WO2006043338A1 - Nouveaux derives polyethylene glycol ou celle de ceux-ci repondant aux normes pharmaceutiques - Google Patents

Nouveaux derives polyethylene glycol ou celle de ceux-ci repondant aux normes pharmaceutiques Download PDF

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Publication number
WO2006043338A1
WO2006043338A1 PCT/JP2004/016220 JP2004016220W WO2006043338A1 WO 2006043338 A1 WO2006043338 A1 WO 2006043338A1 JP 2004016220 W JP2004016220 W JP 2004016220W WO 2006043338 A1 WO2006043338 A1 WO 2006043338A1
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WO
WIPO (PCT)
Prior art keywords
polyethylene glycol
acceptable salt
pharmaceutically acceptable
glycol derivative
minutes
Prior art date
Application number
PCT/JP2004/016220
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English (en)
Japanese (ja)
Inventor
Yoshinobu Tsukada
Original Assignee
Actice Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Actice Co., Ltd. filed Critical Actice Co., Ltd.
Publication of WO2006043338A1 publication Critical patent/WO2006043338A1/fr

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    • 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
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/02—Preparation of oxygen-containing organic compounds containing a hydroxy group
    • 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
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups

Definitions

  • the present invention relates to a polyethylene glycol derivative having a substituted phenyl group.
  • JP-A-2004-51513 describes an anti-tumor agent comprising a mouth-opening anthocyanidin component derived from apple, which is a substance that induces apoptosis
  • JP-A-2002-28690 A prophylactic / therapeutic agent for malignant tumors using TNF_a and IL-4 as site force-in as active ingredients and utilizing their apoptosis-inducing action is described.
  • Japanese Patent Application Laid-Open No. 2000-72749 describes that an apoptosis inducer containing a quinoline derivative as an active ingredient can be used as an anticancer agent.
  • Japanese Patent Application Laid-Open No. 2003-238567 describes that a benzocraton'enimide compound derived from a bacterium belonging to the genus Pseudomonas has cytotoxic activity and is useful as an active ingredient of an antitumor agent.
  • Substances and compounds that induce apoptosis in cancer cells and have a low probability of causing apoptosis in normal cells can be expected to be used as components of anticancer agents.
  • An object of the present invention is to provide a novel compound that can also be used as an active ingredient of an anticancer agent.
  • R represents _C (CH) CH -C (CH), and n represents an integer of 5-13).
  • FIG. 1 is a spectrum chart showing the results of NMR.
  • FIG. 2 is a spectrum chart showing the results of LS / MS measurement.
  • the polyethylene glycol derivative according to the present invention has a structure having an alkyl-substituted phenyl group at the end of the polyethylene glycol chain as shown in the general formula (1), and is a cell death inducer or anticancer agent. Useful as an active ingredient.
  • n 9 and a compound in which n is 10 are particularly preferable.
  • a compound in which n is 9 or 10 can be said to be a polyethylene glycol adduct of 2,4-di-tert-octylphenol or polyethylene glycol mono-, p-diisooctylphenol ether.
  • the compound of the general formula (1) is a fungus (Asupergirus
  • This compound of the general formula (1) is amphiphilic and has the property of inducing apoptosis in cancer cells and hardly causing apoptosis in normal cells. In addition, it has DNA synthesis inhibitory or inhibitory action and is useful as an active ingredient in anticancer agents
  • the pharmacologically acceptable salt of the compound of the above general formula (1) can be obtained by a conventional method, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid or the like. Alternatively, it can be used as a salt with an organic acid such as formic acid, acetic acid, fumaric acid, citrate, maleic acid, oxalic acid, malic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid or the like.
  • organic acid such as formic acid, acetic acid, fumaric acid, citrate, maleic acid, oxalic acid, malic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesul
  • the cell death inducer or anticancer agent in the present invention is at least i selected from the compound of the above general formula (1) and a pharmacologically acceptable salt thereof as a reagent or a carrier or diluent for preparation. It can be prepared by mixing with a reagent or preparation.
  • the dosage form include solid preparations such as tablets, pills, powders, granules, capsules and suppositories, liquid preparations such as injections, suspensions, syrups and emulsions, and semi-preparations such as patches.
  • a solid agent etc. can be mentioned, and it can formulate by selecting suitably the carrier according to these dosage forms, a diluent, an excipient
