WO1999012884A1 - Derives d'acide benzoique a substitution en 4 et cancerostatiques renfermant ces derives comme ingredient actif - Google Patents

Derives d'acide benzoique a substitution en 4 et cancerostatiques renfermant ces derives comme ingredient actif Download PDF

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Publication number
WO1999012884A1
WO1999012884A1 PCT/JP1998/003992 JP9803992W WO9912884A1 WO 1999012884 A1 WO1999012884 A1 WO 1999012884A1 JP 9803992 W JP9803992 W JP 9803992W WO 9912884 A1 WO9912884 A1 WO 9912884A1
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compound
group
lower alkyl
acid
ethyl
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PCT/JP1998/003992
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English (en)
Japanese (ja)
Inventor
Nobuhiro Haga
Kenji Sugita
Susumu Kamata
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Shionogi & Co., Ltd.
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Priority to AU89983/98A priority Critical patent/AU8998398A/en
Priority to JP2000510697A priority patent/JP4125868B2/ja
Publication of WO1999012884A1 publication Critical patent/WO1999012884A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/94—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of polycyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/10—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
    • C07C65/40—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups containing singly bound oxygen-containing groups

Definitions

  • the present invention relates to a novel 4-substituted benzoic acid derivative and an anticancer agent containing the same.
  • oncogenes are represented by dar, src, ras, myc, etc. Group.
  • many of these oncogenes were found to transduce a single oncogenic signal pathway rather than transmitting cancer signals in parallel (LevitzkiA. & Gazit A. , Science, 261, 1782, (1995)).
  • PDGF platelet-derived growth factor
  • receptor tyrosine kinase ⁇ -> ⁇ ras ⁇ raf ⁇ > ⁇ fos ⁇ --- ⁇ canceration.
  • sis oncogene targeted this time is a mutant of a growth factor, and its signal is thought to lead to canceration through the above pathway (Bishop, JM Cell, il, 23, (1985) )).
  • Substances that inhibit the signal from the sis oncogene include not only those that directly act on the sis oncogene product, but also those that act on downstream factors. It is thought that these inhibitors specific for canceration signals will lead to anticancer drugs with high specificity for cancer.
  • Trichostatins A, B, and C were isolated from the culture of actinomycetes (streptmyces hygro scopicus) in 1976-78, and their structure was determined and acted on molds such as Trichophyton and Epidermophyton. (N. Tsuj i, M. Kobayash i, K. Nagashima, Y. Waki saka, K. Koizumi, J. Antibiot., 29, 1 (1976), N. Tsuj i, M. Kobayashi, ibid., 31, 939 (1978)).
  • dimethylaniline derivative represented by (1) has a cancer cell differentiation-inducing activity (Japanese Patent Laid-Open Publication No. 3-291256).
  • the dimethylaniline derivative represented by the formula (1) has a cancer cell differentiation-inducing activity (Japanese Patent Laid-Open No. 3-291256).
  • Japanese Patent Application Laid-Open No. 2-124883 discloses an isoflavone derivative having an antioxidant effect. Disclosure of the invention
  • An object of the present invention is to provide a novel compound that does not act on normal cells and specifically detransforms cells transformed with various oncogenes, and an anticancer agent containing the same.
  • the present inventors have conducted intensive studies in view of the above, and as a result, have found that the novel compound has an activity of specifically detransforming cells transformed with a cancer gene, and have completed the present invention. Reached. That is, the present invention
  • R 1 represents hydrogen or lower alkyl
  • NR 2 R 3 where R 2 and R 3 are the same or different and are hydrogen, lower alkyl or hydroxyl group
  • R 2 and R 3 may together form a nitrogen-containing heterocyclic ring with an adjacent nitrogen atom
  • G 2 is hydrogen or halogen
  • G 3 and G 4 are such that G 3 is hydrogen or a hydroxyl group.
  • G 4 is a lower alkylcarbonyloxy and G 4 is lower alkyl, or G 3 and G 4 may together form one O—CH 2 —;
  • G 5 is OR 4 ( Here, R 4 represents hydrogen or lower alkyl) or NR 5 R 6 (where R 5 represents a hydroxyl group or an optionally substituted cyclic group, and R 6 represents hydrogen or lower alkyl). (However, but is and G 5 is oR 1 unless an oR 4) compound or a salt thereof] the Hydrates thereof,
  • G 5 is a hydroxyl group or NR 5 R 6 (where R 5 represents a hydroxyl group or a cyclic group optionally substituted with a hydroxyl group); the compound according to (1), a salt thereof, or a salt thereof; Hydrate,
  • (5) is NR 2 R 3 and G 3 and G 4 together form —O—CH 2 —, or the compound according to (1), or a salt or hydrate thereof, and
  • G QR 1 (where R 1 represents hydrogen or lower alkyl) or NR 2 R 3 (where R 2 and R 3 are the same or different and are hydrogen, lower alkyl or hydroxyl group) Or R 2 and R 3 may together form a nitrogen-containing heterocyclic ring with an adjacent nitrogen atom):
  • G 2 is hydrogen or halogen;
  • G 3 and G 4 are such that G 3 is hydrogen, hydroxyl Or G 4 is a lower alkylcarbonyloxy and G 4 is a lower alkyl, or G 3 and G 4 may together form one O—CH 2 —;
  • G 5 is ⁇ R 4 (Where R 4 represents hydrogen or lower alkyl) or NR 5 R 6 (where R 5 represents a hydroxyl group or an optionally substituted cyclic group, and R 6 represents hydrogen or lower alkyl).
