WO1999055689A1 - Derives de radicicol - Google Patents

Derives de radicicol Download PDF

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Publication number
WO1999055689A1
WO1999055689A1 PCT/JP1999/002138 JP9902138W WO9955689A1 WO 1999055689 A1 WO1999055689 A1 WO 1999055689A1 JP 9902138 W JP9902138 W JP 9902138W WO 9955689 A1 WO9955689 A1 WO 9955689A1
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Prior art keywords
substituted
unsubstituted
compound
acceptable salt
pharmaceutically acceptable
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PCT/JP1999/002138
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English (en)
Japanese (ja)
Inventor
Yoji Ino
Nobuyoshi Amishiro
Mayumi Miyata
Tsutomu Agatsuma
Chikara Murakata
Shiro Akinaga
Shiro Soga
Yukimasa Shiotsu
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Kyowa Hakko Kogyo Co., Ltd.
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Priority to AU35344/99A priority Critical patent/AU3534499A/en
Publication of WO1999055689A1 publication Critical patent/WO1999055689A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom

Definitions

  • the present invention relates to a radicicol derivative or a pharmacologically acceptable salt thereof, which exhibits a tyrosine kinase inhibitory activity and has an antitumor or immunosuppressive action.
  • Radicicol which is represented by the formula (B) and is a metabolite of microorganisms, has antifungal and anticancer effects [Nature, 171: 344 (1953); Neoplasma
  • a radicicol derivative in which a phenolic hydroxyl group is modified with various acyl groups has an antitumor effect (Japanese Patent Application Laid-Open No. 4226991). Furthermore, a radicicol derivative in which the phenolic hydroxyl group is modified with an acyl group or an alkyl group has an inhibitory effect on angiogenesis (JP-A-6-279279) or an inhibitory effect on interleukin-11 production (JP-A-8-40893). ) Is disclosed.
  • the oxime derivative of genone of the radicicol derivative represented by the formula (C) exhibits an antitumor effect and an immunosuppressive effect (W096 / 33989).
  • R 1P and R 2P represent hydrogen, alkanoyl, alkenoyl or tert-butyldimethylsilyl
  • Y p represents hydrogen or substituted or unsubstituted lower alkyl
  • R 4P represents hydrogen, alkanoyl or alkenoyl, etc.
  • X p represents a single bond together with a halogen atom or R 4P
  • R 1Q and R 2Q represent a hydrogen atom or acyl, and X Q represents a halogen atom, hydroxy or lower alkoxy
  • the ansamycin antibiotic geldanamycin of the formula (E) is a tyrosine kinase. It is known to have inhibitory activity and antitumor activity [Cancer's Research (Cancer Research), Vol. 52, 1721 ⁇ - ⁇ (1992) and Cancer Research (Cancer Research), Vol. 54, 2724 ⁇ - ⁇ (1994) etc.]. These effects are due to the binding of geldanamycin to the molecular chaperone Hsp (heat shock / stress protein) 90, which forms a complex with Hsp90 to express functions, such as Src, ErbB-2, and Lck.
  • Hsp heat shock / stress protein
  • Tyrosine kinase is an enzyme that catalyzes the transfer of its arsenic acid group to the hydroxyl group of a specific tyrosine residue of a substrate protein using ATP as a phosphate donor, and plays an important role in the regulatory mechanism in intracellular signal transduction Is responsible for.
  • Various tyrosine kinase families are known, and the activity of each tyrosine kinase such as Src in colorectal cancer, ErbB-2 in breast cancer and gastric cancer, and Abl in leukemia is known.
  • An uncontrolled increase in tyrosine kinase activity causes abnormalities in cell differentiation and proliferation. Therefore, a specific inhibitor of tyrosine kinase is useful for prevention and treatment of various diseases including antitumor agents.
  • Lck is a cytosine kinase that is activated when T lymphocytes are activated by antigen stimulation, and inhibitors of this enzyme are useful as immunosuppressants.
  • Src is known to be involved in bone resorption in osteoclasts, and this tyrosine kinase inhibitor is thought to act as a bone resorption inhibitor, and is useful as a therapeutic agent for osteoporosis.
  • various growth factor receptor tyrosine kinases EGF-R (epithelial cells) Vesicle growth factor receptor: epidermal growth factor receptor, FGF-R (fibroblast growth factor receptor), PDGF-R (platelet-derived growth factor receptor), etc. are useful as a solid cancer growth inhibitor, an angiogenesis inhibitor, a vascular smooth muscle growth inhibitor, and the like. Disclosure of the invention
  • An object of the present invention is to provide a novel radicicol derivative or a pharmacologically acceptable salt thereof which exhibits a tyrosine kinase inhibitory activity and has an antitumor or immunosuppressive activity.
  • the present invention provides a compound represented by the general formula (I)
  • R 1 and R 2 are the same or different and represent hydrogen, alkanoyl, alkenoyl, alkadienol, alkatrienoyl, trialkylsilyl, triarylsilyl, monoalkyldiarylsilyl or dialkylmonoarylsilyl.
  • R 3 is NR 5 R 6 (where R 5 is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted higher alkyl, substituted or unsubstituted Represents a lower cycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group, wherein R 6 is a substituted lower alkyl, a substituted or unsubstituted higher alkyl, a substituted or unsubstituted lower cycloalkyl , Represents a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group), NR 7 C ⁇ R 8 [wherein R 7 represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted higher alkyl, substituted or unsubstituted lower
  • NRUCOR 12 (where R 11 is substituted or unsubstituted) Represents lower alkyl, substituted or unsubstituted higher alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heterocyclic group.
