A kind of 4-oxo-2-thiothiazolidinyl derivative and its preparation method and application

A thiothiazolidine and derivative technology, applied in the field of biomedicine, can solve the problems of reduced activity of promoting microtubule assembly, impact on dynamic behavior of microtubules, cell death, etc., to prevent tubulin depolymerization and treat Alzheimer's disease. Hymer's disease, the effect of protecting nerve cells

Inactive Publication Date: 2019-08-27
GUANGDONG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

NFTs themselves are harmless to cells, but the absence of Tau protein will greatly affect the dynamic behavior of microtubules. Microtubules tend to dissociate due to the loss of Tau protein stabilization, resulting in the collapse of the cytoskeleton, affecting the axonal transport function and Transmission of nerve signals, even cell death
Hyperphosphorylation of Tau protein not only reduces its activity of promoting microtubule assembly, but also further destroys microtubules by consuming normal Tau protein, microtubule-associated proteins MAP1 and MAP2, and affects the synthesis, transportation, release and uptake of neurotransmitters. Causes a breakdown in communication between nerve cells, leading to neurodegeneration
In addition, many studies have confirmed that the abnormal modification of Tau causes Tau to become a toxic molecule and accumulate into PHF, resulting in neuron fibrosis

Method used

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  • A kind of 4-oxo-2-thiothiazolidinyl derivative and its preparation method and application
  • A kind of 4-oxo-2-thiothiazolidinyl derivative and its preparation method and application
  • A kind of 4-oxo-2-thiothiazolidinyl derivative and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Synthesis of ethyl 2-(4-oxo-2-thiothiazolidin-3-yl)acetate 1a1

[0029] Add glycine ethyl ester hydrochloride (500mg, 3.6mmol, 1eq) to 2,2'-(thiocarbonyl(thio))diacetic acid (976mg, 4.32mmol, 1.2eq) in isopropanol (4mL) , and then drop Et into the system 3 N (1 mL, 7.2 mmol, 2 eq). The reaction system was heated to 82°C and stirred for 1 h. After the reaction was monitored by TLC, after concentration to dryness, the product 1a1 (638mg, 2.91mmol) was obtained by silica gel column separation, a yellow crystalline solid, melting point: 55°C, yield 81%.

[0030] 1 H NMR (400MHz, CDCl 3 )δ=4.65(s, 2H), 4.19(q, J=7.8Hz, 2H), 4.01(s, 2H), 1.22(t, J=7.8Hz, 3H); ESI-MS m / z: 220.2[ M+H] + .

Embodiment 2

[0032]Synthesis of tert-butyl 2-(4-oxo-2-thiothiazolidin-3-yl)acetate 1a2

[0033] Glycine tert-butyl ester hydrochloride (500mg, 3mmol, 1eq) and trithiocarbonate (813mg, 3.6mmol, 1.2eq) were isolated according to the operation process of Example 1 to obtain compound 1a2 (504mg), yellow crystalline solid, Melting point: 56°C, yield 68%.

[0034] 1 H NMR (400MHz, CDCl 3 )δ=4.62(s,2H),4.07(s,2H),1.46(s,9H); ESI-MS m / z:248.2[M+H] + .

Embodiment 3

[0036] Synthesis of ethyl 2-(4-oxo-2-thiothiazolidin-3-yl)propionate 1b1

[0037] 3-aminopropionic acid ethyl ester hydrochloride (500mg, 3.27mmol, 1eq) and 2,2'-(thiocarbonyl (sulfur)) diacetic acid (886mg, 3.92mmol, 1.2eq), refer to the operation process of Example 1 , isolated product 1b1 (708mg), yellow crystalline solid, melting point: 53°C, yield 93%.

[0038] 1 H NMR (400MHz, CDCl 3 )δ4.30(t, J=7.8Hz, 2H), 4.18(q, J=7.8Hz, 2H), 4.00(s, 2H), 2.68(t, J=7.8Hz, 2H), 1.27(t, J=7.7Hz,3H); ESI-MS m / z:234.1[M+H] + .

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Abstract

Belonging to the technical field of biomedicine, the invention discloses a 4-oxo-2-thiothiazolidine containing derivative, a preparation method and application thereof. The derivative involved in the invention contains a compound shown as general formula I, wherein n is an integer 1 or 2; R1 is an ester group or amide or acid group; R2 is one of hydrogen, isopropyl or methoxy. Most compounds of the type have an inhibiting effect on tau protein polymerization, also has a stabilizing effect on tubulin, and can be effectively used for treatment of Alzheimer's disease.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and specifically relates to a 4-oxo-2-thiothiazolidinyl derivative and its preparation method and application. Background technique [0002] Alzheimer's disease (Alzheimer's disease, AD) is dementia caused by chronic progressive central nervous system degenerative disease, is the most common cause of dementia and the most common senile dementia. AD is characterized by neuropsychiatric symptoms such as progressive memory impairment, cognitive impairment, personality changes, and language impairment. Often onset in old age or early old age, more slowly onset, gradually progressing, with dementia as the main manifestation. The cause of disease is unknown so far, and there is no specific medicine or method for curing it. However, the number of patients is increasing year by year around the world. There are currently 5 million patients in China, and it will reach 10 million by 2020. By 2050, th...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/06A61P25/28
Inventor 陈惠雄帕斯卡·道黄广华叶飞飞
Owner GUANGDONG UNIV OF TECH
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