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Polyethyleneglycol modified scutellarin compound and preparation thereof

A technology of scutellarin and polyethylene glycol, which is applied in the field of PEG-modified prodrugs and its preparation, can solve the problems of research, low solubility, no pharmacokinetics and pharmacodynamics, etc., to improve water solubility, The effect of enhancing biological activity

Inactive Publication Date: 2009-07-22
JIANGSU SIMCERE PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Although scutellarin has great application value and economic benefits, there are obvious disadvantages in its wide application: the solubility of scutellarin in water is low (0.056mg / ml), and the half-life is short (3-4 minutes). Poor oral bioavailability (0.4%), meanwhile, the activity needs to be further improved
Although the authors determined the solubility of the modified product (800 mg / mL), the authors did not conduct further pharmacokinetic and pharmacodynamic studies

Method used

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  • Polyethyleneglycol modified scutellarin compound and preparation thereof
  • Polyethyleneglycol modified scutellarin compound and preparation thereof
  • Polyethyleneglycol modified scutellarin compound and preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0110] Example 1: Synthesis of scutellarin-polyethylene glycol (400) monomethyl ether-6 "-ester (compound I-400)

[0111]

[0112] Add 9.24g of scutellarin, 12g of mPEG(400), 4.05g of HOBt, and 6.18g of DCC (molar ratio 1:1.5:1.5:1.5) into 80mL of DMF to dissolve, protect the reaction system with nitrogen gas, and heat to 40°C Reacted for 6 hours, and TLC detected the reaction end point (CH 2 Cl 2 :CH 3 OH:HCOOH=10:1:0.2), after the reaction is completed, add water to terminate the reaction, filter out part of the solid, concentrate the filtrate under reduced pressure to remove DMF and water, and the thick product of the viscous material is subjected to CH 2 Cl 2 :CH 3 The eluent of OH:HCOOH=10:1:0.1 was separated and purified through a silica gel column for three times to obtain 7.65 g of a light yellow powdery solid with a yield of 45.3%.

[0113] 1H NMR (DMSO-d6, 300MHz): δH 6.81 (1H, S, C 3 -H), 7.00 (1H, S, C 8 -H), 7.93 (2H, d, J=8.9Hz, C 2’，6’ -H), 6.96 (2H, ...

Embodiment 2

[0115] Example 2: Synthesis of scutellarin-polyethylene glycol (600) monomethyl ether-6 "-ester (compound I-600)

[0116] Add 13.86g of scutellarin, 27g of mPEG(600), 6.07g of HOBt, and 9.27g of DCC (molar ratio 1:1.5:1.5:1.5) into 120mL of DMF to dissolve, protect the reaction system with nitrogen gas, and heat to 45°C Reacted for 8 hours, and TLC detected the reaction end point (CH 2 Cl 2 :CH 3 OH:HCOOH=10:1:0.2), after the reaction is completed, add water to terminate the reaction, filter out part of the solid, concentrate the filtrate under reduced pressure to remove DMF and water, and pass the viscous material crude product through CH 2 Cl 2 :CH 3 The eluent of OH:HCOOH=10:1:0.1 was separated and purified through a silica gel column for three times to obtain 12.62 g of a light yellow powdery solid with a yield of 40.3%.

[0117] 1 H NMR (DMSO-d6, 300MHz): δH 6.81 (1H, S, C3-H), 7.00 (1H, S, C 8 -H), 7.93 (2H, d, J=8.9Hz, C 2’，6’ -H), 6.96 (2H, d, J=8.9Hz, C 3’，5’...

Embodiment 3

[0119] Example 3: Synthesis of scutellarin-polyethylene glycol (1000) monomethyl ether-6 "-ester (compound I-1000)

[0120] Add 9.24g of scutellarin, 30g of mPEG(1000), 4.05g of HOBt, and 6.18g of DCC (molar ratio 1:1.5:1.5:1.5) into 150mL of DMF to dissolve, protect the reaction system with nitrogen gas, and heat to 50°C Reacted for 10 hours, and TLC detected the reaction end point (CH 2 Cl 2 :CH 3 OH:HCOOH=10:1:0.2), after the reaction is completed, add water to terminate the reaction, filter out part of the solid, concentrate the filtrate under reduced pressure to remove DMF and water, and pass the viscous crude product through CH 2 Cl 2 :CH 3 The eluent of OH:HCOOH=10:1:0.1 was separated and purified through a silica gel column for three times to obtain 10.54 g of a light yellow powdery solid with a yield of 36.5%.

[0121] 1 H NMR (DMSO-d6, 300MHz): δH 6.82 (1H, S, C3-H), 7.03 (1H, S, C8-H), 7.94 (2H, d, J=8.9Hz, C2', 6'- H), 6.95 (2H, d, J=8.9Hz, C3', 5'-H), 5.27 ...

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Abstract

The invention discloses a PEGylated scutellarin compound and a preparation method thereof. The PEGylated scutellarin compound is as the shown formula (IV) and the PEGylated scutellarin compound can be applied to preparing medicaments applied to treating cerebral thrombosis, cerebral infarction, cerebral apoplexy, sequelaes caused by cerebral apoplexy, coronary heart disease or angina. Compared with the original scutellarin compound, the water solubility of the scutellarin compound is increased obviously; simultaneously, pharmacodynamics experiment on the mice model of cerebral ischemia-reperfusion shows that: compared with the original medicament, the biological activity of the scutellarin promedicament is strengthened obviously.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a PEG-modified prodrug, a preparation method and application thereof. Background technique [0002] Scutellarin, that is, 4', 5, 6-trihydroxyflavone-7-glucuronide, has the functions of scavenging active oxygen, dilating blood vessels, increasing cardiac coronary flow, increasing cerebral blood flow, and reducing cerebrovascular It can be used for cardiovascular and cerebrovascular diseases, such as cerebral infarction, post-stroke hemiplegia, coronary heart disease, angina pectoris, etc., with good curative effect. And it has been used clinically for more than 20 years, and no serious side effects have been found. Its existing preparations include common tablets, injections and injection powders. [0003] Although scutellarin has great application value and economic benefits, there are obvious disadvantages in its wide application: the solubility of scutellarin in...

Claims

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Application Information

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IPC IPC(8): C07H17/07C08G65/34A61K31/7048A61K31/765C07H1/00A61P9/10A61P9/00
Inventor 成昌梅王义明赵兴俄路娟胡跃飞华垚王森檀爱民
Owner JIANGSU SIMCERE PHARMA
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