WO1997048712A1 - Asialotrisaccharide moranoline derivatives and drugs - Google Patents

Abstract

Novel asialotrisaccharide moranoline derivatives represented by general formula (I) which inhibit selectins and thus are useful in the treatment of diseases such as inflammation wherein R represents (a) or (b); one of R?1 and R2¿ represents galactopyranosyl optionally substituted at all or some of the hydroxyl groups by -SO¿3?H, -CH2COOH or (c) while another represents fucopyranosyl; A represents -(CH2)m-NR?e¿-CO-O-, -CO-O-, -(CH¿2?)n-CO-O-, -C2H4(OC2H4)z-NR?e¿-CO-O-, -C¿2?H4(OC2H4)y-OCH2-CO-O- or -(CH2)n-O-; R?a and Rb¿ are the same or different and each represents a saturated or unsaturated hydrocarbon group or a saturated or unsaturated fatty acid residue; R?c and Rd¿ are the same or different and each represents hydroxy, alkyl or alkoxy; and Re represents H or alkyl.

Description

 Description Asia oral trisaccharide moranoline derivative and pharmaceutical technical field

 The present invention relates to a trisaccharide moranoline derivative in the ash mouth. More specifically, the present invention relates to an asia-mouthed trisaccharide moranolin derivative containing a saccharide of moranoline, galactose, and fucose trisaccharide, and a drug therefor. Further, the present invention also relates to intermediates useful for producing the same and a method for producing the same. Background art

 Diseases such as inflammation and thrombus formation associated with inflammation, rheumatism, blood circulation, reperfusion injury, asthma, infectious diseases, immune diseases, AIDS, and cancer are caused, for example, by adhesion between leukocyte tumor cells and vascular endothelial cells ( Cell adhesion) as one step. Such cell adhesion is mainly expressed on the ganglioside Lewis type sugar chain ligand and sialyl Lewis type sugar chain ligand present on the cell surface, L-selectin present on the surface of leukocyte MB vesicles, and on the surface of vascular endothelial cells and platelets. It is known to occur through the interaction with E- and P-selectin ("Ayumi of Medicine", Vol. 174, No. 1, 36-40 (1995), etc.).

Near S, attention has been paid to the above-mentioned sugar chain ligand-selectin interaction relating to cell adhesion, and research on sugar chains (sugar chain derivatives) as counter ligands that inhibit the interaction has been actively conducted. Among them, a natural shea-mouth tetrasaccharide Lewis type, which comprises sialic acid, D-galactose, DN-acetylglucosamine, and L-fucose tetrasaccharide, which constitutes an in vivo sugar chain ligand It has been reported that sugar chain derivatives inhibit the activity of selectin as the counter ligand and also inhibit cell adhesion (C. Foxall. Et al., J. Cell Biology, Vol. 117, No. 4, 895-902). (1992), Richard M. Nelson et al., J. Clin. Invest., Vol. 91, 1157-1166 (1993)), and natural type acrylates in which sulfate groups are combined with sialic acid. Mouth trisaccharide Lewis-type sugar chain Derivatives have also been reported to inhibit selectin activity and cell adhesion (Glycobiology, Vol. 3, No. 6, 633-639 (1993), etc.). PCT WO94 / 20514 indicates that similar trisaccharide Lewis-type sugar chain derivatives inhibit cell adhesion between leukocyte ^ ffl vesicles and vascular endothelial cells, and are therefore useful for treatment of inflammatory diseases and autoimmune diseases. It is also described in the gazette and Japanese Patent Publication No. Hei 7-501341.

 In addition, the present applicants have also proposed that non-natural type triacetate triglyceride glycan derivatives having moranoline as a constituent sugar instead of N-acetylglucosamine also bind selectin activity by binding to selectin. It has been found that it is useful as a therapeutic agent for inflammation and the like because it antagonistically inhibits and inhibits cell adhesion, and has filed various patent applications (PCT WO95 / 26970, PCT / JP96 / 01146, Japanese Patent Application No. 7-155776, Japanese Patent Application No. 7-165122). Disclosure of the invention

 An object of the present invention is to treat diseases caused by selectin involvement, such as inflammatory diseases, such as ischemia, heart attack, trauma, reperfusion injury accompanying blood flow recovery after surgical treatment, and pulmonary hypertension. Reperfusion injury, ischemia reperfusion injury caused by cryotherapy, muscle ischemia / reperfusion injury frequently caused by traffic accidents, acute nephritis, adult respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC) ), Splenitis, acute lung injury, arterial occlusion, myocardial reperfusion injury, various shocks (hemorrhagic shock, infectious shock, etc.), organ transplantation, transplantation organ preservation, contact dermatitis, atopy —Asia oral trisaccharide useful for dermatitis, pressure ulcers, colitis, various vascular inflammations, arthritis, arteriosclerosis, suppression of leukocyte increase, rheumatism, asthma, infectious diseases, immune diseases, AIDS, cancer, etc. An object of the present invention is to provide a novel derivative of moranoline.

The present inventors have conducted intensive studies and have found that the triglyceride moranolin derived from asia mouth represented by the following one-sided formula [I] and its pharmaceutically acceptable metal salt (hereinafter referred to as “ The present invention has been found to inhibit the activity of selectin and inhibit cell adhesion by binding to selectins involved in cell adhesion, thus completing the present invention.

式中、 Rは、

Where R is

Represents c

Rl or R2 is either galactobilanosyl or all or part of the hydroxyl group H

-SO3H one CH ₂ COOH, or

 Represents galactobilanosyl substituted with any one of the above groups, and the other represents fucobilanosyl.

A is one (CH2) m-,-CO-0-,-(CH 2) _n- NR ^e -CO-0-,-CCH ₂ ) _n -C0-0- -C 2H4 (0C 2H4) y- OCH2—CO—0—, —C 2 H 4 (0C 2 H 4) _z —NR ^e —CO—0—, or — (CH 2) _n— 0—.

R ^a and R ^b are the same or different and represent a saturated or unsaturated aliphatic hydrocarbon group or a saturated or unsaturated fatty acid residue. R ^c and R ^d are the same or different and each represents an alkyl group, an optionally substituted alkoxy or water. Re represents H or alkyl. m represents an integer of 0 to 12, and n represents an integer of 2 to 12. y represents an integer of 0 to 3, and z represents an integer of 1 to 4.

Hereinafter, the present invention will be described in detail. In the present invention, examples of the “alkyl” include linear or branched ones having 1 to 4 carbon atoms. Representative examples include methyl, ethyl, propyl, isopropyl, butyl, and isobutyl. Can be mentioned.

 Examples of the “alkoxy” include straight or branched carbon atoms having 1 to 6 carbon atoms. Representative examples include methoxy, ethoxy, propoxy, 3,3-diphenylpropoxy, and the like. Butoxy and 5-carboxypentoxy. Further, they may be substituted with arylarylcarboxy.

 In the present invention, the “saturated or unsaturated aliphatic hydrocarbon group” includes a chain or branched C 5-30, preferably straight-chain C 12-20 alkyl or alkyl group. Examples include pentyl, hexyl, octyl, nonyl, decyl, dodecyl, myristyl, normityl, stearyl, eicosanyl, docosanyl, tetracosanil, hexacosanyl, octacosanil, isohexyl, and 9 -Dodecenyl, 9-tetradecenyl, 9-hexadecenyl, 6-octadecenyl, saiyl, 9-eicosenyl, 13-docosenyl, linoleyl, y-linolenyl, a-linolenyl. Examples of the “saturated or unsaturated fatty acid residue” include straight-chain or branched-chain acyl having 5 to 30 carbon atoms, and preferably straight-chain having 12 to 20 carbon atoms. , Valeryl, Isovaleryl, Hexanoyl, Octanoyl, Decanoyl, Lauroyl, Myristil, No, 'Lumitoyl, Stearoyl, Oreoil, 6-Octadesenoyl, 13-Docosenoyl, Arakidoyle, 9,12-Yoyl Decadienol, 6,9,12-octadecenol, and 9,12,15-octadecenol are available. Of these, oleyl and oleoyl are preferred.

 In the present invention, the “pharmaceutically acceptable metal salt” includes sulfonic acid, carboxylic acid, phosphoric acid, and alkyl phosphoric acid of the present compound [I], for example, lithium salt, sodium salt, potassium salt and the like. And alkaline earth metal salts, such as alkyl metal salts, magnesium salts, calcium salts, and potassium salts.

Among them, the ash mouth trisaccharide moranoline represented by the following general formula [Ia] or [Ix] Derivatives are preferred

 [la] [Ix]

 X is

 o

 II

 One cO

S0 ₃ H, one CH2 COOH, or represents an P-R.

 RcO and RdO are the same or different and represent water, alkyl or an optionally substituted alkoxy.

 Specific examples of the compound of the present invention include the following.

 0- (3-0-S -y3-D-force * Lacquer-(l-3) -0- [(aL-fucoviranosyl)-(1-4)] -N- (2,3-bis (Rei W Kishi) F'guchi Building) -1,5-Site

0- (3-0-S Λ-β force * Lac 'lanosyl)-(1 → 3) -0- [(a -L-fucobira-(1-4)] -N- (2,3-h * (Orei Woxy) ⁷ · π Building) -1,5-Te-Seki 1,5-imine D-Kenthol sodium salt,

 O-0-OW- β -D-force * lactovilanosyl)-(1-3) -0- [(a-lefcoviral)-(1 → 4)] -N- (2,3-hy's (lauri / W xi) 7 mouths)-1,5-Cyte- 1,5-imino-D-co-toluene sodium salt,

 0- (3-0-S Λ--D-force 'lac viranosyl)-(l → 3) -0- [(a-L-fucoviranosyl)-(1 → 4)] -N- (2,3- Bis (myristix) 7-lohi) -1,5-shi *

0- (3-0- -β-D-force 'lactovilanosyl)-(1-3) -0- [(a-lefcoviranosyl)-(1 ^→ ) -N- (2,3-hy * s (c' Michi W xy) fu'guchi building) -1,5-S 'te' oxy-1,5-imidin D- ク

0- (3-0-S 1-β-D-force * Lactoyl'lanosyl)-(l → 3) -0- [(a-Lefcoviranosi- (1-4)]-N- (2,3-bis (Lily W. Kishi) F'guchi Building) -1,5- '' * ** 1,5-imino-D- ク 0- (3-0-s--D-force * lactoviranosyl)-(l → 3) -0- [(a fucoviranosyl)-(1 → 4)] -N- (2,3-bisキ フ '口' 口 口 '口 口 口

 0- (3-0-S ^--D-force ♦ Lactobilanosyl)-(l-3) -0- [(a-Lefcoviranos-(1-4)] -N- (2,3-Hy's ( Lauroy W (Kishifu) B Building)-1,5-shi ♦ 7-year-old-1,5-Imin D-ku ♦ Λτ

 0- (3-0-S ^--D-force ♦ Lactobilanosyl)-(1-3) -0- [(a-Lefcolanlanosyl)-(1 → 4)] -N- (2,3-S (Miristoi W xy) fu guchi)-1,5-shi, te-shiki- 1,5-imi nin D-ku * Λτ Tolnarium salt,

 0- (3-0-S Λ4-β-D-force 'Lacto'lanos 3) -0- [(a-Lefcoviranosyl)-(1 → 4)] -N- (2,3-H * S (C 'Lumitoyl succinyl) 7 ・ π-Bill)-1,5-cy'teoxy-1, 5-imino-D-co-lucitol sodium salt,

 0- (3-0-SΛ / JD-force * lactovilanosyl)-(1-3) -0- [(a-lefcoviranosyl)-(1-4)]-N- (2,3-bis (ryl2 W x) / c1)-1,5-'Te'-six-1,5-imino-D-k * ^ / Thor sodium salt,

 0- (3-0-force 'xymethyl force lactovilanoshi-(l → 3) -0- [(a-lefcoviranosyl)-(1 ~ * 4)] -N- (2,3-bis (oleix)) 7・ Mouth building) -1,5-site

0 (3-0 phospho / 3-D-force 'easy' Ranoshi 3) -O- [(a -L-7 Kobiranoshiru) - (1 → ^{4)]-N-(2, 3} 'bis Ray W Π Π Π Building>-1,5-Simate *-1,5-Imino-D-quint- Sodium salt,

0- (3-0-Methyl 7-nico)--D-force lactoviranone- (1-3) -0- [-Lefcohi 'lanosyl)-(1 ^→ 4)] -N- (2,3-bis (Orei / Wxy) Fu mouth pill) -1,5-Site * Oxy-1,5-Imin D-Kent * Kentole sodium salt,

 Ο-0-Ο-S W. / SD-force 'Lactoyl' lanosyl)-(1-3) -0- [(α-Lefcoviranosyl) -N- (2,3-bis Mouth Building) -1,5-Site

0- (3-0-S W- 3-D-force ♦ Lak 'lanosyl)-(1 → 3) -0- [(a-Lefkohi'lanosyl)-(1 ^→ 4)] -N- (l, 3-bis (age WW-ki) 7 "rohan (2-y; xy-nil) -1,5- te-shi-ki 1,5-imine D-kn * sodium salt,

 0- (3-0-S Λ-β -D-force 'lactopyrazosyl)-(l ~ * 3) -0- [(a -lefcoviranosyl)-(1 → 4)] -N- (l, 3-h 'S (Shi Wai) W α-S-2-i / ^ Xikalho'nil) -1,5-S' S 'S-Shi -1,5-I'm D- Sodium sodium salt,

 0. (3-0-S ^ -β-Ό-lactovilanone Hl-4) -0- [(a-Shi 7 lanthanyl 3)]-N- (2,3-Srei W xish) 7 Mouth Building)-1,5-site

0- (3-0-S ^-jS-D-force 'Rack Viral)-(1 ^→ 4) -0- [(α-Lefcoviranosyl)-(1-3)] -Ν- (2,3- Bis (Lauri W. Kishifu) mouth building)-1,5-cytoxy- 1,5-imino-D-quinol sodium salt, O-I 3-0-S /?-D-Force * Lactobiral)-(1-4) -0- [(a-le7coviral)-(1-3)] -N- (2,3- Bis (oleoy W xy) · π)-1,5-citrate * xy -1,5-imine D-quintole sodium salt,

 0- (3-0-S / V * -β-D-force * Lactohylanosyl HI— 4) -0- [(a-Lefcohylanosyl)-(1-3)] -N- (2,3 -His (Laroy W Kissi) Flo-Hil)-1,5-Si

 0- (3-0-force / Xymethyl-β-D-force'lactovilanosyl)-(l "* 4) -0-[((a-lefcoviranosyl)-(1-3)]-N- (2,3- Bis (Sai Lei; W Kishi) 7-guchi Building) -1,5-'Te 'Seki Kishi -1,5-Imin D-Kun * sodium sodium salt,

0- (3-0-phosphono- / 3-D-force 'lactovilanosyl)-(1-4) -0- [(a-shifucoviranosyl)-(1 → 3)] -N- (2,3-s (Sai Rei; W-Kis) ⁷・ Β Building) -1,5-Site * Shi-Shi 1,5-Imino-D-C '/ Vi-Sodium Salt,

0- (3-0-Methi sphinico- /? -D-force * lactoviranosyl)-(1-4) -0- [(α-L-7cohi 'lanosyl)-(1 ^→ 3)] -Ν- ( 2,3-His (Sai Rei W Kishi) 7 mouth building) -1,5-shi * Tei Kishi -1,5-Imin D-Ku * Tol sodium salt,

 CM3-0-S Zl-/?-D-force 'lactovilanosyl-(1 → 4) -0- [(fl -L-7 koviranosyl)-(1-3)] -N- [3- [N- [ (1,3-His Leoi W Kissi) 7 Rohan's 2-yl) Talents Λ 'Nil] Amino] 7-Mouth Building] -1,5-Si' Te 'Tae Kissi -1 , 5-Imin D-Kentol,

0- (3-0-S-/ 3-D-force * lactovilanosyl)-(1 ~ »4) -0- [(a-L-fucohi'lanosyl>-(1-3)] -Ν- [3 -[Ν- [(1,3-Bis (Sweet Leoi W Kissi) 7 Rohan'-2-yl) Tasukika ^ * Nil] Amino] 7-Mouth Building] -1,5-Si * Te * Sai-Kin-1,5-Imin D- ^ sodium salt,

0- (3-0-S / W- -D-force 'lactohyal')-(1 → 4) -0- [( _0- shi-fucoviranosyl) -0-)] -Ν- [3- [ Ν- [(1,3-Hy * su (Lauroyl) 7 ・ Rohan-2-yl) Xyxalpho * nil] Amino] 7′Rohyl] -1,5-Si “Te” Xy-1,5-imino-D-quinthorna thorium salt,

 0- (3-0-S- / 3-D-force'lacto-vilanosin 4) -0-[(a-L-7 covilan)-(1-3)]-N- [3- [N-[( 1,3-bis (steaalloy Wxy) 7-lohan'-2-yl) xylcar * nil] amino D-methyl sodium salt,

0- (3-0-S / 1--D-force * lactoviranosyl)-( ^1-4 ) -0- [(aL-fucoviranone-(1 to * 3)] -N- [3- [N- [ (1,3-Bis (H-Lumitoi W-Kishi) Flo-Han-2-yl) Ability ΛΦ · Nil] Amino] 7'α-Hil] -1,5-Sh * Tele Xy-1,5-imin D-quintole sodium salt,

0 · (3-0-S -D-force 'lactovilanosyl)-(1 → 4) -0- [(aL-fucoviranosyl)-(1-3)] -N- [3- [N- [(1, 3-bis (myristoi W xy) 7.loha'n-2-yl) sixicarbo'nil] amino] f'mouth pill] -1,5-si'te'oxy-1,5-imino-D- * 7

 8 salt,

0- (3-0-s W-^-D-force 'lactovilanosyl)-(l-4) -0- (: (a-lefcohilanosyl)-(1 ^→ 3)) -N- [3- [ N-[(1,3-bis (linoleni; W-kis)) α-ha-n-2-yl) -1,5-Imin D-co-Na sodium salt,

 Ο- -Ο-S JV *-/ JD-force ♦ Lactobilanosyl)-(1-4) -0- [(α-Lefcovirane)-(卜》 3)] -Ν- [6- [Ν- [( 1,3 -Bis 才 W キ シ Π Π '-2- -2- 2) 1 * ニ ル * * * 1 1 ニ ル ニ ル ミ ノ 1 ニ ル-Immin D-ku '/ "Mont-Luna Tridum Salt,

 0- (3-0-S force lactovilanosyl)-(1-4) -0- [(na-L-7colane- (1 → 3)] -Ν- [8- [Ν- [(1 , 3 -Bis (Student Leoi W Kissi) Floha'n-2-Sil) Sweetness / 1 * Nil] Amino] Shityl] -1,5-Te D-C '"

 0 · (3-0-S; W5- JD-force 'lactovilanosyl)-(1-4) -0- [(a-L-fucoviranosyl)-(1-3)] -N- [9- [N- [(1,3 -Hye's (Student Leoi Kin) FuΠha'n-2-yl) Student ability W 2] Amino] Nonyl] -1,5-Si * Te * oxy -1,5 -Imino-D-Q '^ Thornadium salt,

 CH3-0-S ^-/ 3-D-force * Lactobilanosyl)-(1 → 4) -0- [(σ-L-fucohi 'lanosyl)-(1-3)] -Ν- [12 CN- [ (1,3-Bis (Sweet Leoi; W-Kis) 7π /, 2-N-yl) oxy / Nil] Amino] 1,5-Imino-D-kunt monosodium salt,

0 (3-0-Met / 1 Sphiniko- /? -D-force 'Lactohi' lanosyl)-(1 ^→ 4) -0- [(nana- L-fucohi 'lanosyl)-(1 → 3)] -Ν -[3- [Ν-[(1,3-hi's)] [amino] fu]] -1 , 5-Sh * te * oxy -1,5-Imin D-ku '/ ^

 0- (3-Ο-methisphinico-yS-D-force * lactoviranosyl)-(1-4) -0-[(aL-fucoviranosyl)-(1-3)]-N- [3- [N- [ (1,3-His (Lauroy W-Kishi) 7-Rohan-2-yl) oxy-power / 1-Nil] Amino] 7-Mouth Building] -1,5-Site 1,5-Imin D-C 'sodium salt,

 0- (3-0-Methi sphinico- -D-force 'Lacto'lanosyl)-(1-4) -0- [(na-refcolal)-(1-3)] -Ν- [6- [ Ν-[(1,3-Bis (Wai-Shi-W-Wishi) Floha-N-2-Il-Shi-Sika ^ ♦ Nil] Amino] Hexyl] -1,5-Shi-Te-Wish -1,5-Immin D-Kun Tolnadium salt,

CK3-0-Met; ^ S 7 nico-3-D-force * Lac viranosyl)-(1 ^→ 4) -0- [(.'Refukoviranl)-(1 → 3)] -Ν- [2-Ν -[ (1,3-bis (oleoy Wxy) fluoran-2-yl) talent; 1 * nil] aminoethyl] -1,5-site * te * talent -1,5-imino -D-kun * Luna salt