  • R 12 represents lower alkyl, lower alkoxy, lower alkenyloxy, lower alkadienyloxy or lower alkatrienyloxy), substituted lower alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkenyloxy, substituted or unsubstituted alkatrienyloxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkadienyl, substituted or unsubstituted alkatrienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted Substituted or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isooxazolyl, substituted or unsubstituted thiazolyl,
  • R 1 A and R 2 A have the same meanings as R 1 and R 2 , respectively, X A represents an octogen atom, W represents ⁇ or N—O—Y A —R 3 A (formula among relates Y a and R 3 a salts previous SL Y and R 3 and the Radishiko Le derivative or a pharmaceutically represented by representing] a a a) representing the representative] a ⁇ synonymous allowable respectively.
  • compound (I) the compound represented by the general formula (I).
  • compound (I) the compound represented by the general formula (I).
  • lower means up to 1 to 8 carbon atoms and higher means up to 9 to 30 carbon atoms, unless otherwise specified.
  • the alkanoyl includes straight or branched ones having 1 to 30 carbon atoms, for example, formyl, acetyl, propanoyl, isopropanol, bushynoyl, forceproyl, lauroyl, myristoyl, palmitoyl, stearoyl and the like.
  • Alkenols include straight-chain or branched ones having 3 to 30 carbon atoms, such as acryloyl, methacryloyl, crotonyl, isocrotonyl, and palmitoleyl.
  • Alkadienoyl is a straight or branched chain having 5 to 30 carbon atoms, for example, 2,4-diene dienol, 2,4-hexadienol, 3,5-hepadienol, linoleoyl, 3,5-diene Decadienol, 10, 12-Penya Decadienol and 12,15-Henikosagenol are included.
  • Alkatrienoyl is a straight or branched chain having 7 to 30 carbon atoms, for example, 2,4,6-hepnotrienol, linolenoyl, 2,4,6-docosatri. Enol, 8,11,14-icosatrienoyl and 12,15,18-hexosatrienoyl are included.
  • Lower alkyl and the alkyl moiety of lower alkoxy include straight-chain or branched, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, terbutyl, pentyl, isopentyl, neopentyl, hexyl, Heptyl, octyl, isooctyl and the like are included, and one of the carbon atoms may be replaced by a silicon atom.
  • the alkylene portion of aralkyloxy is a group obtained by removing one hydrogen atom from these lower alkyl groups. Included.
  • the alkyl part of the trialkylsilyl, monoalkyldiarylsilyl and dialkylmonoarylsilyl has the same meaning as the lower alkyl.
  • Higher alkyls include straight-chain or branched, for example, decyl, dodecyl and hexadecyl.
  • aryl examples include phenyl, naphthyl and anthranyl having 6 to 14 carbon atoms.
  • the aryl moiety in aralkyloxy, triarylsilyl, monoalkyldiarylsilyl and dialkylmonoarylsilyl has the same meaning as the above aryl.
  • alkenyl moiety in alkenyl and alkenyloxy examples include straight-chain or branched having 2 to 30 carbon atoms, for example, vinyl, aryl, toprobenyl, 2-butenyl, 1-pentenyl, 2-hexenyl, dodecenyl and Hexadecenyl and the like are included.
  • Examples of the lower alkenyl moiety in lower alkenyloxy include those having 2 to 8 carbon atoms in the alkenyl, for example, vinyl, aryl, toprobenyl, 2-butenyl, 1-pentenyl, 2-hexenyl and the like. Include.
  • alkadienyl moiety in alkadienyl and alkadienyloxy examples include 1,3-pentagenenyl, 1,3-hexadenyl, 2,4-hexadenyl, having 4 to 30 carbon atoms, linoleyl, 2,4-decadenyl, .9, 1-tetradecadienyl, 11, 14-icosagenyl and the like are included.
  • Examples of the lower alkadienyl moiety in the lower alkadienyloxy include those having 4 to 8 carbon atoms in the alkadienyl, for example, 1,3-pentenyl, 1,3-hexenyl, and 2,4-hexenyl. .
  • the alkatrienyl moiety in al-trienyl and al-trienyloxy includes 1,3,5-hexatriene having 6 to 30 carbon atoms.
  • Nyl linolenyl, 1,3,5-docosatrienyl, 7,10,13-nonadecatrienyl, 11,14,17-icosatrienyl and the like.
  • Examples of the lower alkenyl group in the lower alkarylenyl group include those having 6 to 8 carbon atoms in the above alkenyl group, such as 1,3,5-hexatrienyl.
  • Lower cycloalkyl includes those having 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and the like.
  • the heterocyclic group includes an alicyclic heterocyclic group and an aromatic heterocyclic group.
  • Examples of the alicyclic heterocyclic group include, for example, 2-pyridonyl, 3-pyridonyl, 4-pyridonyl, 2-pyrrolidonyl, 3-pyrrolidonyl, dioxolanyl, pyrrolidinyl, morpholino, morpholinyl, thiomorpholino, thiomorpholinyl, piperazinyl, pyridolinidinyl, piperidinyl Homopiperazinyl, piperidyl, imidazolinyl, imidazolidinyl, 2-oxazolidonyl, 4-oxazolidinyl, 5-oxazolidinyl, 2-piperidonyl, 3-piperidonyl, 4-piperidonyl, pahydro-2-azepinonyl, perhydro-3-azepinonyl, pahydro 1-hydro-4-azepinonyl, succinimide, phthalimide, gluimide, hydantoin
  • aromatic heterocyclic group examples include peracylyl, pyrrolyl, tetrazolyl, phenyl, pyridyl, pyrazolyl, pyrazinyl, indolyl, isoindolyl, furyl, quinolyl, phthalazinyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolyl, thiazolyl, and thiazolyl. Etc. are included.
  • a nitrogen-containing heterocyclic group formed integrally with adjacent N (the nitrogen-containing heterocyclic group formed integrally with adjacent N may further include ⁇ , S, or another N ) includes, for example, pyrrolidinyl, morpholino, thiomorpholino, piperazinyl, virazolidinyl, pyrazolinyl, piperidino, homopiperazinyl, indolinyl, isoindolinyl, perhydroazepinyl, perhydroazosinyl, indolyl, isoindrill and the like.
