Carbamate derivative as well as synthetic method and application thereof

A carbamate and carbamate technology, applied in the field of carbamate derivatives and their synthesis, can solve the problems of low activity, short half-life, and large molecular weight of compounds

Inactive Publication Date: 2016-12-07
CENT SOUTH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] However, currently commercially available anti-senile dementia drugs have liver toxicity, peripheral side effects, short half-life or intestinal side effects, so the further discovery and development of new and efficient acetylcholinesterase inhibitors is of great significance for the treatment of Alzheimer's disease (Liu H, Huang X, Lou D, Liu X, Liu W, Wang Q. Bioorg, Med. Chem. Lett, 2014, 24(19): 4749-4753.)
In 2012, Chinese patent CN 102603675B disclosed piperazine compounds containing carbamate bonds as acetylcholinease inhibitors, but the activity of the synthesized compounds was relatively low, and the highest inhibition rate at 10 μM was 64.96%.
In 2010, the international patent WO2008097546 (A2) disclosed a series of carbamate acetylcholinease inhibitors, but the applied compounds were designed according to the principle of drug combination, and the compounds had large molecular weight and poor druggability

Method used

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  • Carbamate derivative as well as synthetic method and application thereof
  • Carbamate derivative as well as synthetic method and application thereof
  • Carbamate derivative as well as synthetic method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Methyl 3-((1H-indazol-1-yl)methyl)phenyldimethylcarbamate (I 1 ) preparation

[0024] (1) Synthesis of m-tolyldimethylcarbamate

[0025] 4g of m-cresol was dissolved in 15mL of DMF, and 1.2g of sodium hydride was added. After stirring for 15 min, 4 g of dimethylcarbamoyl chloride were added dropwise. After reacting for 2 hours, 15 mL of water was added, and then extracted three times with 10 mL of ethyl acetate. After combining the three organic phases, the ethyl acetate was removed by rotary evaporation. Place it in a vacuum drying oven at 45° C. for 24 hours to obtain 5.9 g of a light pink transparent liquid product with a yield of 71.7%.

[0026] 1 H NMR (500MHz, CDCl 3 )δ7.25(t, J=7.8Hz, 1H, Ar-H), 7.02(d, J=7.6Hz, 1H, Ar-H), 6.93(m, J=13.6, 5.5Hz, 2H, Ar- H),3.12(s,3H,N-CH 3 ),3.03(s,3H,N-CH 3 ),2.37(s,3H,Ar-CH 3 ).

[0027] (2) Preparation of 3-(bromomethyl) phenyl dimethyl carbamate

[0028] Add 0.5g methyl m-tolyldimethylcarbamate, 0.593g bromosuccini...

Embodiment 2

[0034] 3-[(Imidazol-1-yl)methyl]phenyldimethylcarbamate (I 2 ) preparation

[0035]Dissolve 68 mg of imidazole in 5 mL of DMF, add 130 mg of potassium carbonate and 200 mg of 3-(bromomethyl)phenyldimethylcarbamate, and stir at room temperature. After the reaction was complete after about 4 hours, 5 mL of water was added and extracted three times with 10 mL of ethyl acetate. The organic phases were combined, and the ethyl acetate was distilled off under reduced pressure. Then, 5 mL of hydrochloric acid (1N) was added, and washed three times with 2 mL of ethyl acetate. Then the pH of the aqueous phase was adjusted to alkaline with anhydrous potassium carbonate, and then extracted three times with 5 mL of ethyl acetate, and the organic phases were combined and dried with anhydrous magnesium sulfate. Ethyl acetate was removed by rotary evaporation, and dried in a vacuum oven at 45°C to obtain 144 mg of a colorless transparent liquid with a yield of 76%.

[0036] 1 H NMR (500M...

Embodiment 3

[0038] Methyl 3-(anilinomethyl)phenyldimethylcarbamate (I 3 ) preparation

[0039] Dissolve 93 mg of aniline in 5 mL of DMF, add 130 mg of potassium carbonate and 200 mg of 3-(bromomethyl)phenyldimethylcarbamate, and stir at room temperature. After the reaction was complete after about 4 hours, 5 mL of water was added and extracted three times with 10 mL of ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, ethyl acetate was distilled off under reduced pressure, separated by column chromatography, and dried in a vacuum oven at 45°C to obtain 141 mg of a yellow solid with a yield of 67%.

[0040] 1 H NMR (500MHz, CDCl 3 )δ7.35 (t, J=7.8Hz, 1H, Ar-H), 7.24–7.16 (m, 4H, Ar-H), 7.04 (m J=8.0, 1.8Hz, 1H, Ar-H), 6.77 –6.71(m,1H,Ar-H),6.65(m,J=11.6,4.0Hz,2H,Ar-H),4.36(s,2H,N-CH 2 -Ar),3.12(s,3H,N-CH 3 ),3.03(s,3H,N-CH 3 ).

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Abstract

The invention relates to a medical composition having the effect of restraining acetyl cholinesterase, as well as a synthetic method and an application of the medical composition, in particular to a carbamate compound with a general formula (I), wherein the definition of a symbol A is as shown in the description. The invention discloses the structure of the carbamate compound, the synthetic method thereof and the application of the carbamate compound in restraining the in vitro activity of acetyl cholinesterase, and an insecticide and a new medicine for treating Alzheimer's diseases can be further developed from the carbamate compound.

Description

technical field [0001] The invention belongs to the technical field of medicines, and relates to carbamate derivatives as well as their synthesis method and application. Background technique [0002] Acetylcholinesterase is a serine protease and a membrane-bound protein. The transmission of nerve signals in the synaptic cleft is through the presynaptic membrane secreting the neurotransmitter acetylcholine to the synaptic cleft, acting on the acetylcholine receptor of the post-synaptic membrane, and stimulating the next nerve cell to generate a nerve impulse. Acetylcholinease terminates nerve impulses by rapidly hydrolyzing acetylcholine, breaking it down into choline and acetate molecules. Therefore, acetylcholinesterase is an important drug design target, and acetylcholinesterase inhibitors can increase the concentration of neurotransmitter acetylcholine in the synaptic cleft by inhibiting acetylcholinesterase to hydrolyze acetylcholine, thereby prolonging and enhancing th...

Claims

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Application Information

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IPC IPC(8): C07D231/56C07D233/60C07C271/44C07C269/06C07D295/096C07D209/08A61K31/416A61K31/4174A61K31/27A61K31/4453A61K31/404A61P25/28A01N47/22A01P7/04
Inventor 蒋玉仁杜阳森肖丹丹王希周礼云
Owner CENT SOUTH UNIV
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