WO2004024141A1 - Inhibiteurs de proteines de la famille hsp90 - Google Patents

Inhibiteurs de proteines de la famille hsp90 Download PDF

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Publication number
WO2004024141A1
WO2004024141A1 PCT/JP2003/011087 JP0311087W WO2004024141A1 WO 2004024141 A1 WO2004024141 A1 WO 2004024141A1 JP 0311087 W JP0311087 W JP 0311087W WO 2004024141 A1 WO2004024141 A1 WO 2004024141A1
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Prior art keywords
substituted
unsubstituted
protein
hsp90
unsubstituted lower
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PCT/JP2003/011087
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English (en)
Japanese (ja)
Inventor
Tsutomu Agatsuma
Yutaka Kanda
Hideyuki Onodera
Noriko Matsushita
Tatsuhiro Ogawa
Shiro Akinaga
Shiro Soga
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Kyowa Hakko Kogyo Co., Ltd.
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Priority to AU2003264356A priority Critical patent/AU2003264356A1/en
Priority to JP2004535890A priority patent/JPWO2004024141A1/ja
Publication of WO2004024141A1 publication Critical patent/WO2004024141A1/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • the present invention relates to a heat shock protein 90 (Hsp90) family protein inhibitor which contains a cyclic phenylacetic acid derivative as an active ingredient and is useful as a pharmaceutical such as an antitumor agent.
  • Hsp90 heat shock protein 90
  • a geldanamycin derivative [17 -. AAG, in Vu Est game conditioner Honoré ⁇ two U Drugs (. L nves t New Drugs) , 17, 361-373 (1999)] Oyopi Radi Shikoru derivatives [Cancer 'Research (Cancer Research), 59, 2931-2938 (1999), Blood, 96, 2284-2291 (2000), Cancer ⁇ Cancer Chemotherapy and Pharmacology, 48, 435-445 (Cancer Chemotherapy and Pharmacology) 2001), W096 / 33989, WO98 / 18780, W099 / 55689, WO02 / 16369] have been reported to exhibit antitumor effects.
  • Hsp90 family proteins include Hsp90a protein, Hsp90B protein, grp94, hsp75 / TRAPl, etc. [Pharmacology & Therapeutics, 79, 129-168 (1998), Molecular And Molecular Endocrinology, 13, 1435-1448 (1999)].
  • curvularin Curvularin
  • Tetrahedron 54, 15937-15958 (1998)].
  • An object of the present invention is to provide an Hsp90 family protein inhibitor and the like, which contains a cyclic phenylacetic acid derivative or a pharmacologically acceptable salt thereof as an active ingredient, which is useful as a pharmaceutical such as an antitumor agent. .
  • the present invention relates to the following (1) to (24).
  • RR 2 , R 3 and: R 4 are the same or different and each represents a hydrogen atom, hydroxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, halogen Substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkanoyloxy, substituted or unsubstituted aroyloxy, substituted or unsubstituted aralkyloxy, substituted or unsubstituted lower alkoxyl-poeroxy, di-rubamoyloxy, substituted Or unsubstituted lower alkylaminocarbonylcarbonyl, substituted or unsubstituted di-lower alkylaminocarboxy, amino, substituted or unsubstituted lower alkylamino, substituted or unsubstituted di-lower alkylamino, substitute
  • X represents an oxygen atom, a sulfur atom, one NOR 5 ) — (wherein R 5 represents a hydrogen atom or a substituted or unsubstituted lower alkyl) or one CH 2 —,
  • a is CR al R a2 — wherein 1 and Ra2 are the same or different and each represents a hydrogen atom, a hydroxy, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkoxy, a substituted or unsubstituted Substituted aryloxy, substituted or unsubstituted aryloxy, (Wherein Ra 3 is a substituted or unsubstituted lower alkyl, Substituted or unsubstituted lower alkoxy, amino, substituted or unsubstituted lower alkylamino, substituted or unsubstituted di-lower alkylamino, substituted or unsubstituted arylamino or substituted or unsubstituted aralkylamino), substituted or unsubstituted Represents an aryl group or a substituted or unsubstituted heterocyclic group, or Ral and Ra 2 together form
  • c is one (CRdRc ⁇ CHRcsCR Rc — (wherein, n and p have the same meanings as m, Rcl and Re 2 have the same meanings as Ral and Ra2, respectively, and R c3, Rc4 and R c5 have the same meanings as Ral and Ra2, respectively) R b3 , R b4 and R b5 have the same meanings),
  • R d is — (CRdiCR d2 ) q — (wherein q has the same meaning as m, R dl and R d2 have the same meanings as R al and R a2 , respectively) or one CHR d3 CR d4 R d5 — ( In the formula, R d3 , R d4 and R d5 represent the above-mentioned R 3 ⁇ 43 , respectively: R b4 and R b5 ),
  • e is one CR e 3 ⁇ 4 e2 — (wherein R el and; R e2 are the same or different and each represents a hydrogen atom or A heat-shock protein 90 (Hsp90) family protein inhibitor comprising, as an active ingredient, a cyclic phenylacetic acid derivative represented by ⁇ , which represents substituted or unsubstituted lower alkyl).
