WO2002096921A1 - Nouveau derive glucose induisant l'apoptose, procede de production et utilisation comme medicament - Google Patents

Nouveau derive glucose induisant l'apoptose, procede de production et utilisation comme medicament Download PDF

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Publication number
WO2002096921A1
WO2002096921A1 PCT/JP2002/005197 JP0205197W WO02096921A1 WO 2002096921 A1 WO2002096921 A1 WO 2002096921A1 JP 0205197 W JP0205197 W JP 0205197W WO 02096921 A1 WO02096921 A1 WO 02096921A1
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group
hydrogen
general formula
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different
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PCT/JP2002/005197
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English (en)
Japanese (ja)
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Toshio Suguro
Koji Kawamura
Koichi Katsuyama
Sei-Ichi Tanuma
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Nisshin Seifun Group Inc.
Kyorin Pharmaceutical Co., Ltd.
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Priority to JP2003500100A priority Critical patent/JP4182218B2/ja
Publication of WO2002096921A1 publication Critical patent/WO2002096921A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
    • C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
    • C07H9/04—Cyclic acetals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
    • C07H13/06—Fatty acids

Definitions

  • the present invention relates to a novel acetal derivative of glucose capable of inducing apoptosis, a method for producing the same, and a medicament containing the same as an active ingredient. More specifically, it is intended to treat and / or prevent by inducing apoptosis.
  • Glucose that is effective for the treatment and Z or prophylaxis of diseases that can be expected for example, 8 ulcers, colon polyposis, autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus, viral infections, and inflammatory diseases TECHNICAL FIELD
  • the present invention relates to a novel compound which is an acetal derivative of the present invention, a method for producing the same, and a use thereof as a medicine.
  • Apoptosis is a gene-programmed form of cell death. It can be seen in the morphogenesis of an individual's developmental processes and in the cell alteration of adult blood cells and epidermal cells. . The form of cell death is achieved by cell condensation, loss of microvilli, fragmentation of the nucleus, and cleavage of genomic DNA at nucleosome units, formation of apoptotic bodies and their predation [Cell, 88, 347-354, 1997 and Science, 267, 1456-1462, 1995].
  • Apoptosis has been highlighted in relation to the disease because (1) it is involved in the elimination of self-reactive immunocompetent cells, (2) it is involved in viral infections such as AIDS virus and hepatitis virus, (3) Involvement in the development of neurodegenerative diseases such as Alzheimer's disease and cerebral meningitis, which is an autoimmune disease. (4) Involvement in the natural disappearance of tumor cells at cancer foci ⁇ and cell death by anticancer drugs. Is mentioned.
  • Drugs for various diseases caused by such abnormal control of apoptosis have been actively searched for.
  • substances that promote apoptosis S is found in many substances including conventional anticancer drugs. While these substances are very potent and are quite effective at the cellular level as an assessment of their activity alone, at the same time, these drugs have strong cytotoxicity almost in parallel with their apoptosis-promoting action.
  • the present inventors have set a dalcos at a water-soluble central portion and chemically modified the dalcos to synthesize a compound capable of dissociating a desired apoptosis-inducing ability from toxicity. Tried.
  • a molecule that enhances water solubility and promotes incorporation into the body which are essential requirements for a drug.
  • the present inventors have found that the novel acetal derivative of glucose described below can selectively induce apoptosis in unnecessary or pathogenic cells, for example, cancer cells, and have completed the present invention.
