Carbohydrate derivatives and their solid-phase synthesis

Details Carbohydrate derivatives and their solid-phase synthesis Carbohydrate derivatives and their solid-phase synthesis

1998-10-21

2001-06-05

Celsa, Bennett (Department: 1627)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S001110, C536S018500, C525S054200

Reexamination Certificate

active

06242583

ABSTRACT:

This application is a 371 of PCT/EP97/02393, filed May 25, 1996.
The invention relates to carbohydrate derivatives, to a process for their preparation and to their use.
1. Background of the Invention
In classical research to find active substances, the biological effect of novel compounds has been tested in a random screening on the whole organism, for example the plant or the micro-organism. In this case, the limiting factor was the biological testing in constrast to the synthetic chemistry. The provision of molecular test systems by molecular and cell biology has drastically changed the situation.
A large number of molecular test systems such as receptor binding assays, enzyme assays and cell-cell interaction assays has been and is being developed for modern research looking for active substances. Automation and miniaturization of these test systems makes a high sample throughput possible. This development allows an increasing number of chemicals to be tested in ever shorter times for their biological effect in random screening and thus for possible use as lead structure for an active substance in medicine, veterinary medicine or crop protection.
A modern automated test system allows 100,000 or more chemicals to be tested for their biological effect in a mass screening per year.
Classical synthetic chemistry has become, owing to this development, the limiting factor in research looking for active substances.
If the efficiency of these test systems is to be fully exploited, there must be a considerable increase in the efficiency of the chemical synthesis of lead structures for active substances.
Combinatorial chemistry can contribute to this necessary increase in efficiency, in particular when it makes use of automated solid-phase synthetic methods (see, for example, review articles J. Med. Chem. 1994, 37 (1994) 1233 and 1385). Combinatorial chemistry makes it possible to synthesize a wide range of different chemical compounds, called substance libraries. Solid-phase synthesis has the advantage that by-products and excess reactants can easily be removed so that elaborate purification of the products is unnecessary. The finished synthetic products can be passed onto the mass screening directly, ie. bound to the support, or after elimination from the solid phase. Intermediates can also be tested in the mass screening.
2. Description of Prior Art
Applications described to date are mainly restricted to the peptide and nucleotide sectors (Lebl et al., Int. J. Pept. Prot. Res. 41 (1993) 203 and WO 92/00091) or their derivatives (WO 96/00391). Since peptides and nucleotides have only limited use as drugs because of their unfavorable pharmacological properties, it is desirable to utilize the solid-phase synthetic methods which are known and of proven use in peptide and nucleotide chemistry for synthetic organic chemistry.
U.S. Pat. No. 5,288,514 reports one of the first combinatorial solid-phase syntheses in organic chemistry outside peptide and nucleotide chemistry. U.S. Pat. No. 5,288,514 describes sequential synthesis of 1,4-benzodiazepines on a solid phase.
WO 95/16712, WO 95/30642 and WO 96/00148 describe other solid-phase syntheses of potential active substances in combinatorial chemistry.
However, in order to utilize fully the possibilities of modern test systems in mass screening it is necessary continually to feed novel compounds with maximum structural diversity into the mass screening. This procedure makes it possible considerably to reduce the time for identifying and optimizing a novel lead structure of active substances.
It is therefore necessary continually to develop novel different combinatorial solid-phase syntheses. It is sensible for this to be aimed at biologically active compounds.
Carbohydrates and their derivatives are compounds which are in demand in many areas and are difficult to synthesize. Thus, some polysaccharides such as schizophylhan, are used as antitumor agents.
A large number of antibiotics have carbohydrate residues, such as antibiotics from the group of macrolides, anthracyclines or enediynes or consist entirely of carbohydrates, such as streptomycin which is used, for example, in veterinary medicine or in the treatment of plant diseases.
Glycoconjugates such as glycoproteins and/or glycolipids play a crucial part in cell-cell interaction, in the transformation of normal body cells into tumor cells and in inflammatory or allergenic processes in the body. Thus, for example sialyl-Lewis X is a glycoconjugate which has been intensively researched and which is distinguished by its antiunflammatory effect.
Schuster et al. (Abstr. Pap. Am. Chem. Soc., 1994, 207 Meet. Pt. 1, CARB29 and J. Am. Chem. Soc., 1994, 116, 1135-36) describe an enzymatic solid-phase synthesis of a carbohydrate derivative using glycosyltransferases. Schuster et al. use for their synthesis a glycopeptide which has been bound by a linker which can be cleaved by proteases to an aminoprdpyl-silica gel support. This glycopeptide is used as acceptor for glycosyltransferase-catalyzed glycosylation reactions for assembling a sialyl-Lewis X residue. The disadvantages of this method are that glycosyltransferases are sensitive enzymatic catalysts which are not available generally and in the desired amount. It has not been possible to achieve complete conversion of the reactants, so that reaction mixtures were obtained after elimination. Their high specificity, which is advantageous for the individual reaction, results in not every sugar and every position on the various sugars being amenable to enzymatic glycosylation reactions. The linker which can be cleaved by proteases is only provisionally suitable for chemical sugar synthesis, so that a combination of chemical and enzymatic sugar synthesis in order to extend to all sugars and positions on the sugar equally well is impossible with this linker.
Kahn et al. describe, in J. Am. Chem. Soc. 116 (1994) 6953 et seq. a carbohydrate synthesis on a thiophenol-resin. The disadvantage of this method is that to eliminate the glycoside it is necessary to use mercury trifluoroacetate which is toxic and difficult to remove. This makes further purification of the synthetic products necessary. The elimination of the glycoside from the support additionally results only in the free sugars without it being possible to form a new linkage at the cleaved bond and thus introduce a new substituent.
The glycosylation reaction can be carried out in this method only with highly reactive sulfoxides at low temperatures, and very stable protective groups are additionally necessary.
The solid-phase synthesis described by Danishefsky et al. (Science, 260 (1993) 1307 et seq. and 269 (1995) 202 et seq.) for glycosides are [sic] restricted to glycals as precursors, ie. as donors. In addition, only 1-6 glycosidic linkages can be formed and, as in the case of Kahn et al., no other new substituent can be introduced on elimination from the support.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a rapid and efficient solid-phase process for preparing carbohydrate derivatives which does not have the abovementioned disadvantages and meets the requirements of combinatorial chemistry.
DETAILED DESCRIPTION OF THE INVENTION
We have found that this object is achieved by a process for preparing carbohydrate derivatives of the formula I
in which the variables and substituents have the following meanings:
(P) a solid phase
(L) an aliphatic linker having 2 to 12 carbon atoms,
R
1
CHR
5
R
6
, R
5
R
2
, R
3
, R
4
independently of one another hydrogen, XH, substituted or unsubstituted
 (C
1
-C
4
-alkyl )
3
SiO, diaryl (C
1
-C
5
-alkyl )SiO, aryl(C
1
-C
5
-dialkyl)SiO or R
7
and m=0, 1; n=0, 1; p=0, 1
or two adjacent radicals R
2
, R
3
, R
4
, R
6
independently of one another form a substituted or unsubstituted arylalkylidene acetal or an alkylidene acetal,
R
5
hydrogen, substituted or unsubstituted C
1
-C
20
-alkyl, C
3
-C
20
alkenyl, arylalkylene arylalkyl or aryl,
R
6
hydrogen, XH, substituted or unsubstituted
&

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