WO2006129842A1 - Nouveau derive aminopyridine ayant une activite d’inhibition selective de l’aurora-a - Google Patents

Nouveau derive aminopyridine ayant une activite d’inhibition selective de l’aurora-a Download PDF

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Publication number
WO2006129842A1
WO2006129842A1 PCT/JP2006/311179 JP2006311179W WO2006129842A1 WO 2006129842 A1 WO2006129842 A1 WO 2006129842A1 JP 2006311179 W JP2006311179 W JP 2006311179W WO 2006129842 A1 WO2006129842 A1 WO 2006129842A1
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methyl
piperazine
group
compound
anticancer
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PCT/JP2006/311179
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English (en)
Japanese (ja)
Inventor
Tetsuya Kato
Nobuhiko Kawanishi
Takashi Mita
Mitsuru Ohkubo
Toshiyasu Shimomura
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Banyu Pharmaceutical Co., Ltd.
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Priority claimed from PCT/JP2005/019957 external-priority patent/WO2006046734A2/fr
Application filed by Banyu Pharmaceutical Co., Ltd. filed Critical Banyu Pharmaceutical Co., Ltd.
Publication of WO2006129842A1 publication Critical patent/WO2006129842A1/fr

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    • 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
    • C07D417/12—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 chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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 is useful in the field of medicine. More specifically, the present invention includes a novel aminopyridine derivative that inhibits tumor cell growth and exerts an antitumor effect based on the selective inhibition of Aurora A, and includes the same Aurora A It relates to a selective inhibitor and an anticancer agent. Background art
  • Aurora kinase is a serine Z threonine kinase involved in cell division. Aurora kinase is currently known in three subtypes: A, B, and C, and has very high similarity (homology) to each other. Aurora A is involved in centrosome maturation and partitioning and spindle formation. On the other hand, ⁇ Ra B is thought to be involved in chromosome aggregation, pairing, spindle checkpoint and cytokinesis [Natiya Reviews Molecular Molecular Biology (Na t. Rev. Mo 1. Ce ll Bio 1), No. 4, 842—854]. Aurora C is also thought to interact with Aurora B and work in the same way [Journal of Biological Chemistry. B i o 1.
  • the present inventors have synthesized a wide range of novel aminopyridine derivatives, and a compound represented by the following general formula [I] has excellent Aurora A selective inhibitory activity and cell growth suppression based thereon
  • the present invention was completed by demonstrating the effects and synergistic effects when used in combination with other anticancer agents.
  • a compound according to the present invention by administering a compound according to the present invention to a cancer that has not been able to be cured completely due to its side effects and drug resistance in existing anticancer drugs such as paclitaxel, or
  • the combined use of the compound according to the present invention and other anticancer agents is expected to provide excellent anticancer effects (including enhanced action of the other pile cancer agents) and side effects. Is done.
  • n 2 is 1, 2 or 3;
  • n 2 is 0 or 1;
  • i is any integer from 1;
  • j is an integer from 1 to m 2 ;
  • R is an optionally substituted aryl group, heteroaryl group, or cycloalkyl group;
  • R ai and! ⁇ Is the same or different and is a hydrogen atom or a lower alkyl group, and
  • R bj and R bj ′ are the same or different and are a hydrogen atom or a lower alkyl group, where
  • Is 2 or 3 and i is i. (I. Is an integer from 1 to 1), and when m 2 is 2 or 3, and j is j 0 (j is any of 1 to m 2 R ai 0 and R ai . 'And one of R w . And R b j.
  • One of ' may be joined together to form 1 (CH 2 ) n- (where n is 1 or 2);
  • R c , R d , and R e are the same or different and are a hydrogen atom or a lower alkyl group; Is CH, CX la or N (where X la is an optionally substituted lower alkyl group);
  • X 2 is CH, CX 2a or N (where
  • X 2 a is a lower alkyl group
  • X 2 a is a substituent selected from the substituent group A, or is a lower alkyl group substituted by one or more substituents selected from the same or different substituents selected from the ⁇ substituent group A!>?
  • ⁇ substituent group A> is a halogen atom; a cyano group; a hydroxy group; a lower alkylamino group; a di-lower alkylamino group; one or more hydroxy groups may be substituted or lower alkoxy; A lower alkylthio group; and a lower alkylsulfonyl group.
  • R 2 and R 3 are the same or different and are a hydrogen atom, an optionally substituted lower alkyl group or a cycloalkyl group, or R 2 and R 3 are together with the nitrogen atom to which they are bonded. That is, it may form a 5-membered or 6-membered aliphatic heterocyclic group containing at least one atom selected from N, O and S which may be substituted,
  • R 4 and R 5 are the same or different and each represents a hydrogen atom, an optionally substituted lower alkyl group or a cycloalkyl group. ; Or
  • X 2 a is an optionally substituted 5-membered or 6-membered aliphatic alkyl group containing at least one atom selected from N, O and S (wherein Two hydrogen atoms bonded to the same carbon atom of the aliphatic heterocyclic group may be substituted with an oxo group, and adjacent carbon atoms constituting the ring of the aliphatic heterocyclic group are double bonds. Or a lower alkyl group substituted with the aliphatic heterocyclic group; or
  • X 2 a may have a substituent, a 5-membered or 6-membered aromatic heterocyclic group containing at least one atom selected from N, ⁇ and S, or the aromatic heterocyclic ring A lower alkyl group substituted with a group;
  • X 3 is CH, CX 3 a or N (where X 3 a is an optionally substituted lower alkyl group);
  • X 4 is CH or N
  • X 2 , X 3 and X 4 are N or 1 or 2;
  • Y have Y 2
  • Upsilon 3 are the same or different, is a CH or New, however, is Upsilon 1 force CH, when R e is a hydrogen atom, the two hydrogen atoms are Okiso group May be substituted with;
  • Zj and Z 2 are the same or different and are CH or N;
  • W is the following group:
  • Wj is CH, N, NH, O or S
  • w 2 is CH, cw 2a , N, Nw 2b , o or s (where The same or different, a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group having 1 to 2 carbon atoms, a cycloalkyl group having 3 to 5 carbon atoms, or one with a halogen atom or It is a lower alkyl group having 1 to 2 carbon atoms which may be substituted two or more. ;
  • W 3 is C or N
  • At least one of Wj, W 2 , and W 3 is a carbon atom, but two of , W 2 , and W 3 are not O and S at the same time.
  • the invention provides:
  • n 2 is 1, 2 or 3;
  • ri j is 0 or 1;
  • n 2 is 0 or 1;
  • i is any integer from 1;
  • j is an integer from 1 to m 2 ;
  • R is an optionally substituted aryl group, heteroaryl group, or cycloalkyl group;
  • R ai and R a are the same or different and are a hydrogen atom or a lower alkyl group,
  • R b j and R bj 'Is the same or different and is a hydrogen atom or a lower alkyl group,
  • Is 2 or 3 and i is i. (I. Is an integer from 1 to rn ⁇ ), and when m 2 is 2 or 3, and j force is 0 (j 0 is any of 1 to m 2 ), R ai . And R ai . , And one of R b j. Rai R bj . , And together may form one (CH 2 ) n — (where n is 1 or 2);
  • R c , R d , and R e are the same or different and are a hydrogen atom or a lower alkyl group; ⁇ is CH, CX la, or N (where X la may be substituted) A good lower alkyl group.);
  • X 2 is CH or N
  • X 3 is CH, CX 3a or N (where X 3a is an optionally substituted lower alkyl group) is there. ;
  • X 4 is CH or N
  • X 2 , X 3 and X 4 are N or 1 or 2;
  • Y 2 , Y 2 , and ⁇ 3 are the same or different and are CH or ⁇ , provided that i CH and R e is a hydrogen atom, the two hydrogen atoms are substituted with an oxo group. May be;.
  • ZJ and Z 2 are the same or different and are CH or N;
  • W is the following group:
  • W 2 is CH, CW 2a , N, NW 2b , ⁇ or S (where W 2a and W 2b are the same or different and are a hydrogen atom, a halogen atom, a cyano group, a carbon number of 1 1 to 2 lower alkyl groups, 3 or 5 cycloalkyl groups, or 1 or 2 lower alkyl groups that may be substituted with one or more divalent atoms. Group.);
  • W 3 is C or N
  • At least one of Wi, W 2 , and W 3 is a carbon atom, but two of Wi, W 2 , and W 3 are not O and S at the same time.
  • the present invention also provides a combination preparation for simultaneous, separate or sequential administration in cancer treatment, wherein two separate preparations:
  • a preparation comprising a compound represented by the above general formula [I] or a pharmaceutically acceptable salt or ester thereof together with a pharmaceutically acceptable carrier or diluent, and
  • Anticancer alkylating agents are nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, mitopronitol, carbocone, thiotepa, ranimustine, dimustine, temozolomide or carmustine
  • Anticancer antimetabolites include methotrexate, 6-mercaptopurine riboside, mercaptopurine,
  • Anticancer antibiotics are actinomycin D, doxorubicin, daunorubicin, neocarcinnostatin, bleomycin, peplomycin, mitomycin C, aclarubicin, pirarubicin, epilubicin, dinostatin stimalama, idarubicin, sirolimus, or valrubicin
  • the plant-derived pile cancer drug is vincristine, vinblastine, vindesine, etoposide, sopoxan, docetaxel, paclitaxel, or vinorelbine,
  • the anticancer platinum coordination compound is cisplaten, carpoplatin, nedaplatin, or oxaliplatin,
  • the anticancer camptothecin derivative is irinotecan, topotecan, or camptothecin
  • the anticancer tyrosine kinase inhibitor is gefitinib, imatinip, or el mouthtinib
  • the monoclonal antibody is cetuximab, bevacizumab, rituximab Bevacizumab, alemuzumab or trastuzumab
  • Interferon is interferon, interferon ⁇ 1 2a, interferon ⁇ -2b, interferon ⁇ , interferon ⁇ -1a, or interferon ⁇ -n1, and biological response modifiers are krestin, lentinan, schizophyllan, Pisibanil, or Ubenimex, and
  • anticancer drugs include mitoxantrone, L-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pentostatin, tretinoin, arfacept, darbepoetin alfa, anastromol, exemstan, bicalutamide, leuprorelin, flutami Or fulvestrant, pegaptanibu-octasodium, denileukin diftitotus, aldesleukin, thyrotropin alfa, arsenic trioxide, bortezomib, force pecitabine, or goserelin. :
  • a combination formulation comprising:
  • the present invention relates to a compound represented by the above general formula [I] or a pharmaceutically acceptable salt or ester thereof, as well as an anticancer property, together with a pharmaceutically acceptable carrier or diluent.
  • a pharmaceutically acceptable carrier or diluent Alkylating agent, anticancer agent, anticancer agent, anticancer antibiotic, plant-derived pile cancer agent, anticancer platinum coordination compound, anticancer camptothecin derivative, anticancer tyrosine
  • the present invention relates to a pharmaceutical composition comprising an agent or a pharmaceutically acceptable salt or ester thereof.
  • the present invention also provides a therapeutically effective amount of a compound represented by the above general formula [I], or a pharmaceutically acceptable salt or ester thereof, an anticancer alkylating agent, an anticancer antimetabolite, Anticancer antibiotics, plant-derived anticancer agents, pile cancerous platinum coordination compounds, anticancer camptothecin derivatives, anticancer tyrosine kinase inhibitors, monoclonal antibodies, interferons, biological response modifiers And other anticancer agents (wherein the definitions of each anticancer agent are the same as described above) or a pharmaceutically acceptable
  • the present invention relates to a method for treating cancer, characterized by being administered simultaneously, separately or sequentially in combination with a obtainable salt or ester.
  • the present invention relates to the use of an Aurora A selective inhibitor for the manufacture of a medicament for treating cancer, and a combination with an anticancer agent for producing a medicament for treating cancer.
  • a method of treating cancer in a mammal, particularly a human comprising administering to the mammal a therapeutically effective amount of an Aurora A selective inhibitor.
  • a method characterized by: Mammals (especially humans) A method of treating cancer in a patient, comprising administering a therapeutically effective amount of an Aurora A selective inhibitor to the mammal in combination with a therapeutically effective amount of a stake cancer moxibustion About the method.
  • the present invention also provides a cancer therapeutic agent containing an Aurora A selective inhibitor as an active ingredient, and a cancer therapeutic agent containing an Aurora A selective inhibitor as an active ingredient together with an anticancer agent, About.
  • the “lower alkyl group” in the above formula (I) means a linear or branched alkyl group having 1 to 6 carbon atoms.
  • aryl group in the above formula (I) refers to a monocyclic, bicyclic, or tricyclic aromatic hydrocarbon group having 6 to 14 carbon atoms. Examples include phenyl group, naphthyl group, indenyl group, and anthranyl group. Among them, phenyl group is preferable.
  • a 5-membered to 7-membered monocyclic heterocyclic group, and a condensed heterocyclic group obtained by condensing a 3-membered to 8-membered ring specifically, a chenyl group, Pyrrolyl group, furyl group, thiazolinol group, imidazolyl group, virazolyl group, oxazolyl group, 'pyridyl group, birazinyl group, pyrimidinyl group, pyridazinyl group, isoxazolyl group, isoquinolyl group isoindolyl group, quinazolyl group, quinazolyl group, indolyl group, indolyl group, indoaryl group, indo
  • the “cycloalkyl group J” in the above formula (I) is a 3- to 8-membered aliphatic cyclic group, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group. , Cyclooctyl group, etc. can be fisted.
  • “5-membered or 6-membered aliphatic heterocyclic group” means at least one atom selected from a nitrogen atom, an oxygen atom, and a sulfur atom in addition to a carbon atom.
  • 5-membered or 6-membered aliphatic cyclic group (1) and examples thereof include pyrrolidininole group, piperidinyl-nore group, piperazininole group, monoreforino group, tetrahydrofuranyl group, imidazolidinyl group, and thiomorpholino group.
  • two hydrogen atoms bonded to the same carbon atom may be substituted with an oxo group, and adjacent carbon atoms constituting the ring of the aliphatic heterocyclic group May be a double bond.
  • the “5-membered or 6-membered aromatic heterocyclic group” in the above formula (I) includes, in addition to the carbon atom, at least one atom selected from a nitrogen atom, an oxygen atom, and a sulfur atom.
  • a 5-membered or 6-membered aromatic cyclic group for example, a chenyl group, a pyrrolyl group, a furyl group, a thiazolyl group, an imidazolyl group, or a oxazolyl group.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc. Among them, for example, a fluorine atom, a chlorine atom, or a bromine atom is preferable.
  • the “lower alkoxy group” in the above formula (I) means a group in which a “lower alkyl group” is bonded to an oxygen atom, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group. Sec-butoxy group, tert-butoxy group, pentyloxy group, neopentyloxy group, hexyloxy group, isohexyloxy group and the like.
