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2,4-(1H, 3H)-quinazolinedione derivative and synthesis method and use thereof

A technology of quinazoline diones and derivatives, which is applied in the field of medicine, and can solve the problems of compounds with low activity, undisclosed acetylcholinesterase inhibitory activity, and low caspase inhibitory activity

Inactive Publication Date: 2016-11-23
CENT SOUTH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In 2006, U.S. Patent US2006 / 0135557 disclosed a kind of isoquinoline-1,3,4-triketone compound and its synthesis method and application in medicine, to cysteine-containing aspartic acid protein Hydrolase (Caspase) has inhibitory activity, can delay cell apoptosis, can be developed for the treatment of neurodegenerative diseases, especially as a drug for the treatment of Alzheimer's disease, stroke and local ischemic injury, but This type of compound has low inhibitory activity on Caspase, and its IC 50 The value is above 80mM, and the inhibitory activity of this type of compound on acetylcholinesterase has not been disclosed
In 2006, Chinese patent CN101356159A disclosed isoquinolin-1,3-(2H,4H)-diones, 1-thio-1,4-dihydro-2H-isoquinolin-3-ones and 1 , 4-dihydro-3-(2H)-isoquinolinone compounds and their preparation methods and applications in medicine have inhibitory activity on kinases and can be developed as drugs for the treatment of cancer, but this class of compounds has not been disclosed Inhibitory activity against acetylcholinesterase
In 2011, Chinese patent CN101550103B disclosed a 1,2,3,4-tetrahydroisoquinoline compound and its salt, its preparation method and application in medicine. This type of compound has inhibitory activity on acetylcholinesterase and can Further research and development of new drugs for the treatment of Alzheimer's disease, but the activity of this type of compound is not too high, the IC for the inhibition of acetylcholinesterase 50 Values ​​above 7.5nM

Method used

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  • 2,4-(1H, 3H)-quinazolinedione derivative and synthesis method and use thereof
  • 2,4-(1H, 3H)-quinazolinedione derivative and synthesis method and use thereof
  • 2,4-(1H, 3H)-quinazolinedione derivative and synthesis method and use thereof

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Experimental program
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Embodiment 1

[0021] 3-[(N-phenyl)benzamide-3-methylene]-2,4(1H)-quinazolinedione (I 1 ) preparation

[0022] (1) Preparation of 2,4-(1H,3H)-quinazolinedione (II)

[0023] Add 7g of anthranilic acid and 21.62g of urea into a dry 100mL round bottom flask, and react at 160°C for 12h. After the reaction, cool the reaction system to 100°C, add 20mL of water and stir for 1h. Cool the reaction system to room temperature, filter with suction and wash with water to obtain the off-white powder of the crude product, stir the powder in 100 mL of 1mol / L sodium hydroxide solution for 1 hour, filter with suction and dry to obtain the product 2,4-(1H,3H)-quinazole Phenyldione 6.4 g , the yield is 78%, and the melting point is greater than 290°C.

[0024] 1 H NMR (500MHz, DMSO-d 6 )δ11.20 (br, 2H, NH), 7.92-7.84 (m, 1H, Ar-H), 7.68-7.46 (m, 1H, Ar-H), 7.23-7.07 (m, 2H, Ar-H) .

[0025] (2) Preparation of methyl m-toluate (III)

[0026] Add 8g of m-toluic acid and 50mL of methanol into a 100mL three...

Embodiment 2

[0040] 3-[(N-m-tolyl)benzamide-3-methylene]-2,4(1H)-quinazolinedione (I 2 ) preparation

[0041] Dissolve 50uL of m-toluidine in 3mL of anhydrous tetrahydrofuran, and add 100uL of triethylamine as an acid-binding agent into a 50mL single-necked round-bottom flask, cool the reaction system to 0°C in a low-temperature reactor, and stir 100mg of V at low temperature Slowly added to the reaction system under the conditions, and then stirred at room temperature for 3h. During the reaction, a white solid precipitated out. TLC followed the reaction (developing solvent: ethyl acetate:cyclohexane=1:1), filtered to obtain a white solid after the completion of the reaction, and the solid was washed with ethyl acetate and water to obtain I 2 . The yield is 50%, and the melting point is greater than 290°C.

