WO2012165394A1 - 抗腫瘍剤 - Google Patents

抗腫瘍剤 Download PDF

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WO2012165394A1
WO2012165394A1 PCT/JP2012/063686 JP2012063686W WO2012165394A1 WO 2012165394 A1 WO2012165394 A1 WO 2012165394A1 JP 2012063686 W JP2012063686 W JP 2012063686W WO 2012165394 A1 WO2012165394 A1 WO 2012165394A1
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compound
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ddd
nmr
mhz
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French (fr)
Japanese (ja)
Inventor
麗子 杉浦
修 村岡
望 筒井
綾子 喜多
樹 久能
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Kindai University
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Kindai University
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Priority to EP12792042.9A priority Critical patent/EP2716293B1/en
Priority to US14/122,308 priority patent/US9828406B2/en
Priority to CN201280025929.9A priority patent/CN103608019B/zh
Publication of WO2012165394A1 publication Critical patent/WO2012165394A1/ja
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7012—Compounds having a free or esterified carboxyl group attached, directly or through a carbon chain, to a carbon atom of the saccharide radical, e.g. glucuronic acid, neuraminic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to an antitumor agent comprising a novel glycolipid glycoside compound or a pharmacologically acceptable salt thereof as an active ingredient.
  • the present invention is an antitumor agent comprising, as an active ingredient, a novel compound discovered by a novel screening method developed by the present inventors.
  • This compound which has pentitol and hexitol chains as aglycone and all the hydroxyl groups on the mannose ring as the mother nucleus are esterified with medium chain fatty acids, is a novel glycolipid glycoside that suppresses particularly excellent tumor cell growth. Yes, it is useful as an antitumor agent. It is not known at all that the glycolipid glycoside of the present invention has an antitumor action.
  • the compound of Patent Document 1 is clearly different from the glycolipid glycoside compound of the present invention in that it has no glycosidic bond, and is used for the treatment of seborrheic dry skin, and has an antitumor effect. I don't have it.
  • the present invention is intended to provide an excellent antitumor agent.
  • the present invention provides the formula (1) ... (1) (Wherein R 1 to R 4 are the same or different and each represents an alkanoyl group or a hydrogen atom, and A represents a sugar alcohol residue or a polyhydric alcohol residue) And an pharmacologically acceptable salt thereof as an active ingredient.
  • the present invention also relates to a glycolipid in which in formula (1), R 1 to R 4 are the same or different and are a higher or lower alkanoyl group or a hydrogen atom, and A is a sugar alcohol residue or a polyhydric alcohol residue. It is a glycoside compound.
  • R 1 to R 4 are the same or different and are an alkanoyl group having 3 to 16 carbon atoms or a hydrogen atom, and A is a sugar alcohol residue having 4 to 7 carbon atoms Alternatively, it is a glycolipid glycoside compound which is a polyhydric alcohol residue having 2 to 3 carbon atoms.
  • the present invention provides a compound represented by formula (1a) ... (1a) (Wherein, f, h, m and n each represents an integer of 1 to 14, and k represents an integer of 1 to 5) It is characterized by being an antitumor agent comprising a glycolipid glycoside compound represented by the above or a pharmacologically acceptable salt thereof as an active ingredient.
  • f, h, m and n represent an integer of 2 to 8
  • —CH 2 (CHOH) k CH 2 OH is a sugar alcohol having 4 to 7 carbon atoms. It is a residue or a glycerin residue.
  • the present invention provides Formula (1) ... (1) (Wherein R 1 to R 4 are the same or different and each represents an alkanoyl group or a hydrogen atom, and A represents a sugar alcohol residue or a polyhydric alcohol residue) A glycolipid glycoside compound represented by or a pharmacologically acceptable salt thereof, An antitumor agent comprising an antitumor agent as an active ingredient.
  • the glycolipid glycoside compound represented by the formula (1) or a pharmacologically acceptable salt thereof exhibits a growth inhibitory effect on various tumor cells and is useful as an antitumor agent.
  • An antitumor agent comprising a glycolipid glycoside compound represented by the formula (1) or a pharmacologically acceptable salt thereof and an antitumor agent as an active ingredient is a glycoside compound (1) or an antitumor agent. As compared with the case where each is used alone, it exhibits a growth inhibitory effect on tumor cells synergistically and is useful as an antitumor agent.
  • FIG. 6 is a graph comparing the concentration of the glycoside compound (1) (Production Example 24) with respect to normal fetal kidney-derived cells (HEK293F) and human acute lymphoblastic leukemia T-cells (Molt-4) and the cell growth inhibition rate.
  • 1 shows the growth curve of human acute lymphoblastic leukemia T-cell (Molt-4)
  • 2 shows the growth curve of normal fetal kidney-derived cell (HEK293F).
  • Examples 17 and (q) show the chemical formula of the glycolipid glycoside compound of the glycolipid glycoside compound obtained in Production Example 18 and (r) in Production Example 19. It is a chemical formula of the glycolipid glycoside compound obtained by the manufacture example of this invention, (s) is manufacture example 20, (t) is manufacture example 21, (u) is manufacture example 22, (v) is manufacture. Examples 23 and (w) show the chemical formulas of the glycolipid glycoside compounds obtained in Production Example 24 and (x) in Production Example 25. It is a chemical formula of the glycolipid glycoside compound obtained by the manufacture example of this invention, (y) shows the chemical formula of the glycolipid glycoside compound obtained by manufacture example 28 in the figure.
  • glycolipid glucoside compound which is an active ingredient of the present invention, Formula (1) ... (1) (Wherein, R 1 to R 4 are the same or different and each represents an alkanoyl group or a hydrogen atom, and A represents a sugar alcohol residue or a polyhydric alcohol residue) And an pharmacologically acceptable salt thereof as an active ingredient.
  • R 1 to R 4 are the same or different and are higher or lower alkanoyl groups or Represents a hydrogen atom, and A represents a sugar alcohol residue or a polyhydric alcohol residue.
  • examples of the alkanoyl group represented by R 1 to R 4 include alkanoyl groups having 20 or less carbon atoms, such as formyl group, acetyl group, propionyl group, butanoyl group, pentanoyl group, hexanoyl group.
  • Eighteen alkanoyl groups are preferred, with propionyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl or hexadecanoyl being particularly preferred.
  • the glycolipid glycoside bond may be an ⁇ -glycoside bond or a ⁇ -glycoside bond, but the ⁇ -glycoside bond is desirable from the viewpoint of the antitumor effect.
