WO1997031928A1 - Derives de trisaccharide 1-deoxymannojirimycine - Google Patents

Derives de trisaccharide 1-deoxymannojirimycine Download PDF

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Publication number
WO1997031928A1
WO1997031928A1 PCT/JP1997/000593 JP9700593W WO9731928A1 WO 1997031928 A1 WO1997031928 A1 WO 1997031928A1 JP 9700593 W JP9700593 W JP 9700593W WO 9731928 A1 WO9731928 A1 WO 9731928A1
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Prior art keywords
compound
added
mixture
dissolved
methanol
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PCT/JP1997/000593
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English (en)
Japanese (ja)
Inventor
Tadaaki Ohgi
Yosuke Kyotani
Hirotsugu Ogawa
Naoyuki Taniguchi
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Nippon Shinyaku Co., Ltd.
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Publication of WO1997031928A1 publication Critical patent/WO1997031928A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings

Definitions

  • the compound according to the present invention is useful as a therapeutic or diagnostic agent for cancer and a ligand for GnT-V affinity chromatography.
  • Glycoconjugate molecules and oligosaccharide chains present on the cell membrane surface are responsible for various biological functions such as receptor function for physiologically active substances such as hormones and bacterial toxins, cell-cell adhesion and information exchange function, and cell-substrate adhesion function. And is deeply involved in the roots of life phenomena. Research and development are being actively conducted to develop useful drugs by applying the physiological activities of these sugar chains to drugs and pharmaceuticals.
  • GnT-V is introduced into the mannose core of an N-linked sugar chain as shown in the following formula, and catalyzes a reaction to produce bisecting N-acetyltylcolasamine.
  • GlcpNAc represents N-acetylglucosamine
  • Manp represents mannose
  • Asn represents asparagine
  • UDF represents peridine-5'-diphosphate.
  • sugar chain derivatives having a GnT-V inhibitory activity known so far are all triglycerides composed of natural sugar chains of N-acetyltilcosamine, mannose and glucose.
  • the compound according to the present invention in which a xymannojirimycin derivative is combined as a constituent sugar is a novel substance not described in the literature.
  • An object of the present invention is to provide a useful substance having an inhibitory effect on GnT-V, which is closely related to the migration of cancer cells. Further, the present invention provides a useful substance as a ligand for GnT-V affinity oral chromatography, which can easily carry out GnT-V, which has been conventionally difficult. Disclosure of the invention
  • R 2 hydrogen, acetyl, benzyl, butoxycarbon, or a straight-chain or branched-chain alkyl having 11 or less carbon atoms which may be substituted with a hydroxyl group, cyano or amino is represented by R 2.
  • R 3 is hydrogen, aminoalkylcarbo- Runu represents an acidic group.
  • Ac represents acetyl.
  • straight-chain or branched-chain alkyl having 11 or less carbon atoms which may be substituted with a hydroxyl group, cyano or amino are methyl, ethyl, propyl, isopropyl and 3-cyanobutyl.
  • the acidic groups represented by R 3, a sulfo group, phospho group, a carboxymethyl group can and Ageruko.
  • the aminoalkylcarbol include an aminoalkylcarbol having a straight-chain alkyl having 2 to 11 carbon atoms, and among them, 7-aminohexylcarbyl and 6-amino Xylcarbyl and 5-aminopentylcarbol are preferred.
  • Physiologically acceptable salts include inorganic salts such as salt, nitrate, sulfate, hydrobromide, vinegar, succinate, fumaru, maleate, malate, salt, tartaric acid.
  • Organic salts such as salts, oxalates, methanesulfonates and tosylates can be mentioned.
  • the hydrochloride of the compound according to the present invention can be obtained by dissolving it in an alcohol solution of hydrochloric acid. .
  • Solvates (including hydrates) of the compounds or salts thereof according to the present invention are also included in the present invention.
  • the solvate may be obtainable by recrystallization of the solvate from the corresponding solvent or a suitable mixed solvent containing the corresponding solvent,
  • a hydrate of the compound according to the present invention may be obtained by recrystallization from a hydroalcoholic.
  • the compounds according to the invention may take crystalline polymorphs.
  • the crystal polymorph is also included in the present invention.
  • the compounds according to the present invention have low toxicity.
  • the present invention relates to the introduction of 1-dexoximannojirimycin in place of glucoviranose, a trisaccharide compound that is a GnT-V inhibitor, to introduce various recommended replacement groups into 1-doxyman.
