WO2016194390A1 - Composition pharmaceutique pour utilisation dans le traitement du cancer - Google Patents

Composition pharmaceutique pour utilisation dans le traitement du cancer Download PDF

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WO2016194390A1
WO2016194390A1 PCT/JP2016/002706 JP2016002706W WO2016194390A1 WO 2016194390 A1 WO2016194390 A1 WO 2016194390A1 JP 2016002706 W JP2016002706 W JP 2016002706W WO 2016194390 A1 WO2016194390 A1 WO 2016194390A1
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compound
pharmaceutical composition
antibody
lower alkyl
cancer
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PCT/JP2016/002706
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English (en)
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Yukihiko Mashima
Tomonari KINOSHITA
Tomonori Yaguchi
Yutaka Kawakami
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R-Tech Ueno, Ltd.
Keio University
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Publication of WO2016194390A1 publication Critical patent/WO2016194390A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present application relates to a method and a pharmaceutical composition for treating cancer.
  • Vascular adhesion protein-1 (referred to as VAP-1 hereafter) is an amine oxidase that is abundant in human plasma also called as semicarbazide sensitive amine oxidase, SSAO. VAP-1 expression in vascular endothelium and vascular smooth muscle is significantly increased in inflammatory lesions. Physiological roles of VAP-1 have not been elucidated although VAP-1 gene was cloned in 1998. VAP-1 is reported as a membrane protein that is regulated by inflammatory cytokines and controls rolling and migration of lymphocytes and NK cells by acting as an adhesion molecule.
  • a physiological substrate for SSAO is methylamine; and that VAP-1 produces, through its amine oxidase activity, hydrogen peroxides and aldehydes, which are known to play a significant role for its adhesion activity.
  • the inventors have found that compounds having VAP-1 inhibitory activity disclosed in WO2009/096609 and WO2009/145360 reduced tumor volume in tumor model mice, and further showed synergistic anti-tumor effect in combination with an anti-CTLA-4 antibody, or with an anti-CTLA-4 antibody and an anti-PD-1 antibody.
  • the present application provides a pharmaceutical composition for treating cancer, which comprises a compound having VAP-1 inhibitory activity or a pharmaceutically acceptable salt thereof.
  • the present application provides a method of treating cancer, comprising administering a compound having VAP-1 inhibitory activity or a pharmaceutically salt thereof to a mammal in need thereof.
  • the present application provides use of a compound having VAP-1 inhibitory activity or a pharmaceutically salt thereof for the manufacture of a medicament for treating cancer.
  • the present application provides a compound having VAP-1 inhibitory activity or a pharmaceutically salt thereof for use in the treatment of cancer.
  • the present application provides a pharmaceutical composition for treating cancer comprising an anti-CTLA-4 antibody, which is for use in combination with a compound having VAP-1 inhibitory activity or a pharmaceutically acceptable salt thereof.
  • the present application provides a pharmaceutical composition for treating cancer comprising an anti-PD-1 antibody, which is for use in combination with a compound having VAP-1 inhibitory activity or a pharmaceutically acceptable salt thereof and an anti-CTLA-4 antibody.
  • the compound having VAP-1 inhibitory activity shows anti-tumor effects and further synergistic effects in combination with an anti-CTLA-4 antibody, or with an anti-CTLA-4 antibody and an anti-PD-1 antibody.
  • Provided by the present disclosure is useful for treating cancer.
  • Fig. 1A shows the decrease of tumor volume in tumor model mice by administration of 2-(4- ⁇ 2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl ⁇ phenyl)acetohydrazide (hereafter, "Compound A”).
  • VAP-1 indicates a compound having VAP-1 inhibitory activity, i.e., a VAP-1 inhibitor.
  • a VAP-1 inhibitor includes, e.g. Compound A as stated above, Compound B as defined later and the like.
  • the label VAP-1 in Fig. 1A indicates the result of Compound A.
  • Fig. 1A indicates the result of Compound A.
  • FIG. 1B shows tumor antigen-specific IFN- ⁇ production by CD8 + cells obtained from tumor mass or draining lymph node.
  • TIL Tumor-infiltrating lymphocytes
  • dLN Draining lymph node.
  • Fig. 1C shows the direct effects of Compound A on cancer cells.
  • Fig. 2 shows the combination effects of Compound A and an anti-CTLA-4 antibody on tumor volume.
  • Fig. 3 shows the reduction of soluble VAP-1 (sVAP-1) by Compound A in serum of tumor model mice.
  • Fig. 4 shows the effects of Compound A in a different mouse tumor model.
  • Fig. 5 shows the effects of Compound A in NOG mouse model and CD8 depletion model.
  • FIG. 6 shows the results of FACS (Fluorescence Activated Cell Sorting) analysis of tumor-infiltrating lymphocytes.
  • Fig. 7 shows the change in the population of tumor-infiltrating lymphocytes induced by Compound A.
  • Fig. 8 shows the change of activated T cells in tumor-infiltrating lymphocytes induced by Compound A.
  • Fig. 9 shows the effects of Compound A on T cell population in draining lymph node.
  • Fig. 10 shows the change in myeloid-derived suppressor cells in tumor induced by Compound A.
  • Fig. 11 shows the effects of Compound A on dendritic cell activation in tumor.
  • Fig. 12 shows the decrease of tumor volume in tumor model mice by Compound B (4- ⁇ 2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl ⁇ benzyl hydrazinecarboxylate).
  • Fig. 13 shows the combination effects of Compound A and an anti-PD-1 antibody on tumor volume.
  • Fig. 14 shows the increase of PD-1 positive cells by Compound A.
  • Fig. 15 shows the effects on tumor volume of Compound A, doublet combination of an anti-CTLA-4 antibody and an anti-PD-1 antibody, or triplet combination of Compound A, an anti-CTLA-4 antibody, and an anti-PD-1 antibody.
  • the present application provides a pharmaceutical composition for treating cancer, which comprises a compound having VAP-1 inhibitory activity or a pharmaceutically acceptable salt thereof.
  • the compound is a compound represented by the formula (I): X-Y-A-B-D-E (I) wherein X is wherein A 1 is a residue derived from benzene or a heterocycle containing at least one nitrogen or sulfur atom; B 1 is hydrogen, hydroxy, halogen, lower alkyl, lower cycloalkyl, lower haloalkyl, lower alkoxy, acyl, acylamino, optionally substituted carbamoyl, (lower alkyl)sulfonylamino, or (lower alkyl)carbonyloxy, with the proviso that, when A 1 is a residue derived from thiazole, B 1 is not acylamino; B 2 is hydrogen or a group containing at least one nitrogen atom, with the proviso that, when A 1 is a residue derived from
  • halogen includes fluorine, bromine, chlorine, and iodine.
