WO2011082519A1 - Dérivés de la geldanamycine, leurs procédés de préparation et leurs utilisations - Google Patents

Dérivés de la geldanamycine, leurs procédés de préparation et leurs utilisations Download PDF

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Publication number
WO2011082519A1
WO2011082519A1 PCT/CN2010/002196 CN2010002196W WO2011082519A1 WO 2011082519 A1 WO2011082519 A1 WO 2011082519A1 CN 2010002196 W CN2010002196 W CN 2010002196W WO 2011082519 A1 WO2011082519 A1 WO 2011082519A1
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WO
WIPO (PCT)
Prior art keywords
formula
geldanamycin
reaction
product
mhz
Prior art date
Application number
PCT/CN2010/002196
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English (en)
Chinese (zh)
Inventor
林国强
冯陈国
Original Assignee
杭州华东医药集团生物工程研究所有限公司
上海任洲生化科技有限公司
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Application filed by 杭州华东医药集团生物工程研究所有限公司, 上海任洲生化科技有限公司 filed Critical 杭州华东医药集团生物工程研究所有限公司
Publication of WO2011082519A1 publication Critical patent/WO2011082519A1/fr

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Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel class of geldanamycin derivatives, a process for preparing such compounds, and the use of such compounds for the preparation of cell killing activity cell killing agents, cell proliferation inhibitors and antitumor drugs. Background technique
  • Heat shock protein 90 is the most active molecular chaperone in the cell, many signaling pathways are dependent on heat shock eggs White 90, and its expression in tumor cells is 2 to 10 times higher than that of normal cells, and may play an important regulatory role in tumor cell growth and survival.
  • Geldanamycins can specifically bind to heat shock protein 90 and inhibit their function, leading to the degradation of various oncogene products and cell cycle regulatory proteins, thereby showing various biological activities such as anticancer, and therefore, such compounds It has received great attention and in-depth research by cancer researchers. Among them, 17-allylamine-17-demethoxygeldanamycin (17-AAG) is undergoing clinical trials for the treatment of tumors in the United States.
  • the geldanamycin derivative of the present invention belongs to an ansamycin antibiotic, and structurally, all of the geldanamycin compounds which have been described so far have not been observed to have the same structure as the compound of the present invention. Similar compounds. Summary of the invention
  • the present invention aims to provide a geldanamycin derivative having cell killing activity, cell proliferation inhibiting activity and antitumor activity.
  • a class of geldanamycin derivatives having cell killing activity, cell proliferation inhibitory activity and antitumor activity are selected from the following formulas (1) to (14):
  • the modifications described in the present invention are all carried out at the 17 position in the formula (15).
  • the present invention also provides a method of synthesizing the geldanamycin derivatives represented by the formulae (1) to (14).
  • the separation and purification includes conventional methods of separation and purification using natural products well known to those skilled in the art, such as liquid-liquid extraction, column chromatography, thin layer chromatography, and recrystallization.
  • the present invention also provides a method of inhibiting cell growth, inhibiting cell proliferation, or treating a tumor, comprising administering to a subject a therapeutically effective amount of any geldanamycin derivative represented by the chemical formulas (1) to (14).
  • the step of the substance or its salt may be a pharmaceutically acceptable inorganic or organic salt.
  • the compound having a basic group in the formula I of the present invention may form a pharmaceutically acceptable salt with a mineral acid, such as a sulfate or a hydrochloric acid.
  • Salts, hydrobromides, phosphates also form pharmaceutically acceptable salts with organic acids, such as acetates, oxalates, citrates, gluconates, succinates, tartrates, p-toluenesulfonates , mesylate, benzoate, lactate, maleate, etc.
  • the compound having an acidic group in the formula I of the present invention may form a pharmaceutically acceptable salt with an alkali metal or an alkaline earth metal, preferably but not limited to a sodium salt. , potassium, magnesium or calcium salts.
  • the compounds of formula I of the present invention can be combined with various pharmaceutically acceptable carriers, excipients or adjuvants to form antitumor agents for the treatment of tumors.
  • the compounds of the invention may be administered alone or in the form of a pharmaceutical composition.
  • the route of administration may be oral, parenteral or topical.
  • the pharmaceutical composition can be formulated into various suitable dosage forms depending on the route of administration.
  • composition of the compound of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration, such as subcutaneous, intravenous, intramuscular, intraperitoneal, sheath Inside, intraventricular, intrasternal and intracranial injection or input, or by means of an explant reservoir.
  • oral, intraperitoneal or intravenous administration is preferred.
  • the compounds of the invention may be formulated in any orally acceptable form including, but not limited to, tablets, capsules, aqueous solutions or aqueous suspensions.