  • Nojirimycin can be easily bound to the nitrogen atom. That is, according to the present invention, it is dramatically and easily possible to bond a substituent directly to a molecule of a trisaccharide compound.
  • the compound according to the present invention has various anticancer agents bound to the nitrogen atom of 1-dexoximannojirimycin, and utilizes the affinity of the compound according to the present invention for GnT-V, It is also expected to be a low molecular carrier (drug carrier) used in targeting therapy for cancer tissues.
  • the compound according to the present invention has a high affinity for GnT-V, and therefore can be used as a ligand for GnT-V affinity oral chromatography.
  • affinity chromatography the compound of the present invention may be bound to activated sepharose in a conventional manner.
  • the ligand a linear or branched alkyl group having 11 or less carbon atoms in which is substituted with an amino group in the general formula [I] is preferable, and particularly, aminodecyl is preferable.
  • Examples of the compound according to the present invention include the following compounds in addition to the compounds described in the examples relating to the production method described below, but these are only examples of some of the compounds of the present invention. The compounds are not limited to these.
  • D-mannobiranose compound 5
  • acetic anhydride 75 ml
  • acetic anhydride 75 ml
  • the reaction solution was concentrated under reduced pressure to obtain 43 g of a crude residue of 1,2,3,4,6-penta-0-acetyl-D-mannobiranose quantitatively.
  • the crude residue was azeotropically dehydrated with an appropriate amount of toluene and dissolved in 400 ml of dichloromethane. Under ice cooling, 130 ml of a 31% hydrogen bromide acetic acid solution was added, and the mixture was returned to room temperature and stirred for 2 hours.
  • the reaction solution was added to ice water, dichloromethane was added, and the mixture was washed with ice water and saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude compound 6.
  • the crude residue was dissolved in a mixture of 300 ml of dichloromethane and 200 ml of methanol, 50 ml of 2,6-lutidine was added, and the mixture was stirred at room temperature overnight.
  • the reaction (2) was concentrated under reduced pressure, and then partitioned between dichloromethane and water. The dichloromethane layer was dried over anhydrous sodium sulfate and reduced under reduced pressure to obtain a crude compound 7 powder.
  • the liquid m was washed with ice water, a saturated aqueous solution of sodium hydrogen carbonate and ice water, dried over anhydrous sodium sulfate, and reduced at room temperature under reduced pressure.
  • the residue was purified by silica gel column chromatography (Wakogel C-300, 500 g, hexane Z ethyl acetate (5: 1)) to obtain 14 g of compound 16, elemental analysis (as C ⁇ H ⁇ NOu).
  • the crude residue was dissolved in 90 ml of methanol, a catalytic amount of a methanol solution of sodium methoxide was added, and the mixture was stirred at room temperature for 1.5 hours.
  • the reaction solution was poured into 200 ml of Dowex50wx2 (H + ), washed with water, eluted with a 1N aqueous solution of ammonia, and concentrated under reduced pressure to obtain 2.5 g of compound 22.
  • Methyl- ⁇ -D-mannoviranoside compound 23 15 g, triphenyl phosphine 30.3 g, iodine 27.3 g, imidazole 15.9 g, 750 ml of toluene were added, and the mixture was stirred at 70 ° C. for 3 hours. Thereafter, water was added and the mixture was stirred for 15 minutes. After extracting the toluene calendar with water, the aqueous layer was subjected to pressure reduction to obtain a crude residue of methyl-6-deoxy-6-chloride-a mannoviranoside.
  • the crude residue was azeotropically dehydrated with toluene and pyridine, dissolved again in 150 ml of pyridine, added with 50 ml of acetic anhydride, and stirred at room temperature overnight. Methanol was added to the reaction solution, the pressure was reduced by ift, toluene was added, and insolubles were separated. The toluene layer was washed with water, dried over anhydrous sodium sulfate, and lysed under reduced pressure.
  • the reaction solution was decompressed and the residue was dissolved in dichloromethane, washed with an aqueous hydrochloric acid solution and a saturated aqueous sodium hydrogen carbonate solution, and the methane layer at the mouth of the tube was dried over anhydrous sodium sulfate and decompressed.
  • the residue was purified by silica gel column chromatography (Wakogel C-300, 400 g, hexane / ethyl acetate (1: 1 to 2: 3)) to give 8.57 g of compound 36.
  • reaction solution was compressed under reduced pressure, dissolved in water, poured into 70 ml of Dowex50wx2 (H + ), washed with water, eluted with an IN-ammonium aqueous solution, and concentrated under reduced pressure to give 3.1 g of compound 39 quantitatively.