  • the sugar alcohol residue or polyhydric alcohol residue represented by A means one obtained by removing one hydroxyl group from the sugar alcohol or polyhydric alcohol.
  • sugar alcohols examples include sugar alcohols having 4 to 7 carbon atoms. Specific examples include sugar alcohols having 4 carbon atoms such as erythritol and threitol, and sugars having 5 carbon atoms such as ribitol, arabinitol, and xylitol. Examples thereof include sugar alcohols having 6 carbon atoms such as alcohol, sorbitol, mannitol and galactitol, and sugar alcohols having 7 carbon atoms such as perseitol, boremitol, and D-glycerol-D-gluco-heptitol.
  • sugars or sugar alcohols have various optical isomers or stereoisomers, and any of them can be used in the present invention.
  • hexitol having a stereochemistry such as D-glucose and pentitol such as L-arabinose is preferable.
  • polyhydric alcohols include dihydric or trihydric alcohols having 2 to 3 carbon atoms such as ethylene glycol and glycerin.
  • residues of sugar alcohols such as erythritol, threitol, ribitol, arabinitol, xylitol, sorbitol, mannitol, and galactitol
  • residues of polyhydric alcohols such as ethylene glycol and glycerin are preferable. It is preferably a residue of xylitol, sorbitol, or galactitol.
  • Preferred examples of the glycoside compound (1) include those in which R 1 to R 4 are the same or different and formyl group, acetyl group, propionyl group, butanoyl group, pentanoyl group, hexanoyl group, heptanoyl group, octanoyl group, nonanoyl group, decanoyl group
  • An alkanoyl group having 1 to 18 carbon atoms such as a group, undecanoyl group, dodecanoyl group, tridecanoyl group, tetradecanoyl group, pentadecanoyl group, hexadecanoyl group, heptadecanylnoyl group, octadecanylnoyl group
  • the sugar alcohol is a sugar alcohol having 4 carbon atoms such as erythritol and threitol, a sugar alcohol having 5 carbon atoms such as ribitol,
  • More preferable glycoside compounds include compounds represented by the formula (1a).
  • an alkanoyl group represented by R 1 to R 4 is a propionyl group, a butanoyl group, a pentanoyl group, A hexanoyl group, a heptanoyl group, an octanoyl group or a hexadecanoyl group
  • A is a sugar alcohol having 4 carbon atoms such as erythritol and threitol, a sugar alcohol having 5 carbon atoms such as ribitol, arabinitol and xylitol, sorbitol, mannitol,
  • a sugar alcohol residue having 4 to 7 carbon atoms such as a sugar alcohol having 6 carbon atoms such as galactitol, a sugar alcohol having 7 carbon atoms such as perseitol, boremitol, D-glycerol-D-gluco-heptito
  • the alkanoyl group represented by R 1 to R 4 preferably has 4 to 10 carbon atoms.
  • An example of such a compound of the present invention is, for example, D-galactitolyl 3,4,6-tri-O-hexanoyl-2-O-octanoyl- ⁇ -D-mannopyranoside (galactitol-1-yl 3,4,6-trihexanoyl-2-O -Octanoyl- ⁇ -D-mannopyranoside) D-glucitol-1-yl 3,4,6-trihexanoyl-2-O-octanoyl- ⁇ -D-mannopyranoside D-lyxitolyl 3,4,6-tri-O-hexanoyl-2-O-octanoyl- ⁇ -D-mannopyranoside (D-arabinitol-5-yl 3,4,6-trihexanoyl-2-O-octanoyl
  • the glycoside compound (1) contains renal cancer cells (ACHN), acute lymphoblastic leukemia T-cells (Molt-4), cervical cancer cells (HeLa), gastric cancer cells (MKN45). ), Suppresses the growth of solid and liquid cancers such as human bladder cancer cells (T24) at low concentrations.
  • ACBN renal cancer cells
  • Molt-4 acute lymphoblastic leukemia T-cells
  • HeLa cervical cancer cells
  • MKN45 gastric cancer cells
  • T24 human bladder cancer cells
  • the antitumor action of the glycoside compound (1) is derived from the Ca 2+ signal antagonistic action of the glycoside compound (1).
  • MAP kinase mitogen-activated protein kinase: MAPK
  • MAPK mitogen-activated protein kinase
  • the Pmk1 MAPK pathway of fission yeast is an important signal pathway in analyzing the control mechanism of the cell growth signal of higher organisms because it shows high homology with the ERK1 / 2 pathway involved in cell growth and canceration of higher organisms.
  • Calcineurin a protein phosphatase
  • CN fission yeast Ppb1 is not essential for cell growth, but in addition to abnormal cytokinesis Cl - indicate the abnormal homeostasis revealed. That is, CN knockout cells are lethal in the presence of MgCl 2 at a low concentration that allows wild cells to grow. However, when the MAPK signal is suppressed or MAPK is knocked out, CN knockout cells can grow in the presence of MgCl 2 .
  • a compound capable of suppressing CN knockout can control MAPK and its upstream cell growth, an inhibitor of canceration signal transduction pathway, and further tumor growth.
  • Glycoside compound (1) is a compound that antagonizes calcium CN signal and exhibits MAPK signal inhibitory activity, and these compounds can be used for various tumor cells based on the above action even when actual tumor cells are used. Since the growth is strongly suppressed, it can be seen that in the present invention, the glycoside compound has a strong antitumor effect using Ca 2+ signal antagonism as an index.
  • the antitumor effect of the glycolipid glycoside compound of the present invention or a pharmacologically acceptable salt thereof can be exerted on any tumor.
  • tumors include tongue cancer, gingival cancer, malignant melanoma, maxillary cancer, nasal cancer, nasal cavity cancer, laryngeal cancer, and pharyngeal cancer.
  • Malignant tumors of the pharynx, malignant tumors of the cranial nerve such as glioma, meningioma, glioma, thyroid cancer such as papillary adenocarcinoma, follicular thyroid cancer, medullary thyroid cancer, squamous cell carcinoma ,
  • Respiratory cancer such as adenocarcinoma, alveolar epithelial cancer, breast cancer such as breast cancer, breast pacingjet disease, breast sarcoma, acute myeloid leukemia, acute lymphocytic leukemia, adult T-cell leukemia, malignant lymphoma
  • Blood cancer such as esophageal cancer, stomach cancer, pancreatic / gallbladder cancer, duodenal cancer, colon cancer, primary liver cancer and other digestive organ
  • pharmacologically acceptable salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate and phosphate, acetate, tartrate and fumarate.
  • Organic salts such as maleate, citrate, lactate, methanesulfonate, benzenesulfonate, alkali metal salts such as sodium salt and potassium salt, alkali metal salts such as calcium salt and magnesium salt It is done.
