WO1999043690A1 - Compose de l-4'-arabinofuranonucleoside et composition medicinale le contenant - Google Patents

Compose de l-4'-arabinofuranonucleoside et composition medicinale le contenant Download PDF

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WO1999043690A1
WO1999043690A1 PCT/JP1999/000827 JP9900827W WO9943690A1 WO 1999043690 A1 WO1999043690 A1 WO 1999043690A1 JP 9900827 W JP9900827 W JP 9900827W WO 9943690 A1 WO9943690 A1 WO 9943690A1
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group
compound
formula
nucleoside
compound represented
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PCT/JP1999/000827
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English (en)
Japanese (ja)
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Hiroshi Sato
Yuichi Yoshimura
Noriyuki Ashida
Kenji Sudo
Tomoyuki Yokota
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Rational Drug Design Laboratories
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom

Definitions

  • the present invention relates to an L-4′-thioarabinofuranonucleoside compound and a pharmaceutical composition containing the compound as an activity, particularly to an anti-hepatitis virus agent.
  • L-nucleosides having an unnatural structure have been shown to have an anti-viral effect, and are attracting attention due to their low toxicity. For example, it has been reported that 2'-fluoro-5-methyl-13-L-arabinofuranosylperacil (L-FMAU) has anti-B virus (HBV) activity and low cytotoxicity.
  • L-FMAU 2'-fluoro-5-methyl-13-L-arabinofuranosylperacil
  • HBV anti-B virus
  • Antiviral Chemistry & Chemotherapy (1995), 6 (3), 138-142 include a-L-arabinofuranosylcytosine, ⁇ -L-xylofuranosylcytosine and Although some anti-HCMV (human cytomegalovirus) activity was confirmed in one L-anomer of a-L-FMAU, anti-H CMV was observed in other ⁇ -L anomers and ⁇ -L anomers of the above compounds. No activity has been confirmed.
  • Japanese Patent Publication No. 8-504753 discloses that 2 ', 3'-didehydro-2', 3'-dideoxy-14'-thio- ⁇ -l-cytidine and 2 ', 3'didehydro 2', 3 ' The anti-HIV activity and anti-HBV activity of only the 3-D-anomer of 1-dideoxy 5-fluoro-4'-thio- ⁇ -L-cytidine have been reported.
  • J. Med. Chem., (1994), 37 (6), 798-803 further describes 2 ', 3'-dideoxy L-cytidine and 2', 3'-dideoxy-l-5-fluoro-L-cytidine. It has been reported that the ⁇ -anomer and the 9-anomer have different activities in anti-HIV activity and anti-HBV activity.
  • the antiviral activity of the heavenly nucleoside cannot be referred to at all, and the synthesized ⁇ J is an a-L anomer or a ⁇ -L-anomer. Depending on this, the activity changes greatly.
  • the present inventors screened various compounds in order to find a compound having anti-hepatitis virus activity.
  • the L-1 4'-thioarabinofuranonucleoside compound showed an even higher selectivity.
  • the present inventors have found that they have hepatitis virus activity and have made the present invention. It has been reported that L-arabinofuranonucleoside compounds have no significant antiviral activity against various RNA and DNA viruses (excluding hepatitis virus) (NUCLEOSIDES & NUCLEOTIDES, 10 (6). 1345 -1376 (1991)), which was quite surprising. Disclosure of the invention
  • the present invention based on the above findings provides an L-1 4′-thioarabinofuranonucleoside-modified ⁇ I represented by the following formula [I] and a medicine containing the compound as an active ingredient! ! ⁇ Products, in particular, anti-hepatitis virus compositions ⁇
  • B represents a nucleobase selected from the group consisting of pyrimidine, purine, azapurine, and azapurine, and is a halogen atom, an alkyl group, a haloalkyl group, an alkenyl group, a haloalkenyl group, an alkynyl group, an amino group.
  • the L-4′-thioarabinofuranonucleoside compound of the present invention is an L-arabinofuranonucleoside compound represented by the above formula [I].
  • the base represented by B represents a nucleobase selected from the group consisting of pyrimidine, purine, azapurine, and azapurine, and includes a halogen atom, an alkyl group, a haloalkyl group, an alkenyl group, and a haloalkenyl.
