WO1995001361A1 - Derive de galactosylmoranoline - Google Patents

Derive de galactosylmoranoline Download PDF

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Publication number
WO1995001361A1
WO1995001361A1 PCT/JP1994/001080 JP9401080W WO9501361A1 WO 1995001361 A1 WO1995001361 A1 WO 1995001361A1 JP 9401080 W JP9401080 W JP 9401080W WO 9501361 A1 WO9501361 A1 WO 9501361A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
galactoviranosyl
toviranosyl
deoxy
mmol
Prior art date
Application number
PCT/JP1994/001080
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 AU70835/94A priority Critical patent/AU7083594A/en
Publication of WO1995001361A1 publication Critical patent/WO1995001361A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/26—Preparation of nitrogen-containing carbohydrates
    • 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 novel galactosylmoranoline derivative represented by the following general formula [I].
  • R represents an acyl, aryloxycarbonyl, alkyloxycarbonyl or aralkyloxycarbonyl having 1 to 18 carbon atoms which may contain an unsaturated bond.
  • R 2 represents a hydroxyl group or acetamide.
  • R 3 and R are different from each other and represent a hydroxyl group or 1-galactosyl.
  • R 5 represents hydrogen, or R 5 and R 1 together represent carbonyl.
  • the compound according to the present invention is a useful starting material when a sialyl Lewis type sugar chain derivative, which is a sugar chain antigen useful as a medicine, is produced by enzymatic synthesis using fucosyltransferase.
  • sialyl Lewis-type carbohydrate antigen acts as an epitope when leukocytes cause cell adhesion to vascular endothelial cells at sites of inflammation (Lowe, JB, etc; Cell, 63, 475- 484 (1990)).
  • the tetrasaccharide sialyl Lewis-type sugar chain derivative containing galactosylmoranoline as a component according to the present invention has an effect of inhibiting cell adhesion and is useful as a pharmaceutical.
  • International Application No. PCT / JP93 / 00106 since the international application is for producing a sialyl Lewis-type sugar chain derivative purely by organic chemical synthesis, the production cost and the yield / yield are disadvantageous.
  • An object of the present invention is to provide a method for synthesizing an enzyme capable of using fucosyltransferase and sialyltransferase in order to enable high-yield synthesis of a sialyl Lewis-type sugar chain derivative that is useful as a medicament.
  • the present invention provides a novel substance as a starting material in the production of a sylyl Lewis-type sugar chain derivative by the above method. Disclosure of the invention
  • R 1 represents an acyl, aryloxycarbonyl, alkyloxycarbonyl or aralkyloxycarbonyl having 1 to 18 carbon atoms which may contain an unsaturated bond.
  • R 2 represents a hydroxyl group or acetamide.
  • R 3 and R 4 are different from each other and represent a hydroxyl group or 1-galactosyl.
  • R 5 represents hydrogen, or R 5 and R 1 are linked together to represent carbonyl.
  • the compound according to the present invention is a substance not described in the literature.
  • the acyl represented by 1 is preferably a linear or branched, saturated or unsaturated one having 1 to 18 carbon atoms which may contain an aromatic hydrocarbon.
  • Phenyloxycarbonyl is preferred as aryloxycarbonyl.
  • alkyloxycarbonyl linear or branched ones having 2 to 10 carbon atoms, which are saturated or unsaturated, are preferable, and methoxycarbonyl, t-butoxycarbonyl and the like are more preferable.
  • aralkyloxycarbonyl benzyloxycarbonyl, phenylethoxycarbonyl, phenylpropoxycarbonyl and the like are preferable.
  • the sialyl Lewis-type sugar chain derivative filed by the applicants internationally is basically a tetrasaccharide sugar composed of ⁇ (2-3) sialyl and a (1 ⁇ 3 or 1 ⁇ 4) fucosylated lactosamino structure. Chain antigen.
  • a synthesis method using a glycosyltransferase is generally used.
  • fucosyltransferase which is an essential enzyme for enzymatic synthesis of sialyl Lewis-type sugar chain derivatives, has the basicity of galactosylmoranoline when R 1 is a hydrogen atom in general formula (I). Therefore, it is known that as a result of strongly inhibiting fucosyltransferase, it cannot catalyze the transfer reaction of fucose (J. Am. Chem. Soc. 1992. 114. 9283-9298).
  • the present inventors changed the R 1 of the compound of the present invention represented by the general formula [I] to acyl, alkyloxycarbonyl, aralkyloxycarbonyl, etc., and lost the basicity of galactosylmoranoline. As a result, they discovered that they did not inhibit fucosyltransferase activity, and consequently completed the present invention which enabled the enzymatic synthesis of sialyl Lewis-type sugar chain derivatives by enabling the transglycosylation reaction by fucosyltransferase. did.
  • the compound according to the present invention enables production of a sialyl Lewis-type sugar chain derivative using fucosyltransferase, and is useful as a starting material at that time. This time, by making it possible to produce sialylglycan derivatives using fucosyltransferase, sullabylglycan derivatives can be induced. Conductors can be manufactured efficiently and in large quantities.
  • Examples of the compound 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. These are examples of the — part of the compound of the present invention. The compounds are not limited to these.
  • 1,3-galactosyl 2-acetamido 2—doxymoranolin (compound 8) was synthesized, and then moranolin was synthesized. After reacting with a suitable reagent that reacts with the nitrogen atom, -1,4-galactosyl 2-acetamido 2-N-substituted derivative of deoxymoranolin or /? — 1,3-galactosyl Shows a route for synthesizing N- substituted derivatives of over 2 Aseta Mi de one 2-Doki Shimoranorin.
  • a preferred method is exemplified by dissolving Compound 7 in an aqueous acetic acid solution and reacting at room temperature to 1001 C for several tens minutes to several hours to obtain an acid. Perform hydrolysis. Then, it is dissolved in a solvent such as methanol, ethanol, ethyl acetate, acetic acid, etc., and in a hydrogen atmosphere, using a catalyst such as palladium-carbon, at room temperature to 50 at normal pressure or under pressure for several tens of minutes to 2 days. Let react.
  • a solvent such as methanol, ethanol, ethyl acetate, acetic acid, etc.
  • Cleavage of the benzylidene ring can be performed, for example, by dissolving Compound 2 in a suitable solvent such as tetrahydrofuran and adding an excess amount of sodium cyanoborohydride in the presence of a powdery desiccant such as Molecular Sieve 3 ⁇ . After that, the reaction can be performed by stirring and reacting at room temperature for several hours usually while dropwise adding a hydrogen chloride noether solution.
  • the coupling reaction, deprotection reaction and product isolation operation for obtaining the target compound 5 from the compound 3 can be carried out in the same manner as described above.
  • compound 6 (wherein X represents acyl, aryloxycarbonyl, alkyloxycarbonyl and aralkyloxycarbonyl) and compound 9 (wherein X is a compound according to the present invention) Wherein X is acyl, aryloxycarbonyl, alkyloxycarbonyl and aralkyloxy
  • X is acyl, aryloxycarbonyl, alkyloxycarbonyl and aralkyloxy
  • compound 5 and compound 8 are dissolved in methanol, dimethylformamide, a mixed solvent thereof, etc., and acetic anhydride, trifluoroacetic anhydride, butyric anhydride, crotonic anhydride, and stearic anhydride are dissolved.
  • the reaction can be carried out usually by adding an acid anhydride such as phthalic anhydride and reacting at room temperature for several hours to several days.
  • acid halides such as acetyl chloride, trifluoroacetyl chloride, stearate chloride, and phthalyl chloride are dissolved in the same solvent, and sodium carbonate, sodium hydrogen carbonate, and potassium carbonate are dissolved.
  • the reaction can be carried out by adding an inorganic or organic basic compound such as potassium hydrogencarbonate, pyridine, or triethylamine and reacting the mixture at room temperature for several hours to several days, and t-butyl chloroformate, benzyl chloroformate, etc. Can be carried out in the same manner by using various chloroformates of the above.
  • the present invention will be described in more detail with reference to Reference Examples and Examples of the present invention.
  • the measured temperature of the optical rotation was 20 tons. (Reference example)
  • Scheme 2 shows a typical synthetic route for /? — D-galactobyranosyl (1-4) -molanolin (compound 17).
  • Scheme 2 Synthesis of D-galactobilanosyl- (1 ⁇ 4) -molanolin
  • Example 10 0——D—galacto viranosyl (1-4) —N— (tert-butoxycarbonyl) moranoline (compound 18)
  • reaction solution was concentrated under reduced pressure, dissolved in chloroform, poured into ice water, and the organic layer was washed with hydrochloric acid and water in that order. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography Wakoge 1C-300, 100 g, and eluted with dichloromethane Z methanol (80/1) to obtain Compound 25 as a foamy solid (1.8 g, yield 97.33 ⁇ 4). .