  • the antitumor agent comprising the glycoside compound (1) as an active ingredient can be administered orally or parenterally, and the dosage of the glycoside compound (1) as an antitumor agent depends on the type of tumor and tumor Can be selected within the range of 0.001 to 100 mg per kg body weight, preferably 0.001 although it varies depending on the degree of progression of the disease, age, weight, nutritional status, sex, administration method, etc. of the patient. -10 mg, more preferably 0.001-1 mg.
  • the glycoside compound (1) is a known method generally used for pharmaceutical preparations in the pharmaceutical field, and is mixed as it is or with a pharmacologically acceptable carrier, for example, tablets, powders, granules, Solid preparations such as capsules, suppositories and ointments, injections, emulsions, suspensions, syrups, elixirs, lotions and the like can be prepared.
  • a pharmacologically acceptable carrier for example, tablets, powders, granules, Solid preparations such as capsules, suppositories and ointments, injections, emulsions, suspensions, syrups, elixirs, lotions and the like can be prepared.
  • pharmacologically acceptable carriers include excipients, lubricants, binders and disintegrants in solid formulations, or solvents, solubilizers, suspending agents, isotonic agents, buffers in liquid formulations. Formulation aids such as agents and soothing agents. If necessary, additives such as conventional preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.
  • excipients include lactose, starch, dextrin, sucrose, tragacanth, crystalline cellulose, glucose, lactose, sucrose, corn starch, starch, sorbitol, glycine, xylitol, erythritol, maltitol, sorbitol, maltose, trehalose, mannitol,
  • excipients include calcium citrate, potassium phosphate, calcium phosphate, calcium hydrogen phosphate, magnesium metasilicate aluminate, and the like.
  • the lubricant examples include magnesium stearate, talc, polyethylene glycol, silica, talc, light anhydrous silicic acid, hydrous silicon dioxide, alkaline earth metal stearate (for example, magnesium stearate, calcium stearate), higher sucrose fatty acid
  • examples thereof include esters (for example, sucrose stearic acid ester and sucrose behenic acid ester), glycerin higher fatty acid esters (for example, glycerin behenic acid ester), and the like.
  • binders include syrup, gum arabic, gelatin, sorbit, tragacanth, polyvinylpyrrolidone, starch, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, dextrin, ethylcellulose, cellulosic binder (eg, hydroxypropylcellulose),
  • binders include syrup, gum arabic, gelatin, sorbit, tragacanth, polyvinylpyrrolidone, starch, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, dextrin, ethylcellulose, cellulosic binder (eg, hydroxypropylcellulose),
  • polyvinyl binders for example, polyvinyl pyrrolidone.
  • Disintegrants include potato starch, starch, carboxymethylcellulose, carboxymethylcellulose calcium, low substituted hydroxypropylcellulose, corn starch, potato starch, sodium carboxymethyl starch, partially pregelatinized starch, crosslinked carboxymethylcellulose sodium, crosslinked polyvinylpyrrolidone, crystals Examples include cellulose.
  • solvent examples include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
  • solubilizer examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • suspending agent examples include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose.
  • surfactants such as stearyl triethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose.
  • hydrophilic polymers such as sodium, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.
  • isotonic agent examples include glucose, sputum D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
  • buffer examples include phosphate, acetate, carbonate, citrate and the like.
  • soothing agents examples include benzyl alcohol.
  • preservative examples include parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • antioxidant examples include sulfite, ascorbic acid, ⁇ -tocopherol and the like.
  • coloring agents ⁇ -carotene, tar pigment, lake pigment, caramel, iron oxide, copper chlorophyll, edible red No. 2, No. 3, edible yellow No. 4, No. 5, edible green No. 3, edible blue No. 1, 2 No., these aluminum lakes, iron sesquioxide, yellow iron sesquioxide, etc., and sweeteners include saccharin, aspartame (manufactured by Ajinomoto Co., Inc., 1-methyl NL- ⁇ -aspartyl-L-phenylalanine), Examples include stevia and acesulfame potassium.
  • the glycoside compound (1) when used in combination with another antitumor agent, exhibits a synergistically high antitumor effect as compared to the case where the glycoside compound (1) or the other antitumor agent is used alone. be able to.
  • antitumor agents are not particularly limited, and examples include microtubule depolymerization inhibitors, antitumor antibiotics, and platinum complexes.
  • a microtubule depolymerization inhibitor is a drug typified by a taxane antitumor agent, which stabilizes the polymerized state of microtubules and stops cell mitosis, leading to apoptosis.
  • a taxane antitumor agent which stabilizes the polymerized state of microtubules and stops cell mitosis, leading to apoptosis.
  • Specific examples include paclitaxel and docetaxel.
  • Antitumor antibiotics are drugs that inhibit DNA polymerase and prevent cell division, and specifically include doxorubicin, epirubicin, daunorubicin, bleomycin and the like.
  • Platinum complex is a drug that inhibits cell division by crosslinking DNA, and specific examples include cisplatin, carboplatin, oxaliplatin, and the like.
  • paclitaxel paclitaxel
  • doxorubicin doxorubicin
  • cisplatin paclitaxel
  • One of these antitumor agents may be used in combination with the glycoside compound (1), or two or more thereof may be used in combination with the glycoside compound (1).
  • the combination means that the glycoside compound (1) and the other antitumor agent are administered so as not to impair the respective medicinal effects, and are not particularly limited. Or two types of preparations obtained by separately formulating each other at the same administration route, and further, two types of preparations obtained by formulating each separately are administered with a time difference. This means that two types of preparations obtained by separate formulation are administered simultaneously by different administration routes, or two types of preparations obtained by separate preparation are administered at different time intervals by different administration routes To do.
  • the dosage form can be appropriately selected from the above preparations, and each of the above components can be used as a preparation aid.
  • the combination ratio of the glycoside compound (1) and the other antitumor agent can be appropriately selected within the range of the respective doses, and is not particularly limited.
  • both components are made into a single preparation.
  • the weight ratio is usually in the range of 1: 100 to 100: 1, preferably in the range of 1:10 to 10: 1.
  • two or more other antitumor agents can be used in combination and further used in combination with the glycoside compound (1).
  • the combination ratio with other antitumor agents can be appropriately selected within the range of the respective doses, and is not particularly limited.
  • taxane antitumor agents and antitumor agents When using tumor antibiotics, a combined ratio in the range of 1: 100 to 100: 1 is preferred.
