WO1998031697A1 - Composes aryle c-glycoside et esters sulfates de ces derniers - Google Patents

Composes aryle c-glycoside et esters sulfates de ces derniers Download PDF

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Publication number
WO1998031697A1
WO1998031697A1 PCT/US1998/000701 US9800701W WO9831697A1 WO 1998031697 A1 WO1998031697 A1 WO 1998031697A1 US 9800701 W US9800701 W US 9800701W WO 9831697 A1 WO9831697 A1 WO 9831697A1
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Prior art keywords
doublet
group
aryl
fucopyranosyl
glycoside
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PCT/US1998/000701
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English (en)
Inventor
Susumu Sato
Takeshi Kuribayashi
Shigeru Ushiyama
Takashi Yasumoto
Kazuhiko Tanzawa
Masaaki Takahashi
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Sankyo Company, Limited
Glycomed Incorporated
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Priority to AU60249/98A priority Critical patent/AU6024998A/en
Publication of WO1998031697A1 publication Critical patent/WO1998031697A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
    • C07H7/04—Carbocyclic radicals

Definitions

  • the present invention provides a series of aryl C-glycoside compounds in the form of chemically and physiologically stable glycomimics of glycoepitopes that can serve as the active center of polysaccharides which govern various intercellular actions, interactions between cells and interstitial tissue (cell differentiation and growth, recognition and adhesion, fertilization and implantation, canceration, immunity and aging) and receptor functions (with respect to hormones, toxins, bacteria and viruses), sulfated forms thereof, pharmacologically acceptable salts thereof and preparations containing the same.
  • the present invention provides a series of aryl C-glycoside compounds in the form of chemically and physiologically stable glycomimics that may inhibit interactions between cells and between cells and interstitial tissue mediated by glycosides, sulfated esters thereof, pharmacologically acceptable salts thereof and preparations containing the same, which can be used in the treatment and/or prevention of inflammatory diseases, autoimmune diseases, infections, cancer and cancer metastasis, reperfusion disorders, thrombosis, ulcer, wounds, osteoporosis and other selective-mediated disorders.
  • the compounds of the present invention can preferably bind to E, L and P-selectin.
  • Sugar chains are located on the cell surface in the form of constituents of glycolipids or glycoproteins, or in the extracellular matrix (interstitial tissue) in the form of constituents of proteoglycans, and are known to function as receptors of various hormones (bFGF, tPA, erythropoietin, renin, etc.), toxins (cholera toxin, tetanus toxin, botulinus toxin, chlostridium toxin, Shiga toxin, enteritis vibriosis heat-resistant toxin, etc.), bacteria (colibacillus, pneumococcus, staphylococcus, actinomycetes, gonococcus, pseudomonas, etc.), and viruses (influenza virus, Sendai virus, Newcastle virus, hepatitis B virus, polio virus, AIDS virus, etc.).
  • hormones bFGF, tPA, erythropoietin, renin, etc.
  • Glycoreceptors for viruses Paulson J.C., The Receptors, Vol. II, edited by Conn, P.M. Academic Press, (1985), 131 Glycoreceptors for bacteria: Stromberg et al., EMBO J. , (1990) , 9_, 2001
  • Glycoreceptors for toxins Karsson et al., Sourcebook of Bacterial Protein Toxins, edited by Alouf, J.E., Freer J.H., Academic Press, (1990), 5_6, 3537; T. Tamaya, Mebio (1993), 10(5), 26; and Y. Tanaka, Mebio, (1993), 10(5), 56
  • Glycoreceptors for carcinoma metastasis H. Komazawa, M. Kojima, Y. Igarashi, I. Saiki, Mebio, (1993), 10(5), 99
  • Inhibitors of these interactions and receptor functions are expected to be effective therapeutic and preventive agents against each of the diseases to which these are related or against each of the diseases that occur in cases in which these interactions and receptor functions have become excessive or abnormal .
  • related diseases include acute or chronic inflammatory diseases such as rheumatoid arthritis, asthma, allergy, psoriasis and septic shock, or transplanted tissue rejection reactions, reperfusion disorders, adult dyspnea syndrome, ischemia, ulcerative colitis, atherosclerosis, thrombosis, ulcer, infections, cancer and cancer metastasis, wounds and osteoporosis (see Mulligan, M.S., et al., Nature, (1993), 364, 149; Mulligan, M.S., et al., J.
  • sugar chain derivatives are closely related to these diseases, synthesis of numerous sugar chain derivatives has been attempted for the purpose of developing new and effective pharmaceuticals having different modes of action from those in the past.
  • chemical, enzymatic and chemo-enzymatic synthesis of sialyl Lewis X (sLe x ) and its derivatives, a terminal tetrasaccharide of membrane glycolipids and glycoproteins, which has been identified as a native ligand for the E-, L-, P-selectins (adhesion molecules) have been discussed in the following publications :
  • the oligosacchrides may lack chemical and physiological stability. Since sugar chains are basically composed of an O-glycoside bond having a hemiacetal structure, they are essentially unstable under acidic conditions. In particular, the O-glycoside bonds of sialic acid and fucose found in sialyl Lex that form the important active site in intercellular interactions and receptor functions, are known to be unstable under acidic conditions. In addition, since these oligosacchrides naturally serve as substrates of numerous glycotransferases and glycohydrolases, it is considered difficult for them to maintain a constant concentration in the blood for a sustained period of time.
  • the oligosacchrides may not have an appropriate rate of biological absorption. Since the surface of a sugar chain is covered with many hydroxyl groups, they are typically highly hydrophilic, and consequently cannot be expected to be absorbed orally from the gastric mucosa. In addition, they also have a low degree of cell membrane permeability, which results in the undesirable property of lowering their rate of biological absorption.
  • the sialyl LeX terminal tetrasaccharide glycoepitope of glycolipids and glycoproteins expressed on the cell surface of leukocytes, has been identified as a primary ligand for selectins (E-, L-, P-) which mediates the initial stage of adhesion of leukocytes to activated endthelial cells in areas of inflammation. Thereafter, leukocytes migrate the sites of inflammation. Adhesion of leukocytes to the "activated" endothelium is the critical process that initiates the host defense, as well as the progression of the inflammatory response. Intervention in this cell-cell interaction process can therefore provide novel therapeutics for the treatment of pathophysiological conditions arising due to uncontrolled migration of leukocytes under acute and/or chronic conditions.
  • sialyl Lex-type carbohydrates a number of which are expressed on circulating leukocytes, play a dominant role in their initial attachment to the endothelial cells that line the blood capillaries. This locking-on is mediated through a family of adhesion proteins known as P-, E-and L-selectins. Of these, L (leukocyte) -selectin (LECAM-1, LAM-1) is constitutively present on the surface of the leukocyte. Originally described as MEL-14, it is involved in the trafficking of granulocytes and lymphocytes in the peripheral lymph nodes. (McEver, R.P., Curr. Opin. Immunol.
  • P (platelet) -selectin also known as granule membrane protein-140 (GMP-140) (Johnston, G.I., et al., Cell (1989), 5_6, 1033-1044) or platelet activation-dependent granule-external membrane (PADGEM) (Hsu-Lin, S.C, et al., J. Biol. Chem. (1984), 2J5_9, 9121-9126) protein, currently designated CD62, is found on activated platelets as well as activated endothelium.
  • GMP-140 granule membrane protein-140
  • PADGEM platelet activation-dependent granule-external membrane
  • E(endotheiial) -selectin also known as endothelium leukocyte adhesion molecule-1 (ELAM-1)
  • ELAM-1 endothelium leukocyte adhesion molecule-1
  • the three known members of this family contain a domain with homology to the calcium-dependent lectins, an EGF-like domain, and several complement binding protein-like domains
  • Buerke et al. have demonstrated the important role in inflammatory states, such as ischemia- reperfusion injury in cats (Buerke, M. et a., J. Chin. Invest. , (1994), 9_3' 1140).
  • Turunen et al. have demonstrated the role of sLe x and L-selectin in site-specific lymphocyte extravasation in renal transplants during acute rejection (Turunen, J.P. et al., Eur. J. Immunol., (1994), 2 , 1130).
  • P-selectin has been shown to be centrally involved, particularly as related to acute lung injury. Mulligan et al.
  • E-selectin is particularly interesting because of its transient expression on endothelial cells in response to IL-1 or TNF (Bevilacqua et al., Science, (1989), 243, 1160). The time course of this induced expression (2-8 hours) suggests a role for this receptor in initial neutrophil extravasation in response to infection and injury. Indeed, Gundel et al. have shown that an antibody to E-selectin blocks the influx of neutrophils in a primate model of asthma and thus is beneficial for preventing airway obstruction resulting from the inflammatory response (Gundel R.H. et al., Chin. Invest., (1991), 8_8_ 1407).
  • Fucosyltransferase is the key enzyme of sLe x synthesis that transfers fucose to sugar chain as the substrate of GDP-fucose in the final step of sLe x biosynthesis (Natsuka et al., Cur. Opi. Struc Biol., 1995, 4 (632-697) . There is evidence that this fucosyltransferase is able to be regulated by cell adhesion mediated by selectin (Lowe et al., Cell, (1990), 631, 475-484) . Until now, there have been known to exist five isoforms of fucosyltransferase ranging from type III to type VII.
  • type VII has been clearly shown to be involved with the endothelial cells of leukocytes (Sasaki et al., J. Biol. Chem. , (1994), 269, 14730-14737).
  • FT fucosyltransferase
  • Such compounds will have the potential for treatment of pathological processes such as cardiogenic shock (ischaemia-reperfusion injury) , stroke, thrombosis, rheumatism, psoriasis, dermatitis, acute respiratory distress syndrome (ARDS) , and even metastasis in which sLe x and related structures have been implicated (Ogawa, J. , et al., Cancer, (1994), 72!, 1177-1183; Aruffo, A., et al., Proc Natl. Acad. Sci.
