Sulfonated sugar compounds, pharmaceutical compositions which contain the same, and methods of treating tumors with the same

Abstract

Sulfoquinovosylacyl propanediol compounds represented by formula (I):wherein R1 is an acyl residue of a fatty acid, Y is a number of 1, 2 or 3, and M represents a cation having a positive charge equal to Y and pharmaceutically acceptable salts thereof are effective for treating tumors.

Description

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] The present application is a divisional application of application Ser. No. 12 / 322,151, filed Jan. 29, 2009, which is a continuation application of International Application No. PCT / JP2008 / 063056, filed on Jul. 18, 2008, and claims priority to Japanese Patent Application No. 2007-190120, filed on Jul. 20, 2007, all of which applications are incorporated herein by reference in their entireties.BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates to novel sulfonated sugar compounds and pharmaceutical compositions containing the same. The present invention also relates to novel methods of making such a compound and novel intermediates useful for making such a compound. The present invention further relates to novel methods for treating a tumor by administering such a compound.

[0004] 2. Discussion of the Background

[0005] At present, in Japan, malignant tumors, cardiac disease, and cerebrovascular disease...

Examples

example i

[0161]The steps for preparing the sulfoquinovosylacyl propanediol compound according to the present invention are described below taking, as an example, a sodium salt of α-sulfoquinovosyl stearoyl propanediol.

[0162]A) A-1. allyl alcohol, trifluoromethanesulfonic acid, 80° C., 48 hours;

[0163]A-2. benzaldehyde dimethyl acetal, p-toluene sulfonic acid monohydrate, acetonitrile, 40° C., 4 hours,

[0164]B) benzyi bromide, sodium hydroxide, N,N-dimethylformamide, room temperature, 24 hours, 84.4%;

[0165]C) lithium hydride aluminum, aluminum chloride, dichloromethane, diethyl ether, heating under reflux, 4 hours, 90.2%;

[0166]D) p-toluenesulfonyl chloride, 4-dimethylaminopyridine, pyridine, room temperature, 16 hours, 87.9%;

[0167]E) 9-borabicyclononane, tetrahydrofuran, room temperature, 10 hours; water, sodium hydroxide, hydrogen peroxide water, room temperature, 12 hours, 94.4%;

[0168]F) potassium thioacetate, N,N-dimethylforrnamide, 90° C., 3 hours, 90.8%;

[0169]G) stearoyl chloride, pyridine...

example i-1

Step A: 1-O-allyl-4,6-O-benzylidene-α-D-glucopyranose (2)

[0173]The compound (1) (100 g, 555 mmol) as the starting substance was suspended in allyl alcohol (500 ml), to which trifluoromethanesulfonic acid (1.00 ml) was added at 0° C., and the reaction liquid was vigorously stirred at 80° C. for 48 hours. After the sufficient progress of the reaction was confirmed, triethylamine (3 ml) was added to stop the reaction, and the reaction liquid was concentrated under reduced pressure. Subsequently, the residue was suspended in anhydrous acetonitrile (500 ml), to which benzaldehyde dimethyl acetal (127 g, 1.5 equivalent) and p-toluenesulfonic acid monohydrate (5.28 g, 0.05 equivalent) were added. The reaction liquid was stirred at, 40° C. for 4 hours, to which triethylamine (10 ml) was added to stop the reaction, and the reaction liquid was concentrated under reduced pressure. The residue was poured to hexane (2000 ml) and water (500 ml), and the mixed liquid was vigorously stirred. The ge...

example i-2

Step B; 1-O-allyl-2,3-di-O-benzyl-4,6-O-benzylidene-α-D-glucopyranose (3)

[0176]To a solution of the compound (2) (30.0 g, 97.3 mmol) in anhydrous N,N-dimethylformamide (DMF, 300 ml) were added benzyl bromide (41.6 g, 2.5 equivalents) and sodium hydroxide (11.7 g, 3.0 equivalents), and the reaction liquid was vigorously stirred at room temperature for 24 hours. After the sufficient progress of the reaction was confirmed, the reaction liquid was poured to chilled water (900 ml), and extracted with ethyl acetate (3×300 ml). The organic layers were combined and washed with saturated saline (2×100 ml), dried with sodium sulfate, filtered, concentrated under reduced pressure. The obtained residue was crystallized twice from heated ethanol to obtain the title compound (3) in the form of colorless needle crystals (33.5 g). The filtrate was concentrated, purified with silica gel chromatography (hexane-ethyl acetate, 15:1→10:1→8:1), crystallized from heated ethanol to obtain the compound (3) ...

