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WO1997000881A1 - Derives de la moranoline - Google Patents

Derives de la moranoline Download PDF

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Publication number
WO1997000881A1
WO1997000881A1 PCT/JP1996/001730 JP9601730W WO9700881A1 WO 1997000881 A1 WO1997000881 A1 WO 1997000881A1 JP 9601730 W JP9601730 W JP 9601730W WO 9700881 A1 WO9700881 A1 WO 9700881A1
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WO
WIPO (PCT)
Prior art keywords
compound
alkyl
substituted
sodium salt
moranoline
Prior art date
Application number
PCT/JP1996/001730
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English (en)
Japanese (ja)
Inventor
Tadaaki Ohgi
Takashi Seto
Kazuya Mori
Akira Hasegawa
Original Assignee
Nippon Shinyaku Co., Ltd.
HASEGAWA, Noriyo
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., HASEGAWA, Noriyo filed Critical Nippon Shinyaku Co., Ltd.
Publication of WO1997000881A1 publication Critical patent/WO1997000881A1/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

  • the present invention relates to a novel moranoline derivative which is useful as a therapeutic agent in the field of medicine, for example, an anti-inflammatory agent “prevention of ischemia and reperfusion injury”.
  • High-chain compounds such as sialic acid-containing glycolipids and glycoproteins have hormone, bacterial toxin, virus and other receptor functions, and also recognize, differentiate, grow, adhere, cancer, immunize, and age cells. It is a substance that has attracted attention because it is deeply involved in basic and dynamic life phenomena such as. In particular, sialyl Lewis type ⁇ chains containing sialic acid have useful physiological activities, and their application to pharmaceuticals is being actively studied.
  • sialyl Lewis type ⁇ chain derivative has a basic structure of a tetrasaccharide of sialic acid, galactose, dalcosamine and fucose, and its production requires many steps and complicated operations. For this reason, there has been a problem in conducting economical and efficient mass production of sialyl Lewis type sugar chain derivatives on an industrial scale.
  • sialic acid derivatives exist as trace components in the natural world, it has been extremely difficult to obtain them as pure single compounds from living organisms. Therefore, research on the application of sialic acid derivatives to pharmaceuticals has attracted much attention as a new research field.
  • the present inventors have filed an international application for a trisaccharide-type Lewis-type sugar chain derivative containing moranoline obtained by mimicking sialic acid with hydroxysulfol (PCT / JP95 / 00610).
  • the compound according to the applicant's invention has moranolin instead of glucosamine, and is structurally different from the compound according to the invention of the above-mentioned natural sugar chain derivative using dalcosamine as a constituent sugar. is there,
  • An object of the present invention is to provide a trisaccharide hydroxysulfur Lewis-type moranoline derivative which is a novel substance useful as a medicament described below and an intermediate useful for producing the same.
  • R 1 is phenyl, alkoxycarbonyl, cyano, alkylrubamoyl, butyr, acylamino, alkylthio, alkanesulfonamide, alkoxyalkoxyalkoxyamide, aralkyloxyamide, hydroxyl group Or a lower alkyl substituted with aryloxy, a benzene ring having a hydroxyl group, alkoxy, alkyl, halogen, halogenated alkyl, cyano, rubamoyl, mono- or dialkyl rubamoyl, nitro, acylamino, alkylthio, mono- or dialkylamino Or phenyl-lower alkyl, which may be substituted with 1 to 3 substituents selected from carboxy, and 3 substituted with alkyl. May be a lower alkyl substituted with a 5-membered unsaturated heterocyclic ring, alkaryl, alkarylalk
  • the lower alkyl of the lower alkyl substituted with aryloxy is preferably a straight-chain or branched-chain lower alkyl having 1 to 6 carbon atoms.
  • Examples of the file include those having 1 to 6 carbon atoms. Those having 3 to 5 carbon atoms are preferred, and propioyl, valeryl and vivaloyl are preferred.
  • alkoxycarbonyl examples include alkoxy having an alkyl portion having 1 carbon atom. Alkoxy having 1 to 3 carbon atoms is preferred, and methoxycarbyl, ethoxycarbol, and propoxycarbonyl are particularly preferred.
