WO2010090234A1 - Dérivés de 12-désoxyfusicoccine à chaîne de sucre modifiée et leurs utilisations - Google Patents

Dérivés de 12-désoxyfusicoccine à chaîne de sucre modifiée et leurs utilisations Download PDF

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WO2010090234A1
WO2010090234A1 PCT/JP2010/051537 JP2010051537W WO2010090234A1 WO 2010090234 A1 WO2010090234 A1 WO 2010090234A1 JP 2010051537 W JP2010051537 W JP 2010051537W WO 2010090234 A1 WO2010090234 A1 WO 2010090234A1
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compound
group
isir
cells
carbon atoms
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修雄 加藤
崇嗣 井上
友理子 丸山
孟 新田
良夫 本間
武史 佐々
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国立大学法人大阪大学
国立大学法人島根大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • the present invention relates to a novel water-soluble compound having a cell differentiation-inducing action. More specifically, the present invention relates to a 12-deoxy derivative of fusicoccin having the above properties and having a modified sugar chain (hereinafter, also simply referred to as “12-deoxyfusucocin sugar chain-modified derivative”). Furthermore, the present invention relates to a cell differentiation inducer and an antitumor agent comprising such a 12-deoxyfusicoccin sugar chain-modified derivative as an active ingredient.
  • chemotherapeutic agents in tumor treatment are cytotoxic substances and may have serious side effects depending on the dose and method of administration.
  • Tumor cells repeat proliferation while remaining undifferentiated during differentiation. Therefore, focusing on this property of tumor cells, a method of suppressing the proliferation of tumor cells by differentiating undifferentiated tumor cells using a cell differentiation inducer is a trial for treating tumors, particularly malignant tumors (cancers). (See Patent Document 1).
  • Non-Patent Document 1 cotylenin C, a diterpene glycoside having a plant hormone-like activity (plant growth promoting activity), induces differentiation of mouse myeloid leukemia cells into mature cells, Although it was thought that it had a potential as an anticancer agent for a long time (see Patent Document 2), it was later found that it alone has an effect of inducing differentiation of tumor cells of patients with acute myeloid leukemia into normal mature cells. It is expected to be a therapeutic drug for leukemia (see Non-Patent Document 1).
  • cell differentiation inducers are effective in tumors such as cancer by inducing apoptosis when used in combination with interferon ⁇ .
  • cotylenin when used in combination with interferon ⁇ as a cell differentiation inducer, it exerts a strong apoptosis-inducing activity against various tumor cells and a remarkable tumor growth-inhibiting effect resulting from it.
  • a remarkable effect is also shown against cellular lung cancer (see Non-Patent Document 2) and ovarian cancer (see Non-Patent Document 3).
  • cotylenin is also effective against cell lines that are resistant to cisplatin and taxol.
  • Cochilenin is effective not only for cultured cells but also for cells collected from actual ovarian cancer patients.
  • cotylenin also shows a remarkable synergistic effect when used in combination with the cell cycle inhibitor rapamycin, and it has been demonstrated using breast cancer cells that the tumor growth inhibitory effect of cell cycle G1 phase arrest is shown (non-patented). Reference 4).
  • cotylenin is highly expected as a new active ingredient of an antitumor agent that is effective for intractable tumors resistant to various antitumor agents and has low toxicity.
  • clinical application of cotylenin has not yet been made.
  • Fusicoccin which is chemically similar to cotyrenin, is stably produced by Pomoopsis amygdali. Although the fusicoccin has a plant hormone-like activity equivalent to that of cotyrenin, it has almost no cell differentiation-inducing activity.
  • the 12-deoxy derivative of the fusicoccin (12-deoxyfusicoccin derivative) exhibits cell differentiation-inducing activity similar to cotyrenin (Patent Document 3).
  • a representative compound is 4 ', 6'-isopropylidene-12-deoxyfusicoccin J (ISIR-005).
  • Such a 12-deoxyfusicoccin derivative has a good differentiation-inducing activity against leukemia tumor cells in addition to low toxicity, and it can induce apoptosis in various solid tumors when used in combination with interferon ⁇ . From the viewpoint of induction, it is expected as an active ingredient of antitumor agents. However, there is a problem that it is poor in water solubility and it is difficult to adjust to various dosage forms including liquids such as injections.