  • the carrier used for the tablet generally comprises lactose and corn starch, and a lubricant such as magnesium stearate may also be added.
  • the diluent used in the capsule preparation generally comprises lactose and dried corn starch.
  • Aqueous suspension formulations are usually prepared by admixing the active ingredient with a suitable emulsifier or suspension.
  • some of the above oral preparation forms may also contain some sweeteners, fragrances or colorants.
  • the compounds of the invention may be formulated in the form of a suitable ointment, lotion or cream preparation in which the active ingredient is suspended or dissolved in one or more carriers.
  • Carriers for ointment preparations include, but are not limited to: mineral oil, liquid petroleum jelly, White petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; detergents or creams can be used, including but not limited to: mineral oil, sorbitan monostearate, Tween 60, ten Hexadecane wax, hexadecene aromatic alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the compounds of the present invention can also be administered in the form of a sterile injectable preparation, including sterile aqueous or oily suspension or sterile injection solutions.
  • a sterile injectable preparation including sterile aqueous or oily suspension or sterile injection solutions.
  • carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution.
  • sterilized, fixed oils may be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.
  • the dosage and method of use of the compounds of the invention depend on a number of factors, including the age, weight, sex, natural health, nutritional status of the compound, the strength of the compound, the time of administration, the rate of metabolism, the severity of the condition, and the diagnosis and treatment. Subjective judgment of the physician.
  • the preferred dosage is between 0.01 and 100 mg/kg body weight per day.
  • the compounds of the formula (1) - (14) of the present invention can also be used as a low molecular biological probe for inhibiting cell cycle in life science research.
  • the compound represented by the formula (1) - (14) is used in life science research, it is soluble in methanol or aqueous sterol, and is also soluble in an aqueous solution of dimethyl sulfoxide.
  • Test Materials Nuclear magnetic resonance was measured by a Varian EM-360A, EM-390 or Bruker AMX-300 instrument. Mass spectra were determined by a Finnigan 4021, HP5989A, Finnigan FTMS-2000 instrument. Flash column chromatography was performed on silica gel (300-400 mesh).
  • TLC was assayed with HSGF254 high efficiency plates using UV lamp 254 and 365 nm wavelength or 5% phosphomolybdate ethanol solution. The completion endpoint of the reaction was determined by TLC assay.
  • the reagents used in the experiments were all commercial reagents and were used without purification.
  • the amine fragments used in the experiment were partially purchased through commercialization, and could not be purchased by the following two synthetic routes. Get it,
  • Example 1 Add dopamine hydrochloride (1.35 g) to geldanamycin (2 g), then add dichloromethane (100 mL), triethylamine (1.5 mL), methanol (33 mL), stir at room temperature reaction.
  • the reaction formula is as follows: The reaction system was initially orange-red and gradually darkened to black. The reaction was completed for 2.5 days. The solvent was evaporated under reduced pressure and purified (EtOAcjjjjjjjjjjjjjjjjjj The product was subjected to analytical testing to obtain the following spectral data:
  • HZ ' « ⁇ 6 - ⁇ 8* ⁇ -(HZ IS -Z9 ' « 8 ⁇ -9 ⁇
  • HG-DMEM + 10% NBS medium MCF-7 HCT116 and HepG2 cell lines
  • RPMI 1640 + 10% FBS medium A2780, A549 and AGS cell lines
  • Drug Dilution All drugs were dissolved in DMSO and formulated into a 10 mg/ml stock solution, which was prepared by dilution with medium before administration.
  • the cells were cultured on a flat-bottom 96-well plate; after 24 h, a final concentration of ⁇ was added. After 72 h, add 20 ⁇ l of MTT solution at a concentration of 5 mg/ml (dissolved in PBS, sterilized by filtration, stored at 4 ° C in the dark); incubate at 37 ° C for 4 h; aspirate MTT from ⁇ L with a lance Be careful not to touch the cells; add ⁇ 100% DMSO to each well; vortex for 15 min at room temperature; 570 nm wavelength reading (Thermo Multiskan Spectrum).
  • A549, MCF-7, AGS, A2780 and HEPG-2 represent lung adenocarcinoma, breast cancer, gastric cancer, ovarian cancer and liver cancer cell lines, respectively, and represent the Geldardella shown in the chemical formulas (1) - (14).
  • the slightly larger black italic in the table is a positive result. The above results indicate that the compound of the present invention has excellent cell killing activity and cell growth inhibitory activity, and generally has excellent anticancer activity in vitro, especially for gastric cancer.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention a pour objet des dérivés de la geldanamycine, leurs procédés de préparation et leurs utilisations dans la fabrication de médicaments d'agents cytotoxiques, d'inhibiteurs de la prolifération cellulaire et d'agents antitumoraux.
PCT/CN2010/002196 2010-01-05 2010-12-29 Dérivés de la geldanamycine, leurs procédés de préparation et leurs utilisations WO2011082519A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201010000138.3 2010-01-05
CN201010000138.3A CN102115460B (zh) 2010-01-05 2010-01-05 格尔德霉素衍生物及其制备方法和用途

