JPH10251152A - Medicine for treating ischemic reperfusion disorder - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject preventing or treating medicine effective for ischemic reperfusion disorders by including a specific asialo trisaccharide moranoline derivative (salt) or the solvate of either of the derivative (salt) as an active ingredient. SOLUTION: This medicine contains 0.01-99.5% of an asialo trisaccharide moranoline derivative (salt) of formula I A is (CH2 )m , (CH2 )n -NR<e> -CO-O, etc., [R<e> is H, a lower alkyl; (m) is 0-12; (n) is 2-12]; R is a group of formula II, a group of formula III [R<a> , R<b> are each an (un)saturated aliphatic hydrocarbon, an (un)saturated acyl]; one of W and Y is 1-galactopyranosyl (H or 3-OH group is substituted by SO3 H, CH2 COOH, etc.), and the other is 1-fucopyronosyl; or A and R together form a (substituent-containing) linear or branched 1-30C alkyl, etc.} or the solvate of either of the derivative (salt) of formula I, and, if necessary, a carrier. The medicine is preferably administered at a daily dose of 10mg to 10g (as the active ingredient) per adult.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a preventive or therapeutic agent for ischemia-reperfusion injury comprising a Lewis-type sugar chain derivative as an active ingredient.

[0002]

2. Description of the Related Art After a tissue is in an ischemic state, blood flow is re-opened and blood is supplied to the tissue, and after a while, further tissue damage or dysfunction of an organ or tissue is caused.
Such ischemia-reperfusion injury is observed in almost all tissues or organs and is involved in various diseases such as spinal cord injury, gastric ulcer, hepatitis and the like.

[0003] Ischemic reperfusion injury is also a problem during surgery and organ transplantation. In organ transplantation, reduction in organ dysfunction caused by ischemia-reperfusion injury is a major factor in determining the success or failure of transplantation surgery, as well as avoiding rejection. In addition, dysfunction of organs due to ischemia / reperfusion injury due to infarction, surgery, etc. in various organs,
Serious cases can lead to patient death, a major problem.

It has become clear that activated leukocytes and free radicals are involved in the cause of such ischemia-reperfusion injury. Therefore, interleukin-8 production inhibitors (JP-A-Hei.
8-231413 publication), batroxobin (JP-A-9-12475),
Superoxide dismutase-inducing substance (Japanese Unexamined Patent Publication No. 5-31
No. 0579), natural sialyl Lewis type sugar chain derivatives (J
ournal of the AmericanCollege of Surgeons. March 1
996. Vol 182, 251-256) and the like have been filed for therapeutic agents, and the development of pharmaceuticals is being actively pursued. However, what has been put to practical use in clinical practice has not been known so far.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to provide a prophylactic / therapeutic agent which is effective against ischemia-reperfusion injury using a Lewis type sugar chain derivative as an active ingredient.

[0006]

Means for Solving the Problems As a result of the present inventors' earnest efforts to solve the above problems, a composition comprising a compound represented by the following general formula or a pharmaceutically acceptable salt thereof as an active ingredient is imagined. The inventors have found that the present invention is effective for prevention and treatment of blood reperfusion injury, and have completed the invention.

[0007] The present invention is a preventive / therapeutic agent for ischemia-reperfusion injury comprising a Lewis-type sugar chain derivative represented by the following general formula [I] as an active ingredient.

Embedded image Wherein, -A- _{is, - (CH 2) m -} , - (CH 2) n -NR e
-CO-O -, - CO- O -, - (CH 2) n -CO-O
-, or - (CH ₂₎ n represents an -O- (R ^e represents a hydrogen atom or a lower alkyl, m represents an integer of 0 to 12, n is an integer of 2 to 12). R is

Embedded image

(R ^a and R ^b are the same or different and each represents a saturated or unsaturated aliphatic hydrocarbon group or a saturated or unsaturated acyl.) W and Y are different from each other, one represents 1-galactopyranosyl, the other 1
-Represents fucopyranosyl. This 1-galactopyranosyl has a hydrogen atom at the 3-position hydroxyl group,

Embedded image

(R ^c and R ^d may be the same or different and each represents a lower alkyl, a lower alkenyl or a hydroxyl group). Alternatively, A and R together form a linear or branched alkyl having 1 to 30 carbons, alkenyl having 3 to 30 carbons, alkynyl having 3 to 30 carbons, Alkoxycarbonyl,
Alternatively, it represents aralkyl having 7 to 20 carbon atoms. Further, the Lewis-type sugar chain derivative according to the present invention includes a sialyl Lewis-type sugar chain derivative represented by any of the following structural formulas [II] and [III].

Embedded image

Embedded image

In the formula, E is a straight-chain or branched alkyl having 1 to 30 carbon atoms and a nitrogen atom of 2
Represents molanoline which may be substituted by alkenyl having from 30 to 30 or alkynyl having from 2 to 30 carbon atoms. Neu5Ac represents sialic acid, Gal represents calactose, and Fuc represents L-fucose (the same applies hereinafter). Hereinafter, the present invention will be described in detail.

In the present invention, the term "saturated or unsaturated aliphatic hydrocarbon group" refers to a linear or branched one having 1 to 30 carbon atoms, for example, pentyl, hexyl, octyl, decyl, dodecyl. , Tetradecyl, palmityl,
Stearyl, icosanyl, docosanil, tetracosanil, hexacosanyl, octacosanyl, isohexyl,
9-dodecenyl, 9-tetradecenyl, 9-hexadecenyl,
Examples thereof include 6-octadecenyl, oleyl, 9-icosenyl, 13-docosenyl, linoleyl, γ-linolenyl, and α-linolenyl, and among them, linear alkyl or alkenyl having 12 to 20 carbon atoms is preferable.

In the present invention, the term "saturated or unsaturated acyl" refers to a straight-chain or branched-chain acyl having 1 carbon atom.
~ 30, such as valeryl, isovaleryl, hexanoyl, octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl,
6-octadecenoyl, 13-docosenoyl, arachidoyl, elideyl, 9,12-octadecadienoyl, 6,9,
Examples include 12-octadecatrienoyl and 9,12,15-octadecatrienoyl. Among them, straight-chain acyl having 12 to 20 carbon atoms is preferable.

In the present invention, the “lower alkyl” of lower alkyl, lower alkoxy, lower alkylcarbamoyl, lower alkylthio and lower alkylamino includes
For example, straight or branched ones having 1 to 6 carbon atoms can be mentioned, and as typical examples, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and hexyl can be mentioned. In the present invention, the “lower alkenyl” includes, for example, a straight-chain or branched-chain
To 6, and typical examples include vinyl, allyl, propenyl, isopropenyl, 2-butenyl, 2-pentenyl, and 2-hexenyl.