  • n is an integer of 0 to 5
  • Me is a methyl group
  • R 1 is an alkyl group having 1 to 6 carbon atoms, or an amino group represented by the following formula:
  • R 2 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
  • R 3 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an acyl group having 1 to 7 carbon atoms, or an amidyl group (—CNHNH 2 ).
  • the compound represented by the formula has cell differentiation-inducing activity superior to ISIR-005, and good apoptosis-inducing activity in combination with interferon ⁇ , and the compound (1) has the desired water solubility. It was confirmed.
  • the inventors of the present application said that a part of the compounds included in the compound (1) group more significantly suppresses the growth of solid tumor cells in a Hypoxia (hypoxia) state in addition to the above action. It was found to have a very rare and useful action that was not seen with ISIR-005. The inside of the developed tumor tissue is often under hypoxia, which causes treatment resistance in radiation therapy and chemotherapy. Therefore, it is extremely important in cancer treatment strategies to exert an effective growth inhibitory effect even in a hypoxic environment and to increase the sensitivity of tumor cells to anticancer agents in a hypoxic environment.
  • the above compounds can be expected to have an effective antitumor effect against malignant tumors that have developed and become difficult to treat with conventional radiation therapy and chemotherapy, and in a hypoxia state unlike normal cells. It is believed that certain tumor cells (especially solid tumor cells) can be selectively targeted.
  • n is an integer of 0 to 5
  • Me is a methyl group
  • R 1 is an alkyl group having 1 to 6 carbon atoms, —N 3 group or an amino group represented by the following formula:
  • R 2 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
  • R 3 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an acyl group having 1 to 7 carbon atoms, or a p-nitrophenylsulfonyl group. Alternatively, it represents an amidyl group (—CNHNH 2 ).
  • R 1 is an alkyl group having 1 to 6 carbon atoms, or an amino group represented by formula (2) (wherein R 3 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, The compound according to (I-1), which is an acyl group of 7 or an amidyl group (-CNHNH 2 ).
  • n 0 and R 1 is a methyl group, or n is an integer of 2 to 5, and R 1 is an amino group represented by the following formula (2):
  • R 2 represents a hydrogen atom
  • R 3 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an acyl group having 1 to 7 carbon atoms, or an amidyl group.
  • Cell differentiation inducer (II) A cell differentiation inducer comprising as an active ingredient the compound described in any one of (I-1) to (I-4) or a pharmaceutically acceptable salt thereof.
  • (III) Antitumor agent against hematological malignancy comprising as an active ingredient the compound according to any one of (III-1) (I-1) to (I-4) or a pharmaceutically acceptable salt thereof Agent.
  • III-3) An antitumor agent comprising a combination of the compound described in any of (I-1) to (I-4) or a pharmaceutically acceptable salt thereof and interferon ⁇ .
  • composition according to (III-4) which is a composition comprising the compound according to any one of (I-1) to (I-4) or a pharmaceutically acceptable salt thereof and interferon ⁇ .
  • Antitumor agent (III-5) a drug containing the compound according to any one of (I-1) to (I-4) or a pharmaceutically acceptable salt thereof and a drug containing interferon ⁇ as an active ingredient,
  • the antitumor agent according to (III-3) which is provided as a separately packaged combination kit.
  • III-6 The antitumor agent according to (III-3), wherein the target tumor is a lung tumor or a breast tumor.
  • a method for treating a tumor comprising: (IV-3) The hematological malignancy selected from the group consisting of leukemia, malignant lymphoma and malignant myeloma, or a solid cancer selected from the group consisting of breast cancer, pancreatic cancer, lung cancer and ovarian cancer
  • IV-4) The compound according to any one of (I-1) to (I-4) or a pharmaceutically acceptable salt thereof, which is used for treating a tumor.
  • (IV-5) The hematological malignancy selected from the group consisting of leukemia, malignant lymphoma and malignant myeloma, or a solid cancer selected from the group consisting of breast cancer, pancreatic cancer, lung cancer and ovarian cancer
  • (IV-6) A compound according to any one of (I-1) to (I-4) or a pharmaceutically acceptable salt thereof and a combination of interferon ⁇ and used for the treatment of tumors.
  • (IV-7) Any hematological malignancy selected from the group consisting of leukemia, malignant lymphoma and malignant myeloma, or solid cancer selected from the group consisting of breast cancer, pancreatic cancer, lung cancer and ovarian cancer The combination described in (IV-6).
