WO2019103050A1 - Médicament liant des protéines - Google Patents

Médicament liant des protéines Download PDF

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Publication number
WO2019103050A1
WO2019103050A1 PCT/JP2018/043032 JP2018043032W WO2019103050A1 WO 2019103050 A1 WO2019103050 A1 WO 2019103050A1 JP 2018043032 W JP2018043032 W JP 2018043032W WO 2019103050 A1 WO2019103050 A1 WO 2019103050A1
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group
compound
acceptable salt
pharmaceutically acceptable
mmol
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PCT/JP2018/043032
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Japanese (ja)
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幸倫 庄子
一弥 小竹
巧 森下
達哉 北尾
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京都薬品工業株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical

Definitions

  • the present invention binds to a protein such as albumin in the body after administration, effectively accumulates in a target organ such as a tumor tissue, and specifically low pH environment or specificity in pericellular or intracellular lysosomes such as tumor cells.
  • the present invention relates to a novel compound or a pharmaceutically acceptable salt thereof which is hydrolyzed by a selective enzyme to release an active drug.
  • the present invention also relates to a pharmaceutical composition comprising the above novel compound or a pharmaceutically acceptable salt thereof.
  • the present invention relates to an anticancer agent comprising the above novel compound or a pharmaceutically acceptable salt thereof, and an agent for preventing and / or treating cancer metastasis and / or cancer recurrence.
  • the present invention relates to a method for binding the above novel compound to a protein or polymer such as albumin, transferrin or globulin, and purifying it to form a protein or polymer-bound preparation.
  • the anticancer drug is derivatized, and after drug administration, it selectively and efficiently migrates and accumulates in the tumor tissue, and selectively and efficiently releases the active drug in the vicinity of the tumor cell and in the target site in the cell.
  • the anticancer drug is derivatized, and after drug administration, it selectively and efficiently migrates and accumulates in the tumor tissue, and selectively and efficiently releases the active drug in the vicinity of the tumor cell and in the target site in the cell.
  • EPR effect Phenomenon
  • liposome-encapsulated preparation (patent documents 1, 2, 3), polymer conjugate preparation (patent document 4), derivative which forms a conjugate with protein in vivo (patent documents 7, 8, 9, 10, 11, non-patent document 3), antibody drug complex (ADC) (patent document 5), etc.
  • ADC antibody drug complex
  • polymer conjugated preparation and derivatives for producing in vivo protein and conjugate have not been commercialized yet.
  • Polymer conjugates, derivatives that generate conjugates with proteins in vivo, and antibody drug complexes are all covalently bonded to macromolecules or proteins through specific reactive groups, and are hydrolyzed by the environment or enzymes of the tumor tissue.
  • amide bond a hydrazone bond, an ester bond or the like is used as a bond to a polymer or a protein.
  • Hydrolysis is a low pH environment and enzymes highly expressed in tumor tissue, such as ⁇ -glutathione transpeptidase (GGT), matrix metalloproteinase (MMP), prostate specific antigen (PSA) overexpressed in prostate cancer , Trypsin and lysosomal enzyme cathepsin etc.
  • GTT ⁇ -glutathione transpeptidase
  • MMP matrix metalloproteinase
  • PSA prostate specific antigen
  • a derivative that produces a conjugate with an in vivo protein is a derivative in which a maleimide side chain is bound to a maleimide side chain to various anticancer agents, for example, rapidly binds to the SH group of cysteine-34 of albumin after intravenous administration.
  • a albumin conjugate it migrates and accumulates in tumor tissue by the EPR effect. It is well known that in the tumor tissue, albumin is accumulated by the EPR effect and stays for a long time (Non-patent Document 3).
  • albumin also penetrates tumor blood vessels by the carrier protein gp60 receptor, is taken up into tumor cells by SPARC (Secreted Protein, Acidic and Rich in Cysteine), and the low pH of lysosome hydrolyses hydrazone bond to release an anticancer drug. It is known to do (nonpatent literature 4). So far, derivatives such as aldoxorubicin and DK-049 have been studied, but none have been successfully developed. In particular, in the case where the anticancer agent to which the maleimide side chain is attached is a sparingly soluble compound, it is necessary to introduce an appropriate soluble group for injection, but there has been no example of successful development.
  • the object of the present invention is to rapidly bind to blood albumin after in vivo administration, to circulate continuously throughout the body, to be efficiently transferred and accumulated in tumor tissue, and then to stay for a long time, release the active drug, and to increase It is to provide a compound that exhibits tumor tissue concentration, exhibits excellent antitumor activity, and has reduced side effects. Furthermore, it is to provide the compound having excellent water solubility which can be injected. Another object of the present invention is to provide a compound for producing a protein conjugate preparation bound to albumin or an antibody (globulin) or a polymer conjugate preparation having a polymer bound thereto.
  • Patent Document 10 a compound in which a group capable of binding to a protein (maleimidyl group) is introduced by hydrazone bond has been reported.
  • the present inventors focused on the problems of these small molecule drugs and the specific environment of the tumor tissue and as a result of earnestly research, they found a novel derivatization method and came to complete the present invention. . That is, a malonic acid type enamine bond that dissociates at low pH is introduced into the amino group of a low molecular weight drug having a primary amino group, a secondary amino group, or a cyclic amino group (that is, an active drug).
  • a compound in which a group capable of binding to a protein (maleimidyl group) is linked (hereinafter sometimes referred to as “the compound of the present invention”) or a pharmaceutically acceptable salt thereof is a plasma protein, for example, after systemic administration.
  • Drugs by covalently binding to plasma albumin staying in blood for a long time, efficiently accumulating in tumor tissue, reaching tumor tissue, and efficiently releasing the active drug under its low pH environment As an excellent anti-cancer effect.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof can reduce the concentration of the active drug in normal tissues as compared to tumor tissues and can reduce side effects.
  • the compound of the present invention can be conveniently obtained by reacting a derivative obtained from malonic acid which can be obtained easily and inexpensively with an active drug having the amino group.
  • the carboxyl group in the malonic acid structure can impart water solubility to a poorly soluble active drug, and a carboxyl group, amino group or hydroxy group can be easily introduced into the side chain, more water solubility can be achieved. It can be enhanced.
  • the water solubility can also be adjusted by introducing a lipid soluble side chain or a water soluble side chain into the carboxyl group or linker moiety of the malonic acid structure.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof has excellent anti-cancer activity on cancer cells after administration and can be an excellent anti-cancer agent with less side effects.
  • the compounds of the present invention can also be used to produce albumin conjugated formulations, antibody conjugated formulations or macromolecular conjugated formulations.
  • R 1 represents a hydrogen atom or an alkyl group which may be substituted
  • A represents a spacer
  • B represents a group capable of binding to a protein
  • E represents an oxygen atom or a single bond
  • the group represented by is a residue of an active drug having an amino group, and in the formula, N represents a nitrogen atom of the amino group, and the amino group is a primary amino group or a secondary amino group. Represents a group or a cyclic amino group. Or a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as “compound (I)”) or a pharmaceutically acceptable salt thereof.
  • R 1 is a hydrogen atom or an alkyl group which may be substituted with a carboxy group, a sulfo group, a phospho group, a hydroxy group or an amino group
  • B is a maleimidyl group, a haloacetoamino group, a haloacetoxy group, a pyridyldithio group (-S-S-Py), an N-succinimidyloxycarbonyl group or an isothiocyanato group which may be substituted, respectively;
  • E is an oxygen atom or a single bond, and
  • N is as defined in the above [1]
  • N is a residue of an active drug having an amino group
  • the compound of the above-mentioned [2] or an pharmaceutically acceptable salt thereof, wherein the active drug having an amino group is an anticancer agent.
  • the compound of the above-mentioned [2] or a pharmaceutically acceptable salt thereof, wherein the active drug having an amino group is a kinase inhibitor.
  • the compound of the above-mentioned [2] or a pharmaceutically acceptable salt thereof, wherein the active drug having an amino group is an antimetabolite.
  • A is a C 1-10 alkylene group which may have one or more -O- and may be substituted by a carboxy group, a hydroxy group or an amino group, and Or a pharmaceutically acceptable salt thereof according to any one of the above [1] to [16], which is a maleimidyl group optionally substituted with a halogen atom.
  • R 1 is a hydrogen atom or a C 1-6 alkyl group optionally substituted with a carboxy group Salt.
  • the active drug having an amino group is gemcitabine, 5'-deoxy-5-fluorocytidine, amrubicin, parvocyclib, ibrutinib, plararisib, AZD-5363, tushidinostat, crizotinib or imatinib as described above [1] to [18]. Or a pharmaceutically acceptable salt thereof.
  • the active drug having a [19 '] amino group is gemcitabine, 5'-deoxy-5-fluorocytidine, amrubicin, parvocyclib, tusidinostat, crizotinib or imatinib according to any one of the above [1] to [18] A compound or a pharmaceutically acceptable salt thereof.
  • R 1 is a hydrogen atom
  • A is a C 1-6 alkylene group which may have one or more -O- and may be substituted by a carboxy group
  • B is a maleimidyl group
  • E is an oxygen atom
  • R 1 is a hydrogen atom
  • A is a C 1-6 alkylene group which may have one or more -O- and may be substituted by a carboxy group
  • B is a maleimidyl group
  • E is an oxygen atom
  • R 1 is a hydrogen atom or a C 1-6 alkyl group
  • A is a C 1-6 alkylene group which may have one or more -O- and may be substituted by a carboxy group
  • B is a maleimidyl group
  • E is an oxygen atom
  • the compound according to the above [1] or a pharmaceutically acceptable salt thereof which is a residue of an active drug represented by [23]
  • a protein or a polymer wherein a compound or a pharmaceutically acceptable salt thereof described in any of the above-mentioned [1] to [22] is bound to a protein or a polymer having albumin, globulin, transferrin, or sulfanyl group Molecular conjugate.
  • a pharmaceutical composition comprising the compound of any of the above-mentioned [1] to [23] or a pharmaceutically acceptable salt thereof, or a conjugate as an active ingredient.
  • An anticancer agent which comprises the compound according to any one of the above [1] to [23] or a pharmaceutically acceptable salt thereof, or a conjugate as an active ingredient.
  • An agent for the prophylaxis or treatment of cancer, cancer metastasis and / or cancer recurrence which comprises the compound according to any one of the above [1] to [23] or a pharmaceutically acceptable salt thereof, or a conjugate as an active ingredient about.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof is a compound that binds to plasma proteins after being administered in vivo, and is efficiently converted to an active drug after reaching tumor tissue. Or useful as a preventive / therapeutic agent for cancer recurrence.
  • the compounds of the present invention are rapidly coupled by coexistence with human plasma albumin at physiological pH (about 7.4) and temperature (35-40 ° C. (preferably 37 ° C.)), and in tumor tissue
  • the active drug can be released over time under assumed weak acid conditions (pH 3 or more and less than 7).
  • the conjugate is persistently retained in the blood, and the blood concentration of the active drug is low, thereby reducing tumor tissue accumulation of the conjugate and reducing normal tissue toxicity of the active substance. I can expect it.