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] The present application is a divisional application of application Ser. No. 12 / 322,151, filed Jan. 29, 2009, which is a continuation application of International Application No. PCT / JP2008 / 063056, filed on Jul. 18, 2008, and claims priority to Japanese Patent Application No. 2007-190120, filed on Jul. 20, 2007, all of which applications are incorporated herein by reference in their entireties.BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates to novel sulfonated sugar compounds and pharmaceutical compositions containing the same. The present invention also relates to novel methods of making such a compound and novel intermediates useful for making such a compound. The present invention further relates to novel methods for treating a tumor by administering such a compound.

[0004] 2. Discussion of the Background

[0005] At present, in Japan, malignant tumors, cardiac disease, and cerebrovascular disease...

Examples

example i

[0161]The steps for preparing the sulfoquinovosylacyl propanediol compound according to the present invention are described below taking, as an example, a sodium salt of α-sulfoquinovosyl stearoyl propanediol.

[0162]A) A-1. allyl alcohol, trifluoromethanesulfonic acid, 80° C., 48 hours;

[0163]A-2. benzaldehyde dimethyl acetal, p-toluene sulfonic acid monohydrate, acetonitrile, 40° C., 4 hours,

[0164]B) benzyi bromide, sodium hydroxide, N,N-dimethylformamide, room temperature, 24 hours, 84.4%;

[0165]C) lithium hydride aluminum, aluminum chloride, dichloromethane, diethyl ether, heating under reflux, 4 hours, 90.2%;

[0166]D) p-toluenesulfonyl chloride, 4-dimethylaminopyridine, pyridine, room temperature, 16 hours, 87.9%;

[0167]E) 9-borabicyclononane, tetrahydrofuran, room temperature, 10 hours; water, sodium hydroxide, hydrogen peroxide water, room temperature, 12 hours, 94.4%;

[0168]F) potassium thioacetate, N,N-dimethylforrnamide, 90° C., 3 hours, 90.8%;

[0169]G) stearoyl chloride, pyridine...

example i-1

Step A: 1-O-allyl-4,6-O-benzylidene-α-D-glucopyranose (2)

[0173]The compound (1) (100 g, 555 mmol) as the starting substance was suspended in allyl alcohol (500 ml), to which trifluoromethanesulfonic acid (1.00 ml) was added at 0° C., and the reaction liquid was vigorously stirred at 80° C. for 48 hours. After the sufficient progress of the reaction was confirmed, triethylamine (3 ml) was added to stop the reaction, and the reaction liquid was concentrated under reduced pressure. Subsequently, the residue was suspended in anhydrous acetonitrile (500 ml), to which benzaldehyde dimethyl acetal (127 g, 1.5 equivalent) and p-toluenesulfonic acid monohydrate (5.28 g, 0.05 equivalent) were added. The reaction liquid was stirred at, 40° C. for 4 hours, to which triethylamine (10 ml) was added to stop the reaction, and the reaction liquid was concentrated under reduced pressure. The residue was poured to hexane (2000 ml) and water (500 ml), and the mixed liquid was vigorously stirred. The ge...

example i-2

Step B; 1-O-allyl-2,3-di-O-benzyl-4,6-O-benzylidene-α-D-glucopyranose (3)

[0176]To a solution of the compound (2) (30.0 g, 97.3 mmol) in anhydrous N,N-dimethylformamide (DMF, 300 ml) were added benzyl bromide (41.6 g, 2.5 equivalents) and sodium hydroxide (11.7 g, 3.0 equivalents), and the reaction liquid was vigorously stirred at room temperature for 24 hours. After the sufficient progress of the reaction was confirmed, the reaction liquid was poured to chilled water (900 ml), and extracted with ethyl acetate (3×300 ml). The organic layers were combined and washed with saturated saline (2×100 ml), dried with sodium sulfate, filtered, concentrated under reduced pressure. The obtained residue was crystallized twice from heated ethanol to obtain the title compound (3) in the form of colorless needle crystals (33.5 g). The filtrate was concentrated, purified with silica gel chromatography (hexane-ethyl acetate, 15:1→10:1→8:1), crystallized from heated ethanol to obtain the compound (3) ...

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