  • a novel compound (1) which has a cell differentiation inducing action and is useful as a cell differentiation inducer and as an active ingredient of an antitumor agent, particularly an anti-hematologic malignant tumor agent or an intermediate thereof.
  • the compound (1) (excluding the intermediate) has an effect of enhancing the tumor activity of an antitumor agent such as interferon ⁇ and is useful as an active ingredient of an antitumor agent itself. It is also useful as an antitumor effect enhancer of antitumor agents such as
  • ISIR-040 Compound (3)
  • ISIR-041 Compound (4)
  • ISIR-042 Compound (5)
  • ISIR-043 Compound (6)
  • ISIR -044 This represents a synthesis scheme of the compound (7).
  • the abbreviations and abbreviations of substituents in the drawings mean the following terms (the same applies to FIGS. 2 and 3).
  • Me methyl group
  • Ac acetyl group
  • Ms methanesulfonyl group
  • Ns 4-nitrobenzenesulfonyl group
  • Cbz benzyloxycarbonyl group
  • AcCl acetyl chloride
  • DMAP dimethylaminopyridine
  • PPTS pyridinium p-toluenesulfonic acid
  • MsCl Methanesulfonyl chloride
  • ISIR-051 Compound (11)
  • ISIR-052 Compound (12)
  • ISIR-040 (compound (3)), ISIR-042 (compound (5)), ISIR-062 (compound (8)), ISIR-082 (compound (10)) for human monocytic leukemia cells (U937 cells) 1 is a graph showing the cell differentiation-inducing activity of ISIR-005 and Cochirenin A (CN-A) (Test Example 1).
  • ISIR-041 (compound (4)), ISIR-042 (compound (5)), ISIR-043 (compound (6)), ISIR-044 (compound (7)) for human monocytic leukemia cells (U937 cells) 2 is a graph showing the cell differentiation-inducing activity of ISIR-005 (Test Example 1).
  • the vertical axis represents the number of viable cells (%) relative to the control.
  • the growth inhibitory effect with respect to the pancreatic cancer cell (MiaPaca-2) of the known anticancer drug Gemcitabin is shown in a result of measurement under normal oxygen concentration (21%) and hypoxia (1%) (Test Example 3).
  • the vertical axis represents the number of viable cells (%) relative to the control.
  • the results of measuring the inhibitory effect of ISIR-042, ISIR-005, and CN-A on pancreatic cancer cells (MiaPaca-2) under normal oxygen concentration (21%) and hypoxia (1%) are shown ( Test Example 3).
  • the vertical axis represents the number of viable cells (%) relative to the control.
  • R 1 means a linear or branched alkyl group having 1 to 6 carbon atoms, —N 3 group, or an amino group represented by the following general formula (2):
  • examples of the linear or branched alkyl group having 1 to 6 carbon atoms represented by R 1 include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a pentyl group, an isopentyl group, A hexyl group and an isohexyl group are included. Particularly preferred is a methyl group.
  • R 2 is a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. Preferably it is a hydrogen atom.
  • examples of the linear or branched alkyl group having 1 to 6 carbon atoms include the above-described alkyl groups.
  • R 3 represents a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, an acyl group having 1 to 7 carbon atoms, a p-nitrophenylsulfonyl group, or an amidyl group ( -CNHNH 2 ). Particularly preferred is a hydrogen atom.
  • examples of the linear or branched alkyl group having 1 to 6 carbon atoms include the above-described alkyl groups.
  • the acyl group having 1 to 7 carbon atoms represented by R 3 means a group represented by CO—R 4 .
  • R 4 includes an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, and an alkynyl group having 2 to 6 carbon atoms.
  • examples of the alkyl group having 1 to 6 carbon atoms include the above-described alkyl groups.
  • a methyl group is preferred.
  • Examples of the alkenyl group having 2 to 6 carbon atoms include a vinyl group, a propenyl group, a butenyl group, a pentenyl group, and a hexenyl group.
  • a vinyl group is preferred.
  • alkynyl group having 2 to 6 carbon atoms examples include ethynyl group, propynyl group, butyryl group, pentynyl group, and hexynyl group.
  • An ethynyl group is preferable.
  • the preferred acyl group acetyl group R 4 is a methyl group having one carbon atom, and R 4 is an ethynyl group or an ethynyl group having 2 carbon atoms.
  • n represents an integer of 0 to 5.
  • R 1 is an alkyl group having 1 to 6 carbon atoms
  • n is preferably 0.
