JPH10195097A - C-glycoside derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new chemically and physiologically stable compound having a substituted amide group at the 6-position, having an excellent cell adhesion-inhibiting activity. SOLUTION: A compound of formula I (R<1> is a 1-18C alkyl, phenyl(1-12C) alkyl; R<2> , R<3> are each D-galactopyranosyl, L-fucopyranosyl; R<4> is a 1-6C alyl, an aromatic heterocyclic group, etc.), e.g. (α-L-fucopyranosyl-(1→4)-0-[(β-D- galactosylphyranosyl)-(1→3)-0]-(6-naphthamido-1α-propyl-1,2,6-trideoxy-D- alabinohexopyranose). The compound is obtained e.g. by successively applying a reaction with a carbon-nucleophilic agent, a hydrolysis reaction, etc., to a compound of formula II (R<5> is an aroyl, benzyl, etc.; Z<1> is a releasable group), reacting the product with a compound of formula III (R<10> is benzyl; Z<2> is Z<1> ), applying a protecting group-removing reaction, a hydrolysis reaction, etc., to the reaction product, reacting the product with a compound of formula IV (R<12> is aroyl, etc.; Z<3> is Z<1> ), and further applying a protecting group-removing reaction, etc., to the reaction product.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to derivatives of Lewis a and Lewis x-type sugar chains, ie, C-glycoside derivatives. Such derivatives have cell adhesion inhibitory activity and are useful as medicaments for treating and ameliorating diseases such as inflammation, ischemia reperfusion injury, autoimmune diseases or cancer metastasis.

[0002]

PRIOR ART E-selectin, a neutrophil adhesion molecule expressed on vascular endothelial cells, P-selectin, a neutrophil adhesion molecule expressed on vascular endothelial cells and platelets, and L, a homing receptor for lymphocytes -Selectin is known to recognize as a ligand a sugar chain structure such as Lewis x, Lewis a, sialyl Lewis x and sialyl Lewis a (hereinafter referred to as Lewis sugar chain) (Morowaka Shigeaki et al., Hematopoietic factor, 6 , 17 (1995)). The onset of various inflammatory diseases starts from the interaction through the binding of these selectins and ligands, so it is predicted that substances that inhibit such adhesion may be anti-inflammatory agents ( MP Bevilacqua et al., Thrombosis Haemostasis, 70 ,
152 (1993)). Accordingly, derivatives of Lewis sugar chains are expected to be applied to diseases involving these selectins, and application of Lewis sugar chains to therapeutic agents has been attempted. As an in vivo pathological model in which the effect of Lewis type sugar chain is recognized, I
gG immune complex (MS Mulligan et al., J. Exp. Med.,
178 , 623 (1993)), lung damage due to cobra toxin (MS)
Mulligan et al., Nature, 364 , 149 (1993)), reperfusion injury after cardiac ischemia (D. Lefer et al., J. Clin. Invest., 93 ,
1140 (1994)). Therefore, it is extremely important for conducting research on various derivatives synthesis with analogues of Lewis a and Lewis x-type sugar chains as key compounds and finding derivatives having better activity in creating therapeutic agents for various diseases. is there.

[0003]

However, most of such derivative studies are concerned with O-glycosides at the reducing end. On the other hand, derivatives that are more stable chemically and physiologically and have improved in vivo stability are expected in the creation of therapeutic agents for various diseases. The object of the present invention is to use Lewis-type sugar chain derivatives that are more stable chemically and physiologically and have excellent cell adhesion inhibitory activity, ie, C-glycoside derivatives, and pharmaceutical compositions containing them as an active ingredient, and It is to provide those applications.

[0004]

Means for Solving the Problems The present inventors (alpha-L
-Fucopyranosyl)-(1 → 4) -O-[(β-D-galactopyranosyl)-(1 → 3) -O]-(6-substituted amido-1,2,6-trideoxy-1α-alkyl -D
-Arabinohexopyranose) derivatives, (α-L-fucopyranosyl)-(1 → 3) -O-[(β-D-galactopyranosyl)-(1 → 4) -O]-(6-substituted amido -
2-Deoxy-C-Glycoside derivatives having a substituted amido group at the 6-position, such as 1,2,6-trideoxy-1α-alkyl-D-arabinohexopyranose) derivatives, inhibit the adhesion between selectins and neutrophils The present invention has been completed. That is, the present invention has a general formula

[Chemical formula 2] [Wherein, R ¹ represents a C ₁ -C ₁₈ alkyl group or phenyl C _1-
It is a C ₁₂ alkyl group. R ² and R ³ are different from each other, D-
It is a galactopyranosyl group or an L-fucopyranosyl group. R ⁴ represents a C ₁ -C ₆ alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aromatic heterocyclic group, or a C _1- group terminated with an aryl group or an aromatic heterocyclic group
It is a C ₆ alkyl group. The present invention relates to a C-glycoside derivative represented by the formula:

The substituents in the present invention are described below. The substituted amido group is a substituent R ⁴ as described below
With the amido group having a carbonyl carbon atom.
The C ₁ -C ₁₈ alkyl group for R ¹ in the above formula is a linear or branched alkyl group consisting of 1 to 18 carbon atoms, and specifically, a methyl group, an ethyl group, n -Propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group, 3-pentyl group, isopentyl group, neopentyl group, n-hexyl group, n-heptyl group, 4-heptyl group , N-octyl group, n-nonyl group, 5-nonyl group, n-decyl group, n-undecyl group, 6
-Undecyl group, n-dodecyl group, n-tridecyl group, 7
-Tridecyl group, n-tetradecyl group, n-pentadecyl group, 8-pentadecyl group, n-hexadecyl group, n-heptadecyl group, 9-heptadecyl group, n-octadecyl group and the like.

The phenyl C ₁ -C ₁₂ alkyl group in R ¹ is a linear or branched alkyl group consisting of 1 to 12 carbon atoms having a phenyl group at the end, and specifically, benzyl Group, phenethyl group, phenylpropyl group, phenylbutyl group, phenylpentyl group, phenylhexyl group, phenylheptyl group, phenyloctyl group, phenylnonyl group, phenyldecyl group, phenylundecyl group, phenyldodecyl group, etc. it can.

The C ₁ -C ₆ alkyl group in R ⁴ is a linear or branched alkyl group having 1 to 6 carbon atoms, and specific examples thereof include a methyl group, an ethyl group and an n-group. Propyl, isopropyl, n-butyl, isobutyl, t
And -butyl, n-pentyl, 3-pentyl, isopentyl, neopentyl, n-hexyl and the like.

The aryl group for R ⁴ is a five-membered monocyclic, six-membered monocyclic, fused polycyclic fused six-membered ring and five-membered ring, or fused polycyclic fused six-membered ring. The aromatic ring hydrocarbon group of the formula is meant. That is, it represents, for example, a monocyclic aromatic hydrocarbon group such as a phenyl group, for example, a fused polycyclic aromatic hydrocarbon group such as a naphthyl group, anthracenyl group (anthryl group), and phenanthrenyl group. As a naphthyl group, (beta) -naphthyl group is preferable.

The aromatic heterocyclic group for R ⁴ is a 5-membered monocyclic, 6-membered monocyclic, 6-membered ring and 5-membered ring containing one or two oxygen atoms, sulfur atoms or nitrogen atoms. This represents a fused fused polycyclic or fused fused aromatic heterocyclic group in which six-membered rings are fused. That is, for example, furyl group, thienyl group, pyridyl group, pyrazinyl group, benzo [b] furanyl group, benzo [c] furanyl group, benzo [b] thienyl group, benzo [c] thienyl group, pyrimidinyl group, pyridazinyl group, quinolinyl Groups, isoquinolinyl groups, quinoxalinyl groups, naphthyridinyl groups, phthalazinyl groups, quinazolinyl groups and the like. The position of the bonding branch in forming a group can be arbitrarily selected from all possible positions.

The substituted aryl group and substituted aromatic heterocyclic group for R ^{4 have} one or more of one or more of the substituents described below on the aromatic ring. As such a substituent, a halogen atom, a nitro group, a trifluoromethyl group, a hydroxyl group, for example, a methyl group, an ethyl group, n-
Propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, 3-pentyl,
Isopentyl group, neopentyl group, n-hexyl group, n-
Heptyl group, 4-heptyl group, n-octyl group, n-nonyl group, 5-nonyl group, n-decyl group, n-undecyl group,
6-undecyl group, n-dodecyl group, n-tridecyl group,
A straight chain having 1 to 18 carbon atoms such as 7-tridecyl group, n-tetradecyl group, n-pentadecyl group, 8-pentadecyl group, n-hexadecyl group, n-heptadecyl group, 9-heptadecyl group and n-octadecyl group Or branched alkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, (4-cyclohexyl) cyclohexyl group, etc. cycloalkyl group having 1 to 18 carbon atoms ,
Phenyl group such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, pentyloxy group, cyclopentyloxy group, hexyloxy group, cyclohexyloxy group, heptyloxy group, octyloxy group, nonyloxy group, decyloxy group, A linear or chain having 1 to 18 carbon atoms such as undecyloxy group, dodecyloxy group, tridecyloxy group, tetradecyloxy group, pentadecyloxy group, hexadecyloxy group, heptadecyloxy group, octadecyloxy group, etc. Branched alkoxy group or cycloalkoxy group, phenoxy group, benzyloxy group, (substituted benzyl) oxy group, amino group, benzylamino group, (substituted benzyl) amino group, linear or branched having 1 to 18 carbon atoms A branched monoalkylamino group or monolith And each alkyl chain is a dialkylamino group having 1 to 18 carbon atoms or a dicycloalkylamino group, a linear or branched alkyl group having 1 to 18 carbon atoms, and 1 to 18 carbon atoms. Amino group having a cycloalkyl group, linear or branched alkylbenzylamino group having 1 to 18 carbon atoms in the alkyl chain, cycloalkylbenzylamino group having 1 to 18 carbon atoms in the alkyl chain, Acetylamino group, propionylamino group, butyrylamino group, valerylamino group, pentanoylamino group, cyclopentanecarboxamide group, hexanoylamino group, cyclohexanecarboxamide group, heptanoylamino group, octanoylamino group, nonanoylamino group, decanoyl Amino group, undecanoylamino group, dodecanoyl Linear having 1 to 18 carbon atoms, such as mino, tridecanoylamino, tetradecanoylamino, pentadecanoylamino, hexadecanoylamino, heptadecanoylamino, octadecanoylamino, etc. Or branched alkanoylamino group (alkyl carboxamido group) or cycloalkanoyl group (cycloalkyl carboxamido group), such as benzoylamino group, naphthoylamino group, etc. aroylamino group having 1 to 10 carbon atoms, carboxyl group, for example methylcarbamoyl Group, ethyl carbamoyl group, propyl carbamoyl group, butyl carbamoyl group, pentyl carbamoyl group, cyclopentyl carbamoyl group, hexyl carbamoyl group, cyclohexyl carbamoyl group, heptyl carbamoyl group, octyl carbamoyl group, no Nylcarbamoyl, decylcarbamoyl, undecylcarbamoyl, dodecylcarbamoyl, tridecylcarbamoyl, tetradecylcarbamoyl, pentadecylcarbamoyl, hexadecylcarbamoyl, heptadecylcarbamoyl, octadecylcarbamoyl, etc. C1-C18 linear or branched alkylcarbamoyl group (alkylaminocarbamoyl group) or cycloalkylcarbamoyl group, arylcarbamoyl group, carbon number is 1 to 1
Examples of eight linear or branched alkylthio groups, arylthio groups, linear or branched alkylsulfonyl groups having 1 to 18 carbon atoms, cycloalkylsulfonyl groups, arylsulfonyl groups, cyano groups, etc. Can.

Further, a C ₁ -C ₆ alkyl group terminated with an aryl group in R ⁴ is, for example, phenyl C ₁
A C ₆ alkyl group, that is, a linear or branched alkyl group consisting of 1 to 6 carbon atoms having a phenyl group at the end, specifically a benzyl group, a phenethyl group,
A phenylpropyl group, a phenylbutyl group etc. can be mentioned. The C ₁ -C ₆ alkyl group having an aromatic heterocyclic group at the end as R ⁴ is a linear or branched alkyl group having 1 to 6 carbon atoms having an aromatic heterocyclic group at the end is there.