In the present invention, the "alkyl having 1 to 30 carbon atoms" represented by A and R together includes a linear or branched alkyl, such as methyl, ethyl, propyl, Isopropyl, butyl, t-butyl, iso-
Butyl, sec-butyl, hexyl, octyl, decyl, lauryl, myristyl, hexadecyl, stearyl, eicosyl, 2-tetradecylhexadecyl and the like, among which ethyl, propyl, butyl, 3-ethylbutyl, octyl, decyl , Lauryl, myristil,
Hexadecyl, stearyl, eicosyl, 2-tetradecylhexydecyl are preferred.

The "alkyl having 1 to 30 carbons" represented by A and R together represents an acyl having 2 to 6 carbons, an alkoxycarbonyl having 2 to 6 carbons, cyano, lower alkylcarbamoyl, nitro, It may be substituted with lower acylamino, lower alkylthio, hydroxyl group, or aryloxy having 6 to 8 carbon atoms. For example, acetylmethyl,
Propionylmethyl, valerylethyl, pivaloylpropyl, methoxycarbonylbutyl, ethoxycarbonylpentyl, propoxycarbonylhexyl, 3-cyanopropyl, methylcarbamoylethyl, propylcarbamoylpentyl, 6-nitrohexyl, acetamidemethyl, butyrylaminoethyl, methylthiopropyl, Ethylthiobutyl, propylthiopentyl, butylthiohexyl, 2-hydroxyethyl, 2,3-dihydroxypropyl, 5-hydroxypentyl, 2,4,6-trihydroxyhexyl, 2-phenoxyethyl, 4-phenoxybutyl, 6 -Phenoxyhexyl and the like.

Further, the "alkyl having 1 to 30 carbon atoms" represented by A and R together includes an alkyl substituted with a 5-membered unsaturated heterocyclic ring substituted or unsubstituted with lower alkyl. it can. Examples of the 5-membered unsaturated heterocyclic ring include those having 1 to 2 sulfur, oxygen, and nitrogen as hetero atoms. For example, thiophene, furan, pyrrole, or imidazole, for example,
Furfuryl, 5-methyl-furfuryl, 2-thenyl, 5-methyl-2-thenyl and the like are preferred.

In the present invention, the "alkenyl having 3 to 30 carbon atoms" represented by A and R together is preferably allyl, isopropenyl, pentenyl, hexenyl, oleyl, vaccenyl, linoleyl, or arachidonyl.
In the present invention, “A and R together represent“ C 3
Examples of the alkynyl of -30 to 30 "include, for example, 2-propynyl, 3-butynyl, 2-octynyl, 9-decynyl, 9
-Octadecinyl, 9-pentacosinyl and the like.

In the present invention, "alkoxycarbonyl having 2 to 30 carbon atoms" represented by A and R together,
Preferred are methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, octyloxycarbonyl, tesiloxycarbonyl, pentadecyloxycarbonyl and the like. In the present invention, examples of “aralkyl” represented by A and R together include aralkyl which may be substituted with alkoxy having 1 to 20 carbon atoms.
Methoxybenzyl, propoxyphenethyl, pentyloxyphenylpropyl, heptoxybenzyl, nonyloxybenzyl, undecyloxybenzyl, tridecyloxybenzyl, pentadecyloxybenzyl, heptadecyloxybenzyl, eicosiloxyphenylpropyl, and the like are preferred, and hexyloxybenzyl is particularly preferred. Is preferred.

Further, as "aralkyl" represented by A and R together, a benzene ring is unsubstituted or as at least one substituent, a hydroxyl group, a lower alkoxy having 1 to 6 carbon atoms,
Examples thereof include lower alkyl, lower alkylamino, halogen, cyano, carbamoyl, nitro, acylamino lower alkyl having 2 to 6 carbon atoms, lower alkylthio or carboxy-substituted phenyl lower alkyl having 7 to 20 carbon atoms. For example, m-methoxyphenethyl, p-fluorophenethyl, 4- (m-dimethylaminophenyl) butyl, 5- (m-cyanophenyl) pentyl, 6- (p
-Carbamoylphenyl) hexyl, 3- (2,4-dinitrophenyl) propyl, particularly (3,4-dihydroxyphenyl) propyl, (4-hydroxy-3-methoxyphenyl) propyl, p-methylbenzyl, m -Bromobenzyl, p-hexyloxybenzyl, m- (propionylaminomethyl) benzyl, p- (valerylaminoethyl) phenethyl, 4- (3-methylthio-4-hydroxyphenyl)
Butyl and p-carboxybenzyl are preferred.

The straight-chain or branched-chain alkyl having 1 to 30 carbon atoms to be substituted by moranoline represented by E includes methyl, ethyl, propyl, isopropyl, butyl, t-butyl, iso-butyl, sec-butyl -Butyl, hexyl, octyl, decyl, lauryl, myristyl, hexadecyl, stearyl, eicosyl, 2-tetradecylhexadecyl and the like, among which ethyl, propyl, butyl, 3-ethylbutyl and heptyl are preferred.

The straight-chain or branched alkenyl having 2 to 30 carbon atoms to be substituted by moranoline represented by E is vinyl, allyl, isopropenyl, pentenyl, hexenyl, oleyl, vacenyl, linoleyl, or arachidonyl. Is preferred. Above all, 2-pentenyl,
1,3-Butadienyl, 2-butenyl, 1-propenyl, allyl, vinyl are preferred.

Examples of the straight-chain or branched alkynyl having 2 to 30 carbon atoms to be substituted with moranoline represented by E include ethynyl, 2-propynyl, 3-butynyl, 2-octynyl and 9-decynyl. , 9-octadecynyl, 9-pentacosynyl and the like. Among them, 4-pentenyl, 3-butynyl, 2-propynyl and ethynyl are preferred.

The compound of the present invention can be used for treatment as it is, but can be used in the form of a pharmaceutically acceptable salt by a known method. In the present invention, "pharmaceutically acceptable salts" include hydrochloric acid, hydrobromic acid,
Salts of mineral acids such as sulfuric acid and phosphoric acid, acetic acid, citric acid, tartaric acid,
Salts of organic acids such as maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid and the like can be mentioned.

Further, the salts of the compound [I] of the present invention having a sulfonic acid, a carboxylic acid, a phosphoric acid, and an alkyl phosphoric acid include, for example, alkyl metal salts such as lithium salt, sodium salt and potassium salt, magnesium salt, calcium salt and the like. And alkaline earth metal salts such as salts and barium salts.

These salts can be obtained by a conventional method.
For example, the hydrochloride can be obtained by dissolving the compound according to the present invention in an alcoholic solution of hydrochloric acid. Solvates (including hydrates) of the compounds or salts thereof according to the present invention
Are also included in the present invention. The solvate may be obtained by recrystallizing the solvate from the corresponding solvent or a suitable mixed solvent containing the corresponding solvent.

For example, the hydrate of the compound according to the present invention is
In some cases, it can be obtained by recrystallization from aqueous alcohol. The compounds according to the invention may take crystalline polymorphs. The crystalline polymorph is also included in the present invention. Some unsaturated aliphatic hydrocarbon groups and unsaturated acyl have isomers of E and Z, both of which are included in the present invention.

