sodium hydroxide solution by mass fraction, heat to reflux for 2 hours, cool down to room temperature, adjust the pH to 5-6 with dilute hydrochloric acid with a mass fraction of 3.65%, a large amount of light yellow solid precipitates, filter , recrystallized to obtain 18.3 g of 5-(4-chlorophenyl)-3-mercapto-1,2,4-triazole, yield 86.7%, ESI-MS (m / z): 212.3 (M+H )+.

[0019] Add 0.6mol of 5-(4-chlorophenyl)-3-mercapto-1,2,4-triaz...

Embodiment 2

[0023] N,N-Dimethyl-2-{2-(4-chlorophenyl)thiazolo[3,2-b][1,2,4]triazol-6-yl}-acetamide (L1) preparation of

[0024] Add 10mmol dimethylamine hydrochloride, 10mmol 2-{2-(4-chlorophenyl)thiazolo[3,2-b][1,2,4]triazol-6-yl}acetic acid, and 20mL dichloromethane In the round bottom flask, then add 12mmolEDCI, 12mmolHOBt and triethylamine 10mmol, after room temperature reaction 12h, reaction solution is successively washed with 5%HCl, 5%NaHCO3, saturated NaCl solution, after drying, column chromatography separates to obtain white solid, Yield 32%.

[0025] 1H-NMR (300MHz, DMSO), δ(ppm): 7.50 (2H, d, J = 8.4Hz), 7.41 (1H, s), 7.38 (2H, d, J = 8.4Hz), 4.89 (2H, s ), 3.96 (3H, s), 3.02 (3H, s); ESI-MS (m / z): 321.4 (M+H)+.

Embodiment 3

[0027] N,N-Diethyl-2-{2-(4-chlorophenyl)thiazolo[3,2-b][1,2,4]triazol-6-yl}-acetamide (L2) preparation of

[0028] Dimethylamine hydrochloride was replaced with diethylamine, and the synthesis method was referred to Example 2, and the yield was 34%.

[0029] 1H-NMR (300MHz, DMSO), δ(ppm): 7.52 (2H, d, J = 9.0Hz), 7.42 (1H, s), 7.37 (2H, d, J = 9.0Hz), 4.86 (2H, s ), 3.98 (2H, m), 3.32 (2H, m), 1.18 (3H, t), 1.05 (3H, t); ESI-MS (m / z): 349.0 (M+H)+.

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Abstract

The invention discloses a thiazole [3,2-b] [1,2,4]-triazole-6-acetamide derivative as shown in formula I or a pharmaceutically acceptable hydrate and salt thereof. The derivative comprises a stereisomer or tautomer thereof; R1 in the formula I is hydrogen, methyl, halogen, hydroxy, methoxy group, acetyl, propionyl, nitro or alkoxy; R2 and R3 are independently selected from C1-C6 alkyl or R2 and R3 and nitrogen atoms connected with the R2 and R3 are formed into pyrryl, piperidyl, morpholinyl, N-methyl piperazine and N-phenylpiperazine. The thiazole [3,2-b] [1,2,4]-triazole-6-acetamide derivative disclosed by the invention has an obvious restraining function to acetylcholin esterase and is used for enhancing the memory of the patients suffering from dementia and Alzheimer's disease. The invention also relates to a preparation method of the compound and application of the compound for preparing the drug for treating the senile dementia.

Description

technical field [0001] The present invention belongs to the technical field of medicine, and in particular relates to thiazolo[3,2-b][1,2,4]-triazole-6-acetamide 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 enha...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D513/04A61P25/28
CPCC07D513/04
Inventor 刘斯婕郭瑞霞王娟史兰香张宝华
Owner SHIJIAZHUANG POLEE PHARMA CO LTD
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