US20150274715A1 - Cancer cell inhibitory drug and cancer stem-cell detection probe - Google Patents

Cancer cell inhibitory drug and cancer stem-cell detection probe Download PDF

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Publication number
US20150274715A1
US20150274715A1 US14/408,778 US201314408778A US2015274715A1 US 20150274715 A1 US20150274715 A1 US 20150274715A1 US 201314408778 A US201314408778 A US 201314408778A US 2015274715 A1 US2015274715 A1 US 2015274715A1
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group
general formula
alkyl group
cancer
compound
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Taichi Shintou
Tsuyoshi Nomoto
Kohei Watanabe
Takeshi Miyazaki
Toshio Tanaka
Yasuhito Shimada
Yuhei Nishimura
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Canon Inc
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Canon Inc
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Assigned to CANON KABUSHIKI KAISHA reassignment CANON KABUSHIKI KAISHA ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SHIMADA, YASUHITO, NISHIMURA, YUHEI, TANAKA, TOSHIO, MIYAZAKI, TAKESHI, NOMOTO, TSUYOSHI, SHINTOU, TAICHI, WATANABE, KOHEI
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0038—Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0032—Methine dyes, e.g. cyanine dyes
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a cancer cell inhibitory drug, particularly to a cancer stem cell inhibitory drug, and a cancer stem-cell detection probe.
  • the chemotherapy is a method for suppressing cancer by use of an anticancer therapeutic agent made of various types of low-molecular compounds.
  • the therapy using an anticancer therapeutic agent is directed to reduce the size of a solid tumor.
  • the most part of a tumor is occupied by differentiated cancer cells which no longer have a function as a cancer stem cell and it is pointed out in a general anticancer agent treatment that the differentiated cancer cells are only targeted to reduce the size thereof.
  • cancer stem cells have cells having nature of stem cells, called cancer stem cells.
  • the cancer stem cells which were first identified in 1997 in an acute myeloid leukemia, are now increasingly found in various types of cancers including solid cancers, and recently, a new way of thinking, called “cancer stem cell hypothesis” that cancer would be developed from cancer stem cells as an origin, has been proposed (NPL 1).
  • NPL 2 an anticancer therapeutic agent
  • a compound containing radioactive Cu-ATSM is known (PTL 1).
  • the radioactive compound may affect normal cells. Therefore, when a radioactive compound is used, safety becomes a matter of concern.
  • cancer stem cells may develop strong resistance to radiation.
  • Cancer stem cells have high resistance to radiation therapies and chemotherapies conventionally used and are casual cells from which cancer growth, recurrence and metastasis occur. Up to present, where cancer stem cells are present cannot be clearly detected. This was a issue remaining unsolved. To completely cure cancer, it has been strongly desired to detect cancer stem cells and develop a drug inhibiting cancer cells, in particular, cancer stem cells.
  • the present inventors intensively made studies with a view to solving the aforementioned problem. As a result, they found that a compound represented by the following general formula (1) has an inhibitory effect on cancer cells and is selectively taken into particularly cancer stem cells among the cancer cells and inhibits them. Based on the finding, the present invention was accomplished.
  • the compound of the present invention has a luminescence property. Owing to this, the position of cancer cells can be identified (determined) by detecting luminescence of the compound selectively taken into cancer cells. Based on the finding, the present inventors arrived at the present invention. Note that, in the specification, luminescence includes fluorescence and phosphorescence. Since the compound of the present invention is taken into particularly cancer stem cells in a high ratio, cancer stem cells can be selectively detected.
  • the compound of the present invention contains a compound represented by general formula (1):
  • R 1 independently represents an alkyl group, a carboxylalkyl group, an alkoxycarbonylalkyl group or an alkylcarbonyloxyalkyl group
  • R 2 to R 5 each independently represent a hydrogen atom, an alkyl group, an aryl group, an alkoxy group, a halogen atom, an alkoxysulfonyl group, a N-alkylsulfamoyl group, an alkyloxycarbonyl group or a N-alkylcarbamoyl group.
  • R 6 and R 7 each independently represent a hydrogen atom, an alkyl group or a phenyl group
  • R 8 and R 9 each independently represent a hydrogen atom, an alkyl group, an alkenyl group or a halogen atom
  • R 10 and R 11 each independently represent an alkyl group, an aryl group or an aralkyl group.
  • R 9 and R 10 may bind together to form a nitrogen atom-containing hetero ring.
  • X 1 ⁇ represents an anionic group.
  • Y 1 represents an oxygen atom, a sulfur atom, a nitrogen atom binding to an alkyl group or —C(R 12 )(R 13 )— where R 12 and R 13 each independently represent an alkyl group. R 12 and R 13 may bind together to form an aliphatic ring.
  • L is absent (in this case, carbons at both sides of L are bound via a double bond), represented by general formula (2) or represents ⁇ C(R 15 )—C(R 16 ) ⁇ where R 15 and R 16 each independently represent a hydrogen atom or an alkyl group.
  • R 14 represents an alkyl group, a carboxylalkyl group, an alkoxycarbonylalkyl group or an alkylcarbonyloxyalkyl group.
  • cancer cell inhibitory drug provided by the present invention, growth suppression, cellular division suppression, metastasis suppression, functional inhibition and cytocidal action of cancer cells can be mediated even in sites where cancer cells are overlooked by surgical excision and hardly excised out.
  • cancer cells particularly against cancer stem cells, these effects are significantly exerted.
  • cancer stem cells can be easily detected and the site of the cancer stem cells can be accurately determined. More specifically, the present invention provides a cancer stem-cell detection probe.
  • the compound of the present invention is effective as a cancer cell inhibitory drug.
  • the compound of the present invention is selectively taken into cancer stem cells among cancer cells, thereby inhibiting them.
  • the compound of the present invention is effective as a cancer stem-cell detection probe.
  • the cancer cell inhibitory drug has an effect of inhibiting growth and survival of cancer cells.
  • the cancer stem-cell detection probe is selectively taken into cancer stem cells and successfully detects the cancer stem cells.
  • the cancer cell inhibitory drug contains a compound represented by general formula (1).
  • the cancer cell inhibitory drug refers to a composition having functions of suppressing growth, cellular division, metastasis and function of cancer cells and killing cancer cells. Furthermore, cancer cells can be detected and observed by measuring luminescence of the compound of the present invention.
  • R 1 independently represents an alkyl group, a carboxylalkyl group, an alkoxycarbonylalkyl group or an alkylcarbonyloxyalkyl group
  • R 2 to R 5 each independently represent a hydrogen atom, an alkyl group, an aryl group, an alkoxy group, a halogen atom, an alkoxysulfonyl group, a N-alkylsulfamoyl group, an alkyloxycarbonyl group or a N-alkylcarbamoyl group.
  • R 6 and R 7 each independently represent a hydrogen atom, an alkyl group or a phenyl group
  • R 8 and R 9 each independently represent a hydrogen atom, an alkyl group, an alkenyl group or a halogen atom
  • R 10 and R 11 each independently represent an alkyl group, an aryl group or an aralkyl group.
  • R 9 and R 10 may bind together to form a nitrogen atom-containing hetero ring.
  • X 1 ⁇ represents an anionic group.
  • Y 1 represents an oxygen atom, a sulfur atom, a nitrogen atom binding to an alkyl group or —C(R 12 )(R 13 )— where R 12 and R 13 each independently represent an alkyl group. R 12 and R 13 may bind together to form an aliphatic ring.
  • L is absent (in this case, carbons at both sides of L are bound via a double bond), represented by general formula (2) or represents ⁇ C(R 15 )—C(R 16 ) ⁇ where R 15 and R 16 each independently represent a hydrogen atom or an alkyl group.
  • R 14 represents an alkyl group, a carboxylalkyl group, an alkoxycarbonylalkyl group or an alkylcarbonyloxyalkyl group.
  • examples of the alkyl group represented by R 1 include, but are not particularly limited to, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group and a hexyl group.