Specific examples of the compound of the present invention include the following. O-β-D-Carlactohyperanosyl- (1 → 3) -O-[(α-L-fucohyperanosyl)-
(1 → 4))-N-[(2,3-dioleyloxy) fluoro] -1,5-dioxy-
1,5-Imino-D-Culcitol O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 3) -O- [(α-L-fucohydranosyl)-(1 → 4) ] -N-[(2,3-dioleyloxy) fluoro] -1,5
-Citoxy-1,5-imino-D-qulcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 3) -O- [(α-L-fucohydranosyl)- (1 → 4)) -N-[(2,3-peryluryloxy) propyl] -1,5
-Citoxy-1,5-imino-D-qulcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 3) -O- [(α-L-fucohydranosyl)- (1 → 4)) -N-[(2,3-dimethylmyristyloxy) propyl]-
1,5-cydoxy-1,5-imino-D-qulcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 3) -O- [(α-L- (Fucopyranosyl)-(1 → 4)) -N-[(2,3-spermityloxy) fluoro]]-
1,5-cydoxy-1,5-imino-D-qulcitol sodium salt

O- (3-O-sulfo-β-D-carbactylpyranosyl)-(1 → 3)-
O-[(α-L-fucopyranosyl)-(1 → 4)]-N-[(2,3-perinoleyloxy) fluoro] sodium-1,5-cytoxy-1,5-imino-D-coulcitol sodium Salt O- (3-O-sulfo-β-D-carbactylpyranosyl)-(1 → 3) -O-[(α-L-fucohydranosyl)-(1 → 4)]-N-[(2, 3-thioleoyloxy) propyl]-
1,5-cydoxy-1,5-imino-D-qulcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 3) -O- [(α-L- (Fucopyranosyl)-(1 → 4)) -N-[(2,3-dilauroyloxy) fluoro]]-
1,5-cydoxy-1,5-imino-D-qulcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 3) -O- [(α-L- (Fucopyranosyl)-(1 → 4)) -N-[(2,3-dimethylristoyloxy) fluoro]-
1,5-cydoxy-1,5-imino-D-qulcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 3) -O- [(α-L- (Fucopyranosyl)-(1 → 4)) -N-[(2,3-dimethylamitoyloxy) fluoro]-
1,5-cydoxy-1,5-imino-D-qulcitol sodium salt

O- (3-O-sulfo-β-D-carbactylpyranosyl)-(1 → 3)-
O- [(α-L-fucopyranosyl)-(1 → 4)] -N-[(2,3-perinorenyloxy) fluoro] sodium-1,5-cytoxy-1,5-imino-D-qulcitol sodium Salt O- (3-O-carboxymethyl-β-D-galactopyranosyl)-(1 → 3) -O- [
(α-L-fucopyranosyl)-(1 → 4)]-N-[(2,3-dioleyloxy) fluoro] -1,5-citroxy-1,5-imino-D-qulcitol sodium salt O- ( 3-O-phospho-β-D-d-galactopyranosyl)-(1 → 3) -O-[(α-L-fucodylanosyl)-(1 → 4)]-N-[(2,3-dioleyl (Oxy) fluoro] -1,5-
Peroxy-1,5-imino-D-qulcitol sodium salt O- (3-O-methylphosphono-β-D-galactopyranosyl)-(1 → 3) -O- [(α
-L-fucohydranosyl)-(1 → 4))-N-[(2,3-dioleyloxy) fluoro]
-1,5-Dioxy-1,5-imino-D-qulcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 3) -O- [(α-L -Fucopyranosyl)-(1 → 4))-N-[(2,3-dioleyloxy) fluoro] -1,5-
Citoxy-1,5-imino-D-calcitol potassium salt

O- (3-O-sulfo-β-D-carbactylpyranosyl)-(1 → 3)-
O-[(α-L-fucopyranosyl)-(1 → 4)]-N- (1,3-dioleyloxyfluoro-2-yloxycarbonyl) -1,5-cydeoxy-1,5-imino-D -Culcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 3) -O- [(α-L-fucohyperanosyl)-(1 → 4)]-N- ( 1,3-Dioleoyloxyfluoro-2-yloxycarbonyl) -1,5-dioxy-1,5-imino-D-glucositol sodium salt O- (3-O-sulfo-β-D-galacthydrano (Syl)-(1 → 4) -O- [(α-L-fucohydranosyl)-(1 → 3)]-N-[(2,3-dioleyloxy) fluoro] -1,5-
Peroxy-1,5-imino-D-qulcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 4) -O- [(α-L-fucohydranosyl)-( 1 → 3))-N-[(2,3-perilauryloxy) fluoro] -1,5-
Peroxy-1,5-imino-D-qulcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 4) -O- [(α-L-fucohydranosyl)-( 1 → 3))-N-[(2,3-dioleoyloxy) fluoro]]-1,
5-cytoxy-1,5-imino-D-qulcitol sodium salt

O- (3-O-sulfo-β-D-carbactylpyranosyl)-(1 → 4)-
O-[(α-L-fucopyranosyl)-(1 → 3)]-N-[(2,3-dilauroyloxy)
(Propyl) -1,5-cytoxy-1,5-imino-D-qulcitol sodium salt O- (3-O-carboxymethyl-β-D-carbacthydranosyl)-(1 → 4) -O- [
(α-L-fucopyranosyl)-(1 → 3)]-N-[(2,3-dioleyloxy) fluoro] -1,5-citroxy-1,5-imino-D-glucositol sodium salt O- ( 3-O-phospho-β-D-d-galactopyranosyl)-(1 → 4) -O-[(α-L-fucopyranosyl)-(1 → 3)]-N-[(2,3-dioleyl (Oxy) fluoro] -1,5-
Peroxy-1,5-imino-D-qulcitol sodium salt O- (3-O-methylphosphono-β-D-galactopyranosyl)-(1 → 4) -O- [(α
-L-fucohydranosyl)-(1 → 3))-N-[(2,3-dioleyloxy) fluoro]
-1,5-cydoxy-1,5-imino-D-glucositol sodium salt O-β-D-galactopyranosyl- (1 → 4) -O- [(α-L-fucohydranosyl)-
(1 → 3)]-N- [3-N-[(1,3-dioleoyloxyfluoro-2-yl) oxycarbonyl] aminopropyl] -1,5-cydeoxy-1,5-imino-D -Qulucitol