  • they can be bound to globulin and the active drug can be released over time under weak acid conditions, they can be used for the production of antibody-bound preparations.
  • a medicament containing the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is a highly safe therapeutic agent for cancer, metastasis of cancer and / or agent for the prophylaxis or treatment of cancer recurrence since its side effects are small. obtain.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof is not limited to them, and includes, but is not limited to, breast cancer, head and neck cancer, lung cancer, ovarian cancer, pancreatic cancer, colorectal cancer, prostate cancer, esophageal cancer, nasopharyngeal cancer, pituitary Cancer, gallbladder cancer, thyroid cancer, salivary adenocarcinoma, bladder cancer, renal cell cancer, melanoma, hepatocellular carcinoma, cervical cancer, endometrial cancer, Kaposi's sarcoma, Ewing sarcoma, medulloblastoma, sarcoma, brain tumor, gastric cancer It is useful as a preventive / therapeutic agent for multiple myeloma, leukemia or lymphoma.
  • halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • alkyl means a linear or branched monovalent hydrocarbon group having one or more carbon atoms, particularly when there is no limitation on the carbon number range, It is an alkyl group having 1 to 20 carbon atoms, among which an alkyl group having 1 to 12 carbon atoms is more preferable, and an alkyl group having 1 to 6 carbon atoms (C 1-6 alkyl group) is particularly preferable.
  • C 1-6 alkyl group for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, 4-methylpentyl, hexyl and the like Can be mentioned.
  • C 1-6 alkoxy is a group in which the above “C 1-6 alkyl” group is bonded to an oxygen atom, that is, a linear or branched alkoxy group having 1 to 6 carbon atoms
  • C 1-6 alkoxy for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, 1-ethylpropyloxy And hexyloxy.
  • C 1-6 alkylsulfonyl is a monovalent group in which the “C 1-6 alkyl” group is bonded to a sulfonyl group, that is, a linear or branched alkyl group having 1 to 6 carbon atoms It means a sulfonyl group.
  • C 1-6 alkylsulfonyl for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl, neo And pentylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl and the like.
  • C 1-6 alkylsulfonyloxy means a monovalent group in which the above “C 1-6 alkylsulfonyl” group is bonded to an oxygen atom.
  • C 1-6 alkylsulfonyloxy for example, methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, isopropylsulfonyloxy, butylsulfonyloxy, isobutylsulfonyloxy, sec-butylsulfonyloxy, tert-butylsulfonyloxy And pentylsulfonyloxy, isopentylsulfonyloxy, neopentylsulfonyloxy, 1-ethylpropylsulfonyloxy, hexylsulfonyloxy and the like.
  • C 3-8 cycloalkyl means a monovalent group derived from a saturated hydrocarbon ring having 3 to 8 carbon atoms.
  • the C 3-8 cycloalkyl may also be bridged.
  • C 3-8 cycloalkyl for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like can be mentioned.
  • C 3-8 cycloalkyl C 1-6 alkyl means a monovalent group in which the above “C 3-8 cycloalkyl” group is substituted on the above “C 1-6 alkyl”.
  • C 3-8 cycloalkyl C 1-6 alkyl for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl and the like can be mentioned.
  • C 1-6 alkyl-carbonyl means a monovalent group in which the above “C 1-6 alkyl” group is bonded to carbonyl.
  • Examples of the “C 1-6 alkyl-carbonyl” include acetyl, propionyl, butyryl, isobutyryl, pentanoyl, isopentanoyl, 1-methylbutyryl, pivaloyl, hexanoyl, isohexanoyl, 3, 3-dimethylbutyryl, 1 -Ethyl butyryl, 4-methylhexanoyl, heptanoyl and the like.
  • C 1-6 alkyl-carbonyloxy means a monovalent group in which the above “C 1-6 alkyl-carbonyl” group is bonded to an oxygen atom.
  • C 1-6 alkyl-carbonyloxy for example, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, isopentananoyloxy, 1-methylbutyryloxy, pivaloyloxy, hexanoyloxy , Isohexanoyloxy, 3,3-dimethyl butyryloxy, 1-ethyl butyryloxy, 4-methylhexanoyloxy, heptanoyloxy and the like.
  • C 1-6 alkoxy-carbonyl is a monovalent group in which the above “C 1-6 alkoxy” group is bonded to carbonyl, that is, linear or branched alkoxy having 1 to 6 carbon atoms.
  • C 1-6 alkoxy-carbonyl for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, iso And pentyloxycarbonyl, neopentyloxycarbonyl, 1-ethylpropyloxycarbonyl, hexyloxyoxycarbonyl and the like.
  • C 1-6 alkoxy-carbonyloxy means a monovalent group in which the above “C 1-6 alkoxy-carbonyl” group is bonded to an oxygen atom.
  • C 1-6 alkoxy-carbonyloxy for example, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, isopropoxycarbonyloxy, butoxycarbonyloxy, isobutoxycarbonyloxy, sec-butoxycarbonyloxy, tert- Examples include butoxycarbonyloxy, pentyloxycarbonyloxy, isopentyloxycarbonyloxy, neopentyloxycarbonyloxy, 1-ethylpropyloxycarbonyloxy, hexyloxyoxycarbonyloxy and the like.
  • C 3-8 cycloalkyl-carbonyl means a monovalent group in which the above “C 3-8 cycloalkyl” group is bonded to carbonyl.
  • Examples of the “C 3-8 cycloalkyl-carbonyl” include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl and the like.
  • C 3-8 cycloalkyl C 1-6 alkyl-carbonyl means a monovalent group in which the above “C 3-8 cycloalkyl C 1-6 alkyl” group is bonded to carbonyl.
  • Examples of the “C 3-8 cycloalkyl C 1-6 alkyl-carbonyl” include cyclopropylmethylcarbonyl, cyclobutylmethylcarbonyl, cyclopentylmethylcarbonyl, cyclohexylmethylcarbonyl, cycloheptylmethylcarbonyl, cyclooctylmethylcarbonyl and the like. It can be mentioned.
  • C 3-8 cycloalkyl-carbonyloxy means a monovalent group in which the above “C 3-8 cycloalkyl-carbonyl” group is bonded to an oxygen atom.
  • Examples of the “C 3-8 cycloalkyl-carbonyloxy” include cyclopropylcarbonyloxy, cyclobutylcarbonyloxy, cyclopentylcarbonyloxy, cyclohexylcarbonyloxy, cycloheptylcarbonyloxy and the like.
  • C 3-8 cycloalkyloxy means a monovalent group in which the above “C 3-8 cycloalkyl” group is bonded to an oxygen atom.
  • Examples of the “C 3-8 cycloalkyloxy” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and the like.
  • C 3-8 cycloalkyloxy-carbonyl means a monovalent group having the above “C 3-8 cycloalkyloxy” group bonded to carbonyl.
  • Examples of the “C 3-8 cycloalkyloxy-carbonyl” include cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, cycloheptyloxycarbonyl and the like.
  • C 3-8 cycloalkyloxy-carbonyloxy means a monovalent group in which the above “C 3-8 cycloalkyloxy-carbonyl” group is bonded to an oxygen atom.
  • Examples of the “C 3-8 cycloalkyloxy-carbonyloxy” include cyclopropyloxycarbonyloxy, cyclobutyloxycarbonyloxy, cyclopentyloxycarbonyloxy, cyclohexyloxycarbonyloxy, cycloheptyloxycarbonyloxy and the like.
  • C 2-6 alkenyl is a linear or branched monovalent hydrocarbon group having one or more carbon-carbon double bonds and having 2 to 6 carbon atoms. means.
  • the “C 2-6 alkenyl” for example, vinyl, 1-propenyl (allyl), 2-propenyl, isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2 -Buten-2-yl, 3-methyl-2-butenyl, 3-methyl-2-buten-2-yl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-penten-2-yl 2-penten-3-yl, 4-methyl-1-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, butadienyl (eg, buta-1,3-dien-1-yl), pentadienyl (eg, Penta-1,3-dien
  • C 2-6 alkynyl means a linear or branched monovalent hydrocarbon group having one or more carbon-carbon triple bonds and having 2 to 6 carbon atoms.
  • C 2-6 alkynyl for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 3-methyl-2-butynyl, 1-pentynyl, 2-pentynyl And 3-pentynyl, 4-pentynyl, 4-methyl-1-pentynyl and the like.
  • aryl means a monovalent aromatic hydrocarbon group having 6 to 14 carbon atoms.
  • examples of the “aryl” include C 6-14 aryl groups such as phenyl, naphthyl (eg, 1-naphthyl, 2-naphthyl), acenaphthylenyl, azulenyl, anthryl, phenanthryl and the like.
  • a C 6-10 aryl group is preferable, and phenyl is particularly preferable.
  • aryl C 1-6 alkyl means a monovalent group in which the above “C 1-6 alkyl” is substituted by the above “aryl” group.
  • aryl C 1-6 alkyl for example, benzyl, naphthylmethyl, 2-phenylethyl, 1-phenylethyl, 1-phenylpropyl and the like can be mentioned.
  • aryl C 1-6 alkoxy means a monovalent group in which the above “aryl C 1-6 alkyl” group is bonded to an oxygen atom.
  • examples of the “aryl C 1-6 alkoxy” include benzyloxy, naphthylmethyloxy, 2-phenylethyloxy, 1-phenylethyloxy, 1-phenylpropyloxy and the like.
  • C 6-14 aryl-carbonyl means a monovalent group in which the above “C 6-14 aryl” group is bonded to carbonyl.
  • Examples of the “C 6-14 aryl-carbonyl” include benzoyl, naphthylcarbonyl, acenaphthylenylcarbonyl, azulenylcarbonyl, anthrylcarbonyl, phenanthrylcarbonyl and the like.
  • C 6-14 aryl-carbonyloxy means a monovalent group in which the above “C 6-14 aryl-carbonyl” group is bonded to an oxygen atom.
  • Preferred examples of the "C 6-14 aryl-carbonyloxy” include benzoyloxy and the like.
  • C 6-14 aryloxy-carbonyl means a monovalent group having the above “C 6-14 aryloxy” group bonded to carbonyl.
  • Examples of the “C 6-14 aryloxy-carbonyl” include phenoxycarbonyl, naphthyloxycarbonyl, acenaphthylenyloxycarbonyl, azulenyloxycarbonyl, anthryloxycarbonyl, phenanthryloxy carbonyl and the like.
  • C 6-14 aryloxy-carbonyloxy means a monovalent group in which the above “C 6-14 aryloxy-carbonyl” group is bonded to an oxygen atom.
  • C 6-14 aryloxy-carbonyloxy for example, phenoxycarbonyloxy, naphthyloxycarbonyloxy, acenaphthylenyloxycarbonyloxy, azulenyloxycarbonyloxy, anthryloxy carbonyloxy, phenanthryloxy Carbonyloxy etc. are mentioned.
  • C 6-14 arylsulfonyl means a monovalent group in which the above “C 6-14 aryl” group is bonded to a sulfonyl group.