  • pathological processes such as cardiogenic shock (ischaemia-reperfusion injury) , stroke, thrombosis, rheumatism, psoriasis, dermatitis, acute respiratory distress syndrome (ARDS) , and even metastasis in which sLe x and related structures have been implicated (Ogawa, J. , et al., Cancer, (1994), 72!, 1177-1183; Aruffo, A., e
  • the present invention relates to aryl C-glycoside compounds comprising an aryl part and a glycosyl part, wherein the aryl part represents a phenyl acetic acid moiety which provides an anti-inflammation effect, which is unsubstituted or can be substituted with more than one 1 ' -lycosyl compound and the glycosyl part represents a natural or artificial monosaccharide having an ⁇ or ⁇ bond, or a disaccharide, a trisaccharide or a tetrasaccharide of said monosaccharide, the saccharides being unsubstituted or substituted by at least with a carboxyalkyl group or an acyl group; or a sulfate ester thereof or a pharmaceutically acceptable salt thereof.
  • Particularly preferred compounds are described throughout the specification.
  • the present invention is further directed to a method for treating or preventing an inflammatory disease, an auto-immune disease, an infection, cancer, a reperfusion disorder, thrombosis, ulcer, a wound or osteoporosis in a mammal, such as a human, comprising administering to mammal (such as a human) a pharmaceutically effective amount of the aryl C-glycosides
  • the present invention also concerns processes for the preparation of the invention compounds.
  • aryl C-glycoside compounds and their sulfated forms have various pharmacological activities related to sugar chains.
  • the aryl part is a phenyl acetic acid moiety which provides an anti-inflammatory effect, examples of which include the following:
  • the present invention also concerns an aryl C-glycoside of the formula (I)
  • glycosyl part of the compounds of the present invention and R 1 of the compounds of formula (I) are a natural monosaaccharide having an a or ⁇ bond, which may be a D-form or a L-form, preferably a natural form of the sugar.
  • examples of such groups include glucose, glucosamine, galactose, gaiactosamine, fucose, mannose, sialic acid, ribose, rhamnose,
  • R 1 can also be an artificial monosaccharide having an ⁇ or ⁇ bond, which may be a D-form or a L-form.
  • groups include a pyranose and furanose, which has an oxygen atom in a ring, in which a hydroxy group is attached to the carbon atom next to the ring oxygen atom and some hydroxy groups may be substituted.
  • R 5 represents a hydrogen atom or an acyl group
  • p represents an integer of 1 to 5
  • q represents an integer of 1 or 2
  • r represents 0 or 1.
  • R 1 represents a disaccharide having an ⁇ or ⁇ bond
  • this may be a D-form or a L-form, preferably a natural form of the sugar.
  • examples of such groups include natural
  • disaccharides such as lactose, maltose, cellobiose, gentiobiose and melibiose and artificial disaccharides comprising a dimer of sugar-like compounds (an oxygen atom is contained in a ring, a hydroxy group is attached to the carbon atom next to the ring oxygen atom and some hydroxy groups may be substituted) , of which natural disaccharides are preferred.
  • R 1 in the compounds of formula (1) represents a trisaccharide having an ⁇ or ⁇ bond
  • this may be a D-form or a L-form, preferably a natural form of the sugar.
  • examples of such groups include natural trisaccharides, such as maltotriose and artificial trisacchardies comprising a trimer of sugar-like compounds, of which natural trisaccharides are preferred.
  • R 1 of the compounds of formula (I) represents a tetrasaccharide having an ⁇ or ⁇ bond
  • this may be a D-form or a L-form, preferably a natural form of the sugar.
  • examples of such groups include natural tetrasaccharides such as maltotetraose and artificial tetrasaccharides comprising a tetramer of sugar-like compounds, of which natural trisaccharides are preferred.
  • lA ⁇ , of the compounds of formula (I) represents an aromatic compound, this may be a mono aryl compound, a biaryl compound or a triaryl compound, containing from 6 to 18 carbon atoms, preferably from 6 to 12 carbon atoms.
  • Examples of such groups include an aryl compound such as benzene, naphthalene, anthracene, phenanthrene, indene, fluorene, stilbene, indan, 1, 2, 3, 4-tetrahydronaphthalene, 9, 10-dihydroanthracene, 9, 10-dihydrophenanthrene, aromatic steroids, e.g., estradiol; a biaryl compound; such as biphenyl, diphenylmethane, diphenylethane, diphianyl ether; or a triaryl compound, of which benzene and naphthalene are preferred.
  • an aryl compound such as benzene, naphthalene, anthracene, phenanthrene, indene, fluorene, stilbene, indan, 1, 2, 3, 4-tetrahydronaphthalene, 9, 10-dihydroanthracene, 9, 10-dihydrophenanthrene, aromatic steroids, e.g
  • heteroaryl compound which may optionally be condensed.
  • the ring members of which heterocyclic aromatic compound include 1 to 3 sulfur, oxygen and/or nitrogen atoms. may also be a bi-heteroaryl compound or a tri-heteroaryl compound, containing from 6 to 18 carbon atoms, preferably from 6 to 12 carbon atoms.
  • Examples of such compounds include xanthene, furan, benzofuran, dibenzofuran, chromanone, flavone, flavanone, thiophene, thianaphthene, pyrrole, pyrazole, imidazole, oxazole, isoxazole, isothiazole, thiazole, 1, 2, 3-oxadiazole, triazole, tetrazole, thiadiazole, pyridine, pyridazine, pyrimidine, purazine, indole, indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbozole, carboline, phenanthridine or acridine; of which is preferred an aromatic, 5-to 10-membered, heterocyclic group which may optionally be condensed, among the ring members of which 1 to 2
  • R 2 of the compounds of formula (I) also represents a halogen atom, which may be a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom; of which is preferred a flourine atom and a chlorine atom.
  • R 2 of the compounds of formula (I) also represents a straight, branched or cyclic alkyl group, containing from 1 to 10 carbon atoms, preferably from 1 to 8 carbon atoms.
  • groups include a straight or branched alkyl group such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, pentyl, 1-methylbutyl, 2- methylbutyl, 3-methylbutyl, 1, 1-dimethylpropyl,
  • R 2 of the compounds of formula (I) represents a straight, branched or cyclic alkyl group
  • this group can be cyclized with the group to a condensed ring group.
  • an aryl C-glycoside of the formula (I) represents a salt thereof
  • this may be a metal salt of a carboxy group, a carboxyalkyl group or a sulfonic acid group.
  • metal salts include salts of alkali metals such as sodium, potassium or lithium; alkaline earth metals such as barium or calcium; and another metal such as magnesium, aluminum, iron, zinc, copper, nickel or cobalt, of which is preferred an alkali metal .
  • R 3 of the compounds of formula (I) represents an alkyl such alkyl group is as defined above for R 2 .
  • R 1 , R 3 , R 4 or R 5 of the compounds of formula (I) rerpresents an acyl group, this may be a straight or branched acyl group containing from 1 to 10 carbon atoms, preferably from 1 to 3 carbon atoms, more preferably an acetyl group.
  • aliphatic acyl groups preferably acyl groups having from 1 to 25 carbon atoms, more preferably from 1 to 20 carbon atoms, still more preferably from 1 to 6 carbon atoms, and most preferably from 1 to 4 carbon atoms, such as the formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl, isovaleryl, hexanoyl, heptanoyl, octanoyl, lauroyl, myristoyl, tridecanoyl, palmitoyl and stearoyl groups, of which the acetyl group is most preferred; halogenated alkanoyl groups having from 2 to 6 carbon atoms, preferably halogenated acetyl groups, such as the chloroacetyl, dichloroacetyl, trichloroacetyl and trifluoroacetyl groups; lower alkoxyacy
  • the substituents A include halogen atoms such as fluorine, chlorine, bromine and iodine; an alkyl group such as defined above for R' ; an alkoxy group having 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms; a carboxy group, a nitro group; an alkoxycarbonyl group with the alkoxy group thereof having 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms; and an aryl group as defined above.
  • halogen atoms such as fluorine, chlorine, bromine and iodine
  • an alkyl group such as defined above for R'
  • an alkoxy group having 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms a carboxy group, a nitro group
  • an alkoxycarbonyl group with the alkoxy group thereof having 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms and an aryl group as defined above.
  • R 1 or R 4 represents a carboxyalkyl group
  • the alkyl part thereof is as defined above in the definition of R 2 .
  • the compounds of the present invention may contain one or more asymmetric carbon atoms in their molecules, and, in such a case, can thus form optical isomers.
  • the present invention includes both the individual, isolated isomers and mixtures, including racemates thereof. Where stereospecific synthesis techniques are employed or optically active compounds are employed as starting materials, individual isomers may be prepared directly. On the other hand, if a mixture of isomers is prepared, the individual isomers may be obtained by conventional resolution techniques.
  • Preferred classes of compounds of the present invention are those compounds of formula (I) and pharmaceutically acceptable salts and sulfate esters thereof in which:
  • R 1 represents a natural or artificial monosaccharide having an ( ⁇ or ⁇ bond, wherein the saccharide is unsubstituted or is substituted with carboxyalkyl groups or acyl groups; (2) R 1 represents a natural monosaccharide having an ( ⁇ or ⁇ bond;
  • n represents an integer of 1 to 2;
  • R 2 represents a straight, branched or cyclic alkyl group which is unsubstituted or is substituted with an oxo group, a hydroxy group, a carboxy group or a sulfonic acid group, and R 2 represents a straight, branched or cyclic alkyl group, this group can be cyclized with the r) group to a condensed ring group;
  • ⁇ 1 ) R 2 represents a straight or branched alkyl group which is substituted by at least with a carboxy group or a sulfonic acid group, and this group can be cyclized with the lA_ry group to a condensed ring group;
  • R 2 represents a straight or branched alkyl group which is substituted by at least with a carboxy group or a sulfonic acid group
  • R 2 represents a cyclic alkyl group which is substituted by at least with an oxo group, a carboxy group or a suifonic acid group;
  • (10) k represents an integer of 1 to 2) ; when k does not represent 1, the R 2 groups are the same or different;
  • R represents a hydrogen atom or an alkyl group
  • n an integer of 1 to 2;
  • R 1 represents the following formula (II): wherein,
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom; p represents an integer of 1 to 5; q represents an integer of 1 or 2; and r represents zero.