  • the glycoside compound (1) has the formula (2) ... (2) (Wherein, R 5 to R 8 are the same or different and each represents an alkanoyl group, a hydrogen atom or a protecting group, and R 9 represents a hydrogen atom, a protecting group, or a group which can be a leaving group together with X. , X represents an oxygen atom, a sulfur atom or a nitrogen atom, and X and R 9 may represent a leaving group represented by XR 9 ), and a formula (3) HO-AP (3) (Wherein, AP represents a sugar alcohol residue or a polyhydric alcohol residue in which the hydroxyl group is protected) Is reacted with a sugar alcohol or a polyhydric alcohol represented by formula (4) ... (4) (In the formula, AP and R 5 to R 8 have the same meaning as described above.) Made
  • the protecting group is removed from the alcohol represented by the formula (4), and the hydroxyl group after the elimination is alkanoylated, or after the hydroxyl group of the compound represented by the formula (4) is alkanoylated, another protecting group is obtained. Can be produced by desorption.
  • examples of the alkanoyl group and protecting group for R 5 to R 8 and the protecting group for R 9 include the alkanoyl groups and the hydroxyl protecting groups for R 1 to R 4 .
  • protecting group examples include ether protecting groups such as benzyl group (Bn), paramethoxyphenyl group, p-methoxybenzyl group (PMB), t-butyl group, methoxymethyl group (MOM), 2-tetrahydropyranyl.
  • ether protecting groups such as benzyl group (Bn), paramethoxyphenyl group, p-methoxybenzyl group (PMB), t-butyl group, methoxymethyl group (MOM), 2-tetrahydropyranyl.
  • An acetal protecting group such as a group (THP), an ethoxyethyl group (EE), an acyl protecting group such as an acetyl group (Ac), a pivaloyl group (Piv), a benzoyl group (Bz), a trimethylsilyl group, a triethylsilyl group, Examples thereof include silyl ether protecting groups such as tert-butyldimethylsilyl group (TBS), triisobutylsilyl group and t-butyldiphenylsilyl group, and acetal protecting groups such as benzylidene acetal group and acetonide group.
  • TMS tert-butyldimethylsilyl group
  • acetal protecting groups such as benzylidene acetal group and acetonide group.
  • benzyl, methoxymethyl, paramethoxyphenyl, t-butyldimethylsilyl, paramethoxybenzyl, benzylidene acetal, and acetonide are preferred.
  • the leaving group may be any group that can be removed when the mannose derivative and a sugar alcohol or a polyhydric alcohol are subjected to a condensation reaction. Even things can be used. Such leaving groups include those such as tosylate, phenyl sulfoxide or trichloroacetimidate, of which phenyl sulfoxide is preferred.
  • sugar alcohol or polyhydric alcohol in which a hydroxyl group other than the hydroxyl group at the site of glycosidic bonding with the mannose derivative is protected include the sugar alcohol or polyhydric alcohol, and the hydroxyl protecting group is as described above. Things can be raised.
  • the condensation reaction between the mannose derivative of formula (2) and the sugar alcohol or polyhydric alcohol in which the hydroxyl group of formula (3) is protected can be carried out in an organic solvent under cooling in the presence of a reaction accelerator. .
  • organic solvent solvents such as methylene chloride, DMF, and dimethyl ether can be used.
  • reaction accelerator include bases such as 2,6-di-tert-butyl-4-methylpyridine (DTBMP) such as trifluoromethanesulfonic anhydride (Tf20).
  • DTBMP 2,6-di-tert-butyl-4-methylpyridine
  • Tf20 trifluoromethanesulfonic anhydride
  • the sugar alcohol or polyhydric alcohol in which the hydroxyl group is protected is preferably used in an amount of 1.1 to 1.5 equivalents based on the mannose derivative of the formula (2), and the reaction accelerator is 1 equivalent to the mannose derivative. It is preferable to use an amount of 1 to 1.5.
  • the condensation reaction can be carried out at about ⁇ 78 to 0 ° C. under cooling, and is generally completed in about 0.5 to 1 hour.
  • the obtained reaction solution is added with saturated aqueous sodium hydrogen carbonate, extracted with an extraction solvent such as methylene chloride, and the crude product is purified by column chromatography to obtain the compound of formula (4). .
  • the resulting condensate represented by the formula (4) is a condensate obtained by removing a protecting group to form a hydroxyl group and then alkanoylating the hydroxyl group, depending on the final target product.
  • the target glycolipid glycoside compound represented by the formula (1) can be obtained by alkanoylating the hydroxyl group and then removing other protecting groups.
  • the method for removing the protecting group can be carried out by a conventional method in this technical field.
  • the protecting group is a benzyl group (Bn), a paramethoxyphenyl group, a p-methoxybenzyl group (PMB), or a t-butyl group.
  • a condensate of formula (4) can be eliminated by hydrogenation in the presence of a catalyst such as palladium or palladium carbon, and if it is a t-butyl group, It can be eliminated by treating the trifluoroacetic acid with strong acidification.
  • the protecting group is an ether protecting group such as p-methoxybenzyl group (PMB), treat with 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) or ceric ammonium nitrate. Can also be eliminated.
  • PMB p-methoxybenzyl group
  • DDQ 2,3-dichloro-5,6-dicyano-p-benzoquinone
  • ceric ammonium nitrate ceric ammonium nitrate.
  • the protecting group is an acetal protecting group such as a methoxymethyl group (MOM), 2-tetrahydropyranyl group (THP), ethoxyethyl group (EE), etc.
  • MOM methoxymethyl group
  • THP 2-tetrahydropyranyl group
  • EE ethoxyethyl group
  • the protecting group is an acyl protecting group such as acetyl group (Ac), pivaloyl group (Piv), benzoyl group (Bz), is it treated with potassium carbonate in methanol or under basic conditions? Can be eliminated by treatment under strongly basic conditions.
  • acyl protecting group such as acetyl group (Ac), pivaloyl group (Piv), benzoyl group (Bz)
  • the protecting group is a silyl ether protecting group such as trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group (TBS), triisobutylsilyl group, t-butyldiphenylsilyl group.
  • the protecting group is an acetal protecting group such as a benzylidene acetal group or an acetonide group, it can be removed by treatment with an acid.
  • the alkanoylation of the hydroxyl group of the compound of formula (4) is performed by reacting the alkanoyl halide or fatty acid anhydride corresponding to the alkanoyl group with the condensate of formula (4) in the presence of a deoxidizing agent in an inert solvent. Can be implemented.
  • Examples of the inert solvent include DMF, THF, N, N-dimethylacetamide, and examples of the deoxidizer include triethylamine, pyridine, N, N-dimethylaniline, and the like.
