WO2023149548A1 - Novel pharmaceutical composition - Google Patents

Novel pharmaceutical composition Download PDF

Info

Publication number
WO2023149548A1
WO2023149548A1 PCT/JP2023/003580 JP2023003580W WO2023149548A1 WO 2023149548 A1 WO2023149548 A1 WO 2023149548A1 JP 2023003580 W JP2023003580 W JP 2023003580W WO 2023149548 A1 WO2023149548 A1 WO 2023149548A1
Authority
WO
WIPO (PCT)
Prior art keywords
carbon atoms
electron
cancer
pharmaceutical composition
compound
Prior art date
Application number
PCT/JP2023/003580
Other languages
French (fr)
Japanese (ja)
Inventor
スレス アワレ
尚樹 豊岡
Original Assignee
国立大学法人富山大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 国立大学法人富山大学 filed Critical 国立大学法人富山大学
Publication of WO2023149548A1 publication Critical patent/WO2023149548A1/en

Links

Classifications

    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • 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
    • 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
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/24—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in positions 2 and 4
    • C07D265/26—Two oxygen atoms, e.g. isatoic anhydride

Definitions

  • the present invention relates to novel pharmaceutical compositions, particularly novel anticancer pharmaceutical compositions, and novel compounds used in the pharmaceutical compositions.
  • pancreatic cancer has the lowest 5-year survival rate among all solid cancers, and has an extremely poor prognosis.
  • Surgery is the most effective treatment for pancreatic cancer, but chemotherapeutic agents play a major role before and after surgery.
  • chemotherapeutic agents play a major role before and after surgery.
  • Non-Patent Document 1 As a chemotherapeutic agent for pancreatic cancer, gemcitabine was previously used as the first-line drug. However, since administration of Gemcitabine has been reported to cause pancreatic cancer that exhibits resistance to Gemcitabine (Non-Patent Document 1), in recent years, combination therapy with Gemcitabine and other drugs has become mainstream (Non-Patent Document 2, 3).
  • FOLFIRINOX which is used in combination with fluouracil, oxaliplatin, irinotecan, etc.
  • TS-1 which is an oral drug, is also used, although it is only applicable in Japan.
  • Non-Patent Document 4 drug delivery systems such as nab-paclitaxel and onivyde, which aim to reduce side effects, are also utilized as liposome formulations.
  • drug delivery systems such as nab-paclitaxel and onivyde, which aim to reduce side effects, are also utilized as liposome formulations (Non-Patent Document 4).
  • no chemotherapy for pancreatic cancer has been found that provides sufficient therapeutic effects.
  • Cachexia occurs as a result of progressive breakdown of muscle protein and inhibition of protein synthesis, which is the cause of the inability to tolerate cancer treatment.
  • cachectic symptoms worsen over time, and more than 80% of patients with advanced cancer suffer from cachexia, which is associated with extreme weight loss and muscle wasting.
  • Cancer cachexia is the result of a systemic response to inflammation and metabolic imbalance. Clinical trials over the past few years have shown no effective drugs for cachexia and no improvement.
  • an object of the present invention is to provide a novel pharmaceutical composition, particularly a novel anticancer pharmaceutical composition, and a novel compound used in the pharmaceutical composition.
  • the present invention provides novel anticancer compounds, novel anticancer pharmaceutical compositions, and the like, which exhibit cancer therapeutic effects through a mechanism of action different from that of existing anticancer agents for pancreatic cancer. That is, the present invention provides an epoch-making compound that exhibits effects when administered alone or in combination with existing anticancer agents, and is useful in anticancer drug therapy, for example, in combination cancer therapy. It adds a new piece. Preferably, the present invention provides cancer therapeutic agents with reduced side effects in single administration or in combination administration. In particular, the present invention provides a method of treating pancreatic cancer that is resistant to gemcitabine. Furthermore, in a preferred embodiment, the present invention provides means for treating cancer as well as ameliorating or preventing cachexia due to cancer.
  • R 1 represents hydrogen, hydroxy, carboxylic acid ester having 1 to 10 carbon atoms, or alkoxy having 1 to 4 carbon atoms
  • R 2 to R 4 each independently represent hydrogen, an electron-donating group or an electron-withdrawing group
  • R 5 represents hydrogen, hydroxy, carboxylic acid ester having 1 to 10 carbon atoms, alkoxy having 1 to 4 carbon atoms, or a ring formed by combining with R 6
  • R 6 represents hydrogen or a ring formed by combining with R 5
  • R 7 and R 11 each independently represent hydrogen or halogen
  • R 8 to R 10 each independently represent hydrogen, an electron-donating group or an electron-withdrawing group
  • X and Y are each independently carbon or nitrogen; At least one of R 2 -R 4 and R 8 -R 10 is an electron withdrawing group.
  • the electron withdrawing group is halogen, halogenated alkyl having 1 to 4 carbon atoms, carboxylic acid ester having 1 to 10 carbon atoms, acyl having 1 to 4 carbon atoms, cyano (-CN), nitro (-NO 2 ), C 1-4 alkylthio (-SR; R represents alkyl), C 1-4 alkylsulfinyl (-SOR; R represents alkyl), C 1-4 alkylsulfonyl (- SO 2 R; R represents alkyl); or aryl or heteroaryl having these electron-withdrawing groups as substituents.
  • composition of [10] The pharmaceutical composition according to any one of [1] to [9], which is for suppressing the development of cancer stem cells or for killing cancer stem cells.
  • R 1 ' represents hydrogen, hydroxy, carboxylic acid ester having 1 to 10 carbon atoms, or alkoxy having 1 to 4 carbon atoms
  • R 2 ' to R 4 ' each independently represent hydrogen, an electron-donating group or an electron-withdrawing group
  • R 5 ' represents hydrogen, hydroxy, carboxylic acid ester having 1 to 10 carbon atoms, alkoxy having 1 to 4 carbon atoms, or a ring formed by combining with R 6 '
  • R 6 ' represents hydrogen or a ring formed by combining with R 5 '
  • R 7 ' and R 11 ' each independently represent hydrogen or halogen
  • R 8 ' and R 10 ' each independently represent hydrogen or an electron-withdrawing group
  • R 9 ' represents an electron-withdrawing group
  • X' and Y' are each independently carbon or nitrogen; when R 9 ' is hydroxy, then R 2 ' is other than alkoxy; When R 9 ' is cyano or nitro, R 2 ' is other than
  • the electron withdrawing group is halogen, halogenated alkyl having 1 to 4 carbon atoms, carboxylic acid ester having 1 to 10 carbon atoms, acyl having 1 to 4 carbon atoms, cyano (-CN), nitro (-NO 2 ), C 1-4 alkylthio (-SR; R represents alkyl), C 1-4 alkylsulfinyl (-SOR; R represents alkyl), C 1-4 alkylsulfonyl (- SO 2 R; R represents alkyl); or aryl or heteroaryl having these electron-withdrawing groups as substituents, or the compound according to [15], or a pharmacologically acceptable salt thereof.
  • [17] The compound of [15] or [16], wherein the electron-donating group is hydroxy, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or amino, or the pharmacologically acceptable salt.
  • [20] A method for treating or preventing cancer, which comprises administering the compound represented by the above formula (I) or a pharmacologically acceptable salt thereof to a subject.
  • a method for improving cancer treatment survival comprising administering the compound represented by the above formula (I) or a pharmacologically acceptable salt thereof to a subject during cancer treatment.
  • the present invention provides novel pharmaceutical compositions, particularly novel anticancer pharmaceutical compositions, and novel compounds used in the pharmaceutical compositions.
  • FIG. 1 is a diagram (drawing-substituting photograph) showing evaluation results of the metastasis inhibitory activity against PANC-1 of the phenylbenzamide derivative N-42.
  • A is an image observed by a live cell imaging device (from the left, control, N-42 5 ⁇ M treatment, N-42 10 ⁇ M treatment). The upper row is the image at the start, and the lower row is the image 24 hours after the start.
  • B is a graph showing the open area at each time.
  • Figure 2 shows the evaluation results of the in vivo antitumor effect of the phenylbenzamide derivative N-51 (*: P ⁇ 0.05, ** ⁇ 0.01, *** ⁇ 0.001, **** ⁇ 0.0001, Anova -test).
  • A is a graph showing the tumor size of each group.
  • FIG. 4 is a diagram (drawing-substituting photograph) showing the evaluation results of the in vivo antitumor effect of the phenylbenzamide derivative N-42 (excised tumor image).
  • FIG. 4 is a diagram (drawing-substituting photograph) showing the evaluation results of the in vivo antitumor effect of the phenylbenzamide derivative N-42 (excised tumor image).
  • FIG. 5 is a diagram (drawing-substituting photograph) showing the evaluation results of the Akt/mTOR activation inhibitory activity of phenylbenzamide derivatives N-42 and N-51.
  • A shows the results for PANC-1.
  • B shows results for MiaPaCa-2.
  • C shows the evaluation results of pAkt and pmTOR inhibitory activity in PANC-1 (comparison or combined effect with Akt inhibitor and activator IGF-1).
  • FIG. 6 is a diagram (drawing-substituting photograph) showing evaluation results of the SOX2, c-MYC, and OCT-4 inhibitory activity of the phenylbenzamide derivative N-42.
  • A shows the results for PANC-1.
  • B shows results for MiaPaCa-2.
  • FIG. 7 is a schematic diagram of an experimental method for measuring the effects of N-compounds in an orthotopic implantation model. The figure below captures the timeline for tumor implantation and treatment (numbers represent days).
  • FIG. 8 shows photographs (drawing substitute photographs) of mice in each group on day 29 from the start of compound administration in an orthotopic transplantation model.
  • FIG. 9 is a photograph (drawing-substituting photograph) of a tumor transplanted by laparotomy of each group of mice on day 29 from the start of compound administration in an orthotopic transplantation model. Circles indicate tumor sites.
  • FIG. 10 shows the evaluation results of the effects of N-compounds in an orthotopic transplantation model.
  • FIG. 1 is a graph showing changes in body weight (g) over time (A) in orthotopic transplantation model mice and tumor burden (g) on day 29 from the start of compound administration (B).
  • the vertical axis of A indicates mouse body weight (g), and the horizontal axis indicates the number of days elapsed (compound administration is defined as Day 1).
  • the vertical axis of B indicates tumor weight (g) (*: P ⁇ 0.05, ** ⁇ 0.01, *** ⁇ 0.001, **** ⁇ 0.0001, Anova-test).
  • Figure 11 High dose (N-42(H)), low dose (N-42(L)), and Gemcitabine (GEM) of N-42 suspended with gum arabic in tumor-bearing mice.
  • FIG. 4 is a graph showing the results of combined administration of N-42(H) and Gemcitabine.
  • the vertical axis represents tumor volume (mm 3 ), and the horizontal axis represents elapsed days (Days).
  • FIG. 12 is a graph evaluating the in vitro cytotoxic activity of N-compounds and gemcitabine against the growth of human pancreatic cancer-derived cell line PANC-1 in a medium devoid of glucose and serum.
  • the vertical axis indicates cell viability (%), and the horizontal axis indicates each drug concentration (Log) ( ⁇ M).
  • Diamonds (gray) indicate the results of culturing under normoxic (20% O 2 ) conditions, and squares (black) indicate the results of culturing under hypoxic (3% O 2 ) conditions.
  • FIG. 13 is a diagram showing an experimental protocol for testing the antitumor effect and survival rate improvement in an orthotopic pancreatic tumor model by using an N-compound as an anticancer agent in combination with GEM.
  • Figure 14 shows the results of the endpoint study.
  • A is a diagram showing the average body weight per mouse in the control group, Gem group, N-42 group, and Gem+N-42 combination group.
  • B shows the mean tumor weight and standard deviation of the control group, Gem group, N-42 group, and N-42+Gem combination group.
  • the X-axis represents treatment groups including control, N-42, GEM, and the combination of N-42 and GEM.
  • Y-axis represents tumor volume and bars represent mean tumor weight for each treatment group. Error bars represent standard deviation of the mean.
  • Carboxylic acid ester having 1 to 10 carbon atoms as used herein means a group formed by dehydration condensation of alcohol and carboxylic acid, and may be simply referred to as "ester having 1 to 10 carbon atoms". Examples include methyl ester group, ethyl ester group, propyl ester group, butyl ester group, pentyl ester group, hexyl ester group and the like.
  • alkyl having 1 to 10 carbon atoms means a linear, branched or cyclic saturated hydrocarbon group having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, i -propyl, n-butyl, sec-butyl, t-butyl, isobutyl, pentyl, isopentyl, 2,3-dimethylpropyl, hexyl, cyclohexyl and the like.
  • C1-C4 alkyl means a linear or branched saturated hydrocarbon having 1-4 carbon atoms, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec -butyl, t-butyl, isobutyl and the like.
  • C1-3 alkyl means a linear or branched saturated hydrocarbon group with 1-3 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl and the like.
  • alkenyl having 2 to 10 carbon atoms means a linear, branched or cyclic unsaturated hydrocarbon having 2 to 10 carbon atoms and having one or more carbon-carbon double bonds. is a monovalent group obtained by removing one hydrogen atom from any carbon atom of For example vinyl, propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 1-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 1-methyl-2 -butenyl, 1-methyl-3-butenyl, 1-methylidenebutyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 2-methylidenebutyl, 3-methyl-1-butenyl , 3-methyl-2-butenyl, 3-methyl-3-butenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenenyl, 1-e
  • alkynyl having 2 to 10 carbon atoms means one hydrogen from any carbon atom of a linear, branched, or cyclic unsaturated hydrocarbon having one or more carbon-carbon triple bonds. It means a monovalent group having 2 to 10 carbon atoms obtained by removing atoms. Examples include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, pentynyl, hexynyl, phenylethynyl and the like.
  • aryl having 6 to 10 carbon atoms refers to an aromatic hydrocarbon group having 6 to 10 carbon atoms, including benzene and naphthalene.
  • heteroaryl having 3 to 10 carbon atoms means a 3 to 10-membered monocyclic heteroaryl containing at least one heteroatom selected from nitrogen, oxygen, and sulfur atoms. It means a ring group or a 5- to 10-membered condensed heterocyclic group.
  • the heteroaryl may contain, for example, 1-5, 1-4, 1-3, 1-2, 2, 1 heteroatoms.
  • heterocyclic group containing one nitrogen atom a heterocyclic group containing two nitrogen atoms, a heterocyclic group containing three nitrogen atoms, a heterocyclic group containing one oxygen atom, a heterocyclic group containing two oxygen atoms heterocyclic groups containing one oxygen atom and one nitrogen atom, heterocyclic groups containing one sulfur atom, and the like.
  • Heterocyclic groups may be aromatic or non-aromatic.
  • Monocyclic heterocyclic groups are preferably 5- to 6-membered rings.
  • the fused heterocyclic group is preferably an 8- to 10-membered ring.
  • heteroaryl having 5 to 10 carbon atoms examples include piperidyl, piperazyl, morpholyl, quinuclidyl, pyrrolidyl, azetidyl, oxetyl, azetidin-2-one-yl, aziridinyl, tropanyl, furyl, tetrahydrofuryl, thienyl, pyrrolyl, pyrrolyl, pyrrolidinyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxadiazolyl, furazanyl, thiadiazol
  • alkoxy having 1 to 4 carbon atoms is a group to which the aforementioned “alkyl having 1 to 4 carbon atoms” is bonded via an oxygen atom (O).
  • the "carboxylic acid ester having 1 to 10 carbon atoms” may be a group to which the above-mentioned acyl having 1 to 10 carbon atoms is bonded via an oxy group (--O--).
  • halogenated alkyl having 1 to 4 carbon atoms means alkyl having 1 to 4 carbon atoms substituted with halogen.
  • the number of substituted halogens can be, for example, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 3, 2, or 1.
  • alkylthio having 1 to 4 carbon atoms is a group to which the aforementioned “alkyl having 1 to 4 carbon atoms” is bonded via a sulfur atom (S).
  • composition of the present invention is a pharmaceutical composition containing, as an active ingredient, a compound represented by the following formula (I) or a pharmacologically acceptable salt thereof (hereinafter referred to as “pharmaceutical composition of the present invention” there is).
  • a phenylbenzamide derivative that is, a compound represented by the following formula (I)
  • a pharmaceutical composition containing a compound represented by the following formula (I) or a pharmacologically acceptable salt thereof as an active ingredient was developed. That is, pharmaceutical compositions include anticancer agents (anticancer pharmaceutical compositions), multikinase inhibitors, Akt inhibitors, mTORC1 inhibitors, SOX2 inhibitors, c-MYC inhibitors, and OCT-4 inhibitors.
  • anticancer agents anticancer pharmaceutical compositions
  • multikinase inhibitors Akt inhibitors, mTORC1 inhibitors, SOX2 inhibitors, c-MYC inhibitors, and OCT-4 inhibitors.
  • R 1 represents hydrogen, hydroxy, carboxylic acid ester having 1 to 10 carbon atoms, or alkoxy having 1 to 4 carbon atoms
  • R 2 to R 4 each independently represent hydrogen, an electron-donating group, or an electron-withdrawing group
  • R 5 represents hydrogen, hydroxy, carboxylic acid ester having 1 to 10 carbon atoms, alkoxy having 1 to 4 carbon atoms, or a ring formed by combining with R 6
  • R 6 represents hydrogen or a ring formed by combining with R 5
  • R 7 and R 11 each independently represent hydrogen or halogen
  • R 8 to R 10 each independently represent hydrogen, an electron-donating group, or an electron-withdrawing group
  • X and Y are each independently carbon or nitrogen; At least one of R 2 -R 4 and R 8 -R 10 is an electron withdrawing group.
  • the hydrocarbon (R) contained in the carboxylic acid ester has 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, and more preferably 1 to 7 carbon atoms.
  • the hydrocarbon contained in the carboxylic acid ester may be linear, branched, or cyclic. Moreover, it may be saturated or may contain an unsaturated bond.
  • alkyl having 1 to 10 carbon atoms alkenyl having 2 to 10 carbon atoms, alkynyl having 2 to 10 carbon atoms, or aryl having 6 to 10 carbon atoms, preferably linear or branched cyclic and having 1 carbon atoms.
  • 1 to 10 alkyl more preferably linear 1 to 7 alkyl.
  • R 1 is preferably hydrogen, hydroxy, or the like. In one aspect of compound (I), R 1 is hydrogen.
  • R 2 to R 4 each independently represent hydrogen, an electron-donating group, or an electron-withdrawing group.
  • An electron-donating group is a group that donates electrons to a substituted atomic group.
  • the electron-donating group donates electrons to a benzene ring or the like.
  • the electron-donating group is not limited as long as it has such action. Examples of electron-donating groups include, but are not limited to, hydroxy, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, and the like.
  • Electron-withdrawing groups are groups that withdraw electrons from a substituted atomic group.
  • the electron-withdrawing group attracts electrons from a benzene ring or the like.
  • the electron-withdrawing group is not limited as long as it has such action.
  • Electron-withdrawing groups include, but are not limited to, fluorine (-F), chlorine (-Cl), bromine (-Br), halogen (X) such as iodine (-I), trifluoromethyl (-CF 3 ) Alkyl halides having 1 to 4 carbon atoms, carboxylic acid esters having 1 to 10 carbon atoms, acyl having 1 to 4 carbon atoms, cyano (—CN), nitro (—NO 2 ), alkylthio having 1 to 4 carbon atoms, etc.
  • alkylsulfinyl having 1 to 4 carbon atoms, or alkylsulfonyl (—SO 2 R) having 1 to 4 carbon atoms; or 6 to 6 carbon atoms having these electron-withdrawing groups as substituents 10 aryl or heteroaryl having 3 to 10 carbon atoms, and the like.
  • R 2 to R 4 are preferably hydrogen, halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halogenated alkyl having 1 to 4 carbon atoms, cyano or nitro.
  • each of R 2 to R 4 is independently hydrogen, an electron-donating group, or an electron-withdrawing group.
  • at least one of R 2 and R 3 is an electron-withdrawing group, and the others are hydrogen.
  • both R 2 and R 3 are electron-withdrawing groups.
  • the electron-withdrawing group is preferably halogen or nitro.
  • at least one of R 2 and R 3 is an electron-withdrawing group, and the others are electron-donating groups.
  • the electron-withdrawing group is preferably halogen.
  • the electron-donating group is preferably alkyl.
  • R 4 is hydrogen.
  • R 5 is hydrogen, hydroxy, C 1-10 carboxylic acid ester, or C 1-4 alkoxy.
  • R5 may combine with R6 to form a ring.
  • R 5 and R 6 may combine to form a heterocyclic ring via a saturated ring, unsaturated ring, or —O—C—O— chain.
  • Specific examples of the carboxylic acid ester having 1 to 10 carbon atoms are the same as those explained for R 1 .
  • R 5 is preferably hydroxy.
  • R6 represents hydrogen or a ring formed by combining with R6 .
  • R 6 is preferably hydrogen.
  • R7 and R11 each independently represent hydrogen or halogen.
  • one of R 7 and R 11 is hydrogen and the other is halogen.
  • R7 is halogen and R11 is hydrogen.
  • R 7 and R 11 are hydrogen.
  • R 8 to R 10 each independently represent hydrogen, an electron-donating group, or an electron-withdrawing group. Specific examples of electron-donating groups and electron-withdrawing groups are the same as those described for R 2 to R 4 .
  • R 8 to R 10 are preferably selected from hydrogen, hydroxy, halogen, halogenated alkyl having 1 to 4 carbon atoms, cyano and nitro; or halogen, carboxylic acid ester having 1 to 10 carbon atoms, cyano and nitro. Examples thereof include aryl having 6 to 10 carbon atoms and heteroaryl having 3 to 10 carbon atoms having an electron withdrawing group as a substituent.
  • At least one of R 8 to R 10 is halogen, halogenated alkyl having 1 to 4 carbon atoms, cyano, nitro; or halogen, carboxylic acid ester having 1 to 10 carbon atoms, cyano , nitro, aryl having 6 to 10 carbon atoms or heteroaryl having 3 to 10 carbon atoms having an electron-withdrawing group selected from nitro, and others are hydrogen.
  • R 9 is an electron-withdrawing group
  • R 8 and R 10 are each independently hydrogen or an electron-withdrawing group.
  • R 9 is an electron-withdrawing group and R 8 and R 10 are hydrogen.
  • the electron-withdrawing group is preferably a halogenated alkyl having 1 to 4 carbon atoms, nitro; 3-10 heteroaryl.
  • X and Y are each independently carbon or nitrogen. In one aspect of compound (I), at least one of X and Y is nitrogen and the others are carbon. In another aspect of compound (I), X and Y are carbon.
  • At least one of R 2 -R 4 and R 8 -R 10 is an electron withdrawing group. Specific examples of electron-withdrawing groups are the same as those described for R 2 to R 4 .
  • R 9 is an electron withdrawing group.
  • at least one of R 2 and R 3 is an electron-withdrawing group.
  • R 1 is hydrogen, at least one of R 2 and R 3 is an electron-withdrawing group, the others are hydrogen, R 4 is hydrogen, and R 5 is hydroxy and R 6 is hydrogen, R 7 is hydrogen or halogen, R 8 , R 10 , R 11 are hydrogen, R 9 is an electron-withdrawing group, and X and Y are carbon .
  • R 1 is hydrogen, at least one of R 2 and R 3 is halogen or nitro, the others are hydrogen, R 4 is hydrogen, R 5 is hydroxy and R 6 is hydrogen, R 7 is hydrogen or halogen, R 8 , R 10 , R 11 are hydrogen, and R 9 is nitro; or electron-withdrawing selected from halogen, cyano, nitro aryl having 6 to 10 carbon atoms or heteroaryl having 3 to 10 carbon atoms having a group as a substituent, and X and Y are carbon.
  • R 1 is hydrogen, at least one of R 2 and R 3 is an electron-withdrawing group, the others are electron-donating groups, R 4 is hydrogen, and R 5 is hydroxy, R 6 is hydrogen, R 7 is hydrogen or halogen, R 8 , R 10 , R 11 is hydrogen, R 9 is an electron-withdrawing group, X and Y are is carbon.
  • R 1 is hydrogen, at least one of R 2 and R 3 is halogen, the others are alkyl, R 4 is hydrogen, R 5 is hydroxy, R 6 is hydrogen, R 7 is hydrogen or halogen, R 8 , R 10 and R 11 are hydrogen, R 9 is halogenated alkyl having 1 to 4 carbon atoms, and X and Y are carbon is.
  • Examples of compound (I) include, but are not limited to, the compounds shown in Examples below.
  • the compound (I) among them, a compound having a structure represented by the following formula is preferable.
  • compounds N-42, N-50, N-51, N-101, N-110, N-115, NIC-120, NIC-127 and NIC-129 are particularly preferable as compound (I). .
  • Compound (I) can be synthesized by a known synthesis method with reference to Examples below.
  • salts with acidic groups such as carboxylic acid groups include alkali metal and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, calcium; ammonia, methylamine, ethylamine, methanolamine, ethanolamine, dimethylamine, trimethylamine.
  • dicyclohexylamine tris(hydroxymethyl)aminomethane, N,N-bis(hydroxyethyl)piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, amines such as L-glucamine or salts with basic amino acids such as lysine, ⁇ -hydroxylysine, arginine and the like.
  • a basic group salts with hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, boric acid, etc.
  • inorganic acid salts methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid , propionate, acetic acid, lactic acid, fumaric acid, malic acid, oxalic acid, benzoic acid, mandelic acid, cinnamic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, tosylic acid, glycolic acid, glucuronic acid , ascorbic acid, nicotinic acid, salicylic acid and the like (organic acid salts); and salts with acidic amino acids such as aspartic acid and glutamic acid.
  • Alkali metal salts are preferred, and sodium and potassium are particularly preferred.
  • Examples of pharmacologically acceptable salts of compound (I) include, but are not limited to, sodium salt of N-101 and potassium salt of N-101. Preparation of these salts can be carried out by conventional means. In addition, the above examples should not be used to restrict interpretation of "pharmacologically acceptable salts". That is, "pharmacologically acceptable salt” should be interpreted broadly and is a term that includes various salts. Reference to compounds herein also includes hydrates or solvates of such compounds or salts thereof, unless explicitly indicated otherwise.
  • cancer is interpreted broadly and used interchangeably with the term "malignant tumor”.
  • malignant tumor in the stage before the diagnosis is confirmed pathologically, that is, before the tumor is either benign or malignant, it may include benign tumors, benign-malignant borderline lesions, and malignant tumors collectively. could be.
  • cancers are called by the name of the organ from which they originated, or by the name of the originating tissue.
  • cancer salivary gland cancer, esophageal cancer, stomach cancer, small intestine cancer, colon cancer, rectal cancer, liver cancer, biliary tract cancer, gallbladder cancer, pancreatic cancer, lung cancer, breast cancer, thyroid cancer cancer, adrenal cancer, pituitary tumor, pineal tumor, uterine cancer, ovarian cancer, vaginal cancer, bladder cancer, kidney cancer, prostate cancer, urethral cancer, retinoblastoma, conjunctiva Cancer, neuroblastoma, glioma, glioblastoma, skin cancer, medulloblastoma, leukemia, malignant lymphoma, testicular tumor, osteosarcoma, rhabdomyosarcoma, leiomyosarcoma, angiosarcoma, liposarcoma , chondrosarcoma, and Ewing's sarcoma.
  • the site of the organ in which it develops can be classified as upper/middle/hypopharynx cancer, upper/middle/lower esophageal cancer, gastric cardia cancer, gastric pyloric cancer, cervical cancer, endometrial cancer, etc.
  • Subclassifications include, but are not limited to, the description of "cancer” in the present invention.
  • the anticancer pharmaceutical composition of the present invention is effective against “cancer” in general, but it can be particularly preferably used for pancreatic cancer and solid cancer of pancreatic cancer.
  • Pancreatic cancer is a malignant tumor that occurs in the pancreas, and can be classified into invasive pancreatic duct cancer, pancreatic neuroendocrine tumor, malignant intraductal papillary mucinous tumor, and malignant mucocystic tumor. It can be done, but pancreatic cancer generally refers to “invasive pancreatic duct cancer (common pancreatic cancer)”.
  • a "solid cancer” is a solid cancer that is observed as a clear mass in a specific organ, tissue, or the like.
  • Anti-cancer pharmaceutical composition refers to a pharmaceutical composition that exhibits a therapeutic or preventive effect on cancer, which is the target disease or condition.
  • Therapeutic effects include alleviation of symptoms characteristic of cancer or accompanying symptoms (mitigation), prevention or delay of exacerbation of symptoms, and the like. The latter can be regarded as one of preventive effects in terms of preventing aggravation.
  • the therapeutic effect and the prophylactic effect are partially overlapping concepts, and it is difficult to clearly distinguish between them, and there is little practical benefit from doing so.
  • a typical preventive effect is to prevent or delay the recurrence (development) of symptoms characteristic of cancer.
  • it corresponds to the anticancer pharmaceutical composition.
  • the therapeutic or preventive effect on cancer brought about by compound (I) or a combination thereof may include improvement of cancer complications (eg, cachexia). That is, "anti-cancer” and “cancer treatment” in the present specification mean that in addition to effects such as growth suppression and shrinkage on cancer tissue itself, complications (preferably, cachexia ).
  • composition of the present invention can be formulated according to conventional methods, except that compound (I), which is an active ingredient, or a pharmacologically acceptable salt thereof is added.
  • compound (I) or a pharmacologically acceptable salt thereof may be used singly or in any combination of two or more.
  • other pharmaceutically acceptable components e.g., carriers, excipients, disintegrants, buffers, emulsifiers, suspending agents, soothing agents, stabilizers, preservatives, preservatives, interfaces Active agents, lubricants, diluents, coating agents, sugar coating agents, flavoring agents, emulsifying/solubilizing/dispersing agents, pH adjusters, isotonic agents, solubilizing agents, fragrances, coloring agents, solubilizing agents, physiological saline solution, etc.).
  • the dosage form for formulation is also not particularly limited.
  • dosage forms include tablets, powders, fine granules, granules, capsules, syrups, solutions, suspensions, emulsions, jelly, injections, external preparations, inhalants, nasal drops, eye drops, and suppositories. is an agent.
  • the pharmaceutical composition of the present invention contains an amount of active ingredient necessary to obtain the expected therapeutic effect (or preventive effect) (ie, a therapeutically effective amount).
  • the amount of the active ingredient in the pharmaceutical composition of the present invention generally varies depending on the dosage form, but the amount of the active ingredient can be adjusted, for example, in the range of about 0.01% by mass to about 99.9% by mass so as to achieve the desired dosage. can be set within
  • the pharmaceutical composition of the present invention can be administered orally or parenterally (intravenous, intraarterial, subcutaneous, intradermal, intramuscular, intraperitoneal injection, transdermal, nasal, transmucosal, etc.) depending on its dosage form. ) to the subject.
  • routes of administration are not mutually exclusive, and two or more arbitrarily selected routes can be used in combination (for example, intravenous injection or the like is performed at the same time as oral administration or after a predetermined period of time has elapsed).
  • Local administration may be used instead of systemic administration.
  • a drug delivery system (DDS) may be used to deliver the active ingredient in a target tissue-specific manner.
  • the "subject” here is not particularly limited, and includes humans and non-human mammals (pet animals, domestic animals, experimental animals) in need of cancer treatment or prevention. Specifically, for example, mice, rats, guinea pigs, hamsters, monkeys, cows, pigs, goats, sheep, dogs, cats, chickens, quail, etc.). In one preferred aspect, the subject is a human.
  • a method for treating or preventing cancer using the anticancer pharmaceutical composition of the present invention (hereinafter, these two methods are collectively referred to as "therapeutic method, etc.”).
  • the treatment method and the like of the present invention include the step of administering the anticancer pharmaceutical composition of the present invention to a patient suffering from cancer or showing symptoms of cancer.
  • the route of administration is not particularly limited, and examples thereof include oral, intravenous, intraarterial, intradermal, subcutaneous, intramuscular, intraperitoneal, transdermal, transnasal, and transmucosal routes. These administration routes are not mutually exclusive, and two or more arbitrarily selected routes can be used in combination.
  • the dosage of the anticancer pharmaceutical composition may generally vary depending on the patient's symptoms, age, sex, body weight, etc., a person skilled in the art can set an appropriate dosage as appropriate.
  • oral administration for example, about 0.01 mg to 1000 mg per day can be administered to an adult once or in several divided doses.
  • parenteral administration for example, about 0.01 mg to 1000 mg can be administered by subcutaneous injection, intramuscular injection or intravenous injection.
  • As an administration schedule for example, once to several times a day, once every two days, or once every three days can be adopted. In setting the administration schedule, the patient's symptoms, duration of effect of the active ingredient, etc. can be taken into consideration.
  • the present invention there is provided a method for improving the cancer treatment survival rate using the anticancer pharmaceutical composition of the present invention during cancer treatment.