  • Examples of the halogen atom as a substituent include chlorine, fluorine, iodine, and bromine.
  • Examples of the alkyl group include ⁇ -alkyl groups having 1 to 7 carbon atoms, such as methyl and ethyl.
  • Examples of the haloalkyl group include a haloalkyl group having an alkyl of 1 to 1 such as fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, and bromoethyl.
  • Examples of the alkenyl group include alkenyl groups having 2 to 7 carbon atoms, such as butyl and aryl.
  • haloalkenyl groups examples include haloalkenyl groups having a C2-7 alkenyl group such as bromovinyl and chlorovinyl.
  • alkynyl group examples include alkynyl groups having 2 to 7 ⁇ such as ethynyl and propynyl.
  • Examples of the alkylamino group on the ano group include an alkylamino group having an alkyl group having 1 to more than 1 such as methylamino and ethylamino.
  • Examples of the alkoxy group include C1 to C7 alkoxy groups such as methoxy and ethoxy.
  • Examples of the alkyl mercapto group include alkyl mercapto groups having an alkyl group having 1 to 7 carbon atoms, such as methyl mercapto and ethyl mercapto.
  • aryl group examples include a phenyl group; an alkylphenyl group having 1 to 5 carbon atoms such as methylphenyl and ethenylphenyl; an alkoxyphenyl group having 1 to 5 carbon atoms such as methoxyphenyl and ethoxyphenyl; dimethylaminophenyl and getylaminophenyl.
  • Alkylaminophenyl groups having an alkylamino having 1 to 5 carbon atoms, such as halogenophenyl groups such as chlorophenyl and promophenyl; and specific examples of pyrimidine bases include cytosine, peracyl, 5-fluorocytosine, and 5-—.
  • purine bases include purine, 6-aminopurine (adenine), 6-hydroxypurine, 6-fluoropurine, 6-chloropurine, 6-methylaminopurine, 6-dimethylaminopurine, and 6-trifluo.
  • azapurine base and the dazapurine base include 6-amino-3-dazapurine, 6-amino-8-azapurine, 2-amino-6-hydroxy-18-azapurine, 6-amino-7-dazapurine, and 6-amino-1. —Dazaprine, 6-amino-12-azapurine and the like.
  • the L-4′-thioarabinofuranonucleosides according to the present invention may be any of ⁇ -L-14′-thioarabinofuranonucleosides or ⁇ -1L-4′-thioarabinofuranonucleosides.
  • a-L—4′—thioarabinofuranopyrimidine nucleoside, a—L—4′—thioarabinofuranopurine nucleoside, —L-1 4 '-Thioarabinofuranopurine nucleoside is preferred, and particularly preferred is ⁇ -L-4'-thioarabinofuranopyrimidine nucleoside.
  • the L-4′-thioarabinofuranonucleoside compound used in the present invention may be in the form of a salt, hydrate or solvate.
  • salts include acid addition salts with inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid, etc.) or organic acids (fumaric acid, tartaric acid, conodic acid, etc.), sodium salts such as sodium salts and potassium salts.
  • alkaline earth metal salts such as lithium metal salts, calcium salts, magnesium salts and the like, and pharmaceutically acceptable salts such as ammonium salts.
  • Examples of the hydrate or solvate include those obtained by adhering 0.1 to 3. water or a solvent to the compound of the present invention or a salt thereof.
  • the L-1 4′-thioarabinofuranonucleosides of the present invention are explained below. It can be synthesized from four steps.
  • Second step (In the formula, 1 ⁇ represents an alkyl group.)
  • a step of obtaining a compound represented by the formula [III] by treating the hydroxyl group of the compound represented by the formula [II] with a mesylating agent or by subjecting the hydroxyl group to a tosyliding with a tosylating agent, followed by treating with sodium sulfate.
  • D-xylose is alkylated at the 1-position in an alcohol solvent in the presence of an acid, and then the hydroxyl group is protected. Then, the 1-alkyl group is hydrolyzed with a hidden medium and then treated with a reducing agent. This is a step of obtaining a compound represented by the formula [II].