  • Hsp90 heat-shock protein 90
  • R 2 and R 4 are the same or different and each is hydroxy, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkanoyloxy, substituted or unsubstituted aryloyloxy, substituted or unsubstituted
  • the Hsp90 family protein inhibitor according to the above (1) which is an aralkyloxy, lower alkoxyl propylonyloxy, rubamoyloxy, lower alkylaminocarboxy or di-lower alkylamino propyloxy.
  • X is an oxygen atom, a guard CR a 3 ⁇ 4 a2 - a (wherein, R al and R a2 are the same as defined, respectively therewith the), b gar CHR b 3CR b4 R 3 ⁇ 45 - (Wherein R b3 , H b4 and Rb5 are as defined above, respectively), and c is one CR c iRc2— (where R C I and
  • Rc2 are the same meanings as defined above, respectively), d gar CHRd3 C Rd4 R d5 i (wherein, R d3,
  • Rd 4 and Rds is the same meanings as defined above, respectively), and e gar CH (CH 3) - a above (1) to according to any one (4): Bsp90 family protein inhibitor.
  • X is an oxygen atom
  • a is a substituted or unsubstituted divalent heterocyclic group
  • b and C represents a bond
  • d gar CHRd3CRd4 R d5 i (wherein,; Rd3, Rd4 and Rd5 each have the same meanings as defined above) and.
  • Hsp90 Fuamiri protein inhibitor according to any one of e is one CH (CH 3) a _ the above (1) to (4).
  • RR 2 , R 3 , -RX, a, b, c, d and e have the same meanings as described above
  • a therapeutic agent for diseases involving Hsp90 family protein containing a salt as an active ingredient or a protein to which Hsp90 family protein binds Hsp90 client protein.
  • Hsp90 client to which the Hsp90 family protein or Hsp90 family protein according to the above (7) is an alkoxycanoleponinoleoxy, carbamoinoleoxy, lower alkylaminocanolebonyloxy or di-lower alkylaminocarboxy-loxy.
  • a therapeutic agent for diseases involving protein is an alkoxycanoleponinoleoxy, carbamoinoleoxy, lower alkylaminocanolebonyloxy or di-lower alkylaminocarboxy-loxy.
  • X is an oxygen atom, (wherein, Ral and it respectively the same meanings as defined above) a is _ CRalRa2- a, b is one CKRb3 CR b4 R b 5 _ (wherein, R b3, Rb4 Oyo Pi Rb 5 are each the same meanings as defined above), C is one CR cl Ii c2 - a (wherein, Rei and R c2 are the same meanings as defined above, respectively), d is ⁇ CHR d3 CR d4 R d5 — (where,
  • Rd 3, Rd 4 and Rd5 are the same meanings as defined above, respectively), and e is one CH (CH 3) - a is the (7) ⁇ (1 0 Hsp90 family one protein according to any one of) or A therapeutic agent for diseases involving Hsp90 family proteins (Hsp90 client protein).