  • lower refers to a straight-chain or branched group having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms. Represents
  • halogen represented by G 2
  • fluorine, chlorine, bromine and the like Particularly, fluorine and chlorine are preferred.
  • lower alkyl used herein, for example, “lower alkyl” represented by G 4 , R 1 > R 2 , R 3 , R 4 and R 6 include methyl, ethyl, propyl Isopropyl, n-butyl, t-butyl and the like. Of these, methyl is particularly preferred.
  • Examples of the cyclic group of the “optionally substituted cyclic group” for R 5 include an aryl group, a heterocyclic group and an alicyclic hydrocarbon ring group.
  • the above aryl group is a heteroatom (oxygen, nitrogen, (Sulfur).
  • an aryl group having 6 to 20 carbon atoms is preferable, and specific examples thereof include, for example, phenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl, etc.), anthryl, phenanthryl, acenafurenyl, Fluorenyl (9-fluorenyl, 1-fluorenyl) and the like. Of these, phenyl is particularly preferred.
  • the above heterocyclic group means a heterocyclic group containing at least one heteroatom of oxygen, sulfur and nitrogen as atoms constituting a ring system, and is preferably an aromatic heterocyclic group, Examples include an aromatic monocyclic heterocyclic group, a bicyclic or tricyclic fused aromatic heterocyclic group, and the like.
  • the monocyclic heterocyclic group include, for example, furyl, phenyl, pyronyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxaziazolyl, 1,3,4,1-oxadiazolyl , Frazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3—triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyridyl Midinyl, pyrazinyl, triazinyl, quinolyl and the like.
  • bicyclic or tricyclic fused aromatic heterocyclic group examples include, for example, benzofuranyl, isobenzofuranyl, benzo [b] thenyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, and benzoxoxa.
  • the above-mentioned alicyclic hydrocarbon ring group means a saturated or unsaturated cyclic hydrocarbon group having no aromaticity, and includes, for example, a cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl).
  • a cycloalkyl group eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • cycloalkenyl group
  • the substituent of the “optionally substituted cyclic group” for R 5 is preferably an acyclic group (a group other than the above-mentioned cyclic groups), and specific examples thereof include, for example, a halogen, a hydroxyl group , Lower alkyloxy (eg, methoxy, ethoxy, propoxy, butoxy, etc.), lower alkylcarbonyloxy (eg, acetyloxy, etc.), lower alkyl, carbonyl group, lower alkyloxycarbonyl, lower alkylcarbonylamino Group, N-mono-lower alkyl carbamoyl group, N-di-lower alkylcarbamoyl group, N-hydroxycarbamoyl group, N-hydroxy-N-lower-alkyl rubamoyl group, N-phenylcarbamoyl group, N- Substituted phenyl carbamoyl, cyano, amino, mono-lower alkyla
  • sulfo group particularly, hydroxyl group, lower alkyloxy group, rubamoyl group, N-mono-lower alkyl group, rubamoyl group, N- Di-lower alkyl rubamoyl, N-hydroxycarbamoyl, N-hydroxy-N-lower alkyl rubamoyl, N-phenylcarbamoyl, N-substituted phenylcarbamoyl, amino, mono-lower alkylamino And di-lower alkylamino groups are preferred. If there are substituents, the number is 1 to 3, preferably 1. Depending on the type of cyclic group, there is a preferred substituent position (for example, para position for phenyl), but it is not particularly limited.
  • substituted cyclic group represented by R 5 for example, 4-hydroxy-phenylene le, 4- main Tokishifue sulfonyl, 4 one ethoxy-phenylalanine, 4 one n- propoxy-phenylalanine, 4 one n- Butokishifueniru 4-Acetyloxyphenyl, 4-methylphenyl, 4-ethylphenyl, 4-n-propylphenyl, 4-n-butylphenyl, 4-potoxyphenyl, 4-methoxycarbonylphenyl, 4-ethoxycarbonylphenyl , 4 rubamoylphenyl, 4-N-monomethylcarbamoylphenyl, 4-N-monoethylcarbamoylphenyl, 4-N-mono-n-propylcarbamoylphenyl, 4-N-mono-n- Butylcarbamoylphenyl, 4-N-dimethylcarbamoyl, 4-
  • Examples of the nitrogen-containing heterocyclic group of the “optionally substituted nitrogen-containing heterocyclic group” formed by those represented by NR 2 R 3 include, for example, pyrroyl 11-yl, indole-11-yl, Power basazole—9—yl, imidazole—1—yl, pyrazol—1—yl, benz [d] Imidazole—1—yl, benz [b] pyrazole-1—yl, triazole — 1-yl, benztriazole— 1-yl, purine— 1—yl, pyrrolidine-1—yl, pyrroline—1—yl, imidazolidin— 1—yl, imidazoline-1—yl, Examples include virazolidine-11-yl, pyrazoline-1-1-yl, piperidine-1-1-yl, indolin-1-1-yl, piperazine-111-yl, and morpholin-4-yl.
  • pyrroyl-1-yl imidazole-1-yl, pyrazol-11-yl, triazol-11-yl, pyrrolidine_1-yl, pyrroline-1-yl , Imidazolidin-1 -yl, imidazoline-1 -yl, virazolidin-1-yl, pyrazoline-1 -yl, pyridin-1 -yl, piperazine-1-yl, morpholine —
  • a monocyclic nitrogen-containing heterocyclic group such as —yl is preferred.