[0042] 1 H NMR (500MHz, DMSO) δ11.58(s, 1H, NH), 10.18(s, 1H, NH), 7.97(d, J=7.3H z , 1H, Ar-H), 7.88-7.81(m, 2H, Ar-H), 7.69(t, J=7.2Hz, 1H, Ar-H), 7.59(s, 1H, Ar-H), 7.55- 7.5...

Embodiment 3

[0044] 3-[(N-p-nitrophenyl)benzamide-3-methylene]-2,4(1H)-quinazolinedione (I 3 ) preparation

[0045] Dissolve 40mg of p-nitroaniline in 3mL of anhydrous tetrahydrofuran, and add 100uL of triethylamine as an acid-binding agent into a 50mL single-necked round-bottomed flask, cool the reaction system to 0°C in a low-temperature reactor, and place 100mg of V in a low-temperature Slowly added to the reaction system under the condition of stirring, then stirred at room temperature for 10h. TLC followed the reaction (developing solvent: ethyl acetate: cyclohexane = 1: 1). After the reaction was completed, it was spin-dried to give a yellow solid, which was separated and purified by chromatographic column (eluent: ethyl acetate: cyclohexane =1:1) to get product I 3 . The yield is 50%, and the melting point is greater than 290°C.

[0046] 1 H NMR (500MHz, DMSO) δ11.59(s, 1H, NH), 10.84(s, 1H, NH), 8.29-8.26(m, 2H, Ar-H), 8.06-8.03(m, 2H, Ar- H), 7.97(d, J=7.3Hz, 1H, Ar-H), 7.89...

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Abstract

The present invention discloses a 2,4-(1H,3H)-quinazolinedione derivative and a synthesis method and use thereof, belongs to the technical field of medicines, and relates to the 2,4-(1H, 3H)-quinazolinedione derivative shown as general formula(I), wherein R1 is O(CH2)n-1H, n=1-10; or NH(CH2)n-2H, n=2-10; or NH(CH2)n-3(CH3)2, n=3-10; or N(CH2)n-4, n=6-10; or NH(CH2)n-5 C6H4-L, n=5-10; R2 is H; or X-O(CH2)n-1H, n=1-10; or X-NH(CH2)n-2(CH3)2, n=2-10; X is m-CH2C6H4CO; L is independently selected from the group consisting of H, F, Cl, Br, I, CN, NO2, CF3, OCF3, SCF3, OH, SH, NH2, COOR, R, OR, SR, NHR, NRR, OCOR, SCOR and NHCOR, wherein R is C1-6 straight chain alkyl, branched alkyl or alicyclic alkyl or phenyl. Structures and the synthesis method and in-vitro acetylcholin esterase inhibition activity of the compounds are disclosed, and the compounds can be further developed as drugs for treating Alzheimer's disease.

Description

technical field [0001] The invention belongs to the technical field of medicines, and relates to a class of 2,4-(1H,3H)-quinazolinedione derivatives with novel structures, their synthesis method and their application in medicine. technical background [0002] Alzheimer's disease (Alzheimer's disease, AD), also known as Alzheimer's disease, has become the most common type of dementia in the elderly population, accounting for 50%-56% of anatomical and clinical events, and is currently the An important cause of death in the elderly. Alzheimer's disease is a neurodegenerative disease that affects more than 350 million people and causes death within three to nine years of diagnosis. Age growth is the most important factor leading to the disease. The incidence rate of the elderly over 65 years old increases by 5 years, and the incidence rate doubles, and the incidence rate of the elderly over 85 years old is as high as 1 / 3. [0003] At present, based on different perspectives, m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/96A61P25/28
CPCC07D239/96
Inventor 蒋玉仁肖丹丹王希杜阳森
Owner CENT SOUTH UNIV
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