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Multi-arm PEGylated dasatinib derivative and preparation thereof

A technology for dasatinib and derivatives, which is applied to multi-arm PEGylated dasatinib derivatives and their preparation and preparation, as well as the application field in the preparation of anti-tumor drugs, can solve the problem of inability to release and accumulate active ingredients in large quantities , increase the risk of pulmonary arterial hypertension, large proportion of ineffective molecules, etc., to avoid toxic side effects, increase the existence time, and enhance the water solubility.

Inactive Publication Date: 2018-12-07
湖南华腾制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Clinical trials have shown that the efficacy of dasatinib exceeds the efficacy of high-dose imatinib, and no drug resistance has been found, but there are still fever, pleural effusion, and febrile neutropenia during use , gastrointestinal bleeding, pneumonia, thrombocytopenia, dyspnea, anemia, diarrhea and heart failure and other adverse reactions
In addition, FDA also announced in October 2011 that dasatinib may increase the risk of pulmonary hypertension
[0005] Prior art CN103965458A and WO2010120387 disclose modification of tyrosine kinase inhibitors and antineoplastic drugs such as tyrosine kinases with polyethylene glycol. The disadvantages are that the drug load is relatively small and the proportion of ineffective molecules is large, which may cause Problems with metabolism, clearance, etc.
[0006] Prior art CN104225611A discloses that multi-arm PEG connects dasatinib through ester bond and amide bond, and its disadvantage is that the active ingredient cannot be released and accumulated in a large amount at the lesion, and the drug effect is not obvious

Method used

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  • Multi-arm PEGylated dasatinib derivative and preparation thereof
  • Multi-arm PEGylated dasatinib derivative and preparation thereof
  • Multi-arm PEGylated dasatinib derivative and preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] (1) Preparation of Intermediate II

[0030] Dissolve 10 mmol of dasatinib in 100 ml of DMF, add 11 mmol of formic acid and 10 mmol of DMAP at room temperature, and then stir at 100° C. for 10 h. After the reaction was completed, the solution was distilled off under reduced pressure to obtain a crude product. The crude product was purified by chromatography to obtain 9 mmol of intermediate II. Yield: 90.4%. The NMR data are as follows: 1 HNMR(400MHz,DMSO-d6)δppm 2.22(s,3H),2.38(s,3H),2.42-2.48(m,4H),2.58(t,J=5.7Hz,2H),2.7(m,4h) ,3.07(m,2H),3.21to3.38(m,4H),3.44-3.57(m,4H),4.15(t,J=5.7Hz, 2H),6.04(s,1H),7.19-7.31( m,2H),7.38(d,J=5.9Hz,1H),8.22(s,1H), 9.87(s,1H),11.48(s,1H),12.25(bs,1H).

[0031] (2) Preparation of 4arm-PEG24-dasatinib (IV)

[0032] Dissolve 10mmol of intermediate II in 50ml of N,N-dimethylformamide, add 10mmol of EDCI and 10mmol of NHS, and stir at 25°C for 2h. 2 mmol of 4arm-PEG24-NH2 was added to the reaction, and the reaction was carried out at ...

Embodiment 2

[0034] (1) Preparation of Intermediate II

[0035] Dissolve 10 mmol of dasatinib in 100 ml of DMF, add 11 mmol of formic acid and 10 mmol of DMAP at room temperature, and then stir at 100° C. for 8 h. After the reaction was completed, the solution was distilled off under reduced pressure to obtain a crude product. The crude product was purified by chromatography to obtain 9 mmol of intermediate II. Yield: 90%. The NMR data are as follows: 1 HNMR(400MHz,DMSO-d6)δppm 2.22(s,3H),2.38(s,3H),2.42-2.48(m,4H),2.58(t,J=5.7Hz,2H),2.7(m,4h) ,3.07(m, 2H),3.21to3.38(m,4H),3.44-3.57(m,4H),4.15(t,J=5.7Hz,2H),6.04(s, 1H),7.19-7.31( m,2H),7.38(d,J=5.9Hz,1H),8.22(s,1H),9.87(s,1H), 11.48(s,1H),12.25(bs,1H).

[0036] (2) Preparation of 4arm-PEG124-dasatinib (IV)

[0037]Dissolve 10mmol of intermediate II in 50ml of N,N-dimethylformamide, add 10mmol of EDCI and 10mmol of NHS, and stir at 25°C for 2h. 2 mmol of 4arm-PEG124-NH2 was added to the reaction, and the reaction was carried out at 3...

Embodiment 3

[0039] (1) Preparation of Intermediate II

[0040] Dissolve 10 mmol of dasatinib in 100 ml of DMF, add 11 mmol of formic acid and 10 mmol of DMAP at room temperature, and then stir at 120° C. for 10 h. After the reaction was completed, the solution was distilled off under reduced pressure to obtain a crude product. The crude product was purified by chromatography to obtain 9 mmol of intermediate II. Yield: 90%. The NMR data are as follows: 1 HNMR(400MHz,DMSO-d6)δppm 2.22(s,3H),2.38(s,3H),2.42-2.48(m,4H),2.58(t,J=5.7Hz,2H),2.7(m,4h) ,3.07(m, 2H),3.21to3.38(m,4H),3.44-3.57(m,4H),4.15(t,J=5.7Hz,2H),6.04(s, 1H),7.19-7.31( m,2H),7.38(d,J=5.9Hz,1H),8.22(s,1H),9.87(s,1H), 11.48(s,1H),12.25(bs,1H).

[0041] (2) Preparation of 4arm-PEG240-dasatinib (IV)

[0042] Dissolve 10mmol of intermediate II in 50ml of N,N-dimethylformamide, add 10mmol of EDCI and 10mmol of NHS, and stir at 25°C for 2h. 2 mmol of 4arm-PEG240-NH2 was added to the reaction, and the reaction was carried out at...

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Abstract

Based on the characters that multi-arm PEG is toxic-free and is easy to be combined, tetra-arm PEG, hexa-arm PEG and octa-arm PEG are respectively connected with dasatinib. The multi-arm PEG-supporteddasatinib predrug has excellent water solubility; and what is more, one multi-arm PEG chain can be connected with a plurality of dasatinib residues, so that supporting rate of the medicine is greatlyincreased. In addition, the half-life period of the medicine is greatly prolonged, so that the medicine is significantly increased in existing time in blood plasma, thereby improving treatment effect.

Description

technical field [0001] The present invention relates to the field of pharmaceutical synthesis, in particular to a multi-armed PEGylated dasatinib derivative, its preparation, its preparation method and its application in the preparation of antitumor drugs. Background technique [0002] Clinical trials have shown that the efficacy of dasatinib exceeds the efficacy of high-dose imatinib, and no drug resistance has been found, but there are still fever, pleural effusion, and febrile neutropenia during use , Gastrointestinal bleeding, pneumonia, Dasatinib, the trade name is "Prisel", which can block a variety of oncogenic proteins, and was approved by the FDA in 2007 for CML that has failed or is not resistant to previous treatment It is also used to treat adult patients with Philadelphia chromosome-positive ALL who are resistant or intolerant to other therapies. The structural formula of Dasatinib is as follows: [0003] [0004] Clinical trials have shown that the efficac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/60A61K31/506A61P35/00C08G65/333
CPCA61K47/60A61K31/506A61P35/00C08G65/33396
Inventor 张安林成佳邓泽平
Owner 湖南华腾制药有限公司
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