  • important compounds of the present invention include the following:
  • Aryl C-glycoside compounds are not susceptible to hydrolysis under acidic conditions and glycohydrolases as a result of the anomeric carbon of the saccharide being directly connected with an aromatic compound by carbon-carbon bonds.
  • aryl C-glycoside compounds are resistant to modification without being the inherent substrate of glycotransferases, aryl C-glycoside compounds are considered to be stable and active for a sustained period of time in the body.
  • aryl C-glycoside compounds possess both the hydrophilicity of saccharides and the lipophilicity of aromatic compounds, aryl C-glycoside compounds are expected to exhibit suitable solubility in aqueous systems of the compound, as well as permeability with respect to the cell membrane.
  • the following publications concern C-glycosylation:
  • One advantage of the present method for the synthesis of aryl C-glycoside compounds is that numerous saccharides constituting the primary sugar chain in the living body, including glucose, glucosamine, galactose, gaiactosamine, fucose, mannose, sialic acid, ribose, rhamnose and xylose, can serve as the donor substrate.
  • Another advantage of the present method is that easily obtainable and stable 1-lower alkanoyl, 1-benzoyl, 1-lower alkyl and 1-hydroxy derivatives can be used as the donor without the need for special elimination groups.
  • sugars such as sugar halide, sugar imidate or thioglycoside (sugar as such cannot be reacted directly) , which is usually unstable and has a strange odor, were required to glycosylate a material to convert a sugar to a relevant derivative.
  • a sugar per se can be used which is stable and easily obtainable, as a sugar donor. This is an important advantage.
  • the subject compounds can, be synthesized in accordance with the following method:
  • R 1 , R 2 , R 3 , k, m and n are as defined above.
  • X represents a leaving group, where there is no particular limitation upon the nature of the leaving group, provided that it is a group capabie of leaving as a nucleophilic residue, such as are well known in the art.
  • preferred leaving groups include the following: hydroxy groups; halogen atoms, such as fluorine, chlorine, bromine and idodine atoms; alkylcarbonyloxy groups, such as acetoxy, ethylcarbonyloxy, propylcarbonyloxy and butylcarbonyloxy groups; aralkylcarbonyloxy groups, such as benzoyl, benzylcarbonyloxy and phenethylcarbonyloxy groups; lower alkoxycarbonyloxy groups, such as methoxycarbonvloxy and ethoxycarbonyloxy groups; halogenated alkylcarbonyloxy groups, such as chloroacetoxy, dichloroacetoxy, trichicroacetoxy and trifluoroacetoxy groups; lower alkanes
  • alkylcarbonyloxy groups alkylcarbonyloxy groups, aralkylcarbonyloxy groups, hydroxy groups, halogen atoms, lower haloalkanesulfonyloxy groups and arylsulfonyloxy groups are preferred and alkylcarbonyloxy groups and aralkylcarbonyloxy groups are most preferred;
  • t represents an integer of 1 to 2.
  • R 1' represents a different group from R 1 and is as defined above with respect of R 1 .
  • Steps 1 and 2 the compound of the formula (I) or the formula (V) is prepared by a condensation reaction of compounds of the formulae (III) and (IV) in the presence of a mixed catalyst containing a Lewis acid and solvent.
  • the mixed catalyst containing a Lewis acid there is no particular limitation on the mixed catalyst containing a Lewis acid. Any Lewis acid catalyst commonly used in a condensation reaction of this type may be employed. Examples of such catalysts include metal halides such as stannous tetrachloride and gallium chloride and a metal salt of a strong acid such as a silver or mercury salt of trifluoromethanesulfonic acid or trifluoroacetic acid.
  • the reaction is normally and preferably carried out in the presence of a solvent, the nature of which is not critical, provided that it has no adverse effect upon the reaction and that the solvent can dissolve the reagents, at least to some extent.
  • suitable solvents include the following: aliphatic hydrocarbons, such as hexane and heptane; aromatic hydrocarbons, such as benzene, toluene and xylene; halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; esters, such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether;
  • A_T any ratio commonly used in this type reaction may equally be employed.
  • An example of such ratio is 8 : 1 to 1 : 5 (the compound represented by R 1 : the compound represented by ⁇ ) .
  • the number of sugar moieties which are to be introduced can vary according to the molar ratio of the compound represented by R 1 and the compound represented by ⁇ .
  • a further sugar moiety may be introduced by repeating the above condensation reaction, if desired.
  • the reaction can be performed over a wide range of temperatures, and the precise reaction temperature chosed is not critical to the invention. In general, it is convenient to carry out the reaction at a temperature of from -80°C to 100°C, more preferably from 0°C to 300°C.
  • the time required for the reaction may likewise vary widely, depending on many factors, notably the reaction temperature, the starting materials, the solvent employed and the nature of the reagents. However, in most cases, a period of from 30 minutes to 7 days, more preferably from 3 hours to 2 days, will normally suffice for the reaction.
  • the desired compound of formula (I) can be collected from the reaction mixture by conventional means.
  • one suitable recovery procedure comprises, if appropriate, neutralizing the pH; if there is a precipitate, removing the precipitate by filtration; adding water to the residue; and extracting the mixture with a water-immiscible organic solvent, such as ethyl acetate. The extract is then dried over anhydrous magnesium sulfate, after which the solvent is removed by distillation, to give the desired compound.
  • the resulting compounds can be further purified by conventional means, such as recrystallization or the various chromatography techniques, notably column chromatography.
  • the condensation product obtained by this reaction can be converted into the compound of the present invention by performing reactions such as hydrolysis, reduction, amidation, and so forth, that are commonly known to those skilled in the art.
  • Step 3 the compound of formula (VI) is prepared by a further condensation reaction of compounds (V) , as obtained in Step 2, with another sugar moiety represented by (IV) in the presence of a mixed catalyst containing a Lewis acid and a solvent, according to the method as described above for Steps 1 and 2.
  • the compounds represented by lA_r are commercially available products or derivatives that can be easily derived from commercially available products using well known conventional means such as esterification, alkylation, reduction, hydrolysis, and so forth, by those skilled in the art.
  • the biphenyl compound can be synthesized by condensation of an aryl halide and an aryl boronic acid in the presence of a palladium catalyst in accordance with the method of the following publications: 1) Miyaura, N., et al., Synth. Commun., (1981), LI,
  • the subject compounds can be also synthesized via glycosylated aryl tin compounds, as described below.
  • R 1 , R 2 , R 3 , (A_TJ, k, m and n have the same meanings as defined above.
  • R 6 represents a lower alkyl group or phenyl group.
  • Y represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • X is not particularly limited as long as it is a group which can be eliminated as a nucleophilic residue.
  • X may be a hydroxyl group; a halogen atom such as chlorine, bromine and iodine; an alkylcarbonyloxy group such as acetoxy, ethylcarbonyloxy, propylcarbonyloxy and butylcarbonyloxy; an aralkyloxycarbonyl group such as benzoyl, benzylcarbonyloxy and phenethylcarbonyloxy; a lower alkoxycarbonyloxy group such as methoxycarbonyloxy and ethoxycarbonyloxy; a halogenated alkylcarbonyloxy group such as chloroacetoxy, dichloroacetoxy, trichloroacetoxy and trifluoroacetoxy; a lower alkanesulfonyloxy group such as methanesulfonyloxy and ethanesulf
  • X represents an alkylcarbonyloxy group, an aralkylcarbonyloxy group, a hydroxyl group, a halogen atom, a halogenolower aikanesulfonyl group or an arylsulfonyloxy group. Most preferably, X represents an alkylcarbonyloxy group or an aralkylcarbonyloxy group.
  • Step Al is a step of preparing an aryl C-glycosyl compound (I) by a condensation reaction of a sugar derivative (III) with an aryl compound (IV) in the presence of a mixed catalyst containing Lewis acid.
  • the Lewis acid catalyst is not particularly limited so long as it is used in a common condensation reaction.
  • the Lewis acid is a metal halide such as stannous tetrachloride, gallium trichloride, zinc bromide and titanium tetrachloride; a metal salt of a strong acid, such as a silver or mercury salt of trifluoromethanesulfonic acid or trifluoroacetic acid; and perchloric acids such as trimethylsilyl perchlorate and triphenylmethyl perchlorate.
  • the reaction is carried out generally in the presence of a solvent.
  • the solvent to be used is not particularly limited so long as it does not inhibit the reaction and dissolves a starting substance to a certain extent, preferably the solvent is selected from the group of aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; nitriles such as acetonitrile, propionitrile and isobutyronitrile;
  • the reaction temperature is not particularly limited, and the reaction is carried out generally at -80°C to 100° C (preferably 0°C to 30°C) .
  • the reaction time varies depending on the kinds of a starting material, a reagent and a solvent and the reaction temperature, and the reaction is completed generally in 30 minutes (preferably 3 hours) to 7 days (preferably 2 days) .
  • the ratio of the sugar derivative (VI) to the aryl compound (III) in this reaction is not particularly limited, the reaction can be carried out generally at 8:1 to 1:5 [Compound (III) : Compound (IV)], and the number (i.e., "n") of the sugar residues represented by R 1 to be introduced into the aryl C-glycosyl compound (I) varies depending on the molar ratio of the two starting materials in this reaction.
  • a plurality of the sugar residues can be introduced by repeating the above reaction. Further, this step can be also carried out by using the reagent for an aryl C-glycosylation reaction disclosed in WO 97/11066.
  • Step A2 is a step of preparing a compound having the formula (VII) by halogenating the aryl C-glycosyl compound (I) according to a known method, and is carried out by, for example, reacting the aryl C-glycosyl compound (I) with a halogenating agent in a solvent in the presence or absence of a catalyst .
