WO2005061461A1 - Inhibiteurs diriges a l'encontre de membres de la famille de la proteine de choc thermique 90 (hsp90) - Google Patents

Inhibiteurs diriges a l'encontre de membres de la famille de la proteine de choc thermique 90 (hsp90) Download PDF

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Publication number
WO2005061461A1
WO2005061461A1 PCT/JP2004/019784 JP2004019784W WO2005061461A1 WO 2005061461 A1 WO2005061461 A1 WO 2005061461A1 JP 2004019784 W JP2004019784 W JP 2004019784W WO 2005061461 A1 WO2005061461 A1 WO 2005061461A1
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acceptable salt
substituted
derivative
hsp90
compound
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PCT/JP2004/019784
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English (en)
Japanese (ja)
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Hideyuki Onodera
Masami Hamano
Michio Ichimura
Shun-Ichi Ikeda
Makoto Suzuki
Yutaka Kanda
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Kyowa Hakko Kogyo Co., Ltd.
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Priority to JP2005516542A priority Critical patent/JPWO2005061461A1/ja
Publication of WO2005061461A1 publication Critical patent/WO2005061461A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
    • C07D225/04—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D225/06—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • C12N1/205—Bacterial isolates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/10—Nitrogen as only ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
    • C12R2001/465—Streptomyces

Definitions

  • the present invention relates to a heat shock protein 90 (hsp90) family one protein inhibitor useful for pharmaceuticals such as an antitumor agent and an angiogenesis inhibitor, and a benzenoid ansamycin derivative.
  • hsp90 heat shock protein 90
  • hsp90 family one protein, hsp90 o: protein, hsp90 ⁇ protein, grp94, hsp75 / TRAPl, etc. are known [for example, “Pharmacology & Therapeutics", 1998, No. Vol. 79, p. 129-168 and "Molecular Endocrinology", 1999, Vol. 13, p.1435-1448].
  • hsp90 family proteins include geldanamycin (Gelda recitation ycin) and nodibimycin (Herbimycin).
  • Antibiotics and Radicicol are known (eg, "Cell's Stress & Chape rones) 55 , 1998, vol. 3, p. 100-108 and “Journal of Medicinal Chemistry", 1999, vol. 42, p. 260- 266). It has been reported that all of these compounds bind to the hsp90 family 1 protein and exhibit pharmacological activities such as antitumor activity by inhibiting the function of the hsp90 family 1 protein. Therefore, compounds that bind to the hsp90 family protein are considered to be useful as therapeutic agents for diseases involving the hsp90 family protein or the protein to which the sp90 family protein binds (hsp90 client protein).
  • Novobiocin and PU3 have also been reported as compounds that bind to the] isp90 family protein (eg, "Journal of the National Cancer Institute”). , 2000, Vol. 92, pp. 242-248 and “Chemistry & Biology", 2001, Vol. 8, pp. 289-299, etc.).
  • Reblastatin has been reported to arrest the cell cycle in the G1 phase by inhibiting the phosphorylation of retinoblastoma (Rb) protein (see, for example, JP-A-9-286779 and "Journal of Ob'an”).
  • Rb retinoblastoma
  • Autolytimycin and 17-0-Deraethylreblastatin are anti-HSV-1 agents (see, for example, "Chinese Chemistry Letters", 2001, Vol. 12, p. 903-906).
  • Oncostatin M inhibitors see, for example, "Journal of Antibiotics", 2000, Vol. 53, p. 657-663).
  • An object of the present invention is to provide an hsp90 family protein inhibitor useful as a pharmaceutical. More specifically, it is an object of the present invention to provide a medicament useful for prevention and / or treatment of cancer and the like. Still another object of the present invention is to provide a therapeutic agent for various diseases associated with hsp90 family protein and a protein to which hsp90 family protein binds, such as an antitumor agent, an angiogenesis inhibitor, etc. An object of the present invention is to provide a novel benzenoid ansamycin derivative useful as a component. The present invention relates to the following (i) to (29).
  • R 2 represents hydrogen or methyl
  • R 11 and R 18 are the same or different and each represents a hydroxy, a substituted or unsubstituted lower alkoxy or a substituted or unsubstituted lower alkanoyloxy
  • R 17 represents A benzenoid doansamycin derivative represented by hydrogen, hydroxy, substituted or unsubstituted lower alkoxy or substituted or unsubstituted lower alkanoyloxy [hereinafter, a compound represented by the formula (I) I).
  • hsp90 heat shock protein 90 family protein inhibitor which comprises a pharmacologically acceptable salt thereof as an active ingredient.
  • R 2a , R Ua , R 17a and R 18a have the same meanings as R h , R 17 and R 18 , respectively, provided that R 2a is methyl, and both R 11a and R 18a are hydroxy. when it is, 17 a are hydrogen, hydroxy and Penzenoi door Nsamaishin derivative or a pharmacologically acceptable salt thereof represented by any neither) methoxy.
  • R one or both of lla and R 18a is, according to the above (9) to (11) or Re noise is lower alkanoyloxy noisy Ruo alkoxy lower alkoxy, or substituted or unsubstituted substituted or unsubstituted Benzenoy doansamycin derivative or its pharmacologically acceptable
  • a medicament comprising the benzenoidoansamycin derivative or the pharmaceutically acceptable salt thereof according to any of (9) to (12) as an active ingredient.
  • An antitumor agent comprising, as an active ingredient, the benzenoidoansamycin derivative or the pharmaceutically acceptable salt thereof according to any of (9) to (12).
  • An hsp90 family protein inhibitor comprising, as an active ingredient, the benzenoidoansamycin derivative or the pharmaceutically acceptable salt thereof according to any of (9) to (12).
  • a method for inhibiting hsp90 family protein which comprises administering an effective amount of compound (I) or a pharmacologically acceptable salt thereof.