  • the amount of the alkanoyl halide, fatty acid anhydride, or deoxidizer used is usually equivalent to an equivalent amount that is slightly larger than that of the compound of the formula (3). Complete in 24 hours.
  • R 5 to R 8 are protecting groups
  • AP is a sugar alcohol residue or a polyhydric alcohol residue in which a hydroxyl group is protected.
  • a desired alkanoyl group is introduced into the hydroxyl group from which the protecting group for R 5 has been removed, and then the protecting groups for R 5 , R 6 and R 7 are removed.
  • the protecting group of AP is removed to obtain the desired glycolipid glycoside compound.
  • any of the raw material compounds used in the present invention can be produced from known compounds.
  • mannose derivatives the 2-position hydroxyl group of a known mannose derivative (J. Am. Chem. Soc. 2004, 126, 15081-15086) in which the 1, 3-, 4-, and 6-position hydroxyl groups are protected is protected with a TBS group. Thereafter, it can be produced by oxidizing the protecting group at the 1-position.
  • the sugar alcohol or polyhydric alcohol to be condensed with the mannose derivative can be produced from a known substance. After protecting the hydroxyl group at the site to be condensed with the mannose derivative with a protective group, the ring is reduced and opened to protect it. It can be produced by protecting a hydroxyl group that has not been removed and removing the hydroxyl-protecting group at the site to be condensed.
  • the protecting groups exemplified in the compound represented by the above formula (1) can be preferably used.
  • the sugar alcohol has 6 carbon atoms, 2 to 5 In the case of 5 carbon atoms, adjacent hydroxyl groups of 2 to 5 are preferably protected with an acetal group.
  • Example 1 Anti-tumor effects of glycoside compound (1) using normal fetal kidney-derived cells (HEK293F) and human gastric cancer cells (MKN45), renal cancer cell lines (ACHN) and cervical cancer cells (HeLa) as tumor cells Evaluated.
  • HEK293F normal fetal kidney-derived cells
  • MKN45 human gastric cancer cells
  • ACNN renal cancer cell lines
  • HeLa cervical cancer cells
  • glycoside compound (1) As the glycoside compound (1), the compound obtained in Production Example 16 (chemical name: D-mannitol-1-yl 3,4,6-tri-O-hexanoyl-2-O-octanoyl- ⁇ -D-mannopyranoside) was used. Using.
  • ⁇ Evaluation method> Cell culture medium RPMI1640 (Gibco) and DMEM medium (Gibco) were mixed 1: 1, and 7% FCS (fetal calf serum, Nichirei Bioscience) and antibiotic mix (penicillin, streptomycin, amphotericin B) The cells were diluted to 1 ⁇ 10 5 cells / ml in a medium for cell culture supplemented with the above-mentioned mix, 100-fold concentrated solution (manufactured by Nacalai Co., Ltd.), and 400 ⁇ l each was seeded in a 48-well dish.
  • FCS fetal calf serum, Nichirei Bioscience
  • antibiotic mix penicillin, streptomycin, amphotericin B
  • the compound (dissolved in DMSO to a final concentration of 0.5%) was added and cultured in a CO 2 incubator for 24 hours in a 5% CO 2 atmosphere at 36-37 ° C. After incubation, WST-8 assay was performed, The activity value of DMSO control was set to 100%, and the activity of each cell to which the test compound was added was examined.
  • the test compound is sensitive to gastric cancer cells (MKN45) renal cancer cell line (ACHN) and cervical cancer cells (HeLa), and the IC 50 is 18 of HEK293F.
  • gastric cancer cells (MKN45) were 14.9 ⁇ M
  • cervical cancer cells (HeLa) were 16.7 ⁇ M
  • renal cancer cell lines (ACHN) were 17.0 ⁇ M.
  • Example 2 The compound (chemical name: L-arabinitol-1-yl 3,4,6-trihexanoyl-2-O-octanoyl- ⁇ -D-mannopyranoside) obtained in Production Example 20 as a glycoside compound, gastric cancer cells ( IC 50 was determined in the same manner as in Example 1 except that MKN45) and human renal cancer cell line (ACHN) were used.
  • gastric cancer cells IC 50 was determined in the same manner as in Example 1 except that MKN45
  • ACBN human renal cancer cell line
  • test compound was sensitive to gastric cancer cells (MKN45) and human renal cancer cell line (ACHN), and IC 50 was 8.9 ⁇ M for HEK293F, compared to gastric cancer cells (MKN45).
  • MKN45 gastric cancer cells
  • ACBN human renal cancer cell line
  • Example 3 Compound obtained in Production Example 24 as a glycoside compound (chemical name: D-glycero-D-galacto-heptitol-1-yl 3,4,6-trihexanoyl-2-O-octanoyl- ⁇ -D-mannopyranoside), IC 50 was determined in the same manner as in Example 1 except that human acute lymphoblastic leukemia T-cells (Molt-4) and human gastric cancer cells (MKN45) were used as tumor cells.
  • Molt-4 human acute lymphoblastic leukemia T-cells
  • MKN45 human gastric cancer cells
  • Example 4 Compound obtained in Production Example 24 as a glycoside compound (chemical name: D-glycero-D-galacto-heptitol-1-yl 3,4,6-trihexanoyl-2-O-octanoyl- ⁇ -D-mannopyranoside), Using doxorubicin as an antitumor agent to be used in combination and human bladder cancer cells (T24) as tumor cells, the effect when the glycoside compound (1) and the antitumor agent were used in combination was confirmed.
  • doxorubicin as an antitumor agent to be used in combination
  • human bladder cancer cells T24
  • ⁇ Evaluation method> The same procedure as in Example 1 was performed except that 12.5 ⁇ M of the glycoside compound and 10 ⁇ M of doxorubicin were added to the medium immediately after seeding the tumor cells, and the survival rate of the tumor cells was calculated with the activity value of DMSO control as 100%. did.
  • the survival rate of the tumor cells was 79.0%, and in the case of the doxorubicin alone, the survival rate of the tumor cells was 57.3%. In this case, the survival rate of the tumor cells was 36.9%, and when used together, the antitumor effect of the glycoside compound (1) was further enhanced.
  • Example 5 As a glycoside compound obtained in Production Example 20 (chemical name: L-arabinitol-1-yl 3,4,6-trihexanoyl-2-O-octanoyl- ⁇ -D-mannopyranoside), used as an antitumor agent in combination Using paclitaxel, human kidney cancer cell line (ACHN) was used as tumor cells, and the effects when the glycoside compound (1) and an antitumor agent were used in combination were confirmed.