  • Alkylation at the 1-position and protection of water can be performed according to known methods. That is, the alkylation at the 1-position is performed by converting D-xylose into an alcoholic solvent such as methanol, ethanol, or isopropanol, or an organic acid such as p-toluenesulfonic acid, drunkic acid, trifluorofluoroacid, methanesulfonic acid, or hydrochloric acid, or sulfuric acid.
  • the treatment can be carried out at a temperature of 120 ° C. to 100 ° C. in the presence of a mineral acid.
  • the protection of the hydroxyl group is carried out in a single solvent such as THF, DMF or DMSO or in a mixed solvent, in the presence of a base such as sodium hydride, or in the presence of a base such as sodium hydride or an alkyl ether such as benzyl chloride or p-methoxybenzyl chloride.
  • Hil can be formed by reacting the dangling agent at 0 to 40 ° C. with 2 to 10 mol, preferably 3 to 6 mol, per mol of D-xylose.
  • hydrochloric acid As the acid used in the hydrolysis reaction of the 1-position alkyl group, hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid and the like can be mentioned.
  • the hydrolysis reaction can be carried out by reacting the acid catalyst at 10 to 100 ° C. in a mixed solvent of a water-soluble ether solvent such as tetrahydrofuran, dioxane and the like and an aqueous acid solution.
  • a water-soluble ether solvent such as tetrahydrofuran, dioxane and the like
  • the reducing agent used in the reduction include lithium borohydride, sodium borohydride, calcium borohydride, zinc borohydride, aluminum lithium hydride, diisobutylaluminum hydride, and the like.
  • the reduction is carried out in an alcoholic solvent such as methanol or ethanol or an ethereal solvent such as ether, dioxane or THF in a reduction of 1 to 20 moles, preferably 1 to 10 moles, per mole of D-xylose.
  • Agent one hundred to one hundred, More preferably, the reaction can be carried out at a temperature of 80 ° C to 80 ° C.
  • Isolation of the thus prepared compound of formula [II] may be carried out using a conventional sugar separation / purification method. For example, after partitioning with ethyl acetate and water, the mixture is subjected to silica gel column chromatography. And elution with an organic solvent such as ⁇ -hexane monoethyl acetate can be used for separation and purification.
  • the second step is a reaction step in which the hydroxyl group of the compound of the formula [II] is mesylated or tosylated, and then treated with sodium sulfide to obtain the compound of the formula [III].
  • Mesirui-dani and tosylation can be performed based on known methods. For example, in the presence of a base such as pyridine or triethylamine in a solvent such as methylene chloride, acetonitrile, or dimethylformamide, 2 to 10 moles, preferably 2 to 4 moles, per mole of the compound of the formula [II] is used.
  • the reaction can be carried out using a molar mesylating agent (such as mesyl chloride) or a tosylating agent at 0 to 100 ° C.
  • Sulfuric acid Treatment with sodium is performed in dimethylformamide or dimethylsulfoxide in an inert gas atmosphere such as argon or nitrogen, if necessary, in an amount of 1 to 20 moles per mole of the compound of the formula [II].
  • the reaction can be carried out at room temperature to a reaction temperature of 150 using sodium sulfide.
  • the compound of the formula [III] thus prepared may be isolated by a conventional means for separating and purifying a saccharide. For example, after partitioning with ethyl acetate and water, silica gel column chromatography is performed. — Separation and purification can be achieved by elution with an organic solvent such as hexane monoethylate. Third step:
  • the compound of the formula [III] is converted to a sulfoxide form with an oxidizing agent, and further treated with an acid anhydride to perform Pummeler rearrangement to obtain a compound of the formula [IV]. is there.
  • the derivation of the compound of the formula [III] into a sulfoxide may be carried out according to a conventional method.
  • m-chloroperbenzoic acid in methylene chloride under a flow of an inert gas such as argon or nitrogen at -100 to 0 ° C. It can be carried out by treating with an acid or treating with sodium metaperiodate in an alcoholic solvent such as methanol.
  • the Pummeler rearrangement reaction may be similarly carried out according to a conventional method.
  • a compound represented by the formula [IV] can be obtained by treating in an acid anhydride such as anhydrous acetic acid at 60 ° C. to reflux.
