Carboxymethylgalactose derivatives

Details Carboxymethylgalactose derivatives Carboxymethylgalactose derivatives

2001-03-20

2003-01-07

Barts, Samuel (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S023000, C514S061000, C536S004100, C536S018500

Reexamination Certificate

active

06503885

ABSTRACT:

TECHNICAL FIELD
The present invention relates to carboxymethylgalactose derivatives, more specifically carboxymethylgalactose derivatives acting as ligands which bind to a cell adhesion molecule, i.e., selectin, and are useful for treating and preventing various selectin-related diseases such as inflammations and cancerous metastasis.
BACKGROUND ART
It has been noted that the interactions between a selectin, specifically, E-selectin (ELAM-1), P-selectin (GMP-140) or L-selectin (LECAM-1) and sugar chains are associated with various diseases. The above LECAM-1 is an adhesive molecule expressed mainly on leukocytes; ELAM-1 is a cell adhesion molecule expressed mainly on vascular endothelial cells; and GMP-140 is an adhesive molecule mainly expressed on thrombocyte cells.
In cancer cells and spinal cells, sialyl Lewis-a (SLe
a
) or sialyl Lewis-x(SLe
x
) having L-fucose in its molecule appears, and it is specifically recognized by leukocyte adhesion factor (L- or E-selectin) which appears on the surface of vascular endothelial cells stimulated with interleukin-1 (IL-1) or tumor necrosis factor (TNF) (e.g., Science, Vol. 258, p 964-969, 1992). That is, the cancer cells and myeloid cells, which express SLe
a
or SLe
x
on the surface thereof, bind to the vascular endothelial cells.
Incidentally, human thrombocytes and vascular endothelial cells activated by the thrombin express P-selectin which also sharply recognizes SLe
a
or SLe
x
. Therefore, the human thrombocytes and vascular endothelial cells bind to neutrophils and monocyte which express these sugar chains on the surface of the cells (Science, Vol. 258, p 964-969, 1992). It is thought that these phenomena are associated with the progress of inflammation, cancer metastasis, thrombus and other circulatory diseases.
Thus, proposed are various measures to inhibiting selectin-related inflammation, cancer metastasis and the like by blocking the binding of these selectins to SLe
a
or SLe
x
to interrupt the adhesion of the selectin-expression cells to cancer cells, leukocyte cells and thrombocytes (e.g., U.S. Pat. Nos. 5,817,742, 5,648,344 and 5,837,689, European Patent Publications (WO) Nos. 9202527, 9929705, 9731007 and 9731625). Particularly for complicated diseases, a blocker which can bind to various selectins to inhibit cell adhesion is desirable.
Since the SLe
x
was reported for the first time as a ligand for ELAM-1, several SLe
x
derivatives are reported. These derivatives are acidic oligosaccharides and have a sialic acid moiety. Also reported are a number of SLe
x
derivatives which consist of oligosaccharide having a carboxymethyl group or a sulfonate group in place of the sialic acid moiety of the acidic oligosaccharides (e.g., Carbohydrate Research, vol. 303, p 131-133, 1997 and Japanese Unexamined Patent Publication No. 1996-99989).
However, no report has been published on SLe
a
derivatives which consist of oligosaccharide having a carboxymethyl group, or on sulfatide derivatives having a carboxymethylgalactosyl moiety in place of the sulfogalactosyl moiety.
It is reported that SLe
x
and SLe
a
are common ligands for ELAM-1, GMP-140 and LECAM-1, whereas sulfatides have a binding specific for GMP-140 and LECAM-1 and thus are ligands for these GMP-140 and LECAM-1, and also have anti-inflammatory actions (International Immunology, vol. 8, p 1905-1913, 1996).
An object of the present invention is to provide an SLe
a
derivative which functions as a ligand having affinity for various selectins in the selectin family, particularly a novel glycolipid derivative whose sialic acid portion is replaced by carboxymethylgalalctose and a novel sulfatide derivative having carboxymethlylgalactosyl group as a substituent for sulfogalactosyl group.
The inventors have conducted extensive research in order to provide an SLe
a