O- (3-O-sulfo-β-D-carbactylpyranosyl)-(1 → 4)-
O-[(α-L-fucopyranosyl)-(1 → 3)]-N- [3-N-[(1,3-dioleoyloxyfluoro-2-yl) oxycarbonyl] amino] fluoro] -1 , 5-Citoxy-1,5-imino-D-glucositol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 4) -O- [(α-L-fucohydranosyl )-(1 → 3)]-N- [3-N-[(1,3-dilauroyloxyfluoro-2-yl) oxycarbonyl] amino] fluoro] -1,5-cydoxy-1,5-imino -D-Culcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 4) -O- [(α-L-fucohydranosyl)-(1 → 3)]-N -[6-N-[(1,3-Dioleoyloxyfluoro-2-yl) oxycarbonyl] amino] hexyl] -1,5-dioxy-1,5-imino
-D-Culcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 4) -O- [(α-L-fucohydranosyl)-(1 → 3)]-N -[9-N-[(1,3-Dioleoyloxyfluoro-2-yl) oxycarbonyl] amino] nonyl] -1,5-dioxy-1,5-imino
-D-Culcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 4) -O- [(α-L-fucohydranosyl)-(1 → 3)]-N -[12-N-[(1,3-Dioleoyloxyfluoro-2-yl) oxycarbonyl] amino] decyl] -1,5-cydoxy-1,5-imino-D-glucositol sodium salt

O- (3-O-methylphosphono-β-D-carbactylpyranosyl)-(1 →
4) -O- [(α-L-fucohydranosyl)-(1 → 3)]-N- [3-N-[(1,
3-thioleoyloxyphenyl-2-yl) oxycarbonyl] amino] phenyl]-
1,5-cydoxy-1,5-imino-D-qulcitol sodium salt O- (3-O-methylphosphono-β-D-galactopyranosyl)-(1 → 4) -O- [(α
-L-fucopyranosyl)-(1 → 3)]-N- [3-N-[(1,3-dilauroyloxyfluoro-2-yl) oxycarbonyl] amino] fluoro] -1,5-dioxy-
1,5-Imino-D-glucositol sodium salt O- (3-O-methylphosphono-β-D-galactopyranosyl)-(1 → 4) -O- [(α
-L-fucopyranosyl)-(1 → 3)]-N- [6-N-[(1,3-dioleoyloxyfluoro-2-yl) oxycarbonyl] amino] hexyl] -1,5-dioxy- 1,
5-imino-D-glucositol sodium salt O- (3-O-methylphosphono-β-D-galactopyranosyl)-(1 → 4) -O- [(α
-L-fucopyranosyl)-(1 → 3)]-N- [9- N-[(1,3-dioleoyloxyfluoro-2-yl) oxycarbonyl] amino] nonyl] -1,5-dioxy- 1,
5-imino-D-glucositol sodium salt O- (3-O-methylphosphono-β-D-galactopyranosyl)-(1 → 4) -O- [(α
-L-fucopyranosyl)-(1 → 3)]-N- [12-N-[(1,3-dioleoyloxyphenyl-2-yl) oxycarbonyl] amino] todecyl] -1,5-dioxy-
1,5-Imino-D-qulucitol sodium salt

O- (3-O-phospho-β-D-carbactylpyranosyl)-(1 → 4)-
O-[(α-L-fucopyranosyl)-(1 → 3)]-N- [3-N-[(1,3-dioleoyloxyfluoro-2-yl) oxycarbonyl] amino] fluoro] -1 , 5-Citoxy-1,5-imino-D-qulcitol sodium salt O- (3-O-phospho-β-D-galactopyranosyl)-(1 → 4) -O- [(α-L-fucohydranosyl )-(1 → 3)]-N- [3-N-[(1,3-dilauroyloxyfluoro-2-yl) oxycarbonyl] amino] fluoro] -1,5-cydoxy-1,5-imino -D-Culcil sodium sodium salt O- (3-O-phospho-β-D-galactopyranosyl)-(1 → 4) -O- [(α-L-fucohydranosyl)-(1 → 3)]-N -[6-N-[(1,3-Dioleoyloxyfluoro-2-yl) oxycarbonyl] amino] hexyl] -1,5-dioxy-1,5-imino
-D-Culcitol sodium salt O- (3-O-phospho-β-D-galactopyranosyl)-(1 → 4) -O- [(α-L-fucohydranosyl)-(1 → 3)]-N -[9-N-[(1,3-Dioleoyloxyfluoro-2-yl) oxycarbonyl] amino] nonyl] -1,5-dioxy-1,5-imino
-D-Culcitol sodium salt O- (3-O-phospho-β-D-galactopyranosyl)-(1 → 4) -O- [(α-L-fucohydranosyl)-(1 → 3)]-N -[12-N-[(1,3-Dioleoyloxyphenyl-2-yl) oxycarbonyl] amino] todecyl] -1,5-dimethyloxy-1,5
-Imino-D-qulucitol sodium salt

O- (3-O-carboxymethyl-β-D-galactopyranosyl)-(1
→ 4) -O- [(α-L-fucopyranosyl)-(1 → 3)]-N- (3-N-
[(1,3-Dioleoyloxyfluorophenyl-2-yl) oxycarbonyl] amino] fluoro]]-1,5-cytoxy-1,5-imino-D-glucositol sodium salt O- (3-O-carboxymethyl -β-D-Carpalactidranosyl)-(1 → 4) -O- [
(α-L-fucopyranosyl)-(1 → 3)]-N- [3-N-[(1,3-dilauroyloxyfluoro-2-yl) oxycarbonyl] amino] fluoro] -1,5-dioxy -1,5-Imino-D-glucositol sodium salt O- (3-O-carboxymethyl-β-D-galactopyranosyl)-(1 → 4) -O- [
(α-L-fucopyranosyl)-(1 → 3)]-N- [6-N-[(1,3-dioleoyloxyfluoro-2-yl) oxycarbonyl] amino] hexyl] -1,5- Siteoxy
-1,5-Imino-D-glucositol sodium salt O- (3-O-carboxymethyl-β-D-galactopyranosyl)-(1 → 4) -O- [
(α-L-fucopyranosyl)-(1 → 3)]-N- [9-N-[(1,3-dioleyloxyfluorophenyl-2-yl) oxycarbonyl] amino] nonyl] -1,5- Siteoxy
-1,5-Imino-D-glucositol sodium salt O- (3-O-carboxymethyl-β-D-galactopyranosyl)-(1 → 4) -O- [
(α-L-fucopyranosyl)-(1 → 3)]-N- [12-N-[(1,3-dioleoyloxyphenyl-2-yl) oxycarbonyl] amino] todecyl] -1,5- Citoxy-1,5-imino-D-calcitol sodium salt

O- (3-O-sulfo-β-D-carbactylpyranosyl)-(1 → 3)-
O-[(α-L-fucopyranosyl)-(1 → 4)]-N- [3-N-[(1,3-dioleoyloxyfluoro-2-yl) oxycarbonyl] amino] fluoro] -1 , 5-Citoxy-1,5-imino-D-glucositol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 3) -O- [(α-L-fucohydranosyl )-(1 → 4))-N- [3-N-[(1,3-dilauroyloxyfluoro-2-yl) oxycarbonyl] amino] fluoro] -1,5-cydoxy-1,5-imino -D-Culcitol sodium salt O- (3-O-methylphosphono-β-D-galactopyranosyl)-(1 → 3) -O- [(α
-L-fucopyranosyl)-(1 → 4)]-N- [3-N-[(1,3-dioleoyloxyfluoro-2-yl) oxycarbonyl] amino] fluoro] -1,5-dioxy-
1,5-Imino-D-glucositol sodium salt O- (3-O-phospho-β-D-galactopyranosyl)-(1 → 3) -O- [(α-L-fucohydranosyl)-(1 → 4)]-N- [3-N-[(1,3-dioleoyloxyfluoro-2-yl) oxycarbonyl] amino] fluoro] -1,5-cytoxy-1,5-imino-D-qulcitol Sodium salt O- (3-O-carboxymethyl-β-D-galactopyranosyl)-(1 → 3) -O- [
(α-L-fucopyranosyl)-(1 → 4)]-N- [3-N-[(1,3-dioleoyloxyfluoro-2-yl) oxycarbonyl] amino] fluoro] -1,5- Citoxy-1,5-imino-D-calcitol sodium salt