  • the compound of the formula [IV] thus prepared may be isolated using a usual sugar separation / purification method. For example, after neutralization, the organic solvent is distilled off, and then the mixture is subjected to chromatography. It can be extracted from the aqueous layer and separated and purified by silica gel column chromatography. Step 4:
  • the fourth step is a step of introducing a nucleobase to the compound of the formula [IV] by a glycosylation reaction, and further deprotecting the sugar moiety protecting group to obtain the compound of the formula [I].
  • the glycosylation reaction is carried out under a stream of an inert gas such as argon or nitrogen, in a solvent such as methylene chloride, chloroform, dichloroethane, acetonitrile, or dimethylformamide, relative to 1 mole of the compound of the formula [IV].
  • an inert gas such as argon or nitrogen
  • a solvent such as methylene chloride, chloroform, dichloroethane, acetonitrile, or dimethylformamide, relative to 1 mole of the compound of the formula [IV].
  • a nucleic acid base which has been silylated or acylated to form a trimethylsilyl trifluoromethanesulfonate, tin tetrachloride, titanium tetrachloride, titanium chloride, kffi lead, boron trifluoride, etc.
  • isocyanic acid —50 to: can be carried out by treating at L 0 ° C.
  • Deprotection of the sugar moiety protecting group can be carried out by a conventional method depending on the protecting group used. For example, in the case of a benzyl-based protecting group, it should be treated with boron chloride or boron tribromide at ⁇ 100 ° C. to room temperature in an inert gas stream such as argon or nitrogen in methylene chloride. Can deprotect the benzyl protecting group.
  • the L-1 4'-thioarabinofuranonucleosides ⁇ ! can be separated and purified by a method suitable for the isolation and purification of nucleosides of ⁇ . After evaporating the solvent, purify by silica gel column, reverse layer column chromatography, ion exchange column chromatography, adsorption column chromatography such as active column, etc., and crystallize from an appropriate solvent such as ethanol. Depending on: ⁇ can also be obtained.
  • the dosage of the L-14'-thioarabinofuranonucleoside compound will vary depending on the patient's age and weight, disease, severity of the patient, drug tolerability, administration method, etc. Force, which is appropriately determined in the following ⁇ , usually 0.01 to 100 mg / kg body weight per day, preferably 0.01 to: L 0 mg / kg body weight It is administered once or in divided doses.
  • the method of administration can be oral, parenteral, enteral, topical or any other route.
  • Carriers include lactose, kaolin, sucrose, crystalline cellulose, corn starch, talc, agar, pectin, stearic acid, magnesium stearate, lecithin, sodium chloride
  • solid carriers such as thorium
  • liquid carriers such as glycerin, oil drop, polyvinylpyrrolidone, olive oil, ethanol, benzyl alcohol, propylene glycol, and water.
  • the dosage form can take any form.
  • a solid carrier when used, a powdery carrier, a granule, an encapsulating agent, a suppository, a troche, and the like are used.
  • examples include syrup, emulsion, soft gelatin capsule, cream, gel, paint, spray, injection and the like.
  • the solvent was distilled off, the residue was dissolved in 100 ml of DMF, 8.93 g of sodium sulfide nonahydrate was added, and the mixture was reacted at 100 ° C. for 3 hours. After the reaction, the temperature was returned to room temperature, the solvent was distilled off, the residue was dissolved in ethyl acetate, washed with water three times and saturated water, and the organic layer was dried over sodium sulfate. After evaporating the solvent, the residue was purified by a silica gel column to obtain the title compound (4.38 g, 84%).
  • the reaction was stopped by adding a saturated sodium hydrogen carbonate solution, and the insolubles were filtered through celite. The filtrate was extracted three times with a black hole form, and dried. After concentration, purification was carried out using a silica gel column to obtain 445 mg (78%) of a nucleoside conjugate.
