WO2011065541A1 - 抗腫瘍効果増強剤 - Google Patents
抗腫瘍効果増強剤 Download PDFInfo
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- WO2011065541A1 WO2011065541A1 PCT/JP2010/071280 JP2010071280W WO2011065541A1 WO 2011065541 A1 WO2011065541 A1 WO 2011065541A1 JP 2010071280 W JP2010071280 W JP 2010071280W WO 2011065541 A1 WO2011065541 A1 WO 2011065541A1
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- ZBQHBTWRHZETFT-UHFFFAOYSA-N CCC(c1cccc(OCC2CC2)c1)NS(CCCN(C=CC(N1)=O)C1=O)(=O)=O Chemical compound CCC(c1cccc(OCC2CC2)c1)NS(CCCN(C=CC(N1)=O)C1=O)(=O)=O ZBQHBTWRHZETFT-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- 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
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- 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
Definitions
- the present invention relates to an antitumor effect enhancer of an antitumor agent and an antitumor agent using the same.
- Deoxyuridine triphosphatase (hereinafter also referred to as dUTPase (EC 3.6.1.23)) is a preventive DNA repair enzyme.
- dUTPase EC 3.6.1.23
- Non-Patent Documents 1 and 2 In malignant tumors, there is a correlation between the degree of malignancy and the expression level of dUTPase (Non-Patent Documents 1 and 2), and it has been reported that tumors with increased expression show resistance to chemotherapy (Non-patents). Reference 3). Moreover, in cultured cancer cells, it has been shown that reducing the expression level of dUTPase using siRNA enhances the antitumor effect of a thymidylate synthase inhibitor (hereinafter TS inhibitor) (Non-patent Document 4). It has been suggested that dUTPase inhibitors can be targets as antitumor effect enhancers.
- TS inhibitor thymidylate synthase inhibitor
- An object of the present invention is to provide an antitumor effect enhancer of an antitumor agent and an antitumor agent using the same.
- a uracil compound having a sulfonamide structure at the N-1 position of the uracil ring represented by the following formula (I) or a salt thereof is a powerful compound.
- human dUTPase inhibitory action it was found that it has an excellent antitumor effect enhancing action against antitumor agents (particularly antimetabolites), and the present invention was completed.
- X represents a C1-5 alkylene group, and one of the methylene groups constituting the alkylene group may be substituted with an oxygen atom
- R 1 represents a hydrogen atom or a C1-6 alkyl group
- R 2 represents a hydrogen atom or a halogen atom
- R 3 represents a C1-6 alkyl group, a C2-6 alkenyl group, a C3-6 cycloalkyl group
- (C3- 6-cycloalkyl) represents a C1-6 alkyl group, a halogeno C1-6 alkyl group, or a saturated heterocyclic group.
- the antitumor effect enhancer which uses the uracil compound represented by these, or its pharmacologically acceptable salt as an active ingredient is provided.
- the present invention also provides an antitumor agent comprising a combination of the uracil compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof and an antitumor agent.
- the present invention also provides a uracil compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof for use in enhancing the antitumor effect.
- the present invention also provides a combination of a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof and an antitumor agent for treating a tumor.
- the present invention also provides a method for enhancing the antitumor effect, comprising administering an effective amount of the compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof.
- the present invention also provides a method for treating tumors comprising administering a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof in combination.
- the present invention also provides use of the compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof for the production of an antitumor effect potentiator.
- the present invention provides the use of a combination of a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof and an antitumor agent for the production of an antitumor agent.
- novel uracil compound of the present invention or a pharmaceutically acceptable salt thereof is useful as an antitumor effect enhancer of an antitumor agent (particularly an antimetabolite) and an antitumor agent using the same.
- FIG. 3 is a graph showing changes in body weight and antitumor effects when a compound of the present invention is used in combination with TS-1 in nude mice transplanted with human gastric cancer line SC-6.
- FIG. 3 is a graph showing changes in body weight and antitumor effects when a compound of the present invention is used in combination with TS-1 in nude mice transplanted with human gastric cancer line SC-6.
- FIG. 3 is a graph showing changes in body weight and antitumor effects when a compound of the present invention is used in combination with TS-1 in nude mice transplanted with human colon cancer strain LS174T.
- FIG. 3 is a graph showing changes in body weight and antitumor effects when a compound of the present invention is used in combination with TS-1 in nude mice transplanted with human pancreatic cancer strain CFPAC-1.
- FIG. 3 is a graph showing the antitumor effect when TS-1 and a compound of the present invention are used in combination in nude mice transplanted with human breast cancer strain MX-1.
- FIG. 3 is a graph showing the antitumor effect when TS-1 and a compound of the present invention are used in combination in nude mice transplanted with human breast cancer strain MX-1. It is a figure which shows the anti-tumor effect when capecitabine and this invention compound are used together in the nude mouse which transplanted human breast cancer strain MX-1.
- the “C1-5 alkylene group” represented by X includes a linear or branched alkylene group having 1 to 5 carbon atoms, and specifically includes a methylene group, an ethylene group. , Trimethylene group, tetramethylene group, pentamethylene group, propylene group, butylene group, dimethyltrimethylene group, ethyltrimethylene group and the like.
- a case where one of the methylene groups constituting the alkylene group is substituted with an oxygen atom includes —O—C1-4 alkylene.
- X is preferably an ethylene group or —O—CH 2 CH 2 CH 2 —.
- examples of the “C 1-6 alkyl group” represented by R 1 include a straight or branched hydrocarbon group having 1 to 6 carbon atoms, specifically a methyl group, And an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an n-hexyl group, and the like.
- a C1-3 alkyl group is preferable, and a methyl group An ethyl group is more preferable.
- the “halogen atom” represented by R 2 is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom.
- examples of the “C 1-6 alkyl group” represented by R 3 include the same groups as those described above for R 1 , preferably an isobutyl group and a 2-methylbutyl group.
- the “C2-6 alkenyl group” represented by R 3 represents a hydrocarbon group having 2 to 6 carbon atoms including a carbon-carbon double bond, such as a vinyl group, an allyl group, or a methylvinyl group.
- a hydrocarbon group having 2 to 6 carbon atoms including a carbon-carbon double bond such as a vinyl group, an allyl group, or a methylvinyl group.
- examples of the “C 3-6 cycloalkyl group” represented by R 3 include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and the like, and a cyclopentyl group is preferable.
- “(C3-6 cycloalkyl) C1-6 alkyl group” represented by R 3 represents an alkyl group having 1 to 6 carbon atoms having the above cycloalkyl group, preferably cyclopropyl It is a methyl group.
- the “halogeno C 1-6 alkyl group” represented by R 3 represents an alkyl group having 1 to 6 carbon atoms having the above halogen atom, preferably a 2,2-difluoroethyl group, 2 , 2,2-trifluoroethyl group.
- the “saturated heterocyclic group” represented by R 3 is preferably monocyclic or bicyclic having one or two oxygen atoms, nitrogen atoms or sulfur atoms.
- a cyclic saturated heterocyclic group for example, pyrrolidinyl group, piperidinyl group, piperazinyl group, hexamethyleneimino group, morpholino group, thiomorpholino group, homopiperidinyl group, tetrahydrofuryl group, tetrahydropyryl group, etc. Tetrahydrofuryl group and tetrahydropyryl group.
- R 3 is preferably an isobutyl group, 2-methylbutyl group, allyl group, cyclopentyl group, cyclopropylmethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, tetrahydrofuryl group, or tetrahydropyryl group. Group.
- X represents an ethylene group or —O—C1-4 alkylene group
- R 1 represents a hydrogen atom or a C1-3 alkyl group
- R 2 represents a hydrogen atom or a fluorine atom
- R 3 represents a C1-6 alkyl group, a C2-6 alkenyl group, a C3-6 cycloalkyl group, a (C3-6 cycloalkyl) C1-6 alkyl group, a halogeno C1-6 alkyl group or a saturated heterocyclic group. preferable.
- X represents an ethylene group or —O—C1-4 alkylene group
- R 1 represents a hydrogen atom or a C1-3 alkyl group
- R 2 represents a hydrogen atom or a fluorine atom
- R 3 is preferably a C1-6 alkyl group, a C2-6 alkenyl group, a (C3-6 cycloalkyl) C1-6 alkyl group, a halogeno C1-6 alkyl group, a tetrahydrofuryl group or a tetrahydropyryl group.
- X represents an ethylene group or —O—CH 2 CH 2 CH 2 —;
- R 1 represents a hydrogen atom, a methyl group or an ethyl group;
- R 2 represents a hydrogen atom or a fluorine atom. It is shown;
- R 3 is isobutyl, 2-methylbutyl group, an allyl group, a cyclopentyl group, a cyclopropylmethyl group, 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, a tetrahydrofuryl group, or tetrahydropyridinyl Le The case of showing a group is particularly preferred.
- Pharmaceutically acceptable salts of the compound represented by formula (I) include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid.
- inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid.
- Acid addition salts with organic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, paratoluenesulfonic acid, glutamic acid Salt, ammonium salt with inorganic base such as sodium, potassium, magnesium, calcium and aluminum, organic base such as methylamine, ethylamine, meglumine and ethanolamine, or basic amino acid such as lysine, arginine and ornithine .
- the compounds of the present invention include optical isomers and hydrates.
- the uracil compound of the present invention can be produced according to the following reaction process formula.
- Lg represents a leaving group such as a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, or a trifluoromethanesulfonyloxy group.
- DMA N, N-dimethylacetamide
- DMSO dimethyl sulfoxide
- DMF is preferred.
- the base to be used include sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide and other inorganic bases, trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N -Organic amines such as methylmorpholine, pyridine, lutidine, collidine and the like are exemplified, and potassium carbonate is preferred.
- the number of equivalents is 0.8 to 10 equivalents, preferably 1.0 to 5.0 equivalents.
- the number of equivalents of the general formula (2) is 0.8 to 10 equivalents, preferably 1.0 to 5.0 equivalents.
- the reaction temperature is 20 to 150 ° C., preferably 50 to 130 ° C.
- the reaction time is 0.5 to 24 hours, preferably 1.0 to 12 hours.
- a compound represented by the general formula (4) is obtained by condensing a readily available 3-cyanophenol (1) and an alcohol represented by the general formula (3) by Mitsunobu reaction. It can also be manufactured.
- the reaction solvent to be used is not particularly limited as long as it does not affect the reaction, but dichloromethane, 1,2-dichloroethane (hereinafter DCE), benzene, xylene, toluene, ethyl acetate, propyl acetate, butyl acetate, diethyl Examples include ether, THF, dioxane, acetone, dimethoxyethane, acetonitrile, DMF and the like, preferably THF.
- the reagent used in the Mitsunobu reaction is not particularly limited as long as it is a reagent that can be usually used in the Mitsunobu reaction, but it is a di-lower group such as diethyl azodicarboxylate (hereinafter DEAD) or diisopropyl azodicarboxylate (hereinafter DIAD).
- DEAD diethyl azodicarboxylate
- DIAD diisopropyl azodicarboxylate
- Alkyl azodicarboxylate or azo compounds such as azodicarbonyl such as 1,1 ′-(azodicarbonyl) dipiperidine and triarylphosphine such as triphenylphosphine or tri-lower such as tri-n-butylphosphine A combination of alkylphosphine and the like.
- a combination of DEAD and triphenylphosphine is preferable.
- the number of equivalents of the general formula (3), di-lower alkylazodicarboxylate, and triarylphosphine is 0.8 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents.
- the reaction temperature is ⁇ 20 ° C. to 120 ° C., preferably 0 to 60 ° C.
- the reaction time is 0.1 to 24 hours, preferably 0.2 to 6.0 hours.
- the compound represented by the general formula (5) can be produced by reacting the cyano compound represented by the general formula (4) with a generally known reducing agent.
- the reaction solvent used include methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, dimethoxyethane, diethylene glycol dimethyl ether, diisopropyl ether, diethyl ether, THF, dioxane and the like, depending on the type of reduction reaction used. , Preferably THF.
- LAH lithium aluminum hydride
- metal hydrides such as sodium aluminum hydride, sodium triethoxyaluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, or catalysts such as palladium / carbon, palladium hydroxide, platinum
- LAH is preferred.
- the number of equivalents is 0.5 to 5.0 equivalents, preferably 0.8 to 2.0 equivalents.
- the reaction temperature is 0 to 100 ° C, preferably 20 to 60 ° C.
- the reaction time is 0.1 to 24 hours, preferably 0.2 to 6.0 hours.
- R 1 , R 2 , R 3 and Lg are as defined above.
- R c represents a C 1-6 alkyl group, and Hal represents a halogen atom.
- the compound represented by the general formula (9) can be produced by reacting the compound represented by the general formula (8) with a generally known reducing agent.
