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Multimeric mannosides, a process for preparing the same and their uses as a drug

A technology of compounds and derivatives, applied in the fields of polymannosides and their preparation and their use as medicines, can solve the problems of not easily adapting to pharmacological properties, permeability, affinity and retention, etc.

Inactive Publication Date: 2015-08-26
CENT NAT DE LA RECHERCHE SCI +4
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Furthermore, the aforementioned inhibitors are not easily tailored to the desired pharmacological properties (logP, logO, permeability, solubility, affinity, and persistence) because the mannoside moiety needs to be conserved to maintain specificity, and most hydrophobic aglycone moieties are not Allows structural changes to maintain affinity for FimH

Method used

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  • Multimeric mannosides, a process for preparing the same and their uses as a drug
  • Multimeric mannosides, a process for preparing the same and their uses as a drug
  • Multimeric mannosides, a process for preparing the same and their uses as a drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1384] Example 1: Synthesis of Heptylmannoside Cyclodextrin Compound 2

[1385]

[1386] 8-oxa-undec-10-ynyl 2,3,4,6-tetra-O-acetyl-α-D-mannopyranoside 9’

[1387] Mannosyl pentaacetate (229 mg, 0.587 mmol), compound 8' (150 mg, 0.882 mmol) and silver trifluoroacetate (194 mg, 0.878 mmol) were dissolved in anhydrous dichloromethane (3 mL). Add 1M SnCl 4 Solution in dichloromethane (585 μL), under argon atmosphere, the mixture was stirred at room temperature for 3 hours. The solution was diluted in dichloromethane (10 mL), washed with saturated NaHCO 3 (2 x 10 mL) washes. The organic layer was dried, filtered and evaporated under reduced pressure. The residue was chromatographed on silica gel using ethyl acetate-cyclohexane (2-8) to (3-7) to afford 9' (128 mg, 44%) as a colorless oil. Analytical data were the same as previously described [Gouin, S.G.; Wellens, A.; Bouckaert, J.; Kovensky, J. Chem Med Chem. 2009, 5, 749-755].

[1388] 8-oxa-undec-10-ynyl-α-D-mannopyrano...

Embodiment 2

[1395] Example 2: Synthesis of Heptylmannoside Cyclodextrin Compound 4

[1396] - Compound 16' of the formula:

[1397]

[1398] Compound 15' (112 mg, 423 μmol) of the following formula:

[1399]

[1400] and hepta-6-azido-6-deoxy-β-cyclodextrin (60 mg, 47 μmol) were dissolved in DMF / H 2 O mixture (5 / 1.6mL). Copper sulfate (15 mg, 94 μmol) and sodium ascorbate (37 mg, 187 μmol) were added, and the mixture was stirred at room temperature for 19 hours. The mixture was evaporated under reduced pressure, and the residue was dissolved in DMF (15 mL) together with sodium azide (121 mg, 1.86 mmol). The mixture was stirred at 70°C for 36 hours. The mixture was evaporated under reduced pressure and the residue was purified by preparative HPLC to give 16' (21 mg, 15%) as a white powder after lyophilization.

[1401] [α] D =+84 (c=0.1, H 2 0); Tr=36 minutes; 1 H NMR (500MHz, DMSO) δ = 7.95 (7H, s, H 三唑 ), 6.00, 5.88 (14H, br, OH), 5.08 (7H, br, H-1 I-VII ), 4.50-4.00 (36H...

Embodiment 3

[1437] Example 3: Synthesis of 5-acetyl-2-((α-D-mannopyranosyl)amino)thiazole[6]

[1438] 5-Acetyl-2-((2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyl)amino)thiazole[6a]

[1439]

[1440] α and β ratio (9 / 1):

[1441] 1 H NMR (300MHz, CDCl 3 )δ=9.00(br, 1H, NH), 7.98(s, 0.9H, H8 α ), 7.79(s, 0.1H, CH8 β ), 5.52 (dd, J 2,1 = 1.8Hz,J 2,3 =2.7Hz, 1H, H2), 5.34-5.24(m, 2H, H4 and H3), 5.14(d, 1H, J 1,2 = 1.8Hz, H1 α ), 4.32 (dd, 1H, J 6b,6a =12.0Hz,J 6b,5 =5.4Hz, H6 b ), 4.11-4.01 (m, 2H, H6 a and H5), 2.43 (s, 3H, H11), 2.18, 2.06, 2.01, 2.00 (4s, 12H, CH 3 CO).

[1442] 13 C NMR (300MHz, CDCl 3 )δ=189.8 (C10), 173.1 (C7), 170.8, 170.2, 169.7 (4CH 3 CO), 146.7(C8), 131.5(C9), 82.5(C1), 69.4(C5+C3 or C4), 69.1(C2), 66.0(C3 or C4), 62.2(C6), 26.2(C11), 20.7 (4CH 3 CO).

[1443] MS(CI)m / z=473[M+H] + .

[1444] HRMS (MALDI): calculated value C 19 h 24 N 2 o 10 SH[M+H] +473.1224; found 473.1241

[1445] [a] 26 D +87(c 0.175, CHCl 3 )

[1446] 5-Acetyl-2-((α...

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Abstract

The present invention relates to multimeric mannosides, a process for preparing the same and their uses in medicine for treating Escherichia Coli infections. Exemplary compounds are:

Description

technical field [0001] The present invention relates to mannose derivatives, processes for their preparation and their use as medicines. Background technique [0002] Most Escherichia coli (E. Coli) express several hundred protein rod-shaped organelles up to 1 μm in length called type 1 fimbriae on their cell surface. Type 1 pilus carry the adhesin, FimH, a lectin with high affinity for mannose, at the edge of the flexible tip pilus. The receptor for FimH is a hypermannosylated glycoprotein. Known receptors for FimH are uroplakin 1a on bladder epithelium and CEACAM6 on colonic epithelium. FimH bound to its receptor transduces signals in the cytoplasm of infected epithelial cells and allows bacterial invasion. Epithelial cell invasion and intracellular survival and bacterial replication matched a severe early inflammatory response that preludes recurrent and persistent E. coli infection. [0003] The specificity of the FimH lectin has been identified (Bouckaert, J. et al....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/26C07H17/00C07H19/06A61K31/7056A61P31/04
CPCC07H15/26C07H19/06A61K47/4823A61K39/385C08B37/0012C07H17/00A61K47/61A61P31/04Y02A50/30
Inventor J·布克特S·古因D·丹伊奥德R·比利T·杜米希A·西维格农A·达夫乐-米查德
Owner CENT NAT DE LA RECHERCHE SCI
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