  • examples of the carboxylalkyl group represented by R 1 include, but are not particularly limited to, a carboxylmethyl group, a carboxylethyl group and a carboxylpropyl group.
  • examples of the alkoxycarbonylalkyl group represented by R 1 include, but are not particularly limited to, a methoxycarbonylmethyl group, a methoxycarbonylethyl group, an ethoxycarbonylethyl group, a butoxycarbonylethyl group and a methoxycarbonylpropyl group; and
  • alkylcarbonyloxyalkyl group examples include, but are not particularly limited to, a methylcarbonyloxymethyl group, an ethylcarbonyloxymethyl group, an ethylcarbonyloxyethyl group, an ethylcarbonyloxybutyl group and a propylcarbonyloxymethyl group.
  • examples of the alkyl groups represented by R 2 to R 5 include, but are not particularly limited to, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group and a hexyl group.
  • examples of the aryl groups represented by R 2 to R 5 include, but are not particularly limited to, a phenyl group, a 2-bromophenyl group, a 3-bromophenyl group, a 4-bromophenyl group, a 2-methoxyphenyl group, a 3-methoxyphenyl group, a 4-methoxyphenyl group, a 2-thiomethylphenyl group, a 3-thiomethylphenyl group, a 4-thiomethylphenyl group and a naphthyl group.
  • examples of the alkoxy groups represented by R 2 to R 5 include, but are not particularly limited to, a methoxy group, an ethoxy group, a propoxy group and a butoxy group.
  • examples of the halogen atoms represented by R 2 to R 5 include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • examples of the alkoxysulfonyl groups represented by R 2 to R 5 include, but are not particularly limited to, a methoxysulfonyl group and an ethoxysulfonyl group.
  • examples of the N-alkylsulfamoyl groups represented by R 2 to R 5 include, but are not particularly limited to, a N-methylsulfamoyl group, a N-ethylsulfamoyl group, a N,N-dimethylsulfamoyl group and a N,N-diethylsulfamoyl group.
  • examples of the alkyloxycarbonyl groups represented by R 2 to R 5 include, but are not particularly limited to, a methyloxycarbonyl group, an ethyloxycarbonyl group, a propyloxycarbonyl group and a butyloxycarbonyl group.
  • examples of the N-alkylcarbamoyl groups represented by R 2 to R 5 include, but are not particularly limited to, a N-methylcarbamoyl group, a N-ethylcarbamoyl group, a N,N-dimethylcarbamoyl group and a N,N-diethylcarbamoyl group.
  • R 2 to R 5 each independently represent preferably a hydrogen atom, a halogen atom, a phenyl group or an alkoxy group, and more preferably a hydrogen atom or a phenyl group.
  • examples of the alkyl groups represented by R 6 and R 7 include, but are not particularly limited to, a methyl group, an ethyl group, a propyl group and a butyl group.
  • examples of the alkyl groups and alkenyl groups represented by R 8 and R 9 include, but are not particularly limited to, a methyl group, an ethyl group, a propyl group, a butyl group, a methylene group, an ethylene group and a propylene group. Furthermore, the side chains of the alkyl group and alkenyl group may be further substituted with an alkyl group, an alkenyl group and the like.
  • examples of the halogen atoms represented by R 8 and R 9 include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • examples of the alkyl groups represented by R 10 and R 11 include, but are not particularly limited to, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group and a 2-ethylhexyl group.
  • examples of the aryl groups represented by R 10 and R 11 include, but are not particularly limited to, a phenyl group, a 2-bromophenyl group, a 3-bromophenyl group, a 4-bromophenyl group, a 2-methoxyphenyl group, a 3-methoxyphenyl group, a 4-methoxyphenyl group, a 2-methylthiophenyl group, a 3-methylthiophenyl group, a 4-methylthiophenyl group and a naphthyl group.
  • groups represented by general formula (6) are mentioned.
  • reference symbol * represents a binding site.
  • examples of the aralkyl groups represented by R 10 and R 11 include, but are not particularly limited to, a benzyl group and a phenethyl group.
  • examples of the nitrogen atom-containing hetero ring formed by binding R 9 and R 10 together include, but are not particularly limited to, a pyrrolidine ring, a pyrrole ring, a pyrrolidine ring, an indole ring and a cyclopentapyrrole ring.
  • examples of the anionic group represented by X 1 ⁇ include, but are not particularly limited to, a chloride ion, a bromide ion, an iodide ion, a sulfate ion, a nitrate ion and a methanesulfonate ion.
  • examples of the alkyl group of the nitrogen atom binding to an alkyl group represented by Y 1 include, but are not particularly limited to, a methyl group, an ethyl group, a propyl group and a butyl group.
  • examples of the alkyl groups represented by R 12 and R 13 in Y 1 include, but are not particularly limited to, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group and a 2-ethylhexyl group.
  • R 12 and R 13 are favorably the same substituents.
  • examples of the aliphatic ring formed by binding R 12 and R 13 together in Y 1 include, but are not particularly limited to, a cyclohexane ring and a cyclopentane ring.
  • examples of the alkyl groups represented by R 15 and R 16 in L include, but are not particularly limited to, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group and 2-ethylhexyl group.
  • examples of the alkyl group represented by R 14 include, but are not particularly limited to, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group and a 2-ethylhexyl group.
  • examples of the carboxylalkyl group represented by R 14 include, but are not particularly limited to, a carboxylmethyl group, a carboxylethyl group and a carboxylpropyl group.
  • examples of the alkoxycarbonylalkyl group represented by R 14 include, but are not particularly limited to, a methoxycarbonylmethyl group, a methoxycarbonylethyl group, an ethoxycarbonylethyl group, a butoxycarbonylethyl group and a methoxycarbonyl propyl group; and
  • alkylcarbonyloxyalkyl group examples include, but are not particularly limited to, a methylcarbonyloxymethyl group, an ethylcarbonyloxymethyl group, an ethylcarbonyloxyethyl group, an ethylcarbonyloxybutyl group and a propylcarbonyloxymethyl group.
  • R 17 each independently represents an alkyl group, a carboxylalkyl group, an alkoxycarbonylalkyl group or an alkylcarbonyloxyalkyl group
  • R 18 to R 21 each independently represent a hydrogen atom, an alkyl group, an aryl group, an alkoxy group, a halogen atom, an alkoxysulfonyl group, a N-alkylsulfamoyl group, an alkyloxycarbonyl group or a N-alkylcarbamoyl group.
  • R 22 and R 23 each independently represent a hydrogen atom, an alkyl group or a phenyl group;
  • R 24 represents a hydrogen atom or a halogen atom;
  • R 25 represents an alkyl group, an aryl group or an aralkyl group.
  • X 2 ⁇ represents an anionic group.
  • Y 2 represents an oxygen atom, a sulfur atom, a nitrogen atom binding to an alkyl group or —C(R 26 )(R 27 )— where R 26 and R 27 each independently represent an alkyl group. R 26 and R 27 may bind together to form an aliphatic ring.
  • Reference symbol A represents a cyclopentane ring or a benzene ring.
  • examples of the alkyl group represented by R 17 include, but are not particularly limited to, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group and a hexyl group.
  • examples of the carboxylalkyl group represented by R 17 include, but are not particularly limited to, a carboxylmethyl group, a carboxylethyl group and a carboxylpropyl group.
  • examples of the alkoxycarbonylalkyl group represented by R 17 include, but are not particularly limited to, a methoxycarbonylmethyl group, a methoxycarbonylethyl group, an ethoxycarbonylethyl group, a butoxycarbonylethyl group and a methoxycarbonylpropyl group; and
  • alkylcarbonyloxyalkyl group examples include, but are not particularly limited to, a methylcarbonyloxymethyl group, an ethylcarbonyloxymethyl group, an ethylcarbonyloxyethyl group, an ethylcarbonyloxybutyl group and a propylcarbonyloxymethyl group.
  • examples of the alkyl groups represented by R 18 to R 21 include, but are not particularly limited to, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group and a hexyl group.