  • the alkylene the lower alkyl or higher alkyl It includes groups obtained by removing one hydrogen atom from alkyl.
  • the halogen atom includes fluorine, chlorine, bromine and iodine atoms.
  • Substituents in the substituted lower alkyl, substituted higher alkyl and substituted lower alkoxy are the same or different and have 1 to 3 substituents, such as hydroxy, lower cycloalkyl, lower cycloalkenyl, lower alkoxy, lower alkoxy lower alkoxy, lower alkoxy.
  • Lucanoyloxy azide, di-lower alkanoylamino, lower alkenyloxy-power luponylamino, lower alkadienyloxycarbonylamino, lower alkatrienylyloxycarbonylamino, halogen atom, lower alkanol, substituted or unsubstituted aryl, A substituted or unsubstituted heterocyclic group, a substituted or unsubstituted succinimide, a substituted or unsubstituted phthalimide, a substituted or unsubstituted daltarimide, C RNR 13A R 14A (where R 13A and R 14A are the same or Differently, water Element, hydroxy, lower alkyl, lower cycloalkyl, higher alkyl, alkenyl, lower alkoxy, aryl, heterocyclic group or NR 15A R 16A (wherein R 15A and R 16A are the same or different, and hydrogen, lower alkyl
  • R 2GA represents hydrogen, lower alkyl, higher alkyl, lower cycloalkyl, aryl or heterocyclic group
  • R 21A represents hydrogen, lower alkyl, aryl, aromatic heterocyclic group, lower alkoxy, aralkyloxy.
  • NR 22A R 23A (wherein, R 22A and R 23A are the same or different, hydrogen, lower alkyl, or represents Ariru or aromatic heterocyclic group, the N integral with R 22 a and R 23 a are adjacent To form a substituted or unsubstituted nitrogen-containing heterocyclic group).
  • Substituents in the substituted alkylene may be the same or different and have 1 to 3 substituents, such as hydroxy, lower alkoxy, lower alkanoyloxy, azide, di-lower alkanoylamino, lower alkenyloxyl-ponylamino, lower alkadenyloxy.
  • alkenyl moiety for lower alkyl, higher alkyl, lower cycloalkyl, lower alkoxy, halogen atom, aryl, heterocyclic group, aromatic heterocyclic group, nitrogen-containing heterocyclic group formed integrally with adjacent N, alkenyl and alkenyloxy
  • alkenyl moiety, the alkadienyl moiety in alkadienyl and alkadienyloxy, the alkatrienyl moiety in alkatrienyl and alkatrienyloxy, and aralkyloxy are as defined above, respectively.
  • the lower alkyl moiety in the lower alkoxy lower alkoxy has the same meaning as the lower alkyl, and the lower alkylene moiety represents a group obtained by removing one hydrogen atom from the lower alkyl.
  • the lower alkenyl in the lower alkenyloxycarbonylamino include those having 2 to 8 carbon atoms in the alkenyl, for example, vinyl, aryl, topropropenyl, 2-butenyl, 1-pentenyl, 2-hexenyl and the like.
  • Examples of the lower alkadienyl in the lower alkadienyloxycarbonylamino include those having 4 to 8 carbon atoms in the alkadienyl, for example, 1,3-pentenyl, 1,3-hexenyl, 2,4-hexenyl. Etc. are included.
  • the lower alkenyl group in the lower alkenyl group includes those having 6 to 8 carbon atoms, for example, 1,3,5-hexatrienyl and the like in the alkatrienyl.
  • Lower cycloalkenyl includes those having 4 to 8 carbon atoms, for example, Includes 2-cyclopentenyl, 2-cyclohexenyl and 1,3-cyclopentenyl.
  • the lower alkanol in the lower alkanol, lower alkanoyloxy and di-lower alkanoylamino includes straight-chain or branched C 1-8 carbon atoms in the above-mentioned alkanoyl, for example, formyl, acetyl, propanol, isopropanol, and the like. And the like.
  • the aryl portion in arylo and arylcarbamoyl is as defined above.
  • the heterocyclic group moiety in the carbonyl bonded to the heterocycle has the same meaning as described above. Examples of the group including carbonyl include fluoryl, tenyl, nicotinol, and isonicotinoyl.
  • One embodiment of the present invention is a compound in which X is a halogen atom in compound (I).
  • Another embodiment of the present invention is a compound (I) in which X is a single bond together with R 4 .
  • a compound in which R 1 and R 2 are hydrogen is a preferred example. More preferably, but in a compound is a single bond together with R 4, R 1 and R 2 are hydrogen, R 3 is substitution or unsubstituted pyrrolyl, substituted or unsubstituted furyl, substituted Or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted Or unsubstituted tetrazolyl, substituted or unsubstituted pyrimidin
  • R 1 and R 2 are hydrogen and R 3 is substituted or unsubstituted oxazolidonyl, substituted or unsubstituted piperidonyl, substituted Or unsubstituted perhydroazepinonyl, substituted or unsubstituted succinimide, substituted or unsubstituted phthalimide, substituted or unsubstituted dalyl imide, substituted or unsubstituted hydantoinyl, substituted or unsubstituted thiazolidinediamine
  • the compound include oxonyl, substituted or unsubstituted oxopyrrolidonyl, substituted or unsubstituted maleimide, substituted or unsubstituted thiazolidonyl, and substituted or unsubstituted oxazolidinedionyl. it can.
  • the pharmacologically acceptable salts of compound (I) include acid addition salts, metal salts, ammonium salts, organic amine addition salts and amino acid addition salts, and the acid addition salts include hydrochloride and odor.