  • lower as used for a functional group means that the group has 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise specified.
  • lower alkyl includes straight chain or branched chain alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, or hexyl. Preferred is C 1 -C 4 alkyl.
  • lower haloalkyl includes lower alkyl substituted with halogen. When two or more halogen substituents are present, the substituents may be the same or different. Examples of the lower haloalkyl include trifluoromethyl, trichloromethyl, and pentafluoroethyl.
  • lower alkylene includes straight chain or branched chain alkylene having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, propylene, ethylidene, or propylidene. Preferred is C 1 -C 4 alkylene.
  • lower alkenylene includes straight chain or branched chain alkenylene having 2 to 6 carbon atoms.
  • Examples of such lower alkenylene include vinylene, 1-propenylene, 1-methyl-l-propenylene, 2-methyl-1-propenylene, 2-propenylene, 2-butenylene, 1-butenylene, 3-butenylene, 2-pentenylene, 1-pentenylene, 3-pentenylene, 4-pentenylene, 1,3-butadienylene, 1,3-pentadienylene, 2-penten-4-ynylene, 2-hexenylene, 1-hexenylene, 5-hexenylene, 3-hexenylene, 4-hexenylene, 3,3-dimethyl-1-propenylene, 2-ethyl-1-propenylene, 1,3,5-hexatrienylene, 1,3-hexadienylene, and 1,4-hexadienylene.
  • Preferred is C 2 -C 4 alkenylene
  • lower alkenylene may be in an E- or Z-form.
  • the compound of the formula (I) may be a geometric isomer having E- or Z-configuration in the lower alkenylene moiety.
  • lower alkynylene includes straight chain or branched chain alkynylene having 2 to 6 carbon atoms and 1 to 3 triple bonds.
  • Examples of such lower alkynylene include ethynylene, 1-propynylene, 1-methyl-1-propynylene, 2-methyl-1-propynylene, 2-propynylene, 2-butynylene, 1-butynylene, 3-butynylene, 2-pentynylene, 1-pentynylene, 3-pentynylene, 4-pentynylene, 2-pentyn-4-ynylene, 2-hexynylene, 1-hexynylene, 5-hexynylene, 3-hexynylene, 4-hexynylene, 3,3-diethyl-1-propynylene, and 2-ethyl-1-propynylene.
  • Preferred is C 2 -C 4 alkynylene.
  • aryl includes C 6 -C 10 aryl such as phenyl or naphthyl.
  • the aryl may be optionally substituted at any one or more positions.
  • substituents on the aryl include methyl, ethyl, hydroxy, methoxy, amino, acetyl, and halogen. When two or more substituents are present, the substituents may be the same or different.
  • aralkyl includes aralkyl whose aryl moiety has 6 to 10 carbon atoms (i.e., the aryl moiety is C 6 -C 10 aryl as defined herein about the term “aryl”) and whose alkyl moiety has 1 to 6 carbon atoms (i.e., the alkyl moiety is C 1 -C 6 alkyl as defined herein about the term “lower alkyl”).
  • aralkyl include benzyl, phenethyl, 1-naphthylmethyl, 2-naphthylmethyl, 3-phenylpropyl, 4-phenylbutyl, and 5-phenylpentyl.
  • lower cycloalkyl includes cycloalkyl having 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • heterocycle includes “aromatic heterocycle” and "non-aromatic heterocycle”.
  • the aromatic heterocycle includes 5- to 10-membered aromatic heterocycle containing 1 to 3 hetero atoms selected from nitrogen, oxygen, and sulfur atoms. Examples of such aromatic heterocycle include thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyridazine, pyrimidine, and pyrazine.
  • the non-aromatic heterocycle includes 5- to 10-membered non-aromatic heterocycle containing 1 to 3 hetero atoms selected from nitrogen, oxygen, and sulfur atoms.
  • non-aromatic heterocycle examples include pyrrolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, homopiperazine, triethylenediamine, morpholine, thiomorpholine, dioxolane, oxazolidine, thiazolidine, triazolidine, and 2,5-diazabicyclo[2.2.1]heptane.
  • acyl includes (lower alkyl)carbonyl, (lower cycloalkyl)carbonyl, and arylcarbonyl.
  • (lower alkyl)carbonyl includes alkylcarbonyl whose alkyl moiety has 1 to 6 carbon atoms (i.e., the alkyl moiety is C 1 -C 6 alkyl as defined herein about the term “lower alkyl”), such as acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, or hexanoyl.
  • (lower cycloalkyl)carbonyl includes cycloalkylcarbonyl whose cycloalkyl moiety has 3 to 6 carbon atoms (i.e., the cycloalkyl moiety is C 3 -C 6 cycloalkyl as defined herein about the term "lower cycloalkyl”), such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, or cyclohexylcarbonyl.
  • arylcarbonyl includes arylcarbonyl whose aryl moiety has 6 to 10 carbon atoms (i.e., the aryl moiety is C 6 -C 10 aryl as defined herein about the term “aryl”), such as benzoyl or naphthoyl.
  • acylamino includes acylamino whose acyl moiety is the acyl as defined herein.
  • examples of such acylamino include acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino, isovalerylamino, pivaloylamino, hexanoylamino, cyclopropylcarbonylamino, cyclobutylcarbonylamino, cyclopentylcarbonylamino, cyclohexylcarbonylamino, benzoylamino, and naphthoylamino.
  • lower alkoxy includes straight chain or branched chain alkoxy having 1 to 6 carbon atoms. Examples of such lower alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, tert-pentoxy, and hexoxy. Preferred is C 1 -C 4 alkoxy.
  • the lower alkoxy may be optionally substituted with one or more substituents. Examples of the substituents include halogen, acyl, and aminocarbonyl (the terms “halogen” and "acyl” are as defined herein). When two or more substituents are present, the substituents may be the same or different.
  • alkoxy includes optionally substituted alkyloxy, lower cycloalkyloxy, and aralkyloxy.
  • alkyloxy in the term “optionally substituted alkyloxy” includes alkyloxy whose alkyl moiety has 1 to 10 carbon atoms. Examples of such alkyloxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, tert-pentyloxy, hexyloxy, and decyloxy. Examples of substituents on the "optionally substituted alkyloxy” include halogen, acyl, and aminocarbonyl (the terms “halogen” and "acyl” are as defined herein). The alkyloxy may be substituted at any or more positions. When two or more substituents are present, the substituents may be the same or different.
  • lower cycloalkyloxy includes cycloalkyloxy whose cycloalkyl moiety has 3 to 6 carbon atoms (i.e., the cycloalkyl moiety is C 3 -C 6 cycloalkyl as defined herein about the term “lower cycloalkyl”), such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, or cyclohexyloxy.