  • X is an oxygen atom
  • a is a substituted or unsubstituted divalent heterocyclic group
  • b and c represent a bond
  • d is -CHR d3 CR d4 R d5 — (wherein, R d3 , R d4 and R d5 are as defined above, respectively, and e is -CH (CH 3 )-
  • R 2 and R 4 are the same or different and are hydroxy, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkanoyloxy, substituted or unsubstituted aroyloxy, substituted or unsubstituted (13)
  • the antitumor agent according to any one of (16) and said R 3 is a hydrogen atom (1 3) - (1 5).
  • X is an oxygen atom
  • a is —CR al R a2 — (wherein, R al and R a2 have the same meanings as above)
  • b is —CHR b3 CRb4Rb5 (formula Wherein , R b3, Rb4 and R b5 are as defined above
  • c is —CR cl R c2 — (wherein Rci and ⁇ R c2 are as defined above, respectively).
  • d is —CHRd 3 CRd 4 Rd 5 — (wherein K d3 . R d4 and R d5 are each as defined above)
  • e is —CH (CH 3 ) — )
  • the antitumor agent according to any one of (1) to (16).
  • X is an oxygen atom
  • a is a substituted or unsubstituted divalent heterocyclic group
  • b and c represent a bond
  • d is one CH d3 CR d4 R d5 —
  • R d3 , Rd4 and Hd 5 are the same as defined above, respectively
  • e is one CH (CH 3 ) — -The antitumor agent c according to any of (16);
  • a method for inhibiting Hsp90 family protein which comprises administering an effective amount of a commercially acceptable salt.
  • a method for treating a disease involving the Hsp90 family protein or a protein to which the Hsp90 family protein binds comprising administering an effective amount of a commercially acceptable salt.
  • Salty A method for treating a malignant tumor, which comprises administering an effective amount.
  • Examples of the lower alkyl moiety of amino, lower alkylsulfonylamino, lower alkylthio and lower alkoxycarboxy include, for example, straight-chain or branched alkyl having 1 to 8 carbon atoms, more specifically methyl, ethyl.
  • the two lower alkyl moieties in the di-lower alkylamino, di-lower alkylaminocarbonyldioxy and lower dialkyl moieties may be the same or different.
  • the lower alkenyl for example, a straight-chain or branched alkenyl having 2 to 8 carbon atoms, more specifically, vinyl, aryl, 1-propenyl, methacrylic, crotyl, 1-butenyl, 3-butane , Teninole, 2-pentenigle, 4-pentenole, 2-hexenyl, 5-hexenyl, 2-heptur, 2-octenyl, and the like.
  • the lower alkynyl includes, for example, straight-chain or branched alkynole having 2 to 8 carbon atoms, more specifically, ethur, propynole, butcher, pentinole, hexinyl, heptur, otatur and the like. .
  • lower alkanoyl moiety of lower alkanol, lower alkanol and lower alkanol examples include, for example, straight-chain or branched alkanol having 1 to 7 carbon atoms, more specifically formyl, acetyl, propioel, Butyryl, isoptyryl, norrelyl, isovaleryl, vivaloyl, hexanoyl, heptanyl and the like.
  • Aryl, aryloxy, arylamino, arylthio, arylo and aryloyl of aryloyl include, for example, aryl having 6 to 14 carbon atoms, More specifically, phenyl, indenyl, naphthyl, anthryl and the like can be mentioned.
  • aralkyl moiety of aralkyl, aralkyloxy and aralkylamino examples include aralkyl having 7 to 15 carbon atoms, more specifically, benzyl, phenethyl, benzhydryl, naphthylmethyl and the like.
  • heterocyclic group examples include an aromatic heterocyclic group and an alicyclic heterocyclic group.
  • aromatic heterocyclic group include at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom.
  • alicyclic heterocyclic group examples include a 5- or 6-membered monocyclic alicyclic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, a 3- to 8-membered ring And a condensed alicyclic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and more specifically a pyrrolidinyl group.
  • Halogen means atoms of fluorine, chlorine, bromine and iodine.
  • Arylene represents a group in which one hydrogen atom has been removed from aryl
  • a divalent heterocyclic group represents a group in which one hydrogen atom has been removed from the heterocyclic group.
  • the substituents in the substituted di-lower alkyl group rubamoylamino, the substituted lower alkoxycarbonylamino, the substituted lower alkylthio and the substituted lower alkoxycarbonyl are, for example, the same or different, and have 1 to 3 substituents such as hydroxy, cyano, Examples include carboxy, substituted or unsubstituted lower al
  • the substitution position of the substituent is not particularly limited.