  • ACBN human kidney cancer cell line
  • ⁇ Evaluation method> The survival rate of tumor cells was calculated in the same manner as in Example 4 except that 5 ⁇ M of the glycoside compound and 29 nM of paclitaxel were added to the medium immediately after seeding the tumor cells.
  • the survival rate of the tumor cells was 65.8%, and in the case of the paclitaxel alone, the survival rate of the tumor cells was 63.8%. In this case, the survival rate of the tumor cells was 40.6%, and when used together, the antitumor effect of the glycoside compound (1) was further enhanced.
  • Example 6 Compound obtained in Production Example 24 as a glycoside compound (chemical name: D-glycero-D-galacto-heptitol-1-yl 3,4,6-trihexanoyl-2-O-octanoyl- ⁇ -D-mannopyranoside), Using cisplatin as an antitumor agent to be used in combination and cervical cancer cells (HeLa) as tumor cells, the effect of using a glycoside compound (1) and an antitumor agent in combination was confirmed.
  • a glycoside compound chemical name: D-glycero-D-galacto-heptitol-1-yl 3,4,6-trihexanoyl-2-O-octanoyl- ⁇ -D-mannopyranoside
  • ⁇ Evaluation method> ⁇ Survival rate after 2 hours> The survival rate of tumor cells was calculated in the same manner as in Example 4 except that 15 ⁇ M of the glycoside compound and 333 ⁇ M of cisplatin were added to the medium immediately after seeding the tumor swell and cultured for 2 hours.
  • Example 7 ⁇ Measurement of MAP kinase signal transduction inhibitory action> After culturing fission yeast calcineurin gene knockout cells (h + leu1 ura4-D18 ppb1 :: ura4 + ) to the logarithmic growth phase (YPD liquid medium), calcineurin gene knockout cells on YPD agar medium supplemented with 0.11M MgCl 2 was seeded at a rate of 2.0 ⁇ 10 5 cells / plate. A circular filter paper (diameter 3 mm) was placed on the plate, and 5 ⁇ L of a test compound dissolved in DMSO so as to be 100 ⁇ M was added on the filter paper. As a control, a DMSO solution containing no compound was also added to the filter paper, and the plate was incubated at 30 ° C.
  • Production Example 2 (1) 1.14 g of the mannosyl sulfoxide compound of Reference Example 1 and the alcohol form of Reference Example 3 (6-O-tert-butyldimethylsilyl-2,3: 4,5-di-O-isopropylidene-D- Compound (6-O-tert-butyldimethylsilyl-2,3: 4,5-di-O-isopropylidene-D) was treated in the same manner as in Production Example 1 (1) using 0.88 g of glucitol). -Glucitryl 4,6-O-benzylidene-2-Op-methoxybenzyl- ⁇ -D-mannopyranoside) 0.40 g was obtained.
  • Production Example 3 (1) 1.00 g of the mannosyl sulfoxide compound of Reference Example 1 and an alcohol (2,3: 4,5-di-O-isopropylidene-D-lyxitol) (1,2: 3,4-di-O -Isopropylidene-D-arabinitol) 476 mg and treated in the same manner as in Production Example 1 (1) to give the compound (2,3: 4,5-di-O-isopropylidene-D-lyxitryl 3-O- 615 mg of benzyl-4,6-O-benzylidene-2-Op-methoxybenzyl- ⁇ -D-mannopyranoside) was obtained.
  • Production Example 4 (1) In the same manner as in Production Example 1 (1), using 500 mg of the mannosyl sulfoxide compound of Reference Example 1 and 218 mg of alcohol (2,3: 4,5-di-O-isopropylidene-D-arabinitol) The compound (2,3: 4,5-di-O-isopropylidene-D-arabonitrile 3-O-benzyl-4,6-O-benzylidene-2-Op-methoxybenzyl- ⁇ - 425 mg of D-mannopyranoside) was obtained. Yield 72% The physical and spectroscopic constants of the obtained compound were as follows.
  • Production Example 5 (1) Using 500 mg of the mannosyl sulfoxide compound of Reference Example 1 and 218 mg of alcohol (2,3: 4,5-di-O-isopropylidene ribitol), the same treatment as in Production Example 1 (1) Compound (2,3: 4,5-di-O-isopropylidene-D-ribitolyl 3-O-benzyl-4,6-O-benzylidene-2-Op-methoxybenzyl- ⁇ -D-manno 442 mg of pyranoside) was obtained. Yield 75% The physical and spectroscopic constants of the obtained compound were as follows.
  • Production Example 6 (1) In the same manner as in Production Example 1 (1), using 0.50 g of the mannosyl sulfoxide compound of Reference Example 1 and 0.24 g of an alcohol (1,2: 3,4-di-O-isopropylidenexylitol) The compound (2,3: 4,5-di-O-isopropylidene-L-xylitolyl 3-O-benzyl-4,6-O-benzylidene-2-Op-methoxybenzyl- ⁇ -D -Mannopyranoside) 0.41 g was obtained. Yield 58% The physical and spectroscopic constants of the obtained compound were as follows.
  • Production Example 7 (1) 1.75 g of the mannosyl sulfoxide compound of Reference Example 1 and 0.99 g of the racemic alcohol form (1-O-tert-butyldimethylsilyl-2,3-O-isopropylidene-erythritol) of Reference Example 4
  • the compounds (a) and (b) (1-O-tert-butyldimethylsilyl-2,3-O-isopropylidene-erythritol) 3-O— were treated in the same manner as in Production Example 1 (1).
  • D-erythritol 3,4,6-tri-O-hexanoyl-2-O-octanoyl is obtained by carrying out in the same manner as above using the compound (b) obtained in (1) above. 0.02 g of - ⁇ -D-mannopyranoside (erythritol-1-yl 3,4,6-tri-O-hexanoyl-2-O-octanoyl- ⁇ -D-mannopyranoside) was obtained. Yield 75% The physical and spectroscopic constants of the obtained compound were as follows.
  • Production Example 8 (1) Using 0.50 g of the mannosyl sulfoxide compound of Reference Example 1 and 0.28 g of an alcohol (4-O-tert-butyldimethylsilyl-2,3-O-isopropylidene-L-threitol), The compound (4-O-tert-butyldimethylsilyl-2,3-O-isopropylidene-L-traitryl 3-O-benzyl-4,6-O-benzylidene) was treated in the same manner as in Production Example 1 (1). -2-Op-methoxybenzyl- ⁇ -D-mannopyranoside) 0.37 g was obtained. Yield 59% The physical and spectroscopic constants of the obtained compound were as follows.
