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Novel 3,5 and/or 6 substituted analogues of swainsonine, process for their preparation and their use as therapeutic agents

A halogen, representative technology, applied in the field of swainsonine analogs

Inactive Publication Date: 2000-04-26
格里科设计控股有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The more lipophilic esters 2-benzoyloxy-swainsonine, 2-toluoyloxy-swainsonine, 8-hexadecanoyloxy-swainsonine and 8-tetradecanoyloxy - The inhibitory IC50 value of swainsonine on Golgi oligosaccharide processing was at least 10 times higher, probably due to the lower efficiency of entry of the compound into tumor cells

Method used

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  • Novel 3,5 and/or 6 substituted analogues of swainsonine, process for their preparation and their use as therapeutic agents
  • Novel 3,5 and/or 6 substituted analogues of swainsonine, process for their preparation and their use as therapeutic agents
  • Novel 3,5 and/or 6 substituted analogues of swainsonine, process for their preparation and their use as therapeutic agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0130] Pyridinium chlorochromate (776 mg, 3.6 mmol) was added to flame-dried (flame-dried) 3 Å molecular sieves (3 g) and benzyl 4-azido-2,3-O-isopropylidene-α- In a vigorously stirred suspension of D-mannopyranoside (500mg, 1.49mmol) in anhydrous dichloromethane (50ml). After 30 minutes, the oxidation was complete and the slurry was placed on top of a silica gel column (50 g) and eluted with 1:1 ethyl acetate:hexanes. The aldehyde-containing eluate was concentrated, the residue was dissolved in anhydrous benzene (30ml), the solution was cooled to 0°C, and triphenylphosphoranylidene-2-propanone (1.2g, 3.77mmol) was added Anhydrous tetrahydrofuran (30ml) solution. The solution was stirred overnight at room temperature. The reaction mixture was concentrated to dryness and the residue was purified by chromatography (16 g silica gel, 1:3 ethyl acetate:hexanes) to afford GDLZ1 (340 mg, 61%) as a spontaneously crystalline syrup. Benzyl 4-azido-4,6,7,9-tetradeoxy-2,3-O-isopropylid...

Embodiment 2

[0163] Stirring into benzyl-4-azido-4-deoxy-2,3-O-isopropylidene-α-D-mannopyranoside (1.0 g, 3.0 mmol) in dry THF (10 ml), Add LiAlH to the cooled solution (in an ice bath at 0°C) in small amounts and several times 4 (140 mg, 3.8 mmol). Then the reaction solution was slowly warmed to room temperature. After 4 hours, TLC indicated complete consumption of starting material and formation of a single new product. with 5% NH 4 The reaction was quenched with Cl (10ml), followed by liquid-liquid extraction (H 2 O / CH 2 Cl 2 )deal with. dry (MgSO 4 ) and the combined organic extracts were concentrated to afford the desired amine 1 (0.90 g, 2.9 mmol) as a white crystalline solid in 97% yield. Benzyl-4-benzyloxycarbonylamino-4-deoxy-2,3-O-isopropylidene-α-D-mannopyranoside (2):

[0164] To 1 (215 mg, 0.70 mmol) (1:1) THF:10% NaHCO 3 (15ml) was added dropwise to a stirred, cooled (in ice bath at 0°C) solution of benzyl chloroformate (0.11ml, 0.75mmol). The reaction was then slo...

Embodiment 3

[0172] GD42

[0173] (5R)-5-Benzyloxymethyl swainsonine (5R)-5-Benzyloxymethyl-1,2-O-isopropylidene swainsonine (GDLZ177)

[0174] Sodium hydride (10 mg, 60% in mineral oil) was added in portions to crude (5R)-5-hydroxymethyl-1,2-O-isopropylidene swainsonine (30.7 mg, <0.126 mmol) A solution of benzyl chloride in anhydrous DMF (200ml). After stirring for 2 days, methanol (1 ml) was added and the solution was concentrated. The residue was purified by reverse phase HPLC and GDLZ177 (7.0 mg, about 17%) was obtained. (5R)-5-Benzyloxymethyl swainsonine (GD42)

[0175]Compound GDLZ177 (7.0 mg, 21 mmol) was dissolved in tetrahydrofuran (1 ml), 6M hydrochloric acid (1 ml) was added, and the solution was stirred at room temperature for 2 days. The solution was concentrated to dryness and the residue was purified by reverse phase HPLC to give a colorless residue GD42 (2.3 mg, 38%). (5R)-5-Benzyloxymethyl-1,2-O-isopropylidene swainsonine (GDLZ252)

[0176] Sodium hydride (7 mg, 6...

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Abstract

The invention relates to novel 3, 5, and / or 6 swainsonine analogues, processes for their preparation and their use as therapeutic agents. The invention also relates to pharmaceutical compositions containing the compounds and their use as therapeutics.

Description

[0001] Scope of the invention [0002] The present invention relates to novel swainsonine analogues, processes for their preparation and use as therapeutic agents. Background technique [0003] The structure of carbohydrate compounds present on human tumor cells is related to the onset and metastasis of cancer (Dennis et al., Science 236:582, 1987; Demetriou et al., J Cell Biol. 130:383, 1995). These structures include GlcNAcβ(T1-6) branched N- and O-linked sugar side chains of cell surface glycoproteins. The Golgi enzymes required for this synthesis are β(T1-6) N-acetylglucosamine transferase V (ie GlcNAc-TV) and nuclear 2β(T1-6) N-acetylglucosamine transferase (ie nuclear 2GlcNAc-T). These enzymes are up-regulated in human cancers (Fern and es et al., CancerRes.51: 718-723, 1991), with a phenomenon relevant to the activation of the ras signaling pathway (Dennis et al., Science 236: 582-585, 1987; Dennis et al. Oncogene4: 853-860, 1989)). Furthermore, overexpression of Gl...

Claims

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Application Information

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IPC IPC(8): C07D491/147A61K31/437A61K31/4375A61K31/438A61K31/4745A61K31/5025A61K31/542A61P31/00A61P35/00A61P37/04C07D471/04C07D471/10C07D471/14C07D471/16C07D491/20C07D495/14C07D498/14C07D513/16
CPCC07D471/04A61P31/00A61P35/00A61P37/04
Inventor R·沙J·卡维尔J·马里诺-阿尔波纳斯I·特瓦罗斯卡F·特罗珀J·丹尼斯
Owner 格里科设计控股有限公司
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