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WO2008032817A1 - Chaîne de sucre ayant une activité à l'encontre de l'helicobacter pylori - Google Patents

Chaîne de sucre ayant une activité à l'encontre de l'helicobacter pylori Download PDF

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Publication number
WO2008032817A1
WO2008032817A1 PCT/JP2007/067918 JP2007067918W WO2008032817A1 WO 2008032817 A1 WO2008032817 A1 WO 2008032817A1 JP 2007067918 W JP2007067918 W JP 2007067918W WO 2008032817 A1 WO2008032817 A1 WO 2008032817A1
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Prior art keywords
compound represented
formula
group
compound
following formula
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PCT/JP2007/067918
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English (en)
Japanese (ja)
Inventor
Shino Manabe
Kazuyuki Ishii
Yukishige Ito
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Riken
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Priority to JP2008534404A priority Critical patent/JPWO2008032817A1/ja
Publication of WO2008032817A1 publication Critical patent/WO2008032817A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/18—Acyclic radicals, substituted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems

Definitions

  • the present invention relates to a sugar chain having anti-pylori activity, an intermediate of the sugar chain, and a method for producing them.
  • the present invention further relates to an anti-pylori agent comprising the sugar chain as an active ingredient.
  • Helicobacter pylori causes gastritis and is known to act as a recurrence of gastric duodenal ulcer and a prolongation of healing, and its relevance to gastric cancer has also been pointed out. It was discovered in 2004 that a sugar chain having an ⁇ -N-acetylylcosamine structure at the end of the protein O-linked sugar chain Core2 type has antibacterial activity against H. pylori (Non-patent Document 1 and Patent Document 1). Helicobacter pylori inhabits the surface layer of the stomach. On the other hand, the sugar chain on the stomach surface is different from that of gastric gland mucus (inside).
  • Gastric gland mucus has a unique sugar chain with a 4 GlcNAc structure at the non-reducing end.
  • Nakayama et al Introduced this sugar chain into a Lec2 cell, a mutant of CHO cells, by introducing ⁇ 1,4-GlcNActransferase and Core2 / 31,6-GlcNActransferase together with soluble CD43. They synthesized glycoproteins and found anti-H. Pylori activity (Non-patent Document 1 and Patent Document 1).
  • this method can synthesize a sugar chain as a glycoprotein, its supply amount is limited, and the structure of the compound that can be synthesized is also limited due to the substrate specificity of glycosyltransferases. .
  • Non-Patent Document 1 Science 2004, Vol.305, No.5686, pp.1003-1006, M. Nakayama et al.
  • Patent Document 1 International Publication WO2005 / 081904 Publication
  • An object of the present invention is to solve the above-described problems of the prior art. That is, an object of the present invention is to provide a novel sugar chain having anti-pylori activity and a method for producing the same. Means for solving the problem
  • the present inventors have intensively studied to solve the above-mentioned problems, and by reacting a donor for sugar chain synthesis with an acceptor, a novel formula represented by anti-pylori activity) As a result, the present invention has been completed.
  • Ac represents a acetyl group
  • Bn represents a benzyl group
  • MP represents a methoxyphenyl group
  • Phth represents a phthaloyl group
  • a compound represented by the following formula (6) is produced, which comprises reacting a compound represented by the following formula (4) with a compound represented by the following formula (5).
  • a method is provided.
  • a compound represented by the following formula (10) is produced, which comprises reacting a compound represented by the following formula (4) with a compound represented by the following formula (9). A method is provided.
  • a novel compound represented by the formula (1) having anti-pylori activity can be provided by chemical synthesis.
  • a sugar chain having anti-pylori activity can be provided only in a form bound to a glycoprotein, and it is difficult to produce a sufficient amount of sugar chains necessary for biochemical research.
