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Matrine acid/alkali derivative and its preparation method and use

A compound and alkyl technology, applied in the field of N-substituted matrine derivatives and substituted matrine derivatives and their preparation, can solve the problems of lack of clinical treatment options

Inactive Publication Date: 2016-06-08
CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Diseases related to viral infection are one of the major diseases currently affecting human health. So far, although many antiviral drugs have been discovered one after another, there is still a lack of completely effective clinical treatment options

Method used

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  • Matrine acid/alkali derivative and its preparation method and use
  • Matrine acid/alkali derivative and its preparation method and use
  • Matrine acid/alkali derivative and its preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 2

[0324] The synthesis of embodiment 2N-oxidized matrine (DM-1001):

[0325] Take 5.28g (0.02mol) of matrine, add it to 6.72g (0.12mol, 6eq.) of potassium hydroxide (KOH) in 100ml aqueous solution, heat to reflux for 9h, and then react overnight at room temperature. The reaction solution was cooled in an ice-water bath, adjusted to pH 5-6 with 3N hydrochloric acid, and concentrated to dryness under reduced pressure. Fully dissolve the obtained solid with methanol, filter, wash the filter cake with methanol, combine the filtrates and evaporate to dryness to obtain the crude product N-oxymatrine (DM-1001), and recrystallize the light yellow solid with ethanol / acetone to obtain the pure product DM-10015.1 g (yield: 90.4%), melting point: 184.6-186.9°C.

[0326] MS-ESI(M / Z): 283.3【M+H】 +

[0327] 1 H-NMR (CD 3 OD, δppm): 4.513~4.571(1H, m), 4.272~4.333(1H, t, J=24.4), 3.363~3.383(1H, t, J=8), 3.289~3.302(1H, m), 3.006 ~3.033(2H, d, J=10.8), 2.919~2.962(1H, q, J=17.2), 2.352~...

Embodiment 4

[0333] The synthesis of embodiment 4N-oxymatrine (DM-2001):

[0334] Suspend 0.48 g (0.013 mol) of lithium aluminum tetrahydride in 40 ml of tetrahydrofuran and keep warm at 50°C. Add 0.7 g (0.0025 mol) of compound oxymatrine (DM-1001) in 10 ml tetrahydrofuran suspension dropwise, the addition is completed within 1 h, and the reaction solution is heated to reflux for 3 h. TLC showed that the reaction was complete, and the reaction solution was quenched by adding 0.9 ml of water while cooling in an ice-water bath. Filtration, the filter cake was repeatedly refluxed and filtered with ethyl acetate, the filtrates were combined and evaporated to dryness, and the resulting solid was recrystallized from petroleum ether / ethyl acetate to obtain 0.2 g of compound N-oxymatrine (DM-2001) (yield: 29.8% ), melting point: 142.7~144.6℃.

[0335] MS-ESI(M / Z): 269.2【M+H】 + , 251.2【M-18+H】 +

[0336] 1 H-NMR (CD 3 OD, δppm): 3.495~3.527(2H, t, J=12.8), 3.090~3.151(1H, t, J=24.4), 3.006...

Embodiment 5

[0339] The synthesis of embodiment 5N-acetyl matrine (DM-101)

[0340] Step 1. The synthesis of matrine (DM-100):

[0341] Take 19.84g (0.08mol) of matrine, add it to 26.88g (0.48mol, 6eq.) of potassium hydroxide (KOH) in 500ml aqueous solution, heat to reflux for 9h, and react at room temperature overnight. Cool the reaction solution in an ice-water bath, adjust the pH to 5-6 with 3N hydrochloric acid, and concentrate to dryness under reduced pressure to obtain crude matrine (DM-100). This light yellow solid was added to 500ml of methanol for the next reaction without purification.

[0342] Step 2. Synthesis of diphenylmethyl matrine (DM-100P):

[0343] To the mixture of 23.52g (0.12mol, 1.5eq.) of benzophenone hydrazone and 26.64g (0.12mol) of yellow mercuric oxide, add 300ml of petroleum ether with a boiling range of 60°C to 90°C, stir and react at room temperature for 6h to obtain deep purple solution of diphenyldiazomethane in petroleum ether. Filter this solutio...

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Abstract

The present invention relates to a N-substituted matrinic acid derivative or matrine derivative, and its preparation method and uses. Specifically, the present invention relates to a compound of Formula (I) or (II) (wherein all the definitions of substituted groups are those mentioned in the specification), or a pharmaceutically acceptable salt, geometric isomer, stereoisomer, solvate, ester or prodrug thereof. The present invention further relates to a method for preparing the compound of the present invention, a pharmaceutical composition containing the compound, and uses thereof in manufacture of a medicament. The compound of the present invention can be used for prophylaxis and / or treatment of a disease or disorder associated with viral infection such as hepatitis B and / orhepatitis C and / orAIDS.

Description

technical field [0001] The present invention relates to a class of novel compounds, in particular to matrine acid / base derivatives, especially N-substituted matrine derivatives and substituted matrine derivatives and their preparation methods and uses, especially their use in the prevention and / or Or use in the treatment of viral diseases such as hepatitis B and / or hepatitis C and / or AIDS. Background technique [0002] As early as the early 1930s, people began to study the chemical components of the leguminous plant Sophora flavescens (Sophoraflavescens Ait), and many research work focused on alkaloids. Bases mainly include matrine (Matrine, which may be referred to as MT in this paper, C 15 h 24 N 2 O), oxymatrine (Oxymatrine, also known as matrine, can be referred to as OMT in this paper, C 15 h 24 N 2 o 2 )Wait. In addition, Sophora flavescens also contains some flavonoids such as kurarinol. The chemical structures of matrine and oxymatrine are as follows: [00...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/16C07D471/22A61K31/4375A61P31/14
CPCA61P1/16A61P31/12A61P31/14A61P31/18A61P31/20C07D471/16C07D471/22
Inventor 蒋建东宋丹青杜娜娜彭宗根王宇萍高丽梅韩燕星李新李春鑫
Owner CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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