WO1997000881A1 - Moranoline derivatives - Google Patents

Abstract

Moranoline derivatives represented by structural formula (I), wherein R1 represents lower alkyl substituted by acyl, alkoxycarbonyl, cyano, alkylcarbamoyl, nitro, acylamino, alkylthio, hydroxy or aryloxy, phenyl-lower alkyl wherein the benzene ring optionally has substituent(s) such as hydroxy, lower alkoxy, lower alkyl, halogeno, cyano, lower alkylcarbamoyl, nitro, acylamino, alkylthio or carboxy, lower alkyl substituted by a 5-membered unsaturated heterocycle optionally substituted by lower alkyl, alkenyl, arylalkenyl or higher alkyl; R?2 and R3¿ are different from each other and each represents galactopyranosyl or fucopyranosyl substituted by hydroxysulfonyl or a metal salt thereof; and R4 represents hydroxy or acetamide. The compounds are useful in the medicinal field, for example, as an antiinflammatory agent or a preventive or remedy for ischemia and reflow disorders.

Description

 Specification

 Moranoline derivatives Technical field

 The present invention relates to a novel moranoline derivative which is useful as a therapeutic agent in the field of medicine, for example, an anti-inflammatory agent “prevention of ischemia and reperfusion injury”. Background art

 High-chain compounds such as sialic acid-containing glycolipids and glycoproteins have hormone, bacterial toxin, virus and other receptor functions, and also recognize, differentiate, grow, adhere, cancer, immunize, and age cells. It is a substance that has attracted attention because it is deeply involved in basic and dynamic life phenomena such as. In particular, sialyl Lewis type 耱 chains containing sialic acid have useful physiological activities, and their application to pharmaceuticals is being actively studied.

 However, the sialyl Lewis type 耱 chain derivative has a basic structure of a tetrasaccharide of sialic acid, galactose, dalcosamine and fucose, and its production requires many steps and complicated operations. For this reason, there has been a problem in conducting economical and efficient mass production of sialyl Lewis type sugar chain derivatives on an industrial scale.

 Since these sialic acid derivatives exist as trace components in the natural world, it has been extremely difficult to obtain them as pure single compounds from living organisms. Therefore, research on the application of sialic acid derivatives to pharmaceuticals has attracted much attention as a new research field.

Recent studies have shown that trisialic hydroxysulfonyl Lewis-type glycan derivatives that do not combine sialic acid, in which sialic acid is mimicked with sulfonic acid, are also involved in cell adhesion, as are tetrasaccharide sialyl Lewis-type glycan derivatives. It has been reported that it has an antagonistic inhibitory effect on selectin (Glycobiology vol. 3, no. 6 p. 633-639, 1993). Until now, International Publication WO94 / 20514 and Japanese Patent Publication No. 7-501341 are known as examples of sialic acid mimicked with sulfonic acid or sulfonic acid. The present inventors have filed an international application for a trisaccharide-type Lewis-type sugar chain derivative containing moranoline obtained by mimicking sialic acid with hydroxysulfol (PCT / JP95 / 00610). The compound according to the applicant's invention has moranolin instead of glucosamine, and is structurally different from the compound according to the invention of the above-mentioned natural sugar chain derivative using dalcosamine as a constituent sugar. is there,

 DISCLOSURE OF THE INVENTION An object of the present invention is to provide a trisaccharide hydroxysulfur Lewis-type moranoline derivative which is a novel substance useful as a medicament described below and an intermediate useful for producing the same.

 The present inventors have conducted further studies and studied diligently, and as a result of the above general formula of PCT / JP95AX # 10, a substituent was introduced into the nitrogen atom of a molanolin derivative obtained by mimicking sialic acid with a sulfonic acid ester [ The present inventors have found that the compounds represented by [1], [11] and [ΠΙ] are suitable for the above purpose, and have completed the present invention.

 [¾

In the formula, R ¹ is phenyl, alkoxycarbonyl, cyano, alkylrubamoyl, butyr, acylamino, alkylthio, alkanesulfonamide, alkoxyalkoxyalkoxyamide, aralkyloxyamide, hydroxyl group Or a lower alkyl substituted with aryloxy, a benzene ring having a hydroxyl group, alkoxy, alkyl, halogen, halogenated alkyl, cyano, rubamoyl, mono- or dialkyl rubamoyl, nitro, acylamino, alkylthio, mono- or dialkylamino Or phenyl-lower alkyl, which may be substituted with 1 to 3 substituents selected from carboxy, and ③ substituted with alkyl. May be a lower alkyl substituted with a 5-membered unsaturated heterocyclic ring, alkaryl, alkarylalk

ル, ア ル キ ル higher alkyl, or ⑦3- (fluorescein carbamyl) aminobutyrate, wherein R ² and R ³ are different from each other and are substituted with hydroxysulfol or a metal salt thereof. Represents nosyl or fucopyranosyl. Represents a hydroxyl group or acetamido. In the formula il, a carbonyl, an alkoxycarbol, a cyano, an alkyl group lupamoyl, -toro, an acylamino, an alkylthio, an alkanesulfonamide, an alkoxyalkoxyalkoxyamide, an aralkyloxyamide, a hydroxyl group represented by R ¹ Alternatively, the lower alkyl of the lower alkyl substituted with aryloxy is preferably a straight-chain or branched-chain lower alkyl having 1 to 6 carbon atoms.

 Examples of the file include those having 1 to 6 carbon atoms. Those having 3 to 5 carbon atoms are preferred, and propioyl, valeryl and vivaloyl are preferred.

 Examples of the alkoxycarbonyl include alkoxy having an alkyl portion having 1 carbon atom. Alkoxy having 1 to 3 carbon atoms is preferred, and methoxycarbyl, ethoxycarbol, and propoxycarbonyl are particularly preferred.

 Examples of the alkyl carpamoyl include those having an alkyl moiety of 1 to 7 carbon atoms, preferably an alkyl moiety having 1 to 3 carbon atoms, preferably methylcarbamoyl, ethylcarbamoyl, and propyllimubamoyl. .

 Examples of acylamino include those having 1 to 6 carbon atoms. Those having 2 to 4 carbon atoms are preferred, and acetamide, propio-lamino and petyrylamino are preferred.

As the alkyl group, an S-chain or branched alkylthio group having 1 to 6 carbon atoms is preferable. Examples of the alkane portion of the alkane sulfonamide include alkanes having 1 to 20 carbon atoms. Alkanesulfonamides having an alkane having 5 to 15 carbon atoms are preferred, and decanesulfonamide, nonanesulfonamide and octanesulfonamide are particularly preferred. Examples of the alkoxy moiety of the alkoxyalkoxyalkoxyamide include alkoxy having 1 to 6 carbon atoms. Alkoxy having 1 to 3 carbon atoms is preferable. Preference is given to toxamide, ethoxyxethoxyethoxyamide and propoxypropoxypropoxyamide.

 Examples of the aralkyl moiety of aralkyl oxyamide include those having 7 to 20 carbon atoms, and those having an aralkyl moiety having 7 to 9 carbon atoms are preferable. Benzoxy amide, phenethyloxy amide, phenyl σ Poxyamide is preferred.

 The aryloxy includes those having 6 to 20 carbon atoms. Those having 6 to 10 carbon atoms are preferred, and phenoxy and naphthoxy are preferred.

Therefore, Ashinore represented by R ^1, alkoxycarbonyl - le, Shiano, Karupamoiru, alkyl Rukarupamoiru, nitro, Ashiruamino, alkylthio, alkane sulfonamide, alkoxyalkoxyalkoxy Ami de, hydroxyl or have been specifically lower § Rukinore substituted with Ariruokishi Examples include: propionylmethyl, valerylethyl, bivaloylbrovir, methoxycarberbutyl, ethoxycarbylpentyl, propoxycarbylhexyl, 3-cyanopropyl, methylcarbamoylethyl, propyl-lvamoylpentyl, 6-to-mouth Hexyl, acetamidomethyl, butyrylaminoethyl, methylthiobromo, ethylthiobutyl, propylthiopentyl, butylthiohexyl, 2-hydroxyethyl, 2,3-dihydroxy Propyl, 5-hydroxypentyl, key sill to 2 I 6 Torihidoroshiki, 2- Fuenoshikiechiru, 4-off - Noshikibuchiru, can be mentioned hexyl, etc. to 6 Fuwenokishi.

In the formula [I], represented by R ¹ ; (2) the benzene ring is a hydroxyl group, alkoxy, alkyl, halogeno, alkyl halide, cyano, rubamoyl, mono- or di-alkyl rubamoyl, ethopen, acylamino, alkylthio, mono or dialkyl Lower alkyl of phenyl lower alkyl, which may be substituted with 1 to 3 substituents selected from amino or carboxy, includes straight-chain or branched-chain lower alkyl having 1 to 6 carbon atoms. . Alkyl having 1 to 3 carbon atoms is preferred, and methyl, ethyl, propyl and isopropyl are preferred.

As the alkoxy, straight-chain ^ includes a branched ^ 1 to 6 alkoxy. Those having 1 to 3 carbon atoms are preferred, and methoxy, ethoxy and propoxy are preferred.

 Examples of the alkyl substituted on the benzene ring include a linear or branched alkyl having 1 to 6 carbon atoms. Those having 1 to 3 carbon atoms are preferred, and methyl, ethyl, propyl and isopropyl are preferred.

 Examples of the alkyl in the halogenated alkyl include a straight-chain or branched-chain alkyl having 1 or more carbon atoms. Those having 1 to 3 carbon atoms are preferred, and trifluoromethyl is preferred. The mono- or di-alkyl radicals include alkyls having 1 to 6 carbon atoms which are linear or branched. Alkyl having 1 to 3 carbon atoms is preferred, and methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl and propylcarbamoyl are preferred.

 Examples of acylamino include those having 1 to 6 carbon atoms. Those having 2 to 4 carbon atoms are preferred, and acetamide, propionylamino and butyrylamino are preferred.

 As the alkylthio, a straight-chain or branched alkylthio having 1 to 6 carbon atoms is preferable. Examples of the mono- or dialkylamino alkyl include a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms. Alkyl having 1 to 3 carbon atoms is preferable, and methylamino, dimethylamino, ethylamino, ethylmethylamino, and propylamino are preferable.

Therefore, when the benzene ring represented by R ¹ is a hydroxyl group, an alkoxy, an alkyl, a halogenated halogenated alkyl, a cyano, a carbamoyl, a mono- or dialkylcarbamoyl, a utro, an acylamino, an alkylthio, a mono- or dialkylamino or a carboxy group Specific examples of phenyl lower alkyl, which may be substituted with 1 to 3 substituents selected from: ρ-trifluoromethylphenyl, 4- (m-dimethylaminophenyl) Butyl, 5- (m-cyanoferyl) pentyl, 6- (ρ-potamoylphenol) hexyl, 3. (2,4-dihydroxymethyl) propyl, (3,4-dihydroxyfuryl) Propyl, (4-hydroxy-3 · methoxyphenyl) propyl, ρ-methylbenzyl, m-bromobenzyl, Ρ-hexyloxybenzyl, m-(Bropiouraminomethyl) Njiru, p-(Palais Lil § amino ethyl) phenethyl, 4- (3- Methylthio-4-hydroxyphenyl) butyl and Ρ-carboxybenzyl.

In formula [I], as lower alkyl substituted with a 5-membered unsaturated heterocyclic ring, which may be substituted with alkyl represented by R ¹ in the formula [I], a straight-chain or branched-chain lower alkyl having 1 to 6 carbon atoms. Things. Those having 1 to 3 carbon atoms are preferred, and methyl, ethyl, propyl and isopropyl are preferred. Examples of the 5-membered unsaturated heterocyclic ring of the 5-membered unsaturated heterocyclic ring which may be substituted with alkyl include thiophene, furan, pyrrole, imidazole and pyrazole.