  • the chemical synthesis of the present invention it is possible to synthesize a pure compound in a sufficient amount. It is also easy to synthesize sugar chain derivatives. Since the compound of the present invention has anti-H. Pylori activity, it is effective in removing H. pylori and treats or prevents H.
  • pylori-related diseases for example, stomach, duodenal ulcer, malt lymphoma 'chronic gastritis, gastric cancer, etc.
  • the present invention relates to a compound represented by the formula (1). Further, a compound represented by the following formula (12), a compound represented by the formula (6), (7) or (8), which is a synthetic intermediate of the compound represented by the formula (1), a formula The compound represented by (10) or (11) and the compound represented by formula (4) are also within the scope of the present invention.
  • a synthesis scheme of the compound represented by the formula (1) of the present invention is shown in FIG. 1 and FIG. Details of the reactions shown in FIGS. 1 and 2 are as follows.
  • a compound represented by formula (4) is produced by reacting a compound represented by formula (2) with a compound represented by formula (3). This reaction is carried out by adding N-benzyl-2-amino-6-0 to a suspension containing 2,6-dto-tert-butyl-4-methyl-pyridine, silver trifluoromethanesulfonate and molecular sieve 4A.
  • the compound represented by the formula (6) is produced by reacting the compound represented by the formula (4) with the compound 5.
  • activated molecular sieves (4) were mixed with the compound represented by the formula (4) and compound 5 by CH C1 and N- (phenylthio) - ⁇ -caprolatatam (10 2 mg, 0.460 mmol) can be added, and the mixture can be cooled, and then added by adding Tf ⁇ O.
  • the compound represented by the formula (6) can be converted into the compound represented by the formula (8) via the compound represented by the formula (7) by changing the protecting group of the hydroxyl group. . Specifically, the compound represented by the formula (6) is converted to ammonium cerium 2-tray in CH 3 CN—H 0-toluene.
  • the compound represented by the formula (10) is produced by reacting the compound represented by the formula (4) with the compound 9.
  • a solution containing the compound represented by the formula (4) and the compound 9 in CH C1 and N- (phenylthio) - ⁇ -caprolatatam was added to the activated molecular sieve 4 A, and the mixture was added. After cooling, this can be done by adding Tf 2 O.
  • the compound represented by the formula (11) is produced by mixing the compound represented by the formula (10), the boron-THF complex, and copper trifluoromethanesulfonate (II). To do.
  • the compound represented by the formula (12) can be produced by reacting the compound represented by the formula (8) produced as described above with the compound represented by the formula (11). . Specifically, a mixture of the compound represented by the formula (8), the compound represented by the formula (11), and the molecular sieve 4 A (0.5 g) in CH CI was added at low temperature to boron trifluoride jetyl acetate. The compound represented by the formula (12) can be produced by adding a terate and stirring the mixture at a low temperature (for example, 20 ° C.).
  • the compound represented by the formula (12) can be converted to a compound represented by the formula (1) by deprotecting the protecting group.
  • a compound represented by the formula (12) is suspended in 1-butanol, ethylenediamine is added, and the mixture is heated (for example, 90 ° C.) to obtain de-N-phthaloylated hexasaccharide. .
  • This hexasaccharide is dissolved in 1,4-dioxane, treated with an aqueous NaOH solution, and then neutralized with an aqueous HC1 solution to obtain a deoxy-, ⁇ -acylated hexasaccharide.
  • hexasaccharide is converted into aqueous acetic acid solution Dissolve and hydrogenate over Pd (OH) 2 at 60 ° C.
  • the mixture is filtered, the filtrate is concentrated, the residue is suspended in methanol, and then Ac 0 is added to obtain a compound represented by the formula (1) that is a completely deprotected hexasaccharide. be able to.
  • the present invention further relates to an anti-pylori agent comprising a compound represented by formula (1) as an active ingredient.
  • the anti-pylori agent of the present invention further contains components and additives used for pharmaceuticals, quasi-drugs and the like within the range that does not impair the effects of the present invention.
  • An agent can be optionally selected and used together.