  • reaction mixture was lysed under reduced pressure, dissolved in water, poured into 20 ml of Dowex50 x2 (H +), washed with methanol, eluted with 2N-aqueous ammonia solution Z methanol (1/1), compressed under reduced pressure, and the residue was Asahi Pack NH2P- Purification using 40O yielded 160 mg of compound 46.
  • reaction solution was cooled to pH 7.0 with a 2N aqueous hydrochloric acid solution, and partitioned between ether and water.
  • the aqueous layer was desalted overnight with Asalyzer I (manufactured by Asahi Kasei Corporation) and then dried to dryness to obtain 21 mg of compound 59 as a white powder. • As a 3 / 2H 2 0)
  • 1,10-Decanediol (Compound 60) (5 g) was dissolved in pyridine (50 ml), and P-toluenesulfuryl sulfide (6.6 g) was added thereto while cooling with ice, and the mixture was returned to room temperature and stirred for about 40 hours. (On the way, 4-dimethylaminoviridine (3.5 g) was added.) An appropriate amount of methanol was added and remained!)-After decomposing toluene-sulfoyl chloride, the solution was concentrated under reduced pressure.
  • Lithium aluminum hydride (0.7 g) was ice-cooled while suspended in tetrahydrofuran (10 ml). A tetrahydrofuran solution (10 ml) of the compound (62) (1.2 g) was gradually dropped into the suspension, and the mixture was returned to room temperature and reacted for about 1 hour. (On the way, an appropriate amount of tetrahydrofuran was added because the reaction solution began to solidify.) An appropriate amount of water-saturated ether was added to the reaction solution while cooling with ice to decompose excess lithium aluminum hydride. After the reaction solution was passed through Celite, the solution was decompressed to yield Compound (63) (0.94 g) as a white solid.
  • FAB-MS (neg.): M / z 792 ( ⁇ - ⁇ )
  • the compound of the present invention as it is or in a pharmaceutically acceptable non-toxic and inert carrier, for example, 0.01% to 99.5%, preferably It can be administered to animals including humans as a pharmaceutical composition having 0.1% to 90%.
  • the carrier one or more solid, semi-solid, or liquid diluents, fillers, and other formulation aids are used.
  • the pharmaceutical compositions are desirably administered in unit dosage form.
  • the pharmaceutical composition of the present invention can be administered orally, intramuscularly, topically (such as transdermally), or rectally. Needless to say, it is administered in a dosage form suitable for these administration methods. For example, oral administration and intramuscular administration (particularly intravenous administration) are preferred.
  • glucosamurtransferase V inhibitor should be adjusted in consideration of the patient's condition such as age, weight, etc., administration route, and the nature and extent of the disease.
  • the amount of the active ingredient of the present invention per day is in the range of 0.1 g to 10 g / day human, preferably in the range of lg to 5 gZ day / human. In some cases, lower doses may be sufficient, and conversely, higher doses may be required. It is desirable to administer the drug in 2 or 3 divided doses.
  • solid or liquid dosage units such as powders, braces, fine granules, tablets, dragees, films, capsules, granules, tablets, solutions, syrups, drops, sublinguals This can be done with tablets or other dosage forms.
  • Powders are prepared by comminuting the compound of the present invention to an appropriate degree. Powders are prepared by comminuting the compound of the present invention with a suitable finely divided material and then admixing it with a similarly finely divided medical carrier, for example, edible carbohydrates such as starch and mannitol, and the like. If necessary, flavoring agents, preservatives, dispersing agents, coloring agents, flavors and the like may be added. Capsule preparations are manufactured by first filling powdered powders, powders, or granules as described above into granules as described in the section on capsules, for example, into capsules such as gelatin capsules. Is done.
  • Lubricants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, and solid polyethylene dalicol are mixed into powdery solids and then filled. Can also be performed. Addition of disintegrants and solubilizers such as carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, sodium carboxymethyl starch, calcium carbonate, sodium carbonate It is possible to improve the efficacy of the medicine when the bushel is taken.
  • the powder of the compound according to the present invention can be dispersed in vegetable oil, polyethylene glycol, glycerin, or a surfactant by itself and wrapped in a gelatin sheet to form a capsule.
  • Tablets are prepared by adding an excipient to make a powder mixture, granulating or slugging, and then adding a disintegrant or lubricant to the tablet or directly compressing the powder mixture.