  • the present invention provides a compound represented by the general formula (I):
  • x and ⁇ ⁇ are the same or different and are each hydrogen, a halogenated alkyl group, a hydroxyl group or an alkoxy group, provided that X, ⁇ , and are not hydrogen simultaneously, and R 2 , R 3 is the same or different and is hydrogen or acyl group (C
  • A, B, and C are the same or different and each represents hydrogen, a halogenated alkyl group, a hydroxyl group, an alkoxy group, an alkylsiloxy group, an alkylarylsiloxy group, or an arylsiloxy group; B, C is not equal hydrogen simultaneously, Q, W are the same or different alkyl silyl group, an alkyl ⁇ reel silyl group or Arirushiriru group, and straight or branched chain R 4 is a saturated or unsaturated Is a hydrocarbon group with 3 to 25 carbon atoms in the form of
  • A, B, and C are the same or different and each represents hydrogen, a halogenated alkyl group, a hydroxyl group, an alkoxy group, an alkylsiloxy group, an alkylarylsiloxy group, or an arylsiloxy group; B, C is not equal hydrogen simultaneously, Q is an alkyl silyl group, an alkyl ⁇ reel silyl group or ⁇ Li Rushiriru group, and R 4 is a saturated or unsaturated straight or branched carbon A hydrocarbon group of 3 to 25 atoms],
  • A, B, and C are the same or different and each represents hydrogen, a halogenated alkyl group, a hydroxyl group, an alkoxy group, an alkylsiloxy group, an alkylarylsiloxy group, or an arylsiloxy group; B, C is not equal hydrogen simultaneously, Q is an alkyl silyl group, an alkyl ⁇ reel silyl group or ⁇ Li Rushiriru group, and R 4 is a saturated or unsaturated straight or branched carbon A hydrocarbon group of 3 to 25 atoms], or
  • A, B, and C are the same or different and each represents hydrogen, a halogenated alkyl group, a hydroxyl group, an alkoxy group, an alkylsiloxy group, an alkylaryloxy group, or an aryloxy group; , And C are not simultaneously hydrogen, and at least one of A, B, and C is an alkylsilyl group, an alkylarylsilyl group, or an arylsilyl group, and R 4 is a saturated or unsaturated group. It is a hydrocarbon group having 3 to 25 carbon atoms, which is linear or branched.
  • X, ⁇ , and ⁇ are the same or different and are each hydrogen, a halogenated alkyl group, a hydroxyl group, or an alkoxy group, provided that X, ⁇ , and ⁇ are not hydrogen simultaneously, and R 1 R 2 and R 3 are the same or different and are hydrogen or an acyl group (COR 4 ), provided that I ⁇ , R 2 and R 3 are not simultaneously hydrogen, and may be a saturated or unsaturated linear or A branched hydrocarbon group having 3 to 25 carbon atoms].
  • the present invention relates to a compound of the general formula (I)
  • x, Y, and z are the same or different and each represents hydrogen, a halogenated alkylene group, a hydroxyl group, or an alkoxy group, provided that X, ⁇ , and are not hydrogen at the same time;
  • R 2 and R 3 are the same or different and each represents hydrogen or an acyl group (C
  • the present invention also relates to a medicament for selectively inducing apoptosis of unnecessary or pathogenic cells to treat and / or prevent a disease caused by the cells, comprising a compound represented by the formula:
  • Examples of the acyl group of Ri, R 2 and R 3 in the general formula (I) of the glucose derivative of the present invention include a butyryl group, an isoptyryl group, a bivaloyl group, a valeryl group, an octanoyl group, a decanoyl group, a lauroyl group, Myristoyl group, palmitoleyl group, stearonole group, methacryloyl group, crotonyl group, oleoyl group, linoleoyl group, linolenoyl group, arachidonyl group, 5, 8, 11, 14, 17—eicosapentaenoyl group, 5, 8, 1 1, 14-eicosatetraenoyl group, 4, 7, 10, 13, 16, 19-docosahexaenoyl group and the like.
  • examples of the halogen of the halogenated alkyl group represented by X, ⁇ , and ⁇ in the general formula (I) of the glucose derivative of the present invention include fluorine, chlorine, bromine, and iodine.
  • the alkyl of the halogenated alkyl group may be a straight-chain or branched-chain alkyl, and includes lower alkyl having 1 to 6 carbon atoms. Specific examples include methyl, ethyl, propyl, isopropyl, butyl, isoptyl, t-butyl, pentyl, isopenpentole, neopentyl and the like.
  • a hydrogen atom is partially halogenated.