  • the “lower alkylthio group” in the above formula (I) is a substitution in which the above “lower alkyl” is bonded to a sulfur atom.
  • Group for example, methylthio group, ethylthio group, butylthio group and the like.
  • lower alkylsulfonyl group in the above formula (I) refers to a substituent in which the “lower alkyl” is bonded to a sulfonyl group, and examples thereof include a methylsulfonyl group, an ethylsulfonyl group, a butylsulfonyl group, and the like.
  • the “lower alkylamino group” in the above formula (I) means a substituent in which the above “lower alkyl group” is N-substituted on an amino group, for example, N-methylamino group, N-ethylamino group, N— Examples thereof include a propylamino group, an N-isopropylamino group, an N-butylamino group, an N-isobutylamino group, an N-tert-butylamino group, an N-pentylamino group, and an N xylamino group.
  • the “di-lower alkylamino group” in the above formula (I) refers to a substituent in which the above-mentioned “lower alkyl group” is N, N-disubstituted on an amino group, for example, N, N-dimethylamino group, N, N —Jetylamino group, N, N-dipropylamino group, NN-diisopropylamino group, N, N-dibutylamino group, N, N-diisobutylamino group, N, N-di tert-ptylamino group, N, N-dipentyl Examples include an amino group, N, “N-dihexylamino group, N-ethyl-1-N-methylamino group, N-methyl-N-propylamino group, and the like.
  • the “lower alkanol” in the above formula (I) means a group in which the “lower alkyl group” is bonded to a carbonyl group.
  • a carbonyl group for example, an acetyl group, propionyl group, petityl group, isoptylyl group, valeryl group, isovaleryl group, Group, bivaloyl group, pentanoyl group and the like.
  • the “lower alkanoylamif group” in the above formula (I) means a group in which the above “lower alkanoyl group” is bonded to an amino group.
  • lower alkyl strength ruberamoyl group in the above formula (I) means a substituent in which the above “lower alkyl group” is N-substituted on the strength ruberamoyl group, for example, N-methylcarbamoyl group, N-ethylcarbamoyl.
  • N-propylcarpamoyl group N-isopropyl-powered rubamoyl group
  • N-ptylcarbamoyl group N-isobutylcarbamoyl group
  • ⁇ -tert-ptylcarbamoyl group N-pentylcarbamoyl group
  • N-xylcanololemoyl group Etc N-xylcanololemoyl group Etc.
  • an “Aurora A selective inhibitor” is a compound or drug that selectively inhibits Aurora A compared to Aurora B.
  • the “aurora A selective inhibitor” is preferably a compound or a drug that inhibits Aurora A at least 10 times stronger than Aurora B, and more preferably at least Aurora A compared to Aurora B. It is a compound or drug that inhibits 100 times stronger.
  • cancer treatment means inhibiting the growth of cancer cells by administering a pile cancer agent to a cancer patient.
  • a pile cancer agent e.g., a malignant neoplasm originating from a malignant neoplasm originating from a malignant neoplasm originating from a malignant neoplasm originating from a malignant neoplasm originating from a malignant neoplasm originating from a malignant nadota malignant nadota malignant nadota malignant nitride, or a malignant nitride, neoplasm originating from a malignant neoplasm originating from a malignant neoplasm originating from a malignant neoplasm originating from a malignant neoplasm originating from a malignant neoplasm originating from a malignant neoplasm originating from a malignant neoplasm originating from a malignant
  • cancer refers to solid cancer and hematopoietic cancer.
  • solid cancer is, for example, brain tumor, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, stomach cancer, gallbladder / bile duct cancer, liver cancer, Knee cancer, colon cancer, rectal cancer, ovarian cancer, choriocarcinoma, uterine body Cancer, cervical cancer, renal pelvic / ureteral cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, fetal cancer, virus tumor, skin cancer, malignant melanoma, neuroblastoma These include cell tumor, osteosarcoma, Ewing's tumor, and soft tissue sarcoma.
  • hematopoietic cancers include, for example, acute leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, polycythemia vera, malignant lymphoma, multiple myeloma and non-Hodgkin lymphoma.
  • formulation includes oral and parenteral formulations.
  • oral preparations include tablets, capsules, powders, and granules.
  • parenteral preparations include sterilized liquid preparations such as solutions or suspensions. Is an injection, an infusion, etc., preferably an intravenous injection or an intravenous infusion, and more preferably an intravenous infusion.
  • kit-type formulations or pharmaceuticals refers to two or more formulations for simultaneous, separate or sequential administration in therapy, which are so-called kit-type formulations or pharmaceuticals. It may be a composition.
  • Combination preparation J includes a combination preparation composed of two separate preparations used in cancer treatment as described above and further combined with one or more preparations.
  • Anti-cancer alkylating agents anti-cancer anti-metabolites, anti-cancer antibiotics, together with pharmaceutically acceptable carriers or diluents for the two separate formulations listed above Plant-derived pile cancer drugs, anti-cancer platinum coordination compounds, anti-cancer camptothecin derivatives, anti-cancer tyrosine kinase inhibitors, monoclonal antibodies, interferons, biological response modifiers, and other anti-cancer agents Cancer agent (wherein the definition of each anti-cancer agent is the same as described above.) At least an anti-cancer agent selected from the group of: at least i species or pharmaceutically acceptable salts thereof Alternatively, one or more preparations containing esters can be further combined.
  • the further added one or more formulations may be administered simultaneously, separately or sequentially with the two separate formulations.
  • the combination preparation comprising three preparations includes a preparation containing the compound represented by the general formula (I), a preparation containing 5-fluorouracil, and a preparation containing leucovorin.
  • either one or both of two separate preparations may be a parenteral preparation, preferably an injection or an infusion, and more preferably It may be an intravenous drip.
  • a therapeutically effective amount of the compound of the present invention may be usually contained together with a pharmaceutically acceptable carrier or diluent.
  • a pharmaceutically acceptable carrier or diluent Preferably, together with a pharmaceutically acceptable carrier or diluent, it can be formulated for intravenous infusion or injection in a number of ways well known to those skilled in the art.
  • the term “administration” means parenteral administration and Z or oral administration, preferably parenteral administration, when using the combination preparation according to the present invention. That is, when administering a combination preparation, both may be administered parenterally, one may be administered parenterally and the other may be administered orally, or both may be administered orally.
  • both combination preparations are administered parenterally.
  • parenteral administration is, for example, intravenous administration, subcutaneous administration, intramuscular administration, etc., preferably intravenous administration. Even when three or more preparations are administered in combination, at least one preparation may be administered parenterally, preferably intravenously, more preferably intravenous drip or It may be injected intravenously.
  • the compound represented by the general formula (I) may be administered simultaneously with other pile cancer agents.
  • other stake cancer agents are administered continuously.
  • the compound represented by the above general formula (I) may be continuously administered after the other pile cancer agent is administered.
  • the compound represented by the above general formula (I) may be administered, and another anticancer agent may be administered separately after a certain period of time.
  • the compound represented by the above general formula (I) may be administered separately. The order of administration and the interval between administrations depend on the preparation containing the compound represented by the above general formula (I) and the preparation containing the anticancer drug used in combination with it, the type of cancer cells to be treated, and the condition of the patient.
  • “simultaneously” means that treatment is used at approximately the same time, and “separately” means that treatment is used separately at different times, for example, one day.
  • “Sequentially” means to use in order, for example, when one drug is used first and then another drug is used for treatment after a set period of time. .
  • anti-cancer alkylating agent means an alkylating agent having anti-cancer activity
  • alkylating agent generally refers to an organic compound hydrogen atom as an alkyl group. In the alkylation reaction to be substituted with, an alkyl group is given.
  • examples of the “anticancer alkylating agent” include nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, mitoblonitol, carbocone, tiotepa, ramustine, dimustine, temozolomide, or carmustine. is there.
  • “pile cancer antimetabolite” refers to an antimetabolite having a pile cancer activity, where “substance» 3 ⁇ 4 anti-substance ”is, in a broad sense, an important metabolism for the living body. Because it is structurally or functionally similar to substances (vitamins, coenzymes, amino acids, saccharides, etc.), it is possible to create substances that prevent normal metabolism and high energy intermediates by inhibiting the electron transport system. Includes substances to be eliminated.
  • Anticancer antagonists include, for example, methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5—fluorouracil, tegafur, doxyfluridine, carmofur, cytarabine, cytarabine phosphate, enocitabine, S-1, gemcitabine, fludarabine Or pemetrexed disodium, preferably 5-fluorouracil, S-1, gemcitabine or the like.
  • “stake cancer antibiotics” refers to antibiotics having anticancer activity, where “antibiotics” are produced by microorganisms, and the growth of microorganisms and other biological cells Includes substances that inhibit function.
  • Anticancer antibiotics include, for example, actinomycin D, doxorubicin, daunorubicin, neocarcinnostatin, bleomycin, pepromycin, mitomycin C, aclarubicin, pirarubicin, epirubicin, dinostatin stimamarer, idarubicin, Sirolimus or parrubicin.
  • plant-derived anticancer agent used in the present specification includes a compound having anticancer activity found from a plant, or a compound obtained by chemically modifying the compound.
  • Plant-derived pile cancer agents are, for example, vincristine, vinplastin, vindesine, etoposide, sobuzoxane, docetaxel, paclitaxel, vinorelb, etc., preferably docetaxel and paclitaxel.
  • anticancer camptothecin derivative refers to a cancer cell growth inhibitory compound that includes camptothecin itself and is structurally related to camptothecin.
  • Anti-cancer potent umptothecin derivative examples include, but are not limited to, camptothecin, 10-hydroxycamptothecin, topotecan, irinotecan, 9-aminocamptothecin, and the like, preferably camptothecin, topotenic power, and irinotecan.
  • Irinotecan is metabolized in vivo and exhibits anticancer activity as SN-38. Camptothecin derivatives are considered to have almost the same mechanism of action and activity as camptothecin (Nitta et al., Cancer and Chemotherapy, 14, 850-857 (1987)).
  • anticancer platinum coordination compound refers to a platinum coordination compound having anticancer activity, wherein “platinum coordination compound” provides platinum in the form of ions. Means a platinum coordination compound.
  • Preferred platinum compounds include: cisplatin; cis-diamminediacoplatinum (II) —ion; black mouth (jetylene triamine) monoplatinum ( ⁇ ) chloride; dichloro (ethylenediamine) monoplatinum ( ⁇ ); diammine (1, 1— Cyclobutanedicarboxylate) Platinum ( ⁇ ) (carbobratin); Spirobratin; Iproplatin; Diammine (2-ethylmethylmalonate) Monoplatinum (II); Ethylenediaminmalonatoplatinum (II); Aqua (1, 2-diaminodicycloto Xanthine) sulfatoplatinum (II); aqua (1, 2-diaminodicyclohexane) malonatoplatinum (II).
  • anticancer tyrosine kinase inhibitor refers to a tyrosine kinase inhibitor having anticancer activity
  • tyrosine kinase inhibitor refers to ⁇ / -phosphorus of ATP.
  • a ⁇ monoclonal antibody '' is also referred to as a monoclonal antibody, which is produced by a single clone of antibody-producing cells, such as cetuximab, bepacizumab, rituximab, alemuduzumab, trastuzumab, etc. .
  • interferon refers to interferon having anticancer activity, and is generally a glycoprotein with a molecular weight of about 20,000 that is produced and secreted by almost all animal cells upon viral infection. It has a variety of immune effector effects including not only growth inhibition but also cell growth inhibition (particularly tumor cells) and enhancement of natural killer activity. Examples of “interferon” include interferon ⁇ , interferon ⁇ -2a, interferon ⁇ -2b, interferon ⁇ , interferon ⁇ -1a, interferon ⁇ -n1, and the like.
  • a “biological response modifier” is a so-called biological response modifier (BRM), and generally, the defense mechanism of a living body and the survival, proliferation, and proliferation of tissue cells. Or, it is a generic term for substances and drugs whose purpose is to bring an individual to a tumor, infection or other diseases by regulating biological responses such as differentiation.
  • BRM biological response modifier
  • Biological response modifiers include, for example, krestin, lentinan, Zophyllan, Pisibanil, Ubenimex and so on.
  • anticancer agent refers to an anticancer agent that has anticancer activity and does not belong to any of the above.
  • Other anticancer agents include mitoxantrone, L-rasparaginase, procarbazine, dacarbazine, hydroxycanole amide, pentostatin, tretinoin, arfacebut, danole bepoetin anoleva, anastrozonore, exemstan, Bicanoletamide, Leuprorelin, Flutamide, Fulvestrant, Pegaptanibu Octasodium, Denileukin Difty Totas, Aldesleukin, Thyrotropin Alpha, Arsenic Trioxide, Bortezomib, Capecitabine, Goserelin
  • Anticancer Alkylic Agents “Anticancer Antimetabolites”, “Anticancer Antibiotics”, “Plant-derived Anticancer Agents”, “Anticancer Platinum Coordination Compounds”, “ “Anticancer camptothecin derivatives”, “anticancer tyrosine kinase inhibitors”, “monoclonal antibodies”, “interferons”, “biological response modifiers”, and “other anticancer agents” It is known and commercially available, or can be produced by a person skilled in the art by a method known per se or a known / conventional method. In addition, a method for producing gefitieb is described in, for example, US Pat. No.
  • the method for producing irinotecan is, for example, US Pat. 4, 6 0 4, 4 6 3; the production method of topotecan is, for example, in US Pat. No. 5, 7 3 4, 0 5 6; the production method of temozochone is, for example, ⁇ In this patent publication No. 4-5 0 2 9; The method for producing rituximab is described in Japanese publication No. 2-5 0 3 1 4 3 respectively.
  • nitrogen mustard N-oxide is from Mitsubishi Welpharma as Nitromin (trade name); cyclophosphamide is from Shionogi as Endoxan (trade name); , Ifomide (trade name) from Shionogi & Co .; melphalan from Alkeran (trade name) from Daraxo Smith Klein; busulfan from Mabulyn (trade name) from Takeda; mitobronitol is from miebrol (trade name) ) From Kyorin Pharmaceutical; Carbocon from Sankyo as Esquinone (trade name); Chotepa from Tesmumine as Tespamin (trade name); Ranimustine from Simuel Pharma (trade name); and Nimustine fromAran 'Sankyo from the (trade name); Temozolomide Temodar from Schering as a (trade name); and carmustine, available as Gliadel Uofa (trade name) from Grifo over de, respectively commercially
  • methotrexate is taken from Takeda as methotrexate (trade name); Is from Takeda as Roykerin (trade name); 5-Fluorosil is from Kyowa Hakko as 5-FU (trade name); Tegafur is from Taiho Pharmaceutical as ftafool (trade name); Doxyfluridine is from Flutulon (product) Name) from Japan Roche; Carmofour Is from Yamanouchi Pharmaceutical Co., Ltd.