  • the dosage and the like the contents explained in the therapeutic method and the like of the present invention can be applied.
  • the administration of the anticancer pharmaceutical composition of the present invention is usually one day or more before the start of cancer treatment (chemotherapy, radiotherapy, etc.) other than by the anticancer pharmaceutical composition of the present invention, preferably 2 days or more, preferably 3 days or more, more preferably 1 week or more. In preferred embodiments, it is administered for the duration of the cancer treatment. In addition, there is no problem even if the administration is continued after the end of the treatment period by cancer treatment.
  • Improving cancer treatment survival rate in the present invention means that a subject undergoing cancer treatment, particularly chemotherapy and/or radiotherapy, uses the anticancer pharmaceutical composition of the present invention during the cancer treatment period. Second, it means that the survival rate after a predetermined number of days or a predetermined number of years is improved compared to when the anticancer pharmaceutical composition of the present invention is not used.
  • compound (I) has multikinase inhibitory activity that inhibits multiple kinases that are associated with cancer growth, nutritional starvation resistance, and the like. For this reason, it is thought that excellent therapeutic effects can be brought about against the growth of malignant tumors and resistance to nutritional starvation, for which conventional cytotoxic anticancer agents have little effect.
  • compound (I) since a single drug inhibits multiple kinases without using multiple drugs, it is possible to reduce the number of drugs to be administered in cancer treatment, thereby reducing side effects to patients. can be mitigated.
  • Akt and mTORC1 which are extremely important molecules involved in malignant transformation of cancer and resistance to nutrient starvation, can be obtained. Furthermore, it can be predicted that therapeutic agents for diseases involving Akt and mTORC1 will be obtained.
  • a multikinase inhibitor containing compound (I) or a pharmacologically acceptable salt thereof as an active ingredient.
  • the multikinase inhibitor inhibits Akt.
  • the multikinase inhibitor inhibits mTORC1.
  • said multikinase inhibitor inhibits Akt and mTORC1.
  • a pharmaceutical composition containing compound (I) or a pharmacologically acceptable salt thereof as an active ingredient for selectively killing nutrient-starved tumor cells. be done.
  • compound (I) has multikinase inhibitory activity that inhibits multiple kinases that are associated with cancer growth, nutritional starvation resistance, and the like.
  • the pharmaceutical composition utilizes the multikinase inhibitory activity of compound (I) or a pharmacologically acceptable salt thereof as one of the mechanisms for selectively killing nutrient-starved tumor cells. is.
  • an anticancer pharmaceutical composition containing the multikinase inhibitor as an active ingredient.
  • compound (I) inhibits SOX2, c-MYC, and OCT-4, which is considered to be closely associated with treatment resistance, recurrence, and metastasis of cancer. Inhibits stem cell expression (suppresses development) or kills cancer stem cells. Therefore, it is considered that excellent effects can be brought about against treatment resistance, recurrence, and metastasis of cancer.
  • anticancer compounds exhibiting cancer treatment resistance against pancreatic cancer, that is, resistance against pancreatic cancer, the compound used in the present invention, or the compound used in the present invention Combined use with other (other) anticancer compounds can provide excellent efficacy with little resistance to pancreatic cancer.
  • molecularly targeted therapeutic agents for SOX2, c-MYC, and OCT-4 which are extremely important molecules involved in treatment resistance, recurrence, and metastasis of cancer, can be obtained. Furthermore, it can be expected that therapeutic drugs for diseases involving SOX2, c-MYC, and OCT-4 will be obtained.
  • SOX2 inhibitors, c-MYC inhibitors and OCT-4 inhibitors containing compound (I) or a pharmacologically acceptable salt thereof as an active ingredient are provided. be done.
  • an anticancer pharmaceutical composition, a cancer metastasis inhibitor, and a cancer stem cell containing the SOX2 inhibitor, c-MYC inhibitor, and OCT-4 inhibitor as active ingredients An inhibitor (in one aspect, a cancer stem cell development inhibitor, a cancer stem cell-killing agent) is provided.
  • anticancer compounds are conceivable as anticancer compounds that exhibit resistance to pancreatic cancer, particularly antimetabolites such as enocitabine, carmofur, capecitabine, tegafur, tegafur uracil, tegafur gimeracil, Oteracil potassium, gemcitabine, cytarabine, cytarabine ocphosphate, nerarabine, fluorouracil, fludarabine, pemetrexed, pentostatin, methotrexate, cladribine, doxifluridine, hydroxycarbamide, mercaptopurine, etc., especially gemcitabine is resistant to pancreatic cancer.
  • antimetabolites such as enocitabine, carmofur, capecitabine, tegafur, tegafur uracil, tegafur gimeracil, Oteracil potassium, gemcitabine, cytarabine, cytarabine ocphosphate, nerarabine, fluor
  • the content described in the above ⁇ Pharmaceutical composition for anticancer>> section should be applied to the above-mentioned multikinase inhibitor and SOX2 inhibitor. It can also be applied in In addition, the multikinase inhibitor and SOX2 inhibitor can also be used as reagents, and the manufacture, use, etc. of the reagents can be carried out based on conventional methods in the field of molecular biology.
  • the present invention includes use of compound (I) for manufacturing a pharmaceutical composition for treating cancer.
  • the present invention includes use of compound (I) for the treatment or prevention of cancer.
  • the present invention relates to a method for treating or preventing cancer, comprising administering compound (I).
  • the present invention includes a pharmaceutical composition for treating cancer containing compound (I) and other anticancer agents, and compound (I) for use with other anticancer agents.
  • the present invention relates to a pharmaceutical composition for treating cancer.
  • the present invention includes use of compound (I) for manufacturing a pharmaceutical composition for treating cancer for use with other anticancer agents.
  • the present invention provides the use of compound (I) for treating or preventing cancer, and compound (I) for treating or preventing cancer and Including the use of other anticancer agents. including. Furthermore, the present invention relates to a method for treating or preventing cancer comprising administering compound (I) together with other anticancer agents.
  • the compounding ratio and the like in the combined use can be set according to a conventional method.
  • "to be administered in combination” means that the above agents may be administered at the same time, in succession, or one of them may be administered first and then administered at a later time.
  • Anticancer compounds include, for example, alkylating agents, antimetabolites, microtubule inhibitors, antibiotic anticancer agents, topoisomerase inhibitors, platinum agents, molecular target drugs, hormone agents, biologics, etc., preferably. includes antimetabolites, antibiotic anticancer agents, platinum preparations and the like, more preferably antimetabolites.
  • gemcitabine is particularly preferable because its combined use with gemcitabine is not only effective against gemcitabine-resistant cancer but also exerts a synergistic effect against non-resistant cancer.
  • Antimetabolites include, for example, enocitabine, carmofur, capecitabine, tegafur, tegafur uracil, tegafur gimeracil oteracil potassium, gemcitabine, cytarabine, cytarabine octophosphate, nerarabine, fluorouracil, fludarabine, pemetrexed, pentostatin, methotrexate, Cladribine, doxifluridine, hydroxycarbamide, mercaptopurine and the like.
  • alkylating agents examples include cyclophosphamide, ifosfamide, nitrosourea, dacarbazine, temozolomide, nimustine, busulfan, melphalan, procarbazine, ranimustine and the like.
  • microtubule inhibitors examples include alkaloid anticancer agents such as vincristine, and taxane anticancer agents such as docetaxel and paclitaxel.
  • Antibiotic anticancer agents include, for example, mitomycin C, doxorubicin, epirubicin, daunorubicin, bleomycin, actinomycin D, aclarubicin, idarubicin, pirarubicin, peplomycin, mitoxantrone, amrubicin, and dinostatin stimaramer.
  • topoisomerase inhibitors examples include CPT-11, irinotecan, and topotecan, which have topoisomerase I inhibitory activity, and etoposide and sobuzoxan, which have topoisomerase II inhibitory activity.
  • platinum agents examples include cisplatin, nedaplatin, oxaliplatin, carboplatin, and the like.
  • Hormonal agents include, for example, dexamethasone, finasteride, tamoxifen, astrozole, exemestane, ethinylestradiol, chlormadinone, goserelin, bicalutamide, flutamide, brednisolone, leuprorelin, letrozole, estramustine, toremifene, fosfestrol, mitotane, Methyltestosterone, medroxyprogesterone, mepitiostane and the like.
  • biologics include interferon ⁇ , ⁇ and ⁇ , interleukin 2, ubenimex, dried BCG, and the like.
  • molecular targeted drugs examples include rituximab, alemtuzumab, trastuzumab, cetuximab, panitumumab, imatinib, dasatinib, nilotinib, gefitinib, erlotinib, temsirolimus, bevacizumab, VEGF trap, sunitinib, sorafenib, tocituzumab, bortezomib, gemtuzumab o Zogamicin, ibritumomab ozogamicin , ibritumomab tiuxetan, tamibarotene, tretinoin and the like.
  • Human epidermal growth factor receptor 2 inhibitors Human epidermal growth factor receptor 2 inhibitors, epidermal growth factor receptor inhibitors, Bcr-Abl tyrosine kinase inhibitors, epidermal growth factor tyrosine kinase inhibitors, mTOR inhibitors, in addition to those identified here.
  • Angiogenesis-targeted inhibitors such as vascular endothelial growth factor receptor 2 inhibitors ( ⁇ -VEGFR-2 antibodies), various tyrosine kinase inhibitors such as MAP kinase inhibitors, cytokine-targeted inhibitors, Molecularly targeted drugs such as proteasome inhibitors, antibody-anticancer drug combinations, and the like can also be included. These inhibitors also include antibodies.
  • the compound represented by formula (I)' is a novel compound developed by the present inventors. That is, another aspect of the present invention is a compound represented by the following formula (I)' (hereinafter sometimes referred to as "the compound of the present invention” or “compound (I)'”), and a pharmacological Regarding salts that are acceptable for Compounds represented by formula (I)' and pharmacologically acceptable salts thereof selectively kill nutrient-starved tumor cells and have anticancer activity, and are used as anticancer drugs. It can be used as a composition.
  • the content described in the section ⁇ pharmaceutical composition for anticancer>> is applied to the compound represented by formula (I)′, Alternatively, it can be applied to an anticancer pharmaceutical composition containing a pharmacologically acceptable salt thereof as an active ingredient.
  • the present invention relates to the use of the compound of the present invention, or a pharmacologically acceptable salt thereof, as an anticancer agent that selectively kills nutrient-starved tumor cells.
  • Another aspect of the present invention is the use of the compound of the present invention or a pharmacologically acceptable salt thereof as an anticancer agent that suppresses the development of cancer stem cells or kills cancer stem cells.
  • R 1 ' represents hydrogen, hydroxy, carboxylic acid ester having 1 to 10 carbon atoms, or alkoxy having 1 to 4 carbon atoms
  • R 2 ' to R 4 ' each independently represents hydrogen, an electron-donating group, or an electron-withdrawing group
  • R 5 ' represents hydrogen, hydroxy, carboxylic acid ester having 1 to 10 carbon atoms, alkoxy having 1 to 4 carbon atoms, or a ring formed by combining with R 6 '
  • R 6 ' represents hydrogen or a ring formed by combining with R 5 '
  • R 7 ' and R 11 ' each independently represent hydrogen or halogen
  • R 8 ' and R 10 ' each independently represent hydrogen or an electron-withdrawing group
  • R 9 ' represents an electron-withdrawing group
  • X' and Y' are each independently carbon or nitrogen; when R 9 ' is hydroxy, then R 2 ' is other than alkoxy; When R 9 ' is cyano or nitro, R 2 ' is other
  • Preferred compounds of compound (I)' are the same as those of compound (I), preferably compounds N- (hereinafter sometimes referred to as NIC-) 42, N-50, N-51, N-101 , N-110, N-115, NIC-120, NIC-127 and NIC-129, most preferably compounds N-42, N-50 and N-51.
  • Compound (I)' can be synthesized by a known synthesis method with reference to Examples below.
  • PANC-1 human pancreatic cancer cell line was purchased from the Riken BRC Cell Bank and maintained in standard DMEM supplemented with 10% FBS under a humidified atmosphere of 5% CO and 95% air. , and stored at 37 °C. Human pancreatic cancer cells were seeded in 96-well plates (1.5 ⁇ 10 4 cells/well) and cultured with fresh DMEM for 24 hours at 37° C. under 5% CO 2 and 95% air. After washing the cells twice with PBS, the medium was serially diluted in nutrient-rich medium (DMEM) or nutrient-deficient medium (NDM) for the test compounds listed in Tables 1 and 2, and N-113-115. Changed to sample medium. Each test plate included controls and blanks.
  • DMEM nutrient-rich medium
  • NDM nutrient-deficient medium
  • the composition of NDM was as follows. 0.1 mg L-1 Fe( NO3 ) 3 ( 9H2O ), 265 mg L-1 CaCl2 ( 2H2O ), 400 mg L-1 KCl, 200 mg L-1 MgSO4 (7H2O ) O), 6400 mg L-1 NaCl, 700 mg L-1 NaHCO3 , 125 mg L-1 NaH2PO4 , 15 mg L-1 phenol red , 25 mM L-1 HEPES buffer (pH 7.4), MEM Vitamin solution (Life Technologies, Inc), final pH adjusted to 7.4 with 10% NaHCO 3 aqueous solution.
  • PANC-1 was incubated with each test compound in DMEM and NDM for 24 hours, then washed twice with PBS and replaced with 100 ⁇ L of DMEM containing 10% WST-8 cell counting kit solution. After incubation for 3 hours, absorbance at 450 nm was measured with an EnSpire multimode plate reader (PerkinElmer, Inc., Waltham, Mass., USA) to determine cell viability. Cell viability was calculated from the average value of 3 wells using the following formula.
  • N-compounds exhibited cytotoxic activity against pancreatic cancer-derived cells (Tables 1 and 2).
  • compounds N-42, N-48, N-50, N-51, N-54, N-56, N-68, N-81, N-101, N-110 and N-115 were selected for nutrient starvation
  • the target 50% cell inhibitory concentration (PC 50 ) values were 16 nM, 16 nM, 8 nM, 8 nM, 10 nM, 10 nM, 12 nM, 5 nM, ⁇ 5 nM, ⁇ 5 nM and 3 nM, respectively, showing particularly strong cytotoxic activity.
  • N-120, N-127 and N-129 also exhibited particularly strong cytotoxic activity with PC 50 values of 4.3 nM, 0.46 nM and 0.48 nM, respectively.
  • the potassium or sodium salts of N-101 had more than 300-fold more nutrient-starvation selective cytotoxicity than niclosamide in NDM, and exhibited particularly potent cytotoxic activity.
  • the N-compound which is a phenylbenzamide derivative
  • Phenylbenzamide derivatives have been shown to be useful as anti-austerity agents.
  • Pancreatic tumors are highly metastatic tumors. Metastasis occurs when primary tumor cells migrate through the vasculature to distant organs that have sufficient nutrients to grow and form secondary tumors. This process is partly responsible for the high morbidity and short life span of pancreatic cancer patients. Therefore, we investigated the effect of N-42 on the migration of PANC-1 human pancreatic tumor cells using a quantitative real-time tumor migration assay.
  • FIG. 1B shows changes in the retraction area over time. Control cells showed a higher migration rate. After 48 hours, the control wound area showed wound closure to 100% of the initial wound area.
  • Treatment with compound N-42 at concentrations of 5, 10, 20, and 40 ⁇ M inhibited migration of PANC-1 tumor cells in a concentration-dependent manner, and reduced the initial wound area by about 25% and 25%, respectively. The wound area was 50%, 75%, and 98%.
  • control group ii) Low-dose N compound administration group (10 mg/kg/day; 5 times/week)
  • GEM Gemcitabine
  • administration group 150mg/kg/week; once/week
  • Combination group [Gemcitabine 150 mg/kg/week; once/week + N-42 compound, 30 mg/kg/day, 5 times/week]
  • mice were injected intraperitoneally with N-compounds and/or Gemcitabine (treatment group) or PBS (control group). All mice had free access to solid food and water. Body weight and tumor size were measured twice weekly using the following formula.
  • FIG. 4 shows a photograph of the tumor excised on the 29th day after the start of the experiment.
  • Groups administered with N-42 and N-51 alone showed significant tumor size and weight suppression effects. The effect was concentration dependent.
  • the group that combined Gemcitabine with N-42 or N-51 also showed significant tumor size and weight suppression effects. This indicated that the administration of N-51 and N-42 alone, and the combination of N-51 and Gemcitabine, and the combination of N-42 and Gemcitabine all had anticancer activity. .
  • the combined use of N-51 or N-42 and Gemcitabine was found to be more effective than the administration of each compound alone.
  • N-42 and N-51 had no effect on mouse body weight gain, and no side effects on growth were observed.
  • the gel was subsequently transferred to an Immobilon-P transfer polyvinylidene fluoride membrane (Millipore Corp, Bedford, Mass., USA).
  • the membrane was immediately immersed in blocking buffer [5% non-fat dry milk in TBS-Tween (TBS-T) buffer containing 10 mM Tris, 100 mM NaCl, 0.1% Tween 20, pH 7.5] for 1 hour at room temperature, followed by TBS. After washing with -T buffer for 30 minutes, they were incubated overnight at 4°C with appropriate specific primary antibodies commercially available.
  • FIGS. 5 and 6 The results are shown in FIGS. 5 and 6.
  • concentration-dependent decreases in pAKt, pmTOR, SOX-2, c-MYC, and OCT-4 were observed under nutrient starvation conditions. It inhibited Akt/mTOR activation under nutrient starvation conditions.
  • the serine/threonine kinase Akt (also called protein kinase B) plays a central role in cell signaling, and abnormalities in these signaling affect a wide range of diseases from cancer and diabetes to neurodegeneration.
  • mTOR is also a member of the PI3K-related protein kinase (PIKK) family and functions to propagate growth factor pathway signals, thereby supporting cell growth, proliferation, and survival. Upregulated mTOR signaling has been detected in various cancers.
  • mTOR is the core catalytic unit of two protein complexes, mTORC1 and mTORC2, the mTORC1 complex is rapamycin-sensitive and consists of mTOR, Raptor, and mLST8.
  • mTORC1 controls cell growth and proliferation.
  • Other biological processes are also regulated by mTORC1, including various tumor cell-specific processes such as translation, ribosome biogenesis, autophagy, glucose metabolism, cellular response to hypoxia, and metastasis.
  • Cancer cells generally grow irregularly and rapidly, and often have fragile and disorganized vasculature that expose them to a stressful microenvironment such as glucose deprivation, hypoxia, and other nutrient deficiencies.
  • a stressful microenvironment such as glucose deprivation, hypoxia, and other nutrient deficiencies.
  • cancer cells exhibit an inherent ability to regulate energy metabolism and withstand harsh conditions such as low nutrition and low oxygen supply. Autophagy is thought to be one such mechanism. From these results, it was found that N-compounds are anti-austerity agents that inhibit autophagy and are useful as novel anticancer agents.
  • phenylbenzamide derivatives inhibited SOX2, c-MYC, and OCT-4 under nutrient starvation conditions.
  • Cancer stem cells are cells that have self-renewal ability, multipotency, and strong tumorigenic ability to form cancer at a high rate even from a small number of cells. Cancer stem cells are also thought to be deeply associated with treatment resistance, recurrence, and metastasis of cancer.
  • SOX2, c-MYC, and OCT-4 are known to promote dedifferentiation of cancer cells and confer stemness. Phenylbenzamide derivatives were shown to promote dedifferentiation of cancer cells, inhibit conferment of stemness, and be useful for treatment resistance of cancer and suppression of recurrence and metastasis.
  • the compound used in the present invention inhibits SOX2, c-MYC, and OCT-4, thereby exhibiting excellent efficacy against cancer treatment resistance, that is, pancreatic cancer, without showing almost any resistance. It was suggested that
  • N-compounds in orthotopic transplantation models To further verify the excellent anti-tumor effects of N-compounds in vitro and in vivo, we administered N-compounds to an orthotopic transplantation model in nude mice and confirmed their effects. bottom. Five-week-old male nude mice (CAnN, Cg-Foxn1 ⁇ nu>/CrlCrlJ 5W, Charles Rivers) were purchased from Ninox Lab Supply Co., Ltd., Japan. Mice were housed in a pathogen-free environment with a temperature of 25° C., a 12-hour light-dark cycle, and a relative humidity of 45-50%, and were acclimated to the housing environment for 1 week.
  • CAnN Cg-Foxn1 ⁇ nu>/CrlCrlJ 5W, Charles Rivers
  • mice were anesthetized under isoflurane for solid tumor implantation. A small 1 cm longitudinal skin incision was made in the upper left axillary region of the abdomen of the mouse and the peritoneum was opened to expose the pancreas. A mass of tumor block was implanted into the pancreatic head using 4-0 absorbable surgical sutures (Bicryl Rapid, VR426, Johnson & Johnson). The pancreas was gently placed back into the abdominal cavity and the surgical opening was closed using 6-0 absorbable surgical sutures. All surgeries were performed in a sterile environment. To prevent bacterial infection, enrofloxacin (5 mg/kg) was administered intraperitoneally three times, one day before surgery and two days after surgery. Mice were then randomly divided into 8/group. Drug administration was performed as in the ectopic model. Body weights were measured twice weekly and final tumor data were obtained at endpoint (Day 29). Mice were sacrificed under CO2 anesthesia and the tumors were harvested and weighed by laparotomy.
  • a drug-free control solution was similarly prepared with gum arabic in a mortar to give a 10% (w/v) solution.
  • the prepared drug solution was refrigerated at 4°C.
  • the total amount of frozen MIAPaca2 cells was transferred to a 15 mL sterile tube, and 5 mL of medium (DMEM (High Glucose, Wako 043-30085) + 10% FBS 20 ml) warmed to 37°C was gently added. After centrifugation (3000 rpm, 5 min, 37° C.), the supernatant was removed and 5 mL of medium warmed to 37° C. was gently added and mixed to isolate the cells.
  • DMEM High Glucose, Wako 043-30085
  • the cells were transferred to a T-25 flask and cultured in a CO 2 incubator (37°C, 5% CO 2 ). After 24 hours, the cells were observed and cultured for another 4 days. Thereafter, the cells were transferred to a dish with a diameter of 150 mm (bottom area of 152 cm 2 ) and subculture was continued.
  • Frozen cells were thawed, and 1 ⁇ 10 7 cells were suspended in 200 ⁇ l PBS after 3 weeks from the start of culture.
  • 1 ⁇ 10 7 cells/mouse (1 ⁇ 10 7 cells/200 ⁇ L/head) were subcutaneously transplanted to the flank (1 site per mouse) using a 1 ml syringe with a 25GX1′′ injection needle.
  • Compound administration was initiated 3 days after transplantation.
  • the mean tumor volume was 200 mm 3 3 3 days after transplantation.
  • Gemcitabine was administered weekly intraperitoneally (IP) (150 mg/Kg/week) for a total of 4 doses.
  • IP intraperitoneally
  • N-42 was administered intraperitoneally (IP) ⁇ high dose (150 mg/Kg/week) or low dose (50 mg/Kg/week) ⁇ five times a week for a total of 20 doses.
  • IP intraperitoneally
  • N-42 high dose + Gemcitabine administration group N-42 was administered after administration of Gemcitabine.
  • Each group had 10 animals, and experiments were conducted in the following 5 groups (total number of animals: 50).
  • Gemcitabine administration group (3) NIC-42 high dose group (4) NIC-42 low-dose administration group (5) NIC-42 high dose + Gemcitabine administration group
  • FIG. 11 shows changes in tumor size over time.
  • N-42 high-dose administration group (N-42(H)), low-dose administration group (N-42(L)), Gemcitabine administration group (GEM), N-42 and Gemcitabine combination group were all controls. showed a tumor suppressive effect compared with (Cont).
  • the combined N-42 and Gemcitabine group showed a synergistic effect compared to the high-dose N-42 administration group (N-42(H)) and the Gemcitabine administration group (GEM) alone.
  • N-compounds showed greater sensitivity under conditions mimicking the tumor microenvironment with nutrient deprivation plus oxygen deprivation.
  • Gemcitabine was highly resistant [IC50 (24 h) >100 ⁇ M] against PANC-1 cells under such tumor microenvironment-mimicking conditions (glucose and oxygen deprivation), whereas N-113, N-114, and N-115 exhibited PC50 values of 30 nM, 111 nM, and 0.9 nM under glucose and oxygen deprivation conditions.
  • N-compounds were shown to be approximately 10,000 times more potent than gemcitabine under low-nutrient and hypoxic conditions.
  • mice were administered N-42, GEM, or a combination of N-42 and GEM and subjected to endpoint and global studies.
  • KPCY mouse pancreatic cancer cells were first inoculated subcutaneously and grown in host BALB/c-nu mice for 2-3 weeks. On the day of implantation, tumors in host BALB/c-nu mice were excised and cut into pieces approximately 15 mg in size. Small pieces of this tumor were surgically implanted into the pancreas of C57B1/6 recipient mice.
  • mice were randomly assigned on day 3 after surgery and received N-42, GEM, or a combination of the two drugs from day 3 onwards. For endpoint studies, mice were sacrificed on day 16, and for survival studies, drug administration continued until all mice died. Overall mouse survival was determined using Kaplan-Meier survival plots and analyzed by the Log-rank test.
  • Results of the endpoint study are shown in FIG.
  • the results showed that the control group had the highest mean tumor weight and the N-42 group had a significantly lower mean tumor weight.
  • the combination of N-42 and GEM had the lowest mean tumor weight, significantly lower than all other groups. This demonstrates the strong anti-tumor activity of the combination with N-42 and GEM in reducing orthotopic tumor growth.
  • End-point studies showed that single-agent N-42 significantly inhibited orthotopic tumor growth. When N-42 and GEM were combined, very strong anti-tumor activity was observed and a statistically significant reduction in tumor growth was observed. There was no apparent change in body weight of mice between groups.
  • the results of the overall survival study are shown in Figure 15.
  • the N-compound showed significant overall survival in immune-normal C57B1/6 mice bearing pancreatic tumors, as shown by Kaplan-Meier survival plots and analyzed by the Log-rank test.
  • the median survival of the control group was 28.5 days
  • the median survival of mice treated with N-42 was 41 days
  • the median survival of mice treated with the combination of N-42 and GEM The value was 55.5 days.
  • phenylbenzamide derivatives which are extremely unique compounds that exhibit little toxicity to cancer cells under nutrient-rich conditions and exhibit toxicity to cancer cells only under nutrient-starved conditions. This indicates that serious side effects peculiar to anticancer drugs can be avoided. Phenylbenzamide derivatives also inhibit multiple kinases involved in key mechanisms such as cancer growth and resistance to nutrient starvation. Therefore, it is thought to be effective not only against pancreatic cancer but also against pancreatic cancer showing resistance and cancer in general.
  • cancer stem cells the more they are in a state of nutritional starvation, the higher their proliferative ability, metastatic ability, and malignancy. This is considered to be closely related to cancer stem cells, and in fact, the expression of cancer stem cells is significantly increased under conditions of nutritional starvation. If cancer stem cells are not effectively killed, the cancer will eventually recur, which is extremely serious.
  • the present invention is an approach that specifically focuses on cytotoxicity in the cancer microenvironment, i.e., nutrient starvation, and is very likely to be effective in this cancer stem cell as well.
  • the present invention can be used as a pharmaceutical composition for cancer treatment.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention addresses the problem of providing a novel pharmaceutical composition, and in particular, a novel anti-cancer pharmaceutical composition, and a novel compound used in said pharmaceutical composition.　The present invention provides a pharmaceutical composition containing, as an active component, the compound represented by formula (I), or a pharmacologically acceptable salt thereof.

Description

新規医薬組成物Novel pharmaceutical composition
　本発明は、新規医薬組成物、特に新規抗がん用医薬組成物、および同医薬組成物に用いられる新規化合物に関する。 The present invention relates to novel pharmaceutical compositions, particularly novel anticancer pharmaceutical compositions, and novel compounds used in the pharmaceutical compositions.
　がんの中でも膵臓がんは、全固形がん中で５年生存率が最も低く、極めて予後不良ながんである。膵臓がんの最も効果的な治療は外科手術であるが、術前および術後における化学療法剤の果たす役割は大きい。しかし、現在膵臓がん治療における効果的な化学療法剤は極めて少なく、またその効果も限定的である。 Among all cancers, pancreatic cancer has the lowest 5-year survival rate among all solid cancers, and has an extremely poor prognosis. Surgery is the most effective treatment for pancreatic cancer, but chemotherapeutic agents play a major role before and after surgery. However, there are currently very few effective chemotherapeutic agents in the treatment of pancreatic cancer, and their effects are limited.
　膵臓がんにおける化学療法剤として、以前はgemcitabine（ゲムシタビン）が第一選択薬として使用されていた。しかし、Gemcitabine投与により、Gemcitabineに対して耐性を示す膵臓がんが報告されていることから（非特許文献１）、近年では、Gemcitabineと他剤の併用療法が主流となっている（非特許文献２、３）。Fluorouracil、oxaliplatin、irinotecan等を併用するFOLFIRINOXや、本邦のみに適用ではあるが、経口剤としてTS-1も用いられている。さらに、リポソーム製剤としてnab-paclitaxelやonivyde等副作用軽減を目指したドラッグデリバリーシステムも活用されている（非特許文献４）。しかしながら、十分な治療効果が得られる膵臓がんの化学療法は見つかっていない。 As a chemotherapeutic agent for pancreatic cancer, gemcitabine was previously used as the first-line drug. However, since administration of Gemcitabine has been reported to cause pancreatic cancer that exhibits resistance to Gemcitabine (Non-Patent Document 1), in recent years, combination therapy with Gemcitabine and other drugs has become mainstream (Non-Patent Document 2, 3). FOLFIRINOX, which is used in combination with fluouracil, oxaliplatin, irinotecan, etc., and TS-1, which is an oral drug, is also used, although it is only applicable in Japan. Furthermore, drug delivery systems such as nab-paclitaxel and onivyde, which aim to reduce side effects, are also utilized as liposome formulations (Non-Patent Document 4). However, no chemotherapy for pancreatic cancer has been found that provides sufficient therapeutic effects.
　また、膵臓がん以外のがんについても、治療に決定的な化学療法による治療法は未だ見いだされておらず、新規薬剤の開発が求められている。 Also, for cancers other than pancreatic cancer, no definitive chemotherapy treatment has yet been found, and there is a need for the development of new drugs.
　悪液質は、筋タンパク質の分解が進み、タンパク質合成が阻害された結果生じ、がん治療への耐えられない原因となっている。進行がんにおいては、悪液質症状は時間の経過とともに悪化し、進行がん患者の80％以上が、極端な体重減少と筋肉の減少を伴う悪液質に苦しんでいる。がん悪液質は、炎症や代謝バランスの乱れによる全身の反応の結果として表れる。過去数年間の臨床試験では、悪液質に有効な薬はなく、改善も見られていない。 Cachexia occurs as a result of progressive breakdown of muscle protein and inhibition of protein synthesis, which is the cause of the inability to tolerate cancer treatment. In advanced cancer, cachectic symptoms worsen over time, and more than 80% of patients with advanced cancer suffer from cachexia, which is associated with extreme weight loss and muscle wasting. Cancer cachexia is the result of a systemic response to inflammation and metabolic imbalance. Clinical trials over the past few years have shown no effective drugs for cachexia and no improvement.
　前記の状況を鑑み、本発明は、新規医薬組成物、特に新規抗がん用医薬組成物、および同医薬組成物に用いられる新規化合物を提供することを課題とする。 In view of the above situation, an object of the present invention is to provide a novel pharmaceutical composition, particularly a novel anticancer pharmaceutical composition, and a novel compound used in the pharmaceutical composition.
　本発明は、既存の膵臓がんに対する抗がん剤とは異なる作用機序でがん治療効果を奏する新規抗がん用化合物および新規抗がん用医薬組成物等を提供するものである。すなわち、本発明は、単独投与、および既存の抗がん剤との併用において効果を発揮する画期的な化合物を提供するものであり、抗がん剤治療、例えば、併用によるがん治療に新たなピースを加えるものである。
　好ましくは、本発明は、単独投与または併用投与においても副作用の低減されたがん治療剤を提供するものである。特に、本発明は、Gemcitabineに対して、耐性を示す膵臓がんに対する治療方法を提供するものである。
　更に、好ましい態様において、本発明はがんの治療と共にがんによる悪液質を改善し、または予防するための手段を提供するものである。 The present invention provides novel anticancer compounds, novel anticancer pharmaceutical compositions, and the like, which exhibit cancer therapeutic effects through a mechanism of action different from that of existing anticancer agents for pancreatic cancer. That is, the present invention provides an epoch-making compound that exhibits effects when administered alone or in combination with existing anticancer agents, and is useful in anticancer drug therapy, for example, in combination cancer therapy. It adds a new piece.