  • the halogenating agent to be used is not particularly limited so long as it is used as a halogenating agent in a common reaction, and there may be mentioned, for example, a fluorinating agent such as fluorine (F2) , fluoroxytrifluoromethane, xenon difluoride, cesium acetyl hypofluorite, N-fluorosulfonamide, L diethylaminosulfa trifluoride (DAST) and a N-fluoropyridinium salt (e.g., N- fluoropyridinium, N-fluoro-2, 6-di (methoxycarbonyl) pyridinium, N-fluoro-3, 5-dichloropyridinium, N-fluoro-2, 4 , 6- trimethylpyridinium N-Fluoro-3, 5-dichloropyridinium, N-Fluoro- 2, 4, 6-trimethypyridinium and the like); a chlorinating agent such as
  • brominating agent such as bromine (Br 2 ) , bromine chloride, cupric bromide, silver sulfate-bromine, tetramethylammonium tribromide, trifluoroacetyl hypobromide, dibromoisocyanuric acid (DBI) , 2,4,4, 6-tetrabromocyclohexa-2, 5-dienone, hydrogen bromide-dimethyl sulfoxide, N-bromosuccinimide-dimethyl- formamide and 2, 4-diamino-l, 3-thiazole hydrotribromide; and an iodinating agent such as iodine (12), iodine monochloride
  • IC1 1, 3-diiodo-5, 5-dimethylhydantoin, an iodine-morpholine complex, trifluoroacetyl hypoiodide, iodine-periodic acid, iodine-thalium (I) acetate, fluorine-iodine and ethyleneiodochloride .
  • the solvent to be used is not particularly limited so long as it does not inhibit the reaction, and there may be preferably mentioned aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, chlorotrifluoromethane, dichloroethane, chlorobenzene and dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; nitriles such as acetonitrile, propionitrile and isobutyronitrile; amides such as formamide, N,N-dimethylformamide, N,N- dimethylacetamide, N-methyl-2-pyrrolidone,
  • N-methylpyrrolidinone and hexamethylphosphorotriamide N-methylpyrrolidinone and hexamethylphosphorotriamide; lower aliphatic acids such as formic acid, acetic acid and propionic acid; sulfoxides such as dimethyl sulfoxide, and a mixed solvent of them.
  • the catalyst to be used there may be mentioned, for example, a metal halide such as aluminum chloride and ferric bromide; mercuries such as mercury acetate; and metals such as iron.
  • a metal halide such as aluminum chloride and ferric bromide
  • mercuries such as mercury acetate
  • metals such as iron.
  • the reaction temperature is not particularly limited, and the reaction is carried out generally at -120°C (preferably - 10°C) to 100°C.
  • the reaction time varies depending on the kinds of a starting material, a reagent and a solvent and the reaction temperature, and the reaction is completed generally in 2 minutes (preferably 1 hour) to 2 days.
  • Step A3 is a step of preparing a glycosylated aryl tin compound (VIII) by introducing a tin atom into the compound having the formula (VII) in a solvent in the presence of a palladium catalyst and a base according to a known method.
  • a known method for example, the methods described in the following references may be used:
  • the solvent is not particularly limited so long as it does not inhibit the reaction and dissolves a starting substance to a certain extent, and the solvents described in Step Al may be used.
  • the palladium catalyst to be used is not particularly limited so long as it is a catalyst containing palladium.
  • one of the following palladium catalysts are used: tetrakis (trifluorophosphine) palladium (0) , bis [1, 2-bis (diphenylphosphino) ethane] palladium (0), bis [o-phenylenebis (diethylphosphine) ] palladium (0), bis (cycloocta-1, 5-diene) palladium (0), palladium carbon, palladium black, palladium (II) acetate, palladium (II) acetoacetate, palladium (II) chloride, palladium (II) cyanide, palladium (II) trifluoroacetate, [1,2- bis (diphenylphosphino) ethane] dichloropalladium (II), bis (acetonitrile) dichloropalladium (II) , bis (acetate) bis (triphenylphosphine) palladium (II), bis (benzylpho
  • the base to be used is not particularly limited so long as it is used as a base in a common reaction, and there may be preferably used metal alkoxides such as sodium methoxide; an alkali metal carbonate such as sodium carbonate, potassium carbonate and lithium carbonate; an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, lithium hydroxide and
  • organic bases also may be
  • a reagent for introducing a tin atom is not particularly limited so long as it is a reagent used for introducing tin in a common reaction.
  • the tin containing compound is selected from a trialkyltin compound such as trimethyltin chloride, trimethyltin bromide, tripentyltin chloride, bis (trimethyltin) sulfide, bis (tributyltin) and bis (tributyltin) oxide; and a triphenyltin compound such as triphenyltin chloride and bis (triphenyltin) oxide.
  • the reaction temperature is 0°C to 200°C, preferably 50°C to 150°C.
  • the reaction time varies mainly depending on the reaction temperature and the kind of a starting compound, a reagent or a solvent to be used, and it is generally 1 hour to 5 days, preferably 5 to 10 hours.
  • Process B shown below is another process for preparing the compound having the formula (VII) .
  • Rl, R2, R3, X, Y, k, m and n have the same meanings as described above.
  • Step Bl is a step of preparing a halogenated aryl compound (IX) by halogenating the compound having the formula (III), and is carried out according to Step A2.
  • Step B2 is a step of preparing the compound having the formula (VII) by a condensation reaction of the halogenated aryl compound (IX) with the sugar derivative (IV) , and is carried out according to Step Al .
  • the desired compound is collected from the reaction mixture according to a conventional method.
  • the desired compound is obtained by neutralizing the reaction mixture suitably, or when insolubles exist, after the insolubles are removed by filtration, adding an organic solvent such as ethyl acetate which does not mix with water, washing the resulting mixture with water or the like, separating the organic layer containing the desired compound, drying the organic layer over anhydrous magnesium sulfate and then removing the solvent.
  • an organic solvent such as ethyl acetate which does not mix with water
  • washing the resulting mixture with water or the like separating the organic layer containing the desired compound, drying the organic layer over anhydrous magnesium sulfate and then removing the solvent.
  • the desired compound obtained can be separated and purified according to a conventional method, for example, by suitably combining recrystallization, reprecipitation and a method generally and conventionally used for separation and purification of an organic compound, for example, a method of using a synthetic adsorbent such as adsorption column chromatography using a silica gel, alumina or magnesium-silica gel type carrier such as Florisil; and partition column chromatography using a carrier such as Sephadex LH-20 (produced by Pharmacia Co.), Amberlite XAD-11 (produced by Rohm & Haas Co.) and Diaion HP-20 (produced by Mitsubishi Kasei Corporation) , a method of using an ion exchange chromatograph, or normal phase or reverse phase column chromatography (preferably high performance liquid chromatography) using silica gel or alkylated silica gel, and eluting the desired compound by a suitable eluent.
  • a synthetic adsorbent such as adsorption column chromatography using
  • the starting compounds are available as commercially available products or can be easily synthesized according to a known preparation process.
  • the C-glycosylated aryltin compound in the present invention can be converted into various C-glycosylated derivatives by reacting it various kinds of organic halides and equivalent compounds thereof in the presence of a palladium catalyst under mild conditions.
  • organic halides and equivalent compounds thereof there may be mentioned acid halide, benzyl halide, allyl halide and acetate, vinyl halide and triflate, aryl halide, ⁇ - haloketone and ⁇ -haloester.
  • the subject compounds can be synthesized in accordance with the following method:
  • Rl, R2, R3, Ar, k, m and n are as defined above.
  • R6 represents lower alkyl group having 1 to 10 carbon atoms or phenyl group.
  • R7 represents aryl group substituted with nitro, ketone, ester, carboxy, nitrile, hydroxy, alkoxy, acyloxy, amine, amide, sulfonyl, sulfonamide, or straight, branched or cyclic alkyl groups with or without ketone, ester, carboxy groups; benzyl group substituted with nitro, ketone, ester, carboxy, nitrile, hydroxy, alkoxy, acyloxy, amine, amide, sulfone, sulfonamide, or straight, branched or cyclic alkyl groups with or without ketone, ester, carboxy groups; vinyl group substituted with nitro, ketone, ester, carboxy, niorile, hydroxy, alkoxy, acyloxy, amine, amide, sulfonyl, sulfonamide, or straight, branched or cyclic alkyl groups with or without ketone, ester
  • X represents a leaving groups such as halogen atoms (fluorine, chlorine, bromine and iodine atoms), alkyl carbonyloxy groups (acetoxy, etylcarbonyloxy, propylcarbonyloxy etc.), lower alkanesulfonyloxy groups (methanesulfonyloxy, ethanesulfonyloxy etc.), lower haloalkanesulfonyloxy groups (trifluoromethanesulfonyloxy etc.)
  • palladium catalysts used in this Stille-type palladium mediated cross-coupling reactions Any palladium catalysts commonly used in a coupling reaction of this type may be employed. Examples of such catalysts include palladium (II) acetate, acetylacetonate, chloride, cyanide, trifluoroacetate, [1,2-bis- (diphenylphosphino) ethanedichloropalladium(II) , bis (acetonitrile) dichloropalladium(II) , bis(acetato) bis (triphenylphosphine) palladium (II) , bis (benzonitorile) dichloropalladium(II) , [1, libis (diphenylphosphino) ferrocene] dichloropalladium(II) , (2, 2i-bipyridine) dichloropalladium (II) , (bicyclo [2, 2, 1] h
  • additives which are usually used on the purpose to enhance the reaction.
  • additives include organic bases (triethylamine, diisopropylethylamine, 1, 5-diazabicyclo [4,3,0] non-5-ene, 1,4- diazabicyclo [2,2,2] octane, 1.8-diazabicyclo [5,4,0] undecene, pyridine, lutidine, collidine etc.) or inorganic bases (sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate etc.) or salts (lithium chloride, sodium acetate, copper (I) bromide, iodide, chloride or tetrabutyl ammoniumbromide etc.) or phosphine ligands (triphenylphosphine, tri-o-tolyphosphine, tributylphosphine, triphenylphosphite, tributylphosphite
  • This reaction is normally and preferably carried out in the presence of a solvent, the nature of which is not critical, provided that it has no adverse effect upon the reaction and that the solvent can dissolve the reagents, at least to some extent.