  • aralkyloxy includes aralkyloxy whose aryl moiety has 6 to 10 carbon atoms (i.e., the aryl moiety is C 6 -C 10 aryl as defined herein about the term “aryl”) and whose alkyl moiety has 1 to 6 carbon atoms (i.e., the alkyl moiety is C 1 -C 6 alkyl as defined herein about the term “lower alkyl”).
  • aralkyloxy include benzyloxy, phenethyloxy, 1-naphthylmethyloxy, 2-naphthylmethyloxy, 3-phenylpropyloxy, 4-phenylbutyloxy, and 5-phenylpentyloxy.
  • alkoxycarbonyl includes alkyloxycarbonyl, (lower cycloalkyloxy)carbonyl, and aralkyloxycarbonyl.
  • alkyloxycarbonyl includes alkyloxycarbonyl whose alkyl moiety has 1 to 10 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, tert-pentyloxycarbonyl, hexyloxycarbonyl, or decyloxycarbonyl.
  • (lower alkoxy)carbonyl is alkyloxycarbonyl whose alkyl moiety has 1 to 6 carbon atoms.
  • (lower cycloalkyloxy)carbonyl includes cycloalkyloxycarbonyl whose cycloalkyl moiety has 3 to 6 carbon atoms (i.e., the cycloalkyl moiety is C 3 -C 6 cycloalkyl as defined herein about the term "lower cycloalkyl”), such as cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, or cyclohexyloxycarbonyl.
  • aralkyloxycarbonyl includes aralkyloxycarbonyl whose aryl moiety has 6 to 10 carbon atoms (i.e., the aryl moiety is C 6 -C 10 aryl as defined herein about the term “aryl”) and whose alkyl moiety has 1 to 6 carbon atoms (i.e., the alkyl moiety is C 1 -C 6 alkyl as defined herein about the term "lower alkyl”).
  • aralkyloxycarbonyl examples include benzyloxycarbonyl, phenethyloxycarbonyl, 1-naphthylmethyloxycarbonyl, 2-naphthylmethyloxycarbonyl, 3-phenylpropyloxycarbonyl, 4-phenylbutyloxycarbonyl, and 5-phenylpentyloxycarbonyl.
  • optionally substituted carbamoyl includes unsubstituted carbamoyl, and carbamoyl substituted with one or two substituents.
  • the optionally substituted carbamoyl is represented by the formula -CONR 4 R 5 .
  • R 4 and R 5 may be the same or different, and are independently selected from hydrogen; and lower alkyl, acyl, in particular (lower alkyl)carbonyl, alkoxycarbonyl, in particular (lower alkoxy)carbonyl, aryl, aralkyl, lower cycloalkyl, sulfuryl, sulfinyl, phosphoryl, and heterocyclyl, each of which is optionally substituted with one or more substituents such as hydroxy.
  • acyl in particular (lower alkyl)carbonyl, alkoxycarbonyl, in particular (lower alkoxy)carbonyl, aryl, aralkyl, lower cycloalkyl, sulfuryl, sulfinyl, phosphoryl, and heterocyclyl, each of which is optionally substituted with one or more substituents such as hydroxy.
  • lower alkyl acyl
  • alkoxycarbonyl alkoxycarbonyl
  • aryl alkoxycarbonyl
  • aralkyl lower cycloalkyl
  • heterocyclyl is a residue derived from the "heterocycle” as defined herein.
  • (lower alkyl)sulfonylamino includes alkylsulfonylamino and di(alkylsulfonyl)amino whose alkyl moiety has 1 to 6 carbon atoms (i.e., the alkyl moiety is C 1 -C 6 alkyl as defined herein about the term "lower alkyl").
  • Examples of such (lower alkyl)sulfonylamino include methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylamino, tert-butylsulfonylamino, pentylsulfonylamino, tert-pentylsulfonylamino, and hexylsulfonylamino; and di(methylsulfonyl)amino, di(ethylsulfonyl)amino, and (methylsulfonyl)(ethylsulfonyl)amino).
  • (lower alkyl)carbonyloxy includes alkylcarbonyloxy whose alkyl moiety has 1 to 6 carbon atoms (i.e., the alkyl moiety is C 1 -C 6 alkyl as defined herein about the term “lower alkyl”), such as methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy, tert-butylcarbonyloxy, pentylcarbonyloxy, tert-pentylcarbonyloxy, or hexylcarbonyloxy.
  • (lower alkyl)amino includes alkylamino and dialkylamino whose alkyl moiety has 1 to 6 carbon atoms (i.e., the alkyl moiety is C 1 -C 6 alkyl as defined herein about the term “lower alkyl”).
  • Examples of such (lower alkyl)amino include methylamino, ethylamino, propylamine, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, tert-pentylamino, and hexylamino; and dimethylamino, diethylamino, dipropylamino, ethylmethylamino, methylpropylamino, and ethylpropylamino.
  • a 1 is a residue derived from benzene or a heterocycle containing at least one nitrogen or sulfur atom, such as a residue derived from benzene, pyridine, pyridazine, pyrimidine, pyrazine, pyrrole, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, or thiophene.
  • a 1 binds to Y at any position on the ring.
  • a 1 is a residue derived from benzene, pyridine, pyridazine, pyrimidine, pyrazine, imidazole, thiazole, or thiophene.
  • a 2 is a divalent residue derived from optionally substituted thiazole.
  • Examples of the "divalent residue derived from optionally substituted thiazole", i.e., A 2 , includes
  • the thiazole may be optionally substituted at any one or more positions.
  • substituents on the "optionally substituted thiazole” include the followings: (1) halogen, such as fluoro, chloro, and bromo; (2) alkoxycarbonyl as defined herein, such as ethoxycarbonyl; (3) optionally substituted aryl, wherein the term “aryl” is as defined herein and may be substituted at any one or more positions with, for example, -SO 2 -(lower alkyl) (the term “lower alkyl” is as defined herein), such as phenyl and 4-(methylsulfonyl)phenyl; (4) a group of the formula: -CONR a R b , wherein R a is hydrogen, lower alkyl, aryl, or aralkyl and R b is hydrogen, lower alkyl, aryl, or aralkyl (the terms “lower alkyl", “aryl", and "aralkyl
  • A is a divalent residue derived from optionally substituted benzene or optionally substituted thiophene.
  • the benzene and thiophene may be optionally substituted at any one or more positions.
  • substituents on the "optionally substituted benzene" and the “optionally substituted thiophene” include halogen (e.g., fluoro, chloro, and bromo), lower alkyl (e.g., methyl and ethyl), lower alkoxy (e.g., methoxy), acyl (e.g., acetyl), and haloalkyl (e.g., trifluoromethyl). When two or more substituents are present, the substituents may be the same or different.
