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WO2001053302A1 - 5H-QUINOXALINO[2,3-b]NAPHTO[2,1][1,4]OXAZIN-5-ONE, ET INTERMEDIAIRE ENTRANT DANS LA PREPARATION DUDIT COMPOSE - Google Patents

5H-QUINOXALINO[2,3-b]NAPHTO[2,1][1,4]OXAZIN-5-ONE, ET INTERMEDIAIRE ENTRANT DANS LA PREPARATION DUDIT COMPOSE Download PDF

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Publication number
WO2001053302A1
WO2001053302A1 PCT/JP2001/000261 JP0100261W WO0153302A1 WO 2001053302 A1 WO2001053302 A1 WO 2001053302A1 JP 0100261 W JP0100261 W JP 0100261W WO 0153302 A1 WO0153302 A1 WO 0153302A1
Authority
WO
WIPO (PCT)
Prior art keywords
quinoxalino
naphtho
oxazin
solvents
represented
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP2001/000261
Other languages
English (en)
Japanese (ja)
Inventor
Tadashi Katoh
Fusae Miyata
Kaoru Yamada
Sadamu Yoshida
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sagami Chemical Research Institute
Toppan Inc
Original Assignee
Sagami Chemical Research Institute
Toppan Printing 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 Sagami Chemical Research Institute, Toppan Printing Co Ltd filed Critical Sagami Chemical Research Institute
Priority to AU2001227046A priority Critical patent/AU2001227046A1/en
Publication of WO2001053302A1 publication Critical patent/WO2001053302A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present invention relates to a novel 5H-quinoxalino [2,3-b] naphtho [2,1] [1,4] oxazin-5-one which exhibits cytotoxicity and is expected to be used as an antitumor agent and its production For intermediates.
  • An object of the present invention is to provide a novel cytotoxic 5H-quinoxalino [2,3-b] naphtho [2,1] [1,4] oxazin-5-one, and to produce the compound. To provide useful intermediates.
  • the present invention provides a production intermediate of 5H-quinoxalino [2,3-b] naphtho [2,1] [1,4] oxazin-5-one represented by the above formula (1) .
  • the compound represented by the formula (1) of the present invention is, for example, commercially available triamino-2-naphthol assalt (3)
  • a base is allowed to act on triamino-2-naphthol salt (3) to obtain a compound of formula (4)
  • the base sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, cesium carbonate, ammonia, triethylamine, ethyldiisopropylamine, pyridine, pyrrolidine, piperidine and the like are used.
  • Solvents include water; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, and 2-methyl-2-propanol.
  • Solvents such as getyl ether, diisopropyl ether, dimethoxyethane, tetrahydrofuran, and 1,4-dioxane; halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane, and chloroform; pentane, hexane, Hydrocarbon solvents such as cyclohexane, benzene, and toluene; aprotic polar solvents such as ethyl acetate, acetate nitrile, propionitol, acetone, nitromethane, N, N-dimethylformamide, and dimethyl sulfoxide It is also possible to mix two or more of the above solvents. Absent. The reaction can take place between 0 and the melt flow.
  • Examples of the base used include lithium hydrogen hydride, sodium hydride, potassium hydride, n-butyllithium, sec-butyllithium, tert-butyllithium, lithium diisopropyl pyramide, lithium hexamethyldisilazide, sodium carbonate, Potassium carbonate, cesium carbonate, triethylamine, ethyldiisopropylamine, pyridine and the like are used.
  • the solvent examples include ether solvents such as getyl ether, diisopropyl ether, dimethoxyethane, tetrahydrofuran, and 1,4-dioxane; halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane, and chloroform. Hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene and toluene; ⁇ , ⁇ -dimethylformamide, dimethylsulfoxy An aprotic polar solvent such as a solvent is used, and two or more of the above solvents may be mixed. The reaction can be carried out between 0 ° C and the reflux temperature of the solvent.
  • ether solvents such as getyl ether, diisopropyl ether, dimethoxyethane, tetrahydrofuran, and 1,4-dioxane
  • halogenated hydrocarbon solvents such as dichloromethane
  • the reaction involves the reaction of oxygen-N ,, '-bis (salicylidene) ethylenediaminocobalt (II) (sarcomin), oxygen- 2,2,6,6-tetramethylpiperinidyl- ⁇ -oxide radical (TEMPO) ) —Copper (II) chloride, sodium ditrosodisulfonate (Flemish: ⁇ ), cesium ammonium nitrate (CAN), benzeneselenic anhydride, 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), silver oxide (1), lead oxide (IV), potassium permanganate, potassium ferricyanide, or the like.
  • oxygen-N oxygen-N , '-bis (salicylidene) ethylenediaminocobalt (II) (sarcomin), oxygen- 2,2,6,6-tetramethylpiperinidyl- ⁇ -oxide radical (TEMPO) ) —Co
  • Solvents include ether solvents such as Jethyl ether, diisopropyl propyl ether, dimethoxyethane, tetrahydrofuran, 1,4-dioxane; halogen hydrocarbon hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform.
  • ether solvents such as Jethyl ether, diisopropyl propyl ether, dimethoxyethane, tetrahydrofuran, 1,4-dioxane
  • halogen hydrocarbon hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform.
  • Solvents Hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, and toluene; aprotic polar solvents such as acetonitrile, propionitrile, acetone, nitromethane, N, N-dimethylformamide, and dimethyl sulfoxide It may be used, and two or more of the above solvents may be mixed. The reaction can be carried out between -20 ° C and the reflux temperature of the solvent.
  • Hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, and toluene
  • aprotic polar solvents such as acetonitrile, propionitrile, acetone, nitromethane, N, N-dimethylformamide, and dimethyl sulfoxide It may be used, and two or more of the above solvents may be mixed. The reaction can be carried out between -20 ° C and the reflux temperature of the
  • EIMS (m / Z): 285 (M +), 142, 129, 111, 97, 85, 83, 71, 69, 57, 55, 43, 41.
  • Test Example 1 Malignant tumor cell growth inhibition test
  • Mouse lymphoid leukemia cells (P388) were added to RPMI-1640 medium containing 10% fetal calf serum supplemented with 5 ml of 2-hydroxyethyl disulfide and 100 mg / ml of kanamycin sulfate, and the cultured cells were grown to lxl (T cells / ml).
  • the 5H-quinoxalino of the present invention [2,3- b] naphtho [2, 1] [1, 4] Okisajin - and ⁇ Ka ⁇ 5- one (1) to a predetermined concentration, C0 2 incubator (C0 2 5%, humidity 100, 37 ° C) For 4 days.
  • C0 2 incubator C0 2 5%, humidity 100, 37 ° C
  • To measure the number of viable cells by the MTT colorimetric method it was determined for 50% cell growth inhibition marrow from the growth inhibition rate relative to the control group (IC 5 Q), IC 5 . The value was 18 g / ml.
  • the compound of the present invention is a cytotoxic substance having a completely different chemical structure from that of the existing ulcer agent, and is expected to be used as an antitumor agent having a new mechanism of action.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