analog (especially that which more strongly binds to selectins and blocks their cellular adhesiveness) serving as a ligand for selectins. Consequently, the inventors succeeded in synthesizing a novel glycolipid derivative prepared by substituting the sialic acid portion of the SLe
a
with carboxymethylgalactose and a novel sulfatide derivative having similar carboxymethylgalactosyl group, which were found to achieve the above object. The present invention was accomplished based on these findings.
DISCLOSURE OF INVENTION
The present invention provides carboxymethylgalactose derivatives represented by the formula (1);
and its salts, wherein R represents the following group (1a), (1b) or (1c)
The compounds of the present invention have reactivity to the selecting, ELAM-1, GMP-140 and LECAM-1. Therefore, as a ligand with selecting, the compound inhibits the cell adhesion of these selectins and is useful for treating and preventing various selectin-related diseases. For example, the compound is useful for inhibiting various inflammations, cancer metastasis, etc.
Preparation of the compound of the invention will be described in detail below. The compound of the invention represented by the formula (1) can be prepared by various methods. Particularly, the compound of the invention can be easily prepared by the methods shown in the reaction formula (I)-(IV) below. In the reaction formulas and their explanations below, the following abbreviations are used.
Bz: Benzoyl group,
Bn: Benzyl group,
Me: Methyl group,
SE: 2-(Trimethylsilyl)ethyl group,
TBDPS: t-Butyldiphenylsilyl group,
TMSOTf: Trimethylsilyltrifluoromethanesulfonate,
TfOH: Trifluoromethanesulfonic acid,
Ph
3
P: Triphenylphosphine,
TBAF: Tetrabutylammoniumfluoride,
WSC: Water-soluble carbodiimide,
NaBH
3
CN: Sodium cyanoborohydride,
TFA: Trifluoroacetic acid,
DBU: 1,8-Diazabicyclo-[5,4,0]-7-undecene,
Cl
3
CCN: Trichloroacetonitrile
The compound of the invention represented by the formula (1) in which R is the group (1a) can be prepared by the method shown in the reaction formula (I) below.
According to the above reaction formula (I), a compound (4) can be prepared by the following procedure. In an inert solvent, e.g., methylene chloride and the like, are dissolved the known compound (2) (Carbohydrate Research, vol. 303, p 131-133, 1997) and (2S, 3R, 4E)-2-azido-3-O-(tert-butyldiphenylsilyl)-4-octadecene-1,3-diol (compound(3)) represented by the formula (3). The solution is stirred in the presence of a dehydrating agent, e.g., a molecular sieve and the like, at room temperature for about 1 to about 10 hours. The solution is then cooled to about 0° C., and TMSOTf is added thereto. The mixture is stirred at about 0 to about 30° C., preferably at about 0° C., for about 2 to about 24 hours, preferably for about 12 hours, giving the compound (4). In the above procedure, the amounts of the compound (3), dehydrating agent and TMSOTf are not particularly limited, but are preferably selected from the ranges of about 0.5 to about 1.5 moles, about 2 to about 4 moles and about 0.05 to about 0.5 mole, per mole of the compound (2), respectively.
Subsequently, the resulting compound (4) is dissolved in an inert solvent such as benzene. To the solution is added Ph
3
P, and the mixture is stirred at about 10 to about 40° C., preferably about 30° C., for about 12 to about 96 hours to reduce the azide group of the compound (4) to amino group, giving compound (5). In the above procedure, the amount of Ph
3
P is preferably selected from the range of about 1 to about 3 moles per mole of the material compound (4).
The compound (5) can be isolated by conventional methods. In the present invention, the compound (5) can be used in the subsequent reaction as a reaction solution or its concentrate without being isolated.
The subsequent reaction can be carried out by adding stearic acid and a condensing agent WSC, i.e., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride to the solution of the compound (5) in an appropriate solvent such as the concentrate of the reaction solution, and stirring the mixture at room temperature for about 12 hours, giving a compound (6). In the above procedure, the amounts of stearic acid and the condensing agent (WSC) are preferably sele

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