  • Production Example 9 (1) Using 1.15 g of the mannosyl sulfoxide compound of Reference Example 1 and 0.31 g of alcohol (2,3-O-isopropylidene-D-glycerol), the same treatment as in Production Example 1 (1) Compound (2,3-O-isopropylidene-D-glycerolyl 3-O-benzyl-4,6-O-benzylidene-2-Op-methoxybenzyl- ⁇ -D-mannopyranoside) .62 g was obtained. Yield 53% The physical and spectroscopic constants of the obtained compound were as follows.
  • Production Example 10 (1) Production Example 1 (1) using 1.76 g of the mannosyl sulfoxide compound of Reference Example 1 and 0.48 g of (R)-( ⁇ )-2,2-dimethyl-1,3-dioxolane-4-methanol To give the compound (2,3-O-isopropylidene-L-glycerolyl 3-O-benzyl-4,6-O-benzylidene-2-Op-methoxybenzyl- ⁇ -D-manno 0.69 g of pyranoside) was obtained. Yield 40% The physical and spectroscopic constants of the obtained compound were as follows.
  • Production Example 11 (1) Using 500 mg of the mannosyl sulfoxide compound of Reference Example 1 and 165 mg of 1-tert-butyldimethylsilyl-ethanediol, treating in the same manner as in Production Example 1 (1), the compound (2-O-tert- 397 mg of butyldimethylsilylethyleneglycolyl 3-O-benzyl-4,6-O-benzylidene-2-Op-methoxybenzyl- ⁇ -D-mannopyranoside) was obtained. Yield 73%
  • Production Example 12 (1) 1.24 g of a mannosyl sulfoxide compound (2,3-di-O-benzyl-4,6-O-benzylidene-1-thio- ⁇ -D-mannopyranoside S-oxide) and an alcohol (6-O -Tert-butyldimethylsilyl-2,3: 4,5-di-O-isopropylidene-D-mannitol) and 1.00 g of the compound (6- O-tert-butyldimethylsilyl-2,3: 4,5-di-O-isopropylidene-D-mannonitrile 2,3-di-O-benzyl-4,6-O-benzylidene- ⁇ -D-man 974 mg of nopyranoside) was obtained.
  • a mannosyl sulfoxide compound (2,3-di-O-benzyl-4,6-O-benzylidene-1-thio- ⁇ -D-mannopyrano
  • Compound A (D-mannonitrile 2) was prepared in the same manner as above except that octanoyl chloride, propionyl chloride and palmitoyl chloride were used instead of hexanoic anhydride used in Production Example (3).
  • Production Example 13 (1) 1.82 g of a mannosyl sulfoxide compound (4,6-O-benzylidene-2,3-di-Op-methoxybenzyl-1-thio- ⁇ -D-mannopyranoside S-oxide) and an alcohol ( 6-O-tert-butyldimethylsilyl-2,3: 4,5-di-O-isopropylidene-D-mannitol) 1.23 g and treating in the same manner as in Production Example 1 (1) to give the compound (6-O-tert-butyldimethylsilyl-2,3: 4,5-di-O-isopropylidene-D-mannonitrile 4,6-O-benzylidene-2,3-di-Op-methoxybenzyl 1.98 g of - ⁇ -D-mannopyranoside) was obtained.
  • a mannosyl sulfoxide compound (4,6-O-benzylidene-2,3-di
  • Production Example 14 (1) 200 mg of the compound obtained in Production Example 13 (2) was treated in the same manner except that propionate chloride was used instead of n-octanoyl chloride in Production Example 1 (3) to give compound (6-O -Tert-butyldimethylsilyl-2,3: 4,5-di-O-isopropylidene-D-mannonitrile 4,6-O-benzylidene-2,3-di-O-propionyl- ⁇ -D-manno 171 mg of pyranoside) was obtained. Yield 96% The physical and spectroscopic constants of the obtained compound were as follows.
  • Production Example 15 (1) 200 mg of the compound obtained in Production Example 13 (2) was treated in the same manner except that palmitic acid chloride was used in place of n-octanoyl chloride in Production Example 1 (3) to give compound (6-O -Tert-butyldimethylsilyl-2,3: 4,5-di-O-isopropylidene-D-mannonitrile 4,6-O-benzylidene-2,3-di-O-palmitoyl- ⁇ -D-manno 313 mg of pyranoside) was obtained. Yield 89%
  • Production Example 16 Mannosyl sulfoxide compound (4,6-O-benzylidene-3-Op-methoxybenzyl-2-O- (t-butyldimethylsilyl) - ⁇ -D-mannopyranoside S-oxide ) Using 799 mg and 591 mg of the D-mannitol derivative of Reference Example 2 and treating in the same manner as in Production Example 1 (1), (6-O-benzyl-2,3: 4,5-di-O-isopropylidene- 679 mg of D-mannonitrile 4,6-O-benzylidene-3-Op-methoxybenzyl-2-Ot-butyldimethylsilyl- ⁇ -D-mannopyranoside) was obtained.
  • Production Example 17 (1) Using a mannosyl sulfoxide compound and an alcohol form of a known compound, the compound (1,2: 3,4-di-O-isopropylidene-D-) was treated in the same manner as in Production Example 1 (1).
  • Galactopyranosyl 4,6-O-benzylidene-2-O-tert-butyldimethylsilyl-3-Op-methoxybenzyl- ⁇ -D-mannopyranoside in 89% yield It was.
  • Production Example 18 (1) 0.500 g of the mannosyl sulfoxide compound of Reference Example 1 and 0.320 g of an alcohol (1,2: 3,4-di-O-isopropylidene-5-O-methoxymethyl-D-glucitol) And treated in the same manner as in Production Example 1 (1) to give the compound (1,2: 3,4-di-O-isopropylidene-5-O-methoxymethyl-D-glucitol-6-yl 3-O- 0.360 g of benzyl-4,6-O-benzylidene-2-Op-methoxybenzyl- ⁇ -D-mannopyranoside) was obtained. Yield 56% The physical and spectroscopic constants of the obtained compound were as follows.
  • Production Example 20 (1) Production Example 1 (1) using 0.529 g of the mannosyl sulfoxide compound of Reference Example 1 and 0.252 g of alcohol (2,3: 4,5-di-O-isopropylidene-L-arabinitol) ) To give the compound (2,3: 4,5-di-O-isopropylidene-L-arabinitol-1-yl 3-O-benzyl-4,6-O-benzylidene-2-O—). 0.380 g of p-methoxybenzyl- ⁇ -D-mannopyranoside) was obtained. Yield 61% The physical and spectroscopic constants of the obtained compound were as follows.