  • YAMAFUR trade name
  • CYROLABE trade name
  • CYTALABIN KUFOSFATE is from Nippon Kayaku as STRACID (trade name)
  • Asahi Kasei as the product name
  • S-1 from TS-1 (product name) from Oiso, Shinji
  • Gemcitabine from Lily as Geza "le (product name); Fludarabine as Nihon Sheichi as Furudara (product name) And pemetrexed disodium are commercially available as alimta (trade name) from Eli Lilly.
  • anti-cancer antibiotics examples include: actinomycin D from Manyu Pharmaceutical Cosmegen (trade name);. Doxorubicin from Kyowa Hakko as adriacin (trade name); daunorubicin, daunomycin (trade name) ) From Meiji Seika; Neocalcinostatin from Yamanouchi Pharmaceuticals as Neocartinostatin (trade name); Bleomycin from Nippon Kayaku as bleo (trade name); Pepromycin from Pepro (trade name) From Nippon Kayaku; Mitomycin C is from Kyowa Hakko as Mits Mycin (trade name); Aklarubisi is from Acanosin (trade name) from Yamanouchi Pharmaceutical; Pirrubicin is Pinorbin.
  • vincristine is from Onobin (trade name) from Shionogi Pharmaceutical; vinplastin is from binkyo chin (trade name) from Kyorin Pharmaceutical; vindesine is fildesine ( (Product name) from Shionogi & Co .; Etoposide from Lastet (trade name) from Nippon Kayaku; Sobuzoxan from Peryakurin (trade name) from Zenyaku Kogyo; Docetaxel from Taxotere (trade name) from Aventis; Paclitaxel can be obtained from Bristol under the name Taxol (trade name), and vinorelbine can be obtained from Kyowa Hakko under the name Navelvin (trade name).
  • anti-cancer platinum coordination compounds include, for example, cisbratin from Japan's Kayaku as Randa (trade name); carpoplatin from Bristol as paraplatin (trade name); nedaplatin as akuplatin (trade name) Shionogi and Oxalibratin are commercially available from Sanofi as Eloxatin '(trade name).
  • Examples of the above-mentioned anticancer camptothecin derivatives include irinotecan from Yakult as campto (trade name); topotecan from GlaxoSmithKline as hicamtine (trade name); and force amptothecin from Aldrich Chemical, USA Can be obtained commercially.
  • Examples of the above-mentioned anti-cancer tyrosine kinase inhibitors include gefitinib from AstraZene as Iressa (trade name); imatinip from Novarteis as Darivek (trade name); and el mouth tinib from Tarceva (product) Name) and can be obtained commercially from OSI Pharmaceutical.
  • cetuximap is from Bristol-Myers Squibb as Erbitux (trade name); bevacizumab is from dienetech as Avastin (trade name); rituximab is from Biogen as Rituxan (trade name); Alemudsumab is from Berrex as a Campus (trade name); They can be obtained commercially from Chugai Pharmaceutical.
  • Interferon a is from Sumitomo Pharmaceuticals as Sumiferon (trade name); Interferon ⁇ -2a is from Takeda as Kanferon 1A (trade name); Interferon ⁇ -2 b is from Schering Plow as Intron A (trade name); Interferon / 3 is from Mochida as IFN j3 (trade name); Interferon V— 1 a is Shiono as Imunomatsu Tasichi T / (trade name) And interferon ⁇ — ⁇ 1 can be obtained commercially from Otsuka as Ogamma (trade name).
  • Krestin is from Sankyo as Krestin (trade name); Lentinan is from Aventeis as lentinan (trade name); Sizophyllan is from Kaken Pharmaceutical as Sonifiran (trade name) From; Pisibanil is available from Chugai as Pisibanil (trade name); and Ubemex is available from Nippon Kayaku as Bestatin (trade name). -.
  • the other anti-cancer agents mentioned above are, for example, “Mi” Toxanthrone, Novantrone (trade name) from Nippon Isla Dere; L-asparaginase, Leunase (trade name) from Kyowa Hakko; (Product name) from S book Roche; dacarbazine is dacarbazine
  • anticancer agent means the above “anticancer alkylating agent”, “anticancer antimetabolite”, ⁇ anticancer antibiotic ”,“ plant-derived piles ” , Anticancer platinum coordination compound, anticancer camptothecin derivative, anticancer tyrosine kinase inhibitor, monoclonal antibody, interferon, biological response modulation Agent "and” Other pile cancer agent "A pile cancer agent selected from the strength.
  • aminoviridine derivative refers to a compound containing a pyridine having an amino group, such as a compound represented by the above formula (I), and preferably (a) to (a) to Refers to the compound of (cc).
  • ⁇ 1 is 1, 2 or 3; preferably is 2 or 3; more preferably is 2.
  • 'm 2 is 1, 2 or 3; preferably m 2 is 2.
  • ⁇ 2 is 0 or 1; preferably ⁇ 2 is 0.
  • R is an aryl group, a heteroaryl group, or a cycloalkyl group, which may be substituted.
  • R force is preferably a phenyl group or a 5-membered or 6-membered aromatic heterocyclic group containing at least one atom selected from N, O and S (wherein the phenyl group or aromatic heterocycle
  • the ring groups are:
  • Substituent group A 2 > is a halogen atom, a cyano group, a hydroxy group, an amino group, a lower alkylamino group, a di-lower alkylamino group, a lower alkanoyl group, a lower alkanoylamino group, or a strong rubamoyl group.
  • a 5-membered aromatic heterocyclic group for example, a pyrrolyl group, a furyl group, a chenyl group, a thiazolyl group, a pyrazolyl group, a pyridyl group, a birazinyl group, which may be appropriately substituted. Etc. are preferable.
  • R is more preferably a phenyl group in which the 2-position and 3-position are substituted with the same or different halogen atoms, or the 2-position and 3-position are each a halogen atom, 1 to 3 A phenyl group substituted by a methyl group substituted by a halogen atom.
  • R 3i and R ai ′ are the same or different and are a hydrogen atom or a lower alkyl group
  • R bj and R bj ′ are The same or different, a hydrogen atom or a lower alkyl group.
  • mi is 2 or 3
  • i is i. (I. Is any integer from 1 to mi )
  • m 2 is 2 or 3
  • j is j.
  • J is an integer from 1 to m 2 )
  • R b j is an integer of 1 to
  • One of ' may be joined together to form one (CH 2 ) n — (where n is 1 or 2).
  • n is 1 or 2.
  • R ai and R ai (i is an integer from 1 to) and R bj and R b (j is an integer from 1 to m 2 )
  • R bj and R b (j is an integer from 1 to m 2 )
  • m 2 is 2
  • one of R a 2 and R a 2 ′ and one of R b j and R b ⁇ ′ are joined together to form one CH 2 —.
  • R ai and R ai ′ (where i is an integer from 1 to) and R b j and R b (j is an integer from 1 to m 2 ), mi is 2 or 3, and m 2 is , 2, R ai , R ai ′, R bj , and R b are preferably R ai , R ai ⁇ R bj , and ⁇ R b j, all of which are hydrogen atoms, or R a have R a, R b j, 1 or any of ⁇ Pi R b j 'is a methyl group, the remainder is a hydrogen atom, more preferably, R ai, R ai ⁇ R bj, ⁇ Pi R All of fa j 'are hydrogen atoms. For example, when is 2 and m 2 is 2, R a ., R a ! , R a 2 , R a 2 ′, R b , R b ′,
  • 2 ′ is preferably all hydrogen atoms.
  • R c , R d , and Re are the same or different and are a hydrogen atom or a lower alkyl group.
  • R e is preferably a hydrogen atom.
  • Xj is CH, CX la or N, wherein X la is an optionally substituted lower alkyl group.
  • X is preferably CH.
  • X 2 is CH, CX 2a or N (where
  • X 2a is a lower alkyl group
  • X 2a is a substituent selected from the ⁇ substituent group A i>, or a lower alkyl group substituted by one or more substituents selected from the substituent selected from the substituent group A (wherein, Substituent group A> is a halogen atom; a nano group; a hydroxy group; a lower alkylamino group; a dilower alkylamino group; a lower alkoxy group which may be substituted with one or more hydroxy groups; An alkylthio group; and a lower alkylsulfonyl group.);
  • X 2a is a force that is COOR CONR 2 R 3 , NHCOR NHCONR 2 R 3 , NHS0 2 NR 2 R 3 , NR 4 R 5 , or CH 2 NR 4 R 5 (where-is a hydrogen atom Or an optionally substituted lower alkyl group;
  • ⁇ 2 and 3 are the same or different and are permanent atoms, optionally substituted lower alkyl groups or cycloalkyl groups, or 1 2 and 1 3 are nitrogen atoms to which they are bonded. Together with the optionally substituted 5-membered ring or 'containing at least one atom selected from N, O and S may form a 6-membered aliphatic heterocyclic group ,
  • R 4 and R 5 are the same or different and each represents a hydrogen atom, an optionally substituted lower alkyl group or a cycloalkyl group. ; Or
  • X 2a may have a substituent, and includes at least one atom selected from N, O and S
  • a 5-membered or 6-membered aliphatic heterocyclic group (wherein two hydrogen atoms bonded to the same carbon atom of the aliphatic heterocyclic group may be substituted with an oxo group, and The adjacent carbon atom constituting the ring of the aliphatic heterocyclic group may be a double bond), or a lower alkyl group substituted with the aliphatic heterocyclic group;
  • X 2a may have a substituent, and includes at least one atom selected from N, ⁇ and S
  • X 2 is preferably CH, CX 2a or N (wherein
  • X 2a is a substituent selected from the substituent group A i>, or a lower alkyl group substituted by one or more substituents selected from the substituent group A i>; or ,
  • X 2a is. COOR ⁇ CONRzR ⁇ NHCOR ⁇ NHCONRsR ⁇ NHSC ⁇ NRaR ⁇ NR 4 R 5 or CH 2 NR 4 R 5 (where
  • R 2 and R 3 are the same or different, a hydrogen atom, a force is optionally substituted lower alkyl group or a cycloalkyl group, or, 1 2 and 1 3, and the nitrogen atom to which they are attached.
  • 'R 4 and R 5 are one or different and are a hydrogen atom, an optionally substituted lower alkyl group or a cycloalkyl group.
  • X 2a may be substituted with a lower alkyl group, or a 5-membered aromatic heterocyclic group selected from Substituent Group A 3 > or a lower alkyl group substituted with the aromatic heterocyclic group
  • X 2a may be substituted with a lower alkyl group, or may be substituted with a 5-membered or 6-membered aliphatic heterocyclic group selected from Substituent Group A 4 >, or with the aliphatic heterocyclic group A lower alkyl group;
  • the substituent group A ⁇ > is preferably as follows.
  • X 2 is more preferably CH or N.
  • X 3 is CH, CX 3a or N, where X 3a is an optionally substituted lower alkyl group.
  • X 3 is preferably CH.
  • X 4 is CH or N, preferably N.
  • X 2 , X 3 and X 4 are 1 to 2; preferably X 4 is N and X to X 3 is N , At most one; more preferred Or X 3 is CH, X 2 is CH or N, and X 4 is N; particularly preferably, X 2 , and X 3 are all CH; X 4 is N It is.
  • Wj is CH
  • W 2 is CH or CW 2a
  • W 3 is N
  • X 2 is preferably N
  • X 3a is preferably CH or CX 3a .
  • Y have Y 2
  • Upsilon 3 are the same or different, is a CH or New, however, is 1S CH, when R e is a hydrogen atom, the two hydrogen atoms are substituted with Okiso group May be.
  • Y! Is preferably CH.
  • ⁇ ⁇ and ⁇ 2 are the same or different and are CH or ⁇ .
  • Zj and ⁇ 2 are preferably at least one of N.
  • ⁇ ⁇ and ⁇ 2 are particularly preferably both ⁇ .
  • -W is the following group:
  • Wj is CH, N, NH, O or S
  • 'W 2 is CH, CW 2a , N, NW 2b , O or S (where W 2a and W 2b are the same or different and are a hydrogen atom, a halogen atom, a cyano group, a carbon number, A lower alkyl group having 1 to 2 carbon atoms, a cycloalkyl group having 3 to 5 carbon atoms, or a lower alkyl group having 1 to 2 carbon atoms, which may be substituted with one or more halogen atoms );
  • W 3 is C or N
  • W 2 , and W 3 are at least one carbon atom, but two of Wi, W 2 , and W 3 are not O and S at the same time.
  • W is preferably selected from any of the following.
  • W 2a is a hydrogen atom, a halogen atom, a cyano group, or a methyl group that may be substituted with 1 to 3 fluorine atoms.
  • W is particularly preferably selected from one of the following:
  • W is selected from one of the following:
  • a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof or
  • n 2 is 0;
  • the scale is a phenyl group or a 5-membered or 6-membered aromatic heterocyclic group containing at least one atom selected from ⁇ ⁇ and S (wherein the phenyl group or aromatic heterocyclic group is The following:
  • Substituent group A 2 > is a halogen atom, a cyano group, a hydroxy group, an amino group, a lower alkylamino group, a di-lower alkyl / leamino group, a lower alkanoyl group, a lower alkanoylamino group, a strong rubamoyl group, a lower group An alkyl group, a ruberamoyl group, and a lower alkylsulfonyl group. ) Or a pharmaceutically acceptable salt or ester thereof, or
  • R a , R a ′ R a 2 R a 2 ′ R b R b R b 2 , and R b 2 ′ 1 A hydrogen atom or a compound according to the above (3) A pharmaceutically acceptable salt or ester thereof, or '.
  • X 4 is N, and X or X 3 is N at most; and R is a halogen atom that is the same or different at the 2nd and 3rd positions.
  • X 2a is a substituent selected from ⁇ Substituent Group A j>, or a lower alkyl group substituted by one or more substituents selected from ⁇ Substituent Group A i>; or ,
  • X 2a is COORj, CONRzR ⁇ NHCOR ⁇ NHCONR ⁇ R ⁇ NHSOaNRsRg
  • R 2 and R 3 are the same or different and are a hydrogen atom, an optionally substituted lower alkyl group or a cycloalkyl group, Alternatively, R 2 and R 3 together with the nitrogen atom to which they are attached may be substituted or a 5-membered ring or at least one atom selected from N., O and S Form a 6-membered aliphatic heterocyclic group;
  • R 4 and R 5 are the same or different and each represents a hydrogen atom, an optionally substituted lower alkyl group or a cycloalkyl group. ; Or
  • X 2a is a 5-membered aromatic heterocyclic group selected from ⁇ Substituent group A 3 >, which may be substituted with a lower alkyl group, or a lower alkyl group substituted with the aromatic heterocyclic group Or
  • X 2a may be substituted with a lower alkyl group, substituted with a 5-membered or 6-membered aliphatic heterocyclic group selected from ⁇ Substituent group A 4 >, or the aliphatic heterocyclic group A lower alkyl group;
  • W is selected from one of the following:
  • W 2a is a hydrogen atom, a halogen atom, a cyano group, or a methyl group that may be substituted with 1 to 3 fluorine atoms.
