Multifunctional immunity-targeted micromolecule anti-cancer medicine (Bestazomib citrate) and preparation method and application thereof

A pharmacy and drug technology, applied in anti-tumor drugs, chemical instruments and methods, drug combinations, etc., can solve problems such as increasing treatment costs, and achieve the effect of reducing treatment costs and avoiding dangers

Active Publication Date: 2018-12-21
WEIFANG BOCHUANG INT ACAD OF BIOTECH & MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in the process of drug combination, tumor patients need to receive multiple and large amounts of drug treatment, which makes them more likely to face the danger caused by drug interaction, and also increases the cost of treatment

Method used

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  • Multifunctional immunity-targeted micromolecule anti-cancer medicine (Bestazomib citrate) and preparation method and application thereof
  • Multifunctional immunity-targeted micromolecule anti-cancer medicine (Bestazomib citrate) and preparation method and application thereof
  • Multifunctional immunity-targeted micromolecule anti-cancer medicine (Bestazomib citrate) and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Example 1: (2S,3R)-3-((Benzyloxycarbyl)amino)-2-hydroxy-4-phenylbutyric acid (2)

[0068] AHPA (1, 1.95g, 10.0mmol) was dissolved in a mixed solution of 100mL tetrahydrofuran and 1mol / L sodium hydroxide, and benzyloxycarbonyl chloride (1.88g, 11.0mmol) was added dropwise under ice-cooling conditions. After reacting at room temperature for 6 hours, the tetrahydrofuran in the reaction solution was distilled off, the aqueous phase was adjusted to pH=1 with 1 mol / L hydrochloric acid, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous magnesium sulfate, and evaporated to dryness to obtain a white solid 2( 2.11 g, 64%).

Embodiment 2

[0069] Example 2: (R)-1-((2S,3R)-3-((Benzyloxycarbonyl)amino)-2-hydroxyl-4-phenylbutyrylamino)-3-methylbutylboronic acid pinanedi Alcohol Esters (3)

[0070] Compound 2 (3.29g, 10.0mmol) was dissolved in 50mL of anhydrous DCM, HOBt (1.49g, 11mmol) and EDCI (2.10g, 11.0mmol) were added under ice-bath conditions, after 0.5h, (R)-1- Amino-3-methylbutyl borate pinanediol trifluoroacetate (4.07g, 11.0mmol), triethylamine 1.5mL. Remove the ice bath and react at room temperature for 5h. After the reaction was completed, the organic layer was washed with water, 1M citric acid, saturated sodium bicarbonate, and saturated sodium chloride, respectively. Dry over anhydrous magnesium sulfate, filter, and evaporate the solvent to give 3 (3.05 g, 53%) as a white solid. 1 H-NMR (400MHz DMSO-d6):0.86-0.88(d,3H),0.90-0.92(d,3H),1.03-1.06(s,3H),1.11-1.17(m,4H),1.38-1.53( m,8H),1.76-1.82(m,1H),2.05-2.10(m,1H),2.26-2.31(m,1H),2.78-2.82(m,1H),2.96-3.00(m,1H), 3.42-3.45(t,1H),3.61-3.63(t,1H),4....

Embodiment 3

[0071] Example 3: (R)-1-((2S,3R)-3-((benzyloxycarbonyl)amino)-2-hydroxy-4-phenylbutyrylamino)-3-methylbutylboronic acid (4)

[0072] Compound 3 (2.88g, 5.0mmol) was dissolved in 50mL of anhydrous methanol and n-hexane 1:1 mixed solvent, and isobutylboronic acid (1.27g, 12.5mmol) was added thereto. Under the condition of ice bath, add 1mol / L hydrochloric acid solution and continue to stir for 6h at room temperature. After static separation, the lower layer was dissolved by adding 2mol / L sodium hydroxide, and extracted three times with dichloromethane. The aqueous phase was adjusted to pH=5 with 1N hydrochloric acid, extracted three times with DCM, combined with DCM phases, washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated to dryness to obtain white solid 4 (0.77 g, 35%).

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Abstract

The invention discloses multifunctional immunity-targeted micromolecule anti-cancer medicine (Bestazomib citrate) and a preparation method and application thereof. A structure of the multifunctional immunity-targeted micromolecule anti-cancer medicine (Bestazomib citrate) is shown in the attached figure. The multifunctional immunity-targeted micromolecule anti-cancer medicine (Bestazomib citrate)has activity-inhibiting effect, also has activity-inhibiting effect on tumor proteasome, and can be applied to the development of medicines for treating malignant tumors.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a multifunctional targeted immune small molecule anticancer drug Bestazomib citrate and its preparation method and application. Background technique [0002] Aminopeptidase N (APN / CD13) is a type II transmembrane zinc ion-dependent metalloprotease that belongs to the Gluzincins subfamily of the M1 family and binds to the cell membrane in the form of a homodimeric glycoprotein (Nucleic Acids Res., 1999, 27(1):325-331). APN is expressed on the cell surface of various tissues, such as central nervous system synaptic cells, synovial fluid fibroblasts, activated endothelial cells, liver cells, intestinal mucosal epithelial cells, placenta, bone marrow progenitor cells, monocytes, Osteoclasts, etc., are especially enriched in kidney and intestinal brush border cells (Haema., 2003, 4(6):453-461). In addition, compared with normal cells, APN is expressed at a high level on ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/02A61K31/69A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07F5/025Y02P20/55
Inventor 徐文方张剑饶燏谭乐巧黄永学
Owner WEIFANG BOCHUANG INT ACAD OF BIOTECH & MEDICINE
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