  • Production Example 21 (1) Using Mannosyl sulfoxide compound of Reference Example 1 (0.700 g) and alcohol (1,2: 3,4-di-O-isopropylidene-ribitol) (0.252 g), Production Example 1 (1) and The compound (1,2: 3,4-di-O-isopropylidene-ribitol-5-yl 3-O-benzyl-4,6-O-benzylidene-2-Op-methoxybenzyl) was treated in the same manner. 0.395 g of - ⁇ -D-mannopyranoside) was obtained. Yield 48% The physical and spectroscopic constants of the obtained compound were as follows.
  • Production Example 22 (1) Using 0.500 g of the mannosyl sulfoxide compound of Reference Example 1 and 0.237 g of an alcohol (2,3: 4,5-di-O-isopropylidene-xylitol), The compound (2,3: 4,5-di-O-isopropylidene-xylitol-1-yl 3-O-benzyl-4,6-O-benzylidene-2-Op-methoxybenzyl) was treated in the same manner. 0.389 g of - ⁇ -D-mannopyranoside) was obtained. Yield 66% The physical and spectroscopic constants of the obtained compound were as follows.
  • Production Example 23 (1) Using 1.60 g of the mannosyl sulfoxide compound of Reference Example 1 and 0.850 g of an alcohol form (4-O-tert-butyldimethylsilyl-2,3-O-isopropylidene-D-threitol), The compound (4-O-tert-butyldimethylsilyl-2,3-O-isopropylidene-D-threitol-1-yl 3-O-benzyl-4, treated in the same manner as in Production Example 1 (1), 1.12 g of 6-O-benzylidene-2-Op-methoxybenzyl- ⁇ -D-mannopyranoside) was obtained.
  • Production Example 24 (1) 0.441 g of the mannosyl sulfoxide compound of Reference Example 1 and an alcohol (2,3: 4,5: 6,7-tri-O-isopropylidene-D-glycero-D-galacto-heptitol) The compound (2,3: 4,5: 6,7-tri-O-isopropylidene-D-glycero-D-galacto-heptitol-1 was treated in the same manner as in Production Example 1 (1). 0.25 g of -yl 3-O-benzyl-4,6-O-benzylidene-2-Op-methoxybenzyl- ⁇ -D-mannopyranoside) was obtained.
  • compound A (D-mannitol-1-yl 2) was prepared in the same manner as above except that octanoyl chloride and propionyl chloride were used in place of hexanoic anhydride used in (3) above. , 3,4,6-tetra-O-octanoyl- ⁇ -D-mannopyranoside), compound B (D-mannitol-1-yl 2,3,4,6-tetra-O-propionyl- ⁇ -) D-mannopyranoside) was obtained.
  • the physical and spectroscopic constants of the obtained compounds A and B were as follows.
  • Production Example 27 (1) 4.28 g of the compound (phenyl 4,6-O-benzylidene-3-Op-methoxybenzyl-1-thio- ⁇ -D-mannopyranoside) was treated in the same manner as in Production Example 1 (3). Thus, 9.81 g of the compound (phenyl 4,6-O-benzylidene-3-Op-methoxybenzyl-2-O-octanoyl-1-thio- ⁇ -D-mannopyranoside) was obtained. Yield 94% The physical and spectroscopic constants of the obtained compound were as follows.
  • Production Example 28 (1) Compound (6-O-tert-butyldimethylsilyl-2,3: 4,5-di-O-isopropylidene-D-mannitol-1-yl ⁇ -D- obtained in Production Example 12 (2) Mannopyranoside) 30.0 mg (0.0557 mmol), N, N-dimethyl-4-aminopyridine (DMAP) 34.0 mg (0.278 mmol) in methylene chloride (5.6 mL) in 0.023 mL (0.278 mmol) ) was added and stirred. The butyric anhydride 0.045mL (0.278) was dripped there and it stirred for 8 hours. Water was added to the reaction solution, followed by extraction with methylene chloride.
  • DMAP N, N-dimethyl-4-aminopyridine
  • compound A (D-mannitol-1-) was obtained in the same manner as above except that valeric anhydride and heptanoic anhydride were used in place of butyric anhydride used in (1) above.
  • compound B (D-mannitol-1-yl 2,3,4,6-tetra-O-heptanoyl-) ⁇ -D-mannopyranoside) was obtained.
  • the physical and spectroscopic constants of the obtained compounds A and B were as follows.
  • Reference example 1 (1) Compound (300m) g described in the literature (J. Org. Chem, 2006, 71, 3064-3070) was treated with p-methoxybenzyl chloride in DMF in the presence of sodium hydride. 316 mg of a compound in which the hydroxyl group is protected with a PMB group (phenyl 3-O-benzyl-4,6-O-benzylidene-2-Op-methoxybenzyl-1-thio- ⁇ -D-mannopyranoside) Obtained. Yield 63%
  • Reference example 2 (1) 300 mg of an alcohol compound described in the literature (J. Tetrahedron Lett. 2005, 46, 5393-5397) is treated with benzyl bromide in DMF in the presence of sodium hydride, and only one hydroxyl group is benzyl. 316 mg of the group protected compound (6-O-benzyl-2,3: 4,5-di-O-isopropylidene-D-mannitol) was obtained. Yield 78% The physical and spectroscopic constants of the obtained compound were as follows.
  • Reference example 3 (1) 5.4 g of D-glucose was treated with ethanethiol in concentrated hydrochloric acid to obtain 3.5 g of a compound in which the aldehyde group was thioacetalized.
  • Reference example 4 (1) 1.78 g of an alcohol (2,3-isopropylidene-erythritol) synthesized by the method described in the literature (Org. Biomol. CHem. 2003, 1, 3692-3697) was added to t-butyldimethylsilyl in DMF. By treatment with chloride and sodium hydride, the alcohols (1-O-tert-butyldimethylsilyl-2,3-O-isopropylidenedenerythritol and 4-O-tert-butyldimethylsilyl-2,3- 0.99 g of (O-isopropylidenedenerythritol) was obtained.

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JP6307138B2 (ja) 2018-04-04
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EP2716293A1 (en) 2014-04-09
JP2017036311A (ja) 2017-02-16
EP2716293B1 (en) 2017-09-06
JP6047309B2 (ja) 2016-12-21
JP2013237659A (ja) 2013-11-28
CN103608019A (zh) 2014-02-26
US9828406B2 (en) 2017-11-28

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