 0- (3-0-Met V * sphiniko- /? -D-force 'Lactoyl'lanosyl)-(1-4) -0- [(a-Lefcoviranosyl)-(1 → 3)] -N- [4 -[N-[(1,3-bis (oleoy Woxy) fu 'D han -2-yl) oxy power / 1 * nil] amino] futil] -1,5-si 1,5-imim D-cointole sodium salt,

 0- (3-0-phosphon /?-D-force 'lactohylan' lanosyl 4) -0- [(Nan-fucoviranosyl)-(1-3)] -N- [3- [N- [(1 , 3-Bis (Sweet Leoi / W Kiss) F α-Han-2-yl) Sweetness) 1 * 2; V] Amino] F 'πBil] -1,5-C'te'oxy -1,5-Immine D-butyl sodium salt,

 0- (3-0-phosphono- / 3-D-force'lactoviranosyl)-(1 → 4) -0-[(na-L-fucoviranosyl)-(1-3)]-N- [3- [N -[(1,3-H-S (Lauroy W-kin): 7-Roha-n-2-yl) Talented ^^] Amino] F -1,5-Immine D-Cu 'Vi—Lunarium salt,

0- (3-0-phosphono- / JD-force'lactovilanosyl)-(1 ^→ 4) -0-[(a-lefcolanosyl)-(1 → 3)]-N- [6- [N-[( 1,3-Bis (Soy Leo イ 'Η' Rohan '-2-yl) 才 ^ ニ ニ Amino] Hexyl] -1,5-Si' Te 'oxy -1,5-Imino- D-methyl sodium salt,

 0- (3-0-Phosphono force'lactranosi /)-hi 4) -0- [(aL-fucoviranosyl)-(1-3)] -N- [9- [N- [(1,3- Bis (Ore / Iki) / 'N-2-yl / Kishika / (Nil) Amino / Noel] -1,5-Si / Te / Kisiki-1,5-Imino-D- Sodium sodium salt,

 0- (3-0-Phosphon / 3-D-force 'Lacto'lanosyl)-(1-4) -0-[(Na-Lefkohi'lanosin 3)] -N- [12 · [N- [( 1,3-bis (oleo-oxy) -F-pi-n-2-yl) -0-quine}> — sodium salt,

 O- (3-0-force / ^ ♦ xymethyl force 'lactovilanosyl 4) -0- [(α-L-fucohi' lanosyl HI-3)] -N- [3- [N-[(1,3-bis (Oleoi Kishi) F. Han-2-yl) Ability; 1 * Nil] Amino] 7 Mouth Building] -1,5-shi * te * Ability -1,5-Im D -Cool citrul sodium salt,

0- (3-0-force Λ 'xymethyl-/?-D-force' lactoyl 'lanosyl)-(l ~ »4) -0- [(a-lefkohi'lanosyl)-(1-3)] -N -[3- [N-[(1,3-bis (Laroy Wkin) 7 ・ Rohan'-2-yl) talent; V ** nil] amino] f · π building] -1,5 -Site * oxy-1,5-imino-D-coul * sodium salt of sodium, 0- (3-0-) W * xymethyl--D-force ♦ Lactobilanosyl HI— 4) -0- [-L-7cohi 'lanosyl)-(1-3)] -N- [6- [N- [(1,3-bis (leoL-Woxy) fun-2-yl) ability; 1'nil] ami /] hexyl] -Imino-D-k '/ ^ T -Lunatridium salt,

 0- (3-0-force / * · xymethyl-3-D-force ♦ lactohylanosyl)-(1-4) -0- [(a-L-fucoviranosyl)-(1 ~ * 3)] -N -[9-N- [(1,3-Bis (Taoi Leo W Kissi) Floha'n-2-yl) Talent 力 Λnil] Amino] Nonyl] -1,5-Si'te ' Oxy-1,5-imino-D-c 'sodium salt,

 0- (3-0-ca ^ xymethyl -3-D-force * lactolanosyl)-(1 → 4) -0- [(aL-fucoviranosyl)-(1 → 3)] -N- (12 -N -[(1,3-bis (Sweet Leoi Wxy)) 'Shi-ki-1,5-imi'n D-Cul' citrunalium salt,

 0- (3-0-S / 1-/ 3-D-force * lactolanosyl HI-3) -0- [(na-L-fucohi 'lanosyl)-(1-4)]-N- [3- [N- [(1,3-Bis (Student Leoi W Kissi) Floha'n-2-yl) Squishy ^ * N] Amino] Fu's Building] -1,5-S * T * Xy-1,5-imino-D-coon * sodium lanthanum salt,

0-C3-0-S / 1--D-force * Lac 'lanosyl)-( ^1-3 ) -0- [(.-Lefcoviranosyl)-(l ~)] -N- [3-CN- [( 1,3-Bis (Lauroy W) 7 'Rohan'-2-yl) Deer Λnil] amino] 7-mouth building] -0- * Natrium sodium salt,

 0- (3-0-methine sphinico-force 'lac' lanosyl)-(1-3) [(aL-fucoviranosyl)-(1 → 4)] -N- [3- [N-[(1,3- Bis (Oleoi W Kissi) ロ Rohan '-2-yl) Talent 力 * Nil] Amino]' Mouth Building] -1,5-Site -Kuryl sodium salt,

0 (3-0 phospho N 3-D-force ♦ Rakutobiranoshiru) - (l → 3) -0- [(. 'Refukobiranoshiru) - (1 one ^4)] -N- [3- [N- [( 1,3-Bis (Hybrid) Hxy) Floha'n-2-yl) Hybridity;>'Nil] Amino] 7 · guchi building]-1,5- * * Ύ WJ- 1 / -D-? »\ Sodium salt,

 0- (3-0-force / V * xymethyl-9-D-force 'Lactovilla-(l → 3) -0- [(fl-fucoviranosyl)-(1-4)] -N- [3- [N-[(1,3-bis (oleoy Woxy) 7.loha'n-2-yl) -saltica ^ 'nil] amino] 7-mouth building] -1,5-si'teoxy- 1,5-Imin D-co * Lucitol sodium salt,

0- (3-0-S; lactohydranyl- (1-4) -0-[(a-L-fucoviranosyl)-(1 → 3)]-N- (l, 3-bis (oxo ) 7-Rohan'n-2-yxica ^ * nil) -1,5-Syte * U

0- (3-0-S--D-force * Lactobilanosyl Hl-4) -0- [-Lefcoviranosyl)-(1 → 3)] -N- (l, 3-bis Rohan-2-yxycaroxynyl)-1,5-cytoxy-1,5-imi D-quintol sodium salt,

 0- (3-0-S ^-^ fl-D-force'lactoviranosyl)-(1-4) -0- [(Nan-fucoviranosyl)-(1-3)] -N- (l, 3-bis (lauroy W xy) fluoran -2-y W xycarpho nil, 5-site

 0- (3-0-S Wi- -D-force 'lactovilanosyl)-(l → 4) -0- [-Shifucohi' lanosyl)-(1-3)] -N- (l, 3-bis ( Myristoyl 才 7 ロ Rohan -2-y 力 力 // ^ '2 / V) -l, 5-5-, * * キ シ 1,5-imi イ D-co D * sodium sodium salt ,

 0- (3-0-S / V * -β-D-force * lactovilanosyl)-(1-4) -0- [(a-L-fucohilanosyl)-(1 → 3)]-^ (1 , 3-His (Halmitoy Rohan-2-y Wxika Wnil)

 0- (3-0-s β-D-force lactovilanosyl)-(1 → 4) -0- [(a-L-7 koviral)-(1-3)] -N- (l, 3- S (Ril2W xy) fu · πHan-2-y; ^ Xical Φ'2-1,5-Site salt,

 0- (3-0-s β-D-force * lactovilanosyl)-(1-4) -0- [(a-lefcoviranosyl)-(1 → 3)]--(), 3-bis (olexy ) 7.Rohan's -2- ィ Ϊ Ϊ deer; 1

 0- (3-0-queue-β-D-force 'lac viranosyl H1-4) -0- [(a fucoviranosyl)-(1-3)] -N- (l, 3-hy's (lauri W x) 7-Rohan-2-ix-force VT ell) -1,5-x * f-x 1,5-imino-D-quintole sodium salt,

 0- (3-0-S force * Lacto'lanosyl)-(1 → 4) -0- [(a -L-7 Koviranosyl)-(1-3)] -N- (l, 3-bis (myristine) W xy) α ', / ン -2-i xica Λ 二 yl) -1, 5-cyt * * 才 才--1,5-imino-D-cotyl sodium salt,

 0- (3-0-s β-D-forcelactolanosyl)-(1 → 4) -0- [(na-L-fucoviranosyl)-(1 ~ * 3)]--(1,3-h (S)-(R-mi-l-oxy) 7-lo-hyn-2-y-W-x-yl).

 CK3-0-S / JD-force * Lactobilanosyl)-(1 ~ * 4) -0- [(α-Lefcoviranosyl 3)] -N- (l, 3-bis (lyly W xy)) -2-y ^ xica ^ 'nil)-1,5- te *

 0- (3-0-force xymethyl-β-D-force 'lacto'lanosyl)-(1-4) -0- [(a-L-fucohi'lanosyl)-(1 → 3)] -N- ( l, 3-s (Soy Leoi W-kin) 7 'π-Han-2-y W-xika Λ * nil) -1,5-S'f * o-quin-1,5-imino-D-q ♦ ff Thor Sodium salt,

 0- (3-0-phos-β-D-force ♦ lactovilanosyl)-(1-4) -0- [(a-shi 7-colan)-(1 → 3)] -N- (l, 3-bis (oleoyl) -Iro-hyn-2-yxica / 1 ^ * nil) -1,5-Sythe (cy) -1,5-imino-D-quinodium sodium salt,

0- (3-0-Methi sphinico-β force lactolanosyl)-(1 ~ * 4) -0- [(a-lefcoviranosyl)-(1 → 3)] -N- (l, 3-bis Reoixi) 7-rohan-2-y Wxi 力 ニ ル nil) -1,5-Sythe O i 3-0-S ^-/ 3-D-force 'Lacto' unosyl)-(1-4) -0- [(α-Shifucoviranosyl)-(1 ^→ 3)] -N- (l, 3 -Bis-leoi-W-xy)-. Pi.-Han-2-y-x-a-n-yl) -1,5-cy-tert-oxy-1,5-imino-D-c-n-thanol potassium salt,

 0- (3-0-S A -j3-D-force ♦ Lactobilanosyl HI-4) [(a-L-fucoviranosyl)-(1 → 3)] -Ν- (2,3-bis (oleoy W xy) 1, pi-)).

 0- (3-0-S force * Lactobilanos 4) -0- [-L-7 Koviranosyl)-(1 ~ * 3)] -N- (3-[(1,3-bis (Oleyl) (Ro-ha-n-2-yl) Taikika ^ ♦ nil) 7-mouth building) -1,5-site * Taiki-shi-1,5-imimin D-q '^ HV sodium salt,

 CK3-0-S-/ 9-D-force 'Lacto'lanosyl)-(1-4) -0- [(σ-L-fucolanosyl)-(1 → 3)] -Ν- [3- [( 1,3-Hi * s (lau π-xy) · α-han -2-yl) 力 Λ 7 · ヒImin D-Central Sodium Salt

 0- (3-0-s ^-/ 9-D-force ♦ lactoviranosyl)-(1-4) -0- [(a-L-fucoviranosyl)-(1 → 3)] -Ν- [3- [ (1,3-bis (steer π-W)) * Mouth /, 2-N-yl) oxy- -I-Min D-ku ♦; ^ Thor sodium salt,

0- (3-0-S / I *-/?-D-force 'lactovilanosyl)-(1-4) -0- (; (α-L-fucohi' lanosyl)-(1 ^→ 3)] -N - [3- [(1, ³ 'human' scan (c 'Rumitoi W carboxymethyl) off-[pi Ha' emission-2 I-le) old carboxymethyl force; 1 ^ * 'sulfonyl] 7-mouth buildings] -1, 5-site * * 1,5-imine D-cool sodium salt,

0- <3-0-s A-/ 3-D-force ♦ lactoviranosyl)-(1-4) -0- (: (a -L-fucohi 'lanosyl)-(1-3)] -Ν -[6-[(1,3-bis (o-reyl) 7 ・ α /, -2--2-yl) -yl] hexyl] -1,5-te * oxy-1,5 -Imino-D-coul * sodium sodium salt,

 0- (3-0-S W:-/ 3-D-force 'lactoviranosyl)-(1-4) -0- (; (α-Lefcoviranos) V)-(l-3)] -N- [6 -[(1,3-S (La-Roy; W-Xi) -Flo-Han-2-yl) -Oxy-force Λ 'Nil] -Hexyl] -1,5-C -Imin D-quinthol sodium salt,

 0- (3-0-S ^-3-D-force * Lactopyranosyl)-(1 → 4) -0- [(α-L-fucolanosyl)-(1-3)] -N- [6- [ (1,3-s (stearoxy) -α-an-2-yl) -Kentol sodium salt,

β-Ό-7f '7 ^^)-(1-4) -0- [(aL- ⁷ Kobylanosyl)-( ^1-3 )] -N- [6-[(1,3-S ; H-xy) 7-rohan'-2-yl) virginity; VTnil] hexyl] -1,5- 'te * virgin -1,5-imino-D-q * Λό-sodium salt,

0- (3-0-S / H-/?-D-force * Lactobilanosyl)-(l ^→ 4) -0-[(a-Lefcoviranosyl)-(1-3)]-N- [8-[( 1,3-bis (year-old rail), 'loha'-2-yl) year-old power, nil) year-old 1,5-' texi 4,5-imino-D-quin ' Sodium salt,

 0 · (3-0-s -D-force · lactovilanosyl)-(l ~ * 4) -0- [(na-lefcoviranosyl)-(1-3)] -N- [8- [(1,3- Bis (radioxy) phenyl (2-yl) -producing ability W-nil] -producing octyl] -1,5-cythoxy-1,5-imimin D-octane, Thor sodium salt ,

0- (3-0-S / W;-/?-D-force * lactovilanosyl)-(l ~ * 4) -0- [(a-L-fucoviranosyl)-(1-3)] -N- [ 8-[(1,3-bis (stealloy Wxy) fu · η-Han-2-yl) talent] octyl] -1,5-si * te * oxy -1,5- Imine D-toluene sodium salt, HI -His-/? -D-force 'lactovilanosyl Hl-4) -O- [(na-lefcoviranosyl)-(1-3)] -N- [8- [(1,3-hy * 'Lumitoy / W-kis) 7 ・ Rohan'n-2-yl) Ability Λ' Nil 'octyl] -1,5-Site' Taxi '1,5-Imino-D-C' Sodium salt,

 0- (3-0-s--D-force lactovilanosyl)-(1 "* 4) -0- [(α-lefucoviranosyl)-(1 → 3)] -Ν- [12- [(1,3 -S (Sai Rei W Kissi) 7 Rohan's 2-Il) Oxy Power / 1 ^ 'Nil] Pante ♦ Syl] -1,5-' Te Taikis -1,5-imino- D- Sodium sodium salt,

0- (3-0-force lactovilan)-(1-4) -0- [(α-lefcopiral)-(1 → 3)] -Ν- [12- [(1,3-bis ( Lauroixi) '' D '-2-yl) 才 カ ル カ ル カ ル カ ル カ ル テ テ テ テ テ テ テ テ テ テ テ テsalt,

0- (3-0-S Λ / JD-force 'lactovilanosyl)-(1-4) -0- [(α-lefcohilamecyl)-(1-3)] -Ν- [12- [(1, 3-bis (Stear Dixi) Π Π '-2- 2-)) 才 力 テ テ テ テ ♦ シ ル〕 5- 5- D-Kentol sodium salt,

0- (3-0-force lactovilanosyl Hl → 4) -0- [(a -L-fucohi lanosyl)-(1-3)] -N- [12- [(1,3-bis (c 'Lumithoxy', 'Frohan'-2-yl),〕 テ テ テ テ テ テ テ テ テ テ テ テ テ 5- テ テsalt,

0- (3-0-S ^-/ 3-D-forceLactobilanosyl)-(1 ^→ 4) -0-[(a-L-fucoviranosyl)-(1-3)]-N- [4- [ (1,3-S) (Rei-W-Ki-Shi) -Ro-Han-2-Il) Oxy-power Λ 'Nil] -3--Year-Old. 1,5-Imin D-knitol sodium salt,

0- (3-0-S-J3-D-force'lactohi'lazosyl)-(1-4) -0-[-L-fucohi'lanosyl)-(1-3)]-N- [7- [ (1.3-Bis (La Roy Wxy) 7 ・ Rohan-2-yl) Ability / ^ * Nil] -3,6-Shi + Ho-Ftil] -1,5-Shi Tae-Shi-Ki 1,5-Imi D-Ku *

0- (3-0-S ^ -yS-D-force 'Lacto' lanoshi)-(1-4) -0 · [(α-Lefcoviranosyl)-(1 → 3)] -Ν- [10-[( 1,3-H-S (Steer α-W) F ・ πH-A-2-I) 3--3,6,9-Tri-Y)]-1,5-テ, 才, キ シ, 5-, ミ, D,-, ル

 0- (3-0-S <<-/ 3-D-force'lactovilanosyl)-(1-4) -0-[(α-Lefcohi'lanosyl HI-3>]-N- [13-[(1, 3-Bis (Halmitoy; Voxy) Floha (2-yl) talent / 14 ·) -3.6,9,12-Tetra talent xatrite ♦ -1,5- 1,5-imino-D-quinoline sodium salt,

 0- (3-0-S force ♦ Lactobilanosyl)-(l 4) -0- [(a-Lefcoviranosi-(1-3)] -N- [5-[(1,3-bis W)) ロ 'ハ -2- ィ) ニ ル ニ ル ニ ル ニ ル ニ ル ニ ル ミ ノ ニ ル ミ ノ ミ ノ ミ ノ ミ ノ-ミ ノ ミ ノ ミ ノ ミ ノ ミ ノ ミ ノ ミ ノ ミ ノ ニ ル ミ ノ· Sodium sodium salt,

0- (3-0-S -D-force lactovilanosyl)-(l ~) -0- [(a-lefcoviranosyl HI-3)] -N- [8- [(1,3-bis (La ゥ roy W 2,7-Rohan'-2-yl) Amin 3, N-Amin 3,6-Sin · Λό , Clay,

 0- (3-0-S ¾-/ 3-D-force 'lactovilanosyl)-(1-4) -0- [(a-Lefcoviranosyl)-(1-3)] -N- [11- [(1 , 3-bis (stea αi; ^ xy) fluoro'-2-yl) oxyca ^ 'nil] amino-3,6,9- Te * sai-ki-1,5-imino-D-coulcitr sodium salt,

0- (3-0-s-? -D-force ♦ lactoviranosyl)-(1 → ⁴ ) -0- [(na-lefcoviranosyl)-(1-3)] -N- [14- [(1,3 -Bis (halumitoy; V * xy) 7-rohan-2-yl) virility; V ** nil] amino- 3.6,9,12-tetraoxate latte * sil]-1,5-Si 'Te * saiki 1,5-imino-D-co' ^ sodium salt.

 Preferred compounds of the present invention include, for example,

 0- (3-0-S n-;? -D-force 'lactovilanosyl)-(1-3) -0- [(a-L-fucohi-lanosyl)-(1-4)] -N- (2.3 -Bis (Sai Rei W Kissi) (D-Hil) -1,5-dimethyl -1,5-imidin D-octyl sodium salt,

 0- (3-0-S ^--D-force * lactovilanosyl)-(l → 4) -0- [(a-L-fucoviranosyl)-(1-3)] -N- (l, 3-bis (Oleoi W xy) 7-rohan-2-y; W xy force W yl)-1,5-site

 0- (3-0-s-force * luck 'lanosyl)-(1 ~ * 4) -0- [(a-L-fucoviranosyl)-(1-3)] -N- [7- (1,3 -Bis (Silver Lewis W) Fr α-Han-2-y; Kissing force; Nil) Heftyl)-1,5-Syte * Slitter-l, 5-imino -D- Quintole sodium salt,

 0- (3-0-S force * Lacto'lanosyl)-(1-4) -0- [(Na-Lefcoviranosyl Ml 3)] -N- [3- [N- [(1.3- ^ キ シ ロ ロ ロ ロ ロ ロ ロ ロ ^ ^ ^ ^ ロ ^ ^ ^ 'Λτ-ntuna sodium thorium salt,

0- (3-0-S ^-/ 3-D-force 'Lactoyl' lanosyl)-(1 ^→ 4) -0- [-L-7 Kovilanosi-(1-1-3)] -Ν- [6- [Ν- [(1,3-bis (ole; xy) fu · π-han-2-yl) oxy-force Λ ^ * nil] amino] hexyl] -1,5- -1,5-Imin D-Petol sodium

0- (3-0-S A *-/ 3-D-) T lactohydranyl [(e-L-fucoviranosyl 3)] -Ν- [8- [Ν- [(1,3-vis才 W W 7 · · · · · · · · 才 · · · 才 才 才 · · · · · -Le sodium

^ &,

0- (3-0-S Λ 3-D-** lactovilanosyl)-(1-4) -0-[(a-lefcopyranosyl)-(1 → 3)]-N- [12- [N-[( 1,3-Bis (Sweet Leoi W Wish) fu α-Han _ ² -Will) Sweet Shikika / 1'N] Amino] Te * Sil] -1,5-S * Teoxy-1,5 -Imin D-quinoluna sodium salt. The compound [I] of the present invention can be produced, for example, by the following method.