  • a method for treating a malignant tumor which comprises administering an effective amount of the penzenoid ansamycin derivative or the pharmacologically acceptable salt thereof according to any of (9) to (12). .
  • An hsp90 family protein comprising administering an effective amount of the benzenoidoansamycin derivative or a pharmaceutically acceptable salt thereof according to any of (9) to (12).
  • Inhibiting hsp90 family protein which comprises administering an effective amount of the benzenoidoansamycin derivative or the pharmaceutically acceptable salt thereof according to any of (9) to (12). how to.
  • Streptomyces sp.EH21 (Streptomyces sp. EH21, National Institute of Advanced Industrial Science and Technology, Patent Organism Depositary (1-1 Tsukuba, Higashi, Ibaraki Pref., Japan 1) Chuo No. 6 Postcode 305-8566) FERM BP-08574] strain.
  • a method for producing a compound (lb), comprising culturing the microorganism according to (25) and isolating a compound produced from the obtained culture solution.
  • Examples of the linear or branched alkyl having 1 to 8 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, Examples of tert-pentyl, hexyl, heptyl, octyl and the like, and examples of cycloalkyl having 3 to 8 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • lower alkynyl moiety of lower alkynyloxy examples include linear or branched alkanols having 1 to 7 carbon atoms, specifically, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, Vivaloyl, hexanoyl, heptanoyl and the like can be mentioned.
  • Substituents in the substituted lower alkoxy and the substituted lower alkanoyloxy are the same or different and include, for example, 1 to 3 substituents, specifically, hydroxy, cyano, carboxy, substituted or unsubstituted lower alkoxy and the like. can give.
  • the substitution position is not particularly limited.
  • the lower alkoxy has the same meaning as the lower alkoxy
  • the substituents in the substituted lower alkoxy are the same or different and include, for example, hydroxy having 1 to 3 substituents.
  • Some of the compounds (I) and (la) may have stereoisomers such as geometric isomers and optical isomers, and all possible isomers, including these, and mixtures thereof Can be used as the hp90 family one protein inhibitors of the present invention. Similarly, possible isomers of compound (la) and mixtures thereof are included in the compounds of the present invention.
  • the pharmacologically acceptable salts of compound (I) and compound (la) include, for example, pharmacologically acceptable metal salts, ammonium salts, acid addition salts, organic amine addition salts, amino acid addition salts and the like. I do.
  • Pharmacologically acceptable metal salts include, for example, alkali metal salts such as lithium salt, sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, zinc salt and the like.
  • Examples of pharmacologically acceptable ammonium salts include salts of ammonium, tetramethylammonium and the like.
  • Examples of pharmacologically acceptable acid addition salts include hydrochlorides and sulfates , Nitrates, phosphates and other inorganic salts, acetates, maleates, fumarates, citrates and other organic acid salts.
  • Examples of pharmacologically acceptable organic amine addition salts include: Examples thereof include addition salts of morpholine and piperidine.
  • Examples of the pharmacologically acceptable addition salts of amino acids include glycine, phenylalanine, aspartic acid, and Evening Min acid addition salts such as lysine and the like.
  • Compound (I) and compound (la) and their pharmacologically acceptable salts may exist in the form of adducts with water or various solvents, and these adducts are also disclosed in the present invention.
  • Hsp90 family one protein inhibitor.
  • adducts of compound (la) with water or various solvents are included in the compounds of the present invention.
  • Compound (I) or compound (la) or a pharmacologically acceptable salt thereof has hsp90 family protein binding activity, and is used to prevent various diseases in which hsp90 family protein is involved. And / or can be used as a medicament for treatment.
  • Compound (I) or compound (la) 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.
  • hsp90 family protein inhibition means inhibiting the binding of the hsp90 family protein to the protein to which the hsp90 family protein binds (hsp90 client protein).
  • hsp90 client protein examples include hsp90 sphing protein, hsp90-protein, grp94 hsp75 / TRAPl, etc. [eg, “Pharmacology & Therapeutics”, 1998, Vol. 79 , P.129-168 and "Molecular Endocrinology", 1999, Vol. 13, p.1435-1448].
  • the hsp90 client protein, hsp90 Fuamiri although protein may be any protein which binds, for example EGFR, ErbB2, Bcr- AbU src, Raf-l s AKT, Fit - 3 ⁇ PLK, Weel, FAK, cMET, hTERT , HIF, mutant p53, estrogen receptor, etc. [For example, "Expert Opinion on Biological Therapy", 2002, Vol. 2, p.3-24 reference].
  • benzoquinone ansamycin antibiotics such as geldanamycin and herbimycin, and Radidicol are known (for example, “cell 'stress”). Cell Stress & Chaperones “, 1998, Vol. 3, p.100-108 and” Journal of Medicinal Chemistry “, 1999, No. 42 Vol., ⁇ .260-266 etc.). All of these compounds bind to the hsp90 family protein and inhibit the function of the hsp90 family protein, thereby providing pharmacological activities such as antitumor activity. It is reported to show activity.
  • compound (I) and compound (la) and their pharmacologically acceptable salts can be used as therapeutic agents for diseases involving the hsp90 family protein or the protein to which the hsp90 family protein binds (hsp90 client protein).
  • hsp90 client protein a protein to which the hsp90 family protein binds
  • it is considered to be useful as an antitumor agent and the like, specifically, a therapeutic agent for solid cancer such as breast cancer and a therapeutic agent for blood cancer such as myeloid leukemia).
  • the pharmaceutical preparation according to the present invention may contain Compound (I) or Compound (Ia) or a pharmacologically acceptable salt thereof alone or as an active ingredient in combination with any other active ingredient for treatment. It can be contained as a mixture.
  • these pharmaceutical preparations are produced by mixing the active ingredient with one or more pharmacologically acceptable additives and by any method well known in the technical field of pharmaceutical preparation.
  • the most effective route for treatment can be oral or parenteral, for example, intravenous.