Preferably, the present invention provides cancer therapeutic agents with reduced side effects in single administration or in combination administration. In particular, the present invention provides a method of treating pancreatic cancer that is resistant to gemcitabine.
Furthermore, in a preferred embodiment, the present invention provides means for treating cancer as well as ameliorating or preventing cachexia due to cancer.
　すなわち、本発明の要旨は、以下のとおりである。
［１］　下記式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩を有効成分として含有する、医薬組成物： That is, the gist of the present invention is as follows.
[1] A pharmaceutical composition containing a compound represented by the following formula (I) or a pharmacologically acceptable salt thereof as an active ingredient:
Figure JPOXMLDOC01-appb-C000003
Figure JPOXMLDOC01-appb-C000003
　式中、
　Ｒ１は、水素、ヒドロキシ、炭素数１～１０のカルボン酸エステル、または炭素数１～４のアルコキシを示し、
　Ｒ２～Ｒ４は、それぞれ独立に、水素、電子供与性基または電子吸引性基を示し、
　Ｒ５は、水素、ヒドロキシ、炭素数１～１０のカルボン酸エステル、炭素数１～４のアルコキシ、またはＲ６と結合し形成した環を示し、
　Ｒ６は、水素、またはＲ５と結合し形成した環を示し、
　Ｒ７およびＲ１１は、それぞれ独立に、水素、またはハロゲンを示し、
　Ｒ８～Ｒ１０は、それぞれ独立に、水素、電子供与性基または電子吸引性基を示し、
　ＸおよびＹは、それぞれ独立に、炭素、または窒素であり、
　Ｒ２～Ｒ４およびＲ８～Ｒ１０の少なくとも１つは電子吸引性基である。
［２］　前記Ｒ９が、電子吸引性基である、［１］に記載の医薬組成物。
［３］　前記Ｒ２およびＲ３の少なくとも１つが、電子供与性基または電子吸引性基である、［１］または［２］に記載の医薬組成物。
［４］　前記電子吸引性基が、ハロゲン、炭素数１～４のハロゲン化アルキル、炭素数１～１０のカルボン酸エステル、炭素数１～４のアシル、シアノ（－ＣＮ）、ニトロ（－ＮＯ2）、炭素数１～４のアルキルチオ（－ＳＲ；Ｒはアルキルを示す）、炭素数１～４のアルキルスルフィニル（－ＳＯＲ；Ｒはアルキルを示す）、炭素数１～４のアルキルスルホニル（－ＳＯ２Ｒ；Ｒはアルキルを示す）；またはこれらの電子吸引性基を置換基として有するアリールまたはヘテロアリールである、［１］～［３］のいずれかに記載の医薬組成物。
［５］　前記電子供与性基がヒドロキシ、炭素数１～４のアルキル、炭素数１～４のアルコキシ、またはアミノである、［１］～［４］のいずれかに記載の医薬組成物。
［６］　栄養飢餓状態の腫瘍細胞を選択的に死滅させるための、［１］～［５］のいずれかに記載の医薬組成物
［７］　抗がん用である、［１］～［６］のいずれかに記載の医薬組成物。
［８］　前記がんが、膵臓がんである、［７］に記載の医薬組成物。
［９］　前記膵臓がんが、式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩以外の抗がん化合物に対して耐性を示す膵臓がんである、［８］に記載の医薬組成物。
［１０］　がん幹細胞の発生抑制用、または、がん幹細胞の殺傷用である、［１］～［９］のいずれかに記載の医薬組成物。
［１１］　さらに、式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩以外の抗がん化合物を含有する、［１］～［１０］のいずれかに記載の医薬組成物。
［１２］　式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩以外の抗がん化合物と併用投与されるように用いられる、［１］～［１１］のいずれかに記載の医薬組成物。
［１３］　前記式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩以外の抗がん化合物が、代謝拮抗薬である、［９］、［１１］または［１２］のいずれかに記載の医薬組成物。
［１４］　前記代謝拮抗薬が、ゲムシタビンである、［１３］に記載の医薬組成物。
［１５］　下記式（Ｉ）’で示される化合物、またはその薬理学的に許容可能な塩： During the ceremony,
R 1 represents hydrogen, hydroxy, carboxylic acid ester having 1 to 10 carbon atoms, or alkoxy having 1 to 4 carbon atoms,
R 2 to R 4 each independently represent hydrogen, an electron-donating group or an electron-withdrawing group,
R 5 represents hydrogen, hydroxy, carboxylic acid ester having 1 to 10 carbon atoms, alkoxy having 1 to 4 carbon atoms, or a ring formed by combining with R 6 ,
R 6 represents hydrogen or a ring formed by combining with R 5 ,
R 7 and R 11 each independently represent hydrogen or halogen,
R 8 to R 10 each independently represent hydrogen, an electron-donating group or an electron-withdrawing group,
X and Y are each independently carbon or nitrogen;
At least one of R 2 -R 4 and R 8 -R 10 is an electron withdrawing group.
[2] The pharmaceutical composition of [1], wherein the R9 is an electron-withdrawing group.
[3] The pharmaceutical composition of [1] or [2], wherein at least one of R 2 and R 3 is an electron-donating group or an electron-withdrawing group.
[4] The electron withdrawing group is halogen, halogenated alkyl having 1 to 4 carbon atoms, carboxylic acid ester having 1 to 10 carbon atoms, acyl having 1 to 4 carbon atoms, cyano (-CN), nitro (-NO 2 ), C 1-4 alkylthio (-SR; R represents alkyl), C 1-4 alkylsulfinyl (-SOR; R represents alkyl), C 1-4 alkylsulfonyl (- SO 2 R; R represents alkyl); or aryl or heteroaryl having these electron-withdrawing groups as substituents.
[5] The pharmaceutical composition according to any one of [1] to [4], wherein the electron-donating group is hydroxy, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or amino.
[6] The pharmaceutical composition according to any one of [1] to [5] for selectively killing nutrient-starved tumor cells [7] For anticancer [1] to [6] ] The pharmaceutical composition according to any one of
[8] The pharmaceutical composition of [7], wherein the cancer is pancreatic cancer.
[9] The pancreatic cancer described in [8], wherein the pancreatic cancer is resistant to an anticancer compound other than the compound represented by formula (I) or a pharmacologically acceptable salt thereof. pharmaceutical composition of
[10] The pharmaceutical composition according to any one of [1] to [9], which is for suppressing the development of cancer stem cells or for killing cancer stem cells.
[11] The pharmaceutical composition of any one of [1] to [10], further comprising an anticancer compound other than the compound represented by formula (I) or a pharmacologically acceptable salt thereof. .
[12] The compound according to any one of [1] to [11], which is used in combination with an anticancer compound other than the compound represented by formula (I) or a pharmacologically acceptable salt thereof pharmaceutical composition of
[13] Any of [9], [11] or [12], wherein the anticancer compound other than the compound represented by formula (I) or a pharmacologically acceptable salt thereof is an antimetabolite A pharmaceutical composition according to
[14] The pharmaceutical composition of [13], wherein the antimetabolite is gemcitabine.
[15] A compound represented by the following formula (I)', or a pharmacologically acceptable salt thereof:
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004
　式中、
　Ｒ１’は、水素、ヒドロキシ、炭素数１～１０のカルボン酸エステル、または炭素数１～４のアルコキシを示し、
　Ｒ２’～Ｒ４’は、それぞれ独立に、水素、電子供与性基または電子吸引性基を示し、
　Ｒ５’は、水素、ヒドロキシ、炭素数１～１０のカルボン酸エステル、炭素数１～４のアルコキシ、またはＲ６’と結合し形成した環を示し、
　Ｒ６’は、水素、またはＲ５’と結合し形成した環を示し、
　Ｒ７’およびＲ１１’は、それぞれ独立に、水素、またはハロゲンを示し、
　Ｒ８’およびＲ１０’は、それぞれ独立に、水素、または電子吸引性基を示し、
　Ｒ９’は、電子吸引性基を示し、
　Ｘ’およびＹ’は、それぞれ独立に、炭素、または窒素であり、
　Ｒ９’がヒドロキシである場合、Ｒ２’はアルコキシ以外であり、
　Ｒ９’がシアノまたはニトロである場合、Ｒ２’は塩素以外である。
［１６］　前記電子吸引性基が、ハロゲン、炭素数１～４のハロゲン化アルキル、炭素数１～１０のカルボン酸エステル、炭素数１～４のアシル、シアノ（－ＣＮ）、ニトロ（－ＮＯ2）、炭素数１～４のアルキルチオ（－ＳＲ；Ｒはアルキルを示す）、炭素数１～４のアルキルスルフィニル（－ＳＯＲ；Ｒはアルキルを示す）、炭素数１～４のアルキルスルホニル（－ＳＯ２Ｒ；Ｒはアルキルを示す）；またはこれらの電子吸引性基を置換基として有するアリールまたはヘテロアリールである、［１５］に記載の化合物、またはその薬理学的に許容可能な塩。
［１７］　前記電子供与性基がヒドロキシ、炭素数１～４のアルキル、炭素数１～４のアルコキシ、またはアミノである、［１５］または［１６］に記載の化合物、またはその薬理学的に許容可能な塩。
［１８］　［１５］～［１７］のいずれかに記載の化合物、またはその薬理学的に許容可能な塩の、栄養飢餓状態の腫瘍細胞を選択的に死滅させる抗がん剤としての使用。
［１９］　［１５］～［１７］のいずれかに記載の化合物、またはその薬理学的に許容可能な塩の、がん幹細胞の発生を抑制させる、または、がん幹細胞を殺傷させる抗がん剤としての使用。
［２０］　上記式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩を対象に投与することを含む、がんの治療または予防方法。
［２１］　さらに、式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩以外の抗がん化合物を対象に投与することを含む、［２０］に記載の方法。
［２２］　前記抗がん化合物が、ゲムシタビンである、［２１］に記載の方法。
［２３］　がん治療期間中に、上記式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩を対象に投与することを含む、がん治療生存率を向上させる方法。
［２４］　上記式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩の、がんの治療または予防のための組成物の製造における使用。 During the ceremony,
R 1 ' represents hydrogen, hydroxy, carboxylic acid ester having 1 to 10 carbon atoms, or alkoxy having 1 to 4 carbon atoms,
R 2 ' to R 4 ' each independently represent hydrogen, an electron-donating group or an electron-withdrawing group,
R 5 ' represents hydrogen, hydroxy, carboxylic acid ester having 1 to 10 carbon atoms, alkoxy having 1 to 4 carbon atoms, or a ring formed by combining with R 6 ',
R 6 ' represents hydrogen or a ring formed by combining with R 5 ',
R 7 ' and R 11 ' each independently represent hydrogen or halogen,
R 8 ' and R 10 ' each independently represent hydrogen or an electron-withdrawing group,
R 9 ' represents an electron-withdrawing group,
X' and Y' are each independently carbon or nitrogen;
when R 9 ' is hydroxy, then R 2 ' is other than alkoxy;
When R 9 ' is cyano or nitro, R 2 ' is other than chlorine.
[16] The electron withdrawing group is halogen, halogenated alkyl having 1 to 4 carbon atoms, carboxylic acid ester having 1 to 10 carbon atoms, acyl having 1 to 4 carbon atoms, cyano (-CN), nitro (-NO 2 ), C 1-4 alkylthio (-SR; R represents alkyl), C 1-4 alkylsulfinyl (-SOR; R represents alkyl), C 1-4 alkylsulfonyl (- SO 2 R; R represents alkyl); or aryl or heteroaryl having these electron-withdrawing groups as substituents, or the compound according to [15], or a pharmacologically acceptable salt thereof.
[17] The compound of [15] or [16], wherein the electron-donating group is hydroxy, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or amino, or the pharmacologically acceptable salt.
[18] Use of the compound according to any one of [15] to [17] or a pharmacologically acceptable salt thereof as an anticancer agent that selectively kills nutrient-starved tumor cells.
[19] An anticancer compound of any one of [15] to [17] or a pharmacologically acceptable salt thereof that suppresses the development of cancer stem cells or kills cancer stem cells Use as an agent.
[20] A method for treating or preventing cancer, which comprises administering the compound represented by the above formula (I) or a pharmacologically acceptable salt thereof to a subject.
[21] The method of [20], further comprising administering to the subject an anticancer compound other than the compound represented by formula (I) or a pharmacologically acceptable salt thereof.
[22] The method of [21], wherein the anticancer compound is gemcitabine.
[23] A method for improving cancer treatment survival, comprising administering the compound represented by the above formula (I) or a pharmacologically acceptable salt thereof to a subject during cancer treatment.
[24] Use of the compound represented by formula (I) or a pharmacologically acceptable salt thereof in the manufacture of a composition for treating or preventing cancer.
　本発明は、新規医薬組成物、特に新規抗がん用医薬組成物、および同医薬組成物に用いられる新規化合物を提供する。 The present invention provides novel pharmaceutical compositions, particularly novel anticancer pharmaceutical compositions, and novel compounds used in the pharmaceutical compositions.
図１は、フェニルベンズアミド誘導体N-42のPANC-1に対する転移阻害活性の評価結果を示す図（図面代用写真）である。Ａは、ライブセルイメージング装置による観察像（各図は、左からコントロール、N-42 5μM処置、N-42 10μM処置）である。上段は、開始時、下段は、開始24時間後の像である。Ｂは、各時間の開口領域を示すグラフである。FIG. 1 is a diagram (drawing-substituting photograph) showing evaluation results of the metastasis inhibitory activity against PANC-1 of the phenylbenzamide derivative N-42. A is an image observed by a live cell imaging device (from the left, control, N-42 5 μM treatment, N-42 10 μM treatment). The upper row is the image at the start, and the lower row is the image 24 hours after the start. B is a graph showing the open area at each time. 図２は、フェニルベンズアミド誘導体N-51のin vivo抗腫瘍効果の評価結果を示す図である（*: P<0.05, **<0.01, ***<0.001, ****<0.0001, Anova-test）。Ａは、各群の腫瘍サイズを示すグラフである。Ｂは、各群の腫瘍重量を示すグラフである。Ｃは、各群の体重を示すグラフである。Figure 2 shows the evaluation results of the in vivo antitumor effect of the phenylbenzamide derivative N-51 (*: P<0.05, **<0.01, ***<0.001, ****<0.0001, Anova -test). A is a graph showing the tumor size of each group. B is a graph showing the tumor weight of each group. C is a graph showing the body weight of each group. 図３は、フェニルベンズアミド誘導体N-42のin vivo抗腫瘍効果の評価結果を示す図である（*: P<0.05, **<0.01, ***<0.001, ****<0.0001, Anova-test）。Ａは、各群の腫瘍サイズを示すグラフである。Ｂは、各群の腫瘍重量を示すグラフである。Ｃは、各群の体重を示すグラフである。Figure 3 shows the evaluation results of the in vivo antitumor effect of the phenylbenzamide derivative N-42 (*: P<0.05, **<0.01, ***<0.001, ****<0.0001, Anova -test). A is a graph showing the tumor size of each group. B is a graph showing the tumor weight of each group. C is a graph showing the body weight of each group. 図４は、フェニルベンズアミド誘導体N-42のin vivo抗腫瘍効果の評価結果（摘出腫瘍画像）を示す図（図面代用写真）である。FIG. 4 is a diagram (drawing-substituting photograph) showing the evaluation results of the in vivo antitumor effect of the phenylbenzamide derivative N-42 (excised tumor image). 図５は、フェニルベンズアミド誘導体N-42, N-51のAkt/mTOR活性化阻害活性の評価結果を示す図（図面代用写真）である。Ａは、PANC-1における結果を示す。Ｂは、MiaPaCa-2における結果を示す。Ｃは、PANC-1における、pAktおよびpmTOR阻害活性の評価結果（Akt阻害剤および活性化剤IGF-1との比較または併用効果）を示す。FIG. 5 is a diagram (drawing-substituting photograph) showing the evaluation results of the Akt/mTOR activation inhibitory activity of phenylbenzamide derivatives N-42 and N-51. A shows the results for PANC-1. B shows results for MiaPaCa-2. C shows the evaluation results of pAkt and pmTOR inhibitory activity in PANC-1 (comparison or combined effect with Akt inhibitor and activator IGF-1). 図６は、フェニルベンズアミド誘導体N-42のSOX2、c-MYC、OCT-4阻害活性の評価結果を示す図（図面代用写真）である。Ａは、PANC-1における結果を示す。Ｂは、MiaPaCa-2における結果を示す。Ｃは、PANC-1のNDMにおけるGemcitabineによる幹細胞性誘導下における結果を示す。FIG. 6 is a diagram (drawing-substituting photograph) showing evaluation results of the SOX2, c-MYC, and OCT-4 inhibitory activity of the phenylbenzamide derivative N-42. A shows the results for PANC-1. B shows results for MiaPaCa-2. C shows the results of PANC-1 under stemness induction by Gemcitabine in NDM. 図７は、同所移植モデルにおけるN-化合物の効果を測定した実験方法の模式図である。下の図は腫瘍移植と治療のタイムラインを占めす（数値は日を表す）。FIG. 7 is a schematic diagram of an experimental method for measuring the effects of N-compounds in an orthotopic implantation model. The figure below captures the timeline for tumor implantation and treatment (numbers represent days). 図８は、同所移植モデルの化合物投与開始から29日目の各群のマウスの写真（図面代用写真）である。FIG. 8 shows photographs (drawing substitute photographs) of mice in each group on day 29 from the start of compound administration in an orthotopic transplantation model. 図９は、同所移植モデルの化合物投与開始から29日目に各群のマウスを開腹して移植した腫瘍を撮影した写真（図面代用写真）である。丸は腫瘍部位を示す。FIG. 9 is a photograph (drawing-substituting photograph) of a tumor transplanted by laparotomy of each group of mice on day 29 from the start of compound administration in an orthotopic transplantation model. Circles indicate tumor sites. 図１０は、同所移植モデルにおけるN-化合物の効果の評価結果を示す図である。同所移植モデルマウスの体重（g）の経時変化（Ａ）および化合物投与開始から29日目の腫瘍量（g）（Ｂ）を示すグラフである。Ａの縦軸はマウス体重（g）を示し、横軸は経過日数（化合物投与をDay1とする）を示す。Ｂの縦軸は腫瘍重量（g）を示す（*: P<0.05, **<0.01, ***<0.001, ****<0.0001, Anova-test）。FIG. 10 shows the evaluation results of the effects of N-compounds in an orthotopic transplantation model. 1 is a graph showing changes in body weight (g) over time (A) in orthotopic transplantation model mice and tumor burden (g) on day 29 from the start of compound administration (B). The vertical axis of A indicates mouse body weight (g), and the horizontal axis indicates the number of days elapsed (compound administration is defined as Day 1). The vertical axis of B indicates tumor weight (g) (*: P<0.05, **<0.01, ***<0.001, ****<0.0001, Anova-test). 図１１は、担がんマウスにアラビアゴムを用いて懸濁させたN-42の高用量（N-42(H)）、低用量（N-42(L)）、およびGemcitabine（GEM）、N-42(H)とGemcitabineの併用投与の結果を示すグラフである。縦軸は腫瘍容積（mm3）、横軸は経過日数（Days）を表す。Figure 11. High dose (N-42(H)), low dose (N-42(L)), and Gemcitabine (GEM) of N-42 suspended with gum arabic in tumor-bearing mice. Fig. 4 is a graph showing the results of combined administration of N-42(H) and Gemcitabine. The vertical axis represents tumor volume (mm 3 ), and the horizontal axis represents elapsed days (Days). 図１２は、グルコースと血清を取り除いた培地中のヒト膵臓がん由来細胞株PANC-1の増殖に対するN-化合物およびゲムシタビンのin vitro細胞傷害活性を評価したグラフである。縦軸は細胞生存率（％）、横軸は各薬剤濃度（Log）（μＭ）を示す。ひし形（灰色）は正常酸素（20％O2）の条件下で培養した結果を示し、四角（黒）は低酸素（3％O2）の条件下で培養した結果を示す。FIG. 12 is a graph evaluating the in vitro cytotoxic activity of N-compounds and gemcitabine against the growth of human pancreatic cancer-derived cell line PANC-1 in a medium devoid of glucose and serum. The vertical axis indicates cell viability (%), and the horizontal axis indicates each drug concentration (Log) (μM). Diamonds (gray) indicate the results of culturing under normoxic (20% O 2 ) conditions, and squares (black) indicate the results of culturing under hypoxic (3% O 2 ) conditions. 図１３は、N-化合物の抗がん剤としての使用とGEMとの併用による同所性膵臓腫瘍モデルでの抗腫瘍効果と生存率の改善試験の実験プロトコールを示す図である。FIG. 13 is a diagram showing an experimental protocol for testing the antitumor effect and survival rate improvement in an orthotopic pancreatic tumor model by using an N-compound as an anticancer agent in combination with GEM. 図１４は、エンドポイント試験の結果を示す図である。Ａは、対照群、Gem群、N-42群、Gem+N-42併用群のマウス1匹あたりの平均体重を示す図である。Ｂは、対照群、Gem群、N-42群、およびN-42+Gem併用群の平均腫瘍重量と標準偏差を示す図である。統計解析はBrown-Forsythe and Welch ANOVA test（n=8）を用いて行い、有意性は、*P<0.1、**P<0.01および***P<0.001と表記した。X軸は、対照、N-42、GEM、およびN-42とGEMとの組み合わせを含む治療群を表す。Y軸は腫瘍体積を表し、バーは各治療群の平均腫瘍重量を表している。エラーバーは平均の標準偏差を表している。Figure 14 shows the results of the endpoint study. A is a diagram showing the average body weight per mouse in the control group, Gem group, N-42 group, and Gem+N-42 combination group. B shows the mean tumor weight and standard deviation of the control group, Gem group, N-42 group, and N-42+Gem combination group. Statistical analysis was performed using the Brown-Forsythe and Welch ANOVA test (n=8), and significance was indicated as *P<0.1, **P<0.01 and ***P<0.001. The X-axis represents treatment groups including control, N-42, GEM, and the combination of N-42 and GEM. Y-axis represents tumor volume and bars represent mean tumor weight for each treatment group. Error bars represent standard deviation of the mean. 図１５は、全生存試験の結果を示す図である。同所性膵臓腫瘍モデルにおける対照群、Gem群、N-42群、Gem+N-42併用群の全生存率を示すカプラン-マイヤー（Kaplan-Meier）生存プロットを示す。統計解析はLog-rank（Mantel-Cox）検定を用いて行った（n=8）。Figure 15 shows the results of the overall survival study. Kaplan-Meier survival plots showing overall survival for control, Gem, N-42, and Gem+N-42 combination groups in an orthotopic pancreatic tumor model. Statistical analysis was performed using the Log-rank (Mantel-Cox) test (n=8).
　以下、本発明の実施の形態について、説明する。ただし、本発明は、以下の好ましい実施形態に限定されず、本発明の範囲内で自由に変更することができるものである。なお、本明細書において、数値範囲を「下限～上限」で表現するものに関しては、上限は「以下」であっても「未満」であってもよく、下限は「以上」であっても「超」であってもよい。 Embodiments of the present invention will be described below. However, the present invention is not limited to the following preferred embodiments, and can be freely modified within the scope of the present invention. In this specification, regarding the numerical range expressed as "lower limit to upper limit", the upper limit may be "less than" or "less than", and the lower limit may be "more than" or " It may be "super".
　本明細書において「炭素数１～１０のカルボン酸エステル」とは、アルコールとカルボン酸が脱水縮合してできた基を意味し、単に「炭素数１～１０のエステル」という場合もある。例えば、メチルエステル基、エチルエステル基、プロピルエステル基、ブチルエステル基、ペンチルエステル基、ヘキシルエステル基等が挙げられる。 "Carboxylic acid ester having 1 to 10 carbon atoms" as used herein means a group formed by dehydration condensation of alcohol and carboxylic acid, and may be simply referred to as "ester having 1 to 10 carbon atoms". Examples include methyl ester group, ethyl ester group, propyl ester group, butyl ester group, pentyl ester group, hexyl ester group and the like.
　本明細書において「炭素数１～１０のアルキル」とは、直鎖、分岐または環状の炭素数が１～１０個の飽和炭化水素基を意味し、例えば、メチル、エチル、ｎ－プロピル、ｉ－プロピル、ｎ－ブチル、ｓｅｃ－ブチル、ｔ－ブチル、イソブチル、ペンチル、イソペンチル、２，３－ジメチルプロピル、ヘキシル、およびシクロヘキシル等が挙げられる。
　「炭素数１～４のアルキル」とは、直鎖または分岐状の炭素数が１～４個の飽和炭化水素を意味し、メチル、エチル、ｎ－プロピル、ｉ－プロピル、ｎ－ブチル、ｓｅｃ－ブチル、ｔ－ブチル、イソブチル等が挙げられる。
　「炭素数１～３のアルキル」とは、直鎖または分岐状の炭素数が１～３個の飽和炭化水素基を意味し、メチル、エチル、ｎ－プロピル、ｉ－プロピル等が挙げられる。 As used herein, "alkyl having 1 to 10 carbon atoms" means a linear, branched or cyclic saturated hydrocarbon group having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, i -propyl, n-butyl, sec-butyl, t-butyl, isobutyl, pentyl, isopentyl, 2,3-dimethylpropyl, hexyl, cyclohexyl and the like.
"C1-C4 alkyl" means a linear or branched saturated hydrocarbon having 1-4 carbon atoms, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec -butyl, t-butyl, isobutyl and the like.
"C1-3 alkyl" means a linear or branched saturated hydrocarbon group with 1-3 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl and the like.
　本明細書において「炭素数２～１０のアルケニル」とは、１つ以上の炭素－炭素間の二重結合を有する直鎖、分岐または環状の炭素原子数が２～１０個の不飽和炭化水素の任意の炭素原子から一個の水素原子を除去してなる一価の基を意味する。例えば、ビニル、プロペニル、イソプロペニル、１－ブテニル、２－ブテニル、３－ブテニル、１－ペンテニル、１－ペンテニル、３－ペンテニル、４－ペンテニル、１－メチル－１－ブテニル、１－メチル－２－ブテニル、１－メチル－３－ブテニル、１－メチリデンブチル、２－メチル－１－ブテニル、２－メチル－２－ブテニル、２－メチル－３－ブテニル、２－メチリデンブチル、３－メチル－１－ブテニル、３－メチル－２－ブテニル、３－メチル－３－ブテニル、１－エチル－１－プロペニル、１－エチル－２－プロペニル、１－ヘキセニル、２－ヘキセニル、３－ヘキセニル、４－ヘキセニル、５－ヘキセニル、１－メチル－１－ペンテニル、１－メチル－２－ペンテニル、１－メチル－３－ペンテニル、１－メチル－４－ペンテニル、１－メチリデンペンチル、２－メチル－１－ペンテニル、２－メチル－２－ペンテニル、２－メチル－３－ペンテニル、２－メチル－４－ペンテニル、２－メチリデンペンチル、３－メチル－１－ペンテニル、３－メチル－２－ペンテニル、３－メチル－３－ペンテニル、３－メチル－４－ペンテニル、３－メチリデンペンチル、４－メチル－１－ペンテニル、４－メチル－２－ペンテニル、４－メチル－３－ペンテニル、４－メチル－４－ペンテニル、１－ヘプテニル、２－ヘプテニル、３－ヘプテニル、４－ヘプテニル、５－ヘプテニル、６－ヘプテニル、オクテニル、ノネニル、およびデセニルが挙げられる。 As used herein, "alkenyl having 2 to 10 carbon atoms" means a linear, branched or cyclic unsaturated hydrocarbon having 2 to 10 carbon atoms and having one or more carbon-carbon double bonds. is a monovalent group obtained by removing one hydrogen atom from any carbon atom of For example vinyl, propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 1-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 1-methyl-2 -butenyl, 1-methyl-3-butenyl, 1-methylidenebutyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 2-methylidenebutyl, 3-methyl-1-butenyl , 3-methyl-2-butenyl, 3-methyl-3-butenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5 -hexenyl, 1-methyl-1-pentenyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl, 1-methyl-4-pentenyl, 1-methylidenepentyl, 2-methyl-1-pentenyl, 2 -methyl-2-pentenyl, 2-methyl-3-pentenyl, 2-methyl-4-pentenyl, 2-methylidenepentyl, 3-methyl-1-pentenyl, 3-methyl-2-pentenyl, 3-methyl-3 -pentenyl, 3-methyl-4-pentenyl, 3-methylidenepentyl, 4-methyl-1-pentenyl, 4-methyl-2-pentenyl, 4-methyl-3-pentenyl, 4-methyl-4-pentenyl, 1 -heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, octenyl, nonenyl, and decenyl.
　本明細書において「炭素数２～１０のアルキニル」とは、１以上の炭素－炭素間の三重重結合を有する直鎖、分岐、または環状の不飽和炭化水素の任意の炭素原子から一個の水素原子を除去してなる炭素原子数が２～１０個の一価の基を意味する。例えば、エチニル、１－プロピニル、２－プロピニル、１－ブチニル、２－ブチニル、３－ブチニル、ペンチニル、ヘキシニル、フェニルエチニル等を挙げることができる。 As used herein, "alkynyl having 2 to 10 carbon atoms" means one hydrogen from any carbon atom of a linear, branched, or cyclic unsaturated hydrocarbon having one or more carbon-carbon triple bonds. It means a monovalent group having 2 to 10 carbon atoms obtained by removing atoms. Examples include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, pentynyl, hexynyl, phenylethynyl and the like.
　本明細書において「炭素数６～１０のアリール」とは、６～１０個の炭素原子を有する芳香族炭化水素基のことであり、ベンゼンおよびナフタレンを包含する。 As used herein, "aryl having 6 to 10 carbon atoms" refers to an aromatic hydrocarbon group having 6 to 10 carbon atoms, including benzene and naphthalene.
　本明細書において「炭素数３～１０のヘテロアリール」とは、窒素原子、酸素原子、および硫黄原子から選択される１種類以上のヘテロ原子を少なくとも１個含む３～１０員の単環式複素環基または５～１０員の縮合複素環基を意味する。ヘテロアリールが含有するヘテロ原子の数は、例えば、１～５個、１～４個、１～３個、１～２個、２個、１個であってよい。例えば、窒素原子を１個含む複素環基、窒素原子を２個含む複素環基、窒素原子を３個含む複素環基、酸素原子１個を含む複素環基、酸素原子を２個含む複素環基、酸素原子１個と窒素原子１個を含む複素環基、硫黄原子を１個含む複素環基等様々な組み合わせが存在する。複素環基は、芳香族性であっても、非芳香族性であってもよい。単環式複素環基は、好ましくは、５～６員環である。縮合複素環基は、好ましくは、８～１０員環である。炭素数５～１０のヘテロアリールとしては、例えば、ピペリジル、ピペラジル、モルホリル、キヌクリジル、ピロリジル、アゼチジル、オキセチル、アゼチジン－２－オン－イル、アジリジニル、トロパニル、フリル、テトラヒドロフリル、チエニル、ピロリル、ピロリニル、ピロリジニル、ジオキソラニル、オキサゾリル、オキサゾリニル、イソオキサゾリル、チアゾリル、チアゾリニル、イソチアゾリル、イミダゾリル、イミダゾリニル、イミダゾリジニル、オキサゾリジニル、チアゾリジニル、ピラゾリル、ピラゾリニル、ピラゾリジニル、オキサジアゾリル、フラザニル、チアジアゾリル、１,２,３－トリアゾリル、１,２,４－トリアゾリル、テトラゾリル、ピラニル、ピリジル、ピペリジニル、ピリダジニル、ピリミジニル、ピラジニル、ピペラジニル、ジオキサニル、オキサジニル、モルホリニル、チアジニル、トリアジニル、ベンゾフラニル、イソベンゾフラニル、ジヒドロベンゾフラニル、ジヒドロイソベンゾフラニル、ベンゾチエニル、イソベンゾチエニル、ジヒドロベンゾチエニル、ジヒドロイソベンゾチエニル、テトラヒドロベンゾチエニル、キノリル、イソキノリル、キナゾリニル、フタラジニル、プテリジニル、クマリル、クロモニル、１，４－ベンゾジアゼピニル、インドリル、イソインドリル、ベンズイミダゾイル、ベンゾフリル、プリニル、アクリジニル、フェノキサジニル、フェノチアジニル、ベンゾオキサゾリル、ベンゾチアゾリル、インダゾリル、ベンズイミダゾリル、ベンゾジオキソラニル、ベンゾジオキサニルクロメニル、クロマニル、イソクロマニル、クロマノニル、シンノリニル、キノキサリニル、インドリジニル、キノリジニル、イミダゾピリジル、ナフチリジニル、ジヒドロベンゾオキサジニル、ジヒドロベンゾオキサゾリノニル、ジヒドロベンゾオキサジノニル、およびベンゾチオキサニルを挙げることができる。 As used herein, "heteroaryl having 3 to 10 carbon atoms" means a 3 to 10-membered monocyclic heteroaryl containing at least one heteroatom selected from nitrogen, oxygen, and sulfur atoms. It means a ring group or a 5- to 10-membered condensed heterocyclic group. The heteroaryl may contain, for example, 1-5, 1-4, 1-3, 1-2, 2, 1 heteroatoms. For example, a heterocyclic group containing one nitrogen atom, a heterocyclic group containing two nitrogen atoms, a heterocyclic group containing three nitrogen atoms, a heterocyclic group containing one oxygen atom, a heterocyclic group containing two oxygen atoms heterocyclic groups containing one oxygen atom and one nitrogen atom, heterocyclic groups containing one sulfur atom, and the like. Heterocyclic groups may be aromatic or non-aromatic. Monocyclic heterocyclic groups are preferably 5- to 6-membered rings. The fused heterocyclic group is preferably an 8- to 10-membered ring. Examples of heteroaryl having 5 to 10 carbon atoms include piperidyl, piperazyl, morpholyl, quinuclidyl, pyrrolidyl, azetidyl, oxetyl, azetidin-2-one-yl, aziridinyl, tropanyl, furyl, tetrahydrofuryl, thienyl, pyrrolyl, pyrrolyl, pyrrolidinyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxadiazolyl, furazanyl, thiadiazolyl, 1,2,3-triazolyl, 1,2, 4-triazolyl, tetrazolyl, pyranyl, pyridyl, piperidinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, dioxanyl, oxazinyl, morpholinyl, thiazinyl, triazinyl, benzofuranyl, isobenzofuranyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, benzothienyl , isobenzothienyl, dihydrobenzothienyl, dihydroisobenzothienyl, tetrahydrobenzothienyl, quinolyl, isoquinolyl, quinazolinyl, phthalazinyl, pteridinyl, coumaryl, chromonyl, 1,4-benzodiazepinyl, indolyl, isoindolyl, benzimidazolyl, benzofuryl , purinyl, acridinyl, phenoxazinyl, phenothiazinyl, benzoxazolyl, benzothiazolyl, indazolyl, benzimidazolyl, benzodioxolanyl, benzodioxanylchromenyl, chromanyl, isochromanyl, chromanonyl, cinnolinyl, quinoxalinyl, indolizinyl, quinolidinyl, imidazopyridyl , naphthyridinyl, dihydrobenzoxazinyl, dihydrobenzoxazolinonyl, dihydrobenzoxazinonyl, and benzothioxanyl.