  • the substituent of the ⁇ optionally substituted nitrogen-containing heterocyclic group '' formed by NR 2 R 3 is preferably an acyclic group, and specific examples thereof include, for example, halogen, hydroxyl, Lower alkyloxy (eg, methoxy, ethoxy, propoxy, butoxy, etc.), lower alkylcarbonyloxy (eg, acetyloxy, etc.), lower alkyl, carboxyl group, lower alkoxycarbonyl group, lower alkylcarbonyloxyamino group, carbamoyl group, N —Mono-lower alkyl rubamoyl group, N-di lower alkyl rubamoyl group, N-hydroxycarbamoyl group, N-hydroxy-1-N-lower alkyl rubamoyl group, N-phenylcarbamoyl group, N-substituted phenylcarbamoyl group, Cyano group, amino group, mono-lower alkylamin
  • the number of substituents, if any, is one to three, preferably one.
  • the position of the substituent is not particularly limited.
  • substituted nitrogen-containing heterocyclic group formed by them represented by NR 2 R 3 include, for example, 3 -methyl-pyrrole- 1 -yl, 3 -methyl-imidazo- 1 -yl, 3- Methyl-pyrazole — 1-yl, 4-methyl-triazole — 1-yl, 3-methyl-piperidine 1-yl, 3-methyl-piperyl — 1-yl, 3-methylimid Dazolidine-1-yl, 2-methyl-imidazoline-1-yl, 3-methyl-birazolidine-1-yl, 3-methyl-pyrazoline-1-yl, 4-methyl-piperidine-1--1 4-yl, 4-methyl-piperazine- 1-yl, 2-methyl-morpholine- 4-yl, 3-amino-pyrrol- 1-yl, 4-amino-imidazoyl- 1-yl, 4-Amino-pyrazole-1-yl, 4-Amino-triazole-1-yl, 3- Amino-pyrrolidine- 1-yl, 3-
  • the “salt” of the target compound (I) of the present invention is preferably a pharmacologically acceptable salt, for example, a salt with a base (a salt with an inorganic base, a salt with an organic base) or a salt with an acid Salts (salts with inorganic acids, salts with organic acids), salts with basic or acidic amino acids, and the like are included.
  • a salt with an inorganic base include an alkali metal salt such as a sodium salt and a potassium salt, an alkaline earth metal salt such as a calcium salt, a magnesium salt, and a barium salt, and an aluminum salt and an ammonium salt.
  • salts with an organic base Salts with trimethylamine, triedulamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N 'dibenzylethylenediamine, and the like are included.
  • salts with inorganic acids include salts with hydrochloric acid, hydrofluoric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, perchloric acid, hydroiodic acid, and the like.
  • Salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, cunic acid, succinic acid, malic acid, mandelic acid, ascorbic acid, lactic acid, dalconic acid, methanesulfonic acid, Salts with p-toluenesulfonic acid, benzenesulfonic acid and the like can be mentioned.
  • Salts with basic amino acids include salts with arginine, lysine, orditin
  • salts with acidic amino acids include salts with aspartic acid, glutamic acid, and the like.
  • the "hydrate” of the target compound (I) of the present invention is preferably a pharmacologically acceptable hydrate, and also includes a hydrate. Specific examples include monohydrate, dihydrate, hexahydrate and the like.
  • NR 2 R 3 (where R 2 and R 3 are the same or different and are hydrogen, lower alkyl or hydroxyl group); G 5 is OR 4 (where R 4 is hydrogen or lower) Or NR 5 R 6 (where R 5 represents a hydroxyl group and R 6 represents hydrogen or lower alkyl)], a salt thereof, or a hydrate thereof.
  • OR 1 (where R 1 represents hydrogen or lower alkyl) or NR 2 R 3 (where R 2 and R 3 are the same or different and are hydrogen, methyl or hydroxyl, or R 2 and R 3 may together form a monocyclic nitrogen-containing heterocycle with adjacent nitrogen atoms);
  • G 2 is hydrogen or halogen;
  • G 5 is ⁇ R 4 (where R 4 represents hydrogen or lower alkyl) or NR 5 R 6 (where R 5 represents a hydroxyl group or a phenyl group which may be substituted, and R 6 represents hydrogen or lower alkyl). Its salts or their hydrates.
  • the compound represented by the general formula (I) is a novel compound.
  • Preferred examples of the compound represented by the general formula (I) or the following compounds as preferred examples for inclusion in the anticancer agent of the present invention include the following compounds. .
  • the compound (I) (1) G 3 is hydrogen, compound G 4 is lower alkyl (I one A;), (2) G 3 is hydroxy, compound G 4 is lower alkyl (I one B), (3) a compound in which G 3 is a lower alkyl group, ponylonoxy, and G 4 is a lower alkyl (I—C), (4) When G 3 and G 4 come together — O— CH 2 — to form a compound (I _ D), (5 ) G 5 is hydroxy compound (I one E) and (6) compound G 5 is NR 5 R 6 - broken down by (I F), i.e. The manufacturing methods 1 to 6 will be described.
  • G 2 , G 5 and X are as defined above, X is halogen, and R is lower alkyl
  • the target compound (I-A) is, for example, as described in a publicly known document (Japanese Patent Application Laid-Open No. 3-291264), in the form of an aldehyde (II) in the form of trimethylsilyl cyanide or the like. It can be produced by an alkylation reaction with a halide (III) through a step of reacting a reaction activator.