Specific examples of the compound of the present invention are illustrated below.・ (Α-L-fucopyranosyl)-(1 → 4) -O-
[(Β-D-galactopyranosyl)-(1 → 3) -O]
-(6-naphthamide-1α-propyl-1,2,6,-
Trideoxy-D-arabinohexopyranose) (α-L-fucopyranosyl)-(1 → 4) -O-
[(Β-D-galactopyranosyl)-(1 → 3) -O]
-(6-Acetamido-1α-propyl-1,2,6,-
Trideoxy-D-arabinohexopyranose) (α-L-fucopyranosyl)-(1 → 4) -O-
[(Β-D-galactopyranosyl)-(1 → 3) -O]
-(6-benzoamido-1α-propyl-1,2,6,
-Trideoxy-D-arabinohexopyranose) (α-L-fucopyranosyl)-(1 → 3) -O-
[(Β-D-galactopyranosyl)-(1 → 4) -O]
-(6-naphthamide-1α-propyl-1,2,6,-
Trideoxy-D-arabinohexopyranose) (α-L-fucopyranosyl)-(1 → 3) -O-
[(Β-D-galactopyranosyl)-(1 → 4) -O]
-(6-Acetamido-1α-propyl-1,2,6,-
Trideoxy-D-arabinohexopyranose) (α-L-fucopyranosyl)-(1 → 3) -O-
[(Β-D-galactopyranosyl)-(1 → 4) -O]
-(6-benzoamido-1α-propyl-1,2,6,
-Trideoxy-D-arabinohexopyranose) (α-L-fucopyranosyl)-(1 → 4) -O-
[(Β-D-galactopyranosyl)-(1 → 3) -O]
-(6-naphthamide-1α-phenylpropyl-1,
2,6,-Trideoxy-D-arabinohexopyranose) (α-L-fucopyranosyl)-(1 → 4) -O-
[(Β-D-galactopyranosyl)-(1 → 3) -O]
-(6-Acetamido-1α-phenylpropyl-1,
2,6,-Trideoxy-D-arabinohexopyranose) (α-L-fucopyranosyl)-(1 → 4) -O-
[(Β-D-galactopyranosyl)-(1 → 3) -O]
-(6-benzoamido-1α-phenylpropyl-1,
2,6,-Trideoxy-D-arabinohexopyranose) (α-L-fucopyranosyl)-(1 → 3) -O-
[(Β-D-galactopyranosyl)-(1 → 4) -O]
-(6-naphthamide-1α-phenylpropyl-1,
2,6,-Trideoxy-D-arabinohexopyranose) (α-L-fucopyranosyl)-(1 → 3) -O-
[(Β-D-galactopyranosyl)-(1 → 4) -O]
-(6-Acetamido-1α-phenylpropyl-1,
2,6,-Trideoxy-D-arabinohexopyranose) (α-L-fucopyranosyl)-(1 → 3) -O-
[(Β-D-galactopyranosyl)-(1 → 4) -O]
-(6-benzoamido-1α-phenylpropyl-1,
2,6,-Trideoxy-D-arabinohexopyranose)

The compound (1) of the present invention can be produced from the compound (2) by the method described below. [Scheme A]

[Chemical formula 3]

[Chemical formula 4]

[Chemical formula 5]

[Chemical formula 6]

[Chemical formula 7]

[Image 8] [Wherein, R ¹ and R ² are as defined above. R ⁵ is C ₁
C ₆ alkanoyl, aroyl, benzyl or substituted benzyl. R ⁶ is a C ₁ -C ₁₈ alkyl group, a phenyl C ₁ -C ₁₂ alkyl group, a C ₂ -C ₁₈ alkenyl group, a phenyl C ₂ -C ₁₂ alkenyl group, a C ₂ -C ₁₈ alkynyl group or a phenyl C ₂ -C ₁₂ alkynyl group. R ⁷ is a substituted phenyl group. R ⁸ , R ¹² and R ¹³ are each a C ₁ -C ₆ alkanoyl group or an aroyl group. R ⁹ is a substituted benzyl group. R ¹⁰ is a benzyl group. R ¹¹ is a trialkylsilyl group or a 2,2,2-trichloroethoxycarbonyl group. R ¹⁴ is an azide group or a phthalimido group. Z ¹ , Z ² and Z ³ are leaving groups. ]

(Step A-1) C-glycosylation is carried out by reacting a compound (2) having a leaving group Z ¹ with a carbon nucleophile in the presence of an activating agent such as a Lewis acid or a metal salt. It is possible to produce a graded body (3). Examples of the leaving group Z ¹ on the compound (2) include a halogen atom, a substituted hydroxyl group, a substituted sulfide group and the like (for example, the fourth group).
Plated Experimental Chemistry Lecture, Vol. 26, Organic Synthesis VII, pp. 267-354,
Refer to the Chemical Society of Japan (1992)). Specific examples of the halogen atom include chlorine, bromine, fluorine and the like. In this case, as an activating agent used in the reaction, mainly, silver trifluoromethanesulfonate (silver triflate), mercuric chloride, mercuric chloride Mercuric iodide, mercuric iodide, mercuric cyanide, mercury oxide, silver oxide, silver carbonate, silver perchlorate, first silver chloride, first silver bromide, first silver iodide, silver silicate, Heavy metal salts such as silver tetraboronate, silver zeolite, stannous chloride, stannous bromide, stannous iodide, stannic chloride, stannic bromide, stannic iodide, etc. There may be mentioned quaternary ammonium salts such as tetraethylammonium chloride and tetrabutylammonium chloride, and these may be used in combination as needed. In addition, trimethylsilyl trifluoromethanesulfonate (TMS triflate), ethereal boron trifluoride, silicon tetrafluoride and the like can also be used as the activating agent. Specific examples of the substituted hydroxyl group include acetyloxy group, benzoyloxy group, p-nitrobenzoyloxy group, imidate group, methoxy group and naphthyloxy group. In this case, trimethylsilyl trifluoromethanesulfonate (TMS triflate), p-toluenesulfonic acid, ethereal boron trifluoride, chlorotrimethylsilane, trimethylbromide bromide, mainly as an activating agent used for the reaction.
Trimethyliodosilane, zinc chloride, zinc bromide, zinc iodide, stannous chloride, stannous bromide, stannous iodide,
Stannic chloride, stannic bromide, stannic iodide, titanium tetrachloride, titanium tetrabromide, titanium tetraiodide, ferric chloride,
Ferric bromide, ferric iodide, cupric chloride, cupric bromide,
Lewis acid and protonic acid such as aluminum chloride, aluminum bromide and aluminum iodide may be mentioned, and they may be used in combination as needed. Specific examples of the substituted sulfide group include an alkylthio group, a phenylthio group and a pyridylthio group. In this case, methyl triflate, copper bromide-tetrabutylammonium bromide, N-iodosuccinimide-trifluoromethanesulfonic acid, iodonium dicholidine perchlorate, dimethyl methylthio are mainly used as an activating agent for the reaction. Examples thereof include sulfonium triflate and the like, and these can be used in combination as needed. Furthermore,
Also phenylsulfenyl group, phenylselenyl group, dialkyl phosphoryl group or diphenyl phosphonyl group
It can be mentioned as leaving group Z ¹ (Studies in Natu
ral Products Chemistry, Vol. 10, 337-403, Elsevie
r Science Publishers (1992), MHD Postema, Te
trahedron, Vol. 48, 8545-5559 (1992)). The compound (2) having a leaving group Z ¹ used in this reaction is
3,4,6-tri-O-protected-2-deoxy-D-glucose, alkyl 3,4,6-tri-O-protected-2-
Deoxy-D-glycoside, 1-O-acyl-3,4,4,
It can be prepared by a conventional method using 6-tri-O-protected-2-deoxy-D-glucose (for example, 4th edition Experimental Chemistry Lecture, vol. 26, organic synthesis VII, 267-354).
Pp., Chemical Society of Japan (1992)). In any reaction, examples of carbon nucleophiles used in the reaction include Greenyard's reagent containing a substituent represented by R ⁶ described above, alkenylsilane compounds, alkenyltin compounds, and alkynyl metal compounds. The reaction is preferably carried out in a solvent, and as the solvent to be used, ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane and dioxane, halogen solvents such as methylene chloride and 1,2-dichloroethane, benzene, toluene, chlorobenzene and the like Aromatic solvents, aliphatic hydrocarbon solvents such as hexane and cyclohexane, dimethylformamide (DMF), dimethylacetamide, acetonitrile, propionitrile, polar aprotic solvents such as nitromethane, nitroethane and nitropropane, or acetone It can be mentioned. These are used alone or as a mixed solvent. N, N, N ', N'-tetramethylurea, pyridine, 2,6-di-t-butylpyridine, 2,6- in the reaction system as a scavenger for the acid generated in the system along with the reaction. Lutidine, 2,4,6-collidine, triethylamine or molecular sieves (MS3A, MS
4A or MS 5A) may be coexistent. The reaction is desirably carried out under anhydrous conditions, therefore, it is better to remove as much water as possible for solvents, reagents, substrates, reaction vessels and the like. In some cases, a dehydrating agent such as molecular sieves (MS3A, MS4A or MS5A) or anhydrous calcium sulfate may coexist in the reaction system to remove water. In addition, the reaction using a silver salt should be performed by blocking light. The reaction temperature is -70 ° C to 100 ° C, preferably -2
It is selected in the range of 0 ° C. to 60 ° C. (or the boiling point of the solvent). The reaction time mainly depends on the reaction temperature, the raw material compounds used,
Although it depends on reagents, solvents, etc., it is usually 1 hour to 5 days.

(Step A-2) When R ⁵ in the compound (3) obtained by the above method is a C ₁ -C ₆ alkanoyl group or an aroyl group, hydrolysis is performed under basic conditions in a solvent By doing this, compound (4) can be obtained. As the base, carbonates such as sodium carbonate and potassium carbonate, hydroxides such as sodium hydroxide and potassium hydroxide, bicarbonates such as sodium bicarbonate and potassium bicarbonate, disodium hydrogen phosphate, hydrogen phosphate Potassium, or triethylamine, N, N-diisopropylethylamine, pyridine, dimethylaniline, 1,8
-Diazabicyclo [5.4.0] undecene (DBU),
Organic bases such as hexamethyldisilazane lithium, sodium methoxide, sodium ethoxide and the like can be used. When R ⁵ in compound (3) is a benzyl group or a substituted benzyl group, for example, compound (4) can be obtained by hydrogenation in the presence of palladium on carbon. The amount of palladium carbon used may be a catalytic amount, usually 0.001 to 10 equivalents. Moreover, as a hydrogen source, for example, hydrogen molecule, formic acid, ammonium formate, cyclohexene, 1,4-cyclohexadiene, cis-decalin and the like can be mentioned. These reactions are preferably carried out in a solvent, and examples of the solvent include alcohol solvents such as methanol, ethanol, propanol and isopropanol. These are used alone or as a mixed solvent. Alternatively, when R ⁵ is a p-methoxybenzyl group, deprotection can also be performed using, for example, cerium ammonium nitrate (CAN) or dichlorodicyanoquinone (DDQ) to obtain compound (4). it can. As a solvent
Halogen solvents such as methylene chloride and 1,2-dichloroethane or water can be mentioned. These are used alone or as a mixed solvent. In any reaction, the reaction temperature is selected in the range of -70 ° C to 100 ° C, preferably -20 ° C to 60 ° C (or the boiling point of the solvent). The reaction time mainly depends on the reaction temperature, the starting compounds used, reagents,
Although it depends on the solvent etc, it is usually 1 hour to 1 day.

Step (A-3) A compound (5) can be produced by introducing a cyclic acetal protecting group into the compound (4) obtained by the above method in the presence of an acid catalyst. Specific examples of cyclic acetal protecting agents include substituted benzaldehyde, substituted benzaldehyde dimethyl acetal, and substituted benzaldehyde (trimethylsilyl) acetal. As the acid catalyst, sulfuric acid, p-toluenesulfonic acid, camphor-sulfonic acid and the like can be mentioned. The reaction is preferably carried out in a solvent, and the solvent includes polar aprotic solvents such as dimethylformamide (DMF), dimethylacetamide, acetonitrile, propionitrile, nitromethane, nitroethane, nitropropane and the like. These are used alone or as a mixed solvent. The reaction temperature is -70 ° C
It is selected in the range of from 100 ° C., preferably from 0 ° C. to 60 ° C. (or the boiling point of the solvent). The reaction time depends mainly on the reaction temperature, the raw material compounds used, reagents, solvents and the like, but is usually 1 hour to 2 days.

Step A-4 Compound (6) can be produced by reacting compound (5) obtained by the above method with an acylating agent in the presence of a base.
As the acylating agent, corresponding carboxylic acid halides, carboxylic acid anhydrides and the like can be used. The halogen atom of the halide includes chlorine, bromine, iodine and the like. As a base, triethylamine, N, N-diisopropylethylamine, pyridine, dimethylaniline,
1,8-diazabicyclo [5.4.0] undecene (DB)
Organic bases such as U) can be used. The reaction is preferably carried out in a solvent, which is methylene chloride,
Halogen solvents such as 1,2-dichloroethane and the like can be mentioned. These are used alone or as a mixed solvent. The reaction temperature is -70 ° C to 100 ° C, preferably 0 ° C
It is selected in the range of from 60 ° C. (or the boiling point of the solvent).
The reaction time depends mainly on the reaction temperature, the raw material compounds used, reagents, solvents and the like, but is usually 1 hour to 2 days.