  • the compound of the above formula (I) is more preferably
  • the present invention provides: (a) 6-. ((4- (3-Fluorobenzene 2-Fluorobenzene) Piperazine 1-1-yl) Methyl) 1 N-thiazole 2- 1-amine,
  • the combined preparation comprising two separate preparations according to the present invention
  • one or both of the two separate preparations are parenteral preparations, and more preferably, the two separate preparations. Either or both are injections or drops.
  • 'A combination formulation comprising two separate formulations according to the present invention preferably has one formulation, together with a pharmaceutically acceptable carrier or diluent,
  • Another formulation is a formulation comprising paclitaxel or docetaxel or a pharmaceutically acceptable salt or ester thereof together with a pharmaceutically acceptable carrier or diluent.
  • a combination formulation consisting of two separate formulations according to the present invention is more preferably one formulation together with a pharmaceutically acceptable carrier or diluent,
  • Another formulation is a formulation comprising paclitaxel or docetaxel or a pharmaceutically acceptable salt or ester thereof together with a pharmaceutically acceptable carrier or diluent.
  • a pharmaceutically acceptable carrier or diluent an anticancer alkylating agent, a pile cancer antimetabolite , Anticancer antibiotics, plant-derived anticancer agents, anticancer platinum coordination compounds, anticancer camptothecin derivatives, anticancer tyrosine kinase inhibitors, monoclonal antibodies, interferons, biological
  • An anticancer agent selected from the group consisting of response modifiers and other anticancer agents (wherein the definitions of each anticancer agent are the same as those described above) or a pharmaceutically acceptable product thereof.
  • One or more preparations containing a possible salt or ester may be further combined.
  • composition according to the present invention is preferably combined with a pharmaceutically acceptable carrier or diluent, and includes (a) 6-((4. Benzoinole) Piperazine 1-yl) Methinole) 1 N —thiazole _ 2 -ylpyridine 1-ammine,
  • Step 1 In this step, compound (1, 1) (where LG 1 represents a leaving group such as halogen, and X,, X 2 , X 3 , X 4 , and Re represent the above formulas)
  • Protecting group PG 1 such as tert-butyldimethylsilyl group is introduced into compound (III) (wherein 0 1 and? & 1 are as defined above) And X 2 , X 3 , X 4 , 'and Re are the same as the symbols in formula (I)).
  • Examples of the compound (II) used in this step include (6-bromopyridine-2-yl.) Methanol, 1- (6-bromopyridine-2-yl) ethanol, (3-odophenyl) And the like.
  • the compound (I I) can be produced according to a commercially available force or a known method.
  • Protective group PG 1 has different forces depending on its type.
  • Protective group Protective group methods [Protective 'groups' in oganic synthesis, TW Green (TW Gt eene), John Wiley & Sons (see 1981)] or similar methods.
  • the compound (II) can be synthesized in a solvent such as N, N-dimethylformamide in the presence of a base such as imidazole using tert-butyl dimethylenosilyl.
  • the amount of tert-butyldimethylsilyl chloride is 1 to 10 mol of tert-butyldimethylsilyl salt per 1 mol of compound (II).
  • the reaction temperature is a force that can be appropriately selected by those skilled in the art depending on the starting compound used or the reaction solvent, and is usually 0 ° C. to the boiling point of the solvent.
  • the reaction is usually completed in 1 hour to 24 hours, but the reaction time can be appropriately increased or decreased.
  • the compound (III) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or isolation and purification. It can be attached to the next process.
  • Step 2 This step is the compound (III) obtained in Step 1 above (where 0 1 and 0 1 are as defined above, and X 2 , X 3 , X 4 , and Re are And the compound of formula (I)) and compound (IV) (wherein PG 2 may not be present, and if present, or 4.-methoxybenzyl group, 2 , 4-dimethoxybenzyl group, benzyl group, methoxymethyl group, (2- (trimethylsilyl) ethoxy) methyl group, tert-butyl group, etc., preferably (2- (trimethylsilyl) ethoxy) methyl group, A protective group such as a toximethyl group and a tert-butyl group, and W is as defined above for formula (I).) ′ Is subjected to an amination reaction to give compound (V) (wherein PG 1 and PG 2 are the same as defined above, X, X 2, X 3 , X 4, R e
  • the compound (IV) used in this step includes, for example, 2-aminothiazole-5-power rubonitrile, 2-aminothiazole, 2-amino-5-methylthiazole, 5-amino-1,2,4. -Thiadiazole, 5-methyl-1 ((.2— (trimethylsilyl) ethoxy) methyl) 1 1H—pyrazole-3-amine, 1— ((2— (trimethylsilinole) ethoxy) methyl) 1 1H—pyrazoru 3— And 1-tert-butyl-1-methyl_1H-pyrazole-5-amamine '
  • the compound (IV) can be obtained commercially or by a known method (for example, Phosphorus, Sulfurand Silicon and the Reelated Elements 2002, No. 177-11). 2651-265 pp. And Journal of Chemical Research, Synopses 5 979, pp. 6 198).
  • a method well known to those skilled in the art is used for the amination reaction used in this step. Specifically, as the amination reaction used in this step, for example, the compound (III) and the compound (IV) are converted into 1,4-dioxane, 1,2-dimethoxetane, tetrahydrofuran, and salt.
  • Palladium catalyst such as trisdibenzylideneacetone dipalladium (0), palladium acetate, etc.
  • the ligand is 0.002 to 2 mol, preferably 0.:!
  • the base is 1 to 10 mol, Preferably 1 to 3 moles are used.
  • the reaction temperature is appropriately selected according to the starting compound used or the reaction solvent, and is usually from the 5 ° C boiling point of the solvent used in the reaction.
  • the reaction is usually completed in 1 to 24 hours, but the reaction time can be appropriately increased or decreased. .
  • the compound (V) thus obtained can be isolated or purified by a known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. Without the next
  • Step 3 This step is the compound (V) obtained in Step 2 (wherein PG 1 and PG 2 are as defined above, and X, X 2 , X 3 , X 4 , R e , W, and W are as defined above for the formula (I).)
  • the protecting group PG 1 is deprotected to give a compound (VI) (wherein PG 2 is as defined above, X, X 2 , X 3 , X 4, R e , and are the same as the symbols in formula (I). ,
  • the removal of the protecting group PG 1 used in this process depends on its type and the stability of the compound.
  • the method described in the literature [Protective Groups 'in' Organic Synthesis (P rotect 0 ive Group sin Or ganic Synthesis), TW Green (TW
  • the compound (V) in which PG 1 is a tert-butyldimethylsilyl group can be deprotected using tetraptyl ammonium fluoride in a solvent such as tetrahydrofuran.
  • a solvent such as tetrahydrofuran.
  • the amount of tetra 5-butyl ammonium fluoride is 1 to 10 mol, preferably 1 to 3 with respect to 1 mol of compound (V).
  • the reaction temperature can be appropriately selected by those skilled in the art depending on the starting compound used or the reaction solvent, and is usually from 0 ° C. to the boiling point of the solvent.
  • the reaction is usually completed in 1 hour to 24 hours, but the reaction time can be appropriately increased or decreased.
  • the compound (VI) thus obtained can be obtained by known separation and purification means such as concentration, concentration under reduced pressure, It can be isolated and purified by crystallization, solvent extraction, reprecipitation, chromatography, etc. or can be subjected to the next step without isolation and purification.
  • This step is the step 3' of the compound obtained in (VI) (where, PG 2, the a Ri synonymous der, X had X 2, X 3, X 4 , R e, Ei is the same as the symbol of the above formula (I).)
  • the hydroxy group is converted to a leaving group such as a methanesulfonyloxy group, a black mouth group, etc., and compound (VII) (where LG 2 is represents a leaving group such as methanesulfonyl O alkoxy group or a halogen atom, PG 2 is are the same as defined above, X had X 2., X 3, X 4, R e, ⁇ Hi 1 W, the equation (It is synonymous with the symbol of (I).).
  • the reaction used in this step methods well known to those skilled in the art are used.
  • the compound (VI) is converted to black mouth form, salt methylene, tetrahydrofuran, N, N-dimethylformamide, jetyl ether, ethyl acetate, etc.
  • the compound (VII) in which LG 2 is a tansulfonyloxy group can be obtained by reacting with methanesulfonyl chloride in the presence of a base such as triethylamine, disopropylethylamine, etc. .
  • reaction temperature can be appropriately selected by those skilled in the art depending on the raw material compound used, but it is usually from 0 ° C. to room temperature.
  • the reaction is usually completed in 10 minutes to 2 hours, but the reaction time can be appropriately increased or decreased.
  • the compound (VII) thus obtained can be isolated or purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. or without isolation and purification. It can be attached to the next process.
  • Step 5 This step is the compound (VII) obtained in Step 4 above (where LG 2 and PG 2 are as defined above, and X 2 , X 3 , X 4 , Re , And W are synonymous with the symbols in formula (I).) And Compound (VIII) (where m m 2 , n n 2 , R, R a R ai , R b R bj , R c , R d , Y 2 , Y 3 , and Z 2 have the same meanings as those in the formula (I).)
  • PG 2 is X is X 2 , X 3 , X 4 , R e , and t
  • m is m 2
  • n is n 2
  • R Ra is R ai , R bj , R b j , R c , R d , Y 2 , Y 3 , and.
  • Z 2 are
  • the compound (VIII) used in this step for example, 1- (3-chloro-2-benzoyl) piperazine, 1- (3- (trifluoromethyl) 1-2-fluoro Oral Benzoyl) Piperazine, 1 ((6-Fluoropyridine-2-yl) Carbonyl) Piperazine, Phenyl (Piperidin-4-1) Methanone, 2-Benzyl-1,2, 5-Diazabicyclo [2.2 1] Heptane, 1 1 1 2 ⁇ 1 1 ⁇ 1 4 ⁇ ⁇ .
  • the compound (VIII) can be obtained commercially or by a known method (for example, Journal of Medical Chemistry 1 986, 29-5, 630-634). Can be manufactured according to
  • the compound (VII) and the compound (VIII) are converted into tetrahydrofuran, dimethyl sulfoxide, N, N-dimethylformamide, 1,4-diol. It can be synthesized by using sodium hydrogen carbonate, triethylamine, disopropylethylamine, sodium hydroxide or the like as a base in a solvent such as xanthone, dichloromethane, or black mouth form.
  • compound (VIII) is used in an amount of 1 to: 0 mol, preferably 1 to 3 mol, and 1 to 20 mol, preferably :! Use ⁇ 5 mol.
  • the reaction temperature is a force that can be appropriately selected by those skilled in the art depending on the raw material compound or reaction solvent used.
  • the reaction temperature is usually from room temperature to the boiling point of the solvent.
  • the reaction is usually completed in 1 hour to 24 hours, but the reaction time can be appropriately increased or decreased.
  • the ich compound (IX) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be used in the next step without isolation and purification.
  • the compound (IX) does not require deprotection, the compound (IX) becomes the compound according to the present invention without performing the subsequent step 6.
  • Step 6 This step is the compound obtained in Step 5 (IX) (wherein, PG 2, the a Ri synonymous der, X had X 2, X 3., X 4, R e, And m m 2 , n n 2 , R, R a R ai ′, R bj , R bj ′, R c , R d , Y 2 , Y 3 , and Z 2 are represented by the above formula ( The deprotection reaction of compound (1-1) (where X is X 2 , X 3 , X 4 , R and W, and m is m 2 , n There n 2, R, R a have R ai ', R b j, R b, R c, R d, Y 2, Y 3, ⁇ Pi Z 2 have the same meanings as the symbols in formula (I). ). .
  • the deprotection reaction of PG 2 depends on the type and stability of the compound, but the method described in the literature [Protective 'Gnorapes'In' Organic Synthesis, TW Green (TW According to Grene), Jo ′ ⁇ hn Wiley & Sons (1981)] or a method according thereto, for example, by solvolysis using an acid.
  • the compound (IX) (W is 1H-pyrazole-1-yl group, PG 2 is (2- (trimethylsilyl) ethoxy) methyl group, PG 2 is substituted at the 1-position of pyrazole, and X is X 2 , X 3 , X 4 , and R e , and m is m 2 , n is n 2 , R, R ai , R ai ′, R b is R b j ',: e , R d , Y 2 , Y 3 , and ⁇ 2 are the same as the symbols in the formula (I).) Deprotection reaction by decomposition, corresponding compound (1-1) (W is as defined above, X X 2 , X 3 , X 4 , and R e , and m 2 m 2 , N, n 2 , R, Ra a R ai ⁇ R b j, R b , R
  • the reaction temperature can be appropriately selected by those skilled in the art depending on the raw material compound or the reaction solvent used, and is usually from the temperature to the boiling point of the solvent.
  • the reaction is usually completed in 1 hour to 24 hours, but the reaction time can be appropriately increased or decreased.
  • the compound (I_1) according to the present invention thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, and the like. it can.
  • Compounds according to the present invention (VI II) (wherein,.
  • Step 7 In this step, compound (X) (wherein PG 3 is a protecting group such as tert-butyloxycarbonyl group, m 2 , R ai , R ai ′, R b and R bj 'has the same meaning as that in the formula (I).) And the compound (XI) (where n 2 , R, R d , and Y 3 are the same as those in the formula ( ⁇ -).
  • Examples of the compound (X) used in this step include tert-butyl'piperazine 1 1 monostrengthene rubonic acid ester, tert-butyl 2-methylbiperazine 1 1-carboxylic acid ester, tert-butyl 2, 5- Examples include diazabicyclo [2. 2. 1] heptane-2-strong rubonic acid ester, tert-butyl 1,4-diazepane 1-1 strong rubonic acid ester, and the like.
  • the compound '(X) can be obtained commercially, or can be obtained by a known method (for example, Journal of Medicinal Chemistry 1986, Vol. 29, No. 5, 63.0—page 634.). , +
  • the compound (XI) used in this step for example, 6-fluoropyridine 1- 2-rubberonic acid, thiophene 1-carboxylic acid, 2,3-dichlorobenzoic acid, 3-chloro-2-fluorobenzoic acid 3- (Trifluoromethyl) 1-fluorobenzoic acid, furan 1-carboxylic acid, 2-fluoropyridine 1-3-carboxylic acid, and the like.