  • Inorganic acid salts such as hydride, sulfate and phosphate, formate, acetate, oxalate, benzoate, methanesulfonate, P-toluenesulfonate, maleate, fumarate And organic acid salts such as tartrate, citrate, succinate and lactate.
  • metal salts include alkali metal salts such as lithium salt, sodium salt and potassium salt, and alkali metals such as magnesium salt and calcium salt.
  • Examples include earth metal salts, aluminum salts and zinc salts, etc., and ammonium salts include salts such as ammonium and tetramethylammonium. Include addition salts such as phosphorus and piperidine, Examples of the amino acid addition salts of glycine, phenylene Ruaranin, ⁇ scan aspartic acid, Dar evening include addition salts such as tromethamine acid and lysine.
  • some of the compounds (I) usually produced from radicicol as starting compounds may include various stereoisomers, positional isomers, tautomers and the like.
  • the present invention includes all of these possible isomers and mixtures thereof, and the mixing ratio may be in any ratio.
  • the production process of compound (I) mainly includes oximation (Production method 1), alkylation, Consists of the following reaction steps: substitution reaction (Production method 2), halohydrination (Production method 3), desilylation (Production method 4), or acylation (Production method 5). It can be manufactured in combination.
  • Radicicol or a compound (F) obtained by a method known from radicicol Japanese Patent Laid-Open No. 4-226991
  • radicicol or one of the phenolic hydroxyl groups of radicicol substituted with alkanoyl, alkenoyl, alkadienyl or alkatrienoyl A method known from Radicicol [for example, Journal of the Americas, Chemical, Society (Journal of the
  • R la and R 2a wherein R 1 and trialkylsilyl from R 2, Toriari - Rushiriru a monoalkyl di ⁇ Li one Rushiriru and a group remaining after removing dialkyl mono ants one Rushiriru, scale 115 and Shaku 21
  • R 1 and R 2 has the same meaning as R 1 and R 2 , respectively, wherein at least one of R 1 and R 2 is trialkylsilyl, triarylsilyl, monoalkyldiarylsilyl or dialkylmonoarylsilyl.
  • R 1 R 2 , R 3 and Y are as defined above.
  • Compound (Ia) is prepared by converting compound (F) or compound (G) in the presence or absence of an acid in the presence of H 2 N— ⁇ —Y—R 3 (II) (wherein R 3 and ⁇ are as defined above)
  • the compound (II) represented by the following formula (II) or an acid addition salt thereof can be obtained.
  • a reaction solvent pyridine, chloroform, dichloromethane, ethyl acetate, ether, tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile, etc. are used alone or in combination, and pyridine or ethyl acetate is preferred.
  • c Acids include hydrochloric acid, acetic acid, trifluoroacetic acid, sulfuric acid, p-toluenesulfonic acid, camphorsulfonic acid and the like, and preferably 0.1 to 10 equivalents to compound (F) or compound (G).
  • Examples of the acid addition salts of compound (II) include hydrochloride, hydrobromide, sulfate, nitrate, formate, acetate, trifluoroacetate, methanesulfonate, p-toluenesulfonate, and benzoic acid. Acid salts, oxalates, fumarates, maleates, tartrates and the like are used.
  • an acid addition salt of the salt compound (II) is used, one or more equivalents, preferably 1 to 10 equivalents of a base, for example, pyridine, triethylamine, diisopropylethylamine are used based on the acid addition salt of the compound (II).
  • a base for example, pyridine, triethylamine, diisopropylethylamine
  • Amines such as amines, N, N-dimethylaniline and N, N-ethylylaniline
  • alkali metal carbonates such as sodium carbonate, potassium carbonate and sodium bicarbonate.
  • ⁇ , ⁇ -dimethylaniline or ⁇ , ⁇ -ethylylaniline is used, or pyridine is used also as a solvent.
  • the compound (II) or an acid addition salt thereof is used in an amount of 1 equivalent or more, preferably 1 to 5 equivalents, based on the compound (F) or the compound (G).
  • the reaction is usually carried out at ⁇ 20 to 100 t, preferably at 20 to 60 ° C., and is completed in 1 to 80 hours.
  • Compound (Ia) is obtained by subjecting a hydroxyl group of compound (H) or compound (J) obtained according to a method known from Radicicol (W096 / 33989) to another functional group by alkylation or substitution reaction. Can also be obtained by the step of converting to
  • Compound (Ia) is obtained by reacting compound (H) with compound (III) represented by HO—Y—R 3 (III) (wherein R 3 and Y are as defined above) in the presence of a condensing agent. It can be obtained by reacting.
  • R 3 is a substituted or unsubstituted succinimide, a substituted or unsubstituted phthalimide, a substituted or unsubstituted daryl imide, a substituted or unsubstituted hydantoinyl, a substituted or unsubstituted thiazolidine
  • Compounds that are dionyl, substituted or unsubstituted maleimide, substituted or unsubstituted oxopyrrolidonyl or substituted or unsubstituted oxazolidinedionyl can be prepared by subjecting compound (J) to the presence of a condensing agent.
  • reaction solvent toluene, THF, dichloromethane or the like is used alone or as a mixture.
  • a mixture of a trivalent phosphorus compound such as triphenylphosphine and tributylphosphine and an azo compound such as getyl azodicarboxylate (DEAD) and 1,1- (azodicarbonyl) dipiperidine are used.
  • the compound (III) and the condensing agent are each used in an amount of 1 equivalent or more, preferably 1 to 5 equivalents, based on the compound (H).
  • the unsubstituted oxopyrrolidone or the substituted or unsubstituted oxazolidinedione and the condensing agent are each used in an amount of 1 equivalent or more, preferably 1 to 5 equivalents, based on Compound (J).
  • the reaction is usually carried out at -20 to 80 ° C, preferably 0 to 30 and is completed in 5 minutes to 48 hours.