  • Examples of the administration form include tablets, powders, granules, syrups, injections and the like.
  • Tablets and the like suitable for oral administration can be produced using excipients such as lactose, disintegrants such as corn starch, lubricants such as magnesium stearate, binders such as hydroxypropylcell mouth, and the like. .
  • Suitable for parenteral administration for example, in the case of an injection, can be produced using a salt solution, a glucose solution or a mixture of a salt solution and a pudose solution, or the like.
  • the dosage and frequency of compound (I) or compound (la) or a pharmaceutically acceptable salt thereof will depend on the mode of administration, the age and weight of the patient, the nature or seriousness of the condition to be treated. Orally, 0.01 mg to lg, preferably 0.05 to 50 mg per adult is administered once or several times a day, depending on the degree. In the case of parenteral administration such as intravenous administration, 0.001 to L00 mg, preferably 0.01 to 10 mg, per adult is administered once or several times a day. However, the dose and the number of administrations vary depending on the various conditions described above.
  • the method for producing the compound of the present invention is not particularly limited.
  • the compound can be produced according to the steps described below.
  • the compound (lb) in which R 2 is hydrogen, R 11 and R 18 are hydroxy, and R 17 is hydrogen belongs to the genus Streptomyces and is represented by the formula (lb).
  • a microorganism having the ability to produce a penzenoid doansamycin derivative is cultured in a medium, a compound (lb) is produced and accumulated in the culture, and the compound (lb) is collected from the culture.
  • the microorganism having the ability to produce the benzenoid ansamycin derivative represented by the formula (lb) is a strain belonging to the genus Streptomyces and having the ability to produce the benzenoid ansamycin derivative represented by the formula (lb). Any strain can be used.
  • the benzenoid represented by the formula (lb) Any substance having an ansamycin derivative-producing ability can be used in the present invention.
  • a specific preferred example is Streptomyces sp. EH21 strain.
  • strain EH21 belonging to the genus Streptomyces newly isolated from soil produces a compound (lb).
  • the present inventors have proposed that the above EH21 strain produces a compound (II) in which R 2 is methyl, R 11 and R 18 are hydroxy, and is hydrogen, hydroxy or methoxy in the compound (I). I also found something to do.
  • the representative strain EH21 producing compound (lb) was isolated from soil and has the following bacteriological properties.
  • Presence or absence of spore formation and location formation on aerial hyphae
  • the EH21 strain shows normal or vigorous growth on synthetic and natural media used in the United States, and the underlying mycelium shows a pale yellow to deep reddish yellow.
  • the medium may produce a yellow colored soluble dye.
  • the characteristics of growth and color when cultured on various media at 28 ° C for 14 days are shown below.
  • the color display was in accordance with the classification of colors by the JIS Color Name Book (Japan Standards Association).
  • Soluble pigment Production (yellow)
  • the physiological properties of the EH21 strain are shown below.
  • the growth temperature range is the result after culturing for U days, and the others are the results after culturing for 2 weeks.
  • pre-ham's Gottlieb agar medium As a basal medium, pre-ham's Gott Kunststoff agar medium was used.
  • Streptomyces sp. EH21 Streptomyces sp. EH21
  • FERM BP-08574 at Tsukuba East 1-chome, 1-chome, Chuo No. 6 Postcode 305-8566, Ibaraki Pref.
  • a usual method of culturing actinomycetes is applied.
  • the medium any of a synthetic medium and a natural medium can be used as long as the medium appropriately contains one selected from a carbon source, a nitrogen source, an inorganic ion, an organic nutrient source, and the like, which can be used by microorganisms.
  • glucose, starch, dextrin, mannose, fructose, sucrose, lactose, xylose, arabinose, mannitol, molasses, etc. are used alone or in combination.
  • hydrocarbons, alcohols, organic acids, etc. are used depending on the assimilation ability of the bacteria.
  • Nitrogen sources include ammonium chloride, ammonium nitrate, ammonium sulfate, sodium nitrate, urea and water. Ton, meat extract, yeast extract, dried yeast, corn-steep rice, soybean flour, pupa flour, casamino acid, etc. are used alone or in combination.
  • inorganic salts for example, trace components that promote the growth of the bacterium used and the production of the benzenoid ansamycin derivative can be appropriately added.
  • a liquid culture method particularly a submerged stirring culture method.
  • the cultivation is performed at a temperature of 16 to 37 ° C, preferably 25 to 32 ° C, at a pH of 4 to 10, preferably at a pH of 6 to 8, and the pH of the culture medium is adjusted with ammonia water or an ammonium carbonate solution.
  • Culture Usually complete in 1 to 10 days, but stop culturing when compound (lb) or compound (II) is produced and accumulated in the culture solution and cells, and the amount of production in the culture reaches the maximum. Is preferred.
  • the conventional method for isolating and purifying normal microbial metabolites from the culture can be performed according to the method commonly used for isolating and purifying the compound from the culture.
  • Done For example, add methanol, ethanol, or 2-propanol directly to the culture and extract the active ingredient, or perform two-layer partition extraction with 2-butanol, tert-butanol, and n-butanol. The active ingredient is thereby extracted.
  • the culture is separated into a culture filtrate and cells by filtration, and cell components are extracted from the cells with a solvent such as black-mouthed form, acetone, and methanol.
  • the extract or the culture filtrate is passed through a polystyrene adsorbent, for example, Diaion HP-20, HP-20ss (manufactured by Mitsubishi Chemical Corporation) or the like, to adsorb the active ingredient, and then eluted with methanol, acetone, or the like.
  • a polystyrene adsorbent for example, Diaion HP-20, HP-20ss (manufactured by Mitsubishi Chemical Corporation) or the like, to adsorb the active ingredient, and then eluted with methanol, acetone, or the like.
  • the compound (C) is subjected to gel filtration using, for example, Sephadex LH-20, Toyopearl HW40 or the like, column chromatography using octadecyl-bonded silica gel (0DS), high performance liquid chromatography, column chromatography using silica gel, etc. lb) or compound (II).