  • the alkoxy group is preferably a lower alkoxy group having 1 to 6 carbon atoms. Specifically, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a sec-butoxy group, -Butoxy group and the like.
  • Examples of the diseases for which the promotion of apoptosis is effective for the treatment / prevention thereof include cancer, adult T cell leukemia, polyposis of the large intestine, systemic lupus erythematosus, collagen diseases such as rheumatoid arthritis, and viral diseases such as hepatitis C.
  • the compound of the present invention can be obtained by the following synthesis methods.
  • the compound represented by the general formula (I) is, for example, a compound represented by the general formula (II)
  • A, B, and C are the same or different and each represents hydrogen, a halogenated alkyl group, a hydroxyl group, an alkoxy group, an alkylsiloxy group, an alkylarylsiloxy group or an arylsiloxy group; B, C are not hydrogen and a Rukoto simultaneously, Q, W are the same or different alkyl silyl group, an Arukiruari Rushirinore group or Arirushiriru group, Chokukusarima other branched R 4 is a saturated or unsaturated Is a hydrocarbon group with 3 to 25 carbon atoms in the form of Then, a silylating agent such as tetrabutylammonium fluoride, potassium fluoride or the like is reacted.
  • a silylating agent such as tetrabutylammonium fluoride, potassium fluoride or the like is reacted.
  • alkylsiloxy group examples include a trimethylsiloxy group, a triethylsiloxy group, a triisopropylyloxy group, a t-butyldimethyloxy group and the like.
  • alkylarylsiloxy group examples include a t-butyldiphenylsiloxy group.
  • arylsiloxy group examples include a triphenylsiloxy group.
  • alkylsilyl group include a trimethylsilyl group, a triethylsilyl group, a triisopropylylsilyl group, and a t-butyldimethylsilyl group.
  • alkylarylsilino group examples include a t-butyldiphenylsilyl group.
  • arylsilyl groups examples include triphenylsilyl groups and the like.
  • the compound represented by the general formula (I) is, for example, a compound represented by the general formula (III)
  • A, B, and C are the same or different and each represents hydrogen, a halogenated alkyl group, a hydroxyl group, an alkoxy group, an alkylsiloxy group, an alkylarylsiloxy group or an arylsiloxy group; B, C are not hydrogen and a Rukoto simultaneously, Q is an alkyl silyl group, an alkyl ⁇ reel silyl group or ⁇ Rirushiriru group, R 4 is a straight-chain or branched-chain carbon atoms of the saturated or unsaturated 3 to 25 hydrocarbon groups] with a desilylating agent such as tetrabutylammonium-dimethyl fluoride, potassium fluoride or the like.
  • a desilylating agent such as tetrabutylammonium-dimethyl fluoride, potassium fluoride or the like.
  • Examples of the alkynolexy group include a trimethylsiloxy group, a triethylsiloxy group, a triisopropylsiloxy group, and a t-butyldimethyloxy group. I can do it.
  • Examples of the alkylarylsiloxy group include a t-butyldiphenylsiloxy group.
  • Examples of the arylsiloxy group include a triphenylsiloxy group.
  • Examples of the alkylsilyl group include a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, and a t-butyldimethylsilyl group.
  • Examples of the alkylarylsilyl / le group include a t-butyldiphenylsilyl group.
  • Examples of the arylsilyl group include a triphenylsilinole group.
  • the compound represented by the general formula (I) is, for example, a compound represented by the general formula (IV)
  • A, B, and C are the same or different and each represents hydrogen, a halogenated alkyl group, a hydroxyl group, an alkoxy group, an alkylsiloxy group, an alkylarylsiloxy group or an arylsiloxy group; B, C are not hydrogen and a Rukoto simultaneously, Q is an alkyl silyl group, an alkyl ⁇ reel silyl group or ⁇ Rirushiriru group, R 4 is a straight-chain or branched-chain carbon atoms of the saturated or unsaturated 3 to 25 hydrocarbon groups] with a desilylating agent such as tetrabutylammonium fluoride or fluorinated rim.
