WO1997048712A1 - Derives asialotrisaccharide moranoline et medicaments - Google Patents

Derives asialotrisaccharide moranoline et medicaments Download PDF

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Publication number
WO1997048712A1
WO1997048712A1 PCT/JP1997/002069 JP9702069W WO9748712A1 WO 1997048712 A1 WO1997048712 A1 WO 1997048712A1 JP 9702069 W JP9702069 W JP 9702069W WO 9748712 A1 WO9748712 A1 WO 9748712A1
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compound
force
bis
saturated
added
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PCT/JP1997/002069
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English (en)
Japanese (ja)
Inventor
Tadaaki Ohgi
Kouichi Ishiyama
Kazuya Mori
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Nippon Shinyaku Co., Ltd.
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Priority to AU31074/97A priority Critical patent/AU3107497A/en
Publication of WO1997048712A1 publication Critical patent/WO1997048712A1/fr

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    • 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

  • alkoxy examples 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.
  • Preferred compounds of the present invention include, for example,
  • a reaction solvent methanol, water, tetrahydrofuran, ⁇ , ⁇ -dimethylformamide, and the like can be used.
  • a weakly acidic cow such as acetic acid
  • 1 to 1 mol of the raw material (1) is used under a weakly acidic cow such as acetic acid.
  • 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.
  • 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.
  • a solvent for example, in a temperature range of 0 to 100 for 1 to 48 hours.
  • the reaction solvent include ⁇ , ⁇ -dimethylformamide, pyridine, toluene, tetrahydrofuran, and chloroform.
  • 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.
  • 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-:
  • 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.
  • each of Ra and Rb is a saturated or unsaturated aliphatic hydrocarbon group, and A is — (CH 2 ) m-
  • A is — (CH 2 ) m-
  • 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.
  • the “acyl group” is used as a water reservoir, and includes, for example, an acetyl group, a benzoyl group, and a levulinyl group.
  • 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
  • the starting compound (3) can be produced, for example, according to the above reaction formula.
  • the alcohol derivative (9) is reacted with, for example, ⁇ , ⁇ '-carbonyldiimidavour in a solvent such as pyridine, DMF (N, N-dimethylformamide), THF (tetrahydrofuran) at Ot: ⁇ 100.
  • a solvent such as pyridine, DMF (N, N-dimethylformamide), THF (tetrahydrofuran) at Ot: ⁇ 100.
  • an imidazole derivative can be obtained.
  • 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.
  • a salt such as pyridine or triethylamine
  • the starting compound (4) can be produced, for example, by reacting the alcohol derivative R-OH (9) with ⁇ , ⁇ ′-carbodidiimidazole, phenyl carbonate, or phosgene.
  • 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.
  • 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.))
  • 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 (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.
  • 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.
  • 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.
  • 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.
  • an appropriate solvent such as chlororum, dichloromethane, pyridine, ether, benzene, THF, DMF, or the like, and pyridine, triethylamine, dimethylaniline, or the like.
  • — 1 O 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.
  • 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.
  • the starting compound (8) can be produced, for example, according to the above formula J3 ⁇ 4.
  • the alcohol derivative (9) is reacted with, for example, ⁇ , ⁇ '-carbonyldiimidazole and pyridine, ⁇ , ⁇ -dimethylformamide (DMF), tetrahydrofuran (THF), etc. at a ratio of 0: to 100.
  • 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.
  • a phenyl carbonate derivative obtained 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.
