WO1995006057A1 - Derive de galactosylmoraniline - Google Patents

Derive de galactosylmoraniline Download PDF

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Publication number
WO1995006057A1
WO1995006057A1 PCT/JP1994/001371 JP9401371W WO9506057A1 WO 1995006057 A1 WO1995006057 A1 WO 1995006057A1 JP 9401371 W JP9401371 W JP 9401371W WO 9506057 A1 WO9506057 A1 WO 9506057A1
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WO
WIPO (PCT)
Prior art keywords
carbon atoms
alkyl
compound
moranoline
galact
Prior art date
Application number
PCT/JP1994/001371
Other languages
English (en)
Japanese (ja)
Inventor
Tadaaki Ohgi
Yohsuke Kyotani
Hirotsugu Ogawa
Yohji Ezure
Original Assignee
Nippon Shinyaku Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nippon Shinyaku Co., Ltd. filed Critical Nippon Shinyaku Co., Ltd.
Priority to AU74673/94A priority Critical patent/AU7467394A/en
Publication of WO1995006057A1 publication Critical patent/WO1995006057A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms

Definitions

  • the present invention relates to a galactosylmoranoline derivative useful as a starting material when synthesizing complex sugar chains of sialyl Lewis X type and sialyl Lewis A type which are useful as anti-inflammatory agents, cancer treatments, diagnostic agents, and the like.
  • sialyl Lewis type X and sialyl Lewis type A carbohydrate antigens act as ligands for leukocytes in causing cell adhesion to vascular endothelial cells at sites of inflammation (Lowe, JB, etc; Cels). l, 63, 475-48 (1990)) o
  • sialyl Lewis type sugar chain derivative to the pharmaceutical field and the total synthesis of the sialyl Lewis type sugar chain derivative have been actively studied and achieved with success.
  • the present invention aims to provide a useful intermediate that enables large-scale synthesis of a sialyl Lewis-type sugar chain derivative that is useful as a medicament in a low yield and on an industrial scale.
  • R 1 is carboxyl, lower alkoxycarbonyl, lower alkoxycarbonylaryloxy, lower alkoxycarbonylamino, amino, aroylamino, alkoxyamino, lower alkylamino, dirubamoyl, Lower alkyl alkyl, hydroxyl, lower alkoxy, arylo, aryloxycarbonyl, aralkyloxy, lower alkyl, lower cyclic alkyl, epoxy or aryl which may be substituted, alkyl having 1 to 20 carbon atoms, 10 carbon atoms The following alkenyl, alkynyl having 10 or less carbon atoms or aralkyl having 10 or less carbon atoms are represented.
  • R 2 represents a hydroxyl group or an acetamide group.
  • R 3 and R 4 are different from each other and represent water or a galactosyl group.
  • alkenyl having 10 or less carbon atoms represented by R 1 includes aryl, 2-butenyl, 5-hexenyl and 9-decenyl.
  • examples of the alkynyl represented by R 1 having 10 or less carbon atoms include 2-propynyl.
  • aralkyl having 10 or less carbon atoms which may have a substituent.
  • These aralkyls may have a substituent selected on the benzene ring which is arbitrarily selected from the group consisting of water, carboxy, lower alkyl, lower alkoxy, lower acylamino and lower alkylamino. And the like.
  • the alkyl, alkenyl and alkynyl represented by R 1 are carboxyl, lower alkoxycarbonyl, lower alkoxycarbonylaryloxy, lower alkoxycarbonylamino, amino, aryloamino, lower alkoxyamino, It may be substituted with a lower alkylamino, a carbamoyl, a lower alkyl rubamoyl, a hydroxyl group, a lower alkoxy, an aroyl, an aryloxycarbonyl, an aralkyloxy, a lower alkyl, a lower cyclic alkyl, an epoxy or aryl.
  • R 2 represents a hydroxyl group or acetamide.
  • R 3 and R 4 are different from each other and represent a hydroxyl group or a 1-galactosyl group.
  • the present applicants have found tetrasaccharide sialyl Lewis-type sugar chain derivatives having excellent pharmacological activity, and have filed an international application (PCT / JP93 / 00106).
  • the tetrasaccharide sialyl Lewis type sugar chain derivative according to the international application is a tetrasaccharide sugar chain antigen composed of a (2-3) sialyl and a (1-3 or 1 ⁇ 4) fucosylated lactosamine structure.
  • the sialyl Lewis type sugar chain derivative is a western sugar compound having excellent pharmacological activity, containing molanolin as a constituent sugar.
  • Examples of the compounds according to the present invention include the following compounds in addition to the compounds described in the examples relating to the production method described below, but these are examples of some of the compounds of the present invention.
  • the invention compound is not limited to these.
  • compound 8 it is effective to treat it with a strongly acidic ion exchange resin, taking advantage of the fact that it is converted into a water-soluble basic compound as a result of deprotection. That is, the S solution was passed through a strongly acidic ion-exchange column such as Dowex 50W X 2 or DIAION SK-106, etc., and thoroughly washed with methanol, water, aqueous methanol, etc. After that, means such as elution with aqueous ammonia is effective.
  • a strongly acidic ion-exchange column such as Dowex 50W X 2 or DIAION SK-106, etc.