  • the lower alkoxy has the same meaning as described above, and examples of the substituent in the substituted lower alkoxy include, for example, hydroxy having the number of substitution:!
  • substituent in substituted aryloxy substituted arylalkyl, substituted aryl, substituted aryloyl, substituted arylalkyl, substituted aryloxy, substituted arylamino, substituted arylalkylamino, substituted arylthio, substituted heterocyclic group, substituted arylene and substituted divalent heterocyclic group
  • substitution position of the substituent is not particularly limited, where halogen, lower alkoxycarbonyl, lower alkylamino, di-lower alkylamino, lower alkylamino, and the like.
  • Lower alkyl and lower ⁇ alkoxy have the same meanings as described above, and the substituents in substituted lower alkyl and substituted lower alkoxy are, for example, the same or different, and have 1 to 3 substituents such as hydroxy and halogen.
  • halogen is as defined above.
  • compound (I) the compound represented by the general formula (I) is referred to as compound (I).
  • Pharmaceutically acceptable salts of compound (I) include, for example, pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like.
  • Pharmaceutically acceptable acid addition salts of compound (I) include, for example, inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, acetate, maleate, fumarate, and the like.
  • Organic salts such as citrate can be mentioned, and pharmacologically acceptable metal salts include, for example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and potassium salt, and the like.
  • Aluminum salts, zinc salts, and the like, and pharmacologically acceptable ammonium salts include, for example, salts of ammonium and tetramethylammonium, and pharmacologically acceptable organic amines.
  • addition salts include addition salts such as morpholine and piperidine
  • examples of the pharmacologically acceptable amino acid addition salts include addition salts such as glycine, phenylalanine, lysine, aspartic acid, and glutamic acid. can give.
  • Hsp90 family protein inhibition means inhibiting the binding between Hsp90 family protein and a protein to which Hsp90 family protein binds (Hsp90 client protein).
  • Hsp90 family proteins include Hsp90a protein, Hsp90B protein, grp94, hsp75 / TRA: P1 and the like.
  • the protein to which the Hsp90 family protein binds may be any protein as long as it is a protein to which the Hsp90 family protein binds.
  • EGFR Erb-B2, Bcr-Abl, src, raf-l, AKT, Flt_3, PLK, Weel, FAE: cMET, hTERT, HIFl-a N variant p53, estrogen receptor, androgen receptor, etc.
  • Hsp90 client protein diseases involving the Hsp90 family protein or the protein to which the Hsp90 family protein binds
  • solid cancers eg, retinal blast fibrosis, osteosarcoma, colorectal cancer, breast cancer, gastric cancer, bladder cancer, prostate cancer
  • Multi-cellular carcinoma human papillomavirus cervical cancer, small cell lung cancer, etc.
  • blood cancer eg, acute myeloblastic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, multiple myeloma, Rennel T lymphoma, etc.
  • Malignant tumors such as osteoporosis, atherosclerosis, rheumatoid arthritis, systemic lupus erythematosus, type I diabetes, Hashimoto's thyroiditis, severe myasthenia, multiple sclerosis, systemic sclerosis, Behcet's disease, nodularity Periarteritis, ulcerative colitis,
  • the compound (I) is described, for example, in the literature [Japanese Patent Laid-Open No. 2000-287697, Tetrahedron, 54, 15937-15958 (1998), Chinese 'Chemical' Letters (Chin. Chem. Lett.), 5, 481. -484 (1994), Heterocycles, 32, 307-310 (1991), Tetrahedron Lett., 30, 2241-2244 (1989), Chemistry Letters ), 589-592 (1990), Journal of Nippon Dani Gakkai, 5, 883-885 (1981), Agricultural 'and-noological' chemistry (Agrc. Biol. Chem.), 40, 1663-1664 ( 1976), Journal of Chemical 'Society C (J. Chem. Soc. C), 10, 947-948 (1967), etc.] or a method analogous thereto. it can.
  • each functional group is identified by known methods commonly used in organic synthetic chemistry [eg, Comprehensive Organic Transformations, RC Larock (1989)].