  • a base such as triethylamine may be added to promote the reaction.
  • 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.
  • 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.
  • 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.
  • the compound of the present invention 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
  • compositions according to the present invention are 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Dissolve 5 (5.9 g) in pyridine (300 ml), add viricinyl sulfur trioxide complex (6.0 g), Time ⁇ ⁇ '. 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.
  • 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 ⁇ -form to obtain compound 13 (10.1 g).
  • the above compound can be synthesized by the method described in Example 19 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.
  • the above compound can be synthesized by the method of Example 3 described in the specification of PCT / JP 6/01146.
  • 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.
  • 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). ⁇ , ⁇ '-carbo * ni * imi ⁇ 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).
  • 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) ⁇ ⁇ ⁇ ' imi (hereinafter abbreviated as DCC: 138 g) in 'chloromethane (100 ml) over 30 30. .
  • DCC 'chloromethane
  • 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.
  • Example 10 0- (3-0-phosphono-?-D-force'lactovilanosyl) ⁇ (1 ⁇ 4 ) -0-[( ⁇ -lefcoviranosyl)-(1-3)]- ⁇ - [3- ( ⁇ -((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
  • reaction solution was concentrated under reduced pressure, and purified by silica gel chromatograph raffy (Wakogel C-300, elution with cyclochloromethane-methanol).
  • silica gel chromatograph raffy Wang Chemical Company LLC, 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.
  • Example 12 0- (3-0-ca ⁇ 'xymethyl- -D-force * labyranosyl)-(1 ⁇ 4) -0-[( ⁇ -lefcoviranosyl)-(1-3)] - ⁇ - [3- ( ⁇ -((1,3-S) ( ⁇ - ⁇ --2-yl) oxycarbo * nil ⁇ amino) ⁇ ⁇ ⁇ -bil) -1,5- ⁇ Of 1,5-imino-D-quinitol sodium salt
  • the residue was purified by silica gel chromatography 7- (Wakogel C-300, silica ⁇ -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.
  • 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
  • Example 17 0- (3-0- ⁇ *--D-force * lactovilanosyl)-(1 ⁇ 4) -0-[(a-lefucoviranosyl)-(1-3)]-N- [3- [ ⁇ '-[1,3-bis (hexanoy; W xy) 7.lohan'-2-yl] xoxicarnil] aminoph'mouth pill] -1,5-cy Synthesis of D-Cyrus-Lunarium Salt
  • 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 ⁇ -Hil] -1,5-Si * Te * Sai Kishi -1,5-Imin D-Kent * Synthesis of sodium salt
  • 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.
  • 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.
  • Example 30 0- (3-0-s ⁇ -/?-D-force'lactovilanosyl)-(l-4) -0-[(a-lefcohi'lanosyl)-(1-3)]-N- [ 6- ( ⁇ - (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 ⁇ '-ethyl) cal /, moyl-1,3-sh Synthesis was performed by the method described above to obtain 238 mg of eye!
  • 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 '
  • Example 9 2-0- (11-homylpente * sil) cal, 'moyl-1,3-si'- ⁇ -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.
  • 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.
  • 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 (1 ⁇ 2h. 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.
  • DMAP 4-methylaminobilysine
  • 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
  • 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.
  • -PBS Dulbecco's Phosphate Buffer Saline, manufactured by Nissui Pharmaceutical Co., Ltd.
  • -a -MEM a -Minimum Essential Medium / GIBCO BRL
  • 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) " .
  • 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.
  • a- MEM maintenance medium
  • 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 3 ⁇ 4 at 37 ° C. and the volume was measured.
  • the absorbance of BKG was subtracted from the obtained absorbance, and the untreated absorption:) t3 ⁇ 4 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.
  • 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.