  • the compound (Ib) can be obtained by opening the epoxide of the compound (Ia) to a halohydrin or the like.
  • R 1 R 2 , R 3 and Y are as defined above, X a is a halogen atom, R 4a is hydrogen, formyl, or SO—Z (where Z is as defined above) ) Process 3 _ 1
  • those in which R 4a is hydrogen can be obtained by reacting the compound (Ia) with an acid such as hydrochloric acid or hydrobromic acid or with a Lewis acid such as titanium tetrachloride. it can.
  • dioxane, THF, ether, black form, dichloromethane, DMF, acetonitrile, methanol, ethyl acetate or the like is used alone or as a mixture.
  • the acid or Lewis acid is used in an amount of 1 equivalent or more, preferably 1 to 10 equivalents, relative to compound (Ia).
  • the reaction is usually carried out at -20 to 40 ° C, preferably at 0 to 40, and is completed in 10 minutes to 48 hours.
  • a compound wherein R4a is formyl can be obtained by reacting the compound (Ia) with a phosphorus oxyhalide such as phosphorus oxychloride or phosphorus oxybromide in DMF.
  • a phosphorus oxyhalide such as phosphorus oxychloride or phosphorus oxybromide in DMF.
  • the phosphorus oxyhalide is used in an amount of 1 equivalent or more, preferably 2 to 5 equivalents, relative to compound (Ia).
  • the reaction is usually carried out at -10 to 40 ° C, preferably at 0 to 40, and is completed in 1 to 48 hours.
  • the dimer compound in which R 4a is SO—Z (where Z is as defined above) is obtained by converting the compound (Ia) to a halogenated thiol such as thionyl chloride or thionyl bromide. Can be obtained by reacting with carbonyl.
  • a halogenated thiol such as thionyl chloride or thionyl bromide.
  • As the solvent DMF, chloroform, dichloromethane, dimethylsulfoxide (DMS0), acetonitrile and the like are used alone or as a mixture.
  • the thionyl halide is used in an amount of 1 equivalent or more, preferably 2 to 10 equivalents, based on compound (Ia).
  • the reaction is usually carried out at -10 to 40 ° C, preferably at 0 to 40 ° C, and is completed in 1 to 48 hours.
  • Compound (Ic) in which at least one of R 1 and R 2 of compound (I) is substituted with trialkylsilyl, triarylsilyl, monoalkyldiarylsilyl or dialkylmonoarylsilyl is removed.
  • Compound (Id) can be obtained by silylation.
  • R lb , R 2b , R 3 , RY and X are as defined above, and R lc and R 2c are the above trialkylsilyl, triarylsilyl, monoalkyldiaryl in R lb and R 2b ) Where at least one of silyl or dialkylmonoarylsilyl has been replaced by hydrogen)
  • Compound (Id) can be obtained by reacting compound (Ic) with a desilylating agent.
  • THF trifluoroethyl ether
  • chloroform a mixture of benzylammonium fluoride
  • dichloromethane a compound that is used alone or as a mixture.
  • Tetrabutylammonium fluoride TBAF
  • sodium fluoride sodium fluoride
  • hydrofluoric acid a mixture of benzylammonium fluoride
  • the reaction may be performed by increasing the pH by adding an acid such as acetic acid or hydrochloric acid.
  • the desilylating agent is used in an amount of 0.1 equivalent or more, preferably 1 to 10 equivalents, relative to compound (Ic).
  • the reaction is usually performed at -20 to 50 ° C, and is completed in 5 minutes to 24 hours.
  • Compound (I f) in which at least one of R 1 R 2 and R 4 in compound (I) is alkanoyl, alkenoyl, alkadienol or alkatrienoyl is obtained by acylating the following compound (I e) be able to.
  • R 3 , Y and X are as defined above, and R ld , R 2d and R 4b are as defined above for R 1 , R 2 and R 4 , but at least one of them is hydrogen
  • R le , R 2 e and R 4 c are those wherein at least one of the hydrogens in the above R 1 d , R 2 d and R 4 b is replaced by alkanoyl, alkenoyl, alkadienoyl or alkatrienoyl. is there)
  • Compound (IO is a compound (Ie) comprising at least one equivalent, preferably 1 to 100 equivalents of an acid halide, an acid anhydride or a mixed anhydride containing a desired alkanol, alkenoyl, alkadienoyl or alkatrienoyl, etc. And in the presence of a base.
  • DMF, DMS0, chloroform, dichloromethane, toluene and the like are used alone or as a mixture.
  • An arbitrary hydroxyl group can be modified by appropriately introducing and removing a protective group for a hydroxyl group, but a plurality of hydroxyl groups can be simultaneously modified.
  • the base pyridine, triethylamine, N, N-dimethylaniline, ⁇ , ⁇ -getylaniline and the like are used in an amount of 1 equivalent or more, preferably 1 to 200 equivalents, relative to compound (Ie).
  • a base such as pyridine can be used also as a solvent.
  • DMAP dimethylaminopyridine
  • the reaction is usually performed at -20 to 50, and is completed in 5 minutes to 24 hours.
  • the conversion of the functional group of RR 2 , R 3 , RY or X may be performed by a known method other than the above-mentioned method [for example, Comprehensive Organic Transformations (Comprehensive Organic Transformations, R ⁇ C ⁇ Larock (1989)].
  • the isolation and purification of the product in the above production method can be carried out by appropriately combining methods used in ordinary organic synthesis, for example, filtration, extraction, washing, drying, concentration, crystallization, various types of chromatography, and the like.
  • the intermediate can be subjected to the next reaction without purification.
  • the compound (I) When it is desired to obtain a salt of compound (I), the compound (I) may be purified as it is when a salt thereof is obtained, or may be dissolved or suspended in a suitable solvent when obtained in a free form, An acid or a base may be added to form a salt.