  • R 1 is an amino group represented by the formula (2)
  • n is preferably an integer of 2 to 5.
  • Specific examples of the compound of the present invention represented by the formula (1) include compounds represented by the following formulas (3) to (12) (hereinafter also referred to as compounds (3) to (12)). Can do.
  • compound (4) wherein n is 2 and R 1 is an amino group in formula (1)
  • compound (5) where n is 3 and R 1 is an amino group
  • n is 3 and R 1 is the compound (9) in which R 2 is a hydrogen atom and R 3 is an ethynylcarbonyl group in the formula (2).
  • More preferred are compound (5) and compound (9).
  • a compound in which R 1 is a —N 3 group or R 3 is a p-nitrophenylsulfonyl group is a compound of the present invention having a cell differentiation inducing action. It is useful as a synthetic intermediate for compounds, particularly the above compounds (3) to (12).
  • examples of the compound (1) in which R 1 is a —N 3 group include SI-05 (Production Example 2 (1)), SI-06 (Production Example 3 (1)), SI-07 ( Production Example 4 (1)) and SI-08 (Production Example 5 (1)) can be mentioned, and these are the above-mentioned compound (4) (see ISIR-041: Production Example 2 (2)), compound ( 5) (ISIR-042: See Preparation Example 3 (2)), Compound (6) (ISIR-043: See Preparation Example 4 (2)), and Compound (7) (ISIR-044: Preparation Example 5 (2) (See FIG. 1).
  • Examples of the compound (1) in which R 3 is a p-nitrophenylsulfonyl group include SI-09 (Production Example 9 (1)) and SI-10 (Production Example 9 (2)). These are all synthetic intermediates of the above compound (10) (see ISIR-082: Production Example 9 (3)) (see FIG. 2).
  • the compound of the present invention represented by the general formula (1) is produced, for example, by changing reaction conditions, adding a reaction, omitting a reaction, etc., if necessary, based on the synthetic scheme shown in FIGS. be able to.
  • FIG. 1 is a synthesis scheme using 4 ′, 6′-isopropylidene-12-deoxyfusicoccin J (ISIR-005) described in Patent Document 3 (International Publication WO2008 / 010324) as a starting material. Is a synthesis scheme starting from compound (5) (ISIR-042).
  • FIG. 3 is a synthesis scheme using Compound (4) (ISIR-041) and Compound (5) (ISIR-042) as starting materials.
  • ISIR-005 used as a raw material is synthesized from natural fusicoccins that are stably produced by Pomoopsis ⁇ amygdali, as described in Patent Document 3 (International Publication WO2008 / 010324).
  • Natural fusicocins include, for example, (1) KD Barrow, D. H. R. Barton, Sir E. Chain, C. Conlay, T. C. Smale, R. Thomas, and E. S. Waight, J. Chem. Soc. (C), 1259 (1971); or (2) N. Tajima, M. Nukina, N.Kato, ukand T. Sassa, Biosci. Biotechnol. Biochem., 68, 1125 (2004) (Japan) It can be obtained by the method described in the literature on cultivation of peach branch rot fungus Phomopsis amygdali Niigata 2-A).
  • the compound ISIR-040 is the compound (3) described above
  • ISIR-041 to 044 is the compound (4) to (7) described above
  • ISIR-062 is the compound (8) described above.
  • Compound ISIR-072 corresponds to compound (9) described above
  • ISIR-082 corresponds to compound (10) described above
  • ISIR-051 and ISIR-052 correspond to compounds (11) and (12) described above, respectively.
  • the compound of the general formula (1) in which R 1 represents an alkyl group having 1 to 6 carbon atoms is, for example, the above known compound ISIR-005. Is then acetylated to form compound SI-01, followed by ring-opening reaction (generation of SI-02), sulfonylation (generation of SI-03), deacetylation (generation of SI-04), and ring-closing reaction Manufactured.
  • reaction conditions for acetylation, ring-opening reaction, sulfonylation, deacetylation, and ring-closing reaction known conditions can be widely applied.
  • the compounds of the general formula (1) in which R 1 represents an N 3 — group are compound (3) (compound ISIR-040) produced by the above method.
  • known conditions can be widely applied.
  • it can be produced according to the reaction conditions described in Production Examples 2 to 5 described later.
  • the compounds (4) to (7) (compounds ISIR-041 to 044) obtained here can also be prepared in the form of salts by a conventional method shown in Production Example 6.