- the reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include diethyl ether, diisopropyl ether, THF, dioxane and the like, and preferably THF.
- LAH lithium diethoxyaluminum hydride, lithium triethoxyaluminum hydride, lithium tri-tert-butoxyaluminum hydride, magnesium aluminum hydride, magnesium aluminum hydride chloride, sodium aluminum hydride, hydrogenation
- examples include sodium triethoxyaluminum, sodium bis (2-methoxyethoxy) aluminum hydride, diisobutylaluminum hydride (hereinafter referred to as DIBAL), lithium borohydride and the like, preferably lithium borohydride.
- the number of equivalents is 0.8 to 10 equivalents, preferably 1.0 to 5.0 equivalents.
- the reaction temperature is from 0 ° C. to the boiling point of the solvent, preferably the boiling point of the solvent.
- the reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours.
- the aldehyde compound represented by General formula (10) can be manufactured by making the compound represented by General formula (9) react with a normally well-known oxidizing agent.
- the reaction solvent to be used is not particularly limited as long as it does not affect the reaction, but dichloromethane, chloroform, carbon tetrachloride, DCE, chlorobenzene, toluene, xylene and the like are exemplified, and dichloromethane is preferable.
- oxidizing agents used include chromic anhydride, pyridine and acetic anhydride complex reagents, chromium-based oxidizing agents such as pyridium chlorochromate and pyridium dichromate, high-valent iodine oxidizing agents such as Dess-Martin reagent, DMSO and anhydrous DMSO oxidizing agent, manganese (IV) oxide used in combination with acetic acid, oxalyl chloride, dicyclohexylcarbodiimide (hereinafter DCC), or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (hereinafter EDC ⁇ HCl) 2,2,6,6-tetramethylpiperidine-1-oxyl radical, preferably manganese (IV) oxide.
- DCC dicyclohexylcarbodiimide
- EDC ⁇ HCl 1-ethyl-3- (3-dimethylaminopropyl) carbod
- the number of equivalents is 0.8 to 30 equivalents, preferably 1.0 to 20 equivalents.
- the reaction temperature is ⁇ 20 to 150 ° C., preferably 0 to 100 ° C.
- the reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours.
- R 2 is a hydrogen atom
- the compound represented by the general formula (10) can be produced by a method similar to [A-1] using 3-hydroxybenzaldehyde which is readily available as a starting material. it can.
- the nitrile compound represented by the general formula (4) can be produced by a generally known reduction reaction, for example, the DIBAL reduction method, to produce the compound represented by the general formula (10).
- the compound represented by the general formula (10) or a readily available aldehyde is reacted with 2-methyl-2-propanesulfinamide, which is easily available, under acidic conditions.
- the compound represented by (11) can be produced.
- the reaction solvent to be used is not particularly limited as long as it does not affect the reaction, but examples include diethyl ether, diisopropyl ether, THF, dioxane, dichloromethane, chloroform, carbon tetrachloride, toluene, xylene, and the like. Toluene.
- Examples of the acid used include hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, and Lewis acids such as titanium tetraisopropoxide and titanium tetraethoxide, with titanium tetraisopropoxide being preferred.
- the number of equivalents of 2-methyl-2-propanesulfinamide and titanium tetraisopropoxide is 0.8 to 10 equivalents, preferably 1.0 to 3.0 equivalents.
- the reaction temperature is 20 to 150 ° C, preferably 50 to 120 ° C.
- the reaction time is 0.1 to 24 hours, preferably 0.5 to 6.0 hours.
- the compound represented by the general formula (11) is reacted with a Grignard reagent (12) represented by R 1 MgHal or an organolithium reagent (13) represented by R 1 Li, whereby the general formula ( The compound represented by 14) can be produced diastereoselectively.
- the reaction solvent to be used is not particularly limited as long as it does not affect the reaction, but diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, THF, dimethoxyethane, dioxane, dichloromethane, chloroform, four Examples include carbon chloride, toluene, xylene and the like.
- the equivalent of Grignard reagent or organolithium reagent is 0.8 to 20 equivalents, preferably 1.0 to 10 equivalents.
- the reaction temperature is ⁇ 100 ° C. to 100 ° C., preferably ⁇ 78 ° C. to 50 ° C.
- the reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours.
- the compound represented by the general formula (15) can be produced by treating the compound represented by the general formula (14) with an acid.
- the solvent to be used is not particularly limited as long as it does not affect the reaction, but alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol and 2-butanol, and dioxane, ethyl acetate and the like can be used. Exemplified and preferably methanol.
- the acid to be used include hydrochloric acid, sulfuric acid, phosphoric acid and the like, preferably hydrochloric acid.
- the number of equivalents is 0.1 to 10 equivalents, preferably 1.0 to 2.0 equivalents.
- the reaction temperature is ⁇ 20 ° C.
- R 1 , R 2 and R 3 are as defined above.
- reaction solvent to be used is not particularly limited as long as it does not affect the reaction, but examples include acetone, THF, diethyl ether, diisopropyl ether, dioxane, dichloromethane, chloroform, carbon tetrachloride, DMF, DMA, acetonitrile and the like. Preferably, it is dichloromethane.
- Examples of the base to be used include inorganic bases such as sodium bicarbonate, sodium carbonate and potassium carbonate, and organic amines such as trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine and collidine. Is triethylamine.
- the number of equivalents of base and amine is 0.5 to 10 equivalents, preferably 0.7 to 5.0 equivalents.
- the reaction temperature is ⁇ 20 ° C. to 100 ° C., preferably 0 to 50 ° C.
- the reaction time is 0.1 to 24 hours, preferably 0.2 to 6.0 hours.
- the compound represented by the general formula (18) is methoxymethylated (MOM-ized) by a generally known method, followed by Lewis acid treatment, and then in the presence of iodine, the literature (Nucleoides & Nucleotides, 4, 565-585 (1985)), the compound represented by the general formula (19) can be produced by reaction with 2,4-bis (trimethylsilyloxy) pyrimidine.
- the solvent used for the Lewis acid treatment is not particularly limited as long as it does not affect the reaction, and examples thereof include dichloromethane, chloroform, carbon tetrachloride, DCE, toluene, xylene, and the like, preferably dichloromethane.
- Examples of the Lewis acid include boron trichloride (hereinafter referred to as BCl 3 ), boron trifluoride, boron tribromide and the like, preferably BCl 3 .
- the number of equivalents is 0.01 to 10 equivalents, preferably 0.2 to 0.5 equivalents.
- the reaction temperature is ⁇ 20 to 100 ° C., preferably 0 to 50 ° C.
- the reaction time is 0.1 to 24 hours, preferably 0.5 to 5.0 hours.
- the solvent for the reaction with 2,4-bis (trimethylsilyloxy) pyrimidine is not particularly limited as long as it does not affect the reaction, but dichloromethane, chloroform, carbon tetrachloride, DCE, toluene, xylene and the like can be used. Exemplified and preferably DCE or toluene.
- the number of equivalents of 2,4-bis (trimethylsilyloxy) pyrimidine is 0.8 to 10 equivalents, preferably 0.9 to 5.0 equivalents.
- the equivalent number of iodine is 0.001 to 1.0 equivalent, preferably 0.05 to 0.5 equivalent.
- the reaction temperature is 20 to 150 ° C., preferably 50 to 100 ° C.
- the reaction time is 0.1 to 120 hours, preferably 0.5 to 100 hours.
- R 1 , R 2 and R 3 are as defined above, Bz represents a benzoyl group, and Pg represents a protecting group for a nitrogen atom on the sulfonamide group.
- the compound represented by the general formula (23) can be produced by debenzoylating and depgrating the compound represented by the general formula (22) by a generally known deprotection method.
- the uracil compound represented by the formula (I) has a potent human dUTPase inhibitory action, and when used in combination with various antitumor agents (hereinafter referred to as antitumor agent A), the antitumor agent of the antitumor agent A Has the effect of enhancing the effect.
- Antitumor agent A whose action is enhanced by the antitumor effect potentiator of the present invention is not particularly limited, but for example, alkylating agents such as cyclophosphamide and nimustine, platinum preparations such as cisplatin, carboplatin, and oxaliplatin; Antimetabolites; plant alkaloid antitumor agents such as paclitaxel, docetaxel, irinotecan and the like.
- the antitumor agent A whose action is enhanced by the antitumor effect enhancer of the present invention is preferably an antimetabolite.
- an antimetabolite is a compound having a chemical structure similar to that of a substance used as a nucleic acid material when cancer cells divide or proliferate, or a drug containing the same as an active ingredient, and biosynthesis of nucleic acid.
- it refers to an anticancer agent that inhibits the biosynthetic pathway of nucleic acids and suppresses proliferation.
- 5-fluorouracil 5-fluorouracil
- TS-1 tegafur gimeracil oteracil potassium
- UFT tegafur / uracil combination drug
- capecitabine doxyfluridine
- 5-fluoro-2′-deoxyuridine FdUrd
- pyrimidine antimetabolite such as gemcitabine
- cytarabine examples include purine antimetabolites such as fludarabine, cladribine, and nelarabine, and antifolate antimetabolites such as pemetrexed and methotrexate.
- thymidylate (TMP) synthesis pathway inhibitors are preferred.
- a thymidylate synthesis pathway inhibitor is an antimetabolite, such as a thymidylate synthase inhibitor or a dihydrofolate reductase inhibitor, which directly or indirectly inhibits an enzyme involved in TMP biosynthesis. Or a drug containing the same as an active ingredient.
- the thymidylate synthase inhibitor refers to a compound that inhibits thymidylate synthase or a drug containing the same as an active ingredient, such as 5-fluorouracil (5-FU), tegafur, gimeracil, and oteracil potassium (TS-1).
- Fluorinated pyrimidine antimetabolites such as tegafur uracil (UFT), capecitabine, doxyfluridine, 5-fluoro-2'-deoxyuridine (FdUrd), carmofur (Yamafur), antagonism of folic acid such as pemetrexed, methotrexate, raltitrexed Agents, nolatrexed dihydrochloride, and the like.
- the dihydrofolate reductase inhibitor refers to an inhibitor compound of an enzyme that biosynthesizes tetrahydrofolate essential for de novo synthesis, such as purines and thymidylate, or a drug containing it as an active ingredient, for example, plalatrexate And antifolate inhibitors such as edatrexate, pyrimesamine, brodimoprim, and trimethrexate glucuronate.
- the antitumor agent A whose action is enhanced by the antitumor effect enhancer of the present invention is preferably a thymidylate synthase inhibitor, such as 5-fluorouracil (5-FU), tegafur, gimeracil, oteracil potassium (TS-1), tegafur uracil (UFT), capecitabine, 5-fluoro-2′-deoxyuridine (FdUrd), pemetrexed are particularly preferred.
- a thymidylate synthase inhibitor such as 5-fluorouracil (5-FU), tegafur, gimeracil, oteracil potassium (TS-1), tegafur uracil (UFT), capecitabine, 5-fluoro-2′-deoxyuridine (FdUrd), pemetrexed are particularly preferred.
- the antitumor effect potentiator of the compound of the present invention is not particularly limited as a malignant tumor that can be treated together with the antitumor agent A whose action is enhanced.
- a malignant tumor that can be treated together with the antitumor agent A whose action is enhanced.
- head and neck cancer esophageal cancer, stomach cancer, colon cancer, rectal cancer, Liver cancer, gallbladder / bile duct cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, kidney cancer, bladder cancer, prostate cancer, testicular tumor, bone / soft tissue sarcoma, leukemia, malignant lymphoma, multiple Examples include myeloma, skin cancer, and brain tumor.
- an antitumor agent having an enhanced antitumor effect can be obtained.
- a single-form preparation form containing the uracil compound of the formula (I) or a salt thereof and the antitumor agent A, or a uracil compound of the formula (I) or a salt thereof may be in separate preparation forms.
- the administration means of the composition containing the uracil compound of formula (I) and the administration means of the composition containing the antitumor agent A may be the same or different (for example, oral administration and injection). ).
- the antitumor agent A and the uracil compound of the present invention can be used as a kit.
- each composition constituting the kit can be made into various known preparation forms.
- each composition is stored in various commonly used containers according to the preparation form, It can be set as the kit for cancer treatment in the containing mammal.
- the uracil compound of the present invention or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical composition, it can be combined with a pharmaceutical carrier as necessary, and various dosage forms can be adopted depending on the purpose of prevention or treatment.
- a pharmaceutical carrier examples include oral preparations, injections, suppositories, ointments, patches, and the like, and oral preparations are preferable.
- Each of these dosage forms can be produced by a conventional formulation method known to those skilled in the art.