  • R Ua and R 18a are hydroxy or substituted or unsubstituted lower alkoxy
  • R is hydrogen, hydroxy or substituted or unsubstituted lower alkoxy
  • Compound (III) in which at least one of 18a is substituted or unsubstituted lower alkoxy is a compound (IV) ⁇ commonly used in organic synthetic chemistry from compound (Ib), compound (II) or compound (11)
  • Known methods [for example, by R. C. Larock, "Comprehensive Organic T-ransformations", John, United States-Sands, Inc., USA John Wiley & Sons Inc.), 1989].
  • R 2a are as defined above, 3 and R 18 - 3 represents hydroxy or substituted or unsubstituted lower alkoxy, R 1 represents hydrogen, hydroxy or substituted or non-replacement of the lower alkoxy, R 11 - 3, 3 and R 18 - at least one of 3 substituted or represents unsubstituted lower alkoxy, R 17 - when 3 is hydrogen, R 17 - 4 will display the hydrogen, R 17 When R 3 — is methoxy, R 17 — 4 represents hydroxy or methoxy; when R 17 — 3 is substituted or unsubstituted lower alkoxy or hydroxy except for methoxy, R 17 — 4 represents hydroxy)
  • Compound (III) can be synthesized by alkylating hydroxy of compound (IV) with an appropriate alkylating agent in an inert solvent, if necessary, in the presence of 1 to 100 equivalents of a base.
  • the inert solvent include methanol, acetonitrile, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, chloroform and dichloromethane.
  • the base for example, sodium hydride, oxide, silver, carbonated rim, diisopropylethylamine, pyridine, triethylamine, ⁇ , ⁇ -dimethylaniline or 1,8-bis (dimethylamino) naphthalene, etc. can give.
  • Any suitable alkylating agent may be used as long as it is generally used in the method for alkylating hydroxy, such as trimethylsilyldiazomethane, alkyl halide, alkoxyalkyl halide, alkyl alkane sulfonate or trialkoxy tetra. Fluoroborate and the like.
  • the reaction temperature is preferably from -30 ° C to 150 ° C, and the reaction time is usually from 5 minutes to 150 hours.
  • the compound in which at least one of R 1 i , R 17 — 3 and R 18 — 3 is hydroxy can form the hydroxy by adjusting the reaction conditions and the equivalent of the alkylating agent.
  • a mixture with a substituted or unsubstituted lower alkoxy compound It can be obtained and can be isolated and purified by a separation and purification method commonly used in organic synthetic chemistry, for example, filtration, extraction, washing, drying, 'concentration, recrystallization, various types of chromatography, and the like.
  • R 11la and R 18a are hydroxy, substituted or unsubstituted lower alkoxy or substituted or unsubstituted lower alkanoyloxy, and R 17a is hydrogen, hydroxy, substituted or unsubstituted lower.
  • Compound (V) which is alkoxy or substituted or unsubstituted lower alkanoyloxy and wherein at least one of R 11a , R 17a and R 18a is substituted or unsubstituted lower alkanoyloxy is a compound (VI) ) [The compound (III) or compound (IV)] can be synthesized.
  • R 11 - 5 and R 18 - 5 is hydroxy, a lower alkanoyloxy noisy Ruo alkoxy lower alkoxy, or substituted or unsubstituted substituted or unsubstituted replacement and table
  • R 1M represents hydrogen, hydroxy, lower alkanoyloxy noisy Ruo alkoxy lower alkoxy or substituted or unsubstituted or substituted unsubstituted
  • R "- 5, R 17 - 5 and R 18 - one Kutomo 1 less out of 5 represents a lower alkanoyloxy noisy Ruo carboxymethyl substituted or unsubstituted
  • R 11 - for 5 properly be substituted unsubstituted lower alkanoyloxy noisy Ruo alkoxy or hydroxy
  • R 11 '6 are hydroxy Shi
  • R 11 - 5 If it is substituted or unsubstituted lower alkoxy, 6 represent the same Ku substituted or unsubstituted lower alkoxy and R "_
  • Compound (V) is prepared by subjecting compound (VI) to alkanoylation of hydroxy using 1 to 100 equivalents of an appropriate alkanoinolelating agent in the presence of 1 equivalent to a solvent in a solvent without solvent or in a solvent.
  • the solvent include ,, ⁇ -dimethylformamide, chloroform, or dichloromethane.
  • the base include pyridine, triethylamine, ⁇ , ⁇ ⁇ -dimethylaniline, ethyldiisopropylamine, 4-dimethylaminopyridine and the like.
  • the alkanoylating agent to be used may be any one usually used in a method for alkanoylating hydroxy, such as an acid anhydride or an acid halide.
  • the reaction temperature is preferably from -30 ° C to 150 ° C, and the reaction time is usually from 5 to 150 hours.
  • Compound (V) can also be obtained by reacting compound (VI) with 1 to 100 equivalents of carboxylic acid in a solvent in the presence of 1 to 100 equivalents of a base and 1 to 100 equivalents of a condensing agent. Can be synthesized.
  • the solvent include N, N-dimethylformamide, chloroform, dichloromethane and the like.
  • Examples of the base include pyridine, triethylamine, ⁇ , ⁇ -dimethylaniline, ethyldiisopropylamine, 4-dimethylaminoviridine and the like.
  • Examples of the condensing agent include 1,3-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and carbonyldiimidazole.
  • the reaction temperature is preferably from -30 ° C to 150 ° C, and the reaction time is usually from 5 to 150 hours.
  • the alkanol is The group can be removed.
  • the reaction temperature is preferably from -30 ° C to 150 ° C, and the reaction time is usually from 5 minutes to 150 hours.