 As the 5-membered unsaturated heterocyclic ring which may be substituted with alkyl, furfuryl, 5-methyl-furfuryl, 2-tur and 5-methyl-2-thenyl are preferable.

In the formula [I], examples of the dialkar represented by R ¹ include linear or branched ones having 2 to 35 carbon atoms. Bull, Aryl, Isobutel, Pentyl, Hexyl, Oleil, Linoleyl, Arakidurnoxenyl are preferred.

In formula [I], examples of the reels represented by R ¹ include ferrule and naphthyl. Suchiri Le as _β preferred examples include those described above as alkenyl, cinnamyl is.

In the formula [1], the primary alkyl represented by R ¹ includes linear or branched alkyl having 7 to 36 carbon atoms. Those having 7 to 30 carbon atoms are preferred, and octyl, decyl, lauryl, myristyl, hexadecyl, stearyl, eicosyl and 2-tetradecylhexydecyl are preferred.

Alkali metals and alkaline earth metal salts are exemplified as the metal salts of the hydroxysulfols represented by R ² and R ³ , and lithium salts, sodium salts and potassium salts are preferred as the alkaline metal salts. As the alkaline earth metal salts, magnesium salts, calcium salts, and barium salts are preferable.

 In the following formula [II], n represents an integer of 1 to 10. Among them, those having 6 or less are preferable.

R ² , and are the same as described above. In the following formula [III], R ⁵ and R ⁶ are the same or different and each represent a linear or branched lower alkyl having 1 to 6 carbon atoms, preferably methyl, ethyl, propyl, and butyl. R ^J , R ³ and are the same as described above. ¹ , R ³¹ and ¹ represent those described above as R ² , R ³ and respectively. x: represents an anion. Specifically, there are ΒΓ ·, cr, cr.

 [ΙΠ]

 The compound of the present invention represented by the following general formula [1V] S ^ [V] is an important intermediate for producing the compound of the present invention represented by formula [I], This is a new substance not described.

 The desired compound can be produced by introducing a desired substituent into the nitrogen atom of moranoline represented by the formula [IV], and then deacylating it.

 [IV]

In the formula, R ⁷ and are different from each other and represent 4-0-acetyl-2,6-di-0-benzoyl-3-0-sulfo-β-D-galactova / sil or α-L-fucoviranosyl. Is asil. Is asiloki Represents cysteine or acetamide. The acyl represented by R ⁹ is not limited as long as the reactivity is not hindered, and examples thereof include those described above as the acyl and benzoyl.

Examples of the acyloxy represented by R ¹⁰ include those having 1 to 10 carbon atoms. Those having 2 to 7 carbon atoms are preferred, and acetoxy, propio-loxy, petyryloxy and benzyloxy are preferred.

Further, via an intermediate represented by the formula [V], an aldehyde compound having a desired substituent [R ^11] CHO (R ¹¹¹ is obtained by removing 0% of the base from R ¹ , R ⁵ or R ⁶ above) and is a representative)] or those halides [R ^l X (R ¹ is as defined above, X is reacted with a halogen)], a method of introducing a substituent into Moranori emissions of N Iyako is a special reagent Since the compound according to the present invention can be produced without the necessity, it can be carried out more economically than before.

 [V]

In the formula, R ¹ R ^{1 2} represents 3-0-¾l--Dl-galatatovirane, or Pio, 3,4-tri-0-, iV-a -Ll-fucohi. , R ^{1 (5} is the same as described above.

 Examples of the compound according to the present invention include the following compounds in addition to the compounds described in Examples described later, but these are only examples of some of the compounds of the present invention. However, the present invention is not limited to this.

 0- (3-0-Sul Power Lactohi. 7 / »-(1 → 4) -0-[(a-L-Tlfc ° La / Sil)-(1 → 3)]-N-Orail- 1,5-S-T-S-1,5-N-Hyc-Lucitol Sodium salt

 0-0-Ο- »β-D-lacto I'lanosyl)-(1 → Φ) -0-[(α fucopyranl)-(1 → 3)]-Ν-Λ'-

1.5-/ decyl-1,5-imino-hyglucitol potassium salt

 o o-o--D-La outside. Lanoshi)-(1 → 4) -0- [(na-fucolan)-(I → 3)〗-N-linoleyl-

1,5-dimethyloxy-1,5-imino-D-qulucitol sodium salt

0- (3-0- Η-β · ϋ -Garatat Rahan-(1 → 4) -0-[(α-Fucopyrano'nul)-(1 → 3)]-Ν-Arachito'nil- 1,5-! / 'Desi-ki-1,5-Imi-P-''Lecitr sodium salt

 0. (3-0-su -ζ force 'ratatohi' lanosyl)-(1 → 4) -0-ί (α-refukohi 'lanosyl)-(1 → 3)]-Ν-arohi'one / Μtyl -1,5-dioxy-1,5-imiglucitol sodium salt

 C O-- ^ 0-D-i 'pyranosyl outside Kl →) M (a-JL-7 koviranl; Kl → 3) Imino-D-glucitol sodium salt

 0- (3-0-Sulfo -0-Strength'La-outside.Lanosi-(1 → 4) -0 · [(α-Lefkohi.Ranosi W- (l → 3)]-N-meth / ^ or at 'IV- 1,5-cy' foxy-1,5-imin-higlucitol sodium salt

 0- (3-0-Sulfo force 'Lactohi. Ranosi Λ-(1 → 4 (£ ΐ -Ζτ Fukohi' lanosyl)-(1 → 3)]-Ν- (5 tylfurfuryl). Ι 、 5- シ 'r 1,5-iD-Lucitol sodium salt

 0- <3-0-sulfo- -galacto. Lanosyl)-(l → 4) -0-[(d-fucopyranosyl)-(1 → 3)]-Ν- (2-teel).

1,5 -'- Foxy '1,5-Mino-hike' lucitol sodium salt

 ヒ ΟΤΛ ^ β-Phi outside. Lanosyl Ml → 4 K (a-ir fucovilanosino ΐχΐ → 3)} Ν23 · shi 't yunfu ^ arobi ^ 1,5- · / te'oxy-1,5-imino-hig / rent-l sodium salt

 OOO-H-0-D-il'lactolahanl)-(l → 4 0-[(aL-fucohi. Rano '»-(1 → 3)]-Ν- (2-phenoxicetyl). 1,5-' 'Delesi' 1,5-imino-hig / ^ sodium salt

 Ο- Ο- ^ β -ΐ> 1ί Ratatovirano 'Μ1 →) · Οί (<τ-ίτFuko! T La / Sil H1 → 3) H ^ 3 »Si' Human 'Schif; O) a u built 1,5 -v dezukiji-1,5-imigig / recitol sodium salt

 0- (3-0-sul -9-"force 'lactolan' lanosyl)-(1 → 4) -0- [(na-7 kohi'lanosi Λ-(1 → 3)]-Ν- [3- ( 4-Hydrogen pheasant. 3-Men: :) T ° L] 4,5-Di'-Doxy-l-m- ': Tol sodium salt

 0- (3-0-Sul; fi-iS-Strength 'La Outer' Ranoshi Λ-(1 → 4) -Ο-[(α7co I: ranos / re)-(1 → 3)] -Ν-decyl- 1,5-'one 'foxy-1,5-imicin-lucito-; sodium salt

 0. (3-0-Sulfo--Hai outside °° Lanoshi / Re)-(l → 4) -0-[(a--Fukohi.La/Sil)-(1 → 3) IN- ^ 1,5'-N'-Foxy-1,5-imidyl citrate sodium salt

 0- (3-0- E- -Higalacto t.La/Sil)-(l → 4) -0-[(iz-L-Fucopilahanme- (1 → 3) to NI-Icosyl- 1,5- ' 'Τ-Oxy -1,5 mi!

0- (3-0-ΧΛ *-) 3-ί ラ ク ト 'Lactohi' lanoshi Λ-(1 →) -0-[(α-L- 'La / L)-(1 → 3)]-Ν- ヾエ イ エ イ 1,5-cysteine cis-1,5-imihicullucitol sodium salt

 0- (3-0- ^ ί- β -D-ii lactolanil) / I-(l → 4) -O-[(a -L-7 cholanosyl)-(1 → 3)]-Ν-triacontyl -1,5-Imi Hig / Natrol sodium salt

 0- (3-0-Sul β-Higalacto'lanosyl)-(1 → 4) -0-[(α-Fukohi'lanosyl)-(1 → 3)]-Ν-Heart! ! Acontyl-1,5-dioxy-1,5-imiglucitol sodium salt

O- -O- -β-Ω-ν Lactohi. Lanosyl)-(l → 3) -0-[(a -L-7 coco'lanosyl)-(1 → 4)]-Ν-oleyl-1,5-si ^, deone-1,5-imi D-Clucitol sodium salt

 0- (3-0-Sul ί- 0 -Strength 'Lactohi.Lanosyl)-(1 → 3) -0-[(α-Lefcohi.Lanosyl)-(1 → 4)]-Ν-Xsell-1 5-C'-Foxy-1,5-imino-D-C '' Lecitr sodium salt

0 -D-il 'Lactoyl' lanosyl)-(l → 3) -0-[(<2 -L-fucopyranosyl)-(1 → 4)]-Ν-lylyl -1,5-di'deci -1 , 5-Imino-Hyc-Lucitol Sodium Salt

 0- (3 · 0-sul--higaratatohi.la/sil)-(l → 3) -0-[(a-L-fucohi'lanosyl)-(1 → 4)]-N-arachidonyl-1, 5-D'-Doxy-1,5-Imine £> -T '/ Rent-l sodium salt

 0- (3-0-S /-? -Strength 'ratatohi' run)-(1 → 3) -0-ί (α-fuco!: Lanosil Hl → 4)]-N-a nf i U -1,5-dimethyloxy-1,5-imino-hyglucitol sodium salt

 CKSO-X / l *. Lactobilanosyl M1 → 3> C (Na-L-fucolar> <1 →)

1,5-Si ^, Doxy-1,5-Imin / K '/ Recitr Natricum Salt

Lac virano'nul Κ1 → 3) · 0 [(α-kabirano 'Μ1 → 4)} · Νί {Hatoaroropir}>1,5-c' f c -1,5-imino- "Glucitol sodium salt

 Ο-0-O-Mi- β -Df Lactophylana / re)-(1 → 3) -0- [(na-L-7cohyalal)-(1 → 4)]-Ν- (5 -Methylfurfury-1,5-dimethyloxy-1,5-imino-hycyllucitol sodium salt

 0- (3-0-S /--Hygalactolan.Lanl)-(1 → 3) -0-[(α Fucopyranl)-(1 → 4) to Ν-Thenyl-1,5-cy 'ΐ ί Kishi-1,5-Imihuku's lucit / le sodium salt

 Higaral Ml-3 H (aL-fucovirano): K1 →) K H3 ^ 2 Si 'human' t 7) a D Pilt 1,5- / Te '-1,5-imino-higurushi Sodium sodium salt

O- -Om-0-/ Force 'Lactopyrah: / L Ml → 3) -0-[(aL-Fukohi'lanosyl)-(1 → 4) 1-Ν- (2-F 1,5-dimethyl-1,5-imimhiglucitol sodium salt

 0- (3-0-Sul;); -3-Strength 'Lactopyranosyl)-(1 → 3) -0-[(α-Lefkohi'lanosyl)-(1 → 4)]-Ν- [3- ( 3,4-S'hydroxyfe :: L) F. Lohi. / Re] -1,5-dimethyloxy-1,5-imiditol sodium salt

 0- (3-0-Sulfo force 'lactohydr')-(1 → 3) -0-[(α-Lefco!: 'Lanosyl)-(1 → 4)]-Ν- [3- (4- Hyd π-xy-3-methoxy 7-enif 'D-H.] -1,5-dioxy-1,5-imicin-lucitr sodium salt