  • the compound (XI) can be obtained commercially, or can be produced according to a known method. 'The amidation reaction used in this step can be performed using the carboxylic acid represented by the compound (XI) or a reactive derivative thereof and the compound (X).
  • Examples of the “reactive derivative” of the compound (XI) include mixed acid anhydrides, active esters, active amides, etc., and these can be obtained, for example, by the method described in International Publication WO 98/05641. Can do. Specifically, for example, the compound (X) and the compound (XI) are mixed in a solvent such as tetrahydrofuran, dimethyl sulfoxide, N, N-dimethylformamide, 1,4-dioxane, dichloromethane, black mouth form, It can be synthesized by condensing using a condensing agent such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and 1-hydroxybenzotriazole.
  • a condensing agent such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and 1-hydroxybenzotriazole.
  • reaction temperature is a force appropriately selected according to the raw material mixture used or the reaction solvent. Usually, it is the boiling point of the solvent used in the reaction from room temperature.
  • the reaction is usually completed in 1 to 24 hours, but the reaction time can be appropriately increased or decreased.
  • the compound (XII) thus obtained can be isolated or purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be attached to the next process.
  • Step 8 This step is the compound obtained in Step 7 (XII) (wherein, PG 3 is. Are the same as defined above, m have m 2, R a have R ai ', R bj, and R bj ′, and n 2 , R, R d , and Y 3 have the same meanings as the symbols in the formula (I).)
  • Protecting group PG 3 of (VII 1 -1) ( Here, 1 ⁇ , m 2 , R a i , R a , R bj ., And R b , and n 2 , R, R d , and Y 3 are synonymous with the symbols in the formula (I). .) Is a method for producing a compound represented by ⁇
  • the deprotection reaction used in this step methods well known to those skilled in the art are used.
  • the removal of the protecting group of the compound (XII) in this step varies depending on the type and stability of the compound, but the method described in the literature [Protective Gnorapes' In 'Organic Synthesis' (P nt hesis), TW Greene, see John Wiley & S, ons (1981)] or a similar method.
  • the deprotection reaction of the compound represented by (XII) (wherein PG 3 is a tert_ptyloxycarbonyl group) can be carried out by solvolysis using an acid.
  • the compound (VII 1-1) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be used in the next step without isolation and purification.
  • Step 9 In this step, compound (XIII) (where LG 3 and LG 4 represent a leaving group such as a halogen atom, and XX 2 X 3 and X 4 represent the symbols of formula (I) above. And PG 2 (wherein PG 2 has the same meaning as described above, and W has the same meaning as the symbol in formula (I)). XIV) (where PG 2 and LG 4 are as defined above, and XX 2 X 3 X 4 and W are as defined above for the formula (I)). .
  • Examples of the compound (IV) used in this step include 2-aminothiazole, 5-amino-1,2,4-thiadiazole, 5-methyl-1-((2- (trimethylsilyl) ethoxy) methyl. ) 1 1H-pyrazole-3-ammine, 1- ((2- (trimethylsilyl) ethoxy) methyl) 1 1 H-pyrazole 1-amamine, 1 1 tert-petite 3-methyl-1H-pyrazole-5-amine, etc. Can be mentioned.
  • the compound (IV) can be obtained commercially, or can be obtained by a known method (for example, Phosphorus, Sulfurand Silicon and the Reeled Elements 2002, No. 177). 11, pp. 2651–2659, and Journal of Chemical Research, Synapse (Synopses), 1979, Vol. 6, 198)).
  • Examples of the compound (XI I I) used in this step include 2,6-dichloropyridine, 24-dichloropyrimidine, 2,6-dichlorovirazine and the like.
  • Compound (X I I I) is commercially available or can be produced according to a known method.
  • This step can be carried out by the same method as in step 2, a method according to this, or a combination of these with conventional methods.
  • - ⁇ Xj, X 2 , X 3 , X 4 , and W have the same meanings as those in the formula (I).
  • Step 10 This step is the same as the compound (XIV) obtained in Step 9 (wherein PG 2 and LG 4 are as defined above, and X, X 2 , X 3 , X 4 , and The compound (XV) (wherein R f is a lower alkyl group, and PG 2 is as defined above) by the carbonylation reaction of the above formula (I). ,. X 2 , X 3 , X 4 , and W are the same as the symbols in formula (I)).
  • the carbonyl reaction used in this step includes, for example, the above compound (XIV) with N, N-dimethylacetamide, N-methylpyrrolidone, N, N-dimethylforma- Ligand such as 1, 1 'monobis (diphenylphosphino) phenol and palladium such as palladium (II) in a mixed solvent of methanol and other alcohols such as ethanol
  • the compound (XV) can be synthesized by reacting with carbon monoxide in the presence of a catalyst and a base such as sodium hydrogen carbonate or triethylamine.
  • the palladium catalyst is 0.01 to 1 mol, preferably 0.05 to 0.5 monolayer, and the ligand is 0.02 to 1 mol, preferably 0.1 to 1 mol is used, and 1 to 10 mol, preferably 1 to 3 mol, of the base is used.
  • the reaction temperature can be appropriately selected by those skilled in the art depending on the raw material compound or reaction solvent used, and is usually from 50 ° C. to the boiling point of the solvent used in the reaction. The reaction is usually completed in 1 to 24 hours, but the reaction time can be appropriately increased or decreased.
  • the compound (XV) thus obtained may be isolated or purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be attached to the next process.
  • Step 11-1 This step is the same as the compound (XV) obtained in Step 10 (where R f and PG 2 are as defined above, X 2 , X 3 , X 4 , And t W are synonymous with the symbols in formula (I).)
  • R f and PG 2 are as defined above, X 2 , X 3 , X 4 , And t W are synonymous with the symbols in formula (I).
  • PG 2 is as defined above, x 2 , x 3 , X 4 , and tw are synonymous with the symbols in the formula (I).
  • the hydrolysis reaction used in this step methods well known to those skilled in the art are used. Specifically, as the hydrolysis reaction used in this step, for example, the compound (XV) is used in a solvent such as methanol, ethanol, tetrahydrofuran or the like using a sodium hydroxide aqueous solution or the like as a base.
  • Compound (XV I) can be synthesized. In this case, 1 to 100 mol of the base is used, preferably 1 to 100 mol, per 1 mol of the compound (XV).
  • the reaction temperature can be appropriately selected by those skilled in the art depending on the starting material compound or reaction solvent used, and is usually from room temperature to the boiling point of the solvent. The reaction is usually completed in 1 hour to 24 hours, but the reaction time can be appropriately increased or decreased.
  • the Ich compound (XVI) thus obtained is isolated or purified by a known separation and purification means such as concentration, + concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be used in the next step without purification.
  • Step 1 1 1 2 This step is a compound obtained in the above-mentioned:!: About 1 1 1 1 (XVI) (wherein PG 2 is as defined above, X, X 2 , X 3 , X 4 , and tFW are the same as the symbols in the formula (I).) By the reduction reaction of the compound (VI-1) (where PG 2 is as defined above). And X 2 , X 3 , X 4 , and W are the same as the symbols in formula (I).
  • the reduction reaction used in this step includes, for example, the compound (XVI) in a solvent such as N, N-dimethylformamide, tetrahydrofuran, and N, N′-carbodidiyl.
  • the compound (VI-1) can be synthesized by reacting with imidazole at room temperature for 12 to 24 hours and then reacting with a reducing agent such as sodium borohydride.
  • a reducing agent such as sodium borohydride.
  • 1 to 10 moles, preferably 1 to 3 moles of N, ⁇ ′ monocarbodiimidazole are used per 1 mole of the compound (XVI), and the reducing agent is 1 to 20 moles, preferably 1 to Use 5 moles.
  • the reaction temperature can be appropriately selected by those skilled in the art depending on the raw material compound or reaction solvent used, and is usually from 0 ° C. to room temperature.
  • the reaction is usually completed in 10 minutes to 24 hours, but the reaction time can be appropriately increased or decreased.
  • the compound (VI-1) thus obtained is isolated or purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be attached to the next process without any problems.
  • Step 12 This step is the compound (XV) obtained in Step 10 ′ (where R f and PG 2 are as defined above, and Xi X2 X3, X 4 , and ⁇ W are By the reductive reaction of the formula (I), the compound (VI-1) (wherein PG 2 is as defined above, X 1, X 2 , X 3 , X 4 , And W is the same as the symbol of the formula (I). 'For the reduction reaction used in this step, methods well known to those skilled in the art are used.
  • the compound (XV) is reduced in a solvent such as tetrahydrofuran or 1,4-dioxane, and a reducing agent such as lithium borohydride or lithium aluminum hydride.
  • the compound (VI-1) can be synthesized by reacting with.
  • a reducing agent is added to 1 mol of compound (XV); -20 mol, preferably 1-5 mol.
  • the reaction temperature is a force s that can be appropriately selected by those skilled in the art depending on the starting compound used or the reaction solvent, and is usually from 0 ° C. to the boiling point of the solvent used in the reaction.
  • the reaction is usually completed in 10 minutes to 24 hours, but the reaction time can be appropriately increased or decreased.
  • the compound (VI-1) thus obtained is isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be used in the next step without purification.
  • 'Compound (XV) according to the present invention (where R f is a lower alkyl group, PG 2 is as defined above, and X, X 2 , X 3 , X 4 , and W are Is synonymous with the symbol of formula (I).) Can also be produced, for example, by the following method.
  • Step 1 3) In this step, compound (XV II) (where R f is a lower alkyl group, LG 5 represents a leaving group such as a halogen atom, and X,, X 2 , X 3 , And X 4 are as defined above for the formula (I).) And the compound (IV) (wherein PG 2 is as defined above, and W is as defined above as the symbol for formula (I)).
  • the compound (XV) (wherein Rf is a lower alkyl group, PG 2 is as defined above, and X 2 , X 3 , X 4 , And W are synonymous with the symbols in formula (I).). '.
  • Examples of the compound (IV) used in this process include 2-aminothiazole, 5-amino-1,2,4-thiadiazole, 5-methyl-11 ((2- (trimethylsilyl) ethoxy) methyl). ) 1 1H-pyrazole 1-3-amine, 1- ((2— (trimethinolesilyl) ethoxy) methyl) 1 1H-pyrazole-3-amine, 1- tert-butyl 1-methyl 1 1 H-pyrazole 1 5 —Amine etc .;
  • the compound (IV) can be obtained by commercially available or known methods (for example, Phosphorus: Sulfur and Silicon and Related Elements, 2002, 1 77). ⁇ 1 1, pp. 2651–2659. According to Opi Journal of Chemical Research, Synapse 1 -s, Journalof Cnica Research, Synopses), 1979, Vol. 6, pp. 198) Can be manufactured.
  • Examples of the compound (XV I I) used in this step include 6-chloro-2-pyridinecarboxylic acid methyl ester, 6_chloro-2-methyl-2-pyridinecarboxylic acid methyl ester, and the like.
  • Compound (XV I I) can be obtained commercially, or can be produced according to a known method.
  • This step can be carried out by the same method as in step 2, a method according to this, or a combination of these with conventional methods. .
  • the obtained protected body can carry out the same reaction as in the corresponding step described above, and those compounds can be used in the same manner as in the above step 6, or a method analogous thereto, or a combination thereof.
  • introduced protecting groups can be deprotected.
  • examples of introduction of a protecting group in the compound (IV) and the compound (XV) will be described.
  • a person skilled in the art can appropriately transfer a protecting group to the above-mentioned synthetic intermediate by using a known method and / or a method exemplified below or a method analogous thereto from a commercially available known compound. Can be introduced.
  • Step 14 This step consists of compound (IV) (where 1 W—PG 2 is a 5-methyl-1 H-pyrazol 3-yl group, 5-cyclopropyl 1 1 H-pyrazole 1 3— Group (1H-pyrazol-3-yl group, etc.) by introducing a protecting group into compound (XVI II-1) or compound (XV II 1-2) (where PG 4 is A protective group such as a toximethyl group, (2- (trimethylenosilyl) ethoxy) methyl group, and R g is a substituent such as a hydrogen atom, a methyl group, or a cyclopropyl group.) .
  • PG 4 is A protective group such as a toximethyl group, (2- (trimethylenosilyl) ethoxy
  • R g is a substituent such as a hydrogen atom, a methyl group, or a cyclopropyl group.
  • the protection reaction used in this step includes, for example, the compound (IV) in a solvent such as tetrahydrofuran, NN-dimethylformamide, 1,4-dioxane, toluene, dichloromethane, black mouth form, or a base such as sodium hydride.
  • a solvent such as tetrahydrofuran, NN-dimethylformamide, 1,4-dioxane, toluene, dichloromethane, black mouth form, or a base such as sodium hydride.
  • the corresponding compound (XV II 1-1) or the compound (XV III -2) can be synthesized by using chloromethyl methyl ether, chloromethyl 2- (trimethylsilyl) ethyl ether, or the like.
  • the base is used in an amount of 120 mol, preferably 15 mol
  • the protective reagent is used in an amount of 110 mol, preferably 13 mol, relative to 1 mol of the compound (IV).
  • the compound (XV III-1) or the compound (XV III-2) thus obtained can be obtained by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography.
  • the product can be subjected to the next step without isolation or purification.
  • Step 15 This step is a compound (XV) (wherein R f and PG 2 are as defined above, XX 3 X 4 , and are as defined above for the symbol of formula (I).) Methoxymethyl group, (2 Limethylsilyl) Ethoxy) A protecting group such as methyl group PG 5 introduces a compound (XIX-1) or compound (XIX-2) (where R f and PG 5 are as defined above, X, X 2 , X 3 , and X 4 are the same as the symbols in formula (I).
  • the protection reaction used in this step is, for example, compound (XV) in a solvent such as tetrahydrofuran, N, N-dimethylformamide, 1,4-dioxane, toluene, dichloromethane, chloroform, sodium hydride
  • a solvent such as tetrahydrofuran, N, N-dimethylformamide, 1,4-dioxane, toluene, dichloromethane, chloroform, sodium hydride
  • the reaction can be carried out using a base such as diisopropylethylamine, chloromethyl methyl ether, chloromethyl 2- (trimethylsilyl) ethyl ether, or the like.
  • the base is used in an amount of 1 to 20 mol, preferably 1 to 5 mol
  • the protective reagent is used in an amount of 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of the compound (XV).
  • the reaction temperature is a force S that can be appropriately selected by those skilled in the art depending on the starting compound used or the reaction solvent, and is usually from 0 ° C. to room temperature.
  • the reaction is usually completed in 10 minutes to 24 hours, but the reaction time can be appropriately increased or decreased.