O-β-D-carbylhyperhydranosyl- (1 → 4) -O-[(α-L
-Fucopyranosyl)-(1 → 3)]-N- (1,3-dioleoyloxyfluoro-2-yloxycarboxynyl) -1,5-cydeoxy-1,5-imino-D-calcitol O- (3 -O-Sulfo- β-D-D-galactopyranosyl)-(1 → 4) -O- [(α-L-fucopyranosyl)-(1 → 3)]-N- (1,3-dioleoyloxy (Fluorophenyl-2-yloxycarboxynyl) -1,5-cydoxy-1,5-imino-D-glucositol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 4) -O- [(α-L-fucopyranosyl)-(1 → 3)]-N- (1,3-perilauroyloxyfluoro-2-yloxycarboxynyl) -1,5-dioxy-1,5-imino- D-Culcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 4) -O- [(α-L-fucohyperanosyl)-(1 → 3)]-N- (1,3-dimyristoyloxyfluoro-2-yloxycarboxynyl) -1,5-diphenyl Deoxy-1,5-imino-D-qulcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 4) -O- [(α-L-fucohydranosyl)-( 1 → 3))-N- (1,3-Cypermitoyloxyfluoro-2-yloxycarbonyl) -1,5-cytoxy-1,5-imino-D-calcitol sodium salt

O- (3-O-sulfo-β-D-carbactylpyranosyl)-(1 → 4)-
O-[(α-L-fucopyranosyl)-(1 → 3)]-N- (1,3-perinolenyloxyfluoro-2-yloxycarboxynyl) -1,5-cydoxy-1,5-imino- D-Culcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 4) -O- [(α-L-fucohyperanosyl)-(1 → 3)]-N- (1,3-Dioleyloxyfluoro-2-yloxycarbonyl) -1,5-dioxy-1,5-imino-D-glucositol sodium salt O- (3-O-sulfo-β-D-galacthydrano (Sil)-(1 → 4) -O-[(α-L-fucohydranosyl)-(1 → 3)]-N- (1,3-perilauryloxyfluoro-2-anoxycarbonyl) -1,5- Peroxy-1,5-imino-D-qulcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 4) -O- [(α-L-fucohydranosyl)-( 1 → 3))-N- (1,3-dimethylsyloxyfluorophenyl-2-yloxycal (Denyl) -1,5-cydoxy-1,5-imino-D-qulcitol sodium salt O- (3-O-sulfo-β-D-carbacthydranosyl)-(1 → 4) -O- [( α-L-fucopyranosyl)-(1 → 3)]-N- (1,3-dimethylaminopropyl-2-yloxycarboxynyl) -1,5-cytoxy-1,5-imino-D-glucositol sodium salt

O- (3-O-sulfo-β-D-carbactylpyranosyl)-(1 → 4)-
O-[(α-L-fucopyranosyl)-(1 → 3)]-N- (1,3-perinoleyloxyfluoro-2-anoxycarbonyl) -1,5-cydoxy-1,5-imino- D-Culcitol sodium salt O- (3-O-carboxymethyl-β-D-galactopyranosyl)-(1 → 4) -O- [
(α-L-fucohydranosyl)-(1 → 3)]-N- (1,3-dioleoyloxyfluoro-2
-Yloxycarbonyl) -1,5-cydoxy-1,5-imino-D-glucositol sodium salt O- (3-O-phospho-β-D-galactopyranosyl)-(1 → 4)- O-[(α-L-fucopyranosyl)-(1 → 3)]-N- (1,3-dioleoyloxyfluoro-2-yloxycarbonyl) -1,5-cydoxy-1,5-imino- D-Culcitol sodium salt O- (3-O-methylphosphono-β-D-galactopyranosyl)-(1 → 4) -O- [(α
-L-fucopyranosyl)-(1 → 3)]-N- (1,3-dioleoyloxyfluoro-2-yloxycarboxynyl) -1,5-cytoxy-1,5-imino-D-calcitol Sodium salt O- (3-O-sulfo-β-D-carbactylpyranosyl)-(1 → 4) -O-[(α-L-fucohydranosyl)-(1 → 3)]-N- (1, 3- (dioleoyloxyfluoro-2-yloxycarboxynyl) -1,5-cytoxy-1,5-imino-D-glucositol potassium salt

O- (3-O-sulfo-β-D-carbactylpyranosyl)-(1 → 4)-
O-[(α-L-fucopyranosyl)-(1 → 3)]-N- [1- (2,3-dithioyloxy) fluoro] -1,5-dioxy-1,5-imino-D- Qulucitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 4) -O-[(α-L-fucohyperanosyl)-(1 → 3)]-N- [1 -(2,3-dioleyloxy) fluoro-)-
1,5-cydoxy-1,5-imino-D-qulcitol sodium salt

O- (3-O-sulfo-β-D-carbactylpyranosyl)-(1 → 4)-
O-[(α-L-fucohydranosyl)-(1 → 3)]-1,5-dioxy-1,5-imino
-N-Oleyl-D-qulcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 4) -O-[(α-L-fucohydranosyl)-(1 → 3 ))-1,5-Citoxy-1,5-imino-N-boxenyl-D-
Qulcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 4) -O-[(α-L-fucohyperanosyl)-(1 → 3)]-1,5- Peroxy-1,5-imino-N-linoleyl-D-qulucitol sodium salt O- (3-O-sulfo-β-D-carbacthydranosyl)-(1 → 4) -O-[(α-L- Fucopyranosyl)-(1 → 3))-1,5-cydoxy-1,5-imino-N-arachitodinyl-D
-Culcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 4) -O-[(α-L-fucohydranosyl)-(1 → 3)]-1,5 -Citoxy-1,5-imino-N-fluorodionylmethyl-D-glucositol sodium salt