 0- (3-0-S /-β-Strength 'Lactohi. Ranoshi; Re)-(1 → 4) -0-[(a -L-i' run)-(1 → 3)] · Ν -Te'syl-1,5-cy'the'oxy-1,5-imino-D-c-lucitol sodium salt

 0 · (3-0-Sulfo-β-higalactohi.lanosyl)-(1 → 4) -0-[(α-fucopyra / sil)-(1 → 3W-N-. 'Te.saiki-1,5-imino-hiku' Lucitol sodium salt

 0- (3-0-Sul-0-Hygalactohi.Lahanl)-(1 → 4) -Ο-[(α-Lefkohi'lanosyl)-(1-3)]-Ν-ΐyikoshi / レ -1, 5-si '7-year-old cis-1,5-imino-huku'lucitol sodium salt

 0- (3-0-Sul-Third-3 -Strength 'Ratha Rahan-(1 → 4) -0-[(α-Lefkohi'Lal)-(1 → 3)]-へ -Henta Eicosyl-1 , 5-y Deoxyki-1,5-imino-hyglucitol sodium salt

 O- -O-Ui-0 -D- Ratatohi. Lanosyl)-(1 → 4) -0-[(α-fucohi'lanosyl)-(1 ~ »3)〗-Ν- Ι> Riacontyl-1,5-'/ te'oxy-1,5-imimin Hiku '; Recital / Na salt

CK3-0-Sulfo-3 -Strength 'Lactohi'lanosyl)-(1 → 4) -0- [(Nam-mu-7Kohi'lanosyl Hl → 3)]-N-. Nantria Contyl-1, 5'-Foxy-1,5-imicin lucitol sodium salt

The compound according to the present invention can be produced by the following synthesis scheme),

Synthesis scheme of compound according to the present invention ( ₁₎

 (Example of Lewis X type)

Compound (1), which is a starting material shown in the scheme, can be synthesized by a method applied by the present applicant (Japanese Patent Application No. 7-106257). This compound is reacted with, for example, trimethyl orthoacetate in benzene under the acidity of D, L-camphor-10.sulfonate at room temperature to form an orthoester group at the 3- and 4-hydroxyl groups of the galactose residue. Obtain the introduced compound. Next, for example, a compound (1 ′) in which the 4-position hydroxyl group of the galactose residue is selectively acetylated by acid hydrolysis in an 80% aqueous solution of lactic acid, a mixed solvent of THF and methanol is obtained. . Compound (2) is prepared by reacting compound (Γ) with pyridine-sulfur trioxide complex in, for example, Ν, Ν-dimethylformaldehyde (DMF) at room temperature to sulfonate the 3-position hydroxyl group of galactose residue. Then, the benzyl group and benzyloxycarbol group of the compound (2) are contacted in an alcohol at 20 to 60 ° C. for 2 to 72 hours in the presence of a catalyst such as palladium chloride black. The compound is deprotected by reduction to obtain compound (3), which is reacted with sodium cyanoborohydride and various aldehydes of the desired substituent at pH 3 to 4, for example, in methanol. , Or Ν, Ν-dimethylformaldehyde in the presence of a suitable base such as potassium carbonate at room temperature to 90. The compound (4) ) Can be obtained, for example, by treating this with an alkali such as sodium methylate in methanol to remove the acetyl group and the benzoyl group, thereby obtaining the compound according to the present invention. (5 ') is obtained.

 Alternatively, compound (3) is treated with an alkali in methanol to deprotect the acetyl group and benzoyl group to give compound (6), which is then treated with sodium cyanoborohydride in methanol and various compounds. By reacting the aldehyde at pH 3 to 4 or in the presence of an appropriate base such as potassium carbonate in N-dimethylformamide, the N- The substituted compound (5 ′) according to the present invention is obtained.

Moranoline residue has fucopyranosyl residue at position 3 and galactoviranosyl residue at position 4 Carbonitrile oxygen atom of the nitrogen atom and 6-position of Moranorin as Moranorin compounds of _β further following scheme can also be performed prepared above and the same reaction step for derivative (35) - intermediate crosslinked Le The compound according to the present invention can be produced by another method via An example of the synthesis will be described below using an example of a Lewis Α-type derivative, but a Lewis X-type derivative can be produced in the same manner as this production method.

Synthetic scheme for compounds according to the present invention (2)

 (Example of synthesis of Lewis A type derivative)

 Ac; 7 set *

 Me; Mechi A

The compound (33) is acetylated and sulfonated in the same manner as in Scheme 1 to obtain the compound (34) .The benzoyl group and the acetyl / re group of the compound (34) are converted into, for example, 10 to 60 with alkali in methanol. Deprotection by treatment at 2 ° C. for 2 to 12 hours gives compound (35) The benzyl group of compound (35) is deprotected, for example, by catalytic reduction in the presence of a palladium catalyst. Compound (36) is obtained. Compound (37) is obtained, for example, by subjecting compound (36) to hydrolysis in an aqueous methanol solution. Compound (37) can be prepared, for example, by reacting sodium cyanoborohydride and the target aldehyde in methanol at pH 3 to 4 as in Scheme 1, or by reacting an alkyl halide to form a molanolin residue. The compound of the present invention, which is an N monosubstituted product, is obtained. Alternatively, compound (35) is hydrolyzed at 80 to 100 ° C in an aqueous methanol solution, and sodium borohydride and various aldehydes in methanol are allowed to act at pH 3 to 4, The present invention can also be obtained by deriving an N-substituted moranoline residue and then deprotecting the benzyl group by, for example, catalytic reduction in the presence of a palladium carbon catalyst.

 The method according to the scheme (2) does not use any special reagents as compared with the conventional method, so that the production can be carried out easily and has an economically advantageous advantage. BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in more detail with reference to Examples relating to the production of Lewis X-type sugar chains and Lewis A-type sugar chain derivatives of the present invention, but the present invention is not limited to only these Examples. .

 The measurement temperatures of specific rotations are all 20 ° C. The assembler used was MICRO ACILYZERS1 manufactured by Asahi Kasei Corporation, and AG110 was used for the cartridge unless otherwise noted.

(Production of Lewis X-type sugar chain derivative according to synthesis scheme (1))

 Example 1

 0- (3-0- -β-D-force'lactopyranosi / ri- (1 → 4) -0-[(a-L-fucohi'lanosyl)-(1 → 3)]-Ν-oleyl-1, Synthesis of sodium salt of 5-cyclohexyl-1,5-imidin D-co-lucitol (Ichi compound (5))

 Process 1

0- (4-0-Acetyl-2,6-di'-0-hene, / yl-β-D-lacto I: 'lanosyl)-(1-4) -0- [(2,3 , 4-Tri-O-Hen '/-α-Lefcoviral)-(1 → 3)]-2,6-V-0-Hen, 1,5-site 'te' site-1,5-imi Hidal ';-le (synthesis of compound

0- (2,6-S'-0-Hesyl'-β-D-Strength'Lacto'lanosme- (l → 4) -0- [(2,3,4-Tri-0- ^to, Nshi 'Le - a- Fukobi Ranoshiru) - (1 → 3)] - 2,6- V -0- to' Upsilon, 'I Le - - Bae Nshi' / is alkoxy force / Invite sulfonyl - 1,5 Dissolve 10.0 g of 1,5-imino-hike-pentol (compound (l)) in hexane (500 ml), and add trimethyl orthoacetate (19 ml) and DL-camphor. -Add 10-sulfonic acid (170 mg), stir at room temperature for 3 hours, wash the reaction solution with saturated aqueous sodium hydrogen carbonate solution, further wash the organic layer with distilled water, dry over anhydrous sodium sulfate, and reduce the pressure under reduced pressure. To the resulting residue were added THF (100 mL) methanol (100 mL) and 80% acetic acid (100 mL), and the mixture was stirred overnight at room temperature. The solution was washed with saturated aqueous sodium hydrogen carbonate solution and distilled water, dried over anhydrous sodium sulfate, and subjected to reduced pressure under reduced pressure. Subjected to Gerukaramuku a Matogura 7 (Wako gel C-300,400g), to give compound subjected to elution with click DD Holm a (l ') 10.1g (97.8%).

 Specific rotation [N] D = -56.17 ° (c = 1.093, ΟΚ¾)

Elemental analysis

do it

 Theory C-69.31; H-5.66; N = 1.05%

 Found C = 69.22; H = 5.68; N = 1.27% Step 2

 0- (4-0-Acetyl -2,6-si ') -0-Hen'n'yl -3-0--β-D-force' lacto-t: 'lanosyl)-(1 → 4) -0- [(2,3,4-tri-0-hexyl-a-L-fucohilanosyl)-(1 → 3)]-2,6-si'-0-phenyl-N- Synthesis of sodium hexoxy-1,5-imino-hexyl-l-citryl sodium salt (Compound (2))

1.5 g of the compound (l ') was dissolved in Ν, Ν-methylmethylformamide (22 ml), and a pyricine sulfur trioxide complex (4.8 g) was added thereto, followed by stirring at room temperature overnight. (Meta / -W45 ml at 0 ° C) and stirred for 1 hour.Then, the mixture was compressed under reduced pressure and the resulting residue was purified by column chromatography (Wakogel C300, eluate; 20: 1). The obtained fraction was dissolved in methanol (30 ml), ion-exchange resin Γ / Λ'-Ray IR 120B (Na ⁺ ) was added, and the mixture was stirred at room temperature for 1 hour. The residue was concentrated to dryness to give 4.8 g (89.1%) of the compound (2>).

FABMS mz 1412 [M-Na]- Process 3

Compound (3): 0- (4-0-Acetyl -2,6-di'-0-Pensoyl-3-0-m-β-D-force'ratatohi'lanosyl)-(1 → 4 〉 -0- [(-Fucohilar)-(1 → 3)]-2,6-Shi ^, -0-Hesso /, 5-V-Doxy-1,5-Imino-Hiku Lucitol sodium carrier (Synthesis of compound (3

 Compound (2) (4.2 g) was dissolved in ethanol (125 ml) and acetic acid (25 ml), and activated Λ'Rashi 'ゥ Muf' Lacque (5.1 g) was added.The mixture was stirred at 55 ° C for 15 hours and contacted. Hydrogenation was performed.ラ 'Rashi' W Rataku is separated, washed with I-tar, combined with the base solution and the washing solution, reduced under reduced pressure, and the residue obtained is subjected to column chromatography π-matography-(Wakogel C300, elution wave; 'Dimethane-methano-; 10: 1) to give 2.2 g (70.3%) of compound (3).

Specific rotation ia] _D = +10.5. (C = 0.42, methanol)

As Elemental Analysis _{C 48 H 50 NNaO 21 S ·} 7 / 2Η 2 0

 Theoretical value (%) C-52.65 H-5.25 N-1.28

 Actual value (%) C = 52.29 H = 4.95 N = 1.34

 FABMS m / z 1008 [M-Na]-Step 4

 0- (4-0-Acetyl -2,6-si '-Ο-', '-3-0--β-E Galata' Ranl)-(1 → 4) -0- [(α -L・ Fucobi lanosyl Ml → 3)】-2,6-S '-0-H-' / R-yl-1,5-y-Doxy-1,5-imino-hq'Lucitol-Natric A salt ( Compound (4))

 Dissolve 894 mg of compound (3) in methanol (60 ml), add sodium iodide hydride (73 mg), and illuminat '(695me), adjust the pH to 3-4 with acetic acid, and adjust to 40 ° C. For 3 hours. The residue obtained was subjected to column chromatography under reduced pressure, and the resulting residue was subjected to column chromatography, π-Matrix 'Raffy (Wakogel C300, eluent; cyclo-W-tantanol, 4: 1), to give 837 mg of Compound (4) ( 74.7%).