  • the mixture was mixed with 2 L of Dextrose Broth (Difco) and shake cultured for 5 days as the main culture at 35 ° C. and 120 ⁇ m.
  • the cells were collected from the obtained culture broth, and this was subjected to freezing treatment at 120 ° C for at least 20 hours and thawing treatment by standing at room temperature for 3 hours three times in this order.
  • the last thawed cells in this repeated freeze-thaw treatment were loosened in PBS (-) and further stirred in a mixer. After further adding 10 g of Triton_X to this bacterial cell sample, the whole amount was added to PBS (-), stirred to 2 L, and allowed to stand at 4 ° C.
  • Triton_X was removed using SM-2 adsorbent. The extract from which Triton_X was removed was dialyzed again against distilled water and freeze-dried to obtain sample A.
  • Example 1 The sample A obtained in Example 1 was subjected to HPLC under the following conditions.
  • sample A 20 ml of acetone in a container was added, sealed, and shaken for about 2 hours.
  • the obtained acetone extract was transferred to a centrifuge tube, centrifuged for about 5 minutes, and the supernatant was filtered with a 0.2 ⁇ m pore size filter.
  • the filtrate was concentrated to dryness under a nitrogen stream.
  • DMSO 250 mL was added to the dried solid to dissolve it, and the insoluble matter in the obtained solution was removed with a 0.2 ⁇ m pore size filter to obtain an analytical solution.
  • fraction 1 A fraction showing a plurality of peaks including a fraction having a peak at a retention time of about 59 minutes (fraction 1) was obtained.
  • the sample A was subjected to LSZMS measurement under the following conditions.
  • Desolvation gas Nitrogen (7001 / hour)
  • Ion source temperature 150 ° C
  • Strike range m / zl 50—1000 (2sec / range)
  • UV detector 190-400
  • PEG polyethylene glycol
  • fraction 1 was freeze-dried to obtain sample 1 for assembly. Atsy sample (20mg)
  • MIAPaCa-2 (Dainippon Pharmaceutical Co., Ltd.), a human knee cancer-derived cell, was seeded at 5 IX 10 per well on a 96-well plate in an incubator at 37 ° C, 5 volumes 0 / oC Dulbecco's MEM
  • the medium was cultured for 2 hours in a medium containing 10% by weight urine fetal serum (FBS), 2.5% by weight urinary serum (HS), penicillin and streptomycin. Replace the medium with the above-mentioned Sampu Nolet and incubate for 72 hours in an incubator at 37 ° C and 5% volume by volume, and then add 5mgZmlMTT solution.
  • FBS urine fetal serum
  • HS urinary serum
  • penicillin and streptomycin Replace the medium with the above-mentioned Sampu Nolet and incubate for 72 hours in an incubator at 37 ° C and 5% volume by volume, and then add 5mgZmlMTT solution.
  • Sample A 16 mg was sealed with 35 ml of acetone and shaken for about 2 hours. The extract was transferred to a centrifuge tube and centrifuged for about 5 minutes. The supernatant was filtered using a filter with a pore size of 0.45 zm. The filtrate was concentrated to dryness on a rotary evaporator. The dried product was filtered by adding DMS2 50 ⁇ to the dried product, and the filtrate was used as a preparative solution. Further, the same operation was performed using 200 mg of the sample bowl to obtain a solution for preparative separation.
  • the preparative solution and the preparative solution were each subjected to HPLC treatment under the same conditions as in Example 2, and a retention time peak of about 59 minutes (the fraction of Example 2). (Corresponding to minute 1).
  • Each of the obtained fractions was concentrated with a rotary evaporator, transferred to a vial, and concentrated / dried under a nitrogen stream.
  • the purity of the dried product obtained from the preparative liquid was measured by a conventional chromatographic method, and the purity was 95% or more.
  • Spectroscopy Y H— 1 H-shift correlation two-dimensional NMR method
  • HMBC Heteronuclear Multiple Bond Correlation
  • NOESY Nuclear Overhauser Effect and exchange
  • novel polyethylene glycol derivative and pharmaceutically acceptable salt thereof according to the present invention can be suitably used as an active ingredient of a cell death inducer or an anticancer agent.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Wood Science & Technology (AREA)
  • Veterinary Medicine (AREA)
  • Zoology (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Microbiology (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un nouveau composé possédant une activité induisant l'apoptose. Ce composé est représenté par la formule générale (I) suivante et est isolé d'une culture de champignon filamenteux. Dans cette formule, R représente C(CH3)2CH2-C(CH3)3 et n est un entier compris entre 5 et 13. Ce
PCT/JP2004/016220 2004-10-18 2004-11-01 Nouveaux derives polyethylene glycol ou celle de ceux-ci repondant aux normes pharmaceutiques WO2006043338A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2004303162 2004-10-18
JP2004-303162 2004-10-18