  • a compound in which R 1 is an amino group represented by the general formula (2) (wherein R 2 is a hydrogen atom and R 3 is an acyl group having 1 to 7 carbon atoms) ( 1) (Compound ISIR-062: Compound (8)) is produced, for example, by acetylating compound ISIR-042 (compound (5)) produced by the above method, and R 1 is generally the same as above.
  • a compound (compound ISIR-072: compound (9)) which is an amino group represented by the formula (2) can be produced, for example, by ethynylcarbonylating the above compound ISIR-042 (compound (5)).
  • Compound ISIR-051: Compound (11) and Compound ISIR-052: Compound (12)) are, for example, compound ISIR-041 (compound (4)) and compound ISIR-042 (compound (5)) produced by the above-described method. Can be produced by amidylation.
  • ISIR-041 compound (4)
  • ISIR-042 compound (5)
  • various malignant tumor cells termeast cancer cells, pancreatic cancer cells, lung cancer cells, ovarian cancer cells
  • Demonstrate cell growth inhibitory effect Test Example 3
  • ISIR-042 compound (5)
  • the compound represented by SI is useful as an intermediate of the above compounds (3) to (12) which can be an active ingredient of an antitumor agent.
  • (4) to (7) and (10) having an amino group, and (11) and (12) having a guanidyl group can have a free or salt form.
  • the salt include pharmaceutically acceptable salts such as acid addition salts such as inorganic acids, organic acids, or acidic amino acids.
  • inorganic acids that form acid addition salts include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
  • organic acids include formic acid, acetic acid, lactic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, benzoic acid, citric acid, succinic acid, malic acid, ascorbic acid, methanesulfonic acid, ethanesulfonic acid Benzenesulfonic acid, p-toluenesulfonic acid and the like.
  • acidic amino acids include aspartic acid and glutamic acid.
  • the compound of the present invention represented by the general formula (1) has cell differentiation induction activity.
  • the compounds (3) to (12) are used in the cell differentiation-inducing activity test (testability 1) using human leukemia cells (human myeloid leukemia HL-60 cells or human monocytic leukemia U937 cells) described later. It exhibits an activity similar to that of cotylenin A and has an effect of inducing cell differentiation from abnormal cells such as tumor cells to mature cells. Since the cell differentiation inducing activity induces cell differentiation, the compound (1) of the present invention can suppress the proliferation of cells exhibiting abnormal differentiation such as tumor cells. Therefore, the compound of the present invention represented by the general formula (1) is useful as a cell differentiation inducer.
  • the target tumors include benign tumors and malignant tumors.
  • a malignant tumor is preferred.
  • Examples of the cells in which the cell growth inhibitory action by the cell differentiation-inducing activity of the compound (1) of the present invention is effective include tumor cells such as leukemia cells, malignant lymphomas, and hematological malignancies including malignant myeloma. .
  • Leukemia cells, malignant lymphoma, and malignant myeloma are preferable as growth inhibition targets, and leukemia cells (acute myeloid leukemia cells, monocytic leukemia cells) are more preferable.
  • solid cancers such as breast cancer, pancreatic cancer, lung cancer, and ovarian cancer can also be targeted.
  • the compound (1) of the present invention can also be used in combination with interferon ⁇ .
  • compound (5) can synergistically enhance the antitumor activity of interferon ⁇ when used in combination with interferon ⁇ . Therefore, the compound of the present invention can be used as an antitumor activity enhancer of interferon ⁇ , or can be used as an antitumor agent in combination with interferon ⁇ .
  • the embodiment to be combined here is not particularly limited, and is an embodiment in which the compound of the present invention and interferon ⁇ are mixed in the form of a composition (mixture) from the beginning, and the compound of the present invention and interferon ⁇ are separately packaged in packaging form. And any of the aspects (combination kit) used combining both at the time of use may be sufficient.
  • the compound (5) remarkably suppresses the growth of cancer cells in the Hypoxia state.
  • cancer tissue is hypoxic and resistant to chemotherapeutic agents. Therefore, the compound of the present invention having the above characteristics is extremely effective as an antitumor agent (anticancer agent) that exhibits an antitumor action more effectively.
  • compounds (1) of the present invention compounds (4) to (7) and (10) having an amino group, those having a guanidyl group (11) and (12), and pharmaceutically acceptable compounds thereof
  • the salt has sufficient water solubility and can be prepared as a liquid such as an injection.