 FABMS m / z 1258 [M-NaJ- Step 5

0 (3-0-sul β -D-force 'ratatohi. Lanosyl)-(1 → 4) -0- [(a -L-fucopyranme-hi ~ 3)]-N-oleyl -1,5- Synthesis of shi'-doxy-1,5-iminum glucitol sodium salt (Compound (5)) 803 mg of the compound (4) was dissolved in methanol (60 ml), a 28% sodium methyla-ethanol solution was added until the pH reached 11, and the mixture was stirred at 30 ° C overnight. After confirming the completion of the reaction by TLC, neutralize with 2N hydrochloric acid, compress under reduced pressure to dryness, apply to a column chromatography π-matograph (UChroprep RP18, elution with water → acetone in a gradient), desalting with an acylase '- After freeze-drying, 228 mg (44.4%) of compound (5) was obtained as a white powder.

Elemental analysis

· As 3/2 H ₂₀

 Theoretical value (%) C = 50.81 H = 8.17 N = 1.65

 Actual value (%) C = 50.91 H = 8.32 N = 1.97

 FABMS mz800 [Μ-Na] Example 2

0-0-0-% Η- β-[> force 'lactohi'lanosyl)-(1 → 4) -0- [(a fukohi' lanosyl)-(1 ^→ 3)]-Ν- (2-oxof ' Synthesis of 4,5- · / Doxy-1,5-imino-hy V-tol sodium salt (Compound (7))

 Process 1

 0- (3 0- i-β-D-force'lactobilla- (1 → 4) -0-[(α-le7colanosyl) -h → 3) Synthesis of 5-imi / Darcitol sodium salt (Compound (6))

 1.57 g of the compound (3) was dissolved in methanol (40 ml), and a 28% sodium methylatomethanol solution was added until the pH reached 11, and the mixture was stirred at 40 overnight. After confirming the completion by TLC, the mixture was neutralized with 2N hydrochloric acid and concentrated under reduced pressure to dryness. To the obtained residue, 20 ml of water was added, and the mixture was washed three times with chloroform (K20 ml). The aqueous layer was decompressed under reduced pressure, subjected to Karaku D matogelaphy (UChroprep RP18, eluate; water), desalted with Asilisa '-, dried to dryness, and 730 mg of compound (6) as a white powder (730 mg (83.5% )Obtained.

Specific rotation [a] _D = -35.6 ° (c = 0.48, water)

Elemental analysis C ₁₈ H ₃₂ Na0 ₁₆ S. As 3/2 H ₂₀

 Theoretical (9 &) C = 36.00 H = 5.87 N = 2.33

 Measured him (%) C = 36.29 H = 6.10 N = 2.50

FABMS in / 2550 fM-Na] ' Process 2

 0- (3-0-Sulfo-β-D-force 'lactohi'lanosyl)-(1 → 4) -0- [(aL-fucohi' lanosi / ri- (1 → 3)]-Ν- (2- Synthesis of sodium (1,7) -dimethyl-1,5-imidoxy-1,5-imiditol (Compound (7))

 Dissolve 100 mg of compound (6) in N, N-methylmethylformamide (1.8 ml), and add 1-7′οί-2-futanone (ΙΟΟμ1) and anhydrous carbonic acid l! M (50 nig). In addition, it was heated at 30 ° C for 6 hours. After confirming the completion of the reaction by TLC, the reaction mixture was reduced under reduced pressure, water (4 ml) was added to the obtained residue, and the mixture was washed with ci-I-tetra (4 ml × 3). The aqueous layer was decompressed, subjected to column chromatography (LiChroprep RP18, water-> gradient elution with methanol), purified, desalted with an acylase-, and freeze-dried. 78 mg (43.9%) of compound (7) was obtained as a white powder.

Specific rotation [a] _D = -46.0. (C = 0.49, water)

 FABMSmz620 [M-Na]-Example 3

 0- (3-0-Sul β-D-force 'Lactoyl'lanosyl)-(1 → 4) -〇-[(aL-7 Kobira noshi-(1 → 3)〗-Ν · [4- (methoxy; ί Synthesis of sodium sulfo-1,2-dimethoxy-1,5-imigentole sodium salt (Compound (8))

 Dissolve 100 mg of compound (6) in Ν, Ν-methylmethylformamide (1.5 ml), add methyl-5-phenylesterate (240 μ1) and ϋτ potassium carbonate (50 mg), and add 80 to 7.5 Stirred for some time. Water (10 ml) was added to the reaction solution, which was washed with styrene (10 ml × 3). The aqueous layer was reduced under reduced pressure, and this was subjected to column chromatography (Wakoge III C300, eluent; ππ methane-containing water, 5: 4: 1), which was used for the purpose. 28 mg (24.0%) of compound (8) was obtained as a white powder.

Specific rotation [a] _D = -44.7 ° (c = 0.33, water)

Elemental analysis Ο ,,, ^ Ν ^ Ο, β · 5/2 Η ₂₀

 Theoretical value (%) C = 39.34 Η = 6.47 Ν = 1.91

 Actual! 1 value (%) C = 39.14H = 6.41 N = 1.93

FABMS / 7i / 664 ΓΜ-Na] " Example 4

 0- (3-0-Sulfo-β-D-force 'lactohylan' lanosyl)-(1-4) -0- [(α-L-fucohi'lanosyl)-(l → 3)〗-N- (p Synthesis of 1,5-dimethoxy-1,5-imino-hi / recitol sodium salt (Compound (9))

 Dissolve 100 mg of compound (6) in methanol (7 ml), add 35 mg of p-toluarthyde (100 / ί1) and sodium cyanohydride, adjust the pH to 3-4 with acetic acid, and add Stirred overnight. After confirming the completion of the reaction by TLC, the residue obtained by condensing Shimoko to dryness was subjected to column tamato 'Raffy' (LiChroprep RP18, eluent; water), purified, and then desalted with Asilisa '- After freeze-drying, 78 mg (67.7%) of the target compound (9) was obtained as a white powder.

Specific rotation [a] _D = -51.6 ° (c = 0.47, water)

As Elemental Analysis _{C 26 H 40 NNaO l8 S ·} 3 H 2 0

 Theoretical value (%) C = 44.00 H = 6.67 N = 1.97

 Actual value (%) C = 43.85 H = 6.57 N = 2.06

 FABMS / nz654 [M-Na] 'Example 5

 0 (3-0-sulfo- -ζ force 'ratatohi' lanosyl)-(1 → 4) -0- [(a -L-fucolanosyl)-(l → 3)〗-N- (m-fu 'ni Synthesis of 1,5-S-Doxy-1,5-imino-glucitol sodium salt (Compound (10))

 The same reaction as in Example 4 was carried out using m-7'π-m-'n'-n-n'-l-'n'-arte'-human '(157 mg) to obtain 52 mg (40,8%) of the desired compound (10) as a white powder. Was.

Specific rotation [a] _D = -47.7. (C = 0.51, water)

As elemental analysis QjHjTBrNNaOjgS · 3/2 H ₂ 0

 Theoretical value (%) C = 39.02 H = 5.24 N = 1.82

 Measured value (%) C = 39.14 H = 5.53 N = 1.98

FABMS m z718 [-Na]-Example 6 0. (3-0-Sul-D-force'lactohi.lanosyl)-(1 → 4) -0 · [(α-Lr fucoh.lanosyl)-(1 → 3)]-Ν · (2-Sk mouth Synthesis of 1,3-dimethyl-1,5-imino-hexylcitr sodium salt (Compound (11))

 D-G! The reaction was carried out in the same manner as in Example 4 using Cellardicht 'to obtain 95 mg (86.0%) of the desired compound (11) as a white powder.

Specific rotation [al _D = -56.6 ° (c = 0.51, water)

 FABMS m / z 624 [M-Na]-Example 7

 0-0-0- m- β -D-force 'lactohylanosyl)-(1 → 4) -0. [(Α -L-fucopyranosyl)-(1 → 3)]-N- (pn-hex Synthesis of 1,5-S-Doxy-1,5-imino-hyc-lucitol Sodium Salt (Compound (12))

 The reaction was carried out in the same manner as in Example 4 using 400 mg of the compound (6) and pn-hexyloxybenzene (1.7 ml) to obtain 280 mg (52.6%) of the desired compound (12) as a white powder. Was.

Elemental analysis as C3 _X H _S0 NNaO ₁₇ S-5/2 H

 Theoretical value) C = 46.03 Η = 6.85 Ν = 1.73

 Actual value (%) C = 45.89 H = 6.78 N = 1.96

 FABMS nv¾ 740 [M-Na]-Example 8

 0-0-0-sul β -D-force 'Lacto'lahanme- (1 → 4) -0- [(α -fucopyranosyl)-(1 → 3)]-Ν · [3- (3,4- Synthesis of 1,5-cytoxy-1,5-imino-hythol sodium salt (Compound (13))

Dissolve 100 mg of compound (6) in methanol (20 ml), add 3 · (3,4-c'acetoxif 1nil) ααl ;; fc (131 mg), 33 mg of sodium cyanoborohydride, and add to acetic acid. The mixture was stirred at room temperature for 4 hours and stirred at room temperature for 4 hours.After confirming the completion of the reaction by TLC, the mixture was neutralized with 2N aqueous sodium hydroxide solution, and the residue obtained by drying to dryness under reduced pressure was dissolved in water. The residue obtained by depleting the aqueous layer was subjected to Kara A chromatograph-(LiChroprep RP18, elution of methanol from water with glucose). An 'acetoxy form was obtained, which was dissolved in 5 ml of metal, and 1 ml of V-lysine and 1 M hydrazine's monohydrate / acetic acid-lysine' [3: 2] solution (500 μΐ) Was added, and the mixture was stirred at room temperature for 30 minutes. Then, 800 μL of a hydrazine solution was added, and the mixture was stirred overnight. The residue obtained by decompressing the reaction solution is subjected to column chromatography (LiChroprep R8, 30% metal `` lazyant '' elution from water), and lyophilized to give the desired product as a white powder. Compound (13)

84 mg (66.9%) were obtained.

Specific rotation [a] _D --40.5. (C = 0.49, water)

Elemental analysis C ₂₇ H ₄₂ NNa 0 ₁₈ S. As 2 H ₂₀

 Theoretical value (%) C = 42.69 H = 6.10 N = 1.84

 Actual value (%) C = 42.46 H = 6.27 N = 1.99

 FABMS wz z700 [M-Na] "Example 9

 0-0-0-Sulfo-β-∑force 'lactovilanosyl)-(1 → 4) -0-0 [(a-L-fucohi'lanosyl)-(1 → 3)〗-N-cinnamyl-1,5 Synthesis of sodium 1,5-imi-glucitol sodium salt (Compound (14))

 The reaction was carried out in the same manner as in Example 3 using cinnamyl 'α-mide (80 μl) to obtain 33 mg (27.4%) of the target compound (14) as a white powder.