　本明細書において「炭素数１～４のアルコキシ」とは、前述の「炭素数１～４のアルキル」が酸素原子（Ｏ)を介して結合する基である。 As used herein, "alkoxy having 1 to 4 carbon atoms" is a group to which the aforementioned "alkyl having 1 to 4 carbon atoms" is bonded via an oxygen atom (O).
　本明細書において「アシル」とは、ホルミル、またはアルキル、アルケニル、アルキニル、アリール、またはヘテロアリールがカルボニル基（＞Ｃ＝Ｏ）を介して結合する基であり、炭素数１～１０のアシルとは、ホルミル、または炭素数１～９のアルキル、アルケニル、アルキニル、またはアリールがカルボニル基を介して結合する基であり、炭素数１～４のアシルとは、ホルミル、または炭素数１～３のアルキル、アルケニルまたはアルキニルがカルボニル基を介して結合する基である。「炭素数１～１０のカルボン酸エステル」は、前述の炭素数１～１０アシルがオキシ基（－Ｏ－）を介して結合する基であってもよい。 As used herein, "acyl" is formyl, or a group in which alkyl, alkenyl, alkynyl, aryl, or heteroaryl is bonded via a carbonyl group (>C=O), and acyl having 1 to 10 carbon atoms and is formyl or a group to which alkyl, alkenyl, alkynyl, or aryl having 1 to 9 carbon atoms are bonded through a carbonyl group, and acyl having 1 to 4 carbon atoms is formyl or Alkyl, alkenyl or alkynyl is a group bonded through a carbonyl group. The "carboxylic acid ester having 1 to 10 carbon atoms" may be a group to which the above-mentioned acyl having 1 to 10 carbon atoms is bonded via an oxy group (--O--).
　本明細書において「炭素数１～４のハロゲン化アルキル」とは、ハロゲンで置換された炭素数１～４のアルキルを意味する。置換するハロゲンの数としては、例えば、１～６個、１～５個、１～４個、１～３個、３個、２個、または１個とすることができる。例えば、クロロメチル、ジクロロメチル、トリクロロメチル、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ブロモメチル、ジブロモメチル、トリブロモメチル、イオドメチル、ジイオドメチル、トリイオドメチル、クロロエチル、ジクロロエチル、トリクロロエチル、フルオロエチル、ジフルオロエチル、トリフルオロエチル、ブロモエチル、ジブロモエチル、トリブロモエチル、イオドエチル、ジイオドエチル、トリイオドエチル、クロロメチル、ジクロロメチル、トリクロロメチル、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ブロモメチル、ジブロモメチル、トリブロモメチル、イオドメチル、ジイオドメチル、トリイオドメチル、クロロプロピル、ジクロロプロピル、トリクロロプロピル、フルオロプロピル、ジフルオロプロピル、トリフルオロプロピル、ブロモプロピル、ジブロモプロピル、トリブロモプロピル、イオドプロピル、ジイオドプロピル、トリイオドプロピル、クロロメチル、ジクロロメチル、トリクロロメチル、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ブロモメチル、ジブロモメチル、トリブロモメチル、イオドメチル、ジイオドメチル、トリイオドメチル、クロロブチル、ジクロロブチル、トリクロロブチル、フルオロブチル、ジフルオロブチル、トリフルオロブチル、ブロモブチル、ジブロモブチル、トリブロモブチル、イオドブチル、ジイオドブチル、およびトリイオドブチル等を挙げることができる。 As used herein, "halogenated alkyl having 1 to 4 carbon atoms" means alkyl having 1 to 4 carbon atoms substituted with halogen. The number of substituted halogens can be, for example, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 3, 2, or 1. For example, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, dibromomethyl, tribromomethyl, iodomethyl, diiodomethyl, triiodomethyl, chloroethyl, dichloroethyl, trichloroethyl, fluoroethyl, difluoro ethyl, trifluoroethyl, bromoethyl, dibromoethyl, tribromoethyl, iodoethyl, diiodoethyl, triiodoethyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, dibromomethyl, tribromomethyl , iodomethyl, diiodomethyl, triiodomethyl, chloropropyl, dichloropropyl, trichloropropyl, fluoropropyl, difluoropropyl, trifluoropropyl, bromopropyl, dibromopropyl, tribromopropyl, iodopropyl, diiodopropyl, triiodopropyl, chloromethyl, dichloro methyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, dibromomethyl, tribromomethyl, iodomethyl, diiodomethyl, triiodomethyl, chlorobutyl, dichlorobutyl, trichlorobutyl, fluorobutyl, difluorobutyl, trifluorobutyl, Bromobutyl, dibromobutyl, tribromobutyl, iodobutyl, diiodobutyl, triiodobutyl and the like can be mentioned.
　本明細書において「炭素数１～４のアルキルチオ」とは、前述の「炭素数１～４のアルキル」が硫黄原子（Ｓ)を介して結合する基である。「炭素数１～４のアルキルスルフィニル」とは、前述の「炭素数１～４のアルキルチオ」における硫黄原子が１個の酸素原子（＝Ｏ)と結合している基である。「炭素数１～４のアルキルスルホニル（－ＳＯ２Ｒ）」とは、前述の「炭素数１～４のアルキルチオ」における硫黄原子が２個の酸素原子（＝Ｏ)と結合している基であってもよい。 As used herein, the term "alkylthio having 1 to 4 carbon atoms" is a group to which the aforementioned "alkyl having 1 to 4 carbon atoms" is bonded via a sulfur atom (S). "C1-C4 alkylsulfinyl" is a group in which the sulfur atom in the aforementioned "C1-C4 alkylthio" is bonded to one oxygen atom (=O). “C1-4 alkylsulfonyl (—SO 2 R)” is a group in which the sulfur atom in the aforementioned “C1-4 alkylthio” is bound to two oxygen atoms (=O). There may be.
＜医薬組成物＞
　本発明の一態様は、下記式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩を有効成分として含有する、医薬組成物（以下、「本発明の医薬組成物」ということがある）に関する。 <Pharmaceutical composition>
One aspect of the present invention is a pharmaceutical composition containing, as an active ingredient, a compound represented by the following formula (I) or a pharmacologically acceptable salt thereof (hereinafter referred to as "pharmaceutical composition of the present invention" there is).
　本発明者らは、抗がん活性を有する化合物として、フェニルベンズアミド誘導体、すなわち、下記式（Ｉ）で示される化合物を見出した。また、同化合物が、Akt、mTORC1、SOX2、c-MYC、OCT-4を阻害することを知見した。同知見に基づいて、下記式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩を有効成分として含有する、医薬組成物を開発した。すなわち、医薬組成物としては、抗がん剤（抗がん用医薬組成物）、マルチキナーゼ阻害剤、Akt阻害剤、mTORC1阻害剤、SOX2阻害剤、c-MYC阻害剤、OCT-4阻害剤（Akt、mTORC1、SOX2、c-MYC、OCT-4が関わる疾患治療用医薬組成物）等である。本発明はこのようにして完成されたものである。 The present inventors have found a phenylbenzamide derivative, that is, a compound represented by the following formula (I), as a compound having anticancer activity. They also found that the same compound inhibited Akt, mTORC1, SOX2, c-MYC, and OCT-4. Based on this finding, a pharmaceutical composition containing a compound represented by the following formula (I) or a pharmacologically acceptable salt thereof as an active ingredient was developed. That is, pharmaceutical compositions include anticancer agents (anticancer pharmaceutical compositions), multikinase inhibitors, Akt inhibitors, mTORC1 inhibitors, SOX2 inhibitors, c-MYC inhibitors, and OCT-4 inhibitors. (Pharmaceutical composition for treating diseases involving Akt, mTORC1, SOX2, c-MYC, OCT-4) and the like. The present invention is thus completed.
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
　式中、
　Ｒ１は、水素、ヒドロキシ、炭素数１～１０のカルボン酸エステル、または炭素数１～４のアルコキシを示し、
　Ｒ２～Ｒ４は、それぞれ独立に、水素、電子供与性基、または電子吸引性基を示し、
　Ｒ５は、水素、ヒドロキシ、炭素数１～１０のカルボン酸エステル、炭素数１～４のアルコキシ、またはＲ６と結合し形成した環を示し、
　Ｒ６は、水素、またはＲ５と結合し形成した環を示し、
　Ｒ７およびＲ１１は、それぞれ独立に、水素、またはハロゲンを示し、
　Ｒ８～Ｒ１０は、それぞれ独立に、水素、電子供与性基、または電子吸引性基を示し、
　ＸおよびＹは、それぞれ独立に、炭素、または窒素であり、
　Ｒ２～Ｒ４およびＲ８～Ｒ１０の少なくとも１つは電子吸引性基である。 During the ceremony,
R 1 represents hydrogen, hydroxy, carboxylic acid ester having 1 to 10 carbon atoms, or alkoxy having 1 to 4 carbon atoms,
R 2 to R 4 each independently represent hydrogen, an electron-donating group, or an electron-withdrawing group,
R 5 represents hydrogen, hydroxy, carboxylic acid ester having 1 to 10 carbon atoms, alkoxy having 1 to 4 carbon atoms, or a ring formed by combining with R 6 ,
R 6 represents hydrogen or a ring formed by combining with R 5 ,
R 7 and R 11 each independently represent hydrogen or halogen,
R 8 to R 10 each independently represent hydrogen, an electron-donating group, or an electron-withdrawing group,
X and Y are each independently carbon or nitrogen;
At least one of R 2 -R 4 and R 8 -R 10 is an electron withdrawing group.
≪式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩≫
　以下、式（I）で示される化合物（以下、「本発明に用いられる化合物」または「化合物（I）」ということがある。）について説明する。 <<Compound represented by Formula (I), or a pharmacologically acceptable salt thereof>>
The compound represented by formula (I) (hereinafter sometimes referred to as "compound used in the present invention" or "compound (I)") is described below.
　Ｒ１は、水素、ヒドロキシ、炭素数１～１０のカルボン酸エステル（－Ｏ－Ｃ（＝Ｏ）－Ｒ）、または炭素数１～４のアルコキシを示す。
　カルボン酸エステルに含まれる炭化水素（Ｒ）の炭素数は１～１０であり、好ましくは１～８、より好ましくは１～７である。カルボン酸エステルに含まれる炭化水素は、直鎖、分岐鎖、および環状のいずれであってもよい。また、飽和でもよく、不飽和結合を含んでいてもよい。例えば、炭素数１～１０のアルキル、炭素数２～１０のアルケニル、炭素数２～１０のアルキニル、または炭素数６～１０のアリールであり、好ましくは直鎖、または分岐鎖環状の炭素数１～１０のアルキルであり、より好ましくは直鎖の１～７のアルキルである。 R 1 represents hydrogen, hydroxy, carboxylic acid ester (--O--C(=O)--R) having 1 to 10 carbon atoms, or alkoxy having 1 to 4 carbon atoms.
The hydrocarbon (R) contained in the carboxylic acid ester has 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, and more preferably 1 to 7 carbon atoms. The hydrocarbon contained in the carboxylic acid ester may be linear, branched, or cyclic. Moreover, it may be saturated or may contain an unsaturated bond. For example, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 10 carbon atoms, alkynyl having 2 to 10 carbon atoms, or aryl having 6 to 10 carbon atoms, preferably linear or branched cyclic and having 1 carbon atoms. 1 to 10 alkyl, more preferably linear 1 to 7 alkyl.
　Ｒ１として、好ましくは、水素、またはヒドロキシ等が挙げられる。
　化合物（Ｉ）の一態様では、Ｒ１が、水素である。 R 1 is preferably hydrogen, hydroxy, or the like.
In one aspect of compound (I), R 1 is hydrogen.
　Ｒ２～Ｒ４は、それぞれ独立に、水素、電子供与性基、または電子吸引性基を示す。 R 2 to R 4 each independently represent hydrogen, an electron-donating group, or an electron-withdrawing group.
　電子供与性基は、置換した原子団に、電子を与える基である。本発明において、電子供与性基は、ベンゼン環等に電子を供与する。電子供与性基は、このような作用を有するものであれば限定されない。電子供与性基は、限定されないが、例えば、ヒドロキシ、炭素数１～４のアルキル、炭素数１～４のアルコキシ、またはアミノ等が挙げられる。 An electron-donating group is a group that donates electrons to a substituted atomic group. In the present invention, the electron-donating group donates electrons to a benzene ring or the like. The electron-donating group is not limited as long as it has such action. Examples of electron-donating groups include, but are not limited to, hydroxy, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, and the like.
　電子吸引性基は、置換した原子団から、電子を吸引する基である。本発明において、電子吸引性基は、ベンゼン環等より電子を吸引する。電子吸引性基は、このような作用を有するものであれば限定されない。電子吸引性基は、限定されないが、例えば、フッ素（－Ｆ）、塩素（－Ｃｌ）、臭素（－Ｂｒ）、ヨウ素（－Ｉ）等のハロゲン（Ｘ）、トリフルオロメチル（－ＣＦ３）等の炭素数１～４のハロゲン化アルキル、炭素数１～１０のカルボン酸エステル、炭素数１～４のアシル、シアノ（－ＣＮ）、ニトロ（－ＮＯ２）、炭素数１～４のアルキルチオ（－ＳＲ）、炭素数１～４のアルキルスルフィニル（－ＳＯＲ）、もしくは炭素数１～４のアルキルスルホニル（－ＳＯ２Ｒ）；またはこれらの電子吸引性基を置換基として有する炭素数６～１０のアリールもしくは炭素数３～１０のヘテロアリール等が挙げられる。 Electron-withdrawing groups are groups that withdraw electrons from a substituted atomic group. In the present invention, the electron-withdrawing group attracts electrons from a benzene ring or the like. The electron-withdrawing group is not limited as long as it has such action. Electron-withdrawing groups include, but are not limited to, fluorine (-F), chlorine (-Cl), bromine (-Br), halogen (X) such as iodine (-I), trifluoromethyl (-CF 3 ) Alkyl halides having 1 to 4 carbon atoms, carboxylic acid esters having 1 to 10 carbon atoms, acyl having 1 to 4 carbon atoms, cyano (—CN), nitro (—NO 2 ), alkylthio having 1 to 4 carbon atoms, etc. (—SR), alkylsulfinyl (—SOR) having 1 to 4 carbon atoms, or alkylsulfonyl (—SO 2 R) having 1 to 4 carbon atoms; or 6 to 6 carbon atoms having these electron-withdrawing groups as substituents 10 aryl or heteroaryl having 3 to 10 carbon atoms, and the like.
　Ｒ２～Ｒ４として、好ましくは、水素、ハロゲン、炭素数１～４のアルキル、炭素数１～４のアルコキシ、炭素数１～４のハロゲン化アルキル、シアノ、またはニトロ等が挙げられる。 R 2 to R 4 are preferably hydrogen, halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halogenated alkyl having 1 to 4 carbon atoms, cyano or nitro.
　化合物（Ｉ）の一態様では、Ｒ２～Ｒ４が、それぞれ独立に、水素、電子供与性基、または電子吸引性基である。
　化合物（Ｉ）の別の一態様では、Ｒ２およびＲ３の少なくとも一方が、電子吸引性基であり、それ以外が水素である。化合物（Ｉ）の別の一態様では、Ｒ２およびＲ３の両方が、電子吸引性基である。電子吸引性基として、好ましくは、ハロゲン、またはニトロである。
　化合物（Ｉ）の別の一態様では、Ｒ２およびＲ３の少なくとも一方が、電子吸引性基であり、それ以外が電子供与性基である。電子吸引性基として、好ましくは、ハロゲンである。電子供与性基として、好ましくは、アルキルである。
　化合物（Ｉ）の別の一態様では、Ｒ４が、水素である。 In one aspect of compound (I), each of R 2 to R 4 is independently hydrogen, an electron-donating group, or an electron-withdrawing group.
In another aspect of compound (I), at least one of R 2 and R 3 is an electron-withdrawing group, and the others are hydrogen. In another aspect of compound (I), both R 2 and R 3 are electron-withdrawing groups. The electron-withdrawing group is preferably halogen or nitro.
In another aspect of compound (I), at least one of R 2 and R 3 is an electron-withdrawing group, and the others are electron-donating groups. The electron-withdrawing group is preferably halogen. The electron-donating group is preferably alkyl.
In another aspect of compound (I), R 4 is hydrogen.
　Ｒ５は、水素、ヒドロキシ、炭素数１～１０のカルボン酸エステル、または炭素数１～４のアルコキシである。Ｒ５は、Ｒ６と結合し環を形成していてもよい。具体的には、例えば、Ｒ５とＲ６が結合し、飽和環、不飽和環、または、－Ｏ－Ｃ－Ｏ－鎖等を介してヘテロ環を形成していてもよい。炭素数１～１０のカルボン酸エステルの具体例は、Ｒ１で説明されたものと同様である。
　Ｒ５として、好ましくは、ヒドロキシが挙げられる。 R 5 is hydrogen, hydroxy, C 1-10 carboxylic acid ester, or C 1-4 alkoxy. R5 may combine with R6 to form a ring. Specifically, for example, R 5 and R 6 may combine to form a heterocyclic ring via a saturated ring, unsaturated ring, or —O—C—O— chain. Specific examples of the carboxylic acid ester having 1 to 10 carbon atoms are the same as those explained for R 1 .
R 5 is preferably hydroxy.
　Ｒ６は、水素、またはＲ６と結合し形成した環を示す。Ｒ６として、好ましくは、水素が挙げられる。 R6 represents hydrogen or a ring formed by combining with R6 . R 6 is preferably hydrogen.
　Ｒ７およびＲ１１は、それぞれ独立に、水素、またはハロゲンを示す。
　化合物（Ｉ）の一態様では、Ｒ７およびＲ１１の一方が、水素、それ以外がハロゲンである。例えば、Ｒ７がハロゲン、およびＲ１１が水素である。
　化合物（Ｉ）の別の一態様では、Ｒ７およびＲ１１が、水素である。 R7 and R11 each independently represent hydrogen or halogen.
In one aspect of compound (I), one of R 7 and R 11 is hydrogen and the other is halogen. For example, R7 is halogen and R11 is hydrogen.
In another aspect of compound (I), R 7 and R 11 are hydrogen.
　Ｒ８～Ｒ１０は、それぞれ独立に、水素、電子供与性基、または電子吸引性基を示す。電子供与性基、および電子吸引性基の具体例は、Ｒ２～Ｒ４で説明されたものと同様である。
　Ｒ８～Ｒ１０として、好ましくは、水素、ヒドロキシ、ハロゲン、炭素数１～４のハロゲン化アルキル、シアノ、ニトロ；または、ハロゲン、炭素数１～１０のカルボン酸エステル、シアノ、ニトロから選ばれる電子吸引性基を置換基として有する炭素数６～１０のアリールもしくは炭素数３～１０のヘテロアリール等が挙げられる。 R 8 to R 10 each independently represent hydrogen, an electron-donating group, or an electron-withdrawing group. Specific examples of electron-donating groups and electron-withdrawing groups are the same as those described for R 2 to R 4 .
R 8 to R 10 are preferably selected from hydrogen, hydroxy, halogen, halogenated alkyl having 1 to 4 carbon atoms, cyano and nitro; or halogen, carboxylic acid ester having 1 to 10 carbon atoms, cyano and nitro. Examples thereof include aryl having 6 to 10 carbon atoms and heteroaryl having 3 to 10 carbon atoms having an electron withdrawing group as a substituent.
　化合物（Ｉ）の一態様では、Ｒ８～Ｒ１０の少なくとも一つが、ハロゲン、炭素数１～４のハロゲン化アルキル、シアノ、ニトロ；または、ハロゲン、炭素数１～１０のカルボン酸エステル、シアノ、ニトロから選ばれる電子吸引性基を置換基として有する炭素数６～１０のアリールもしくは炭素数３～１０のヘテロアリール、それ以外が水素である。
　化合物（Ｉ）の別の一態様では、Ｒ９が、電子吸引性基であり、Ｒ８およびＲ１０が、それぞれ独立に、水素、または電子吸引性基である。
　化合物（Ｉ）の別の一態様では、Ｒ９が、電子吸引性基であり、Ｒ８およびＲ１０が水素である。電子吸引性基として、好ましくは、炭素数１～４のハロゲン化アルキル、ニトロ；または、ハロゲン、シアノ、ニトロから選ばれる電子吸引性基を置換基として有する炭素数６～１０のアリールもしくは炭素数３～１０のヘテロアリールである。 In one embodiment of compound (I), at least one of R 8 to R 10 is halogen, halogenated alkyl having 1 to 4 carbon atoms, cyano, nitro; or halogen, carboxylic acid ester having 1 to 10 carbon atoms, cyano , nitro, aryl having 6 to 10 carbon atoms or heteroaryl having 3 to 10 carbon atoms having an electron-withdrawing group selected from nitro, and others are hydrogen.
In another aspect of compound (I), R 9 is an electron-withdrawing group, and R 8 and R 10 are each independently hydrogen or an electron-withdrawing group.
In another aspect of compound (I), R 9 is an electron-withdrawing group and R 8 and R 10 are hydrogen. The electron-withdrawing group is preferably a halogenated alkyl having 1 to 4 carbon atoms, nitro; 3-10 heteroaryl.
　ＸおよびＹは、それぞれ独立に、炭素、または窒素である。
　化合物（Ｉ）の一態様では、ＸおよびＹの少なくとも一方が窒素、それ以外が炭素である。
　化合物（Ｉ）の別の一態様では、ＸおよびＹが、炭素である。 X and Y are each independently carbon or nitrogen.
In one aspect of compound (I), at least one of X and Y is nitrogen and the others are carbon.
In another aspect of compound (I), X and Y are carbon.
　Ｒ２～Ｒ４およびＲ８～Ｒ１０の少なくとも１つは電子吸引性基である。電子吸引性基の具体例は、Ｒ２～Ｒ４で説明されたものと同様である。
　化合物（Ｉ）の一態様では、Ｒ９が、電子吸引性基である。
　化合物（Ｉ）の別の一態様では、Ｒ２およびＲ３の少なくとも一方が、電子吸引性基である。 At least one of R 2 -R 4 and R 8 -R 10 is an electron withdrawing group. Specific examples of electron-withdrawing groups are the same as those described for R 2 to R 4 .
In one aspect of compound (I), R 9 is an electron withdrawing group.
In another aspect of compound (I), at least one of R 2 and R 3 is an electron-withdrawing group.
　化合物（Ｉ）の別の一態様では、Ｒ１が水素であり、Ｒ２およびＲ３の少なくとも一方が電子吸引性基、それ以外が水素であり、Ｒ４が水素であり、Ｒ５がヒドロキシであり、Ｒ６が水素であり、Ｒ７が水素、またはハロゲンであり、Ｒ８、Ｒ１０、Ｒ１１が水素であり、Ｒ９が電子吸引性基であり、ＸおよびＹが炭素である。
　化合物（Ｉ）の別の一態様では、Ｒ１が水素であり、Ｒ２およびＲ３の少なくとも一方がハロゲン、またはニトロ、それ以外が水素であり、Ｒ４が水素であり、Ｒ５がヒドロキシであり、Ｒ６が水素であり、Ｒ７が水素、またはハロゲンであり、Ｒ８、Ｒ１０、Ｒ１１が水素であり、Ｒ９がニトロ；またはハロゲン、シアノ、ニトロから選ばれる電子吸引性基を置換基として有する炭素数６～１０のアリールもしくは炭素数３～１０のヘテロアリールであり、ＸおよびＹが炭素である。
　化合物（Ｉ）の別の一態様では、Ｒ１が水素であり、Ｒ２およびＲ３の少なくとも一方が電子吸引性基、それ以外が電子供与性基であり、Ｒ４が水素であり、Ｒ５がヒドロキシであり、Ｒ６が水素であり、Ｒ７が水素、またはハロゲンであり、Ｒ８、Ｒ１０、Ｒ１１が水素であり、Ｒ９が電子吸引性基であり、ＸおよびＹが炭素である。
　化合物（Ｉ）の別の一態様では、Ｒ１が水素であり、Ｒ２およびＲ３の少なくとも一方がハロゲン、それ以外がアルキルであり、Ｒ４が水素であり、Ｒ５がヒドロキシであり、Ｒ６が水素であり、Ｒ７が水素、またはハロゲンであり、Ｒ８、Ｒ１０、Ｒ１１が水素であり、Ｒ９が炭素数１～４のハロゲン化アルキルであり、ＸおよびＹが炭素である。 In another aspect of compound (I), R 1 is hydrogen, at least one of R 2 and R 3 is an electron-withdrawing group, the others are hydrogen, R 4 is hydrogen, and R 5 is hydroxy and R 6 is hydrogen, R 7 is hydrogen or halogen, R 8 , R 10 , R 11 are hydrogen, R 9 is an electron-withdrawing group, and X and Y are carbon .
In another aspect of compound (I), R 1 is hydrogen, at least one of R 2 and R 3 is halogen or nitro, the others are hydrogen, R 4 is hydrogen, R 5 is hydroxy and R 6 is hydrogen, R 7 is hydrogen or halogen, R 8 , R 10 , R 11 are hydrogen, and R 9 is nitro; or electron-withdrawing selected from halogen, cyano, nitro aryl having 6 to 10 carbon atoms or heteroaryl having 3 to 10 carbon atoms having a group as a substituent, and X and Y are carbon.
In another aspect of compound (I), R 1 is hydrogen, at least one of R 2 and R 3 is an electron-withdrawing group, the others are electron-donating groups, R 4 is hydrogen, and R 5 is hydroxy, R 6 is hydrogen, R 7 is hydrogen or halogen, R 8 , R 10 , R 11 is hydrogen, R 9 is an electron-withdrawing group, X and Y are is carbon.
In another embodiment of compound (I), R 1 is hydrogen, at least one of R 2 and R 3 is halogen, the others are alkyl, R 4 is hydrogen, R 5 is hydroxy, R 6 is hydrogen, R 7 is hydrogen or halogen, R 8 , R 10 and R 11 are hydrogen, R 9 is halogenated alkyl having 1 to 4 carbon atoms, and X and Y are carbon is.
　化合物（I）として、限定されないが、例えば、後記実施例に示される化合物が挙げられる。化合物（I）としては、それらのうち、下記式で示される構造の化合物が好ましい。化合物（I）としては、それらのうち、化合物N-42、N-50、N-51、N-101、N-110、N-115、NIC-120、NIC-127、NIC-129が特に好ましい。 Examples of compound (I) include, but are not limited to, the compounds shown in Examples below. As the compound (I), among them, a compound having a structure represented by the following formula is preferable. Among them, compounds N-42, N-50, N-51, N-101, N-110, N-115, NIC-120, NIC-127 and NIC-129 are particularly preferable as compound (I). .
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
　化合物（I）は、後記実施例を参照し、公知の合成方法により合成することができる。 Compound (I) can be synthesized by a known synthesis method with reference to Examples below.
　本明細書における「薬理学的に許容可能な塩」とは、無機または有機の塩基または酸と結合して形成した塩であって、医薬として体内に投与することが許容可能な塩のことである。このような塩は、例えば、Ｂｅｒｇｅら、Ｊ．Ｐｈａｒｍ．Ｓｃｉ．６６：１－１９（１９７７）等に記載されている。カルボン酸基等の酸性基との塩としては、リチウム、ナトリウム、カリウム、マグネシウム、カルシウム等のアルカリ金属およびアルカリ土類金属塩；アンモニア、メチルアミン、エチルアミン、メタノールアミン、エタノールアミン、ジメチルアミン、トリメチルアミン、ジシクロヘキシルアミン、トリス（ヒドロキシメチル）アミノメタン、Ｎ，Ｎ－ビス（ヒドロキシエチル）ピペラジン、２－アミノ－２－メチル－１－プロパノール、エタノールアミン、Ｎ－メチルグルカミン、Ｌ－グルカミン等のアミンの塩；またはリジン、δ－ヒドロキシリジン、アルギニン等の塩基性アミノ酸との塩を形成することができる。塩基性基が存在する場合には、塩酸、臭化水素酸、リン酸、硫酸、硝酸、ホウ酸等との塩（無機酸塩）；メタンスルホン酸、ベンゼンスルホン酸、パラトルエンスルホン酸、ギ酸、プロピオン酸塩、酢酸、乳酸、フマル酸、リンゴ酸、シュウ酸、安息香酸、マンデル酸、ケイ皮酸、マレイン酸、酒石酸、クエン酸、コハク酸、マロン酸、トシル酸、グリコール酸、グルクロン酸、アスコルビン酸、ニコチン酸、サリチル酸等との塩（有機酸塩）；またはアスパラギン酸、グルタミン酸等の酸性アミノ酸との塩等を挙げることができる。好ましくは、アルカリ金属塩であり、特に好ましくは、ナトリウム、カリウムである。化合物（I）の薬理学的に許容可能な塩として、限定されないが、例えば、N-101のナトリウム塩およびN-101のカリウム塩が例示される。
　これらの塩の調製は慣用手段によって行なうことができる。なお、以上の例示は、「薬理学的に許容可能な塩」が限定解釈されるために用いられるべきではない。即ち、「薬理学的に許容可能な塩」は、広義に解釈されるべきであり、各種の塩を含む用語である。本明細書における化合物は、それが明らかに適さない場合を除き、明示されていない場合にも、当該化合物またはその塩の水和物または溶媒和物をも含む。 The term "pharmacologically acceptable salt" as used herein means a salt formed by combining with an inorganic or organic base or acid, and is acceptable for administration into the body as a pharmaceutical. be. Such salts are described, for example, in Berge et al., J. Am. Pharm. Sci. 66:1-19 (1977). Salts with acidic groups such as carboxylic acid groups include alkali metal and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, calcium; ammonia, methylamine, ethylamine, methanolamine, ethanolamine, dimethylamine, trimethylamine. , dicyclohexylamine, tris(hydroxymethyl)aminomethane, N,N-bis(hydroxyethyl)piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, amines such as L-glucamine or salts with basic amino acids such as lysine, δ-hydroxylysine, arginine and the like. When a basic group is present, salts with hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, boric acid, etc. (inorganic acid salts); methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid , propionate, acetic acid, lactic acid, fumaric acid, malic acid, oxalic acid, benzoic acid, mandelic acid, cinnamic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, tosylic acid, glycolic acid, glucuronic acid , ascorbic acid, nicotinic acid, salicylic acid and the like (organic acid salts); and salts with acidic amino acids such as aspartic acid and glutamic acid. Alkali metal salts are preferred, and sodium and potassium are particularly preferred. Examples of pharmacologically acceptable salts of compound (I) include, but are not limited to, sodium salt of N-101 and potassium salt of N-101.