Step (A-5) The compound (7) can be produced by performing regioselective reductive cleavage reaction on the compound (6) obtained by the above method.
As the reducing agent used for the reaction, sodium cyanoborohydride, borane-trimethylamine complex salt, lithium aluminum hydride and the like can be mentioned (PJ Garegg et al., Carboh
ydro. Res., 108 , 97 (1982), P. Fugedi et al., ibid.,
104 , 55 (1982), PJ Garegg et al., J. Carbohydro. Ch.
em., 2 , 305 (1983)), and these can be used in combination as needed. The reaction is preferably carried out in the presence of an acid, and the acid used is trifluoroacetic acid, hydrochloric acid,
There may be mentioned trimethylsilane chloride or a Lewis acid such as aluminum chloride, aluminum bromide or aluminum iodide, and these may be used in combination as required. The reaction is preferably carried out in a solvent, and examples of the solvent to be used include ether solvents such as tetrahydrofuran, diethyl ether, dimethoxyethane, dioxane and the like. These are used alone or as a mixed solvent. The reaction temperature is selected in the range of -70 ° C to 100 ° C, preferably -20 ° C to 60 ° C (or the boiling point of the solvent). The reaction time depends mainly on the reaction temperature, the raw material compounds used, reagents, solvents and the like, but is usually 1 hour to 2 days.

Step (A-6) The compound (7) obtained by the above method is treated with a compound (8) having a leaving group Z ² in the presence of an activating agent such as a Lewis acid or a metal salt, and A- By reacting in the same manner as in step 1, a glycosidation grade (9) can be produced. The leaving group Z ² on the compounds used in this reaction (8), the same as the leaving group Z ¹ is used. Compound (8) is 2,3,4-tri-O-protected-L-fucopyranose, alkyl 2,3,
4-tri-O-protected-L-fucopyranoside or
The acyl 2,3,4-tri-O-protected-L-fucopyranoside can be prepared by a conventional method (for example, 4th edition Experimental Chemistry Lecture, vol. 26, organic synthesis VII, 267-
See page 354, edited by The Chemical Society of Japan (1992)).

Step (A-7) The compound (9) obtained by the above method is subjected to deprotection using cerium ammonium nitrate (CAN) or dichlorodicyanoquinone (DDQ) to give a compound (10) You can get it. Examples of the solvent include halogen based solvents such as methylene chloride and 1,2-dichloroethane or water. These are used alone or as a mixed solvent. The reaction temperature is -70 ° C to 100 ° C, preferably -20 ° C to 60 ° C.
(Or the boiling point of the solvent) is selected. The reaction time depends mainly on the reaction temperature, the raw material compounds used, reagents, solvents and the like, but is usually 1 hour to 1 day.

(Step A-8) 6 of the 2-deoxy-glucose moiety of the compound (10) obtained by the above method
By protecting the hydroxyl group, compound (11) can be produced. As a method of protection, when such a protective group is a trialkylsilyl group, for example, “Protective Gro
ups in Organic Synthesis "(TW Greene, PGM
Wuts, Second Edition, John Wiley & Sons, Inc. (1991)
On pages 68 to 86). That is, the reaction is preferably carried out in the presence or absence of a base, and the compound (11) can be produced by reacting with a trialkylsilylating agent. Examples of trialkylsilylating agents include trialkylsilyl halides and trialkylsilyl triflates. Examples of trialkylsilyl halides include trimethylsilyl chloride, triethylsilyl chloride, triisopropylsilyl chloride, dimethylisopropylsilyl chloride, diethylisopropylsilyl chloride, dimethyltexenyl chloride, t-butyldimethylsilyl chloride, t-butyldiphenylsilyl chloride, and tribenzyl. Silyl chloride, tri-p-xylsilyl silyl chloride, triphenyl silyl chloride, diphenylmethyl silyl chloride, t-
And butyl methoxyphenyl silyl chloride and the like. As trialkylsilyl triflate, triethylsilyl triflate, triisopropylsilyl triflate, t-butyldimethylsilyl triflate, t-
And butyl diphenyl silyl triflate and the like.
In addition, when such a protective group is a 2,2,2-trichloroethoxycarbonyl group, in the presence of a base,
Compound (11) can be produced by reacting with 2-trichloroethoxycarbonyl chloride. As a base used for these reactions, imidazole, pyridine, triethylamine, 2,6-lutidine,
Dimethylaminopyridine, N, N-diisopropylethylamine and the like can be mentioned. The reaction is preferably carried out in a solvent, and solvents such as methylene chloride, halogen solvents such as 1,2-dichloroethane, dimethylformamide (DMF), dimethylacetamide, acetonitrile, propionitrile, nitromethane, nitroethane, nitropropane and the like And polar aprotic solvents and the like.
These are used alone or as a mixed solvent. It is desirable to carry out the reaction under anhydrous conditions and thus the solvent
It is better to remove water as much as possible for reagents, substrates, reaction vessels, etc. The reaction temperature is -70 ° C to 100 ° C,
Preferably from -20 ° C to 60 ° C (or the boiling point of the solvent)
It is chosen in the range of The reaction time depends mainly on the reaction temperature, the raw material compounds used, reagents, solvents and the like, but is usually 1 hour to 5 days.

Step (A-9) The compound (12) can be produced by hydrolyzing the compound (11) obtained by the above method under basic conditions in a solvent. As a base, sodium methoxide, sodium ethoxide etc. can be used, for example. Examples of the solvent include alcohol solvents such as methanol, ethanol, propanol and isopropanol, aromatic solvents such as acetone, water, benzene, toluene and chlorobenzene, and halogen solvents such as methylene chloride and 1,2-dichloroethane. These are used alone or as a mixed solvent. The reaction temperature is -70 ° C to 100
° C, preferably 0 ° C to 60 ° C (or the boiling point of the solvent)
It is chosen in the range of The reaction time depends mainly on the reaction temperature, the raw material compounds used, reagents, solvents and the like, but is usually 1 hour to 2 days.

Step (A-10) The compound (12) obtained by the above method is treated with a compound (13) having a leaving group Z ³ and an A-containing compound in the presence of an activating agent such as a Lewis acid or a metal salt. By reacting in the same manner as in step 6, a glycosidation grade (14) can be produced. The leaving group Z ³ on the compounds used in this reaction (13), the same as the leaving group Z ² is used. The compound (13) is
2,3,4,6-Tetra-O-protected-D-galactose, alkyl 2,3,4,6-tetra-O-protected-D
Galactoside or acyl 2,3,4,6-
The tetra-O-protected-D-galactoside can be produced by a conventional method (for example, 4th edition Experimental Chemistry Lecture, Volume 26, Organic Synthesis VII, pp. 267-354, edited by The Chemical Society of Japan)
(1992)).

Step (A-11) The compound (14) obtained by the above method can be easily deprotected by hydrogenation in the presence of palladium on carbon,
Compound (15) can be obtained. The amount of palladium carbon used is usually 0.001 to 10 equivalents. Moreover, as a hydrogen source, for example, hydrogen molecule, formic acid, ammonium formate, cyclohexene, 1,4-cyclohexadiene, cis-decalin and the like can be mentioned. The reaction is preferably carried out in a solvent, and examples of the solvent include alcohol solvents such as methanol, ethanol, propanol and isopropanol. These are used alone or as a mixed solvent. The reaction temperature is -70 ° C to 10
The temperature is selected in the range of 0 ° C., preferably 0 ° C. to 60 ° C. (or the boiling point of the solvent). The reaction time depends mainly on the reaction temperature, the raw material compounds used, reagents, solvents, etc.
Usually 1 hour to 1 day.

(Step A-12) The compound (15) obtained by the above method is treated with an acylating agent and A- in the presence of a base.
Compound (16) can be produced by reacting in the same manner as in step 4.

(Step A-13) Only the protecting group on the 6-position hydroxyl group of the 2-deoxy-glucose moiety of the compound (16) obtained by the above method is selectively deprotected to give a compound (17) It can be manufactured. As a method of deprotection, for example, “Protective Groups in Organic Synthes
is "(TW Greene, PGM Wuts, co-author, 2nd edition, Jo
The methods described on pages 68 to 86 of hn Wiley & Sons, Inc. (1991)) can be mentioned. In actual deprotecting,
Among these methods, it is preferable to appropriately select a method capable of selectively deprotecting only the protective group on the 6-position hydroxyl group of the 2-deoxy-glucose site. When such a protecting group is a trialkylsilyl group, for example, by using p-toluenesulfonic acid monohydrate, tetrabutylammonium fluoride, potassium fluoride, hydrogen fluoride or hydrogen fluoride-pyridine complex. Can be easily deprotected. The reaction is preferably carried out in a solvent, and examples of the solvent include acetonitrile, tetrahydrofuran, water and the like. These are used alone or as a mixed solvent.
In addition, when such a protective group is a 2,2,2-trichloroethoxycarbonyl group, for example, it can be easily deprotected by reacting with zinc or a zinc-copper complex. Solvents include methanol and acetic acid.
In these reactions, the reaction temperature is -70 ° C to 100
° C, preferably 0 ° C to 60 ° C (or the boiling point of the solvent)
It is chosen in the range of The reaction time depends mainly on the reaction temperature, the raw material compounds used, reagents, solvents and the like, but is usually 1 hour to 1 day.

(Step A-14) When the substituent R ¹⁴ on the compound (18) is an azide group, the compound (17) obtained by the above method is subjected to sulfonic acid esterification and azide reaction. By applying, compound (18) can be produced. The sulfonic acid esterification of compound (17) can be carried out by reacting with a sulfonic acid esterification agent in the presence of a base. As the sulfonic acid esterification agent, for example, sulfonyl halides such as p-toluenesulfonyl chloride (tosyl chloride) and methanesulfonyl chloride (mesyl chloride), sulfonic acid anhydride and the like can be used. As a base used for the reaction, pyridine, triethylamine,
Examples include 2,6-lutidine, dimethylaminopyridine, N, N-diisopropylethylamine and the like. The reaction is preferably carried out in a solvent, which is methylene chloride,
Halogen solvents such as 1,2-dichloroethane and the like can be mentioned. These are used alone or as a mixed solvent. The reaction temperature is -70 ° C to 100 ° C, preferably 0 ° C
It is selected in the range of from 60 ° C. (or the boiling point of the solvent).
The reaction time depends mainly on the reaction temperature, the raw material compounds used, reagents, solvents and the like, but is usually 1 hour to 1 day. Subsequently, compound (18) can be produced by reacting the compound obtained by sulfonic acid esterification of compound (17) with a metal azide.
Examples of metal azides include sodium azide, lithium azide, potassium azide and the like. The reaction is preferably carried out in a solvent, and as the solvent, polar aprotic solvents such as dimethylformamide (DMF), dimethylacetamide, dimethylsulfoxide (DMSO) and acetonitrile, alcohol solvents such as methanol, ethanol, propanol and isopropanol, Examples include acetone and water. These are used alone or as a mixed solvent. Further, when the substituent R ¹⁴ on the compound (18) is a phthalimide group, the compound (17) obtained by the above method is diethyl in the presence of diethyl azodicarboxylate (DEAD) and triphenylphosphine Ether, tetrahydrofuran, dimethoxyethane,
Compound (18) can be produced by reaction with phthalimide in an ether solvent such as dioxane. In any reaction, the reaction temperature is -70 ° C
It is selected in the range of from 100 ° C., preferably from 0 ° C. to 60 ° C. (or the boiling point of the solvent). The reaction time depends mainly on the reaction temperature, the raw material compounds used, reagents, solvents and the like, but is usually 1 hour to 1 day.

(Step A-15) When the substituent R ¹⁴ on the compound (18) obtained by the above method is an azide group, hydrogenation is carried out, for example, in the presence of palladium on carbon Compound (19) can be produced. The amount of palladium carbon used may be a catalytic amount, usually 0.001 to 10 equivalents. Moreover, as a hydrogen source, for example, hydrogen molecule, formic acid, ammonium formate, cyclohexene, 1,4-cyclohexadiene, cis-decalin and the like can be mentioned. The reaction is preferably carried out in a solvent, and examples of the solvent include alcohol solvents such as methanol, ethanol, propanol and isopropanol. These are used alone or as a mixed solvent. The reaction temperature is -70 ° C to 100 ° C, preferably-
It is selected in the range of 20 ° C. to 60 ° C. (or the boiling point of the solvent). The reaction time depends mainly on the reaction temperature, the raw material compounds used, reagents, solvents and the like, but is usually 1 hour to 1 day. When the substituent R ¹⁴ on the compound (18) is a phthalimido group, the compound (19) can be produced, for example, by treating with hydrazine or methylamine to deprotect the phthalimido group. (For example, “Protective Groups in
Organic Synthesis ”(TW Greene, PGM Wuts
Co-author, 2nd edition, 3 of John Wiley & Sons, Inc. (1991))
See the method described on pages 58-359. ).