Specific rotation [a] _D = -63.9. (C = 0.46, water)

Elemental analysis

· As H ₂₀

 Theoretical value (%) C-45.83 H = 5.98 N = 1.98

 Actual value (%) C = 45.62 H = 6.12 N = 2.06

FABMS

[M-Na] 'Example 10

 0-0-0--0 'D-force' lactohylanosyl)-(l → 4) -0- [(α-lefcohylan)-(1 → 3)]-N- (4-calho ' Synthesis of (1,5-dimethyl) -1,5-imi //-hiku '/ ^ tornato!) Dimethyl salt (compound (15))

The reaction was carried out in the same manner as in Example 4 using terephthalate / lealdehyde acid (130 mg) to obtain 72 mg (58.4%) of the desired compound (15) as a white powder. Specific rotation [a] _D = -51.0. (C-0.47, water)

Elemental analysis

As · 3H ₂ 0

 Theoretical value (&) C = 41.00 H = 5.82 N = 1.84

 Observed value (%) C-40.68 H = 5.85 N = 1.89

 FABMS m z684 [M-Na〗-Example 11

 0-0-0-Sul β -D-force 'Lactoyl'))-(1 → 4) -0- [(a -Lr Fukohi 'Lanosyl)-(1. → 3)]-Ν- (5 ) Synthesis of -1,5-di'oxy-1,5-imig / Recitol Sodium Salt (Compound (16))

 Dissolve 150 mg of compound (3) in methanol (20 ml), add 5-methylfurfural (72 μl) and sodium cyanoborohydride (45 mg), adjust to ρΗ3 to 4 with acetic acid, and bring to room temperature. The reaction mixture was compressed under reduced pressure, and the resulting residue was subjected to column chromatography (Wakogel C300, eluent; silicone ππ (tan-methanol, 5: 1)) to give the N-substituted product. This was dissolved in methanol (30 ml), 1 ml of 28% sodium; I-methyl methanol solution was added, and the mixture was stirred for 2 days at 40 C. After confirming the completion of the reaction by TLC, 2 N was determined. The mixture was neutralized with hydrochloric acid, reduced under reduced pressure, added with a small amount of methanol, filtered to remove insolubles, reduced to dryness under reduced pressure, dried in water, washed with water and washed with water. The resulting residue was subjected to column chromatography π-matography (LiChroprep RP18, eluent; water), dried and dried to obtain 69 mg (71.1%) of compound (16) as a white powder.

Specific rotation [a] _D = -56.4. (C = 0.45, water>

Elemental analysis

· As 3/2 H

 Theoretical value (%) C = 41.50 H = 5.95 N = 2.02

 Actual value (%) C = 41.45 H-5.99 N = 1.94

 FABMS m z644 [Μ-Na] ·

 Example 12

 0- (3-0-Sulfo-0-D-force'lactolanosyl)-(l → 4) -0-[(a-L-fucolanosyl)-(1 → 3)]-Ν-2-thenyl- Synthesis of 1,5-dioxy-1,5-imidoxylcitrate sodium salt (Compound (17))

The same reaction as in Example 11 was carried out using 100 mg of compound (3) and 22% (33%) of the compound (17) was obtained as a white powder.

Elemental analysis ^^ NNaO ^ 7/2 H ₂ 0

 Theoretical value (%) C = 37.70 H = 5.92 N-1.91

 Measured value (%) C = 37.83 H = 5.79 N = 1.87

 FABMS 646 [M-Na] Example 13

 0-C3-0-Sulfo-β-D-force'Lacto. Lanosyl)-(1 → 4) -0- [(a-lanoshi / le)-(1 → 3)]-Ν- (2-phenoxheti -1,5-si'-doxy -1,5-imi-glucito- Of Sodium Salt (Compound (18))

 The same reaction as in Example 3 was carried out using 100 mg of the compound (6) and-7 'D-morph I-net // 200 # 1) to obtain 25 mg (23%) of the target compound (18) as a white powder. Obtained.

Specific rotation [a〗 _D = -44.7. (C = 0.49, water)

 FABMS m / 670 [M-Na] 'Example 14

 0- (3-0-Sul β -D-force 'Lactohi' lanoshi W- (l → 4) -0- [(aL-7 koranoshi Λ-(1 → 3)]-Ν- [3-Of ^ ft) T nt * Synthesis of 1,5-dimethyl 1,5-imidium sodium salt (Compound (19))

 The same reaction as in Example 4 was carried out using 120 mg of compound (6) and 3-mt) T 't / W human' (200 / ^ 1), and the target compound (19) was converted into a white powder of 105 mi ( 79%).

Specific rotation [a] _D = -49.8 ° (c = 0.60, water)

 FABMS / 73 / z638 [M-Na] 'Example 15

0- <3-0 · sul-β-D-force. Lanoshi W- (l → 4) -0- [(a L-fucohi. La W- (l → 3)]-N- [3- (3-methoxy-4-hydrido Doxy 7ι2 7 nfc ° Λ] Synthesis of -1,5-S-Foxy-1,5-Imino-Hyc-Lucito-Lenatricum Salt (Compound (20>)) 4-Hyd α-X-3--3-Toxicinnamarte 'Human' (1.4 g) was dissolved in lysine (30 ml), and benzoic anhydride (2.5 g) was added. In addition, a small amount of NfV was added, and the mixture was stirred at room temperature overnight. The reaction solution was decompressed and condensed, and crystallized in toluene, to obtain 4-hydroxy-3-methoxycinnamaldehyde (2.0 g). The same reaction as in Example 4 was carried out using 150 mg of this compound and 100 mg of compound (6) to obtain an N-substituted product (90 nig), which was dissolved in methanol (3 ml) to give 28% sodium; -Tano- solution (01 ml) was added, and the mixture was stirred at room temperature for 3 hours.After confirming the completion of the reaction by TLC, the mixture was neutralized with 2 N hydrochloric acid and depressurized, and the residue was dissolved in water. -After washing with tellurium, the aqueous layer was squeezed under reduced pressure.

LiChroprep RP18, 30% methanol was eluted with water from the mixture of water to obtain 55 mg of the dehydrogenated / isomer. This was dissolved in 5 ml of methanol and 1 ml of acetic acid. Add 50 mg of Rashi-Dumf Lakku, stir at room temperature for 3 hours, and perform contact hydrogenation. Separate the Rashi-Dumf Lakku, wash with Etano, and combine the liquid and the wash liquid. The concentrate was concentrated under reduced pressure, and the resulting residue was subjected to column chromatography (LiChraprep RP18, elution with 30% metal from water) to obtain 22 mg (18%) of compound (20).

Elemental analysis

· As 3/2 H ₂₀

 Theory 碴 (%) C = 42.40 H = 6.37 N = 1.82

 Observed value (9 &) C = 42.48 H = 6.37 N = 1.77

 FAB S 7V¾714 [Μ-Na] · Example 16

 0-0-0- »β -D- il 'i'lanosyl)-(l → 4) -0- [(α -Ιτfucolanosyl)-(1 → 3)〗-N- n-octyl -1, Synthesis of 5-cis-r-xyl-1,5-imidarcitol thorium salt (compound (21))

 3) 556 mg was subjected to the same reaction as in Example 2 Step 1 to obtain the reaction product (6) (^ and the reaction product), and the residue was dissolved in methanol (20 ml). Sodium (107 mg) and octyl art 't' (156 µm) were added, adjusted to ΡΗ3 to 4 with acetic acid, and stirred for 7 hours at 40. The reaction solution was neutralized with 2Νaqueous sodium hydroxide solution. The residue obtained was subjected to column chromatography, and the residue was subjected to column chromatography ti Mat 'Raffi (UChroprep RP18, elution with water → meta / -lash), desalted with asil-, freeze-dried to give a compound as a white powder.

339 mg (91.6%) of (21) was obtained.

Elemental analysis ^^ sN aO ^ · 3/2 H ₂ 0 Theoretical value (%) C = 43.81 H-7.21 N = 1.97

 Observed value (%) C = 43.69 H-7.32 N-2.03

 FABMS m / z662 [M-Na] "Example 17

 0- (3 · 0-s; re tree. -Higaratatohi.Ranl)-(1 → 4) -0 (61-core fucopyranosyl)-(1-3)]-Ν- (6-Hydroxyhexyl 1 Of 1,5-S-Doxy-1,5-imino-hyc-lucitol (Compound (22))

 Compound (3) (500 mg) was dissolved in methanol / (20 ml), and the same reaction as in Example 11 was carried out to obtain 210 mg (89.6%) of compound (22) as a white powder.

Elemental analysis C ₂ , H ₄₅ N0 ₁₇ S-5 2H ₂₀

 Theoretical value C-41.37 H-7.23 N = 2.01

 Actual value (%) C = 41.41 H = 7.24 N = 2.95

 FABMS m ^ r650 [-H] 'Example 18

 0- (3-0-sul-higaratatra / sil)-(l → 4) -0-i (a-L-fucohilar)-(1 → 3)]-Ν-ί3- (hex Synthesis of -1,5 'te'oxy-1,5-imino-clucito-sodium salt (Compound (23))

 The same reaction as in Example 4 was carried out using 200 mg of compound (6), 3- (n-hexanoamide) a of if and do (ISOmg) to obtain the desired compound (23) as a white powder. 160 mg (63%) were obtained.

Elemental analysis Q ^^ aO ^ · 2H ₂ 0

 Theoretical value (%) C-42.40 H = 6.99 N = 3.66

 Measured he <%) C = 42.15 H = 7.00 N = 3.73

FABMS m / z 751 [MH-Na] ⁺ , 705 [M-Na] 'Example 19

0- (3-0-Sul β-Higa 7lH'La / Sil)-(1 → 4) -0-[(α-Fucopyrano'nul)-(l → 3)]-N-[(3-to Ki 'Ml de> Synthesis of 1,5-cytoxy-1,5-imino-hydroxylcitrol sodium salt (Compound (24)) Compound (6> 200 mg and 3- ( The same reaction as in Example 4 was carried out using n-hexate'canamido) phenylthiophene (350 mg) to obtain 180 mg (59%) of the target compound (24) as a white powder.

Elemental analysis Ο, τΗ ,, Ν ^ Ο ^ · 5 / 2Η ₂₀

 Theoretical value (%) C = 48.62 H = 8.16 N = 3.06

 Actual value (%) C = 48.51 H = 8.23 N = 3.04

 FABMS mjz 845 [Μ-Na] Example 20

 0- (3-0-Sul--Strength 'Lactohi'lanosyl)-(l → 4) -0-[(a -Lm ° Lanosi Λ-(1 → 3)]-Ν- [3- (η- Synthesis of 1,2,5-imine-lucitr sodium salt (Compound (25))

 The same reaction as in Example 4 was carried out using 200 mg of the compound (6) and 3- (n-octanesulfonamide:) arohi'onarte'human '(246 mg) to give the desired compound (25) as a white powder 183 mg (65%)

 Elemental analysis as C ^ Hs ^ N ^ aO S · 5 / 2H

 Theoretical value (%) C = 40.89 H = 7.10 N = 3.29

 Actual value (%) C = 41.00 H = 7.14 N = 3.27

 FABMS mjz 783 [M-Na] -Example 21

 0- (3-0-Sul ί- / 3-Strength 'lacto-ylano) ί- (1 → 4) -0-[(α-L-7cohi'lanosyl)-(1 → 3)]-Ν- Synthesis of η-dodecyl-1,5-dioxy-1,5-imino-cyclocitrol sodium salt (Compound (26))

 The same anti-JS as in Example 4 was carried out using 700 mg of compound (6) and Tote Wf IV (U5 ml) to obtain 0 mg (68.5%) of target compound (26) as a white powder.

Elemental analysis

· 3Η as ₂ 0

 Theoretical value (%) C = 45.27 H = 7.85 N = 1.76

Actual value (%) C = 5.25 H = 7.66 N = 1.69 FABMS w / z 718 [M-Na] "Example 22

 0- (3-0-Sulfo-) 3-Hiki's Lactohi. Lanoshi / ri- (1 → 4) -0-[(α-fucolanosyl)-(1 → 3)]-Ν-octactate'syl-1,5-si'de Synthesis of K '/ Rentol sodium salt (Compound (27))

 Compound (6) (500 mg) was dissolved in water (5 ml), and metal (50 ml) was added. It was adjusted to ρΗ3-4 with acetic acid, and sodium / sodium hydrogen hydride (274 mg) and octate 'a' hydride (1.5 g) were added. To this was added THF (40 ml), and the mixture was stirred at room temperature overnight. The mixture was neutralized with a 2N aqueous sodium hydroxide solution and concentrated under reduced pressure. The obtained residue was subjected to Karamuk D Matota® Raffy (Wakogel C-300, eluate; black outlet; f-tan; petano, 2: 1). The purified product is dissolved in a small amount of water, desalted with acid -'- (force-trish '; Α 乾燥 -20), freeze-dried, and 240 mg (33.3%) of the desired compound (27) is obtained as a white powder. %)Obtained.