  • the anti-pylori agent of the present invention can be used in combination with pharmaceuticals and quasi-drugs in addition to being used as a single pharmaceutical.
  • the compound represented by the formula (1) of the present invention can be combined with food and drink to exert anti-pylori action. Specific examples of foods and drinks include soft drinks, drinks, health foods, foods for specified health use, functional foods, functionally active foods, dietary supplements, supplements, feeds, feed additives, etc. Health foods or supplements that contain
  • the form of a preparation is not particularly limited, and is in an appropriate form most suitable for the purpose from among preparation forms for oral administration or parenteral administration. Can be selected.
  • Examples of the dosage form suitable for oral administration include tablets, capsules, powders, drinks, granules, fine granules, syrups, solutions, emulsions, suspensions, and chewables. I can help.
  • Formulation forms suitable for parenteral administration include, for example, injections (subcutaneous injection, intramuscular injection, intravenous injection, etc.), external preparations, drops, inhalants, sprays, and the like.
  • Liquid preparations suitable for oral administration for example, solutions, emulsions, syrups, and the like include sugars such as water, sucrose, sorbit, fructose, Daricols such as polyethylene glycol and propylene glycol, sesame oil and olive oil. It can be produced using oils such as soybean oil, preservatives such as p-hydroxybenzoic acid esters, and flavors such as strawberry flavor and peppermint.
  • solid preparations such as capsules, tablets, powders or granules
  • excipients such as lactose, glucose, sucrose and mannitol, starch
  • disintegrants such as sodium alginate, magnesium stearate
  • Lubricants such as talc
  • polybi Binders such as neil alcohol, hydroxypropyl cellulose, and gelatin
  • surfactants such as fatty acid esters, and plasticizers such as glycerin can be used.
  • An injection or infusion formulation suitable for parenteral administration preferably comprises the active ingredient dissolved or suspended in a sterile aqueous medium isotonic with the blood of the recipient.
  • a solution can be prepared using a salt solution, a glucose solution, or an aqueous medium composed of a mixture of salt water and a glucose solution.
  • the dose and frequency of administration of the anti-pylori agent of the present invention can be appropriately set according to various factors including the purpose of administration, the mode of administration, the age, body weight, sex, etc. of the recipient.
  • the dose of active ingredient is 0.;! To 1000 mg / kg per day, preferably;! To 1000 mg / kg.
  • Molecular sieve 4 A (3 g) was activated by heating at 170 ° C under reduced pressure in a 100 mL two-necked round bottom flask. The flask was filled with argon and cooled to room temperature. Donor (compound 4) (410 mg, 0.460 mmol) and acceptor (compound 5) (411 mg, 0.691 mmol) in CH CI (40 mL) and N_ (phenylthio) - ⁇ -caprolatatam (102 mg, 0.460 m mol) was added to the flask. The mixture was cooled to 120 ° C and Tf 2 O (78 ⁇ L, 0. 460 mmol) was added slowly. After the mixture was stirred at 20 ° C. for 45 min, the mixture was quenched with saturated aqueous NaHCO 3 and filtered through celite. The filtrate was extracted with CHC1. Together
  • Molecular sieve 4 A (3 g) was activated by heating at 170 ° C. under reduced pressure in a 100 mL two-necked round bottom flask. The flask was filled with argon and cooled to room temperature.
  • Donor (Compound 4) (424 mg, 0.476 mmol) and Benzinore 2-azido-4,6-0-benzylidene-2-deoxy- ⁇ -D-galactopyranoside (Compound 9) (219 mg, 0.571 mmol )
  • CH CI 40 mL
  • N- (phenylthio) - ⁇ -force prolatatam 105 mg, 0.476 mmol
  • Hexasaccharide was dissolved in 1,4-dioxane (4 mL) and treated with 1 M NaOH aqueous solution (4 mL) at 80 ° C. The mixture was cooled to 0 ° C., neutralized by the addition of 1 M HCl aqueous solution, and the solvent was removed by a stream of nitrogen. The residue was dissolved in methanol and the precipitate was removed by filtration. The filtrate was fractionated by size-exclusion chromatography (S-labeled hadex LH-20, MeOH) to obtain de- ⁇ , ⁇ -asynoleated hexasaccharide.
  • Hexasaccharide was dissolved in 80% aqueous acetic acid (6 mU and hydrogenated over Pd (OH) (50 mg) at 60 ° C.