  • suitable solvents include aromatic hydrocarbons (benzene, toluene, xylene) , esters (ethyl acetate, propyl acetate) , ethers (tetrahydrofurane, dioxane, dimethoxyethane) , nitriles (acetonitrile, isobutyronitrile) , amides (formamide, dimethylformamide, dimethylacetamide) , sulfoxides and sulfones (dimethylsulfoxide, sulfolene) .
  • aromatic hydrocarbons benzene, toluene, xylene
  • esters ethyl acetate, propyl acetate
  • ethers tetrahydrofurane, dioxane, dimethoxyethane
  • nitriles acetonitrile, isobutyronitrile
  • amides formamide, dimethylformamide, dimethylacetamide
  • the reaction can place over a wide range of temperature, and the precise reaction temperature chosen is not critical to the invention. In general, it is convenient to carry out the reaction at a temperature of from 0°C to 200°C, more preferably from 50°C to 150°C.
  • the time required for the reaction may likewise vary widely, depending on many factors, notably the reaction temperature, the starting materials, the solvent employed and the nature of the reagents. However, in most cases, a period of from 1 hour to 7 days, more preferably from 3 hours to 3 days, will normally suffice for the reaction.
  • the compound of the present invention can be typically administered intravenously, orally, parenterally, or in the form of an implant, as a general rule, it can also be rectally administered.
  • suitable solid or liquid forms of the preparation include granules, powders, tablets, coated enteric pills, microcapsules, suppositories, syrups, emulsions, suspensions, aerosols, drops, injection preparations in ampule form, as well as preparations in which release of the active compound is prolonged.
  • Excipients, additives and/or auxiliaries are normally used in the manufacturing of these preparations, examples of which include disintegrating agents, binders, coating agents, swelling agents, lubricants, fragrances, sweeteners and solubilizing agents.
  • bases or auxiliaries examples include magnesium carbonate, titanium dioxide, lactose, mannitol, other saccharides, talc, milk protein, gelatin, starch, vitamins, cellulose, its derivatives, animal oils, vegetable oils, polyethylene glycol and solvents such as sterile water, alcohols, glycerol and polyvalent alcohols.
  • the preparation of the compound of the present invention for administration is preferably manufactured in individual doses.
  • Solid individual doses are in the form of tablets, capsules and suppositories.
  • Different daily doses are respectively required in the treatment of the patient according to compound activity, dosing method, properties of the disease, condition, patient age and body weight. However, the daily dose should be suitably increased or decreased depending on the specific circumstances.
  • the dose for the compound of the present invention is preferably 1 to 500 mg/day and more preferably 10 to 300 mg/day.
  • Administration of a daily dose is performed either by administering once in a single dose unit or in the form of several smaller dose units, or by giving several administrations of smaller doses at specific intervals.
  • the daily dose that is administered is additionally dependent on the number of receptors that appear during the course of the disease.
  • the compound of the present invention is suitable for the production of an antibody for diagnosis and measurement of ligands that are not easily approached, do not have sufficient immunoantigenicity or are unknown.
  • autoimmune diseases and tumors a considerable number of specific ligands or antigens on the cell membrane are regulated. However, these are frequently unknown, are unable to be isolated in pure form, or do not have sufficient antigenicity to produce an antibody from them.
  • the compound of the present invention can be used in the production of an antibody that cross-reacts with epitopes of natural ligands that are unknown or not easy to approach. Antibody produced in this manner is considered to be able to be used in both diagnosis and treatment (A.N., Houghton, D.A. , Scheinberg, Semin.
  • the compound of the present invention can be used to treat and/or prevent the following diseases and conditions: rheumatoid arthritis, asthma, allergy, psoriasis, osteoarthritis, septic shock, transplanted tissue rejection reaction, reperfusion disorders, adult dyspnea syndrome, ischema, ulcerative colitis, atherosclerosis, thrombosis, ulcer, infections, cancer, cancer metastasis, wounds, osteoporosis, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, and diabetes mellitus.
  • diseases and conditions rheumatoid arthritis, asthma, allergy, psoriasis, osteoarthritis, septic shock, transplanted tissue rejection reaction, reperfusion disorders, adult dyspnea syndrome, ischema, ulcerative colitis, atherosclerosis, thrombosis, ulcer, infections, cancer, cancer metastasis, wounds, osteoporosis, systemic lupus ery
  • Example 1(a) A procedure similar to that described in Example 1(a) above was followed, but using L-fucose 1, 2, 3, 4-tetraacetate and methyl 3- (4-methoxyphenyl) propionate [prepared using 3- (4 methoxyphenyl) propionic acid as described in Example 2(a), above], to give methyl 3- [4-methoxy-3- (2, 3, 4-tri-O-acetyl- ⁇ -L- fucopyranosyl) phenyl] propionate as a foam in a yield of 91%.
  • Example 13 4- [ ⁇ -L-Fucopyranosyl) -7-methoxybenzofuran-2-carboxylic acid A procedure similar to that described in Example 1(a) above was followed, but using L-fucose 1, 2, 3, 4-tetraacetate and methyl 7-methoxybenzofuran-2-carboxylate (prepared using
  • Example 31 4-Dimethoxy-2- ( ⁇ -D-galactopyranosyl) benzene
  • Example 1 (b) above was followed, but using 1, 4-dimethoxy-2- (2, 3, 4, 6-tetra-O-acetyl- ⁇ -D-galactopyranosyl) benzene to give the titled compound as a foam in a yield of
  • Example 38 (c) (2 ' -Methoxy-3 ' - ⁇ -L-fucopyranosyl) biphenyl-2-yl] acetic acid
  • methyl [2 ' -methoxy-3 ' and 5 1 - (2,3, 4-tri-0-acetyl-?-L-fucopyranosyl) biphenyl-2-yl] acetate prepared as described in Example 38 (b) above
  • Example 39(c) 2 ' -Methoxy-3 ' - (3-L-fucopyranosyl) biphenyl-4-carboxylic acid A procedure similar to that described in Example 1(b) above was followed, but using methyl 2 ' -methoxy-3' - (2, 3, 4-tri- 0-acetyl-?-L-fucopyranosyl) biphenyl-4-carboxylate (prepared as described in Example 39(b) above) to give the titled compound as a freeze-dried product in a yield of 78%.
  • Example 46 A procedure similar to that described in Example 46 above was followed, but using 1, 4-dimethoxy-2- (/3-L-fucopyranosyl) benzene (prepared from 1, 4-dimethoxy-2- (2, 3, 4-tri-0-acetyl-?-L- fucopyranosyl) benzene as described in Example 31 above, but using L-fucose 1, 2, 3, 4-tetraacetate and 1, 4-dimethylbenzene) to give the titled compound as a white solid in a yield of 39%.
  • 1, 4-dimethoxy-2- (/3-L-fucopyranosyl) benzene prepared from 1, 4-dimethoxy-2- (2, 3, 4-tri-0-acetyl-?-L- fucopyranosyl) benzene as described in Example 31 above, but using L-fucose 1, 2, 3, 4-tetraacetate and 1, 4-dimethylbenzene

Abstract

Aryle C-glycoside de la formule (I), dans laquelle R1 est un monosaccharide naturel ou artificiel présentant une liaison α ou β ou un disaccharide, trisaccharide ou tétrasaccharide du monosaccharide; m est un nombre compris entre 1 et 4; Ar est un aromatique ou un aromatique hétérocyclique; R2 est hydrogène, hydroxy, amino, halogène, carboxy ou alkyle linéaire, ramifié ou cyclique; k est un nombre compris entre 1 et 4; et n est un nombre compris entre 1 et 4. L'aryle C-glycoside peut être utilisé dans le traitement ou la prévention des maladies inflammatoires, des maladies auto-immunes, des infections, des cancers et des métastases cancéreuses, des problèmes liés aux perfusions répétées, des thromboses, des ulcères, des plaies et de l'ostéoporose.