  • the nucleoside compound (417 mg) was dissolved in methylene chloride (1 Oml) and cooled to 178. To this solution, 4.38 ml of a 1M methylene chloride solution was added dropwise and stirred at 178 ° C for 30 minutes. The temperature was raised to 120 ° C, and the mixture was further stirred for 3 hours, and the reaction was stopped by adding a saturated sodium hydrogen carbonate solution. The solvent was distilled off, 5 ml of methanol and 5 ml of concentrated aqueous ammonia were added to the residue, and the mixture was stirred at room temperature for 10 minutes. The solvent was distilled off, and the residue was azeotroped with ethanol three times, and purified by a silica gel column. The obtained anomeric mixture was purified by ODS column chromatography and the anomers were separated to obtain the enantiomer of the title ⁇ ! (64 mg, 34%) and the) S-anomer (36 mg, 19%).
  • Adenine (16 mg) and ⁇ anomer (106 mg, crude) as the title compounds were obtained in the same manner as described above, except that adenine was used instead of N 4 -acetylcytosine.
  • HB611 Proc. Natl. Acad. Sci. USA 84, 444-448 (1987)
  • the method of Shuto et al. (Microbiol. Immunol., 40 (2), 153-159 (1996)), and the anti-V activity of the drug was measured.
  • ⁇ 611 cells were suspended in Dulbecco's modified MEM containing 10% bovine i3 ⁇ 4fil, 1001 UZm1 benisiri G, 100 g / m1 streptomycin and lmg / m1 geneticin. 20,000 pieces per 1 well of a 96-well multiwell plate were applied.
  • the cells were cultured in a carbon dioxide incubator at 37 ° C. for 3 days, and the cells were grown to confluent and then subjected to a test.
  • the test drug was added to the cells, usually diluted with medium, in four steps of 10-fold serial dilution from a concentration of 100 / ig / inl, and cultured. The medium was replaced two to four days later with the medium containing the drug. Control cells were cultured in a drug-free medium. Seven days later, the culture supernatant was recovered from each well and transferred to another 96-well multiwell plate. Saved in C.
  • Anti-HBV surface antigen mouse antibody diluted to 10 ( ⁇ gZml) with isotonic phosphate buffer (PBS) in each well of a 96-well multiwell plate (Korning)
  • PCR For PCR, a commercially available kit, TaKaRa Taq (manufactured by Takara Shuzo) and Gene Amp system 9600 (manufactured by Perkin Elmer) were used.
  • the primers used were designed so that Nos. 372 to 483 in the S residue of HBV were amplified. That is, the primer of (+) 372-401 (5'-biotin-TCGCTGGATGTGTCTGCGGCGTTTT AT) and the primer (1) of 460-483 (5'-TAGAGGACAA Using.
  • PCR mixed solution 45 ⁇ 1 (Fiber: 10 mM Tris-monohydrochloride buffer (pH 8.3), 5 OmM KC 1, 1.5 mM MgCl 2 , 0.2 mM of DNA dNTP, 6.25 pmo 1 of each primer, 1.25 U Amp 1 i Taq DNA polymerase) and PCR. 94. C. After 5 minutes incubation, 30 cycles of 94, 30 seconds and 55, 15 seconds—72 ° C., 1 minute were performed, and finally the reaction was performed at 72 ° C. for 5 minutes, and stored at 4.
  • Streptavidin diluted to lO ⁇ gZml with 5 OmM quenched buffer (pH 9.6) in each well of a flat-bottomed 96-well multiwell plate (manufactured by Koingen) was added at 75 ° C. each, and the mixture was left at 4 ° C. for about 16 hours. The liquid layer in each well was discarded, PBS 100 // 1 containing 0.1% BSA was added, the mixture was incubated at 37 ° C for 2 hours, and stored at 4 ° C until immediately before use. After washing twice with 0.1 XS SPE solution containing 0.1% Tween 20 (0.1 XS SPE-0.
  • 0.1 XS SPE After washing 3 times with 0.05% Tween 20 and 2 times with PBS, add 100 1 of 2000-fold diluted alkaline phosphatase-conjugated anti-dioxygenin antibody (manufactured by Boehringer Mannheim GmbH) and add room temperature. For 1 hour. After washing 4 times with 0. 1 XS S PE- 0. 05% Twe en 20, 1 0 OmM Na C 1 and 5 OmM Mg C 1 2 and 100 mM Tris monohydrochloride buffer containing of (pH 9. 5 ), Adjusted to 1 mg / m 1 with 1002 trophenylphosphite solution 1001, and incubated at 37 ° C for 5 to 15 minutes until color development.