  • examples of the aryl groups represented by R 18 to R 21 include, but are not particularly limited to, a phenyl group, a 2-bromophenyl group, a 3-bromophenyl group, a 4-bromophenyl group, a 2-methoxyphenyl group, a 3-methoxyphenyl group, a 4-methoxyphenyl group, a 2-thiomethylphenyl group, a 3-thiomethylphenyl group, a 4-thiomethylphenyl group and a naphthyl group.
  • examples of the alkoxy groups represented by R 18 to R 21 include, but are not particularly limited to, a methoxy group, an ethoxy group, a propoxy group and a butoxy group.
  • examples of the halogen atoms represented by R 18 to R 21 include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • examples of the alkoxysulfonyl groups represented by R 18 to R 21 include, but are not particularly limited to, a methoxysulfonyl group and an ethoxysulfonyl group.
  • examples of the N-alkylsulfamoyl groups represented by R 18 to R 21 include, but are not particularly limited to, a N-methylsulfamoyl group, a N-ethylsulfamoyl group, a N,N-dimethylsulfamoyl group and a N,N-diethylsulfamoyl group.
  • examples of the alkyloxycarbonyl groups represented by R 18 to R 21 include, but are not particularly limited to, a methyloxycarbonyl group, an ethyloxycarbonyl group, a propyloxycarbonyl group and a butyloxycarbonyl group.
  • examples of the N-alkylcarbamoyl groups represented by R 18 to R 21 include, but are not particularly limited to, a N-methylcarbamoyl group, a N-ethylcarbamoyl group, a N,N-dimethylcarbamoyl group and a N,N-diethylcarbamoyl group.
  • R 18 to R 21 each independently represent preferably a hydrogen atom, a halogen atom, a phenyl group or an alkoxy group, and more preferably a hydrogen atom or a phenyl group.
  • examples of the alkyl groups represented by R 22 and R 23 include, but are not particularly limited to, a methyl group, an ethyl group, a propyl group and a butyl group.
  • examples of the halogen atom represented by R 24 include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • examples of the alkyl group represented by R 25 include, but are not particularly limited to, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group and a 2-ethylhexyl group.
  • examples of the aryl group represented by R 25 include, but are not particularly limited to, a phenyl group, a 2-bromophenyl group, a 3-bromophenyl group, a 4-bromophenyl group, a 2-methoxyphenyl group, a 3-methoxyphenyl group, a 4-methoxyphenyl group, a 2-methylthiophenyl group, a 3-methylthiophenyl group, a 4-methylthiophenyl group and a naphthyl group.
  • groups represented by general formula (6) are mentioned.
  • reference symbol * represents a binding site.
  • examples of the aralkyl group represented by R 25 include, but are not particularly limited to, a benzyl group and a phenethyl group.
  • examples of the anionic group represented by X 2 include, but are not particularly limited to, a chloride ion, a bromide ion, an iodide ion, a sulfate ion, a nitrate ion and a methanesulfonate ion.
  • examples of the alkyl group of the nitrogen atom binding to an alkyl group represented by Y 2 include, but are not particularly limited to, a methyl group, an ethyl group, a propyl group and a butyl group.
  • examples of the alkyl groups represented by R 26 and R 27 in Y 2 include, but are not particularly limited to, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group and a 2-ethylhexyl group.
  • R 26 and R 27 are favorably the same substituents.
  • examples of the aliphatic ring formed by binding R 26 and R 27 together in Y 2 include, but are not particularly limited to, a cyclohexane ring and a cyclopentane ring.
  • R 17 to R 25 , X 2 ⁇ , Y 2 and A are the same as defined in R 17 to R 25 , X 2 ⁇ , Y 2 and A in general formula (3).
  • a compound (A) is coupled with a compound (B) to obtain a compound represented by general formula (3).
  • the coupling method is not particularly limited to; however, for example, the method shown below is specifically mentioned as an embodiment.
  • the use amount of compound (B) in the coupling step relative to compound (A) (1 mole) is 0.1 to 10 times by mole, preferably 0.5 to 3 times by mole, and more preferably 0.8 to 2 times by mole.
  • the coupling step can be performed in the absence of a solvent; however, it is favorably performed in the presence of a solvent.
  • the solvent is not particularly limited as long as it is not involved in a reaction.
  • the solvent include ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate and butyl acetate; nitrile solvents such as acetonitrile, propionitrile and benzonitrile; aromatic solvents such as benzene, toluene, xylene, ethylbenzene, chlorobenzene and mesitylene; ether solvents such as diisopropyl ether, methyl-tert-butyl ether and tetrahydrofuran; alcohol solvents such as methanol, ethanol, n-propyl alcohol, iso-propyl alcohol, butyl alcohol and diethylene glycol; ketone solvents such as acetone and methylethyl ketone;
  • alcohol solvents such as methanol, ethanol, n-propyl alcohol, iso-propyl alcohol, butyl alcohol and diethylene glycol, water and acetic acid, and more preferably e.g., ethanol, iso-propyl alcohol and diethylene glycol and acetic acid are mentioned.
  • two or more types of solvents can be used in combination and the mixing ratio of solvents used in combination can be determined at discretion.
  • reaction solvent in the coupling step relative to compound (A) falls within the range of 0.1 to 1000 times by weight, preferably 0.5 to 500 times by weight, and more preferably 1.0 to 150 times by weight.
  • the reaction temperature in the coupling step falls within the range of ⁇ 80 to 250° C., preferably ⁇ 20 to 200° C., and more preferably ⁇ 5 to 150° C.
  • the reaction is generally completed within 24 hours.
  • the acid to be used is not particularly limited.
  • the acid include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; organic acids such as p-toluenesulfonic acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid and acetic anhydride; strongly acidic ion exchange resins such as Amberlite (Rohm and Haas) and Amberlyst (Rohm and Haas); and inorganic acid salts such as ammonium formate and ammonium acetate.
  • inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid
  • organic acids such as p-toluenesulfonic acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid and acetic anhydride
  • strongly acidic ion exchange resins such as Amberlite (Rohm and Haas) and Amberlyst (Rohm and Haas)
  • an inorganic acid salt such as ammonium formate or ammonium acetate, and more preferably ammonium acetate is mentioned.
  • the use amount of acid relative to compound (A) (1 mole) is 0.001 to 50 times by mole, preferably 0.01 to 10 times by mole, and more preferably 0.1 to 5 times by mole.
  • the base to be used in the coupling step include metal alkoxides such as potassium tert-butoxide, sodium tert-butoxide, sodium methoxide and sodium ethoxide; organic bases such as piperidine, pyridine, 2-methylpyridine, dimethylaminopyridine, diethylamine, triethylamine, isopropylethylamine, sodium acetate, potassium acetate, 1,8-diazabicyclo[5,4,0]undec-7-ene (hereinafter, simply referred to as DBU) and ammonium acetate; organic bases such as N-butylithium and tert-magnesium chloride; and inorganic bases such as sodium borohydride, metallic sodium, sodium hydride and sodium carbonate.
  • metal alkoxides such as potassium tert-butoxide, sodium tert-butoxide, sodium methoxide and sodium ethoxide
  • organic bases such as piperidine, pyridine, 2-methylpyridine
  • potassium tert-butoxide, sodium methoxide, sodium ethoxide, piperidine, dimethylaminopyridine, sodium acetate and ammonium acetate; and more preferably sodium methoxide, piperidine, sodium acetate and ammonium acetate are mentioned.
  • the use amount of base as mentioned above relative to compound (A) (1 mole) is 0.1 to 20 times by mole, preferably 0.5 to 8 times by mole, and more preferably 1.0 to 4 times by mole.
  • reaction product is diluted with water or precipitated with an acid such as hydrochloric acid to obtain a compound represented by general formula (3).
  • isolation/purification methods generally used for organic compounds can be applied.
  • a reaction solution is acidified with an acid such as hydrochloric acid to precipitate a solid substance.
  • the solid substrate is separated by filtration, neutralized with e.g., sodium hydroxide and concentrated to obtain a crude product.
  • the crude product is further purified by e.g., recrystallization using e.g., acetone or methanol, or a column using silica gel.
