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Multivalent polyglycol (PEG) modifier for camptothecin and derivatives thereof and application of multivalent PEG modifier

A technology of modifiers and camptothecin, applied in the field of related drugs, can solve the problems of high proportion of invalid molecules and small effective drug loading

Active Publication Date: 2013-03-27
CHENGDU YIPING MEDICAL SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, at present, in the selection of the structure of PEG modification, monofunctional or bifunctional linear molecules are mostly used. In fact, this kind of traditional modifier is suitable for the modification of protein and polypeptide drugs, but when it is used for the modification of small molecule drugs, it has obvious shortcomings. The effective drug loading is small and the proportion of ineffective molecules is high

Method used

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  • Multivalent polyglycol (PEG) modifier for camptothecin and derivatives thereof and application of multivalent PEG modifier
  • Multivalent polyglycol (PEG) modifier for camptothecin and derivatives thereof and application of multivalent PEG modifier
  • Multivalent polyglycol (PEG) modifier for camptothecin and derivatives thereof and application of multivalent PEG modifier

Examples

Experimental program
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Effect test

Embodiment 1

[0049] Compound 1: [(Irinotecan-O-CO-CH 2 CH 2 -CO-) 2 -Lys-] 2 -PEG 20k Synthesis

[0050]

[0051] (1) Synthesis of irinotecan-20-succinic acid monoester (AA1)

[0052]

[0053] Irinotecan (5.86g, 10mmol), succinic anhydride (3g, 30mmol) and N,N-dimethyl-4-aminopyridine (DMAP, 300mg, 2.46mmol) were placed in a 100ml two-necked bottle under nitrogen protection , add 50ml of anhydrous pyridine. The reaction was stirred at room temperature for 12 hours, and the reaction progress was monitored by thin-layer chromatography until the reaction was complete. Concentrate under reduced pressure, pour the residue into ice water, place it, and filter to obtain a light yellow solid (5.28 g), with a yield of 77%.

[0054] ESI-MS m / z: 687.38 (M+H) +

[0055] 1 H-NMR (DMSO): δ 0.92 (t, 3H, CH 2 -CH 3 ), 2.13 (m, 7H), 2.49 (m, 2H), 2.7-2.8 (m, 13H), 5.27 (s, 2H), 5.47 (s, 2H), 7.05 (s, 1H), 7.50 (m, 2H), 8.07 (d, 1H), 8.55 (s, 1H), 12.26 (s, broad, 1H).

[0056] (2) Synth...

Embodiment 2

[0064] Compound 2: [(Camptothecin -O-CO-CH 2 CH 2 -CO-) 2 -Lys-] 2 -PEG 20k Synthesis

[0065]

[0066] (1) Synthesis of camptothecin-20-succinic acid monoester (BB1)

[0067]

[0068] Camptothecin (3.46g, 10mmol), succinic anhydride (3g, 30mmol) and N,N-dimethyl-4-aminopyridine (DMAP, 300mg, 2.46mmol) were placed in a 100ml two-necked bottle under nitrogen protection , add 50ml of anhydrous pyridine. The reaction was stirred at room temperature for 12 hours, and the reaction progress was monitored by thin-layer chromatography until the reaction was complete. Concentrate under reduced pressure, pour the residue into ice water, let it stand, and filter to obtain a light yellow solid (3.53 g), with a yield of 78.9%.

[0069] ESI-MS m / z: 449.79 (M+H) +

[0070] 1 H-NMR(DMSO): 2.13(m, 7H), 2.50(m, 2H), 2.7-2.8(m, 2H), 5.27(s, 2H), 5.50(s, 2H), 7.10(s, 1H) , 7.62 (m, 2H), 8.07 (d, 1H), 8.55 (s, 1H), 12.37 (s, broad, 1H).

[0071] (2) [(Camptothecin-O-CO-CH 2 CH ...

Embodiment 3

[0074] Embodiment 3: Determination of compound 2 blood drug concentration-time curve

[0075] 3 nude mice (20-25g) with a dose of 200mg / kg (equivalent to about 12.4mg / kg of camptothecin), injected compound 2 through the tail vein, and at different time points, the reversed-phase-high performance liquid chromatography Determination of the concentration of camptothecin in their plasma. The results showed that, 72 hours after administration, the total concentration of camptothecin in blood plasma could be maintained above 100ng / ml ( figure 1 ), indicating that multivalent polyethylene glycol-modified camptothecin can obtain long-acting effects.

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Abstract

The invention relates to a multivalent polyglycol (PEG) modifier in a general formula (1) for camptothecin and derivatives thereof and application of the multivalent PEG modifier. In the general formula, POLY refers to PEG residue with the molecular weight of 200-100,000Da; X refers to amino or oxygen; Y refers to a biamino-containing amino acid structure compound, carboxyl of the compound and X form an amido bond or an ester band, and a multi-amino functional group is led towards a far end; n and m refer to the polymerization degree of Y, and are any integer from 1 to 12, and r and t refer to the number of methylene of a connection arm, and are nay integer from 1 to 12; and D refers to residue after camptothecin compounds are esterified.

Description

field of invention [0001] The invention relates to a multivalent PEG coupling of camptothecin and its derivatives, and its use in preparing anti-tumor and other related drugs. Background technique [0002] Camptothecin (CPT), a natural product isolated from Camptotheca acuminata, is the only one that selectively inhibits DNA topoisomerase I (Topo I) Plant anticancer drugs. Since Wall et al. reported this compound in 1966, it was introduced into the clinic due to its excellent anticancer activity in the early 1970s, but its clinical application was greatly limited due to the characteristics of the drug itself. First of all, camptothecin has poor water solubility and fat solubility. It was made into water-soluble sodium salt in the 1970s, but it was terminated due to low clinical efficacy and high toxicity; secondly, the content of camptothecin and its derivatives The ester ring is very unstable, and it is easy to open the ring and decompose into the form of carboxylic acid ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C08G65/48A61K47/48A61K31/4745A61K31/695A61K31/496A61P35/00
Inventor 梁远军余晓军刘克良贾启燕冯思良李晋峰杨强张祖兵
Owner CHENGDU YIPING MEDICAL SCI & TECH