  • C 6-14 arylsulfonyl for example, phenylsulfonyl, naphthylsulfonyl, acenaphthylenylsulfonyl, azulenylsulfonyl, anthrylsulfonyl, phenanthrylsulfonyl and the like can be mentioned.
  • C 6-14 arylsulfonyloxy means a monovalent group in which the above “C 6-14 arylsulfonyl” group is bonded to an oxygen atom.
  • Examples of the “C 6-14 arylsulfonyloxy” include phenylsulfonyloxy, naphthylsulfonyloxy, acenaphthylenylsulfonyloxy, azulenylsulfonyloxy, anthrylsulfonyloxy, phenanthrylsulfonyloxy and the like.
  • aryl C 1-6 alkoxy-carbonyl means a monovalent group in which the above “aryl C 1-6 alkoxy” group is bonded to carbonyl.
  • Examples of the “aryl C 1-6 alkoxy-carbonyl” include benzyloxycarbonyl, naphthylmethyloxycarbonyl, 2-phenylethyloxycarbonyl, 1-phenylethyloxycarbonyl, 1-phenylpropyloxycarbonyl and the like.
  • aryl C 1-6 alkoxy-carbonyloxy means a monovalent group in which the above “aryl C 1-6 alkoxy-carbonyl” group is bonded to an oxygen atom.
  • Examples of the “aryl C 1-6 alkoxy-carbonyloxy” include benzyloxycarbonyloxy, naphthylmethyloxycarbonyloxy, 2-phenylethyloxycarbonyloxy, 1-phenylethyloxycarbonyloxy, 1-phenylpropyloxycarbonyl Oxy and the like.
  • aryl C 1-6 alkyl-carbonyl means a monovalent group in which the above “aryl C 1-6 alkyl” group is bonded to carbonyl.
  • Examples of the “aryl C 1-6 alkyl-carbonyl” include benzylcarbonyl, naphthylmethylcarbonyl, 2-phenylethylcarbonyl, 1-phenylethylcarbonyl, 1-phenylpropylcarbonyl and the like.
  • aryl C 1-6 alkyl-carbonyloxy means a monovalent group in which the above “aryl C 1-6 alkyl-carbonyl” group is bonded to an oxygen atom.
  • Examples of the “aryl C 1-6 alkyl-carbonyloxy” include benzylcarbonyloxy, naphthylmethylcarbonyloxy, 2-phenylethylcarbonyloxy, 1-phenylethylcarbonyloxy, 1-phenylpropylcarbonyloxy and the like. .
  • alkylene means a linear or branched divalent saturated hydrocarbon group having 1 to 20 carbon atoms.
  • alkylene examples include methylene, ethylene, propylene, trimethylene, 1,3-butylene, 1,4-butylene, pentylene, hexylene, heptylene, 2,2-dimethylethylene, 2,2-dimethylpropylene and the like.
  • cycloalkylene refers to a divalent alicyclic hydrocarbon group having 3 to 12 carbon atoms. Preferably, it means a cyclic alkylene group having 3 to 8 carbon atoms (C 3-8 cycloalkylene group).
  • cyclopropane-1,1-diyl cyclopropane-1,2-diyl, cyclobutane-1,2-diyl, cyclopentane-1,3-diyl, cyclohexane-1,4-diyl, cyclo And octane-1,5-diyl and the like
  • cyclopropane-1,2-diyl having 3 to 6 carbon atoms, cyclobutane-1,2-diyl, cyclopentane-1,3-diyl, and the like.
  • It is a cyclic alkylene group (C 3-6 cycloalkylene group) such as cyclohexane-1,4-diyl.
  • alkenylene means a linear or branched divalent hydrocarbon group having one or more carbon-carbon double bonds and having 2 to 20 carbon atoms.
  • alkynylene means a linear or branched divalent hydrocarbon group having one or more carbon-carbon triple bonds and having 2 to 20 carbon atoms.
  • alkynylene examples include ethynylene (—C-C—), propynylene (eg, —CH 2 —C ⁇ C—, —C-C—CH 2 —), butynylene (eg, —CH 2 —C ⁇ C-CH 2 -, - CH 2 -CH 2 -C ⁇ C -, - C ⁇ C-CH 2 -CH 2 -), pentynylene (eg, -C ⁇ C-CH 2 -CH 2 -CH 2 - , -CH 2 -CH 2 -CH 2 -C ⁇ C -, - C (CH 3) 2 -C ⁇ C -, - C ⁇ C-C (CH 3) 2 - - - , etc.), hexynylene (e.g., hexyn
  • arylene means a divalent aromatic hydrocarbon group derived from the above “aryl” group.
  • examples of the “arylene” include, for example, benzene-1,4-diyl (hereinafter also referred to as 1,4-phenylene), benzene-1,3-diyl, benzene-1,2-diyl (hereinafter 1,2- Also known as phenylene), naphthalene-1,8-diyl (hereinafter, also referred to as 1,8-naphthylene), naphthalene-1,5-diyl (hereinafter, also referred to as 1,5-naphthylene), anthracene-1,4-diyl And C 6-14 arylene, preferably C 6-10 arylene, and more preferably 1,4-phenylene.
  • the "heterocyclic group” is a 3- to 14-membered (monocyclic, bicyclic or tricyclic ring system) containing at least one hetero atom selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom. It means a heterocyclic group and includes aromatic heterocyclic group and non-aromatic heterocyclic group.
  • the "aromatic heterocyclic group” is a monovalent 5- to 14-membered monocyclic aromatic group containing at least one hetero atom selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom. It means a heterocyclic group and a fused aromatic heterocyclic group.
  • the fused aromatic heterocyclic group in the present invention is a 2 or 3 ring system, and may have hetero atoms in a plurality of rings.
  • the monocyclic aromatic heterocyclic group includes a 5- or 6-membered ring group, and the fused aromatic heterocyclic group includes a group in which each ring constituting the group is a 5- or 6-membered ring.
  • aromatic heterocyclic group examples include 5- or 6-membered members such as furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and the like.
  • Monocyclic aromatic heterocyclic group indolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzoimidazolyl (eg, 5-benzoimidazolyl), benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, benzoxazinyl, benzothiazinyl, Furo [2,3-b] pyridyl, thieno [2,3-b] pyridyl, naphthyridinyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl, quinoxalinyl, quinazolyl Le, pyridopyrazinyl, carbazolyl, include 8-14 membered fused aromatic heterocyclic groups such as a dibenzothiophenyl.
  • non-aromatic heterocyclic group is a monovalent 3- to 14-membered monocyclic non-cyclic ring containing at least one hetero atom selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom. It means an aromatic heterocyclic group and a fused non-aromatic heterocyclic group.
  • the fused non-aromatic heterocyclic group in the present invention is a two- or three-ring system, and may have a hetero atom in both rings.
  • the monocyclic non-aromatic heterocyclic group includes a 3- to 9-membered cyclic group (preferably a 4- to 7-membered cyclic group), and the fused non-aromatic heterocyclic group includes each ring constituting the group. And groups in which 5 or 6 membered ring.
  • non-aromatic heterocyclic group examples include oxetanyl (eg, 3-oxetanyl), tetrahydrofuryl (eg, tetrahydrofuran-3-yl), dioxolyl (eg, 1,3-dioxol-4-yl), Dioxolanyl (eg, 1,3-dioxolan-4-yl), oxazolidinyl, imidazolinyl (eg, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl), aziridinyl (eg, 1-aziridinyl, 2-aziridinyl), azetidinyl (eg, 1-azetidinyl, 2-azetidinyl, 3-azetidinyl), pyrrolidinyl (eg, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl),
  • the "heterocycle C 1-6 alkyl” means a monovalent group in which the "heterocyclic group” is substituted on the “C 1-6 alkyl”.
  • the "heterocyclic C 1-6 alkyl” for example, azetidin-1-ylmethyl, Morufuhorin-4-ylmethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, tetrahydropyran-4-ylmethyl and the like Can be mentioned.
  • heterocycle oxy means a monovalent group in which the above “heterocycle group” is bonded to an oxygen atom.
  • Preferred examples of the “heterocyclyloxy” include tetrahydropyran-2-yloxy and the like.
  • heterocycle carbonyl means a monovalent group in which the above “heterocycle group” is bonded to carbonyl.
  • Preferred examples of the “heterocycle carbonyl” include morpholinyl carbonyl, piperidin-4-ylcarbonyl and the like.
  • heterocycle carbonyloxy means a monovalent group in which the above “heterocycle carbonyl” group is bonded to an oxygen atom.
  • Preferred examples of the “heterocycle carbonyloxy” include, for example, tetrahydropyran-4-ylcarbonyloxy, piperidine-4-ylcarbonyloxy, pyrrolidin-2-ylcarbonyloxy, azetidine-3-ylcarbonyloxy Etc.
  • heterocyclic sulfonyl means a monovalent group in which the above “heterocyclic group” is bonded to sulfonyl.
  • heterocyclylsulfonyl include, for example, tetrahydropyran-2-ylsulfonyl and the like.
  • heterocycle sulfonyloxy means a monovalent group in which the above “heterocycle sulfonyl” group is bonded to an oxygen atom.
  • heterocyclylsulfonyloxy examples include tetrahydropyran-2-ylsulfonyloxy and the like.
  • heterocyclic oxycarbonyl means a monovalent group in which the above “heterocyclic oxy” group is bonded to carbonyl.
  • heterocyclic oxycarbonyl examples include tetrahydropyran-4-yloxycarbonyl and the like.
  • heterocyclic oxycarbonyloxy means a monovalent group in which the above “heterocyclic oxycarbonyl” group is bonded to an oxygen atom.
  • heterocyclic oxycarbonyloxy examples include tetrahydropyran-4-yloxycarbonyloxy and the like.
  • spacer refers to a divalent organic group of 1 to 20 carbon atoms and includes aliphatic carbon chains (linear, branched, cyclic) and / or aromatic rings. .
  • substituents examples include a halogen atom, a hydroxy group, a carboxy group, a cyano group, a nitro group, an amino group, a sulfonic acid group (sulfo group), a phosphoric acid group (phospho group), and a diC 1-6 alkyl phosphoric acid group, C 1-6 alkyl, C 1-6 alkoxy group, C 3-8 cycloalkyl group, C 2-6 alkenyl, C 2-6 alkynyl group, an aryl group, an aryl C 1-6 alkyl group, a heterocyclic A ring group etc. are mentioned, and these may be further substituted by the carboxy group, the amino group, or the hydroxy group, respectively.
  • water-soluble substituents such as carboxy group, sulfo group, phospho group, hydroxy group and amino group; halogen atoms; nitro group; cyano group; substituted by carboxy group, sulfo group, phospho group, hydroxy group or amino group (more preferably, a carboxyl group, optionally substituted by a hydroxy group or an amino C 1-6 alkyl group) is also a C 1-6 alkyl group optionally; carboxy group, sulfo group, phospho group, hydroxy group or (more preferably, a carboxyl group, optionally substituted by a hydroxy group or an amino C 1-6 alkoxy group) a C 1-6 alkoxy group optionally substituted with an amino group are preferable.
  • a group capable of binding to a protein means a group capable of forming a bond with a protein of the present invention or a pharmaceutically acceptable salt thereof.