Preparation of these salts can be carried out by conventional means. In addition, the above examples should not be used to restrict interpretation of "pharmacologically acceptable salts". That is, "pharmacologically acceptable salt" should be interpreted broadly and is a term that includes various salts. Reference to compounds herein also includes hydrates or solvates of such compounds or salts thereof, unless explicitly indicated otherwise.
≪抗がん用医薬組成物≫
　本発明において、用語「がん」は広義に解釈され、用語「悪性腫瘍」と互換的に使用される。また、病理学的に診断が確定される前の段階、すなわち腫瘍としての良性、悪性のどちらかが確定される前には、良性腫瘍、良性悪性境界病変、悪性腫瘍を総括的に含む場合もあり得る。一般に、がんはその発生の母体となった臓器の名、もしくは発生母組織の名で呼ばれ、主なものを列記すると、舌がん、歯肉がん、咽頭がん、上顎がん、喉頭がん、唾液腺がん、食道がん、胃がん、小腸がん、大腸がん、直腸がん、肝臓がん、胆道がん、胆嚢がん、膵（臓）がん、肺がん、乳がん、甲状腺がん、副腎がん、脳下垂体腫瘍、松果体腫瘍、子宮がん、卵巣がん、膣がん、膀胱がん、腎臓がん、前立腺がん、尿道がん、網膜芽細胞腫、結膜がん、神経芽腫、神経膠腫、神経膠芽細胞腫、皮膚がん、髄芽種、白血病、悪性リンパ腫、睾丸腫瘍、骨肉腫、横紋筋肉腫、平滑筋肉腫、血管肉腫、脂肪肉腫、軟骨肉腫、ユーイング肉腫等である。そして、さらに発生臓器の部位の特徴によって、上・中・下咽頭がん、上部・中部・下部食道がん、胃噴門がん、胃幽門がん、子宮頚がん、子宮体がん等と細分類されているが、これらが限定的ではなく本発明の「がん」としての記載に含まれる。本発明の抗がん用医薬組成物は、「がん」全般に効果を奏するものであるが、特に膵臓がん、膵臓がんの固形がんに好ましく用いられ得る。膵臓がんとは、膵臓にできた悪性腫瘍のことであり、浸潤性膵管がんや、膵神経内分泌腫瘍、悪性の膵管内乳頭粘液性腫瘍、悪性の粘液嚢胞性腫瘍等に分類することができるが、一般的に膵臓がんと言えば、「浸潤性膵管がん（通常型膵臓がん）」をあらわす。また、「固形がん」とは、特定の臓器や組織等に、明らかな塊として認められる充実性のがんである。 ≪Anticancer pharmaceutical composition≫
In the present invention, the term "cancer" is interpreted broadly and used interchangeably with the term "malignant tumor". In addition, in the stage before the diagnosis is confirmed pathologically, that is, before the tumor is either benign or malignant, it may include benign tumors, benign-malignant borderline lesions, and malignant tumors collectively. could be. In general, cancers are called by the name of the organ from which they originated, or by the name of the originating tissue. cancer, salivary gland cancer, esophageal cancer, stomach cancer, small intestine cancer, colon cancer, rectal cancer, liver cancer, biliary tract cancer, gallbladder cancer, pancreatic cancer, lung cancer, breast cancer, thyroid cancer cancer, adrenal cancer, pituitary tumor, pineal tumor, uterine cancer, ovarian cancer, vaginal cancer, bladder cancer, kidney cancer, prostate cancer, urethral cancer, retinoblastoma, conjunctiva Cancer, neuroblastoma, glioma, glioblastoma, skin cancer, medulloblastoma, leukemia, malignant lymphoma, testicular tumor, osteosarcoma, rhabdomyosarcoma, leiomyosarcoma, angiosarcoma, liposarcoma , chondrosarcoma, and Ewing's sarcoma. Furthermore, depending on the characteristics of the site of the organ in which it develops, it can be classified as upper/middle/hypopharynx cancer, upper/middle/lower esophageal cancer, gastric cardia cancer, gastric pyloric cancer, cervical cancer, endometrial cancer, etc. Subclassifications include, but are not limited to, the description of "cancer" in the present invention. The anticancer pharmaceutical composition of the present invention is effective against "cancer" in general, but it can be particularly preferably used for pancreatic cancer and solid cancer of pancreatic cancer. Pancreatic cancer is a malignant tumor that occurs in the pancreas, and can be classified into invasive pancreatic duct cancer, pancreatic neuroendocrine tumor, malignant intraductal papillary mucinous tumor, and malignant mucocystic tumor. It can be done, but pancreatic cancer generally refers to “invasive pancreatic duct cancer (common pancreatic cancer)”. A "solid cancer" is a solid cancer that is observed as a clear mass in a specific organ, tissue, or the like.
　「抗がん用医薬組成物」とは、標的の疾病ないし病態である、がんに対する治療的または予防的効果を示す医薬組成物のことをいう。治療的効果には、がんに特徴的な症状または随伴症状を緩和すること（軽症化）、症状の悪化を阻止ないし遅延すること等が含まれる。後者については、重症化を予防するという点において予防的効果の一つと捉えることができる。このように、治療的効果と予防的効果は一部において重複する概念であり、明確に区別して捉えることは困難であり、またそうすることの実益は少ない。なお、予防的効果の典型的なものは、がんに特徴的な症状の再発発現（発症）を阻止ないし遅延することである。なお、がんに対して何らかの治療的効果または予防的効果、あるいはこの両者を示す限り、抗がん用医薬組成物に該当する。また、化合物（I)またはその併用剤がもたらすがんに対する治療的または予防的効果は、がんの合併症（例えば、悪液質）の改善を含んでいてもよい。すなわち、本明細書における「抗がん」や「がん治療」とは、がん組織そのものに対して増殖抑制や縮小等の効果を奏することに加えて、合併症（好ましくは、悪液質）を改善することを含んでいてもよい。 "Anti-cancer pharmaceutical composition" refers to a pharmaceutical composition that exhibits a therapeutic or preventive effect on cancer, which is the target disease or condition. Therapeutic effects include alleviation of symptoms characteristic of cancer or accompanying symptoms (mitigation), prevention or delay of exacerbation of symptoms, and the like. The latter can be regarded as one of preventive effects in terms of preventing aggravation. Thus, the therapeutic effect and the prophylactic effect are partially overlapping concepts, and it is difficult to clearly distinguish between them, and there is little practical benefit from doing so. A typical preventive effect is to prevent or delay the recurrence (development) of symptoms characteristic of cancer. In addition, as long as it shows some therapeutic effect or preventive effect, or both, against cancer, it corresponds to the anticancer pharmaceutical composition. In addition, the therapeutic or preventive effect on cancer brought about by compound (I) or a combination thereof may include improvement of cancer complications (eg, cachexia). That is, "anti-cancer" and "cancer treatment" in the present specification mean that in addition to effects such as growth suppression and shrinkage on cancer tissue itself, complications (preferably, cachexia ).
　本発明の医薬組成物の製剤化は、有効成分である化合物（Ｉ）、またはその薬理学的に許容可能な塩を配合すること以外は、常法に従って行うことができる。化合物（Ｉ）、またはその薬理学的に許容可能な塩は、１種のみまたは任意の２種以上を組み合わせて用いられ得る。
　製剤化する場合には、製剤上許容される他の成分（例えば、担体、賦形剤、崩壊剤、緩衝剤、乳化剤、懸濁剤、無痛化剤、安定剤、保存剤、防腐剤、界面活性剤、滑沢剤、稀釈剤、被覆剤、糖衣剤、矯味矯臭剤、乳化・可溶化・分散剤、pH調製剤、等張剤、可溶化剤、香料、着色剤、溶解補助剤、生理食塩水等）を含有させることができる。製剤化する場合の剤形も特に限定されない。剤形の例は錠剤、散剤、細粒剤、顆粒剤、カプセル剤、シロップ剤、液剤、懸濁剤、乳剤、ゼリー剤、注射剤、外用剤、吸入剤、点鼻剤、点眼剤および座剤である。本発明の医薬組成物には、期待される治療効果（または予防効果）を得るために必要な量（即ち治療上有効量）の有効成分が含有される。本発明の医薬組成物中の有効成分量は一般に剤形によって異なるが、所望の投与量を達成できるように有効成分量を、例えば、約０．０１質量％～約９９．９質量％の範囲内で設定し得る。 The pharmaceutical composition of the present invention can be formulated according to conventional methods, except that compound (I), which is an active ingredient, or a pharmacologically acceptable salt thereof is added. Compound (I) or a pharmacologically acceptable salt thereof may be used singly or in any combination of two or more.
When formulating, other pharmaceutically acceptable components (e.g., carriers, excipients, disintegrants, buffers, emulsifiers, suspending agents, soothing agents, stabilizers, preservatives, preservatives, interfaces Active agents, lubricants, diluents, coating agents, sugar coating agents, flavoring agents, emulsifying/solubilizing/dispersing agents, pH adjusters, isotonic agents, solubilizing agents, fragrances, coloring agents, solubilizing agents, physiological saline solution, etc.). The dosage form for formulation is also not particularly limited. Examples of dosage forms include tablets, powders, fine granules, granules, capsules, syrups, solutions, suspensions, emulsions, jelly, injections, external preparations, inhalants, nasal drops, eye drops, and suppositories. is an agent. The pharmaceutical composition of the present invention contains an amount of active ingredient necessary to obtain the expected therapeutic effect (or preventive effect) (ie, a therapeutically effective amount). The amount of the active ingredient in the pharmaceutical composition of the present invention generally varies depending on the dosage form, but the amount of the active ingredient can be adjusted, for example, in the range of about 0.01% by mass to about 99.9% by mass so as to achieve the desired dosage. can be set within
　本発明の医薬組成物は、その剤形に応じて、経口投与または非経口投与（静脈内、動脈内、皮下、皮内、筋肉内、または腹腔内注射、経皮、経鼻、経粘膜等）によって対象に適用される。これらの投与経路は互いに排他的なものではなく、任意に選択される二つ以上を併用することもできる（例えば、経口投与と同時にまたは所定時間経過後に静脈注射等を行う等）。全身投与によらず、局所投与することにしてもよい。ドラッグデリバリーシステム（ＤＤＳ）を利用して標的組織特異的に有効成分が送達されるように投与してもよい。ここでの「対象」は特に限定されず、がんの治療または予防が必要なヒトおよびヒト以外の哺乳動物（ペット動物、家畜、実験動物を含む。具体的には例えばマウス、ラット、モルモット、ハムスター、サル、ウシ、ブタ、ヤギ、ヒツジ、イヌ、ネコ、ニワトリ、ウズラ等である）を含む。好ましい一態様では、適用対象はヒトである。 The pharmaceutical composition of the present invention can be administered orally or parenterally (intravenous, intraarterial, subcutaneous, intradermal, intramuscular, intraperitoneal injection, transdermal, nasal, transmucosal, etc.) depending on its dosage form. ) to the subject. These routes of administration are not mutually exclusive, and two or more arbitrarily selected routes can be used in combination (for example, intravenous injection or the like is performed at the same time as oral administration or after a predetermined period of time has elapsed). Local administration may be used instead of systemic administration. A drug delivery system (DDS) may be used to deliver the active ingredient in a target tissue-specific manner. The "subject" here is not particularly limited, and includes humans and non-human mammals (pet animals, domestic animals, experimental animals) in need of cancer treatment or prevention. Specifically, for example, mice, rats, guinea pigs, hamsters, monkeys, cows, pigs, goats, sheep, dogs, cats, chickens, quail, etc.). In one preferred aspect, the subject is a human.
　本発明のさらなる態様として、本発明の抗がん用医薬組成物を使用した、がんに対する治療方法または予防方法（以下、これら二つの方法をまとめて「治療方法等」という）が提供される。本発明の治療方法等は、上記本発明の抗がん用医薬組成物を、がんを罹患するまたはがんの兆候を認める患者に投与するステップを含む。投与経路は特に限定されず、例えば、経口、静脈内、動脈内、皮内、皮下、筋肉内、腹腔内、経皮、経鼻、経粘膜等を挙げることができる。これらの投与経路は互いに排他的なものではなく、任意に選択される二つ以上を併用することもできる。抗がん用医薬組成物の投与量は一般に、患者の症状、年齢、性別、および体重等によって変動し得るが、当業者であれば適宜適当な投与量を設定することが可能である。限定されないが、例えば、経口投与では、成人に対して、例えば、１日約０．０１ｍｇ～１０００ｍｇを１回、または数回に分けて投与することができる。また、非経口投与では、例えば、１回約０．０１ｍｇ～１０００ｍｇを皮下注射、筋肉注射または静脈注射によって投与することができる。投与スケジュールとしては例えば１日１回～数回、２日に１回、あるいは３日に１回等を採用できる。投与スケジュールの設定においては、患者の症状や有効成分の効果持続時間等を考慮することができる。
　また、本発明のさらなる態様として、がん治療期間中に、本発明の抗がん用医薬組成物を使用した、がん治療生存率を向上させる方法が提供される。投与量等については、本発明の治療方法等において説明した内容を適用できる。本発明の抗がん用医薬組成物の投与は、通常は本発明の抗がん用医薬組成物による以外のがん治療（化学療法または放射線療法等）の開始の１日以上前、好ましくは２日以上前、さらに好ましくは３日以上前、さらに好ましくは１週間以上前から行われる。好ましい実施の態様において、がん治療が行われている期間の間、投与される。また、がん治療による治療期間の終了の後に、投与されて続けていても何ら問題はない。
　本発明におけるがん治療生存率向上とは、がん治療、特に化学療法および／または放射線療法を受ける対象が、がん治療期間中に、本発明の抗がん用医薬組成物を使用した場合に、本発明の抗がん用医薬組成物を使用しない場合と比較して、所定日数後または所定年数後に生存している率が向上していることをいう。　 As a further aspect of the present invention, there is provided a method for treating or preventing cancer using the anticancer pharmaceutical composition of the present invention (hereinafter, these two methods are collectively referred to as "therapeutic method, etc."). . The treatment method and the like of the present invention include the step of administering the anticancer pharmaceutical composition of the present invention to a patient suffering from cancer or showing symptoms of cancer. The route of administration is not particularly limited, and examples thereof include oral, intravenous, intraarterial, intradermal, subcutaneous, intramuscular, intraperitoneal, transdermal, transnasal, and transmucosal routes. These administration routes are not mutually exclusive, and two or more arbitrarily selected routes can be used in combination. Although the dosage of the anticancer pharmaceutical composition may generally vary depending on the patient's symptoms, age, sex, body weight, etc., a person skilled in the art can set an appropriate dosage as appropriate. Although not limited, for oral administration, for example, about 0.01 mg to 1000 mg per day can be administered to an adult once or in several divided doses. In parenteral administration, for example, about 0.01 mg to 1000 mg can be administered by subcutaneous injection, intramuscular injection or intravenous injection. As an administration schedule, for example, once to several times a day, once every two days, or once every three days can be adopted. In setting the administration schedule, the patient's symptoms, duration of effect of the active ingredient, etc. can be taken into consideration.
In addition, as a further aspect of the present invention, there is provided a method for improving the cancer treatment survival rate using the anticancer pharmaceutical composition of the present invention during cancer treatment. As for the dosage and the like, the contents explained in the therapeutic method and the like of the present invention can be applied. The administration of the anticancer pharmaceutical composition of the present invention is usually one day or more before the start of cancer treatment (chemotherapy, radiotherapy, etc.) other than by the anticancer pharmaceutical composition of the present invention, preferably 2 days or more, preferably 3 days or more, more preferably 1 week or more. In preferred embodiments, it is administered for the duration of the cancer treatment. In addition, there is no problem even if the administration is continued after the end of the treatment period by cancer treatment.
Improving cancer treatment survival rate in the present invention means that a subject undergoing cancer treatment, particularly chemotherapy and/or radiotherapy, uses the anticancer pharmaceutical composition of the present invention during the cancer treatment period. Second, it means that the survival rate after a predetermined number of days or a predetermined number of years is improved compared to when the anticancer pharmaceutical composition of the present invention is not used.
≪マルチキナーゼ阻害剤およびがん幹細胞の発生抑制またはがん幹細胞殺傷剤≫
　後記実施例に記載のとおり、化合物（Ｉ）は、がんの増殖や栄養飢餓耐性等に関連するとされる複数のキナーゼを阻害するマルチキナーゼ阻害活性を有する。このため、従来の細胞障害性抗がん剤では効果がほとんどなかった悪性腫瘍の増殖や栄養飢餓耐性に対して優れた治療効果をもたらすことができると考えられる。また、本発明によれば、複数の薬剤を使用せずに、単一の薬剤により複数のキナーゼを阻害するため、がん治療において投与する薬剤を少なくすることができ、これにより患者に対する副作用を軽減することができる。また、本発明によれば、栄養飢餓状態においてのみ細胞に毒性を示すため、がんに特異的に作用することを可能とし、これにより抗がん剤特有の深刻な副作用を回避することができる。また、本発明によれば、がんの悪性化や栄養飢餓耐性に関与する極めて重要な分子であるAkt、mTORC1に対する分子標的治療薬が得られる。さらに、Akt、mTORC1が関わる疾患の治療薬が得られると予測できる。 ≪Multi-kinase inhibitors and cancer stem cell development inhibitors or cancer stem cell-killing agents≫
As described in Examples below, compound (I) has multikinase inhibitory activity that inhibits multiple kinases that are associated with cancer growth, nutritional starvation resistance, and the like. For this reason, it is thought that excellent therapeutic effects can be brought about against the growth of malignant tumors and resistance to nutritional starvation, for which conventional cytotoxic anticancer agents have little effect. In addition, according to the present invention, since a single drug inhibits multiple kinases without using multiple drugs, it is possible to reduce the number of drugs to be administered in cancer treatment, thereby reducing side effects to patients. can be mitigated. In addition, according to the present invention, since it exhibits toxicity to cells only in a state of nutrient starvation, it is possible to act specifically on cancer, thereby avoiding serious side effects peculiar to anticancer agents. . Moreover, according to the present invention, molecularly targeted therapeutic agents for Akt and mTORC1, which are extremely important molecules involved in malignant transformation of cancer and resistance to nutrient starvation, can be obtained. Furthermore, it can be predicted that therapeutic agents for diseases involving Akt and mTORC1 will be obtained.
　したがって、本発明の別のさらなる態様として、化合物（Ｉ）、またはその薬理学的に許容可能な塩を有効成分として含有する、マルチキナーゼ阻害剤が提供される。
　一態様では、前記マルチキナーゼ阻害剤は、Aktを阻害する。
　別の一態様では、前記マルチキナーゼ阻害剤は、mTORC1を阻害する。
　さらに別の一態様では、前記マルチキナーゼ阻害剤は、AktおよびmTORC1を阻害する。
　本発明の別の態様として、栄養飢餓状態の腫瘍細胞を選択的に死滅させるための、化合物（Ｉ）、またはその薬理学的に許容可能な塩を有効成分として含有する、医薬組成物が提供される。上記のとおり、化合物（Ｉ）は、がんの増殖や栄養飢餓耐性等に関連するとされる複数のキナーゼを阻害するマルチキナーゼ阻害活性を有する。上記医薬組成物は、栄養飢餓状態の腫瘍細胞を選択的に死滅させるためのメカニズムの１つとして、化合物（Ｉ）、またはその薬理学的に許容可能な塩のマルチキナーゼ阻害活性を利用するものである。
　本発明の別のさらなる態様として、前記マルチキナーゼ阻害剤を有効成分として含有する、抗がん用医薬組成物が提供される。 Therefore, as another further aspect of the present invention, there is provided a multikinase inhibitor containing compound (I) or a pharmacologically acceptable salt thereof as an active ingredient.
In one aspect, the multikinase inhibitor inhibits Akt.
In another aspect, the multikinase inhibitor inhibits mTORC1.
In yet another aspect, said multikinase inhibitor inhibits Akt and mTORC1.
As another aspect of the present invention, there is provided a pharmaceutical composition containing compound (I) or a pharmacologically acceptable salt thereof as an active ingredient for selectively killing nutrient-starved tumor cells. be done. As described above, compound (I) has multikinase inhibitory activity that inhibits multiple kinases that are associated with cancer growth, nutritional starvation resistance, and the like. The pharmaceutical composition utilizes the multikinase inhibitory activity of compound (I) or a pharmacologically acceptable salt thereof as one of the mechanisms for selectively killing nutrient-starved tumor cells. is.
As another further aspect of the present invention, there is provided an anticancer pharmaceutical composition containing the multikinase inhibitor as an active ingredient.
　また、後記実施例に記載のとおり、化合物（Ｉ）はSOX2、c-MYC、OCT-4を阻害することで、がんの治療抵抗性、再発・転移と深く結び付いているとされるがん幹細胞の発現を阻害（発生を抑制）、または、がん幹細胞を殺傷する。このため、がんの治療抵抗性、再発・転移に対して優れた効果をもたらすことができると考えられる。特に、膵臓がんに対してがんの治療抵抗性、すなわち膵臓がんに対して耐性を示す抗がん化合物が存在する中で、本発明に用いられる化合物、あるいは本発明に用いられる化合物とそれ以外の（他の）抗がん化合物を併用することによって、膵臓がんに対してほとんど耐性を示すことなく、優れた効果をもたらすことができる。また、本発明によれば、がんの治療抵抗性、再発・転移に関与する極めて重要な分子であるSOX2、c-MYC、OCT-4に対する分子標的治療薬が得られる。更に、SOX2、c-MYC、OCT-4が関わる疾患の治療薬が得られると予測できる。 In addition, as described in Examples below, compound (I) inhibits SOX2, c-MYC, and OCT-4, which is considered to be closely associated with treatment resistance, recurrence, and metastasis of cancer. Inhibits stem cell expression (suppresses development) or kills cancer stem cells. Therefore, it is considered that excellent effects can be brought about against treatment resistance, recurrence, and metastasis of cancer. In particular, among the existence of anticancer compounds exhibiting cancer treatment resistance against pancreatic cancer, that is, resistance against pancreatic cancer, the compound used in the present invention, or the compound used in the present invention Combined use with other (other) anticancer compounds can provide excellent efficacy with little resistance to pancreatic cancer. Moreover, according to the present invention, molecularly targeted therapeutic agents for SOX2, c-MYC, and OCT-4, which are extremely important molecules involved in treatment resistance, recurrence, and metastasis of cancer, can be obtained. Furthermore, it can be expected that therapeutic drugs for diseases involving SOX2, c-MYC, and OCT-4 will be obtained.
　したがって、本発明の別のさらなる態様として、化合物（Ｉ）、またはその薬理学的に許容可能な塩を有効成分として含有する、SOX2阻害剤、c-MYC阻害剤、OCT-4阻害剤が提供される。
　本発明の別のさらなる態様として、前記SOX2阻害剤、c-MYC阻害剤、OCT-4阻害剤を有効成分として含有する、抗がん用医薬組成物、がん転移抑制剤、およびがん幹細胞阻害剤（一態様では、がん幹細胞の発生抑制剤、がん幹細胞の殺傷剤）が提供される。 Therefore, as another further aspect of the present invention, SOX2 inhibitors, c-MYC inhibitors and OCT-4 inhibitors containing compound (I) or a pharmacologically acceptable salt thereof as an active ingredient are provided. be done.
As another further aspect of the present invention, an anticancer pharmaceutical composition, a cancer metastasis inhibitor, and a cancer stem cell containing the SOX2 inhibitor, c-MYC inhibitor, and OCT-4 inhibitor as active ingredients An inhibitor (in one aspect, a cancer stem cell development inhibitor, a cancer stem cell-killing agent) is provided.
　膵臓がんに対して耐性を示す抗がん化合物としては、様々な抗がん化合物が考えられるが、特に代謝拮抗剤、例えば、エノシタビン、カルモフール、カペシタビン、テガフール、テガフール・ウラシル、テガフール・ギメラシル・オテラシルカリウム、ゲムシタビン、シタラビン、シタラビンオクホスファート、ネララビン、フルオロウラシル、フルダラビン、ペメトレキセド、ペントスタチン、メトトレキサート、クラドリビン、ドキシフルリジン、ヒドロキシカルバミド、メルカプトプリン等が挙げられ、特にゲムシタビンが膵臓がんに対して耐性を示すことがある。 Various anticancer compounds are conceivable as anticancer compounds that exhibit resistance to pancreatic cancer, particularly antimetabolites such as enocitabine, carmofur, capecitabine, tegafur, tegafur uracil, tegafur gimeracil, Oteracil potassium, gemcitabine, cytarabine, cytarabine ocphosphate, nerarabine, fluorouracil, fludarabine, pemetrexed, pentostatin, methotrexate, cladribine, doxifluridine, hydroxycarbamide, mercaptopurine, etc., especially gemcitabine is resistant to pancreatic cancer. may indicate
　なお、任意成分、投与量、対象となるがん、予防または治療対象等については、上記≪抗がん用医薬組成物≫の項で説明した内容を、前記マルチキナーゼ阻害剤、およびSOX2阻害剤においても適用することができる。また、前記マルチキナーゼ阻害剤、およびSOX2阻害剤は、試薬としても使用可能であり、試薬の製造、使用等は、分子生物学分野における常法に基づいて、行うことができる。 Regarding optional ingredients, doses, target cancers, preventive or therapeutic targets, etc., the content described in the above <<Pharmaceutical composition for anticancer>> section should be applied to the above-mentioned multikinase inhibitor and SOX2 inhibitor. It can also be applied in In addition, the multikinase inhibitor and SOX2 inhibitor can also be used as reagents, and the manufacture, use, etc. of the reagents can be carried out based on conventional methods in the field of molecular biology.
　なお、本発明に用いられる化合物は、単独で、上記効果等を発揮し得る。そのため、本発明の薬剤は、これらの効果および／または作用を有する他の成分を含まなくとも、その所望の効果を発揮することができるが、薬理作用を有する他の成分が含有されていてもよい。よって、本発明は、がん治療用医薬組成物を製造するための、化合物（I）の使用を含む。あるいは、本発明は、がんの治療若しくは予防のための化合物（I）の使用を含む。更に、本発明は、化合物（I）を投与することを含む、がんの治療方法若しくは予防方法に関する。 It should be noted that the compound used in the present invention can exhibit the above effects and the like by itself. Therefore, the agent of the present invention can exert its desired effect without containing other ingredients having these effects and/or actions, but even if it contains other ingredients having pharmacological action, good. Accordingly, the present invention includes use of compound (I) for manufacturing a pharmaceutical composition for treating cancer. Alternatively, the present invention includes use of compound (I) for the treatment or prevention of cancer. Furthermore, the present invention relates to a method for treating or preventing cancer, comprising administering compound (I).
≪併用のための医薬組成物≫
　化合物（I）（その塩も含む。本段落において以下同様。）は、他の抗がん化合物とともに医薬組成物とすることができ、また、他の抗がん化合物と併用することができる。これにより、より向上した効果を発揮することも可能である。よって、本発明は、化合物（I）および他の抗がん剤を含有するがん治療用医薬組成物、および、他の抗がん剤と共に使用するための、化合物（I）を含有するがん治療用医薬組成物に関する。あるいは、本発明は、他の抗がん剤と共に使用するためのがん治療用医薬組成物を製造するための、化合物（I）の使用を含む。あるいは、本発明は、他の抗がん剤と共に投与されるための、がんの治療若しくは予防のための化合物（I）の使用、およびがんの治療若しくは予防のための化合物（I）および他の抗がん剤の使用を含む。を含む。更に、本発明は、他の抗がん剤と共に化合物（I）を投与することを含む、がんの治療方法若しくは予防方法に関する。併用における配合比等は、常法に基づいて、設定することができる。なお、本発明において「併用して投与する」とは、上記薬剤を同時に、連続して、あるいは、一方を先に投与した後、時間をおいて投与してもよい。 <<Pharmaceutical composition for combined use>>
Compound (I) (including salts thereof; the same applies hereinafter in this paragraph) can be made into a pharmaceutical composition together with other anticancer compounds, and can be used in combination with other anticancer compounds. Thereby, it is also possible to exhibit a more improved effect. Therefore, the present invention includes a pharmaceutical composition for treating cancer containing compound (I) and other anticancer agents, and compound (I) for use with other anticancer agents. The present invention relates to a pharmaceutical composition for treating cancer. Alternatively, the present invention includes use of compound (I) for manufacturing a pharmaceutical composition for treating cancer for use with other anticancer agents. Alternatively, the present invention provides the use of compound (I) for treating or preventing cancer, and compound (I) for treating or preventing cancer and Including the use of other anticancer agents. including. Furthermore, the present invention relates to a method for treating or preventing cancer comprising administering compound (I) together with other anticancer agents. The compounding ratio and the like in the combined use can be set according to a conventional method. In the present invention, "to be administered in combination" means that the above agents may be administered at the same time, in succession, or one of them may be administered first and then administered at a later time.
　他の抗がん化合物としては、特に制限されず、各種抗がん化合物を用いることができる。抗がん化合物としては、例えばアルキル化剤、代謝拮抗剤、微小管阻害剤、抗生物質抗がん剤、トポイソメラーゼ阻害剤、白金製剤、分子標的薬、ホルモン剤、生物製剤等が挙げられ、好ましくは代謝拮抗剤、抗生物質抗がん剤、白金製剤等が挙げられ、より好ましくは代謝拮抗剤である。これらの化合物のうち、ゲムシタビン（Gemcitabine）との併用は、ゲムシタビン耐性がんに効果があるのみならず、非耐性がんに対しても相乗効果を発揮することから、特に好ましくはゲムシタビンである。 Other anticancer compounds are not particularly limited, and various anticancer compounds can be used. Anticancer compounds include, for example, alkylating agents, antimetabolites, microtubule inhibitors, antibiotic anticancer agents, topoisomerase inhibitors, platinum agents, molecular target drugs, hormone agents, biologics, etc., preferably. includes antimetabolites, antibiotic anticancer agents, platinum preparations and the like, more preferably antimetabolites. Among these compounds, gemcitabine is particularly preferable because its combined use with gemcitabine is not only effective against gemcitabine-resistant cancer but also exerts a synergistic effect against non-resistant cancer.
　代謝拮抗剤としては、例えば、エノシタビン、カルモフール、カペシタビン、テガフール、テガフール・ウラシル、テガフール・ギメラシル・オテラシルカリウム、ゲムシタビン、シタラビン、シタラビンオクホスファート、ネララビン、フルオロウラシル、フルダラビン、ペメトレキセド、ペントスタチン、メトトレキサート、クラドリビン、ドキシフルリジン、ヒドロキシカルバミド、メルカプトプリン等が挙げられる。 Antimetabolites include, for example, enocitabine, carmofur, capecitabine, tegafur, tegafur uracil, tegafur gimeracil oteracil potassium, gemcitabine, cytarabine, cytarabine octophosphate, nerarabine, fluorouracil, fludarabine, pemetrexed, pentostatin, methotrexate, Cladribine, doxifluridine, hydroxycarbamide, mercaptopurine and the like.
　アルキル化剤としては、例えばシクロホスファミド、イホスファミド、ニトロソウレア、ダカルバジン、テモゾロミド、ニムスチン、ブスルファン、メルファラン、プロカルバジン、ラニムスチン等が挙げられる。 Examples of alkylating agents include cyclophosphamide, ifosfamide, nitrosourea, dacarbazine, temozolomide, nimustine, busulfan, melphalan, procarbazine, ranimustine and the like.
　微小管阻害剤としては、例えば、ビンクリスチン等のアルカロイド系抗がん剤、ドセタキセル、パクリタキセル等のタキサン系抗がん剤が挙げられる。 Examples of microtubule inhibitors include alkaloid anticancer agents such as vincristine, and taxane anticancer agents such as docetaxel and paclitaxel.
　抗生物質抗がん剤としては、例えば、マイトマイシンC、ドキソルビシン、エピルビシン、ダウノルビシン、ブレオマイシン、アクチノマイシンD、アクラルビシン、イダルビシン、ピラルビシン、ペプロマイシン、ミトキサントロン、アムルビシン、ジノスタチンスチマラマー等が挙げられる。 Antibiotic anticancer agents include, for example, mitomycin C, doxorubicin, epirubicin, daunorubicin, bleomycin, actinomycin D, aclarubicin, idarubicin, pirarubicin, peplomycin, mitoxantrone, amrubicin, and dinostatin stimaramer.
　トポイソメラーゼ阻害剤としてはトポイソメラーゼI阻害作用を有するCPT-11、イリノテカン、ノギテカン、トポイソメラーゼII阻害作用をもつエトポシド、ソブゾキサンが挙げられる。 Examples of topoisomerase inhibitors include CPT-11, irinotecan, and topotecan, which have topoisomerase I inhibitory activity, and etoposide and sobuzoxan, which have topoisomerase II inhibitory activity.