  • the mixture was syringe filtered (Millipore Millex LG, hydrophilic PTFE 0.2 ⁇ m cartridge), the cartridge was washed with methanol and water, the filtrate was concentrated under reduced pressure, and the residue was suspended in methanol (3 mL). After the addition, the mixture became a clear solution, and then the solution was stirred for 1 hour and concentrated under reduced pressure.
  • Compound 1 (6 mg) was dissolved in water and treated with NaBH (10 mg) at room temperature for 8 hours. The mixture was fractionated by size exclusion chromatography (S-sign hadex LH-20, 1: 1, water MeOH) and lyophilized to obtain Compound 1 ′ (5 mg, 83%) as a white powder.
  • Example 10 p-methoxyphenyl (N-benzyl-2-amino-6-0-benzyl-2-N, 3-0-carbonyl-2-deoxy-a-D-darcobilanosyl)-( 1?> 4)-(6-0-benzyl- ⁇ _D_galactopyranosyl)-(1-> 4) -2-amino- 3,6-di-0-benzyl-2-deoxy- / 3-D- Darcopyrano Cid
  • Phthalimide (318 mg, 0.231 mmol) was dissolved in 1-butanol (8 mL) and ethylenediamine (0.8 mL), and stirred at 80 ° C overnight. After concentration, silica gel column chromatography (14: 1 CH
  • Example 11 p_methoxyphenyl (2-benzylamino-6-0-benzyl-2-deoxy-a _D_ darcobilanosyl)-(1-> 4)-(6-0-benzyl- / 3-D-galactopyr Nosyl)-(1-> 4) -2-Amino-3,6-di-0-benzyl-2-deoxy- ⁇ -D-
  • the oxazolidinone compound (78 mg, 0.074 mmol) was dissolved in 1,4-dioxane (4 mL) and 1 M NaOH (4 mL) aqueous solution and stirred at 60 ° C. for 2 days. The mixture was diluted with ethyl acetate and washed with water. The separated aqueous layer was extracted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography (10: 1 CHC1 / MeOH) to obtain NHBn form (77 mg, 98%).
  • Example 12 p-methoxyphenyl (2-acetamido-2-deoxy-a _D_darcopyranosyl)-(1-> 4)-(13-D-galactopyranosyl)-(1-> 4 ) -2-acetamido-2-deoxy-13-D-darcopyranoside
  • the resin was filtered. After concentration, vacuum dry, add acetic anhydride and methanol ((3: 7, v / v, 10 mL) and stir for 6 hours at room temperature. After concentration, dissolve the residue in MeOH (3 mL) and dissolve. The solution was adjusted to pH 9 with 0.1 M NaOMe, stirred for 3 hours, and neutralized with Amberkist 15. The resin was filtered and concentrated, and then a molecular sieve column ((S-mark hadex LH-20; 1: 1, MeOH-water ), S-pack C-18 cartridge (2: 1, water / MeOH) and purified to obtain NHAc (69 mg, 73%).
  • Example 13 Methyl (N-benzylamino-6-0-benzyl-a _D_darcoviranosyl)-(1_> 4) -2,3,6-tri-0-benzyl-a-D-galactopyrano Sid
  • the oxazolidinone compound (215 mg, 0.237 mmol) was dissolved in 1,4-dioxane (8 mL) and 1 M NaOH (8 mL) aqueous solution and stirred at 80 ° C. overnight. The mixture was diluted with ethyl acetate and washed with water. The separated aqueous layer was extracted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration and concentration, (10: 1 C
  • Example 14 Methyl (2-acetamido-2-deoxy-a _D_darcobilanosyl)-(1_> 4) -a _D -galatatoviranoside
  • the resin was filtered. After concentration, vacuum dry, add acetic anhydride and methanol ((3: 7, v / v, 10 mL) and stir at room temperature for 6 hours. After concentration, dissolve the residue in MeOH (3 mL), The solution was adjusted to pH 9 with 0.1 M NaOMe, stirred for 3 hours, and neutralized with Amberkist 15. After filtration and concentration of the resin, a molecular sieve column ((S mark hadex LH—20; 1: 1, MeOH-water) , Sep-pack C—18 cartridge (1: 1, water / MeOH) to obtain NHAc (66 mg, 73%).
  • Example 15 Methyl (2-benzylamino-6-0-benzyl-2-deoxy-a _D_darcopyranosyl)-(1-> 4)-(6-0_benzyl- / 3-D-galacto Pyranosyl) -2-azido-4-0-benzyl-2-deoxy-a-D-galactopyranoside
  • the oxazolidinone compound (301 mg, 0.276 mmol) was dissolved in 1,4-dioxane (5 mL) and 1 M NaOH (5 mL) aqueous solution and stirred at 80 ° C. overnight. The mixture was diluted with ethyl acetate and washed with water. The separated aqueous layer was extracted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration and concentration, 1 C
  • Example 16 Methyl (2-acetamido-2-deoxy-a-D-darcoviranosyl)-(1-> 4)-( ⁇ D_galactopyranosyl) _2-acetamido-2-deoxy-a _D_galactopyr Nosid
  • the compound of the present invention has anti-H. Pylori activity, it is effective in removing H. pylori and is effective in H. pylori-related diseases (for example, gastric 'duodenal ulcer, maltolymphoma' chronic gastritis, gastric cancer, etc.). Useful for treatment and prevention. Since the compound (sugar chain) of the present invention is originally present in the stomach, it can be expected that there are few side effects.
  • FIG. 1 shows a synthesis scheme (first half) of the sugar chain of the present invention.
  • FIG. 2 shows a synthesis scheme (second half) of the sugar chain of the present invention.