O- (3-O-sulfo-β-D-carbactylpyranosyl)-(1 → 4) -O
-[(Α-L-fucopyranosyl)-(1 → 3)]-1,5-dioxy-1,5-imino-
N- (4-Methoxycarbonylbutyl) -D-qulcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 4) -O-[(α-L-fucohydranosyl) -(1 → 3)]-1,5-cydoxy-1,5-imino-N-methylthiophenol-D-qulcitol sodium salt O- (3-O-sulfo-β-D-carbacthydranosyl)-( 1 → 4) -O-[(α-L-fucopyranosyl)-(1 → 3)]-1,5-cydoxy-1,5-imino-N- (5-methylfurfuryl) -D-qulcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 4) -O-[(α-L-fucohydranosyl)-(1 → 3)]-1,5-dioxy-1 , 5-Imino-N-thenyl-D-qulcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 4) -O-((α-L-fucohydranosyl)- (1 → 3))-1,5-cytoxy-1,5-imino-N- (2,3-cytoxyphenyl) phenyl-D-c Rushitoru sodium salt

O- (3-O-sulfo-β-D-carbactylpyranosyl)-(1 → 4) -O
-[(Α-L-fucopyranosyl)-(1 → 3)]-1,5-dioxy-1,5-imino-
N- (2-phenoxyethyl) -D-qulucitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 4) -O-[(α-L-fucohydranosyl)- (1 → 3)]-1,5-Dioxy-1,5-imino-N- (3,4-dihydroxypropyl) fluoro-D-glucositol sodium salt O- (3-O-sulfo-β-D-galactoate (Hyperanosyl)-(1 → 4) -O-[(α-L-fucohyperanosyl)-(1 → 3)]-1,5-cydetoxy-1,5-imino-N- (4-human-peroxy-
3-methoxyphenyl) fluoro-D-qulcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 4) -O-[(α-L-fucohydranosyl)-(1 → 3))-1,5-Citoxy-1,5-imino-N-decyl-D-qulcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 4) -O- [(α-L-fucohydranosyl)-(1 → 3)]-1,5-cydetoxy-1,5-imino-N-pentanatecyl-D
-Qulucitol sodium salt

O- (3-O-sulfo-β-D-carbactylpyranosyl)-(1 → 4) -O
-[(Α-L-fucopyranosyl)-(1 → 3)]-1,5-dioxy-1,5-imino-
N-eicosyl-D-glucositol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 4) -O-[(α-L-fucohydranosyl)-(1 → 3) -1,5-Citoxy-1,5-imino-N-pentaeicosyl-
D-Culcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 4) -O-[(α-L-fucohydranosyl)-(1 → 3)]-1, 5-cydoxy-1,5-imino-N-triacontyl-D-
Qulcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 4) -O-[(α-L-fucohydranosyl)-(1 → 3)]-1,5- Peroxy-1,5-imino-N-pentantriacontyl-D-glucositol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 3) -O-[(α -L-fucopyranosyl)-(1 → 4)]-1,5-cydoxy-1,5-imino-N-oleyl-D-qulcitol sodium salt

O- (3-O-sulfo-β-D-carbactylpyranosyl)-(1 → 3) -O
-[(Α-L-fucopyranosyl)-(1 → 4)]-1,5-dioxy-1,5-imino-
N-Baxenyl-D-calcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 3) -O-[(α-L-fucohyperanosyl)-(1 → 4) ) -1,5-Dioxy-1,5-imino-N-linoleyl D-Culcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 3) -O- [ (Α-L-fucopyranosyl)-(1 → 4)]-1,5-cydoxy-1,5-imino-N-arachitodinyl-D
-Culcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 3) -O-[(α-L-fucohydranosyl)-(1 → 4)]-1,5 -Cytoxy-1,5-imino-N-fluorodionylmethyl-D-glucositol sodium salt O- (3-O-sulfo-β-D-carbacthydranosyl)-(1 → 3) -O-[(α- (L-fucopyranosyl)-(1 → 4)]-1,5-cydoxy-1,5-imino-N- (4-methoxycarbonylbutyl) -D-glucositol sodium salt

O- (3-O-sulfo-β-D-carbactylpyranosyl)-(1 → 3) -O
-[(Α-L-fucopyranosyl)-(1 → 4)]-1,5-dioxy-1,5-imino-
N-methylthiophenol-D-glucositol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 3) -O-[(α-L-fucohydranosyl)-(1 → 4 ))-1,5-Diethoxy-1,5-imino-N- (5-methylfurfuryl) -D-qulcitol sodium salt O- (3-O-sulfo-β-D-carbactylpyranosyl)-( 1 → 3) -O-[(α-L-fucopyranosyl)-(1 → 4)]-1,5-cydoxy-1,5-imino-N-thenyl-D-qulcitol sodium salt O- (3-O -Sulfo-β-D-D-galactopyranosyl)-(1 → 3) -O-[(α-L-fucopyranosyl)-(1 → 4)]-1,5-cydoxy-1,5-imino-N -(2,3-Diacetylhydroxyphenyl) fluoro-D-glucositol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 3) -O-[(α-L-fucohydranosyl )-(1 → 4))-1,5-Dioxy-1,5-imino-N- (2-phenoxyethyl) -D-qulcitol Thorium salt

O- (3-O-sulfo-β-D-carbactylpyranosyl)-(1 → 3) -O
-[(Α-L-fucopyranosyl)-(1 → 4)]-1,5-dioxy-1,5-imino-
N- (3,4-dihydroxypropylphenyl) fluoro-D-glucositol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 3) -O-[(α-L- (Fucopyranosyl)-(1 → 4))-1,5-cytoxy-1,5-imino-N- [3- (4-humanperoxy-3-methoxyphenyl) fluoro]]-D-qulcitol sodium salt O- (3- O-sulfo-β-D-caracthyperanosyl)-(1 → 4) -O-[(α-L-fucohyperanosyl)-(1 → 3)]-1,5-cydoxy-1,5-imino- N-decyl-D-glucositol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 4) -O-[(α-L-fucohydranosyl)-(1 → 3) -1,5-Citoxy-1,5-imino-N-pentanatecil-D
-Culcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 4) -O-[(α-L-fucohydranosyl)-(1 → 3)]-1,5 -Citoxy-1,5-imino-N-eicosyl-D-qulcitol sodium salt

O- (3-O-sulfo-β-D-carbactylpyranosyl)-(1 → 4) -O
-[(Α-L-fucopyranosyl)-(1 → 3)]-1,5-dioxy-1,5-imino-
N-pentaynecosyl-D-qulcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 4) -O-[(α-L-fucohydranosyl)-(1 → 3 ))-1,5-Dioxy-1,5-imino-N-triacontyl-D
-Culcitol sodium salt O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 4) -O-[(α-L-fucohydranosyl)-(1 → 3)]-1,5 -Citoxy-1,5-imino-N-phenantriacontyl-D-qulcitol sodium salt

Preferred compounds of the present invention include, for example,
O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 3) -O-[(α-L-fucohyperanosyl)-(1 → 4)]-N- [1- (2 , 3-Dioleyloxy) fluoro]
-1,5-cydoxy-1,5-imino-D-qulcitol sodium salt, O- (3-O-sulfo-β-D-carbactylpyranosyl)-(1 → 4) -O-[(α- (L-fucohydranosyl)-
(1 → 3)]-N- [3- [N-[(1,3-dioleoyloxyfluoro-2-yl) oxycarbonyl] amino] fluoro] -1,5-cytoxy-1,5-imino -D-Qulucitol sodium salt.