  • alkyl carpamoyl examples include those having an alkyl moiety of 1 to 7 carbon atoms, preferably an alkyl moiety having 1 to 3 carbon atoms, preferably methylcarbamoyl, ethylcarbamoyl, and propyllimubamoyl. .
  • acylamino examples include those having 1 to 6 carbon atoms. Those having 2 to 4 carbon atoms are preferred, and acetamide, propio-lamino and petyrylamino are preferred.
  • alkyl group an S-chain or branched alkylthio group having 1 to 6 carbon atoms is preferable.
  • alkane portion of the alkane sulfonamide include alkanes having 1 to 20 carbon atoms. Alkanesulfonamides having an alkane having 5 to 15 carbon atoms are preferred, and decanesulfonamide, nonanesulfonamide and octanesulfonamide are particularly preferred.
  • alkoxy moiety of the alkoxyalkoxyalkoxyamide include alkoxy having 1 to 6 carbon atoms. Alkoxy having 1 to 3 carbon atoms is preferable. Preference is given to toxamide, ethoxyxethoxyethoxyamide and propoxypropoxypropoxyamide.
  • aralkyl moiety of aralkyl oxyamide examples include those having 7 to 20 carbon atoms, and those having an aralkyl moiety having 7 to 9 carbon atoms are preferable. Benzoxy amide, phenethyloxy amide, phenyl ⁇ Poxyamide is preferred.
  • the aryloxy includes those having 6 to 20 carbon atoms. Those having 6 to 10 carbon atoms are preferred, and phenoxy and naphthoxy are preferred.
  • the benzene ring is a hydroxyl group, alkoxy, alkyl, halogeno, alkyl halide, cyano, rubamoyl, mono- or di-alkyl rubamoyl, ethopen, acylamino, alkylthio, mono or dialkyl
  • Alkyl having 1 to 3 carbon atoms is preferred, and methyl, ethyl, propyl and isopropyl are preferred.
  • straight-chain ⁇ includes a branched ⁇ 1 to 6 alkoxy. Those having 1 to 3 carbon atoms are preferred, and methoxy, ethoxy and propoxy are preferred.
  • alkyl substituted on the benzene ring examples include a linear or branched alkyl having 1 to 6 carbon atoms. Those having 1 to 3 carbon atoms are preferred, and methyl, ethyl, propyl and isopropyl are preferred.
  • alkyl in the halogenated alkyl examples include a straight-chain or branched-chain alkyl having 1 or more carbon atoms. Those having 1 to 3 carbon atoms are preferred, and trifluoromethyl is preferred.
  • the mono- or di-alkyl radicals include alkyls having 1 to 6 carbon atoms which are linear or branched. Alkyl having 1 to 3 carbon atoms is preferred, and methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl and propylcarbamoyl are preferred.
  • acylamino examples include those having 1 to 6 carbon atoms. Those having 2 to 4 carbon atoms are preferred, and acetamide, propionylamino and butyrylamino are preferred.
  • alkylthio a straight-chain or branched alkylthio having 1 to 6 carbon atoms is preferable.
  • examples of the mono- or dialkylamino alkyl include a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms.
  • Alkyl having 1 to 3 carbon atoms is preferable, and methylamino, dimethylamino, ethylamino, ethylmethylamino, and propylamino are preferable.
  • the benzene ring represented by R 1 is a hydroxyl group, an alkoxy, an alkyl, a halogenated halogenated alkyl, a cyano, a carbamoyl, a mono- or dialkylcarbamoyl, a utro, an acylamino, an alkylthio, a mono- or dialkylamino or a carboxy group
  • phenyl lower alkyl which may be substituted with 1 to 3 substituents selected from: ⁇ -trifluoromethylphenyl, 4- (m-dimethylaminophenyl) Butyl, 5- (m-cyanoferyl) pentyl, 6- ( ⁇ -potamoylphenol) hexyl, 3.
  • 5-membered unsaturated heterocyclic ring which may be substituted with alkyl, furfuryl, 5-methyl-furfuryl, 2-tur and 5-methyl-2-thenyl are preferable.