 I. Synthesis of compound [I] of the present invention

(a) When A is-(CH ₂ ) m-:

2A)

Compound of the present invention

 o = c

し "—OR⁶

"—OR ⁶

 (2B) (2B ')

 (Wherein, R, Rl, R2, Ra, Rb, and m are as defined above. R is an integer of 0 to 11). The compound of the above general formula (1) and the general formula (2A) or (2B) Alternatively, the compound [I] of the present invention can be produced by subjecting a compound of the formula (2B ′) to Liaoyu-alkylation. Specifically, for example, it can be produced by performing reductive alkylation with sodium cyanoborohydride. As a reaction solvent, methanol, water, tetrahydrofuran, Ν, Ν-dimethylformamide, and the like can be used. For example, under a weakly acidic cow such as acetic acid, 1 to 1 mol of the raw material (1) is used. The reaction can be carried out in a temperature range of 3 mol, preferably 1.5 to 2 mol, 1 to 24 hours, and 0 ° to 100.

(b) When A is-(CH ₂ ) n-NRe—cO-0-:

 o

 II

Raw material () OHC- (CH ₂ ) _p -NC-0-R Compound of the present invention [

 I

R ^e

 ()

 (Wherein, R and Re are as defined above. P represents an integer of 1 to 11.)

As in the above formula, the raw material (1) and the compound of the general formula (3) are reduced according to the above (a), The compound [I] of the present invention can be produced by performing a selective alkylation reaction.

(c) When A is -CO-0-:

 O

 Raw material (1) + Y-C-0-R → "Compound of the present invention"

()

 (In the formula, R is as defined above. Y is a group capable of activating a carbonyl group. Examples thereof include an imidazolyl group, halogen such as fluorine, chlorine, bromine and iodine, and a phenoxy group. it can. )

 As shown in the above reaction formula, the compound of the present invention is obtained by reacting the compound of the raw material (1) and the compound of the general formula (4) in a solvent, for example, in a temperature range of 0 to 100 for 1 to 48 hours. [I] can be produced. Examples of the reaction solvent include Ν, Ν-dimethylformamide, pyridine, toluene, tetrahydrofuran, and chloroform.

(d) When A is-(CH2) n-CO O-:

 o

Raw material (1) + OHC- (CH2) _p -C-0-R-one compound of the present invention [I]

 ( Five )

 (Wherein, R and p are as defined above.)

The compound (I) of the present invention is produced by subjecting the raw material (1) and the compound of the general formula (5) to a reductive alkylation _J ^ according to the above (a) as in the S formula. can do.

(c) When A is-(CH2) n-0-:

Raw _{(1) + OHC- (CH 2} ) p -0-R The compounds of formula

6)

(In the formula, R and p are as defined above.)

As in the above reaction formula, the raw material (1) and the compound of general formula (6) are converted according to the above (a). The compound [I] of the present invention can be produced by performing an elementary alkylation reaction. (When A is -C2H4- (OC ₂ H4) _y -OCH2-COO-:

Raw _{(1) + OHC-CH 2} - (OC 2 H 4) y-OCH 2 -COOR - ^ present compound [E]

 (7)

 (Wherein, R and R have the same meanings as described above. Y represents an integer of 0 to 3.)

 As in the above reaction scheme, the compound (I) of the present invention is produced by subjecting the raw material (1) and the compound of the general formula (7) to a reduction alkylation reaction according to the above (a). be able to.

(g) A _{is, -C 2 H 4 - (OC} 2 H 4) For _z -NR * -CO Monument:

Raw material (1) + OHC-CH ₂ (OC ₂ H ₄ ) _z -NR ^e -COOR ----Compound of the present invention [I]

 (8)

(In the formula, R and ^Re are as defined above. Z represents an integer of 1 to 4.)

 As in the above reaction formula, the compound (I) of the present invention is produced by subjecting the raw material (1) and the compound of the general formula (8) to a reduction alkylation reaction according to the above (a). Can be.

(h) Others: In the above-mentioned production methods (a) to ( _e ), each of Ra and Rb is a saturated or unsaturated aliphatic hydrocarbon group, and A is — (CH ₂ ) m- When manufacturing this month's compound [I], which is 1- (CH ₂ ) n-NRe-CO-0- or 1- (CH ₂ ) n-0-, the galactose residue of the raw material compound (1) Each reaction is carried out with all or part (preferably all) of the hydroxyl group of the thiol group and the molanolin residue protected by the acyl group, and then deprotected by an alkali such as sodium methylate by a conventional method. To produce the compound [I] of the present invention. Here, the “acyl group” is used as a water reservoir, and includes, for example, an acetyl group, a benzoyl group, and a levulinyl group.

 I I. Synthesis of raw materials

 (a) Synthesis of raw material ^ ^ compound (1)

The compound (1) is described in, for example, PCT WO93 / 15098, PCT WO95 / 26970, PCT / JP96 / 01 I46, Japanese Patent Application No. 7-155776, and Japanese Patent Application No. 7-165122. It can be manufactured according to. For example, it can be produced according to the following synthesis scheme. R5 »p Boc: benzyloxycarbonyl

R ²⁰ O Me: methyl

 OH

 Ει; ethyl

Pd-Black, H ₂

EtOH-AcOH g ^{08 Z} , H OBz

 CSA: DL-Camphor 10-sulfonic acid

NaOMcMeOH THF: Tetrahidrofuran

 DN4F.N.N-Dimethylformamide Original) IBM Rider (1)

[In the formula, one of R10 and R20 represents H, and the other represents -D-force'lactovilanosyl. Rll R21, one of which is 2,6-S 0-Soil-/?-D-force * Lactobilanosyl, the other is 2,34-Tri-0-S Represents R3 R4 represents one of 2,6--0-one 'pile-3-0-ethoxy Wnylmethyl-3-D-force' lactovilanosyl, and the other represents 234-tri-0-hexyl- represents α-lefcoviranosyl. R ⁵ Ro is one of 4-O-yl -2,6-cy-〇- へ-* '' pile- /?-D-; T lactoyl 'lanosyl, and the other is 2,3.4-f '/-0-h-n-le-o-lefcoviranosyl. One of R50 and R60 represents 4-0-acetyl-2,6-di--0-hex-pyn-3-0-s β-D-force lactobilalnarium salt and the other power , 3,4-Tri-0-hexyl-a-L-fucohilanosyl. R51, R61 are either 4-0-Wall -2,6-S-P-P-S-P-S-S-S And the other represents 2,3,4-tri-0-hexyl-α-refcol. One of R ⁵² and R62 represents 4-O-tol -2,6-di-O-Hen-Pile-3-0-Methylsphinico-?-D-force'Lactobiranosyl, and the other represents 2,3 Tri-0-hexyl-α-L-fucoviral. One of R7 and R8 represents a- to 7-covilanosyl, and the other represents 2,6-di'-0-hexyl-3-O-ethoxycarbonyl Wnylmethyl-β-D-force 4-0-a "t -2,6-c '-0-h' pyr-3-0-s V *-β force * Lac 'lanosyl sodium salt, 4-0-a W -2,6-S -'- 0-Hen-S-yl-3-0-Phospho-D-force Lactral or 4-0-W-L-2,6-S-H-S 'Yl-3-0-methodine sphinico-β-Ό-force, representing sodium lactovyranosyl.]

 Starting material a can be obtained, for example, by the methods described in PCT WO95 / 01361, PCT WO95 / 06057, and Japanese Patent Application No. 7-65468. The substance b can be obtained, for example, by the method described in the literature (H. Lonn. Carbohydr. Res., 139, 105-113 (1985)). The production from the starting material a to the substance c can be performed, for example, according to Reference Examples 1 (1) to (4) and Reference Examples 2 (1) to (3) described later.

 (b) Synthesis of starting compounds (2A) (2B) (2B ')

 The starting compounds (2A), (2B) and (2B ') are described in PCTW094 / 19314, page 48 reference example 1, page 50 reference example 3, page 53 reference example 5, and page 54 reference example. An alcohol derivative R-OH (9) (R is as defined above) which can be produced according to the description of 6 etc. is converted to a suitable oxidizing agent, for example, dimethyl sulfoxide (DMS0), Ν, Ν'-dicyclohexylcarpoxide It can be manufactured by oxidizing with imid (DCC), pyridinium chromate, and Dess-Manin reagent.

 (c) Synthesis of starting compound (3)

 Alcohol derivative 誘導 体) ΐ ^ -Ν ^^ 酸化 oxidation

_{R'OH (9) HO- (CH 2} ) n -NC-0-R material _{(3 ii) HO- (CH 2} ) B -NHR e

(Wherein, R, Re, and _n are as defined above.) The starting compound (3) can be produced, for example, according to the above reaction formula.

 The alcohol derivative (9) is reacted with, for example, Ν, Ν'-carbonyldiimidavour in a solvent such as pyridine, DMF (N, N-dimethylformamide), THF (tetrahydrofuran) at Ot: ~ 100. By doing so, an imidazole derivative can be obtained. In addition, the alcohol derivative (9) is reacted with phenyl carbonate and chloroform in a solvent such as chloroform and 0 to 150 at 0 to 150 in the presence of a salt such as pyridine or triethylamine to form a phenyl carbonate derivative. Obtainable. By reacting an imino alcohol derivative with these imidabule derivatives or fuunyl carbonate derivatives in a solvent such as DMF, pyridine, toluene, benzene, THF at 0X to 150, a ketolbamate can be obtained. In addition, a base such as triethylamine may be added to promote the reaction.

 The carbamate is converted to a suitable oxidizing agent, for example, dimethylsulfoxide (DMSO) -N, N-dicyclohexylcarbodiimide (DCC) in benzene, or pyridium chromate in chloroform, Dess-Martin The aldehyde form of the raw material conjugate (3) can be obtained by oxidizing at 0X: to 50 by a method such as a reagent.

 (d) Synthesis of starting compound (4)

 The starting compound (4) can be produced, for example, by reacting the alcohol derivative R-OH (9) with Ν, Ν′-carbodidiimidazole, phenyl carbonate, or phosgene.

 (e) Synthesis of starting compound (5)

Al ^ ^ derivative RO (C _{H2) D} -COOH 9 i) Deprotection

R-OH (9) R * 0- (CH ₂ ) _n -C-0-R —— -Raw material (5)

^{00 (2} ii) oxidation

 (In the formula, R and n are as defined above. R * represents a water-protecting group, and examples thereof include a benzyl group, a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, and a levulinyl group. Can be.)

The starting compound (5) is obtained, for example, by subjecting an alcohol derivative (9) and a hydroxycarboxylic acid derivative having a protected hydroxyl group to DMF, dichloromethane by DCC or the like according to the above reaction formula. Condensates at temperatures between 0 and 100 in solvents such as dichloromethane, chloroform and THF. If necessary, the reaction can be promoted by adding an appropriate catalyst, pyridine, N, N-dimethylaminoviridine or the like. The compound (5) can be produced by deprotecting the protecting group of the obtained compound by a conventional method and oxidizing it with a suitable oxidizing agent, for example, DMSO-DCC, pyridinum chromate, or Dess-Martin reagent. it can.

 Further, it can be produced by the following method.

R * O- (CH ₂ ) rrC00H ► R * O- {CH ₂ ) n-C0CI alcohol derivative R * 0—H ₂ ) rr "COCI D

u. -R * 0- (CH ₂ ) rrCOOR raw material (5)

^R OH 0) Base 2)

 (Wherein, R n is as defined above. R * is a protecting group for water (eg, benzyl group, t-butyldimethylsilyl group,, t-butyldiphenylsilyl group, levulinyl group, etc.))

 The hydroxycarboxylic acid derivative having a protected hydroxyl group is mixed with thionyl chloride, phosphorus trichloride, phosphorus pentachloride, quinolyl chloride or the like according to the above reaction formula, and if necessary, in an inert solvent such as benzene at room temperature. Can lead to acid chloride under conditions of reflux. At this time, pyridine or the like (hereinafter abbreviated as HMPA) may be added to DMF or hexamethylphosph Φ-triami as a reaction catalyst. The obtained acid chloride is combined with an alcohol derivative (9) and an appropriate solvent, for example, a base such as pyridine, triethylamine or dimethylaniline in a solvent such as chloroform, dichloromethane, pyridine, ether, benzene or THF DMF. In the presence of — 10X: After condensation between ~ 50, the ί¾¾ group is deprotected by removal and a suitable oxidizing agent, such as DMSO-DCC, bichromium bichromate, Dess-Martin test The compound (5) can be produced by oxidizing with a drug in a solvent such as chloroform, dichloromethane, benzene, and acetonitrile at 0X to 60.

 (f) Synthesis of starting compound (6)

Al _{誘導 体 ul} derivative _Ha ,. _{(CH OOR} ..

R-OH (9) R " OOC- (CH 2) D-0-R material (6) p ii) oxidation (Wherein, R and p are synonymous with so-called self. R ′ ′ represents alkyl. Hal represents fluorine, chlorine, bromine, or iodine.)

 The starting compound (6) is obtained, for example, by reacting an alcohol derivative (9) with a halogenated ester derivative in the presence of a base such as sodium hydride according to the above reaction formula. Produced by reducing the alcohol with a reducing reagent, for example, lithium aluminum hydride, and oxidizing it with an appropriate oxidizing agent, for example, DMSO-DCC, viridinium chromate, or Dess-Martin reagent. be able to.

 (g) Synthesis of starting compound (7)

Alcohol derivative _{R. 0. (C2} „ _{40) y} . _CH2C02H 9

R-OH (9) '- RO- (C 2 H 4) y-CH C-0-R

 I i) Deprotection

 (ii) Raw materials (7)

 (In the formula, R and y are as defined above. R * is a hydroxyl-protected group (eg, benzyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, levulinyl group, etc.))

 The starting compound (7) is prepared, for example, by reacting an alcohol derivative (9) with a hydroxycarboxylic acid derivative having a protected hydroxyl group by DCC or the like according to the above reaction formula using a solvent such as DMF, dichloromethane, chloroform, THF, or the like. Medium, O: condenses at a temperature of ~ 100. If necessary, a suitable catalyst, pyridine, N, N-dimethylamino pyridine or the like can be added to accelerate the reaction. The compound (7) is produced by deprotecting the protecting group of the obtained compound by a conventional method and oxidizing it with an appropriate oxidizing agent, for example, DMSO-DCC, pyridinium chromate, or Dess-Martin reagent. can do.

Further, it can be produced by the following method. R »0 (C ₂ H ₄ 0) y-CH ₂ COOH ^soa 2, etc _R * _O (C ₂ H ₄ O) y-CH ₂ C0Cl alcohol derivative

ROH (9)

 Raw materials (7)

 (In the formula, R and y have the same meanings as described above. Is a hydroxyl-protecting group (eg, benzyl group, t-butyldimethylsilyl group, tert-butyldiphenylsilyl group, levulinyl group, etc.))

 Mix the hydroxycarboxylic acid derivative protected with water with thionyl chloride, trichlorine chlorin, phosphorus pentachloride, oxalyl chloride, etc. according to the above reaction formula, and in an inert solvent such as benzene if necessary. However, it can be led to an acid chloride under the conditions of room temperature to high pressure. At this time, DMF, HMPA, pyridine or the like may be added as a reaction catalyst. The obtained acid chloride is combined with an alcohol derivative (9) in an appropriate solvent such as chlororum, dichloromethane, pyridine, ether, benzene, THF, DMF, or the like, and pyridine, triethylamine, dimethylaniline, or the like. In the presence of a base, — 1 O: After condensing between ~ 50, the protecting group is deprotected by a conventional method, and a suitable oxidizing agent, for example, DMSO-DCC, pyridinium chromate, Dessess -The starting compound (7) can be produced by oxidizing between Ot: to 6 in a solvent such as chloroform, dichloromethane, benzene, and acetonitrile using a Martin reagent or the like.

 (h) Synthesis of starting compound (8)

 Alcohol derivatives i) ¾ ^

― _Λ ,, soidazole

R-OH "9) ^ HO -C 2 H 4 - (OC.H 4) NR * R

_{ii) HO-C 2 H 4} - (OC, H 4) z-NHR e

 Oxidation raw materials (8)

(Wherein, R, Re, and _z have the same meanings as described above.) The starting compound (8) can be produced, for example, according to the above formula J¾. The alcohol derivative (9) is reacted with, for example, Ν, Ν'-carbonyldiimidazole and pyridine, Ν, Ν-dimethylformamide (DMF), tetrahydrofuran (THF), etc. at a ratio of 0: to 100. As a result, an imidazole derivative can be obtained. The alcohol derivative (9) is obtained by subjecting the alcohol derivative (9) to a salt such as pyridine or triethylamine in a solvent such as phenyl carbonate and chloroform, DMF, etc. at Ot: O150 to obtain a phenyl carbonate derivative. be able to. By reacting the imidazole derivative or phenyl carbonate derivative with an amino alcohol derivative in a solvent such as DMF, pyridine, toluene, benzene or THF at 0X to 150, a olebamate can be obtained. In addition, a base such as triethylamine may be added to promote the reaction.

 The above olebamate is oxidized with a suitable oxidizing agent, for example, DMSO-DCC in benzene, or pyridium chromate in chloroform, Dess-Martin reagent at Ot-50 to obtain the starting compound (8 ) Can be obtained.

 The pharmaceutically acceptable metal salt of the compound [I] of the present invention can be prepared by the method for producing the compound of the present invention. In addition, for example, the present invention of a free acid can be passed through a suitable ion exchange resin. They can also be manufactured.

 The compound of the present invention thus produced can be produced in a manner known per se in the form of a free acid or a metal salt, for example, by condensation, greed conversion, phase transfer, solvent extraction, crystallization, fractionation. Simple purification can be performed by chromatography or the like.

 As is clear from the test examples described below, the compound of the present invention has a favorable antagonistic action on selectin (E, P, L) and a cell adhesion inhibitory action. A pharmaceutical composition that is effective for the treatment of thrombosis associated with i¾ or inflammation, rheumatism, ischemia, reperfusion injury, asthma, infectious diseases, immune diseases, AIDS, cancer, or other therapeutic agents Can be. Further, since the toxicity of the compound of the present invention is low, the safety of the compound of the present invention for animals including humans can be expected to be high.

When the compound of the present invention is administered as a medicament, the compound of the present invention is used alone or in a pharmaceutically acceptable non-toxic and inert carrier, for example, 0.1% to 99.5%, preferably 0.5% to 90%. Can be administered to animals, including humans, as a pharmaceutical composition containing

 As the carrier, one or more solid, semi-solid, or liquid diluents, fillers, and other formulation aids are used. The pharmaceutical composition according to the present invention is desirably administered in a unit dosage form. The composition of the present invention can be administered orally, intra-tissue (eg, intravenous injection), topical (eg, transdermal, ophthalmic, nasal, etc.) or rectally, with intra-tissue administration being particularly preferred. Needless to say, it is administered in a dosage form suitable for these administration methods.

 The dose of the compound of the present invention as a medicament is desirably adjusted in consideration of the patient's condition such as age and weight, the administration route, the nature and degree of the disease, the indication, the compound of the present invention to be selected, and the like. In the case of administration into a tissue, the amount of the active ingredient of the compound of the present invention for an adult is usually 100 mg to 3 gZ / day, preferably 500 mg to 1 g / day. is there. In some cases, lower doses may be sufficient, and conversely, higher doses may be required. It can also be administered in divided doses two to three times a day.

 Oral administration is carried out in solid or liquid dosage units, such as powders, capsules, powders, dragees, granules, powders, suspensions, solutions, syrups, drops, sublingual tablets, and other dosage forms be able to.

 A powder can be produced by making the compound of the present invention finely divided. Powders can be prepared by admixing the compound of the present invention with a suitable fine particle and then mixing it with a similarly finely divided pharmaceutical carrier, for example, an edible compound such as starch and mannitol. If necessary, flavoring agents, preservatives, dispersing agents, coloring agents, flavors and the like can be mixed.

Capsules are first prepared by filling powdered powders, powders or granules as described in the section above into granules as described in the section on capsules such as gelatin capsules. be able to. Lubricants and fluidizers, such as colloidal silica, talc, magnesium stearate, calcium stearate, and solid polyethylene glycol, are mixed with the powder and then filled. You can also. Disintegrants and solubilizers such as carboxymethylcellulose, Addition of calcium cellulose, low-substituted hydroxypropyl pill cellulose, croscarmellose sodium, sodium carboxymethyl starch, calcium carbonate, sodium carbonate, etc., improves the efficacy of the drug when a power busel is taken can do. Further, a fine powder of the compound of the present invention can be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, or a surfactant, and wrapped with a gelatin sheet to prepare a soft capsule.