The compounds according to the present invention are described, for example, in Japanese Patent Application
155801 specification, JP-B-59-43459, international publication WO95
/ 13068, JP-A-61-205455, and the like, or can be produced according to them. In addition, the compounds according to the invention have very low toxicity.

[0051]

When the compound of the present invention is administered as an agent for preventing or treating ischemia-reperfusion injury, it may be used alone or
Alternatively, it can be applied by combining or mixing with a medicine that can be administered simultaneously.

The compound of the present invention may be used alone or in a pharmaceutically acceptable non-toxic and inert carrier, for example, from 0.01% to 9%.
It can be administered to animals, including humans, as a pharmaceutical composition containing 9.5%, preferably 0.1% to 90%.

As the carrier, one or more solid, semi-solid, or liquid diluents, fillers, and other prescription auxiliaries are used. Desirably, the pharmaceutical compositions are administered in dosage unit form. The pharmaceutical composition of the present invention can be administered orally, intraosseously, topically (such as transdermally) or rectally. It is needless to say that the composition is administered in a dosage form suitable for these administration methods. For example, oral administration or intra-tissue administration (particularly intravenous administration) is preferred.

The dose as a therapeutic agent for ischemia-reperfusion injury is preferably adjusted in consideration of the patient's condition such as age, weight, etc., administration route, and the nature and extent of the disease. On the other hand, the amount of the active ingredient of the present invention ranges from 10 mg to 10 g / day / human, preferably 100 m
A range of g to 5 g / day / human is common. In some cases, lower doses may be sufficient, and conversely, higher doses may be required. It is also desirable to administer the drug divided into two to three times a day.

For oral administration, solid or liquid dosage units such as powders, powders, fine granules, tablets, sugar coatings, films,
Capsules, granules, suspensions, solutions, syrups, drops, sublingual tablets and other forms can be used. Powders are prepared by comminuting the compound of the present invention to an appropriate degree. Powders of the compound according to the invention are of a suitable degree of fineness, then similarly finely divided pharmaceutical carriers,
Produced by mixing with edible carbohydrates such as starch, mannitol and the like. If necessary, flavoring agents, preservatives, dispersants, coloring agents, fragrances and the like may be mixed.

The capsule is prepared by first filling the powdered powder, powder or tablet granulated as described above in the form of a capsule such as a gelatin capsule. It is manufactured by Lubricants and fluidizers, such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol, and the like may be mixed with the powdered state, and then the filling operation may be performed. it can. When a disintegrating agent or a solubilizing agent such as carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxymethylstarch sodium, calcium carbonate, or sodium carbonate is added, the capsule is ingested. Can improve the efficacy of the drug.

A fine powder of the compound of the present invention can be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin and a surfactant, and wrapped in a gelatin sheet to form a soft capsule. Tablets are made by adding an excipient to make a powder mixture, granulating or slugging, and then adding a disintegrating or lubricating agent or tableting the powder mixture directly. The powder mixture is prepared by mixing the appropriately powdered material with the diluents and bases described above and, if necessary, a binder (e.g., sodium carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, gelatin,
Polyvinylpyrrolidone, polyvinyl alcohol, etc.),
A dissolution retardant (eg, paraffin, wax, hydrogenated castor oil, etc.), a resorbent (eg, quaternary salt) and an adsorbent (eg, bentonite, kaolin, dicalcium phosphate, etc.) may also be used in combination. The powder mixture can first be moistened with a binder such as syrup, starch paste, gum arabic, cellulose solution or polymer solution, stirred and mixed, dried and ground to form granules. Instead of granulating the powder in this way, first run it on a tableting machine,
It is also possible to crush the resulting incomplete slag into granules.

The granules thus produced can be prevented from adhering to each other by adding stearic acid, stearic acid salt, talc, mineral oil and the like as a lubricant. The lubricated mixture is then tableted.

The uncoated tablet thus produced can be coated with a film or coated with sugar. Further, the compound according to the present invention may be directly tableted after being mixed with a fluid inert carrier without going through the steps of granulation and slag formation as described above. A transparent or translucent protective coating consisting of a shellac hermetic coating, or alternatively or on top, a coating of sugar or a polymeric material, and a polish coating of wax may also be used.

Other oral dosage forms such as solutions, syrups, elixirs and the like can also be presented in dosage unit form so that a given quantity contains a fixed amount of a compound according to the present invention. Syrups are prepared by dissolving the compound according to the invention in an aqueous solution containing a suitable sweetening agent, and elixirs are prepared through the use of a non-toxic alcoholic carrier. Suspensions are formulated by dispersing the compound of the invention in a non-toxic carrier. Solubilizers and emulsifiers (eg, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters), preservatives, flavoring agents (eg, peppermint oil, saccharin) and the like can also be added as necessary. .

If desired, dosage unit formulations for oral administration may be microencapsulated. The formulations can also provide an extended period of action or sustained release by coating or embedding in polymers, waxes, and the like.

Administration into tissues can be carried out by using liquid dosage units for subcutaneous / muscular or intravenous injection, for example, solutions and suspensions. In these, a certain amount of the compound of the present invention is suspended or dissolved in a non-toxic liquid carrier suitable for injection, such as an aqueous or oily medium, and the suspension or solution is then sterilized. It is manufactured by Non-toxic salts or salt solutions may be added to make the injection solution isotonic. Rectal administration can be carried out by preparing the compound of the present invention from a water-soluble or insoluble low-melting solid and using it as a suppository.

[0063]

The present invention will be described more specifically with reference to formulation examples and test examples of the preparation of the compound according to the present invention, but the present invention is not limited thereto. As the compound of the present invention, O- (3-O-sulfo-β-D-carbactylpyranosyl)-(1 → 4) -O-[(α
-L-fucohydranosyl)-(1 → 3)]-N- [4-N-[(1,3-dioleoyloxy-2-
[Propyl) oxycarbonyl] aminobutyl] -1,5-citroxy-1,5-imino-D-glucositol sodium salt was used.

Formulation Example 1 Compound of the present invention 100 mg Lactose 25 mg Corn protein 10 mg Low-substituted human hydroxypropyl cellulose 7.5 mg Human hydroxypropyl cellulose 2.5 mg Macnesium stearate 5 mg Each tablet is weighed at the above ratio, mixed, and then pressed into a tableting machine. Is used to produce tablets.

Formulation Example 2 The compound of the present invention is dissolved in physiological saline to prepare a 10 W / V /% solution. After filtering this solution through a membrane filter, 1 ml, 2
Each ml, 5 ml, 10 ml or 20 ml is filled into an ampoule corresponding to each volume and sterilized in an autoclave to produce an injection.