  • the thus obtained compound (XIX-1) or compound [ ⁇ IX-2] is obtained by known separation and purification means, for example, concentration> concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be subjected to the next step without isolation or purification. Further, the introduction or conversion of X la , 23 or 3! 1 can be carried out at any stage of the above-mentioned synthetic intermediate optionally having a protecting group.
  • a compound represented by the formula (I) (where X iC H, X 2 is CX 2a , X 3 is CH, X 4 is N, ⁇ 1 , m 2 , ni , N 2 , i, j, R, R a R ai ', R bj , R bj ', R c , R d , Re , Y Y Y Y 3 , Z 2 , and IW
  • the compound (V) (wherein R ⁇ PG ⁇ XiXsXgX4 and W are as defined above); and the compound (V).
  • the compound of the formula (V) in the description of the step (18-2) may have a protective group as appropriate at the substitution position where the protective group can be introduced.
  • x la , x 2a, or x 3a from known compounds that are commercially available by using a known method and / or a method exemplified below or a method analogous thereto. Introduction or conversion of groups can be performed.
  • Step 16 is a method of synthesizing compound (XX) from compound (I), and is exemplified below in (Step 16-1) or (Step 16-7).
  • Step 16-1 This step consists of Compound (I).
  • X is CH
  • X 2 is CX 2a
  • X 2 a is a bromine atom
  • X 3 is CH
  • X 4 is n
  • m have m 2
  • n have n 2
  • W are defined by the formula (I) Synonymous with symbol.
  • This step can be carried out by the same method as in Step 10 above, a method according to this, or a combination of these and conventional methods.
  • Step 16-2 This step consists of compound (I) (wherein X 3 ⁇ 4CH, X 2 is CX 2a , X 2 a is an alkoxycarbo group, and X 3 is CH.
  • X 4 is n, m have m 2, n l n 2, i., j ⁇ R, R a have R al ⁇ R bj, R bj ', R c, R d, R have Y have W Zj , Z 2 , and Y are the same as the symbols in formula (I).)
  • compound (XX) (where X is CH, X 2 is CX 2a , X 2a is a carboxy group, X 3 is CH, X 4 is N, m is m 2 , n is n 2 , i, j, R, R a is R ai , R b is R bj , R c , R d , Re , Y, Y 2 , Y 3 , Z 2 , and W are synonymous with the symbols in the formula (I)).
  • This step can be carried out by the same method as in step 11 above, a method according to this, or a combination of these with conventional methods.
  • the thus obtained compound (XX) according to the present invention can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.
  • Step 16-3 This step consists of compound (I) (where X is CH, X 2 is CX 2a , X 2 ,, a is a carboxy group, and X 3 is CH. , X 4 is N, mi , m 2 , n n 2 , i, j, R, R ai , R ai ', R bj- , R b j,, R c , R d , R e , Y Y 3 , Z x , Z 2 , and are the same as the symbols in the formula (I).)
  • compound (XX) (where X 2a is a force rubamoyl group) in and, m have m 2, n have n 2, i, j, R , R a have R ai, ⁇ R b have R b, 'R c, R d, R e, Y have Y 2, Y 3, Zj, Z
  • This step can be performed by the same method as in step '7, a method according to this, or a combination of these with conventional methods.
  • the amine used in this step include dimethylamine, methylamine, pyrrolidine and 2-hydroxyethylamine.
  • the thus obtained compound (XX) according to the present invention can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.
  • Step 16-4 In this step, compound (I) (where X is CH, X 2 is CX 2a , X 2 a is a carboxy group, X 3 is CH, X 4 is N, m is m 2 , n is n 2 , i, j, R, R a is R ai ′, R bj , R bj ′, R c , R d , R is Y Y 2 , Y 3 ,, Z 2 , and W are as defined in the above formula (I).) From the reduction reaction, Compound (XX) (where X 2a is a hydroxymethyl group, m m 2, n have n 2, i, j, R , R a have R al ⁇ R b R bj Bruno, R c, R d, R have Y physician ⁇ 2, ⁇ 3, ⁇ ⁇ z 2, and w , Which is synonymous with the symbol in formula (i).
  • This step can be carried out
  • the compound (XX) according to the present invention thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like. .
  • Step 16-5 In this step, compound (I) (where is CH, X 2 is CX 2a , X 2 a is a hydroxymethyl group, X 3 is CH, X 4 is N, m is m 2 , n is n 2 , i, j, R, R a is R ai ⁇ R bj , R bj ', R c , R d , R is Y Y 2 , Y 3 , Z 1, Z 2 , and W are as defined above in formula (I).)
  • x 2a is a methanesulfonyloxymethyl group, m
  • n have n 2 i, j, R , R a have R ai ', R bj, R bj Roh, R c, R 4, R e, Y have Y 2, Y 3, Z 1 Z 2 ,
  • W are synonymous with the symbols in formula (I).
  • This step can be carried out by the same method as in step '4, a method according to this, or a combination of these with conventional methods.
  • the thus obtained compound (XX) according to the present invention can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.
  • Step 16-6 This step comprises compound (I) (where X iCH, X 2 is CX 2a , X 2 a is a methanesulfonyloxymethyl group, and X 3 is CH. Yes, X 4 is N, m m 2 , n n 2 , i, j, R, R a R ai ', R b R bJ- ', R c , R d R R e , Y Y 2, Y 3, Z, , Z 2,, and W are the same meanings as the symbols of the formula (I).) the force al substitution reaction, the compound (XX) (wherein, x 2 a is RiR h NCH 2 — group (where Ri and R h are the same or different and are a hydrogen atom, an optionally substituted lower alkyl group, or the like, or Ri and R h together, substituted ..
  • m have m 2
  • n have n 2
  • i, j, R , R a have R ai ', R bj - , R bj , R c , R d
  • R and Y are Y 2 , Y 3 , Z, Z 2 , and W have the same meanings as those in the formula (I). Is a method of manufacturing.
  • the substitution reaction used in this step is, for example, compound (I) (where, is CH, X 2 is CX 2a , X 2a is a methanesulfonyloxymethyl group, and 3 is 011.
  • X 4 is N, m m 2 , n n 2 , i, j., R, R a R ai ' ⁇ R b R bj , R c , R d , R e ⁇ Y 2 , Y 3 , Z 2 , and are the same as the symbols in the formula (I).), Chloroform, chloromethylene, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, etc.
  • a base such as potassium carbonate, tritinoreamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] unde force 7-en, dimethylamine, 1, 2, 3 - Toriazoru, 1, 2, by reaction with a nucleophilic agent represented by RiR h NH such as 4 bets Riazor, can be synthesized .
  • the base is used in an amount of 1 to 20 mol, preferably 1 to 5 mol
  • the nucleophile is used in an amount of 1 to 10 mol, preferably 1 to 3 mol, relative to 1 mol of the compound (I).
  • the reaction temperature is a force that can be appropriately selected by those skilled in the art depending on the raw material mixture or reaction solvent used.
  • the reaction temperature is usually from room temperature to the boiling point of the solvent used in the reaction.
  • the reaction is usually completed in 1 to 24 'hours, but the reaction time can be appropriately increased or decreased.
  • the compound (XX) according to the present invention thus obtained can be obtained by a known separation and purification means such as concentration, It can be isolated and purified by vacuum concentration, crystallization, solvent extraction, reprecipitation, chromatography and the like.
  • Step 16-7 This step consists of compound (I) (where X iCH, X 2 is CX 2a , X 2 a is a bromine atom, X 3 is CH, X 4 is n, m have m 2, ni, n 2, i, j, R, R a have R ai ', R b R b j', R c, R d, R e, Y have Y 2, Y 3 ,, Z 2 , and W are as defined in the above formula (I).) Through a coupling reaction, compound (XX) (where X 2a is an RjR k N — group (where ! ⁇ And scale!
  • ⁇ Is the same or different and is a hydrogen atom, a lower alkyl group that may be substituted, a lower acyl group, a lower force rubermoyl group, a lower alkoxycarbonyl group, or the like, or Rj and R k together form an optionally substituted heterocyclic group.
  • R bj Bruno, R c, R d, R e, Y have Y 2, Y 3, ZZ 2
  • W Is a method for producing the symbols is as defined above.) Of the formula (I).
  • This step can be carried out by the same method as in step 2, a method according to this, or a combination of these with conventional methods.
  • the nucleophile used in this step include 1-tyl-2-imidazolidinone, 2-pyrrolidone, 2-oxazolidone, piperazine, and amines represented by Rj R k NH such as monorephorin, Amides, ureas or carbamates may be mentioned. '
  • the thus obtained compound (XX) according to the present invention can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like. it can.
  • Step 17 In this step, compound (XV) (where R f is a lower alkyl group, PG 2 is as defined above, X i is CH, and X 2 is CX 2 a , X 2 a is a benzoxy group, X 3 is CH, X 4 is N, and W is as defined above for the formula (I).
  • f is a method for producing a compound (XX I) (wherein R f , PG 2 and are as defined above) by removing a benzyl group which is a protecting group.
  • the removal of the protecting group in this step can be carried out by a method described in the literature (for example, Protective Group in Organic Synthesis, TW Gr een, 2nd edition, John Wiley & Sons 1991, etc.), a method according to it, or a combination thereof with a conventional method, for example, catalytic hydrogenation using a palladium hydroxide-carbon catalyst can be used.
  • the amount of the catalyst is usually from 01 to 1000 equivalents, preferably from 0.1 to 10 equivalents.
  • the reaction solvent used in this reaction is not particularly limited as long as it does not interfere with the reaction, and examples thereof include methanol, ethanol and the like.
  • the compound (XX I) according to the present invention thus obtained is obtained by a known separation and purification means such as concentration, It can be isolated and purified by vacuum concentration, crystallization, solvent extraction, reprecipitation, chromatography and the like.
  • Step 18 is a method of synthesizing compound (XXII) from compound (V), and is exemplified below in (Step 18-1) and (Step 18-2).
  • Step 18-1) This step consists of compound (V) (wherein R e , W, PG 1 and PG 2 are as defined above, X i is CH, and X 2 is CX 2 . a der Ri, X '2 a non -. de, a mouth key sheet group, X 3 is CH, X 4 is Ru N. der from), the compound (XX ⁇ I) (wherein , R e, W,? & 1 and 0 2 are the same as defined above, X 2 a is a process for producing a an Application Benefits off Ruo b meth Nsu sulfo Niruoki sheet group.). .
  • the reaction used in this step includes, for example, the above compound (V) with black mouth.form, chlorohymethylene, tetrahydric mouth furan, N, N-dimethylformamide, jetinorelite, ethyl acetate and the like.
  • a base such as 4-dimethylaminopyridine, triethylamine, disopropylethylamine, etc.
  • G 2 is are the same as defined above, X 2 a can obtain an Application Benefits off Ruo b meth emissions sulfo Niruo key sheet group.).
  • 1 to 10 moles, preferably 1 to 3 moles of trifluoromethanesulfonic anhydride and 1 to 20 moles, preferably 1 to 6 moles of a base are used with respect to 1 mole of the compound (V).
  • the reaction temperature can be appropriately selected by those skilled in the art depending on the starting compound used, and is usually from 0 ° C. to room temperature. The reaction is usually completed in 10 minutes to 2 hours, but the reaction time can be appropriately increased or decreased.
  • the compound (XX II) thus obtained can be isolated or purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be attached to the next process.
  • Step 18-2 This step is in the compound (V) (wherein, R e, W, PG 1 ⁇ Pi PG 2, the a Ri synonymous der, X is Ri CH der, X 2 is CX 2 a , X 2 a is a trifluoromethanesulfonyl group, X 3 is CH, and X 4 is N.)
  • the compound ( XX II) (wherein, R e, W, PG 1 and PG 2 are are the same as defined above, X 2 a is a method of producing alcohol key deer carbonyl group der Ru.).
  • This step can be carried out by the same method as in step 10, a method according to this, or a combination of these with conventional methods. .
  • the thus obtained compound (XX II) according to the present invention can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like. it can.
  • introduction or conversion of a substituent to W can be carried out at any stage of the above-mentioned synthetic intermediate or its protector.
  • Step 19 This step comprises compound (V) (where 1 W—PG 2 is a thiazole 1-2 grave, PG 1 is as defined above, R e , X 2 , X 3 and X 4 have the same meanings as those in the formula (I).) Force ⁇ By the halogenation reaction, compound (XX III) (where G is a halogen atom such as chlorine, bromine, iodine, etc.) And PG 1 is as defined above, and R e , Xi X2 X3, and X 4 are as defined above for the formula (I).
  • the halogenation reaction used in this step is, for example, a compound (V) (wherein W—PG 2 is a thiazole-2-yl group, PG 1 is as defined above, R e , Xj, X 2 , X 3 , and X 4 are as defined in the above formula (I)), tetrahydrofuran, water, acetic acid, methanol, ethanol, 1,4-dioxane, methylene chloride, It can be carried out by reacting with a halogenating reagent such as N-chlorosuccinimide, N-bromosuccinimide, N-chlorosuccinimide, etc. in a solvent such as chloroform or toluene.
  • a halogenating reagent such as N-chlorosuccinimide, N-bromosuccinimide, N-chlorosuccinimide, etc. in a solvent such as chloroform or toluene.
  • reaction 1 to 3 moles, preferably 1 mole of the halogenating reagent is used per 1 mole of compound (V).
  • reaction temperature is appropriately selected depending on the raw material compound or the reaction solvent used, and is usually 0 ° C. to boiling point.
  • the reaction is usually completed in 1 to 24 hours, but the reaction time can be appropriately increased or decreased.
  • the Ich compound (XX III) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be used in the next step without isolation and purification.
  • Step 20 In this step, compound (XX IV) (where PG 5 is a protecting group such as methoxymethyl group, (2- (trimethylsilyl) ethoxy) methyl group, etc.), and PG 1 is as defined above. And R e ,,, X 2 , X 3 , and X 4 have the same meanings as those in the formula (I).)
  • PG 5 is a protecting group such as a methoxymethyl group, (2- (trimethyZresilinole) ethoxy
  • PG 1 is as defined above, and R e , X 2 , X 3 , and X 4 are And is synonymous with the symbol of the formula (I). .
  • the fluorination reaction used in this step is, for example, a protective group such as a compound (XX IV) (where PG 5 is a methoxymethyl group, (2- (trimethylsilyl) ethoxy) methyl group), and PG 1 is R e ,, X 2 , X 3 , and X 4 are as defined above in formula (I).)
  • a protective group such as a compound (XX IV) (where PG 5 is a methoxymethyl group, (2- (trimethylsilyl) ethoxy) methyl group), and PG 1 is R e ,, X 2 , X 3 , and X 4 are as defined above in formula (I).
  • reaction temperature is appropriately selected depending on the raw material compound or the reaction solvent used, but is usually from 178 degrees to 120 degrees.