- the pharmaceutical carrier various organic or inorganic carrier substances commonly used as pharmaceutical materials are used. Excipients, binders, disintegrants, lubricants, colorants in solid preparations; solvents, dissolution aids, suspensions in liquid preparations. It is blended as a turbidity agent, tonicity agent, buffering agent, soothing agent and the like. Moreover, formulation additives such as preservatives, antioxidants, colorants, sweeteners, stabilizers and the like can be used as necessary.
- a tablet is prepared by a conventional method. Coated tablets, granules, powders, capsules and the like can be produced.
- excipient examples include lactose, sucrose, D-mannitol, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, and anhydrous silicic acid.
- binder examples include water, ethanol, 1-propanol, 2-propanol, simple syrup, glucose solution, ⁇ -starch solution, gelatin solution, D-mannitol, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, Shellac, calcium phosphate, polyvinylpyrrolidone and the like can be mentioned.
- Examples of the disintegrant include dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose.
- Examples of the lubricant include purified talc, sodium stearate, magnesium stearate, borax, and polyethylene glycol.
- Examples of the colorant include titanium oxide and iron oxide.
- Examples of the flavoring / flavoring agent include sucrose, orange peel, citric acid, tartaric acid and the like.
- an oral solution, a syrup, an elixir or the like can be produced by adding a flavoring agent, a buffer, a stabilizer, a flavoring agent and the like to the compound of the present invention by a conventional method.
- the flavoring / flavoring agent may be those listed above
- examples of the buffering agent include sodium citrate
- examples of the stabilizer include tragacanth, gum arabic, and gelatin.
- an enteric coating or a coating can be applied to the oral preparation by a known method for the purpose of sustaining the effect. Examples of such a coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80 (registered trademark), and the like.
- a pH adjuster, buffer, stabilizer, tonicity agent, local anesthetic, etc. are added to the compound of the present invention, and subcutaneous, intramuscular and intravenous injections are prepared by conventional methods.
- the pH adjuster and buffer include sodium citrate, sodium acetate, and sodium phosphate.
- the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid and the like.
- local anesthetics include procaine hydrochloride and lidocaine hydrochloride.
- isotonic agents include sodium chloride, glucose, D-mannitol, glycerin and the like.
- a formulation carrier known in the art such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride, etc., and an interface such as Tween 80 (registered trademark) are added to the compound of the present invention as necessary. After adding an activator etc., it can manufacture by a conventional method.
- bases, stabilizers, wetting agents, preservatives and the like that are usually used for the compound of the present invention are blended as necessary, and mixed and formulated by a conventional method.
- the base include liquid paraffin, white petrolatum, white beeswax, octyldodecyl alcohol, paraffin and the like.
- the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, and propyl paraoxybenzoate.
- the ointment, cream, gel, paste or the like may be applied to a normal support by a conventional method.
- a woven fabric, nonwoven fabric, soft vinyl chloride, polyethylene, polyurethane film or foam sheet made of cotton, suf, chemical fiber is suitable.
- the amount of the uracil compound of the present invention to be blended in each dosage unit form is not constant depending on the symptoms of the patient to which the uracil compound is to be applied, or its dosage form, etc.
- the daily dose of the drug having the above-mentioned dosage form varies depending on the patient's symptoms, body weight, age, sex, etc., and cannot be determined unconditionally.
- the dose is about 5000 mg, preferably 0.1 to 1000 mg, and is preferably administered once a day or divided into about 2 to 3 times a day.
- each preparation may be any one before, after administration of one component, or after administration of one component.
- Other ingredients can be administered at certain times. It is preferable to administer at the same time or within 6 hours before and after administration of one component.
- the dose of the antitumor agent A can be used by reducing the dose at which the antitumor agent A is usually used. Ordinarily used doses may be used.
- the antitumor effect enhancer of the present invention or a salt thereof and the antitumor agent A are not particularly limited as long as the antitumor effect is enhanced within the range where the effect of enhancing the antitumor effect is achieved.
- the compound of the present invention or a salt thereof may be about 0.01 to 100 mol, preferably about 0.07 to 64 mol.
- the administration or blending ratio of the antitumor agent A is based on the amount of the active ingredient that exhibits the antitumor effect.
- the compound of the present invention or a salt thereof is added in an amount of 0.01 to 100 per 1 mol of tegafur per day.
- the molar amount is preferably about 0.15 to 64 mol.
- the compound of the present invention or a salt thereof may be about 0.01 to 100 mol, preferably about 0.07 to 8 mol, per 1 mol of capecitabine.
- THF tetrahydrofuran
- LAH lithium aluminum hydride
- Water (10 mL), aqueous sodium hydroxide (1.0 M, 10 mL), and water (5.0 mL) were slowly added to the reaction solution at 0 ° C.
- the resulting precipitate was filtered off, washed with 10% methanol / THF (400 mL), and the combined filtrate was concentrated under reduced pressure.
- the reaction mixture was concentrated under reduced pressure, ethyl acetate (20 mL) was added, and the organic layer was washed with aqueous sodium hydroxide solution (1.0 M, 5.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
- the residue was purified by silica gel column chromatography (50% ethyl acetate / hexane). The obtained compound was dissolved in toluene (6.5 mL), and (S)-( ⁇ )-2-methyl-2-propanesulfinamide (330 mg) and titanium tetraisopropoxide (1.1 mL) were added at 75 ° C. For 6 hours.
- DIBAL diisobutylaluminum hydride
- a saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution at 0 ° C. over 10 minutes, and the mixture was extracted with ethyl acetate (100 mL ⁇ 2). The organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate / hexane). The obtained compound was dissolved in methanol (70 mL), hydrochloric acid-dioxane solution (4.0 M, 13 mL) was added, and the mixture was stirred at room temperature for 30 min. The reaction solution was concentrated under reduced pressure, and the residue was azeotroped with toluene (40 mL ⁇ 3) to obtain the title compound (9.09 g).
- the obtained compound was dissolved in THF (5.0 mL), and diphenylphosphoryl azide (875 ⁇ L) and DBU (592 ⁇ L) were added dropwise at room temperature, followed by stirring for 1 hour. Saturated brine (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL ⁇ 2). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate / hexane).
- the obtained compound was dissolved in methanol (7.5 mL), 10% palladium-carbon (180 mg) was added, and the reaction mixture was stirred at room temperature for 2 hr in a hydrogen atmosphere.
- the insoluble material was filtered off using celite, washed with methanol (100 mL), and the combined filtrate was concentrated under reduced pressure to obtain the title compound (740 mg) as a crude product.
- the obtained compound was dissolved in a 5-10% hydrochloric acid / methanol solution (100 mL) and heated to reflux at 80 ° C. for 1 hour. The reaction solution was allowed to cool and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (66% ethyl acetate / hexane). The obtained compound was dissolved in dichloromethane (80 mL), N, N-diisopropylethylamine (14.1 mL) and chloromethyl methyl ether (4.1 mL) were added, and the mixture was stirred at room temperature for 1 hr.
- a saturated aqueous ammonium chloride solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with saturated aqueous ammonium chloride solution (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate / hexane). A part (440 mg) of the obtained compound (446 mg) was dissolved in a methanol solution of methylamine (40%, 5.0 mL) and stirred at room temperature for 20 minutes.
- N- (3- (cyclopropylmethoxy) benzyl) -3- (methoxymethoxy) propane-1-sulfonamide (6.8 g) obtained in Reference Example 20 was dissolved in dichloromethane (20 mL), and boron trichloride ( A dichloromethane solution (1.0 M, 6.7 mL) of BCl 3 ) was added at 0 ° C., and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 1,2-dichloroethane (hereinafter DCE, 25 mL).
- DCE 1,2-dichloroethane
- Example 2 (R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) propane-1 -Sulfonamide
- Example 3 3-((2,4-Dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) -N-((R) -1- (3-((R) -tetrahydrofuran-3-yloxy) Phenyl) ethyl) propane-1-sulfonamide
- Example 4 Implementation of N- (3- (cyclopropylmethoxy) -4-fluorobenzyl) -3-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) propane-1-sulfonamide
- Example 5 (R) -N
- Example 6 N- (1- (3- (cyclopropylmethoxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) propane-1-sulfonamide
- Example 7 N- (3- (cyclopentyloxy) benzyl) -3-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) propane-1-sulfonamide
- Example 8 (R) -N- (1- (3- (cyclopropylmethoxy) -4-fluorophenyl) propyl) -3-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) Methoxy) propane-1-sulfonamide
- Example 9 (R) -N- (1- (3- (cyclopentyloxy) -4-fluorophen
- Example 10 (R) -3-((2,4-Dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) -N- (1- (3- (2,2,2-trifluoroethoxy) Phenyl) ethyl) propane-1-sulfonamide
- Example 11 (R) -3-((2,4-Dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) -N- (1- (3-isobutoxyphenyl) ethyl) propane-1-sulfone Amide
- Example 12 3-((2,4-Dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) -N-((R) -1- (3-((S) -2-methylbutoxy) phenyl ) Ethyl) propane-1-sulfonamide
- Example 13 (R) -N- (1- (3- (2,2-difluoroethoxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy ) Propane-1-sulfonamide
- Example 14 (R) -3-((2,4-Dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) -N- (1- (3- (tetrahydro-2H-pyran-4-yloxy) Phenyl) ethyl) propane-1-sulfonamide
- Example 15 (R) -3-((2,4-Dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) -N- (1- (4-fluoro-3- (2,2,2- Trifluoroethoxy) phenyl) ethyl) propane-1-sulfonamide
- Example 16 (R) -N- (1- (3- (2,2-difluoroethoxy) -4-fluorophenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -Yl) methoxy) propane-1-sulfonamide
- Example 17 (R) -N- (1- (3- (allyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) propane-1- Sulfonamide
- Example 18
- the obtained compound was dissolved in dioxane (25 mL), a hydrochloric acid-dioxane solution (4.0 M, 25 mL) was added, and the mixture was stirred at room temperature for 1 hr.
- the reaction solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution (40 mL) at 0 ° C., and extracted with ethyl acetate (50 mL ⁇ 2).
- the organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
- the residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain the title compound (2.0 g, yield 39%).
- Test Example 1 human dUTPase inhibitory action
- the inhibitory activity against human dUTPase of the compounds of the present invention by the following method [5- 3 H] deoxyuridine triphosphate (hereinafter, [5- 3 H] dUTP) from [5- 3 H] deoxyuridine monophosphate (hereinafter, It was determined by measuring the production of [5- 3 H] dUMP).
- 1 ⁇ M dUTP (containing 588 Bq / mL [5- 3 H] dUTP) 0.02 mL, 0.2 M Tris buffer (pH 7.4) 0.05 mL, 16 mM magnesium chloride 0.05 mL, 20 mM 2-mercaptoethanol
- a total of 0.2 mL of 02 mL, 0.02 mL of 1% fetal bovine serum-derived albumin aqueous solution, 0.02 mL of purified compound solution or 0.02 mL of purified water expressed and purified using Escherichia coli as a control or various concentrations of test compound solution The reaction was allowed to proceed at 37 ° C for 15 minutes.
- Elution was performed with a 30 minute concentration gradient from a 4: 6 mixture of 5.6 mM tetrabutylammonium, 30% methanol) to mobile phase B.
- Eluent 1 2 scintillator in a ratio (Perkin Elmer, Ultima-FloAP) were mixed and, Radiomatic Flow Scintillation Analyzer (Perkin Elmer, 525TR) were generated by [5- 3 H] dUMP (RT10 . 2 min) was measured.
- the inhibitory activity of the test compound was determined by the following formula, and the concentration of the test solution that inhibits the amount of [5- 3 H] dUMP produced by human dUTPase by 50% is shown in Table 10 as IC 50 ( ⁇ M).
- the following table shows human dUTPase inhibitory activity data.
- the test solution of tegafur, gimeracil, and oteracil potassium (TS-1, manufactured by Taiho Pharmaceutical Co., Ltd.) alone group had a TS-1 dose of 8.3 mg / kg / day as the amount of tegafur (FT), The final concentrations were 0.5% hydroxypropylmethylcellulose, 2.5% dimethylacetamide, 2.5% Tween 80, and 10% cremophor, respectively.
- the test solution of the combination group of TS-1 and the compound of the present invention is 200 mg / kg / day + TS-1 (8.3 mg / kg / day) of the test drug for the compounds 6, 4, 7, 8 of the present invention.
- test drug 100 mg / kg / day + TS-1 (8.3 mg / kg / day), and for comparative compound 1, test drug 200 mg / kg / day + TS-1 (8.3 mg / day) kg / day) was prepared in the same manner as the test solution of TS-1 alone group.
- Administration was orally administered daily for 14 days from day 1 to the test animals, each with a test solution dose of 10 mL / kg.
- TV at day 15 was measured, relative tumor volume (RTV) relative to day 0 was calculated, and T / C (%) was calculated by the following formula to evaluate the antitumor effect.
