Application of coumarin-dithiocarbamate derivatives to pharmacy
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A drug and pharmaceutical technology, applied in the field of medicine, can solve the problems of undiscovered synthesis method of coumarin-dithiocarbamate derivatives, reduction of acetylcholine receptors, hindering receptor regeneration, etc., and achieves good application prospects , Inhibition of acetylcholinesterase, low toxicity effect
Active Publication Date: 2018-02-27
广西壮族自治区肿瘤防治研究所
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Problems solved by technology
At present, it is generally believed that the acetylcholine receptor antibody (AchRab) is one of the main factors in the pathogenesis of myasthenia gravis. Regeneration reduces the number of acetylcholine receptors, and the resulting end-plate potential cannot induce muscle cells to generate action potentials, so that the muscles cannot contract, resulting in myasthenia gravis
However, no relevant reports have been found on coumarin-dithiocarbamate derivatives and their synthesis methods and their application in the treatment of AD and other diseases.
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Embodiment 1
[0063] Embodiment 1: the preparation of intermediate 2 (7-hydroxyl-4-methylcoumarin)
[0064] Measure 15ml of dioxane (which can also be methanol or ethanol), add resorcinol (10mmol, 1.1g) to it, and add 4ml of concentrated sulfuric acid dropwise under ice bath conditions. Add ethyl acetoacetate (10mmol, 1.3g) into the solution, stir and heat to 60°C, and react for 4h. Recrystallized from methanol to obtain white needle-like solid crystals with a yield of 91%. 1 H NMR (600MHz, acetone-d 6 )δ7.61 (1H, d, J = 9.0Hz), 6.85 (1H, dd, J = 9.0, 2.5Hz), 6.75 (1H, d, J = 2.5Hz), 6.09 (1H, s), 2.40 ( 3H,s).ESI-MS m / z:175.0[M-H] - .
Embodiment 2
[0065] Example 2: General procedure for the preparation of intermediates 3a-f
[0066] Add 5.0mmol of intermediate 2 and 50mmol of dibromoalkane while stirring in acetone (also can be DMF, acetonitrile or tetrahydrofuran), and then add anhydrous K 2 CO 3 (1.4g, 10mmol) to adjust 9-11 of the system, react at room temperature for 4h, and then filter with suction after cooling to collect the filter residue, which is purified by silica gel column (petroleum ether:ethyl acetate=15:1, volume ratio), and finally 3a-f were obtained as white solids.
Embodiment 3
[0067] Embodiment 3: The yield of intermediate 7-(8-bromoethoxy)-4-methylcoumarin (3a), NMR data and mass spectrometry data
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Abstract
The invention discloses application of coumarin-dithiocarbamate derivatives to pharmacy. The derivatives to which the invention relates are synthesized according to the following steps of: 1, by usingconcentrated sulfuric acid as a catalyst, taking resorcinol and ethyl acetoacetate and place same in a first organic solvent to perform a reaction so as to obtain an intermediate 2; 2, taking the intermediate 2 and dibromo alkane and place same in a second organic solvent, and performing a reaction under the condition that pH is greater than or equal to 8 so as to obtain an intermediate 3; 3, taking the intermediate 3, carbon disulfide and secondary amine in a third organic solvent, and performing a reaction under the condition that pH is greater than or equal to 8 so as to obtain a corresponding target compound. Experiments of an applicant show that the coumarin-dithiocarbamate derivatives show excellent selective acetylcholin esterase inhibitory activity, Abeta1 to 42 resistant self-gathering activity and blood-brain barrier permeability; part of the compounds are low in toxicity for nerve cells, and can penetrate blood-brain barriers and show ideal low-toxicity or non-toxicity effect; the coumarin-dithiocarbamate derivatives have excellent application prospect in the aspect of treating diseases such as the AD (Alzheimer's disease).
Description
technical field [0001] The invention relates to the technical field of medicine, in particular to the application of coumarin-dithiocarbamate derivatives in pharmacy. Background technique [0002] Alzheimer's disease (AD), also known as senile dementia, is a common neurodegenerative disease in the elderly. With the advent of an aging society, the problem of dementia is becoming more and more serious. Current drugs for the treatment of AD mainly rely on acetylcholinesterase (AChE) inhibitors (donepezil, galantamine, rivastigmine) and N-methyl-D-aspartate (NMDA) receptor antagonists (memantine) . Although these drugs can alleviate AD symptoms, they cannot fundamentally improve the disease state or terminate the disease process. [0003] Alzheimer's disease has a complex pathogenic mechanism. Although the pathogenesis of Alzheimer's disease is not fully understood, multiple interacting factors have been identified to be involved in the onset and progression of the disease. ...
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