  • Various compounds (I) can be produced by conversion.
  • protection and deprotection of each functional group [for example, Protective Groups in Organic Synthesis ⁇ Protective Groups in Organic Synthesis, by TW Greene, John 'Wiley' and ⁇ John Wiley & Sons Inc. (1999), etc.] can be used to produce target compounds having various functional groups.
  • Some compounds (I) A specific example of the production of is described in Reference Examples described later.
  • Some of the compounds (I) may have stereoisomers such as geometric isomers and optical isomers.
  • stereoisomers such as geometric isomers and optical isomers.
  • all possible isomers, including these, and mixtures thereof are included. Can be used.
  • compound (I) when it is desired to obtain a salt of compound (I), when compound (I) is obtained in the form of a salt, it may be purified as it is. When compound (I) is obtained in a free form, compound (I) may be converted to an appropriate solvent. Dissolve or suspend, add acid or base, and isolate and purify.
  • Compound (I) and its pharmacologically acceptable salts may exist in the form of adducts with water or various solvents, and these adducts may be used in the present invention. it can.
  • Table 1 shows specific examples of the compound (I).
  • Test Example 1 Hsp90 protein binding activity test
  • Hsp90 protein (58% purity) purified from cereal brain according to the method described in Archives of Biochemistry and Biophysics, 282, 290-296 (1990) was diluted with Tris-buffered saline (TBS, pH 7.4) to a concentration of 1 ⁇ g / mL, and aliquoted at 75 / L / well into a 96-well ELISA Assay plate manufactured by Sumitomo Bei-Clait. After the injection, it was left at 4 ° C for 1 hour to solidify.
  • TBS Tris-buffered saline
  • test compound (compounds 1 to 12) was diluted with TBST from a maximum concentration of 0.5 mmol / L to “10-fold dilution in 8 steps” to prepare a solution in another container.
  • Add 20 / iL / well to the Atsell plate previously dispensed in step 1 and leave at room temperature for 1 hour, where dimethylsulfoxide was used as a positive control for the final concentration of lL / well and a negative control.
  • Radicicol was used at a final concentration of 0.25 / iinol / L, and the same operation as in the case of using the test compound arranged on the same plate as the test compound was performed.
  • the binding rate of the well containing the test compound is calculated from the measured value of each well. did.
  • Compounds 1 to 4 and 6 to 12 inhibited the binding of biotinylated radicicol to Hsp90 protein by 50% or more at concentrations of ⁇ / L or less, indicating that they have binding activity to Hsp90 protein. .
  • compound 8 inhibited the binding of 16 ⁇ mol / L biotinylated radicicol to Hsp90 by 50%.
  • 1X10 3 Z-well HCT116 cells were dispensed into a 96-well microtiter plate (MS-8196F, manufactured by Sumitomo Beit-Client) and cultured in a 5% CO 2 incubator at 37 ° C for 24 hours. . Thereafter, the test compound diluted stepwise is added. The cells were cultured at 37 ° C for 72 hours in a 5% carbon dioxide gas incubator. XTT so that it becomes lmg / mL.
  • Compound 1 and Compound 11 inhibited cell proliferation by 50% or more at a concentration of 100 // mol / L or less.
  • Compound (I) or a pharmacologically acceptable salt thereof can be administered alone as it is, but it is usually desirable to provide it as various pharmaceutical preparations.
  • the pharmaceutical preparations are used for animals and humans.
  • the pharmaceutical preparation according to the present invention may contain Compound (I) or a pharmacologically acceptable salt thereof alone or as a mixture with any other active ingredient for treatment as an active ingredient. it can.
  • such pharmaceutical preparations are produced by mixing the active ingredient with one or more pharmaceutically acceptable carriers, and by any method well known in the technical field of pharmaceuticals.
  • the most effective route for treatment can be oral or parenteral, for example, intravenous.
  • Dosage forms include, for example, tablets, injections and the like.
  • Suitable for oral administration for example, tablets are excipients such as lactose and mannitol, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, fatty acid esters, etc. It can be produced by using a surfactant such as a plasticizer such as glycerin.
  • Formulations suitable for parenteral administration comprise sterile aqueous solutions containing the active compound, which is preferably isotonic with the blood of the recipient.