  • the compound of the present invention can be orally or non-humanly administered to humans or mammals other than humans in a known manner, in known unit dosages, and as a pharmaceutical composition together with known carriers or excipients or pharmaceutically acceptable additives.
  • Administer orally eg, intramuscular, subcutaneous, intravenous injection or infusion, transpulmonary administration), or topical (mucosal administration) or external preparation (suppository, ointment, cream, patch, etc.) Can do.
  • the compound of the present invention is converted into a conventional pharmaceutical preparation, for example, a solid preparation such as tablet, capsule, granule, fine granule, powder, lozenge, troche, jelly; or solution, emulsion (water-in-oil type) Emulsions, etc.), suspensions, syrups, etc.
  • a solid preparation such as tablet, capsule, granule, fine granule, powder, lozenge, troche, jelly; or solution, emulsion (water-in-oil type) Emulsions, etc.), suspensions, syrups, etc.
  • one or more of the compounds of the present invention can be combined with conventional excipients (sodium citrate, lactose, microcrystalline cellulose, starch, etc.), lubricants (anhydrous silicic acid, Hydrogenated castor oil, magnesium stearate, sodium lauryl sulfate, talc, etc.), binders (starch paste, glucose, lactose, gum arabic, gelatin, mannitol, etc.) and other normal additives (flavors, colorants, antioxidants) Preservatives including surfactants, surfactants, suspending agents, emulsifiers and the like), and the mixture is formulated by a known method.
  • a known liquid carrier such as water, physiological saline or oil is used.
  • the compound of the present invention is used as a sterile oily or aqueous preparation. Injections are usually prepared by dissolving the compound of the present invention in distilled water for injection and then buffering or isotonizing with glucose, saline, etc. if necessary.
  • the external preparation is preferably an ointment, but includes liniments, lotions, oil-in-water or water-in-oil emulsions (for example, creams), solutions, suspensions, and the like.
  • Ointments are prepared in a known manner by conventional ointment bases such as fats, fatty acids (olive oil, sesame oil, triglycerides of medium chain fatty acids, etc.), lanolin, wax, paraffin, glycols, higher alcohols, surfactants and the like. Can be manufactured together.
  • conventional ointment bases such as fats, fatty acids (olive oil, sesame oil, triglycerides of medium chain fatty acids, etc.), lanolin, wax, paraffin, glycols, higher alcohols, surfactants and the like.
  • the dose of the compound or pharmaceutical composition of the present invention varies depending on the administration method, the sex and age of the patient, the degree of symptoms, etc., but when administered parenterally, such as subcutaneous injection, About 1 to 100 mg / kg, preferably about 3 to 40 mg / kg is used. When administered orally, although not limited, 3 to 300 mg / kg, preferably about 9 to 120 mg / kg, of the compound can be used per day for an adult.
  • the compound of the present invention may be administered alone or in combination with another antitumor agent (for example, interferon ⁇ ).
  • another antitumor agent for example, interferon ⁇
  • the amount used is not particularly limited as long as the antitumor action of the other antitumor agent is enhanced, but preferably 100 parts by weight of the other antitumor agent 0.0001 to 500 parts by weight, more preferably 0.001 to 300 parts by weight.
  • the compound of the present invention was produced based on the synthetic schemes shown in FIG. 1, FIG. 2 and FIG.
  • the starting material ISIR-005 was synthesized according to the method described in Patent Document 3 (International Publication WO2008 / 010324).
  • ESI-MS m / z 603.3165 (M + Na + ).
  • Production Example 3 Production of Compound (5) (FIG. 1, ISIR-042) (1) Synthesis of SI-06 SI-04 (53 mg (0.081 mmol)) synthesized in Production Example 1 (4) was synthesized in the same manner as the synthesis of SI-05 described in Production Example 2 (1). Reaction with azido-1-propanol gave 37.7 mg of SI-06. Yield 83%. The 13 C-NMR data and ESI-MS data of SI-06 are shown below.
  • Production Example 4 Production of Compound (6) (FIG. 1, ISIR-043) (1) Synthesis of SI-07 SI-04 (17 mg (0.026 mmol)) synthesized in Production Example 1 (4) was converted to 4-azido-, similarly to the synthesis of SI-05 in Production Example 2 (1). Reaction with 1-butanol gave 9.8 mg of SI-07. Yield 66%.
  • the 1 H-NMR data of SI-07 is shown below.