- RTV relative tumor volume
- T / C (%) was calculated by the following formula to evaluate the antitumor effect.
- * indicates that a statistically significant difference was observed with respect to the TS-1 alone group.
- Test Example 3 (Anti-tumor effect enhancing action against TS-1) Human breast cancer strain MX-1 was transplanted into the right breast of 5-6 week old male BALB / cA Jcl-nu mice and used in the same manner as in Test Example 2.
- the test solution of TS-1 alone group was prepared so that the dose of TS-1 was 10 mg / kg / day with FT amount.
- the test solution of the combination group of TS-1 and the compound of the present invention is 300 mg / kg / day + TS-1 (10 mg / kg / day) of the compound of the present invention (5, 14, 3, 15, 16, and 17).
- Each was prepared and evaluated in the same manner as in Test Example 2. The results are shown in FIG. In the figure, * indicates that a statistically significant difference was observed with respect to the TS-1 alone group.
- Test Example 4 Anti-tumor effect enhancing action against 5-FU
- the human ovarian cancer line OVCAR-3 was transplanted into the right breast of male BALB / cA Jcl-nu mice aged 5 to 6 weeks and used in the same manner as in Test Example 2.
- the test solution of the 5-FU single group was prepared by dissolving in 7% Melon adjusted to pH 9.0 so that the dose of 5-FU was 15 mg / kg / day, and the test solution of the compound of the present invention was The compound of the present invention was prepared by suspending in 0.5% hydroxypropylmethylcellulose to give 300 mg / kg / day.
- the 5-FU single group was continuously administered subcutaneously using alzet sonic mini-pump model 2002 (flow rate 0.5 ⁇ l / h) for 1 to 14 days.
- 5-FU was continuously administered subcutaneously using alzetotic mini-pump model 2002 (flow rate 0.5 ⁇ l / h) for 1 to 14 days.
- the test solution of the inventive compound was orally administered to a test animal every day at 10 mL / kg and evaluated in the same manner as in Test Example 2. The results are shown in FIG. In the figure, * indicates that a statistically significant difference was observed with respect to the 5-FU single group.
- Test Example 5 Human breast cancer strain MX-1 was transplanted into the right breast of 5-6 week old male BALB / cA Jcl-nu mice and used in the same manner as in Test Example 2.
- the test solution of capecitabine alone group was prepared by suspending in 0.5% hydroxypropylmethylcellulose so that the dose of capecitabine was 270 mg / kg / day.
- a mixed test solution of capecitabine and the compound of the present invention was prepared by suspending in 0.5% hydroxypropylmethylcellulose so that the compound of the present invention was 300 mg / kg / day + capecitabine (270 mg / kg / day). Evaluation was performed in the same manner. The results are shown in FIG. In the figure, * indicates that a statistically significant difference was observed with respect to capecitabine alone group.
- Test Example 6 Human breast cancer strain MX-1 was transplanted into the right breast of 5-6 week old male BALB / cA Jcl-nu mice and used in the same manner as in Test Example 2.
- a test solution of 5-fluoro-2′-deoxyuridine (FdUrd) alone group was prepared by dissolving in physiological saline so that the dose of FdUrd was 250 mg / kg / day.
- the test solution was prepared by suspending in 0.5% hydroxypropylmethylcellulose so that the compound of the present invention was 300 mg / kg / day.
- the FdUrd alone group was administered from the tail vein for 1 to 3 days.
- FdUrd was administered from the tail vein for 1 to 3 days, and the test solution of the compound of the present invention was applied to the test animal at 10 mL / kg from the day 1 to 3 days. It was orally administered every day and evaluated as day 15 in the same manner as in Test Example 2. The results are shown in FIG. In the figure, * indicates that a statistically significant difference was observed with respect to the FdUrd alone group.
- Test Example 7 (Enhancement of antitumor effect against pemetrexed) Human breast cancer strain MX-1 was transplanted into the right breast of 5-6 week old male BALB / cA Jcl-nu mice and used in the same manner as in Test Example 2.
- the test solution of the pemetrexed alone group was prepared by dissolving with physiological saline so that the dose of pemetrexed was 25 mg / kg / day.
- the test solution of the compound of the present invention was 300 mg / kg / day of the compound of the present invention. It was prepared by suspending in 0.5% hydroxypropylmethylcellulose so as to be a day.
- the pemetrexed alone group was administered from day 1 and day 8 via the tail vein.
- pemetrexed was administered to day 1 and day 8 from the tail vein, and the test solution of the compound of the present invention was applied to the test animal at 10 mL / kg from day 1 to 14 days. Orally administered every day and evaluated in the same manner as in Test Example 2. The results are shown in FIG. In the figure, * indicates that a statistically significant difference was observed with respect to the pemetrexed alone group.
- Test Example 8 Human breast cancer strain MX-1 was transplanted into the right breast of male F344N Jcl-rnu rats 5 to 6 weeks old and used in the same manner as in Test Example 2.
- a mixed test solution of UFT and the compound of the present invention was prepared by suspending in 0.5% hydroxypropylmethylcellulose so that the compound of the present invention was 300 mg / kg / day + UFT (30 mg / kg / day).
- the UFT alone group was orally administered daily for 21 days from day 1.
- the combination group of UFT and the compound of the present invention was also orally administered daily for 21 days from day 1 and evaluated as day 22 in the same manner as in Test Example 2.
- the results are shown in FIG. In the figure, * indicates that a statistically significant difference was observed with respect to the UFT single group.
- Test Example 9 (Balance study of toxicity and antitumor effect) To evaluate the safety when the compound of the present invention is used in combination, the toxicity and antitumor effect when the compound of the present invention is used in combination at a high dose were evaluated.
- Human gastric cancer line SC-6, human colorectal cancer line LS174T and human pancreatic cancer line CFPAC-1 were transplanted into the right breast of 5-6 week old male BALB / cA Jcl-nu mice. After tumor transplantation, the major axis (mm) and minor axis (mm) of the tumor are measured, and after calculating the tumor volume (TV), the average TV of each group is equalized using the MiSTAT grouping program.
- the test solution of the TS-1 alone group was prepared using 0.5% hydroxypropylmethylcellulose at a TS-1 dose of 10 mg / kg / day as the FT amount.
- the test solution of the combination group of TS-1 and the compound of the present invention was the same as the test solution of the TS-1 single group so that the test compound (600 mg / kg / day) + TS-1 (10 mg / kg / day) was obtained.
- Administration was orally administered daily for 14 days from day 1 to the test animals, each with a test solution dose of 10 mL / kg.
- the change in body weight over time was measured as an indicator of toxicity.
- the average weight change rate [body weight change, BWC (%)] of day 15 with respect to day 0 was calculated by the following formula.
- BWC (%) [(BW on Day 15)-(BW on Day 0)] / (BW on Day 0) x 100
- the uracil compound of formula (I) or a salt thereof has an effect of remarkably enhancing the antitumor effect of an antitumor agent, particularly an antimetabolite.
- Comparative Compound 1 also has a strong dUTPase inhibitory action, an enhancing action of the antitumor effect was not recognized.
- the uracil compound of the formula (I) or a salt thereof has no toxicity in combination with the antitumor agent because there is no difference in weight loss compared with the administration of the antitumor agent alone. The antitumor effect of the antitumor agent was enhanced without any enhancement.
- Test Example 10 (Examination of combined molar ratio necessary for enhancing antitumor effect 1)
- the combination ratio at which an antitumor effect enhancing action was obtained was evaluated in mice.
- the test solution of TS-1 alone group was 8.3 mg / kg / day in terms of FT dose of TS-1, and the test solution of compound 2 alone group was 1200 mg / kg / day, 0.5% hydroxy Prepared using propylmethylcellulose.
- the test solution of the combination group of TS-1 and the compound of the present invention was TS-1 so that the compound of the present invention (1200, 600, 300, 150 mg / kg / day) + TS-1 (8.3 mg / kg / day) was obtained.
- Administration was carried out by orally administering a test liquid dose of 10 mL / kg daily for 14 days from day 1 to the test animals and evaluated in the same manner as in Test Example 2. The results are shown in FIG. In the figure, * indicates that a statistically significant difference was observed with respect to the TS-1 alone group.
- Test Example 11 (Study of a combined molar ratio necessary for enhancing the antitumor effect 2)
- the combination ratio at which an antitumor effect enhancing action was obtained was evaluated in rats.
- the test solution of TS-1 alone group was prepared using 0.5% hydroxypropylmethylcellulose with TS-1 dose of FT amount of 18 mg / kg / day.
- the test solution of the combination group of TS-1 and the compound of the present invention is the compound of the present invention (100, 50, 25, 12.5, 6.25 mg / kg / day) + TS-1 (18 mg / kg / day) Thus, it was prepared in the same manner as the test solution of TS-1 alone group.
- Administration was carried out for 28 days from day 1 and a test liquid dose of 10 mL / kg was orally administered to test animals every day, and TV at day 29 was measured and evaluated in the same manner as in Test Example 2. The results are shown in FIG. In the figure, * indicates that a statistically significant difference was observed with respect to the TS-1 alone group.
- Test Example 12 (Examination of combination molar ratio necessary for enhancing antitumor effect 3)
- the combination ratio at which an antitumor effect enhancing action was obtained was evaluated in mice.
- Test liquids for capecitabine alone group were 160, 359, and 809 mg / kg / day, and were prepared using 0.5% hydroxypropylmethylcellulose.
- the test solution of the combination group of capecitabine and the compound of the present invention has the combination of the compound of the present invention (75, 300, 600, 1200, 1600 mg / kg / day) + capecitabine (160, 359, 809 mg / kg / day) in the figure.
- it was prepared in the same manner as the test solution of capecitabine alone group.
- Administration was carried out by orally administering a test liquid dose of 10 mL / kg daily for 14 days from day 1 to the test animals and evaluated in the same manner as in Test Example 2. The results are shown in FIG. In the figure, * indicates that a statistically significant difference was observed with respect to the corresponding capecitabine alone group.