  • groups capable of binding to proteins include, for example, maleimidyl group, haloacetoamino group, haloacetoxy group, pyridyldithio group (-S-S-Py), N-succiimidyloxycarbonyl group, isothiocyanato group and the like.
  • these groups include one or more substituents (for example, a halogen atom, a nitro group, a cyano group, a C 1-6 alkyl group, a C 1-6 alkoxy group and the like, preferably a halogen atom And may be substituted by
  • the “optionally substituted” means an embodiment which is unsubstituted or substituted by 1 to 4 substituents. In the case of 2 to 4 substitution, each substituent may be the same or different.
  • substituted refers to embodiments substituted with 1 to 4 substituents. In the case of 2 to 4 substitution, each substituent may be the same or different.
  • optionally substituted alkyl means an alkyl group which is unsubstituted or substituted with 1 to 4 substituents.
  • the substituent of the "alkyl which may be substituted" for example, a halogen atom; hydroxy group; a carboxy group; a cyano group; a nitro group; an optionally substituted amino group; a sulfo group; a phospho group; di C 1 -6 alkyl phosphoric acid group; a C 1-6 alkoxy group which may be substituted with a carboxy group, a sulfo group, a phospho group, a hydroxy group or an amino group; a C 3-8 cycloalkyl group; a heterocyclic group; A sulfo group, a phospho group, a C 1-6 alkylcarbonyloxy group which may be substituted with a hydroxy group or an amino group; a heterocyclic carbonyloxy group; a C 3-7 cycloalky
  • optionally substituted alkylene group (or C 1-20 alkylene group or C 1-10 alkylene group)”, “optionally substituted alkenylene group (or C 2-20 alkenylene group” Group “,” “optionally substituted alkynylene group (or C 2-20 alkynylene group)” or “optionally substituted cycloalkynyl group” is unsubstituted or substituted with one or more substituents.
  • an alkylene group, an alkenylene group, an alkynylene group or a cycloalkynyl group is unsubstituted or substituted with one or more substituents.
  • substituent of “optionally substituted alkylene group, alkenylene group, alkynylene group or cycloalkynylene group” include, for example, a halogen atom, a hydroxy group, a carboxy group, a cyano group, a nitro group, an amino group and a sulfo group , Phospho group, di C 1-6 alkyl phosphate group, C 1-6 alkyl group, C 1-6 alkoxy group, C 3-8 cycloalkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group,
  • the aryl group, the aryl C 1-6 alkyl group, the heterocyclic group and the like may be mentioned, and these may be further substituted with a carboxy group, an amino group or a hydroxy group, respectively.
  • water-soluble substituents such as carboxy group, sulfo group, phospho group, hydroxy group and amino group; halogen atoms; nitro group; cyano group; substituted by carboxy group, sulfo group, phospho group, hydroxy group or amino group (more preferably, a carboxyl group, optionally substituted by a hydroxy group or an amino C 1-6 alkyl group) is also a C 1-6 alkyl group optionally; carboxy group, sulfo group, phospho group, hydroxy group or (more preferably, a carboxyl group, optionally substituted by a hydroxy group or an amino C 1-6 alkoxy group) a C 1-6 alkoxy group optionally substituted with an amino group are preferable.
  • the "optionally substituted amino group” means an amino group which may be unsubstituted or mono- or di-substituted.
  • the substituent of the "amino group which may be substituted" for example, C 1-6 alkyl group, C 3-8 cycloalkyl group, C 3-8 cycloalkyl C 1-6 alkyl group, C 6-10 And aryl groups, C 6-10 aryl C 1-6 alkyl groups, heterocyclic groups, heterocyclic C 1-6 alkyl groups, C 2-6 alkenyl groups, C 2-6 alkynyl groups, acyl groups, etc.
  • C 1-6 alkyl group a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 3-8 cycloalkyl group, a C 6-14 aryl group, a heterocyclic group, a halogen atom, a hydroxy group, It may be substituted by a carboxy group, an amino group, a phospho group, a sulfo group, a carbamoyl group, a cyano group, a nitro group, an oxo group, an amino group or the like.
  • an active drug having an amino group is a chemical substance that exhibits a pharmacological action by being administered in vivo, and an amino group (a primary amino group (aliphatic primary A drug having an amino group, an aromatic primary amino group), a secondary amino group (aliphatic secondary amino group, aromatic secondary amino group) or a cyclic amino group is included.
  • Antifungal agents that may be included include flucytosine Anticancer agents encompassed by the active drug are not only compounds that are currently being used or being tested for cancer chemotherapy, Also included are compounds whose clinical use has been abandoned due to strong toxicity or side effects, and further compounds which will be provided as anticancer agents in the future, if they meet the object of the present invention.
  • anticancer agents include, but are not limited to, anthracycline antibiotics such as, but not limited to, doxorubicin, idarubicin, epirubicin, pirarubicin, amrubicin, daunorubicin, aclarubicin; endene antibiotics such as calicheamicin; gemcitabine, 5 ' -Antimetabolites such as deoxy-5-fluorocytidine, cytarabine, azacitidine, fludarabine, nelarabine, clofarabin, cladribine, methotrexate; parvocyclic, AT-7519, cyclin dependent kinase (CDK) inhibitors such as ribocyclib; MEN-1611, Phosphatidylinositol 3-kinase (PI3K) inhibitors such as buparusiv and pyralarisyl; Bruton type tyrosine kinase (BTK) inhibitor
  • the “cyclic amino group” means a secondary saturated or partially unsaturated nitrogen-containing non-aromatic heterocyclic group which is formed together with the nitrogen atom of the amino group.
  • the “cyclic amino group” may have a hetero atom selected from oxygen atom, sulfur atom and nitrogen atom in addition to carbon atom as another ring constituent atom of nitrogen atom of amino group, and has 4 to 7 members ( Preferred are 5- or 6-membered monocyclic nitrogen-containing non-aromatic heterocyclic group and fused nitrogen-containing non-aromatic heterocyclic group.
  • cyclic amino group examples include, for example, azetidinyl, pyrrolidinyl, pyrrolinyl, piperidyl, azepanyl, morpholinyl, thiomorpholinyl, piperazinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, oxazolinyl, thiazolinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, dihydropyridyl, tetrahydropyridyl, 4- to 7-membered monocyclic nitrogen-containing non-aromatic heterocyclic group such as tetrahydropyrimidinyl, dihydrotriazolyl, tetrahydrotriazolyl, etc., and the monocyclic nitrogen-containing non-aromatic heterocyclic group has one or two carbons And secondary cyclic amino groups such as a fused nitrogen-containing non-ar
  • the “residue of an active drug having an amino group” means a primary amino group (aliphatic primary amino group or aromatic primary amino group) present in the active drug, It means a group in which a hydrogen atom of a secondary amino group (aliphatic secondary amino group or aromatic secondary amino group) or a cyclic amino group is removed.
  • a primary amino group aliphatic primary amino group or aromatic primary amino group
  • a hydrogen atom of a secondary amino group aliphatic secondary amino group or aromatic secondary amino group
  • a cyclic amino group is removed.
  • the group represented by represents an active drug residue having an amino group as described below, but is not limited thereto
  • R 1 represents a hydrogen atom or an alkyl group which may be substituted
  • A represents a spacer
  • B represents a group capable of binding to a protein
  • E represents an oxygen atom or a single bond
  • the group represented by is a residue of an active drug having an amino group, and in the formula, N represents a nitrogen atom of the amino group, and the amino group is a primary amino group or a secondary amino group. Represents a group or a cyclic amino group. ] (I.e., compound (I)).
  • R 1 represents a hydrogen atom or an alkyl group which may be substituted.
  • R 1 is preferably a hydrogen atom, or a C 1-6 alkyl group which may be substituted with a carboxy group, a sulfo group, a phospho group, a hydroxy group or an amino group (eg, methyl, ethyl, 2-carboxyethyl, 2,3-Dihydroxypropyl, tert-butyl), more preferably a hydrogen atom or a C 1-6 alkyl group optionally substituted with a carboxy group (eg, methyl, ethyl, 2-carboxyethyl) And particularly preferably a hydrogen atom.
  • A represents a spacer
  • A is more preferably a group consisting of -O-, -S-, -SO-, -SO 2- , -NR- (wherein R represents a hydrogen atom or a C 1-6 alkyl group) and a phenylene group.
  • a C 1-20 alkylene group, a C 2-20 alkenylene group, or a C 2-20 alkynylene group which may have one or more groups selected from the above, and may be substituted internally or at the end, and may be substituted respectively
  • a cycloalkylene group which may be substituted with a carboxy group, a sulfo group, a phospho group, a hydroxy group or an amino group, and more preferably one or more of -O- may be contained therein
  • B represents a group capable of binding to a protein.
  • B is preferably each optionally substituted maleimidyl group, haloacetoamino group, haloacetoxy group, pyridyldithio group (-S-S-Py), N-succinimidyloxycarbonyl group or isothiocyanato group
  • a maleimidyl group or an N-succinimidyloxycarbonyl group which may be substituted with a halogen atom, a nitro group, a cyano group, a C 1-6 alkyl group or a C 1-6 alkoxy group.
  • a maleimidyl group which may be substituted with a halogen atom and particularly preferably a maleimidyl group.
  • E represents an oxygen atom or a single bond.
  • E is preferably an oxygen atom.
  • the group represented by is a residue of an active drug having an amino group, and in the formula, N represents a nitrogen atom of the amino group, and the amino group is a primary amino group or a secondary amino group. Represents a group or a cyclic amino group.
  • the active drug in the residue of the active drug having an amino group is preferably an anticancer agent, more preferably gemcitabine (aromatic primary amino group), 5'-deoxy-5-fluoro Cytidine (aromatic primary amino group), amrubicin (aliphatic primary amino group), parvocyclib (aliphatic secondary amino group), ibrutinib (aromatic primary amino group), pyralarisib (aliphatic primary 1) Secondary amino group), AZD-5363 (aliphatic primary amino group), tsushidinostat (aromatic primary amino group), crizotinib (aliphatic secondary amino group) or imatinib (aromatic secondary amino group) And more preferably gemcitabine or amrubicin.
  • gemcitabine aromatic primary amino group
  • 5'-deoxy-5-fluoro Cytidine aromatic primary amino group
  • amrubicin aliphatic primary amino group
  • parvocyclib aliphatic secondary amino group
  • ibrutinib aromatic primary amino group
  • a kinase inhibitor in the residue of the active drug having an amino group, represented by the following, a kinase inhibitor, an antimetabolite, a CDK inhibitor, an anthracycline anticancer drug, an HDAC inhibitor, an FGFR inhibitor,
  • a PARP inhibitor PI3K inhibitor, BTK inhibitor, AKT inhibitor, TLR7 agonist, or topoisomerase inhibitor
  • acarabultinib aromatic Primary amino group
  • cytarabine aromatic primary amino group
  • ribocyclic rib aliphatic secondary amino group
  • niraparib aliphatic secondary amino group
  • AT-7519 aliphatic secondary amino group
  • Bupulsive aromatic primary amino group
  • delazantinib aliphatic secondary amino group
  • MEN-1611 aromatic primary amino group
  • milansertib aliphatic primary amino group
  • PF-4878691 arachidib
  • Compound (I), wherein the group represented by is a residue of an anticancer agent.