[Test Example] Effect of the compound of the present invention on rat hepatic ischemia-reperfusion model 1) Animal model of hepatic ischemia-reperfusion Male Wistar rats (220-280 g, 6 weeks old) were fasted for 24 hours.
Anesthetized with ketamine hydrochloride (100 mg / kg, ip). The abdomen was opened along the midline to expose the liver tissue. The middle and left lobes were completely ischemic by stopping the portal vein and the left branch vessel of the hepatic artery with a clip. The right lobe was not ligated to avoid intestinal congestion. Plastic rats to prevent abdominal dryness of rats during hepatic ischemia
Covered. After 120 minutes of ischemia, release the ligation of the left branch vessel,
At the same time, the portal vein, hepatic artery and the right branch vessel of the bile duct were ligated. This treatment was performed so that the portal vein flow and the hepatic artery flow all flowed into the ischemic middle and left lobe tissues. The animals in the sham operation group did not perform ischemia in the middle and left lobes, and stopped the blood flow in the right lobe. Compound A of the present invention was dissolved in a 5% aqueous solution of glucose and 15 mg / kg was injected intravenously 30 minutes before reperfusion. The control group received only a 5% aqueous solution of coulose.

2) Measurement of Liver Tissue Blood Flow A flow of a laser blood flow meter (ALF21N; Atdance) was placed on the left side of the middle lobe of the liver, and blood flow was continuously measured. The blood flow was shown as a relative value (%) to the pre-ischemic value.

3) Measurement of plasma GPT and GOT activity In order to measure plasma GPT and GOT activity, reperfusion was performed.
After time, plasma was separated and collected. These enzyme activities are reacted using a transaminase activity measurement kit, and a multi-analyzer
(Olympus). The activity value was read from a calibration curve and expressed as an average value of 5 or 6 animals in each group.

4) Statistical Analysis Statistical analysis was performed using a one-way analysis of variance of the Scheffe method.

5) Results Hepatic Tissue Blood Flow The effect of the compound of the present invention on the recovery of blood flow in the middle and left lobe liver tissues is shown in FIG. The blood flow in both the control group and the administration group decreased to about 30% of the pre-ischemic value at the beginning of reperfusion due to ischemia.
The time course after reperfusion recovered to about 40% of the pre-ischemic value 1 hour after reperfusion and returned to more than 50% after 3 hours in the control group.
On the other hand, in the group administered with the compound of the present invention, the recovery was already almost 60% after 1 hour of reperfusion, and returned to about 70 to 80% after 2 to 3 hours. (p <0.01). GOT and GPT concentrations in plasma

The concentrations of GPT and GOT in plasma, which are indicative of liver tissue cell injury, increase with time after injury and reach a maximum 6 hours after reperfusion. FIGS. 2 and 3 show the activity of GPT and GOT in plasma 6 hours after reperfusion and the action of the compound of the present invention. 120 minutes of ischemia followed by reperfusion is GPT and GOT
Both activities increased about 4 times in the sham operation group. The compound of the present invention administered 30 minutes before reperfusion reduced the activity of both enzymes increased by injury by about 1/2 (p <0.01).

[0072]

From the above results, it can be seen that the compound of the present invention can quickly recover from a decrease in blood flow due to vascular damage, etc.
It also markedly suppresses hepatic tissue injury caused by activated leukocytes after reperfusion, and was shown to be useful as a therapeutic agent for disorders associated with ischemia-reperfusion injury.

[Brief description of the drawings]

FIG. 1 shows the effect of the compound of the present invention on hepatic blood flow in a hepatic ischemia-reperfusion injury model. n represents the number of animals.

FIG. 2: GPT in plasma in hepatic ischemia-reperfusion injury model
2 shows the effect of the compound of the present invention on the concentration. n represents the number of animals. The horizontal and vertical lines to the right of the white circle represent the average and standard deviation, respectively.

FIG. 3. GOT in plasma in a hepatic ischemia-reperfusion injury model
2 shows the effect of the compound of the present invention on the concentration. n represents the number of animals. The horizontal and vertical lines to the right of the white circle represent the average and standard deviation, respectively.

Claims (4)

[Claims] An asialo-trisaccharide moranoline derivative represented by the following structural formula [I] or a pharmaceutically acceptable salt thereof:
Or a preventive or therapeutic agent for ischemia-reperfusion injury, comprising a solvate of any of them as an active ingredient. Embedded image Wherein, -A- _{is, - (CH 2) m -} , - (CH 2) n -NR e -CO
-O -, - CO-O - , - (CH 2) n -CO-O-, or - (CH ₂₎ n represents an -O- (R ^e represents a hydrogen atom or a lower alkyl, m is 0 Represents an integer of 12, and n is 2 to 12
Represents an integer). R is (R ^a and R ^b are the same or different and each represents a saturated or unsaturated aliphatic hydrocarbon group or a saturated or unsaturated acyl). W and Y are different from each other, one is 1
-Galactopyranosyl, the other 1-fucopyranosyl. This 1-galactopyranosyl has a hydrogen atom at the 3-position hydroxyl group, (R ^c and R ^d are the same or different and each represents a lower alkyl, a lower alkenyl, or a hydroxyl group). Alternatively, A and R together form a linear or branched alkyl having 1 to 30 carbons, an alkenyl having 3 to 30 carbons, an alkynyl having 3 to 30 carbons,
Alkoxycarbonyl having 2 to 30 carbon atoms, or 7 carbon atoms
Represents up to 30 aralkyls. The alkyl and aralkyl may have a substituent. 2. The method of claim 1, wherein the asialotrisaccharide moranoline derivative is O-
(3-O-sulfo-β-D-galactopyranosyl)-(1
→ 3) -O-[(α-L-fucopyranosyl)-(1 → 4)]
-N- (2,3-dioleyloxy-1-propyl)-
1,5-dideoxy-1,5-imino-D-glucitol or O- (3-O-sulfo-β-D-galactopyranosyl)-(1 → 4) -O-[(α-L- Fucopyranosyl)
-(1 → 3)]-N- [4- [N-[(1,3-dioleoyloxy-2-propyl) oxycarbonyl] amino] butyl] -1,5-dideoxy-1,5-imino −
The agent for preventing or treating ischemia-reperfusion injury according to claim 1, which is D-glucitol or a pharmaceutically acceptable salt thereof, or a solvate thereof. (3) A sialyl Lewis-type sugar chain derivative represented by any of the following structural formulas (II) or (III) or a pharmaceutically acceptable salt thereof, or a solvate of any of them, comprising: An agent for preventing or treating blood reperfusion injury. Embedded image Embedded image In the formula, E may be substituted even if the nitrogen atom of moranoline is substituted with linear or branched alkyl having 1 to 30 carbons, alkenyl having 2 to 30 carbons, or alkynyl having 2 to 30 carbons. Represents a good moranolin. Neu5Ac represents sialic acid, Gal represents calactose, and Fuc represents L-fucose. 4. The preventive / therapeutic agent for a disease based on ischemia-reperfusion injury according to claim 1, wherein the ischemia-reperfusion injury is liver ischemia-reperfusion injury.