  • the benzene or thiophene is substituted with (i.e., binds to) Y and B at any two positions.
  • the benzene may be ortho-, meta- or para-substituted.
  • the thiophene may be substituted at any two positions of positions 2, 3, 4, and 5.
  • the benzene is preferably meta- or para-substituted with Y and B as shown below:
  • the thiophen is preferably substituted with Y and B at positions 2 and 5 (or 5 and 2), or positions 2 and 4 (or 5 and 3) as shown below:
  • a 1 is substituted with B 1 and B 2 at any two positions.
  • B 1 is hydrogen, hydroxy, halogen, lower alkyl, lower cycloalkyl, lower haloalkyl, lower alkoxy, acyl, acylamino, optionally substituted carbamoyl, (lower alkyl)sulfonylamino, or (lower alkyl)carbonyloxy, with the proviso that, when A 1 is a residue derived from thiazole, B 1 is not acylamino.
  • halogen means "lower alkyl”, “lower cycloalkyl”, “lower haloalkyl”, “lower alkoxy”, "acyl”, “acylamino”, “optionally substituted carbamoyl”, “(lower alkyl)sulfonylamino", and “(lower alkyl)carbonyloxy” are as defined herein.
  • B 1 examples include hydrogen; hydroxy; halogen, such as fluoro, chloro, or bromo; lower alkyl, such as methyl, ethyl, or isopropyl; lower cycloalkyl, such as cyclopropyl; lower haloalkyl, such as trifluoromethyl; lower alkoxy, such as methoxy, ethoxy, trifluoromethoxy, or aminocarbonylmethoxy; acyl, such as acetyl or ethylcarbonyl; acylamino, such as acetylamino or ethylcarbonylamino; optionally substituted aminocarbonyl (carbamoyl), such as aminocarbonyl, N-methylaminocarbonyl, or N,N-dimethylaminocarbonyl; (lower alkyl)sulfonylamino, such as methylsulfonylamino, ethylsulfonylamino,
  • B 1 is preferably hydrogen, methyl, trifluoromethyl, acetylamino, aminocarbonyl (carbamoyl), aminocarbonylmethoxy, methylsulfonylamino, ethylsulfonylamino, or methylcarbonyloxy.
  • B 2 is hydrogen or a group containing at least one nitrogen atom, with the proviso that, when A 1 is a residue derived from thiazole, B 2 is not acylamino.
  • group containing at least one nitrogen atom may be acylamino; (lower alkyl)amino optionally substituted with amino or acetylamino; optionally substituted heterocyclyl containing at least one nitrogen atom; or methyl substituted with (lower alkyl)amino or optionally substituted heterocyclyl containing at least one nitrogen atom.
  • acylamino and “(lower alkyl)amino” are as defined herein.
  • heterocyclyl containing at least one nitrogen atom of the term “optionally substituted heterocyclyl containing at least one nitrogen atom” is a residue derived from a heterocycle that contains at least one nitrogen atom as defined herein.
  • substituents on the "optionally substituted heterocyclyl containing at least one nitrogen atom” include lower alkyl (e.g., methyl), (lower alkyl)carbonyl (e.g., acetyl), and hydroxy. When two or more substituents are present, the substituents may be the same or different.
  • B 2 include acylamino, such as acetylamino or ethylcarbonylamino; (lower alkyl)amino optionally substituted with amino or acetylamino, such as methylamino, ethylamino, dimethylamino, diethylamino, dipropylamino, ethylmethylamino, methylpropylamino, ethylpropylamino, ethyl(aminoethyl)amino, or ethyl(acetylaminoethyl)amino; heterocyclyl that is derived from a heterocycle containing at least one nitrogen atom, such as pyrrolidine, piperidine, piperazine, homopiperadine, morpholine, triethylenediamine, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, pyrrole, imidazole,
  • B 2 is preferably hydrogen, dimethylamino, diethylamino, dipropylamino, ethylmethylamino, methylpropylamino, ethylpropylamino, acetylamino, morpholino, piperidino, piperidinyl, piperazinyl, pyrrolidinyl, pyrazolyl, N-methylpiperazinyl, N-acetylpiperazinyl, N-acetylpiperidinyl, morpholinomethyl, piperazinylmethyl, 2,5-diazabicyclo[2.2.1]hept-2-yl, or 5-acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl.
  • B 1 and B 2 may together form a cyclic structure.
  • the term "cyclic structure" may be 5- to 7-membered heterocyclic structure having at least one nitrogen atom as a ring-constituting atom, such as morpholine or piperazine.
  • the "cyclic structure” may be optionally substituted, for example, with oxo, lower alkyl (e.g., methyl), lower haloalkyl (e.g., trifluoromethyl), or lower acyl (e.g., acetyl). When two or more substituents are present, the substituents may be the same or different.
  • Y is a group of the formula (II): J-L-M, wherein J is a bond, lower alkylene, lower alkenylene, lower alkynylene, -(CH 2 ) n -O-, -(CH 2 ) n -NH-, -(CH 2 ) n -CO-, or -(CH 2 ) n -SO 2 -; L is a bond, -O-, -NH-, -CO-, or -SO 2 -; and M is a bond, lower alkylene, lower alkenylene, or lower alkynylene; with the proviso that, when J is -(CH 2 ) n -O-, L is not -O-, -NH-, or -SO 2 -; when J is -(CH 2 ) n -NH-, L is not -O- or -NH-; when J is -(CH 2 ) n -M
  • Examples of the group of the formula (II) include -(CH 2 ) n -, -(CH 2 ) n -NH-(CH 2 ) n' -, -(CH 2 ) n -O-(CH 2 ) n' -, -(CH 2 ) n -CO-O-(CH 2 ) n' -, -(CH 2 ) n -O-CO-(CH 2 ) n' -, -(CH 2 ) n -CO-NH-(CH 2 ) n' -, -(CH 2 ) n -NH-CO-(CH 2 ) n' -, -(CH 2 ) n -SO 2 -NH-(CH 2 ) n' -, -(CH 2 ) n -NH-SO 2 -(CH 2 ) n' -, vinyl, and ethynylene, wherein n and n' are independently an
  • the group of formula (II) is preferably -(CH 2 ) n -, -(CH 2 ) n -NH-(CH 2 ) n' -, -(CH 2 ) n -O-(CH 2 ) n' -, -(CH 2 ) n -CO-O-(CH 2 ) n' -, -(CH 2 ) n -CO-NH-(CH 2 ) n' -, or ethynylene, and more preferably, -(CH 2 ) n - or ethynylene.
  • group of formula (II) include -(CH 2 ) 2 -, -CH 2 -O-, -CH 2 -NH-, -CO-O-, -CO-NH-, and ethynylene.
  • Y is preferably -(CH 2 ) 2 - or ethynylene.