  • the above-mentioned production method 1 includes, for example, a step 1 for activating the aldehyde compound (II), a step 2 for reacting with the octogenide (III), and a step 3 for removing a group corresponding to the reaction activator. Can be manufactured.
  • Examples of the activator for the aldehyde compound (II) include, for example, an O-silylation group having a trimethylsilyl group (TMS :), t-butyldimethylsilyl group, t-butyldiphenylsilyl group or triisopropyl group.
  • Examples of such a reagent include a reagent having a t-butyl group, a trityl group, a benzyl group, a P-methoxybenzyl group, or the like.
  • the cyanide compound (IV) can be obtained, for example, from known literature (MHayashi, TMatsuda, NOguni, J. Chem Soc, Chem Commun 1990 (19), pl364, 1990, Torii S, Inokuchi T, Takagishi S, Horike H, Kuroda H, Undeyama K, B Chem Soc JPN 60 (6), 2173-2188 (1987), DA Evans, LK Truesdale, and GL Carroll, JCS Chem.
  • the compound (II) is reacted with trimethylsilyl cyanide to produce the compound as described above, or as described in a known literature (R Yoneda, T Kurihara, et al, Synthesis (12), pl054, 1986). It can be produced by reacting both trimethylsilyl halide and cyanide such as lithium cyanide, sodium cyanide, lithium cyanide, etc. it can.
  • the catalyst examples include anhydrous zinc iodide, zinc chloride, tetramethoxyaluminum potassium, zinc cyanide and the like.
  • the reaction temperature is ⁇ 78 ° C. to 70 °, preferably 0 ° (: to 25 ° C.).
  • the reaction time varies depending on the compound, but is from 0.03 hours to 48 hours, preferably from 2 hours to 6 hours.
  • Solvents that can be used include ether solvents (eg, tetrahydrofuran, getyl ether, dioxane, etc.), halogenated hydrocarbons (eg, tetrachloromethane, dichloromethane, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.) ), Saturated hydrocarbons (eg, heptane, hexane, etc.), etc., or a mixed solvent thereof.
  • ether solvents eg, tetrahydrofuran, getyl ether, dioxane, etc.
  • halogenated hydrocarbons eg, tetrachloromethane, dichloromethane, etc.
  • aromatic hydrocarbons eg, benzene, toluene, xylene, etc.
  • Saturated hydrocarbons eg, heptane, hexane, etc.
  • Trimethylsilyl cyanide is used in an amount of 1.0 relative to the aldehyde (II).
  • the reaction is preferably performed in an argon or nitrogen atmosphere.
  • the obtained cyanide compound (IV) can be used in the next step after purifying it as a reaction solution or in a crude form, or by a conventional method (eg, column chromatography, recrystallization, etc.).
  • Compound (V) can be obtained, for example, from known literature (Fischer K, Hunig S, Tetrahedron 42 (19), 5337-5340 (1986), Delera AR, Saa JM, Suau R, Castedo L, J Heterocyclic chem 24 (1) , 95-100 (1987), Fischer K, Hunig S, J Org Chem 52 (4), 564-569 (1987), As described in Ian Fleming and Javed Iqbal, Tetrahedron 39 (6), 841-846 (1983)), it can be produced by an alkylation reaction of a cyanide compound (IV) and an octalogenide (III). .
  • reagent examples include lithium p-trimethylsilyl amide, sodium hydride, lithium diisopropyl amide (LDA), sodium ethoxide, potassium t-butoxide, 1,8-diazabicyclo [5.4.0] pendeck_7 — (BU).
  • LDA lithium diisopropyl amide
  • BU 1,8-diazabicyclo [5.4.0] pendeck_7 —
  • the reaction temperature is from 1 78 ° (: to 110 T :, preferably from 120 to 25 ° C.
  • the reaction time varies depending on the compound, but is from 0.1 to 13 hours, preferably from 1 to 13 hours. 2 hours to 4 hours.
  • Solvents that can be used include ether solvents (eg, tetrahydrofuran, getyl ether, dioxane, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), saturated hydrocarbons (eg, heptane, hexane, etc.) ) Or a mixed solvent thereof.
  • ether solvents eg, tetrahydrofuran, getyl ether, dioxane, etc.
  • aromatic hydrocarbons eg, benzene, toluene, xylene, etc.
  • saturated hydrocarbons eg, heptane, hexane, etc.
  • the amount of the reagent used is 1.0 equivalent to 2.0 equivalents, preferably 1.0 equivalent to 1 based on the cyanide form (IV). 2 equivalents.
  • the amount of the halide (III) to be used is 1.0 equivalent to 1.2 equivalents relative to the cyanide form (IV).
  • the obtained compound (V) can be used in the next step after purification as a reaction solution or a crude product, or by a conventional method (eg, column chromatography, recrystallization, etc.).
  • the target compound (I-A) can be produced by removing the group (TMS) corresponding to the reaction activator from the compound (V).
  • reaction conditions for example, an excess of fluoride tetra - as tetrahydrofuran solution of n- Petit Ruan monitor ⁇ beam (nB u 4 NF), as tetrahydrofuran / Sakusan'nosui (1: 1: 1) mixture of fluorinated Examples include conditions such as a pyridine salt of hydrogen, a mixed solution of 48% hydrogenacetonoacetonitrile (1: 7), and an aqueous hydrochloric acid solution.