  • the absorbance at 405 nm of each well was measured with a microplate reader to calculate the anti-HBV activity of the test drug.
  • the concentration of the test drug that reduces the absorption of the control to which no drug was added by 50% was increased by the 50% effective concentration (EC 50)
  • the cytotoxicity of the test drug was measured by the MTT method. After the culture supernatant was recovered, HB61 1 cells were added with a fresh medium 100 1 and a 7.5 mg / m 1 MTT solution 201, and cultured at 37 ° C for 3 hours in a carbon dioxide gas incubator. Formalzan was eluted by adding 10 1 of a hidden isopropanol (500 ml of isopropanol to which 2 ml of concentrated hydrochloric acid was added) containing 10% (v / v) Triton X-100. After the formasan was completely dissolved, the absorbance at 540 and 690 nm was measured using a microplate reader to calculate the cytotoxicity of the test drug. The test drug that reduced the absorbance of the control to which no drug was added by 50% was defined as 50% cytotoxicity i «(cc 50 ).
  • Fine powdered cellulose 25.Omg
  • the L-4′-thioarabinofuranonucleoside compound of the present invention has no toxicity and has a remarkable inhibitory effect on hepatitis B virus (HBV).
  • Hepatitis virus ⁇ especially anti-hepatitis B virus It is useful as an agent and can be expected to be developed as a pharmaceutical.
  • the method for synthesizing the above-mentioned L-4′-thioarabinofuranonucleoside compound is an extremely practical method that can derive the desired compound from the natural sugar D-xylose by a simple method.

Abstract

Composé de L-4'-thiorabinofuranonucléoside représenté par la formule (1) dans laquelle B représente une base d'acide nucléique sélectionné dans pyrimidine, purine, azapurine et déazupurine, dont chacune peut être substituée par un atome d'halogène, un groupe alkyle, un groupe haloalkyle, un groupe alkényle, un groupe haloalkényle, un groupe alkinyle, un groupe amino, un groupe alkylamino, un groupe hydroxyle, un groupe hydroxyamino, un groupe aminoxy, un groupe alkoxy, un groupe mercapto, un groupe alkylmercapto, un groupe aryle, un groupe aryloxy ou un groupe cyano, et une composition médicinale contenant ce composé en tant que constituant actif, en particulier, composition contre le virus de l'hépatite.
PCT/JP1999/000827 1998-02-25 1999-02-24 Compose de l-4'-arabinofuranonucleoside et composition medicinale le contenant WO1999043690A1 (fr)

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WO2015125782A1 (fr) * 2014-02-18 2015-08-27 富士フイルム株式会社 Procédé de production d'un composé saccharidique de type à squelette de thiolane ainsi que composé saccharidique de type à squelette de thiolane
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JP2016185979A (ja) * 2012-08-13 2016-10-27 富士フイルム株式会社 １−（２−デオキシ−２−フルオロ−４−チオ−β−Ｄ−アラビノフラノシル）シトシンの合成中間体およびチオヌクレオシドの合成中間体ならびにそれらの製造法
US9815812B2 (en) 2014-02-19 2017-11-14 Fujifilm Corporation Thiopyranose compound and method for producing same
US9884882B2 (en) 2014-02-18 2018-02-06 Fujifilm Corporation Method for producing thiolane skeleton-type glycoconjugate, and thiolane skeleton-type glycoconjugate
US9896471B2 (en) 2012-03-28 2018-02-20 Fujifilm Corporation Salt of 1-(2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl)cytosine
US9968628B2 (en) 2000-05-26 2018-05-15 Idenix Pharmaceuticals Llc Methods and compositions for treating flaviviruses and pestiviruses
US10059734B2 (en) 2014-10-31 2018-08-28 Fujifilm Corporation Thionucleoside derivative or salt thereof, and pharmaceutical composition
US11141421B2 (en) 2018-01-29 2021-10-12 Fujifilm Corporation Antitumor agent for biliary tract cancer and method for treating biliary tract cancer
US11369625B2 (en) 2016-08-31 2022-06-28 Fujifilm Corporation Anti-tumor agent, anti-tumor effect enhancer, and anti-tumor kit

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