　白金製剤としては、例えば、シスプラチン、ネダプラチン、オキサリプラチン、カルボプラチン等が挙げられる。 Examples of platinum agents include cisplatin, nedaplatin, oxaliplatin, carboplatin, and the like.
　ホルモン剤としては、例えば、デキサメタゾン、フィナステリド、タモキシフェン、アストロゾール、エキセメスタン、エチニルエストラジオール、クロルマジノン、ゴセレリン、ビカルタミド、フルタミド、ブレドニゾロン、リュープロレリン、レトロゾール、エストラムスチン、トレミフェン、ホスフェストロール、ミトタン、メチルテストステロン、メドロキシプロゲステロン、メピチオスタン等が挙げられる。 Hormonal agents include, for example, dexamethasone, finasteride, tamoxifen, astrozole, exemestane, ethinylestradiol, chlormadinone, goserelin, bicalutamide, flutamide, brednisolone, leuprorelin, letrozole, estramustine, toremifene, fosfestrol, mitotane, Methyltestosterone, medroxyprogesterone, mepitiostane and the like.
　生物製剤としては、例えば、インターフェロンα、βおよびγ、インターロイキン2、ウベニメクス、乾燥BCG等が挙げられる。 Examples of biologics include interferon α, β and γ, interleukin 2, ubenimex, dried BCG, and the like.
　分子標的薬としては、例えば、リツキシマブ、アレムツズマブ、トラスツズマブ、セツキシマブ、パニツムマブ、イマチニブ、ダサチニブ、ニロチニブ、ゲフィチニブ、エルロチニブ、テムシロリムス、ベバシズマブ、VEGF trap、スニチニブ、ソラフェニブ、トシツズマブ、ボルテゾミブ、ゲムツズマブ・オゾガマイシン、イブリツモマブ・オゾガマイシン、イブリツモマブチウキセタン、タミバロテン、トレチノイン等が挙げられる。ここに特定する分子標的薬以外にも、ヒト上皮性増殖因子受容体2阻害剤、上皮性増殖因子受容体阻害剤、Bcr-Ablチロシンキナーゼ阻害剤、上皮性増殖因子チロシンキナーゼ阻害剤、mTOR阻害剤、血管内皮増殖因子受容体2阻害剤（α-VEGFR-2抗体）等の血管新生を標的にした阻害剤、MAPキナーゼ阻害剤等の各種チロシンキナーゼ阻害剤、サイトカインを標的とした阻害剤、プロテアソーム阻害剤、抗体－抗がん剤配合体等の分子標的薬等も含めることができる。これら阻害剤には抗体も含む。 Examples of molecular targeted drugs include rituximab, alemtuzumab, trastuzumab, cetuximab, panitumumab, imatinib, dasatinib, nilotinib, gefitinib, erlotinib, temsirolimus, bevacizumab, VEGF trap, sunitinib, sorafenib, tocituzumab, bortezomib, gemtuzumab o Zogamicin, ibritumomab ozogamicin , ibritumomab tiuxetan, tamibarotene, tretinoin and the like. Human epidermal growth factor receptor 2 inhibitors, epidermal growth factor receptor inhibitors, Bcr-Abl tyrosine kinase inhibitors, epidermal growth factor tyrosine kinase inhibitors, mTOR inhibitors, in addition to those identified here. Angiogenesis-targeted inhibitors such as vascular endothelial growth factor receptor 2 inhibitors (α-VEGFR-2 antibodies), various tyrosine kinase inhibitors such as MAP kinase inhibitors, cytokine-targeted inhibitors, Molecularly targeted drugs such as proteasome inhibitors, antibody-anticancer drug combinations, and the like can also be included. These inhibitors also include antibodies.
＜新規化合物＞
　式（Ｉ）で示される化合物のうち、式（Ｉ）’で示される化合物は、本発明者らによって開発された新規化合物である。すなわち、本発明の別の一態様は、下記式（Ｉ）’で示される化合物（以下、「本発明の化合物」、または「化合物（Ｉ）’」ということがある）、およびその薬理学的に許容可能な塩に関する。式（Ｉ）’で示される化合物、およびその薬理学的に許容可能な塩は、栄養飢餓状態の腫瘍細胞を選択的に死滅させ、また、抗がん活性を有し、抗がん用医薬組成物として用いることができる。なお、任意成分、投与量、対象となるがん、予防または治療対象等については、上記≪抗がん用医薬組成物≫の項で説明した内容を、式（Ｉ）’で示される化合物、またはその薬理学的に許容可能な塩を有効成分として含有する、抗がん用医薬組成物においても適用することができる。さらに、別の態様として、本発明は、本発明の化合物、またはその薬理学的に許容可能な塩の、栄養飢餓状態の腫瘍細胞を選択的に死滅させる抗がん剤としての使用に関する。別の態様として、本発明は、本発明の化合物、またはその薬理学的に許容可能な塩の、がん幹細胞の発生を抑制させる、または、がん幹細胞を殺傷させる抗がん剤としての使用に関する。 <New compound>
Among the compounds represented by formula (I), the compound represented by formula (I)' is a novel compound developed by the present inventors. That is, another aspect of the present invention is a compound represented by the following formula (I)' (hereinafter sometimes referred to as "the compound of the present invention" or "compound (I)'"), and a pharmacological Regarding salts that are acceptable for Compounds represented by formula (I)' and pharmacologically acceptable salts thereof selectively kill nutrient-starved tumor cells and have anticancer activity, and are used as anticancer drugs. It can be used as a composition. Regarding optional ingredients, doses, target cancers, preventive or therapeutic targets, etc., the content described in the section <<pharmaceutical composition for anticancer>> is applied to the compound represented by formula (I)′, Alternatively, it can be applied to an anticancer pharmaceutical composition containing a pharmacologically acceptable salt thereof as an active ingredient. Furthermore, in another aspect, the present invention relates to the use of the compound of the present invention, or a pharmacologically acceptable salt thereof, as an anticancer agent that selectively kills nutrient-starved tumor cells. Another aspect of the present invention is the use of the compound of the present invention or a pharmacologically acceptable salt thereof as an anticancer agent that suppresses the development of cancer stem cells or kills cancer stem cells. Regarding.
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
　式中、
　Ｒ１’は、水素、ヒドロキシ、炭素数１～１０のカルボン酸エステル、または炭素数１～４のアルコキシを示し、
　Ｒ２’～Ｒ４’は、それぞれ独立に、水素、電子供与性基、または電子吸引性基を示し、
　Ｒ５’は、水素、ヒドロキシ、炭素数１～１０のカルボン酸エステル、炭素数１～４のアルコキシ、またはＲ６’と結合し形成した環を示し、
　Ｒ６’は、水素、またはＲ５’と結合し形成した環を示し、
　Ｒ７’およびＲ１１’は、それぞれ独立に、水素、またはハロゲンを示し、
　Ｒ８’およびＲ１０’は、それぞれ独立に、水素、または電子吸引性基を示し、
　Ｒ９’は、電子吸引性基を示し、
　Ｘ’およびＹ’は、それぞれ独立に、炭素、または窒素であり、
　Ｒ９’がヒドロキシである場合、Ｒ２’はアルコキシ以外であり、
　Ｒ９’がシアノまたはニトロである場合、Ｒ２’は塩素以外である。 During the ceremony,
R 1 ' represents hydrogen, hydroxy, carboxylic acid ester having 1 to 10 carbon atoms, or alkoxy having 1 to 4 carbon atoms,
R 2 ' to R 4 ' each independently represents hydrogen, an electron-donating group, or an electron-withdrawing group,
R 5 ' represents hydrogen, hydroxy, carboxylic acid ester having 1 to 10 carbon atoms, alkoxy having 1 to 4 carbon atoms, or a ring formed by combining with R 6 ',
R 6 ' represents hydrogen or a ring formed by combining with R 5 ',
R 7 ' and R 11 ' each independently represent hydrogen or halogen,
R 8 ' and R 10 ' each independently represent hydrogen or an electron-withdrawing group,
R 9 ' represents an electron-withdrawing group,
X' and Y' are each independently carbon or nitrogen;
when R 9 ' is hydroxy, then R 2 ' is other than alkoxy;
When R 9 ' is cyano or nitro, R 2 ' is other than chlorine.
　Ｒ１’～Ｒ１１’、Ｘ’およびＹ’のそれぞれの基の具体例は、化合物（Ｉ）におけるＲ１～Ｒ１１で説明されたものと同様である。 Specific examples of each group of R 1 ' to R 11 ', X' and Y' are the same as those explained for R 1 to R 11 in compound (I).
　化合物（I）’の好ましい化合物としては、化合物（Ｉ）と同様であり、好ましくは、化合物N-（以下、NIC-と称することもある）42、N-50、N-51、N-101、N-110、N-115、NIC-120、NIC-127およびNIC-129であり、最も好ましくは、化合物N-42、N-50およびN-51である。
　化合物（I）’は、後記実施例を参照し、公知の合成方法により、合成することができる。 Preferred compounds of compound (I)' are the same as those of compound (I), preferably compounds N- (hereinafter sometimes referred to as NIC-) 42, N-50, N-51, N-101 , N-110, N-115, NIC-120, NIC-127 and NIC-129, most preferably compounds N-42, N-50 and N-51.
Compound (I)' can be synthesized by a known synthesis method with reference to Examples below.
　以下、実施例により、本発明をさらに具体的に説明するが、本発明はその要旨を超えない限り、これらの実施例に限定されるものではない。 The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples as long as it does not exceed the gist thereof.
＜方法＞
１．フェニルベンズアミド誘導体を基にした化合物の合成
　予備的に見出した抗がん活性を有するフェニルベンズアミド骨格を有する化合物をリード化合物とし、誘導体化合物を以下の方法により合成した。 <Method>
1. Synthesis of Compounds Based on Phenylbenzamide Derivatives A compound having a phenylbenzamide skeleton having anticancer activity, which was found in advance, was used as a lead compound, and derivative compounds were synthesized by the following method.
　参考文献：
Scheme 1 塩化アシルの合成：(a) P. Stoessel, et al. PCT Int. Appl., 2014094962, 26 Jun 2014. ((COCl)2を用いたとき)
                           (b) Y. Xu, et al. Med. Chem. Res., 2019, 28, 1618-1627. (SOCl2を用いたとき)
Scheme 1 縮合反応：C. A. D. Caiuby, et al. J. Org. Chem., 2020, 85, 7433-7445.
Scheme 1 脱メチル化：W. Huang, et al. J. Org. Chem., 2019, 84, 2941-2950. References:
Scheme 1 Synthesis of acyl chlorides: (a) P. Stoessel, et al. PCT Int. Appl., 2014094962, 26 Jun 2014. (when using (COCl) 2 )
(b) Y. Xu, et al. Med. Chem. Res., 2019, 28, 1618-1627. (when using SOCl2 )
Scheme 1 Condensation Reaction: C. A. D. Caiuby, et al. J. Org. Chem., 2020, 85, 7433-7445.
Scheme 1 Demethylation: W. Huang, et al. J. Org. Chem., 2019, 84, 2941-2950.
　参考文献：
Scheme 2 塩化アシルの合成：P. Stoessel, et al. PCT Int. Appl., 2014094962, 26 Jun 2014.
Scheme 2 縮合反応：C. A. D. Caiuby, et al. J. Org. Chem., 2020, 85, 7433-7445. References:
Scheme 2 Synthesis of acyl chlorides: P. Stoessel, et al. PCT Int. Appl., 2014094962, 26 Jun 2014.
Scheme 2 Condensation Reaction: C. A. D. Caiuby, et al. J. Org. Chem., 2020, 85, 7433-7445.
　参考文献：
Scheme 3 塩化アシルの合成：P. Stoessel, et al. PCT Int. Appl., 2014094962, 26 Jun 2014.
Scheme 3 縮合反応：C. A. D. Caiuby, et al. J. Org. Chem., 2020, 85, 7433-7445.
Scheme 3 環状ウレタンの形成：R. E. Stenseth, et al. J. Med. Chem., 1963, 6, 212-213. References:
Scheme 3 Synthesis of Acyl Chlorides: P. Stoessel, et al. PCT Int. Appl., 2014094962, 26 Jun 2014.
Scheme 3 condensation reaction: C. A. D. Caiuby, et al. J. Org. Chem., 2020, 85, 7433-7445.
Scheme 3 Formation of cyclic urethanes: R. E. Stenseth, et al. J. Med. Chem., 1963, 6, 212-213.
　参考文献：
Scheme 4 縮合反応：A. Imramovsky, et al. Tetrahedron Lett., 2006, 47, 5007-5011. References:
Scheme 4 Condensation Reaction: A. Imramovsky, et al. Tetrahedron Lett., 2006, 47, 5007-5011.
　参考文献：
Scheme 5 縮合反応：M. Kratky, et al. Eur. J. Med. Chem., 2019, 181, 111578. References:
Scheme 5 Condensation Reaction: M. Kratky, et al. Eur. J. Med. Chem., 2019, 181, 111578.
＜結果＞
　予備的に見出した抗がん活性を有するフェニルベンズアミド骨格を有する化合物をリード化合物とし、構造最適化研究を行った。合成した化合物のNMRスペクトル値を以下に示す。 <Results>
A compound having a phenylbenzamide skeleton with anticancer activity that was found preliminarily was used as a lead compound, and structural optimization studies were conducted. The NMR spectrum values of the synthesized compound are shown below.
3,5-Dibromo-4-hydroxy-N-(4-nitrophenyl)benzamide (NIC-2)1H-NMR (400 MHz, DMSO-d6) δ: 8.02 (2H, d, J = 9.6 Hz), 8.18 (2H, s), 8.25 (2H, d, J= 9.6 Hz), 10.67 (1H, s) 3,5-Dibromo-4-hydroxy-N-(4-nitrophenyl)benzamide (NIC-2) 1H -NMR (400 MHz, DMSO- d6 ) δ: 8.02 (2H, d, J = 9.6 Hz), 8.18 (2H, s), 8.25 (2H, d, J = 9.6Hz), 10.67 (1H, s)
3,5-Dibromo-N-(4-fluorophenyl)-4-methoxybenzamide (NIC-3)
1H-NMR (400 MHz, DMSO-d6) δ: 3.89 (3H, s), 7.20 (2H, t, J = 9.2 Hz), 7.75 (2H, dd, J = 9.2, 5.2 Hz), 8.23 (2H, s), 10.39 (1H, s) 3,5-Dibromo-N-(4-fluorophenyl)-4-methoxybenzamide (NIC-3)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 3.89 (3H, s), 7.20 (2H, t, J = 9.2 Hz), 7.75 (2H, dd, J = 9.2, 5.2 Hz), 8.23 ( 2H, s), 10.39 (1H, s)
3,5-Dibromo-N-(4-fluorophenyl)-4-hydroxybenzamide (NIC-4)
1H-NMR (400 MHz, DMSO-d6) δ: 7.18 (2H, t, J = 9.2 Hz), 7.74 (2H, dd, J = 9.2, 5.2 Hz), 8.16 (2H, s), 10.25 (1H, s), 10.70 (1H, s) 3,5-Dibromo-N-(4-fluorophenyl)-4-hydroxybenzamide (NIC-4)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.18 (2H, t, J = 9.2 Hz), 7.74 (2H, dd, J = 9.2, 5.2 Hz), 8.16 (2H, s), 10.25 ( 1H, s), 10.70 (1H, s)
3,5-Dibromo-N-(3-fluorophenyl)-4-methoxybenzamide (NIC-5)
1H-NMR (400 MHz, DMSO-d6) δ: 3.83 (3H, s), 6.92 (1H, td, J = 8.0, 2.8 Hz), 7.37 (1H, dd, J = 11.2, 8.0 Hz), 7.49 (1H, dd, J = 8.0, 1.2 Hz), 7.67 (1H, dt, J = 11.2, 2.8 Hz), 8.19 (2H, s), 10.48 (1H, s) 3,5-Dibromo-N-(3-fluorophenyl)-4-methoxybenzamide (NIC-5)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 3.83 (3H, s), 6.92 (1H, td, J = 8.0, 2.8 Hz), 7.37 (1H, dd, J = 11.2, 8.0 Hz), 7.49 (1H, dd, J = 8.0, 1.2 Hz), 7.67 (1H, dt, J = 11.2, 2.8 Hz), 8.19 (2H, s), 10.48 (1H, s)
3,5-Dibromo-N-(2-fluorophenyl)-4-methoxybenzamide (NIC-6)
1H-NMR (400 MHz, DMSO-d6) δ: 3.86 (3H, s), 7.19-7.33 (3H, m), 7.56 (1H, td, J = 8.0, 1.2 Hz), 8.24 (2H, s), 10.29 (1H, s) 3,5-Dibromo-N-(2-fluorophenyl)-4-methoxybenzamide (NIC-6)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 3.86 (3H, s), 7.19-7.33 (3H, m), 7.56 (1H, td, J = 8.0, 1.2 Hz), 8.24 (2H, s ), 10.29 (1H, s)
3,5-Dibromo-N-(2-fluorophenyl)-4-hydroxybenzamide (NIC-7)
1H-NMR (400 MHz, DMSO-d6) δ: 7.19-7.33 (3H, m), 7.55 (1H, td, J = 8.0, 1.2 Hz), 8.17 (2H, s), 10.14 (1H, s), 10.74 (1H, s) 3,5-Dibromo-N-(2-fluorophenyl)-4-hydroxybenzamide (NIC-7)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.19-7.33 (3H, m), 7.55 (1H, td, J = 8.0, 1.2 Hz), 8.17 (2H, s), 10.14 (1H, s ), 10.74 (1H, s)
3,5-Dibromo-N-(4-chlorophenyl)-4-methoxybenzamide (NIC-8)
1H-NMR (400 MHz, DMSO-d6) δ: 3.86 (3H, s), 7.42 (2H, d, J = 8.8 Hz), 7.77 (2H, d, J = 8.8 Hz), 8.22 (2H, s), 10.45 (1H, s) 3,5-Dibromo-N-(4-chlorophenyl)-4-methoxybenzamide (NIC-8)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 3.86 (3H, s), 7.42 (2H, d, J = 8.8 Hz), 7.77 (2H, d, J = 8.8 Hz), 8.22 (2H, s), 10.45 (1H, s)
3,5-Dibromo-N-(4-chlorophenyl)-4-hydroxybenzamide (NIC-9)
1H-NMR (400 MHz, DMSO-d6) δ: 7.42 (2H, d, J = 9.2 Hz), 7.77 (1H, d, J = 9.2 Hz), 8.16 (2H, s), 10.31 (1H, s), 10.73 (1H, s) 3,5-Dibromo-N-(4-chlorophenyl)-4-hydroxybenzamide (NIC-9)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.42 (2H, d, J = 9.2 Hz), 7.77 (1H, d, J = 9.2 Hz), 8.16 (2H, s), 10.31 (1H, s), 10.73 (1H, s)
3,5-Dichloro-N-(4-fluorophenyl)-4-methoxybenzamide (NIC-10)
1H-NMR (400 MHz, DMSO-d6) δ: 3.89 (3H, s), 7.20 (2H, t, J = 9.2 Hz), 7.75 (1H, dd, J = 9.2, 4.8 Hz), 8.06 (2H, s), 10.39 (1H, s) 3,5-Dichloro-N-(4-fluorophenyl)-4-methoxybenzamide (NIC-10)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 3.89 (3H, s), 7.20 (2H, t, J = 9.2 Hz), 7.75 (1H, dd, J = 9.2, 4.8 Hz), 8.06 ( 2H, s), 10.39 (1H, s)
3,5-Dichloro-N-(4-fluorophenyl)-4-hydroxybenzamide (NIC-11)
1H-NMR (400 MHz, DMSO-d6) δ: 7.19 (2H, t, J = 9.2 Hz), 7.74 (2H, dd, J = 9.2, 4.8 Hz), 7.99 (2H, s), 10.24 (1H, s), 10.96 (1H, s) 3,5-Dichloro-N-(4-fluorophenyl)-4-hydroxybenzamide (NIC-11)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.19 (2H, t, J = 9.2 Hz), 7.74 (2H, dd, J = 9.2, 4.8 Hz), 7.99 (2H, s), 10.24 ( 1H, s), 10.96 (1H, s)
3,5-Dichloro-N-(3-fluorophenyl)-4-methoxybenzamide (NIC-12)
1H-NMR (400 MHz, DMSO-d6) δ: 3.89 (3H, s), 6.95 (1H, td, J = 8.0, 2.4 Hz), 7.40 (1H, dd, J = 14.8, 8.0 Hz), 7.52 (1H, dd, J = 8.0, 2.0 Hz), 7.70 (1H, dt, J = 11.6, 2.0 Hz), 8.07 (2H, s), 10.51 (1H, s) 3,5-Dichloro-N-(3-fluorophenyl)-4-methoxybenzamide (NIC-12)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 3.89 (3H, s), 6.95 (1H, td, J = 8.0, 2.4 Hz), 7.40 (1H, dd, J = 14.8, 8.0 Hz), 7.52 (1H, dd, J = 8.0, 2.0Hz), 7.70 (1H, dt, J = 11.6, 2.0Hz), 8.07 (2H, s), 10.51 (1H, s)
3,5-Dichloro-N-(2-fluorophenyl)-4-methoxybenzamide (NIC-13)
1H-NMR (400 MHz, DMSO-d6) δ: 3.90 (3H, s), 7.19-7.33 (3H, m), 7.57 (1H, t, J = 7.6 Hz), 8.08 (2H, s), 10.29 (1H, s) 3,5-Dichloro-N-(2-fluorophenyl)-4-methoxybenzamide (NIC-13)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 3.90 (3H, s), 7.19-7.33 (3H, m), 7.57 (1H, t, J = 7.6 Hz), 8.08 (2H, s), 10.29 (1H, s)
3,5-Dichloro-N-(2-fluorophenyl)-4-hydroxybenzamide (NIC-14)
1H-NMR (400 MHz, DMSO-d6) δ: 7.18-7.32 (3H, m), 7.57 (1H, td, J = 7.6, 1.2 Hz), 7.99 (2H, s), 10.13 (1H, s), 10.99 (1H, s) 3,5-Dichloro-N-(2-fluorophenyl)-4-hydroxybenzamide (NIC-14)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.18-7.32 (3H, m), 7.57 (1H, td, J = 7.6, 1.2 Hz), 7.99 (2H, s), 10.13 (1H, s ), 10.99 (1H, s)
3,5-Dichloro-N-(4-chlorophenyl)-4-methoxybenzamide (NIC-15)
1H-NMR (400 MHz, DMSO-d6) δ: 3.89 (3H, s), 7.42 (2H, d, J = 8.8 Hz), 7.77 (1H, d, J = 8.8 Hz), 8.06 (2H, s), 10.45 (1H, s) 3,5-Dichloro-N-(4-chlorophenyl)-4-methoxybenzamide (NIC-15)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 3.89 (3H, s), 7.42 (2H, d, J = 8.8 Hz), 7.77 (1H, d, J = 8.8 Hz), 8.06 (2H, s), 10.45 (1H, s)
3,5-Dichloro-N-(4-chlorophenyl)-4-hydroxybenzamide (NIC-16)
1H-NMR (400 MHz, DMSO-d6) δ: 7.40 (2H, d, J = 9.2 Hz), 7.77 (2H, d, J = 9.2 Hz), 7.99 (2H, s), 10.30 (1H, s), 10.99 (1H, s) 3,5-Dichloro-N-(4-chlorophenyl)-4-hydroxybenzamide (NIC-16)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.40 (2H, d, J = 9.2 Hz), 7.77 (2H, d, J = 9.2 Hz), 7.99 (2H, s), 10.30 (1H, s), 10.99 (1H, s)
3,5-Dibromo-N-(3,5-dichloro-4-hydroxyphenyl)-4-methoxybenzamide (NIC-17)
1H-NMR (400 MHz, CDCl3) δ: 3.93 (3H, s), 5.74 (1H, s), 7.53 (1H, br), 7.59 (2H, s), 7.97 (2H, s) 3,5-Dibromo-N-(3,5-dichloro-4-hydroxyphenyl)-4-methoxybenzamide (NIC-17)
1 H-NMR (400 MHz, CDCl 3 ) δ: 3.93 (3H, s), 5.74 (1H, s), 7.53 (1H, br), 7.59 (2H, s), 7.97 (2H, s)
3,5-Dibromo-N-(3,5-dichloro-4-hydroxyphenyl)-4-hydroxybenzamide (NIC-18)
1H-NMR (400 MHz, DMSO-d6) δ: 7.78 (2H, s), 8.14 (2H, s), 9.98 (1H, s), 10.20 (1H, s) 3,5-Dibromo-N-(3,5-dichloro-4-hydroxyphenyl)-4-hydroxybenzamide (NIC-18)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.78 (2H, s), 8.14 (2H, s), 9.98 (1H, s), 10.20 (1H, s)
N-(3,5-Dichloro-4-hydroxyphenyl)-2,4,5-trimethoxybenzamide (NIC-19)
1H-NMR (400 MHz, DMSO-d6) δ: 3.73 (3H, s), 3.87 (3H, s), 3.96 (3H, s), 6.79 (1H, s), 7.35 (1H, s), 7.81 (2H, s), 9.89 (1H, s), 9.94 (1H, s) N-(3,5-Dichloro-4-hydroxyphenyl)-2,4,5-trimethoxybenzamide (NIC-19)
1H -NMR (400 MHz, DMSO- d6 ) δ: 3.73 (3H, s), 3.87 (3H, s), 3.96 (3H, s), 6.79 (1H, s), 7.35 (1H, s), 7.81 (2H, s), 9.89 (1H, s), 9.94 (1H, s)
3,5-Dibromo-N-(3-chlorophenyl)-4-methoxybenzamide (NIC-20)
1H-NMR (400 MHz, DMSO-d6) δ: 3.86 (3H, s), 7.18 (1H, ddd, J = 8.0, 2.0, 0.8 Hz), 7.39 (1H, t, J = 8.0 Hz), 7.67 (1H, ddd, J = 8.0, 2.0, 0.8 Hz), 7.91 (1H, t, J = 2.0 Hz), 10.48 (1H, s) 3,5-Dibromo-N-(3-chlorophenyl)-4-methoxybenzamide (NIC-20)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 3.86 (3H, s), 7.18 (1H, ddd, J = 8.0, 2.0, 0.8 Hz), 7.39 (1H, t, J = 8.0 Hz), 7.67 (1H, ddd, J = 8.0, 2.0, 0.8 Hz), 7.91 (1H, t, J = 2.0 Hz), 10.48 (1H, s)
5-Chloro-N-(3,5-dibromo-4-hydroxyphenyl)-2-hydroxybenzamide (NIC-21)
1H-NMR (400 MHz, DMSO-d6) δ: 7.00 (1H, d, J = 9.2 Hz), 7.46 (1H, dd, J = 9.2, 2.4 Hz), 7.88 (1H, d, J = 2.4 Hz), 7.94 (2H, s), 9.83 (1H, s), 10.35 (1H, s), 11. 64 (1H, s) 5-Chloro-N-(3,5-dibromo-4-hydroxyphenyl)-2-hydroxybenzamide (NIC-21)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.00 (1H, d, J = 9.2 Hz), 7.46 (1H, dd, J = 9.2, 2.4 Hz), 7.88 (1H, d, J = 2.4 Hz), 7.94 (2H, s), 9.83 (1H, s), 10.35 (1H, s), 11.64 (1H, s)
5-Chloro-N-(2-chlorophenyl)-2-hydroxybenzamide (NIC-22)
　既知化合物
1H-NMR (400 MHz, DMSO-d6) δ: 7.06 (1H, d, J = 8.8 Hz), 7.19 (1H, ddd, J = 8.8, 7.6, 1.6 Hz), 7.39 (1H, dd, J = 8.8, 2.8 Hz), 7.50 (1H, dd, J = 8.8, 2.8 Hz), 7. 56 (1H, dd, J = 7.6, 1.6 Hz), 7.98 (1H, d, J = 2.8 Hz), 8.38 (1H, dd, J = 7.6, 1.6 Hz), 10.88 (1H, s), 12.27 (1H, s) 5-Chloro-N-(2-chlorophenyl)-2-hydroxybenzamide (NIC-22)
known compound
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.06 (1H, d, J = 8.8 Hz), 7.19 (1H, ddd, J = 8.8, 7.6, 1.6 Hz), 7.39 (1H, dd, J = 8.8, 2.8 Hz), 7.50 (1H, dd, J = 8.8, 2.8 Hz), 7. 56 (1H, dd, J = 7.6, 1.6 Hz), 7.98 (1H, d, J = 2.8 Hz), 8.38 (1H, dd, J = 7.6, 1.6Hz), 10.88 (1H, s), 12.27 (1H, s)
N-(3-Chloro-4-nitrophenyl)-2-hydroxybenzamide (NIC-23)
1H-NMR (400 MHz, DMSO-d6) δ: 6.97 (1H, td, J = 8.0, 0.8 Hz), 7.01 (1H, d, J = 8.0 Hz), 7.44 (1H, td, J = 8.0, 2.0 Hz), 7.82 (1H, dd, J = 8.0, 2.0 Hz), 7.87 (1H, dd, J = 9.2, 2.0 Hz), 8.16 (1H, d, J = 9.2 Hz), 8.20 (1H, d, J = 0.8 Hz), 10.80 (1H, s), 11.25 (1H, s) N-(3-Chloro-4-nitrophenyl)-2-hydroxybenzamide (NIC-23)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 6.97 (1H, td, J = 8.0, 0.8 Hz), 7.01 (1H, d, J = 8.0 Hz), 7.44 (1H, td, J = 8.0 , 2.0 Hz), 7.82 (1H, dd, J = 8.0, 2.0 Hz), 7.87 (1H, dd, J = 9.2, 2.0 Hz), 8.16 (1H, d, J = 9.2 Hz), 8.20 (1H, d , J = 0.8 Hz), 10.80 (1H, s), 11.25 (1H, s)
5-Chloro-N-(2-chloro-4-cyanophenyl)-2-hydroxybenzamide (NIC-24)
　既知化合物