L'invention concerne composé 5H-quinoxalino[2,3-b]naphto[2,1][1,4]oxazin-5-one (1), qui exerce une action cytotoxique sur des cellules tumorales malignes et peut s'utiliser comme médicament antitumoral (ou médicament anticancéreux). L'invention concerne en outre un intermédiaire (2) entrant dans la préparation dudit composé.
PCT/JP2001/000261 2000-01-24 2001-01-17 5H-QUINOXALINO[2,3-b]NAPHTO[2,1][1,4]OXAZIN-5-ONE, ET INTERMEDIAIRE ENTRANT DANS LA PREPARATION DUDIT COMPOSE Ceased WO2001053302A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001227046A AU2001227046A1 (en) 2000-01-24 2001-01-17 5h-quinoxalino(2,3-b)naphtho(2,1)(1,4)oxazin-5-one and intermediate for the preparation thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2000-13700 2000-01-24
JP2000013700 2000-01-24

Publications (1)

Publication Number Publication Date
WO2001053302A1 true WO2001053302A1 (fr) 2001-07-26

Family

ID=18541254

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2001/000261 Ceased WO2001053302A1 (fr) 2000-01-24 2001-01-17 5H-QUINOXALINO[2,3-b]NAPHTO[2,1][1,4]OXAZIN-5-ONE, ET INTERMEDIAIRE ENTRANT DANS LA PREPARATION DUDIT COMPOSE

Country Status (2)

Country Link
AU (1) AU2001227046A1 (fr)
WO (1) WO2001053302A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08119920A (ja) * 1994-10-18 1996-05-14 Kyowa Hakko Kogyo Co Ltd 三環式アニリド誘導体
JPH0952879A (ja) * 1995-08-08 1997-02-25 Taiho Yakuhin Kogyo Kk 縮合インダン化合物及びその塩
WO1999030709A1 (fr) * 1997-12-17 1999-06-24 Merck & Co., Inc. Antagonistes du recepteur de l'integrine
JP2000198788A (ja) * 1998-10-28 2000-07-18 Toppan Printing Co Ltd 有機薄膜ｅｌ素子及びそれに用いるキノキサリノベンゾオキサジン誘導体

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08119920A (ja) * 1994-10-18 1996-05-14 Kyowa Hakko Kogyo Co Ltd 三環式アニリド誘導体
JPH0952879A (ja) * 1995-08-08 1997-02-25 Taiho Yakuhin Kogyo Kk 縮合インダン化合物及びその塩
WO1999030709A1 (fr) * 1997-12-17 1999-06-24 Merck & Co., Inc. Antagonistes du recepteur de l'integrine
JP2000198788A (ja) * 1998-10-28 2000-07-18 Toppan Printing Co Ltd 有機薄膜ｅｌ素子及びそれに用いるキノキサリノベンゾオキサジン誘導体

Also Published As

Publication number Publication date
AU2001227046A1 (en) 2001-07-31

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