  • the obtained target compound (I-A) may be used as a reaction mixture or in crude form, or purified by a conventional method (eg, column chromatography, recrystallization, etc.) and used for the production of other target compounds. Can be.
  • the compound (I-B) of the present invention can be produced by using known methods, for example, the methods described below and specifically shown in Examples.
  • the aldehyde (VII) can be produced from the compound (VI) by a known simple method, Vilsmeier reaction.
  • the reaction temperature is 130 to 25 ° C.
  • the reaction time varies depending on the compound, but is 2 hours to 30 hours.
  • the amount of phosphorus oxychloride to be used is preferably 1.0 equivalent to 1.2 equivalent based on compound (VI).
  • the obtained aldehyde compound (VII) can be used in the next step after purifying it as a reaction solution or a crude product, or by a conventional method (eg, column chromatography, recrystallization, etc.).
  • the compound (VII) is produced by protecting the hydroxyl group of the compound (VII) with a t-butyldimethylsilyl (TBDMS) group.
  • the reaction temperature is -20 to 8080.
  • the reaction time varies depending on the compound, but is 0.2 to 60 hours.
  • the solvent that can be used is not particularly limited as long as it does not inhibit the reaction, in addition to N, N-dimethylformamide (DMF) described above.
  • DMF N, N-dimethylformamide
  • halogenated hydrocarbons eg, chloroform, dichloromethane, etc.
  • ethers eg, ethyl ether, tetrahydrofuran, dioxane, dimethoxetane, etc.
  • aromatic hydrocarbons eg, benzene, toluene, etc.
  • the obtained target compound (I-B) can be used as a reaction solution or in a crude form, or by a conventional method (eg, It can be purified by column chromatography, recrystallization, etc. and used in the next step.
  • the target compound (I-I-B) can be produced by a method similar to the method described in Production method 1 for reacting the compound (VIII) with the halide (III).
  • TDMS t-butyldimethylsilyl
  • the obtained target compound (I-B) can be used as a reaction mixture or in crude form, or purified by a conventional method (eg, column chromatography, recrystallization, etc.) and used for the production of other target compounds. it can.
  • a conventional method eg, column chromatography, recrystallization, etc.
  • the compound (I-C) of the present invention can be produced using a known method, for example, a method described below or specifically shown in Examples.
  • the target compound (IC) is produced by subjecting the compound (IB) to, for example, an acylation reaction. be able to.
  • the acylation may be carried out by a known method.
  • the acylating agent include an acyl halide or an alkylsulfonyl halide or an anhydride thereof (eg, acetic anhydride, 3-acetoxy-1,5,5-trimethylhydantoin, etc.). ) Or mixtures thereof.
  • the reaction temperature is —10 ° (: ⁇ 100).
  • the reaction time varies depending on the compound, but is from 0.5 hours to 100 hours.
  • the solvent that can be used is not particularly limited as long as it is a nonpolar solvent.
  • Pyridine is particularly preferred, but others include 1,4-dioxane, dichloromethane, getyl ether, benzene and the like.
  • the obtained target compound (I_C) can be used as is in the reaction solution or in crude form, or purified by a conventional method (eg, column chromatography, recrystallization, etc.) and used for the production of other target compounds. it can.
  • a conventional method eg, column chromatography, recrystallization, etc.
  • the compounds (ID) of the present invention are produced by known methods, for example, by using the methods described below (Steps 1 to 3) and specifically shown in Examples.
  • Step 1 The following are the halogenation reaction (Step 1), the dehydrohalogenation reaction (Step 2), An example of the case of producing via deacetylation reaction and ring closure reaction (step 3) will be described. (step 1 )
  • the halide (X) is produced by halogenating the compound (IX).
  • the octalogenation is preferably performed under strong acid conditions, for example, under the condition of a mixed solvent of acetic acid and sulfuric acid.
  • the reaction temperature is O: 1100 ° C., preferably around room temperature.
  • the reaction time varies depending on the compound, but is from 0.3 hours to 72 hours.
  • the obtained halide (X) can be used in the next step after purification as a reaction solution or a crude product, or by a conventional method (eg, column chromatography, recrystallization, etc.).
  • Compound (XI) is produced by subjecting halide (X) to a dehydrohalogenation reaction.
  • the method of the dehydrohalogenation reaction may be a known method, for example, a salt of an organic acid (e.g., a silver salt of an organic acid such as silver methanesulfonate, silver P-toluenesulfonate, silver acetate, Reaction in the presence of a copper salt of an organic acid).
  • the reaction temperature is 0 to 100.
  • the reaction time varies depending on the compound, but is from 0.3 hours to 50 hours.
  • a polar solvent is preferable.
  • acid amides eg, N,
  • N-dimethylformamide, etc. N-dimethylformamide, etc.), acetonitrile, etc., or a mixed solvent thereof and the like.
  • the obtained compound (XI) can be used in the next step after purifying it as a reaction solution or in a crude form, or by a conventional method (eg, column chromatography, recrystallization, etc.).
  • G, G 2 , G 5 and R are as defined above.
  • the target compound (ID) can be produced by subjecting compound (XI) to deacylation and ring closure.
  • the method may be a known method, for example, the addition of a metal salt of an alcohol (eg, sodium methoxide / methanol or the like) with an alcohol-based solvent.
  • a metal salt of an alcohol eg, sodium methoxide / methanol or the like
  • the reaction temperature is between 40 ° C and 80 :.