  • examples of the dialkar represented by R 1 include linear or branched ones having 2 to 35 carbon atoms. Bull, Aryl, Isobutel, Pentyl, Hexyl, Oleil, Linoleyl, Arakidurnoxenyl are preferred.
  • examples of the reels represented by R 1 include ferrule and naphthyl.
  • Suchiri Le as ⁇ preferred examples include those described above as alkenyl, cinnamyl is.
  • the primary alkyl represented by R 1 includes linear or branched alkyl having 7 to 36 carbon atoms. Those having 7 to 30 carbon atoms are preferred, and octyl, decyl, lauryl, myristyl, hexadecyl, stearyl, eicosyl and 2-tetradecylhexydecyl are preferred.
  • Alkali metals and alkaline earth metal salts are exemplified as the metal salts of the hydroxysulfols represented by R 2 and R 3 , and lithium salts, sodium salts and potassium salts are preferred as the alkaline metal salts.
  • As the alkaline earth metal salts magnesium salts, calcium salts, and barium salts are preferable.
  • n represents an integer of 1 to 10. Among them, those having 6 or less are preferable.
  • R 2 and are the same as described above.
  • R 5 and R 6 are the same or different and each represent a linear or branched lower alkyl having 1 to 6 carbon atoms, preferably methyl, ethyl, propyl, and butyl.
  • R J , R 3 and are the same as described above.
  • 1 , R 31 and 1 represent those described above as R 2 , R 3 and respectively.
  • x: represents an anion. Specifically, there are ⁇ ⁇ , cr, cr.
  • the compound of the present invention represented by the following general formula [1V] S ⁇ [V] is an important intermediate for producing the compound of the present invention represented by formula [I], This is a new substance not described.
  • the desired compound can be produced by introducing a desired substituent into the nitrogen atom of moranoline represented by the formula [IV], and then deacylating it.
  • R 7 are different from each other and represent 4-0-acetyl-2,6-di-0-benzoyl-3-0-sulfo- ⁇ -D-galactova / sil or ⁇ -L-fucoviranosyl.
  • Is asiloki represents cysteine or acetamide.
  • the acyl represented by R 9 is not limited as long as the reactivity is not hindered, and examples thereof include those described above as the acyl and benzoyl.
  • Examples of the acyloxy represented by R 10 include those having 1 to 10 carbon atoms. Those having 2 to 7 carbon atoms are preferred, and acetoxy, propio-loxy, petyryloxy and benzyloxy are preferred.
  • an aldehyde compound having a desired substituent [R 11] CHO (R 111 is obtained by removing 0% of the base from R 1 , R 5 or R 6 above) and is a representative)] or those halides [R l X (R 1 is as defined above, X is reacted with a halogen)]
  • a method of introducing a substituent into Moranori emissions of N Iyako is a special reagent Since the compound according to the present invention can be produced without the necessity, it can be carried out more economically than before.
  • R 1 R 1 2 represents 3-0-3 ⁇ 4l--Dl-galatatovirane, or Pio, 3,4-tri-0-, iV-a -Ll-fucohi.
  • R 1 (5 is the same as described above.
  • Examples of the compound according to the present invention include the following compounds in addition to the compounds described in Examples described later, but these are only examples of some of the compounds of the present invention. However, the present invention is not limited to this.
  • Higaral Ml-3 H (aL-fucovirano): K1 ⁇ ) K H3 ⁇ 2 Si 'human' t 7) a D Pilt 1,5- / Te '-1,5-imino-higurushi Sodium sodium salt
  • the compound according to the present invention can be produced by the following synthesis scheme),
  • Compound (1) which is a starting material shown in the scheme, can be synthesized by a method applied by the present applicant (Japanese Patent Application No. 7-106257).
  • This compound is reacted with, for example, trimethyl orthoacetate in benzene under the acidity of D, L-camphor-10.sulfonate at room temperature to form an orthoester group at the 3- and 4-hydroxyl groups of the galactose residue.
  • a compound (1 ′) in which the 4-position hydroxyl group of the galactose residue is selectively acetylated by acid hydrolysis in an 80% aqueous solution of lactic acid, a mixed solvent of THF and methanol is obtained. .