  • the reaction is normally completed in 15 minutes to 2 hours. The reaction time can be increased or decreased as appropriate.
  • the compound (XXV) thus obtained can be isolated or purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be attached to the next process.
  • separation and purification means for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc.
  • Aurora with histidine tac 'fused to the amino terminal A cDNA was incorporated into the expression vector and highly expressed in E. coli BL21—C odon Plu s (D E 3) — R I L strain. After recovering and solubilizing Escherichia coli, the histidine-tagged Aurora A protein was adsorbed on a nickel chelate column, eluted from power ram with imidazole, and the active fraction was desalted with desalting power ram to obtain a purified enzyme.
  • the substrate is a synthetic peptide, Kemptide (Leu-Arg-ArGalSer-LeuGly) (SEQ. ID NO.: 1), Sigma (SI [Certificateofanalysis (upst ate)].
  • the reaction was carried out by partially modifying the method of Upstate [K in as Profiler TM Assay Protocols].
  • the reaction volume is 21.
  • reaction buffer 1 ⁇ L
  • composition of the reaction buffer is 5 OmM Tris-HCl buffer (pH 7.4) / 1 5 mM magnesium acetate / 0.2 mM ethylenediamine N, N,, ', N' Tetraacetic acid (EDTA) purified there with 100 ⁇ substrate peptide, 20 ⁇ unlabeled adenosine triphosphate ( ⁇ ) and 0.5 ⁇ Ci [ ⁇ — 33 P] labeled ATP (2500 Ci / mm o 1 e or more) was added and reacted at 30 ° C for 20 minutes. Thereafter, 350 ⁇ / i L of 350 mM phosphate buffer was added to the reaction system to stop the reaction.
  • EDTA Tetraacetic acid
  • the substrate peptide was adsorbed on a 96-well plate of P81 paper filter, washed several times with 13 OmM phosphate buffer, and the radioactivity was measured with a liquid scintillation counter.
  • Label ATP was purchased from Amersham Biosciences. -The test compound was added to the reaction system by first preparing a dimethyl sulfoxide (DMSO) dilution series of the compound and adding 1.1 ⁇ L thereof. A control system was prepared by adding 1.1 ⁇ L of DMSO to the reaction system.
  • DMSO dimethyl sulfoxide
  • Aurora c c D ⁇ ⁇ fused with a histidine tag at the amino terminal was incorporated into an expression vector and expressed in E. coli BL21—CodonPlu s (DE3) —RI strain. After recovering and solubilizing Escherichia coli, the histidine-tagged Caurora B protein was adsorbed onto a nickel chelate column, eluted from the column with imidazole, and the active fraction was desalted with a desalting column to obtain a purified enzyme.
  • the substrate is a synthetic peptide, Kemptide (LeuA rg -A rg -A 1 aS er-Le uG ly) (SEQ. ID D. NO .: 1) [Certificateofanalysis (upstate)] Q reaction was used by partially modifying the method for measuring the activity of oral A.
  • the reaction volume is 21.1 ⁇ L, and the composition of the reaction buffer (R 2 buffer) is 5 OmM Tris-HCl buffer (pH7.4) / 15 mM magnesium acetate / 0.2 mM ethylenediamine N, N, ⁇ ', N' Tetraacetic acid (EDTA) with purified Aurora B, 10 ⁇ ⁇ substrate peptide, 10 ⁇ ⁇ unlabeled adenosine triphosphate ( ⁇ ) and 1 ⁇ C i — 33 P] -labeled ATP (2500 Ci / mm o 1 e or more) was added and reacted at 30 ° C for 20 minutes.
  • R 2 buffer is 5 OmM Tris-HCl buffer (pH7.4) / 15 mM magnesium acetate / 0.2 mM ethylenediamine N, N, ⁇ ', N' Tetraacetic acid (EDTA) with purified Aurora B, 10 ⁇ ⁇ substrate peptide, 10 ⁇ ⁇ unlabeled
  • test compound was added to the reaction system by first preparing a dimethyl sulfoxide (DMSO) dilution series of the compound, and adding 1.1 / iL thereto.
  • a control system was prepared by adding 1.1 ⁇ L of DMSO to the reaction system.
  • DMSO dimethyl sulfoxide
  • Table 1 the compound according to the present invention exhibits an excellent Aurora ⁇ selective inhibitory activity.
  • Fetal calf serum (F C S) was obtained from Morgate, and DMEM medium was obtained from Invitrogene.
  • WST-8 was purchased from Kishida Chemical Co., Ltd. ,
  • Human cervical cancer cells (H e L a S 3) were obtained from the American Type Culture Collection (Am e r iC e T C e l C u e T e C e l e c t i o n; ATCC). c) Effect determination method ''
  • the cells were suspended in DMEM medium supplemented with 10% FCS, and 100 microliters of cell suspension of 7500 cells per well were dispensed into 96-well plastic plates. 3 7 ° C, 5% C_ ⁇ 2 - 1 ⁇ cultured at 95% air.
  • the drug was serially diluted with dimethyl sulfoxide and further diluted with DMEM medium supplemented with 10% FCS, and then dispensed into a plate on which cells had been seeded in an amount of 100 microliters.
  • the cells were further cultured for 3 days at 37 ° C, 5% CO 2 -95% in air. After culture, cell proliferation was measured by the WST-8 method (H. Tomaga, eta 1., An a 1.
  • the WST-8 method means that 20 microliters of WST-8 reagent solution is added to each well, and the incubation is continued at 37 ° C for 45 minutes, and the amount of formazan produced after stirring the plate.
  • This is a method to determine the inhibition rate of a drug by measuring the colorimetry using a colorimetric method. 50% growth inhibitory concentration of the compound (EC 5., ⁇ ) the determined metadata.
  • the compound according to the present invention exhibits an excellent cell growth inhibitory effect against human cancer cells (He La S 3).
  • FC S Fetal calf serum
  • DMEM medium from Invitrogen
  • paclitaxel trade name Taxol
  • WS T-8 Kishida Chemical Co., Ltd. Purchased from.
  • He L a S 3 Human cervical cancer cells (He L a S 3) were obtained from the American Type Culture Collection (Ame r iC ant Cyp te C e l e C e l c i t i o nt; ATCC). c) Effectiveness judgment method
  • the cells were suspended in DMEM medium supplemented with 10% FCS, and the cell suspension at 750 cells / 100 microliters per well was dispensed into two 96-well plastic plates.
  • the cells were cultured at 37 ° C for 5% CO 2 in 95% air.
  • 100 microliters were dispensed into each plate previously seeded with cells.
  • the final concentration of paclitaxel is 1 nM.
  • concentrations of the compound of the present invention when administered alone are 0.03, 0.1, 0.3, 1 and 3 ⁇ .
  • the cell proliferation after the culture was measured by WST-83 ⁇ 4 (H. Tom inaga, eta 1., An a 1. Commu n., 36, 47-50 (199 9)).
  • WST-8 method refers to adding 20 microliters of WST-8 reagent solution to each well, continuing incubation at 37 ° C for 45 minutes, then stirring the plate, and then comparing the amount of produced formazan. This is a method of measuring the inhibition rate of a drug by measuring with a color method.
  • the growth inhibitory effect of paclitaxel and the compound according to the present invention was determined when the value of DMSO alone treatment was 0%.
  • the compound according to the present invention exhibits an excellent cell growth inhibitory effect against human-derived cancer cells (He La S 3) and also exhibits a synergistic effect with paclitaxel.
  • the compound according to the present invention exhibits not only a cell growth inhibitory action based on the excellent aurora ⁇ selective inhibitory activity, but also exhibits a synergistic effect when used in combination with other anticancer agents. It is considered useful. That is, a pharmaceutical composition containing the novel aminoviridine derivative according to the present invention or a pharmaceutically acceptable salt or ester thereof and an Aurora A selective inhibitor, or a compound according to the present invention or a pharmaceutically acceptable salt thereof. Alternatively, pile cancer drugs containing esters are considered effective in the treatment of cancer patients.
  • the pharmaceutical composition, the inhibitor, and the anticancer agent may contain a pharmaceutically acceptable carrier or diluent.
  • pharmaceutically acceptable carrier or diluent refers to excipients (eg, fats, beeswax, semi-solid and liquid polyols, natural or hardened oils, etc.); water (eg, distilled water, in particular, Distilled water for injection), physiological saline, alcohol (eg, ethanol), glycerol, polyol, aqueous dextrose, mannitol, vegetable oil, etc .; additives (eg, bulking agents, disintegrants, binders, lubricants, wetting) Agent, stabilizer, emulsifier, dispersant, preservative, sweetener, colorant, seasoning or fragrance, thickener, Diluent, buffer substance, solvent or solubilizer, drug for achieving storage effect, salt for changing osmotic pressure, coating agent, or antioxidant].
  • excipients eg,
  • suitable tumors for which the therapeutic effect of the compound according to the present invention is expected include human solid cancers.
  • human solid cancers include brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell cancer, non-small cell cancer, breast cancer, stomach cancer, gallbladder's bile duct cancer, and liver.
  • vaginal cancer vaginal cancer, colon cancer, rectal cancer, ovarian cancer, choriocarcinoma cancer, endometrial cancer, cervical cancer, renal pelvis / ureteral cancer, bladder cancer, prostate cancer, penis Cancer, testicular cancer, fetal cancer, Wilms cancer, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, igma, soft tissue sarcoma. '
  • the compound according to the present invention can be used as a pharmaceutically acceptable salt thereof.
  • pharmaceutically acceptable salts include salts with alkali metals such as sodium and potassium, hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate and the like.
  • Inorganic acid salts such as acetate, propionate, lactate, maleate, fumarate, tartrate, phosphonate, kenate, and ascorbate; for example, methanesulfonate And sulfonates such as isethionate, benzenesulfonate and toluenesulfonate; acidic aminoates such as aspartate and glutamate.
  • the salt of the compound of the formula (I) is preferably an inorganic acid salt such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate, and more preferably The hydrochloride salt.
  • the method for producing a pharmaceutically acceptable salt of the compound according to the present invention can be carried out by appropriately combining methods commonly used in the field of synthetic organic chemistry. Specifically, neutralization titration of a free solution of the compound according to the present invention with an alkaline solution or an acidic solution can be mentioned.
  • ester of the compound according to the present invention examples include methyl ester and ethyl ester. These esters can be produced by esterifying a free-force lupoxy group according to a conventional method.
  • Each of the preparations in the combination preparation according to the present invention can be selected from various forms, for example, oral preparations such as tablets, capsules, powders, granules or liquids, or solutions or suspensions, for example. Examples include sterilized liquid parenteral preparations, suppositories, and ointments.
  • -Solid preparations can be produced in the form of tablets, force-pellants, granules or powders as they are, but can also be produced using appropriate carriers (additives).
  • Such carriers include, for example, sugars such as lactose or glucose; starches such as corn, wheat or rice; eg fatty acids such as stearic acid; eg magnesium aluminate metasilicate or phosphoric anhydride.
  • Inorganic salts such as calcium; Synthetic polymers such as polybutylpyrrolidone or polyalkylenedaricol; Fatty acid salts such as calcium stearate or magnesium stearate; Alcohols such as stearyl alcohol or benzyl alcohol; For example, methyl cellulose, carboxy Synthetic cellulose derivatives such as cymethylcellulose, ethylcellulose or hydroxypropylmethylcellulose; other commonly used additives such as gelatin, tanolec, vegetable oil, gum arabic, etc. It is below.
  • solid preparations such as tablets, capsules, granules and powders are generally based on the weight of the whole preparation.
  • the compound represented by the above formula (I) may contain 0.1 to 10% by weight, preferably 5 to 98% by weight of an active ingredient.
  • liquid preparations For liquid preparations, use appropriate additives usually used in liquid preparations such as water, alcohols or plant-derived oils such as soybean oil, peanut oil, sesame oil, etc., suspensions, syrups, injections It is manufactured in the form of a drip infusion (intravenous infusion).
  • appropriate additives usually used in liquid preparations such as water, alcohols or plant-derived oils such as soybean oil, peanut oil, sesame oil, etc., suspensions, syrups, injections It is manufactured in the form of a drip infusion (intravenous infusion).
  • suitable solvents or diluents for parenteral administration in the form of intramuscular injection, intravenous injection or subcutaneous injection include, for example, distilled water for injection, aqueous lidocaine hydrochloride (for intramuscular injection), physiological Saline, dextrose solution, ethanol, polyethylene glycol, propylene glycol, intravenous injection liquid (for example, aqueous solution of citrate and sodium taenoate) or electrolyte solution (for intravenous infusion and intravenous injection), etc. Or these mixed solutions are mentioned.
  • injections may be dissolved in advance, or may be in powder form or dissolved with an appropriate carrier (additive).
  • These injection solutions may contain, for example, 0.1 to 10% by weight of the active ingredient based on the weight of the entire preparation.
  • suspensions for oral administration liquid preparation such as syrup, based on the weight of the total formulation, for example, 0.
  • each of the preparations in the combination preparation according to the present invention can also be easily produced by those skilled in the art according to conventional methods or conventional techniques.
  • a preparation containing another anticancer agent used in combination with the compound represented by the above general formula (I) when it is an oral preparation, for example, an appropriate amount of the anticancer agent and an appropriate amount of lactose are mixed, It can be produced by filling hard gelatin capsules suitable for oral administration.
  • the preparation containing the anticancer agent is an injection, for example, it is produced by mixing an appropriate amount of the anticancer agent with an appropriate amount of 0.9% physiological saline and filling the mixture into an injection vial. be able to.
  • preferred therapeutic units are the administration form of the compound represented by the general formula (I), the kind of the compound represented by the general formula (I) used, the general formula (I) used
  • the dosage form of the compound indicated by) the type, dosage form, dosage form, etc. of other pile cancer drugs used in combination; and the cancer cells to be treated, the patient's condition, etc.
  • the optimal treatment for a given condition can be determined by one skilled in the art based on conventional treatment decision units and / or in view of the present specification.
  • the therapeutic unit of the compound represented by the above general formula (I) specifically includes the type of compound used, the type of the formulated composition, the frequency of application, and the treatment should be performed.
  • the dose per adult per day is for oral administration
  • it can be in the range of 1 to 1 OOO mg.
  • parenteral administration preferably intravenous administration, and more preferably intravenous drip infusion, for example, it can be within the range of 1 to 10 O mg / m 2 (body surface area) per day.
  • intravenous infusion in the case of intravenous infusion, for example, it may be administered continuously for 1 to 48 hours.
  • the frequency of administration varies depending on the administration method and symptoms, but is, for example, 1 to 5 times a day. It can also be used in administration methods such as alternate day administration and intermittent day administration.
  • the treatment withdrawal period in the case of parenteral administration is, for example, 1 to 6 weeks.