  • the reaction time varies depending on the compound, but is from 0.3 hours to 50 hours.
  • the obtained target compound (ID) can be purified by a conventional method (eg, column chromatography, recrystallization, etc.).
  • G, G 2 , G 3 , G 4 and R are as defined above, and A represents hydrogen or metal
  • the target compound (IE) can be produced by hydrolysis using the ester (XII) as a raw material.
  • the target compound is a metal salt, for example, a sodium salt, it is produced by reacting sodium hydroxide.
  • the target compound is a carboxylic acid, the compound is produced, for example, by adding hydrochloric acid or the like to the above-mentioned metal salt to make it acidic.
  • the obtained target compound (IE) can be used as is in the reaction solution or in crude form, or purified by a conventional method (eg, column chromatography, recrystallization, etc.) and used for the production of other target compounds. it can.
  • a conventional method eg, column chromatography, recrystallization, etc.
  • the compound (IF) of the present invention can be produced using a known method, for example, a method described below or specifically shown in Examples.
  • the target compound (IF) is obtained by reacting a carboxylic acid form (XIII) with a carboxylic acid activator to produce a reactive derivative at the carbonyl group, and then reacting the hydroxylamine or substituted aniline derivative corresponding to the target compound. (XIV).
  • examples of the carboxylic acid activator include thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, and chlorocarbonate (eg, methyl chlorocarbonate, ethyl chlorocarbonate).
  • oxalyl chloride carbonyldiimidazole
  • carbodiimides for example, N, N-dicyclohexylcarboimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimid hydrochloride , N, N-di-isopropylcarbodiimide, N, N-di-p-tolyl carbodiimide, etc.
  • hydroxyamino derivatives eg, N-hydroxybenzotriazole, N-hydroxysuccinimide etc.
  • This reaction is usually carried out in the presence of halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as tetrahydrofuran, dioxane, dimethyl ether, dimethyl ether and isopropyl ether, or a mixed solvent thereof. Is done. This reaction is carried out at a reaction temperature of 0 to 50 ° C., preferably around room temperature, for 0.5 to 10 hours, preferably 1 to 3 hours, depending on the compound.
  • halogenated hydrocarbons such as methylene chloride and chloroform
  • ethers such as tetrahydrofuran, dioxane, dimethyl ether, dimethyl ether and isopropyl ether, or a mixed solvent thereof. Is done.
  • This reaction is carried out at a reaction temperature of 0 to 50 ° C., preferably around room temperature, for 0.5 to 10 hours, preferably 1 to 3 hours, depending on the compound.
  • the acid anhydride, acid halide or active ester obtained by reacting with a carboxylic acid activator in this reaction is then reacted with a hydroxyamine or a substituted aniline derivative (XIV).
  • This reaction is carried out in a solvent such as dichloromethane, tetrahydrofuran, dioxane, or acetone, in the presence of a deoxidizing agent such as pyridine, triethylamine, potassium carbonate, sodium carbonate, potassium hydrogencarbonate, or sodium hydrogencarbonate. It is carried out under the condition of containing water. Further, this reaction is carried out at a reaction temperature of 0 to 50 ° C., preferably around room temperature for 0.1 to 10 hours, preferably 0.5 to 2 hours.
  • Hydroxamines and substituted aniline derivatives are defined as Mine, N-methylhydroxylamine and their hydrochlorides, sulfates and the like, or P-hydroxyaniline, P-methoxyaniline and their hydrochlorides and the like.
  • the obtained target compound (IF) can be isolated and purified by a conventional method (eg, column chromatography, recrystallization, etc.).
  • the compound (I) of the present invention is compounded with a pharmacologically acceptable carrier to prepare a solid preparation such as tablets, capsules, granules, powders, powders, and suppositories, or a syrup, injection, suspension, or the like. It can be administered orally or parenterally as liquid preparations such as preparations, solutions and sprays.
  • Pharmaceutically acceptable carriers include excipients, lubricants, binders, disintegrants, disintegration inhibitors, absorption enhancers, adsorbents, humectants, solubilizing agents, stabilizing agents, Solvents, dissolution aids, suspending agents, isotonic agents, buffers, soothing agents and the like in liquid preparations.
  • a substance having an anticancer effect other than the compound represented by the general formula (I), a salt thereof or a hydrate thereof may be added to the anticancer agent of the present invention.
  • Parenteral routes of administration include intravenous injection, intramuscular injection, nasal, rectal, vaginal and transdermal.
  • Excipients in solid preparations include, for example, glucose, lactose, sucrose, D-mannitol, crystalline cellulose, starch, calcium carbonate, light anhydrous caffeic acid, sodium chloride, kaolin and urea.
  • lubricant in the solid preparation for example, magnesium stearate, calcium stearate, powdered boric acid, colloidal citric acid, talc, polyethylene dalicol and the like can be mentioned.
  • binder in the solid preparation examples include water, ethanol, propanol, sucrose, D-mannitol, crystalline cellulose, dextrin, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, starch solution, gelatin solution, and poly (polyester). Vinylpyrrolidone, calcium phosphate, potassium phosphate, shellac and the like.
  • disintegrants in solid preparations include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, agar powder, laminaran powder, croscarmellose sodium, carboxymethyl starch sodium, sodium alginate, sodium hydrogen carbonate, calcium carbonate,
  • examples include polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, starch, monosalicylate monostearate, lactose, and calcium calcium dalicholate.