  • the crude product can be highly purified by employing these methods alone or in combination with two or more.
  • R 28 each independently represents an alkyl group, a carboxylalkyl group, an alkoxycarbonylalkyl group or an alkylcarbonyloxyalkyl group
  • R 29 to R 32 each independently represent a hydrogen atom, an alkyl group, an aryl group, an alkoxy group, a halogen atom, an alkoxysulfonyl group, a N-alkylsulfamoyl group, an alkyloxycarbonyl group or a N-alkylcarbamoyl group.
  • R 33 and R 34 each independently represent a hydrogen atom, an alkyl group or a phenyl group;
  • R 35 represents an alkyl group, a carboxylalkyl group, an alkoxycarbonylalkylgroup or an alkylcarbonyloxyalkyl group;
  • R 36 represents a hydrogen atom or a halogen atom;
  • R 37 represents an alkyl group, an aryl group or an aralkyl group.
  • X 3 ⁇ represents an anionic group.
  • Y 3 represents an oxygen atom, a sulfur atom, a nitrogen atom binding to an alkyl group or —C(R 38 )(R 39 )— where R 38 and R 39 each independently represent an alkyl group. R 38 and R 39 may bind together to form an aliphatic ring.
  • Reference symbol B represents a cyclopentane ring or a benzene ring.
  • examples of the alkyl group represented by R 28 include, but are not particularly limited to, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group and a hexyl group.
  • examples of the carboxylalkyl group represented by R 28 include, but are not particularly limited to, a carboxylmethyl group, a carboxylethyl group and a carboxylpropyl group.
  • examples of the alkoxycarbonylalkyl group represented by R 28 include, but are not particularly limited to, a methoxycarbonylmethyl group, a methoxycarbonylethyl group, an ethoxycarbonylethyl group, a butoxycarbonylethyl group and a methoxycarbonylpropyl group; and
  • alkylcarbonyloxyalkyl group examples include, but are not particularly limited to, a methylcarbonyloxymethyl group, an ethylcarbonyloxymethyl group, an ethylcarbonyloxyethyl group, an ethylcarbonyloxybutyl group and a propylcarbonyloxymethyl group.
  • examples of the alkyl groups represented by R 29 to R 32 include, but are not particularly limited to, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group and a hexyl group.
  • examples of the aryl groups represented by R 29 to R 32 include, but are not particularly limited to, a phenyl group, a 2-bromophenyl group, a 3-bromophenyl group, a 4-bromophenyl group, a 2-methoxyphenyl group, a 3-methoxyphenyl group, a 4-methoxyphenyl group, a 2-thiomethylphenyl group, a 3-thiomethylphenyl group, a 4-thiomethylphenyl group and a naphthyl group.
  • examples of the alkoxy groups represented by R 29 to R 32 include, but are not particularly limited to, a methoxy group, an ethoxy group, a propoxy group and a butoxy group.
  • examples of the halogen atoms represented by R 29 to R 32 include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • examples of the alkoxysulfonyl groups represented by R 29 to R 32 include, but are not particularly limited to, a methoxysulfonyl group and an ethoxysulfonyl group.
  • examples of the N-alkylsulfamoyl groups represented by R 29 to R 32 include, but are not particularly limited to, a N-methylsulfamoyl group, a N-ethylsulfamoyl group, a N,N-dimethylsulfamoyl group and a N,N-ethylsulfamoyl group.
  • examples of the alkyloxycarbonyl groups represented by R 29 to R 32 include, but are not particularly limited to, a methyloxycarbonyl group, an ethyloxycarbonyl group, a propyloxycarbonyl group and a butyloxycarbonyl group.
  • examples of the N-alkylcarbamoyl groups represented by R 29 to R 32 include, but are not particularly limited to, a N-methylcarbamoyl group, a N-ethylcarbamoyl group, a N,N-dimethylcarbamoyl group and a N,N-diethylcarbamoyl group.
  • R 29 to R 32 each independently represent preferably a hydrogen atom, a halogen atom, a phenyl group or an alkoxy group, and more preferably a hydrogen atom or a phenyl group.
  • examples of the alkyl groups represented by R 33 and R 34 include, but are not particularly limited to, a methyl group, an ethyl group, a propyl group and a butyl group.
  • examples of the alkyl group represented by R 35 include, but are not particularly limited to, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group and a hexyl group.
  • examples of the carboxylalkyl group represented by R 35 include, but are not particularly limited to, a carboxylmethyl group, a carboxylethyl group and a carboxylpropyl group.
  • examples of the alkoxycarbonylalkyl group represented by R 35 include, but are not particularly limited to, a methoxycarbonylmethyl group, a methoxycarbonylethyl group, an ethoxycarbonylethyl group, a butoxycarbonylethyl group and a methoxycarbonylpropyl group; and
  • alkylcarbonyloxyalkyl group examples include, but are not particularly limited to, a methylcarbonyloxymethyl group, an ethylcarbonyloxymethyl group, an ethylcarbonyloxyethyl group, an ethylcarbonyloxybutyl group and a propylcarbonyloxymethyl group.
  • examples of the halogen atom represented by R 36 include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • examples of the alkyl group represented by R 37 include, but are not particularly limited to, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group and a 2-ethylhexyl group.
  • examples of the aryl group represented by R 37 include, but are not particularly limited to, a phenyl group, a 2-bromophenyl group, a 3-bromophenyl group, a 4-bromophenyl group, a 2-methoxyphenyl group, a 3-methoxyphenyl group, a 4-methoxyphenyl group, a 2-methylthiophenyl group, a 3-methylthiophenyl group, a 4-methylthiophenyl group and a naphthyl group.
  • groups represented by general formula (6) are mentioned.
  • reference symbol * represents a binding site.
  • examples of the aralkyl group represented by R 37 include, but are not particularly limited to, a benzyl group and a phenethyl group.
  • examples of the anionic group represented by X 3 ⁇ include, but are not particularly limited to, a chloride ion, a bromide ion, an iodide ion, a sulfate ion, a nitrate ion and a methanesulfonate ion.
  • examples of the alkyl group of the nitrogen atom binding to an alkyl group represented by Y 3 include, but are not particularly limited to, a methyl group, an ethyl group, a propyl group and a butyl group.
  • examples of the alkyl groups represented by R 38 and R 39 in Y 3 include, but are not particularly limited to, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group and a 2-ethylhexyl group.
  • R 38 and R 39 are favorably the same substituents.
  • examples of the aliphatic ring formed by binding R 38 and R 39 together in Y 3 include, but are not particularly limited to, a cyclohexane ring and a cyclopentane ring.
  • R 28 to R 36 , X 3 ⁇ , Y 3 and B are the same as defined in R 28 to R 36 , X 3 ⁇ , Y 3 and B in general formula (4).
  • a compound (C) is coupled with a compound (D) to obtain a compound represented by general formula (4).
  • the coupling method is not particularly limited to; however, for example, the method shown below is specifically mentioned as an embodiment.
  • the use amount of compound (D) in the coupling step relative to compound (C) (1 mole) is 0.1 to 10 times by mole, preferably 0.5 to 3 times by mole, and more preferably 0.8 to 2 times by mole.
  • the coupling step can be performed in the absence of a solvent; however, it is favorably performed in the presence of a solvent.
  • the solvent is not particularly limited as long as it is not involved in a reaction.
  • the solvent include ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate and butyl acetate; nitrile solvents such as acetonitrile, propionitrile and benzonitrile; aromatic solvents such as benzene, toluene, xylene, ethylbenzene, chlorobenzene and mesitylene; ether solvents such as diisopropyl ether, methyl-tert-butyl ether and tetrahydrofuran; alcohol solvents such as methanol, ethanol, n-propyl alcohol, iso-propyl alcohol, butyl alcohol and diethylene glycol; ketone solvents such as acetone and methylethyl ketone;
  • alcohol solvents such as methanol, ethanol, n-propyl alcohol, iso-propyl alcohol, butyl alcohol and diethylene glycol, water and acetic acid, and more preferably e.g., ethanol, iso-propyl alcohol and diethylene glycol and acetic acid are mentioned.