  • Production Example 5 Production of Compound (7) (FIG. 1, ISIR-044) (1) Synthesis of SI-08 SI-04 (19.5 mg (0.030 mmol)) synthesized in Production Example 1 (4) was converted to 4-azido-, similarly to the synthesis of SI-05 in Production Example 2 (1). Reaction with 1-pentanol gave 11.5 mg of SI-08. Yield 65%. The 13 C-NMR data of SI-08 is shown below.
  • Production Example 6 Production of Compound (5) Salt (Hydrochloride, Ascorbic Acid, Citrate, Benzoate) Compound (5) (ISIR-042) synthesized in Production Example 3 (2) was added to an anhydrous diethyl ether solution. By adding the equivalent amount of hydrogen chloride ether solution, ascorbic acid, citric acid or benzoic acid and diluting with petroleum ether, the resulting powder is filtered to obtain the corresponding hydrochloride salt and ascorbate salt of compound (5). Citrate or benzoate was obtained.
  • Production Example 7 Production of Compound (8) ( Figure 2, ISIR-062)
  • Compound (5) (ISIR-042) (23.8 mg, 44 ⁇ mol) synthesized in Production Example 3 (2) is dissolved in 1.0 mL of dichloromethane, and 0.1 mL of pyridine and 8.3 ⁇ L (88 ⁇ mol) of acetic anhydride are dissolved under ice cooling. And then stirred at room temperature for 1.5 hours. Dilute with saturated aqueous NH 4 Cl and extract with dichloromethane. The organic layer was washed successively with saturated NaHCO 3 and aqueous NaCl solution, dried over Na 2 SO 4 and concentrated under reduced pressure.
  • Production Example 8 Production of Compound (9) (FIG. 2, ISIR-072)
  • Compound (5) (ISIR-042) (21.4 mg, 40 ⁇ mol) synthesized in Production Example 3 (2) was dissolved in 1.0 mL of dichloromethane and immobilized at 133 mg (equivalent to 0.2 mmol) of polystyrene resin at room temperature.
  • N-cyclohexylcarbodiimide (PS-Carbodiimide) and 10 ⁇ L (0.160 mmol) of propiolic acid were added and stirred for 13.5 hours. The reaction solution was concentrated.
  • Test Example 1 Measurement of cell differentiation inducing activity (1) Cells and cell culture Suspend human acute myeloid leukemia cells (HL-60 cells) or human monocytic leukemia cells (U937 cells) in RPMI-1640 medium supplemented with 10% fetal bovine serum. The cells were cultured in humidified air at 37 ° C. containing 5% CO 2 .
  • leukemia cells (5 ⁇ 10 4 cells / mL) were added to test compounds (ISIR-040 (compound (3)), ISIR-042 ( Compound (5)), ISIR-062 (Compound (8)), ISIR-072 (Compound (9)), ISIR-082 (Compound (10), ISIR-005, Cotyrenin A (CN-A))
  • the cells were cultured in the absence of 12-O-tetradecanoylphorbol-13-acetate (TPA) as a promoter, and the oxidase activity to generate superoxide was measured using the ability to reduce NBT as an indicator.
  • TPA 12-O-tetradecanoylphorbol-13-acetate
  • NBT reducing ability was measured by incubating the cells in RPMI-1640 medium containing NBT (1 mg / mL) and TPA (100 ng / ml) for 60 minutes at 37 ° C. After the reaction was completed, the cells were centrifuged. The formazan precipitate generated by the reaction in the cells was dissolved in dimethyl sulfoxide and colorimetric (wavelength 560 nm or The activity was expressed as absorbance per 10 7 cells.
  • FIG. 4 shows the evaluation results of ISIR-040 (compound (3)) on HL-60 cells, together with the results of cotylenin A (CN-A).
  • FIG. 5 shows the evaluation of ISIR-040 (compound (3)), ISIR-042 (compound (5)), ISIR-062 (compound (8)), and ISIR-082 (compound (9)) on U937 cells. The results are shown together with the results of CN-A and ISIR-005.
  • FIG. 6 shows the evaluation results of ISIR-041 (compound (3)), ISIR-042 (compound (5)), ISIR-043 (compound (6)), and ISIR-044 (compound (7)) on U937 cells. Is shown together with the result of ISIR-005.
  • FIG. 7 shows the evaluation results of ISIR-042 (compound (5)) and ISIR-072 (compound (9)) on U937 cells.