  • a desilylating agent such as tetrabutylammonium fluoride or fluorinated rim.
  • Examples of the alkylsiloxy group include a trimethylcyclooxy group, a triethylsiloxy group, a triisopropylsiloxy group, a t-butyldimethylcyclooxy group, and the like.
  • Examples of the alkylarylsiloxy group include a t-butyldiphenylsiloxy group.
  • the arylsiloxy group includes, for example, a triphenyloxy group.
  • Examples of the alkylsilyl group include a trimethylsilyl group, a triethynolesilinole group, a triisopropylylsilyl group, and a t_butinoresimetinolyl group. And a silyl group.
  • Examples of the alkylarylsilyl group include a t-butyldiphenylsilyl group.
  • Examples of the arylsilyl group include a triphenylsilyl group.
  • the compound represented by the general formula (II) is, for example, a compound represented by the general formula (V)
  • carboxylic acid represented by R 4 COOH examples include butyric acid, isobutyric acid, bivalic acid, valeric acid, octanoic acid, decanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, methacrylic acid, crotonic acid, Oleic acid, linoleic acid, linolenic acid, arachidonic acid, 5,8,11,14,17-eicosapentaenoic acid, 5,8,11,14-eicosatetraenoic acid, 4,7,10, 13, 16 and 19 docosahexaenoic acid.
  • the compound represented by the general formula (V) is, for example, a compound represented by the general formula (VI)
  • A, B, C, and Q have the same meanings as described for the general formula ( ⁇ )]
  • trimethylsilyl chloride triethylsilyl chloride
  • Alkyl silylating agents such as oral lids, triisopropylidylsilyl chloride, t-butyldimethylsilyl chloride, or alkylaryl silinolelating agents such as t-butyldiphenylsilyl chloride or triphenylsilyl chloride It can be obtained by reacting an aryl silylating agent or the like.
  • A, B, C, and Q have the same meanings as described for general formula (II), and a carboxylic acid represented by R 4 COOH or a functional derivative thereof I can do it.
  • a carboxylic acid represented by R 4 COOH the same one as described above is used.
  • the compound of the general formula (VI) is, for example, a compound of the general formula (VII)
  • the compound of the general formula (VII) is, for example, a compound of the general formula (VIII)
  • the compound of the general formula (VIII) is, for example, a commercially available compound of the general formula ( ⁇ )
  • a compound represented by the formula (1) for example, an alkyl silylating agent such as trimethylsilyl chloride, triethylsilyl chloride, triisopropylsilyl chloride, t-butyldimethylsilyl chloride, or t- butyldiphenylsilyl chloride; It can be obtained by reacting an alkylaryl silylating agent such as a lid or an arylsilyling agent such as triphenylsilyl chloride.
  • an alkyl silylating agent such as trimethylsilyl chloride, triethylsilyl chloride, triisopropylsilyl chloride, t-butyldimethylsilyl chloride, or t- butyldiphenylsilyl chloride.
  • the compound represented by the general formula (I) is, for example, a compound represented by the general formula (X)
  • A, B, and C are the same or different, and each represents hydrogen, an alkyl halide group, a hydroxyl group, an alkoxy group, an alkylsiloxy group, or an alkylarylsiloxy group.
  • A, B, and C are not hydrogen simultaneously, and at least one of A, B, and C is an alkylsilyl group, an alkylarylsilyl group, or an arylsilyl group.
  • R 4 is a saturated or unsaturated linear or branched hydrocarbon group having 3 to 25 carbon atoms.
  • Compounds such as tetrabutylammonium fluoride, potassium fluoride, etc. It can be obtained by reacting with a desilylating agent.
  • alkylsiloxy group examples include a trimethylsiloxy group, a triethylsiloxy group, a triisopropylsiloxy group, and a t-butyldimethyloxy group.
  • alkylarylsiloxy group examples include a t-butyldiphenylsiloxy group.
  • arylsiloxy group examples include a triphenylsiloxy group.