1H-NMR (400 MHz, DMSO-d6) δ: 7.19 (1H, d, J = 8.8 Hz), 7.51 (1H, dd, J = 8.8, 2.8 Hz), 7.81 (1H, dd, J = 8.8, 2.0 Hz), 7.98 (1H, d, J = 2.0 Hz), 8.10 (1H, d, J = 2.8 Hz), 8.80 (1H, d, J = 8.8 Hz), 10.95 (1H, s), 11.29 (1H, s) 5-Chloro-N-(2-chloro-4-cyanophenyl)-2-hydroxybenzamide (NIC-24)
known compound
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.19 (1H, d, J = 8.8 Hz), 7.51 (1H, dd, J = 8.8, 2.8 Hz), 7.81 (1H, dd, J = 8.8 , 2.0 Hz), 7.98 (1H, d, J = 2.0 Hz), 8.10 (1H, d, J = 2.8 Hz), 8.80 (1H, d, J = 8.8 Hz), 10.95 (1H, s), 11.29 ( 1H, s)
5-Chloro-2-hydroxy-N-(4-hydroxy-3-nitrophenyl)benzamide (NIC-25)
1H-NMR (400 MHz, DMSO-d6) δ: 7.00 (1H, d, J = 8.8 Hz), 7.15 (1H, d, J = 8.8 Hz), 7.47 (1H, dd, J = 8.8, 2.8 Hz), 7.79 (1H, dd, J = 8.8, 2.8 Hz), 7.91 (1H, d, J = 2.8 Hz), 8.38 (1H, d, J = 2.8 Hz), 10.48 (1H, s), 10.89 (1H, s), 11.71 (1H, s) 5-Chloro-2-hydroxy-N-(4-hydroxy-3-nitrophenyl)benzamide (NIC-25)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.00 (1H, d, J = 8.8 Hz), 7.15 (1H, d, J = 8.8 Hz), 7.47 (1H, dd, J = 8.8, 2.8 Hz), 7.79 (1H, dd, J = 8.8, 2.8 Hz), 7.91 (1H, d, J = 2.8 Hz), 8.38 (1H, d, J = 2.8 Hz), 10.48 (1H, s), 10.89 ( 1H, s), 11.71 (1H, s)
N-(2-Bromo-4-(trifluoromethyl)phenyl)-2-hydroxybenzamide (NIC-27)
1H-NMR (400 MHz, DMSO-d6) δ: 6.97 (1H, td, J = 8.8, 0.8 Hz), 7.01 (1H, d, J = 8.8 Hz), 7.44 (1H, td, J = 8.8, 2.0 Hz), 7.82 (1H, dd, J = 8.8, 2.0 Hz), 7.87 (1H, dd, J = 8.8, 2.0 Hz), 8.16 (1H, d, J = 8.8 Hz), 8.20 (1H, d, J = 0.8 Hz), 10.80 (1H, s), 11.25 (1H, s) N-(2-Bromo-4-(trifluoromethyl)phenyl)-2-hydroxybenzamide (NIC-27)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 6.97 (1H, td, J = 8.8, 0.8 Hz), 7.01 (1H, d, J = 8.8 Hz), 7.44 (1H, td, J = 8.8 , 2.0 Hz), 7.82 (1H, dd, J = 8.8, 2.0 Hz), 7.87 (1H, dd, J = 8.8, 2.0 Hz), 8.16 (1H, d, J = 8.8 Hz), 8.20 (1H, d , J = 0.8 Hz), 10.80 (1H, s), 11.25 (1H, s)
2-Hydroxy-N-(2-iodo-4-(trifluoromethyl)phenyl)benzamide (NIC-28)
1H-NMR (400 MHz, Acetone-d6) δ: 7.04 (1H, d, J = 7.2 Hz), 7.08 (1H, d, J = 9.2 Hz), 7.51 (1H, td, J = 7.2, 2.0 Hz), 7.81 (1H, dd, J = 9.2, 2.0 Hz), 8.12 (1H, dd, J = 7.2, 1.2 Hz), 8.23 (1H, d, J = 1.2 Hz), 8.44 (1H, d, J = 9.2 Hz), 10.23 (1H, s), 11.29 (1H, s) 2-Hydroxy-N-(2-iodo-4-(trifluoromethyl)phenyl)benzamide (NIC-28)
1 H-NMR (400 MHz, Acetone-d 6 ) δ: 7.04 (1H, d, J = 7.2 Hz), 7.08 (1H, d, J = 9.2 Hz), 7.51 (1H, td, J = 7.2, 2.0 Hz), 7.81 (1H, dd, J = 9.2, 2.0 Hz), 8.12 (1H, dd, J = 7.2, 1.2 Hz), 8.23 (1H, d, J = 1.2 Hz), 8.44 (1H, d, J = 9.2 Hz), 10.23 (1H, s), 11.29 (1H, s)
N-(5-Chloropyridin-3-yl)-2-hydroxybenzamide (NIC-29)
1H-NMR (400 MHz, Acetone-d6) δ: 6.95-7.02 (2H, m), 7.50 (1H, td, J = 8.0, 1.6 Hz), 8.00 (1H, dd, J = 8.0, 1.6 Hz), 8.37 (1H, d, J = 1.6 Hz), 8.41 (1H, t, J = 1.6 Hz), 8.82 (1H, d, J = 1.6 Hz), 10.09 (1H, s), 11.68 (1H, s) N-(5-Chloropyridin-3-yl)-2-hydroxybenzamide (NIC-29)
1 H-NMR (400 MHz, Acetone-d 6 ) δ: 6.95-7.02 (2H, m), 7.50 (1H, td, J = 8.0, 1.6 Hz), 8.00 (1H, dd, J = 8.0, 1.6 Hz ), 8.37 (1H, d, J = 1.6 Hz), 8.41 (1H, t, J = 1.6 Hz), 8.82 (1H, d, J = 1.6 Hz), 10.09 (1H, s), 11.68 (1H, s )
N-(2-Bromo-4-(trifluoromethyl)phenyl)-2-hydroxy-5-methoxybenzamide (NIC-31)
1H-NMR (400 MHz, DMSO-d6) δ: 7.00 (1H, d, J = 8.8 Hz), 7.10 (1H, dd, J = 8.8, 3.2 Hz), 7.53 (1H, d, J = 3.2 Hz), 7.80 (1H, dd, J = 8.8, 1.6 Hz), 8.23 (1H, d, J = 1.6 Hz), 8.43 (1H, d, J = 8.8 Hz), 10.84 (1H, s), 11.58 (1H, s) N-(2-Bromo-4-(trifluoromethyl)phenyl)-2-hydroxy-5-methoxybenzamide (NIC-31)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.00 (1H, d, J = 8.8 Hz), 7.10 (1H, dd, J = 8.8, 3.2 Hz), 7.53 (1H, d, J = 3.2 Hz), 7.80 (1H, dd, J = 8.8, 1.6 Hz), 8.23 (1H, d, J = 1.6 Hz), 8.43 (1H, d, J = 8.8 Hz), 10.84 (1H, s), 11.58 ( 1H, s)
5-Chloro-N-(5-chloropyridin-3-yl)-2-hydroxybenzamide (NIC-32)
1H-NMR (400 MHz, Acetone-d6) δ: 7.05 (1H, d, J = 8.8 Hz), 7.51 (1H, dd, J = 8.8, 2.4 Hz), 8.03 (1H, d, J = 2.4 Hz), 8.38 (1H, d, J = 2.4 Hz), 8.41 (1H, d, J = 2.0 Hz), 8.22 (1H, s), 10.18 (1H, s) 5-Chloro-N-(5-chloropyridin-3-yl)-2-hydroxybenzamide (NIC-32)
1 H-NMR (400 MHz, Acetone-d 6 ) δ: 7.05 (1H, d, J = 8.8 Hz), 7.51 (1H, dd, J = 8.8, 2.4 Hz), 8.03 (1H, d, J = 2.4 Hz), 8.38 (1H, d, J = 2.4 Hz), 8.41 (1H, d, J = 2.0 Hz), 8.22 (1H, s), 10.18 (1H, s)
N-(4-Cyanopyridin-2-yl)-2-hydroxy-5-methoxybenzamide (NIC-33)
1H-NMR (400 MHz, Acetone-d6) δ: 3.91 (3H, s), 7.41 (1H, d, J = 9.6 Hz), 7.45 (1H, dd, J = 9.6, 2.8 Hz), 7.46 (1H, d, J = 2.0 Hz), 8.00 (1H, dd, J = 5.2, 2.0 Hz), 8.04 (1H, d, J = 2.8 Hz), 8.96 (1H, d, J = 5.2 Hz) N-(4-Cyanopyridin-2-yl)-2-hydroxy-5-methoxybenzamide (NIC-33)
1 H-NMR (400 MHz, Acetone-d 6 ) δ: 3.91 (3H, s), 7.41 (1H, d, J = 9.6 Hz), 7.45 (1H, dd, J = 9.6, 2.8 Hz), 7.46 ( 1H, d, J = 2.0 Hz), 8.00 (1H, dd, J = 5.2, 2.0 Hz), 8.04 (1H, d, J = 2.8 Hz), 8.96 (1H, d, J = 5.2 Hz)
N-(3,5-Dichloro-4-hydroxyphenyl)-2-hydroxy-5-methoxybenzamide (NIC-34)
　既知化合物
1H-NMR (400 MHz, Acetone-d6) δ: 3,79 (3H, s), 6.92 (1H, d, J = 8.8 Hz), 7.09 (1H, dd, J = 8.8, 3.2 Hz), 7.56 (1H, d, J = 3.2 Hz), 7.82 (2H, s), 9.95 (1H, s), 11.47 (1H, s) N-(3,5-Dichloro-4-hydroxyphenyl)-2-hydroxy-5-methoxybenzamide (NIC-34)
known compound
1 H-NMR (400 MHz, Acetone-d 6 ) δ: 3,79 (3H, s), 6.92 (1H, d, J = 8.8 Hz), 7.09 (1H, dd, J = 8.8, 3.2 Hz), 7.56 (1H, d, J = 3.2Hz), 7.82 (2H, s), 9.95 (1H, s), 11.47 (1H, s)
N-(3,5-Dibromo-4-hydroxyphenyl)-2-hydroxy-5-methoxybenzamide (NIC-35)
1H-NMR (400 MHz, Acetone-d6) δ: 3.84 (3H, s), 6.97 (1H, d, J = 8.8 Hz), 7.02 (1H, dd, J = 8.8, 2.8 Hz), 7.95 (1H, d, J = 2.8 Hz), 8.23 (2H, s), 10.81 (1H, s), 11.91 (1H, s) N-(3,5-Dibromo-4-hydroxyphenyl)-2-hydroxy-5-methoxybenzamide (NIC-35)
1 H-NMR (400 MHz, Acetone-d 6 ) δ: 3.84 (3H, s), 6.97 (1H, d, J = 8.8 Hz), 7.02 (1H, dd, J = 8.8, 2.8 Hz), 7.95 ( 1H, d, J = 2.8 Hz), 8.23 (2H, s), 10.81 (1H, s), 11.91 (1H, s)
N-(3,5-Dibromo-4-hydroxyphenyl)-2-hydroxy-4-methoxybenzamide (NIC-36)
1H-NMR (500 MHz, Acetone-d6) δ: 3.84 (3H, s), 6.46 (1H, d, J = 9.0, 2.5 Hz), 6. 49 (1H, dd, J = 9.0, 2.5 Hz), 7.88 (1H, d, J = 9.5 Hz), 7.99 (2H, s), 8.46 (1H, s), 9.52 (1H, s), 12.38 (1H, s) N-(3,5-Dibromo-4-hydroxyphenyl)-2-hydroxy-4-methoxybenzamide (NIC-36)
1 H-NMR (500 MHz, Acetone-d 6 ) δ: 3.84 (3H, s), 6.46 (1H, d, J = 9.0, 2.5 Hz), 6.49 (1H, dd, J = 9.0, 2.5 Hz ), 7.88 (1H, d, J = 9.5 Hz), 7.99 (2H, s), 8.46 (1H, s), 9.52 (1H, s), 12.38 (1H, s)
4-Chloro-N-(3,5-dibromo-4-hydroxyphenyl)-2-hydroxybenzamide (NIC-37)
1H-NMR (400 MHz, Acetone-d6) δ: 6.96 (1H, dd, J = 8.0, 1.6 Hz), 7.04 (1H, d, J = 1.6 Hz), 8.03 (2H, s), 8.08 (1H, d, J = 8.0 Hz), 9.97 (1H, s) 4-Chloro-N-(3,5-dibromo-4-hydroxyphenyl)-2-hydroxybenzamide (NIC-37)
1 H-NMR (400 MHz, Acetone-d 6 ) δ: 6.96 (1H, dd, J = 8.0, 1.6 Hz), 7.04 (1H, d, J = 1.6 Hz), 8.03 (2H, s), 8.08 ( 1H, d, J = 8.0 Hz), 9.97 (1H, s)
3-(3,5-Dibromo-4-hydroxyphenyl)-5-hydroxy-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (NIC-38)
1H-NMR (400 MHz, Acetone-d6) δ: 6.85 (1H, d, J = 8.8 Hz), 6.87 (1H, d, J = 8.8 Hz), 7.71 (1H, t, J = 8.8 Hz), 7.80 (2H, s), 9.08 (1H, s), 10.71 (1H, s) 3-(3,5-Dibromo-4-hydroxyphenyl)-5-hydroxy-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (NIC-38)
1 H-NMR (400 MHz, Acetone-d 6 ) δ: 6.85 (1H, d, J = 8.8 Hz), 6.87 (1H, d, J = 8.8 Hz), 7.71 (1H, t, J = 8.8 Hz) , 7.80 (2H, s), 9.08 (1H, s), 10.71 (1H, s)
3-(3,5-Dichloro-4-hydroxyphenyl)-5-hydroxy-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (NIC-39)
1H-NMR (400 MHz, Acetone-d6) δ: 6.86 (1H, d, J = 8.4 Hz), 6.88 (1H, d, J = 8.4 Hz), 7.61 (2H, s), 7.71 (1H, t, J = 8.4 Hz), 9.35 (1H, s), 10.71 (1H, s) 3-(3,5-Dichloro-4-hydroxyphenyl)-5-hydroxy-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (NIC-39)
1 H-NMR (400 MHz, Acetone-d 6 ) δ: 6.86 (1H, d, J = 8.4 Hz), 6.88 (1H, d, J = 8.4 Hz), 7.61 (2H, s), 7.71 (1H, t, J = 8.4 Hz), 9.35 (1H, s), 10.71 (1H, s)
N-(2-Chloro-4-nitrophenyl)-2-hydroxy-5-methoxybenzamide (NIC-40)
1H-NMR (500 MHz, DMSO-d6) δ: 6.99 (1H, d, J = 8.0 Hz), 7.12 (1H, dd, J = 8.0, 3.2 Hz), 7.52 (1H, d, J = 3.2 Hz), 8.29 (1H, dd, J = 9.6, 2.8 Hz), 8.43 (1H, d, J = 2.8 Hz), 8.84 (1H, d, J = 9.6 Hz), 11.50 (1H, s), 11.75 (1H, s) N-(2-Chloro-4-nitrophenyl)-2-hydroxy-5-methoxybenzamide (NIC-40)
1 H-NMR (500 MHz, DMSO-d 6 ) δ: 6.99 (1H, d, J = 8.0 Hz), 7.12 (1H, dd, J = 8.0, 3.2 Hz), 7.52 (1H, d, J = 3.2 Hz), 8.29 (1H, dd, J = 9.6, 2.8 Hz), 8.43 (1H, d, J = 2.8 Hz), 8.84 (1H, d, J = 9.6 Hz), 11.50 (1H, s), 11.75 ( 1H, s)
N-(2-Chloro-4-nitrophenyl)-2,5-dihydroxybenzamide (NIC-41)
1H-NMR (400 MHz, DMSO-d6) δ: 6.87 (1H, s), 6.88 (1H, d, J = 2.4 Hz), 7.41 (1H, d, J = 1.2 Hz), 8.26 (1H, dd, J = 9.6, 2.4 Hz), 8.40 (1H, d, J = 2.4 Hz), 8.83 (1H, d, J = 9.6 Hz), 9.21 (1H, s) N-(2-Chloro-4-nitrophenyl)-2,5-dihydroxybenzamide (NIC-41)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 6.87 (1H, s), 6.88 (1H, d, J = 2.4 Hz), 7.41 (1H, d, J = 1.2 Hz), 8.26 (1H, dd, J = 9.6, 2.4 Hz), 8.40 (1H, d, J = 2.4 Hz), 8.83 (1H, d, J = 9.6 Hz), 9.21 (1H, s)
5-Chloro-N-(2-chloro-4-nitrophenyl)-4-fluoro-2-hydroxybenzamide (NIC-42)
1H-NMR (500 MHz, DMSO-d6) δ: 7.01 (1H, d, J = 10.5 Hz), 8.11 (1H, d, J = 9.0 Hz), 8.29 (1H, dd, J = 9.0, 2.5 Hz), 8.43 (1H, d, J = 2.5 Hz), 8.78 (1H, d, J = 9. 0 Hz), 11.23 (1H, s) 5-Chloro-N-(2-chloro-4-nitrophenyl)-4-fluoro-2-hydroxybenzamide (NIC-42)
1 H-NMR (500 MHz, DMSO-d 6 ) δ: 7.01 (1H, d, J = 10.5 Hz), 8.11 (1H, d, J = 9.0 Hz), 8.29 (1H, dd, J = 9.0, 2.5 Hz), 8.43 (1H, d, J = 2.5 Hz), 8.78 (1H, d, J = 9.0 Hz), 11.23 (1H, s)
N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-5-methoxybenzamide (NIC-43)
1H-NMR (500 MHz, DMSO-d6) δ: 3.74 (3H, s), 7.00 (1H, d, J = 7.2 Hz), 7.10 (1H, dd, J = 7.2, 2.8 Hz), 7.53 (1H, d, J = 2.8 Hz), 7.77 (1H, d, J = 6.8 Hz), 7.98 (1H, s), 8.76 (1H, d, J = 6.8 Hz), 11.30 (1H, s), 11.64 (1H, s) N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-5-methoxybenzamide (NIC-43)
1 H-NMR (500 MHz, DMSO-d 6 ) δ: 3.74 (3H, s), 7.00 (1H, d, J = 7.2 Hz), 7.10 (1H, dd, J = 7.2, 2.8 Hz), 7.53 ( 1H, d, J = 2.8 Hz), 7.77 (1H, d, J = 6.8 Hz), 7.98 (1H, s), 8.76 (1H, d, J = 6.8 Hz), 11.30 (1H, s), 11.64 ( 1H, s)
N-(2-Bromo-4-(trifluoromethyl)phenyl)-2-hydroxy-5-methoxybenzamide (NIC-44)
1H-NMR (500 MHz, DMSO-d6) δ: 3.73 (3H, s), 6.98 (1H, d, J = 8.0 Hz), 7.13 (1H, dd, J = 8.0, 2.8 Hz), 7.54 (1H, d, J = 2.8 Hz), 7.69 (1H, d, J = 7.6 Hz), 8.01 (1H, s), 8.77 (1H, d, J = 7.6 Hz), 11.31 (1H, s) N-(2-Bromo-4-(trifluoromethyl)phenyl)-2-hydroxy-5-methoxybenzamide (NIC-44)
1 H-NMR (500 MHz, DMSO-d 6 ) δ: 3.73 (3H, s), 6.98 (1H, d, J = 8.0 Hz), 7.13 (1H, dd, J = 8.0, 2.8 Hz), 7.54 ( 1H, d, J = 2.8 Hz), 7.69 (1H, d, J = 7.6 Hz), 8.01 (1H, s), 8.77 (1H, d, J = 7.6 Hz), 11.31 (1H, s)
2-Hydroxy-N-(2-iodo-4-(trifluoromethyl)phenyl)-5-methoxybenzamide (NIC-45)
1H-NMR (400 MHz, DMSO-d6) δ: 3.74 (3H, s), 7.00 (1H, d, J = 8.8 Hz), 7.10 (1H, dd, J = 8.8, 3.2 Hz), 7.53 (1H, d, J = 3.2 Hz), 7.80 (1H, dd, J = 8.8, 1.6 Hz), 8.23 (1H, d, J = 1.6 Hz), 8.43 (1H, d, J = 8.8 Hz), 10.85 (1H, s), 11.58 (1H, s) 2-Hydroxy-N-(2-iodo-4-(trifluoromethyl)phenyl)-5-methoxybenzamide (NIC-45)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 3.74 (3H, s), 7.00 (1H, d, J = 8.8 Hz), 7.10 (1H, dd, J = 8.8, 3.2 Hz), 7.53 ( 1H, d, J = 3.2 Hz), 7.80 (1H, dd, J = 8.8, 1.6 Hz), 8.23 (1H, d, J = 1.6 Hz), 8.43 (1H, d, J = 8.8 Hz), 10.85 ( 1H, s), 11.58 (1H, s)
2-((2-Chloro-4-(trifluoromethyl)phenyl)carbamoyl)-4-methoxyphenyl octanoate (NIC-46)
1H-NMR (400 MHz, CDCl3) δ: 0.85 (3H, t, J = 7.2 Hz), 1.12-1.32 (8H, m), 1.62-1. 70 (2H, m), 2.60 (2H, t, J= 7.2 Hz), 3.85 (3H, s), 7.06 (1H, s), 7.07 (1H, d, J = 1.2 Hz), 7.46-7.48 (1H, m), 7.57 (1H, d, J = 8.4 Hz), 7.67 (1H, d, J = 1.2 Hz), 8.75 (1H, d, J = 8.4 Hz), 8.90 (1H, s) 2-((2-Chloro-4-(trifluoromethyl)phenyl)carbamoyl)-4-methoxyphenyl octanoate (NIC-46)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.85 (3H, t, J = 7.2 Hz), 1.12-1.32 (8H, m), 1.62-1.70 (2H, m), 2.60 (2H, t , J = 7.2 Hz), 3.85 (3H, s), 7.06 (1H, s), 7.07 (1H, d, J = 1.2 Hz), 7.46-7.48 (1H, m), 7.57 (1H, d, J = 8.4 Hz), 7.67 (1H, d, J = 1.2 Hz), 8.75 (1H, d, J = 8.4 Hz), 8.90 (1H, s)
5-Cyano-N-(4'-cyano-[1,1'-biphenyl]-4-yl)-2-hydroxybenzamide (NIC-47)
1H-NMR (400 MHz, DMSO-d6) δ: 7.14 (1H, d, J = 8.8 Hz), 7.85 (1H, dd, J = 8.8, 2.0 Hz), 7.83-7.90 (4H, m), 7.90 (4H, s), 8.28 (1H, d, J = 2.0 Hz), 10.54 (1H, s) 5-Cyano-N-(4'-cyano-[1,1'-biphenyl]-4-yl)-2-hydroxybenzamide (NIC-47)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.14 (1H, d, J = 8.8 Hz), 7.85 (1H, dd, J = 8.8, 2.0 Hz), 7.83-7.90 (4H, m), 7.90 (4H, s), 8.28 (1H, d, J = 2.0Hz), 10.54 (1H, s)
5-Chloro-N-(4'-cyano-[1,1'-biphenyl]-4-yl)-2-hydroxybenzamide (NIC-48)
1H-NMR (400 MHz, DMSO-d6) δ: 7.02 (1H, d, J = 9.2 Hz), 7.47 (1H, dd, J = 9.2, 1.2 Hz), 7.83-7.90 (4H, m), 7.90 (4H, s), 7.93 (1H, d, J = 2.8 Hz), 10.53 (1H, s), 11.75 (1H, s) 5-Chloro-N-(4'-cyano-[1,1'-biphenyl]-4-yl)-2-hydroxybenzamide (NIC-48)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.02 (1H, d, J = 9.2 Hz), 7.47 (1H, dd, J = 9.2, 1.2 Hz), 7.83-7.90 (4H, m), 7.90 (4H, s), 7.93 (1H, d, J = 2.8Hz), 10.53 (1H, s), 11.75 (1H, s)
5-Chloro-2-hydroxy-N-(4'-nitro-[1,1'-biphenyl]-4-yl)benzamide (NIC-49)
1H-NMR (400 MHz, DMSO-d6) δ: 7.03 (1H, d, J = 8.8 Hz), 7.47 (1H, dd, J = 8.8, 2.8 Hz), 7.83-7.90 (4H, m), 7.93 (1H, d, J = 2.8 Hz), 7.98 (2H, d, J = 8.8 Hz), 8.30 (2H, d, J = 8.8 Hz), 10.55 (1H, s), 11.74 (1H, s) 5-Chloro-2-hydroxy-N-(4'-nitro-[1,1'-biphenyl]-4-yl)benzamide (NIC-49)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.03 (1H, d, J = 8.8 Hz), 7.47 (1H, dd, J = 8.8, 2.8 Hz), 7.83-7.90 (4H, m), 7.93 (1H, d, J = 2.8Hz), 7.98 (2H, d, J = 8.8Hz), 8.30 (2H, d, J = 8.8Hz), 10.55 (1H, s), 11.74 (1H, s)
4,5-Dichloro-N-(4'-cyano-[1,1'-biphenyl]-4-yl)-2-hydroxybenzamide (NIC-50)
1H-NMR (400 MHz, DMSO-d6) δ: 7.25 (1H, s), 7.79 (2H, d, J = 8.8 Hz), 7.85 (2H, d, J = 8.8 Hz), 7.87-7.89 (4H, m), 8.09 (1H, s), 10.51 (1H, s) 4,5-Dichloro-N-(4'-cyano-[1,1'-biphenyl]-4-yl)-2-hydroxybenzamide (NIC-50)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.25 (1H, s), 7.79 (2H, d, J = 8.8 Hz), 7.85 (2H, d, J = 8.8 Hz), 7.87-7.89 ( 4H, m), 8.09 (1H, s), 10.51 (1H, s)
4,5-Dichloro-2-hydroxy-N-(4'-nitro-[1,1'-biphenyl]-4-yl)benzamide (NIC-51)
1H-NMR (400 MHz, DMSO-d6) δ: 7.25 (1H, s), 7.76-7.83 (4H, m), 7.97 (2H, d, J = 8.8 Hz), 8.09 (1H, s), 8.29 (2H, d, J = 8.8 Hz), 10.54 (1H, s), 12.00 (1H, s) 4,5-Dichloro-2-hydroxy-N-(4'-nitro-[1,1'-biphenyl]-4-yl)benzamide (NIC-51)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.25 (1H, s), 7.76-7.83 (4H, m), 7.97 (2H, d, J = 8.8 Hz), 8.09 (1H, s), 8.29 (2H, d, J = 8.8Hz), 10.54 (1H, s), 12.00 (1H, s)
4-Chloro-N-(4'-cyano-[1,1'-biphenyl]-4-yl)-2-hydroxybenzamide (NIC-52)
1H-NMR (400 MHz, DMSO-d6) δ: 7.03-7.06 (2H, m), 7.79 (2H, d, J = 8.8 Hz), 7.85 (2H, d, J = 8.8 Hz), 7.88-7.98 (5H, m), 10.49 (1H, s), 12.01 (1H, s) 4-Chloro-N-(4'-cyano-[1,1'-biphenyl]-4-yl)-2-hydroxybenzamide (NIC-52)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.03-7.06 (2H, m), 7.79 (2H, d, J = 8.8 Hz), 7.85 (2H, d, J = 8.8 Hz), 7.88- 7.98 (5H, m), 10.49 (1H, s), 12.01 (1H, s)
4-Chloro-2-hydroxy-N-(4'-nitro-[1,1'-biphenyl]-4-yl)benzamide (NIC-53)
1H-NMR (400 MHz, DMSO-d6) δ: 7.02-7.06 (2H, m), 7.82-7.87 (4H, m), 7.88-7.94 (1H, m), 7.98 (2H, d, J = 9.2 Hz), 8.29 (2H, d, J= 8.8 Hz), 10.51 (1H, s), 11.97 (1H, s) 4-Chloro-2-hydroxy-N-(4'-nitro-[1,1'-biphenyl]-4-yl)benzamide (NIC-53)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.02-7.06 (2H, m), 7.82-7.87 (4H, m), 7.88-7.94 (1H, m), 7.98 (2H, d, J = 9.2 Hz), 8.29 (2H, d, J = 8.8 Hz), 10.51 (1H, s), 11.97 (1H, s)
4-Chloro-N-(3',5'-dichloro-[1,1'-biphenyl]-4-yl)-2-hydroxybenzamide (NIC-54)
1H-NMR (400 MHz, DMSO-d6) δ: 7.03-7.05 (2H, m), 7.56 (1H, t, J = 2.0 Hz), 7.75 (2H, d, J = 2.0 Hz), 7.76-7.84 (4H, m), 7.93 (1H, d, J = 8.4 Hz), 10.49 (1H, s) 4-Chloro-N-(3',5'-dichloro-[1,1'-biphenyl]-4-yl)-2-hydroxybenzamide (NIC-54)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.03-7.05 (2H, m), 7.56 (1H, t, J = 2.0 Hz), 7.75 (2H, d, J = 2.0 Hz), 7.76- 7.84 (4H, m), 7.93 (1H, d, J=8.4Hz), 10.49 (1H, s)
Methyl 4'-(4-Chloro-2-hydroxybenzamido)-[1,1'-biphenyl]-4-carboxylate (NIC-55)
1H-NMR (400 MHz, DMSO-d6) δ: 3.87 (3H, s), 7.02-7.05 (2H, m), 7.78 (2H, d, J = 8.8 Hz), 7.83-7.86 (4H, m), 7.88-7.98 (1H, m), 8.03 (2H, d, J = 8.8 Hz), 10.51 (1H, s), 12.03 (1H, s) Methyl 4'-(4-Chloro-2-hydroxybenzamido)-[1,1'-biphenyl]-4-carboxylate (NIC-55)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 3.87 (3H, s), 7.02-7.05 (2H, m), 7.78 (2H, d, J = 8.8 Hz), 7.83-7.86 (4H, m ), 7.88-7.98 (1H, m), 8.03 (2H, d, J = 8.8 Hz), 10.51 (1H, s), 12.03 (1H, s)
4,5-Dichloro-N-(3',5'-dichloro-[1,1'-biphenyl]-4-yl)-2-hydroxybenzamide (NIC-56) 1H-NMR (400 MHz, DMSO-d6) δ: 7.24 (1H, s), 7.56 (1H, t, J = 2.0 Hz), 7.75 (2H, d, J = 2.0 Hz), 7.76-7.83 (4H, m), 8.08 (1H, s), 10.52 (1H, s), 12.05 (1H, s) 4,5-Dichloro-N-(3',5'-dichloro-[1,1'-biphenyl]-4-yl)-2-hydroxybenzamide (NIC-56) 1H -NMR (400 MHz, DMSO-d 6 ) δ: 7.24 (1H, s), 7.56 (1H, t, J = 2.0 Hz), 7.75 (2H, d, J = 2.0 Hz), 7.76-7.83 (4H, m), 8.08 (1H, s) , 10.52 (1H, s), 12.05 (1H, s)
Methyl 4'-(4,5-Dichloro-2-hydroxybenzamido)-[1,1'-biphenyl]-4-carboxylate (NIC-57)
1H-NMR (400 MHz, DMSO-d6) δ: 3.87 (3H, s), 7.25 (1H, s), 7.78 (2H, d, J = 7.2 Hz), 7.84 (4H, d, J = 8.8 Hz), 8.03 (2H, d, J = 7.2 Hz), 8.10 (1H, s), 10.51 (1H, s), 12.03 (1H, s) Methyl 4'-(4,5-Dichloro-2-hydroxybenzamido)-[1,1'-biphenyl]-4-carboxylate (NIC-57)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 3.87 (3H, s), 7.25 (1H, s), 7.78 (2H, d, J = 7.2 Hz), 7.84 (4H, d, J = 8.8 Hz), 8.03 (2H, d, J = 7.2 Hz), 8.10 (1H, s), 10.51 (1H, s), 12.03 (1H, s)
N-(4'-Cyano-[1,1'-biphenyl]-4-yl)-2-hydroxy-4-(trifluoromethyl)benzamide (NIC-59)
1H-NMR (400 MHz, DMSO-d6) δ: 7.45 (2H, d, J = 8.8 Hz), 7.74-8.04 (9H, m) N-(4'-Cyano-[1,1'-biphenyl]-4-yl)-2-hydroxy-4-(trifluoromethyl)benzamide (NIC-59)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.45 (2H, d, J = 8.8 Hz), 7.74-8.04 (9H, m)
2-Hydroxy-N-(4'-nitro-[1,1'-biphenyl]-4-yl)-4-(trifluoromethyl)benzamide (NIC-60)
1H-NMR (400 MHz, DMSO-d6) δ: 7.48 (2H, d, J = 8.8 Hz), 7.86 (1H, d, J = 8.0 Hz), 7.97-8.06 (5H, m), 8.31 (1H, d, J = 8.0 Hz), 8.36 (2H, d, J = 8.8 Hz), 11.10 (1H, s) 2-Hydroxy-N-(4'-nitro-[1,1'-biphenyl]-4-yl)-4-(trifluoromethyl)benzamide (NIC-60)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.48 (2H, d, J = 8.8 Hz), 7.86 (1H, d, J = 8.0 Hz), 7.97-8.06 (5H, m), 8.31 ( 1H, d, J = 8.0Hz), 8.36 (2H, d, J = 8.8Hz), 11.10 (1H, s)
N-(4'-Cyano-[1,1'-biphenyl]-4-yl)-4-fluoro-2-hydroxybenzamide (NIC-61)
1H-NMR (400 MHz, DMSO-d6) δ: 7.45 (1H, d, J = 8.8 Hz), 7.81 (2H, d, J = 8.8 Hz), 7.90 (4H, s), 7.94-7.99 (2H, m), 8.03 (2H, d, J = 8.8 Hz), 11.07 (1H, s) N-(4'-Cyano-[1,1'-biphenyl]-4-yl)-4-fluoro-2-hydroxybenzamide (NIC-61)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.45 (1H, d, J = 8.8 Hz), 7.81 (2H, d, J = 8.8 Hz), 7.90 (4H, s), 7.94-7.99 ( 2H, m), 8.03 (2H, d, J = 8.8 Hz), 11.07 (1H, s)
4-Bromo-2-hydroxy-N-(4'-nitro-[1,1'-biphenyl]-4-yl)benzamide (NIC-62)
