Diketone derivative as well as preparation method and application thereof

A technology of derivatives and diketones, which is applied in the field of diketone derivatives and its preparation, can solve problems affecting the polymerization process of tau protein, protect nerve cells, prevent tubulin depolymerization, and treat Alzheimer's disease Effect

Inactive Publication Date: 2016-12-07
GUANGDONG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The research on treating Alzheimer's disease with tau protein as a target is still in its infancy. Most of the small drug molecules are still in the theoretical design stage, and only a small part has entered the second phase of clinical trials, such as methylene blue ( MTC), a phenothiazine compound that prevents tau-tau interactions, not only partially disintegrates isolated double-helical filaments (PHFs), but also affects the polymerization process of tau protein

Method used

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  • Diketone derivative as well as preparation method and application thereof
  • Diketone derivative as well as preparation method and application thereof
  • Diketone derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Synthesis of 5-bromo-2-(2,6-diisopropyl-phenyl)-isoindole-1,3-dione 1a

[0033] Weigh 4-bromophthalic anhydride (0.67mmol, 1eq) and compound 2,6-diisopropylaniline (0.80mmol, 1.2eq) in a 25mL round bottom bottle, dissolve it in acetonitrile (3mL) After that, add DPPOx (1.34mmol, 2eq) prepared by reference (Tetrahedron, 1982,39 (20): 3253), Et 3 N (0.18mL, 1.29mmol, 1.9eq), the reaction continued for 2.5h under the condition of reflux, and the reaction was monitored by TLC until the raw materials disappeared completely, the reaction solution was spin-dried, and the reactant was redissolved in ethyl acetate, respectively With HCl (30mL, 3M) and NaHCO 3 (30mL, 3M) washed with water and extracted. The extract was collected and dried, spin-dried, and purified by column chromatography to obtain product 1a, a white solid, melting point: 165° C., yield 92%.

[0034] 1 H NMR (400MHz, CDCl 3 )δ8.11(d, J=3.8Hz, 1H), 7.96(dd, J=7.9, 1.4Hz, 1H), 7.84(d, J=7.9Hz, 1H), 7.46(t, J=...

Embodiment 2

[0036]Synthesis of 5-bromo-2-(3,4,5-trimethoxy-phenyl)-isoindole-1,3-dione 1b

[0037] Compound 4-bromophthalic anhydride (0.67mmol) and compound 3,4,5-trimethoxyaniline (0.80mmol) were separated according to the operation process of Example 1 to obtain compound 1b, a white solid, melting point: 200°C,

[0038] Yield 88%.

[0039] 1 H NMR (400MHz, CDCl 3 )δ8.09(d, J=0.8Hz, 1H), 7.94(dd, J=7.9, 1.3Hz, 1H), 7.82(d, J=7.9Hz, 1H), 6.63(s, 2H), 3.89( s,3H),3.88(s,6H); ESI-MS m / z:392.1[M+H] + .

Embodiment 3

[0041] Synthesis of 6-(2,6-diisopropyl-phenyl)pyrrolo(3,4-b)pyridine-5,7-dione 1c

[0042] Compound 2,3-pyridinedicarboxylic acid anhydride (0.67mmol) and compound 2,6-diisopropylaniline (0.80mmol), according to the operation process of Example 1, were separated to obtain compound 1c, a white solid, melting point: 170 ° C, collected rate 56%.

[0043] 1 H NMR (400MHz, DMSO) δ9.11 (dd, J = 5.0, 1.4Hz, 1H), 8.46 (dd, J = 7.7, 1.4Hz, 1H), 7.92 (dd, J = 7.7Hz, 1H), 7.54 (t, J=7.7Hz, 1H), 7.37(d, J=7.7Hz, 2H), 2.73(hept, J=6.8Hz, 2H), 1.07(d, J=7.7Hz, 12H); ESI-MS m / z:309.2[M+H] + .

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Abstract

The invention discloses a diketone derivative, as well as a preparation method and application thereof, and belongs to the technical field of biological medicines. The derivative comprises compounds in the general formula I and pharmaceutically-acceptable salt, wherein X is C or N; Y is C or N; R1 is one of hydrogen, chlorine, bromine or thiophene; R2 is one of hydrogen, isopropyl or methoxy. The most of compounds of the diketone derivative not only has an inhibiting effect on tau protein polymerization, but also plays a role in stabilizing microtubulin; the diketone derivative can be effectively used for treating the Alzheimer's disease.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and specifically relates to a diketone derivative and a preparation method and application thereof. Background technique [0002] Alzheimer's disease (AD) is a degenerative brain nervous system disease, which is one of the most common senile dementias. Its clinical manifestations include social impairment, memory loss, cognitive function (time-spatial orientation ability) weakening, thinking and understanding behavior decline, loss of visuospatial function and daily self-care ability, apathy and withdrawn personality, and other symptoms. life threatening. Epidemiological research results show that senile dementia has become the fourth cause of death of the elderly after cancer, stroke and heart disease in developed countries. With the rapid increase in the number of patients, it has caused a heavy burden on families and society. Due to the strong concealment of the onset of AD, the slow co...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D487/04C07D409/04A61P25/28
CPCC07D409/04C07D471/04C07D487/04
Inventor 陈惠雄帕斯卡·道叶飞飞黄广华
Owner GUANGDONG UNIV OF TECH
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