  • the powder mixture is made by mixing an appropriately powdered material with the diluents and bases described above and, if necessary, a binder (e.g., sodium carboxymethylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxybutyryl methylcellulose, gelatin, Polybutylpyrrolidone, polybutyl alcohol, etc., dissolution retarders (eg, paraffin, wax, hydrogenated castor oil, etc.), resorbents (eg, quaternary salts) and adsorbents (eg, bentonite, kaolin, diphosphate) Calcium, etc.).
  • a binder e.g., sodium carboxymethylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxybutyryl methylcellulose, gelatin, Polybutylpyrrolidone, polybutyl alcohol, etc.
  • dissolution retarders eg, paraffin, wax, hydrogenated castor oil, etc.
  • resorbents eg, quatern
  • the powder mixture can first be moistened with a binder such as syrup, starch paste, acacia, cellulose solution or polymer solution, stirred and mixed, dried and pulverized to obtain granules, Instead of granulating the powder in this way, it is also possible to first use a tableting machine and then crush the resulting incompletely shaped slag into granules.
  • a binder such as syrup, starch paste, acacia, cellulose solution or polymer solution
  • the granules thus produced can be prevented from adhering to each other by adding stearic acid, stearic acid salts, talc, mineral oil and other lubricants. it can.
  • the lubricated mixture is then tableted.
  • the uncoated tablet thus produced can be coated with a film or coated with sugar.
  • the compound according to the present invention is mixed with a fluid inert carrier without going through the steps of granulation and slag formation as described above.
  • the tablet may be directly compressed later.
  • a transparent or translucent protective coating consisting of a shellac hermetic coating, or alternatively or on top of it, a coating of sugar or a polymeric material, and a polish coating of wax can also be used.
  • compositions such as solutions, syrups, elixirs and the like can also be made into unitary bran so that a given quantity contains a certain amount of the compound according to the invention.
  • Sylob is produced by dissolving the compound of the present invention in an aqueous solution containing a suitable sweetener, and elixir is produced by using a non-toxic alcoholic carrier.
  • Suspensions are formulated by dispersing the compound of the invention in a non-toxic carrier.
  • Solubilizers and emulsifiers eg, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters
  • preservatives eg, ⁇ pamint oil, saccharin
  • flavoring agents eg, ⁇ pamint oil, saccharin
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulation can also provide a prolonged action or sustained release by coating or embedding in molecules, etc.,
  • Intradermal administration can be carried out by using a liquid dosage unit form for subcutaneous, intramuscular or intravenous injection, for example, a solution or suspension. These can be prepared by suspending or dissolving a fixed amount of the compound of the present invention in a non-toxic carrier such as an aqueous or oily medium suitable for injection purposes, and then sterilizing the attractive solution or solution. A non-toxic clay salt solution may be added to make the injection solution isotonic. Rectal administration can be carried out by preparing the compound of the present invention as a solid soluble or insoluble in water having a low melting point and using a suppository.
  • a liquid dosage unit form for subcutaneous, intramuscular or intravenous injection for example, a solution or suspension.
  • a non-toxic carrier such as an aqueous or oily medium suitable for injection purposes
  • a non-toxic clay salt solution may be added to make the injection solution isotonic.
  • Rectal administration can be carried out by preparing the compound of the present invention as a solid soluble
  • composition of reaction solution (each concentration is indicated by final concentration)
  • the purified GnT-V and an inhibitory compound (final concentration lOmM) were added to the above reaction solution for the activity measurement, and the reaction was measured by adjusting the final volume to 50 ml.
  • GnT-V was purified from the culture supernatant of human lung cancer cell line QG cells according to the purification method of Gu et al. (Gu et al, J. Biochem., 113, 614-619.) (16.0 nmol / h / mg).
  • the purified GnT-V and the inhibitory compound (GNT-V were put in the above reaction solution for measuring the activity, and the final volume was adjusted to 50 ml, and the reaction was measured by an ordinary method.
  • FIG. 1 is a graph showing the inhibitory activity of a compound according to the present invention on GnT-V.
  • the horizontal axis shows the reciprocal of the substrate port, and the vertical axis shows the reciprocal of the maximum enzyme reaction rate.
  • the compound according to the present invention has the potential to be used as a therapeutic agent and diagnostic agent for cancer, and has affinity for GnT-V, so that it can be used in affinity chromatography.
  • affinity for GnT-V so that it can be used in affinity chromatography.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)