  • Compound (I) or a pharmaceutically acceptable salt thereof may be present in the form of an adduct with water or various solvents, and these adducts are also included in the present invention.
  • Specific examples of the compound (I) are shown in Tables 1 (1) to 1 (3) and 2 (1) to 2 (2).
  • Me, Et, l Bu is each methyl in the table described below, Echiru means tert- butyl.
  • SR-3Y1 cells were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal calf serum (FCS), supplemented with radicicol derivatives at each test concentration, and cultured at 37 t: 5% CO2 for 40 hours.
  • Lysis buffer [50 niM Hepes NaOH, H 7.4, 25 m salt (NaCl), 1% nonidet ⁇ -40 ( ⁇ 40), 0.1 ⁇ ⁇ ⁇ ⁇ ⁇ sodium dodecyl sulfonate (SDS) mM Dithiothreitol, 1 mM Ethylenediaminetetraacetic acid (EDTA), 1 mM Phenylmethylsulfonyl fluoride
  • Tyrosine phosphorylation inhibitory activity of La Defense Ishikoru derivatives can be represented by a derivative such as the percentage of protein as compared to the case without the addition of drug has tyrosine phosphorylation is halved concentration (IC 5 0).
  • test compound shows a strong inhibitory activity on intracellular tyrosine kinase activity, and compound (I) is useful as an inhibitor of tyrosine kinase.
  • Test example 2 Rat normal fibroblast 3 ⁇ cell line and its growth inhibition test on V-src oncogene transformed cell SR-3Y1 cell line
  • a 96-well microplate 1000 rat normal fibroblast 3Y1-B cell lines or a V-s rc oncogene-transformed cell SR-3Y1 cell line per well were spread.
  • the cells were pre-cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal calf serum (FCS) in a 5% carbon dioxide incubator at 37 ° C for 24 hours.
  • DMEM Dulbecco's modified Eagle's medium
  • FCS fetal calf serum
  • the DMS0 solution of each test compound adjusted to 10 mM was serially diluted in a culture medium, and 501 was added to each well.
  • the cells were cultured in a 5% CO 2 incubator at 37 for 72 hours.
  • the 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolidine dissolved in the culture medium was adjusted to a final concentration of 1 mg / ml 5 hours before the end of the culture.
  • Dembromide (3- (4,5-dimethylthiazol-2-y 0 -2,5-diphenyl tetrazolium bromide (manufactured by Sigma), hereinafter abbreviated as MTT)) is 50 i 1 per well.
  • DMS0 was dispensed at 150 1 per well, and vigorously stirred using a plate mixer. MTT-formazan crystals were completely dissolved. Then, the difference in absorbance between 550 nM and 630 nM was measured using a microplate reader (manufactured by Wako Pure Chemical Industries, Ltd.).
  • the cell growth inhibitory activity was calculated as the 50% growth inhibitory concentration (IC 5 ) using the formula of the measurement software (Soft Max Pro) attached to the microplate reader.
  • test compound showed stronger cell strength in SR-3Y1 cells compared to 3Y1-B cells.
  • Compound (I) is useful as an antitumor agent since it exhibits vesicle growth inhibitory activity.
  • mice are arbitrarily divided into groups of 5 mice, and 7.5% cremophor EL (Sigma) / 5% dimethylacetamide (DMA) /87.5% concentration in saline solution
  • the test compound dissolved at 10 mg / ml was administered intravenously to mice at a dose of 100 mg / kg once daily for 5 days.
  • the antitumor activity of the test compound was represented by the ratio (TZC) of the tumor volume (T) of the test compound-administered group to the tumor volume (C) of the non-drug-treated control group on day 7 after administration of the test compound.
  • test compound shows excellent antitumor activity
  • compound (I) is useful as an antitumor agent.
  • Test Example 4 Intracellular Raf-1 protein reduction activity and Erk2 phosphorylation inhibitory activity Activated K-ras transgenic rat renal epithelial cells
  • KNRK 5.2 Cells contain 10% fetal calf serum (FCS) Dulbecco Radase at each test concentration in denatured Eagle's medium (DMEM) Isicol derivative was added, and the cells were cultured at 37 under 5% carbon dioxide for 40 hours. Lysis buffer with cooled cells [HEPES 50 mM NaOH, pH 7.4, 250 mM NaCl
  • PVDF polyvinylidene difluoride
  • a horseradish peroxidase-labeled primary antibody that reacts with each of the primary antibodies (anti-horse Ig antibody, or anti-mouse Ig antibody,
  • the Erk2 phosphorylation inhibitory activity of a radicicol derivative was calculated by calculating the ratio of phosphorylated Erk2 protein (phosphorylated Erk2 protein mass / Erk2 total protein mass) from the results obtained from samples at each drug concentration. It can be indicated by the derivative concentration (IC 50 ) such that the ratio is reduced by half compared to the case where no drug is added.
  • Raf-1 protein mass / Erk2 total protein mass the ratio of Raf-1 protein to Erk2 protein (Raf-1 protein mass / Erk2 total protein mass), which does not change the protein mass due to drug treatment, was determined from the sample at each drug concentration. It can be calculated from the results obtained, and can be indicated by the derivative concentration (IC 5Q ) that halves the ratio compared to the case where no drug is added.
  • test compound showed an effect of reducing intracellular Raf-1 protein content and an effect of inhibiting Erk2 phosphorylation.
  • Compound (I) or a pharmaceutically acceptable salt thereof is administered as it is or orally or parenterally as various pharmaceutical compositions.
  • dosage form of such a pharmaceutical composition include tablets, pills, powders, granules, capsules, suppositories, injections, and drops.