  • Compound (2) is prepared by reacting compound ( ⁇ ) with pyridine-sulfur trioxide complex in, for example, ⁇ , ⁇ -dimethylformaldehyde (DMF) at room temperature to sulfonate the 3-position hydroxyl group of galactose residue. Then, the benzyl group and benzyloxycarbol group of the compound (2) are contacted in an alcohol at 20 to 60 ° C. for 2 to 72 hours in the presence of a catalyst such as palladium chloride black. The compound is deprotected by reduction to obtain compound (3), which is reacted with sodium cyanoborohydride and various aldehydes of the desired substituent at pH 3 to 4, for example, in methanol.
  • DMF dimethylformaldehyde
  • the compound (4) Can be obtained, for example, by treating this with an alkali such as sodium methylate in methanol to remove the acetyl group and the benzoyl group, thereby obtaining the compound according to the present invention. (5 ') is obtained.
  • compound (3) is treated with an alkali in methanol to deprotect the acetyl group and benzoyl group to give compound (6), which is then treated with sodium cyanoborohydride in methanol and various compounds.
  • an appropriate base such as potassium carbonate in N-dimethylformamide
  • Moranoline residue has fucopyranosyl residue at position 3 and galactoviranosyl residue at position 4
  • Carbonitrile oxygen atom of the nitrogen atom and 6-position of Moranorin as Moranorin compounds of ⁇ further following scheme can also be performed prepared above and the same reaction step for derivative (35) - intermediate crosslinked Le
  • the compound according to the present invention can be produced by another method via An example of the synthesis will be described below using an example of a Lewis ⁇ -type derivative, but a Lewis X-type derivative can be produced in the same manner as this production method.
  • the compound (33) is acetylated and sulfonated in the same manner as in Scheme 1 to obtain the compound (34) .
  • the benzoyl group and the acetyl / re group of the compound (34) are converted into, for example, 10 to 60 with alkali in methanol.
  • Deprotection by treatment at 2 ° C. for 2 to 12 hours gives compound (35)
  • the benzyl group of compound (35) is deprotected, for example, by catalytic reduction in the presence of a palladium catalyst.
  • Compound (36) is obtained.
  • Compound (37) is obtained, for example, by subjecting compound (36) to hydrolysis in an aqueous methanol solution.
  • Compound (37) can be prepared, for example, by reacting sodium cyanoborohydride and the target aldehyde in methanol at pH 3 to 4 as in Scheme 1, or by reacting an alkyl halide to form a molanolin residue.
  • the compound of the present invention which is an N monosubstituted product, is obtained.
  • compound (35) is hydrolyzed at 80 to 100 ° C in an aqueous methanol solution, and sodium borohydride and various aldehydes in methanol are allowed to act at pH 3 to 4,
  • the present invention can also be obtained by deriving an N-substituted moranoline residue and then deprotecting the benzyl group by, for example, catalytic reduction in the presence of a palladium carbon catalyst.
  • the measurement temperatures of specific rotations are all 20 ° C.
  • the assembler used was MICRO ACILYZERS1 manufactured by Asahi Kasei Corporation, and AG110 was used for the cartridge unless otherwise noted.
  • the aqueous layer was decompressed under reduced pressure, subjected to Karaku D matogelaphy (UChroprep RP18, eluate; water), desalted with Asilisa '-, dried to dryness, and 730 mg of compound (6) as a white powder (730 mg (83.5% )Obtained.
  • Karaku D matogelaphy Uhroprep RP18, eluate; water
  • Asilisa '- dried to dryness
  • Example 4 The same reaction as in Example 4 was carried out using m-7' ⁇ -m-'n'-n-n'-l-'n'-arte'-human '(157 mg) to obtain 52 mg (40,8%) of the desired compound (10) as a white powder.
  • m-7' ⁇ -m-'n'-n-n'-l-'n'-arte'-human '(157 mg) was carried out using m-7' ⁇ -m-'n'-n-n'-l-'n'-arte'-human '(157 mg) to obtain 52 mg (40,8%) of the desired compound (10) as a white powder.
  • Example 11 The same reaction as in Example 11 was carried out using 100 mg of compound (3) and 22% (33%) of the compound (17) was obtained as a white powder.