  • R "- 5 , R 17 - 5 and R 18 - by compound at least one of the five is a hydro alkoxy is, to adjust the equivalent reaction conditions and Arukanoiru agent, the In some cases, hydroxy can be obtained as a mixture with a substituted or unsubstituted lower alkanoyloxy compound, and can be isolated and purified or selectively produced in the same manner as in Step 2.
  • the intermediates and target compounds in the above Steps 1 and 2 are subjected to separation and purification methods commonly used in organic synthetic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, various chromatographies, etc. It can be isolated and purified. Further, the intermediate can be subjected to the next reaction without purification.
  • compound (I) and the compound (la) when it is desired to obtain a salt of the compound (I) and the compound (la), when the compound (I) and the compound (la) are obtained in the form of a salt, they may be purified as they are, and in the free form. When used, compound (I) and compound (la) may be dissolved or suspended in an appropriate solvent, and then isolated and purified by adding an acid or a base.
  • Test example 1 hsp90 protein binding activity test
  • the diluted hsp90 protein (58% purity) was diluted to 1 g / mL with Tris-buffered saline (TBS, pH 7.4) and added to a 96-well ELISA assay plate manufactured by Sumitomo Belite Co., Ltd. After dispensing at a volume of ⁇ L / well, the mixture was allowed to stand at 4 ° C for 1 ⁇ for immobilization. The supernatant was removed, and TBS containing 1% serum albumin (BSA) was dispensed at a volume of 300 zL / ml for blocking.
  • BSA serum albumin
  • Tris-buffered saline containing 0.05% Tween 20 at a volume of 500 / L / ⁇ ⁇ .
  • the operation of washing the solid phase was repeated 3 'times.
  • Each solution was prepared by diluting the test compound with TBST in eight steps at a concentration of 10 square root from the highest concentration of 0.5 ol / L.
  • This test compound solution was used as a protease inhibitor confe. Reed EDTA-free (Roche) and Perfloc SC (Pefabloc SC, Roche), 1 tablet / 40 mL and 0.4 TB ol / L TBST containing 80 ⁇ L / ⁇ L, respectively.
  • DMS0 dimethyl sulfoxide
  • radicicol was used as a negative control at a final concentration of 0.25 ⁇ mol / L on the same plate as the test compound.
  • the operation was performed.
  • the biotinylated radicicol represented by formula (A) ["Bioorganic & Medicinal Chemistry", 200 years, 10 volumes, so that the final concentration is 0.1 mol / L. , P.3445- 3454], and left at room temperature for 1 hour to conduct a competitive reaction of the binding of the test compound to the immobilized hsp90 protein.
  • a fluorescence enhancing solution [Wallac Oy] was added in an amount of 100 ⁇ L / ⁇ l, and a color reaction was performed at room temperature for 5 minutes.
  • a multilabel counter [ARV0 TM , Wallac Oy's] was used. The time-resolved fluorescence was measured at an excitation wavelength of 340 nm and a measurement wavelength of 615 nm. Positive control Binding rate of 100% a measurement of time-resolved fluorescence, as binding 0% measurement value of the negative control, the concentration IC 5 test compound combine 50% inhibition of the Piochin of Radeishikoru and hsp90. (nmol / L) was calculated.
  • Test Example 2 Growth inhibition test on human breast cancer-derived KPL-4 cells
  • a 96-well microplate manufactured by Nunc
  • 2,000 KPL-4 cells derived from human breast cancer are plated per well, and in Dulbecco's modified Eagle's medium containing 10% fetal calf serum (FCS) (DMEM)
  • FCS fetal calf serum
  • Preincubation was performed at 37 ° for 24 hours in a 5% carbon dioxide gas incubator overnight.
  • a DMS0 solution of each test compound prepared at 10 ol / L was serially diluted with a culture medium and added to make a total of 100 L per well.
  • the cells were cultured at 37 ° C. for another 72 hours in a 5% CO 2 incubator.
  • WST-1 ⁇ 4- [3- (4-iodophenyl) -2- (4-nitrophenyl) -2H-5-tetrazolio] -1,3 diluted 2-fold with the culture medium -Benzenedisulfonic acid (4- [3- (4-Iodophenyl) -2-( ⁇ nitrophenyD-SH-S-tetrazol iol ⁇ -benzene disul.fonate) labeled mixture (Roche Diagnostics) ⁇ , Add 20 L per liter, and incubate for 1 hour at 37 ° C in a 5% CO 2 incubator, and use a microplate spectrophotometer (Bio-Rad, Model 550).
  • the absorbance was measured at 450 nm and 655 ° C.
  • the cell growth inhibitory activity was shown as a 50% growth inhibitory concentration GI 5G GI 5.
  • the calculation method is described below: From the absorbance at 450 nm of each well at 655 ° C. The value (difference in absorbance) obtained by subtracting the absorbance of the test compound was calculated. The difference in absorbance obtained from the control cells was 100 ° /. And then, by comparing the difference absorbance obtained in cells treated with the compounds of the test concentration, and calculate the concentration of the compound in inhibiting the growth of cells by 50%, which the GI 5. Indicated by. Table 3 shows the results. According to Table 3, the test compound shows a cell growth inhibitory activity against human breast cancer-derived KPL-4 cells, and is useful as an antitumor agent.
  • a 24-well microplate manufactured by Nunc
  • 50,000 KPL-4 cells derived from human breast cancer per 1 ⁇ l are seeded, and the medium is added to a Dulbecco's modified single medium containing 10% fetal calf serum (FCS) ( (DMEM) and 5% CO 2 incubator at 37 ° C for 24 hours.
  • FCS fetal calf serum
  • DMEM fetal calf serum
  • a DMS0 solution of each test compound adjusted to 10 mol / L was diluted stepwise with a culture medium and added to each well to the test concentration. Then, the cells were further cultured at 37 ° C for 40 hours in a 5% CO 2 incubator.