 Tablets can be made by adding an excipient to form a powder mixture, granulating or slugging, then adding a disintegrant or lubricant and compressing. The powder mixture is prepared by mixing an appropriately powdered substance with the diluents and bases described above and, if necessary, mixing agents (e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, gelatin, bolivyl pyrrolidone, Polyvinyl alcohol, etc.), dissolution dispersing agents (eg, paraffin, etc.), resorbents (eg, quaternary salts) and adsorbents (eg, bentonite, kaolin, dicalcium phosphate, etc.) it can. The powder mixture is first mixed with a mixing agent such as syrup, Nada powder paste, gum arabic, cellulose solution or

The powdered substance solution can be mixed, mixed by visual agitation, dried and ground to form granules. Instead of granulating the powder in this way, it is also possible to first apply a tableting machine and then crush the incompletely formed slug into granules. The granules thus produced can be prevented from adhering to each other by adding stearic acid, stearic acid salt, talc, mineral oil or the like as a lubricant. The lubricated mixture can then be tableted. The uncoated tablet thus produced can be coated with a film coating.

 Further, the compound of the present invention can be directly tableted after being mixed with a fluid inert carrier without going through the granulating or slugging steps as described above. Transparent or translucent protective coatings consisting of a shellac hermetic coating, coatings of sugar or polymeric materials, and polish coatings made of wax can also be used.

Other oral dosage forms such as solutions, syrups, troches, and elixirs -The dosage can be in dosage unit form so that the determination contains a predetermined amount of the compound of the present invention. Sylobes can be produced by dissolving the compound of the present invention in an appropriate aqueous flavor solution, and elixirs can be produced by using a non-toxic alcoholic carrier. The turbidity agent is formulated by dispersing the compound of the present invention in a non-toxic carrier. Solubilizers and emulsifiers (eg, ethoxylated isostearyl alcohols, boroxyethylene sorbitol esters), preservatives, flavor enhancers (eg, palmit oil, saccharin), etc. are also required Can be added according to

 If desired, dosage unit formulations for oral administration can be micro-assisted. The formulation can also provide an extended period of action or sustained release by coating or embedding in molecular wax.

 Administration into tissues can be carried out using liquid dosage unit forms for subcutaneous, intramuscular or intravenous injection, for example, in the form of solutions or suspensions. These can be prepared by suspending or dissolving a fixed amount of the compound of the present invention in a non-toxic liquid carrier suitable for injection, such as an aqueous or oily medium, and then sterilizing the suspension or solution. Can be manufactured. Non-toxic salts or salt solutions can be added to make the injection solution isotonic. Furthermore, stabilizers, preservatives, emulsifiers and the like can be used in combination.

 For rectal administration, the compounds of the present invention are soluble in low-melting water and are insoluble in solids, such as polyethylene glycol, cocoa butter, semi-synthetic fats and oils (such as Witebsol, registered trademark), higher esters (such as myristyl palmitate). Ester) and a suppository produced by dissolving or turbidity in a mixture thereof.

In addition, topical administration can be carried out in the form of ointments, cataplasms, blasters, patches, liniments, eye drops, and transdermal preparations. The preparations include fats, fatty oils, lanolin, petrolatum, glue, laffine, wax, resins, plastics, glycols, higher alcohols, glycerin, water, emulsifiers, suspending agents or other suitable additives. The compound of the present invention may be added to or mixed with the starting materials or based on these materials. The poultice is prepared by mixing the powder of the present invention with glycerin, water or other suitable liquid substance, It can be produced by adding essential oil components. The plaster is made from fat, fatty oil, fatty acid soot, wax, resin, plastic, refined lanolin, rubber, or a mixture thereof, or based on these, and uniformly mixed with the compound of the present invention. can do. Ophthalmic solutions can be produced by dissolving or suspending a certain amount of the compound of the present invention in sterile purified water, physiological saline, distilled water for injection, or the like, to a constant volume. BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples, and Test Examples. The measurement temperatures of specific rotation were all 20.

Reference Example 1 0- (3-0-S yS -D-force 'lactovilanosyl)-(l ^→ 3) -0 C (α-Lefcolanosyl)-(1 → 4)] -1,5-S' Τ Synthesis of 1,5-imi-D-quinol (Compound 9)

 (1) 0- (3,4-0-Iso 7 'π-Hyrite * -β-force * Lactobilan)-(1 → 3) -Ν-He Synthesis of 1,5-imino-D-c '; V "control (compound 1)

 0-β-D-force * Lactobilanosyl- (1-3)-1,5-theoxy-1,5-imino-D-knitol (100g.0.307mol), sodium carbon (38.7g , 0.461 mol) was dissolved in water (1000 ml), and chloroform (1000 ml) was added, followed by vigorous stirring. Then, benzyl chloride 1'-nil chloride (132 ml, 0.924 mol) was gradually added dropwise while cooling with ice, and the mixture was vigorously stirred at room temperature. The reaction solution was poured into a separatory port;! Jdf was washed twice with chloroform (1000 ml), adjusted to pH 3 with 2N-HC ice solution, and concentrated under reduced pressure. Methanol (500 ml) was added to the residue to separate insolubles. Allow the solution to stand at room temperature for 2 days.

(57.6 g, 40.8%). The crude crystals (57.6 g, 0.125 mol) were dissolved in Ν, Ν-methylformamide (1000 ml), and p. Ensenoic acid 1 (4.77 g, 25.08 mmol), 2,2-methoxymethyl Rohan (30.9 ml, 0.25 mol) was added, and the mixture was stirred at 60 t: for 3 hours. After neutralization with trietamine, the mixture was strained under reduced pressure. The residue was purified using silica gel column chromatography (Wakogel C-300 (registered trademark, the same applies hereinafter), 1 kg, g. Mouth form: methanol = 20: 1 to 16: 1). Compound 1 was obtained as a colorless syrophe '(39.3 g, 62.8%).

 FABMS (pos.) 522 [M + Na] ♦

(2) 0- (2,6-*-O-N-Syl-3,4-0-iso-fluoro-*-β-D-force lactovilanosyl)-(1-3) -2,6-S * To -0- Synthesis of Hexinoxyl-1,5-Te * Synthetic 1,5-imid D-knitol (Compound 2)

 Compound 1 (39.3 g, 78.68 mmol) was dissolved in viricin (500 ml), and benzoic anhydride (89 g, 0,393 mol) and 4-methylaminoricin (4 g, 32.74 mmol) were added. : The mixture was stirred for 2.5 hours. Methanol was added to remove excess benzoic anhydride, and the solution was subjected to vacuum crimping. The residue was dissolved in chloroform (500 ml), washed with a dilute salt solution of pH 3 (500 ml), and dried over anhydrous sodium sulfate, followed by crimping under reduced pressure. Ether was added to the residue, and the mixture was filtered to obtain powdery crystals of the title compound 2 (20.5 g, 28.4%).

Elemental analysis value C ₅₁ H ₄₉ N0 ₁₅

 Calculated value (%) C: 66.23, H: 5.45, N: 1.51

 Obtained value (%) C: 66.44, H: 5.27, N: 1.59

 FABMS (pos.) 916 [M + H] *

(3) 0- (2,6-S * -O-Hesyl) -3.4-0-Iso 7-Robilite-β-D-Force * Lac 'Lanosyl)-(1-3)- 0- [(2,3,4-tri-benzoyl- _α -shifucopyranosyl)-(1-4)] -2,6-si * -0- to n-so-yl -N- to * Synthesis of * · nil-1,5-cy'the * oxy-1,5-imine D-knol (Compound 3)

 Compound 2 (8 g, 8.73 mmol) and ethyl 2,3,4-tri- 0-hexyl-2-thi-3-copyranoside (

6.4 g, 19.23 mmol> was azeotropically dehydrated with an appropriate amount of toluene, dissolved in 'ππ methane (250 ml), added with Molexura-4A (15 g), and left at room temperature under an alcohol stream for 1 hour. Stirred. Then, the mixture was cooled to -40, N-succinimide (3.92 g, 17.42 mmol) trifluoromethane acid (0.154 ml, 1.74 mmol) was added, and the mixture was stirred for 2 hours.

 The solution was diluted with dichloromethane and filtered, and / g was washed with a saturated aqueous solution of sodium carbonate (containing sodium sulfate) (150 tnl) and ice water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. . The resulting residue was purified by silica gel column chromatography (Wakogd C-300, 290 g, n-hexane: ethyl acetate = 6: 1 to 3: 1) to give the title as a white foamy solid. Compound 3 (I 1.68 g; 80.3% from compound 2) was obtained.

' 1/2H として Elemental analysis value

'As 1 / 2H

 Calculated value (%) C: 69.84, H: 5.86, N: 1.0

 Obtained value (%) C: 69.73, H: 5.73, N: 1.09

 FABMS (pos.) 1332 [M + H) *

(4) 0- (2,6-si · -〇- '' n 'pile- / 3- -D-force' lactovilanoshi JV)-(1-3)-0- ((2,3,4-tri- 0-He'nshi, Le-a-Lefkobira Nosyl -2,6-S '-O-H''Pile-N-H' * Synthesis of compound (compound 4)

 Compound 3 (11.44 g, 8.59 mmol) was dissolved in 1,4-dioxane (130 ml), a 2N salt solution (50 ml) was added, and the mixture was stirred at 60 for 1.5 hours. Add 100ml of fresh oxane). The reaction solution was reduced under reduced pressure to about 1/3, and acetyl acetate (100 ml) was added. Wash with water (150 ml), sodium carbonate aqueous solution (100 ml) and water (UX) ml), dry over anhydrous sodium sulfate A, and compress under reduced pressure to give the title compound 4 (33 g, 92.3%) as a white foam. Obtained as a solid.

As Elemental analysis _{C 75 H 73 N0 19 '1} / 2HP

 % \ Value (%) C: 69.22, H.-5.73, N: 1.08

 Observed value (%) C: 69.23, H: 5.60, N: 1.15

 FABMS (pos.) 1292 [M + H] +

 (5) 0- (4-0-Wall -2,6-S-Hen *, Pile--D-force ♦ Lactobilanosyl)-(1-3) -0-[(2,3,4- Tori **-a -L-fucohilanosyl)-(1 → 4)) -2,6- * he * nso * il -N-he * shi * Wkisika Λ · nil-1,5 -Synthesis of 1,5-imino -D-c-fj tol (compound 5)

 Compound 4 (10.1 g) was dissolved in hexane (500 nil), and trimethyl acetate (18.5 ml, 148 mmol) and DL-camphor-10-sulfonic acid (170 mg, 0.68 mmol) were added. The mixture was stirred at room temperature for 2.5 hours. The reaction solution was washed with a saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was further purified with distilled water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Lofran (110 ml), methanol (110 ml) and 80% acetic acid (UOml) were added to the obtained residue, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solution was concentrated under reduced pressure, dissolved in dichloromethane (300 ml), washed with a saturated sodium carbonate aqueous solution (300 ml) and distilled water (300 ml), and dried over sodium sulfate. The title compound 5 (10.5 g, 99%) was obtained under reduced pressure.

 FABMS (pos.) 1356 (M + Na)

 (6) 0- (4-0-7W-2,6- * -O-Hen, -3-yl--3-β-D-force, lactovilanosyl)-(1-3) -0- [(2,3,4-tri-0- to * sil-a-L-fucoviranosyl)-(1 "* 4)] -2,6-si, -0-to- Synthesis of sodium 1,5-imino-D-octanol sodium salt (compound 6)

Dissolve 5 (5.9 g) in pyridine (300 ml), add viricinyl sulfur trioxide complex (6.0 g), Time 拢 扦 '. 0 Methanol (65 ml) was added at 1C, and the mixture was stirred for 1 hour. After condensing under reduced pressure, the obtained residue was dissolved in ethyl acetate (300 ml), washed with distilled water (300 mbc2), and sulfuric acid was added. After drying over sodium, the mixture was concentrated under reduced pressure. The obtained residue was dissolved in methanol (50 ml), ion exchange resin Anha'-Ray IR 120B (Na +) (registered trademark, the same applies hereinafter) was added, and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure to dryness, the title compound (5.5 g, 86.9%) was obtained. This was used for the next reaction without further purification.

 FABMS (neg.); 1412 [M-Na]

 (7) Ο- -Ο-λ-/ 3 -D-force 'lactovilanosyl)-(l → 3) -0-[(2,3,4-tri-0-hemane' le-β-refco lanone )-(1 → 4)) -Ν, 6-0-force ^ 'nyl-1,5-cysteine xy-1,5-imin D-quintulnarium salt (compound 7) Synthesis of

 Compound 6 (5.4 g) was dissolved in methanol (270 ml), 28 ml of a methanol solution of sodium methylate was added, and the mixture was stirred overnight at room temperature. After neutralizing the reaction solution with 2 N hydrochloric acid, it was concentrated under reduced pressure, and the residue was washed with a small amount of ether. Methanol (100 ml) was added to the mixture, white insolubles were separated, and the residue was reduced under reduced pressure. The resulting residue was purified by column chromatography (RaChroprep RP18 (registered trademark, hereinafter referred to as)). % → 60% methanol-lunowater elution) to give the title compound 7 (3. Ig, 91.5%).

· 3/2 H として Elemental analysis value

· As 3/2 H

 Theoretical value (%) C.-53.57, H: 5.73, N: 1.56

 Obtained value (%) C: 53.40, H.-5.61, N: 1.68

 FABMS (ncg.) 846 (M-Na)

(8) 0 (3-0--^ -D-forceLactranosyl)-(l ^→ 3) -0-[(a -lefcopyranosyl)-(1-4)] -N.6-0- t * -Synthesis of sodium 1,5-theloxy-1,5-imino-D-cool * sodium salt (Compound 8)

 Compound 7 (3.0 g) was dissolved in methanol (90 ml) and acetic acid (10 ml), and 10% potassium hydroxide (2.8 g) was added. Stirred overnight. Then, the washing water is separated, washed with methanol, the combined liquid and washing liquid are compressed under reduced pressure, and the obtained residue is subjected to column chromatography. Kurafi-(

LiChroprep RP18, eluate; water), and the purified product was desalted with Asilisa'- (force-Trissi; AC110-20) and lyophilized to give the title compound 8 (1.2 g). .

 Specific rotation [σ] D = -14.7 '(c = 0.38, water)

As elemental analysis _{C 19 H JO NNaO l7 S ·} 5/2 0 Theoretical value (%) C: 35.41, H: 5.47, N: 2.17

 Measured value (%) C: 35.16, H: 5.68, N: 2.12

 FABMS (neg.) 576 (M-Na)

(9) 0- (3-0-S / 3-D-force'lactoviranosyl HI-3) -0-[( _α- fucoviranosyl)-(1 ^→ 4)]-1,5-'Teoxy-1, Synthesis of 5-Imin D-Kentole Sodium Salt (Compound 9)

 Compound 8 (1.9 g) was dissolved in a 50% aqueous methanol solution (64 ml), a 2N aqueous sodium hydroxide solution (8.5 ml) was added, and the mixture was stirred at 90 for 6 hours. After completion of the reaction, the mixture was neutralized with a 2N salt solution, concentrated under reduced pressure, and the resulting residue was subjected to column chromatography (IChroprep RP18, eluent; water). After desalting with '-(Catorushi'; AC110-20), the mixture was lyophilized to give the title compound (0.9 g). Elemental analysis value As CuH ^ NO ^ S ■ 3H

 Theoretical value (¾) C: 35.70, H: 6.49, N: 2.31

 Obtained value (%) C: 35.47, H: 6.57, N: 2.33

Example 2 0- (3-0-S-/ 3-D-force, lactovilanosyl)-(l-4) -0- [(a-L-fucohi'lanosyl) -hi ^→ 3)]-1,5- Synthesis of 1,5-imino-D-quinol (compound 16)

 (1) 0- (2,6- シ ♦ -0-Hen, -3,4-0-Isoph 'πH-Li-Ten-β-D-Strength lactovilanosyl)-(1— 4) -2,6-S '-0-H' 'Pil -'- H' 'H' * W Kishika Λ · Nil -1,5-S * Synthesis of tall (compound 10)

0-β-D-force 'Lactobilanosyl- (1-4)-1,5-'Te'-Sixi-1,5-imino-D-co' HK20g, 61.28mmol, Sodium Carbonate (7.74g , 92.2 mmol) in water (200 ml), add H-form (200 ml), add dropwise chloro carboxylic acid (65.8 ml, 461 mmol) while cooling with ice, and mix at room temperature. We stirred vigorously. Then, the reaction solution was poured into a separating funnel; ^ was adjusted to pH 6 with 2N hydrochloric acid, and washed twice with a black hole form. ^ Was reduced under reduced pressure, and 残渣, Ν-methylmethylamide was added to the residue. The insolubles were separated, and the urea solution was concentrated under reduced pressure.赚 was dissolved in Ν, Ν-methyl-1-lumami (300 ml), and 2.3 g of 2,2-dimethyl 7 · loha '^ (15.13 mU23 mmol), ρ · transonic acid l 7 12mniol) and stirred at 60 for 2 hours. After neutralization with triethylamine, the residue was swelled under reduced pressure. The residue was dissolved in phosphorus (350 ml), cooled to -40, and dropwise added, and stirred at the same temperature for 2 hours. After adding 50 ml of methanol and stirring for 30 ^, the mixture was subjected to reduced pressure. The remaining brew was dissolved in cyclomethane and washed with 2Ν hydrochloric acid, saturated sodium carbonate and water. ' The tan a layer was separated by dehydration with anhydrous sodium sulfate, and the resulting solution was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (Rakochi, Wakogel C-300, lkg, ethyl acetate: hexane = 1: 4 to 1: 3) to give 30.4 g (54.0% ) I humiliated.

 Specific rotation [N] D = -11.94 · (c = 0.536, black holm)

Elemental analysis value C ₅₁ H ₄₉ NO ₁₅

 Calculated value (%) C66.88, H: 5.39, N: 1.53

 Actual value (%) C: 66.50, H: 5.41, N.1.59

(2) 0- (2,6-S'-0-Hen * Sil-3,4-0-Isof 'Rohi'Retain'-/--0-Ka'Lactohi'lanosyl)-(1 —4)-0- [(2,3,4-Tri-O-Hensil * L- _α -L-Fucohilanano 1-3)] -2,6-S * -0-Hen ' Synthesis of Nyl-1,5-Te

Compound 10 (15.3 g) and ethyl 2,3,4-tri-0-hexane (12.0 g) were dissolved in dichloromethane (300 ml) in 1,3-lefcoviranone. , Molexura-shifu 4A (20 g) was added, and the mixture was stirred for 1 hour under an air current. Thereafter, the mixture was cooled to -40, and N-io-succinic acid imi (7.5 g) and trif / W-methanoic acid (295 ^ 1.3.3 mmol) were added dropwise, followed by stirring for 1 hour. After neutralization with triethylamine, the molecular sieve '4A was filtered off, and the aqueous solution was washed with saturated sodium carbonate and an aqueous solution of sodium sulfate. The α-methane layer was dehydrated with anhydrous sodium sulfate and separated, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography D Matoku'raffy- (WakogeI C-300, 350 g, n-hexane: ethyl acetate = ₄ ) to obtain 13.8 g of the title compound 11.

 Specific rotation C α) D = -46.60 "(c = 0.575, black-holm)

Elemental analysis value C _7i H „N0 ₁₉

 Calculated value (%) C-.70.31, H-.5.82, N: 1.05

 Obtained value (%) C: 69.69, H-.5.89, N: 1.34

(3) 0- (2,6-si * -0-hexyl-?-D-force ♦ lactoviranosyl)-(l ^→ 4) -0-[(2,3,4-tri-0 -He- * n-le-α-Lefucobyl nosyl)-(1-3)] -2,6-S- -0-He-n-Pile * W-Kiska W-nil- 1,5-S * ♦ Synthesis of 1,5-imino-D-knitol (12)

Compound 11 (13.8 g) was dissolved in 1,4-dioxane (260 ml), 2N salt solution (60 ml) was added, and the mixture was stirred at 60 for 2 hours. The reaction solution was concentrated under reduced pressure to about 1/3, and acetyl acetate was added. Washed with thorium and water. The ethyl acetate layer was separated by dehydration with anhydrous sodium sulfate, and the flow was reduced under reduced pressure. The obtained residue was recrystallized from n-hexane-ethyl acetate M to give Compound 12 (10.9 g) as white powdery crystals.

 Melting point 182-183 "C o

 Specific rotation [a] D = -58.16 * (c = 1.011, black mouth form)

Elemental analysis value as C ₇₅ H _{lNO l9}

 Calculated value (%) C: 69.59, H: 5.84, N.1.08

 Obtained value (%) C: 69.44, H: 5.71. N: 1.42

 (4) 0- (4-0-α-t-le-2,6-di-en-pile- -D-ka * lactovilanosyl Η1 → 4) -0-((2,3,4-tri H * n '' L-a-Lefkohi 'lanosyl)-(1-3)) -2,6-S * H-N'H-N-H \ H Synthesis of 1,5-imino-D-quintol (compound 13)

 Compound 12 (10.0 g) was dissolved in benzene (500 ml), and trimethyl orthoacetate (19 ml) and DL-camp-10-sulfonic acid (170 mg) were added, followed by stirring at room temperature for 3 hours. SJi: The solution was washed with a saturated aqueous solution of sodium carbon, the organic layer was washed with distilled water, dried over anhydrous sodium sulfate, and then compressed under reduced pressure. Tetra-k-drofuran (100 ml), methanol (100 ml) and 80% acetic acid (100 ml) were added to the obtained residue, and the mixture was stirred at room temperature with stirring. The reaction solution was concentrated under reduced pressure at 20 t :, dissolved in dichloromethane, washed with a saturated aqueous solution of sodium carbonate and distilled water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel C-300, 400 g) and eluted with α-form to obtain compound 13 (10.1 g).