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Abstract
Description
R1は水素原子又はC1-6アルキル基を示し、R2は水素原子又はハロゲン原子を示し、R3はC1-6アルキル基、C2-6アルケニル基、C3-6シクロアルキル基、(C3-6シクロアルキル)C1-6アルキル基、ハロゲノC1-6アルキル基、又は飽和複素環基を示す。)
で表されるウラシル化合物又はその薬学的に許容される塩を有効成分とする抗腫瘍効果増強剤を提供するものである。
また、本発明は、上記式(I)で表されるウラシル化合物又はその薬学的に許容される塩と、抗腫瘍剤とを組み合せてなる抗腫瘍薬を提供するものである。
また、本発明は、抗腫瘍効果増強に使用するための、上記式(I)で表されるウラシル化合物又はその薬学的に許容される塩を提供するものである。
また、本発明は、腫瘍を治療するための、上記式(I)で表される化合物又はその薬学的に許容される塩と抗腫瘍剤との組み合わせを提供するものである。
また、本発明は、上記式(I)で表される化合物又はその薬学的に許容される塩の有効量を投与することを特徴とする抗腫瘍効果増強方法を提供するものである。
また本発明は、上記式(I)で表される化合物又はその薬学的に許容される塩とを組み合わせて投与することを特徴とする腫瘍治療方法を提供するものである。
また本発明は、抗腫瘍効果増強剤製造のための、上記式(I)で表される化合物又はその薬学的に許容される塩の使用を提供するものである。
さらに本発明は、抗腫瘍剤製造のための、上記式(I)で表される化合物又はその薬学的に許容される塩と抗腫瘍剤との組み合わせの使用を提供するものである。
Xとして好ましくは、エチレン基、又は-O-CH2CH2CH2-である。
式(I)において、R2で表される「ハロゲン原子」は、フッ素原子、塩素原子、臭素原子、ヨウ素原子であり、好ましくはフッ素原子である。
式(I)において、R3で表される「C1-6アルキル基」としては、上記R1と同じものが挙げられ、好ましくはイソブチル基、2-メチルブチル基である。
式(I)において、R3で表される「C3-6シクロアルキル基」としては、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基等が挙げられ、好ましくはシクロペンチル基である。
式(I)において、R3で表される「(C3-6シクロアルキル)C1-6アルキル基」は、上記のシクロアルキル基を有する炭素数1~6のアルキル基を示し、好ましくはシクロプロピルメチル基である。
式(I)において、R3で表される「飽和複素環基」は、好ましくは酸素原子、窒素原子、硫黄原子のいずれかの原子を、好ましくは1個又は2個有する単環性又は二環性の飽和複素環基を示し、例えばピロリジニル基、ピペリジニル基、ピペラジニル基、ヘキサメチレンイミノ基、モルホリノ基、チオモルホリノ基、ホモピペリジニル基、テトラヒドロフリル基、テトラヒドロピリル基等が挙げられ、好ましくはテトラヒドロフリル基、テトラヒドロピリル基である。
R3として好ましくは、イソブチル基、2-メチルブチル基、アリル基、シクロペンチル基、シクロプロピルメチル基、2,2-ジフルオロエチル基、2,2,2-トリフルオロエチル基、テトラヒドロフリル基又はテトラヒドロピリル基である。
[工程A]
(a)本工程では、容易に入手可能な3-シアノフェノール(1)と一般式(2)で表されるアルキルハライド、アルキルメシレート、アルキルトシレート、又はアルキルトリフルオロメタンスルホネート等を塩基存在下反応させることで、前記一般式(4)で表される化合物を製造できる。
用いる反応溶媒としては、反応に影響を及ぼさないものであれば特に制限はないが、ジエチルエーテル、テトラヒドロフラン(以下THF)、ジオキサン、アセトン、ジメトキシエタン、アセトニトリル、N,N-ジメチルホルムアミド(以下DMF)、N,N-ジメチルアセトアミド(以下DMA)、ジメチルスルホキシド(以下DMSO)等が例示され、好ましくはDMFである。
用いる塩基としては、炭酸水素ナトリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、水素化ナトリウム、水素化カリウム、水酸化ナトリウム、水酸化カリウム等の無機塩基やトリメチルアミン、トリエチルアミン、トリプロピルアミン、ジイソプロピルエチルアミン、N-メチルモルホリン、ピリジン、ルチジン、コリジン等の有機アミン類が例示され、好ましくは炭酸カリウムである。その当量数は0.8~10当量であり、好ましくは1.0~5.0当量である。
一般式(2)の当量数は0.8~10当量であり、好ましくは1.0~5.0当量である。反応温度は20~150℃であり、好ましくは50~130℃である。反応時間は0.5~24時間であり、好ましくは1.0~12時間である。
用いる反応溶媒としては、反応に影響を及ぼさないものであれば特に制限はないが、ジクロロメタン、1,2-ジクロロエタン(以下DCE)、ベンゼン、キシレン、トルエン、酢酸エチル、酢酸プロピル、酢酸ブチル、ジエチルエーテル、THF、ジオキサン、アセトン、ジメトキシエタン、アセトニトリル、DMF等が例示され、好ましくはTHFである。
光延反応に用いられる試薬としては、通常光延反応に用いることができる試薬であれば特に制限はないがジエチルアゾジカルボキシレート(以下DEAD)、ジイソプロピルアゾジカルボキシレート(以下DIAD)のようなジ低級アルキルアゾジカルボキシレート、又は1,1’-(アゾジカルボニル)ジピペリジンのようなアゾジカルボニル等のアゾ化合物とトリフェニルホスフィンのようなトリアリールホスフィン又はトリ-n-ブチルホスフィンのようなトリ低級アルキルホスフィン等の組み合わせである。好ましくはDEAD、トリフェニルホスフィンの組み合わせである。
一般式(3)、ジ低級アルキルアゾジカルボキシレート、トリアリールホスフィンの当量数は、それぞれ0.8~5.0当量であり、好ましくはそれぞれ1.0~2.0当量である。反応温度は-20℃~120℃であり、好ましくは0~60℃である。反応時間は0.1~24時間であり、好ましくは0.2~6.0時間である。
本工程では、一般式(4)で表されるシアノ化合物を通常公知の還元剤と反応させることで、一般式(5)で表される化合物を製造できる。
用いる反応溶媒としては、用いる還元反応の種類によって異なるがメタノール、エタノール、1-プロパノール、2-プロパノール、tert-ブチルアルコール、ジメトキシエタン、ジエチレングリコールジメチルエーテル、ジイソプロピルエーテル、ジエチルエーテル、THF、ジオキサン等が例示され、好ましくはTHFである。
用いる還元剤としては、水素化アルミニウムリチウム(以下LAH)、水素化ジエトキシアルミニウムリチウム、水素化トリエトキシアルミニウムリチウム、水素化トリ-tert-ブトキシアルミニウムリチウム、水素化アルミニウムマグネシウム、水素化アルミニウム塩化マグネシウム、水素化アルミニウムナトリウム、水素化トリエトキシアルミニウムナトリウム、水素化ビス(2-メトキシエトキシ)アルミニウムナトリウムのような金属水素化物、又はパラジウム/炭素、水酸化パラジウム、白金のような触媒を用いた接触還元が例示され、好ましくはLAHである。その当量数は、0.5~5.0当量であり、好ましくは0.8~2.0当量である。反応温度は0℃~100℃であり、好ましくは20~60℃である。反応時間は、0.1~24時間であり、好ましくは0.2~6.0時間である。
[工程B]
本工程では、容易に入手可能な化合物(6)のカルボキシル基を、アルコール化合物(7)で通常公知の方法によりエステル化した後、[A-1]の工程と同様の方法で、一般式(8)で表される化合物を製造できる。
本工程では、一般式(8)で表される化合物を通常公知の還元剤と反応させることで、一般式(9)で表される化合物を製造できる。
用いる反応溶媒としては、反応に影響を及ぼさないものであれば特に制限はないが、ジエチルエーテル、ジイソプロピルエーテル、THF、ジオキサン等が例示され、好ましくはTHFである。
用いる還元剤としては、LAH、水素化ジエトキシアルミニウムリチウム、水素化トリエトキシアルミニウムリチウム、水素化トリ-tert-ブトキシアルミニウムリチウム、水素化アルミニウムマグネシウム、水素化アルミニウム塩化マグネシウム、水素化アルミニウムナトリウム、水素化トリエトキシアルミニウムナトリウム、水素化ビス(2-メトキシエトキシ)アルミニウムナトリウム、水素化ジイソブチルアルミニウム(以下DIBAL)、水素化ホウ素リチウム等が例示され、好ましくは水素化ホウ素リチウムである。その当量数は、0.8~10当量であり、好ましくは1.0~5.0当量である。反応温度は0℃~溶媒の沸点温度であり、好ましくは溶媒の沸点温度である。反応時間は、0.1~24時間であり、好ましくは0.5~12時間である。
本工程では、一般式(9)で表される化合物を通常公知の酸化剤と反応させることで、一般式(10)で表されるアルデヒド化合物を製造できる。
用いる反応溶媒としては、反応に影響を及ぼさないものであれば特に制限はないが、ジクロロメタン、クロロホルム、四塩化炭素、DCE、クロロベンゼン、トルエン、キシレン等が例示され、好ましくはジクロロメタンである。
用いる酸化剤としては、無水クロム酸、ピリジン及び無水酢酸の複合試薬、ピリジウムクロロクロメート、ピリジウムジクロメート等のクロム系酸化剤、Dess-Martin試薬等の高原子価ヨウ素酸化剤、DMSOと無水酢酸、塩化オキザリル、ジシクロヘキシルカルボジイミド(以下DCC)、又は1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩(以下EDC・HCl)とを組み合わせて用いるDMSO系酸化剤、酸化マンガン(IV)、2,2,6,6-テトラメチルピペリジン-1-オキシルラジカルが例示され、好ましくは酸化マンガン(IV)である。その当量数は、0.8~30当量であり、好ましくは1.0~20当量である。反応温度は-20~150℃であり、好ましくは0~100℃である。反応時間は、0.1~24時間であり、好ましくは0.5~12時間である。
またR2が水素原子の場合には、容易に入手可能な3-ヒドロキシベンズアルデヒドを出発原料として、[A-1]と同様の方法により一般式(10)で表される化合物を製造することができる。さらに、一般式(4)で示されるニトリル化合物を通常公知の還元反応、例えばDIBAL還元法により、一般式(10)で表される化合物を製造することもできる。
本工程では、前記一般式(10)で表される化合物又は容易に入手可能なアルデヒドを、容易に入手可能な2-メチル-2-プロパンスルフィンアミドと酸性条件下反応させることで、前記一般式(11)で表される化合物を製造できる。
用いる反応溶媒としては、反応に影響を及ぼさないものであれば特に制限はないが、ジエチルエーテル、ジイソプロピルエーテル、THF、ジオキサン、ジクロロメタン、クロロホルム、四塩化炭素、トルエン、キシレン等が例示され、好ましくはトルエンである。
用いる酸としては、塩酸、硫酸、パラトルエンスルホン酸、或いはチタニウムテトライソプロポキシド、チタニウムテトラエトキシド等のルイス酸が例示され、好ましくはチタニウムテトライソプロポキシドである。2-メチル-2-プロパンスルフィンアミドとチタニウムテトライソプロポキシドの当量数は、それぞれ0.8~10当量であり、好ましくは1.0~3.0当量である。反応温度は20~150℃であり、好ましくは50~120℃である。反応時間は0.1~24時間であり、好ましくは0.5~6.0時間である。
本工程では一般式(11)で表される化合物を、R1MgHalで表されるGrignard試薬(12)又はR1Liで表される有機リチウム試薬(13)と反応させることで、一般式(14)で表される化合物をジアステレオ選択的に製造できる。
用いる反応溶媒としては、反応に影響を及ぼさないものであれば特に制限はないが、ジエチルエーテル、ジイソプロピルエーテル、tert-ブチルメチルエーテル、シクロペンチルメチルエーテル、THF、ジメトキシエタン、ジオキサン、ジクロロメタン、クロロホルム、四塩化炭素、トルエン、キシレン等が例示される。Grignard試薬又は有機リチウム試薬の当量は0.8~20当量であり、好ましくは1.0~10当量である。反応温度は、-100℃~100℃であり 、好ましくは-78℃~50℃である。反応時間は0.1~24時間であり、好ましくは0.5~12時間である。
本工程では、一般式(14)で表される化合物を酸で処理することで、一般式(15)で表される化合物を製造できる。
用いる溶媒としては反応に影響を及ぼさないものであれば特に制限はないが、メタノール、エタノール、1-プロパノール、2-プロパノール、1-ブタノール、2-ブタノールなどのアルコール類及びジオキサン、酢酸エチル等が例示され、好ましくはメタノールである。
用いる酸としては塩酸、硫酸、リン酸などが例示され、好ましくは塩酸である。その当量数は、0.1~10当量であり、好ましくは1.0~2.0当量である。反応温度は-20℃~100℃であり、好ましくは0~50℃である。反応時間は0.01~24時間であり、好ましくは0.1~1.0時間である。
また、R1が水素原子で、且つR2がフッ素原子の場合には、一般式(9)で表される化合物を通常公知の方法でアジド化した後、通常公知の還元剤(例えばLAH)で処理することで、一般式(15)で表される化合物を製造することもできる。さらに、一般式(15)で表される化合物をラセミ体で得る場合には、一般式(10)で表される化合物を工程B-5と同様の方法によりアルコール化合物へと変換し、通常公知の方法でアジド化した後、通常公知の方法で還元することで、一般式(15)で表される化合物を製造することもできる。
[工程C]
本工程では、容易に入手可能な3-クロロプロパンスルホニルクロリド(16)を一般式(5)又は(15)で表されるいずれかのアミンと、塩基存在下反応させることで、一般式(17)で表される化合物を製造できる。
用いる反応溶媒としては、反応に影響を及ぼさないものであれば特に制限はないが、アセトン、THF、ジエチルエーテル、ジイソプロピルエーテル、ジオキサン、ジクロロメタン、クロロホルム、四塩化炭素、DMF、DMA、アセトニトリル等が例示され、好ましくはジクロロメタンである。
用いる塩基としては、炭酸水素ナトリウム、炭酸ナトリウム、炭酸カリウム等の無機塩基やトリメチルアミン、トリエチルアミン、トリプロピルアミン、ジイソプロピルエチルアミン、N-メチルモルホリン、ピリジン、ルチジン、コリジン等の有機アミン類が例示され、好ましくはトリエチルアミンである。塩基及びアミンの当量数はそれぞれ0.5~10当量であり、好ましくは0.7~5.0当量である。反応温度は-20℃~100℃であり、好ましくは0~50℃である。反応時間は0.1~24時間であり、好ましくは0.2~6.0時間である。
本工程では、一般式(17)で表されるクロロ化合物を、通常公知の方法によりアセトキシ化試薬と反応してアセトキシ化した後、通常公知の脱アセチル化方法により、一般式(18)で表されるアルコール化合物を製造できる。
本工程では、一般式(18)で表される化合物を、通常公知の方法によりメトキシメチル化(MOM化)し、続いてルイス酸処理した後、ヨウ素存在下、文献(Nucleosides & Nucleotides,4,565-585(1985))記載の方法で得られる2,4-ビス(トリメチルシリルオキシ)ピリミジンと反応させることで、一般式(19)で表される化合物を製造できる。
ルイス酸処理に用いる溶媒としては、反応に影響を及ぼさないものであれば特に制限はないが、ジクロロメタン、クロロホルム、四塩化炭素、DCE、トルエン、キシレン等が例示され、好ましくはジクロロメタンである。ルイス酸としては三塩化ホウ素(以下、BCl3)、三フッ化ホウ素、三臭化ホウ素等が例示され、好ましくはBCl3である。その当量数は0.01~10当量であり、好ましくは0.2~0.5当量である。反応温度は-20~100℃であり、好ましくは0~50℃である。反応時間は0.1~24時間であり、好ましくは0.5~5.0時間である。
2,4-ビス(トリメチルシリルオキシ)ピリミジンと反応させる際の溶媒としては、反応に影響を及ぼさないものであれば特に制限はないが、ジクロロメタン、クロロホルム、四塩化炭素、DCE、トルエン、キシレン等が例示され、好ましくはDCE又はトルエンである。2,4-ビス(トリメチルシリルオキシ)ピリミジンの当量数は0.8~10当量であり、好ましくは0.9~5.0当量である。ヨウ素の当量数は0.001~1.0当量であり、好ましくは0.05~0.5当量である。反応温度は20~150℃であり、好ましくは50~100℃である。反応時間は0.1~120時間であり、好ましくは0.5~100時間である。