  • Cleavage of the benzylidene ring can be accomplished, for example, by dissolving compound 2 in a suitable solvent such as tetrahydrofuran and adding an excess of sodium cyanoborohydride in the presence of a powdery desiccant such as molecular sieves 3 ⁇ . Thereafter, the reaction can be carried out by stirring and reacting at room temperature for several hours usually while dropwise adding a hydrogen chloride-ether solution.
  • a suitable solvent such as tetrahydrofuran
  • the force-pulling reaction to obtain the desired compound 5 from the compound 3, de-, and the product isolation can be carried out in the same manner as described above.
  • compounds 6 (wherein R 1 represents a hydrogen, alkyl or aralkyl group) and compound 9 (where R 1 represents a hydrogen, alkyl or aralkyl group)
  • compounds 5 and 8 are dissolved in a solvent such as methanol or hydrated methanol, and appropriate aldehydes such as formaldehyde, ⁇ -butyraldehyde, ⁇ -pandecylaldehyde and sodium cyanoborohydride are added, and acetic acid and the like are added.
  • a solvent such as methanol or hydrated methanol
  • appropriate aldehydes such as formaldehyde, ⁇ -butyraldehyde, ⁇ -pandecylaldehyde and sodium cyanoborohydride are added, and acetic acid and the like are added.
  • it can be carried out usually at room temperature for several hours to several days with ⁇ 4.
  • ⁇ , ⁇ -dimethy Dissolve in formamide, etc. and add suitable alkyl halides such as n-butyl bromide and benzyl bromide, and aralkyl halides in the presence of inorganic basic compounds such as sodium carbonate, sodium carbonate, potassium carbonate, and potassium carbonate, usually at room temperature. It can be carried out for several hours to several days at ⁇ 80.
  • 1,2,3,4,6-Penta-0-acetyl- -D-galactobiranose 50 g, 128 mmol
  • dichloromethane 500 ml
  • ethanethiol 14.2 ml, 192 mmol
  • boron trifluoride getyl ether 18.9 ml, 154 parts
  • the compound 17 (300 mg, 0.92 mol) was dissolved in 2 ml of water, and 8 ml of methanol was added. After adding sodium cyanoborohydride (67 mg, 1.06 mmol) and an aqueous solution of formalin (37 °) (140 ⁇ 1, 1.72 mmol), the mixture was adjusted to pH 4 with acetic acid and stirred at room temperature. On the way, sodium cyanoborohydride (30 mg, 0.48 mmol) and an aqueous solution of formalin (373 ⁇ 4) (140 ⁇ 1.72 ol) were added and allowed to stand for 6 hours.
  • the reaction solution was concentrated under reduced pressure, diluted with water, poured on a diagonal fat and oil (Dowex 50wx2 (H +), 15 ml), washed with water, and eluted with an aqueous IN-ammonia solution.
  • the eluate was concentrated under reduced pressure, and crystallized from methanol-ethanol to obtain 234 mg (yield 78.4%) of white powdery crystals.
  • Example 4.0 Synthesis of 0--D-galactopyranosyl- (1 ⁇ 4) -N- (n-pandecyl) moranoline
  • Compound 17 300 mg, 0.92 mmol
  • 8 ml of methanol was added.
  • sodium cyanoborohydride (7 g, 1.19 mmol) and n-pandecylaldehyde (600 ⁇ 1, 2.91 mmol) the mixture was adjusted to pH 4 with acetic acid and stirred at room temperature for 15 hours.
  • reaction solution was applied to a cation exchange resin (Dowex 50wx2 (H +), 15 ml), washed with methanol, and eluted with a 1N aqueous solution of monoammonia Z methanol / 2. After the eluate was concentrated under reduced pressure, it was crystallized from chloroform-methanol to give 230 mg (52% yield) of white powdery crystals.
  • a cation exchange resin Dowex 50wx2 (H +), 15 ml
  • the compound 17 (300 mg, 0.92 marl ol) was dissolved in about .5 ⁇ 1 and 7 ml of methanol was added.
  • Sodium cyanoborohydride (60mg, 0.95mmol), Terephthalaldehyde acid
  • the eluate was concentrated under reduced pressure, the residue was applied to an anion exchange resin (Dowex 1x2 ( ⁇ ), 15 ml), washed with water, and eluted with a 1N-g ⁇ f solution. .
  • the eluate was concentrated under reduced pressure and crystallized from methanol-ethyl acetate to obtain 360 mg of white powdery crystals (yield: 85.0%).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Saccharide Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Le nouveau dérivé de galactosylmoraniline qui est représenté par la formule (I) ci-dessous est un intermédiaire pour un dérivé de la chaîne sialyle-sucre de Lewis utilisée comme médicament. Dans cette formule, R1 représente un alkyle C¿1?-C20, un alcényle C10 ou inférieur, un alcynyle C10 ou inférieur, les uns ou les autres pouvant être remplacés par un carboxy, un alcoxycarbonyle inférieur, un alcoxycarbonylaryloxy inférieur, un alcoxycarbonylamino inférieur, un amino, un aroylamino, un alcoxyamino inférieur, un alkylamino inférieur, un carbamoyl, un alkylcarbamoyle inférieur, un hydroxy, un alcoxy inférieur, un aroyle, un aryloxycarbonyle, un aralkyloxy, un alkyle inférieur, un cycloalkyle inférieur, un époxy ou un aryle; R?2¿ représente un hydroxy ou un acétamido; R3 et R4 sont différents l'un de l'autre, et représentent chacun soit un hydroxy, soit un 1-galactosyle.
PCT/JP1994/001371 1993-08-23 1994-08-19 Derive de galactosylmoraniline WO1995006057A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU74673/94A AU7467394A (en) 1993-08-23 1994-08-19 Galactosylmoranoline derivative