  • two or more types of solvents can be used in combination and the mixing ratio of solvents used in combination can be determined at discretion.
  • reaction solvent in the coupling step relative to compound (C) falls within the range of 0.1 to 1000 times by weight, preferably 0.5 to 500 times by weight, and more preferably 1.0 to 150 times by weight.
  • the reaction temperature in the coupling step falls within the range of ⁇ 80 to 250° C., preferably ⁇ 20 to 200° C., and more preferably ⁇ 5 to 150° C.
  • the reaction is generally completed within 24 hours.
  • the acid to be used is not particularly limited.
  • the acid include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; organic acids such as p-toluenesulfonic acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid and acetic anhydride; strongly acidic ion exchange resins such as Amberlite (Rohm and Haas) and Amberlyst (Rohm and Haas); and inorganic acid salts such as ammonium formate and ammonium acetate.
  • inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid
  • organic acids such as p-toluenesulfonic acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid and acetic anhydride
  • strongly acidic ion exchange resins such as Amberlite (Rohm and Haas) and Amberlyst (Rohm and Haas)
  • an inorganic acid salt such as ammonium formate or ammonium acetate, and more preferably ammonium acetate is mentioned.
  • the use amount of acid relative to compound (C) (1 mole) is 0.001 to 50 times by mole, preferably 0.01 to 10 times by mole, and more preferably 0.1 to 5 times by mole.
  • the base to be used in the coupling step include metal alkoxides such as potassium tert-butoxide, sodium tert-butoxide, sodium methoxide and sodium ethoxide; organic bases such as piperidine, pyridine, 2-methylpyridine, dimethylaminopyridine, diethylamine, triethylamine, isopropylethylamine, sodium acetate, potassium acetate, 1,8-diazabicyclo[5,4,0]undec-7-ene (hereinafter, simply referred to as DBU) and ammonium acetate; organic bases such as N-butylithium and tert-magnesium chloride; and inorganic bases such as sodium borohydride, metallic sodium, sodium hydride and sodium carbonate.
  • metal alkoxides such as potassium tert-butoxide, sodium tert-butoxide, sodium methoxide and sodium ethoxide
  • organic bases such as piperidine, pyridine, 2-methylpyridine
  • potassium tert-butoxide, sodium methoxide, sodium ethoxide, piperidine, dimethylaminopyridine, sodium acetate and ammonium acetate; and more preferably sodium methoxide, piperidine, sodium acetate and ammonium acetate are mentioned.
  • the use amount of base as mentioned above relative to compound (C) (1 mole) is 0.1 to 20 times by mole, preferably 0.5 to 8 times by mole, and more preferably 1.0 to 4 times by mole.
  • reaction product After completion of the reaction, a reaction product is diluted with water or precipitated with an acid such as hydrochloric acid to obtain a compound represented by general formula (4).
  • isolation/purification methods generally used for organic compounds can be applied.
  • a reaction solution is acidified with an acid such as hydrochloric acid to precipitate a solid substance.
  • the solid substrate is separated by filtration, neutralized with e.g., sodium hydroxide and concentrated to obtain a crude product.
  • the crude product is purified by e.g., recrystallization using e.g., acetone or methanol, or a column using silica gel.
  • the crude product can be highly purified by employing these methods alone or in combination with two or more.
  • R 40 each independently represents an alkyl group, a carboxylalkyl group, an alkoxycarbonylalkyl group or an alkylcarbonyloxyalkyl group
  • R 41 to R 44 each independently represent a hydrogen atom, an alkyl group, an aryl group, an alkoxy group, a halogen atom, an alkoxysulfonyl group, a N-alkylsulfamoyl group, an alkyloxycarbonyl group or a N-alkylcarbamoyl group.
  • R 45 and R 46 each independently represent, an alkyl group or an aryl group.
  • Y 4 represents an oxygen atom, a sulfur atom, a nitrogen atom binding to an alkyl group or —C(R 47 )(R 48 )— where R 47 and R 48 each independently represent an alkyl group. R 47 and R 48 may bind together to form an aliphatic ring.
  • examples of the alkyl group represented by R 40 include, but are not particularly limited to, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group and a hexyl group.
  • examples of the carboxylalkyl group represented by R 40 include, but are not particularly limited to, a carboxylmethyl group, a carboxylethyl group and a carboxylpropyl group.
  • examples of the alkoxycarbonylalkyl group represented by R 40 include, but are not particularly limited to, a methoxycarbonylmethyl group, a methoxycarbonylethyl group, an ethoxycarbonylethyl group, a butoxycarbonylethyl group and a methoxycarbonylpropyl group; and
  • alkylcarbonyloxyalkyl group examples include, but are not particularly limited to, a methylcarbonyloxymethyl group, an ethylcarbonyloxymethyl group, an ethylcarbonyloxyethyl group, an ethylcarbonyloxybutyl group and a propylcarbonyloxymethyl group.
  • examples of the alkyl groups represented by R 41 to R 44 include, but are not particularly limited to, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group and a hexyl group.
  • examples of the aryl groups represented by R 41 to R 44 include, but are not particularly limited to, a phenyl group, a 2-bromophenyl group, a 3-bromophenyl group, a 4-bromophenyl group, a 2-methoxyphenyl group, a 3-methoxyphenyl group, a 4-methoxyphenyl group, a 2-thiomethylphenyl group, a 3-thiomethylphenyl group, a 4-thiomethylphenyl group and a naphthyl group.
  • examples of the alkoxy groups represented by R 41 to R 44 include, but are not particularly limited to, a methoxy group, an ethoxy group, a propoxy group and a butoxy group.
  • examples of the halogen atoms represented by R 41 to R 44 include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • examples of the alkoxysulfonyl groups represented by R 41 to R 44 include, but are not particularly limited to, a methoxysulfonyl group and an ethoxysulfonyl group.
  • examples of the N-alkylsulfamoyl groups represented by R 41 to R 44 include, but are not particularly limited to, a N-methylsulfamoyl group, a N-ethylsulfamoyl group, a N,N-dimethylsulfamoyl group and a N,N-ethylsulfamoyl group.
  • examples of the alkyloxycarbonyl groups represented by R 41 to R 44 include, but are not particularly limited to, a methyloxycarbonyl group, an ethyloxycarbonyl group, a propyloxycarbonyl group and a butyloxycarbonyl group.
  • examples of the N-alkylcarbamoyl groups represented by R 41 to R 44 include, but are not particularly limited to, a N-methylcarbamoyl group, a N-ethylcarbamoyl group, a N,N-dimethylcarbamoyl group and a N,N-diethylcarbamoyl group.
  • R 41 to R 44 each independently represent preferably a hydrogen atom, a halogen atom, a phenyl group or an alkoxy group, and more preferably a hydrogen atom or a phenyl group.
  • examples of the alkyl groups represented by R 45 and R 46 include, but are not particularly limited to, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group and a 2-ethylhexyl group.
  • examples of the aryl groups represented by R 45 and R 46 include, but are not particularly limited to, a phenyl group, a 2-bromophenyl group, a 3-bromophenyl group, a 4-bromophenyl group, a 2-methoxyphenyl group, a 3-methoxyphenyl group, a 4-methoxyphenyl group, a 2-thiomethylphenyl group, a 3-thiomethylphenyl group, a 4-thiomethylphenyl group and a naphthyl group.
  • examples of the anionic group represented by X 4 ⁇ include, but are not particularly limited to, a chloride ion, a bromide ion, an iodide ion, a sulfate ion, a nitrate ion and a methanesulfonate ion.
  • examples of the alkyl group of the nitrogen atom binding to an alkyl group represented by Y 4 include, but are not particularly limited to, a methyl group, an ethyl group, a propyl group and a butyl group.
  • examples of the alkyl groups represented by R 47 and R 48 in Y 4 include, but are not particularly limited to, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group and a 2-ethylhexyl group.
  • R 47 and R 48 are favorably the same substituents.