  • B is -(CH 2 ) m -CO-, -(CH 2 ) m -O-CO-, -(CH 2 ) m -S-CO-, or -(CH 2 ) m -NR 2 -CO-, wherein m is an integer of from 0 to 6, and R 2 is hydrogen, lower alkyl, or acyl.
  • R 2 is hydrogen, lower alkyl, or acyl.
  • the terms "lower alkyl” and “acyl” are as defined herein.
  • m is an integer of from 0 to 3.
  • B examples include -CO- (i.e., -(CH 2 ) m -CO- wherein m is 0), -CH 2 -CO-, -(CH 2 ) 2 -CO-, -O-CO-, -CH 2 -O-CO-, -(CH 2 ) 2 -O-CO-, -(CH 2 ) 3 -O-CO-, -CH 2 -NH-CO-, -(CH 2 ) 2 -NH-CO-, -(CH 2 ) 3 -NH-CO-, -S-CO-, -CH 2 -S-CO-, and -(CH 2 ) 2 -S-CO-.
  • D is -NR 3 -, wherein R 3 is hydrogen, lower alkyl, acyl, or (lower alkoxy)carbonyl.
  • R 3 is hydrogen, lower alkyl, acyl, or (lower alkoxy)carbonyl.
  • the terms "lower alkyl”, “acyl”, and “(lower alkoxy)carbonyl” are as defined herein.
  • D may be -NH- or -N(CH 3 )-, preferably -NH-.
  • E is optionally substituted amino, including unsubstituted amino, and amino substituted by one or two substituents.
  • optionally substituted amino is represented by the formula: -NR 6 R 7 .
  • R 6 and R 7 may be the same or different, and independently selected from hydrogen, optionally substituted lower alkyl, acyl, in particular (lower alkyl)carbonyl, alkoxycarbonyl, in particular (lower alkoxy)carbonyl, aryl, aralkyl, lower cycloalkyl, sulfuryl, sulfinyl, phosphoryl, and heterocyclyl.
  • acyl in particular (lower alkyl)carbonyl, alkoxycarbonyl, in particular (lower alkoxy)carbonyl, aryl, aralkyl, lower cycloalkyl, sulfuryl, sulfinyl, phosphoryl, and heterocyclyl.
  • the terms “lower alkyl”, “acyl”, “(lower alkyl)carbonyl”, “alkoxycarbonyl”, “(lower alkoxy)carbonyl”, “aryl”, “aralkyl”, and “lower cycloalkyl” are as defined here
  • each of R 6 and R 7 include hydrogen, lower alkyl (e.g., methyl or ethyl), acetyl, butanoyl, decanoyl, 3-hydroxypropanoyl, 6-hydroxyhexanoyl, ethoxycarbonyl, butoxycarbonyl, decyloxycarbonyl, and 2-hydroxyethoxycarbonyl.
  • E is preferably -NH 2 .
  • E may be an amino that is protected with R 6 and/or R 7 by methods such as those described in "Protective Groups in Organic Synthesis 3rd Edition” (John Wiley and Sons, 1999) (i.e., R 6 and/or R 7 may be an amino protecting group).
  • the -B-D-E moiety of the formula (I) preferably has -CO-, -O-CO-, -CH 2 -CO-, -(CH 2 ) 2 -CO-, -CH 2 -O-CO-, -(CH 2 ) 2 -O-CO-, -(CH 2 ) 3 -O-CO-, -CH 2 -NH-CO-, -(CH 2 ) 2 -NH-CO- or -(CH 2 ) 3 -NH-CO- as B; -NH- as D; and -NH 2 as E.
  • the -B-D-E moiety is preferably -CO-NH-NH 2 , -O-CO-NH-NH 2 , -CH 2 -CO-NH-NH 2 , -(CH 2 ) 2 -CO-NH-NH 2 , -CH 2 -O-CO-NH-NH 2 , -(CH 2 ) 2 -O-CO-NH-NH 2 , -(CH 2 ) 3 -O-CO-NH-NH 2 , -CH 2 -NH-CO-NH-NH 2 , -(CH 2 ) 2 -NH-CO-NH-NH 2 , or -(CH 2 ) 3 -NH-CO-NH-NH 2 .
  • the present disclosure encompasses all enantiomers and diastereomers of the compound.
  • the compound of the formula (I) is 2-(4- ⁇ 2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl ⁇ phenyl)acetohydrazide of the following formula:
  • the compound of the formula (I) is (4- ⁇ 2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl ⁇ benzyl hydrazinecarboxylate of the following formula:
  • the pharmaceutically acceptable salt as used herein includes salts with inorganic or organic base, and acid addition salts.
  • salts with inorganic or organic base include alkali metal salts (e.g., sodium salt and potassium salt), alkaline earth metal salts (e.g., calcium salt and magnesium salt), ammonium salts, and amine salts (e.g., triethylamine salt and N-benzyl-N-methylamine salt).
  • the acid addition salts include salts with mineral acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid), and salts with organic acids (e.g., tartaric acid, acetic acid, trifluoroacetic acid, citric acid, malic acid, lactic acid, fumaric acid, maleic acid, benzoic acid, glycol acid, gluconic acid, succinic acid, and arylsulfonic acid such as p-toluenesulfonic acid).
  • mineral acids e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid
  • organic acids e.g., tartaric acid, acetic acid, trifluoroacetic acid, citric acid, malic acid, lactic acid, fumaric acid, maleic acid, benzoic acid, glycol
  • the compound of the formula (I) may be prepared by methods as described in WO 2009/096609 or WO 2009/145360.
  • the compound having VAP-1 inhibitory activity is useful for the treatment of cancer.
  • treatment of cancer or “treating cancer” includes therapeutic and prophylactic treatment of cancer, such as prophylaxis of symptoms, and cure, amelioration, reduction, prevention of exacerbation, or any other control of symptoms.
  • the cancer includes leukemia, lymphoma, blastoma, carcinoma (malignant tumor derived from epithelial cells) and sarcoma (malignant tumor arising from connective tissue derived from non-epithelial cells).
  • the cancer include large intestine cancer (including colon cancer and rectal cancer), melanoma (e.g., metastatic malignant melanoma), kidney cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone-refractory prostate adenocarcinoma), breast cancer, lung cancer (e.g., non-small-cell lung cancer), bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or orbital malignant melanoma, uterine cancer, ovarian cancer, anal cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, non-Hodgkin's lymphoma,
  • the pharmaceutical composition of the present application is particularly useful for the treatment of carcinoma (malignant tumor derived from epithelial cells), or large intestine cancer (including colon cancer and rectal cancer), melanoma (e.g., metastatic malignant melanoma), kidney cancer, prostate cancer, breast cancer, and lung cancer (e.g., non-small-cell lung cancer).