  • Preferred examples of the disintegration inhibitor in the solid preparation include hydrogenated oil, sucrose, stearin, cocoa butter, and hardened oil.
  • absorption enhancer in a solid preparation examples include quaternary ammonium bases and sodium lauryl sulfate.
  • Examples of the adsorbent in the solid preparation include starch, lactose, kaolin, bentonite, and colloidal keic acid.
  • humectant in the solid preparation examples include glycerin, starch and the like.
  • solubilizer in the solid preparation examples include arginine, glutamic acid, and aspartic acid.
  • Examples of the stabilizer in the solid preparation include human serum albumin, lactose and the like.
  • tablets, pills and the like When preparing tablets, pills and the like as solid preparations, they may be coated with a film of a gastric or enteric substance (sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.) as necessary.
  • Tablets include tablets coated with ordinary skin as required, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or double tablets, and multilayer tablets.
  • Capsules include hard capsules and soft capsules.
  • Preferable examples of the solvent in the liquid preparation include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like.
  • Preferred examples of solubilizers in liquid preparations include polyethylene dalicol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate and sodium citrate. Is mentioned.
  • the suspending agent in the liquid preparation include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate.
  • hydrophilic polymers such as polypinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyshethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose.
  • Preferable examples of the tonicity agent in the liquid preparation include sodium chloride, glycerin, D-mannitol and the like.
  • buffer in the liquid preparation examples include buffers such as phosphate, acetate, carbonate, and citrate.
  • the soothing agent in the liquid preparation include benzyl alcohol, benzalkonium chloride and procaine hydrochloride.
  • preservative in the liquid preparation include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • Preferred examples of the antioxidant in the liquid preparation include sulfite, ascorbic acid, -tocopherol and cysteine.
  • solutions and suspensions are sterilized and isotonic with blood. It is preferable that Usually, these are sterilized by filtration using a bacteria-retaining filter or the like, blending of a bactericide or irradiation. Further, after these treatments, solidified by freeze-drying and other methods, and sterile water or sterile injectable diluent (lidocaine hydrochloride aqueous solution, physiological saline solution, glucose aqueous solution, ethanol or a mixture thereof, etc.) immediately before use. ) May be added.
  • the pharmaceutical preparations may contain coloring agents, preservatives, flavorings, flavors, sweeteners and the like, as well as other agents.
  • the proportion of the active ingredient in the anticancer agent of the present invention may vary depending on the dosage form, but is usually 0.1 to 70% by weight irrespective of the administration form. Dosage will, of course, the patient's age, sex, symptom, the desired therapeutic effect, but is to be determined in consideration of the administration period and the like, usually, per day per adult 0.01 ⁇ 1000M g based on the (active ingredient amount) These can be administered as 1 to 4 times a day.
  • NMR spectrum was measured using CDCls or CDC1 3 + CD 3 0D as solvent. All ⁇ values are given in ppm. In addition, the meaning of the symbol in NMR is shown below. s Singlet, d: doublet, t: triplet, dd: double doublet, m: multiplet, q: quaternary carbon.
  • Ogizaryl chloride (87 l, 1.05 mmol) was added to a suspension of sodium 4- [1- (4-dimethylaminobenzoyl) ethyl] benzoate (compound No. 15, 319 mg, lmmol) in anhydrous benzene (22 ml). Was added and reacted at room temperature for 5 hours.
  • the resulting reaction solution was prepared by reacting hydroxylamine hydrochloride (286 mg, 2 mmol) and caustic soda (188 mg , 4.58 mmol) in methanol (22 ml) at 0 ° C for 30 minutes and then at room temperature for 1 hour.
  • the hydroxylamine solution was added to the solution under ice-cooling, and reacted at 0 for 1 hour and then at room temperature for 1 hour.
  • the reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in a mixture of chloroform and methanol and washed with water.
  • the organic layer was dried over magnesium sulfate and concentrated under reduced pressure.
  • the obtained crude product was triturated with ether, filtered, and then washed with a small amount of ethyl acetate to obtain the title compound (286 mg, yield 91.6%). mp l89-190 ° C
  • a 1N sodium methoxide methanol solution (18.4) was added to a solution of 4- (7-dimethylamino-4-oxo-chroman-3-yl) ethyl benzoate (Compound No. 36, 6.25 g) in methanol (122 ml). ml, 18.4 mmol), distilled water (18.4 ml) and tetrahydrofuran (18.4 ml), and the mixture was heated under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, and to the residue obtained, ethyl acetate, water and 20 ml of 1N hydrochloric acid were added.
  • Example 1 2.5 mg of the compound of the invention was dissolved in a mixture of purified sesame oil lg and aluminum stearate gel lOOmg. 0.5 ml of the resulting solution was dispensed into capsules to give oral capsules.
  • a culture solution was prepared as follows. Dulbecco Eagle MEM medium (Nissui Pharmaceutical) 9.5 g and 7% sodium bicarbonate were added to 20 ml and 1 L of distilled water, and then fetal bovine serum (Flow Laboratories, Inc.) was added to a final concentration of 10% by volume. Added.
  • NIH3T3 cells transformed with the v-sis gene (100 L) were inoculated into a 96-well plastic dish manufactured by Sumitomo Bei-Client Co., Ltd. in a 5 ⁇ 10 3 cell well, and then incubated at 37 ° C. In a 5% CO 2 incubator.
  • test samples were added in a two-fold dilution series, and after 24 hours, the cell morphology was observed to determine the detransformation activity. The results are shown in Table 1 below.