Step (A-16) Compound (20) can be produced by reacting compound (19) obtained by the above reaction with an electrophilic agent under various reaction conditions. The electrophilic agent in the case of reaction in the presence of a base includes a carboxylic acid halide containing a substituent represented by R ⁴ described above, a carboxylic acid anhydride, a haloformic acid ester, a pyrocarbonate, a sulfonic acid halide or a sulfonic acid Anhydride etc. can be used. The halogen atom of the halide includes chlorine, bromine, iodine and the like. As the base, carbonates such as sodium carbonate and potassium carbonate, hydroxides such as sodium hydroxide and potassium hydroxide, bicarbonates such as sodium bicarbonate and potassium bicarbonate, disodium hydrogen phosphate, hydrogen phosphate potassium,
Alternatively, organic bases such as triethylamine, N, N-diisopropylethylamine, pyridine, dimethylaniline, 1,8-diazabicyclo [5.4.0] undecene (DBU) and the like can be used. As the electrophilic agent in the case of reaction under neutral conditions, isocyanate containing a substituent represented by R ⁴ described above, isothiocyanate and the like can be used. As an electrophilic agent in the case of making it react in condensation agent coexistence, carboxylic acid, a sulfonic acid, thiocarboxylic acid etc. which contain the substituent represented by said R ⁴ can be used. As a condensing agent, dicyclohexyl carbodiimide (DCC), diisopropyl carbodiimide (DIP)
C) N-ethyl-N'-3-dimethylaminopropyl carbodiimide (WSCI) and its hydrochloride (WSC.HCl),
Benzotriazol-1-yl-tris (dimethylamino) phosphonium hexafluorophosphate salt (BOP),
Diphenyl phosphoryl azide (DPPA) etc. can be used. These are used alone or in combination with N-hydroxysuccinimide (HONSu), 1-hydroxybenzotriazole (HOBt), 3-hydroxy-4-oxo-3,4-.
It is used in combination with dihydro-1,2,3-benzotriazine (HOObt) and the like. The reaction is preferably carried out in a solvent, and examples of the solvent include halogen solvents such as methylene chloride and 1,2-dichloroethane. These are used alone or as a mixed solvent. Reaction temperature is -70
C. to 100.degree. C., preferably 0.degree. C. to 60.degree. C. (or the boiling point of the solvent). The reaction time depends mainly on the reaction temperature, the raw material compounds used, reagents, solvents and the like, but is usually 1 hour to 2 days.

(Step A-17) The compound (20) obtained by the above method is hydrolyzed in a solvent under basic conditions in the same manner as in step A-9 to obtain the compound (1) of the present invention. It can be manufactured.

The substituents in this Scheme A are described below. C _1- at R ⁵ , R ⁸ , R ¹² and R ¹³ in the formula
The C ₆ alkanoyl group is a linear or branched alkylcarbonyl group having 1 to 6 carbon atoms, or a cycloalkanecarbonyl group. Specifically, formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, pentanoyl group, isopentanoyl group, neoisopentanoyl group, hexanoyl group, cyclopentane carbonyl group Etc. The aroyl group in R ⁵ , R ⁸ , R ¹² and R ¹³ has the same meaning as the arylcarbonyl group, and specifically, benzoyl group, naphthoyl group, p-
A methoxy benzoyl group, p-nitro benzoyl group etc. can be mentioned. The substituted benzyl group in R ⁵ and R ⁹ is a benzyl group having a substituent at the para position, and specific examples thereof include p-methoxybenzyl group and p-methylbenzyl group. The C ₂ -C ₁₈ alkenyl group in R ⁶ is a linear or branched alkenyl group having 2 to 18 carbon atoms, and specific examples thereof include a vinyl group and an allyl group. The phenyl C ₂ -C ₁₂ alkenyl group in R ⁶ means a carbon number of 2 to 12 having a phenyl group at the end
A linear or branched alkenyl group consisting of
Specifically, a phenyl vinyl group, a phenyl allyl group, etc. are mentioned. The C ₂ -C ₁₈ alkynyl group for R ⁶ is
It is a linear or branched alkynyl group which consists of C2-C18, and an ethynyl group, 1-propyryl group etc. are specifically mentioned. The phenyl C ₂ -C ₁₂ alkynyl group in R ⁶ means that the carbon number having a phenyl group at the end is 2 to 1
It is a linear or branched alkynyl group consisting of two, and specific examples thereof include a phenylethynyl group.
The substituted phenyl group in R ⁷ is a phenyl group having a substituent at the para position, and specific examples thereof include a p-methoxyphenyl group and a p-tolyl group.

The compound (21) of the present invention can be produced from compound (4) by the method described below. [Scheme B]

Embedded image

[Image 10]

[Image 11]

[Chemical formula 12]

Embedded image [Wherein, R ¹ , R ² , R ⁶ , R ¹⁰ , R ¹¹ , R ¹² , R ¹⁴ ,
Z ¹ , Z ² and Z ³ are as defined above. R ¹⁵ is a phenyl group or substituted phenyl group. ]

(Step B-1) A compound (4) obtained in Step A-2 is obtained by introducing a cyclic acetal protecting group in the presence of an acid catalyst in the same manner as in Step A-3. 22) can be manufactured. Specific examples of cyclic acetal protecting agents include benzaldehyde, substituted benzaldehyde, benzaldehyde dimethyl acetal,
Examples include substituted benzaldehyde dimethyl acetal, benzaldehyde (trimethylsilyl) acetal, and substituted benzaldehyde (trimethylsilyl) acetal.

(Step B-2) The compound (22) obtained by the above method is treated with a compound (8) having a leaving group Z ² in the presence of an activating agent such as a Lewis acid or a metal salt, and A- 6
By reacting in the same manner as in the step, a glycosidation grade (23) can be produced.

(Step B-3) The compound (23) obtained by the above method is obtained, for example, in the presence of palladium on carbon
Compound (24) can be obtained by performing hydrogenation. The amount of palladium carbon used may be a catalytic amount, usually 0.001 to 10 equivalents. Moreover, as a hydrogen supply source, a hydrogen molecule, ammonium formate etc. can be mentioned, for example. The reaction is preferably carried out in a solvent, and examples of the solvent include alcohol solvents such as methanol, ethanol, propanol and isopropanol, and acetic acid. These are used alone or as a mixed solvent. Alternatively, when R ¹⁵ is a p-methoxyphenyl group, deprotection can also be performed using, for example, cerium ammonium nitrate (CAN) or dichlorodicyanoquinone (DDQ) to obtain compound (24). it can. Examples of the solvent include halogen based solvents such as methylene chloride and 1,2-dichloroethane or water. These are used alone or as a mixed solvent. Furthermore, the compound (23) can be deprotected even under acidic conditions such as an aqueous sulfuric acid solution or an aqueous acetic acid solution, and the compound (2
4) can be obtained. In any reaction, the reaction temperature is selected in the range of -70 ° C to 100 ° C, preferably -20 ° C to 60 ° C (or the boiling point of the solvent). The reaction time mainly depends on the reaction temperature, the starting compounds used, reagents,
Although it depends on the solvent etc, it is usually 1 hour to 1 day.

(Step B-4) 6 of the 2-deoxy-glucose moiety of the compound (24) obtained by the above method
The hydroxy group is protected in the same manner as in the A-8 step to give compound (25). In this reaction, only the highly reactive 6-position primary hydroxyl group can be selectively protected by limiting the amount of the reagent.

[0037] (B-5 step) The compound obtained by the process (25), the presence of an activating agent such as Lewis acids or metal salts, compounds having a leaving group Z ³ and (13) A-
By reacting in the same manner as in step 10, a glycosidation grade (26) can be produced.

(Step B-6) The compound (26) obtained by the above method is A-11 in the presence of palladium on carbon.
Deprotection can be easily carried out by hydrogenation in the same manner as in the step, and compound (27) can be obtained.

(Step B-7) The compound (27) obtained by the above method is treated with an acylating agent and A-1 in the presence of a base.
Compound (28) can be produced by reacting in the same manner as in the two steps.

(Step B-8) 6-deoxy-glucose portion of compound (28) obtained by the above method
Only the protective group on the hydroxyl group can be selectively deprotected in the same manner as in the A-13 step to give compound (29).

(Step B-9) The compound (29) obtained by the above method is subjected to sulfonic acid esterification and azide reaction in the same manner as in step A-14, whereby the substituent R ¹⁴ is an azide group. Compound (30) can be produced. Moreover, the compound (30) in which the substituent R ¹⁴ is a phthalimide group can be produced by reacting the compound (29) obtained by the above method with phthalimide in the same manner as in step A-14. .

(Step B-10) In the case where the substituent R ¹⁴ on the compound (30) obtained by the above method is an azide group, for example, hydrogenation may be carried out in the presence of palladium on carbon
Compound (3) by carrying out in the same manner as in step-15;
1) can be manufactured. When the substituent R ¹⁴ on the compound (30) is a phthalimide group, the compound (31) can be produced, for example, by treating with hydrazine or methylamine to deprotect the phthalimide group. (As a method of deprotection, for example, “Prot
ective Groups in Organic Synthesis "(TW Green
e, PGM Wuts, second edition, John Wiley & Sons, In
c. (1991)), pp. 358-359. ).

Step (B-11) Compound (32) can be produced by reacting compound (31) with an electrophilic agent under various reaction conditions in the same manner as in step A-16.

(Step B-12) The compound (32) obtained above is hydrolyzed in a solvent under basic conditions in the same manner as in the step A-17 to produce the present compound (21). be able to.

The compounds of the present invention, as pharmaceutical compositions, can block or inhibit cell adhesion associated with a number of diseases. For example, many inflammatory diseases are associated with selectins expressed on vascular endothelial cells and platelets and can be treated with pharmaceutical compositions containing the compounds of the present invention. As used herein, the term "inflammation" refers to the response of both specific and nonspecific defense systems. The response of a specific defense system is the response of a specific immune system to an antigen. Examples of specific defense system responses include the response of antibodies to antigens, such as viruses, and delayed hypersensitivity. The nonspecific defense system response is a white blood cell mediated inflammatory response that is generally incapable of immunological memory. Such cells include macrophages, eosinophils and neutrophils. Examples of nonspecific reactions include immediate swelling after bee sting, collection of white blood cells at the site of bacterial infection (eg,
Infiltration of the lung in bacterial pneumonia and formation of pus in abscess). Other treatable diseases may include the following: For example, rheumatoid arthritis,
Tissue damage due to white blood cells after ischemia (reperfusion injury), myocardial infarction, frostbite injury or shock, systemic inflammatory response syndrome (SIRS), neutrophil acute lung injury [eg adult respiratory distress syndrome (ARDS), etc. ], Asthma, traumatic shock, septic shock, multiple organ failure (MOF), nephritis,
Acute and chronic inflammation (eg, atopic dermatitis, psoriasis, inflammatory bowel disease, etc.) can be treated.
Platelet-related various pathologies such as atherosclerosis, disseminated intravascular coagulation (DIC) and embolism etc. can also be treated. Furthermore, tumor metastasis can be inhibited or prevented by inhibiting adhesion of cancer cells circulating in the bloodstream. Examples of such tumor cells include colon cancer and melanoma. It is also applicable to post-operative restenosis in percutaneous coronary angioplasty (PTCA) and percutaneous coronary thrombolysis (PTCR).

For pharmaceutical compositions comprising a C-glycoside derivative according to the invention, the dose of the compound may, for example, be the particular compound, the mode of administration, the particular disease to be treated and its extent, the overall health of the patient, And it is usually changing according to the prescribing doctor. For example, the dosage used for treatment of reperfusion injury is in the range of about 0.5 mg to about 2,000 mg per day for a 70 kg patient. Ideally, administration for treatment should begin as soon as possible after myocardial infarction or other injury. The pharmaceutical composition containing the compound of the present invention is administered parenterally, topically, orally or percutaneously. These pharmaceutical compositions are administered for the purpose of prophylactic and / or therapeutic treatment. These pharmaceutical compositions can be administered in various unit dosage forms depending on the method of administration. For example, unit dosage forms suitable for oral administration include powders, tablets,
Includes pills, capsules and dragees. Unit dosage forms suitable for topical administration include, for example, an aerosol. Preferably, the pharmaceutical composition comprising the compound of the present invention is administered intravenously. Compositions for intravenous administration comprise a solution of the compound of the present invention dissolved or suspended in a pharmaceutically acceptable carrier, preferably an aqueous carrier. As the aqueous carrier, for example, water, buffered water, 0.4% saline and the like can be used. These compositions may be sterilized by conventional, well known sterilization techniques, or
Alternatively, it can be sterile filtered. The resulting aqueous solution can be packaged as is or lyophilized.
The lyophilised preparation is combined with a sterile aqueous solution prior to administration. The composition is, as required for the physiological condition in close proximity, pharmaceutically acceptable adjuvants, such as pH adjusters and buffers, tonicity agents, wetting agents, etc., such as sodium acetate, sodium lactate, Sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate,
It can contain teriethanolamine oleate and the like.