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  • Communicable Diseases (AREA)
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  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)

Abstract

L'invention concerne une nouvelle chaîne de sucre qui a une activité à l'encontre de l'Helicobacter pylori et un procédé de fabrication de celle-ci. À savoir, l'invention concerne un composé représenté par la formule générale suivante (1) : (1) dans laquelle Ac représente un groupe acétyle.
PCT/JP2007/067918 2006-09-14 2007-09-14 Chaîne de sucre ayant une activité à l'encontre de l'helicobacter pylori WO2008032817A1 (fr)

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JP2008534404A JPWO2008032817A1 (ja) 2006-09-14 2007-09-14 抗ピロリ菌活性を有する糖鎖

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JP2006-248936 2006-09-14
JP2006248936 2006-09-14

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010041746A1 (fr) * 2008-10-10 2010-04-15 財団法人野口研究所 Inhibiteur de prolifération de bactérie helicobacter pylori
US8575117B2 (en) 2007-01-12 2013-11-05 The Noguchi Institute Proliferation inhibitor of helicobacter pylori including alpha-n-acetyl-glucosaminyl bond-containing monosaccharide derivatives
WO2014132468A1 (fr) * 2013-03-01 2014-09-04 独立行政法人理化学研究所 Composé à chaîne de sucre et son procédé de production

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004537538A (ja) * 2001-06-29 2004-12-16 バイオティ セラピィーズ コープ 胃疾患を治療するための方法および組成物
JP2007246426A (ja) * 2006-03-15 2007-09-27 Shinshu Univ Ｎ−アセチルグルコサミンの誘導体を含有するピロリ菌増殖抑制剤

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004537538A (ja) * 2001-06-29 2004-12-16 バイオティ セラピィーズ コープ 胃疾患を治療するための方法および組成物
JP2007246426A (ja) * 2006-03-15 2007-09-27 Shinshu Univ Ｎ−アセチルグルコサミンの誘導体を含有するピロリ菌増殖抑制剤

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KAWAKUBO M. ET AL.: "Natural Antibiotic Function of a Human Gastric Mucin Against Helicobacter Pylori Infection", SCIENCE, vol. 305, 2004, pages 1003 - 1006, XP002404566 *
MANABE S. ET AL.: "Synthesis of a Natural Oligosaccharide Antibiotic Active against Helicobacter pylori", JOURNAL OF ORGANIC CHEMISTRY, vol. 72, no. 16, 2007, pages 6107 - 6115, XP003021593 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8575117B2 (en) 2007-01-12 2013-11-05 The Noguchi Institute Proliferation inhibitor of helicobacter pylori including alpha-n-acetyl-glucosaminyl bond-containing monosaccharide derivatives
WO2010041746A1 (fr) * 2008-10-10 2010-04-15 財団法人野口研究所 Inhibiteur de prolifération de bactérie helicobacter pylori
JP5383692B2 (ja) * 2008-10-10 2014-01-08 公益財団法人野口研究所 ピロリ菌増殖抑制剤
US8859511B2 (en) 2008-10-10 2014-10-14 The Noguchi Institute Proliferation inhibitor of Helicobacter pylori bacteria
WO2014132468A1 (fr) * 2013-03-01 2014-09-04 独立行政法人理化学研究所 Composé à chaîne de sucre et son procédé de production
JPWO2014132468A1 (ja) * 2013-03-01 2017-02-02 国立研究開発法人理化学研究所 糖鎖化合物および糖鎖化合物の製造方法

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