  • the group represented by is a kinase inhibitor, antimetabolite, a CDK inhibitor, an anthracycline anticancer drug, an HDAC inhibitor, an FGFR inhibitor, a PARP inhibitor, a PI3K inhibitor, a BTK inhibitor, an AKT inhibitor, a TLR7 agonist, Or Compound (I), which is a residue of a topoisomerase inhibitor.
  • R 1 is a hydrogen atom or a C 1-6 alkyl group which may be substituted with a carboxy group, a sulfo group, a phospho group, a hydroxy group or an amino group (eg methyl, ethyl, 2-carboxyethyl, 2, 3 -Dihydroxypropyl, tert-butyl) (preferably, a C 1-6 alkyl group which may be substituted with a carboxy group (eg, methyl, ethyl, 2-carboxyethyl)),
  • A is selected from the group consisting of -O-, -S-, -SO-, -SO 2- , -NR- (wherein R represents a hydrogen atom or a C 1-6 alkyl group) and a phenylene group C 1-20 alkylene group, C 2 which may have one or more groups at each of the interior or the end, and may be substituted with a carboxy group, a sulf
  • the group represented by is a residue of gemcitabine, 5'-deoxy-5-fluorocytidine, amrubicin, parvocyclib, ibrutinib, plararisib, AZD-5363, tushidinostat, crizotinib or imatinib (preferably gemcitabine, 5'-deoxy- 5-Fluoro cytidine, amrubicin, parvocyclic, tusidinostat, crizotinib or imatinib residues) which is the compound (I).
  • R 1 is a hydrogen atom or a C 1-6 alkyl group which may be substituted with a carboxy group, a sulfo group, a phospho group, a hydroxy group or an amino group (eg methyl, ethyl, 2-carboxyethyl, 2, 3 -Dihydroxypropyl, tert-butyl) (preferably, a C 1-6 alkyl group which may be substituted with a carboxy group (eg, methyl, ethyl, 2-carboxyethyl)),
  • A is selected from the group consisting of -O-, -S-, -SO-, -SO 2- , -NR- (wherein R represents a hydrogen atom or a C 1-6 alkyl group) and a phenylene group C 1-20 alkylene group, C 2 which may have one or more groups at each of the interior or the end, and may be substituted with a carboxy group, a s
  • Compound (I), wherein the group represented by the above is a residue of acarabultinib, cytarabine, ribocyclib, niraparib, AT-7519, buparibus, delazantinib, MEN-1611, mirancertib, PF-4878691, resiquimod or entinostat.
  • R 1 is a hydrogen atom or a C 1-6 alkyl group optionally substituted with a carboxy group (eg, methyl, ethyl, 2-carboxyethyl),
  • A is a C 1-10 alkylene group (preferably C 1-6 which may have one or more -O- and may be substituted with a carboxy group, a hydroxy group or an amino group) Alkylene group),
  • B is a maleimidyl group which may be substituted by a halogen atom, E is an oxygen atom, and
  • R 1 is a hydrogen atom
  • A is a C 1-6 alkylene group which may have one or more -O- and may be substituted by a carboxy group
  • B is a maleimidyl group
  • E is an oxygen atom
  • R 1 is a hydrogen atom
  • A is a C 1-6 alkylene group which may have one or more -O- and may be substituted by a carboxy group
  • B is a maleimidyl group
  • E is an oxygen atom
  • R 1 is a hydrogen atom
  • A is a C 1-6 alkylene group which may have one or more -O- and may be substituted by a carboxy group
  • B is a maleimidyl group
  • E is an oxygen atom
  • Preferred specific examples of the compound (I) include the compounds of Examples 1 to 60 described in the following Examples and Tables 1-1 to 1-9 (hereinafter, the compounds (I-1) to the compounds (I-). 60), and among them, (1) 2-( ⁇ (2S, 4R) -2-acetyl-4-[(2S, 4S, 5R) -4,5-dihydroxytetrahydropyran-2-yloxy] -5,12-dihydroxy-6,11 -Dioxo-1,2,3,4,6,11-hexahydronaphthacene-2-ylamino ⁇ methylene) malonic acid mono 5- (2,5-dioxo-2,5-dihydropyrrol-1-yl) pentyl (Compound (I-1)), (2) 2-( ⁇ 1-[(2R, 4R, 5R) -3,3-difluoro-4-hydroxy-5-hydroxymethyltetrahydrofuran-2-yl] -2-oxo-1,2-dihydroxy
  • the compound of the present invention contains an optical isomer, stereoisomer, regioisomer, or rotational isomer, these are also contained as a compound of the present invention.
  • the compounds of the present invention can be converted into their pharmaceutically acceptable salts by methods known per se.
  • the compound of the present invention has an acidic group or a basic group, it can be converted to a basic salt or an acidic salt by reacting with a base or an acid.
  • the pharmaceutically acceptable “basic salt” of the compound of the present invention is preferably an alkali metal salt such as sodium salt, potassium salt or lithium salt; alkaline earth metal salt such as magnesium salt or calcium salt; Methyl morpholine salt, ethanolamine salt, piperazine salt, diethylamine salt, triethylamine salt, tributylamine salt, tert-butylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, meglumine salt, tromethamine salt, choline salt, benzathine Organic base salts such as salts, 4-phenylcyclohexylamine salts, pyridine salts, 4-pyrrolidinopyridine salts and picoline salts or amino acid salts such as lysine salts, arginine salts and ornithine salts, preferably alkali metal salts is there.
  • alkali metal salt such as sodium salt, potassium salt
  • the pharmaceutically acceptable “acid salt” of the compound of the present invention is preferably a hydrohalide such as a hydrogen fluoride, a hydrochloride, a hydrobromide, a hydroiodide or the like, a nitrate, Inorganic acid salts such as perchlorate, sulfate and phosphate; lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate, benzenesulfonate, p-toluenesulfonic acid
  • Aryl sulfonates such as salts, acetates, trifluoroacetates, malates, fumarates, succinates, citrates, ascorbates, tartrates, borates, borates and organic acid salts such as maleates And amino acid salts such as glycine salt, glutamate, and aspartate, and most preferably hydrohalide (in particular
  • a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof is formulated into a mammal (eg, mouse, rat, hamster, rabbit, cat, dog, etc.) in combination with a pharmaceutically acceptable carrier and the like. Administration to cattle, sheep, monkeys, humans, etc.).
  • a mammal eg, mouse, rat, hamster, rabbit, cat, dog, etc.
  • excipients eg, starch, lactose, sugar, calcium carbonate, calcium phosphate etc.
  • binders eg, starch, gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose etc.
  • lubricants Eg, magnesium stearate, talc etc.
  • disintegrants eg, carboxymethyl cellulose, talc etc.
  • solvents eg, water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, Olive oil, cottonseed oil etc.
  • solubilizer eg polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine Sodium carbonate, sodium citrate, sodium salicylate, sodium acetate etc.
  • suspending agents eg stearyltriethanolamine, sodium laulose
  • Food dyes include water-insoluble lake dyes (eg, aluminum salts of the above-mentioned water-soluble food tar dyes), natural dyes (eg, ⁇ -carotene, chlorophyll, bengara) etc., sweeteners (eg Dipotassium, aspartame, stevia etc.
  • water-insoluble lake dyes eg, aluminum salts of the above-mentioned water-soluble food tar dyes
  • natural dyes eg, ⁇ -carotene, chlorophyll, bengara
  • sweeteners eg Dipotassium, aspartame, stevia etc.
  • the mixture is subjected to a method known per se, for example, for oral administration such as capsules, tablets, fine granules, granules, dry syrup, etc., or injections (eg, subcutaneous injection, intravenous injection) Agent, intramuscular injection, intraperitoneal injection, drip, etc., external preparation (eg, percutaneous absorption type preparation, ointment, lotion, patch), suppository (eg, rectal suppository, vaginal suppository)
  • the composition can be formulated for parenteral administration such as pellets, transnasal agents, pulmonary agents (inhalants), eye drops and the like. Among them, preparations for parenteral administration such as injections are preferable.
  • the content of the compound of the present invention or a pharmaceutically acceptable salt thereof in the pharmaceutical composition of the present invention varies depending on the form of the preparation, but is usually in the range of about 0.01 to 100% by weight based on the whole preparation. Preferably, it is in the range of about 0.1 to 50% by weight, and more preferably in the range of about 0.5 to 20% by weight.
  • the compound of the present invention can be produced by applying various known production methods, utilizing the characteristics based on the basic skeleton or the type of substituent. Examples of known methods include those described in "ORGANIC FUNCTIONAL GROUP PREPARATIONS", Second Edition, ACADEMIC PRESS, INC., 1989, “Comprehensive Organic Transformations”, VCH Publishers Inc., 1989, and the like. At that time, depending on the type of functional group, it is effective in production technology to protect the functional group at the raw material or intermediate stage with a suitable protecting group or to replace it with a group which can be easily converted to the functional group.
  • Such functional groups include, for example, amino group, hydroxy group, carboxyl group and the like, and as their protective groups, for example, "Protective Groups in Organic Synthesis (Third Edition, 1999) by TW Greene and PG Wuts".
  • the protective group described in the above can be appropriately selected and used according to the reaction conditions. According to such a method, after the reaction is carried out by introducing the substituent, a desired compound can be obtained by removing the protecting group or converting it into a desired group as necessary.
  • the process for producing the compound of the present invention is described below. However, the production method is not limited to the following method.
  • Production method 1 is a compound represented by general formula (I) by reacting a compound represented by general formula (1) with a compound represented by general formula (2) (compound (2)) It is a method of producing (compound (I)).
  • Compound (2) used in the present production method can be produced from malonic acid according to a method known per se.
  • R 1 , A, B and E are as defined above, R 2 represents a C 1-6 alkyl group, and C-NH-D represents an active drug having an amino group.
  • reaction of compound (1) with compound (2) in production method 1 is carried out in an inert solvent, and may be carried out in the presence of an organic base such as triethylamine or diisopropylethylamine, or a base such as an inorganic salt such as potassium carbonate. .
  • the inert solvent used is, for example, alcohols such as methanol, ethanol, propanol, 2-propanol, butanol and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-, Ethers such as dioxane and 1,2-dimethoxyethane; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, hexamethylphosphorotriamide and the like Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, fluorobenzene, trichloromethylbenzene, tri
  • reaction conditions such as the reaction temperature and the reaction time vary depending on the reaction reagent to be used, the reaction solvent and the like, but are usually -20 to 150 ° C. for 30 minutes to 48 hours.
  • the amount of compound (2) to be used is not particularly limited, and is usually 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (1).
  • the amount of the base used is not particularly limited; 1) It is usually 1 to 5 mol, preferably 1 to 3 mol, per 1 mol.
  • Production method 2 is a method of producing a compound (I) by reacting the compound (1) with the compound (compound (3)) represented by the general formula (3).