  • carcinoma malignant tumor derived from epithelial cells
  • large intestine cancer including colon cancer and rectal cancer
  • melanoma e.g., metastatic malignant melanoma
  • kidney cancer e.g., prostate cancer, breast cancer
  • lung cancer e.g., non-small-cell lung cancer
  • the compound having VAP-1 inhibitory activity may be used in combination with a different agent or therapy that is effective for the treatment of cancer.
  • the compound having VAP-1 inhibitory activity is used in combination with an anti-CTLA-4 antibody.
  • the compound having VAP-1 inhibitory activity is used in combination with an anti-CTLA-4 antibody and an anti-PD-1 antibody.
  • the antibody includes monoclonal and polyclonal antibodies and antibody fragments.
  • the antibody may be a chimeric, humanized, or human antibody.
  • the antibody fragments include heavy and light chain variable regions (VH and VL), F(ab')2, Fab', Fab, Fv, Fd, single-domain FV (sdFv), single-chain FV (scFV), and complexes thereof.
  • CTLA-4 refers to Cytotoxic T-Lymphocyte Antigen 4, i.e., a member of the immunoglobulin superfamily, which is expressed on the surface of Helper T cells and transmits an inhibitory signal to T cells.
  • anti-CTLA-4 antibody refers to an antibody that selectively binds to a CTLA-4 polypeptide.
  • An exemplary anti-CTLA-4 antibody includes, but not limited to, e.g. ipilimumab and tremelimumab.
  • PD-1 refers to programmed cell death protein 1, or a protein originally isolated from a T-cell hybridoma undergoing T-cell receptor activation-induced cell death.
  • PD-1 is a cell surface receptor that belongs to the immunoglobulin superfamily and is expressed on T cells and pro-B cells.
  • anti-PD-1 antibody refers to an antibody that selectively binds to a PD-1 polypeptide.
  • An exemplary anti-PD-1 antibody includes, but not limited to, e.g. nivolumab and pembrolizumab.
  • the subject according to the present application is a mammal such as human, mouse, rat, swine, dog, cat, horse, or bovine.
  • the subject is human.
  • the pharmaceutical composition may comprise a pharmaceutically acceptable carrier together with the compound having VAP-1 inhibitory activity as an active ingredient.
  • the pharmaceutically acceptable carrier may be any carrier generally used in pharmaceutical compositions unless it has undesired physicochemical properties such as solubility or reactivity for the compound having VAP-1 inhibitory activity, or it is not suitable for the route of administration.
  • the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition may vary depending on the type of formulation, and it is typically 0.00001 to 10.0 % by weight, 0.001 to 5 % by weight, or 0.001 to 1 % by weight.
  • Dosage forms, dosage amounts, and frequency of administration are appropriately determined according to diseases to be treated, condition of the subject, and target sites.
  • Dosage forms for oral administration includes solid dosage forms (such as capsule, tablet, and powder) or liquid dosage forms (such as solution and suspension).
  • Dosage forms for parenteral administration includes aseptic solutions or suspensions for injection or infusion.
  • the oral solid formulation may contain a conventional vehicle.
  • the oral liquid formulation may contain one or more additives such as aromatics, colorants, preservatives, stabilizers, solubilizers, or suspending agents.
  • the parenteral formulation may be aseptic, aqueous or nonaqueous solutions or suspensions and may contain additives such as preservatives, stabilizers, buffer agents, solubilizers, and suspending agents. Where necessary, the formulation may further contain isotonic agents.
  • the pharmaceutical composition may be administered by any route.
  • the route of administration includes systemic administration (such as oral administration or administration by injection) and local administration (such as ocular instillation, intraocular administration, or transdermal administration).
  • the pharmaceutical composition may also be administered by transmucosal administration such as intranasal, buccal, intravaginal, intrarectal, or sublingual administration.
  • the compound of the formula (I) may be administered about 0.03 ng/kg body weight/day to about 300 mg/kg body weight/day, preferably about 0.003 ⁇ g/kg body weight/day to about 10 mg/kg body weight/day.
  • Dosage regimens such as frequency of administration per day and intervals of administration are appropriately adjusted.
  • a daily dose may be administered by a single dose or several divided doses (such as two, three, or four doses) or continuously.
  • the administration of the compound may be daily administration, or once every few days, once a week, once every few weeks, once a month, or once every few months.
  • the anti-CTLA-4 antibody and the anti-PD-1 antibody may be administered at about 0.0001 to 100 mg/kg body weight, preferably 0.01 to 10 mg/kg body weight, more preferably 0.3 to 10 mg/kg body weight/day, respectively.
  • the antibody may be administered at about 0.3 mg/kg body weight, about 1 mg/kg body weight, about 2 mg/kg body weight, about 3mg/kg body weight, about 5 mg/kg body weight, about 9 mg/kg body weight, or about 10 mg/kg body weight.
  • the dosage amount of the antibody may be administered by a single dose or several divided doses (such as two, three, or four doses) or continuously.
  • the administration of the antibody may be daily administration, or once every few days, once a week, once every few weeks, once a month, or once every few months.
  • the antibody may be administered once a week, once every two weeks, once every three weeks, once every four weeks, once a month, once every three months, or once every three to six months.
  • the anti-CTLA-4 antibody and the anti-PD-1 antibody are administered intravenously.
  • the compound having VAP-1 inhibitory activity and an agent used in combination may be contained in separate formulations, respectively, or in a single formulation.
  • the compound having VAP-1 inhibitory activity and the combined agent may be provided in a kit.
  • the kit comprises a pharmaceutical composition comprising the compound having VAP-1 inhibitory activity and a pharmaceutical composition comprising an anti-CTLA-4 antibody, and optionally a pharmaceutical composition comprising an anti-PD-1 antibody.
  • the pharmaceutical composition and kit of the present application may be distributed with package inserts that indicate dosage and administration of the compound having VAP-1 inhibitory activity, or dosage and administration of the compound having VAP-1 inhibitory activity for use in combination with the combined agent, and where appropriate, packages and/or written instructions.
  • the compound having VAP-1 inhibitory activity and the combined agent may be administered concurrently or separately.
  • concurrently means that the compound having VAP-1 inhibitory activity and the combined agent are administered in the same administration schedule, and the compound and the agent may be contained in separate formulations, respectively, or in a single formulation.
  • separatately means that the compound having VAP-1 inhibitory activity and the combined agent are administered in different administration schedules, both of which may be individually determined.
