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Novel sulfated oligosaccharide derivatives

A compound, the technology of the general formula compound, applied in the field of new sulfated oligosaccharide derivatives, can solve the problems such as not showing anti-IIa activity

Active Publication Date: 2010-10-27
PROGEN PHARMA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, PI-88 does not interact with ATIII and therefore does not exhibit anti-Xa or AT III-mediated anti-IIa activity 12，13

Method used

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  • Novel sulfated oligosaccharide derivatives
  • Novel sulfated oligosaccharide derivatives
  • Novel sulfated oligosaccharide derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] Example 1: Dodecyl 2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyl-(1→3)-2,4,6-tri-O-acetyl Base-α-D-mannopyranosyl-(1→3)-2,4,6-tri-O-acetyl-α-D-mannopyranosyl-(1→3)-2,4 , 6-tri-O-acetyl-α-D-mannopyranosyl-(1→2)-3,4,6-tri-O-acetyl-α-D-mannopyranoside (2)

[0083] trichloroacetate imidate 1 28 (0.469g, 0.285mmol) in DCM (15mL) was added 1-dodecanol (0.849mmol, 3 equiv) and MS (50 mg). The mixture was stirred at -20°C for 20 minutes. TMSOTf (103 μL, 0.57 mmol, 2 equiv) was added and washed with Et 3 The mixture was stirred at -20°C for 50 minutes before being quenched with N (38 μL, 0.285 mmol, 1 equiv). After warming to room temperature, the mixture was filtered and the solids were rinsed with DCM. The combined filtrate and washings were evaporated on silica gel and purified by column chromatography (silica 2 x 20 cm, CHCl 3 , CHCl 3 -methanol 99:1 to 98:2 gradient elution) to obtain glycoside 2 as a colorless gum. Two fractions of BnNHAc (76 mg, 2:BnNHAc=5:3; 179 mg...

Embodiment 2

[0088] Example 2: 12-Azido-1-dodecanol

[0089] 12-Bromo-1 was treated with sodium azide (121 mg, 1.855 mmol, 2 equiv), tetrabutylammonium iodide (17 mg, 0.0464 mmol, 0.05 equiv) and saturated aqueous sodium bicarbonate (0.9 mL) in the following order - A mixture of dodecanol (246 mg, 0.927 mmol) in tert-butanol (1.8 mL, 0.5M). The mixture was stirred at room temperature for 4 days. The mixture was filtered through a plug of Celite and the filter cake was rinsed with ethyl acetate (20 mL). The combined filtrate and washings were evaporated on silica gel and purified by flash column chromatography (2.5 x 18 cm, gradient elution with hexane-ethyl acetate 6:1, 4:1 to 2:1) to give colorless 12-Azido-1-dodecanol (193 mg, 92%) as an oil. 1 H NMR (CDCl3 , 400MHz): 3.62(t, 2H, J=7.0, OCH 2 ), 3.24(t, 2H, J=7.0, NCH 2 ), 1.61-1.51(m, 4H), 1.35-1.25(m, 16H).

[0090] 12-Azidododecyl 2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyl-(1→3)-2,4,6-tri-O- Acetyl-α-D-mannopyranosyl-(1→3)-2,4,6...

Embodiment 3

[0096] Example 3: 12-(4-Naphthyl-1-yl-[1,2,3]triazol-1-yl)dodecyl 2,3,4,6-tetra-O-acetyl-α -D-mannopyranosyl-(1→3)-2,4,6-tri-O-acetyl-α-D-mannopyranosyl-(1→3)-2,4,6- Tri-O-acetyl-α-D-mannopyranosyl-(1→3)-2,4,6-tri-O-acetyl-α-D-mannopyranosyl-(1→2 )-3,4,6-tri-O-acetyl-α-D-mannopyranoside (9)

[0097] Azide 5 (86 mg, 50.3 μmol), tert-butanol (100 μL, 0.4 M), 1-ethynylnaphthalene (83 μmol, 2 equiv), copper sulfate solution (0.3 M, 14 μL, 4.2 μmol, 10 mol%) and sodium ascorbate solution (1 M in water, 12.4 μL, 12.4 μmol, 30 mol%). The mixture was stirred at room temperature for 11 days. The mixture was then evaporated on silica gel and flash column chromatography (1×18 cm, gradient elution with hexane-ethyl acetate 6:1, 4:1, 2:1, 1:1, 1:2 to 1:3 ) to give naphthyltriazole 9 (24.2 mg, 26%) as a colorless gum. 1 H NMR (CDCl 3 , 400MHz) δ8.38-8.33 (m, 1H), 7.92-7.86 (m, 2H), 7.80 (s, 1H, triazole-CH), 7.72 (dd, 1H, J=7.3, 1.5), 7.54- 7.48(m, 3H), 5.31-5.15(m, 8H), 5.03-4.87(m,...

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Abstract

The invention relates to novel compounds that have utility as inhibitors of heparan sulfate-binding proteins; compositions comprising the compounds, and use of the compounds and compositions thereof for the antiangiogenic, antimetastatic, anti-inflammatory, antimicrobial, anticoagulant and / or antithrombotic treatment of a mammalian subject.

Description

technical field [0001] The invention described herein relates to compounds having activity as inhibitors of heparan sulfate-binding proteins, including heparanases. In particular, the invention relates to sulfated oligosaccharide derivatives, although the scope of the invention is not necessarily limited thereto, but in particular, the invention relates to polysulfated oligosaccharides modified with specific, highly lipophilic groups. The present invention also relates to methods for preparing said compounds, compositions comprising said compounds, and said compounds and compositions thereof for use in mammalian subjects for anti-angiogenesis, anti-metastasis, anti-inflammatory, antimicrobial, anticoagulant and / or use in antithrombotic therapy. The compound also has a prophylactic effect on the aforementioned conditions when administered to a mammalian subject. Background technique [0002] Known as PI-88 1，2 The sulfated oligosaccharide agent is a promising inhibitor of ...

Claims

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Application Information

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IPC IPC(8): C07H11/00A61P31/00C07H15/04A61K31/7016A61P35/00C07H15/24A61K31/702A61P35/04C07H17/02A61P7/02C07H3/04C07J9/00A61P9/00C07H3/06A61P29/00C07H5/04
CPCC07J41/0094C07H15/24C07H5/02C07H3/04C07H5/06C07J17/005C07H17/02C07H15/26C07J41/0088C07H5/04C07H15/207C07H15/04C07H3/06C07H11/00A61P29/00A61P31/00A61P31/04A61P31/12A61P35/00A61P3/06A61P35/04A61P7/02A61P9/00C07J31/006C07J43/003
Inventor V·费尔罗T·卡洛丽刘立功P·N·汉德雷K·D·约翰斯通N·韦默E·T·哈蒙德
Owner PROGEN PHARMA LTD
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