  • Compound (3) used in the present production method can be produced from malonic acid according to a method known per se.
  • R 1 , A, B, E and C-NH-D are as defined above, and R 3 represents C 1-6 alkyl or aryl.
  • reaction of compound (1) with compound (3) in production method 2 is carried out in an inert solvent.
  • the inert solvent used is, for example, alcohols such as methanol, ethanol, propanol, 2-propanol, butanol and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-, Ethers such as dioxane and 1,2-dimethoxyethane; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, hexamethylphosphorotriamide and the like Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, fluorobenzene, trichloromethylbenzene, tri
  • reaction conditions such as the reaction temperature and the reaction time vary depending on the reaction reagent to be used, the reaction solvent and the like, but are usually -20 to 150 ° C. for 30 minutes to 20 hours.
  • the amount of compound (3) to be used is not particularly limited, and is usually 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (1).
  • Production method 3 is a method of producing a compound (I) by reacting the compound (1) with the compound (compound (4)) represented by the general formula (4).
  • Compound (4) to be used in the present production method can be produced from malonic acid according to a method known per se.
  • R 1 , A, B, E and C-NH-D are as defined above.
  • reaction of compound (1) with compound (4) in production method 3 is carried out in an inert solvent.
  • the inert solvent used is, for example, alcohols such as methanol, ethanol, propanol, 2-propanol, butanol and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-, Ethers such as dioxane and 1,2-dimethoxyethane; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, hexamethylphosphorotriamide and the like Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, fluorobenzene, trichloromethylbenzene, tri
  • reaction conditions such as the reaction temperature and the reaction time vary depending on the reaction reagent to be used, the reaction solvent and the like, but are usually -20 to 150 ° C. for 30 minutes to 20 hours.
  • the amount of compound (4) to be used is not particularly limited, and is usually 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (1).
  • Production method 4 is a method of producing a compound (I) by reacting the compound (1) with the compound (compound (5)) represented by the general formula (5).
  • Compound (5) used in the present production method can be produced from malonic acid according to a method known per se.
  • R 1 , A, B, E and C-NH-D are as defined above, and X represents a halogen atom, or a leaving group such as a trifluoromethanesulfonyloxy group.
  • the reaction of the compound (1) with the compound (5) in the production method 4 is carried out in an inert solvent in the presence of an organic base such as triethylamine or diisopropylethylamine, or a base such as an inorganic salt such as potassium carbonate.
  • an organic base such as triethylamine or diisopropylethylamine
  • a base such as an inorganic salt such as potassium carbonate.
  • the inert solvent used is, for example, alcohols such as methanol, ethanol, propanol, 2-propanol, butanol and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-, Ethers such as dioxane and 1,2-dimethoxyethane; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, hexamethylphosphorotriamide and the like Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, fluorobenzene, trichloromethylbenzene, tri
  • reaction conditions such as the reaction temperature and the reaction time vary depending on the reaction reagent to be used, the reaction solvent and the like, but are usually -20 to 150 ° C. for 30 minutes to 20 hours.
  • the amount of the compound (5) to be used is not particularly limited, and is usually 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (1).
  • the amount of the base used is compound (1) 1
  • the amount is usually 0.05 to 2 moles, preferably 0.05 to 1 mole, per mole.
  • Production method 5 is a method of producing a compound (I) by reacting the compound (1) with the compound (compound (6)) represented by the general formula (6).
  • Compound (6) used in the present production method can be produced from malonic acid according to a method known per se.
  • R 1 , A, B, E and C-NH-D are as defined above.
  • reaction of compound (1) with compound (6) in production method 5 is carried out in an inert solvent.
  • the inert solvent used is, for example, alcohols such as methanol, ethanol, propanol, 2-propanol, butanol and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-, Ethers such as dioxane and 1,2-dimethoxyethane; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, hexamethylphosphorotriamide and the like Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, fluorobenzene, trichloromethylbenzene, tri
  • reaction conditions such as the reaction temperature and the reaction time vary depending on the reaction reagent to be used, the reaction solvent and the like, but are usually -20 to 150 ° C. for 30 minutes to 20 hours.
  • the amount of compound (6) to be used is not particularly limited, and is usually 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (1).
  • Production method 6 is a method known per se to a compound (compound (7)) represented by compound (1) to a compound represented by formula (7) and then a compound represented by formula (8) (compound (8))
  • This is a method of producing a compound (I) by reacting the compound (8) represented by the general formula (9) with the obtained compound (8).
  • Compound (9) used in the present production method can be produced from malonic acid according to a method known per se.
  • R 1 , A, B, E and C-NH-D are as defined above.
  • reaction from compound (1) to compound (7) can be carried out by formylation of the secondary amino group of compound (1) by a method known per se.
  • reaction from compound (7) to compound (8) can be carried out by converting the amide group of compound (7) into a thioamide group by a method known per se using Lawesson's reagent etc. .
  • reaction of compound (8) with compound (9) is carried out according to a method known per se (eg, the method described in J. Org. Chem., 2014, 79, 7405-7414, etc.) Can.
  • the desired compound can be obtained by removing the protective group as necessary.
  • the method of removing each protective group can be carried out, for example, according to the method described in "Protective Groups in Organic Synthesis (Third Edition, 1999)" by T. W. Greene and P. G. Wuts.
  • the compounds of the present invention produced by the above methods can be isolated and purified by known methods, for example, extraction, precipitation, distillation, chromatography, fractional recrystallization, recrystallization and the like.
  • optical isomers exist when the compound of the present invention or an intermediate in the preparation thereof has an asymmetric carbon. These optical isomers can be isolated and purified by a conventional method such as fractional recrystallization (salt resolution) or recrystallization with an appropriate salt.
  • the above-mentioned isomer can also be produced by asymmetric synthesis.
  • the dose of the compound of the present invention or a pharmaceutically acceptable salt thereof varies depending on the subject, symptoms, and other factors, for example, when parenterally administered to adult cancer patients, the dose is usually about 1 dose.
  • the amount is preferably 0.01 to 500 mg / kg body weight, preferably 0.1 to 100 mg / kg body weight, more preferably 1 to 50 mg / kg body weight, and it is desirable to administer this amount once to 3 times a day.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof covalently bonds to plasma proteins such as plasma albumin in the body, selectively and efficiently after being transferred to tumor tissue, active under the low pH environment. It is a compound that efficiently releases a drug and exhibits extremely excellent anticancer activity as a drug, and is useful as an anticancer agent, a preventive / therapeutic agent for cancer metastasis and / or cancer recurrence.
  • the type of cancer to be prevented or treated is not particularly limited.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof can be used in combination with other agents, for example, existing anticancer agents, as long as the efficacy of the compound is not impaired.
  • the administration time is not limited, and they may be administered simultaneously to the administration subject, or may be administered with a time lag.
  • the dose can be appropriately selected based on the dose clinically used.
  • the compounding ratio of the compound of the present invention or a pharmaceutically acceptable salt thereof and the like and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, condition, combination and the like.
  • anticancer agents examples include chemotherapeutic agents, hormone therapeutic agents, immunotherapeutic agents, molecular targeting agents, immune checkpoint inhibitors (anti-PD-1 antibody, anti-PD-L1 antibody) and the like.
  • chemotherapeutic agent for example, alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents and the like are used.
  • alkylating agent examples include nitrogen mustard, nitrogen mustard hydrochloride-N-oxide, chlorambucil, cyclophosphamide, ifosfamide, thiotepa, carbocon, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, mel Phalaen, dacarbazine, lanimustine, sodium estramustine phosphate, triethylenemelamine, carmustine, lomustine, streptozocin, pipobroman, etolequiside, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, alretamine, ambamustin, dibrospidium hydrochloride, fotemustine, Prednismustine, pumithepa, ribomustine, temozolomide, treosulphan, trofosfamide, Roh statins scan chima
  • Examples of the “metabolic agents” include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, pemetrexed, penetrexed, enocitabine, cytarabine, cytarabine ocfosfate, ancitabine hydrochloride, 5-FU drugs (eg, fluorouracil, tegafur, UFT, doxifluridine, carmofur, galocitabine, emitefur, capecitabine), aminopterin, nelzalavin, leucovorin calcium, tabloid, butosin, folinate calcium, levoforinate calcium, cladolibine, emiteful, fludarabine, gemcitabine, hydroxycarbamide, hydroxy carbamide Idoxyuridine, Mitoguazone, Thiazofrine, Ambamustine, Bendamustine, and them DDS formulation or the like is used.
  • 5-FU drugs eg, fluorour
  • anticancer antibiotic examples include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, pepromycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride Neocarzinostatin, misuramycin, sarkomycin, carcininophilin, mitotane, zolubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride, and their DDS preparations are used.
  • plant-derived anticancer agent for example, etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, vinorelbine, and their DDS preparations and the like are used.
  • hormone therapeutic agents include phosphestrol, diethylstilbestrol, chlorotrianisene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, gestrinone, mepaltricin, Raloxifene, olmeloxifene, levormeloxifene, anti-estrogen (eg, tamoxifen citrate, toremifene citrate), pill formulation, mepithiostan, testolactone, aminoglutethiimide, LH-RH agonist (eg, goserelin acetate, buserelin Leuprorelin), droloxifene, epithiostanol, ethynyl estradiol sulfonate, aromatase inhibitors (eg, fadrozole hydrochloride, anastrozo
  • biological response modifiers for example, picibanil, krestin, schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, Corynebacterium parvum, levamisole, polysaccharide K, procodazole, anti-CTLA4 antibody, etc. are used.
  • molecular-targeted drugs examples include tositumomab, ibritzumab, alemtuzumab, axitinib, bevacizumab, afatinib, bortezomib, bosutinib, carfilzomib, cetuximab, dasatinib, denosumab, edrocolomab, erlotinib, everolimus, vismodegib, gefibib , Imatinib, ipilimumab, lapatinib, lenalidomide, nilotinib, nimotuzumab, olaparib, panitumumab, pazopanib, pertuzumab, rituximab, siltuximab, sorafenib, sunitinib, tamibarotene, temidolimus, thalidomide
  • the “immune checkpoint inhibitor” for example, nivolumab, pembrolizumab, averumab, atezolizumab and the like are used.
  • the active drug used for the synthesis of the following example compounds can be easily obtained commercially and can be used as it is (gemcitabine (Examples 2, 3, 7-13, 16, 21, 27-27, 29) 35-37 and 40), flucytosine (Examples 15 and 28), amrubicin (Examples 1, 4 and 18), imatinib (Example 17), 5'-deoxy-5-fluorocytidine (Example 14), Nirapalib (Example 50), Buparsib (Example 51), Acaraburutinib (Example 52), Resiquimod (Example 53), Cytarabine (Example 45), or a method known per se (Palvocyclic Example (Examples 5, 20) 31 and 41; WO 2014/128588), crizotin
  • ribocyclic rib (Example 44; US 2012115878), AT-7519 (Example 46; WO 2006/77414), milansertib (Example 47; J. Med. Chem. 59 (13), 6455-669, 201 6), delazantinib (Example 48; WO2010 / 078421), and MEN-1611 (Example 49; US8022205)), or those prepared according to methods analogous thereto can also be used.
