7H-benzo-isoxazole-[7,6-e][1,3]oxazine derivatives and application

A technology of benzisoxazole, 6-e, applied in the field of medicine, can solve problems such as drug resistance or pharmacokinetic defect

Inactive Publication Date: 2015-09-30
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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  • 7H-benzo-isoxazole-[7,6-e][1,3]oxazine derivatives and application
  • 7H-benzo-isoxazole-[7,6-e][1,3]oxazine derivatives and application
  • 7H-benzo-isoxazole-[7,6-e][1,3]oxazine derivatives and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Preparation of 3-methyl-6-hydroxy-benzoisoxazole

[0020] Add 8.3g (0.12mol) of hydroxylamine hydrochloride and 11.5g (0.14mol) of sodium acetate into a 100 mL round bottom flask, add 50 mL of water, stir to dissolve, add 15.2g (0.1mol) of 2',5'-dihydroxyacetophenone ), heated to 70°C in a water bath, and kept stirring for 6 h. After the reaction was completed, cooled to room temperature, white crystals were precipitated, filtered with suction, washed with water, dried, and recrystallized from absolute ethanol to obtain 2'5'-dihydroxyacetophenone oxime 13.2 g, yield 79.0%.

[0021] Add 8.35g (0.05mol) of 2'5'-dihydroxyacetophenone oxime and 40mL of acetic anhydride into a 100mL round bottom flask, stir and dissolve at room temperature, then add 12.2g (0.1mol) of 4-dimethylaminopyridine, and react at room temperature , TLC detection of the reaction progress, the reaction is completed, the reaction solution was poured into 200mL of crushed ice, precipitated, recrystalliz...

Embodiment 2

[0024] Preparation of 3-methyl-8-(4-fluorophenyl)-7H-benzisoxazolo[7,6-e][1,3]oxazine (L1)

[0025] Mix 2.4 mL of 37% formaldehyde aqueous solution with 10 mmol of 4-fluoroaniline dissolved in 5 mL of 95% ethanol, heat to reflux and stir for 5 minutes, then add 3-methyl-6-hydroxy-benzene dissolved in 20 mL of 95% ethanol Diisoxazole 10 mmol was heated to reflux and stirred overnight, the ethanol was evaporated under reduced pressure, and recrystallized from absolute ethanol to obtain 1.32 g of white crystals, with a yield of 46.32%. 1 H-NMR (300MHz, DMSO) δ (ppm): 2.55 (3H, s), 4.86 (2H, s), 5.36 (2H, s), 6.82 (2H, d, J =8.4Hz), 6.89(1H, d, J =9.0Hz), 7.03(2H, d, J =8.4Hz), 7.32(1H, d, J =9.0Hz ); ESI-MS (m / z): 285.1 (M+H) + .

Embodiment 3

[0027] Preparation of 3-methyl-8-(4-chlorophenyl)-7H-benzisoxazolo[7,6-e][1,3]oxazine (L2)

[0028] Mix 2.4 mL 37% formaldehyde aqueous solution with 10 mmol 4-chloroaniline dissolved in 5 mL 95% ethanol, heat and reflux and stir for 5 minutes, then add 3-methyl-6-hydroxy- 10 mmol of benzisoxazole was heated to reflux and stirred overnight, the ethanol was evaporated under reduced pressure, and 1.15 g of white crystals were obtained by recrystallization from absolute ethanol, with a yield of 38.33%. 1 H-NMR (300MHz, DMSO) δ (ppm): 2.55 (3H, s), 4.85 (2H, s), 5.37 (2H, s), 6.71 (2H, d, J =8.4Hz), 6.89(1H, d, J =9.0Hz), 7.30(2H, d, J =8.4Hz), 7.39(1H, d, J =9.0Hz ); ESI-MS (m / z): 301.1 (M+H) + .

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Abstract

The invention discloses 7H-benzo-isoxazole-[7,6-e][1,3]oxazine derivatives as shown in the formula I or pharmaceutically acceptable hydrates/salts thereof, and further discloses stereoisomers or tautomers of the 7H-benzo-isoxazole-[7,6-e][1,3]oxazine derivatives. According to the formula I, R1 represents a hydrogen group, a methyl group, an ethyl group, a halogen group, a methoxyl group, an ethoxy group, a nitro group or an alkoxyl group. The 7H-benzo-isoxazole-[7,6-e][1,3]oxazine derivatives have an obvious effect in inhibiting acetyl cholinesterase, and can be used for enhancing the memory of patients suffering from dementia and the Alzheimer's disease. The invention further relates to preparation methods of the derivatives and application of the derivatives to preparation of medicine used for treating the Alzheimer's disease.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to 7H-benzisoxazolo[7,6-e][1,3]oxazine derivatives and a preparation method thereof and as an acetylcholinesterase inhibitor for improving the Memory application for 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. [0004]...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/04A61K31/5365A61P25/28
CPCC07D498/04
Inventor 刘斯婕史兰香何敬宇贾鹏飞张宝华雷霓
Owner SHIJIAZHUANG UNIVERSITY
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