Abstract

Cette invention concerne des dérivés de 1-déoxymannojirimycine correspondant à la formule générale (I) où R1 représente hydrogène, acétyle, benzyle, butoxycarbonyle, ou un alkyle éventuellement hydroxylé, cyanisé ou aminé qui est linéaire ou ramifié et possède 11 atomes de carbone ou moins. R2 représente hydrogène ou hydroxyle, et R3 représente un groupe acide ou aminoalkylcarbonyle. Ces dérivés sont utiles en qualité de remèdes contre le cancer et en qualité de ligands en chromatographie d'affinité GnT-V.
PCT/JP1997/000593 1996-03-01 1997-02-27 Derives de trisaccharide 1-deoxymannojirimycine WO1997031928A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP8/44589 1996-03-01
JP4458996 1996-03-01
JP8/252074 1996-09-24
JP25207496 1996-09-24

Publications (1)

Publication Number Publication Date
WO1997031928A1 true WO1997031928A1 (fr) 1997-09-04

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004244418A (ja) * 2003-01-21 2004-09-02 Toray Fine Chemicals Co Ltd Ｎ−メチル含窒素環状アルコールの製造方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05236985A (ja) * 1992-02-26 1993-09-17 Amano Pharmaceut Co Ltd セルラーゼ阻害剤およびその製造法
WO1994004546A1 (fr) * 1992-08-14 1994-03-03 Nippon Shinyaku Co., Ltd. Derive de moranoline

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05236985A (ja) * 1992-02-26 1993-09-17 Amano Pharmaceut Co Ltd セルラーゼ阻害剤およびその製造法
WO1994004546A1 (fr) * 1992-08-14 1994-03-03 Nippon Shinyaku Co., Ltd. Derive de moranoline

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004244418A (ja) * 2003-01-21 2004-09-02 Toray Fine Chemicals Co Ltd Ｎ−メチル含窒素環状アルコールの製造方法

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