  • Example 3 The same reaction as in Example 3 was carried out using 100 mg of the compound (6) and-7 'D-morph I-net // 200 # 1) to obtain 25 mg (23%) of the target compound (18) as a white powder. Obtained.
  • Example 4 The same reaction as in Example 4 was carried out using 120 mg of compound (6) and 3-mt) T 't / W human' (200 / ⁇ 1), and the target compound (19) was converted into a white powder of 105 mi ( 79%).
  • Example 4 The same reaction as in Example 4 was carried out using 150 mg of this compound and 100 mg of compound (6) to obtain an N-substituted product (90 nig), which was dissolved in methanol (3 ml) to give 28% sodium; -Tano- solution (01 ml) was added, and the mixture was stirred at room temperature for 3 hours.After confirming the completion of the reaction by TLC, the mixture was neutralized with 2 N hydrochloric acid and depressurized, and the residue was dissolved in water. -After washing with tellurium, the aqueous layer was squeezed under reduced pressure.
  • LiChroprep RP18, 30% methanol was eluted with water from the mixture of water to obtain 55 mg of the dehydrogenated / isomer. This was dissolved in 5 ml of methanol and 1 ml of acetic acid. Add 50 mg of Rashi-Dumf Lakku, stir at room temperature for 3 hours, and perform contact hydrogenation. Separate the Rashi-Dumf Lakku, wash with Etano, and combine the liquid and the wash liquid. The concentrate was concentrated under reduced pressure, and the resulting residue was subjected to column chromatography (LiChraprep RP18, elution with 30% metal from water) to obtain 22 mg (18%) of compound (20).
  • Example 4 The same reaction as in Example 4 was carried out using 200 mg of compound (6), 3- (n-hexanoamide) a of if and do (ISOmg) to obtain the desired compound (23) as a white powder. 160 mg (63%) were obtained.
  • Example 4 The same reaction as in Example 4 was carried out using 200 mg of the compound (6) and 3- (n-octanesulfonamide:) arohi'onarte'human '(246 mg) to give the desired compound (25) as a white powder 183 mg (65%)
  • Example 4 The same anti-JS as in Example 4 was carried out using 700 mg of compound (6) and Tote Wf IV (U5 ml) to obtain 0 mg (68.5%) of target compound (26) as a white powder.
  • the purified product is dissolved in a small amount of water, desalted with acid -'- (force-trish '; ⁇ ⁇ -20), freeze-dried, and 240 mg (33.3%) of the desired compound (27) is obtained as a white powder. %)Obtained.
  • the reaction mixture was vacuumed and subjected to column chromatography ⁇ -mat (Wakogel C300, eluent acid ⁇ ///, 2: 1 elution with ethyl acetate) and colorless dye D Kufu'-like compound S- [2- (2-1 ethoxyethoxy) ethoxycarboyleneamino] fuu / real alcohol (6.5 g, 56%) was obtained.
  • Compound (36) 1. was dissolved in a 50% aqueous solution of ethanol (64 ml), a 2N aqueous sodium hydroxide solution (8.5 ml) was added, and the mixture was stirred at 90 ° C. for 6 hours. Neutralize with an aqueous solution, compress under reduced pressure, apply the resulting residue to column chromatography 'Raffi- (LiChroprep RP-18, eluent; water), desalinate the product with Azylisa'- Lyophilization yielded 0.9 g (47.4%) of compound (37).
  • Example 4 The same reaction as in Example 4 was carried out using 100 mg of the compound (37) and ⁇ -talactyl aldehyde (1331) to obtain 89 mg (76.3%) of the desired compound (38) as a white powder.
  • Example 4 The same reaction as in Example 4 was carried out using 200 mg of compound (37) and 1-to-the-canal (3741) to obtain 11 lmg (44.1%) of the desired compound (39) as a white powder.
  • Example 4 The same reaction as in Example 4 was carried out using 200 mg of compound (37) and 1-to-the-canal (3741) to obtain 11 lmg (44.1%) of the desired compound (39) as a white powder.