Specific rotation [a] D = -56.17. (C-1

として Elemental analysis value

As

 Theoretical value (%) C: 69.31, H: 5.66, N: 1.05

 Measured value (%) C: 69.22, H: 5.68, N: 1.27

 (5) 0- (4-0-Fal -2,6-S '' -0-Hes * yl-3-0-S / V * -β-D-force ♦ Lactobilanosyl)-(1— 4) -0-[(2,3,4-tri-0-he-sil-a-fucoviranosyl)-(1-3)] -2,6-shi ♦ -〇-he * n, pile-Ν · * Nishi * Synthesis of Wnika-1,5'-dimethyloxy-1,5-imine D-quinone sodium salt (Compound 14)

Compound 13 (1.5 g) was dissolved in Ν, Ν-methylmethylamine (22 ml), biline'sulfur trioxide conjugate (4. 加 え) was added, and the mixture was stirred at room temperature for one minute. (45 ml) and stirred for 1 hour. The residue was subjected to silica gel column chromatography- (Wakogel C300, eluent; dichloromethane-methanol, 20: 1). The obtained fraction was dissolved in methanol (30 ml), and ion-exchanged fat //-light IR 120B (Na +) was added.The mixture was stirred at room temperature for 1 hour, and the resin was separated and concentrated under reduced pressure. Dry to give the title compound 13 (4.8 g, 89.1%).

 FABMS (ncg.) 1412 [M-Na]

(6) 0- (4-0-α-t--2,6-sin *, pyr-3-0-s-β-D-force) lactoviranosyl)-(1-4) -0- [(A-fufuviranosyl)-(1 ^→ 3)] -2,6-si'-0-hene, vir-1,5-si'te'ki-shi-1,5-imin D- Synthesis of potassium sodium salt (Compound 15)

Compound 14 (4.2 g) was dissolved in ethanol (125 ml) and acetic acid (25 ml), and activated ',' Rashi 'and' Pmfu 'rusks (5.1 g) were stirred. The mixture was stirred at 551C for 15 hours and contacted. The mixture was separated from water, washed with ethanol, combined with the washing solution and the washing solution, concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography. (WakogdC-300, eluent; Shi ♦ chloromethane: Metall = 10: 1) was subjected to as a compound 15 (2.2 g) was obtained elemental analysis _{C 4S H 50 NNaO 2l S ·} 7 / 2Η 2 0.

 Theoretical value (%) C52.65, Η: 5.25, Ν: 1.28

 Obtained value (%) C: 52.29, H: 4.95, N: 1.34

 FABMS (ncg.) 1008 [M-Na]

(7) 0- (3-0-S ^--D-force 'Lacto'lanosyl)-(1 ^→ 4) · 0-[(.-Shifuco'lanosyl)-(1 ^→ 3)] -1, 5-Site-Synthesis of 1,5-Immine D-C ') V "Toluene Sodium Salt (Egg Compound 16)

 Compound 15 (1.57 g) was dissolved in methanol (40 ml), an appropriate amount of a methanol solution of sodium methylate was added, and the mixture was stirred at 40 X: overnight. After confirming the completion of the reaction by TLC, the mixture was neutralized with 2N hydrochloric acid, reduced to dryness under reduced pressure by jft, and 20 ml of water was added to the obtained residue. Reduce i Jf under reduced pressure, and purify it by applying it to a column of ケ カ ラ ム カ ラ ム カ ラ ム マ ク ク ク ク ク ク ク (LiChroprep RP18, eluent: water), desalting with で ラ イ サ サThe title compound (730 mg) was obtained as a powder.

 Specific rotation [a] D = -35.6 '(c = 0.48, water)

· 3/2 Hpとして Elemental analysis value

· As 3/2 Hp

Theoretical value (%) C: 36.00, H: 5.87, N: 2.33 Measured value (%) C: 36.29, H: 6.10, N: 2.50

 FABMS (neg.) 550 (M-Na)

 Reference Example 3 0- (3-0-phosphon / 3-D-force 'lactovilanone')-(l ~ »)-0- [(na-L-fucoviranosyl 3)] -1,5-cy Synthesis of xy-1,5-imino-D-c

 The above compound can be synthesized by the method described in Example 19 of PCT JP96 / 01810.

 Reference Example 4 0- (3-0-phos- / SD-force, lactovilanosyl)-(1-3) -0- [(α-L-fucoviranosyl)-(1 → 4)] -1,5-si Synthesis of Te-Shi-Xi-1,5-Imin D-C '/ V "

 According to the method described in Example 19 of the specification of PCT JP96 / 01810, the compound was prepared as follows: 0- (4-0-a "tf--2,6-s'" * n'pile-force ♦ lactoviranosyl )-(1-3) -0- [(2,3,4-triphenyl-a-L-7-copyranosyl)-(1 → 4)] -2,6-cy It can be synthesized from pile-N-hexyl-1,5-dimethyl-1,5-imino-D-ethanol.

 Reference Example 5 0- (3-0-Methyl sphinico-; SD-forceLactobilanosyl)-(1-3) -0- [(aL-7 Koviranosyl)-(1 → 4)]-1,5-Si * Synthesis of 1,5-imino-D-cactol

 The above compound can be synthesized by the method described in Example 1 of PCT JP96 / 01810.

 Reference Example 6 0- (3-0 meth JV * sphinico- / 3-D-force ♦ lactoviranosyl)-(1-4) -0- [(a-L-fucoviranosyl)-(1 → 3)]-1, Synthesis of 5-site * 1,5-imine D-quintitol

 The above compound can be synthesized by the method described in Example 11 of PCT JP96 / 01810.

 Reference Example 7 0- (3-0-force * quinmethyl-? -D-force 'lactoviranosyl)-(1 → 3) -0- [(α-lefcoviranosyl 4)] -1,5-di'-ethoxy- Synthesis of 1,5-imine D-co * Λό Ηΐ

 The above compound can be synthesized by the method of Example 3 described in the specification of PCT / JP 6/01146.

Reference Example 8 0- (3-0-force; xymethyl- -D-force 'lactoviranosyl)-(l → 4) -0- [(a-lefucoviranosyl)-(1 → 3)]-1,5-si' 7 * years old-1,5-imino-D-quint The above compound can be synthesized by the method of Example 1 described in the specification of PCT / JP96 / 01146.

 Reference Example 9 Synthesis of 2,3-S'-0-

 PCT W094 / 19314, page 48, page 48 Reference Example 1 was prepared by dissolving 1,2-c * -0-oleic'lizerol (l.Og) in anhydrous toluene (10 ml). , Si, methylsoxy (10 ml), viricin * (0.14 ml), trif-W-prosuccinic acid (0.07 ml) and ci'cyclohexylca ^ 'si'imide (1.04 g) were added and stirred at room temperature overnight. . Then, hexane (30 ml) was added to the reaction mixture, and the precipitated insoluble material was filtered off. The hexane layer was washed with water, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. did. The resulting residue was purified by column chromatography (Wakogel C300, eluent: stepwise elution from n-hexane to 2% ethyl acetate / π-hexane), and the eluted fraction was concentrated. Dry to give the title compound (1.07 g, 97%).

 Reference Example 1 0 1-[[1,3-S (Shi-reo-ixi) fu · π-han-2-yl] swift / 1 · l] Imita · ν

し、 クロロホルム層を硫酸ナトリウムで乾燥後、 减圧で谩縮を行い、 標記化合物 (280mg)を得た。 PCT W094 / 19314, p. 54, p. 54 Reference Example 6 was prepared by dissolving 1,3-c'-04 leoink lysyl (245 mg, 0.39 mmol) in lysine (2 ml). Ν, Ν'-carbo * ni * imi ミ pearl (70 mg, 0.43 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Then, after distilling off the viricin under reduced pressure,

Then, the chloroform layer was dried over sodium sulfate, and then subjected to compression under reduced pressure to obtain the title compound (280 mg).

 Example 1 Synthesis of 2-0- (formylethyl) carha'moyl-1,3-si'-0-reacted-Irk ♦ Lyserol (Ech Compound 20)

 (1) Synthesis of 7π /, 2-N-one-1,3-short (Compound 17)

 The dihydroxyacetone dimer (27.4 g) was suspended in cyclohexane (800 ml), and a solution of maleic acid (171.8 g) in cyclomethane (60 ml) was added. Add 'methylaminovirine' (9.3 g), and add a solution of 'cyclohexyl) Μ · シ' imi (hereinafter abbreviated as DCC: 138 g) in 'chloromethane (100 ml) over 30 30. . After the dropwise addition, the temperature was returned to room temperature, and the mixture was stirred overnight. After removing the precipitated urea, the chloromethane layer was washed with a 5% solution of disodium phosphate, dried over sodium sulfate, and compressed under reduced pressure. The obtained residue was recrystallized from methanol to obtain 169 g of Compound 17 as a white crystal.

 FABMS (pos.) 619 [M + H] ♦

(2) Synthesis of 1,3-cyl '-Ο-oleoylok' lyserol (compound 18) Compound 17 (164 g) was dissolved in THF (3 L) and water (0.2 L), 10% acetic acid (165 ml) was added under ice-cooling, and sodium borohydride (15 g) was added. Stirred. After adjusting the pH to 4 by adding acetic acid, the solution was concentrated under reduced pressure to a volume of about 1/5. The residual brew was dissolved in n-hexane, washed with acetonitrile, and the n-hexane layer was concentrated under reduced pressure to obtain an oily compound 18 (161 g).

 FABMS (pos.) 621 [M + H] ♦

 (3) Synthesis of 2-0- (3-Hyd.xif'.Hil) Kalha * Moyl-1,3-S * -0-year-old oil lysyl (compound 19)

 Compound 18 (154 g) was azeotropically dried with a small amount of lysine, and arsenic (500 ml) was added. The Ν, Ν'-force, nin'imita, and pal (44.2 g) were added. ) And stirred at room temperature overnight. To the reaction mixture was added 3-aminopropyl alcohol (37.3 g), and the mixture was stirred at room temperature for 3 hours. After the reaction solution was ffi-concentrated, dichloromethane was added thereto, washed with an ice-cooled dilute solution, an ice-cooled sodium bicarbonate solution, and water, and then the sodium chloromethane layer was diluted with sodium (½1) and concentrated under reduced pressure. The obtained residue was slightly prepared using silica gel column chromatography Raffy (Wakogel C-300, 25% ethyl acetate-n-hexane elution) to obtain the title compound 19 (I35 g).

 (4) Synthesis of 2-0- (2-formylethyl) carha * moyl-1,3-cy

 Compound 19 (I 15.5 g) was dissolved in hexane (500 ml), and methyl chloride (600 ml) was added.Hydroxyl (19ηι1) and Trif WO acetic acid (9.5 ml) were added under ice cooling. Was added. A solution of DCC (99 g) in hexane (100 ml) was added dropwise under ice-cooling for 3 minutes, then the temperature was returned to room temperature, and the mixture was stirred overnight. Hensene (1.51) was added to the reaction solution, and the mixture was washed with ice-cooled diluted hydrochloric acid, ice-cooled sodium bicarbonate solution, and water, and the organic layer was dried over sodium sulfate. The residue obtained by condensing under reduced pressure was purified by silica gel column chromatography (Wakogel C-300, eluted with 20% ethyl acetate-n-hexane) to give the title compound 20 (79 g ).

As C "H ₇₉ N0 _7; Elementary analysis

 Theoretical value (%) C: 71.72, H: 10.78, N: 1.95

 Measured value (%) C: 71.40, H: 10.66, N: 1.96

 Example 2 Synthesis of 2-0- (2-formylethyl) carha'moyl-1,3-c * -0-lauguchi-iruku * lysole

 Synthesis was performed in the same manner as in Example 1 except that lauric acid was used instead of oleic acid.

として Elemental analysis values;

As

Theoretical value (%) C: 66.99, H: 10.34, N: 2.52 Obtained value (%) C.66.91, H: 10.20, N.2.64

 Example 3 Synthesis of 2-0- (2-formyl tyl) carno, 'moyl-1,3-di-O-hexanoylc, lycerol

 Synthesis was performed in the same manner as in Example 1 except that hexanoic acid was used instead of oleic acid.

Elemental analysis: _{Cl 9} H ₁₃ N 0 ₇ · 1 / 2H ₂₀

 Theoretical value (%) C: 57.56, H.-8.64, N: 3.57

 Obtained value (%) C: 57.89, H: 8.45, N: 3.57

 Example 4 2-0- (5-holmethylene);, 'moyl-1,3-c'-Ο-year-old iruku * Lyserol synthesis

 In the same manner as in Example 1 except that 6-aminoaminohexanol was used in place of 3-aminophenyl alcohol.

 FAB MS (pos.); 762 [M + H] *

 Example 5 2-0-U1-formylpente'sil) carha'moyl-1,3-cy'-0-year-old Irk * Synthesis of Licerol

In Example 1, 12-amino 1-dote ^Φ phenol obtained by reduction of 12-amino small tert'canic acid by a conventional method was used instead of 3-aminophenol π-ville alcohol. Synthesized in the same manner.

 FAB MS (pos.); 846 (M + H) *

 Example 6 Synthesis of 2-0- (7-holmi · 7 チ) kalha * moyl-1,3-cholesterol

 After a tosyl group is introduced into one of the hydroxyl groups of 1,8-octane'-ol, it is reacted with sodium hydride, leading to an alkanol, which is then converted to lithium hydride by lithium aluminum hydride. The 8-aminoaminoethanol obtained by reducing the 'group to amine was synthesized in the same manner as in Example 1 except that the 3-amino 7-mouth alcohol used in Example 1 was used.

 Example 7 0- (3-0--/?-D-force ♦ lactoviranosyl)-(l "* 3) -0-[(aL-fucoviranosyl 4)]-N- [2,3-s [Woxy) Fuguchi Building] -1,5-Synthesis of 'Te'oxy-1,5-imin D-co' ^ Tourna Mdium salt

0- (3-0-S / 3-D-force 'lactoviranosyl) according to Reference Example 1 in which 2,3-year-old Reirk, {7} hydr (307 mg) according to Reference Example 9 was dissolved in methano-; 30 mL). -(1 → 3) -0- [( _α -lefcoviranosyl)-(1-4)] -1,5-hydroxy-1,5-imidin D-quinol (lOOmg) In addition, the pH was adjusted to 3 to 4 by further adding acetic acid, and sodium cyanoborohydride (33 mg) was added, followed by overnight at room temperature. After the reaction solution was neutralized with 2N sodium hydroxide, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography * raffy (Wakogel C300, cyclochloromethane). -Methanol (50%) and LiChroprep RP18, eluent; 50% -80% acetone-water) to give the title compound (43 mg) as a white powder.

 Elemental analysis value C H ^ NaOwS · 2H

 Theory £ (%) C: 57.80, H: 9.36, N: 1.18

 Obtained value (%) C: 57.45, H: 9.17, N: 1.32

 FABMS (ncg.) 1124 (M-Na) ''

 Example 8 0- (3-0-XM-? -D-force 'lacto-vilanoshi 4) -0-[(α-fucohi' ranone-(1-3)] -Ν- [1,3-s才 W W 7 7 · ハ · -2- -2- -2- 合成 才 合成 合成 合成 合成 合成 合成 合成 合成 合成 合成 · · 合成 · 合成 · · · 合成 7

 1-[[1,3-bis (aluminum)] 7-rohan-2-yl] according to Reference Example 10: キ シ = 'nil] Imita ♦, val (lOOmg) 0- (3-ΟλΛ *-?-D-force, lactopranyl) according to Reference Example 2 dissolved in Ν, Ν- シ * methylformamide (3 ml)-(1-* 4) -0- [( α-Lefcoviranosyl)-(1 → 3)] -1,5-cyte * t * ki 1,5-imino-D-co- · / tol (250mg, 0.35mmol) 'Methylaminobilicine' (21 mg, 0.nmmol) was added, and the pressure was increased at 100 for 15 hours. After distilling off the solvent under reduced pressure, the solution was separated with black mouth A-S NaH ^ PO, and the black mouth form layer was dried over sodium sulfate and dried to dryness under low pressure. The obtained residue was purified by reverse phase chromatography (Preparative C18 (registered trademark), manufactured by Waters, eluent: 50% -80% acetone / water) to obtain the title compound (48 mg). Was.

FABMS (neg.) 1196 [M-Na]-Example 9 0- (3-0-λ / Ι-/ 3-D-force * lactoviranosyl)-(l-4) -0-[(a-L- Fucolanosyl)-(1 ^→ 3))-N- [3- [N-[[1,3-bis (oleoyloxy) fluoro-2-an / 1)] Mouth Building] Synthesis of -1,5-cyth * oxy-1,5-imino-D-ethanol sodium salt

メチ ルムァ 'ヒに（30ml)に溶解した参考例 2に係る 0-(3-0-ス 力 *ラクトビラノシル )-(1— 4)-0 - 〔（ a -L-フコビラノシル )-(1— 3)〕 -1,5-シ'テ'才キ シ -1,5-イミん D-ク ン H l.50g)を加えた後、 酢酸にて pHを 3〜4に調整した。 シァノ水素化ホウ 素ナトリウム (0.33g)を加え、 室温下 3時間反応を行った。 2N 水酸化ナトリウムにて中和後、 反応 液を減圧 ift縮し、 残渣をクロ口ホルム-飽和食塩水にて分液抽出を行った。 クロ口ホルム層を減圧港 4i 縮し、 得られた残渣をシリカケ'ルクロマトク♦ラフィ- (Wakogcl C-300、 クロ口ホルム-メタノ-ル =10:1〜？：1 溶 出）にて精製を行い目的とする標記化合物が 2.72g得られた。 20g (3.77g) of methanol

0- (3-0-force * lactovilanosyl)-(1-4) -0-[(a-L-fucoviranosyl)-(1-3 in Reference Example 2 dissolved in methyl alcohol (30 ml) )]], And the pH was adjusted to 3 to 4 with acetic acid. Sodium borohydride (0.33 g) was added, and the mixture was reacted at room temperature for 3 hours. After neutralization with 2N sodium hydroxide, the reaction solution was reduced by ift under reduced pressure, and the residue was separated and extracted with chloroform-saturated saline. Decompression port at the Kuroshiki Holm layer 4i, and the residue obtained is purified by silica gel chromatography (Wakogcl C-300, chloroform-formanol = 10: 1 to?: 1) to give the title compound of interest. 2.72 g was obtained.

Elemental analysis value C _ei H _lw N ₂ NaOS · 30

 Theory 值 (%) C: 55.02, H: 8.70, N: 2.10

 Actual value (%) C54.76, H.8.76, N.2.30

 FABMS (neg.) 1253 (M-Na) ''

Example 10 0- (3-0-phosphono-?-D-force'lactovilanosyl) · (1 ^{→ 4} ) -0-[(α-lefcoviranosyl)-(1-3)]-Ν- [3- (Ν -((1,3-bis (year-old) W *) 7 * D-Han-2-i) 1-year-old xycarho * nil) amino) 7 · guchi building] -1,5-shi * te-oxy Synthesis of 1,5-imino-D-kent-lunarium salt

 Compound 20 (400 mg) dissolved in methanol solution (50 ml) according to Reference Example 3 0- (3-0-phosphono-/ 3 force * lactovilanosyl)-(l → 4) -0- [(a-lefcoviranosyl 3)] -1,5-Simet テ 1,5-imino-D-quantum (

After addition of acetic acid (5 ml), the mixture was vigorously stirred at room temperature for 1 hour. (7 mg of sodium borohydride) was added and the mixture was stirred for 1 hour. The Sit and the solution were concentrated under reduced pressure, and the residue was purified by silica gel im kraphy-(Wakogel C-300, eluted with chloromethane-methanol).

 The eluted fraction was filtered under reduced pressure, redissolved in water, filtered through a cotton plug, and lyophilized to obtain 350 mg of the desired compound.

 Elemental analysis value CwH ^ NZNaC ^ P · 4.5Hp

 Theoretical value (%) C: 53.92, H: 8.83, N.2.06

 Observed value (%) C: 53.84, H: 8.54, N: 2.20

FABMS (neg.) 1253 (M-Na)-Example 11 0 "(3-0-methyl フ ィ sphinico- / 3-D-force 'Luck' lanosyl)-(1-4) -0-[(a- (L-fucovirane)-(1 ^→ 3)) -N- (3- (Ν-((1,3-bis- (leo-oil-oil))-'rohan'-2-yl) oxycarpho * namino) Building] -1,5-Site * Synthesis of 1,5-Imin D-coon * -Lunarium salt

Compound 20 (600 mg) dissolved in methanol solution (20 ml) according to Reference Example 6 0- (3-0-Methyl M-sphinico-β-D-force ♦ lactoviranosyl)-(1-4) -0- [ (A-Lefcoviranosyl)-(1 → 3)] -1,5-cysteine xy-1,5-imino-D-octyl (300 mg) and acetic acid (2 ml) The mixture was vigorously stirred at room temperature for 1 hour. Cyano borohydride Sodium hydroxide (80 mg) was added and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and purified by silica gel chromatograph raffy (Wakogel C-300, elution with cyclochloromethane-methanol). The eluted fraction was compressed under reduced pressure, redissolved in water, dried with cotton plug, and dried by freezing to obtain 503 mg of the desired compound.