  • the active drug (CDK 8 inhibitor) used for the synthesis of the compounds of Examples 54 to 60 was produced by the method shown in the following Synthesis Examples 1 to 7.
  • the filtrate was concentrated under reduced pressure, and the precipitated powder was further added with diethyl ether, and the insoluble matter was separated by filtration.
  • the filtrate was concentrated under reduced pressure and purified by column chromatography (n-hexane: diethyl ether, 5: 1 ⁇ 4: 1 ⁇ 1: 1, V / V).
  • the solvent of the target fraction was evaporated under reduced pressure to give a colorless oil (2.29 g, yield 51%) of the title compound.
  • the ethyl acetate layer was washed successively with water and saturated brine, dried (Na 2 SO 4 ), and the solvent was evaporated under reduced pressure.
  • 500 mL of ethanol was added to the obtained residue and 3.80 g of 10% palladium carbon, and catalytic hydrogenation was performed at 0.4 MPa and room temperature for 25 hours. After filtering off palladium carbon, ethanol was distilled off under reduced pressure. 50 mL of n-heptane was added, and n-heptane was distilled off under reduced pressure. Further, 50 mL of n-heptane was added, and left at 0 ° C. for 30 minutes.
  • 6-Methoxy-2-methylpyrrolo [3,2-c] pyridine 1.55 g (9.56 mmol), benzyl 4- (4-iodophenyl) piperazine-1-carboxylate 4.04 g (9.56 mmol), copper iodide (I ) Suspending 182 mg (0.956 mmol), trans-N, N'-dimethylcyclohexane-1,2-diamine 0.45 mL (2.9 mmol) and tripotassium phosphate 4.27 g (20.1 mmol) in 15 mL of toluene, After bubbling, the mixture was stirred at 110 ° C. for 22 hours under a nitrogen atmosphere.
  • the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 1: 1 ⁇ 1: 2, V / V).
  • the solvent of the objective fraction is distilled off under reduced pressure, and benzyl (3- ⁇ 1- [4- (3-acetyl-5,6-dimethoxy-2-methylindol-1-yl) phenyl] piperidin-4-yl is obtained. 210 mg of a colorless oil of (propyl) carbamate was obtained.
  • N-methoxycarbonylmaleimide (7.05 g, 68.3 mmol) in saturated aqueous sodium bicarbonate (400 mL), add 5-amino-1-pentanol (10.6 g, 68.3 mmol) under ice-cooling, and mix at the same temperature. Stir for 4 hours.
  • the reaction solution was extracted with methylene chloride six times, and the organic layers were combined and dried (Na 2 SO 4 ).
  • the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 7: 3 ⁇ 2: 8, V / V).
  • the resulting solution was purified by column chromatography (Chromatorex COOH MB 100-75 / 200 (Fuji Silysia), chloroform: methanol, 10: 0 ⁇ 9: 1, V / V).
  • the solvent of the target fraction was evaporated under reduced pressure, ethyl acetate-tert-butyl methyl ether (1: 4) (2 mL) was added to the obtained residue, the insoluble matter was collected by filtration, and orange powder (294 mg) Got).
  • the obtained powder was purified by column chromatography (ethyl acetate: chloroform, 5: 5 ⁇ 0: 1, chloroform: methanol, 1: 0 ⁇ 9: 1, V / V).
  • the solvent of the target fraction is distilled off under reduced pressure, and the obtained residue is again subjected to column chromatography (ethyl acetate: chloroform, 5: 5 ⁇ 0: 1, chloroform: methanol, 1: 0 ⁇ 9: 1, V / V) and purified.
  • the solvent of the target fraction is distilled off under reduced pressure, and 2-( ⁇ (2S, 4R) -2-acetyl-4-[(2S, 4S, 5R) -4,5-dihydroxytetrahydropyran-2-yloxy] is obtained.
  • the compound (1c) (50 mg, 0.13 mmol) and gemcitabine (34 mg, 0.13 mmol) are dissolved in a mixture of 1,4-dioxane (2.1 mL) and dimethylsulfoxide (0.7 mL), and heated at 100 ° C. for 63 hours It stirred.
  • the compound (1c) (585 mg, 1.53 mmol) and gemcitabine (403 mg, 1.53 mmol) are dissolved in a mixture of 1,4-dioxane (25 mL) and dimethylsulfoxide (8.3 mL) and heated at 100 ° C. for 46 hours It stirred.
  • the reaction solution was combined, ethyl acetate was added, and after washing with water, the aqueous layer was extracted with ethyl acetate.
  • the organic layers were combined, washed three times with water and once with saturated brine, and then dried (Na 2 SO 4 ).
  • the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (chloroform: methanol, 1: 0 ⁇ 9: 1, V / V).
  • the solvent of the target fraction was evaporated under reduced pressure to give a pale yellow powder (376 mg).
  • Tetrahydrofuran (0.23 mL) is added to the reaction solution, and the precipitate is collected by filtration, and the obtained powder is washed twice with ethyl acetate (0.5 mL) to give 2-( ⁇ (2S, 4R) -2-acetyl- 4-[(2S, 4S, 5R) -4,5-dihydroxytetrahydropyran-2-yloxy] -5,12-dihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydro Reddish-brown powder (22 mg, naphthacene-2-ylamino) methylene) malonic acid mono 5- (2, 5-dioxo-2, 5-dihydropyrrol-1-yl) pentyl sodium (compound (I-4)) Rate of 60%).
  • the compound of (5a) (3.90 g, 13.9 mmol) is dissolved in tetrahydrofuran (40 mL), triethylamine (3.86 mL, 27.8 mmol) and acetyl chloride (1.04 mL, 14.8 mmol) are added under ice-cooling, and the mixture is heated to the same temperature. The mixture was stirred for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted 7 times with ethyl acetate, and hydrochloric acid was added to the aqueous layer to adjust to pH 2.
  • the aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined and dried (Na 2 SO 4 ).
  • the solvent was evaporated under reduced pressure, and the obtained residue was purified by column chromatography (Chromatorex COOH MB 100-75 / 200 (Fuji Silysia), chloroform: methanol, 1: 0 ⁇ 9: 1, V / V).
  • the solvent of the target fraction was evaporated under reduced pressure to obtain a yellow oil (2.83 g, yield 63%) of 2-acetoxy-6-benzyloxycarbonylaminohexanoic acid.
  • the compound of (5b) (2.73 g, 8.44 mmol) is dissolved in tert-butanol (6 mL), a solution of di-tert-butyl dicarbonate (2.21 g, 10.1 mmol) in tert-butanol (2 mL), N , N-dimethylaminopyridine (129 mg, 1.06 mmol) was added and stirred at room temperature for 4 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried (Na 2 SO 4 ).
  • the solvent of the objective fraction was distilled off under reduced pressure, and colorless oil of malonic acid 1-tert-butoxycarbonyl-5- (2,5-dioxo-2,5-dihydropyrrol-1-yl) pentyl ethyl (1.57 g, yield 80%).
  • the solvent of the target fraction was evaporated under reduced pressure, and the obtained residue was suspended in ethyl acetate (2 mL) and tert-butyl methyl ether (6 mL), and then subjected to ultrasonic irradiation to filter off insolubles. .
  • the obtained powder was washed with tert-butyl methyl ether (2 mL) to give a yellow powder (298.2 mg).
  • the obtained powder was again purified by column chromatography (chloroform: methanol, 1: 0 ⁇ 95: 5 ⁇ 90: 10, V / V), and the solvent of the target fraction was distilled off under reduced pressure.
  • the resulting residue was suspended in ethyl acetate (1.5 mL) and n-hexane (1.5 mL), and then subjected to ultrasonic irradiation.
  • the insolubles were collected by filtration and washed with n-hexane (1 mL).
  • the obtained yellow powder was suspended in ethyl acetate (1 mL), and the mixture was irradiated with ultrasonic waves.
  • Insolubles were collected by filtration and washed with ethyl acetate (1 mL) to obtain a yellow powder (100.8 mg).
  • the obtained powder was purified by column chromatography (Chromatorex DM1020T ODS (Fuji Silysia), 0.01 M NaH 2 PO 4 -Na 2 HPO 4 (pH 7.0) -acetonitrile, 80: 20 ⁇ 70: 30 ⁇ 65: 35, V / V).
  • the solvent of the target fraction was evaporated under reduced pressure, and the obtained residue was saturated with sodium chloride and extracted three times with chloroform.
  • the organic layers were combined, dried (Na 2 SO 4 ), the solvent was evaporated under reduced pressure, ethyl acetate was added to the obtained residue, and the mixture was irradiated with ultrasonic waves to be powdered.
  • Example 6 2- [4- (4- ⁇ 6-amino-5- [1- (2,6-dichloro-3-fluorophenyl) ethoxy] pyridin-3-yl ⁇ pyrazol-1-yl) piperidin-1-ylmethylene] Malonic acid 1-carboxy-5- (2,5-dioxo-2,5-dihydropyrrol-1-yl) pentyl ethyl (compound (I-6))
  • the compound of (5i) (396.3 mg, calculated as 0.904 mmol) was dissolved in tetrahydrofuran (9.0 mL), crizotinib (489 mg, 1.08 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours.
  • the solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (chloroform: methanol, 1: 0 ⁇ 90: 10, V / V).
  • the solvent of the target fraction was evaporated under reduced pressure, and the obtained residue was suspended in ethyl acetate (1 mL) and tert-butyl methyl ether (4 mL) and then irradiated with ultrasonic waves.
  • the insoluble material was collected by filtration and washed with tert-butyl methyl ether (2 mL) to give a pale yellow powder (248.2 mg).
  • the obtained pale yellow powder was purified by column chromatography (chloroform: methanol, 1: 0 ⁇ 95: 5 ⁇ 85: 15, V / V).
  • the solvent of the target fraction was evaporated under reduced pressure, and the obtained residue was suspended in ethyl acetate (2 mL), and then the solvent was evaporated under reduced pressure.
  • the obtained residue was suspended in ethyl acetate (1 mL) and n-hexane (1 mL), and the mixture was irradiated with ultrasonic waves, and the insolubles were collected by filtration.
  • the solvent of the target fraction is distilled off under reduced pressure, and 2-( ⁇ 1-[(2R, 4R, 5R) -3,3-difluoro-4-hydroxy-5-hydroxymethyltetrahydrofuran-2-yl] -2 is obtained.
  • 2-( ⁇ 1-[(2R, 4R, 5R) -3,3-difluoro-4-hydroxy-5-hydroxymethyltetrahydrofuran-2-yl] -2 is obtained.
  • a foamy powder (562 mg, 55% yield) was obtained.
  • the reaction mixture was diluted with ethyl acetate, acidified with 6.0 M hydrochloric acid, and the two layers were separated.
  • the obtained organic layer was washed with saturated brine and dried (Na 2 SO 4 ), and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 7: 3 ⁇ 0: 1, V / V).
  • the solvent of the target fraction was evaporated under reduced pressure to give a colorless oil (425 mg, 26% yield) of 1- [2- (2-hydroxyethylsulfanyl) ethyl] pyrrole-2,5-dione .