Publications (1)

Publication Number Publication Date
WO2011082519A1 true WO2011082519A1 (fr) 2011-07-14

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Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102603635B (zh) * 2011-01-21 2016-08-03 杭州华东医药集团生物工程研究所有限公司 格尔德霉素衍生物及其制备方法和用途
CN103450164B (zh) * 2012-05-31 2017-02-01 杭州华东医药集团生物工程研究所有限公司 格尔德霉素衍生物及其制备方法和用途
CN103360312B (zh) * 2013-07-22 2015-06-03 山东大学 一组格尔德霉素衍生物及其应用
CN103819457B (zh) * 2014-02-12 2016-08-31 复旦大学附属上海市第五人民医院 一类能够抑制去势抵抗性前列腺癌和成骨转移的格尔德霉素衍生物及其应用
CN103819456B (zh) * 2014-02-12 2015-10-28 复旦大学附属上海市第五人民医院 一组格尔德霉素衍生物及其应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007059116A2 (fr) * 2005-11-14 2007-05-24 Abraxis Bioscience, Inc. Derives de geldanamycine et compositions pharmaceutiques associees
CN101220068A (zh) * 2008-01-18 2008-07-16 中国医学科学院医药生物技术研究所 一组格尔德霉素衍生物及其制备方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1997632A (zh) * 2004-03-26 2007-07-11 范安德尔研究协会 格尔德霉素及其衍生物抑制癌侵入及识别新靶点

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007059116A2 (fr) * 2005-11-14 2007-05-24 Abraxis Bioscience, Inc. Derives de geldanamycine et compositions pharmaceutiques associees
CN101220068A (zh) * 2008-01-18 2008-07-16 中国医学科学院医药生物技术研究所 一组格尔德霉素衍生物及其制备方法

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CN102115460B (zh) 2014-08-20
CN102115460A (zh) 2011-07-06

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