  • the compound of the general formula (X) is, for example, a compound of the general formula (XI)
  • R 4 is a saturated or unsaturated, straight-chain or branched-chain hydrocarbon group having 3 to 25 carbon atoms
  • 3—A—4-B—5—C It can be obtained by reaction with a benzaldehyde derivative.
  • A, B, and C are general formulas
  • the compound of the general formula (XI) is, for example, a compound of the general formula (XII)
  • R 4 has the same meaning as described for general formula (XI)
  • the compound can be obtained by removing the benzyl group (Bn) by catalytic hydrogenation using palladium carbon or the like.
  • the compound of the general formula (XII) is, for example, a commercially available compound of the general formula (IX)
  • the desilylation reaction of the compound represented by the general formula (11), the general formula (111), the general formula (IV) or the general formula (X) is performed under reaction conditions commonly used in this technical field, For example, organic solvents such as methanol, ethanol, isopropanol, dimethyl ether, isopropyl ether, acetone, methinoleethynole ketone, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, etc., water, or these organic solvents and water.
  • a desilylating agent such as tetrabutylammonium fluoride or fluorinated lithium.
  • the reaction can be carried out in a wide range from the boiling point to the freezing point of the solvent, but is usually carried out at a temperature of about 10 ° C. to room temperature.
  • the reaction time depends on the reaction temperature, but is usually from several hours to one day and night.
  • the compound represented by the general formula (I) is, for example, a compound represented by the general formula (XIII)
  • R L , R 2 , and R 3 are the same or different and are hydrogen or an acyl group (COR 4 ), except that I ⁇ , R 2 , and R 3 are not simultaneously hydrogen, and R 4 is A saturated or unsaturated, straight-chain or branched-chain hydrocarbon group having 3 to 25 carbon atoms], which is represented by the general formula (XIV)
  • the compound can be obtained by reacting with the compound represented by This reaction is carried out in a suitable solvent, for example, an organic solvent such as methanol, ethanol, isopropanol, getyl ether, isopropyl ether, acetone, methyl ethyl ketone, methylene chloride, dioxane, tetrahydrofuran, dimethylformamide, and dimethyl sulfoxide.
  • a suitable solvent for example, an organic solvent such as methanol, ethanol, isopropanol, getyl ether, isopropyl ether, acetone, methyl ethyl ketone, methylene chloride, dioxane, tetrahydrofuran, dimethylformamide, and dimethyl sulfoxide.
  • the reaction is carried out in the presence or absence of a condensation catalyst such as pyridinum para toluenesulfonate.
  • a condensation catalyst such as pyridinum para toluenesulfonate.
  • the reaction can be carried out in a wide range from the boiling point to the freezing point of the solvent, but is usually carried out at a temperature of about 11 ° C. to room temperature.
  • the reaction time depends on the reaction temperature, but is usually from several hours to one day and night.
  • the compound of the present invention having the above formula (I) is administered in various forms.
  • the administration form include oral administration using tablets, capsules, granules, powders, syrups, etc., and parenteral administration using injections (intravenous, intramuscular, subcutaneous), infusions, and suppositories. it can.
  • injections intravenous, intramuscular, subcutaneous
  • infusions and suppositories.
  • suppositories it can.
  • these various formulations are commonly used in the pharmaceutical formulation technical field such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, suspending agents, coating agents, etc. It can be formulated using known adjuvants.
  • these adjuvants include water, glucose, ratatose, ⁇ starch, gelatin, manitol, starch paste, magnesium tricate, keratin, colloidal silica, potato starch, and urea.
  • the dosage varies depending on symptoms, age, weight, and method of administration, but is usually
  • FIG. 1 shows the apoptotic effect and the death effect of the cells by the compound of the present invention. Hata in the figure indicates cells that have undergone apoptosis, and ⁇ indicates cells that have died.
  • FIG. 2 shows the activation of caspase-19 (FIG. 2A), caspase-8 (FIG. 2B), and caspase-3 (FIG. 2C) by the compound of the present invention.
