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Novel synthetic c-glycolipids, their synthesis and use to treat infections, cancer and autoimmune diseases

A disease and glycolipid technology, applied in the field of new synthetic C-glycolipids, which can solve the problems of reducing in vivo efficacy and short half-life of α-GalCer

Inactive Publication Date: 2007-05-16
NEW YORK UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As a result, α-GalCer has a short half-life, thereby reducing its efficacy in vivo

Method used

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  • Novel synthetic c-glycolipids, their synthesis and use to treat infections, cancer and autoimmune diseases
  • Novel synthetic c-glycolipids, their synthesis and use to treat infections, cancer and autoimmune diseases
  • Novel synthetic c-glycolipids, their synthesis and use to treat infections, cancer and autoimmune diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0337] A further understanding of the compounds of the invention, their preparation, and methods of use may be provided by the examples illustrating some of the methods of making or using these compounds. These examples do not limit the invention. Variations of the invention known or further developed are considered to fall within the scope of the invention, as hereinafter claimed.

[0338] Compounds and Chemical Synthesis

[0339]

Embodiment A

[0340] Example A: Y 5 : Preparation of CBZ or tBoc

[0341] The reaction process proceeds as follows:

[0342]

[0343] condition:

[0344] Step (a):

[0345] For benzyl carbamate: CBZCl (1.1 eq.), 1N NaHCO 3 , 1,4-dioxane, ethyl acetate, rt (room temperature), overnight, the yield was 90%;

[0346] For tert-butyl carbamate: 1N NaOH (1.5 eq.), (t-Boc) 2 O (1.5 eq.), ethanol, water, rt, 1h;

[0347] Step (b):

[0348] For benzyl carbamate: TBSCl (tert-butyldimethylsilyl chloride) (1.2 eq.), Et 3 N (1.1 eq.), 4-DMAP (4-dimethylaminopyridine) (0.05 eq.), DCM (dichloromethane), DMF (dimethylformamide), 0°C, 1h, 96%;

[0349] For tert-butyl carbamate: The overall yield of steps (a) and (b) was 93%.

[0350] Step (c):

[0351] For benzyl carbamate: 2,2-dimethoxypropane (5-10 eq.), PPTs (pyridinium p-toluenesulfonate) (0.07 eq.), DCM, rt, 2h, yield 99% ;

[0352] For tert-butyl carbamate: The reaction product was used directly in the next step without purification.

[0...

Embodiment B

[0362] Example B: Y 1 , Y 2 , Y 3 and Y 4 Each independently is Ac or Bn; n=1 or 0 preparation

[0363] The reaction process proceeds as follows:

[0364]

[0365] condition:

[0366] Step (c):

[0367] o 3 , DCM, -78°C;

[0368] Step (d):

[0369] NaBH 4 , DCM, MeOH, the yield is 40% (three steps);

[0370] Step (e):

[0371] Allyltrimethylsilane (3.0 eq.), BF 3 .OEt 2 (5.0 eq.), 0-10 ° C, 3 days, the yield is 77%;

[0372] Step (f):

[0373] NaOMe (0.1 eq.), MeOH, rt, 1h;

[0374] Step (g):

[0375] NaH (2.0 eq.), BnBr (1.5 eq.), TBAI (catalytic amount), DMF, THF, rt, 14h, the yield is 93% (2 steps);

[0376] Step (h):

[0377] PdCl 2 (PhCN) 2 , benzene, reflux, 20h, yield is 73%; (i) (COCl) 2 (2.25 eq.), DMSO (5.50 eq.), DCM, -78°C, 0.5-1h, then Et 3 N (6.0eq.), to 0°C, 2h, the yield was 83%.

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PUM

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Abstract

The invention is directed to novel compounds of formulae (I), (II) and (III): wherein X is O or NH; R<3> is OH or a monosaccharide and R<4> is hydrogen, or R<3> is hydrogen and R<4> is OH or a monosaccharide; R<5> is hydrogen or a monosaccharide; and pharmaceutically acceptable salts or esters thereof. The invention is also directed to the use of the compounds both directly and as immune adjuvants for treating cancer, infectious diseases and autoimmune diseases. The invention is also directed to syntheses of the intermediates which can be used to make these novel compounds.

Description

[0001] This invention was made with Government support under Lot No. R21AI47840-01A1 awarded by National Institute of Health / National Institute of Allergy and Infectious Diseases and Lot No. R01 GM60271 awarded by National Institute of Health / General Medical Sciences. Accordingly, the US Government has certain rights in this invention. field of invention [0002] The present invention relates to a new type of synthetic C-glycolipid, which can be used in the treatment of infectious diseases, cancer and autoimmune diseases (direct administration and as an adjuvant by improving the immunogenicity of various antigens). Methods of making this novel synthetic C-glycolipid are also disclosed. Background of the invention [0003] Glycolipids are molecules normally present in the plasma membrane of animal and plant cells. Glycolipids contain oligosaccharides bonded to lipid components. Glycosphingolipids are complex glycolipids containing ceramides as lipid components. One class o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01N43/04A61K31/70A61K31/7008
CPCC07H7/02C07H13/00C07D309/10A61P31/04A61P35/00A61P37/04A61P37/08
Inventor 辻守哉理查德·弗兰克陈光武
Owner NEW YORK UNIV
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