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Microbiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Saccharide Compounds (AREA)

Abstract

Nouveau dérivé de galactosylmoranoline représenté par la formule (I), dans laquelle R1 représente acyle C¿1?-C18 éventuellement insaturé, aryloxycarbonyle, alkyloxycarbonyle ou aralkyloxycarbonyle; R?2¿ représente hydroxy ou acétamido; R3 et R4 sont différents l'un de l'autre et représentent respectivement hydroxy et 1-galactosyle; R5 représente hydrogène ou est combiné avec R1 pour représenter carbonyle. Le composé (I) est efficace en tant que matériau de départ de synthèse enzymatique au moyen de fucosyltransférase d'un dérivé sialyle de chaîne glucidique de Lewis qui est un dérivé de chaîne glucidique efficace en tant que médicament.
PCT/JP1994/001080 1993-07-02 1994-07-01 Derive de galactosylmoranoline WO1995001361A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU70835/94A AU7083594A (en) 1993-07-02 1994-07-01 Galactosylmoranoline derivative

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP19092593 1993-07-02
JP5/190925 1993-07-02

Publications (1)

Publication Number Publication Date
WO1995001361A1 true WO1995001361A1 (fr) 1995-01-12

Family

ID=16265975

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1994/001080 WO1995001361A1 (fr) 1993-07-02 1994-07-01 Derive de galactosylmoranoline

Country Status (2)

Country Link
AU (1) AU7083594A (fr)
WO (1) WO1995001361A1 (fr)

Cited By (2)

* 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

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02215394A (ja) * 1989-02-14 1990-08-28 Nippon Shinyaku Co Ltd モラノリン誘導体の製法
WO1991018915A1 (fr) * 1990-06-08 1991-12-12 Merrell Dow Pharmaceuticals Inc. NOUVEAUX INHIBITEURS D'α-GLUCOSIDASE

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02215394A (ja) * 1989-02-14 1990-08-28 Nippon Shinyaku Co Ltd モラノリン誘導体の製法
WO1991018915A1 (fr) * 1990-06-08 1991-12-12 Merrell Dow Pharmaceuticals Inc. NOUVEAUX INHIBITEURS D'α-GLUCOSIDASE

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
J. CARBOHYDRATE CHEMISTRY, Vol. 11, No. 5, 1992, MAKOTO KISO et al., pages 627-644. *

Cited By (2)

* 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

Also Published As

Publication number Publication date
AU7083594A (en) 1995-01-24

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