  • the production examples show some specific examples of the production of synthetic intermediates of the compounds of the present invention, the examples show specific examples of the production of the compounds of the present invention, and the production examples use the compounds of the present invention as active ingredients.
  • 1 shows specific examples of pharmaceutical preparations. It should be noted that these are merely descriptions of the present invention and should not be construed as limiting the present invention.
  • the extract was washed successively with water, a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium bicarbonate and a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • 3-Methoxy) benzylidene 3-O-triethylsilyl-D_glucopyranoside (1.llg, yield 97%) was obtained.
  • Getyl ether was added, and the mixture was washed successively with water, a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium bicarbonate, and a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Each component was uniformly mixed to obtain a powder for direct compression, and the resulting mixture was converted into a tablet having a diameter of 7.5 mm and a weight of 200 mg using a single-tablet tableting machine.
  • an aqueous solution of B is added and kneaded, sized by an extrusion granulation method, and then dried by a 60 ° C dryer.
  • the dried granules have a particle size of 300 ju ⁇ ! 171700 jum is used as granules.
  • the amount per package is 20 Omg.
  • Sucrose, D-sorbitol, ethyl para-hydroxybenzoate, p-hydroxy benzoate Dissolve the mouth pill and the active substance in 60 g of warm water. After cooling, a solution of the flavoring agent in glycerin and ethanol is added. Then add water to make 10 O mL.
  • the compounds of the present invention induce apoptosis and inhibit the growth of cancer cells. Furthermore, the compounds of the present invention induce cell necrosis, albeit slightly.
  • Apoptosis can be induced by two basic signaling pathways.
  • Casbase-8 is activated by a death signal (death sigh n a l) generated by binding of ligands such as Fas / CD95 and TNF-cell to a cell surface receptor.
  • the pathways induced by a number of apoptotic stimuli, such as anticancer drugs and X-ray irradiation, are those in which cytochrome c is released from the mitochondria into the cytoplasm, which activates caspase-19 and the like. Subsequent to the activation of the initiator caspases caspase-8 and caspase-19, the effect caspases caspase-13, caspase-16 and caspase-17 are activated.
  • the compounds of the present invention convert procaspase-18, procaspase-9 and procaspase-13 into activated caspase-8, caspase-19 and caspase-13. Therefore, it was investigated which caspases the present compound controls the induction of apoptosis by activating. Inhibitors of caspase-18 inhibited DNA fragmentation by the compounds of the present invention, whereas inhibitors of caspase-Ze9 did not. This indicated that the compounds of the present invention induce apoptosis mainly by activation of caspase-18.
  • the compound of the present invention mainly activates caspase 8 and, at the same time, activates caspase 9 1 "in a bypass manner via Bid.
  • Cell viability was determined by mitochondrial dehydrogenase activity of surviving cells.
  • the cancer cells were seeded on a 96-well plate at a cell density of 4 XI04 cells, and added to give the compound of Example 8 (concentration: 0-100 / M).
  • cells were added to a 96-well plate at 4 ⁇ 10 3 cells per well, cultured overnight, and then the compound of Example 8 was added in the same manner.
  • Cell Proliferation Kit II reagent (Roche Mo1 ecu1 arBio chemi ca 1) was added. After culturing at 37 ° C for 4 hours, the absorbance was measured at 490 nm and 650 nm. At least three experiments were performed for each cell type. IC 50 values were calculated from non-linear regression curves. Table 1 shows the results.
  • HL-60 cells human promyelocytic leukemia cells
  • HL-60 cells 5xl0 5 cells
  • Table 2 shows the results.
  • Apoptosis-inducing activity in HL-60 cells determined by DNA fragmentation ability
  • the apoptosis-inducing activity of the compound of the present invention was evaluated by the percentage of colonic adenoma cells (SW480 cells) in which nuclei were aggregated or fragmented, and the DM fragmentation ability.