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Abstract

L'invention concerne de nouveaux dérivés asialotrisaccharide moranoline représentés par la formule générale (I), qui inhibent les sélectines et ainsi sont utiles dans le traitement de maladies telles que l'inflammation. Dans la formule (I), R représente (a) ou bien (b); l'un de R1 et R2 représente galactopyranosyle éventuellement substitué au niveau de la totalité ou de certains des groupes hydroxyles par -SO¿3?H, -CH2COOH ou bien (c), tandis que l'autre représente fucopyranosyle; A représente -(CH2)m-, -(CH2)n-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- ou bien -(CH2)n-O-; R?a et Rb¿ sont identiques ou différents et chacun représente un groupe hydrocarbure saturé ou insaturé ou bien un résidu acide gras saturé ou insaturé; Rc et Rd sont identiques ou différents et chacun représente hydroxy, alkyle ou alcoxy; et Re représente H ou alkyle.
PCT/JP1997/002069 1996-06-17 1997-06-16 Derives asialotrisaccharide moranoline et medicaments WO1997048712A1 (fr)

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AU31074/97A AU3107497A (en) 1996-06-17 1997-06-16 Asialotrisaccharide moranoline derivatives and drugs

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Application Number Priority Date Filing Date Title
JP8/155801 1996-06-17
JP15580196 1996-06-17
JP9/103419 1997-04-21
JP10341997 1997-04-21

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WO1997048712A1 true WO1997048712A1 (fr) 1997-12-24

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AU (1) AU3107497A (fr)
TW (1) TW351720B (fr)
WO (1) WO1997048712A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998051315A1 (fr) * 1997-05-12 1998-11-19 Nippon Shinyaku Co., Ltd. Agent therapeutique pour rhumatismes articulaires
WO2008096690A1 (fr) * 2007-02-05 2008-08-14 Nippon Shinyaku Co., Ltd. Dérivé de polyéthylène glycol
US9301923B2 (en) 2009-12-23 2016-04-05 Novartis Ag Lipids, lipid compositions, and methods of using them
EP3167889A4 (fr) * 2014-07-11 2017-07-05 Tokyo University of Science Foundation Activateur du récepteur immunitaire des cellules dendritiques, procédé d'activation du récepteur immunitaire des cellules dendritiques, inhibiteur de formation d'ostéoclastes, procédé pour inhiber la formation d'ostéoclastes, inhibiteur de différenciation/prolifération de cellules dendritiques, procédé d'inhibition de différenciation/prolifération de cellules dendritiques, inhibiteur de production de cytokines, procédé pour inhiber la production de cytokines, méthode de traitement, et procédé de criblage
JP2019052102A (ja) * 2017-09-13 2019-04-04 株式会社東芝 生分解性化合物、脂質粒子、脂質粒子を含む組成物、およびキット
US10342761B2 (en) 2014-07-16 2019-07-09 Novartis Ag Method of encapsulating a nucleic acid in a lipid nanoparticle host

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997000881A1 (fr) * 1995-06-22 1997-01-09 Nippon Shinyaku Co., Ltd. Derives de la moranoline

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997000881A1 (fr) * 1995-06-22 1997-01-09 Nippon Shinyaku Co., Ltd. Derives de la moranoline

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Title
CHEMISTRY AND PHYSICS OF LIPIDS, (1988), 47, W.TH.M. DE GROOT et al., "Synthesis of Some Oxo- and Hydroxyacyl-Glycerols", p. 75-80. *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998051315A1 (fr) * 1997-05-12 1998-11-19 Nippon Shinyaku Co., Ltd. Agent therapeutique pour rhumatismes articulaires
WO2008096690A1 (fr) * 2007-02-05 2008-08-14 Nippon Shinyaku Co., Ltd. Dérivé de polyéthylène glycol
US8466255B2 (en) 2007-02-05 2013-06-18 Nippon Shinyaku Co., Ltd. Polyethylene glycol derivative
JP5347510B2 (ja) * 2007-02-05 2013-11-20 日本新薬株式会社 ポリエチレングリコール誘導体
US9301923B2 (en) 2009-12-23 2016-04-05 Novartis Ag Lipids, lipid compositions, and methods of using them
EP3167889A4 (fr) * 2014-07-11 2017-07-05 Tokyo University of Science Foundation Activateur du récepteur immunitaire des cellules dendritiques, procédé d'activation du récepteur immunitaire des cellules dendritiques, inhibiteur de formation d'ostéoclastes, procédé pour inhiber la formation d'ostéoclastes, inhibiteur de différenciation/prolifération de cellules dendritiques, procédé d'inhibition de différenciation/prolifération de cellules dendritiques, inhibiteur de production de cytokines, procédé pour inhiber la production de cytokines, méthode de traitement, et procédé de criblage
US10342761B2 (en) 2014-07-16 2019-07-09 Novartis Ag Method of encapsulating a nucleic acid in a lipid nanoparticle host
JP2019052102A (ja) * 2017-09-13 2019-04-04 株式会社東芝 生分解性化合物、脂質粒子、脂質粒子を含む組成物、およびキット

Also Published As

Publication number Publication date
TW351720B (en) 1999-02-01
AU3107497A (en) 1998-01-07

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