  • examples of the aliphatic ring formed by binding R 47 and R 48 together in Y 4 include, but are not particularly limited to, a cyclohexane ring and a cyclopentane ring.
  • R 40 to R 46 and X 4 ⁇ , Y 4 are the same as defined in R 40 to R 46 and X 4 ⁇ , Y 4 in general formula (5).
  • a compound (E) is coupled with a compound (F) to obtain a compound represented by general formula (5).
  • the coupling method is not particularly limited to; however, for example, the method shown below is specifically mentioned as an embodiment.
  • the use amount of compound (F) in the coupling step relative to compound (E) (1 mole) is 0.1 to 10 times by mole, preferably 0.5 to 3 times by mole, and more preferably 0.8 to 2 times by mole.
  • the coupling step can be performed in the absence of a solvent; however, it is favorably performed in the presence of a solvent.
  • the solvent is not particularly limited as long as it is not involved in a reaction.
  • the solvent include ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate and butyl acetate; nitrile solvents such as acetonitrile, propionitrile and benzonitrile; aromatic solvents such as benzene, toluene, xylene, ethylbenzene, chlorobenzene and mesitylene; ether solvents such as diisopropyl ether, methyl-tert-butyl ether and tetrahydrofuran; alcohol solvents such as methanol, ethanol, n-propyl alcohol, iso-propyl alcohol, butyl alcohol and diethylene glycol; ketone solvents such as acetone and methylethyl ketone;
  • alcohol solvents such as methanol, ethanol, n-propyl alcohol, iso-propyl alcohol, butyl alcohol and diethylene glycol, water and acetic acid, and more preferably e.g., ethanol, iso-propyl alcohol and diethylene glycol and acetic acid are mentioned.
  • two or more types of solvents can be used in combination and the mixing ratio of solvents used in combination can be determined at discretion.
  • reaction solvent in the coupling step relative to compound (E) falls within the range of 0.1 to 1000 times by weight, preferably 0.5 to 500 times by weight, and more preferably 1.0 to 150 times by weight.
  • the reaction temperature in the coupling step falls within the range of ⁇ 80 to 250° C., preferably ⁇ 20 to 200° C., and more preferably ⁇ 5 to 150° C.
  • the reaction is generally completed within 24 hours.
  • the acid to be used is not particularly limited.
  • the acid include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; organic acids such as p-toluenesulfonic acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid and acetic anhydride; strongly acidic ion exchange resins such as Amberlite (Rohm and Haas) and Amberlyst (Rohm and Haas); and inorganic acid salts such as ammonium formate and ammonium acetate.
  • inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid
  • organic acids such as p-toluenesulfonic acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid and acetic anhydride
  • strongly acidic ion exchange resins such as Amberlite (Rohm and Haas) and Amberlyst (Rohm and Haas)
  • an inorganic acid salt such as ammonium formate or ammonium acetate, and more preferably ammonium acetate is mentioned.
  • the use amount of acid relative to compound (E) (1 mole) is 0.001 to 50 times by mole, preferably 0.01 to 10 times by mole, and more preferably 0.1 to 5 times by mole.
  • the base to be used in the coupling step include metal alkoxides such as potassium tert-butoxide, sodium tert-butoxide, sodium methoxide and sodium ethoxide; organic bases such as piperidine, pyridine, 2-methylpyridine, dimethylaminopyridine, diethylamine, triethylamine, isopropylethylamine, sodium acetate, potassium acetate, 1,8-diazabicyclo[5,4,0]undec-7-ene (hereinafter, simply referred to as DBU) and ammonium acetate; organic bases such as N-butylithium and tert-butylmagnesium chloride; and inorganic bases such as sodium borohydride, metallic sodium, sodium hydride and sodium carbonate.
  • metal alkoxides such as potassium tert-butoxide, sodium tert-butoxide, sodium methoxide and sodium ethoxide
  • organic bases such as piperidine, pyridine, 2-
  • potassium tert-butoxide, sodium methoxide, sodium ethoxide, piperidine, dimethylaminopyridine, sodium acetate and ammonium acetate; and more preferably sodium methoxide, piperidine, sodium acetate and ammonium acetate are mentioned.
  • the use amount of base as mentioned above relative to compound (E) (1 mole) is 0.1 to 20 times by mole, preferably 0.5 to 8 times by mole, and more preferably 1.0 to 4 times by mole.
  • reaction product is diluted with water or precipitated with an acid such as hydrochloric acid to obtain a compound represented by general formula (5).
  • isolation/purification methods generally used for organic compounds can be applied.
  • a reaction solution is acidified with an acid such as hydrochloric acid to precipitate a solid substance.
  • the solid substrate is separated by filtration, neutralized with e.g., sodium hydroxide and concentrated to obtain a crude product.
  • the crude product is purified by e.g., recrystallization using e.g., acetone or methanol, or a column using silica gel.
  • the crude product can be highly purified by employing these methods alone or in combination with two or more.
  • the compounds of the present invention are characterized by emitting light upon irradiation with excitation light of 350 to 800 nm in wavelength.
  • the emission light, i.e., luminescence, referred to in the present invention can include fluorescence and phosphorescence.
  • the cancer cell inhibitory drug of the present invention is characterized in that growth suppression, cellular division suppression, metastasis suppression, functional inhibition and cytocidal action of cancer cells are mediated by taking a compound represented by general formula (1) of the present invention selectively into the cancer cells. At the same time, cancer cells can be detected and observed by measuring luminescence of the compound of the present invention.
  • the cancer cell inhibitory drugs of the present invention can be used alone or in combination of two or more types, and may be used in combination with a known anti-cancer drug(s).
  • a large effect is selectively exerted particularly on cancer stem cells among cancer cells.
  • the cancer stem cells refer to cancer cells having properties of the stem cells.
  • the stem cells refer to cells having two functions, i.e., self-replication ability and pluripotency (ability to differentiate into various types of cells).
  • the cancers to which the cancer cell inhibitory drugs of the present invention are applicable are not particularly limited.
  • the cancers include breast cancer, brain tumor, stomach cancer, prostatic cancer, pancreatic cancer, lung cancer, large bowel cancer, small intestine cancer, colon cancer, rectal cancer, esophagus cancer, duodenal cancer, tongue cancer, pharyngeal cancer, liver cancer, endometrium cancer, uterine cervix cancer, renal cancer, bile duct cancer, ovarian cancer, bladder cancer, skin cancer, blood vessel cancer, salivary gland cancer, thyroid cancer, parathyroid gland cancer, nasal cavity cancer, paranasal sinus cancer, penile cancer, infant solid cancer, malignant lymphoma, malignant melanoma, retina sarcoma, testicular tumor, myeloma, sarcoma, blood vessel fibroma and leukemia.
  • pancreatic cancer, prostatic cancer and leukemia are mentioned.
  • applicable cancers may include cancer stem
  • Examples of the subject used in a test for checking whether a compound of the present invention suppresses a cancer or not include, but are not particularly limited to, vertebral animals including bony fish such as Takifugu (Japanese pufferfish), Takifugu niphobles, green spotted pufferfish (Tetraodon nigroviridis), killifish and zebra fish, amphibians such as Xenopus , birds such as fowl and quail, mammalians such as human, monkey, chimpanzee, calf, horse, pig, dog, cat, mouse, rat, guinea pig, and hamster and rabbit; small animals such as rat, mouse and hamster; and large animals such as goat, pig, dog, cat, calf and horse, monkey and chimpanzee.
  • vertebral animals including bony fish such as Takifugu (Japanese pufferfish), Takifugu niphobles, green spotted pufferfish (T
  • dosage forms When a compound of the present invention is used as a medicinal drug, various types of dosage forms can be selected depending upon the administration route. Examples of dosage forms that can be used include liquid, syrup, fine granule, granule, tablet, capsule, pasting medicine and drug delivery system (DDS) such as liposome.
  • DDS drug delivery system
  • the administration method of a compound of the present invention is not limited and oral or parenteral administration may be used.