· 3.5H として Elemental analysis value

· As 3.5H

 Theoretical value (%) C-.55.63, H: 8.96, N: 2.09

 Observed value (%) C: 55.64, H.9.02, N.2.27

 FABMS (neg.) 1251 [M-Na]

 Example 12 0- (3-0-ca ^ 'xymethyl- -D-force * labyranosyl)-(1 → 4) -0-[(α-lefcoviranosyl)-(1-3)] -Ν- [3- (Ν-((1,3-S) (口-ハ--2-yl) oxycarbo * nil〉 amino) フ ・ π-bil) -1,5- シOf 1,5-imino-D-quinitol sodium salt

 Compound 20 (285 mg) was dissolved in Ν, Ν-methylmethylamine (4.5 ml) and methanol (30 ml) according to Reference Example 8, and the 0- (3-0-force W quinmethyl-/ 3- -D- Lactobaranossi 4) -0- [(a-L-7 coco 'lanosyl)-(1-3)] -1,5-cysteine 1,5-imi D-kun HV (150mg ) And acetic acid (0.3 ml), and then sodium cyanohydride (36 mg). After stirring at room temperature for 1.5 hours, the mixture was neutralized with a sodium hydroxide solution and concentrated under reduced pressure. The residue was purified by silica gel chromatography 7- (Wakogel C-300, silica α-mouth tan-methanoate), and the eluted fraction was concentrated under reduced pressure. After re-dissolving in water, drying was performed to obtain 238 mg of the target compound.

· 4H₂0として Elemental analysis value

As · 4H ₂ 0

 Theoretical value (%) C: 57.00, H: 9.03, N.2.11

 Observed value (%) C: 57.04, H: 8.79, N: 2.19

 FABMS (neg.) 1231 (M-Na)

 Example 13 0- (3-0-ΧΛΦ- -D-force'lactovilanosyl)-(l → 4) -0-[(a-L-7cohilananosyl)-(1 → 3)]-N- [ 2,3-Bis (Sai-rei; W-Xi-fu · π-Bil) -1,5-Sy-S-*-S-ki-S- 1,5-I-Min D-Kentle Sodium salt synthesis

A solution of 2,3-c'-0-oleic'reser'hide (600 mg) according to Reference Example 9 (0.2 ml) in chloroform (0.2 ml) was prepared according to Reference Example 2 at 0- (3-0-S ^--D- Strength 'lactoviranosyl)-(1-4) -0 [(a-lefcoviranosyl)-(1 → 3)] -1,5-cyte'oxy'-1,5-imi D-quantol (250mg) Was added to an aqueous solution (0.25 ml), and acetic acid was added to adjust the pH to 3. methanol, After adding a small amount of chromium σ-form to make a homogeneous solution, the mixture was stirred at room temperature for 1 hour, added with ン (7-hydrogen hydride), (150 mg), and stirred at 45 overnight. The reaction solution was evacuated under reduced pressure, washed with n-hexane (50 ml), added with water and water (20 ml), and subjected to liquid separation and extraction with a mouth-mouth form (20 ml) (three times). After the organic layer was dried over sodium sulfate, it was subjected to vacuum depressurization, and the residue was subjected to silica gel chromatography (Wakogel C-300, silica gel-methano-elution). The eluted fraction was concentrated under reduced pressure, dissolved in water again, and freeze-dried to obtain 117 mg of the desired title compound.

 Elemental analysis as C H NaO ^ S ■ 3H

 Theoretical value (%) C: 56.93, H: 9.39, N: 1.16

 Observed value (%) C: 56.53, H: 9.00, N: 1.53

 FABMS (neg.) 1124 [M-Na]-Example 14 0- (3-0-phosphono- -D-force 'lactovilanosyl)-(1-4) -0-[(a-L-fucoviranosyl)-( 1-3)] -N- [2,3-Bis (Sairei Woxy) 7-robil]-Synthesis of 1,5-tetraxoxy-1,5-imino-D-quinodium sodium salt

 The 2,3--0-year-old Reiruk 'reserua ^ * human * QWmg) according to Reference Example 9 was compared with 0- (3-0-phosphono-β-D-force ♦ lac viranosyl)-(1- 4) -0-[(α-Lefcoviranosyl)-(1-3)] -1,5-cythoxy-1,5-imino-D-quinol (lOOmg) in methanol (10ml ) And acetic acid (0.5 ml), and then sodium cyanoborohydride (23 mg). After stirring at room temperature overnight, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (Wakogel C-300, eluted with chloromethane-methanol). The eluted fraction was concentrated under reduced pressure, dissolved in water, washed with cotton plug, and lyophilized to obtain 65 mg of the target compound.

 FABMS (ncg.) 1124 (M-Na)

 Example 15 0- (3-0-methinosphinico- (3-D-force ♦ lactovilanosyl)-(1 to * 4) -0-[(.- lefcoviranosyl)-(1-3)]-Ν- [2 , 3-Bis (rexy) fu · α-bill] -1,5-cysteine Synthesis of sodium 1,5-imino-D-cyclohexane sodium salt

2,3- -04 Reiruk 'Reserua' according to Reference Example 9 (621 mg) was applied to Reference Example 6 0- (3-0-Met W sufinico--D-force * Rak Vilanoshi-(1 → 4 ) -0- [(a-Shifucoviranosyl)-(1 → 3)] -1,5-cytoxy-1,5-imin D-quintole (300 mg) in metal solution (15 ml), acetic acid (1.5 ml) was added, and the mixture was vigorously stirred for 1 hour, and potassium cyanoborohydride (66 mg) was added, and the mixture was stirred at room temperature overnight, and concentrated under reduced pressure. The obtained residue is purified with silica gel "Chromatoku" rough jin (Wakogel C-300, chloromethane-;! Tanol elution). did. The eluted fraction was concentrated under reduced pressure, then purified by reverse-phase preparative chromatography, KSilica gel 60 Silanized (Merck), eluting with 30% to 100% acetone, concentrated under reduced pressure and lyophilized to obtain 230 mg of the target compound. . Elemental analysis value As C ^ H ^ NNaC ^ P SH

 Theoretical value (%) C: 57.60, H: 9.67, N: 1.16

 Obtained value (%) C.-57.59, H: 9.49, N: 1.29

 FABMS (neg.) 1 122 (M-Na)

 Example 16 0- (3-0-force W xymethyl-/ 3-D-force 'lac' lanosyl)-(1-4) -0-[(α-lefcoviranosyl)-(1 to * 3)] -Ν -[2,3-Bis (Sairei Wxii) alpha] Synthesis of sodium salt

 2,3-Di'-04 Reiruk * Reserua ^ 'hi (500 mg) in tetrahi and loflurane solution (25 ml) were added to Ν, シ -shi' methyl; Ι muami (7.5 ml) and methanol ( 0- (3-0-force Λ ^ * xymethyl--D-Λ · lactovilanosyl)-(l-4) -0- [(<1-lefcoviranosyl)-(1 → 3)] In addition to -1,5-cysteine oxy-1,5-imidin D-quinol (250 mg) and acetic acid (0.5 ml), sodium borohydride (60 mg) was added. ) And stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, subjected to liquid separation treatment with n-hexane and metal, and the methanol layer was adjusted to pH 9 with sodium hydroxide and then reduced under reduced pressure. The residue was slightly prepared using silica gel ク kuto raffy (Wakogel C-300> chloromethane-metal elution), and further reverse-phase column chromatography (LiChroprep. RP-18 (Merck), 50% Purification was performed using methanol water to 90% methanol water elution, and lyophilization yielded 137 mg of the target compound.

As elemental analysis C ₅₉ H _10s NNaO _l7 · 3Η

 (Theoretical value C¾) C: 60.03, H: 9.73, N: 1.19

 Observed value (%) C: 60.07, H: 9.74, N: 1.28

 FABMS (ncg.) 1102 [M-Na] "

 Example 17 0- (3-0-λΛ *--D-force * lactovilanosyl)-(1 → 4) -0-[(a-lefucoviranosyl)-(1-3)]-N- [3- [Ν '-[1,3-bis (hexanoy; W xy) 7.lohan'-2-yl] xoxicarnil] aminoph'mouth pill] -1,5-cy Synthesis of D-Cyrus-Lunarium Salt

2-0-(* Rumylethyl) carha according to Example 3 * Moyl-1, 3-dimethyl * -0-hexabulk * Lice α-yl (600 mg) in methanol (I5ml) and ί /, -dimethylamino Compound (16 mg, 300 mg) according to Reference Example 2 dissolved in (7.5 ml) (Iml), sodium cyanoborohydride (30 mg) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was compressed under reduced pressure, and the residue was made from rice bran using silica gel * chromatography * raffy (Wakogd C-300, cyclo α methane-methano-extract). The eluted fraction was concentrated under reduced pressure, dissolved in water, filtered through a cotton plug, and lyophilized to obtain the desired compound (301 mg).

As Elemental analysis _{C "H 65 N2Na0 22 S ·} 3 0

 Theory (%) C: 44.48, H: 7.16. N: 2.80

 Obtained value (%) C: 44.58, H: 7.07, N: 2.85

 FABMS (neg.) 921 [M-Na] "

 Example 18 0- (3-0-SΛ- / 3-D-force'lactohi'lanosyl)-(l → 3) -0-[(a-lefcohi'lanosyl)-(to> 4)]-N -[3- (Ν-((1,3-bis (lauroyxy) 7-roh-2-yl) talent * nil) amino) 13'-yl]-1,5-cy * Te * Siki 1,5-imino-D-co * Synthesis of sodium citrate

 2-0- (2-Formyl chill) carha according to Example 2 * Moyl-1,3-Sil '-Ο-lauguchi Irk', roll (388 mg) in methanol (17 ml) and U ^ .N -In addition to the compound 1 (200 mg) of Reference Example 1 dissolved in (3 ml) in methylamine, acetic acid (0.5 ml) was added, and thionium borohydride (44 mg) was added. For 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified with silica gel * chromatography (Wakogel C-300, silicone ππ-methanol), and further purified by reversed-phase column chromatography (UChroprep. RP-18 (Merck And water-acetone elution). The purified product was dissolved in water again and freeze-dried to obtain 260 mg of the target compound.

Elemental analysis value C ₄₉ H „N2NaO _M S ■ 3H ₂₀

 Theoretical value (%) C: 50.46, H: 8.21, N.2.40

 Observed value (%) C.50.37, H: 8.17, N: 2.44

 FABMS (neg-) 1089 [M-Na] "

Example 19 0- (3-0-phos-9-D-force ♦ lactoviranosyl)-(l → 3) -0-[(a-L-fucoviranosyl)-(1 ^→ 4)]-N- [3- (Ν-((1,3-Bis (Laroy Wxy) Floha'n-2-yl) talent Λ * nil) amino) Fu Πbil) -1,5-Site * Synthesis of sodium cis-1,5-imino-citrate sodium salt

2-0- (2-Formylethyl) kalha * moyl-1,3-si * -0-lau πiruku * recess- / K388rng according to Example 2 in methanol (20 ml) 97/02069

According to the reference example 4 was dissolved in 46 0- (3-0-'† Suhon pD- force' Lac Biranoshiru) - (1- ³⁾ -O- [- Refukopira - (1-4)] 1,5 -'Texyl-1,5-imid D'kol '/ "Toluene (200 mg), sulfuric acid (lml), and sodium cyanohydride Φ ゥ sodium (44 mg). The reaction mixture was concentrated under reduced pressure, and the residue was purified with silica gel * α-Matoku 'Raffin (Wakogel C-300, chloromethane-methanol). Purification was performed using LiChroprep.RP-18 (manufactured by Merclc, eluting with water and acetone) .The purified product was dissolved in water again and lyophilized to obtain 50 mg of the desired compound.

· 2HjDとして Elemental analysis value

· As 2HjD

 Theoretical value (%) C: 51.21, H: 8.24, N: 2.44

 Obtained value (%) C: 51.24, H: 8.37, N: 2.42

 FABMS (neg.) 1089 (M-Na)

 Example 20 0- (3-0-phosphon / 3-D-force 'lactovilanosyl)-(l → 3) -0-[(σ-L-fucoviranosyl)-(1-4)]-N- (2 , 3-Bis (Sairei / Wxy) Fuguchi Building] Synthesis of 1,5-cy-tert-oxy-1,5-imino-D-cure sodium salt

 In Example 14, the compound of Reference Example 4 was used in place of the compound of Reference Example 3, and synthesis was carried out in the same manner to obtain 252 mg of the target compound.

Elemental analysis C „H _{i07 NaO 18} P · 5 ·

 Theory (%) C55.28. H: 9.52, N.1.13

 Obtained value (%) C: 55.18, H: 9.52, N: 1.36

 FABMS (neg.) 1124 (M-Na) ''

Example 21 0- (3-0-methyl sphinico-pD-force * lactoviranosyl)-(1-3) -0-[(a-L-fucoviranosyl) -h ^{→ 4} )]-N- [2,3 -Bis (Sai Rei W Kishi) F α-Hil] -1,5-Si * Te * Sai Kishi -1,5-Imin D-Kent * Synthesis of sodium salt

 In Example 15, the compound of Reference Example 5 was used in place of the compound of Reference Example 6 to synthesize in the same manner, and 148 mg of the target compound was obtained.

Elemental analysis C „H ₁₀₉ NNaO ₁₇ P '20

 Theoretical value (%) C: 58.91, H: 9.63, N: 1.18

 Observed value (%) C: 58.98, H: 9.44, N: 1.49

FABMS (neg.) 1122 (M-Na) Example 22 0- (3-0-force Λ · xymethyl-/? -D-force 'lactoviranosyl)-(1-3) -0-[(.- lefcoviranosyl)-(1-4)]-N- [ 2,3-Bis (Sairei W-Kisi) 7 · guchi Building] Synthesis of -1,5-Shi-Te * Sai-Ski-1,5-Imino-D-Cou * Toluate Sodium Salt

 In Example 16, the compound of Reference Example 7 was used in place of the compound of Reference Example 8 to synthesize in the same manner, and 154 mg of the desired compound was obtained.

Elemental analysis: C ₅₉ H _1M NNaO _l7

 Theory (%) C: 59.13, H: 9.76, N: 1.17

 Observed value (%) C: 59.17, H: 9.40, N.1.38

 FABMS (ncg.) 1102 (M-Na)

 Example 23 0- (3-0-S ^-/ 3-D-force * Lactobilanosyl)-(l → 3) -0-[(.- Lefcohilananosyl)-(1 → 4)]-N- [ 3- (Ν-((1,3-bis- (leo-leoxy-W-xy))-π-han-2-yl)-(キ シ -nil) amino-)-(pi-bill) -1,5- * Synthesis of sodium salt of tert-oxy-1,5-imino-D-chlorocitrate

 In Example 9, the compound of Reference Example 1 was used in place of the compound of Reference Example 2 to synthesize in the same manner, and 32 mg of the desired compound was obtained.

9H として Elemental analysis value

As 9H

 Theoretical value (%) C50.89, H: 8.89, N: 1.95

 Actual value (%) Q50.92, H: 8.91, N: 1.84

 FABMS (neg.) 1253 [M-Na] "

 Example 24 0- (3-0-phosphono- -D-force ♦ lactovilanosyl)-(1 → 3) -0-[(a-L-fucohi'lanosyl)-(1 → 4)]-N- [3 -(Ν-((1,3-Bis (Shi-Rei-Wii-Ski) Flo-Ha-N-2-I-L> Shi-Shi Λ Λ :: ΛAmino) F α-Pill) -1,5-S Synthesis of 1,5-imisitol sodium salt

 In Example 10, the compound of Reference Example 4 was used in place of the compound of Reference Example 3 to carry out synthesis in the same manner, to obtain 245 mg of the target compound.

Elemental analysis C _e , Η, ^ N ^ aO ^ P · 7H

 Theoretical value (%) C: 52.20, H: 8.90, N: 2.00

 Observed value (%) C: 52.06, H-.8.72, N: 2.11

FABMS (neg.) 1253 (M-Na) Example 25 0- (3-0-methylsphinico-3-D-force'lactovilanosyl)-(1-3) [(a-L-fucoviranosyl)-(1-4)]-N- [3- (N -((1.3-Bis (leoyloxy) 7-lohan'-2-yl) lixixalyoxy * nil) amino) F 'Q']-1,5-Si'-l-oxy-1,5- Synthesis of Imin D-Kentole Sodium Salt

 In Example 11, the compound of Reference Example 5 was used in place of the compound of Reference Example 6 to synthesize in the same manner, and 270 mg of the desired compound was obtained.

Elemental analysis value C _M H _ll2 N2 a0 ₂₁ P

 Theoretical value (%) C: 56.01, H: 8.95, N: 2.11

 Actual i-law value (%) Q55.93, H: 8.92, N: 2.27

 FABMS (neg.) 1251 (M-Na)

Example ²⁶ 0- (3-0-force Λ · ximethy ^^-D-force ♦ lactoviranosyl)-( ^1-3 ) -0-[((a-L-fucoviranosyl)-(1 ^{→ 4} )]-N- [3- (Ν-((1,3-bis (oleoyl)) · Π'-2-yl) oxycarbol) amino) フ. -1,5-Cyte * oxy-1,5-imino-D-co · Λ ^ Synthesis of sodium sodium salt

 In Example 12, the compound of Reference Example 7 was used in place of the compound of Reference Example 8 to synthesize in the same manner, and 274 mg of the target compound was obtained.

· 3H₂0として Elemental analysis value

As · 3H ₂ 0

 Theoretical value (%) C: 57.78, H: 9.00, N: 2.14

 Measured value (%) C: 57.57, H: 8.81, N: 2.25

 FABMS (neg.) 1231 [M-Na] ''

 Example 27 Ο-0-Ο-ΛΜ-/?-D-force 'lactopyranosyl)-(1-3) -O-[(a-L-fucoviranosyl)-(1-4)]-N- [3- (Ν-((1,3-Si'hexanoy / W xyph 'rohan' -2-yl) talent ^ * nil) amino) fu. Bill] -1,5-cy * te * sai xi 1,5-imi D-q

 In Example 17, the compound 9 of Reference Example 1 was used in place of the compound 16 of Reference Example 2, and synthesis was carried out in the same manner to obtain 152 mg of the target compound.

 Elemental analysis: C H ^ ^ aO ^-3.5 Hp

 Theoretical value (%) C: 44.09, H: 7.20, N: 2.78

Observed value (%) C: 44.03, H: 7.22, N.2.73 FABMS (ncg.) 921 (M-Na)

Example 28 0- (3-0- (3,3-cy * phenyl) α-hydroxy) phosphinico-force lactovilanosyl)-(1-4) -0-[((a-L-fucovilanosyl)-( 1 ^→ 3)) -N- [3-Ν-((1,3-bis (oleoy Wxy) fu · πhan'-2-yl) Synthesis of 1,5-cysteine 1,5-imine D-quintulnarium Salt (Compound 25)

(1) 0- (4-0-Acetyl -2,6-si 'ene ^, pile-3-0- (3,3-si * phenyl ropho' xy) phosphinico-3 / -D-force 'lactovilanosyl )-(1-4) -0- [(2,3,4-tri-0-hexyl-a-refukohi'lanosyl)-(1 ~ * 3)] -2,6-si *- 0-Hen 'Pile-N-Hen'W'Wixica'Nyl-1,5-cy'te'Synthesis of X-1,5-imin D-tolu (Compound 21)

 Compound 13 (2.0 g) in Reference Example 2 was dissolved in dry viricin (40 ml), and phosphorous oxychloride (209 1) was gradually added dropwise, and the mixture was stirred for about 2 hours at room temperature under an atmosphere of alcohol. Stirred. Next, 3,3-phenyl-1-7'loha'nor (9001) was added, and the mixture was further stirred overnight. A 50% aqueous phosphorus solution (40 ml) was added to the reaction solution, and the mixture was stirred overnight at room temperature. To the reaction solution, a 0.2 M aqueous solution of triethylammonium carbonate (300 ml) and ice were added, and the mixture was partitioned with dichloromethane (300 ml). The crude o-methane layer was dried over sodium sulfate and concentrated under reduced pressure to obtain a crude compound Diff of Compound 21. It was directly used for the next reaction.

 C 2) 0- (3-0- (3,3-sh * Furnil 'mouth pho') phosphinico-3-D-force * lactovilanosyl)-(1 → 4) -0- ((2, 3,4-Tri-0-Henyl-. -L-fucoviranosyl)-(1-3)] -N, 6-0-force ^ * nil-1,5-si, te Of 2,5-imidine D-quinol sodium salt (Compound 22)

 Crude Syroch 'of Compound 21 was dissolved in methanol (50 ml), a 28% sodium methylatomethanol solution (2 ml) was added, and the mixture was stirred at room temperature for about 19 hours. After neutralization with a 2N salt solution, the solution was vacuum strained. The residue was purified by reversed-phase preparative chromatography ff7 Silica gel 60 Silanized (Merck, eluting with water-acetone) to obtain 550 mg of a colorless compound 22 of Compound 22.