  • Cooled lysis buffer [HEPES 50 NaOH, pH 7.4, 250 mmol / L NaCl, lmmol / L Ethylenediaminetetraacetic acid (EDTA), 1% Nonidet P-40 (NP -40), one thigh ol / L dithiothreitol (DTT), one thigh ol / L futsudani phenylmethylsulfonyl (PMSF), 5 jg / mL leptin (leupeptin)] ' After lysing the cells for 30 minutes at ° C, they were centrifuged at 20000G for 10 minutes.
  • the protein concentration of the obtained supernatant was measured, and samples were prepared to have the same protein content in each lane.
  • the protein was separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Done.
  • SDS-PAGE sodium dodecyl sulfate-polyacrylamide gel electrophoresis
  • the separated protein sample was transferred to a polyvinylidene difluoride (PVDF) membrane (Millipo) and then used as a primary antibody as an anti-ErbB2 antibody [anti-c-Ne, Ab-3, Oncogene).
  • PVDF polyvinylidene difluoride
  • Anti-Erk-2 antibody [anti-Erk2, manufactured by Upstate Biotechnolgy]
  • Anti-Raf-1 antibody [anti-Raf-1 (C-12), manufactured by Santa Cruz Biotechnology, Inc.] was added and reacted with the protein on the membrane.
  • a secondary antibody a horseradish peroxidase (Horseradish Peroxidase) -labeled secondary antibody that reacts with each primary antibody [anti-Egret Ig antibody or anti-mouse Ig antibody, Amersham] is reacted.
  • Detection was performed using the ECL reagent [PIERCE], and the band obtained on the X-ray film was examined.
  • the test compound is considered to be useful as a therapeutic agent for human breast cancer because it has a selective elimination effect on Raf-l and ErbB2 involved in the growth and malignancy of human breast cancer .
  • Bcr-Abl ' a translocation gene product, is known as a causative gene of human chronic myeloid leukemia (CML), but this protein itself is a hsp90 client protein, and Bcr-Abl-expressing human chronic bone marrow Hsp90 inhibitors such as radicicol and its derivatives, or benzoquinon ansamycin conjugates (geldanamycin, herbimycin A), etc., indirectly inhibit the function of Bcr-Abl on myeloid leukemia cell line K562 It has been reported that it has anticellular activity and also has the activity of differentiating leukemic cells into erythroid cells [see Blood, 2000, vol. 96, p. 3312-3318].
  • K562 cells (1 ⁇ 10 5 cel ls / mL) were seeded in 6-well plates (Falcon) at 5 mL per well, and 0.1% of a test compound diluted to each concentration with DMSO was added.
  • the cells were added to the drug at 37 ° C, 5% C0 2 under cultivation, suspended in 10mL cell pack (Toa Medical Electrical) by sampling the fine alveolar fluid of 0.2mL for anti-cell activity measurement The cells became turbid, and the number of cells was measured using an automatic blood cell counter F-300 (Toa Medical Electric). The remaining cell solution was transferred to a 15 ⁇ tube (Falcon), centrifuged at 100 rpm for 10 minutes, the medium was removed by suction, and the cells were washed with a phosphate buffer (PBS) by the same operation.
  • PBS phosphate buffer
  • the cells collected by centrifugation are suspended in PBS containing 0.1% serum albumin (BSA), and glycophorin A, a cell surface protein that is specifically expressed in erythroid cells, is recognized.
  • BSA serum albumin
  • glycophorin A a cell surface protein that is specifically expressed in erythroid cells.
  • GPA serum albumin
  • Pharmindin ⁇ mouse antr GPA antibody
  • GPA surface antigen FITC fluorescence wavelength: 515-545 nm
  • FACScan Becton Dickinson
  • FIG. 2 shows the results of an experiment using compound 6 (the acetyl compound of compound 1).
  • Radicicol derivative [See “Bioorganic & Medicinal Chemistry", 2002, Vol. 10, p. 3445-3454] In addition to showing the inhibition of proliferation of K562 cells as well as the increase in erythroid markers, it was confirmed that it has the activity of inducing the hsp90 inhibitor, which is one of the activities of the hsp90 inhibitor. . As shown in Table 5, the same activity was confirmed for other evaluated benzenoid ansamycin derivatives.
  • the anticellular activity was expressed as a relative value when the number of cells of the test compound untreated cells after 40 hours of culture was 100%. Differentiation-inducing activity is expressed as the ratio of cells with increased fluorescence intensity out of 10,000 cells based on the GPA expression level (fluorescence intensity) of cells in which test compound-untreated cells were labeled only with the secondary antibody after 40 hours of culture. expressed.
  • FIG. 1A is a view showing the action of compound 1 for eliminating intracellular Hsp90 client proteins Raf-1 and Raf-2.
  • B represents compound 2
  • C represents compound 4
  • D represents compound 6.
  • FIG. 2 is a diagram showing the anti-cell activity and differentiation-inducing activity of compound 6 and the Radicicol derivative on K562 cells.
  • Type 1 medium and type 2 medium include glucose 10 g / L, soluble starch 10 g / L, meat extract 3 g / L, yeast extract 5 g / L, tryptone 5 g / L, and lithium dihydrogen phosphate lg / A medium having a composition of L (pH 7.0) was used. Glycerol-preserved inoculum was inoculated into a total of eight tubes of 0.5 mL each in 10 mL of a first-class medium in a 70 mL test tube, and cultured with shaking at 28 ° C for 192 hours.
  • This first-class culture solution was inoculated into a total of 31 tubes of 2.5 mL each in 50 mL of a second-type medium in a 300 mL Erlenmeyer flask, and cultured with shaking at 28 ° C. for 96 hours.
  • the second-type culture obtained was inoculated into 12 liters (36 L in total) of 75 mL each in 3 L of the main fermentation medium placed in a 5-L jar amen, and aerated and agitated at 28 ° C for 144 hours (rotation speed). 200 rpm).