  • Examples of the administration method that can be used include exposure to a living body (e.g., liquid); administration such as oral, intravascular (through e.g., a vein or an artery), peroral, sublingual, intrarectal, intraperitoneal, dermal, subcutaneous, intracutaneous, intravesical, tracheal (via bronchia), intraocular and intranasal administrations; and injection, spray and application into ear or the like.
  • a compound of the present invention may contain pharmacologically or pharmaceutically acceptable additives such as a moisturizer, a surface tension moderator, a thickener, a pH moderator, a pH buffer, a preservative, an antibacterial agent, a sweetening agent, a flavor, a solubilizer, a solubilizing agent, a coating agent and a binder.
  • pharmacologically or pharmaceutically acceptable additives such as a moisturizer, a surface tension moderator, a thickener, a pH moderator, a pH buffer, a preservative, an antibacterial agent, a sweetening agent, a flavor, a solubilizer, a solubilizing agent, a coating agent and a binder.
  • the dose of the cancer cell inhibitory drug of the present invention is appropriately determined depending upon a purpose for therapy or prophylaxis, and conditions such as sexuality, age, weight of a test subject, an administration route, and degree of a disease.
  • a transplant model animal in order to monitor behavior of metastatic cancer, particularly, a transplant model animal can be used.
  • vertebral animals including bony fish such as Takifugu (Japanese pufferfish), Takifugu niphobles, green spotted pufferfish (Tetraodon nigroviridis), killifish and
  • mice and rats are often generally used in an initial study. In this case, it is necessary to maintain an environment by use of e.g., a clean room in the period (usually, at least 3 to 6 months) during which the study is carried out. In addition, extraordinary labor cost for management during this period is required.
  • zebra fish is particularly preferably used in view of cost and speed (usually at least a week).
  • Zebra fish has been recently and already recognized as a third model animal which comes next to mice and rats in the United States and the United Kingdom. It has been elucidated that, the entire genomic sequence of zebra fish has a 80% homology to that of a human and the number of genes of zebra fish is virtually the same as that of a human. Furthermore, development and structure of major organs/tissues are mutually quite resembled.
  • zebra fish the inside of which can be observed non-invasively
  • zebra fish lay about 200 or more fertilized eggs per time. Since zebra fish having the same genetic background are obtained, zebra fish is advantageous for screening.
  • the method for administering a compound of the present invention is not particularly limited; however, a cancer cell inhibitory drug may be suspended in the form of a complex with an appropriate surfactant or in the form of an emulsion in breeding water.
  • the cancer cell inhibitory drug may be mixed in feed or food and orally or parenterally (e.g., injection) administered.
  • a compound of the present invention can selectively detect cancer stem cells, it can be favorably used as a cancer stem cell detection probe. More specifically, the present invention encompasses a cancer cell detection probe.
  • the ratio of the present invention particularly taken into cancer stem cells among the cancer cells is large.
  • cancer stem cells can be selectively detected. Detection and confirmation of behavior of cancer stem cells by the present invention can be carried out all in vitro, ex vivo or in vivo.
  • a method for detecting cancer stem cells by use of a compound of the present invention is a method for capturing state and change of a biological sample as an image.
  • visible light, near infrared light or infrared light is applied to cancer stem cells and an image is visually observed by e.g., a camera or CCD, namely, visible light observation, near infrared light observation and infrared light observation are mentioned.
  • observation by a laser microscope fluorescence observation in which excitation light is applied to a biological sample from an excitation-light source and fluorescence emitted from the biological sample is observed by a fluorescent endoscope or the like; observation by a fluorescent microscope; observation by a fluorescent endoscope; observation by a cofocus fluorescence microscope; or observation by a multiphoton excitation fluorescence microscope is mentioned.
  • narrow-band light observation; colight interference tomogram observation (OCT) or observation by a soft X ray microscope is mentioned. Particularly, fluorescence observation is favorable.
  • the wavelength of light for exciting a compound of the present invention varies depending upon the compound represented by general formula (1) and the wavelength of the excitation light is not particularly limited as long as a compound of the present invention efficiently emits light.
  • the wavelength is preferably, 200 to 1010 nm, more preferably 400 to 900 nm, and more preferably 480 to 800 nm.
  • the wavelength that is used is preferably 600 to 1000 nm, and more preferably 680 to 900 nm, which is excellent in permeability through a living body.
  • the source of fluorescent excitation light for exciting a compound of the present invention is not particularly limited and various types of laser light sources can be used.
  • these laser light sources include a dye laser light source, a semiconductor laser light source, an ion laser light source, a fiber laser light source, a halogen lamp, a xenon lamp and a tungsten lamp.
  • a favorable excitation wavelength can be obtained and fluorescence alone can be detected.
  • cancer stem cells can be photographed, a luminescent site can be easily detected. Furthermore, if an image in light field, which is obtained by applying visible light, is combined with a fluorescent image, which is obtained by applying excitation light, with the help of an image processing unit, cancer stem cells can be more specifically observed. Furthermore, if a confocal microscope is used, a sectional optical image can be favorably obtained. Furthermore, a multiphoton excitation fluorescence microscope, since it is highly permeable to a deep portion and a spatial resolution, is favorably used for observing inside a tissue.
  • the desired product was confirmed by 1 H nuclear magnetic resonance spectroscopic analysis (ECA-400, manufactured by JEOL Ltd.) and LC/TOF MS (LC/MSD TOF, manufactured by Agilent Technologies).
  • DMSO dimethylsulfoxide solution
  • Viable cell count was analyzed in the same manner as in Experimental Example 1 except that Compound (1) was changed to comparative compounds 1 to 4.
  • KLM-1 growth suppression
  • the growth rate in Examples herein is a numerical value of the number of cells obtained after culture relative to the number of cells (regarded as 100) grown in a medium containing 0.1% DMSO. Evaluation of cancer cell inhibition against the pancreatic cancer cells (KLM-1) was made as follows.
  • the compounds of the present invention have a high cancer cell inhibitory (growth suppressive) effect against the pancreatic cancer cells (KLM-1), compared to the comparative compounds.
  • Prostatic cancer cells PC-3 were pre-cultured in RPMI1640 medium containing 10% FBS at 37° C. in a 5% CO 2 ambient. Thereafter, 4,000 cells were seeded per well of a 96-well plate and further cultured for 24 hours. Subsequently, Compound (11) was added to the medium so as to obtain a final concentration of 10 ⁇ g/mL and cultured at 37° C. for 24 hours in a 5% CO 2 ambient. The cultured cells were analyzed for viable cell count according to CellTiter-Glo Luminescent Cell Viability Assay (manufactured by Promega KK.).
  • DMSO dimethylsulfoxide solution
  • the growth rate in Examples herein is a numerical value of the number of cells obtained after culture relative to the number of cells (regarded as 100) grown in a medium containing 0.1% DMSO. The results are shown in Table 3.
  • the compounds of the present invention have a high cancer cell inhibitory (growth suppressive) effect against the prostatic cancer cells (PC-3), compared to comparative compounds.
  • Human chronic myelocytic leukemia cells, K562 were pre-cultured in RPMI1640 medium containing 10% FBS at 37° C. in a 5% CO 2 ambient. Then, a fraction containing 80% or more of cancer stem cells was extracted by use of ALDEFLUOR reagent (manufactured by VERITAS Corporation) and FACSAria flow cytometry (manufactured by Nippon Becton, Dickinson and Company). Subsequently, Compound (5) was added to the medium so as to obtain a final concentration of 10 ⁇ g/mL and cultured at 37° C. for 24 hours in a 5% CO 2 ambient.
  • ALDEFLUOR reagent manufactured by VERITAS Corporation
  • FACSAria flow cytometry manufactured by Nippon Becton, Dickinson and Company
  • the cultured cells were analyzed for viable cell count according to CellTiter-Glo Luminescent Cell Viability Assay (manufactured by Promega KK.).
  • DMSO dimethylsulfoxide solution
  • DMSO dimethylsulfoxide solution
  • cancer stem cells were evaluated by comparing cancer stem cells to cancer cells based on the following criteria.