  • Example 4 The same reaction as in Example 4 was performed using 100 mg of the compound (37) and 100 mg of ril realte hydride to obtain 99 mg (70.6%) of the desired compound (40) as a white powder.
  • HUVEC> human vascular endothelial cells
  • HUVEC> 1% Se' co with keratin - you encountered a 96-well microphone Pai7 'Uyuru per 2 ⁇ 10 4 Les DOO . pieces were seeded 37.C of C0 2 ink: to I '- after over ⁇ cultured in data, RPMVFCS / HEPES medium the cell layer 100 ⁇ 1 (RPMMI-1640, 10% F CS, 25mM HEPES, pH7 Wash twice with .4), and add lOU / ml of I: l ⁇ containing RFMI / FCS / HEPES to 100
  • a kit containing only RPMI / FCS HEFES alone (KBasal) was prepared. After washing twice with RFMI-1640 (RFMI HEFES) that does not contain FCS, Susan human leukemia cells HL60 are suspended in 10 ml of RFMI / FCS / HEPES medium containing 0.5% tartaraldehyde, and placed on ice. Fixed for 20 minutes.
  • the cells were washed three times with RPMI / H EPES, diluted with RPMI FCS / HEFES so that the cell number was 2 ⁇ 10 8 ⁇ 11 ⁇ / 111 ⁇ , and stored on ice until use. .
  • the HUVECs were washed three times with 100 ⁇ l of RPMI / FCS / HEPES, and each compound of I dissolved in 50 # 1 RPMI / FCS / HEFES (Control) and RPMI / FCS / HEPES (lms / ml ) Or anti-E-selectin antibody (25 ⁇ g ml), and incubate at room temperature for 30 minutes.
  • 1 ⁇ 10 5 (50 ml) of the immobilized HL60 cells were added to each cell, and the cells were incubated at room temperature for 45 minutes. Fill each chill with RPMI FCS / H EPES, seal it with a miter Dale seal so that no air bubbles enter, then let the plate fall and let stand for 1 hour To remove unbound HL60 cells.
  • the number of adherent cells was determined based on the activity of mi-It'luxita'-ze (MPO), an enzyme present in HL60 cells. Add 0.5% hexadecid bromide to each well; add 1 ⁇ _timonicum (HTAB>! Acid buffer (50 mM, pH 6.0) and incubate at room temperature for 30 minutes to remove ⁇ Solubilized from within O 97/00881
  • Anti-E-seletin antibody 6 4.2 ⁇ 1.1
  • Plasma Platelet Rich Plasma, (PRP) O 97/00881
  • Incubator i Effect on leukemia cell HL60 on PIN-dependent adhesion (2) Test compound Portability (mg ml) n Cell adhesion rate f%)
  • the compounds according to the present invention exhibited remarkable cell adhesion inhibitory activity against perylene and ⁇ -selen. From the above, it can be seen that the compound of the present invention inhibits the adhesion between leukocytes or cells and endothelial cells by competitively inhibiting secretin present in endothelial cells. O 97/00881
  • the compound of the present invention When the compound of the present invention is administered as a medicament, the compound of the present invention contains 0.19 & 99.5%, preferably 0.5%-90% as it is or in a pharmaceutically acceptable non-toxic and inert carrier. As a composition, it can be administered to animals containing humans.
  • the carrier one or more solid, semi-solid, or liquid diluents, fillers, and other formulation auxiliaries are used.
  • the pharmaceutical compositions are administered in dosage unit form.
  • the pharmaceutical composition of the present invention can be administered in a tissue, topically (eg, transdermally), or rectally. It is needless to say that the composition is administered in a dosage form suitable for these administration methods. For example, intra-tissue administration is particularly preferred.
  • the dosage as an anti-inflammatory agent is desirably prepared in consideration of the patient's condition such as age, body weight, etc., the administration route, the nature and extent of the disease, and the like.
  • the amount of the ingredient is generally in the range of 100 mg to 3 g / day / human, preferably in the range of 500 mg to: lg / day / human per day. In some cases, lower doses may be sufficient and conversely, higher doses may be required. It is also desirable to administer the drug in 1 to 3 divided doses a day. The same applies to other pharmaceutical uses.