Publications (1)

Publication Number Publication Date
WO2006043338A1 true WO2006043338A1 (fr) 2006-04-27

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PCT/JP2004/016220 WO2006043338A1 (fr) 2004-10-18 2004-11-01 Nouveaux derives polyethylene glycol ou celle de ceux-ci repondant aux normes pharmaceutiques
PCT/JP2005/010978 WO2006043353A1 (fr) 2004-10-18 2005-06-15 Agent inducteur d’apoptose et agent anticancéreux

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009256214A (ja) * 2008-04-11 2009-11-05 Senka Pharmacy:Kk ポリエチレングリコールの誘導体およびその中間体の製造方法
JP2011084632A (ja) * 2009-10-14 2011-04-28 Senka Pharmacy:Kk ポリエチレングリコールの誘導体およびそれを有効成分として含む抗腫瘍剤

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4283553A (en) * 1979-09-24 1981-08-11 Ivanchev Sergei S Hydroperoxide derivatives of hydroxyethylated compounds and method of producing same
JPS58217567A (ja) * 1982-06-07 1983-12-17 Konishiroku Photo Ind Co Ltd インクジエツト記録用インク組成物およびインクジエツト記録方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3800051A (en) * 1970-09-21 1974-03-26 Dow Chemical Co Reducing serum cholesterol with certain substituted phenols
JPH1077297A (ja) * 1996-09-04 1998-03-24 Senka:Kk 制癌作用を有する生理活性物質、その生産菌、製造方法および用途
JPH11246595A (ja) * 1998-02-25 1999-09-14 Senka:Kk 制癌作用を有する生理活性物質、その生産菌、製造方法および用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4283553A (en) * 1979-09-24 1981-08-11 Ivanchev Sergei S Hydroperoxide derivatives of hydroxyethylated compounds and method of producing same
JPS58217567A (ja) * 1982-06-07 1983-12-17 Konishiroku Photo Ind Co Ltd インクジエツト記録用インク組成物およびインクジエツト記録方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KORENEV K.D. ET AL.: "Alkylphenol reagents for the oil and gas industry", CHEMISTRY AND TECHNOLOGY OF FUELS AND OILS, vol. 36, no. 4, 2000, pages 274 - 277, XP002983158 *
STOLZENBERG G.E.: "Adv. thin layer chromatogr.", 1982, article "Analysis of ethoxylated nonionic surfactants", pages: 503 - 516, XP002983159 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009256214A (ja) * 2008-04-11 2009-11-05 Senka Pharmacy:Kk ポリエチレングリコールの誘導体およびその中間体の製造方法
JP2011084632A (ja) * 2009-10-14 2011-04-28 Senka Pharmacy:Kk ポリエチレングリコールの誘導体およびそれを有効成分として含む抗腫瘍剤

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