  • MIC Minimum transformation inhibitory activity
  • the compounds of the present invention exhibited a detransformation activity at MIC of 0.03 / ig / ml at 10 g / ml.
  • a novel compound that specifically detransforms cells transformed with various oncogenes and a carcinostatic agent containing the same are provided.

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Abstract

Cette invention a trait à de nouveaux composés, représentés par la formule générale suivante (I), qui n'ont aucune action sur les cellules normales mais biotransforment de manière spécifique des cellules ayant subi une transformation maligne provoquée par divers oncogènes. Elle porte également sur les sels ou les hydrates de ces composés. Dans la formule, G1 représente OR?1 ou NR2R3 (R2 et R3¿ étant identiques ou différents et représentant, chacun, un hydrogène, un alkyle de faible poids moléculaire ou un hydroxy ou bien formant avec l'atome d'hydrogène qui leur est adjacent un hétérocycle contenant de l'azote), G¿2? représente un hydrogène ou un halogéno et, lorsque G3 représente un hydrogène, un hydroxy ou un alkylcarbonyloxy de faible poids moléculaire, G4 représente alors un alkyle de faible poids moléculaire ou bien encore G3 et G4 constituent, ensemble, -O-CH2- et G5 représente OR?4 ou NR5R6 (R5¿ représentant un hydroxy ou un groupe cyclique éventuellement substitué et R6 représentant un hydrogène ou un alkyle de faible poids moléculaire).
PCT/JP1998/003992 1997-09-09 1998-09-07 Derives d'acide benzoique a substitution en 4 et cancerostatiques renfermant ces derives comme ingredient actif WO1999012884A1 (fr)

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AU89983/98A AU8998398A (en) 1997-09-09 1998-09-07 4-substituted benzoic acid derivatives and carcinostatics containing the same asthe active ingredient
JP2000510697A JP4125868B2 (ja) 1997-09-09 1998-09-07 ４−置換安息香酸誘導体およびそれを有効成分として含有する制癌剤

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7098241B2 (en) 2002-12-16 2006-08-29 Hoffmann-La Roche Inc. Thiophene hydroxamic acid derivatives
EP1874755A2 (fr) * 2005-04-20 2008-01-09 Merck & Co., Inc. Derives benzothiophene d'acide hydroxamique
EP3461480A1 (fr) 2017-09-27 2019-04-03 Onxeo Combinaison d'inhibiteurs de point de contrôle du cycle cellulaire de réponse à un dommage à l'adn et de belinostat pour traiter le cancer
EP3461488A1 (fr) 2017-09-27 2019-04-03 Onxeo Combinaison d'une molécule dbait et un inhibiteur de hdac pour le traitement du cancer
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation
WO2023041805A1 (fr) 2021-09-20 2023-03-23 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés pour l'amélioration de l'efficacité d'une thérapie par inhibiteur de hdac et la prédiction de la réponse à un traitement comprenant un inhibiteur de hdac
WO2023194441A1 (fr) 2022-04-05 2023-10-12 Istituto Nazionale Tumori Irccs - Fondazione G. Pascale Combinaison d'inhibiteurs de hdac et de statines pour une utilisation dans le traitement du cancer du pancréas

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6110528A (ja) * 1984-04-27 1986-01-18 インペリアル・ケミカル・インダストリ−ズ・ピ−エルシ− フエノ−ル誘導体、その製造法、および該化合物を含有する抗エストロゲン作用を有する医薬組成物

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6110528A (ja) * 1984-04-27 1986-01-18 インペリアル・ケミカル・インダストリ−ズ・ピ−エルシ− フエノ−ル誘導体、その製造法、および該化合物を含有する抗エストロゲン作用を有する医薬組成物

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7098241B2 (en) 2002-12-16 2006-08-29 Hoffmann-La Roche Inc. Thiophene hydroxamic acid derivatives
EP1874755A2 (fr) * 2005-04-20 2008-01-09 Merck & Co., Inc. Derives benzothiophene d'acide hydroxamique
EP1874755A4 (fr) * 2005-04-20 2010-04-28 Merck Sharp & Dohme Derives benzothiophene d'acide hydroxamique
US7772238B2 (en) 2005-04-20 2010-08-10 Merck Sharp & Dohme Corp. Benzothiophene hydroxamic acid derivatives
EP3461480A1 (fr) 2017-09-27 2019-04-03 Onxeo Combinaison d'inhibiteurs de point de contrôle du cycle cellulaire de réponse à un dommage à l'adn et de belinostat pour traiter le cancer
EP3461488A1 (fr) 2017-09-27 2019-04-03 Onxeo Combinaison d'une molécule dbait et un inhibiteur de hdac pour le traitement du cancer
WO2019063649A1 (fr) 2017-09-27 2019-04-04 Onxeo Combinaison d'une molécule dbait et d'un inhibiteur hdac pour le traitement du cancer
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation
WO2023041805A1 (fr) 2021-09-20 2023-03-23 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés pour l'amélioration de l'efficacité d'une thérapie par inhibiteur de hdac et la prédiction de la réponse à un traitement comprenant un inhibiteur de hdac
WO2023194441A1 (fr) 2022-04-05 2023-10-12 Istituto Nazionale Tumori Irccs - Fondazione G. Pascale Combinaison d'inhibiteurs de hdac et de statines pour une utilisation dans le traitement du cancer du pancréas

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