Compositions containing the compounds of the present invention are administered for prophylactic and / or therapeutic treatments. In therapeutic applications, the composition is administered to a patient already afflicted with the disease, as described above, in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. . An amount adequate to accomplish this is defined as "therapeutically effective dose." Amounts effective for this use will depend on the degree of illness and the weight and general state of the patient, but generally about 0.5 mg to about 0.5 mg of a compound of the invention per day for a 70 kg patient
In the range of 2,000 mg, preferably about 5 mg of the compound of the present invention per day, for a patient weighing 70 kg
Use a dose in the range of 1000 mg. In prophylactic applications, compositions containing the compounds of the invention are administered to a patient susceptible to or otherwise at risk of a particular disease. The amount used in such cases is defined as a "prophylactically effective amount". In such use, the exact amount will depend on the condition and weight of the healthy patient, but in general, for patients weighing 70 kg, 1
The compound of the present invention is in the range of about 0.5 mg to about 2,000 mg per day, preferably for a patient weighing 70 kg.
Dosages of the compounds of the present invention in the range of about 5 mg to about 1000 mg per day are used. Upon administration of the compounds of the present invention, single or multiple administrations of the composition can be performed, the level and pattern of administration being selected by the physician. In any case, the pharmaceutical formulation should provide a sufficient amount of the compound of the present invention to effectively treat the patient. The compounds of the invention can also be used as diagnostic reagents. For example, using a labeled compound
Areas of inflammation or tumor metastasis can be sought in patients suspected of having inflammation. For this,
The compounds can be labeled with ¹²⁵ I, ¹⁴ C or tritium.

[0048]

The present invention will be described in more detail by way of the following examples. Example 1 The structural formulas of compounds ( 1 ) to ( 15 ) in Example 1 are shown.

[Image 14]

[Image 15]

Embedded image

[Image 17]

[Image 18]

[Image 19]

[Image 20]

Example 1-1 Synthesis of 3,4,6-tri-O-acetyl-1,2-dideoxy-1α- (2-propenyl) -D-arabinohexopyranose ( 2 ) 2-deoxy -1,3,4,6-Tetra-O-acetyl-D-arabinohexopyranose ( 1 ) (6.65 g, 20.0)
The mmol) was dissolved in acetonitrile (67 ml), allyltrimethylsilane (6.4 ml, 40.3 mmol) was added, and the mixture was stirred under ice cooling. After boron trifluoride-diethyl ether complex (2.6 ml, 21.1 mmol) was added dropwise to this mixture, the mixture was warmed to room temperature and stirred at room temperature for 2 hours. After confirming the completion of the reaction, the reaction solution was concentrated, the residue was diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate solution and then with saturated brine. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated to give a residue containing the target compound 2 (6.29 g of theory). This was used for the next reaction without purification.

Example 1-2 1,2-Dideoxy-1α- (2-propenyl) -D-
Synthesis of Arabinohexopyranose ( 3 ) Compound 2 (6.29 g theoretical) obtained in Example 1-1 was
It was dissolved in methanol (40 ml), 28% sodium methoxide solution (0.2 ml of methanol solution) was added, and the mixture was stirred at room temperature for 3 days. After completion of the reaction, the reaction solution was neutralized with an acidic ion exchange resin (DOWEX 50W-X8), filtered, and the filtrate was concentrated to obtain a residue containing the target compound 3 (theoretical amount: 3.76 g). This was used for the next reaction without purification.

Example 1-3 Synthesis of 1,2-Dideoxy-4,6-O-p-methoxybenzylidene-1α- (2-propenyl) -D-arabinohexopyranose ( 4 ) Example 1- The residue containing compound 3 obtained in 2 (3.76 g theoretical amount) is dissolved in acetonitrile (130 ml) and p-methoxybenzaldehyde dimethyl acetal (6.8 ml,
39.9 mmol) and p-toluenesulfonic acid monohydrate (11
4 mg, 0.599 mmol) was added and stirred at room temperature overnight.
After confirming the completion of the reaction, the reaction mixture was diluted with triethylamine (0.17 ml,
After neutralization with 1.2 mmol), the reaction mixture was concentrated, the residue was diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate solution and then with saturated brine. The organic layer is dried over magnesium sulfate and filtered. The filtrate is concentrated, and the residue is washed with hexane (100 ml) and filtered to give the target compound 4 (5.37).
g, 17.5 mmol, 87.6% yield in three steps from compound 1 )
Was obtained as a pale yellow solid. ¹ H-NMR (270 MHz, CDCl ₃ ) δ 1.88 (1 H, ddd, J = 6.3, 11.2, 13.5 Hz, H-2 ax), 2.0
5 (1H, ddd, J = 1.0, 5.3, 13.2 Hz, H-2 eq), 2.27-2.38
(1H, m, H-1 '), 2.54 (1H, br s, OH), 2.54-2.67 (1H,
m, H-1 '), 3.44 (1H, dd, J = 8.9, 8.9 Hz, H-4), 3.60
(1H, ddd, J = 4.3, 9.2, 9.9 Hz, H-5), 3.68 (1H, dd, J =
9.9, 9.9 Hz, H-6ax), 3.81 (3H, s, MeO), 4.01-4.14
(2H, m, H-1, 3), 4.21 (1H, dd, J = 3.6, 9.7 Hz, H-6e
q), 5.09-5.17 (2H, m, H-3'x2), 5.53 (1H, s, p-MeOC
₆ H ₄ CH- ), 5.57-5.85 (1 H, m, H-2 '), 6.88-6. 93 (2 H, m,
p-MeO C ₆ H ₄ ), 7.37-7.48 (2H, m, p-MeO C ₆ H ₄ )

Example 1-4 3-O-acetyl-1,2-dideoxy-4,6-O-
p-Methoxybenzylidene-1α- (2-propenyl)
Synthesis of -D-arabinohexopyranose ( 5 ) Compound 4 obtained in Example 1-3 (105 mg, 0.343 mmo)
l) was dissolved in dichloromethane (3 ml) and pyridine (0.055 ml, 0.680 mmol) was added, followed by acetic anhydride (0.065 ml, 0.689 mmol), 4-dimethylaminopyridine (3 mg) under ice-cooling Was added and stirred overnight at room temperature. After confirming the completion of the reaction, methanol (1 ml) was added to the reaction system under ice-cooling, and the mixture was stirred overnight at room temperature. Concentrate the reaction solution,
The residue was diluted with ethyl acetate and washed with saturated aqueous copper sulfate solution, saturated aqueous sodium bicarbonate solution and then brine. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain target compound 5 (107 mg, yield 89.5%) as a white solid. ¹ H-NMR (270 MHz, CDCl ₃ ) δ 1.86 (1 H, ddd, J = 6.3, 11.2, 13.2 Hz, H-2 ax), 2.0
6 (3H, s, OAc), 2.17 (1H, ddd, J = 1.3, 5.3, 13.2, H
-2 eq), 2.34-2.44 (1 H, m, H-1 '), 2.6 1-2. 72 (1 H, m,
H-1 '), 3.60-3.76 (3H, m), 3.80 (3H, s, MeO), 4.04
-4.12 (1H, m), 4.16-4.25 (1H, m), 5.09-5.28 (3H,
m, H-3'x2), 5.51 (1 H, s, p-MeOC ₆ H ₄ CH ), 5.69-5. 84 (1
H, m, H-2 ' ), 6.86-6.91 (2H, m, p-MeO C 6 H 4), 7.37-7.
42 (2H, m, p-MeO C ₆ H ₄ )

Example 1-5 3-O-acetyl-1,2-dideoxy-6-Op-
Synthesis of Methoxybenzyl-1α- (2-propenyl) -D-arabinohexopyranose ( 6 ) Compound 5 (708 m obtained in the same manner as in Example 1-4
g, 2.03 mmol), N, N-dimethylformamide (16.5)
sodium cyanoborohydride (639 mg, after dissolving in 1 ml) and adding molecular sieves 4A (708 mg)
10.2 mmol) and trifluoroacetic acid (1.6 ml, 20.8 mmo)
A mixed solution of l) and N, N-dimethylformamide (12 ml) was added dropwise under ice-cooling. After raising temperature to room temperature after 80 minutes,
Stir overnight. After confirmation of completion of the reaction, saturated sodium bicarbonate aqueous solution was added to the reaction system under ice-cooling, followed by filtration, and the filtrate was diluted with ethyl acetate and washed with saturated sodium bicarbonate aqueous solution and then saturated brine. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The residue is purified by silica gel column chromatography to give target compound 6 (580 mg, 1.66 m
mol, yield 81.5%) was obtained as a white solid. ¹ H-NMR (270 MHz, CDCl ₃ ) δ 1.78 (1 H, ddd, J = 5.6, 11.2, 13.2 Hz, H-2ax), 2.0
2 (1H, ddd, J = 2.0, 5.0, 13.2 Hz, H-2 eq), 2.09 (3H,
s, OAc), 2.27-2.38 (1H, m, H-1 '), 2.51-2.63 (1H, m,
H-1 ') 2.96 (1H, br s, OH), 3.59-3.74 (4H, m), 3.8
0 (3H, s, 4-MeO), 4.00-4.09 (1H, m, H-1), 4.46-4.
56 (2H, m, H-6x2), 5.00-5. 18 (3H, m, H-3'x2), 5.69
-5. 84 (1 H, m, H-2 '), 6.84-6.90 (2 H, m, p-MeO C ₆ H ₄ ),
7.23-7.28 (2H, m, p-MeO C ₆ H ₄ )

Example 1-6 (2,3,4-Tri-O-benzyl-α-L-fucopyranosyl)-(1 → 4) -O- [3-O-acetyl-1,
2-dideoxy-6-Op-methoxybenzyl-1α
Synthesis of-(2-propenyl) -D-arabinohexopyranose] ( 8 ) Compound 6 (280 mg, 0.799 mmo) obtained in Example 1-5
l) was dissolved in diethyl ether (2 ml) and trimethylsilyl trifluoromethanesulfonate (6 μl, 0.
031 mmol) was added and stirred at room temperature under argon atmosphere for 20 minutes. O- (2, 3, 4-) was added to this mixture at room temperature.
A diethyl ether solution (1.5 ml) of tri-O-benzyl-α-L-fucopyranosyl) trichloroacetimidate ( 7 ) (463 mg, 0.800 mmol) was added dropwise, and the mixture was stirred for 3 hours. Furthermore, the diethyl ether solution (1.5 ml) of compound 7 (463 mg, 0.800 mmol) was dripped, and it stirred overnight. After confirmation of completion of the reaction, the reaction solution was diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate solution and then with saturated brine. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The residue is purified by silica gel column chromatography to obtain target compound 8
(535 mg, 0.698 mmol, yield 87.3%) was obtained. And its stereoisomer (2,3,4-tri-O-benzyl-
β-L-fucopyranosyl)-(1 → 4) -O- [3-O
-Acetyl-1,2-dideoxy-6-O-p-methoxybenzyl-1α- (2-propenyl) -D-arabinohexopyranose] (45 mg, 0.059 mmol, yield 7.4
%) Was also obtained. 8 ; ¹ H-NMR (270 MHz, CDCl ₃ ) δ 1.10 (3 H, d, J = 6.3 Hz, H-6 × 3 of Fuc), 1.72 (1 H, 1 H,
ddd, J = 5.6, 10.6, 13.2 Hz, H-2ax of Glc), 1.96-2.04
(1H, m), 2.01 (3H, s, OAc), 2.25-2.36 (1H, m, H-
1 ') 2.48-2.59 (1 H, m, H-1'), 3.46-3. 79 (5 H, m), 3.
73 (3H, s, MeO), 3.86 (1H, dd, J = 2.6, 10.3 Hz), 3.9
1-4.08 (3H, m), 4.34 (2H, br s), 4.58 (1 H, d, J = 1
1.5 Hz, O ₂ CH ₂ Ph), 4.64 (1 H, d, J = 11.5 Hz, O ₂ CH ₂ Ph), 4.
69 (1 H, d, J = 11.5 Hz, O CH ₂ Ph), 4.76 (1 H, d, J = 11.9 H
z, O CH ₂ Ph), 4.77 (1 H, d, J = 11.5 Hz, O CH ₂ Ph), 4.96
(1H, d, J = 11.2 Hz, O ₂ CH ₂ Ph), 4.98 (1 H, d, J = 2.6 Hz, H
-1 ofFuc), 5.05-5.16 (3H, m, H-3'x2), 5.69-5.85 (1
H, m, H-2 ' ), 6.79-6.87 (2H, m, p-MeO C 6 H 4), 7.15-7.
20 (2H, m, p-MeO C ₆ H ₄ ), 7.23-7.65 (15 H, m, OCH ₂ Ph x
3)