Elemental analysis

As

 Theoretical value (%) C = 49.13 H = 8.48 N = 1.59

 Actual value (%) C = 48.90 H = 8.45 N = 1.68

 FABMS m / z 802 [M-Na] 'Example 23

 1,5-bis {[0- (3-0-sulfo-strength 'la outside lan')-(l → 4) -0- [(na-7 kolanosyl Hl → 3)]-1,5 -Site-le-n-1,5-mino-hike-lucitol sodium salt]

960 mg of the compound (6) was dissolved in water (10 ml) and metal (10 ml), and adjusted to ρΗ3 with vinegar. To this was added sodium borohydride (40 mg) and a 5% aqueous solution of potassium hydroxide (120 1), and the mixture was stirred at room temperature overnight, neutralized with a 2N aqueous sodium hydroxide solution, and subjected to pressure reduction under reduced pressure. . The obtained residue was dissolved in water, and the solution was applied to a column matrix filled with a strongly acidic cation exchange resin (Tax 5GW X "2 (H ⁺ )). The residue was recrystallized from 80% i-tano to give 320 mg of compound (28), and the mother liquor was further purified by column chromatography 7 (eluate; water) packed with Sephades G10. The obtained purified product was concentrated under reduced pressure to obtain 50 mg of compound (28) as a white powder. The product (28) was obtained (yield from chloromethol / rete'hid 45.9%).

 FABMS mjz 1169 (M-2Na + HJ Example 24

 Ο- -Ό-ΐΗ- β -D- Lactohi. Lanosyl)-(1 → 4) -0-[(<2-7 coco'lanosyl)-(1 → 3)〗-Ν- {3- [2- (2-1 toxetoxy) ethoxy; : · Nirami /] fu 'pi hi. Synthesis of sodium 1,5 sodium salt (Compound (29))

'Ethylenek' Rico-W-Noethyl: Dissolve L-Tel (5.7g) in Bilysin (37.5g), and add Ι, Γ-Carki 'Nil-Dari's -1Η-Imida ΐ-L (9.7 g) After stirring at room temperature for 1 day, the reaction solution was cooled to 0 ° C., and 3-amine (2-7 · ′ ′-/-10.5 ml) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was vacuumed and subjected to column chromatography π-mat (Wakogel C300, eluent acid ί ///, 2: 1 elution with ethyl acetate) and colorless dye D Kufu'-like compound S- [2- (2-1 ethoxyethoxy) ethoxycarboyleneamino] fuu / real alcohol (6.5 g, 56%) was obtained. Add “Pirisi” to the stomach mouth methane (200 ml) ;: Add mucchi mouth wit (7.3 g) and sera (6 g), and add 3- [2- (2-ethoxyethoxy) ethoxy) 7 · nf al: H 4g) was added thereto and stirred overnight. After filtration of the reaction mixture, the residue was subjected to column compression under reduced pressure, and the resulting residue was subjected to column chromatography (Wakogel C-300, eluent; I-yl acetate: n-hexane-3: 1). Purified, colorless 3- (2- (2-ethoxy) ethoxy) ethoxy

D hi. m hydrate (0.9 g, 23%) was obtained. The same reaction as in Example 4 was carried out using this compound (50 mg) and compound (6) 90 mg to obtain 60 mg (47%) of the desired compound (29) as a white powder.

Elemental analysis C ^ H ^ r ^ NaO · 2Η ₂₀

 Theoretical value (%) C-45.68 Η = 6.70 Ν = 3.39

 Actual value (%) C = 40.63 H = 6.85 N = 3.49

 FABMS m / z 767 [M-NaJ

 Example 25

0- (3-0- ^ force lactovilan)-<1— 4) -0-[(α-fucohilanosyl)-(l → 3)]-N- tyl -Ν-futhyl-1, Synthesis of sodium salt (compound 0)) Process 1

 C 3-0-S / Ι / 3 -Strength 'Lactohi' lanosyl)-(1 → 4) -0-[(α-Lefkohi 'Ranoshi; Ri- (1 → 3)]-Ν-Futyl- Synthesis of sodium salt of 1,5-dimethyl-1,5-imino-clucitol

 Using 3.8 g of the compound (6) and phthalic acid / dealdehyde (1.8 ml), the same reaction as in Example 4 was performed, and 0- (3-0-; W <i-0-D-force 'Lact!:' Ranl '-(l → 4) -0-[(ct-fukodani' ran / V)-(l → 3)]-Nn-futyl-1,5-si ' Deoxy-1,5-imi D-butyl sodium salt (3.3 g, 80.8%) was obtained as a white powder.

Elemental analysis

As

 Theoretical value (%) C = 41.05 H = 7.05 N-2.18

 Actual value (%) C = 41.20 H = 7.05 N = 2.34

 FABMS m / z 606 [-H] 'Step 2

 0- (3-0-Sulfo- / 3-higalactohi'lanosyl)-(1 → 4 0-[(α-fucohi'lanosi Λ-(1 → 3)]-Ν-meth / h /, 5- Synthesis of sodium salt of di'deci-1,5 mino-hike 'or sodium thiotide (compound (30))

 0- (3-0-Sulfo-/ 9 -Strength 'Ratatohi.La /)-(1 → 4) -0- [(Nana-7 Kohi' lanosyl)-(1 → 3)]-N-F ' 50 mg of sodium salt of chill-1,5-dimethylphenyl-1,5-imino-cyclopentyl in water (1.0 ml), THF (l.Oml), and sodium hydroxide (0.3 ml) After dissolution at room temperature, methyl iodide / K 0.2 ml) was added. After stirring the reaction solution at room temperature for 2 hours, meth / yl (0.2 ml), 1N sodium hydroxide (0.2 ml), iodide;! Tyl (1.0 ml) were added, and the mixture was refluxed for 3 hours. Then, the residue is concentrated to dryness under reduced pressure, and the resulting residue is purified using column chromatography (Prep C-18, eluent; water), and lyophilized to give the desired compound (30) in yellow. 17 mg (28%) were obtained as an orange powder.

 FABMS m / z 620 [-H-Nal]-

Example 26

0- (3-0-Sur -0 -Hikishi'La outside hen.Ranoshi / Re)-(1 → 4) -0-[(<2-7 Kohi'la / Sill)-(1 → 3)] -Ν- [3- (N-Hetoxyloxy or nilamino /) alloyl] -1,5-cyr r-1,5-Mino-hicyllucitol sodium salt (compound (31 Synthesis of)) The same reaction as in Example 4 was carried out using 287 mg of the compound (6) and 3- (N-hydroxyl-xyloxyl-nil) aminol nl: 'onarte' hydride (156 mg) to give the desired compound (31) 295m (78.0%) was obtained as a white powder.

Elemental analysis C ^^ sN ^ NaOwS · 3 2Η ₂₀

 Theoretical value (%) C = 43.99 H-6.il N = 3.54

 Actual value (%) C = 43.96 H = 6.29 N = 3.48

 FABMS m / z 741 [M-Na] 'Example 27

 0- (3-0-su /--higaracto-d'la / sil)-(l → 4) -0-[(i-L-fucoviranosyl)-(1 → 3)]-Ν- [3- ( Synthesis of 1,4-diamino-1,5-imino-hyg; citru (Compound (32))

 0- (3-0-S / I-3-D-force 'ratatohi' lanosyl) obtained by catalytic hydrogenation reaction of compound (31)-(1 → 4) -0-[(. -L- 7Co-lanosi W- (l → 3)]-N- (3-aminophenyl) -1,5-di-doxy-1,5-imino-D-glucitol sodium salt (18mg) Was dissolved in 0.1 M sodium carbonate-sodium bicarbonate A buffer (pH = 9, 4 nil), and the mixture was added to acetone-hydrogen chloride (6 mg) of a flourine-stained cyanate (type I, 36 mg). 1> solution (0.63 ml), stirred overnight at room temperature, concentrated under reduced pressure, purified by column chromatography (LiChroprep RP-18, eluent; water), and lyophilized This gave 13 mg (44.7%) of the desired compound (32) as a yellow-orange powder.

 A US m / z 997 [Μ]

[Production of Lewis A-type sugar chain derivative by synthesis scheme (2)] Example 28

0 · (3-0-S /--Galatatovirane)-<l → 3) -0-[(a-L-fucopyranosyl)-(1 → 4) to 6-0-cal :: l · 1,5 shea 'Dokishi 1,5-imine click' Rushitoru sodium ¹ Eta salt (compound (36>) synthesis of

 Process 1

0 ((4-0-a i 2,6-si '-0-to', / Ί 'Higara ^ villa / sill)-(1 → 3) -0-[(2,3,4-tri -0-Henshi f ^-a -L -Fukopyranoshi-(1 → 4)]-2,6-shi '-〇-Hen'yl -N-Henoxy or 2 /, 5 Synthesis of -di-roxy-1,5-imidine 'or methyl (compound (33'>)) 0- (2,6 -'- O-He ', / yl-β-D-lactobilla / Sil)-(l → 3) -0-[(2,3,4-Tri-0-he' (シ → 4)]-2,6-ν -Ο-Α'n 、 n'l へ l キ シ k キ シ force; ϊ · nil -1,5- シ ' The cis-ethyl-1,5-mihitol (compound (33), lO.lg) was subjected to selective acetylation in the same manner as in Example 1. After completion of the reaction, the reaction mixture was decompressed, dissolved in cyclohexane (300 ml), saturated aqueous sodium hydrogen carbonate solution (300 ml), and distilled water.

(300 ml), dried over sodium sulfate, and reduced under reduced pressure to give 10,5 g (99%) of compound (33 ').

FABMS m zl356 [M + Na] ⁺

Process 2

 0- (4-0-Acetyl -2,6-S '-0-He'n' / 'Ill -3-0-S-' Ratatodani 'Lanosil Ml → 3) -0- [(2,3 , 4-Tri-0-ben VI-a-7 kohi'lanosyl)-(1 → 4)]-2,6-si'-0-to ', / ,,' Synthesis of xycarho '^-1,5-y-doxy-1,5-imic'dicitr (compound (34))

 Compound (33 ′) 5 was dissolved in 300 ml of pyricine, to which was added irisyl sulfur trioxide complex (6.0 g), and the mixture was stirred for 4 hours. After adding nor (65 ml) at 0 ° C and stirring for 1 hour, lysis was performed under reduced pressure, and the obtained residue was dissolved in ethyl acetate (300 ml) and washed with distilled water (300rnl X 2) The residue was dissolved in Tano- / K50ml), ion-exchange resin 7-lite IR 120B (Na +) was added, and the mixture was stirred at room temperature for 1 hour. Then, the resin was separated and lysed under reduced pressure to obtain 5.5 g (S6.9%) of compound (34). It was used for the next reaction without further purification.

 FABMS m z 1412 [M-Na]-Step 3

 0- (3-0-S /--Hygalacto t ° lanosyl)-(1 → 3) -0-[(2,3,4-tri-0-hexyl-β-refco !: Lanosyl)-(1 → 4)]-Ν, 6-0-Calho ': Synthesis of 1M.5-C'-decyl-1,5-imino-hyglucitol sodium salt (Compound (35))

5.4 g of the compound (34) was dissolved in methanol (270 ml), 28 ml of a 28% sodium / I-cholesterol solution was added, and the mixture was stirred overnight at room temperature. The residue was washed with a small amount of methanol, and added with meta /-(KlOOml), and the white insolubles were separated therefrom. Remaining The residue was subjected to column chromatography (LiChroprep RP-18, 30% → 60% methanol / water elution with crush) to obtain 3.1 g (91.5%) of compound (35).

