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Triptolide targeting prodrug and preparation method and application thereof

A technology of triptolide and pharmaceutical preparations, applied in the field of medicine, can solve problems such as application limitations, narrow therapeutic window, and high toxicity, and achieve the effects of effective development and utilization, reduced toxicity, and improved bioavailability

Active Publication Date: 2018-12-18
郭可点
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Triptolide is poorly soluble in water, but easily soluble in methanol, dimethyl sulfoxide, absolute ethanol, ethyl acetate, chloroform, etc.; due to poor water solubility of triptolide, narrow therapeutic window, high toxicity, and adverse reaction rate reaching 44%, so its application is limited

Method used

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  • Triptolide targeting prodrug and preparation method and application thereof
  • Triptolide targeting prodrug and preparation method and application thereof
  • Triptolide targeting prodrug and preparation method and application thereof

Examples

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preparation example Construction

[0033] The specific steps of the preparation method of the triptolide targeted prodrug provided by the invention are:

[0034] 1. Activation of triptolide succinic acid terminal carboxyl group (active ester intermediate)

[0035] Using THF-water (v:v) = 10:1.5 as solvent, stirring and dissolving triptolide succinate with 1 part by weight, adding triethylamine with 2.02 to 4.06 parts by weight and stirring evenly, batchwise slowly Add 0.52-2.29 parts by weight of activator, stir and activate at room temperature for 45min-1h, after TLC detects that the activation is complete, cool to -5°C to -30°C in a low-temperature reactor, and stir for later use.

[0036] 2. Active ester intermediate amidation stage

[0037] In addition, weigh 1.23-2.36 parts by weight of amino acid, dissolve it in 500 μL of water, adjust the pH of the aqueous solution of amino acid to the isoelectric point of the amino acid, and use a micropipette to add the aqueous solution of amino acid dropwise in five ...

Embodiment 1

[0040] The preparation of embodiment 1 triptolide succinate L-arginine amide

[0041] The preparation method of triptolide targeting prodrug comprises the following steps:

[0042] A 1 : Activation of triptolide succinate terminal carboxyl group

[0043] Such as figure 1The preparation process shown. Use THF-water (v:v) = 10:1.5 as solvent, stirring and dissolving triptolide succinate with 1 part by weight, adding triethylamine with 2.02-4.06 parts by weight and stirring evenly, batchwise slowly Add 0.52-2.29 parts by weight of the activator, stir and activate at room temperature for 45min-1h, after TLC detects that the activation is complete, cool to -5°C to -30°C in a low-temperature reactor, and stir for later use.

[0044] B 1 : Active ester intermediate amidation stage

[0045] Another 25 mg (0.141 mmol) of L-arginine was weighed, dissolved in 500 μL of water, the pH of the aqueous solution of L-arginine was adjusted to 11, and the aqueous solution of amino acid was...

Embodiment 2

[0050] Example 2 Preparation of triptolide succinate L-arginine amidomethyl ester

[0051] The preparation method of triptolide targeting prodrug comprises the following steps:

[0052] A 2 : Activation of triptolide succinate terminal carboxyl group

[0053] Such as figure 2 The preparation process shown. Use THF-water (v:v) = 10:1.5 as solvent, stirring and dissolving triptolide succinate with 1 part by weight, adding triethylamine with 2.02-4.06 parts by weight and stirring evenly, batchwise slowly Add 0.52-2.29 parts by weight of the activator, stir and activate at room temperature for 45min-1h, after TLC detects that the activation is complete, cool to -5°C to -30°C in a low-temperature reactor, and stir for later use.

[0054] B 2 : Active ester intermediate amidation stage

[0055] Another 25 mg (0.141 mmol) of L-arginine was weighed, dissolved in 500 μL of water, the pH of the aqueous solution of L-arginine was adjusted to 11, and the aqueous solution of amino a...

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Abstract

The invention relates to the technical field of medicines, in particular to a targeting inducible nitric oxide synthase (iNOS) triptolide prodrug, and a preparation method and application thereof. R1of the triptolide targeting prodrug is L-arginine, L-arginine methyl ester, L-Nomega-NO-arginine, L-N omega-NO-arginine methyl ester, L-proline, L-citrulline, L-thiocitrulline or L-ornithine. The highexpression characteristic of the inducible nitric oxide synthase (iNOS) at an inflammatory site is utilized, and the triptolide is semi-synthesized by an iNOS specific substrate (group) to prepare the prodrug, the toxicity of the triptolide is reduced and the bioavailability are improved through the targeting property of the prodrug, the anti-inflammatory effect is significantly better than thatof the triptolide, and the triptolide can be effectively developed and utilized.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a targeted inducible nitric oxide synthase (iNOS) triptolide targeted prodrug and a preparation method and application thereof. Background technique [0002] Triptolide is also known as triptolide and triptolide, with a CAS number of 38748-32-2 and a molecular formula of C 20 h 24 o 6 , the molecular weight is 360.4, and its chemical structure is shown in formula Ⅱ. It is an abietane diterpene lactone extracted from the root, leaf, flower and fruit of Euonymus plant Tripterygium wilfordii. [0003] [0004] Modern pharmacological studies have shown that triptolide has anti-inflammatory, anti-tumor, and immunosuppressive effects, especially for rheumatoid arthritis (RA). Triptolide can significantly relieve joint pain in a short period of time. Compared with traditional hormonal drugs and non-steroidal anti-inflammatory drugs, it can relieve swelling and pain and improve jo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J73/00A61K31/585A61P29/00A61P35/00A61P37/06
CPCA61P29/00A61P35/00A61P37/06C07J73/003
Inventor 郭可点
Owner 郭可点
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