Example 1-7 (2,3,4-Tri-O-benzyl-α-L-fucopyranosyl)-(1 → 4) -O- [3-O-acetyl-1,
Synthesis of 2-dideoxy-1α- (2-propenyl) -D-arabinohexopyranose] ( 9 ) Compound 8 (173 mg, 0.226 mmo) obtained in Example 1-6
solution was dissolved in dichloromethane (2.3 ml) and water (0.13 ml), and 2,3-dichloro-5,6-dicyano-1,4-
Benzoquinone (62 mg) was added and stirred at room temperature for 1 day. After confirming the completion of the reaction, the reaction mixture was diluted with dichloromethane, and washed with saturated aqueous sodium bicarbonate solution and then with saturated brine. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The residue was purified by preparative TLC plate to give target compound 9 (94 mg, 0.145 mmol, yield 64.3%). ¹ H-NMR (270 MHz, CDCl ₃ ) δ 1.06 (3 H, d, J = 6.6 Hz, H-6 × 3 of Fuc), 1.72 (1 H, 1 H,
ddd, J = 5.9, 11.2, 13.2 Hz, H-2ax of Glc), 1.94 (1 H,
ddd, J = 1.3, 5.3, 13.2 Hz, H-2 eq of Glc), 2.00 (3H,
s, OAc), 2.24-2.35 (1 H, m, H-1 '), 2.50-2.61 (1 H,
m, H-1 '), 3.35 (1H, br s, OH), 3.50-3.64 (4H, m),
3.77-4.04 (5H, m), 4.65 (1H, d, J = 11.5 Hz, O CH ₂ Ph),
4.72 (1H, d, J = 11.9Hz, O CH 2 Ph), 4.73 (1H, d, J = 1
1.9 Hz, O CH ₂ Ph), 4.78 (1 H, d, J = 12.0 Hz, O CH ₂ Ph), 4.
85 (1H, J = 2.6 Hz, H-1 of Fuc), 4.88 (1H, d, J = 11.6 H
z, O CH ₂ Ph), 4.95 (1 H, d, J = 11.5 Hz, O CH ₂ Ph), 5.06-
5.16 (3H, m, H-4a, H-3'x2), 5.66-5.82 (1H, m, H-
2 '), 7.25-7.41 (15 H, m, OCH ₂ Ph x 3)

EXAMPLE 1-8 (2,3,4-Tri-O-benzyl-α-L-fucopyranosyl)-(1 → 4) -O- [3-O-acetyl-6-
O-t-Butyldimethylsilyl-1,2-dideoxy-
Synthesis of 1α- (2-propenyl) -D-arabinohexopyranose] ( 10 ) Compound 9 (800 m obtained in the same manner as in Example 1-7
g, 1.24 mmol), N, N-dimethylformamide (23 m)
After dissolving in l) and adding imidazole (253 mg, 3.72 mmol) and stirring at room temperature for 20 minutes, t-butyldimethylchlorosilane (280 mg, 1.86 mmol) was added and stirred at room temperature for 5 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate solution and then with saturated brine. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated. This was used for the next reaction without purification. ¹ H-NMR (270 MHz, CDCl ₃ ) δ -0.01 (3 H, s, 3 H of Si Me ₂ t-Bu), 0.01 (3 H, s, 3 H)
_{of Si Me 2 t-Bu)} , 0.86 (9H, s, 9H of SiMe 2 t-Bu), 1.0
9 (3H, d, J = 6.3 Hz, H-6 x 3 of Fuc), 1. 68 (1 H, ddd, J =
5.3, 9.9, 13.2 Hz, H-2ax of Glc), 1.94-2.02 (1 H, m,
H-2 eq of Glc), 2.02 (3H, s, OAc), 2.24-2.32 (1H,
m, H-1 '), 2.46-2.54 (1 H, m, H-1'), 3.52-3. 66 (3 H,
m), 3.82 (1 H, dd, J = 5.3, 11.2 Hz), 3.90 (1 H, dd, J =
2.6, 10.2 Hz), 3.94-4.05 (4 H, m), 4. 65 (1 H, d, J = 1
1.6 Hz, O CH ₂ Ph), 4.69 (1 H, d, J = 10.2 Hz, O CH ₂ Ph), 4.
73 (1H, d, J = 10.9 Hz, O ₂ CH ₂ Ph), 4.78 (1 H, d, J = 11.6 H
z, O CH ₂ Ph), 4.83 (1 H, d, J = 11.6 Hz, O CH ₂ Ph), 4.96
(1H, d, J = 11.6 Hz, O ₂ CH ₂ Ph), 5.03-5.15 (4H, m, H-4 of
Glc, H-1 of Fuc, H-3'x2), 5.72-5.87 (1H, m, H-
2 '), 7.28-7.40 (15 H, m, OCH ₂ Ph x 3)

Example 1-9 (2,3,4-Tri-O-benzyl-α-L-fucopyranosyl)-(1 → 4) -O- [6-O-t-butyldimethylsilyl-1 Synthesis of 2, 2-Dideoxy-1α- (2-propenyl) -D-arabinohexopyranose] ( 11 ) The residue containing Compound 10 (theoretical amount 944 mg) obtained in Example 1-8 was methanol (28 ml) The solution was dissolved in 28% sodium methoxide solution (0.28 ml of methanol solution) and stirred at room temperature for 7 hours. After confirmation of completion of the reaction, the reaction solution is neutralized with an acidic ion exchange resin (DOWEX 50W-X8),
Filter and concentrate the filtrate. The residue was purified by silica gel column chromatography to give target compound 11 (761 mg,
06 mmol, a yield of 85.4% in two steps from compound 9 ) was obtained as a white solid. ¹ H-NMR (270 MHz, CDCl ₃ ) δ 0.00 (3 H, s, 3 H of Si Me ₂ t-Bu), 0.02 (3 H, s, 3 H
_{of Si Me 2 t-Bu)} , 0.87 (9H, s, 9H of SiMe 2 t-Bu), 1.17
(3H, d, J = 6.3 Hz, H-6 x 3 of Fuc), 1.65-1. 74 (1 H, m,
H-2ax of Glc), 1.93-1.98 (1H, m, H-2 eq of Glc),
2.20-2.28 (1H, m, H-1 '), 2.49-2.54 (1H, m, H-1'),
3.16 (1 H, dd, J = 8.6, 8.9 Hz), 3.46-3.51 (1 H, m), 3.6
9-4.12 (8H, m), 4.48 (1H, d, J = 1.3 Hz, H-1 of Fuc),
4.65 (1 H, d, J = 11.2 Hz, O ₂ CH ₂ Ph), 5.74-5.84 (8 H, m),
5.74-5.84 (1H, m, H-2 '), 7.26-7.39 (15H, m, OCH ₂ P
h x 3)

Example 1-10 (2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyl)-(1 → 3) -O-[(2,3,4)
-Tri-O-benzyl-α-L-fucopyranosyl)-
(1 → 4) -O]-[6-O-t-butyldimethylsilyl-1,2-dideoxy-1α- (2-propenyl)-
Synthesis of D-arabinohexopyranose] ( 13 ) Compound 11 (761 mg, 1.06 mmo) obtained in Example 1-9
solution of l) in 1,2-dichloroethane (23 ml), molecular sieves 4A (1.58 g), mercury cyanide (10
69 mg, 4.23 mmol) and mercury bromide (496 mg, 1.38 mmo)
l) was added at room temperature. This mixture was added at room temperature
3,4,6-Tetra-O-acetyl-α-D-galactopyranosyl bromide ( 12 ) (565 mg, 1.38 mmol)
Of 1, 2-dichloroethane solution (4.5 ml) was added dropwise.
After stirring at room temperature for 6 hours, a solution of 2,2,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide ( 5 ) (565 mg, 1.38 mmol) in 1,2-dichloroethane is further added. (4.5 ml) was added and stirred overnight. Again, 2,3,4,6-tetra-O-acetyl-α-D-
Galactopyranosyl bromide ( 5 ) (565 mg, 1.38 m
A solution of (mol) in 1,2-dichloroethane (4.5 ml) was added and stirred for 2 hours. After confirmation of completion of the reaction, the reaction solution was filtered through Celite, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate and then brine. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The residue is purified by silica gel column chromatography to give the target compound 13
(229 mg, 0.218 mmol, yield 20.6%) was obtained as a white solid. ¹ H-NMR (270 MHz, CDCl ₃ ) δ 0.06 (3 H, s, Si (t-Bu) Me ₂ ), 0.08 (3 H, s, Si (t B)
u) Me ₂ ), 0.89 (9 H, s, Si (t- Bu ) Me ₂ ), 1. 15 (3 H, d, J =
6.3 Hz, H-6 x 3 of Fuc), 1.51-1.62 (1H, m, H-2 of Gl
c), 1.77-1.83 (1H, m, H-2 of Glc), 1.97 (3H, s, OA)
c), 1.99 (3H, s, OAc), 2.01 (3H, s, OAc), 2.02 (3
H, s, OAc), 2.04-2.21 (1H, m, H-1 '), 2.34-2.45 (1
H, m, H-1 '), 3.67-4.12 (12H, m), 4.29 (1H, ddd, J =
6.6, 6.6, 12.9 Hz), 4.43 (1 H, d, J = 7.9 Hz, H-1 of Ga
l), 4.68 (1 H, d, J = 11.6 Hz, O ₂ CH ₂ Ph), 4.72 (1 H, d, J =
11.6 Hz, O CH ₂ Ph), 4.76 (1 H, d, J = 11.6 Hz, O CH ₂ Ph),
4.79 (1H, d, J = 11.9Hz, O CH 2 Ph), 4.84 (1H, d, J = 11.
6 Hz, O CH ₂ Ph), 4.95-5. 16 (6 H, m, O CH ₂ Ph, H-3 'x ₂ , et
c.), 5.35-5.36 (1H, m), 5.69-5.85 (1H, m, H-2 '),
7.22-7.43 (15H, m)

Example 1-11 (2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyl)-(1 → 3) -O-[(α-L-fucopyranosyl] )-(1 → 4) -O]-[6-O-t-butyldimethylsilyl-1,2-dideoxy-1α- (2
-Propenyl) -D-arabinohexopyranose] ( 1
Synthesis of 4 ) Compound 13 (229 mg, 0.218 obtained in Example 1-10)
The mmol) was dissolved in ethanol (16 ml), ammonium formate (48 mg), 10% Pd-C (wet. 96 mg) was added and refluxed for 1 hour. Furthermore ammonium formate (48 m
g) 10% Pd-C (wet. 96 mg) was added and refluxed for 1 hour. This addition was repeated seven times. After confirmation of completion of the reaction, the reaction solution is filtered through Celite, and the filtrate is concentrated to give the target compound 14
(170 mg theoretical) was obtained as a white solid. This was used for the next reaction without purification.