  • a pharmaceutical composition for treating cancer which comprises a compound having VAP-1 inhibitory activity or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of item 1 wherein the compound is represented by the formula (I): X-Y-A-B-D-E (I) wherein X is wherein A 1 is a residue derived from benzene or a heterocycle containing at least one nitrogen or sulfur atom; B 1 is hydrogen, hydroxy, halogen, lower alkyl, lower cycloalkyl, lower haloalkyl, lower alkoxy, acyl, acylamino, optionally substituted carbamoyl, (lower alkyl)sulfonylamino, or (lower alkyl)carbonyloxy, with the proviso that, when A 1 is a residue derived from thiazole, B 1 is not acylamino; B 2 is hydrogen or a group containing at least one nitrogen atom, with the proviso that, when A 1 is a residue derived from thi
  • a 1 is a residue derived from benzene, pyridine, pyridazine, pyrimidine, pyrazine, imidazole, thiazole, or thiophene.
  • B 1 is hydrogen, methyl, trifluoromethyl, acetylamino, aminocarbonyl (carbamoyl), aminocarbonylmethoxy, methylsulfonylamino, ethylsulfonylamino, or methylcarbonyloxy. 5.
  • B 2 is hydrogen, dimethylamino, diethylamino, dipropylamino, ethylmethylamino, methylpropylamino, ethylpropylamino, acetylamino, morpholino, piperidino, piperidinyl, piperazinyl, pyrrolidinyl, pyrazolyl, N-methylpiperazinyl, N-acetylpiperazinyl, N-acetylpiperidinyl, morpholinomethyl, piperazinylmethyl, 2,5-diazabicyclo[2.2.1]hept-2-yl, or 5-acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl.
  • B 1 is hydrogen.
  • B 2 is morpholino, piperidino, piperidinyl, piperazinyl, pyrrolidinyl, pyrazolyl, N-methylpiperazinyl, N-acetylpiperazinyl, N-acetylpiperidinyl, morpholinomethyl, or piperazinylmethyl.
  • Y is -(CH 2 ) n - and n is an integer of from 0 to 3.
  • the pharmaceutical composition of any one of items 2-13, wherein -Y-A-B- is 15.
  • a 1 is a residue derived from benzene, pyridine, pyridazine, pyrimidine, pyrazine, imidazole, thiazole, or thiophene
  • B 1 is hydrogen, methyl, trifluoromethyl, acetylamino, aminocarbonyl (carbamoyl), aminocarbonylmethoxy, methylsulfonylamino, ethylsulfonylamino, or methylcarbonyloxy
  • B 2 is hydrogen, dimethylamino, diethylamino, dipropylamino, ethylmethylamino, methylpropylamino, ethylpropylamino, acetylamino, morpholino, piperidino, piperidinyl, piperazinyl, pyrrolidinyl, pyrazolyl, N-methylpiperazinyl, N
  • X is wherein A 1 is a residue derived from pyridine; B 1 is hydrogen; B 2 is morpholino, piperidino, piperidinyl, piperazinyl, pyrrolidinyl, pyrazolyl, N-methylpiperazinyl, N-acetylpiperazinyl, N-acetylpiperidinyl, morpholinomethyl, or piperazinylmethyl; Y is -(CH 2 ) n -, wherein n is an integer of from 0 to 3; -Y-A-B- is B is -(CH 2 ) m -CO-, wherein m is an integer of from 0 to 3; D is -NH-; and E is -NH 2 .
  • 24. The pharmaceutical composition of any one of items 1-23, wherein the pharmaceutical composition is for use in combination with an anti-CTLA-4 antibody. 25.
  • the pharmaceutical composition of item 24, wherein the anti-CTLA-4 antibody is ipilimumab or tremelimumab.
  • 26. The pharmaceutical composition of any one of items 1-25, wherein the pharmaceutical composition is for use in combination with an anti-PD-1 antibody.
  • 27. The pharmaceutical composition of item 26, wherein the anti-PD-1 antibody is nivolumab or pembrolizumab.
  • 28. The pharmaceutical composition of any one of items 1-27, wherein the cancer is large intestine cancer, melanoma, kidney cancer, prostate cancer, breast cancer, or lung cancer. 29.
  • a pharmaceutical composition for treating cancer comprising an anti-CTLA-4 antibody, which is for use in combination with a compound having VAP-1 inhibitory activity or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition for treating cancer comprising an anti-PD-1 antibody, which is for use in combination with a compound having VAP-1 inhibitory activity or a pharmaceutically acceptable salt thereof and an anti-CTLA-4 antibody.
  • 38. A method of treating cancer, comprising administering a compound having VAP-1 inhibitory activity or a pharmaceutically salt thereof to a mammal in need thereof. 39. The method of item 38, further comprising administering an anti-CTLA-4 antibody to the mammal. 40. The method of item 38 or 39, further comprising administering an anti-PD-1 antibody to the mammal. 41. Use of a compound having VAP-1 inhibitory activity or a pharmaceutically salt thereof for the manufacture of a medicament for treating cancer. 42.
  • An anti-CTLA-4 antibody for use in the treatment of cancer wherein the anti-CTLA-4 antibody is for use in combination with a compound having VAP-1 inhibitory activity or a pharmaceutically salt thereof.
  • Use of an anti-PD-1 antibody for the manufacture of a medicament for treating cancer wherein the medicament is for use in combination with a compound having VAP-1 inhibitory activity or a pharmaceutically salt thereof and an anti-CTLA-4 antibody.
  • An anti-PD-1 antibody for use in the treatment of cancer wherein the anti-PD-1 antibody is for use in combination with a compound having VAP-1 inhibitory activity or a pharmaceutically salt thereof and an anti-CTLA-4 antibody.
  • Methods (1) Administration of a VAP-1 inhibitor Colon carcinoma MC38 cells (5 ⁇ 10 5 cells/100 ⁇ l) were subcutaneously transplanted into lateral abdominal sites of C57/B6j mice (female, 6 weeks; CLEA Japan, Inc.). Five days after transplantation, development of tumor was confirmed and tumor volume was calculated according to the following formula: (maximum tumor diameter) x (minimum tumor diameter) x (minimum tumor diameter)/2. The mice were divided into two groups showing no significant difference.
  • Compound A (2-(4- ⁇ 2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl ⁇ phenyl)acetohydrazide) (10 mg/kg in 100 ⁇ l of saline, pH 6.0) was intraperitoneally administered daily, once per day, for two weeks.
  • 100 ⁇ l of the solvent saline, pH 6.0
  • the tumor volume was determined once every two or three days. After the two-week administration, effects of the compound were analyzed.
  • NOG mice Central Institute for Experimental Animals
  • BALB/c mice female, 6 weeks; CLEA Japan, Inc.
  • MC38 cells and colon carcinoma CT26 cells were also examined in the same manner as the C57/B6j mice.