[3] 0- (3-0- (3,3-diphenyl 7-lopho'oxy) phos 7 nico-force ♦ lactovilanosyl)-(l "» 4) -0- [(2,3,4- Tri-O-hexyl * a-le-fucoviranosyl)-(1 ~ »3)] -1,5-cytoxy-1,5-imino-0-octanol sodium salt ( Synthesis of Compound 23) Compound 22 (550 mg) was dissolved in methanol (50 ml) and water (25 ml), a 2N aqueous solution of lithium hydroxide (10 ml) was added, and the mixture was refluxed at 90 overnight. (On the way, 15 ml of 2N aqueous sodium hydroxide solution was added.) While ice-cooling, the mixture was neutralized with a 2N salt solution and compressed under reduced pressure.The residue was subjected to reverse phase chromatography (LiChroprep RP-18 (Merck), Water-acetone elution) to produce compound 23 as a white solid 190 mg were obtained.

 [4] 0- (3-0- (3,3-diphenyl-7-roxy-phosphinico) -D-force'lactovilanosyl)-(1-4) -0-[(β-shifucohi (Sil)-(卜 3)] -1,5-Syte * oxy * 1,5-Imin D-co '/ ^ Tolu sodium salt

 Compound 23 (180 mg) was dissolved in methanol (20 ml) and acetic acid (2 ml), and calories were added. Was done. The catalyst was filtered off from the reaction solution, and concentrated under reduced pressure to obtain a crude residue of compound 24, which was subjected to the next reaction.

 [5] 0- (3-0- (3,3-diphenyl) .foxy) phosphinico-J-D-force * lactovilanosyl)-(1 → 4) -0- [(a -L-fucopi Lanosyl)-(1 ~ »3)) -N- [3-Ν-((1,3-bis (year-old wis)) ) Aminophyl]]-Synthesis of 1,5-cytidine * 1,5-imi D-octyl-sodium salt (Compound 25)

 The crude residue of compound 24 was dissolved in a mixture of methanol (15 ml) and acetic acid (0.5 ml). Compound 20 of Example 1 (250 mg) and sodium cyanoborohydride (22 mg) were added, and the mixture was ground at room temperature overnight. The reaction solution was reduced in pressure and reduced, and the residue was purified by silica gel column chromatography 7 Toku Raffy (Wakogcl C-300. Elution with methanol) The product was dissolved in water and freeze-dried. This gave a white powder (56 mg) of the title compound.

· 4H として Elemental analysis value:

· As 4H

 Theoretical value (%) (:: 59.13 H: 8.62 N: 1.81

 Obtained value (%) C: 59.10 H: 8.35 N: 2.03

 FABMS (neg.) 1447 [M-Na] "

 Example 29 0- (3-0- (5-force; * 'xy'Winch) Φ sphinico- /? -D-force'lactovilanosyl)-(l-4) -0-[(a-refco HI 'lanosyl)-(1 ~ -3)) -N- (3-Ν-((1,3-bis) V * 'ul) Aminoff'. [Hyrr]-1,5-/ * Synthesis of 1,5-imine D-kenthol sodium salt (Compound 30)

 (1) 0 (4-0-Wall -2,6-Six-〇-Hen, pie-3-0- (5-ΐToxica ♦ 2Λ ^ -N-toxy) phosphinico- / 3- D-force 'Lactohi' lanosyl)-(1-4) -0- [(2,3,4-tri-0-Henshi '-a -lefcoviranosyl)-(1 → 3)] -2,6- * -0-to * n, pile to N-to-n · w · W-force; 1 ^ * nil-1,5-te * oxy-1,5-imin D-k · Λτ 26) Synthesis

Compound 13 (5 _g ) in Reference Example 2 was dissolved in dry lysine (100 ml), and phosphorus oxychloride (7001) was gradually added dropwise at room temperature under an atmosphere of αα-inkase. The mixture was stirred for about 3 hours. Then, ethyl 6-hydroxyhexanate (3.7 ml) was added thereto!] And further stirred overnight. Add 50% aqueous solution of viridin (60 ml) to the solution, and add room temperature. 7070 t: and stirred overnight. To the solution was added a 0.2 M aqueous solution of carbon monoxide (500 ml) and ice, and the mixture was extracted twice with dichloromethane. The chloromethane layer was dried over sodium sulfate and compressed under reduced pressure. The residue was subjected to elution using reverse phase preparative chromatography (LiChroprep RP-18 (Merdc), elution with water-metal) to obtain Compound 26 as a colorless Syroch '(3.7 g).

 (2) 0- (3-0- (5-Methoxycarbonyl) / Wxy) phosphinico-J-D-force'lactovilanosyl)-(1-4) -0- ((2,3,4- Tri-O-sil-a-L-fucohi 'lanosyl)-(1-3)] -N, 6-0-force1 *' nyl-1,5-si 'te' Synthesis of Imin D-Ketol Sodium Salt (Compound 27)

 Compound 26 (1.4 g) was dissolved in methanol (20 ml), 28% sodium methylatomethanol solution (lml) was added, and the mixture was stirred at room temperature for about 3 hours under an alcohol atmosphere. The mixture was refluxed for about 1.5 hours at 80 in an atmosphere of 'ink'. The reaction solution was neutralized with a 2N salt solution and concentrated under reduced pressure. The residue is subjected to reverse phase preparative chromatography (

Purification was performed using LiChroprcp RP-18 (Merck), elution with water-acetone) to obtain Compound 27 as a white solid (0.59 g).

 [3] 0- (3-0- (5-methoxy power; ψ * 2Λ ^ · WW xy) phos 7 nico-y3-D-force 'lactoviranosyl)-(1-4) -0-[(. -L-fuco viranosyl)-(1-3)] -Ν.6-0-force-1,5-dimethyl--1,5-imino-D-co * Λτ-menthol sodium salt Synthesis of (Compound 28)

 Compound 27 (0.51 g) was dissolved in methanol (50 m, acetic acid (2.5 ml), and added with 'Harashi' Dum-Black (500 mg), and the mixture was subjected to catalytic reduction in a hydrogen atmosphere at room temperature to 30 overnight. The catalyst was filtered off from the reaction solution and reduced under reduced pressure to obtain a crude residue of compound 28, which was subjected to the next reaction.

 [4] 0- (3-0- (5-ka ^, quinn-woxy) phosphinico-3-D-force * lacto-vilanoshi 4) -0- [(a-lefcolanosyl)-(1 → 3 )]-1,5-cysteine * Synthesis of 1,5-imino-D-octanol sodium salt (Compound 29)

 The crude residue of compound 28 was dissolved in meta (45 ml), 2N aqueous sodium hydroxide solution (5.lml) was added, and the mixture was refluxed for about 22 hours and 90 hours. (On the way, water (25 ml) and a 2N aqueous sodium hydroxide solution (5 ml) were added.) The reaction solution was neutralized with a 2N aqueous hydrochloric acid solution, and the pressure was reduced. The residue was dissolved in water, desalted with Microacilizer'- (manufactured by Asahi Kasei Corporation), reduced in pressure, and a crude residue of compound 29 was obtained.

[5] 0- (3-0- (5-force ΛΨ 'へ' チ チ チ チ チ ホ ス) phosphinico-/ Ϊ -D- ♦ lactoviranosyl)-(l → 4) -0- [( Sill Ml— 3)) -N- [3- (Ν- (1,3-H-S) Mouth Building)-1,5-site * te * Synthesis of xy-1,5-imin 0-ethanol sodium salt (Compound 30)

 The crude residue of compound 29 was dissolved in methanol (40 ml) and acetic acid (2 ml), compound 20 (734 mg) and sodium cyanoborohydride (64 mg) were added, and the mixture was stirred at room temperature for about 3 hours. The reaction mixture was concentrated under reduced pressure. , Water-acetone elution). The purified product was dissolved in water and freeze-dried to obtain a white powder (41 mg) of the target compound.

Elemental analysis: C ₆₇ H _1J0 N2NaO _M P ■ 6HjO

 Theoretical value (%) C: 8.87 H: 53.66 N: 1.87

 Measured value) C: 9.10 H: 53.43 N: 1.97

 FABMS (neg.) 1367 (M-Na)

 Example 30 0- (3-0-s ^-/?-D-force'lactovilanosyl)-(l-4) -0-[(a-lefcohi'lanosyl)-(1-3)]-N- [ 6- (Ν- (1,3-Bis (leoixi) fluoran-2-yl) liquor / 1nil) amihaxyl]-1,5-si Of 1,5-imino-D-knitol sodium salt

 Example 9 is the same as Example 9 except that the compound 20 was replaced with the 2-CK5-formin Λ'-ethyl) cal /, moyl-1,3-sh Synthesis was performed by the method described above to obtain 238 mg of eye!

· 2H20として Elemental analysis value:

· As 2H20

 Theoretical value (%) C: 56.70 H: 8.85 N: 2.07

 Actual value (%) C: 56.65 H: 8.78 N: 2.29

 FABMS (neg.) 1295 [M-Na] "

 Example 31 0- (3-O-S n-/ 3-D-force ♦ lactoviranosyl)-(1-4) -0- [(na-L-fucohi 'lanosyl)-(1 → 3)] -N -[12- (N- (1,3-bis (year-old-year-old W-kin) fu-ro-han -2-yl) oxy-force W-nil) amino-te-sil]-1, 5-shi ' Synthesis of sodium salt of V "-toluene 1,5-imino-D-c '

 In Example 9, 2-0- (11-homylpente * sil) cal, 'moyl-1,3-si'-Ο-oleoylok' lyserole according to Example 5 was replaced with compound 20 in place of compound 20 by ffl. Synthesis was performed in the same manner to obtain 270 mg of the target compound.

· 2Hpとして Elemental analysis value:

· As 2Hp

Theoretical value (%) C: 58.39 H: 9.17 N: 1.95 Observed value (%) C: 58.31 H: 9.05 N: 2.14

 FABMS (neg.) 1379 [M-Na] "

 Example 32 0- (3-0-S--D-force'lactopyra- (1-4) -O-[(α-lefucoviranosyl)-(1-3)]-N-C (8- (Ν- (1,3,3) Synthesis of 1,5-imino-0-quintol sodium salt

 In Example 9, synthesis was performed by the same method using 2-0- (7-formityl) carha 'moyl-1.3-0-' oleoylc 'lycerol according to Example 6 instead of compound 20, 201 mg of the target compound was obtained.

· 2H として Elemental analysis value:

· As 2H

 Theoretical value (%) C: 57.29 H: 8.96 N: 2.02

 Obtained value (%) C: 57.15 H: 8.99 N: 2.11

 FABMS (neg.) 1346 [M-Na] "

 Example 33 Ο- -Ο-λΗ- / 3-D-force 'lactovilanosyl)-(1-4) -0- [(.-lefcohilananosyl)-(1-3)] -N- [7- ( (1,3-bis) (7, Rohan's -2-y) Syntheses of D-kn * l-lunatium salt

 [1] Compound 31 (1,8-octane-ole) was dissolved in 60 ml of DMF, and 5.6 g of imita-sol * _ol and 5 g of t-butyl W methyl chloride π-silane chloride (TBDMSCl) were added. The mixture was stirred at room temperature. After completion of the reaction, the mixture was concentrated under reduced pressure, and the obtained residue was subjected to 150 g of silica gel column chromatography-Raffy-C-300. After elution, the compound was subjected to cyclohexane methane: methanol = 150: I to give a compound. 32 (3.56 g) was obtained.

(31) ( ³² )

[2] Compound 32 (3 g) was dissolved in a mixed solution of 100 ml of dichloromethane and 8 ml of lysine, 18 g of Dess-Martin reagent was added, and the mixture was stirred at room temperature for 3 minutes. After the completion of the reaction, 150 ml of saturated sodium carbonate solution and 150 ml of saturated sodium sulfate solution were added, and the mixture was stirred for 1 hour. Then, the organic layer was washed with water and dried over sodium sulfate. Dried. The solid was filtered off, washed with dichloromethane, and the filtrate and washings were combined and concentrated under reduced pressure.The obtained residue 33 was dissolved in 50 ml of an 80% aqueous solution of sulfuric acid and cooled on ice. 4.2 g of sodium chlorite and 2.3 g of amic acid were added, and the mixture was stirred at 0 for 3 (½h. After completion, the resultant was subjected to low pressure dripping, and the obtained residue was dissolved in ethyl acetate, and the organic g was dissolved in 2N. The residue was washed with hydrochloric acid and water, dried over sodium sulfate, separated from the solid, washed with chloromethane, combined with the filtrate and the washings, and reduced under reduced pressure. The mixture was dissolved in 80 ml of sensene, 35 g of the compound (7, 7 g), 4.3 g of DCC, and 0.47 g of 4-methylaminobilysine (hereinafter, abbreviated as DMAP) were added, followed by stirring at room temperature. After completion, the mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel “column chromatography” Raffy-c-300, 300 g, and the eluate, chloromethane: methanol = 100: 3 Compound 36 was shame the 4.45 g.

(32) _ »." Y ^^^^ OTBDMS ^ ^H ° "^^^ OTBDMS

 O O

 (33)

 (34)

 (36)

 [3] The compound 36 and 4.45 g were dissolved in THF 40 ml, acetic acid 1.6 ml and IN tetraphenylammonium fury-THF solution 9.98 ml were added, and the mixture was stirred at room temperature-晚. After completion, the solution was compressed under reduced pressure, the obtained residue was dissolved in ethyl acetate, and the organic layer was washed with water and dried over sodium sulfate. The solid was separated, washed with ethyl acetate, and then the combined washing liquid and washing liquid were compressed under reduced pressure. The obtained residue was subjected to silica gel column chromatography Raffy-C-300, 300 g, and eluted. Thus, compound 37, 2.05 g was obtained in a ratio of cycloalkylmethane: methanol = 75: 1.

(37) 250 mg of Compound 37 was dissolved in 3 ml of dichloromethane, 550 mg of Dess-Martin reagent was added, and the mixture was stirred at room temperature for 3 minutes. After completion of the reaction, sodium carbonate and saturated sodium thiosulfate solution (3 ml each) were added, and the mixture was stirred for 1 minute. Then, the organic layer was washed with water and dried over sodium sulfate. The solid was separated, washed with dichloromethane, and the solution and the washing solution were combined and compressed under reduced pressure to obtain 224 mg of compound 38.

 (38)

(4) Compound 16, 130 mg and Compound 38, 224 mg were dissolved in a mixture of 5 ml of Ν, Ν-dimethyl / V * lumami, 0.5 ml of dichloromethane, and 1 ml of water, and adjusted to pH 4 by adding acetic acid. . To this, 33.3 mg of sodium cyanoborohydride was added and stirred overnight. After confirming the completion of the reaction, the reaction solution was reduced in pressure. The obtained residue was subjected to silica gel column chromatography Raffy-NAM-300H, 25 g, to obtain 40, 207.7 mg of a compound from chloromethane: methanol-5: 1.

 (38)

元素分析値

Elemental analysis value

(As C _M H _u6 NNaO _J2 S · 3.5H ₂₀ ) S6 Barrier value C 56.50% H 8.97% 1.01%

 Measured value C 56.23% H 8.67% N 1.33%

 FAB MAS 1294 (M-Na) -Example 34 0- (3-0-S ^ -Lactylanosyl)-(1-* 4) -0-[(a-Lefcohi'lanosyl)-(1-3)]- N- [5-((l, 3-Hydroxy) 7'lohan-2-yl) oxyl force; 1 * nil) 1,5-cyl * oxy * oxy-1, Synthesis of sodium salt of 5-imino-D-knitol

 [1] To 6-hexanolataton (compound 41, 1.14 g) was added 2N-NaOH (10 ml) and MeOH (20 ml), and the mixture was stirred at 60 for 2 hours. After adding 2N-HCl (5 ml) under ice-cooling, the mixture was concentrated under reduced pressure, and dried with a vacuum pump. To the residue was added molecular sieves 4 A (2 g) and N, N-si'meth / ^ lumamite * (20 ml), and the mixture was stirred at room temperature for 1 hour. Then, methyl chloromethyl silane (1.95 g) was added and the mixture was stirred at room temperature for 1 minute. The molecular sieve 4A was separated, washed with ethyl acetate, and the washing solution and the washing solution were subjected to pressure reduction. Ethyl acetate was added to the residue, and the mixture was washed with an aqueous HC1 solution and water, and the organic layer was dried over anhydrous sodium sulfate and reduced under reduced pressure.

The residue was subjected to silica gel column chromatography Raffy-Wakogel c-300, 50 g), and eluted with ethyl acetate: hexane = 1: 5 to give compound 42 (1.8 g) as a colorless chip. Obtained.

 (41) (42)

 [2] Compound 42 (400 mg) was dissolved in chloromethane (10 ml), and 500 mg was added to Shiki α mouth Shiruka Shimi (hereinafter abbreviated as DCC) and stirred for 30 ^. Compound 43 (500 mg) and 4-cymethylaminobiricine (30 mg) were added, and the mixture was stirred at room temperature for a while. The insolubles were separated, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (Wakogel c-300, 30 g), eluted with ethyl acetate: hexane = 1: 30, and compound 44 (640 mg ) And obtained as a colorless yaf '.

(44) [C 3] Compound 44 (2.0 g) was dissolved in tetrahydrofuran (30 ml), acetic acid (lml) and 1M-tetrafutylammonium muff W-perfluorohydrofuran solution (6.32 ml) were added, and the mixture was stirred at room temperature for one hour. did. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, insolubles were separated, and the solution was concentrated under reduced pressure.

The residue was subjected to silica gel column chromatography &pgr; Matk 'raffy (Wakogel c-300, 60 g), and ethyl acetate: hexane = 1: 5 "Ci was taken out to obtain compound 45 (1.73 g) as a colorless syrup.

 (45)

 [] Compound 45 (300 mg) was dissolved in chloroform (4 ml), Dess-Martin reagent (522 mg) was added, and the mixture was stirred at room temperature for 30 ^ *. Since the raw material remained, Dess-Manin reagent (250 mg) was added, and 30 minutes later, Dess-Manin reagent (250 mg) was added. After 3 minutes, ether, saturated aqueous sodium carbonate and saturated aqueous sodium thiosulfate were added, and the mixture was stirred for 10 minutes, and the organic layer was washed twice with water. The organic layer was dried over anhydrous sodium sulfate, and subjected to pressure reduction under reduced pressure. The residue was subjected to silica gel column chromatography α-matrix-(Wakogel c-300, 10 g), and eluted with ethyl acetate: hexane = 1: 3 to obtain Compound 46 (220 mg) as a colorless syrup.

(45)

 (46)

[5] Compound 16 (140 mg) was dissolved in water, and after decompression, the mixture was dissolved in a mixture of methanol (12 ml) and N, N-methyl-V * lumami (3 ml) to give compound 46 (220 mg) Then, acetic acid (0.5 ml) was added and stirred for 1 hour. Sodium borohydride (33 mg) was added, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (Wakogel c-300, 15 g) to give cyclomethane D methane: methanol-15 / 1, 10 / 1,5 Eluted in the order of eight. Lyophilization gave Compound 47 (141 mg) as a pale yellow powder. S8

 (46)

, OH ..H

 Elemental analysis value

(As the _{C M H U2 NNaO J2 S ·} 2H 2 0)

 Theory C 57.04% H 8.81% N 1.06%

 Measured value C 57.1 1% H 8.79% N 1.24%

 FAB MAS 1266 (M-Na) '

 Example 35 0- (3-0-S-β-D-force'lactovilanosyl)-(1-4) -0-[(a-lefkohi'lanosyl)-(l → 3) J

-N- [7- [1,3-bis (six years old) 7'n-2-yl] years old / 1 ^ * nilto 3,6-six years old -1,5-Synthetic compound * Synthesis of 1,5-iminum D-quinoline sodium salt

 [1] To triethylene glycol (compound 48) was added 27.5 g of ethyl chlorobenzene (abbreviated as TBDPS) and 300 ml of DMF and dissolved. Under ice-cooling, 0.4 g of Imita's solvent was added and dissolved. The mixture was returned to room temperature, stirred overnight, reduced in pressure, dissolved in ethyl acetate, and washed twice with NaC ice. The organic layer was dried over sulfuric acid, reduced under reduced pressure, and then subjected to silica gel chromatography (ethyl acetate: hexane-5) to give compound 49, 32 g of colorless Sirov '.

OTBDPS

ΗΟ 'Ο HO

 (48)

 (49)

(2) Compound 49, 4.8 g, dichloromethane 100 ml, pyricine 12 ml, Dess-Martin reagent 17 g, After stirring at room temperature overnight, dichloromethane was added and washed twice with water. The organic layer was dried over sodium sulfate, decompressed / dusted, and subjected to column chromatography (NAM600HF254, ethyl acetate: hexane 5) to give a compound 50 tefey mouthpiece and 3.1 g of humiliated _0.