Example 1-12 (2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyl)-(1 → 3) -O-[(2,3,4
-Tri-O-acetyl-α-L-fucopyranosyl)-
(1 → 4) -O]-[6-O-t-butyldimethylsilyl-1,2-dideoxy-1α- (2-propenyl)-
Synthesis of D-arabinohexopyranose] ( 15 ) Compound 14 obtained in Example 1-11 (theoretical amount: 170 m)
The residue containing g) was dissolved in pyridine (10.7 ml), acetic anhydride (6.4 ml) and 4-dimethylaminopyridine (11 mg) were added under ice-cooling, and the mixture was stirred overnight at room temperature. After confirming the completion of the reaction, methanol (2.2 ml) was added to the reaction system under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Concentrate the reaction solution,
The residue was diluted with ethyl acetate and washed with saturated aqueous copper sulfate solution, saturated aqueous sodium bicarbonate solution and then brine. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain target compound 15 (131 mg, 0.144 mmol, yield 66.3% in two steps from compound 13 ) as a white solid. ¹ H-NMR (270 MHz, CDCl ₃ ) δ 0.06 (3 H, s, Si (t-Bu) Me ₂ ), 0.07 (3 H, s, Si (t B)
u) Me ₂ ), 0.89 (9 H, s, Si (t- Bu ) Me ₂ ), 0.94 (3 H, t, 6.
9 Hz, (CH ₂ ) ₂ CH ₃ ), 1.18 (3 H, d, J = 6.3 Hz, H-6 × 3 of Fu
c), 1.23-1.40 (4H, m, (CH ₂ ) ₂ CH ₃ ), 1.58-1.83 (2H,
m, H-2 x 2 of Glc), 1.97 (3H, s, OAc), 1.98 (3H, s, O
Ac), 2.04 (3H, s, OAc), 2.06 (3H, s, OAc), 2.07 (3
H, s, OAc), 2.16 (3H, s, OAc), 2.17 (3H, s, OAc),
3.47-3.49 (1H, m), 3.65-3.96 (6H, m), 4.16 (1H, d)
d, J = 7.9, 11.2 Hz), 4.34 (1 H, dd, J = 5.9, 11.2 Hz),
4.48 (1H, d, J = 7.9 Hz, H-1 of Gal), 4.76-4.78 (1H,
m), 5.01 (1 H, dd, J = 3.3, 10.6 Hz), 5.10-5.21 (3 H,
m), 5.29-5.31 (2H, m), 5.39-5.40 (1SH, m)

Example 1-13 (2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyl)-(1 → 3) -O-[(2,3,4
-Tri-O-acetyl-α-L-fucopyranosyl)-
(1 → 4) -O]-[1,2-dideoxy-1α- (2
-Propenyl) -D-arabinohexopyranose] ( 1
Synthesis of 6 ) Compound 15 obtained in Example 1-12 (131 mg, 0.144)
mmol), acetonitrile (2.6 ml) and water (0.26 ml)
And p-toluenesulfonic acid monohydrate (3 mg, 0.0158 mmol) was added thereto, and the mixture was stirred at room temperature for 6 hours. After confirming the completion of the reaction, the reaction solution is diluted with ethyl acetate,
The mixture was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain target compound 16 (101 mg, 0.127 mmol, yield 88.
2%) was obtained as a pale yellow solid. ¹ H-NMR (270 MHz, CDCl ₃ ) δ 0.96 (3 H, t, J = 6.9 Hz, (CH ₂ ) ₂ CH ₃ ), 1.21 (3 H, d,
J = 6.6 Hz, H-6 × 3 of Fuc), 1.31-1.41 (2H, m, ( CH ₂ ) ₂ CH
_{3), 1.61-2.16 (5H, m} , (CH 2) 2 CH 3, H-2x2 of Glc, -O
H), 1.97 (3H, s, OAc), 1.98 (3H, s, OAc), 2.04 (3
H, s, OAc), 2.07 (3H, s, OAc), 2.08 (3H, s, OAc),
2.16 (3H, s, OAc), 2.16 (3H, s, OAc), 3.51-3.70 (4
H, m), 3.88-4.03 (3H, m), 4.16 (1 H, dd, J = 7.9, 11.
2 Hz), 4.39 (1 H, dd, J = 5.9, 11.2 Hz), 4.51 (1 H, d, J
= 7.6 Hz, H-1 of Gal), 4.86 (1 H, dd, J = 6.3, 12.9 Hz),
4.99-5.41 (7H, m)

Example 1-14 (2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyl)-(1 → 3) -O-[(2,3,4
-Tri-O-acetyl-α-L-fucopyranosyl)-
(1 → 4) -O]-[1,2-dideoxy-6-O-p
-Toluenesulfonyl-1α- (2-propenyl) -D
Synthesis of -arabinohexopyranose] ( 17 ) Compound 16 obtained in Example 1-13 (100 mg, 0.126)
After dissolving the mmol) in dichloromethane (3 ml) and adding pyridine (0.44 ml, 5.44 mmol), p-
Toluenesulfonyl chloride (48 mg, 0.252 mmol)
Were added, and the mixture was stirred for 30 minutes under ice-cooling and overnight at room temperature. Then p-toluenesulfonyl chloride (total 2)
64 mg (138 mmol) was added in three portions and stirred for 2 days. After confirming the completion of the reaction, the reaction solution is diluted with ethyl acetate,
It wash | cleaned twice by the saturated salt solution. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The residue is purified by silica gel column chromatography to obtain the target compound.
17 (113 mg, 0.119 mmol, 94.7% yield) was obtained as a white solid. ¹ H-NMR (270 MHz, CDCl ₃ ) δ 0.90 (3 H, t, J = 6.6 Hz, (CH ₂ ) ₂ CH ₃ ), 1. 16 (3 H, d,
J = 6.6 Hz, H-6x3 of Fuc), 1.23-1.32 (2H, m), 1.41-1.
66 (3H, m), 1.73-1. 82 (1 H, m), 1. 97 (3 H, s, OAc),
1.99 (3H, s, OAc), 2.04 (3H, s, OAc), 2.05 (3H, s,
OAc), 2.07 (3H, s, OAc), 2.17 (3H, s, OAc), 2.18
(3H, s, OAc), 2.45 (3H, s, Me C 6 H 4), 3.58 (1H, dd,
J = 5.6, 5.6 Hz), 3.70 (1H, br m), 3.80-3.83 (1H, m),
3.87-3.98 (2H, m), 4.11-4.30 (4H, m), 4.44-4.56 (2
H, m), 4.97-5.03 (2H, m), 5.11-5.28 (4H, m), 5.34-
5.40 (1H, m), 7.33-7.37 (2H, m), 7.77-7.84 (2H, m)

Example 1-15 (2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyl)-(1 → 3) -O-[(2,3,4)
-Tri-O-acetyl-α-L-fucopyranosyl)-
Synthesis of (1 → 4) -O]-[6-Azido-1,2,6-trideoxy-1α- (2-propenyl) -D-arabinohexopyranose] ( 18 ) Obtained in Example 1-14 Compound 17 (113 mg, 0.119)
The mmol) was dissolved in N, N-dimethylformamide (3.3 ml), sodium azide (39 mg, 0.595 mmol) was added, and the mixture was stirred at room temperature for 1 day. After confirming the completion of the reaction, the reaction mixture was diluted with ethyl acetate, and washed with water and then saturated brine. The organic layer is dried over magnesium sulfate and filtered.
The filtrate was concentrated. The residue was purified by silica gel column chromatography to give target compound 18 (93 mg, 0.114 mmo)
L, yield 95.5%) as a pale yellow solid. ¹ H-NMR (270 MHz, CDCl ₃ ) δ 0.96 (3 H, t, J = 6.9 Hz, (CH ₂ ) ₂ CH ₃ ), 1.20 (3 H, d,
J = 6.6 Hz, H-6 x 3 of Fuc), 1.30-1. 46 (3 H, m), 1. 60-1.
74 (2H, m), 1.81-1.92 (1H, m), 1.98 (3H, s, OAc),
1.99 (3H, s, OAc), 2.05 (3H, s, OAc), 2.07 (3H, s,
OAc), 2.07 (3H, s, OAc), 2.16 (3H, s, OAc), 2.16
(3H, s, OAc), 3.33 (1 H, dd, J = 3.6, 13.2 Hz), 3.44
(1H, dd, J = 6.3, 13.2 Hz), 3.61 (1H, dd, J = 6.6, 6.6H
z), 3.66 to 3.72 (1H, m), 3.87 to 4.01 (3H, m), 4.15 (1
H, dd, J = 7.6, 11.2 Hz) 4.33 (1 H, dd, J = 6.3, 11.2 Hz),
4.50 (1H, d, J = 7.9, H-1 of Gal), 4.69 (1H, dt, J =
6.3, 6.6 Hz, H-5 of Fuc), 5.02 (1 H, dd, J = 3.3, 10.2
Hz), 5.11-5.17 (3H, m), 5.25-5.30 (2H, m), 5.40-5.
41 (1H, m)

Example 1-16 (2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyl)-(1 → 3) -O-[(2,3,4)
-Tri-O-acetyl-α-L-fucopyranosyl)-
Synthesis of (1 → 4) -O]-[6-Amino-1,2,6-trideoxy-1α- (2-propenyl) -D-arabinohexopyranose] ( 19 ) Obtained in Example 1-15 Compound 18 (45 mg, 0.055 m
Mol) was dissolved in ethanol (4 ml), ammonium formate (12 mg), 10% Pd-C (wet. 24 mg) was added and refluxed for 1 hour. After confirmation of completion of the reaction, the reaction mixture is filtered through Celite, and the filtrate is concentrated to give the target compound 19 (theoretical weight 44).
mg) as a white solid. This is without purification
It was used for the next reaction.

Example 1-17 (2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyl)-(1 → 3) -O-[(2,3,4)
-Tri-O-acetyl-α-L-fucopyranosyl)-
(1 → 4) -O]-[1,2,6-trideoxy-6-
Synthesis of naphthamide-1α- (2-propenyl) -D-arabinohexopyranose] ( 20 ) Compound 19 obtained in Example 1-16 (theoretical amount 44 mg)
The residue containing is dissolved in dichloromethane (3 ml), sodium hydrogencarbonate (7 mg, 0.0825 mmol) at room temperature, β- chloride
Naphthoyl (16 mg, 0.0825 mmol) was added and stirred overnight. After confirmation of completion of the reaction, methanol (0.
1 ml) and pyridine (0.1 ml) were added and stirred at room temperature for 30 minutes. The reaction mixture was concentrated, diluted with ethyl acetate, washed with water and then with brine. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The residue is purified on a preparative TLC plate to give the target compound 20.
(34 mg, 0.0359 mmol, yield in two steps from compound 18
65.4%) was obtained as a white solid. ¹ H-NMR (270 MHz, CDCl ₃ ) δ 0.93 (3 H, t, J = 6.9 Hz, (CH ₂ ) ₂ CH ₃ ), 1.21 (3 H, d,
J = 6.6 Hz, H-6 × 3 of Fuc), 1.28-1.40 (4 H, m) 1.68-1.93
(2H, m, H-2x2 of Glc), 1.98 (3H, s, OAc), 1.99 (3
H, s, OAc), 2.05 (3H, s, OAc), 2.08 (3H, s, OAc),
2.16 (3H, s, OAc), 2.17 (3H, s, OAc), 2.24 (3H, s,
OAc), 3.47-3.59 (2H, m), 3.77-3.83 (1H, m), 3.88-
4.07 (4H, m), 4.20 (1H, dd, J = 7.3, 11.5 Hz), 4.35
(1H, dd, J = 6.3, 11.2 Hz), 4.53 (1 H, d, J = 7.9 Hz, H-1
of Gal), 4.83 (1H, dt, J = 6.3, 6.6 Hz, H-5 of Fuc),
5.03 (1H, dd, J = 3.3, 10.6 Hz), 5.12-5.19 (2H, m),
5.26-5.36 (3H, m), 5.40-5.41 (1H, m) 6.64-6.68 (1H, m)
m, N H CO-β-Naph), 7.50-0. 63 (2H, m, 2H of β-Nap)
h), 7.79-7.98 (4H, m, 4H of β-Naph), 8.29 (1H, br
s, 1H of β-Naph)

Example 1-18 (β-D-Galactopyranosyl)-(1 → 3) -O-
[(Α-L-fucopyranosyl)-(1 → 4) -O]-
[6-naphthamide-1,2,6-trideoxy-1α-
(2-propenyl) -D-arabinohexopyranose]
Synthesis of ( 21 ) Compound 20 obtained by the same method as in Example 1-17
(50 mg, 0.053 mmol) was dissolved in methanol (1.5 ml), a 28% sodium methoxide solution (methanol solution 0.015 ml) was added, and the mixture was stirred overnight at room temperature. After completion of the reaction, after completion of the reaction, the reaction solution was neutralized with an acidic ion exchange resin (DOWEX 50W-X8), filtered, and the filtrate was concentrated. The resulting residue is purified by column chromatography using a polyacrylamide gel and lyophilized.
Target compound 21 (23 mg, 0.0276 mmol, yield 67.5%)
Was obtained as a white solid. ¹ H-NMR (270 MHz, CD ₃ OD) δ 0.81 (3 H, t, J = 6.9 Hz, (CH ₂ ) ₂ CH ₃ ), 1. 16 (3 H, d,
J = 6.6 Hz, H-6 × 3 of Fuc), 1.28-1.46 (4H, m, (CH ₂ ) ₂ CH
₃ ), 1.65-1.83 (2H, m, H-2x2 of Glc), 3.41-3.49 (2
H, m), 3.54-3.73 (7H, m), 3.76-3.81 (2H, m), 4.04-
4.19 (5H, m), 4.28 (1H, d, J = 7.6 Hz, H-1 of Gal),
4.79 (8H, s, OHx7, NH), 4.87 (1H, d, J = 3.3 Hz, H-1
of Fuc), 7.46-7.55 (2H, m), 7.80-7.95 (4H, m), 8.3
0 (1H, m)

EXAMPLE 2 Structural formulas of compounds ( 22 ) to ( 23 ) in Example 2 are shown.

