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BCL-2 selective inhibitor with sugar ring structure and application thereof

A sugar ring, selected technology, applied in the field of new BCL-2 selective inhibitors, can solve the problems of poor water solubility of Venetoclax and increased occurrence of clinical side effects

Inactive Publication Date: 2017-05-03
SUZHOU GUOKUANG PHARMTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, due to reasons such as poor water solubility of Venetoclax, it needs to be given in large doses in clinical practice, such as 800-1200mg / day (http: / / theoncologist.alphamedpress.org / site / misc / ASH2014_D2A1.xhtml)
And such a large dose will inevitably lead to an increase in the occurrence of clinical side effects

Method used

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  • BCL-2 selective inhibitor with sugar ring structure and application thereof
  • BCL-2 selective inhibitor with sugar ring structure and application thereof
  • BCL-2 selective inhibitor with sugar ring structure and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0143] 3-nitro-4-((((2R,3R,4R,5R)-3,4,5-tris((trimethylsilyl)oxy)tetrahydrofuran-2-yl)methyl)amino)benzene Preparation of sulfonamide (intermediate 1)

[0144]

[0145] 4-Chloro-3-nitrobenzenesulfonamide (5.0g, 21.1mmoL), ((2R,3R,4R,5R)-3,4,5-tris((trimethylsilyl)oxy)tetrahydrofuran -2-yl)methylamine (11.2g, 30.5mmoL) and DIPEA (8.8g) were added to anhydrous acetonitrile, reacted overnight in an oil bath at 80°C, and the completion of the reaction was monitored by TLC. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the residue was separated by flash column chromatography. The eluent was n-hexane / ethyl acetate=1 / 1 to obtain 8.0 g of white solid with a yield of 60%. 1 H NMR (DMSO-d6, 400MHz): 1 H NMR (DMSO-d6, 400MHz): δ8.62(t, 1H), 8.27(d, 1H), 7.68(dd, 1H), 7.29(s, 2H), 7.18(d, 1H), 5.56(d ,1H),4.06(m,1H),3.80(m,2H),3.74(m,1H),3.65(m,1H),0.12(m,27H).

Embodiment 2

[0147] 2-((1H-pyrrole[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5, 6-tetrahydro-[1,1'-diphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((((2R,3S,4R ,5S)-3,4,5-trihydro-2H-pyran-2-yl)methyl)amino)phenyl)sulfonyl)benzamide (compound 1)

[0148]

[0149] Intermediate 1 (2.42 g, 4.28 mmoL), DMAP (1.05 g, 8.59 mmoL), EDCI (1.07 g, 5.58 mmoL) and dichloromethane (30.0 mL) were added to Reaction Flask 1 . Then 4-[4-[[2-(4-chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazine]-2-( 1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoic acid (2.5g, 4.4mmoL), triethylamine (0.87g) and dichloromethane (12.0mL) were added to reaction flask 2 . Finally, slowly drop the solution in the reaction bottle 2 into the reaction bottle 1, stir overnight after the addition, and monitor the completion of the reaction by TLC. Add N,N'-dimethylethylenediamine (0.94g), heat the oil bath to 55°C, add 10% acetic acid (18.5mL), and stir overnight. Cool and separate the liquid. The ...

Embodiment 3

[0151] 4-((((2R,3S,5R)-3,5-bis((trimethylsilyl)oxy)tetrahydrofuran-2-yl)methyl)amino)-3-nitrobenzenesulfonamide ( Preparation of Intermediate 2)

[0152]

[0153] Except that instead of ((2R,3R,4R,5R)-3 , Except for 4,5-tris((trimethylsilyl)oxy)tetrahydrofuran-2-yl)methanamine, the preparation of intermediate 2 was the same as that of intermediate 1, and the yield was 78%. 1 H NMR (DMSO-d6, 400MHz): δ8.78(t, 1H), 8.32(d, 1H), 7.68(dd, 1H), 7.20(s, 2H), 7.32(d, 1H), 5.48(d ,1H),4.06(m,1H),3.80(m,2H),3.57(m,1H),2.27(m,2H),0.15(s,18H).

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Abstract

The invention discloses a BCL-2 selective inhibitor with a sugar ring structure and application of the BCL-2 selective inhibitor in medicine for treating diseases like tumors, immune and autoimmune diseases, and the like, caused by BCL-2 overexpression. The BCL-2 selective inhibitor is characterized in that a sugar ring is monosaccharide and alkyl, thioether or alkenyl derivatives thereof, or oligosaccharide and alkyl, thioether or alkenyl derivatives thereof; monosaccharide is selected from glucose, mannose, galactose, fructose, xylose, arabinose, ribose, desoxyribose, allose, altrose, gulose, idose, talose or threose; and oligosaccharide is selected from saccharose, maltose, cellobiose, lactose or raffinose.

Description

technical field [0001] The invention relates to the field of medical technology, in particular to a novel BCL-2 selective inhibitor containing a sugar ring structure, and its use in the treatment of BCL-2 overexpression diseases such as tumors, immune and autoimmune diseases and other drugs . Background technique [0002] Sugars are one of the most abundant organic compounds in nature. They have a unique ring structure with multiple hydroxyl groups and multiple chiral centers, and perform diverse biological functions such as structural support, energy supply, signal transduction, and immune control. According to chemical structure, sugars can be divided into monosaccharides, disaccharides, oligosaccharides and polysaccharides; according to chemical properties, they can be divided into reducing sugars and non-reducing sugars. At present, glycosylated drugs have been widely used clinically, such as antibiotics lincomycin, erythromycin, etc., antidiabetic drugs such as dapagli...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/26C07H1/00A61K31/7064A61P35/00A61P35/02A61P37/02
Inventor 梅德盛刘爱风
Owner SUZHOU GUOKUANG PHARMTECH CO LTD
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