  • the therapeutic units of other pile cancer drugs used in combination with the compound represented by the above general formula (I) are not particularly limited, but those skilled in the art may determine as necessary according to known literature. it can. For example, as shown below.
  • the therapeutic unit for 5-Fluorouracil is, for oral administration, for example, .200 to 300 5 mg per day, administered 1 to 3 times daily, and for injections, for example, 5 -15 mg / kg intravenously or intravenously once daily for the first 5 days, and thereafter 5 to 7.5 mg / kg intravenously or intravenously once daily every other day. May be increased or decreased as appropriate).
  • the treatment unit for S—1 is, for example, the first dose (one dose) adjusted to the body surface area as the next standard dose, and one day after breakfast and dinner. Dosing twice a day for 28 days, orally for 0 days, then withdrawn for 14 days. Repeat this as a course.
  • the initial reference amount per body surface area is less than 1.25 m2: 4 Omg / time, 1.25 m2 or more to less than 1.5 m2: 50 mg / time, 1.5 m2 or more: 6 Omg / Times, increase or decrease as appropriate according to the patient's condition. —
  • the therapeutic unit for gemcitabine is, for example, 1 g m2 of gumcitabine given as an intravenous infusion over 30 minutes, once a week for 3 consecutive weeks, and withdrawal from the fourth week. Repeat this as a course.
  • the dose should be reduced according to age, symptoms 5 or side effects.
  • the therapeutic unit for doxorubicin is intravenous injection, for example, once a day at l Omg (0.2 mg / kg) (titer) for 4-6 days after intravenous one-shot administration, Take a 7- to 10-day break, make this a course, and repeat 2-3 courses.
  • the total dose is preferably 500 mg (titer) / m2 (body surface area) or less, and may be appropriately increased or decreased within the range.
  • the therapeutic unit of etoposide is intravenous administration, for example, 60 to 1 day: L 00 mg / m 2 (body surface area), administered for 5 consecutive days, and then withdrawn for 3 weeks. May be) Repeat this as one course.
  • L 00 mg / m 2 body surface area
  • oral administration for example, 175 to 200 mg per day is administered continuously for 5 days and is withdrawn for 3 weeks (the dose may be increased or decreased as appropriate). Repeat this as one course.
  • the therapeutic unit for docetaxel (docetaxenore hydrate) is, for example, once a day, 605 mg / m2 (body surface area) of docetaxel is administered intravenously at intervals of 3 to 4 weeks over 1 hour. It can be increased or decreased as appropriate).
  • the therapeutic unit for paclitaxel is, for example, 210 mg / m2 (body surface area) once a day given by intravenous infusion over 3 hours and then withdrawn for at least 3 weeks. Repeat this as one course.
  • the dose can be increased or decreased as appropriate.
  • the therapeutic unit for cisbratine is intravenous injection, for example, once a day with S O Y OmgZmS (body surface area) and withdrawn for 3 weeks or longer (dosage may be increased or decreased as appropriate). Repeat this as one course.
  • the therapeutic unit for carboplatin is, for example, once a day, 300-400 mg m2 is infused intravenously over 30 minutes and is withdrawn for at least 4 weeks (S dosage may be increased or decreased as appropriate). Repeat this as 5 courses.
  • the therapeutic unit for oxalibratine is 85 mg m2 intravenously once a day, followed by a 2-week rest, and this is repeated as a course.
  • the therapeutic unit for irinotecan (eg, irinotecan hydrochloride) is, for example, 100 mg / m2 once a day, 3 to 4 times at weekly intervals, and withdrawn for at least 2 weeks.
  • the therapeutic unit for topotecan is, for example, once a day, 1.5 mg / m2 intravenously administered for 5 days, and then withdrawn for at least 3 weeks.
  • the therapeutic unit for cyclophosphamide may be intravenously injected, for example, once daily at 10 Omg intravenously, and if the patient can tolerate, the dose may be increased to 20 Omg daily, for a total dose of 3000-800 Omg. You can increase or decrease the force appropriately. Moreover, you may inject or inject into an intramuscular, intrathoracic cavity, or a tumor as needed. On the other hand, in the case of oral administration, for example, it is administered at 100 to 20 Omg per day.
  • the therapeutic unit for gefitinib is, for example, 250 mg orally once a day.
  • the therapeutic unit for cetuximab is, for example, 40 OmgZmS on the first day, followed by 250 mg Zm2 every week.
  • the therapeutic unit for bevacizmap is, for example, .3 mg / kg intravenously administered weekly.
  • the unit of treatment for trastuzumab is, for example, usually for adults: 1. Once a day, 4 mg / kg (body weight) at the first dose of trastuzumab; Inject intravenously.
  • the therapeutic unit for exemestane is, for example, usually 25 mg once a day for adults given orally after meals.
  • the therapeutic unit for reuprorelin eg, reuprorelin acetate
  • reuprorelin acetate is, for example, usually 11.25 mg subcutaneously once every 12 weeks for adults.
  • the unit of treatment for imatinib is, for example, usually 40 ⁇ g orally once a day after meals for adults with chronic myelogenous leukemia.
  • the treatment unit for the combination of 5—FU and leucovorin is, for example, that 5—FU 425xng / m2 and leucovorin 200 mg Zm 2 are infused intravenously from day 1 to day 5 at intervals of 4 weeks. Repeat.
  • the MS spectrum was measured using JMS-SX102A (JEOL (JEOL)) or QUATTRO II (Micromass).
  • the NMR spectrum is Gem ini—200 (20 OMH z; Va rian), Gem ini—300 (30 OMHz; V arian), VXR-300 (30 OMH z; Va rian), Mercury 400 (40 OMH z V arian), or I nova 400 (40 OMHz; V arian) spectrometer, and all ⁇ values are given in p pm.
  • 38 g (20. 6 mmol) was dissolved in 1,4 mono-dioxane 60 ml and brought to room temperature.
  • N-promosuccinimide 3.67 g (20.6 mmo 1) was added.
  • the reaction mixture was heated to reflux for 30 minutes, then returned to room temperature, diluted with 200 ml of ethyl acetate, and washed 3 times with 150 ml of water.
  • Example 1 To a mixture of 509 mg (1.28 mmol) of the compound obtained in (6), 5 ml of black mouth form, and 14 ml of methanol, add hydrochloric acid _ 1, 4 _ dioxane solution (4 M, 5 ml). The mixture was stirred at room temperature for 10 hours. To the reaction mixture was added 1 ml of hydrochloric acid 1-1.4.dioxane solution 1 ml, and the mixture was further stirred at room temperature for 18 hours. 'The reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and washed with 1M aqueous sodium hydroxide solution and saturated brine.
  • Example 3 8.5 mg (0.017 mm o 1) of the compound obtained in (2) was dissolved in 1 ml of methanol, 10 mg of 10% palladium carbon was added, and the mixture was added under a hydrogen atmosphere at normal pressure and room temperature. Stir for hours. After the reaction solution was filtered and the solvent was concentrated under reduced pressure, the resulting residue was purified by preparative thin-layer chromatography to obtain 4. lmg (0.01 Ommo 1) of the title compound as a colorless amonorefus. . The spectrum date of the title compound is shown below.
  • Example 5 2-Bromo _ 6— (((tert-Ptyl (dimethyl) silyl) oxy) methyl) pyridine obtained in (1) and 1 _ ((2- (trimethylsilyl) obtained in Reference Example 2 ) Ethoxy) Methyl)-The title compound was obtained in the same manner as in Examples 5 (2) to (3) using 1-H-pyrazole 1-amine.
  • Examples 17-31 were synthesized in the same manner as in Example 16 above.
  • the obtained organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated.
  • Ethanol was added to the obtained solid and dissolved by heating to 80 ° C. After adding heptane to this solution, the heating was stopped and the solution was slowly cooled to room temperature. After further addition of heptane, the solid was filtered and dried to obtain crystals of the title compound.
  • Example 5 6-(((tert-Butyl (dimethyl) silyl) oxy) methyl) -N-thiazol-2-ylpyridine-2-aminomine 2 g obtained in (2) to 1,4-dioxane 2 Oml After dissolution, 832 mg of N-chlorosuccinimide was added at room temperature. The reaction mixture was heated to reflux for 2 hours, then returned to room temperature, diluted with ethyl acetate, washed with water and saturated brine, and the resulting organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound.
  • Example 5 using 6-(((tert-ptyl (dimethyl) silyl) oxy) methyl) -N-thiazol-2-ylpyridine-1-2-amine and N-promosuccinimide obtained in (2) In the same manner as in Example 61-1 (1), the title compound was obtained.
  • Example 79 Example 79
  • Example 81-(4) Promo obtained in (9) 6 1 ((4- (3-Chloro-2-fluorine benzoyl) Piperazine 1-11) Methyl) 1 N— (3— ( (Methoxymethyl) monothiazole-2 (3H) -ylidene) amino) pyridine-2-amimine was used in the same manner as in Example 1 (2) to give the title compound.
  • Example 82 2 — ((4 (3—Black mouth 2—Fonole benzoinole) Piperazine 1 1 1) Methyl) 6 1 ((3- (Methoxymethyl) — Thiazole-2 (3H) -ylidene) amino)
  • the title compound was obtained in the same manner as in Example 44- (3) using isonicotinic acid methyl ester.
  • Example 83 2— ((4— (3—Chromium 1-Fluorobenzoin) Piperazine —1—yl) Methyl) 6— ((3— (Methoxymethyl) obtained in (1) ) Monothiazole-2 (3H) monoylidene) Amino) Using isonicotinic acid and pyrrolidine, the amidation reaction was carried out in the same manner as in Example 3- (2), followed by the deprotection reaction. A gourd compound was obtained. ⁇

Abstract

L’invention concerne un composé représenté par la formule générale [I] : (I) [où m1 et m2 valent chacun 1, 2, ou 3 ; n1 et n2 valent chacun 0 ou 1 ; i est un nombre entier de 1 à m1 ; j est un nombre entier de 1 à m2 ; R représente un groupe aryle, hétéroaryle ou cycloalkyle éventuellement substitué ; Rai et Rai’ représentent chacun un atome d’hydrogène, etc. ; Rbj et Rbj’ représentent chacun un atome d’hydrogène, etc. ; Rc, Rd, et Re représentent chacun un atome d’hydrogène, etc. ; X1 représente CH, CX1a, ou N ; X2 représente CH, N, etc. ; X3 représente CH, N, etc. ; X4 représente CH ou N ; Y1, Y2 et Y3 sont identiques ou différents et représentent chacun CH ou N ; Z1 et Z2 sont identiques ou différents et représentent chacun CH ou N ; et W est un hétérocycle aromatique à cinq chaînons, par exemple, le pyrazole ou le thiazole] ou un sel ou un ester pharmaceutiquement acceptable du composé ; et un inhibiteur sélectif de l’Aurora-A ou un agent anticancéreux contenant chacun le composé, le sel, ou l'ester. L’invention prévoit également l’utilisation de l'agent anticancéreux en combinaison avec un autre agent anticancéreux.
PCT/JP2006/311179 2005-06-01 2006-05-30 Nouveau derive aminopyridine ayant une activite d’inhibition selective de l’aurora-a WO2006129842A1 (fr)

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Cited By (5)

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Publication number Priority date Publication date Assignee Title
WO2008026769A1 (fr) * 2006-08-31 2008-03-06 Banyu Pharmaceutical Co., Ltd Nouveau dérivé d'aminopyridine présentant une activité d'inhibition sélective de l'aurora a
WO2009130900A1 (fr) * 2008-04-24 2009-10-29 日本曹達株式会社 Dérivé d’oxime, composé intermédiaire et agent de lutte contre des maladies végétales
US8044052B2 (en) 2006-10-18 2011-10-25 Pfizer Inc. Biaryl ether urea compounds
JP2016509047A (ja) * 2013-02-27 2016-03-24 エピセラピューティクス アーペーエス ヒストン脱メチル化酵素の阻害剤
CN111004284A (zh) * 2019-12-26 2020-04-14 重庆大学 一种多取代2-氨基吡啶衍生物的合成方法及用途

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JP2003509342A (ja) * 1999-09-10 2003-03-11 メルク エンド カムパニー インコーポレーテッド チロシンキナーゼ阻害薬
JP2004535437A (ja) * 2001-06-22 2004-11-25 メルク　エンド　カムパニー　インコーポレーテッド チロシンキナーゼ阻害剤
WO2006046735A1 (fr) * 2004-10-29 2006-05-04 Banyu Pharmaceutical Co., Ltd. Nouveaux derives d'aminopyridine presentant une action d'inhibition selective de la proteine kinase aurora a

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JP2003509342A (ja) * 1999-09-10 2003-03-11 メルク エンド カムパニー インコーポレーテッド チロシンキナーゼ阻害薬
JP2004535437A (ja) * 2001-06-22 2004-11-25 メルク　エンド　カムパニー　インコーポレーテッド チロシンキナーゼ阻害剤
WO2006046735A1 (fr) * 2004-10-29 2006-05-04 Banyu Pharmaceutical Co., Ltd. Nouveaux derives d'aminopyridine presentant une action d'inhibition selective de la proteine kinase aurora a

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008026769A1 (fr) * 2006-08-31 2008-03-06 Banyu Pharmaceutical Co., Ltd Nouveau dérivé d'aminopyridine présentant une activité d'inhibition sélective de l'aurora a
WO2008026768A1 (fr) * 2006-08-31 2008-03-06 Banyu Pharmaceutical Co., Ltd Nouveaux dérivés d'aminopyridine présentant une action d'inhibition sélective de l'aurora a
JP2010047602A (ja) * 2006-08-31 2010-03-04 Banyu Pharmaceut Co Ltd オーロラａ選択的阻害作用を有する新規アミノピリジン誘導体
US8044052B2 (en) 2006-10-18 2011-10-25 Pfizer Inc. Biaryl ether urea compounds
WO2009130900A1 (fr) * 2008-04-24 2009-10-29 日本曹達株式会社 Dérivé d’oxime, composé intermédiaire et agent de lutte contre des maladies végétales
JPWO2009130900A1 (ja) * 2008-04-24 2011-08-11 日本曹達株式会社 オキシム誘導体、中間体化合物および植物病害防除剤
JP2013144699A (ja) * 2008-04-24 2013-07-25 Nippon Soda Co Ltd 化合物
JP2016509047A (ja) * 2013-02-27 2016-03-24 エピセラピューティクス アーペーエス ヒストン脱メチル化酵素の阻害剤
CN111004284A (zh) * 2019-12-26 2020-04-14 重庆大学 一种多取代2-氨基吡啶衍生物的合成方法及用途
CN111004284B (zh) * 2019-12-26 2022-08-05 重庆大学 一种多取代2-氨基吡啶衍生物的合成方法及用途

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