  • ALDH (+) represents cancer stem cells; whereas ALDH ( ⁇ ) represents general cancer cells.
  • the compounds of the present invention has a selective inhibitory effect against cancer stem cells. More specifically, when a general anticancer agent, Imatinib, was used, an inhibitory effect against general cancer cells was observed; however, no inhibitory effect was confirmed when comparative compounds were used.
  • a fraction (ALDH (+)) containing 80% or more of cancer stem cells was extracted by use of a cancer stem cell marker, ALDEFLUOR reagent (manufactured by VERITAS Corporation) and FACSAria flow cytometry (manufactured by Nippon Becton, Dickinson and Company).
  • the ALDH (+) fraction and a ALDH ( ⁇ ) fraction of general cancer cells were transplanted separately to zebra young fish (Mie Komachi lineage, 2 days after fertilization) and the fish were raised in a 32° C. environment.
  • Compound (16) was added to breeding water so as to obtain a final concentration of 0.5 ⁇ m and fish were raised for two days in a 32° C. environment.
  • Cells transplanted to the zebra young fish were observed under MZ16F fluorescent stereoscopic microscope (manufactured by Leica Microsystems) and a fluorescent image of the cells after 24 hours was photographed and then fluorescent intensity was quantified.
  • the inhibition rate herein was obtained according to the expression: 100 ⁇ (1 ⁇ F1/F0), where the fluorescent intensity of cells when a test substance was added is represented by F1, and the fluorescent intensity of cells when a reference substance (DMSO) was added is represented by F0.
  • the growth suppressive effect in metastatic foci region within 300 to 450 ⁇ m from a transplanted tumor was evaluated based on the following criteria.
  • Inhibition rate is 70 or more (growth suppressive effect against metastatic foci (region within 300 to 450 ⁇ m from a transplanted tumor) of cancer stem cells is extremely high)
  • the cancer stem-cell inhibition drug of the present invention has a higher metastasis suppressive effect than known anticancer agents used as comparison.
  • the compound provided by the present invention is useful as a cancer cell inhibitory drug. Furthermore, owing to the cancer cell inhibitory drug provided by the present invention, growth suppression, cellular division suppression, metastasis suppression, functional inhibition and cytocidal action of cancer cells, particularly cancer stem cells, can be mediated. In addition, cancer stem cells can be easily detected and the site of cancer stem cells can be accurately specified.
  • the compound of the present invention is expected to widely contribute to the medical industry.

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9764046B2 (en) 2008-12-25 2017-09-19 Canon Kabushiki Kaisha Labeling composition for intraocular tissue, labeling method of intraocular tissue, and screening method
US10041937B2 (en) 2013-05-30 2018-08-07 Canon Kabushiki Kaisha Macrophage identification agent, and identification method, sorting method, evaluation method, screening method and kit using the macrophage identifier agent
US10278965B2 (en) 2012-10-26 2019-05-07 Canon Kabushiki Kaisha Method of detecting cancer stem cell, method of screening cancer stem cell, and method of inhibiting cancer stem cell
CN111943948A (zh) * 2020-08-03 2020-11-17 南通大学 β-咔啉吲哚鎓盐及其制备方法与应用

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10058542B1 (en) 2014-09-12 2018-08-28 Thioredoxin Systems Ab Composition comprising selenazol or thiazolone derivatives and silver and method of treatment therewith
CN104629754B (zh) * 2015-01-30 2016-08-03 山西大学 咔唑类比率型pH荧光探针及其制备方法和应用
CN106588750B (zh) * 2016-12-07 2018-11-02 山东大学 一种含十八碳烷基链的免洗且快速靶向线粒体的荧光探针及其应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010074325A1 (fr) * 2008-12-25 2010-07-01 Canon Kabushiki Kaisha Composition de marquage pour tissu intra-oculaire, procédé de marquage de tissu intra-oculaire, et procédé de criblage

Family Cites Families (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU1596099A (en) * 1998-11-23 2000-06-13 Eisai Co. Ltd. Aryl and heteroaryl compounds useful as fibroblast growth factor antagonists
AU1576401A (en) * 2000-10-27 2002-05-06 Praelux Inc Method and apparatus for screening chemical compounds
US7049093B2 (en) 2000-11-08 2006-05-23 Sysmex Corporation Method of classifying and counting nucleated bone marrow cells
WO2003045929A1 (fr) 2001-11-26 2003-06-05 Takeda Chemical Industries, Ltd. Derive bicyclique, procede de production de ce derive et utilisation correspondante
JP2003221386A (ja) * 2001-11-26 2003-08-05 Takeda Chem Ind Ltd 二環性誘導体、その製造法およびその用途
US20050042213A1 (en) * 2003-08-14 2005-02-24 Insight Biopharmaceuticals Ltd. Methods and pharmaceutical compositions for modulating heparanase activation and uses thereof
JP2010013380A (ja) 2008-07-02 2010-01-21 Univ Of Fukui がん幹細胞の検出剤並びにがん治療剤
JP2010169666A (ja) * 2008-12-25 2010-08-05 Canon Inc 複合体、それを用いる診断用マーカー及び診断薬、それを用いる検出方法、検出キット
EP2370111B1 (fr) 2008-12-25 2014-11-05 Canon Kabushiki Kaisha Sonde pour échantillon biologique, procédé de marquage et procédé de criblage utilisant la sonde
EP2397139B1 (fr) 2009-01-29 2014-09-17 Hayashibara Co., Ltd. Agent anti-maladie neurodégénérative
KR20100102273A (ko) 2009-03-11 2010-09-24 서울대학교산학협력단 형광-표면증강라만산란 도트를 이용한 다중 마커의 정량 분석법
JP2010269666A (ja) 2009-05-20 2010-12-02 Toyota Motor Corp 車両用スタビライザ装置
US20120208204A1 (en) * 2009-06-03 2012-08-16 The Brigham And Women's Hospital, Inc. Compositions and Methods for Inhibiting Tumor Growth
WO2011017219A1 (fr) * 2009-08-03 2011-02-10 The Regents Of The University Of California Imidazoquinoxalinones et traitement anti-tumoral
WO2011077751A1 (fr) 2009-12-25 2011-06-30 キヤノン株式会社 Composition pour marquer des tissus du système nerveux central, procédé pour marquer des tissus du système nerveux central, et procédé de criblage utilisant la composition pour marquer des tissus du système nerveux central
EP2517732B1 (fr) 2009-12-25 2016-09-21 Canon Kabushiki Kaisha Composition transnasale de marquage pour des tissus du système nerveux central
JP5888904B2 (ja) 2011-02-16 2016-03-22 国立大学法人三重大学 中枢神経移行性評価用プローブ、中枢神経移行性評価方法、及び、中枢神経移行性評価用プローブを用いたスクリーニング方法
JP6057574B2 (ja) 2012-07-11 2017-01-11 キヤノン株式会社 造血幹細胞識別用プローブ
JP6384821B2 (ja) 2012-10-26 2018-09-05 国立大学法人三重大学 がん細胞阻害薬、がん幹細胞検出用プローブ

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010074325A1 (fr) * 2008-12-25 2010-07-01 Canon Kabushiki Kaisha Composition de marquage pour tissu intra-oculaire, procédé de marquage de tissu intra-oculaire, et procédé de criblage

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9764046B2 (en) 2008-12-25 2017-09-19 Canon Kabushiki Kaisha Labeling composition for intraocular tissue, labeling method of intraocular tissue, and screening method
US10278965B2 (en) 2012-10-26 2019-05-07 Canon Kabushiki Kaisha Method of detecting cancer stem cell, method of screening cancer stem cell, and method of inhibiting cancer stem cell
US10041937B2 (en) 2013-05-30 2018-08-07 Canon Kabushiki Kaisha Macrophage identification agent, and identification method, sorting method, evaluation method, screening method and kit using the macrophage identifier agent
CN111943948A (zh) * 2020-08-03 2020-11-17 南通大学 β-咔啉吲哚鎓盐及其制备方法与应用

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