PCT/US1998/000701 1997-01-15 1998-01-14 Composes aryle c-glycoside et esters sulfates de ces derniers WO1998031697A1 (fr)

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Cited By (70)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999029706A2 (fr) * 1997-12-08 1999-06-17 Glycomed Incorporated IMITATEURS DE L'OLIGOSACCHARIDE SIALYL-LEWISx A BASE D'ANALOGUES DE DISALICYLATE
WO2001027128A1 (fr) * 1999-10-12 2001-04-19 Bristol-Myers Squibb Company Inhibiteurs de sglt2 a base de glucoside c-aryle
WO2001044264A2 (fr) * 1999-12-16 2001-06-21 Aventis Pharma Deutschland Gmbh Nouveaux inhibiteurs de la stromelysine
WO2002083066A2 (fr) * 2001-04-11 2002-10-24 Bristol-Myers Squibb Company Complexes acides amines de glugocides c-aryle pour le traitement du diabete et procede correspondant
US6515117B2 (en) 1999-10-12 2003-02-04 Bristol-Myers Squibb Company C-aryl glucoside SGLT2 inhibitors and method
US6555519B2 (en) 2000-03-30 2003-04-29 Bristol-Myers Squibb Company O-glucosylated benzamide SGLT2 inhibitors and method
WO2003035656A1 (fr) * 2001-10-19 2003-05-01 Interalia S.R.L. Sels d'argent de saccharose-octasulfate
US6683056B2 (en) 2000-03-30 2004-01-27 Bristol-Myers Squibb Company O-aryl glucoside SGLT2 inhibitors and method
WO2004013118A1 (fr) * 2002-08-05 2004-02-12 Yamanouchi Pharmaceutical Co., Ltd. Derives d'azulene et leurs sels
WO2004080990A1 (fr) * 2003-03-14 2004-09-23 Astellas Pharma Inc. Derives de c-glycoside et sels correspondants
US6936590B2 (en) 2001-03-13 2005-08-30 Bristol Myers Squibb Company C-aryl glucoside SGLT2 inhibitors and method
WO2006121391A1 (fr) * 2005-05-09 2006-11-16 Astrazeneca Ab Nouveaux composes i
JP2007502259A (ja) * 2003-08-14 2007-02-08 グラクソ　グループ　リミテッド マトリックスメタロプロテイナーゼの阻害剤
WO2007093610A1 (fr) 2006-02-15 2007-08-23 Boehringer Ingelheim International Gmbh Dérivés de benzonitrile substitués par glucopyranosyle, compositions pharmaceutiques contenant de tels composés, leurs applications et un procédé pour leur fabrication
JP2008505146A (ja) * 2004-07-06 2008-02-21 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｄ−キシロピラノシル置換フェニル、前記化合物を含む薬物、その使用、及びその製造方法
JP2008508213A (ja) * 2004-07-27 2008-03-21 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｄ−グルコピラノシル−フェニル置換環状体、そのような化合物を含有する医薬品、それらの使用及びその製造方法
WO2008069440A1 (fr) * 2006-12-06 2008-06-12 Samchully Pharm. Co., Ltd. Procédé de préparation de 2-desoxy-l-ribose
WO2008090210A1 (fr) * 2007-01-26 2008-07-31 Boehringer Ingelheim International Gmbh Procédé permettant de prévenir et traiter des maladies neurodégénératives
US7419959B2 (en) 2004-10-01 2008-09-02 Boehringer Ingelheim International, Gmbh D-pyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture
WO2009004096A1 (fr) * 2007-07-05 2009-01-08 Centre National De La Recherche Scientifique Nouveaux composés hétérocycliques contenant du phosphore, analogues de sucres, et compositions ayant une activité anticancéreuse les contenant
US7579449B2 (en) 2004-03-16 2009-08-25 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture
US7662790B2 (en) 2005-04-15 2010-02-16 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted (heteroaryloxy-benzyl)-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
US7683160B2 (en) 2005-08-30 2010-03-23 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted benzyl-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
US7687469B2 (en) 2004-12-16 2010-03-30 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
US7713938B2 (en) 2005-05-03 2010-05-11 Boehringer Ingelheim International Gmbh Crystalline form of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments
US7723309B2 (en) 2005-05-03 2010-05-25 Boehringer Ingelheim International Gmbh Crystalline forms of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments
US7772191B2 (en) 2005-05-10 2010-08-10 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein
US7772378B2 (en) 2005-02-23 2010-08-10 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted ((hetero)arylethynyl-benzyl)-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
US7776830B2 (en) 2006-05-03 2010-08-17 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture
EP2226076A1 (fr) 2009-02-25 2010-09-08 Henning Vollert Support d'enregistrement thermosensible et procédé d'enregistrement
US7795228B2 (en) 2006-12-28 2010-09-14 Theracos, Inc. Spiroheterocyclic glycosides and methods of use
US7803778B2 (en) 2006-05-23 2010-09-28 Theracos, Inc. Glucose transport inhibitors and methods of use
US7847074B2 (en) 2005-09-15 2010-12-07 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted (ethynyl-benzyl)-benzene derivatives and intermediates thereof
US7851602B2 (en) 2005-07-27 2010-12-14 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted ((hetero)cycloalkylethynyl-benzyl)-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
US7973012B2 (en) 2006-05-19 2011-07-05 Taisho Pharmaceutical Co., Ltd C-phenyl glycitol compound
US8039441B2 (en) 2006-08-15 2011-10-18 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted cyclopropylbenzene derivatives, pharmaceutical compositions containing such compounds, their use as SGLT inhibitors and process for their manufacture
US8129434B2 (en) 2007-12-13 2012-03-06 Theracos, Inc. Benzylphenyl cyclohexane derivatives and methods of use
WO2012055169A1 (fr) 2010-10-27 2012-05-03 上海艾力斯医药科技有限公司 Dérivé de c-arylglucoside, son procédé de préparation et son utilisation
US8198464B2 (en) 2006-12-21 2012-06-12 Astellas Pharma Inc. Method for producing C-glycoside derivative and intermediate for synthesis thereof
US8217064B2 (en) * 2007-12-20 2012-07-10 Envivo Pharmaceuticals, Inc. Tetrasubstituted benzenes
US8283454B2 (en) 2008-08-22 2012-10-09 Theracos, Inc. Processes for the preparation of SGLT2 inhibitors
US8283326B2 (en) 2006-10-27 2012-10-09 Boehringer Ingelheim International Gmbh Crystalline form of 4-(beta-D-glucopyranos-1-yl)-1-methyl-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments
US8466114B2 (en) 2009-10-20 2013-06-18 Novartis Ag Glycoside derivatives and uses thereof
WO2013138563A1 (fr) * 2012-03-16 2013-09-19 University Of Geogia Research Foundation, Inc. Glycomimétiques pour inhiber les interactions pathogène-hôte
US8551957B2 (en) 2007-08-16 2013-10-08 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivate
EP2679229A1 (fr) 2012-06-30 2014-01-01 BioActive Food GmbH Composition pour le traitement de pathologies hyperglycémiques
WO2014100158A1 (fr) * 2012-12-18 2014-06-26 Vertex Pharmaceuticals Incorporated Dérivés de mannose pour le traitement d'infections bactériennes
US8802842B2 (en) 2009-09-30 2014-08-12 Boehringer Ingelheim International Gmbh Method for the preparation of a crystalline form
EP2774619A1 (fr) 2013-03-04 2014-09-10 BioActive Food GmbH Composition pour le traitement de pathologies hyperglycémiques
US8987323B2 (en) 2010-06-12 2015-03-24 Theracos, Inc. Crystalline form of benzylbenzene SGLT2 inhibitor
US9024010B2 (en) 2009-09-30 2015-05-05 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives
EP2944311A1 (fr) 2014-05-16 2015-11-18 BioActive Food GmbH Combinaison de substances biologiques actives destinée au traitement de pathologies hypoglycémiques
US9192617B2 (en) 2012-03-20 2015-11-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US9193751B2 (en) 2012-04-10 2015-11-24 Theracos, Inc. Process for the preparation of benzylbenzene SGLT2 inhibitors
US9464043B2 (en) 2013-10-12 2016-10-11 Theracos Sub, Llc Preparation of hydroxy-benzylbenzene derivatives
CN106279307A (zh) * 2015-05-19 2017-01-04 正大天晴药业集团股份有限公司 芳氨代葡萄糖衍生物、其制备方法及抗肿瘤用途
US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
US9890176B2 (en) 2013-03-12 2018-02-13 Vertex Pharmaceuticals Incorporated Mannose derivatives for treating bacterial infections
US9949998B2 (en) 2013-04-05 2018-04-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US9949997B2 (en) 2013-04-05 2018-04-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US20180185291A1 (en) 2011-03-07 2018-07-05 Boehringer Ingelheim International Gmbh Pharmaceutical compositions
US10406172B2 (en) 2009-02-13 2019-09-10 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US10610489B2 (en) 2009-10-02 2020-04-07 Boehringer Ingelheim International Gmbh Pharmaceutical composition, pharmaceutical dosage form, process for their preparation, methods for treating and uses thereof
WO2020151621A1 (fr) * 2019-01-24 2020-07-30 北京盈科瑞创新药物研究有限公司 Composé, son procédé de préparation et ses applications médicales
CN111471040A (zh) * 2019-01-24 2020-07-31 北京盈科瑞创新药物研究有限公司 一种糖苷类衍生物的合成方法及其中间体和应用
CN111840271A (zh) * 2019-04-25 2020-10-30 北京盈科瑞创新药物研究有限公司 一种糖苷类衍生物新用途
US11634451B2 (en) 2013-08-08 2023-04-25 The Scripps Research Institute Method for the site-specific enzymatic labelling of nucleic acids in vitro by incorporation of unnatural nucleotides
US11666590B2 (en) 2013-04-18 2023-06-06 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
RU2800510C1 (ru) * 2002-05-20 2023-07-21 Астразенека Аб С-арил глюкозидные sglt2 ингибиторы и способ их применения
US11813275B2 (en) 2013-04-05 2023-11-14 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE886879A (fr) * 1979-12-28 1981-06-24 Kureha Chemical Ind Co Ltd Nouveaux derives de l'acide aminobenzoique