  • Carriers used in pharmaceutical compositions include, for example, water, distilled water for injection, physiological saline, glucose, fructose, sucrose, mannitol, lactose, starch, corn starch, cellulose, methylcellulose, carboxymethylcellulose, Hydroxy Propylcellulose, alginic acid, talc, sodium citrate, calcium carbonate, calcium hydrogen phosphate, magnesium stearate, urea, silicone resin, sorbitan fatty acid ester, or glycerin fatty acid ester, etc., depending on the type of preparation. It is appropriately selected.
  • the dose and frequency of administration of the compound (I) used for the above purpose vary depending on the intended therapeutic effect, administration method, treatment period, age, body weight, etc., and are orally administered or parenterally administered (for example, Injection, infusion, rectal administration by suppository, dermal application, etc.), the dose is usually 0.01 to 20 mg / kg per day for adults, and the frequency of administration is once or several times a day.
  • the peak position ( ⁇ ) of the proton nuclear magnetic resonance spectrum (MR) used in Reference Examples and Examples is expressed in parts per million (ppm) from tetramethylsilane to the lower magnetic field side. These were measured at 270 MHz, and the observed shape, coupling constant, and number of protons are shown in parentheses after the ⁇ value of each signal.
  • the peak shape is expressed as follows.
  • the isomer ratio was about 2: 1.
  • the isomer ratio was about 2: 1.
  • the isomer ratio was about 2: 1.
  • the isomer ratio was about 8: 1.
  • the isomer ratio was about 4: 1.
  • the isomer ratio was about 8: 1.
  • the isomer ratio was about 2: 1.
  • the isomer ratio was about 2: 1.
  • the isomer ratio was about 1.9: 1.
  • Example 1 compound 12 was obtained from radicicol and the hydrochloride of compound m.
  • the isomer ratio was about 1.7: 1.
  • Compound 13 was obtained from radicicol and compound n according to Example 11.
  • the isomer ratio was about 2: 1.
  • Compound 14 was obtained from radicicol and compound o according to Example 11.
  • the isomer ratio was about 2: 1.
  • the isomer ratio was about 2: 1.
  • the isomer ratio was about 1.7: 1.
  • the isomer ratio was about 2: 1.
  • the isomer ratio was about 1.8: 1.
  • the isomer ratio was about 1.5: 1.
  • the isomer ratio was about 3: 1.
  • the isomer ratio was about 1.7: 1.
  • Compound 23 was obtained from radicicol and compound x according to Example 11.
  • the isomer ratio was about 1.6: 1.
  • the isomer ratio was about 2.5: 1.
  • the isomer ratio was about 1.7: 1.
  • the isomer ratio was about 2.5: 1.
  • Compound 27 was obtained from radicicol and the compound according to Example 11.
  • the isomer ratio was about 2: 1.
  • compound 33 was obtained from the compound, triphenylphosphine, DEAD and 2,4-thiazolidinedione.
  • Example 31 compound 33 was treated with TBAF and then separated by high performance liquid chromatography to obtain compound 34 (high polarity) and compound 35 (low polarity).
  • compound 36 was obtained from the compound, triphenylphosphine, DEAD and trimethylhydantoin.
  • N- ⁇ 4-[(4-pyridylmethyl) amino] was obtained from tert-butyl N- (4-aminobutyroxy) amine and 4-pyridinecarboxaldehyde according to steps 113 of Reference Example 1.
  • a trifluoroacetate of compound c was obtained according to Steps 1-4 of Reference Example 1.
  • trifluoroacetate of compound f was obtained from tert-butyl N- ⁇ 2-hydroxy-3-[(4-pyridyl) methylamino] propoxy ⁇ potassium rubinate.
  • N-Ethyl-N- [2- (phthalimidoxy) ethyl] tert-butyl rubamate (3.50 g) was dissolved in 30 ml of chloroform and added with 0.60 ml of hydrazine monohydrate. Stir for 15 minutes. The resulting precipitate was separated by filtration, and 3.00 ml of a 4N hydrogen chloride / ethyl acetate solution was added to the filtrate. The solvent was removed under reduced pressure to obtain 2.60 g of the compound i hydrochloride.
  • N-ethyl-N-ethyl-N- (2-hydroxyethyl) carbamate is obtained from N-ethyl-N- (2-hydroxyethyl) carbamate, N-hydroxyfurimide, triphenylphosphine and DEAD.
  • the hydrochloride of compound j was obtained according to Steps 9-13 of Reference Example 9.
  • Step 9_2 of Reference Example 9 2- [3- (6-methyl-2-pyridyl) propoxy] ethanol, N-hydroxyfurimide, triphenylphosphine and N- ⁇ 2- [ After obtaining 3-(6-methyl-2-pyridyl) propoxy] ethoxy ⁇ phthalimide, a hydrochloride of the compound m was obtained according to Step 9-13 of Reference Example 9.
  • N- (cinnamyloxy) furimide was obtained from cas alcohol, N-hydroxyphenylimide, triphenylphosphine and DEAD, and then the compound was prepared according to Reference Example 11. got n.
  • Step 15-4 of Reference Example 15 a hydrochloride of Compound Q was obtained from 4-[(phthalimidoxy) methyl] imidazole.
  • trimethyl-2-imidazole carboxyaldehyde was obtained from 2-imidazolecarboxaldehyde, carboxylamide and methyl iodide.
  • Step 9-2 of Reference Example 9 2-hydroxymethyl-1-methylimidazole, N-hydroxyphthalimide, triphenylphosphine, and N-[(trimethyl-2-imidazolyl) methoxy] phenol were obtained from DEAD. After obtaining the imide, a hydrochloride of the compound r was obtained according to Step 15-4 of Reference Example 15.
  • Reference Example 1 9 [(3,5-Dimethyl-4-isoxazolyl) methoxy] amine (compound) According to Step 1-1 of Reference Example 1, 4-chloromethyl-3,5-dimethylisoxazole was used. After obtaining 4-[(phthalimidoxy) methyl] -3,5-dimethylisoxazole, a hydrochloride of compound t was obtained according to Step 15-4 of Reference Example 15.