本工程では、一般式(17)で表される化合物のスルホンアミド基上窒素原子を、通常公知の方法により、例えばメトキシメチル基、tert-ブトキシカルボニル基等の保護基により保護した後、[C-2]と同様の方法により、一般式(20)で表される化合物を製造できる。
本工程では、文献(J.Med.Chem.,50,6032-6038(2007))記載の方法に準じて得られる3-ベンゾイルピリミジン-2,4(1H,3H)-ジオン(21)と、一般式(20)で表されるアルコール化合物を、[工程 A-1](b)と同様に光延反応することにより、一般式(22)で表される化合物を製造できる。
本工程では、一般式(22)で表される化合物を、通常公知の脱保護方法により、脱ベンゾイル化、脱Pg化することにより、一般式(23)で表される化合物を製造できる。
本発明の抗腫瘍効果増強剤により、その作用が増強される抗腫瘍剤Aは特に限定されないが、例えばシクロフォスファミド、ニムスチン等のアルキル化剤、シスプラチン、カルボプラチン、オキサリプラチン等のプラチナ製剤;代謝拮抗剤;パクリタキセル、ドセタキセル、イリノテカン等の植物アルカロイド系抗腫瘍剤等が挙げられる。本発明の抗腫瘍効果増強剤により、その作用が増強される抗腫瘍剤Aとしては代謝拮抗剤が好ましい。
本発明の抗腫瘍効果増強剤により、その作用が増強される抗腫瘍剤Aとしては、チミジル酸合成酵素阻害剤がより好ましく、5-フルオロウラシル(5-FU)、テガフール・ギメラシル・オテラシルカリウム(TS-1)、テガフール・ウラシル(UFT)、カペシタビン、5-フルオロ-2’-デオキシウリジン(FdUrd)、ペメトレキセドが特に好ましい。
抗腫瘍剤Aと本発明ウラシル化合物はキットとすることもできる。該キットでは、これを構成する各組成物は公知の各種の製剤形態とすることができ、一般に各々の組成物は、その製剤形態に応じて、通常用いられる各種の容器に収納され、ヒトを含むホ乳動物における癌治療用キットとすることができる。
結合剤としては、水、エタノール、1-プロパノール、2-プロパノール、単シロップ、ブドウ糖液、α-デンプン液、ゼラチン液、D-マンニトール、カルボキシメチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルスターチ、メチルセルロース、エチルセルロース、シェラック、リン酸カルシウム、ポリビニルピロリドン等が挙げられる。
崩壊剤としては、乾燥デンプン、アルギン酸ナトリウム、カンテン末、炭酸水素ナトリウム、炭酸カルシウム、ラウリル硫酸ナトリウム、ステアリン酸モノグリセリド、乳糖等が挙げられる。
滑沢剤としては、精製タルク、ステアリン酸塩ナトリウム、ステアリン酸マグネシウム、ホウ砂、ポリエチレングリコール等が挙げられる。
着色剤としては、酸化チタン、酸化鉄等が挙げられる。
矯味・矯臭剤としては白糖、橙皮、クエン酸、酒石酸等が挙げられる。
また、前記投与形態を有する薬剤の1日あたりの投与量は、患者の症状、体重、年齢、性別等によって異なり一概には決定できないが、通常成人(体重50kg)1日あたり約0.05~5000mg程度であり、0.1~1000mgが好ましく、これを1日1回又は2~3回程度に分けて投与するのが好ましい。
(3-(シクロプロピルメトキシ)フェニル)メタンアミンの合成
(R)-1-(3-(シクロペンチルオキシ)フェニル)エタンアミン塩酸塩の合成
(R)-1-(3-((R)-テトラヒドロフラン-3-イルオキシ)フェニル)エタンアミン塩酸塩の合成
(3-(シクロプロピルメトキシ)-4-フルオロフェニル)メタンアミンの合成
(R)-1-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)エタンアミン塩酸塩の合成
1-(3-(シクロプロピルメトキシ)フェニル)エタンアミンの合成
以下の表に示すアミンは参考例1~3、5のいずれかの方法に準じて合成した。
N-(3-(シクロプロピルメトキシ)ベンジル)-3-(メトキシメトキシ)プロパン-1-スルホンアミドの合成
以下の表に示す化合物は参考例20の方法に準じて合成した。
(R)-N-(1-(3-(シクロプロピルメトキシ)フェニル)プロピル)-3-ヒドロキシ-N-(メトキシメチル)プロパン-1-スルホンアミドの合成
3-(シクロプロピルメトキシ)-N-(1-(3-(メトキシメトキシ)プロピル)シクロプロピル)ベンゼンスルホンアミドの合成
N-(3-(シクロプロピルメトキシ)ベンジル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミドの合成
以下の化合物は各々参考例21~37で得られた化合物から、実施例1の方法に準じて合成した。結果を以下の表に示す。
(R)-N-(1-(3-(シクロペンチルオキシ)フェニル)エチル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
実施例3
3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)-N-((R)-1-(3-((R)-テトラヒドロフラン-3-イルオキシ)フェニル)エチル)プロパン-1-スルホンアミド
実施例4
N-(3-(シクロプロピルメトキシ)-4-フルオロベンジル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
実施例5
(R)-N-(1-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)エチル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
N-(1-(3-(シクロプロピルメトキシ)フェニル)エチル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
実施例7
N-(3-(シクロペンチルオキシ)ベンジル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
実施例8
(R)-N-(1-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)プロピル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
実施例9
(R)-N-(1-(3-(シクロペンチルオキシ)-4-フルオロフェニル)エチル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
(R)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)-N-(1-(3-(2,2,2-トリフルオロエトキシ)フェニル)エチル)プロパン-1-スルホンアミド
実施例11
(R)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)-N-(1-(3-イソブトキシフェニル)エチル)プロパン-1-スルホンアミド
実施例12
3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)-N-((R)-1-(3-((S)-2-メチルブトキシ)フェニル)エチル)プロパン-1-スルホンアミド
(R)-N-(1-(3-(2,2-ジフルオロエトキシ)フェニル)エチル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
実施例14
(R)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)-N-(1-(3-(テトラヒドロ-2H-ピラン-4-イルオキシ)フェニル)エチル)プロパン-1-スルホンアミド
(R)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)-N-(1-(4-フルオロ-3-(2,2,2-トリフルオロエトキシ)フェニル)エチル)プロパン-1-スルホンアミド
実施例16
(R)-N-(1-(3-(2,2-ジフルオロエトキシ)-4-フルオロフェニル)エチル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
実施例17
(R)-N-(1-(3-(アリルオキシ)フェニル)エチル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
実施例18
(R)-N-(1-(3-(シクロプロピルメトキシ)フェニル)エチル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
(R)-N-(1-(3-(シクロプロピルメトキシ)フェニル)プロピル)-3-(2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)プロパン-1-スルホンアミドの合成
3-(シクロプロピルメトキシ)-N-(1-(3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロピル)シクロプロピル)ベンゼンスルホンアミドの合成
本発明化合物のヒトdUTPaseに対する阻害活性を、下記方法により[5-3H]デオキシウリジントリホスフェート(以下、[5-3H]dUTP)からの[5-3H]デオキシウリジンモノホスフェート(以下、[5-3H]dUMP)の生成を測定することにより求めた。
すなわち、1μMdUTP(588Bq/mLの[5-3H]dUTPを含む)0.02mL、0.2Mトリス緩衝液(pH7.4)0.05mL、16mM塩化マグネシウム0.05mL、20mM2-メルカプトエタノール0.02mL、1%ウシ胎児血清由来アルブミン水溶液0.02mL、種々濃度の被検化合物溶液又は対照として純水0.02mL及び大腸菌を用いて発現させ精製したヒトdUTPase溶液0.02mLの計0.2mLを37℃で15分間反応させた。反応後直ちに100℃で1分間加熱して反応を停止させ、15000rpmで2分間遠心分離した。遠心分離後、得られた上清の一部(150μL)をAtlantisdC18カラム(Waters社製、4.6×250mm)を用いて高速液体クロマトグラフ(島津製作所製、Prominence)にて分析した。流速0.8mL/minで移動相A(10mMリン酸二水素カリウム(pH6.7)、10mMテトラブチルアンモニウム、0.25%メタノール)と移動相B(50mMリン酸二水素カリウム(pH6.7)、5.6mMテトラブチルアンモニウム、30%メタノール)の4:6混液から移動相Bへの30分間濃度勾配により溶離した。溶離液に1:2の比率でシンチレーター(パーキンエルマー社製、Ultima-FloAP)を混和し、Radiomatic Flow Scintillation Analyzer(パーキンエルマー社製、525TR)にて生成した[5-3H]dUMP(RT10.2min)の放射活性を測定した。
被検化合物の阻害活性は次式により求め、ヒトdUTPaseによって生成する[5-3H]dUMPの量を50%阻害する被検液の濃度をIC50(μM)として表10に示した。
ヒト乳癌株MX-1を、生後5~6週齢の雄性BALB/cA Jcl-nuマウスの右側胸部に移植した。腫瘍移植後に腫瘍の長径(mm)及び短径(mm)を測定し、腫瘍体積(tumor volume:TV)を算出後、MiSTATの群分けプログラムを用いて,各群の平均TVが均等になるように各群にマウスを割り付け、この群分け(n=5)を実施した日をday 0とした。
テガフール・ギメラシル・オテラシルカリウム(TS-1、大鵬薬品工業(株)製)単独群の被検液は、TS-1の投与量をテガフール(FT)量として8.3mg/kg/dayとし、終濃度がそれぞれ0.5%ヒドロキシプロピルメチルセルロース、2.5%ジメチルアセトアミド、2.5%Tween80、及び10%クレモフォールとなるよう調製した。
TS-1と本発明化合物の併用群の被検液は、本発明化合物6、4、7、8については被検薬200mg/kg/day+TS-1(8.3mg/kg/day)、本発明化合物19、9、2及び1については被検薬100mg/kg/day+TS-1(8.3mg/kg/day)、比較化合物1については被検薬200mg/kg/day+TS-1(8.3mg/kg/day)となるよう、TS-1単独群の被検液と同様に調製した。
投与はday 1から14日間、被検動物に対し10mL/kgの被検液投与量をそれぞれ連日経口投与した。
day 15におけるTVを測定し,day 0に対する相対腫瘍体積(relative tumor volume:RTV)を算出し,下記式によりT/C(%)を算出して抗腫瘍効果を評価した。結果を図1に示す。図中、*印はTS-1単独群に対して統計学的有意差が認められたことを示す。
T/C(%)=(被検液投与群の平均RTV値)/(対照群の平均RTV値)×100
ヒト乳癌株MX-1を、生後5~6週齢の雄性BALB/cA Jcl-nuマウスの右側胸部に移植し、試験例2と同様に用いた。
TS-1単独群の被検液はTS-1の投与量をFT量として10mg/kg/dayとなるよう調製した。TS-1と本発明化合物の併用群の被検液は、本発明化合物(5、14、3、15、16及び17)300mg/kg/day+TS-1(10mg/kg/day)となるよう、それぞれ調製し、試験例2と同様に評価した。結果を図2に示す。図中、*印はTS-1単独群に対して統計学的有意差が認められたことを示す。
ヒト卵巣癌株OVCAR-3を、生後5~6週齢の雄性BALB/cA Jcl-nuマウスの右側胸部に移植し、試験例2と同様に用いた。
5-FU単独群の被検液は、5-FUの投与量が15mg/kg/dayとなるようpH9.0に調整した7%メイロンに溶解して調製し、本発明化合物の被検液は、本発明化合物300mg/kg/dayとなるよう0.5%ヒドロキシプロピルメチルセルロースに懸濁させ調製した。
5-FU単独群は、day 1から14日間、alzet osmotic mini-pump model 2002(flow late 0.5μl/h)を用いて皮下から持続投与した。5-FUと本発明化合物との併用群は、day 1から14日間、alzet osmotic mini-pump model 2002(flow late 0.5μl/h)を用いて皮下から5-FUを持続投与すると共に、本発明化合物の被検液を、被検動物に対し10mL/kg連日経口投与し、試験例2と同様に評価した。結果を図3に示す。図中、*印は5-FU単独群に対して統計学的有意差が認められたことを示す。
ヒト乳癌株MX-1を、生後5~6週齢の雄性BALB/cA Jcl-nuマウスの右側胸部に移植し、試験例2と同様に用いた。
カペシタビン単独群の被検液はカペシタビンの投与量が270mg/kg/dayとなるよう、0.5%ヒドロキシプロピルメチルセルロースに懸濁させ調製した。カペシタビンと本発明化合物の混合被検液は、本発明化合物300mg/kg/day+カペシタビン(270mg/kg/day)となるよう、0.5%ヒドロキシプロピルメチルセルロースに懸濁させ調製し、試験例2と同様に評価した。結果を図4に示す。図中、*印はカペシタビン単独群に対して統計学的有意差が認められたことを示す。
ヒト乳癌株MX-1を、生後5~6週齢の雄性BALB/cA Jcl-nuマウスの右側胸部に移植し、試験例2と同様に用いた。
5-フルオロ-2’-デオキシウリジン(FdUrd)単独群の被検液は、FdUrdの投与量が250mg/kg/dayとなるように生理食塩液を用いて溶解し調製し、本発明化合物の被検液は、本発明化合物300mg/kg/dayとなるよう0.5%ヒドロキシプロピルメチルセルロースに懸濁させ調製した。
FdUrd単独群は、day 1から3日間、尾静脈から投与した。FdUrdと本発明化合物との併用群は、day 1から3日間、FdUrdを尾静脈から投与すると共に、本発明化合物の被検液を、被検動物に対し10mL/kgをday 1から3日間、連日経口投与し、試験例2と同様にday 15に評価した。結果を図4に示す。図中、*印はFdUrd単独群に対して統計学的有意差が認められたことを示す。