  • SW480 cells colonic adenoma cells
  • the present compound was added to SW480 cells (lxlO 6 cells), were treated for 2 days with 37 ° C, C0 2 incuba- Isseki within one, were double stained with ethylene Puromaido and ⁇ chestnut gin orange. The number of cells whose nuclei were aggregated or fragmented was counted, and the induction rate of apoptotic cells was calculated. In addition, DNA fragmentation was confirmed by agarose electrophoresis.
  • phosphatidylserine moves from the inner layer to the outer layer of the plasma membrane. Phosphatidylserine binds to Annexin V on cells only when it is present in the outer layer (exposed on the cell surface). Apoptotic cells induced by the compound of Example 8 were measured as follows.
  • U- 937 cells were seeded (IX 10 6 cells / ml) in a new plate and treated with the compound of Example 8 at various concentrations. Six hours later, cells were collected and washed twice with PBS. Suspend the cells in annexin V-fluorescein thiosinate (Annexin V-FITC, using Wako Pure Chemical's Annexin V fluorescent staining kit) and leave for 10 minutes. Cells stained with Annexin V—FITC were counted under a fluorescence microscope to determine the percentage of apoptotic cells (FIG. 1A).
  • Example 8 induced necrosis.
  • necrotic cells The permeability of the plasma membrane is lost, and the stomach can easily enter the necrotic cells.
  • the percentage of Positive and Negative cells was calculated as the necrotic cell rate (FIG. 1A).
  • the ginseng in the figure represents apoptotic cells, and the ⁇ represents necrotic cells.
  • the result is the mean standard deviation from that of the three replicas.
  • U-937 cells (1 ⁇ 10 6 cells / ml) were treated with 50 ⁇ of the compound of Example 8 for 0, 3, 6, 9 or 24 hours. After washing the cells, the cells are added to a lysis buffer (25 mM Hepes (pH 7.5), 10% glycerol, 1 mM EDTA, 1 mM E GTA) at a concentration of 1 ⁇ 10 6 cells / 200 ⁇ 1. The mixture was frozen and thawed three times, and the cells were lysed by sonication at each step. After centrifugation at 12000XG for 15 minutes, a supernatant was obtained.
  • a lysis buffer 25 mM Hepes (pH 7.5), 10% glycerol, 1 mM EDTA, 1 mM E GTA
  • the membrane was blocked with 2% nonfat milk in TBST solution, and the primary antibodies against caspase-9, force spasin 8, caspase-3, and DFF 45 (the caspase-9 goat monoclonal antibody was Medica 1). and Casio Lase 8, Casparase 13 and DFE 45 from Santa Cruz) (manufactured by Santa Cruz) and treated overnight at 4 ° C.
  • the membrane was washed with TBS / 0.2% Tween-20 and treated for 1 hour with the corresponding secondary antibody conjugated to horseradish peroxidase. After sufficient washing, detection was carried out by a chemiluminescence method using an ECL reagent (Amersham Pharmacia Biotech.).
  • U-937 cells (1 ⁇ 10 6 cells / ml) were treated with 75 / M of the compound of Example 8 for 0, 3, 6 and 9 hours. Cells were washed with PBS and incubated at 37 ° C for 10 minutes in PBS containing 10 zg / ml digitonin. A cytoplasmic fraction was collected by centrifugation at 1200 Orpm for 20 minutes, a 40% TCA solution was added thereto, and the mixture was left on water for 10 minutes. After washing three times with ice-cold acetone, the precipitated protein was fractionated by 15% SDS-PAGE. The protein band was transferred to a PVDF membrane, and cytochrome c was detected using the anti-cytochrome c antibody described above. As a result, release of cytochrome c into the cytoplasm was observed 4 hours after treatment with the compound of Example 8 c
  • Activated caspase-18 directly and directly degrades Bid (a member of the Be1-2 family of proteins), and the fragmented Bid migrates to mitochondria, releasing cytochrome c. To promote. Whether the signal of activated caspase-18 was transmitted to mitochondria by the fragmented Bid was examined as follows. U-937 cells were treated with 75 / M of the compound of Example 8 for 0, 3, 6 and 9 hours. The cell lysate was subjected to Western blotting using an anti-Bid antibody (manufactured by Medical and Biological Labories) to detect limited degradation of Bid. As a result, it was found that Bid was decomposed in a time-dependent manner. The results showed that the signal of apoptosis by the compound of Example 8 was transmitted to mitochondria via cleaved Bid by caspase-8.