  • Step 9-2 of Reference Example 9 5- (2-hydroxyethyl) -4-methylthiazole, N-hydroxyphthalimide, triphenylphosphine and DEAD were used to give [2- (phthalyl) After obtaining [midoxy) ethyl] -4-methylthiazole, a hydrochloride of compound u was obtained according to Step 15-4 of Reference Example 15.
  • Step 1-1 in Reference Example 1 5-[(phthalimidoxy) methyl] -2- (triphenylmethyl) tetramer was obtained from 5- (chloromethyl) -2- (triphenylmethyl) tetrazole. A sol was obtained.
  • Step 15-1 of Reference Example 15 5-[(phthalimidoxy) methyl] tetrazole was used to give 5-[(phthalimidoxy) methyl] -trimethyltetrazole and 5-[(phthalimidoxy) methyl]- 2-Methyltetrazole was obtained.
  • compound X was obtained from 5-[(phthalimidoxy) methyl] -trimethyltetrazole.
  • Step 15-2 of Reference Example 15 2- (hydroxymethyl) pyrazine was obtained from methyl 2-pyrazinecarboxylate.
  • Step 9-2 of Reference Example 9 2-[(phthalimidoxy) ) After obtaining methyl] pyrazine, a hydrochloride of compound z was obtained according to Step 9-3 of Reference Example 9.
  • step 28-1 and step 28-2 of Example 28 trifluoroacetate of compound dd was obtained using cyclohexanone instead of cyclopentanone.
  • N- (2-hydroxyethoxy) furimide was obtained from 2-bromoethanol, N-hydroxyphthalimide and potassium carbonate.
  • Process 3 0-2 N- (2-hydroxyethoxy) furimide was obtained from 2-bromoethanol, N-hydroxyphthalimide and potassium carbonate.
  • the present invention provides a novel radicicol derivative or a pharmacologically acceptable salt thereof, which has a tyrosine kinase inhibitory activity and has an antitumor or immunosuppressive activity.

Abstract

L'invention concerne des composés représentés par la formule (I), présentant une activité d'inhibition de la tyrosine kinase ou des sels de ceux-ci. Dans cette formule R1 et R2 représentent chacun hydrogène, alcanoyle, etc.; Y représente alkylène éventuellement substitué; R3 représente NR?5R6 (où R5¿ représente hydrogène, alkyle inférieur éventuellement substitué, etc.; et R6 représente alkyle substitué, etc.), NR?7COR8 [où R7¿ représente hydrogène, alkyle éventuellement substitué, etc.; et R8 représente alkyle inférieur substitué, alcoxy inférieur substitué, NR?9R10 (où R9 et R10¿ représentent chacun hydrogène, alkyle inférieur éventuellement substitué, etc.)], NR?11COR12 (où R11¿ représente alkyle inférieur éventuellement substitué, etc.; et R12 représente alkyle inférieur, alcoxy inférieur, etc.), alcoxy inférieur substitué, alkényloxy substitué, etc.; X représente halogéno et forme avec R4 une liaison unique; et R4 forme avec X une liaison unique ou représente hydrogène, alcanoyle, etc.
PCT/JP1999/002138 1998-04-24 1999-04-22 Derives de radicicol WO1999055689A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005000778A1 (fr) 2003-06-27 2005-01-06 Kyowa Hakko Kogyo Co., Ltd. Inhibiteur de proteines de la famille hsp90
JP2006501147A (ja) * 2002-04-25 2006-01-12 ユニバーシティー オブ コネティカット ヘルス センター 非ワクチン治療法の治療効果を改善するための熱ショックタンパク質の使用
US7115651B2 (en) 2000-08-25 2006-10-03 Sloan-Kettering Institute For Cancer Research Macrocycles and uses thereof
WO2009105755A2 (fr) 2008-02-21 2009-08-27 Nexgenix Pharmaceuticals Composés de promédicaments macrocycliques utilisés comme agents thérapeutiques
US8067412B2 (en) 2006-08-11 2011-11-29 Universite De Strasbourg Macrocyclic compounds useful as inhibitors of kinases and HSP90
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996033989A1 (fr) * 1995-04-26 1996-10-31 Kyowa Hakko Kogyo Co., Ltd. Derives de radicicol
WO1998018780A1 (fr) * 1996-10-25 1998-05-07 Kyowa Hakko Kogyo Co., Ltd. Derives de radicicol

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996033989A1 (fr) * 1995-04-26 1996-10-31 Kyowa Hakko Kogyo Co., Ltd. Derives de radicicol
WO1998018780A1 (fr) * 1996-10-25 1998-05-07 Kyowa Hakko Kogyo Co., Ltd. Derives de radicicol

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7115651B2 (en) 2000-08-25 2006-10-03 Sloan-Kettering Institute For Cancer Research Macrocycles and uses thereof
JP2006501147A (ja) * 2002-04-25 2006-01-12 ユニバーシティー オブ コネティカット ヘルス センター 非ワクチン治療法の治療効果を改善するための熱ショックタンパク質の使用
WO2005000778A1 (fr) 2003-06-27 2005-01-06 Kyowa Hakko Kogyo Co., Ltd. Inhibiteur de proteines de la famille hsp90
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection
US8067412B2 (en) 2006-08-11 2011-11-29 Universite De Strasbourg Macrocyclic compounds useful as inhibitors of kinases and HSP90
US8450305B2 (en) 2006-08-11 2013-05-28 Universite De Strasbourg Macrocyclic compounds useful as inhibitors of kinases and HSP90
WO2009105755A2 (fr) 2008-02-21 2009-08-27 Nexgenix Pharmaceuticals Composés de promédicaments macrocycliques utilisés comme agents thérapeutiques

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