Elemental analysis C ₄₀ H ₄₈ NNaO ₁₇ S- 3 / 2¾0

 Theoretical value (%) C = 53.57 H-5.73 N = 1.56

 Observed value (%) C-53.40 H-5.61 N-1.68

 FABMS / n / 846 [-Na] "

0- (3-0-Sulfo--Strength 'Ratatohi. Lanosyl)-(l → 3) -0-[(a -J Fucopyranosyl)-(1 → 4)]-Ν, 6-0-Cal'nil Synthesis of -1,5-diethoxy-1,5-imigine sodium salt (Compound (36))

 Dissolve 3.0 g of compound (34) in methano- / K90 ml) and sulfuric acid (10 ml), add 10% wax (emulsion-horn) (2.8 g), and in a hydrogen atmosphere at 40 ° C. Stirred overnight.ラ Separating ラ ラ ゥ ゥ ゥ-洗 い 壚 洗 い 洗 い 洗 い 洗 い 洗 い 洗 い 洗 い 洗 い メ タ メ タ 洗 い メ タ メ タ メ タ メ タ 壚 壚 メ タ 残渣 残渣 残渣 残渣 残渣 残渣 残渣 残渣 残渣 残渣 残渣 Li 残渣 残渣 残渣 残渣 Li Li 18, eluted; water), desalted the product with Asilisa '-(force-tri'noshi'; AC110-20), freeze-dried (35) 1.2 g (47: 4%) I got

 Specific rotation [na--14.7 ° (c = 0.38, water)

Elemental analysis

As

 Theoretical value (%) C = 35.41 H-5.47 N = 2.17

 Measured value (%) C = 35.16 H = 5.68 N = 2.12

 FABMS m / z516 [M-Na] "Example 29

0 ·--% Η-β -DV Rahi'lanosyl Ml → 3) -0-f (a-lefcohi.lanosyl)-(1 → 4>)-Ν-π-octyl -1,5- ヅ te ' Synthesis of oxy-1,5-iminoc '' / ntol sodium salt (Compound (38)) Process 1

 0- <3-0-Sulfo- -Hygalactos. Lanosyl)-(1 → 3) -0-[(α-I-fucopyranyl)-(1 ~ 4) to 1,5-dimethyloxy-1,5-iminum Synthesis of (37))

 Compound (36) 1. was dissolved in a 50% aqueous solution of ethanol (64 ml), a 2N aqueous sodium hydroxide solution (8.5 ml) was added, and the mixture was stirred at 90 ° C. for 6 hours. Neutralize with an aqueous solution, compress under reduced pressure, apply the resulting residue to column chromatography 'Raffi- (LiChroprep RP-18, eluent; water), desalinate the product with Azylisa'- Lyophilization yielded 0.9 g (47.4%) of compound (37).

Elemental analysis

do it

 Theoretical value () C = 35.70 H = 6.49 N = 2.31

 Measured value) C-35.47 H = 6.57 N = 2.33

 FABMS / n z550 [M-Na]-Step 2

 0- (3-0-sul ί- -higarata 'lanosyl)-(1 → 3) -0-[(-fucopyranosyl)-(l → 4)]-Nn-s-octyl-1,5-s Synthesis of oxy-1,5-imino-glucitol sodium salt (Compound (38))

 The same reaction as in Example 4 was carried out using 100 mg of the compound (37) and η-talactyl aldehyde (1331) to obtain 89 mg (76.3%) of the desired compound (38) as a white powder.

Specific rotation [a] _D = -51.4 ° (c = 0.52, water)

Elemental analysis

do it

 Theoretical value (%) C = 42.21 H = 7.36 N = 1.89

 Actual value (%) C = 42.26 H = 7.17 N = 1.97

FABMS / 7J Z 662 [-Na]- Example 30

 0- (3-0-X -3-z force 'Lactohi. Lanoshi-(l → 3) -0-[(aL-fucohi'lanosyl)-(1 → 4)]-Ν-π-dodecyl-1, Synthesis of sodium salt of 5-cis-1,5-dimethyl-1,5m-lecitole (compound (39))

 The same reaction as in Example 4 was carried out using 200 mg of compound (37) and 1-to-the-canal (3741) to obtain 11 lmg (44.1%) of the desired compound (39) as a white powder. Was.

Specific rotation [a] _D = -48.7 ° (c = 0,56, water)

As elemental analysis _{C3oH J6 NNa0 ls S · 2H 2} 0

 Theoretical value (%) C = 46.32 H = 7.77 N = 1.80

 Actual value (%) C = 46.35 H = 7.87 N-1.90

 FABMS 77 ^ 718 [M-Na] 'Example 31

 0- (3-0-Sulfo-/ 3-Strength 'Lactohi'lanosyl)-(l → 3) -0- [(Na-7 kohila / shi Λ-(1 →)]-Ν-li / Synthesis of Rail-1,5-dimethyl-1,5-imimine / glucitol sodium salt (Compound (40))

 The same reaction as in Example 4 was performed using 100 mg of the compound (37) and 100 mg of ril realte hydride to obtain 99 mg (70.6%) of the desired compound (40) as a white powder.

Specific rotation [fl] _D = -44.3 '(c = 0.59, water)

Elemental analysis 03 ₆₄ ] ^ 30 ₁₆ 3-3 / 2 0

 Theoretical value (%) C = 50.93 H = 7.95 N = 1.65

 Actual value (%) C = 50.72 H = 7.80 N = 1.81

 FABMS / n 798 [M-Na] "Example 32

 1,5-fc * {[0-0 · 0- Η-β -D-il'ratatoviral)-(1 → 3) -0-[(α-lefcohilananosyl)-(1 → 4)]- Synthesis of 1,5-dimethyl-1,5-imi 2 lucito-Μ-Ν, Ν} -pentane (compound (41>))

Dissolve 200m of compound (37) with 50% aqueous solution of methanol / water, and add 50% aqueous To this was added 15 mg of sodium borohydride, adjusted to pH 3 to 4 with acetic acid, and stirred at room temperature overnight. After completion of the reaction, the mixture was neutralized with a 2N aqueous sodium hydroxide solution and shrunk under reduced pressure. The obtained residue was subjected to column chromatography α matto 'raffy (eluate; water) filled with Sephades G10, and the obtained purified product was lyophilized to give 58 mg of compound (40) as a white powder. Yield from 7 aldehyde (27.2%).

Specific rotation

(c = 0.47, water)

Elemental analysis _{C 41 H 74 N 2 0 32} S 2 - as 6H

 Theoretical value C¾) C = 38.50 H-6.78 N-2,19

 Actual value (9 &) C-38.59 H = 6.96 N = 2.25 Example 33

 0- (3 · 0-s / ·? · Β -his' ratato f la / sil)-(1 → 3) -0-[(α-fucopi 7 / νΛ)-(1 → 4)]-Ν -[3- (Fully Inch Μ 'W Mouth Filler' T Synthesis of 1,5-imi citrate (compound ())

Compound (37) Dissolve 10 mg of llOmg in water (2 ml) and methanol (2 ml), adjust the pH to 4 by adding acetic acid, and then add 3- (hydrogen) ) Fent iW hydride (59.6 mg) and sodium cyanoborohydride (18 ms) were added, and the mixture was stirred at room temperature overnight. The reaction mixture is concentrated, neutralized with dilute aqueous sodium hydroxide solution, and purified with ODS KARAMUK U-Mat 'Raffi (LiChroprep RF-18, elution of 75% meth / l-water from water). (3-0-S force's lactolanos)-(1 → 3) -0-[(α-L-ni ° La / ΆΜ1 → 4)]-Ν- [3- ( if Niruamihafu 'mouth pin le] -1,5-Shi' r old carboxymethyl-1,5 Minhiku 'Rushito -. to give a white powder 130ms Le diisocyanatohexane ¹ arm salt the compound (UOM B) acetate - Methano- / Kl: 10, 22 ml), and stirred overnight at room temperature and normal pressure under a hydrogen atmosphere using 5% Λ 'ラ' kumka- ホ '(100 mg) as a catalyst. And the filtrate was concentrated under reduced pressure to obtain 0- (3-0-sul 0 -Df lactohylanosyl)-(1 → 3) -0-[(α--7cohyla / sil)- (1 → 4)]-Ν- (3-Amino / Propyl) -1,5-Cyte-Iki-1,5-Imimig I Recitol Natri ^ Coarse powder of salt (80 mg). This compound (45 mg) was added to 0.1 M sodium carbonate Dissolve in sodium hydrogen buffer solution (pH = 9, 8ml), and add flourcein '/ chain (type I, 90mg) to acetone-cysteine greedy (6: 1, 2.3ml) The mixture was stirred overnight at room temperature.The reaction mixture was lysed under reduced pressure, and purified by column chromatography D-maraf (Li Chroprep RF-18, eluted with 60% meth / l-water from water). The target compound (42) was obtained as a yellow-orange powder in an amount of 50πΐ (68.7%).

FABMS 997 ΓΜ] " O 97/00881

 38

[Test example]

 1. Effect of the compound of the present invention on E-selectin-dependent adhesion of cultured human leukemia cells HL60

1) E-cetatin-dependent HL60 / HUVEC adhesion test method

Collecting usual manner 'culture passaging 5 th generation of human vascular endothelial cells (hereinafter, the abbreviated as HUVEC>,: 1% Se' co with keratin - you encountered a 96-well microphone Pai7 'Uyuru per 2Χ 10 ⁴ Les DOO . pieces were seeded 37.C of C0 ₂ ink: to I '- after over晚cultured in data, RPMVFCS / HEPES medium the cell layer 100 μ 1 (RPMMI-1640, 10% F CS, 25mM HEPES, pH7 Wash twice with .4), and add lOU / ml of I: lβ containing RFMI / FCS / HEPES to 100

/ ^ And cultured for 4 hours (activated). In order to measure cell adhesion in non-activated cells, a kit containing only RPMI / FCS HEFES alone (KBasal) was prepared. After washing twice with RFMI-1640 (RFMI HEFES) that does not contain FCS, Susan human leukemia cells HL60 are suspended in 10 ml of RFMI / FCS / HEPES medium containing 0.5% tartaraldehyde, and placed on ice. Fixed for 20 minutes. After fixation, the cells were washed three times with RPMI / H EPES, diluted with RPMI FCS / HEFES so that the cell number was 2 × 10 ⁸ ∞11§ / 111】, and stored on ice until use. .

After activation, the HUVECs were washed three times with 100 μl of RPMI / FCS / HEPES, and each compound of I dissolved in 50 # 1 RPMI / FCS / HEFES (Control) and RPMI / FCS / HEPES (lms / ml ) Or anti-E-selectin antibody (25 μg ml), and incubate at room temperature for 30 minutes. Next, 1 × 10 ⁵ (50 ml) of the immobilized HL60 cells were added to each cell, and the cells were incubated at room temperature for 45 minutes. Fill each chill with RPMI FCS / H EPES, seal it with a miter Dale seal so that no air bubbles enter, then let the plate fall and let stand for 1 hour To remove unbound HL60 cells.