[Image 21]Example 2-1 (2,3,4,6-Tetra-O-acetyl-β-D-Ga)
Lactopyranosyl)-(1 → 3) -O-[(2, 3, 4)
-Tri-O-acetyl-α-L-fucopyranosyl)-
(1 → 4) -O]-[6-amino-1,2,6-tride
Oxy-1α- (2-propenyl) -D-arabinohex
Sopyranose] (19Synthesis of compound obtained by the same method as in Example 1-1518
(2,3,4,6-tetra-O-acetyl-β-D-ga)
Lactopyranosyl)-(1 → 3) -O-[(2, 3, 4)
-Tri-O-acetyl-α-L-fucopyranosyl)-
(1 → 4) -O]-[6-Azido-1,2,6-Tride
Oxy-1α- (2-propenyl) -D-arabinohex
Sopyranose] (18) (51 mg, 0.062 mmol),
Dissolved in methanol (4.5 ml), ammonium formate (14 m)
g), add 10% Pd-C (wet. 27 mg), return 1 hour
Flowed. Again, ammonium formate (14 mg), 10% P
dC (wet. 27 mg) was added and refluxed for 1 hour. this
The addition was repeated once more. After confirming the completion of the reaction,
Filter through Celite, concentrate the filtrate, and target compound19(theory
An amount of 46 mg) was obtained as a white solid. This is to refine
It was used for the next reaction.

Example 2-2 (2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyl)-(1 → 3) -O-[(2,3,4
-Tri-O-acetyl-α-L-fucopyranosyl)-
Synthesis of (1 → 4) -O]-[6-Acetamido-1,2,6-trideoxy-1α- (2-propenyl) -D-arabinohexopyranose] ( 22 ) Obtained in Example 2-1 The residue containing compound 19 (theoretical amount 46 mg) is dissolved in pyridine (3.4 ml), and acetic anhydride (2 ml), 4-dimethylaminopyridine (3 mg) under ice-cooling
Was added and stirred overnight at room temperature. After confirmation of completion of the reaction, methanol (0.68 ml) was added to the reaction system under ice-cooling,
Stir at room temperature for 30 minutes. The reaction solution was concentrated, the residue was diluted with ethyl acetate, and washed with saturated aqueous copper sulfate solution and then with brine. After drying the organic layer with sodium sulfate,
Filter and concentrate the filtrate. The residue was purified by silica gel column chromatography to give target compound 22 (32 mg,
0.038 mmol, yield 61.9% in two steps from compound 18 )
Was obtained as a white solid. ¹ H-NMR (270 MHz, CDCl ₃ ) δ 0.96 (3 H, t, J = 6.9 Hz, (CH ₂ ) ₂ CH ₃ ), 1.20 (3 H, d,
J = 6.3Hz, H-6x3 of Fuc), 1.23-1.43 (2H, m, CH 2 CH 3),
1.60-1.90 (4H, m, H- 2x2 of Glc, CH 2 CH 2 CH 3), 1.96
(3H, s, NHAc), 1.97 (3H, s, OAc), 1.98 (3H, s, OA)
c), 2.04 (3H, s, OAc), 2.05 (3H, s, OAc), 2.08 (3H, 3H, s)
s, OAc), 2.16 (3H, s, OAc), 2.17 (3H, s, OAc), 3.3
0-3.36 (1H, m), 3.46 (1H, dd, J = 6.9, 7.2 Hz), 3.55-
3.62 (2H, m), 3.88-4.01 (3H, m), 4.17 (1H, dd, J = 7.)
3, 12.2Hz), 4.33 (1H, dd, J = 6.3, 11.2Hz), 4.50 (1
H, d, J = 7.6 Hz, H-1 of Gal), 4.77 (1 H, ddd, J = 6.3,
6.6, 6.6 Hz), 4.99-5.04 (2 H, m), 5.12 (1 H, dd, J = 7).
6, 10.6 Hz), 5.27-5.31 (3 H, m), 5. 39-5. 40 (1 H, m),
5.76-5.78 (1 H, m)

Example 2-3 (β-D-Galactopyranosyl)-(1 → 3) -O-
[(Α-L-fucopyranosyl)-(1 → 4) -O]-
[6-Acetamido-1,2,6-trideoxy-1α-
(2-propenyl) -D-arabinohexopyranose]
Synthesis of ( 23 ) Compound 22 (32 mg, 0.038 mmo) obtained in Example 2-2
l) was dissolved in methanol (0.95 ml), 28% sodium methoxide solution (0.009 ml of methanol solution) was added, and the mixture was stirred overnight at room temperature. After completion of the reaction, the reaction solution was neutralized with an acidic ion exchange resin (DOWEX 50W-X8), filtered, and the filtrate was concentrated. The resulting residue is purified by column chromatography using a polyacrylamide gel.
Lyophilization was carried out to obtain target compound 23 (17 mg, 0.0315 mmo)
l, yield 81.6%) as a white powder. ¹ H-NMR (270 MHz, CD ₃ OD) δ 0.83 (3 H, t, J = 6.6 Hz, (CH ₂ ) ₂ CH ₃ ), 1. 15 (3 H, d,
J = 6.6 Hz, H-6 × 3 OF Fuc), 1.31-1.50 (4H, m, (CH ₂ ) ₂ CH
₃ ), 1.67-1.82 (2H, m, H-2x2 of Glc), 1.95 (3H, s,
NH Ac ), 3.17-3.21 (1H, m), 3.46-4.16 (15H, m), 4.39
(1H, d, J = 7.3 Hz, H-1 of Gal), 4.72 (8 H, OH x 7, N
H), 4.94 (1 H, d, J = 4.0 Hz, H-1 of Fuc)

EXPERIMENTAL EXAMPLE P-selectin adhesion inhibition test was conducted on the compound of the present invention using human platelet / HL-60 cell adhesion evaluation system. [Human Platelet Preparation Method and Test Method] Healthy human blood collected using heparin as an anticoagulant was dispensed into test tubes up to 3 ml and centrifuged at 1000 rpm for 7 minutes. PRP (platelet
The rich plasma) layer was collected and PGE1 was added (final concentration 1 μg
/ ml). Centrifuge for 7 minutes at 3000 rpm and then settle for 1 μg / ml PGE
Resuspend in 3 ml of DPBS containing 1 and centrifuge again at 3000 rpm for 7 minutes, discard the supernatant, resuspend in PGE1-free DPBS, 3000 rpm
Centrifuge for 7 minutes. Suspend in 3 ml of DPBS without PGE1,
After platelet count measurement, it was adjusted to 1 × 10 ⁷ cells / ml with DPBS.
Plates were dispensed at 50 μl / well, and platelets were fixed to the plate by centrifugation at 1600 rpm × 10 min using a plate centrifuge. Use 8 multi-pipettes, 2%
The plate was washed twice with 200 μl / well of MEM medium containing FCS. A fresh 200 μl of MEM medium containing 2% FCS was added to each well (blocking). Wrap the plate in aluminum foil and let stand at room temperature for 1 to 2 hours. The blocking solution was removed from the plate, and 40 μl of a MEM medium containing 10% FCS or a compound dilution with the same medium was added per well. After rapid thawing of frozen HL-60 cells at 37 ° C, 4
1500 r with NWB (neutrophil washing buffer) cooled to ° C
Washing was carried out three times by centrifugation at pm × 5 min. The cells were adjusted to 1 × 10 ⁷ cells / ml with NWB, 20 μl per well was added to the above plate, and left at room temperature for 15 minutes.
Each well contains 200 μl of 2% FCS using an 8-pipette
The MEM medium was washed 4 times by gently passing the wall.
50 μl per well of a citric acid solution containing 0.1% NP-40 (nonidet P-40) at room temperature was added and left at room temperature for 5 minutes. Substrate solution at room temperature (4 mg OPDA, 4 μl
_{30% H 2 O 2/4} ml citrate solution) 50 [mu] l was added per well of, protected from light with aluminum foil and developed for 5 to 20 minutes, the reaction 4 NH ₂ SO ₄ was added 50 [mu] l per well Stopped. The substrate solution was used within 30 minutes after preparation. The absorbance at OD 490 of each well was measured, and the absorbance at OD 490 of the nonspecific adhesion assay well was subtracted from the value of each well. Control the value in the medium only wells (100
%), And the adhesion amount in the well containing the compound ( 21 ) or ( 23 ) of the present invention was calculated by% control to determine the inhibition rate. The compound ( 21 ) of the present invention inhibited P-selectin-dependent adhesion of human platelets to HL-60 cells by 56% at a concentration of 6.6 mM. In addition, the compound of the present invention ( 23 ) is
P-selectin dependent human platelets and HL at a concentration of 6.6 mM
26% inhibition of adhesion to -60 cells.

The sources of experimental materials are as follows. HL-60: ATCC PGE 1 (Prostaglandin E1): Funakoshi Heparin: Mochida Pharmaceutical DPBS (Dulbecco Phosphate Buffered Serine): GIBCO Eagle MEM medium: Nissui Pharmaceutical BSA (bovine serum albumin): sigma HBSS (Hanks) Balanced Salt Solution: GIBCO OPDA (Ortho Phenylene Diamine): Sigma RPMI 1640 Medium: GIBCO FCS (fetal calf serum): GIBCO Plate; Nunclon Nippon Intermeda The present invention compound is prepared to 10 mM with DPBS, pH 7.1 ~
The one adjusted to 7.4 was used. HL-60 was cultured in RPMI 1640 medium supplemented with 10% of fetal bovine serum. RPMI 1640
Frozen in a conventional manner with 1.5 × 10 ⁷ cells per tube using a medium of 80% + fetal bovine serum 10% + DMSO 10% cell freezing solution, and stored at -80 ° C.. When used, it was used aseptically. The composition of NWB is HBSS + 10 mM HEPES + 0.2%
glucose + 1% BSA + 1 mM CaCl ₂ This solution is
Aseptically adjusted. Citric acid solution: 2.33 g of citric acid
And _{^{Na 2 HPO 4. 12H 2 O}} 9.20 g was prepared by dissolving demineralized water 500 ml.

[0072]

According to the present invention, it is possible to provide a C-glycoside derivative which has excellent cell adhesion inhibitory activity and which is stabilized as compared to an O-glycoside derivative. Book C
-A therapeutic or preventive agent for an inflammatory disease is provided by using a glycoside derivative as an active ingredient.

 ── ── ── ── ──続 き 続 き Continuation of the front page (72) Inventor Shoji Hayashi 3-chome, No. 98, Kasuga, Ohana-ku, Osaka-shi Sumiyo Pharmaceutical Co., Ltd.

Claims (17)

[Claim of claim] 1. The general formula [Wherein, R ¹ represents a C ₁ -C ₁₈ alkyl group or phenyl C _1-
It is a C ₁₂ alkyl group. R ² and R ³ are different from each other, D-
It is a galactopyranosyl group or an L-fucopyranosyl group. R ⁴ represents a C ₁ -C ₆ alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aromatic heterocyclic group, or a C _1- group terminated with an aryl group or an aromatic heterocyclic group
It is a C ₆ alkyl group. The C-glycoside derivative represented by these. 2. The C-glycoside derivative according to claim 1, wherein R ² is a β-D-galactopyranosyl group, and R ³ is an α-L-fucopyranosyl group. 3. The C-glycoside derivative according to claim 2, wherein R ¹ is a C ₁ -C ₁₈ alkyl group. 4. The C-glycoside derivative according to claim 3, wherein R ¹ is a propyl group. 5. The C-glycoside derivative according to claim 2, wherein R ¹ is a phenyl C ₁ -C ₁₂ alkyl group. 6. The method according to claim 6, wherein R ⁴ is a C ₁ -C ₆ alkyl group.
The C-glycoside derivative according to any one of claims 5 to 10. 7. The compound according to claim 6, wherein R ⁴ is a methyl group.
-Glycoside derivatives. 8. The C-containing group according to any one of claims 3 to 5, wherein R ⁴ is a substituted or unsubstituted aryl group.
Glycoside derivatives. 9. The C-glycoside derivative according to claim 8, wherein R ⁴ is a naphthyl group. 10. The method according to claim 10, wherein R ² is an α-L-fucopyranosyl group and R ³ is a β-D-galactopyranosyl group.
C-Glycoside derivative as described. 11. The C-glycoside derivative according to claim 10, wherein R ¹ is a C ₁ -C ₁₈ alkyl group. 12. The C-glycoside derivative according to claim 11, wherein R ¹ is a propyl group. 13. The C-glycoside derivative according to claim 10, wherein R ¹ is a phenyl C ₁ -C ₁₂ alkyl group. 14. The C-glycoside derivative according to any one of claims 11 to 13, wherein R ⁴ is a C ₁ -C ₆ alkyl group. 15. The C-glycoside derivative according to claim 14, wherein R ⁴ is a methyl group. 16. The C-glycoside derivative according to any one of claims 11 to 13, wherein R ⁴ is a substituted or unsubstituted aryl group. 17. The C-glycoside derivative according to claim 16, wherein R ⁴ is a naphthyl group.