^ ^ OTBDPS

 (49)

 (50)

[3] To 50 and 3.0 g of the compound were added and dissolved 72 ml of hexane and 24 ml of water. Under ice-cooling, 2.9 _{g of} sodium chlorite and 1.5 _g of aminosulfuric acid were added, and the mixture was stirred for 3 days. Cyclohexane was added, the organic layer was washed with brine, and the organic layer was dried over sodium sulfate and concentrated. Then, the mixture was subjected to silica gel α-Matte Raffy (ΝΑΜ-600 HF254, ethyl acetate: hexane = 1 :) to obtain Compound 51, l.lg.

 (51)

 [4] 40 ml of dichloromethane was added to and dissolved the compound 51, 1 g and the compound 52, 2.3 g. Under ice-cooling, DCC 0.75 g and 4-DMAP 60 mg were added, two hours later, water was added, and the mixture was further stirred for 3 minutes. The reaction solution was suctioned and washed with dichloromethane. The combined filtrate and washings were washed with water and dried over sodium sulfate. After the pressure was reduced, the residue was subjected to column chromatography (M-600HF254, ethyl acetate: hexane = 1: 20) to obtain 1.6 g of the compound (53).

 (53)

[5] Compound 53, 4S0mg was dissolved in TOF 15ml, and acetic acid 0.75ml was added. 1N-Tetraphthylammonium muff V THF solution 2ιτ ^ was added and left at 60 for 3 hours. After the temperature of the reaction solution was returned to room temperature, the solution was reduced under reduced pressure and separated with hexane ice. The hexane layer is dried with sodium sulfate :) ¾¾, silica gel column α mat (C-300 acetyl acetate: Hexane-1 to give 310 mg of compound 54

(53)

 (54)

[6] Compound 54 (250 mg) is dissolved in hexane (12 ml) and DMSO (12 ml). To this solution, under ice-cooling, 30 / ^ 1 of viricin, 15 of triacetic acid, and 200 mg of DCC were added. After stirring for 1 hour, 'Sen' was added and washed three times with water. The organic layer was dried over sodium sulfate and subjected to column chromatography (C-300 ethyl acetate: hexane-2: 3) to obtain 152 mg of compound 55.

 (55)

 [7] A reaction was carried out using 12 ttng of compound 16 and 200 mg of compound 55 in the same manner as in Example 34 [5] to obtain 128 mg of the target compound 56.

 (16) + (55)

Selectin binding inhibitory effect of the compound of the present invention

 Test example 1

 1. Materials and Methods

 (υ Reagent

 -PBS: Dulbecco's Phosphate Buffer Saline, manufactured by Nissui Pharmaceutical Co., Ltd.

 -a -MEM: a -Minimum Essential Medium / GIBCO BRL

 -G418: Geneticin ZGIBCO BRL

 • FCS: モ ル fetal serum nomolke '

 • Protein A-Sepha α-Sfacia

 • Anti-mouse IgG aka * Rose / American Corex Corporation

 • BIGI CHINHIUS IgG 77 manufactured by Siam

 -Hexita '-S' (HP) bond Otin-Streff 'Toabishin' complex 77 Sham

 -HRP substrate (To SUMILON T Kinorino Sumitomo '-Krite Co., Ltd.)

• s x-BSA: natural pentasaccharide sialyl Lewis X “0- (5-acetoamide-3,5-cyte * -shiki-D-co-lysate-α-D-force” ratato-2nuroviranosylic acid) -(2 ~ »3) -0- (? -D-forceLactoyl'lanosyl)-(1 ^→ 4) -0-[(α-Lefcoviranosyl)-(1-3)] -0- (2-acetoami -2-te 'sai xy-β -D-ku * rucoviranosyl)-(1 → 3)-β-D-force' lactoviranose 'ゥ ゥ 淸 淸 フ フ フ / A. Hasegawa. Et al Synthesized according to., J. Carbohydr. Chem., 11, 645-658 (1992) J.

• Tetrasaccharide sLex: Natural tetrasaccharide sialyl Lewis X-type sugar chain: 0- (5-acetoami "-3,5-cy'te'oxy-D-co" lycero-a-D-force "lacto 2-nonuloviranosyl Acid>-(2 → 3) -0- (-D-force * lactovilanosyl) · (1 ^→ 4) -0-[(na-lefcoviranosyl)-(1 ~ -3)] Teoxy-D-colucolananose / Synthesis based on "A. Hasegawa. Ctal" J. Carbohydr. Chem., 11, 645-658 (1992) " .

 • Other reagents manufactured by Nonakarai Tesque or Wako Pure Chemical Industries.

 (2) Experimental method

 a.Selectin IgG chimera molecule expressing cells

From each selectin cDNA, a gene sequence coding for a lectin region, an EGF-like region and two complement-binding protein-like regions was amplified by PCR and cloned. Mouse mie mouth-reverse transcription from RNA ^ Was used to produce mouse cDNA. From this cDNA, a gene sequence encoding the CH2, CH3, and Hinshi 'portions of IgGi was amplified by PCR and cloned, and then ligated to the 3' end of each selectin gene. Incorporated into _(P SV 3-neoR) - This chimeric molecule co - the遗伝Ko sequences into an animal cell expression containing a neomycin resistance gene 'connector. This gene was introduced into Chinese Hamster Ovary (CHO) i by electroporation. After gene transfer, the cells were cultured in the presence of G418 (470 g ml), and the grown colonies were separated and cultured. The amount of mouse IgG Fc in the supernatant of each colony was measured by ELISA, and colonies with the highest secretion were selected. From the selected cells, a cell line highly expressing chimeric molecules was obtained by the limiting dilution method. Each high-expressing cell line was cultured and maintained in _a- MEM (maintenance medium) containing 10% FCS and 235 / zg ml of G418 at 37 in a 5% C02 / 5 Air environment.

 b. Purification of the chimeric molecule

The chimera molecule-expressing cells were seeded on 450 cm ² culture feet and cultured using a maintenance medium. The medium was replaced every 2-3 days, and the culture supernatant was collected each time. The collected supernatant was centrifuged at 1.000 rpm for 5 minutes to remove the detached cells or cell fragments, and stored at −20. The stored culture supernatant was rapidly dissolved in ¾ at 37 ° C. and the volume was measured. To lyse the chimeric molecule in the supernatant, ammonium sulfate (60% saturated) was used in the cell supernatant expressing the Ε-selectin chimera molecule and 50% saturated in the cell supernatant expressing the Ρ- and L-selectin chimera molecule. ) Was added. Each saturated ammonium sulfate solution was centrifuged at 8,000 rpm for 20 ^, and the resulting precipitate was suspended in 30 mM Tris buffer (pH 7.4, buffer A) containing a small amount of 0.5 M NaCl. Dialysis was performed at 4 for 10 minutes. The dialyzed solution is centrifuged at 10,000 rpm for 10 minutes, and ^ Us IgGaka 'π-source (10 ml) previously washed with buffer A is added to the supernatant, and mixed in step 4 to adsorb the chimeric molecule. Inverted gently. After washing the aca-rose with double buffer A (150 ml), 30 mM Tris buffer (pH 7.4, 100 ml) and again with buffer A (50 ml), the bound chimeric molecule was washed with 10 mM Tris-HCl (pH Elution was carried out with 3M thiocyan-Na containing 7.4). The pooled eluate was dialyzed against buffer A at 4 ° C., and the amount of chimeric fraction 7 ″ was measured as the amount of mouse IgG Fc by ELISA.

To the purified chimera molecule solution, 0.02% of final Na was added and stored at -80. c. Chimera molecule binding assay system In order to efficiently immobilize sLcx-BSA, dilute (8 μg / ml) with 50 mM charcoal buffer (hereafter referred to as immobilized solution) with ρΗ9.5 to obtain 96-JJ microtiter tubes. (Maxisorp, Nunc, Roskilde, Denmark). The upper surface of the foot was placed with a sealer at −4 晚 C for 4 hours. The contents of ゥ were discarded, and a 5% BSA PBS solution (100 l / wcll) was added. In order to lock the surface, the plate was left at room temperature for 2 hours and then washed three times with a 20 mM Tris buffer solution (pH 7.4, 120 μl well, hereinafter washing solution) containing 0.15 M NaCl.

Each selectin chimeric molecule (0.8 ug / ml), bitinylated 化 tvus IgG antibody (1: 500) and HRP-conjugated bitin-streptavidin * (1: 500) were added in 0.1% BSA, 3 mM The mixture was mixed in a 20 mM Tris buffer (pH 7.4, hereinafter diluent) containing CaCl ₂ and 0.15 M NaCl. The mixture was allowed to stand at room temperature for 1 hour to form a selectin-bitin-strep-to-avicin complex (hereinafter, selectin-ABC).

 The compound was adjusted to a two-fold concentration using the compound, mixed with the same amount of selectin-ABC solution, and allowed to stand at room temperature for 30 ^. The mixed solution was added to sLex-BSA solid-phase gel rt ^ (50 μl / well), allowed to stand at room temperature for 1 hour, and then washed four times with the same amount of washing solution as described above. The washing solution was removed from the tube, HRP substrate solution (100 / zl / wdl) was added, and the mixture was reacted at room temperature with shaking until an appropriate color was obtained. The reaction stop solution (100/1 well) was added, and the absorbance at 450 nm was measured using a Microtritor-Model 3550 (Hi-Rad, Hercules, CA). The same operation was performed in oJ, in which only 'pi-kink' was performed without immobilizing SLex-BSA, and the absorption of ',' kook 'round' (BKG) was measured.

The absorbance of BKG was subtracted from the obtained absorbance, and the untreated absorption:) t¾ was taken as the binding amount 100% (inhibition rate 0%). The binding amount of each selectin at each concentration was determined for each compound, and the 50% inhibition (IC ₃ ) was calculated.

 (3) Bellflower

 Table 1 shows the results. The values in the table are the average of the determined 50% inhibitory concentrations. When an inhibition rate of 3 mg / ml was not determined to be 50% or more, the inhibition rate at that temperature was shown.

The compound of the present invention had a much stronger inhibitory effect on selectin binding than tetrasaccharide sLex, which is a known natural type of lycan. Table 1 Selectin binding inhibitory effect of the compounds of the present invention

 IC, „(« M)

 Compound E-sclcctin P-selectin L-selectin

 Tetrasaccharide SLex 303.5 # 3000 # <3000 # <

 (38.7% *)

 Example 4 3.94 0.838 0.084

 Example 5 300 # <0.289 0 243

 Example 7 0.186 0.672

Example 8 2.69 3.00 ft

 Example 9 300 <300 270 0

 Example 10 300 # <10.7 1 1

 Example 11 3.92 3.15 0.174

 Example 12 300 <6.78 0.171

 Example 13 300 <300 <90.0

 Example 17 300 # <71.3 12 5

 Example 18 67.3 189.3 0.558

 Example 19 174.2 300 <*

 Example 20 300 <300 60.1

 Example 21 0.552 2.45 0.018

 Example 22 0.772 3.99 0.178

 Example 23 300 300 300 24.2

 Example 25 300 <94.1 6.46

 Example 26 0.197 0.275 0.013

 Example 30 0.02 0.27 0.02

 Example 31 0.02 0.15 0.01

 Example 32 0.02 0.18 0.03

 Example 33 0.04 0.25 0.03

 #: μ g / ml, *:% inhibition at 3mg ml

Test example 2

96-well 7 'coated with Kora Kane (Thailand 7I) (Certite C-17 7-toto 96F, Sumitomo HE Klite) was added to venous endothelial cells (HUVECs), manufactured by Seikagaku Corporation. Was cultured on MCDB10 medium (manufactured by Nissui Pharmaceutical Co., Ltd.) and seeded with 2 × 10 all wells / lOO ^ 1 well. 5% <'to D0 ₂ incubator - data - at 48 hours of culture, was replaced with fresh MCDB10 medium, lng inl (140U / ml) of TNF- a (TNF-H Genzyme manufactured> 4.5 hours the HUVECs with After washing each cell with 1001 RPMM640 medium, each of the cells was dispensed with RPMI-1640 medium. Then, the test conjugate 10/1 prepared at a low temperature was added, the mixture was stirred, and the mixture was incubated at 37 with an incubator for 30 minutes. After washing each of the cells: ^ with 100i RPMI-1640 medium (GIBCO BRL), HL-60 cells previously fluorescently labeled with CFSE (manufactured by Dojindo Laboratories) were cultured at 1 × 10 ⁵ cells / 100 / Vwell. The seeds were seeded in each well with a dredge, and the HL-60 cells were attached to HUVECs by incubating them for 20 minutes in an incubator. After the completion of the adhesion treatment, the solution was inverted and centrifuged (800 rpm x 2 minutes) to remove unadsorbed CFSE ^ HL-60 cells. Of 1% Triton-X 100 PBS (-), and CFSE was eluted from the cells by gentle stirring at room temperature for 5 minutes. After precipitation, 50 μl was added to 1 ml of distilled water, and after dilution, the fluorescence intensity of CFSE (excitation wavelength: 496 nm / measurement wavelength: 516 nm) was measured.

As桔果, whereas the IC _5Q values in tetrasaccharide sLex native has been filed with 251 mu g ml, in the present invention the compound of Example 4 showed a 54 g ml and 5 times higher cell adhesion inhibitory activity . Industrial applicability

 As can be seen from the above test examples, the compound according to the present invention has an excellent inhibitory effect on selectin, so that the inflammatory disease ゃ 虛 blood, heart attack, trauma, blood flow recovery after surgical treatment Reperfusion injuries, reperfusion injury after pulmonary hypertension treatment, ischemia-reffifusion injury caused by cryotherapy, muscle blood reperfusion injury caused by traffic accidents, acute nephritis, ARDS, DIC, knee Inflammation, acute lung injury, human cerebral artery occlusion, myocardial ischemia reperfusion injury, various shocks (hemorrhagic shock, infectious shock, etc.), organ transplantation, preservation of transplanted organs, contact dermatitis, arthritis skin It is useful as a prophylactic drug for treating inflammation, pressure ulcers, colitis, various vascular inflammations, arthritis, arteriosclerosis, leukocyte suppression, rheumatism, asthma, infectious diseases, immunological diseases, AIDS, and cancer.

Claims

The scope of the claims 1. An asia oral trisaccharide moranoline derivative represented by the following general formula [I] or a pharmaceutically acceptable metal salt thereof.

 Where R is Represents

 Rl or R2 is either galactobilanosyl or H of all or a part of the hydroxyl groups.  0 _{- S0 3 H, - CH 2} COOH, or one PR ^c R ^d  Represents galactobilanosyl substituted with any of the groups described above, and the other represents fucobilanosyl. A is one (CH ₂ ) m—, one (CH ₂ ) n ~ NR ^e -CO-0-, one CO— 0—, one (CH ₂ ) _n -CO— 0—, -C ₂ H ₄ ( ^{_{OC 2H4) z - NR C -}} CO- 0 -, -C 2 H 4 (0C 2 H) y-OCH 2 - CO- 0-, or represents an (CH _{2) n} one hundred and one. R ^a and R ^b are the same or different and represent a saturated or unsaturated aliphatic hydrocarbon group or a saturated or unsaturated fatty acid residue. R ^c and R ^d are the same or different, and Represents kill or alkoxy. Re represents H or alkyl.  m represents an integer of 0 to 12, and n represents an integer of 2 to 12. y represents an integer of 0 to 3, and z represents an integer of 1 to 4.  2. The compound represented by the general formula [I], which is represented by the following general formula [Ia] or [Ix], or an ashimo-trisaccharide moranoline derivative or a pharmaceutically acceptable metal salt thereof according to claim 1. .

 [la] [ΓΧ]  Where X is  0  II cO One S0 ₃ H, -CH ₂ COOH, or one P—R  Represents c  dO  R RC0 and RdO are the same or different and represent a hydroxyl group, alkyl or alkoxy.  3. The compound represented by the general formula [I] is  0— (3-0—Sulfo / D-galactoviranosyl) 1 (1 → 3) -0— [(-L-fucoviranosyl) 1 (1 → 4)] -Ν- [2,3-bis 1) 5-Didoxy-1,5-imino-D-glucitol,  0— (3—0—sulfo / 5 / 5—D—galactovyranosyl)-(1 → 4) -0 — [(a-L-fucoviranosyl) 1 (1-3)]-N- 〔1,3 —Bis (oleoyl broth 2) —Yiru xycarbonyl) 1,1,5-dideoxy 1,5—Iminnow D—glu 0— (3—0—Sulfo ^ —D—Galactoviranosyl) 1 (1 → 4) -0— [(.1 L-fucoviranosyl) 1 (1-3)] 1 N— [3—CN- (1,3 —Bis (leoyloxy) propane—2-yloxycarbonylamino) propyl] — 1,5-dideo Kissy 1, 5—Iminnow D—Glucitol  0- (3-0-Sulfo- / 3-D-galactoviranosyl)-(1 → 4) -0-[(0-lefcoviranosyl)-(1 → 3)]-N- [7- (1.3-bis ( Oleoyloxy) propane-2-yloxycarbonyl> heptyl]-1,5-dideoxy-1,5-imino-D-glucitol sodium salt,  0- (3-0-Sulfo- / JD-galacto viranosyl)-(1-4) -0-[(a-lefcoviranosyl)-(1-3)]-N- (6-CN-[(1, 3-Bis (oleoyloxy) propane-2-yl) ability rubonyl] amino] hexyl] -1,5-dideoxy-1,5-imino-D-glucitol salt, 0- (3-0-sulfo- -D-Galactoviranosyl)-(1-4) -0- [i-lefcopyranosyl)-(1-3)] -N- [8- [N- [(1,3-bis (oleoyloxy) propane-2-) Yl) oxy-force ruponyl] amino] octyl]-1,5-dideoxy-1,5-imino-D-glucitol salt or  0- (3-0-sulfo- / SD-galactobyranosyl)-(1 → 4) -0-[(aL-fucopyranosyl)-(1-3)]-N- [12- [N-[(1 , 3-Bis (oleoyloxy) propane-2-yl) oxycarbonyl] amino] dodecyl] -1, 5-dideoxy-1, 5-imino-D-glucitol salt Trisaccharide moranoline derivative or pharmaceutically acceptable gold thereof 4. Ra and Rb are both saturated or unsaturated aliphatic hydrocarbon groups, and A is — (CH ₂ ) m—, one (CH ₂ ) n—NR ^e —CO—0—, one (CH ₂ ) n—CO— 0—, -C 2H4 (OC 2 H 4) _z _NR ^e — CO-0-, -C 2 H ₄ (OC ₂ H) y-0 CH 2 CO— 0—, (I) CO—0— or — (CH ₂ ) n-0—, and wherein all or part of H of water contained in a galactose residue and a moranoline residue is substituted with an acyl group; Item 4. The trisaccharide moranoline derivative according to items 1 to 3 or a pharmaceutically acceptable metal salt thereof. R ^e represents H or alkyl. 5. Glycerol derivative represented by the following structural formula [II] c

Ra and Rb are the same or different and represent a saturated or unsaturated aliphatic hydrocarbon group or a saturated or unsaturated fatty acid residue. R ^e represents H or alkyl. p represents an integer of 1 to 11.  6. A compound represented by the structural formula [II] characterized in that a compound represented by the following structural formula [IIa] is reacted with an amino alcohol, and the generated olebamate is oxidized to form an aldehyde. Of the compound to be prepared.

 [Ha]  Ra and Rb are the same or different and represent a saturated or unsaturated aliphatic hydrocarbon group or a saturated or unsaturated fatty acid residue. X represents imidazolyl or phenoxy.  7. A glycerol derivative represented by the following structural formula [III].

Ra and Rb are the same or different and represent a saturated or unsaturated aliphatic hydrocarbon group or a saturated or unsaturated fatty acid residue. R ^e represents H or alkyl. z represents an integer of 1 to 4. 8. Reaction of an amino alcohol [ni a] represented by the following structural formula with a compound represented by the structural formula [IIa] according to claim 6, and oxidation of the generated olebamate form to form an aldehyde form A method for producing a compound represented by the structural formula [III], characterized by producing:

 ΠΠ] z represents an integer of 1 to 4. R ^e represents H or alkyl.  9. A glycerol derivative represented by the following structural formula [IV].

 [IV] R a and R b are the same or different and represent a saturated or unsaturated aliphatic hydrocarbon group or a saturated or unsaturated fatty acid residue. R ^e represents H or alkyl. y indicates an integer of 0 to 3.  10. A glycerol derivative represented by the following structural formula [V].

 [V] Ra and Rb are the same or different and represent a saturated or unsaturated aliphatic hydrocarbon group or a saturated or unsaturated fatty acid residue. R ^e represents H or alkyl. p represents an integer of 1 to 11.  11. A pharmaceutical composition comprising, as an active ingredient, the ash mouth trisaccharide moranoline derivative according to any one of claims 1 to 4, or a pharmaceutically acceptable metal salt thereof. 12. A cell adhesion inhibitor comprising the ash mouth trisaccharide moranoline derivative according to claim 1 or 4 or a pharmaceutically acceptable metal salt thereof as an active ingredient. 13. An anti-selectin agent comprising the ash mouth trisaccharide moranoline derivative according to claim 1 or 4 or a pharmaceutically acceptable metal salt thereof as an active ingredient.  14. An anti-inflammatory agent comprising the asia oral trisaccharide moranoline derivative according to claim 1 or a pharmaceutically acceptable metal salt thereof as an active ingredient.