US5444050A (en) * 1994-04-29 1995-08-22 Texas Biotechnology Corporation Binding of E-selectin or P-selectin to sialyl Lewisx or sialyl-Lewisa
WO1997001335A1 (fr) * 1995-06-29 1997-01-16 Texas Biotechnology Corporation Inhibiteurs de selectine a petites molecules bivalents et trivalents

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE886879A (fr) * 1979-12-28 1981-06-24 Kureha Chemical Ind Co Ltd Nouveaux derives de l'acide aminobenzoique
US5444050A (en) * 1994-04-29 1995-08-22 Texas Biotechnology Corporation Binding of E-selectin or P-selectin to sialyl Lewisx or sialyl-Lewisa
WO1997001335A1 (fr) * 1995-06-29 1997-01-16 Texas Biotechnology Corporation Inhibiteurs de selectine a petites molecules bivalents et trivalents

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
A.K.BARUS ET AL.: "Phaseoloidin, a Homogentisic Acid Glucoside from Estada phaseoloides", PHYTOCHEMISTRY, vol. 27, no. 10, 1988, pages 3259 - 3261, XP002065256 *
B.DUPRE ET AL.: "Glycomimetic Selectin Inhibitors (alpha-D-mannopyranosyloxy)methylbiphenyls.", BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS, vol. 6, no. 5, 1996, pages 569 - 572, XP002065252 *
CHEMICAL ABSTRACTS, vol. 59, no. 3, 5 August 1963, Columbus, Ohio, US; abstract no. 3114a, S.TOMINO ET AL.: "Occurrence of (3,4-dihydroxyphenyl)acetic Acid Glucoside in Abdomen of Female Locust, Locust Migratoria." column 1; XP002065257 *
D.DERRIEN ET AL.: "Muramyl Dipeptide Bound to Poly-L-Lysine Substituted with Mannose and Glucosyl Residues as Macrophage Activators.", GLYCOCONJUGATE JOURNAL, vol. 6, no. 2, 1989, pages 241 - 255, XP002065254 *
EXPERIMENTIA, vol. 19, 1963, pages 231 - 232 *
J.DAI ET AL.: "Studies on the Indonesian Medicinal Plants. Part 3. Phenylacetic Acid Derivatives and a Thioamide Glycoside from Entada Phaseolides.", PHYTOCHEMISTRY, vol. 30, no. 11, 1991, pages 3749 - 3752, XP002065255 *
M.USHIYAMA ET AL.: "Studies on Plant Tissue Culture. Part 60. Biotransformation of Aromatic Carboxylic Acids by Root Culture of Panax Ginseng.", PHYTOCHEMISTRY, vol. 28, no. 7, 1989, pages 1859 - 1869, XP002065253 *

Cited By (131)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999029706A3 (fr) * 1997-12-08 1999-08-12 Glycomed Inc IMITATEURS DE L'OLIGOSACCHARIDE SIALYL-LEWISx A BASE D'ANALOGUES DE DISALICYLATE
WO1999029706A2 (fr) * 1997-12-08 1999-06-17 Glycomed Incorporated IMITATEURS DE L'OLIGOSACCHARIDE SIALYL-LEWISx A BASE D'ANALOGUES DE DISALICYLATE
AU781009B2 (en) * 1999-10-12 2005-04-28 Astrazeneca Ab C-aryl glucoside SGLT2 inhibitors
WO2001027128A1 (fr) * 1999-10-12 2001-04-19 Bristol-Myers Squibb Company Inhibiteurs de sglt2 a base de glucoside c-aryle
US6414126B1 (en) 1999-10-12 2002-07-02 Bristol-Myers Squibb Company C-aryl glucoside SGLT2 inhibitors and method
US6515117B2 (en) 1999-10-12 2003-02-04 Bristol-Myers Squibb Company C-aryl glucoside SGLT2 inhibitors and method
CZ304522B6 (cs) * 1999-10-12 2014-06-18 Astrazeneca Ab C-Arylglukosidový inhibitor SGLT2, farmaceutická kompozice s jeho obsahem, farmaceutická kompozice či kombinace s jeho obsahem a použití
KR100728085B1 (ko) * 1999-10-12 2007-06-14 브리스톨-마이어스스퀴브컴파니 Ｃ-아릴 글루코시드 ｓｇｌｔ2 억제제
WO2001044264A2 (fr) * 1999-12-16 2001-06-21 Aventis Pharma Deutschland Gmbh Nouveaux inhibiteurs de la stromelysine
US6337411B2 (en) 1999-12-16 2002-01-08 Aventis Pharma Deutschland Gmbh Stromelysin inhibitors
WO2001044264A3 (fr) * 1999-12-16 2002-05-02 Aventis Pharma Gmbh Nouveaux inhibiteurs de la stromelysine
US6683056B2 (en) 2000-03-30 2004-01-27 Bristol-Myers Squibb Company O-aryl glucoside SGLT2 inhibitors and method
US6555519B2 (en) 2000-03-30 2003-04-29 Bristol-Myers Squibb Company O-glucosylated benzamide SGLT2 inhibitors and method
US6936590B2 (en) 2001-03-13 2005-08-30 Bristol Myers Squibb Company C-aryl glucoside SGLT2 inhibitors and method
WO2002083066A2 (fr) * 2001-04-11 2002-10-24 Bristol-Myers Squibb Company Complexes acides amines de glugocides c-aryle pour le traitement du diabete et procede correspondant
US6774112B2 (en) 2001-04-11 2004-08-10 Bristol-Myers Squibb Company Amino acid complexes of C-aryl glucosides for treatment of diabetes and method
WO2002083066A3 (fr) * 2001-04-11 2003-03-06 Bristol Myers Squibb Co Complexes acides amines de glugocides c-aryle pour le traitement du diabete et procede correspondant
US7183315B2 (en) 2001-10-19 2007-02-27 Interalia S.R.L. Silver salts of sucrose-octasulphate
WO2003035656A1 (fr) * 2001-10-19 2003-05-01 Interalia S.R.L. Sels d'argent de saccharose-octasulfate
RU2746132C1 (ru) * 2002-05-20 2021-04-07 Астразенека Аб С-арил глюкозидные sglt2 ингибиторы и способ их применения
RU2800510C1 (ru) * 2002-05-20 2023-07-21 Астразенека Аб С-арил глюкозидные sglt2 ингибиторы и способ их применения
US7169761B2 (en) 2002-08-05 2007-01-30 Astellas Pharma Inc. Azulene derivatives and salts thereof
WO2004013118A1 (fr) * 2002-08-05 2004-02-12 Yamanouchi Pharmaceutical Co., Ltd. Derives d'azulene et leurs sels
US7202350B2 (en) 2003-03-14 2007-04-10 Astellas Pharma Inc. C-glycoside derivatives and salts thereof
US7772407B2 (en) 2003-03-14 2010-08-10 Astellas Pharma Inc. C-glycoside derivatives and salts thereof
JP2009046489A (ja) * 2003-03-14 2009-03-05 Astellas Pharma Inc Ｃ−グリコシド誘導体又はその塩
WO2004080990A1 (fr) * 2003-03-14 2004-09-23 Astellas Pharma Inc. Derives de c-glycoside et sels correspondants
US7977466B2 (en) 2003-03-14 2011-07-12 Astellas Pharma Inc. C-glycoside derivatives and salts thereof
JP2007502259A (ja) * 2003-08-14 2007-02-08 グラクソ　グループ　リミテッド マトリックスメタロプロテイナーゼの阻害剤
EP2295422A2 (fr) 2004-03-16 2011-03-16 Boehringer Ingelheim International GmbH Dérivés de benzol substitués par glucopyranosyl, médicament contenant ces composés, leur utilisation et leur procédé de fabrication
EP2360165A2 (fr) 2004-03-16 2011-08-24 Boehringer Ingelheim International GmbH Derives du benzol substitues par un glucopyranosyle, medicaments renfermant ces composes, leur utilisation et leur procede de production
EP2360164A2 (fr) 2004-03-16 2011-08-24 Boehringer Ingelheim International GmbH Derives de benzene substitues par glucopyranosyle, medicaments renfermant ces composes, leur utilisation et leur procede de fabrication
US7579449B2 (en) 2004-03-16 2009-08-25 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture
US7393836B2 (en) 2004-07-06 2008-07-01 Boehringer Ingelheim International Gmbh D-xylopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture
JP2008505146A (ja) * 2004-07-06 2008-02-21 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｄ−キシロピラノシル置換フェニル、前記化合物を含む薬物、その使用、及びその製造方法
US7417032B2 (en) 2004-07-27 2008-08-26 Boehringer Ingelheim International Gmbh D-xylopyranosyl-phenyl-substituted cycles, medicaments containing such compounds, their use and process for their manufacture
JP2008508213A (ja) * 2004-07-27 2008-03-21 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｄ−グルコピラノシル−フェニル置換環状体、そのような化合物を含有する医薬品、それらの使用及びその製造方法
US7419959B2 (en) 2004-10-01 2008-09-02 Boehringer Ingelheim International, Gmbh D-pyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture
US7687469B2 (en) 2004-12-16 2010-03-30 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
US7772378B2 (en) 2005-02-23 2010-08-10 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted ((hetero)arylethynyl-benzyl)-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
US7662790B2 (en) 2005-04-15 2010-02-16 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted (heteroaryloxy-benzyl)-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
US7713938B2 (en) 2005-05-03 2010-05-11 Boehringer Ingelheim International Gmbh Crystalline form of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments
US7723309B2 (en) 2005-05-03 2010-05-25 Boehringer Ingelheim International Gmbh Crystalline forms of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments
WO2006121391A1 (fr) * 2005-05-09 2006-11-16 Astrazeneca Ab Nouveaux composes i
US10442795B2 (en) 2005-05-10 2019-10-15 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein
US7772191B2 (en) 2005-05-10 2010-08-10 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein
US9127034B2 (en) 2005-05-10 2015-09-08 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivates and intermediates therein
US7851602B2 (en) 2005-07-27 2010-12-14 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted ((hetero)cycloalkylethynyl-benzyl)-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
US7683160B2 (en) 2005-08-30 2010-03-23 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted benzyl-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
US7847074B2 (en) 2005-09-15 2010-12-07 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted (ethynyl-benzyl)-benzene derivatives and intermediates thereof
WO2007093610A1 (fr) 2006-02-15 2007-08-23 Boehringer Ingelheim International Gmbh Dérivés de benzonitrile substitués par glucopyranosyle, compositions pharmaceutiques contenant de tels composés, leurs applications et un procédé pour leur fabrication
US7745414B2 (en) 2006-02-15 2010-06-29 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture
US7776830B2 (en) 2006-05-03 2010-08-17 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture
US7973012B2 (en) 2006-05-19 2011-07-05 Taisho Pharmaceutical Co., Ltd C-phenyl glycitol compound
US7803778B2 (en) 2006-05-23 2010-09-28 Theracos, Inc. Glucose transport inhibitors and methods of use
US8039441B2 (en) 2006-08-15 2011-10-18 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted cyclopropylbenzene derivatives, pharmaceutical compositions containing such compounds, their use as SGLT inhibitors and process for their manufacture
US8283326B2 (en) 2006-10-27 2012-10-09 Boehringer Ingelheim International Gmbh Crystalline form of 4-(beta-D-glucopyranos-1-yl)-1-methyl-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments
KR100849979B1 (ko) 2006-12-06 2008-08-01 주식회사 삼천리제약 2-데옥시-엘-리보오스의 제조방법
GB2456999A (en) * 2006-12-06 2009-08-05 Samchully Pharm Co Ltd The preparation method of 2-deoxy-L-ribose
WO2008069440A1 (fr) * 2006-12-06 2008-06-12 Samchully Pharm. Co., Ltd. Procédé de préparation de 2-desoxy-l-ribose
GB2456999B (en) * 2006-12-06 2011-04-27 Samchully Pharm Co Ltd Method for preparing 2-deoxy-L-ribose
US8114987B2 (en) 2006-12-06 2012-02-14 Samchully Pharm. Co. Ltd. Preparation method of 2-deoxy-L-ribose
US8198464B2 (en) 2006-12-21 2012-06-12 Astellas Pharma Inc. Method for producing C-glycoside derivative and intermediate for synthesis thereof
US7795228B2 (en) 2006-12-28 2010-09-14 Theracos, Inc. Spiroheterocyclic glycosides and methods of use
EP2382972A1 (fr) * 2007-01-26 2011-11-02 Boehringer Ingelheim International GmbH Procédé de prévention et traitement des désorders neurodégénératifs
WO2008090210A1 (fr) * 2007-01-26 2008-07-31 Boehringer Ingelheim International Gmbh Procédé permettant de prévenir et traiter des maladies neurodégénératives
JP2010516742A (ja) * 2007-01-26 2010-05-20 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 神経変性疾患を予防及び治療する方法
WO2009004096A1 (fr) * 2007-07-05 2009-01-08 Centre National De La Recherche Scientifique Nouveaux composés hétérocycliques contenant du phosphore, analogues de sucres, et compositions ayant une activité anticancéreuse les contenant
US8383609B2 (en) 2007-07-05 2013-02-26 Centre National De La Recherche Scientifique Phosphorus containing heterocyclic compounds, sugar analogues, and compositions having anti-cancer activity containing the same
US8551957B2 (en) 2007-08-16 2013-10-08 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivate
US8129434B2 (en) 2007-12-13 2012-03-06 Theracos, Inc. Benzylphenyl cyclohexane derivatives and methods of use
US8217064B2 (en) * 2007-12-20 2012-07-10 Envivo Pharmaceuticals, Inc. Tetrasubstituted benzenes
US8283454B2 (en) 2008-08-22 2012-10-09 Theracos, Inc. Processes for the preparation of SGLT2 inhibitors
US9006403B2 (en) 2008-08-22 2015-04-14 Theracos, Inc. Processes for the preparation of SGLT2 inhibitors
US10406172B2 (en) 2009-02-13 2019-09-10 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
EP2226076A1 (fr) 2009-02-25 2010-09-08 Henning Vollert Support d'enregistrement thermosensible et procédé d'enregistrement
US8802842B2 (en) 2009-09-30 2014-08-12 Boehringer Ingelheim International Gmbh Method for the preparation of a crystalline form
US9873714B2 (en) 2009-09-30 2018-01-23 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives
US9024010B2 (en) 2009-09-30 2015-05-05 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives
US10610489B2 (en) 2009-10-02 2020-04-07 Boehringer Ingelheim International Gmbh Pharmaceutical composition, pharmaceutical dosage form, process for their preparation, methods for treating and uses thereof
US8828951B2 (en) 2009-10-20 2014-09-09 Novartis Ag Glycoside derivatives and uses thereof
US9895389B2 (en) 2009-10-20 2018-02-20 Novartis Ag Glycoside derivatives and uses thereof
US8466114B2 (en) 2009-10-20 2013-06-18 Novartis Ag Glycoside derivatives and uses thereof
USRE49080E1 (en) 2009-10-20 2022-05-24 Novartis Ag Glycoside derivatives and uses thereof
US9834573B2 (en) 2010-06-12 2017-12-05 Theracos Sub, Llc Crystalline form of benzylbenzene SGLT2 inhibitor
US8987323B2 (en) 2010-06-12 2015-03-24 Theracos, Inc. Crystalline form of benzylbenzene SGLT2 inhibitor
US10981942B2 (en) 2010-06-12 2021-04-20 Theracos Sub, Llc Crystalline form of benzylbenzene SGLT2 inhibitor
US10533032B2 (en) 2010-06-12 2020-01-14 Theracos Sub, Llc Crystalline form of benzylbenzene SGLT2 inhibitor
WO2012055169A1 (fr) 2010-10-27 2012-05-03 上海艾力斯医药科技有限公司 Dérivé de c-arylglucoside, son procédé de préparation et son utilisation
US8871726B2 (en) 2010-10-27 2014-10-28 Shanghai Allist Pharmaceuticals, Inc. C-aryl glucoside derivative, preparation method therefor, and use thereof
US20180185291A1 (en) 2011-03-07 2018-07-05 Boehringer Ingelheim International Gmbh Pharmaceutical compositions
US11564886B2 (en) 2011-03-07 2023-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical compositions
US10596120B2 (en) 2011-03-07 2020-03-24 Boehringer Ingelheim International Gmbh Pharmaceutical compositions
US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
US9605014B2 (en) 2012-03-16 2017-03-28 University Of Georgia Research Foundation, Inc. Glycomimetics to inhibit pathogen-host interactions
WO2013138563A1 (fr) * 2012-03-16 2013-09-19 University Of Geogia Research Foundation, Inc. Glycomimétiques pour inhiber les interactions pathogène-hôte
US9192617B2 (en) 2012-03-20 2015-11-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US9725478B2 (en) 2012-04-10 2017-08-08 Theracos Sub, Llc Process for the preparation of benzylbenzene SGLT2 inhibitors
US9193751B2 (en) 2012-04-10 2015-11-24 Theracos, Inc. Process for the preparation of benzylbenzene SGLT2 inhibitors
EP2679229A1 (fr) 2012-06-30 2014-01-01 BioActive Food GmbH Composition pour le traitement de pathologies hyperglycémiques
EP3549587A1 (fr) 2012-06-30 2019-10-09 BioActive Food GmbH Composition pour le traitement de pathologies hyperglycémiques
TWI626247B (zh) * 2012-12-18 2018-06-11 維泰克斯製藥公司 用於治療細菌感染之甘露糖衍生物
US10913761B2 (en) 2012-12-18 2021-02-09 Vertex Pharmaceuticals Incorporated 2,7-dibromospiro[fluorene-9,4′-piperidine] compounds
RU2667060C2 (ru) * 2012-12-18 2018-09-14 Вертекс Фармасьютикалз Инкорпорейтед Производные маннозы для лечения бактериальных инфекций
WO2014100158A1 (fr) * 2012-12-18 2014-06-26 Vertex Pharmaceuticals Incorporated Dérivés de mannose pour le traitement d'infections bactériennes
US11634447B2 (en) 2012-12-18 2023-04-25 Vertex Pharmaceuticals Incorporated Mannose derivatives for treating bacterial infections
US9963478B2 (en) 2012-12-18 2018-05-08 Vertex Pharmaceuticals Incorporated Mannose derivatives for treating bacterial infections
US10669298B2 (en) 2012-12-18 2020-06-02 Vertex Pharmaceuticals Incorporated Mannose derivatives for treating bacterial infections
US9598454B2 (en) 2012-12-18 2017-03-21 Vertex Pharmaceuticals Incorporated Mannose derivatives for treating bacterial infections
AU2013361602B2 (en) * 2012-12-18 2018-02-01 Vertex Pharmaceuticals Incorporated Mannose derivatives for treating bacterial infections
EP2774619A1 (fr) 2013-03-04 2014-09-10 BioActive Food GmbH Composition pour le traitement de pathologies hyperglycémiques
US9890176B2 (en) 2013-03-12 2018-02-13 Vertex Pharmaceuticals Incorporated Mannose derivatives for treating bacterial infections
US9949997B2 (en) 2013-04-05 2018-04-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US11833166B2 (en) 2013-04-05 2023-12-05 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US11813275B2 (en) 2013-04-05 2023-11-14 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US11090323B2 (en) 2013-04-05 2021-08-17 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US9949998B2 (en) 2013-04-05 2018-04-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US11918596B2 (en) 2013-04-05 2024-03-05 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US10258637B2 (en) 2013-04-05 2019-04-16 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US11666590B2 (en) 2013-04-18 2023-06-06 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US11634451B2 (en) 2013-08-08 2023-04-25 The Scripps Research Institute Method for the site-specific enzymatic labelling of nucleic acids in vitro by incorporation of unnatural nucleotides
US10093616B2 (en) 2013-10-12 2018-10-09 Theracos Sub, Llc Preparation of hydroxy-benzylbenzene derivatives
US9464043B2 (en) 2013-10-12 2016-10-11 Theracos Sub, Llc Preparation of hydroxy-benzylbenzene derivatives
EP2944311A1 (fr) 2014-05-16 2015-11-18 BioActive Food GmbH Combinaison de substances biologiques actives destinée au traitement de pathologies hypoglycémiques
WO2015173383A1 (fr) 2014-05-16 2015-11-19 Bioactive Food Gmbh Association de substances bioactives pour le traitement de maladies liées à une hyperglycémie
CN106279307A (zh) * 2015-05-19 2017-01-04 正大天晴药业集团股份有限公司 芳氨代葡萄糖衍生物、其制备方法及抗肿瘤用途
CN111471040B (zh) * 2019-01-24 2023-06-02 北京盈科瑞创新药物研究有限公司 一种糖苷类衍生物的合成方法及其中间体和应用
CN111471040A (zh) * 2019-01-24 2020-07-31 北京盈科瑞创新药物研究有限公司 一种糖苷类衍生物的合成方法及其中间体和应用
WO2020151621A1 (fr) * 2019-01-24 2020-07-30 北京盈科瑞创新药物研究有限公司 Composé, son procédé de préparation et ses applications médicales
CN111840271A (zh) * 2019-04-25 2020-10-30 北京盈科瑞创新药物研究有限公司 一种糖苷类衍生物新用途
CN111840271B (zh) * 2019-04-25 2024-05-14 北京盈科瑞创新药物研究有限公司 一种糖苷类衍生物新用途

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