  • Test Example 2 Inhibitory effect on cancer cell proliferation by combined use of ISIR-042 and interferon ⁇
  • Lung cancer cells (A549) were used as test cells, and these cells were precultured in RPMI 1640 medium.
  • IFN ⁇ interferon ⁇
  • the concentration required to inhibit the growth of lung cancer cell A549 cells by 50% is calculated with ISIR-005 alone and in combination with 400 units / mL interferon ⁇ .
  • the concentration is> 7 ⁇ g / mL or more.
  • the latter was 4.5 ⁇ g / mL, indicating a significant synergistic effect.
  • Test Example 3 Inhibitory effect of ISIR-042 (compound (5)) on cancer cell growth under hypoxia (Hypoxia)
  • the cell growth inhibitory action of the compound of the present invention was reduced to normal oxygen concentration (21%) and hypoxia (1%)
  • the measurement was performed under the following conditions.
  • Breast cancer cells (MCF-7) were used as test cells, and these cells were precultured in RPMI 1640 medium.
  • ISIR-042 at a predetermined concentration (0, 0.5, 1.0, 1.5, 2.0, 2.5 ⁇ g / mL) was added, cultured for 7 days, and the number of viable cells was evaluated. .
  • the number of viable cells was evaluated by MTT assay.
  • FIG. 9 shows the measurement results of ISIR-042 together with the results of CN-A and ISIR-005.
  • the concentration required to inhibit the growth of breast cancer cell MCF-7 by 50% is 1.0 ⁇ g / mL for ISIR-042 when measured under hypoxia, while 2.5 ⁇ g / mL under normal oxygen concentration. A much higher concentration was required than mL.
  • FIG. 11 shows the results of comparing the effects of ISIR-042 (compound (5)) with the effects of ISIR-005 and CN-A on pancreatic cancer cells (MiaPaca-2), measured in the same manner as described above.
  • FIG. 12 shows the effects of ISIR-042 (compound (5)) and ISIR-041 (compound (4)) on pancreatic cancer cells (Panc-1).
  • ISIR-041 compound (4)
  • FIG. 12 shows the effects of ISIR-041 (compound (4)) had the same properties as ISIR-042 (compound (5)), although the effect was slightly inferior.
  • the compound (1) of the present invention is useful as an active ingredient of pharmaceuticals such as cell differentiation inducers and anticancer agents, and in the fields of fusicoccin derivatives and intermediates of various pharmaceuticals.

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Abstract

L'invention porte sur de nouveaux composés hydrosolubles qui ont des effets d'induction de la différenciation sur des cellules de mammifère, des agents induisant la différenciation cellulaire qui comprennent lesdits composés comme principes actifs et des agents antitumoraux. L'invention porte sur des composés et leurs sels qui sont représentés par la formule générale (1) (1) [dans laquelle n représente un entier de 0-5, Me un groupe méthyle et R1 un groupe alkyle de 1 à 6 carbones ou un groupe amino représenté par la formule (2) (2) (dans laquelle R2 représente un atome d'hydrogène ou un groupe alkyle de 1 à 6 carbones, R3 un atome d'hydrogène, un groupe alkyle de 1 à 6 carbones, un groupe acyle de 1 à 7 carbones ou un groupe amidyle (–CNHNH2))].
PCT/JP2010/051537 2009-02-06 2010-02-03 Dérivés de 12-désoxyfusicoccine à chaîne de sucre modifiée et leurs utilisations WO2010090234A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2018143140A1 (fr) * 2017-01-31 2018-08-09 国立大学法人大阪大学 Composé de fusicoccine

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008010324A1 (fr) * 2006-07-19 2008-01-24 Osaka University Dérivé 12-désoxyfusicoccine et agent induisant une différentiation des cellules le contenant en tant que substance active

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2008010324A1 (fr) * 2006-07-19 2008-01-24 Osaka University Dérivé 12-désoxyfusicoccine et agent induisant une différentiation des cellules le contenant en tant que substance active

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KASSOU, M. ET AL.: "Ring Contraction vs Fragmentation in the Intramolecular Reactions of 3-0-(Trifluoromethanesulfonyl)pyranosides. Efficient Synthesis of Branched-Chain Furanosides", JOURNAL OF ORGANIC CHEMISTRY, vol. 60, no. 14, 1995, pages 4353 - 4358 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018143140A1 (fr) * 2017-01-31 2018-08-09 国立大学法人大阪大学 Composé de fusicoccine

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