  • the main fermentation medium is glucose 10 g / L, soluble starch 10 g / L, pupal flour 10 g / L, roasted tea 5 g / L, yeast extract / L, nitrohumic acid 0.25 g / L, M0PS2 g / L, zinc sulfate-7.
  • a medium having a composition of L (pH 6.4) was used.
  • a filter aid (Radiolite 600, manufactured by Showa Chemical Industry Co., Ltd.) was added at a ratio of 10%, followed by suction filtration to separate the culture filtrate and the cells.
  • 16 L of methanol was added, and the mixture was sufficiently stirred and extracted.
  • the mixture was filtered again with a suction filter, and the obtained methanol extract was diluted 3-fold with water to obtain a 48 L cell extract.
  • the culture filtrate and the cell extract were separately passed through a column packed with 2 L of Diaion HP-20 to adsorb the active ingredients. After washing each column with a 30% aqueous methanol solution, the active components were eluted with 50% and 75% aqueous methanol solutions.
  • the active fractions were passed through a column packed with 500 mL of Diaion HP-20ss to adsorb the active ingredients. After that, each column was washed with a 50% aqueous solution of methanol. , 60% and 70 ° /. The active ingredient was eluted with an aqueous solution of methanol. After evaporating the organic solvent under reduced pressure from the active fraction derived from the culture filtrate, the residue was dissolved in methanol, 35 mL of silica gel was added thereto, and methanol was distilled off to adsorb the active ingredient onto the silica gel. .
  • the silica gel on which the active ingredient was adsorbed was placed on a column filled with 300 mL of silica gel, When the mixture was developed with a mixed solution of formaldehyde and methanol, active ingredients eluted in 10% and 20% methanol / chloroform fractions, respectively.
  • the active fraction derived from the bacterial cell extract was similarly adsorbed on 75 mL of silica gel, placed on 300 mL of silica gel that had already been filled, and developed with a methanol / chloroform mixture, resulting in 10% methanol / chloroform.
  • the active component eluted in the lume fraction.
  • the active fraction derived from the supernatant and the cell extract are mixed, and purified on reversed-phase silica gel YMC-GEL ODS-AQ 120-S5O 400 mL MM column (flow rate 2.5 mL / min, mobile phase 55% aqueous methanol solution). The active fraction eluted at a retention time of 260 to 325 minutes was further fractionated. High performance liquid chromatography (column Inertsil 0DS, 020 x 250 mm, column temperature 35 ° C; flow rate 8 mL / min, mobile phase 25% aqueous acetonitrile solution) The active fraction with a retention time of 25 to 28 minutes was collected in the above). Further, purification was carried out by preparative thin-layer chromatography [methanol / form-form mixture (1: 9)] to obtain 7.2 mg of compound 4.
  • the physicochemical properties were measured with the following instruments.
  • Soluble angle solubility Soluble in methanol and dimethyl sulfoxide (DMS0)
  • a filter aid (Radiolite 600, manufactured by Showa Chemical Industry Co., Ltd.) was added at a 10% harmful concentration, and then suction filtration was performed to separate the culture filtrate and the bacterial cells. I did. 16 L of methanol was added to the separated cells, and the mixture was sufficiently stirred and extracted. The mixture was again filtered with a suction filter, and the obtained methanol extract was diluted 3-fold with water to obtain a 48 L cell extract. ⁇ The nutrient filtrate and the bacterial cell extract were separately passed through a column packed with 2 L of Diaion HP-20 to adsorb the active ingredient.
  • a filter aid Radiolite 600, manufactured by Showa Chemical Industry Co., Ltd.
  • the active components were eluted with 50% and 75% aqueous methanol solutions.
  • the active fraction was passed through a column packed with 500 mL of Diaion HP-20ss to adsorb the active ingredients.
  • the active ingredient was eluted with a% aqueous methanol solution.
  • the active fraction derived from the culture filtrate was evaporated under reduced pressure to remove the organic solvent, the residue was dissolved in methanol, 35 mL of silica gel was added thereto, and the methanol was distilled off to adsorb the active ingredient onto silica gel. .
  • the silica gel on which the active ingredient was adsorbed was placed on a column filled with 300 mL of silica gel, and developed with a methanol / chloroform-form mixed solution, which was separated into 10% and 20% methanol / chloroform-form fractions. It eluted the active ingredient.
  • the active fraction derived from the bacterial cell extract was similarly adsorbed on 75 mL of silica gel, placed on a 300 mL silica gel that had already been filled, and developed with a methanol / chloroform mixture. The active ingredient was eluted in the formal fraction.
  • the active fraction from the supernatant and the bacterial cell extract are mixed and retained on a reversed-phase silica gel YMC-GEL ODS-AQ 120-S50 400 mL ⁇ column (flow rate 2.5 mL / min, mobile phase 55% methanol aqueous solution) Each active fraction (55% methanol) was obtained for a time of 385-480 minutes, 325-385 minutes and 260-325 minutes. After evaporating the solvent of the active fraction (55% methanol) with a retention time of 385 to 480 minutes, the mixture was powdered with dichloromethane to obtain 90.4 mg of Compound 1.
  • the active fraction (55% methanol) with a retention time of 325-385 minutes was further separated by preparative high-performance liquid chromatography (column Inertsil ODS ⁇ 20 x 250 thigh, column temperature 35 ° C; flow rate 8 mL / min, migration) An active fraction having a retention time of 20 to 21 minutes was collected by using a 30% aqueous phaseacetonitrile solution) to obtain 23.Omg of Compound 2.
