Gemcitabine-aromatic chlormethine conjugate targeting at high-level ROS (reactive oxygen species) of cancer cells and preparation method and pharmaceutical application thereof

A cancer cell, high-level technology, applied in the field of biomedicine, can solve the problems of high toxicity, lack of selectivity, and low bioavailability in normal tissues, improve lipid solubility and transmembrane ability, reduce drug resistance, and improve biological The effect of utilization

Active Publication Date: 2018-06-12
TAICANG LIBIAO INTELLIGENT TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Clinical studies have shown that the aromatic nitrogen mustard drug bendamustine or chlorambucil combined with gemcitabine can significantly promote the tolerance of drug treatment, synergistically inhibit the growth of malignant tumors, prolong the survival of cancer patients, and can Improve the sensitivity of tumor cells to chemotherapy drugs for the treatment of relapsed / refractory multiple myeloma and lymphoma (Santoro A, Mazza R, Pulsoni A, et al.J Clin Oncol.2016,4(27):3293 -9; Quaglino P, Maule M, Prince HM, et al.Ann Oncol.2017,28(10):2517-2525), but the combination of these drugs lacks selectivity and is highly toxic to normal tissues. The bioavailability of the drug itself is not high, and these problems still need to be further improved
There are no reports of such compounds

Method used

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  • Gemcitabine-aromatic chlormethine conjugate targeting at high-level ROS (reactive oxygen species) of cancer cells and preparation method and pharmaceutical application thereof
  • Gemcitabine-aromatic chlormethine conjugate targeting at high-level ROS (reactive oxygen species) of cancer cells and preparation method and pharmaceutical application thereof
  • Gemcitabine-aromatic chlormethine conjugate targeting at high-level ROS (reactive oxygen species) of cancer cells and preparation method and pharmaceutical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Example 1 4-(4-(bis(2-chloroethyl)amino)phenyl)-N-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxyl-5- (Hydroxymethyl)tetrahydrofuran-2-yl)-2-one-1,2-dihydropyrimidin-4-yl)-butanamide (I 1 ) preparation

[0051] 4-amino-1-((2R,4R,5R)-3,3-difluoro-4-(tert-butyldimethylsilyloxy)-5-(tert-butyldimethylsilyloxymethyl ) Tetrahydrofuran-2-yl)-1H-pyrimidin-2-one (compound 4) preparation

[0052] Gemcitabine (compound 3, 1.0g, 3.80mmol) was dissolved in 10mL dry DMF, TBDMS-Cl (1.15g, 7.64mmol) and 1.03g imidazole were added, stirred at room temperature, after the reaction was detected by thin layer chromatography, added 100ml of water, and an equal amount of ethyl acetate to extract three times, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (mobile phase methanol:dichloromethane=1:25-1:15) to obtain 1.64g, yield 88%.

[0053]

[0054] 4-(4-(bis(2-ch...

Embodiment 2

[0058] Example 2 ((2R,3R,5R)-5-(4-(4-(4-(bis(2-chloroethyl)amino)phenyl)butanylamino-2-oxopyrimidine-1(2H )-yl-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzyl carbonate (I 2 ), (2R,3R,5R)-5-(4-(4-(4-(bis(2-chloroethyl)amino)phenyl)butanylamino-2-oxopyrimidine-1(2H)- Base)-4,4-difluoro-2-(hydroxymethyl)tetrahydrofuran-3-yl)methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Pentyl-2-yl)benzyl carbonate (I 3 ) and ((2R,3R,5R)-5-(4-(4-(4-(bis(2-chloroethyl)amino)phenyl)butanylamino-2-oxopyrimidine-1(2H) -yl)-4,4-difluoro-3-((((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl )oxy)carboxy)oxy)tetrahydrofuran-2-yl)methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl base) carbonate (I 4 ) preparation

[0059] Preparation of (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (compound 2)

[0060] Dissolve p-bromobenzyl alcohol (compound 1, 1.0 g, 5.35 mmol) in 10 mL of dry 1,4-dioxane solution, ad...

Embodiment 3

[0067] Example 3 4-(5-(bis(2-chloroethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)-N-(1-((2R,4R, 5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-one-1,2-dihydropyrimidin-4-yl)-butyramide (I 5 ) preparation

[0068] 4-(5-(bis(2-chloroethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)-N-(1-((2R,4R,5R)- 4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3,3-difluorotetrahydrofuran-2-yl) Preparation of -2-keto-1,2-dihydropyrimidin-4-yl)-butyramide (compound 6b)

[0069] Bendamustine hydrochloride (compound 5b) (454 mg, 1.10 mmol), EDCI (384, 2.00 mmol), DMAP (227 mg, 50%) and compound 4 (492 mg, 1.00 mmol) were dissolved in 10 ml of anhydrous CH 2 Cl 2 , heated at 40°C for 12 hours. After the reaction, the solvent was distilled off under reduced pressure, and the crude product was purified by column chromatography (mobile phase ethyl acetate:petroleum ether=2:1-4:1) to obtain 656mg of a light yellow solid with a yield of 79%. %.

[007...

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Abstract

The invention discloses gemcitabine-aromatic chlormethine conjugate targeting at high-level ROS (reactive oxygen species) of cancer cells and its pharmaceutically acceptable salts, having a structureshown in the general formula I that is shown in the description. The compounds herein can selectively release gemcitabine-aromatic chlormethine conjugate in high-concentration ROS tumor cells, can selectively inhibit the proliferation of tumor cells, can slowly release gemcitabine and aromatic chlormethine further through various esterases or amidases so as to promote the generation of ROS in tumor cells and provide coordinative tumor resistance. The compounds herein can significantly enhance lipid solubility of gemcitabine, can enter cells with no dependence on nucleoside transporter proteins, allows N4-site amino groups of gemcitabine to be less degraded by deaminases, and can improve in-vivo bioavailability of gemcitabine and reduce tolerance of tumor cells to gemcitabine drugs.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to a gemcitabine-nitrogen mustard conjugate targeting high levels of ROS in cancer cells and pharmaceutically acceptable salts thereof, their preparation methods, pharmaceutical compositions containing these derivatives and Their medical use, especially in the preparation of antitumor drugs. Background technique [0002] Gemcitabine (dFdC) is a new antimetabolite anticancer drug approved by the US FDA in 1996. dFdC is a cell cycle-specific antitumor drug. After a series of phosphorylation in cells, dFdC acts as a competitive deoxycytidine triphosphate substrate, which causes DNA double-strand misrecognition by competing for insertion into the DNA double strand, thereby Exert its unique cytotoxic effect, inhibit tumor cell growth and promote cell apoptosis (Jordheim LP, Durantel D, Zoulim F, et al. at Rev Drug Discov, 2013, 12:447-464). Although dFdC has been used clinically, its polarit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H1/00C07H19/073A61K47/55A61K31/7068A61K31/196A61K31/4184A61P35/00
CPCA61K31/196A61K31/4184A61K31/7068C07H1/00C07H19/073A61K2300/00
Inventor 凌勇彭炎福熊彪黄金华汪莹莹陈实钱建强明古旭范艳华张婷
Owner TAICANG LIBIAO INTELLIGENT TECH CO LTD
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