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PKI-587-based anticancer intermediate and polyethylene glycol-coupled anticancer drug, preparation method and application thereof

A technology of PKI-587 and polyethylene glycol, which is applied in the field of cancer treatment, can solve the problems of limited clinical curative effect, achieve significant clinical value, broad market prospects, and reduce toxicity

Active Publication Date: 2019-06-07
CHONGQING UPGRA BIOLOGICAL SCI & TECH LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, clinical efficacy has been greatly limited due to the emergence of resistance to inhibitors of this pathway

Method used

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  • PKI-587-based anticancer intermediate and polyethylene glycol-coupled anticancer drug, preparation method and application thereof
  • PKI-587-based anticancer intermediate and polyethylene glycol-coupled anticancer drug, preparation method and application thereof
  • PKI-587-based anticancer intermediate and polyethylene glycol-coupled anticancer drug, preparation method and application thereof

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Experimental program
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Effect test

preparation example Construction

[0081] The above-mentioned preparation method of the anticancer intermediate shown in formula I, it comprises:

[0082] Step S1: Amidation reaction of PKI-587 with amino acid or peptide and its derivatives to obtain the first intermediate having the N-AC structural unit in the formula I; At least one of the anticancer drugs undergoes an amidation reaction with amino acids or peptides and derivatives thereof to obtain another first intermediate having the N-AC structural unit in the formula I.

[0083] Preferably, the synthesis method of the first intermediate comprises: after amidation linking the amino acid or polypeptide with an amino protecting group and its derivatives with an anticancer drug in the presence of a polypeptide condensation reagent, deprotecting the amino group .

[0084] Wherein, the polypeptide condensation reagent includes HBTU, HOBT, HBTU. The alkaloid DIEA (N,N-diisopropylethylamine) is also added in the reaction, and the reaction temperature is -10-10...

Embodiment 1

[0118] Synthetic drug intermediate shown in formula I-a:

[0119]

Embodiment 1-1

[0121] preparation:

[0122] Glycine (11.1194g, 148.12mmol) was added to a 1L round bottom flask, 1,4-dioxane (150ml) was added to dissolve it, magnetons were added, 2N NaOH (88.88ml, 177.78mmol) was added, and Boc Anhydride (48.5 g, 222.22 mmol). After the reaction was completed, the reaction liquid was transferred to a rotary evaporator for concentration, and the concentrated liquid was transferred to a 1L separatory funnel, and 100 ml of diethyl ether was added for washing, and the reaction was repeated twice. Separate the aqueous phase and the organic phase, and add 1 mol / L hydrochloric acid to the aqueous phase to adjust the pH to pH=4. Extract the aqueous phase (150ml×5) with ethyl acetate, combine the organic phases, add anhydrous sodium sulfate to the organic phases to dry, filter with suction, remove water with toluene, and evaporate to dryness to obtain Compound A with a yield of 100%.

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Abstract

The invention provides an anticancer intermediate based on PKI-587 and a polyethylene glycol coupled anticancer drug, and preparation methods and application thereof, belonging to the field of treatment of cancers. The anticancer intermediate has a general structural formula as described in the specification, and at least one AC in the general structural formula is the anticancer drug PKI-587. Thepolyethylene glycol coupled anticancer drug has a general structural formula as described in the specification. The above two drugs can realize combined medication of the targeting anticancer drug PKI-587 and a plurality of other anticancer drugs, so toxic response caused by mutual influence and pharmacokinetics of a plurality of other anticancer drugs can be prevented during individual administration of the anticancer drugs, multidrug resistance of cancers is overcome, and synergistic effect is exerted; and the two drugs can be used for preparing anticancer drugs with targeting effect and have critical clinical value and wide market prospects.

Description

technical field [0001] The present invention relates to the field of cancer treatment, in particular to a PKI-587-based anticancer intermediate and polyethylene glycol-coupled anticancer drug, as well as its preparation method and application. Background technique [0002] Cancer, a very complex and deadly disease, is a huge health crisis currently being experienced by both developed and developing countries. In 2012, there were more than 14 million new cancer cases worldwide, and by 2020, there will be more than 15 million new cancer patients worldwide, which will have serious consequences for the society, economy and medical treatment of any country. influences. [0003] Clinical outcomes of cancer treatment are generally disappointing, due in large part to the heterogeneity and complexity of this devastating disease. Traditional surgery and radiotherapy are only used for the treatment of localized disease, while hormone therapy, chemotherapy, immunotherapy and targeted ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/60A61K47/64A61K45/06A61K31/5377A61P35/00
CPCA61K31/5377A61K45/06A61K2300/00
Inventor 李高全陈毛芬汪斌李大军张倩税举媛彭良艳黄蕾何婷婷张翠芳吴晓丹李建环
Owner CHONGQING UPGRA BIOLOGICAL SCI & TECH LTD
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