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Polyethylene glycol-amino acid oligopeptide-dasatinib conjugate and pharmaceutical composition thereof

A technology of polyethylene glycol and polyethylene glycol, applied in the direction of drug combination, antineoplastic drugs, pharmaceutical formulations, etc., to achieve the effect of increasing the load rate and improving the clinical effect

Active Publication Date: 2014-08-06
JENKEM TECH CO LTD TIANJIN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Currently, polyethylene glycol-modified small-molecule drugs have not been approved for marketing in the international market, but several products have entered phase II and III clinical trials, such as Nektar's NKTR-102 and NKTR-118
[0010] Although dasatinib has a good drug effect, it still needs to be modified accordingly in order to improve the therapeutic effect of related diseases and reduce toxic and side effects.

Method used

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  • Polyethylene glycol-amino acid oligopeptide-dasatinib conjugate and pharmaceutical composition thereof
  • Polyethylene glycol-amino acid oligopeptide-dasatinib conjugate and pharmaceutical composition thereof
  • Polyethylene glycol-amino acid oligopeptide-dasatinib conjugate and pharmaceutical composition thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Preparation of monomethoxypolyethylene glycol (number average molecular weight 20000)-amino acid pentapeptide-dasatinib conjugate (DSR-1)

[0055]

[0056] 29.4g (0.2mol) of L-(+)-glutamic acid, 40g (0.23mol) of p-toluenesulfonic acid, and 80mL of benzyl alcohol were dissolved in 500mL of toluene, and 11mL of water was separated by reflux under nitrogen protection. 150mL. Cool to 50°C, pour the reaction solution into a beaker filled with 600mL petroleum ether, stir for 1h, and collect the precipitate by filtration. After the filter cake was heated and dissolved with 280 mL of 95% ethanol, the heating was stopped and cooled overnight. The precipitate was collected by filtration and dried in vacuo to obtain 61 g of L-(+)-dibenzyl glutamate p-toluenesulfonate.

[0057] Dissolve 30g (0.06mol) of dibenzyl glutamate p-toluenesulfonate in 500mL of dichloromethane, add 20.86g (0.062mol) of tert-butoxycarbonyl-L-glutamic acid-5-benzyl ester, DMAP7.55g (0.062mol), HOBt8.35g...

Embodiment 2

[0063] Preparation of Y-type polyethylene glycol (number average molecular weight 30000)-amino acid pentapeptide-dasatinib conjugate (DSR-2)

[0064]

[0065] N-tert-butoxycarbonyl glutamate benzyl ester dipeptide (Boc-Glu(obzl)-Glu(obzl)-obzl) 0.78g (Example 1) was dissolved in 7mL of dichloromethane, added 3mL of trifluoroacetic acid, room temperature Reaction 2h. Remove the solvent, add 100mL of dichloromethane, adjust pH=7-8 with 5% sodium bicarbonate solution. Extraction and liquid separation, the organic phase was washed twice with 5% sodium bicarbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was directly added to the reaction flask, and under nitrogen protection, 40.0 g of Y-polyethylene glycol acetic acid (30K), 245 mg (2 mmol) of DMAP, and 135 mg (1 mmol) of HOBt were added, and after all were dissolved, 412 mg (2 mmol) of DCC was added. The reaction was stirred overnight at room temperature. Filter, remove the solvent b...

Embodiment 3

[0067] Preparation of monomethoxy polyethylene glycol (number average molecular weight 40000)-amino acid heptapeptide-dasatinib conjugate (DSR-3)

[0068]

[0069] 6.47 g (0.01 mol) of benzyl N-tert-butoxycarbonyl glutamate dipeptide (Example 1) was dissolved in 15 mL of dichloromethane, 6 mL of trifluoroacetic acid was added, and reacted at room temperature for 2 h. Remove the solvent, add 100mL of dichloromethane, adjust pH=7-8 with 5% sodium bicarbonate solution. Extraction and liquid separation, the organic phase was washed twice with 5% sodium bicarbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was directly added to the reaction flask, under the protection of nitrogen, 3.37g (0.01mol) of tert-butoxycarbonyl-L-glutamic acid-5-benzyl ester, 1.22g (0.01mol) of DMAP and 1.35g (0.01mol) of HOBt were added. mol), DCC2.39g (0.011mol) dichloromethane solution was added dropwise after complete dissolution. After dropping, the closed sys...

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Abstract

The invention discloses a polyethylene glycol-amino acid oligopeptide-dasatinib conjugate represented by a general formula I and a pharmaceutical composition containing the conjugate. In the conjugate, PEG represents polyethylene glycols residues, A1 and A2 represent same or different amino acid residues, m is an integer from 2 to 12, and D is a dasatinib residue connected with A2. In the conjugate, each polyethylene glycol terminal group is connected with multiple dasatinib residues via amino acid oligopeptides, so that the medicine loading rate is substantially increased, the medicine hydrophilia is increased, medicine absorption is improved, the action time is prolonged, and therefore the treatment effect is increased or the toxic and side effects are reduced.

Description

technical field [0001] The invention relates to polyethylene glycol conjugates, especially the conjugates of polyethylene glycol, amino acid oligopeptide and drug dasatinib and their pharmaceutical composition. Background technique [0002] Chronic myelogenous leukemia (CML) is a malignant tumor that affects the blood and bone marrow. It can occur at any age, but most of them are middle-aged or elderly people, and there are slightly more men than women. In Western populations, CML patients account for 15%-20% of all adult leukemias. CML is generally divided into three categories based on clinically meaningful traits and studies. In the absence of an intervening factor, it usually begins with a "chronic phase," followed by an "accelerated phase" over several years, and finally a "blast phase." The blast phase is the final stage of chronic myelogenous leukemia, and its pathological condition is close to that of acute leukemia. If the drug is treated early, it usually stops ...

Claims

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Application Information

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IPC IPC(8): C08G65/00A61K47/48A61K31/506A61P35/02A61P35/00
Inventor 汪进良赵宣王振国
Owner JENKEM TECH CO LTD TIANJIN
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