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Abstract

L'invention concerne des dérivés de la moranoline représentés par la formule développée (I). Dans cette formule, R1 représente un alkyle inférieur substitué par un acyle, alcoxycarbonyle, cyano, alkylcarbamoyle, nitro, acylamino, alkylthio, hydroxy ou aryloxy, phényl-alkyle inférieur où le noyau benzénique porte éventuellement des substituants tels que hydroxy, alcoxy inférieur, alkyle inférieur, halogéno, cyano, alkyl(inférieur)carbamoyle, nitro, acylamino, alkylthio ou carboxy, alkyle inférieur substitué par un hétérocycle insaturé à 5 éléments éventuellement substitué par un alkyle inférieur, alcényle, arylalcényle ou alkyle supérieur; R2 et R3 sont différents et chacun représente un galactopyranosyle ou un fucopyranosyle substitué par un hydroxysulfonyle ou un sel de celui-ci; et R4 représente un hydroxy ou un acétamide. Ces composés sont utiles dans le domaine médical, par exemple comme agents anti-inflammatoires ou pour le traitement préventif ou curatif de l'ischémie et de troubles circulatoires.
PCT/JP1996/001730 1995-06-22 1996-06-21 Derives de la moranoline WO1997000881A1 (fr)

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JP15577695 1995-06-22

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997048712A1 (fr) * 1996-06-17 1997-12-24 Nippon Shinyaku Co., Ltd. Derives asialotrisaccharide moranoline et medicaments
WO1998041214A1 (fr) * 1997-03-14 1998-09-24 Nippon Shinyaku Co., Ltd. Medicaments contre les troubles ischemiques de reperfusion
WO1998051315A1 (fr) * 1997-05-12 1998-11-19 Nippon Shinyaku Co., Ltd. Agent therapeutique pour rhumatismes articulaires
US6225325B1 (en) 1997-11-10 2001-05-01 G.D. Searle & Company Use of alkylated iminosugars to treat multidrug resistance
US6515028B1 (en) 1999-02-12 2003-02-04 G.D. Searle & Co. Glucamine compounds for treating hepatitis virus infections
US6545021B1 (en) 1999-02-12 2003-04-08 G.D. Searle & Co. Use of substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds for treating hepatitis virus infections
US6689759B1 (en) 1998-02-12 2004-02-10 G. D. Searle & Co. Methods of Treating hepatitis virus infections with N-substituted-1,5-dideoxy-1,5-imino-d-glucitol compounds in combination therapy
US6809083B1 (en) 1998-02-12 2004-10-26 Richard A. Mueller Use of N-substituted-1, 5-dideoxy-1, 5-imino-D-glucitol compounds for treating hepatitis virus infections
EP1903034A1 (fr) * 2006-09-19 2008-03-26 Technische Universität Graz Iminosucres glycoconjugués
US7612093B2 (en) 1997-02-14 2009-11-03 United Therapeutics Corporation Compositions of treating hepatitis virus infections with N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds in combination therapy

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993015098A1 (fr) * 1992-01-31 1993-08-05 Nippon Shinyaku Co., Ltd. Derive d'une chaine de sucre du type lewis
WO1994000477A1 (fr) * 1992-06-29 1994-01-06 Glycomed Incorporated Derives de lactose substitues utilises comme inhibiteurs d'adhesion cellulaire

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993015098A1 (fr) * 1992-01-31 1993-08-05 Nippon Shinyaku Co., Ltd. Derive d'une chaine de sucre du type lewis
WO1994000477A1 (fr) * 1992-06-29 1994-01-06 Glycomed Incorporated Derives de lactose substitues utilises comme inhibiteurs d'adhesion cellulaire

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997048712A1 (fr) * 1996-06-17 1997-12-24 Nippon Shinyaku Co., Ltd. Derives asialotrisaccharide moranoline et medicaments
US7612093B2 (en) 1997-02-14 2009-11-03 United Therapeutics Corporation Compositions of treating hepatitis virus infections with N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds in combination therapy
WO1998041214A1 (fr) * 1997-03-14 1998-09-24 Nippon Shinyaku Co., Ltd. Medicaments contre les troubles ischemiques de reperfusion
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