ヒト乳癌株MX-1を、生後5~6週齢の雄性BALB/cA Jcl-nuマウスの右側胸部に移植し、試験例2と同様に用いた。
ペメトレキセド単独群の被検液は、ペメトレキセドの投与量が25mg/kg/dayとなるように生理食塩液を用いて溶解し調製し、本発明化合物の被検液は、本発明化合物300mg/kg/dayとなるよう0.5%ヒドロキシプロピルメチルセルロースに懸濁させ調製した。
ペメトレキセド単独群は、day 1とday 8に尾静脈から投与した。ペメトレキセドと本発明化合物との併用群は、day 1とday 8にペメトレキセドを尾静脈から投与すると共に、本発明化合物の被検液を、被検動物に対し10mL/kgをday 1から14日間、連日経口投与し、試験例2と同様に評価した。結果を図4に示す。図中、*印はペメトレキセド単独群に対して統計学的有意差が認められたことを示す。
ヒト乳癌株MX-1を、生後5~6週齢の雄性F344N Jcl-rnuラット右側胸部に移植し、試験例2と同様に用いた。
テガフール・ウラシル(UFT、大鵬薬品工業(株)製)単独群の被検液は、UFTの投与量をFT量として30mg/kg/dayとなるように0.5%ヒドロキシプロピルメチルセルロースに懸濁させ調製し、UFTと本発明化合物の混合被検液は、本発明化合物300mg/kg/day+UFT(30mg/kg/day)となるよう、0.5%ヒドロキシプロピルメチルセルロースに懸濁させ調製した。
UFT単独群は、day 1から21日間連日経口投与した。UFTと本発明化合物との併用群もday 1から21日間連日経口投与し、試験例2と同様にday22に評価した。結果を図4に示す。図中、*印はUFT単独群に対して統計学的有意差が認められたことを示す。
本発明化合物を併用したときの安全性を評価する目的で,本発明化合物を高用量併用したときの毒性と抗腫瘍効果を評価した。
ヒト胃癌株SC-6、ヒト大腸癌株LS174Tおよびヒト膵臓癌株CFPAC-1を、生後5~6週齢の雄性BALB/cA Jcl-nuマウスの右側胸部に移植した。腫瘍移植後に腫瘍の長径(mm)及び短径(mm)を測定し、腫瘍体積(tumor volume:TV)を算出後、MiSTATの群分けプログラムを用いて、各群の平均TVが均等になるように各群にマウスを割り付け、この群分け(n=5)を実施した日をday 0とした。
TS-1単独群の被検液はTS-1の投与量をFT量として10mg/kg/dayとし、0.5%ヒドロキシプロピルメチルセルロースを用いて調製した。
TS-1と本発明化合物の併用群の被検液は、発明化合物(600mg/kg/day)+TS-1(10mg/kg/day)となるよう、TS-1単独群の被検液と同様に調製した。
投与はday 1から14日間、被検動物に対し10mL/kgの被検液投与量をそれぞれ連日経口投与した。
毒性の指標として経時的な体重変化を測定した。day 0に対するday 15の平均体重変化率[body weight change,BWC(%)]を下記式により算出した。
T/C(%)=(被検液投与群の平均RTV値)/(対照群の平均RTV値)×100
本発明化合物をTS-1と併用したときに、抗腫瘍効果増強作用が得られる併用比をマウスで評価した。
ヒト乳癌株MX-1を、生後5~6週齢の雄性BALB/cA Jcl-nuマウスの右側胸部に移植した。腫瘍移植後に腫瘍の長径(mm)及び短径(mm)を測定し、腫瘍体積(tumor volume:TV)を算出後、MiSTATの群分けプログラムを用いて、各群の平均TVが均等になるように各群にマウスを割り付け、この群分け(n=7)を実施した日をday 0とした。
TS-1単独群の被検液はTS-1の投与量をFT量として8.3mg/kg/dayとし、化合物2単独群の被検液は1200mg/kg/dayとし、0.5%ヒドロキシプロピルメチルセルロースを用いて調製した。
TS-1と本発明化合物の併用群の被検液は、発明化合物(1200、600、300、150mg/kg/day)+TS-1(8.3mg/kg/day)となるよう、TS-1単独群の被検液と同様に調製した。
投与はday 1から14日間、被検動物に対し10mL/kgの被検液投与量をそれぞれ連日経口投与し、試験例2と同様に評価した。結果を図8に示す。図中、*印はTS-1単独群に対して統計学的有意差が認められたことを示す。
本発明化合物をTS-1と併用したときに、抗腫瘍効果増強作用が得られる併用比をラットで評価した。
ヒト乳癌株MX-1を、生後5~6週齢の雄性F344N Jcl-rnuラット右側胸部に移植した。腫瘍移植後に腫瘍の長径(mm)及び短径(mm)を測定し、腫瘍体積(tumor volume:TV)を算出後、MiSTATの群分けプログラムを用いて、各群の平均TVが均等になるように各群にマウスを割り付け、この群分け(n=5、あるいは6)を実施した日をday 0とした。
TS-1単独群の被検液はTS-1の投与量をFT量として18mg/kg/dayとし、0.5%ヒドロキシプロピルメチルセルロースを用いて調製した。
TS-1と本発明化合物の併用群の被検液は、本発明化合物(100、50、25、12.5、6.25mg/kg/day)+TS-1(18mg/kg/day)となるよう、TS-1単独群の被検液と同様に調製した。
投与はday 1から28日間、被検動物に対し10mL/kgの被検液投与量をそれぞれ連日経口投与、day 29におけるTVを測定し,試験例2と同様に評価した。結果を図9に示す。
図中、*印はTS-1単独群に対して統計学的有意差が認められたことを示す。
本発明化合物をカペシタビンと併用したときに、抗腫瘍効果増強作用が得られる併用比をマウスで評価した。
ヒト乳癌株MX-1を、生後5~6週齢の雄性BALB/cA Jcl-nuマウスの右側胸部に移植した。腫瘍移植後に腫瘍の長径(mm)及び短径(mm)を測定し、腫瘍体積(tumor volume:TV)を算出後、MiSTATの群分けプログラムを用いて、各群の平均TVが均等になるように各群にマウスを割り付け、この群分け(n=5)を実施した日をday 0とした。
カペシタビン単独群の被検液は160、359、809mg/kg/dayとし、0.5%ヒドロキシプロピルメチルセルロースを用いて調製した。
カペシタビンと本発明化合物の併用群の被検液は、発明化合物(75、300、600,1200,1600mg/kg/day)+カペシタビン(160、359、809mg/kg/day)を図の組み合わせとなるよう、カペシタビン単独群の被検液と同様に調製した。
投与はday 1から14日間、被検動物に対し10mL/kgの被検液投与量をそれぞれ連日経口投与し、試験例2と同様に評価した。結果を図10に示す。図中、*印は対応するカペシタビン単独群に対して統計学的有意差が認められたことを示す。
Claims (21)
- 一般式(I)中、Xはエチレン基、又は-O-C1-4アルキレン基を示し、
R1は水素原子又はC1-3アルキル基を示し、R2は水素原子又はフッ素原子を示す、請求項1に記載のウラシル化合物又はその薬学的に許容される塩を有効成分とする抗腫瘍効果増強剤。 - 一般式(I)中、Xはエチレン基、又は-O-CH2CH2CH2-基を示し、
R1は水素原子、メチル基又はエチル基を示し、R2は水素原子又はフッ素原子を示し、
R3はイソブチル基、2-メチルブチル基、アリル基、シクロペンチル基、シクロプロピルメチル基、2,2-ジフルオロエチル基、2,2,2-トリフルオロエチル基、テトラヒドロフリル基又はテトラヒドロピリル基を示す、請求項1又は2に記載のウラシル化合物又はその薬学的に許容される塩を有効成分とする抗腫瘍効果増強剤。 - 下記の群から選択される、請求項1に記載のウラシル化合物又はその薬学的に許容される塩を有効成分とする抗腫瘍効果増強剤:
・N-(3-(シクロプロピルメトキシ)ベンジル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・(R)-N-(1-(3-(シクロペンチルオキシ)フェニル)エチル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)-N-((R)-1-(3-((R)-テトラヒドロフラン-3-イルオキシ)フェニル)エチル)プロパン-1-スルホンアミド
・N-(3-(シクロプロピルメトキシ)-4-フルオロベンジル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・(R)-N-(1-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)エチル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・N-(1-(3-(シクロプロピルメトキシ)フェニル)エチル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・N-(3-(シクロペンチルオキシ)ベンジル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・(R)-N-(1-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)プロピル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・(R)-N-(1-(3-(シクロペンチルオキシ)-4-フルオロフェニル)エチル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・(R)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)-N-(1-(3-(2,2,2-トリフルオロエトキシ)フェニル)エチル)プロパン-1-スルホンアミド
・(R)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)-N-(1-(3-イソブトキシフェニル)エチル)プロパン-1-スルホンアミド
・3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)-N-((R)-1-(3-((S)-2-メチルブトキシ)フェニル)エチル)プロパン-1-スルホンアミド
・(R)-N-(1-(3-(2,2-ジフルオロエトキシ)フェニル)エチル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・(R)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)-N-(1-(3-(テトラヒドロ-2H-ピラン-4-イルオキシ)フェニル)エチル)プロパン-1-スルホンアミド
・(R)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)-N-(1-(4-フルオロ-3-(2,2,2-トリフルオロエトキシ)フェニル)エチル)プロパン-1-スルホンアミド
・(R)-N-(1-(3-(2,2-ジフルオロエトキシ)-4-フルオロフェニル)エチル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・(R)-N-(1-(3-(アリルオキシ)フェニル)エチル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・(R)-N-(1-(3-(シクロプロピルメトキシ)フェニル)エチル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・(R)-N-(1-(3-(シクロプロピルメトキシ)フェニル)プロピル)-3-(2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)プロパン-1-スルホンアミド - 請求項1~4のいずれかに記載のウラシル化合物又はその薬学的に許容される塩と、抗腫瘍剤を組み合せてなる抗腫瘍薬。
- 抗腫瘍剤が、代謝拮抗剤である請求項5記載の抗腫瘍薬。
- 抗腫瘍剤が、5-フルオロウラシル(5-FU)、テガフール・ギメラシル・オテラシルカリウム(TS-1)、テガフール・ウラシル(UFT)、カペシタビン、5-フルオロ-2’-デオキシウリジン(FdUrd)、ペメトレキセドのいずれかである請求項5記載の抗腫瘍薬。
- 一般式(I)中、Xはエチレン基、又は-O-C1-4アルキレン基を示し、
R1は水素原子又はC1-3アルキル基を示し、R2は水素原子又はフッ素原子を示す、請求項8に記載のウラシル化合物又はその薬学的に許容される塩。 - 一般式(I)中、Xはエチレン基、又は-O-CH2CH2CH2-基を示し、
R1は水素原子、メチル基又はエチル基を示し、R2は水素原子又はフッ素原子を示し、
R3はイソブチル基、2-メチルブチル基、アリル基、シクロペンチル基、シクロプロピルメチル基、2,2-ジフルオロエチル基、2,2,2-トリフルオロエチル基、テトラヒドロフリル基又はテトラヒドロピリル基を示す、請求項8又は9に記載のウラシル化合物又はその薬学的に許容される塩。 - 下記の群から選択される、請求項8に記載のウラシル化合物又はその薬学的に許容される塩。
・N-(3-(シクロプロピルメトキシ)ベンジル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・(R)-N-(1-(3-(シクロペンチルオキシ)フェニル)エチル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)-N-((R)-1-(3-((R)-テトラヒドロフラン-3-イルオキシ)フェニル)エチル)プロパン-1-スルホンアミド
・N-(3-(シクロプロピルメトキシ)-4-フルオロベンジル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・(R)-N-(1-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)エチル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・N-(1-(3-(シクロプロピルメトキシ)フェニル)エチル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・N-(3-(シクロペンチルオキシ)ベンジル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・(R)-N-(1-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)プロピル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・(R)-N-(1-(3-(シクロペンチルオキシ)-4-フルオロフェニル)エチル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・(R)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)-N-(1-(3-(2,2,2-トリフルオロエトキシ)フェニル)エチル)プロパン-1-スルホンアミド
・(R)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)-N-(1-(3-イソブトキシフェニル)エチル)プロパン-1-スルホンアミド
・3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)-N-((R)-1-(3-((S)-2-メチルブトキシ)フェニル)エチル)プロパン-1-スルホンアミド
・(R)-N-(1-(3-(2,2-ジフルオロエトキシ)フェニル)エチル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・(R)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)-N-(1-(3-(テトラヒドロ-2H-ピラン-4-イルオキシ)フェニル)エチル)プロパン-1-スルホンアミド
・(R)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)-N-(1-(4-フルオロ-3-(2,2,2-トリフルオロエトキシ)フェニル)エチル)プロパン-1-スルホンアミド