2) Method for measuring the number of adherent cells

The number of adherent cells was determined based on the activity of mi-It'luxita'-ze (MPO), an enzyme present in HL60 cells. Add 0.5% hexadecid bromide to each well; add 1 Ψ_timonicum (HTAB>!) Acid buffer (50 mM, pH 6.0) and incubate at room temperature for 30 minutes to remove ΡΟ Solubilized from within O 97/00881

 39

. At the same time, a known number of HL60 cells that had been subjected to the same treatment were collected in a row of 96-elf-) as a standard. Then 0.6mM Shi 'Nni hydrochloride, 0.4 mM H ₂ 0 ₂ a Complex free phosphate buffer (lOOmM pH 5.4) to 200 mu 1 was added and allowed to react at room temperature for 20 minutes, BIO-RAD Inc. Model 3550 The absorbance at 450ηιη was measured using MICRO PLATE READER. A standard curve was created from the absorbance obtained from the cells for the standard, and the number of adherent cells was determined. The experiments were performed using 6 µl of each treatment. Based on the number of adherent cells in each cell, the cell adhesion rate in each treatment when the value of Control was 100% was determined, and the average value and standard error between 6 μl were determined. Tables 1 to 4 show the results. table 1

 Effects of cultured leukemia cells on 培養 -seΕ / dependent adhesion of HL60 (1) 賴 compound η

 Control 6 100.0 ± 8.7

 Basal 6 25.1 ± 3.4 »*

 Anti-E-selen antibody δ 41.0 ± 5.5 **

 sLex # 6 55.2 ± 7.1 **

 Compound (12) 6 59.4 ± 3.6 "

 Compound (13) 6 284 ± 1.6 **

 *: p <0.05 vs Control, **: p <0.01 vs Control

 ^ Natural type 4 7 X X Table 2

 Effect of cultured human leukemia cells HL60 on E-seno-dependent adhesion (2) ヒ ^ compound n ffl bleeding rate f%

 Control 6 100 ± 12.1

 Basal 6 5.9 ± 1.4 *

 Anti-E-seletin antibody 6 4.2 ± 1.1

 sLex # 6 50.3 ± 3.2 *

 Compound (21) 6 58.9 ± 3.8

P <0.01 vs Control, #: Natural tetrasaccharide cyaryl W x 40

 Table 3

 Effect of HL60 on E-selectin-dependent adhesion of cultured leukemia cells in culture (3)

 Control 6 100.0 ± 4.3

 Basal 6 13.1 ± 1.2 *

 sLex # 6 70.2 ± 2.5

 Compound (28) 6 50.6 ± 1.7 »

 ': P <0.01 vs Control, #: Natural type 40 Charyl Lewis X

Table 4

 Effects of cultured human leukemia cells HL60 on E-cutin-dependent adhesion (4) Test compounds! Adhesion rate (%)

 Control 6 100.0 ± 5.4

 Basal 6 19.0 ± 1.8 "

 sLex # 6 83.2 ± 3.5 *

 Compound (37) 6 63.9 ± 4.0 **

 Compound (41) 6 53.9 ± 1.0 "

 *: p <0.05 vs Control, #: Natural tetrasaccharide sialyl X

 **: p <0.01 vs Control

2.Human leukemia cells HL60 effects on cutin-dependent adhesion 1) Cell culture vessel To maintain culture of human cultured leukemia cells HL60, use a 75 cm ² culture flask, 10% FCS, 0.6 mg ml L-cl '/ Letamine, using RPMI4640 (RPML / FCS / HEPES) with 25 mM HEFES37. C ∞ ₂ to incubator for '- data - (5% CO,, 95 % Air) KoTsuta within.

2> platelet separation and activation

Blood was collected from the human vein using a 1/10 volume injection of 3.8% sodium tricitrate, and centrifuged at llOO rpm for 7 minutes using a centrifuge tube to perform platelet rich plasma (Platelet Rich Plasma, (PRP) O 97/00881

 41

Was. 1/10 volume of 7 mM EDTA was added to PRP (final concentration: 7.7 mM), and platelets were separated by centrifugation at 3000 rpm for 10 minutes. The platelets were suspended in 77 mM EDA 0.15 M NaCl 0.15 M Tris-HCl (pH 7.4), and the supernatant was removed by centrifugation at 3000 rpm for 15 minutes.The platelet sediment was removed from lmi Ca ⁺⁺ / Mg 7 Washed with Reak's solution (pH 7.2, Hanlcs (-)) to completely remove residual EDTA, and platelets were compared with Hanks (-). ) Was added at i.ou / ml, closed at room temperature for 10 minutes, activated at room temperature, and an equal amount of 2% Λ 'lamal f hydrid was added, followed by fixing at room temperature for 1 hour.

3) Immobilization of platelets

After fixation, 1/8 of the volume of a 500 mM quricine / 250 rnM Tris solution was added. After standing at room temperature for 15 minutes, the plate was washed three times with Hanks (-), and the platelet count was adjusted to lxlO ⁸ lls / ml. 9 iota / microphone D array - 0.5 g / Svell of Li -Li a g) Shi 'by emissions co -. Collected by the addition of activated platelets solution by 100 to each click iota Le (lxl0 ⁷ / well) § Les -Centrifuge at 1500 rpm for 5 minutes, remove the supernatant, and add 0.03% rt ^ solution containing Ca ⁺ Mg containing 'Laholm 77' IV (Add 100 1 of Hanks (+) and close for 10 minutes. Platelets were immobilized on the lower surface of the cell, and the cell was washed three times with Hanks (+), and then subjected to flocking using Hanks (+) containing 5% FCS for 2 hours at room temperature.

4) Measurement of cell adhesion

Each plate was washed three times with Hanks. The SLE-based compound prepared using RPMI FCS / HEPES (Control) _% PI FCS / HEPES at the indicated end was added in an amount of 50 μl. 'To 30 minutes inks Interview at room temperature - After bets, and 30 minutes閗静location at 37 ° C for addition of 50 1 of HL60 cells a l0 ³ cel well)?. each! 1) Fill with 1 ml of R PMI medium, seal with a ^7- cm D-floor wrap to prevent air bubbles, and incubate the plate at room temperature for 1 hour with the plate turned over. Unbound cells were thereby removed.

To calculate the number of adherent cells, use 0.5% of bromide in each HL using the activity of helium / kexida-II in HL60 cells. The mixture was added with a phosphate buffer (50 mM, pH 6.0) and stirred at room temperature for 30 minutes. At the same time, a known number of HL60 cells treated in the same manner were serially diluted and used as a standard at 96/1 / Ref. 50 1 was added to the rate. 0.6 mM phosphoric acid, 0.4 mM H ₂ O ₂ phosphoric acid Add 200 μl of buffer a00mM pHa 5.4) to each well, and allow to react at room temperature for 20 minutes.Then, absorbance at 450 nm using a microretorator- (Bio-Rad, Model 3550). Was measured. A standard curve was prepared from the absorbance obtained from the cells for the standard, and the number of adherent cells was determined. The experiment was carried out for each treatment using 6 μl.The cell adhesion rate in each treatment was determined from the number of adherent cells in each cau when the cell adhesion number in Control was 100%. And find the standard error. The results are shown in Tables 5 and 6.

Effect of HL60 on P-cetin dependent adhesion of leukemia cells

 Control 6 100.0 ± 6.3

 .sLex # 6 72.4 ± 4.4

 Compound (12) 6 74.9 ± 4.3 **

 Compound (13) 6 69.4 ± 3.9 "

 Compound (14) 6 70.0 ± 3.5 **

 Compound (15> 6 74.2 ± 4.2

 Compound (16> 6 83.1 ± 7.0 *

 *: p <0.05 vs Control *: p <0.01 vs Control

 #: Natural tetrasaccharide chair X Table 6

 Incubator i: Effect on leukemia cell HL60 on PIN-dependent adhesion (2) Test compound Portability (mg ml) n Cell adhesion rate f%)

 Control-6 100.0 δ.2

 sLex # 1.0 6 48.4 ± 2.0 **

 One ^ (_21) _ 0.3 6 ― 54.8 ± 4.4 **

 p <0.05 vs Control, #: Natural tetrasaccharide X

As described above, the compounds according to the present invention exhibited remarkable cell adhesion inhibitory activity against perylene and Ρ-selen. From the above, it can be seen that the compound of the present invention inhibits the adhesion between leukocytes or cells and endothelial cells by competitively inhibiting secretin present in endothelial cells. O 97/00881

 43

 It is useful for the prevention and treatment of inflammation and thrombus formation associated with inflammation, rheumatism, ischemia, reperfusion injury, infectious disease, immunity, and i-potency.

 When the compound of the present invention is administered as a medicament, the compound of the present invention contains 0.19 & 99.5%, preferably 0.5%-90% as it is or in a pharmaceutically acceptable non-toxic and inert carrier. As a composition, it can be administered to animals containing humans.

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

 The dosage as an anti-inflammatory agent is desirably prepared in consideration of the patient's condition such as age, body weight, etc., the administration route, the nature and extent of the disease, and the like. The amount of the ingredient is generally in the range of 100 mg to 3 g / day / human, preferably in the range of 500 mg to: lg / day / human per day. In some cases, lower doses may be sufficient and conversely, higher doses may be required. It is also desirable to administer the drug in 1 to 3 divided doses a day. The same applies to other pharmaceutical uses.

Claims

O 97/00881 44 Claims

1. Moranoline derivative represented by the following general formula [I], a salt thereof, or a solvate thereof.

 [I]

In the formula, R ¹ is benzyl, alkoxycarbol, cyano, alkyl rubamoyl, toro, acylamino, alkylthio, alkanesulfonamide, alkoxyalkoxyalkoxyamide, aralkyloxyamide, lower group substituted by hydroxyl group or aryloxy. The alkyl or dibenzene ring is selected from a hydroxyl group, an alkoxy, an alkyl, a halogen, an alkyl halide, a cyano, a carpamoyl, a mono- or di-alkyl rubamoyl, a -toro, an acylamino, an alkylthio, a mono- or dialkylamino or a carboxy; Lower alkyl optionally substituted with three substituents, ③lower alkyl substituted with a 5-membered unsaturated heterocycle optionally substituted with alkyl, alkaryl, phenylalkyl, リ ー ルAlkyl, or 3- represents (full O receptacle inch O-carbamyl) Aminobu pills, and R ³ are different from each other, hydroxy sulfo - represents the le or galactopyranosyl or Fukobiranoshiru substituted with a metal salt thereof. Represents a hydroxyl group or acetamit '.

 2. The moranolin derivative according to claim 1, wherein the metal salt of hydroxysulfur is an alkali metal salt or an alkaline earth metal salt.

3. The moranoline derivative according to claim 1, wherein: is 1-galactobilanosyl substituted at the 3-position with a sodium salt of hydroxysulfol, and is 1-fucoviranosyl. O 97/00881

 45

4. The moranoline derivative according to claim 1, wherein R ² is 1-fucoviranosyl, and R ³ is 1-galactopyranosyl substituted at the 3-position with a sodium salt of hydroxysulfol.

5. A bismoranolin derivative represented by the following general formula [II].

[II]

π represents an integer of 1 to 10;, R ³ and are the same as those in claim 1; 1, R ³¹ and ¹ are the same as those in claim 1 described as, and R ⁴ respectively. -Represents the thing.

6. Moranolin derivatives represented by the following general formula [III].

Oka 'In the formula, X represents halogen, R ⁶ is the same or different and is alkyl, R ³ R ⁴ is the same as described in claim 1, 7. In the following general formula [IV] Moranoline derivatives represented. 97/00881

 46

 [IV]

Wherein R ⁷ and R ^e are different from each other and are 4-0-acetyl-2,6-di-0-benzoyl3-0-sulfo-β-hygalactovyranosyl or α-fucopyranosyl; Asil, R ¹⁰ is acyloxy or acetamide.

 8. Moranoline derivatives represented by the following general formula [V].

 0

 0

IV)

In the formula, R "and R ¹² are different from each other. 3-0--0-Ό-1-force lacto1: 'la or 2,3,4-tri-0-to-resile- -ίτ 1 -7 Copyranosyl, and R ¹⁰ is acyloxy or acetamide.

 9. The compound of claim 8 is reduced to deprotect the fucose protecting group, and hydrolyzed to decarboxylate moranoline. Next, the compound is reacted with an aldehyde compound or a halide having a desired substituent to introduce a substituent into the nitrogen atom of moranoline. Law.