  • a solution for injection is prepared using a carrier comprising a salt solution, a glucose solution, or a mixture of saline and a glucose solution.
  • the excipients can also be added.
  • auxiliary ingredients selected from agents, binders, surfactants, plasticizers and the like can also be added.
  • the dosage and frequency of compound (I) or a pharmacologically acceptable salt thereof will vary depending on the mode of administration, the age and weight of the patient, and the nature or severity of the condition to be treated. 0.01 mg to lg, preferably 0.05 to 50 mg, per adult is administered once to several times a day. In the case of parenteral administration such as intravenous administration, 0.001 to 100 mg, preferably 0.01 to: LOmg per adult is administered once to several times a day. However, the dose and the number of administrations vary depending on the various conditions described above.
  • Compound 3 Compound 4 ⁇ iZ / ws genus filamentous fungus MPC1009 strain [Accession No. BPBP-7900; Deposit with Higashi 1-chome No. 1 1 Chuo No. 6)] from the agar slant medium, add 50 mL of each platinum loop to the primary seed medium (mash potato 3%, glucose 10%, yeast extract o.5%, pH 6.5) Inoculate four 300 mL Erlenmeyer flasks containing Culture was performed on a rotary stirrer at 28 ° C for 4 days to obtain a primary seed culture solution.
  • the primary seed medium mash potato 3%, glucose 10%, yeast extract o.5%, pH 6.5
  • Secondary seed medium (2% glucose the primary seed culture 75 mL 2.5 L, mashed 2%, 0.5% peptone, ⁇ 2 ⁇ 4 ⁇ .5%, adjusted to ⁇ 6.0, Mg 3 (P04) 2 ⁇ 8 ⁇ ( 0.05% added) was inoculated into a 5 L jar armmenter, and aerated with aeration at 25 ° C for 24 hours.
  • the resulting secondary-seed production medium broth 450 mL of 15 L (2% glucose, mashed 2%, 0.5% peptone, KH2 PO4 0.5%, adjusted to pH 6.0, Mg 3 (P_rei_4) 2 ⁇ 8H 2 O 2 (containing 0.05% O) was inoculated into a 30 L jar fermenter and cultured with aeration and stirring at 25 ° C for 5 days. After completion of the culture, the culture solution (30 L) is separated into cells and supernatant by suction filtration, and the culture supernatant is subjected to column chromatography using Diaion HP20 (1.5 L, Mitsubishi Chemical) previously filled with 30% methanol. After washing with 50% methanol, the mixture was eluted with 100% methanol.
  • a tablet having the following composition is prepared by a conventional method.
  • Compound 140 g, lactose 286.8 g, and potato starch 60 g are mixed, and 120 g of a 10% aqueous solution of hydroxypropyl cellulose is added thereto.
  • the mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting.
  • 1.2 g of magnesium stearate was added and mixed.
  • the mixture was tableted with a tableting machine (RT-15 type, manufactured by Kikusui) having a punch of 8 mm in diameter, and tablets (20 mg of active ingredient per tablet) Is obtained.
  • a disintegrant having the following composition is prepared by a conventional method.
  • Compound 40 (40 g), lactose (286.8 g) and potato starch (60 g) are mixed, and thereto is added a 10% aqueous solution of hydroxypropylcellulose (120 g).
  • the mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting. To this, 1.2 g of magnesium stearate was added and mixed.
  • the mixture was tableted with a tableting machine (RT-15 type, manufactured by Kikusui) having a punch of 8 mm in diameter, and tablets (20 mg of active ingredient per tablet) Is obtained.
  • RT-15 type manufactured by Kikusui
  • An injection having the following composition is prepared by a conventional method.
  • Compound 101 g is dissolved in purified soybean oil 100 g, and purified egg yolk lecithin 12 g and glycerin 25 g for injection are added. After sterile filtration this mixture with Day Supoza Bull type membrane filter of c obtained dispersion 0.2 // m to kneading and emulsified as 1000 mL with distilled water for injection by a conventional method, by 2 mL to the glass vials Fill aseptically to give an injection (containing 2 mg of active ingredient per vial).
  • Formulation Compound 102 mg is prepared by a conventional method.
