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(-)-meptazinol carbamate derivative and/or its salt and their prepn and use

A technology of carbamic acid and derivatives of mebutamol, which is applied in drug combinations, active ingredients of heterocyclic compounds, nervous system diseases, etc., to achieve the effects of good safety, low toxic and side effects, and high therapeutic index

Inactive Publication Date: 2007-08-22
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

(-)-Maprotamol is a moderately strong AChE inhibitor (IC 50 41μmol / L), there is no research report on (-)-mebutanol carbamate derivatives at home and abroad, and it is worthwhile to carry out research and development of AChE inhibitors

Method used

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  • (-)-meptazinol carbamate derivative and/or its salt and their prepn and use
  • (-)-meptazinol carbamate derivative and/or its salt and their prepn and use
  • (-)-meptazinol carbamate derivative and/or its salt and their prepn and use

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] (-)-Maptafol is obtained by resolution, and its preparation method can be found in Chinese patent application (publication number: CN1850804). Embodiment 1 (-)-Mabutaol dimethyl carbamate (R 1 =CH 3 , R 2 =CH 3 ) preparation

[0037] Sodium hydride (80%, 0.15 g, 5.00 mmol) was added to acetonitrile, cooled, and a solution of (-)-mebutamol (0.40 g, 1.71 mmol) in 20 ml of anhydrous acetonitrile was added dropwise. Stir the reaction for 30 min, then add dimethylcarbamoyl chloride (195 μl, 2.06 mmol) dropwise, and react for 2 h. Recover the solvent, add 25ml of water to dilute, extract with ethyl acetate (25ml×2), combine the organic layers, wash with water, anhydrous Na 2 SO 4 dry. After filtration and concentration, 0.50 g of light yellow oil was obtained, with a yield of 96%.

[0038] Dissolve 0.50 g of light yellow oil in 5 ml of ethanol, form a salt with anhydrous HCl-EtOH, recover the solvent, and recrystallize with acetone to obtain light yellow needle crysta...

Embodiment 2

[0039] Embodiment 2 (-)-Mabutaol phenylcarbamate (R 1 = H R 2 =Ph) Preparation

[0040] Sodium hydride (80%, 0.15 g, 5.00 mmol) was added to tetrahydrofuran, cooled, and a tetrahydrofuran solution of (-)-meprotamol (0.40 g, 1.71 mmol) was added dropwise. After stirring for 30 min, phenyl isocyanate (488 μl, 4.48 mmol) was added dropwise and reacted for 4 h. After recovering the solvent, adjust to alkaline with dilute ammonia water, and finally extract with diethyl ether (20ml×2), anhydrous Na 2 SO 4 dry. After filtration and concentration, 0.43 g of off-white solid was obtained, with a yield of 71.7%.

[0041] 0.43 g of off-white solid was dissolved in anhydrous ether, and HCl-anhydrous ether was added dropwise to form a salt, and a solid was precipitated. Filter, wash with a small amount of anhydrous ether, and dry in vacuo. Obtain (-)-mabutamol phenylcarbamate hydrochloride powder 0.39g, yield 82.1%, m.p.122~127 ℃, [α] D = -18.94° (c 0.108, MeOH). 1 HNMR (DMSO-d 6 ...

Embodiment 3

[0042] Embodiment 3 cholinesterase inhibitory activity test method:

[0043] The enzyme inhibitory activity was measured by Ellman colorimetric method. According to the hydrolysis of acetylcholine by acetylcholinesterase, choline and acetic acid were generated, and choline reacted with sulfhydryl chromogen to generate a yellow compound. The quantity reflects the experimental principle of acetylcholinesterase activity, and the cholinesterase activity was determined according to the instructions of the AChE kit provided by Nanjing Jiancheng Biotechnology Co., Ltd. The source of AChE enzyme is 10% homogenate of rat brain tissue (made by adding physiological saline), and the source of BChE enzyme is rat serum. Measure the cholinesterase activity after reacting different concentrations of the drug to be tested with rat brain homogenate supernatant or rat serum for 20 minutes to calculate its IC 50 value.

[0044] Results IC with three measurements 50 Mean value (mean) ± standard...

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Abstract

The present invention is (-)-meptazinol carbamate derivative as shown and / or its salt and their preparation process and use in preparing medicine for treating dementia including Alzheimer disease. The said compound, extracorporeal experiment shows, has very high AChE and BChE inhibiting activity, hundreds times higher than that of available medicine.

Description

technical field [0001] The invention belongs to the field of pharmacy, and relates to (-)-mebutaphenol carbamate derivatives and / or salts thereof, a preparation method and application thereof. Background technique [0002] Acetylcholinesterase (AChE) inhibitors are currently the main clinical drugs for the treatment of Alzheimer's disease (AD), which can alleviate the symptoms of dementia in patients to a certain extent. Four of the five AD drugs approved by the US FDA are AChE inhibitors. Among them, Rivastigmine, as a second-generation, non-competitive AChE inhibitor, was approved by the FDA in 2000 for the treatment of mild and moderate AD. [0003] Rivastigmine, a carbamate drug, is a slow substrate inhibitor. The mechanism of action of this type of drug is: covalently bonded to the serine residue at the catalytic active site of the enzyme, due to the dissociation process of the carbamylated enzyme complex Slow, resulting in the enzyme not being revived in time and inh...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/04A61K31/55A61P25/28
Inventor 仇缀百谢琼陈红专张伟伟王星海王昊盛韦
Owner FUDAN UNIV
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