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Analogues of glycolipids useful as immunoadjuvants

A technology of compounds and hydrocarbon groups, applied in the preparation of sugar derivatives, sugar derivatives, sugar derivatives, etc., can solve problems such as unclear physiological meaning

Active Publication Date: 2011-05-18
路易吉·潘扎
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, its physiological significance in mammals is unclear, as it is unknown why α-galactosylceramide from marine organisms is such a potent agonist

Method used

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  • Analogues of glycolipids useful as immunoadjuvants
  • Analogues of glycolipids useful as immunoadjuvants
  • Analogues of glycolipids useful as immunoadjuvants

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0163] Synthesis of common intermediate 7

[0164] Allyl 2,3,4,6-tetra-O-benzyl-α-D-galactopyranosyl-(1→5)-2,3-O-isopropylidene-α-D-furan Lyxoside (1).

[0165] To 5g 2,3,4,6-tetra-O-benzyl-α-D-galactopyranosyl bromide [Grayson, E.J. et al., J.Org.Chem.(2005), 70,9740-9754] ( 8.34mmol) and 1.5g of allyl 2,3-O-isopropylidene-α-D-lyxofuranoside (6.42mmol) in DCM were added with 4.4mL tris-(1-pyrrolidine)-phosphine oxidation (19.6 mmol) [Mukaiyama, T. and Kobashi, Y., Chem. Lett. (2004), 33, 10-11]. The mixture was stirred at room temperature for 24 hours, then diluted with EtOAc and filtered through celite. After evaporation of the solvent, the crude product was purified by careful flash chromatography (toluene / EtOAc 95 / 5) to yield 4.12 g of 1 (85%).

[0166] 1 H(CDCl3): δ7.50-7.19(m, 20H), 5.92-5.77(m, 1H), 5.33-5.13(m, 2H), 5.01(br s, 1H), 5.00-4.50(m, 9H) , 4.47 (d, J=I 1.8, 1H), 4.41 (d, J=11.8, 1H), 4.25 (dt, J=6.1, J=-3.8, 1H), 4.13-3.83 (m, 7H), 3.58 -3.51(m, 2H); ...

Embodiment 2

[0184] Synthesis of common intermediate 10

[0185] (2S, 3S, 4R)-2-(N-hexacosanoyl (esacosanoyl)amino)-3,4-O-isopropylidene-5-O-pivaloyl-1-O-(2, 3,4,6-tetra-O-benzyl-α-D-galactopyranosyl)-1,3,4,5-pentanethritol (9).

[0186] To a solution of 0.5 g (0.6 mmol) 6 in EtOH (40 mL) under an atmosphere of hydrogen was added a catalytic amount of Lindlar's catalyst and the mixture was stirred for 4.5 hours. 0,107g di(15)0,07). The mixture was diluted with DCM and filtered through celite to afford 0.5 g of crude amine 8 which was used directly in the next step.

[0187] 296 mg (0.75 mmol) hexacosanoic acid was added to 20 mL of a solution of compound 8 prepared in a 3:1 mixture of anhydrous DCM-DMF at 0° C. under an argon atmosphere. To this suspension was added EDC (145mg, 0.75mmol), HOBT (102mg, 0.75mmol) and finally DIPEA (0.26ml, 1.5mmol) in DCM. After 20 hours, the mixture was diluted with EtOAc, washed with 1N HCl, a saturated solution of sodium bicarbonate and brine, dried o...

Embodiment 3

[0191] Synthesis of Oxa Analogs of α-GalCer

[0192] (2S, 3S, 4R)-2-azido-(2-butoxyethyl)-3,4-O-isopropylidene-1-O-(2,3,4,6-tetra- O-benzyl-α-D-galactopyranosyl)-1,3,4,5-pentanethritol (11).

[0193] To a solution of 100 mg (0.135 mmol) 7 in anhydrous DMF (3 mL) under argon atmosphere was added 60% NaH (11 mg, 0.27 mmol) and 2-butoxyethyl methanesulfonate (75 mg, 0.4 mmol). The mixture was stirred at 100°C for 2 hours. Another 2 equivalents of NaH and 2-butoxyethyl methanesulfonate were added. After 2 more hours, the mixture was quenched with ammonium chloride diluted with EtOAc (sat. sol.), washed with water (4x), dried over sodium sulfate and evaporated. Flash chromatography (petroleum ether / AcOEt 80:20) gave 74 mg (65%) of 11.

[0194] 1 H(CDCl 3 ): δ7.51-7.18 (m, 20H), 4.94 (m, 1H), 4.86-4.50 (m, 6H), 4.47 (d, J=I 1.8Hz, 1H), 4,36 (d, J= I 1.8Hz, 1H); 4,33(m, 1H), 4.15-3.94(m, 6H), 3.80(dd, J=10.4, J=4.3, 1H), 3.72-3.44(m, 8H), 1 ,56(m, 2H), 1,40(s, 3H), 1.36(m, 2H...

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Abstract

The invention provides analogs of alpha-galactosyl ceramide that increase the immune response elicited by various antigens. It also provides methods of using such compounds to increase the effectiveness of vaccines.

Description

field of invention [0001] The present invention relates to glycolipid analogs as ligands for NKT cells (Natural Killer T-cells), methods for their preparation and methods for using them as immune adjuvants to increase antibody titer levels after vaccination. Background of the invention [0002] Glycolipids have recently been discovered to have many different immunological properties. Among these, they have been shown to be useful as antigens when presented by CD1 molecules, and they can improve immune responses when administered in combination with vaccines. [0003] CD1 molecules are a family of highly conserved antigen-presenting proteins that are functionally similar to well-known major histocompatibility complex (MHC) molecules. MHC proteins present peptides, while CD1 proteins bind various lipids and glycolipids and display them on T lymphocytes. [0004] In humans, the various CD1 isoforms are classified according to sequence similarity into group I (CD1a, b, c, and ...

Claims

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Application Information

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IPC IPC(8): C07H15/04C07H1/00A61K39/39A61K31/7032A61P37/04
CPCC07H15/18C07H15/26C07H15/10A61P31/04A61P31/10A61P31/12A61P33/02A61P35/00A61P37/04
Inventor 路易吉·潘扎
Owner 路易吉·潘扎
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