  • the active fraction (55% methanol) with a retention time of 260 to 325 minutes was further separated by preparative high performance liquid chromatography (column Inertsil ODS02OX25O mm, column temperature 35 ° C :, flow rate 8 mL / min, mobile phase 25% acetate). An active fraction having a retention time of 28 to 30 minutes was collected by a trilus aqueous solution) to obtain 25.4 mg of compound 3. ,
  • a tablet having the following composition is prepared by a conventional method. 40 g of Compound 4, 286.8 g of lactose and 60 g of corn starch are mixed, and 120 g of a 10% aqueous solution of hydroxypropylcellulose is added thereto. This 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, and the mixture was tableted with a tableting machine equipped with a 8 mm diameter punch (Clean Press Collect 12 manufactured by Kikusui Seisakusho), and tablets (containing 20 mg of active ingredient per tablet) Get)
  • a tablet having the following composition is prepared by a conventional method. 40 g of compound 6, 286.8 g of lactose and 60 g of corn starch are mixed, and 120 g of a 10% aqueous solution of hydroxypropyl cellulose is added. This mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting. Add 1.2g of magnesium stearate to this Mix and compress with a tableting machine equipped with a 8 mm diameter punch (Clean Press Collect 12 manufactured by Kikusui Seisakusho) to obtain tablets (each tablet containing 20 mg of active ingredient).
  • An injection having the following composition is prepared by a conventional method. Dissolve lg of compound 7 and 9 g of sodium chloride in 100 mL of distilled water for injection by a conventional method. The resulting solution is aseptically filtered using a disposable membrane filter (0.2), and aseptically filled into glass vials by 2 mL each to contain an injection (containing 2 mg of active ingredient per vial). obtain.
  • hsp90 family protein inhibitors and the like which are useful as pharmaceuticals such as antitumor agents and contain a penzenoid ansamycin derivative or a pharmacologically acceptable salt thereof as an active ingredient. You.

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Abstract

Des inhibiteurs dirigés à l'encontre de membres de la famille de la protéine de choc thermique 90 (hsp90) contient comme principe actif des dérivés d'ansamycine benzenoïde représentés par la formule générale (I) que l'on utilise comme médicament antitumeur ou comme autres médicaments et leurs sels pharmaceutiquement acceptables, dans laquelle R2 désigne hydrogène ou méthyle; R11 et R18 peuvent être identiques ou différents l'un de l'autre et désignent chacun hydroxy, alcoxy inférieur substitué ou non substitué, alcanoyloxy inférieur substitué ou non substitué; et R17désigne hydrogène, hydroxy, alcoxy inférieur substitué ou non substitué, ou alcanoyloxy inférieur substitué ou non substitué.
PCT/JP2004/019784 2003-12-24 2004-12-24 Inhibiteurs diriges a l'encontre de membres de la famille de la proteine de choc thermique 90 (hsp90) WO2005061461A1 (fr)

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WO2007001049A1 (fr) 2005-06-29 2007-01-04 Kyowa Hakko Kogyo Co., Ltd. Dérivé de l'ansamycine benzénoïde
WO2008038877A1 (fr) * 2006-09-29 2008-04-03 Korea Research Institute Of Bioscience And Biotechnology Dérivés de geldanamycine obtenus par modification de gènes biosynthétiques
WO2008056188A3 (fr) * 2006-11-09 2008-07-31 Biotica Tech Ltd Nouveaux composés et leurs procédés de production
WO2008094438A1 (fr) 2007-01-26 2008-08-07 Kosan Biosciences Incorporated Macrolactames obtenus par biosynthèse modifiée
WO2008104812A2 (fr) * 2007-03-01 2008-09-04 Biotica Technology Limited Nouveaux composés
CN115227692A (zh) * 2022-09-05 2022-10-25 中国医学科学院基础医学研究所 Reblastatin在制备治疗慢性惊厥的药物中的用途

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007001049A1 (fr) 2005-06-29 2007-01-04 Kyowa Hakko Kogyo Co., Ltd. Dérivé de l'ansamycine benzénoïde
EP2361903A1 (fr) 2005-06-29 2011-08-31 Kyowa Hakko Kirin Co., Ltd. Dérivé benzénoïde de l'ansamycine
US7776849B2 (en) 2005-06-29 2010-08-17 Kyowa Hakko Kirin Co., Ltd. Benzenoid ansamycin derivative
WO2008038877A1 (fr) * 2006-09-29 2008-04-03 Korea Research Institute Of Bioscience And Biotechnology Dérivés de geldanamycine obtenus par modification de gènes biosynthétiques
WO2008056188A3 (fr) * 2006-11-09 2008-07-31 Biotica Tech Ltd Nouveaux composés et leurs procédés de production
US8492370B2 (en) 2006-11-09 2013-07-23 Bristol-Myers Squibb Company Compounds and methods for their production
AU2007319014B2 (en) * 2006-11-09 2013-03-28 Bristol-Myers Squibb Company Novel compounds and methods for their production
JP2010509306A (ja) * 2006-11-09 2010-03-25 バイオチカ テクノロジー リミテッド 新規化合物及びそれらの製造方法
JP2010516282A (ja) * 2007-01-26 2010-05-20 コーサン バイオサイエンシーズ， インコーポレイテッド 工学的生合成によるマクロラクタム
EP2121957A1 (fr) * 2007-01-26 2009-11-25 Kosan Biosciences, Inc. Macrolactames obtenus par biosynthèse modifiée
EP2121957A4 (fr) * 2007-01-26 2010-11-10 Kosan Biosciences Inc Macrolactames obtenus par biosynthèse modifiée
US7855192B2 (en) * 2007-01-26 2010-12-21 Kosan Biosciences, Inc. Macrolactams by engineered biosynthesis
WO2008094438A1 (fr) 2007-01-26 2008-08-07 Kosan Biosciences Incorporated Macrolactames obtenus par biosynthèse modifiée
WO2008104812A3 (fr) * 2007-03-01 2008-10-30 Biotica Tech Ltd Nouveaux composés
WO2008104812A2 (fr) * 2007-03-01 2008-09-04 Biotica Technology Limited Nouveaux composés
CN115227692A (zh) * 2022-09-05 2022-10-25 中国医学科学院基础医学研究所 Reblastatin在制备治疗慢性惊厥的药物中的用途

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