・(R)-N-(1-(3-(2,2-ジフルオロエトキシ)-4-フルオロフェニル)エチル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・(R)-N-(1-(3-(アリルオキシ)フェニル)エチル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・(R)-N-(1-(3-(シクロプロピルメトキシ)フェニル)エチル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・(R)-N-(1-(3-(シクロプロピルメトキシ)フェニル)プロピル)-3-(2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)プロパン-1-スルホンアミド - 腫瘍を治療するための、請求項8~11のいずれかに記載のウラシル化合物又はその薬学的に許容される塩と抗腫瘍剤との組み合わせ。
- 抗腫瘍剤が、代謝拮抗剤である請求項12記載の組み合わせ。
- 抗腫瘍剤が、5-フルオロウラシル(5-FU)、テガフール・ギメラシル・オテラシルカリウム(TS-1)、テガフール・ウラシル(UFT)、カペシタビン、5-フルオロ-2’-デオキシウリジン(FdUrd)、ペメトレキセドのいずれかである請求項12記載の組み合わせ。
- 一般式(I)中、Xはエチレン基、又は-O-C1-4アルキレン基を示し、
R1は水素原子又はC1-3アルキル基を示し、R2は水素原子又はフッ素原子を示す、請求項15に記載の方法。 - 一般式(I)中、Xはエチレン基、又は-O-CH2CH2CH2-基を示し、
R1は水素原子、メチル基又はエチル基を示し、R2は水素原子又はフッ素原子を示し、
R3はイソブチル基、2-メチルブチル基、アリル基、シクロペンチル基、シクロプロピルメチル基、2,2-ジフルオロエチル基、2,2,2-トリフルオロエチル基、テトラヒドロフリル基又はテトラヒドロピリル基を示す、請求項15又は16に記載の方法。 - 式(I)の化合物が、下記の群から選択されるものである請求項15記載の方法。
・N-(3-(シクロプロピルメトキシ)ベンジル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・(R)-N-(1-(3-(シクロペンチルオキシ)フェニル)エチル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)-N-((R)-1-(3-((R)-テトラヒドロフラン-3-イルオキシ)フェニル)エチル)プロパン-1-スルホンアミド
・N-(3-(シクロプロピルメトキシ)-4-フルオロベンジル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・(R)-N-(1-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)エチル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・N-(1-(3-(シクロプロピルメトキシ)フェニル)エチル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・N-(3-(シクロペンチルオキシ)ベンジル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・(R)-N-(1-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)プロピル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・(R)-N-(1-(3-(シクロペンチルオキシ)-4-フルオロフェニル)エチル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・(R)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)-N-(1-(3-(2,2,2-トリフルオロエトキシ)フェニル)エチル)プロパン-1-スルホンアミド
・(R)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)-N-(1-(3-イソブトキシフェニル)エチル)プロパン-1-スルホンアミド
・3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)-N-((R)-1-(3-((S)-2-メチルブトキシ)フェニル)エチル)プロパン-1-スルホンアミド
・(R)-N-(1-(3-(2,2-ジフルオロエトキシ)フェニル)エチル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・(R)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)-N-(1-(3-(テトラヒドロ-2H-ピラン-4-イルオキシ)フェニル)エチル)プロパン-1-スルホンアミド
・(R)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)-N-(1-(4-フルオロ-3-(2,2,2-トリフルオロエトキシ)フェニル)エチル)プロパン-1-スルホンアミド
・(R)-N-(1-(3-(2,2-ジフルオロエトキシ)-4-フルオロフェニル)エチル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・(R)-N-(1-(3-(アリルオキシ)フェニル)エチル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・(R)-N-(1-(3-(シクロプロピルメトキシ)フェニル)エチル)-3-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)プロパン-1-スルホンアミド
・(R)-N-(1-(3-(シクロプロピルメトキシ)フェニル)プロピル)-3-(2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)プロパン-1-スルホンアミド - 請求項15~18のいずれかに記載のウラシル化合物又はその薬学的に許容される塩と、抗腫瘍剤を組み合せて投与することを特徴とする腫瘍の治療方法。
- 抗腫瘍剤が、代謝拮抗剤である請求項19記載の方法。
- 抗腫瘍剤が、5-フルオロウラシル(5-FU)、テガフール・ギメラシル・オテラシルカリウム(TS-1)、テガフール・ウラシル(UFT)、カペシタビン、5-フルオロ-2’-デオキシウリジン(FdUrd)、ペメトレキセドのいずれかである請求項19記載の方法。
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
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EP10833385.7A EP2508185B1 (en) | 2009-11-30 | 2010-11-29 | Anti-tumor effect potentiator |
EP20152282.8A EP3673908B1 (en) | 2009-11-30 | 2010-11-29 | Anti-tumor effect potentiator |
CN201080051775.1A CN102612369B (zh) | 2009-11-30 | 2010-11-29 | 抗肿瘤效果增强剂 |
ES10833385T ES2788549T3 (es) | 2009-11-30 | 2010-11-29 | Potenciador de efecto antitumoral |
JP2011543351A JP5336606B2 (ja) | 2009-11-30 | 2010-11-29 | 抗腫瘍効果増強剤 |
AU2010323454A AU2010323454B2 (en) | 2009-11-30 | 2010-11-29 | Anti-tumor effect potentiator |
CA2782280A CA2782280C (en) | 2009-11-30 | 2010-11-29 | Anti-tumor effect potentiator |
MX2012006183A MX2012006183A (es) | 2009-11-30 | 2010-11-29 | Potenciador del efecto antitumoral. |
BR112012013049A BR112012013049A2 (pt) | 2009-11-30 | 2010-11-29 | potencializador do efeito antitumor. |
KR1020127013820A KR101701549B1 (ko) | 2009-11-30 | 2010-11-29 | 항종양 효과 증강제 |
RU2012127309/04A RU2548913C2 (ru) | 2009-11-30 | 2010-11-29 | Усилитель действия противоопухолевого средства |
US13/509,102 US8883759B2 (en) | 2009-11-30 | 2010-11-29 | Anti-tumor effect potentiator |
HK12111795.0A HK1171185A1 (en) | 2009-11-30 | 2012-11-20 | Anti-tumor effect potentiator |
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PCT/JP2010/071280 WO2011065541A1 (ja) | 2009-11-30 | 2010-11-29 | 抗腫瘍効果増強剤 |
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US (1) | US8883759B2 (ja) |
EP (2) | EP2508185B1 (ja) |
JP (1) | JP5336606B2 (ja) |
KR (1) | KR101701549B1 (ja) |
CN (2) | CN103948599B (ja) |
AU (1) | AU2010323454B2 (ja) |
BR (1) | BR112012013049A2 (ja) |
CA (1) | CA2782280C (ja) |
ES (2) | ES2906227T3 (ja) |
HK (2) | HK1171185A1 (ja) |
MX (1) | MX2012006183A (ja) |
MY (1) | MY161094A (ja) |
RU (1) | RU2548913C2 (ja) |
TW (1) | TWI466870B (ja) |
WO (1) | WO2011065541A1 (ja) |
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CN106692173A (zh) * | 2015-11-18 | 2017-05-24 | 北京诺普德医药科技有限公司 | 一种抗肿瘤复方组合物及其应用 |
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RU2706339C1 (ru) * | 2019-07-24 | 2019-11-18 | ФЕДЕРАЛЬНОЕ ГОСУДАРСТВЕННОЕ БЮДЖЕТНОЕ УЧРЕЖДЕНИЕ "РОССИЙСКИЙ НАУЧНЫЙ ЦЕНТР РАДИОЛОГИИ И ХИРУРГИЧЕСКИХ ТЕХНОЛОГИЙ ИМЕНИ АКАДЕМИКА А.М. ГРАНОВА" МИНИСТЕРСТВА ЗДРАВООХРАНЕНИЯ РОССИЙСКОЙ ФЕДЕРАЦИИ / ФГБУ "РНЦРХТ им. ак. А.М. Гранова" Минздрава России | Способ лечения операбельной аденокарциномы головки поджелудочной железы |
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US10577321B2 (en) | 2015-07-08 | 2020-03-03 | University Of Southern California | Deoxyuridine triphosphatase inhibitors |
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WO2021167006A1 (ja) * | 2020-02-18 | 2021-08-26 | 大鵬薬品工業株式会社 | ウラシル誘導体化合物を含有する抗腫瘍効果増強剤 |
US11168059B2 (en) | 2016-11-23 | 2021-11-09 | Cv6 Therapeutics (Ni) Limited | Amino sulfonyl compounds |
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JP7502832B2 (ja) | 2018-05-23 | 2024-06-19 | 国立大学法人高知大学 | 膵癌細胞の浸潤転移抑制剤 |
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- 2010-11-29 KR KR1020127013820A patent/KR101701549B1/ko active IP Right Grant
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AU2010323454A2 (en) | 2012-06-14 |
RU2012127309A (ru) | 2014-01-10 |
ES2906227T3 (es) | 2022-04-13 |
MY161094A (en) | 2017-04-14 |
CN103948599A (zh) | 2014-07-30 |
EP3673908A1 (en) | 2020-07-01 |
RU2548913C2 (ru) | 2015-04-20 |
EP2508185A4 (en) | 2016-05-25 |
HK1171185A1 (en) | 2013-03-22 |
BR112012013049A2 (pt) | 2016-11-22 |
EP2508185A1 (en) | 2012-10-10 |
HK1195733A1 (zh) | 2014-11-21 |
TW201124387A (en) | 2011-07-16 |
AU2010323454A1 (en) | 2012-06-21 |
EP2508185B1 (en) | 2020-03-04 |
KR20120116925A (ko) | 2012-10-23 |
US8883759B2 (en) | 2014-11-11 |
CA2782280A1 (en) | 2011-06-03 |
CA2782280C (en) | 2019-02-26 |
KR101701549B1 (ko) | 2017-02-01 |
MX2012006183A (es) | 2012-06-19 |
CN103948599B (zh) | 2016-03-09 |
CN102612369A (zh) | 2012-07-25 |
US20120225838A1 (en) | 2012-09-06 |
CN102612369B (zh) | 2014-06-18 |
ES2788549T3 (es) | 2020-10-21 |
EP3673908B1 (en) | 2022-01-12 |
JP5336606B2 (ja) | 2013-11-06 |
TWI466870B (zh) | 2015-01-01 |
AU2010323454B2 (en) | 2014-05-08 |
JPWO2011065541A1 (ja) | 2013-04-18 |
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