  • the compound (8b) (1.36 g, 3.96 mmol) is dissolved in acetic anhydride (8.0 mL), triethyl orthoformate (2.0 mL, 12 mmol) and zinc chloride (81 mg, 0.79 mmol) are added, and the mixture is heated to 100 ° C. The mixture was stirred for 2 hours. Zinc chloride (81 mg, 0.79 mmol) was added to the reaction mixture, and the mixture was further stirred at 100 ° C. for 0.5 hour. Water was added to the reaction solution, and the mixture was extracted twice with toluene. The organic layers were combined, washed with saturated brine and dried (Na 2 SO 4 ), and the solvent was evaporated under reduced pressure.
  • the compound (8c) (50 mg, 0.13 mmol) is dissolved in methylene chloride (0.2 mL), m-CPBA (purity: 74.6%) (29 mg, 0.13 mmol) is added under ice-cooling, and Stir for 0.5 h.
  • the reaction solution was dried (Na 2 SO 4 ) and the solvent was evaporated under reduced pressure.
  • the same operation is carried out using the compound (8c) (570 mg, 1.43 mmol), and the residue obtained above is combined with column chromatography (n-hexane: ethyl acetate, 1: 1 ⁇ 0: 1, V / It refine
  • the compound (8d) (200 mg, 0.481 mmol) is dissolved in 1,4-dioxane (0.50 mL) and dimethylsulfoxide (0.20 mL), gemcitabine (190 mg, 0.722 mmol) is added, and the mixture is stirred at 80 ° C. for 11 hours. The mixture was stirred at room temperature for 31 hours. Water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, dried (Na 2 SO 4 ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (chloroform: methanol, 1: 0 ⁇ 9: 1, V / V).
  • the solvent of the target fraction is distilled off under reduced pressure, and 2-( ⁇ 1-[(2R, 4R, 5R) -3,3-difluoro-4-hydroxy-5-hydroxymethyltetrahydrofuran-2-yl] -2 is obtained.
  • 2-( ⁇ 1-[(2R, 4R, 5R) -3,3-difluoro-4-hydroxy-5-hydroxymethyltetrahydrofuran-2-yl] -2 is obtained.
  • a foamy powder (258 mg, 85% yield) was obtained.
  • the solvent of the target fraction is distilled off under reduced pressure, and 2-( ⁇ 1-[(2R, 4R, 5R) -3,3-difluoro-4-hydroxy-5-hydroxymethyltetrahydrofuran-2-yl] -2 is obtained.
  • 2-( ⁇ 1-[(2R, 4R, 5R) -3,3-difluoro-4-hydroxy-5-hydroxymethyltetrahydrofuran-2-yl] -2 is obtained.
  • -Oxo-1,2-dihydroxypyrimidin-4-ylamino ⁇ methylene) malonic acid tert-butyl 2- [2- (2,5-dioxo-2,5-dihydropyrrol-1-yl) ethanesulfonyl] ethyl white color Powder (319 mg, 52% yield) was obtained.
  • Gemcitabine (297 mg, 1.13 mmol) is dissolved in 1,4-dioxane (0.50 mL) and dimethylsulfoxide (0.20 mL), the compound (8c) (300 mg, 0.751 mmol) is added, and the mixture is kept at 80 ° C. for 8 hours The mixture was stirred at room temperature for 14 hours. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine and dried (Na 2 SO 4 ), and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (n-hexane: ethyl acetate, 1: 1 ⁇ 0: 1, V / V).
  • the solvent of the target fraction is distilled off under reduced pressure, and 2-( ⁇ 1-[(2R, 4R, 5R) -3,3-difluoro-4-hydroxy-5-hydroxymethyltetrahydrofuran-2-yl] -2 is obtained.
  • 2-( ⁇ 1-[(2R, 4R, 5R) -3,3-difluoro-4-hydroxy-5-hydroxymethyltetrahydrofuran-2-yl] -2 is obtained.
  • a foamy powder (291 mg, 63% yield) was obtained.
  • Test Example 1 Recovery of Albumin Conjugate to Active Drug A 5.0% human plasma albumin (HSA) saline solution (pH 7.4) was previously incubated at 37 ° C. for 10 minutes, a solution of the example compound was added (final concentration 100 ⁇ M) The binding reaction was initiated at the same temperature. Ten minutes after the addition, it was quenched in an ice bath to obtain an HSA conjugate solution of the example compound. The pH of the reaction solution was adjusted to 5.5 by adding 0.5 M acetate buffer to the solution of each Example compound in the HSA conjugate, and the reaction was initiated by incubating at 37 ° C. Six hours after the start of the reaction, 0.1 M phosphate buffer was added and mixed to adjust to pH 7.4 and used as a sample solution.
  • HSA human plasma albumin
  • Compound (I-1) which is a derivative of an active drug having an aliphatic primary amino group, compound (I-18) and compound (I-47), a derivative of an active drug having an aliphatic secondary amino group
  • Test example 2 Formation and reversibility of ⁇ -globulin conjugate Tris (2-carboxyethyl) phosphine Hydrochloride (final concentration 150 ⁇ M) was added to 10 mg / mL human-derived ⁇ -globulin phosphate buffer solution (pH 7.4), and it was kept at 20 ° C. After incubating for 90 minutes, the disulfide bond of ⁇ -globulin was reduced. Dimethylacetamide is added, and compound (I-3), which is a derivative of an active drug having an aromatic primary amino group, is added 10-fold molar equivalent of globulin, incubated at 20 ° C. for 60 minutes, and N-acetylcysteine aqueous solution added.
  • a ⁇ -globulin conjugate solution containing about 220 ⁇ M of the compound (I-3) was obtained.
  • the pH of the reaction solution was adjusted to 5.5 by adding 0.5 M acetate buffer solution to the ⁇ -globulin conjugate solution, and the mixture was incubated at 37 ° C. to start the reaction.
  • Forty-eight hours after initiation of the reaction 0.1 M phosphate buffer was added to adjust the pH to 7.4, and the active drug concentration was measured by LC / MS / MS (QTRAP6500) to calculate the production rate of the active drug.
  • Incubation of a ⁇ -globulin conjugate sample of compound (I-3) for 48 hours at pH 5.5 at 37 ° C. restored 89% of the bound compound (I-3) to an active drug.
  • Test Example 3 Blood concentration after intravenous administration to mice Male ICR mice (3 animals per group) Preparation solution of the example compound (10 mg equivalent of the active compound of the example compound / 5 mL / kg) was administered tail vein, 0.25, 1 After 8, 24 and 48 hours, heart was collected under deep anesthesia, and centrifuged at 3,000 rpm for 10 minutes at 4 ° C to collect plasma. To 50 ⁇ L of the obtained plasma, 20 ⁇ L of 1 M hydrochloric acid and 130 ⁇ L of acetonitrile were added, incubated at 80 ° C. for 1 hour, and centrifuged at 15,000 rpm for 5 minutes at 4 ° C.
  • the concentration of the example compound in the obtained plasma was measured using LC / MS / MS (QTRAP6500).
  • concentration of the active drug in the plasma-treated supernatant was measured by LC / MS / MS (QTRAP6500).
  • Compound (I-3) which is a derivative of an active drug having an aromatic primary amino group compound (I-4) which is a derivative of an active drug having an aliphatic primary amino group, an aliphatic secondary amino Of Compound (I-5) and Compound (I-6), which are derivatives of active drug having a group, and Compound (I-17), which is derivative of active drug having an aromatic secondary amino group, after 0.25 hours
  • the plasma concentrations of the example compounds showed 174, 45, 89, 35 and 35 ⁇ M, respectively, and then gradually disappeared over 48 hours.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof is useful as an anticancer agent, a preventive / therapeutic agent for cancer metastasis and / or cancer recurrence.
  • the medicament containing the compound of the present invention has an excellent anti-cancer effect and few side effects, it can be a highly safe therapeutic agent for cancer and an agent for preventing and treating cancer metastasis and / or cancer recurrence.

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Abstract

L'invention concerne un composé qui, après administration dans un organisme, se lie rapidement à l'albumine sanguine, circule de manière persistante par voie systémique, et s'accumule efficacement dans un tissu tumoral, puis libère un médicament actif. Le composé présente une concentration élevée dans le tissu tumoral, un excellent effet anti-tumoral et des effets secondaires réduits. La présente invention concerne un composé représenté par la formule générale (I) [les définitions des symboles individuels dans la formule sont telles que décrites dans la description] ou un sel pharmaceutiquement acceptable de celui-ci, qui peut fournir un excellent agent anticancéreux présentant une excellente action anticancéreuse sur des cellules cancéreuses tout en produisant peu d'effets secondaires.
PCT/JP2018/043032 2017-11-21 2018-11-21 Médicament liant des protéines WO2019103050A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020071550A1 (fr) * 2018-10-04 2020-04-09 京都薬品工業株式会社 Inhibiteur de cdk8 et utilisation associée
CN111875587B (zh) * 2020-07-23 2021-07-13 湖南苏阳医疗科技有限公司 5-氟胞嘧啶衍生物、其制备方法及其在5-氟胞嘧啶免疫检测试剂中的应用
CN113135942A (zh) * 2020-01-17 2021-07-20 江苏恒瑞医药股份有限公司 稠合嘧啶类衍生物、其制备方法及其在医药上的应用

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Publication number Priority date Publication date Assignee Title
JPH072895A (ja) * 1993-04-28 1995-01-06 Eli Lilly & Co 抗体−薬物複合体
JP2003501486A (ja) * 1999-06-09 2003-01-14 カーテーベー トゥモーアフォルシュングス ゲゼルシャフト ミット ベシュレンクテル ハフツング 注射可能な医薬調製剤の製法
JP2015508414A (ja) * 2012-01-12 2015-03-19 イエール ユニバーシティ Ｅ３ユビキチンリガーゼによる標的タンパク質および他のポリペプチドの分解増強のための化合物および方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH072895A (ja) * 1993-04-28 1995-01-06 Eli Lilly & Co 抗体−薬物複合体
JP2003501486A (ja) * 1999-06-09 2003-01-14 カーテーベー トゥモーアフォルシュングス ゲゼルシャフト ミット ベシュレンクテル ハフツング 注射可能な医薬調製剤の製法
JP2015508414A (ja) * 2012-01-12 2015-03-19 イエール ユニバーシティ Ｅ３ユビキチンリガーゼによる標的タンパク質および他のポリペプチドの分解増強のための化合物および方法

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020071550A1 (fr) * 2018-10-04 2020-04-09 京都薬品工業株式会社 Inhibiteur de cdk8 et utilisation associée
CN113135942A (zh) * 2020-01-17 2021-07-20 江苏恒瑞医药股份有限公司 稠合嘧啶类衍生物、其制备方法及其在医药上的应用
CN111875587B (zh) * 2020-07-23 2021-07-13 湖南苏阳医疗科技有限公司 5-氟胞嘧啶衍生物、其制备方法及其在5-氟胞嘧啶免疫检测试剂中的应用

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