  • the cells were further treated with 75 M of the compound of Example 8 or dimethylsulfoxide (DMSO) as a control for 8 hours, and DNA fragmentation was detected by agarose gel electrophoresis.
  • Pretreatment of U-937 cells with an inhibitor of caspase-8 completely suppressed DNA fragmentation.
  • inhibitors of PowerSpanze19 did not suppress DNA fragmentation.
  • Bid is also limitedly degraded by the compound treatment of Example 8.
  • Pretreatment with an inhibitor of caspase-18 suppressed the limited degradation of Bid
  • an inhibitor of caspase-9 (Ac—LEHD—fmk) slightly suppressed the limited degradation of Bid I just did.
  • caspase-13 is primarily activated by caspase-8-mediated pathways and partially by caspase-9.
  • the compound of Example 8 caused apoptosis of U-937 by the caspase cascade, indicating that caspase-18 was functioning at the uppermost stream of this cascade.
  • the apoptosis-inducing activity of the compound of Example 3 was evaluated by DNA fragmentation ability using normal human lymphocytes. As a result, the apoptosis-inducing activity was 4 to 8% at the concentrations of 100, 300 and 1000 / M.
  • the effect of the compound of Example 3 on COX of HT-29 cells was evaluated by measuring the amount of PGE2 production after 24 hours.Example 3 was performed at 100 ⁇ M and 200 / M. Did not affect PGE2 secretion in HT-29 cells.
  • the compound of the present invention has an apoptosis-inducing effect and has low or almost no toxicity. Therefore, the compounds of the present invention can be used for treating diseases by causing apoptosis in unwanted cells such as cancer cells.
  • the compound of the present invention Since the compound of the present invention has extremely low toxicity due to the structure of the compound, it is useful as a drug having a wide safety margin.

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Abstract

La présente invention concerne un nouveau dérivé glucose induisant l'apoptose. Ce dérivé glucose est représenté par la formule générale (I) dans laquelle, X, Y et Z sont identiques ou différents, chacun étant hydrogène, halogènoalkyle, hydroxy, ou alcoxy, sous la réserve que l'ensemble des X, Y et Z ne soit pas hydrogène. R1, R2, et R3 sont identiques ou différents, chacun étant hydrogène ou acyle (COR4), sous la réserve que l'ensemble des R1, R2, et R3 ne soit pas hydrogène. Enfin, R4 est un groupe hydrocarbure en C3-25 saturé ou insaturé, linéaire ou ramifié. Ce dérivé glucose induit sélectivement l'apoptose chez les cellules superflues ou pathogènes. Il convient donc comme médicament pour le traitement et/ou la prévention d'affections imputables aux cellules.
PCT/JP2002/005197 2001-05-30 2002-05-29 Nouveau derive glucose induisant l'apoptose, procede de production et utilisation comme medicament WO2002096921A1 (fr)

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Cited By (2)

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CN101157711B (zh) * 2007-09-28 2010-12-08 西安交通大学 一种具有抗肿瘤活性的化合物及其用途
JP2015510869A (ja) * 2012-03-07 2015-04-13 サイノファーム（チャーンシュウ）ファーマシューティカルズ，リミティド ロフルミラストの製造方法

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US9278989B2 (en) * 2012-03-08 2016-03-08 Kyushu University Sugar-derived gelator

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101157711B (zh) * 2007-09-28 2010-12-08 西安交通大学 一种具有抗肿瘤活性的化合物及其用途
JP2015510869A (ja) * 2012-03-07 2015-04-13 サイノファーム（チャーンシュウ）ファーマシューティカルズ，リミティド ロフルミラストの製造方法

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