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP23101493 1993-08-23
JP5/231014 1993-08-23

Publications (1)

Publication Number Publication Date
WO1995006057A1 true WO1995006057A1 (fr) 1995-03-02

Family

ID=16916898

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1994/001371 WO1995006057A1 (fr) 1993-08-23 1994-08-19 Derive de galactosylmoraniline

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AU (1) AU7467394A (fr)
WO (1) WO1995006057A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5965544A (en) * 1995-09-29 1999-10-12 Glycim Oy Synthetic multivalent sLex containing polylactosamines and methods for use
US6191271B1 (en) 1997-09-05 2001-02-20 Glycim Oy Synthetic divalent sLex containing polylactosamines and methods for use
US6294159B1 (en) 1998-10-09 2001-09-25 Colgate Palmolive Company Volumizing hair care compositions

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991018915A1 (fr) * 1990-06-08 1991-12-12 Merrell Dow Pharmaceuticals Inc. NOUVEAUX INHIBITEURS D'α-GLUCOSIDASE
WO1993015098A1 (fr) * 1992-01-31 1993-08-05 Nippon Shinyaku Co., Ltd. Derive d'une chaine de sucre du type lewis

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991018915A1 (fr) * 1990-06-08 1991-12-12 Merrell Dow Pharmaceuticals Inc. NOUVEAUX INHIBITEURS D'α-GLUCOSIDASE
WO1993015098A1 (fr) * 1992-01-31 1993-08-05 Nippon Shinyaku Co., Ltd. Derive d'une chaine de sucre du type lewis

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 117, 1992, Abstract Number 49105. *
J. AM. CHEM. SOC., Vol. 114, No. 24, 1992, (YOSITAKA ICHIKAWA et al.), pages 9283-98. *
J. CARBOHYDR. CHEM., Vol. 11, No. 5, 1992, (MAKOTO MISO et al.), pages 627-44. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5965544A (en) * 1995-09-29 1999-10-12 Glycim Oy Synthetic multivalent sLex containing polylactosamines and methods for use
US6191271B1 (en) 1997-09-05 2001-02-20 Glycim Oy Synthetic divalent sLex containing polylactosamines and methods for use
US6294159B1 (en) 1998-10-09 2001-09-25 Colgate Palmolive Company Volumizing hair care compositions

Also Published As

Publication number Publication date
AU7467394A (en) 1995-03-21

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