  • an Hsp90 family protein inhibitor and the like containing a cyclic acetic acid derivative or a pharmacologically acceptable salt thereof as an active ingredient which is useful as a pharmaceutical such as an antitumor agent.

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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

L'invention concerne un inhibiteur de protéines de la famille Hsp90, etc. comprenant, comme ingrédient actif, un dérivé d'acide phénylacétique cyclique représenté par la formule générale (I), et pouvant être utilisé comme agent thérapeutique, et notamment comme agent anticancéreux, ou son sel pharmacologiquement acceptable. Dans cette formule, R1, R2, R3 et R4 sont identiques ou différents et représentent chacun hydrogène, hydroxy, alkyle inférieur éventuellement substitué, etc., X représente oxygène, soufre, -N(R5)- ou CH2-, a représente CRa1Ra2-, arylène éventuellement substitué, un groupe hétérocyclique divalent éventuellement substitué ou une liaison, b représente (CRb1Rb2)m- ou CHRb3CRb4Rb5-, c représente (CRc1Rc2)n(CHRc3CRc4Rc5)p-, d représente (CRd1CRd2)q- ou CHRd3CRd4Rd5-, et e représente CRe1Re2-.
PCT/JP2003/011087 2002-08-29 2003-08-29 Inhibiteurs de proteines de la famille hsp90 WO2004024141A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2003264356A AU2003264356A1 (en) 2002-08-29 2003-08-29 Hsp90 FAMILY PROTEIN INHIBITORS
JP2004535890A JPWO2004024141A1 (ja) 2002-08-29 2003-08-29 Ｈｓｐ９０ファミリー蛋白質阻害剤

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JP2002-250056 2002-08-29
JP2002250056 2002-08-29

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109010333A (zh) * 2018-11-06 2018-12-18 杭州医学院 脱氢弯孢霉素在抑制Hedgehog通路中的应用
US20210177796A1 (en) * 2017-11-16 2021-06-17 Korea Insititute Of Ocean Science And Technology Composition for preventing or treating inflammatory diseases, containing marine fungus penicillium sp. sf-5859-derived curvularin-type metabolites

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JPH10218768A (ja) * 1997-02-10 1998-08-18 Asahi Chem Ind Co Ltd 増殖性疾患治療剤
WO2000038674A1 (fr) * 1998-12-24 2000-07-06 Novation Pharmaceuticals Inc. COMPOSES MODIFIANT LA STABILITE DE L'ARNm ET UTILISATIONS DE CES COMPOSES
WO2002057258A1 (fr) * 2001-01-18 2002-07-25 Les Laboratoires Servier Derives de cyclo`d!azepane, utiles comme inhibiteurs de farnesyltransferase ainsi que leur procede de preparation
WO2003050295A2 (fr) * 2001-12-12 2003-06-19 Conforma Therapeutics Corporation Essais et mises en oeuvre permettant de determiner et de moduler une activite de liaison hsp90

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JPH10218768A (ja) * 1997-02-10 1998-08-18 Asahi Chem Ind Co Ltd 増殖性疾患治療剤
WO2000038674A1 (fr) * 1998-12-24 2000-07-06 Novation Pharmaceuticals Inc. COMPOSES MODIFIANT LA STABILITE DE L'ARNm ET UTILISATIONS DE CES COMPOSES
WO2002057258A1 (fr) * 2001-01-18 2002-07-25 Les Laboratoires Servier Derives de cyclo`d!azepane, utiles comme inhibiteurs de farnesyltransferase ainsi que leur procede de preparation
WO2003050295A2 (fr) * 2001-12-12 2003-06-19 Conforma Therapeutics Corporation Essais et mises en oeuvre permettant de determiner et de moduler une activite de liaison hsp90

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210177796A1 (en) * 2017-11-16 2021-06-17 Korea Insititute Of Ocean Science And Technology Composition for preventing or treating inflammatory diseases, containing marine fungus penicillium sp. sf-5859-derived curvularin-type metabolites
CN109010333A (zh) * 2018-11-06 2018-12-18 杭州医学院 脱氢弯孢霉素在抑制Hedgehog通路中的应用

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JPWO2004024141A1 (ja) 2006-01-05

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