  • Compound B (4- ⁇ 2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl ⁇ benzyl hydrazinecarboxylate) in 100 ⁇ l of 0.5% methylcellulose solution (100 mg/kg or 500 mg/kg) was orally administered by a probe daily, once per day. Tumor volume was determined in the same manner as the C57/B6j mice that received Compound A.
  • an anti-CD8 antibody (InVivoMAb anti m CD8a, Clone: 53.6.72, Isotype: RatIgG2a, BioXcell, catalog number BE0004-1) or an isotype control thereof (InVivoMAb Polyclonal Rat IgG, Clone: Rat IgG, catalog number BE0094) (100 mg/kg in 100 ⁇ l saline, pH 6.0) was further administered three times in total, on the date of first administration of Compound A (day 1), three days after the first administration (day 4), and six days after the first administration (day 7). Tumor volume was determined as described above. Four-group comparison was performed between the control group, the Compound A group, the anti-CD8 antibody group, and the combination group of Compound A and the anti-CD8 antibody.
  • CD8 positive cells were sorted out from tumor mass or draining lymph node by CD8a (Ly-2) microbeads, mouse (Miltenyi Biotec, 130-049-401).
  • As antigen presenting cells 32 Gy-irradiated spleen cells of a healthy mouse were used.
  • the CD8 positive cells and the antigen presenting cells were mixed and MC38-specific tumor antigen, Gp70, (1 mg/ml) or ⁇ -gal as a control (1 mg/ml) was added to the mixture.
  • the cells were cultured for 5 days to induce tumor-specific CD8 cells.
  • the cells were then collected, and Gp70 (1 mg/ml) or ⁇ -gal (1 mg/ml) was again added to the collected cells. After one day of culture, the supernatant of the cells was collected. The amount of IFN- ⁇ in the supernatant was determined by IFN- ⁇ ELISA Set (Mouse IFN- ⁇ ELISA, SetBD OptEIA TM , catalog number 555138).
  • FACS Single-cell suspension was prepared from tumor mass and treated with 2.4G2 blocking antibody (Anti-mouse CD16/CD32, Clone: 2.4G2, Bay bioscience, catalog number 40-0161). The single-cell suspension was stained with each of the following antibodies. For intranuclear staining of Foxp3, FOXP3 Fix/Perm Buffer Set (Biolegend, catalog number 421403) was used.
  • CD4 PE/Dazzle 594, RatIgG2a, RM4-5, Biolegend 100566) Foxp3 (PC5.5, RatIgG2a, FJK-16s, eBioscience 35-5773-82) CD25 (PC7, RatIgG2b, PC61, BD 552880) CTLA-4 (APC, HamIgG, UC10-4B9, Biolegend 106310) CD8 (Alexa700, RatIgG2a, 53-6.7 Biolegend 100730) PD-1 (APCCY7, RatIgG1 29F.1A12, Biolegend 135224) CD3 (BrilliantViolet421, HamIgG, 145-2c-11, Biolegend 100336) CD45 (V500, RatIgG2b, 30-F11, BD 561487)
  • Cell proliferation assay MC38 cells were seeded onto 96-well flat-bottom plates at 5 x 10 3 cells/well. Direct cytotoxicity was determined with serially-diluted Compound A from 100 ⁇ g/ml, which was 10 times higher than the blood concentration of Compound A in mice intraperitoneally administered at 10 mg/kg in Section 1(1) above (10 ⁇ g/ml).
  • Compound A was added to RPMI medium at 100 ⁇ g/ml, and RPMI medium containing 50, 25, 12.5, 6.25, 3.125, or 1.56 ⁇ g/ml, or at 782, 391, 196, or 98 ng/ml was prepared by two-fold serial dilutions. RPMI medium without Compound A was used as a control.
  • the medium was added to the plate containing MC38 cells, and the cells were cultured for three days.
  • the assays were performed in triplicate. Proliferation of cancer cells were measured by Premix WST-1 Cell Proliferation Assay System (Takara Bio Inc., product code MK400).
  • CD8 + cells were obtained from tumor mass or draining lymph node, and IFN- ⁇ production by the CD8 + cells in response to tumor antigen Gp70 was determined. As shown in Fig. 1B, Compound A, which is labeled as "VAP-1" in the figure, increased tumor antigen-specific IFN- ⁇ production.
  • reaction mixture In a 2 ml polypropylene tube, 50 ⁇ l of plasma sample and 100 ⁇ l of reaction solution (final concentration: 50 mM phosphate buffer, pH 7.4 and 0.5 mM pargyline) were mixed to prepare a reaction mixture. (c) The reaction mixture was pre-incubated on a shaker for 20 min at room temperature. (d) To the reaction mixture, 50 ⁇ l of substrate solution (final concentration: 10 ⁇ M 14 C-benzylamine) was added, and the resulting reaction mixture was mixed gently. (e) The reaction mixture was incubated on a shaker 24 h at 37°C.
  • the amount of radioactivity of the supernatant was calculated from that of the measured sample, and divided by the specific radioactivity of 14 C-benzylamine to calculate the amount of 4 C-benzaldehyde produced (pmol).
  • the amount of 4 C-benzaldehyde was divided by the volume of the measured sample (ml) and reaction time (min) to calculate VAP-1/SSAO activity (pmol/mL/min).
  • the VAP-1/SSAO activity (pmol/mL/min) was divided by the concentration of total protein in the sample measured by Bradford assay to calculate VAP-1/SSAO activity per mg total protein (pmol/mg protein/min).
  • T cell population including the number of activated T cells in draining lymph node was analyzed in MC38-transplanted C57B6j mice. As shown in Fig. 9, Compound A did not change the T cell population in draining lymph node.
  • Anti-tumor effect of Compound B As described in Section 2(1) above, anti-tumor effect of Compound B orally administered to MC38-transplanted C57B6j mice (100 mg/kg or 500 mg/kg, in 100 ⁇ l saline, pH 6.0) was determined. As shown in Fig. 12, Compound B decreased tumor volume in a dose-dependent manner although the difference was not statistically significant.

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Abstract

La présente invention concerne un procédé et une composition pharmaceutique pour le traitement du cancer au moyen d'un composé ayant une activité inhibitrice de VAP-1 ou un sel pharmaceutiquement acceptable de celui-ci. L'invention concerne en outre une utilisation en combinaison du composé ayant une activité inhibitrice de VAP-1 ou un sel pharmaceutiquement acceptable de celui-ci et un anticorps anti-CTLA-4, et l'utilisation en combinaison du composé ayant une activité inhibitrice de VAP-1 ou un sel pharmaceutiquement acceptable de celui-ci, un anticorps anti-CTLA-4 et un anticorps anti-PD-1.
PCT/JP2016/002706 2015-06-05 2016-06-03 Composition pharmaceutique pour utilisation dans le traitement du cancer WO2016194390A1 (fr)

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