1H-NMR (400 MHz, DMSO-d6) δ: 7.40 (2H, d, J = 8.0 Hz), 7.71 (1H, d, J = 8.0 Hz), 7.90-8.05 (3H, m), 8.11 (2H, d, J = 8.0 Hz), 8.33 (1H, d, J = 8.0 Hz), 8.34-8. 36 (2H, m) 4-Bromo-2-hydroxy-N-(4'-nitro-[1,1'-biphenyl]-4-yl)benzamide (NIC-62)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.40 (2H, d, J = 8.0 Hz), 7.71 (1H, d, J = 8.0 Hz), 7.90-8.05 (3H, m), 8.11 ( 2H, d, J = 8.0 Hz), 8.33 (1H, d, J = 8.0 Hz), 8.34-8. 36 (2H, m)
2-Hydroxy-4-iodo-N-(4'-nitro-[1,1'-biphenyl]-4-yl)benzamide (NIC-63)
1H-NMR (400 MHz, DMSO-d6) δ: 7.48 (2H, d, J = 8.8 Hz), 7.86 (1H, d, J = 8.8 Hz), 7.96-8.03 (3H, m), 8.05 (2H, d, J = 8.8 Hz), 8.28 (1H, d, J = 8.8 Hz), 8.35 (2H, d, J =8.8 Hz), 11.10 (1H, s) 2-Hydroxy-4-iodo-N-(4'-nitro-[1,1'-biphenyl]-4-yl)benzamide (NIC-63)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.48 (2H, d, J = 8.8 Hz), 7.86 (1H, d, J = 8.8 Hz), 7.96-8.03 (3H, m), 8.05 ( 2H, d, J = 8.8 Hz), 8.28 (1H, d, J = 8.8 Hz), 8.35 (2H, d, J = 8.8 Hz), 11.10 (1H, s)
Methyl 4'-(2-Hydroxy-4-iodobenzamido)-[1,1'-biphenyl]-4-carboxylate (NIC-64)
1H-NMR (400 MHz, DMSO-d6) δ: 7.34 (1H, dd, J = 8.4, 2.0 Hz), 7.38 (1H, d, J = 2.0 Hz), 7.67 (1H, d, J = 8.4 Hz), 7.77 (2H, d, J = 8.4 Hz), 7.81-7.87 (4H, m), 8.02 (2H, d, J = 8.4 Hz), 10.46 (1H, s), 11.86 (1H, s) Methyl 4'-(2-Hydroxy-4-iodobenzamido)-[1,1'-biphenyl]-4-carboxylate (NIC-64)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.34 (1H, dd, J = 8.4, 2.0 Hz), 7.38 (1H, d, J = 2.0 Hz), 7.67 (1H, d, J = 8.4 Hz), 7.77 (2H, d, J = 8.4 Hz), 7.81-7.87 (4H, m), 8.02 (2H, d, J = 8.4 Hz), 10.46 (1H, s), 11.86 (1H, s)
4-Bromo-N-(3',5'-dichloro-[1,1'-biphenyl]-4-yl)-2-hydroxybenzamide (NIC-65)
1H-NMR (400 MHz, DMSO-d6) δ: 7.14 (1H, dd, J = 10.4, 1.6 Hz), 7.17 (1H, d, J = 1.6 Hz), 7.53 (1H, t, J = 1.6 Hz), 7.72 (2H, d, J = 1.6 Hz), 7.73-7.80 (4H, m), 7.81 (1H, d, J = 8.8 Hz), 10.48 (1H, s) 4-Bromo-N-(3',5'-dichloro-[1,1'-biphenyl]-4-yl)-2-hydroxybenzamide (NIC-65)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.14 (1H, dd, J = 10.4, 1.6 Hz), 7.17 (1H, d, J = 1.6 Hz), 7.53 (1H, t, J = 1.6 Hz), 7.72 (2H, d, J = 1.6 Hz), 7.73-7.80 (4H, m), 7.81 (1H, d, J = 8.8 Hz), 10.48 (1H, s)
N-(4'-Cyano-[1,1'-biphenyl]-4-yl)-2-hydroxy-4-iodobenzamide (NIC-66)
1H-NMR (400 MHz, DMSO-d6) δ: 7.22 (1H, d, J = 8.4 Hz), 7.31 (1H, d, J = 1.2 Hz), 7.47 (1H, d, J = 8.4 Hz), 7.76-7.89 (8H, m), 10.87 (1H, s) N-(4'-Cyano-[1,1'-biphenyl]-4-yl)-2-hydroxy-4-iodobenzamide (NIC-66)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.22 (1H, d, J = 8.4 Hz), 7.31 (1H, d, J = 1.2 Hz), 7.47 (1H, d, J = 8.4 Hz) , 7.76-7.89 (8H, m), 10.87 (1H, s)
4-Fluoro-2-hydroxy-N-(4'-nitro-[1,1'-biphenyl]-4-yl)benzamide (NIC-67)
1H-NMR (400 MHz, DMSO-d6) δ: 6.80 (1H, dd, J = 6.8, 2.8 Hz), 6.86 (1H, dd, J = 8.8, 2.8 Hz), 7.96-8.03 (4H, m), 7.98 (2H, d, J = 8.8 Hz), 8.03 (1H, dd, J = 8.8, 6.8 Hz), 8.29 (2H, d, J =8.8 Hz), 10.55 (1H, s), 11.19 (1H, s) 4-Fluoro-2-hydroxy-N-(4'-nitro-[1,1'-biphenyl]-4-yl)benzamide (NIC-67)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 6.80 (1H, dd, J = 6.8, 2.8 Hz), 6.86 (1H, dd, J = 8.8, 2.8 Hz), 7.96-8.03 (4H, m ), 7.98 (2H, d, J = 8.8 Hz), 8.03 (1H, dd, J = 8.8, 6.8 Hz), 8.29 (2H, d, J = 8.8 Hz), 10.55 (1H, s), 11.19 (1H , s)
N-(4'-Cyano-[1,1'-biphenyl]-4-yl)-2-hydroxy-4-nitrobenzamide (NIC-68)
1H-NMR (400 MHz, DMSO-d6) δ: 7.80-7.84 (2H, m), 7.78-7.88 (4H, m), 7.91-7.97 (4H, m), 8.01 (1H, d, J= 7.6 Hz), 11.07 (1H, s) N-(4'-Cyano-[1,1'-biphenyl]-4-yl)-2-hydroxy-4-nitrobenzamide (NIC-68)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.80-7.84 (2H, m), 7.78-7.88 (4H, m), 7.91-7.97 (4H, m), 8.01 (1H, d, J= 7.6Hz), 11.07 (1H, s)
2-Hydroxy-4-nitro-N-(4'-nitro-[1,1'-biphenyl]-4-yl)benzamide (NIC-69)
1H-NMR (400 MHz, DMSO-d6) δ: 7.72-7.75 (2H, m), 7.78-7.81 (2H, m), 7.85-7.88 (2H, m), 7.88-7.92 (4H, m), 7.95 (1H, d, J = 7.6 Hz), 10.85 (1H, s), 11.85 (1H, s) 2-Hydroxy-4-nitro-N-(4'-nitro-[1,1'-biphenyl]-4-yl)benzamide (NIC-69)
1 H-NMR (400 MHz, DMSO- d6 ) δ: 7.72-7.75 (2H, m), 7.78-7.81 (2H, m), 7.85-7.88 (2H, m), 7.88-7.92 (4H, m) , 7.95 (1H, d, J = 7.6 Hz), 10.85 (1H, s), 11.85 (1H, s)
Methyl 4'-(2-Hydroxy-4-nitrobenzamido)-[1,1'-biphenyl]-4-carboxylate (NIC-70)
1H-NMR (400 MHz, DMSO-d6) δ: 3.87 (3H, s), 7.73-7.80 (4H, m), 7.82-7.88 (4H, m), 7.97 (1H, d, J= 7.2 Hz), 8.01-8.03 (2H, m), 10.76 (1H, s) Methyl 4'-(2-Hydroxy-4-nitrobenzamido)-[1,1'-biphenyl]-4-carboxylate (NIC-70)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 3.87 (3H, s), 7.73-7.80 (4H, m), 7.82-7.88 (4H, m), 7.97 (1H, d, J = 7.2 Hz ), 8.01-8.03 (2H, m), 10.76 (1H, s)
2-Hydroxy-4-methoxy-N-(4-(pyridin-2-yl)phenyl)benzamide (NIC-71)
1H-NMR (400 MHz, DMSO-d6) δ: 3.68 (3H, s), 7.38-7.42 (2H, m), 7.47-7.51 (3H, m), 7.74-7.78 (3H, m), 8.09 (1H, d, J = 8.0 Hz), 8.17 (1H, d, J= 8.0 Hz), 8.70 (1H, s), 10.64 (1H, s) 2-Hydroxy-4-methoxy-N-(4-(pyridin-2-yl)phenyl)benzamide (NIC-71)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 3.68 (3H, s), 7.38-7.42 (2H, m), 7.47-7.51 (3H, m), 7.74-7.78 (3H, m), 8.09 (1H, d, J = 8.0 Hz), 8.17 (1H, d, J = 8.0 Hz), 8.70 (1H, s), 10.64 (1H, s)
2-Hydroxy-4-iodo-N-(4-(pyridin-2-yl)phenyl)benzamide (NIC-72)
1H-NMR (400 MHz, DMSO-d6) δ: 7.36-7.43 (3H, m), 7.49 (2H, t, J = 7.6 Hz), 7.72 (2H, d, J = 7.6 Hz), 7.76 (1H, d, J = 8.8 Hz), 8.17 (1H, dd, J = 8.8, 2.4 Hz), 8.33 (1H, d, J = 8.8 Hz), 8.68 (1H, d, J = 2.4 Hz), 10.87 (1H, s), 12.06 (1H, s) 2-Hydroxy-4-iodo-N-(4-(pyridin-2-yl)phenyl)benzamide (NIC-72)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.36-7.43 (3H, m), 7.49 (2H, t, J = 7.6 Hz), 7.72 (2H, d, J = 7.6 Hz), 7.76 ( 1H, d, J = 8.8 Hz), 8.17 (1H, dd, J = 8.8, 2.4 Hz), 8.33 (1H, d, J = 8.8 Hz), 8.68 (1H, d, J = 2.4 Hz), 10.87 ( 1H, s), 12.06 (1H, s)
4-Chloro-2-hydroxy-N-(4-(pyridin-2-yl)phenyl)benzamide (NIC-73)
1H-NMR (400 MHz, DMSO-d6) δ: 7.07 (1H, dd, J = 8.8, 2.4 Hz), 7.11 (1H, d, J = 2.4 Hz), 7.40 (1H, dd, J = 8.8, 5.6 Hz), 7.46-7.51 (2H, m), 7.72 (2H, d, J = 7.2 Hz), 8.04 (1H, d, J = 8.8 Hz), 8.17 (1H, dd, J = 8.8, 2.4 Hz), 8.33 (1H, d, J = 8.8 Hz), 8.68 (1H, d, J = 2.4 Hz), 10.89 (1H, s), 12.25 (1H, s) 4-Chloro-2-hydroxy-N-(4-(pyridin-2-yl)phenyl)benzamide (NIC-73)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.07 (1H, dd, J = 8.8, 2.4 Hz), 7.11 (1H, d, J = 2.4 Hz), 7.40 (1H, dd, J = 8.8 , 5.6 Hz), 7.46-7.51 (2H, m), 7.72 (2H, d, J = 7.2 Hz), 8.04 (1H, d, J = 8.8 Hz), 8.17 (1H, dd, J = 8.8, 2.4 Hz ), 8.33 (1H, d, J = 8.8 Hz), 8.68 (1H, d, J = 2.4 Hz), 10.89 (1H, s), 12.25 (1H, s)
4,5-Dichloro-2-hydroxy-N-(4-(pyridin-2-yl)phenyl)benzamide (NIC-74)
1H-NMR (400 MHz, DMSO-d6) δ: 7.23 (1H, s), 7.38-7.42 (1H, m), 7.50 (2H, dd, J = 9.6, 2.0 Hz), 7.73 (2H, dd, J = 9.6, 2.0 Hz), 8.17 (1H, s), 8.18-8.20 (1H, m), 8.31 (1H, d, J = 8.8 Hz), 8.68 (1H, d, J= 2.0 Hz), 10.89 (1H, s), 12.41 (1H, s) 4,5-Dichloro-2-hydroxy-N-(4-(pyridin-2-yl)phenyl)benzamide (NIC-74)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.23 (1H, s), 7.38-7.42 (1H, m), 7.50 (2H, dd, J = 9.6, 2.0 Hz), 7.73 (2H, dd , J = 9.6, 2.0 Hz), 8.17 (1H, s), 8.18-8.20 (1H, m), 8.31 (1H, d, J = 8.8 Hz), 8.68 (1H, d, J = 2.0 Hz), 10.89 (1H, s), 12.41 (1H, s)
N-(3',5'-Dichloro-[1,1'-biphenyl]-4-yl)-2-hydroxy-4-iodobenzamide (NIC-75)
1H-NMR (400 MHz, DMSO-d6) δ: 7.22 (1H, d, J = 8.4 Hz), 7.30 (1H, s), 7.55 (1H, t, J = 1.6 Hz), 7.63 (1H, d, J = 8.4 Hz), 7.74 (2H, d, J = 1.6 Hz), 7.74-7.83 (4H, m), 11.05 (1H, s), 11.88 (1H, s) N-(3',5'-Dichloro-[1,1'-biphenyl]-4-yl)-2-hydroxy-4-iodobenzamide (NIC-75)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.22 (1H, d, J = 8.4 Hz), 7.30 (1H, s), 7.55 (1H, t, J = 1.6 Hz), 7.63 (1H, d, J = 8.4 Hz), 7.74 (2H, d, J = 1.6 Hz), 7.74-7.83 (4H, m), 11.05 (1H, s), 11.88 (1H, s)
4-Fluoro-2-hydroxy-N-(4'-nitro-[1,1'-biphenyl]-4-yl)benzamide (NIC-77)
1H-NMR (400 MHz, DMSO-d6) δ: 7.02 (1H, dd, J = 9.2, 4.4 Hz), 7.32 (1H, dd, J = 9.2, 2.8 Hz), 7.74 (1H, dd, J = 9.2, 2.8 Hz), 7.83-7.90 (4H, m), 7.98 (2H, d, J = 9.2 Hz), 8.29 (2H, d, J = 9.2 Hz), 10.55 (1H, s), 11.53 (1H, s) 4-Fluoro-2-hydroxy-N-(4'-nitro-[1,1'-biphenyl]-4-yl)benzamide (NIC-77)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.02 (1H, dd, J = 9.2, 4.4 Hz), 7.32 (1H, dd, J = 9.2, 2.8 Hz), 7.74 (1H, dd, J = 9.2, 2.8 Hz), 7.83-7.90 (4H, m), 7.98 (2H, d, J = 9.2 Hz), 8.29 (2H, d, J = 9.2 Hz), 10.55 (1H, s), 11.53 (1H , s)
4-Bromo-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide (NIC-78)
1H-NMR (400 MHz, DMSO-d6) δ: 7.22-7.24 (2H, m), 7.95 (1H, d, J = 8.8 Hz), 8.29 (1H, dd, J = 9.6, 2.4 Hz), 8.44 (1H, d, J = 2.4 Hz), 8.82 (1H, d, J = 9.6 Hz), 11.32 (1H, s) 4-Bromo-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide (NIC-78)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.22-7.24 (2H, m), 7.95 (1H, d, J = 8.8 Hz), 8.29 (1H, dd, J = 9.6, 2.4 Hz), 8.44 (1H, d, J = 2.4Hz), 8.82 (1H, d, J = 9.6Hz), 11.32 (1H, s)
4-Fluoro-2-hydroxy-N-(4-nitrophenyl)benzamide (NIC-79)
1H-NMR (400 MHz, DMSO-d6) δ: 6.81 (1H, dd, J = 9.2, 1.6 Hz), 6.85 (1H, dd, J = 9.2, 2.8 Hz), 7.94 (1H, dd, J = 9.2, 2.8 Hz), 7.98 (2H, d, J = 9.2 Hz), 8.26 (2H, d, J = 9.2 Hz), 10.75 (1H, s), 11.85 (1H, s) 4-Fluoro-2-hydroxy-N-(4-nitrophenyl)benzamide (NIC-79)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 6.81 (1H, dd, J = 9.2, 1.6 Hz), 6.85 (1H, dd, J = 9.2, 2.8 Hz), 7.94 (1H, dd, J = 9.2, 2.8 Hz), 7.98 (2H, d, J = 9.2 Hz), 8.26 (2H, d, J = 9.2 Hz), 10.75 (1H, s), 11.85 (1H, s)
4-Bromo-5-chloro-2-hydroxy-N-(4-nitrophenyl)benzamide (NIC-80)
1H-NMR (500 MHz, DMSO-d6) δ: 7.37 (1H, s), 7.95 (1H, s), 7.96 (2H, d, J = 9.0 Hz), 8.26 (2H, d, J = 9.0 Hz), 11.82 (1H, s), 11.71 (1H, s) 4-Bromo-5-chloro-2-hydroxy-N-(4-nitrophenyl)benzamide (NIC-80)
1 H-NMR (500 MHz, DMSO-d 6 ) δ: 7.37 (1H, s), 7.95 (1H, s), 7.96 (2H, d, J = 9.0 Hz), 8.26 (2H, d, J = 9.0 Hz), 11.82 (1H, s), 11.71 (1H, s)
4-Bromo-5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide (NIC-81)
1H-NMR (400 MHz, DMSO-d6) δ: 7.39 (1H, s), 8.01 (1H, s), 8.31 (1H, dd, J = 9.6, 2.8 Hz), 8.46 (1H, d, J = 2.8 Hz), 8.80 (1H, d, J = 9.2 Hz), 11.22 (1H, s) 4-Bromo-5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide (NIC-81)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.39 (1H, s), 8.01 (1H, s), 8.31 (1H, dd, J = 9.6, 2.8 Hz), 8.46 (1H, d, J = 2.8 Hz), 8.80 (1H, d, J = 9.2 Hz), 11.22 (1H, s)
4-Bromo-2-hydroxy-N-(4-nitrophenyl)benzamide (NIC-82)
1H-NMR (500 MHz, DMSO-d6) δ: 7.18 (1H, dd, J = 8.5, 2.0 Hz), 7.21 (1H, d, J = 2.0 Hz), 7.76 (1H, d, J = 8.5 Hz), 7.99 (2H, d, J = 9.0 Hz), 8.27 (2H, d, J = 9.0 Hz), 10.78 (1H, s), 11.66 (1H, s) 4-Bromo-2-hydroxy-N-(4-nitrophenyl)benzamide (NIC-82)
1 H-NMR (500 MHz, DMSO-d 6 ) δ: 7.18 (1H, dd, J = 8.5, 2.0 Hz), 7.21 (1H, d, J = 2.0 Hz), 7.76 (1H, d, J = 8.5 Hz), 7.99 (2H, d, J = 9.0 Hz), 8.27 (2H, d, J = 9.0 Hz), 10.78 (1H, s), 11.66 (1H, s)
N-(2-Chloro-4-nitrophenyl)-2-hydroxy-4-iodobenzamide (NIC-83)
1H-NMR (400 MHz, DMSO-d6) δ: 7.41 (1H, dd, J = 8.8, 1.6 Hz), 7.44 (1H, d, J = 1.6 Hz), 7.77 (1H, d, J = 8.8 Hz), 8.30 (1H, d, J = 8.8, 2.4 Hz), 8.45 (1H, d, J = 2.4 Hz), 8.83 (1H, d, J = 8.8 Hz), 11.27 (1H, s) N-(2-Chloro-4-nitrophenyl)-2-hydroxy-4-iodobenzamide (NIC-83)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.41 (1H, dd, J = 8.8, 1.6 Hz), 7.44 (1H, d, J = 1.6 Hz), 7.77 (1H, d, J = 8.8 Hz), 8.30 (1H, d, J = 8.8, 2.4 Hz), 8.45 (1H, d, J = 2.4 Hz), 8.83 (1H, d, J = 8.8 Hz), 11.27 (1H, s)
5-Chloro-N-(2,4-dichlorophenyl)-4-fluoro-2-hydroxybenzamide (NIC-84)
1H-NMR (500 MHz, DMSO-d6) δ: 7.01 (1H, d, J = 10.5 Hz), 7.48 (1H, dd, J = 9.0, 2.5 Hz), 7.74 (1H, d, J = 2.5 Hz), 8.11 (1H, d, J = 9.0 Hz), 8.39 (1H, d, J = 9. 0 Hz), 10.79 (1H, s) 5-Chloro-N-(2,4-dichlorophenyl)-4-fluoro-2-hydroxybenzamide (NIC-84)
1 H-NMR (500 MHz, DMSO-d 6 ) δ: 7.01 (1H, d, J = 10.5 Hz), 7.48 (1H, dd, J = 9.0, 2.5 Hz), 7.74 (1H, d, J = 2.5 Hz), 8.11 (1H, d, J = 9.0 Hz), 8.39 (1H, d, J = 9.0 Hz), 10.79 (1H, s)
5-Chloro-4-fluoro-N-(2-fluoro-4-nitrophenyl)-2-hydroxybenzamide (NIC-85)
1H-NMR (500 MHz, DMSO-d6) δ: 7.01 (1H, d, J = 10.5 Hz), 8.09 (1H, d, J = 9.0 Hz), 8.19 (1H, dd, J = 9.0, 2.5 Hz), 8.27 (1H, dd, J = 10.5, 2.5 Hz), 8.64 (1H, t, J = 9.0 Hz), 11.05 (1H, s) 5-Chloro-4-fluoro-N-(2-fluoro-4-nitrophenyl)-2-hydroxybenzamide (NIC-85)
1 H-NMR (500 MHz, DMSO-d 6 ) δ: 7.01 (1H, d, J = 10.5 Hz), 8.09 (1H, d, J = 9.0 Hz), 8.19 (1H, dd, J = 9.0, 2.5 Hz), 8.27 (1H, dd, J = 10.5, 2.5 Hz), 8.64 (1H, t, J = 9.0 Hz), 11.05 (1H, s)
5-Chloro-N-(4-chloro-2-fluorophenyl)-4-fluoro-2-hydroxybenzamide (NIC-86)
1H-NMR (500 MHz, DMSO-d6) δ: 7.01 (1H, d, J = 10.5 Hz), 7.34 (1H, d, J = 9.5 Hz), 7.58 (1H, dd, J = 9.5, 2.0 Hz), 8.11 (1H, d, J = 9.5 Hz), 8.18 (1H, d, J = 9. 5 Hz), 10.60 (1H, s) 5-Chloro-N-(4-chloro-2-fluorophenyl)-4-fluoro-2-hydroxybenzamide (NIC-86)
1 H-NMR (500 MHz, DMSO-d 6 ) δ: 7.01 (1H, d, J = 10.5 Hz), 7.34 (1H, d, J = 9.5 Hz), 7.58 (1H, dd, J = 9.5, 2.0 Hz), 8.11 (1H, d, J = 9.5 Hz), 8.18 (1H, d, J = 9.5 Hz), 10.60 (1H, s)
5-Chloro-N-(2-chloro-4-fluorophenyl)-4-fluoro-2-hydroxybenzamide (NIC-87)
1H-NMR (400 MHz, DMSO-d6) δ 7.01 (1H, d, J = 10.4 Hz), 7.29 (1H, td, J = 8.8, 2.8 Hz), 7.59 (1H, dd, J = 8.8, 2.8 Hz), 8.13 (1H, d, J = 8.8 Hz), 8.25 (1H, dd, J = 8.8, 5.2 Hz), 10.67 (1H, s) 5-Chloro-N-(2-chloro-4-fluorophenyl)-4-fluoro-2-hydroxybenzamide (NIC-87)
1 H-NMR (400 MHz, DMSO-d 6 ) δ 7.01 (1H, d, J = 10.4 Hz), 7.29 (1H, td, J = 8.8, 2.8 Hz), 7.59 (1H, dd, J = 8.8, 2.8Hz), 8.13 (1H, d, J = 8.8Hz), 8.25 (1H, dd, J = 8.8, 5.2Hz), 10.67 (1H, s)
5-Chloro-N-(2,4-difluorophenyl)-4-fluoro-2-hydroxy benzamide (NIC-88)
1H-NMR (400 MHz, DMSO-d6) δ: 7.01 (1H, d, J = 11.2 Hz), 7.13 (1H, tdd, J = 8.8, 2.8, 1.6 Hz), 7.40 (1H, ddd, J = 11.2, 8.8, 6.8 Hz), 8.03 (1H, td, J = 8.8, 6.8 Hz), 8.12 (1H, d, J = 6.8 Hz), 10.48 (1H, s) 5-Chloro-N-(2,4-difluorophenyl)-4-fluoro-2-hydroxy benzamide (NIC-88)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.01 (1H, d, J = 11.2 Hz), 7.13 (1H, tdd, J = 8.8, 2.8, 1.6 Hz), 7.40 (1H, ddd, J = 11.2, 8.8, 6.8 Hz), 8.03 (1H, td, J = 8.8, 6.8 Hz), 8.12 (1H, d, J = 6.8 Hz), 10.48 (1H, s)
5-Chloro-N-(3-chloro-4-nitrophenyl)-4-fluoro-2-hydroxybenzamide (NIC-89)
1H-NMR (400 MHz, DMSO-d6) δ: 7.01 (1H, d, J = 10.8 Hz), 7.86 (1H, dd, J = 8.8, 2.4 Hz), 8.00 (1H, d, J = 8.8 Hz), 8.14-8.19 (2H, m), 10.80 (1H, s) 5-Chloro-N-(3-chloro-4-nitrophenyl)-4-fluoro-2-hydroxybenzamide (NIC-89)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.01 (1H, d, J = 10.8 Hz), 7.86 (1H, dd, J = 8.8, 2.4 Hz), 8.00 (1H, d, J = 8.8 Hz), 8.14-8.19 (2H, m), 10.80 (1H, s)
5-Chloro-N-(2,6-dichloro-4-nitrophenyl)-4-fluoro-2-hydroxybenzamide (NIC-90)
1H-NMR (400 MHz, DMSO-d6) δ: 6.94 (1H, d, J = 11.2 Hz), 8.06 (1H, d, J = 8.4 Hz), 8.42 (2H, s) 5-Chloro-N-(2,6-dichloro-4-nitrophenyl)-4-fluoro-2-hydroxybenzamide (NIC-90)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 6.94 (1H, d, J = 11.2 Hz), 8.06 (1H, d, J = 8.4 Hz), 8.42 (2H, s)
4,5-Dichloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide (NIC-91)
1H-NMR (400 MHz, DMSO-d6) δ: 7.25 (1H, s), 8.11 (1H, s), 8.29 (1H, dd, J = 7.2, 2.0 Hz), 8.43 (1H, d, J = 2.0 Hz), 8.78 (1H, d, J = 7.2 Hz), 11.21 (1H, s) 4,5-Dichloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide (NIC-91)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.25 (1H, s), 8.11 (1H, s), 8.29 (1H, dd, J = 7.2, 2.0 Hz), 8.43 (1H, d, J = 2.0 Hz), 8.78 (1H, d, J = 7.2 Hz), 11.21 (1H, s)
5-Chloro-N-(2,6-dichlorophenyl)-4-fluoro-2-hydroxybenzamide (NIC-92)
1H-NMR (400 MHz, DMSO-d6) δ: 7.06 (1H, d, J = 10.8 Hz), 7.42 (1H, t, J = 8.4 Hz), 7.61 (2H, d, J = 8.4 Hz), 8.21 (1H, d, J = 8.4 Hz), 10.49 (1H, s), 12.44 (1H, s) 5-Chloro-N-(2,6-dichlorophenyl)-4-fluoro-2-hydroxybenzamide (NIC-92)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.06 (1H, d, J = 10.8 Hz), 7.42 (1H, t, J = 8.4 Hz), 7.61 (2H, d, J = 8.4 Hz) , 8.21 (1H, d, J = 8.4 Hz), 10.49 (1H, s), 12.44 (1H, s)
5-Chloro-N-(2-chloro-4-cyanophenyl)-4-fluoro-2-hydroxybenzamide (NIC-93)
1H-NMR (400 MHz, DMSO-d6) δ: 7.00 (1H, d, J = 10.4 Hz), 7.86 (1H, dd, J = 8.8, 2.0 Hz), 8.08 (1H, d, J = 8.8 Hz), 8.17 (1H, d, J = 2.0 Hz), 8.66 (1H, d, J = 8. 8 Hz), 11.09 (1H, s) 5-Chloro-N-(2-chloro-4-cyanophenyl)-4-fluoro-2-hydroxybenzamide (NIC-93)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.00 (1H, d, J = 10.4 Hz), 7.86 (1H, dd, J = 8.8, 2.0 Hz), 8.08 (1H, d, J = 8.8 Hz), 8.17 (1H, d, J = 2.0 Hz), 8.66 (1H, d, J = 8.8 Hz), 11.09 (1H, s)
5-Chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)-4-fluoro-2-hydroxybenzamide (NIC-94)
1H-NMR (400 MHz, DMSO-d6) δ: 7.01 (1H, d, J = 10.8 Hz), 7.78 (1H, dd, J = 8.8, 2.0 Hz), 7.99 (1H, d, J = 2.0 Hz), 8.11 (1H, d, J = 8.8 Hz), 8.68 (1H, d, J = 8. 8 Hz), 11.04 (1H, s) 5-Chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)-4-fluoro-2-hydroxybenzamide (NIC-94)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.01 (1H, d, J = 10.8 Hz), 7.78 (1H, dd, J = 8.8, 2.0 Hz), 7.99 (1H, d, J = 2.0 Hz), 8.11 (1H, d, J = 8.8 Hz), 8.68 (1H, d, J = 8.8 Hz), 11.04 (1H, s)
N-(2,4-Bis(trifluoromethyl)phenyl)-5-chloro-4-fluoro-2-hydroxybenzamide (NIC-95) 1H-NMR (400 MHz, DMSO-d6) δ: 6.77 (1H, d, J = 11.6 Hz), 7.98-8.00 (2H, m), 8.06 (1H, d, J = 9.2 Hz), 8.66 (1H, d, J = 7.2 Hz) N-(2,4-Bis(trifluoromethyl)phenyl)-5-chloro-4-fluoro-2-hydroxybenzamide (NIC-95) 1 H-NMR (400 MHz, DMSO- d6 ) δ: 6.77 (1H, d , J = 11.6 Hz), 7.98-8.00 (2H, m), 8.06 (1H, d, J = 9.2 Hz), 8.66 (1H, d, J = 7.2 Hz)
5-Chloro-4-fluoro-2-hydroxy-N-(3-(trifluoromethyl)phenyl)benzamide (NIC-96)
1H-NMR (500 MHz, DMSO-d6) δ: 7.01 (1H, d, J = 10.5 Hz), 7.73 (2H, d, J = 8.5 Hz), 7.92 (2H, d, J = 8.5 Hz), 8.07 (1H, d, J = 8.5 Hz), 10.59 (1H, s), 12.07 (1H, s) 5-Chloro-4-fluoro-2-hydroxy-N-(3-(trifluoromethyl)phenyl)benzamide (NIC-96)
1 H-NMR (500 MHz, DMSO-d 6 ) δ: 7.01 (1H, d, J = 10.5 Hz), 7.73 (2H, d, J = 8.5 Hz), 7.92 (2H, d, J = 8.5 Hz) , 8.07 (1H, d, J = 8.5 Hz), 10.59 (1H, s), 12.07 (1H, s)
5-Chloro-4-fluoro-2-hydroxy-N-(3-(trifluoromethyl)phenyl)benzamide (NIC-97)
1H-NMR (400 MHz, DMSO-d6) δ: 7.02 (1H, d, J = 10.4 Hz), 7.49 (1H, d, J = 7.6 Hz), 7.61 (1H, t, J = 7.6 Hz), 7.92 (1H, d, J = 7.6 Hz), 8.08 (1H, d, J = 7.6 Hz), 8.17 (1H, s), 10.58 (1H, s), 12.06 (1H, s) 5-Chloro-4-fluoro-2-hydroxy-N-(3-(trifluoromethyl)phenyl)benzamide (NIC-97)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.02 (1H, d, J = 10.4 Hz), 7.49 (1H, d, J = 7.6 Hz), 7.61 (1H, t, J = 7.6 Hz) , 7.92 (1H, d, J = 7.6 Hz), 8.08 (1H, d, J = 7.6 Hz), 8.17 (1H, s), 10.58 (1H, s), 12.06 (1H, s)
5-Chloro-4-fluoro-2-hydroxy-N-(2-(trifluoromethyl)phenyl)benzamide (NIC-98)
1H-NMR (400 MHz, DMSO-d6) δ: 7.01 (1H, d, J = 10.4 Hz), 7.42 (1H, t, J = 8.0 Hz), 7.72 (1H, t, J = 8.0 Hz), 7.77 (1H, d, J = 8.0 Hz), 8.12 (1H, d, J = 8.0 Hz), 8.13 (1H, d, J = 9.2 Hz), 10.64 (1H, s) 5-Chloro-4-fluoro-2-hydroxy-N-(2-(trifluoromethyl)phenyl)benzamide (NIC-98)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.01 (1H, d, J = 10.4 Hz), 7.42 (1H, t, J = 8.0 Hz), 7.72 (1H, t, J = 8.0 Hz) , 7.77 (1H, d, J = 8.0 Hz), 8.12 (1H, d, J = 8.0 Hz), 8.13 (1H, d, J = 9.2 Hz), 10.64 (1H, s)
5-Chloro-N-(2,6-difluorophenyl)-4-fluoro-2-hydroxybenzamide (NIC-99)
1H-NMR (400 MHz, DMSO-d6) δ: 7.05 (1H, d, J = 10.8 Hz), 7.23 (2H, t, J = 8.4 Hz), 7.39-7.48 (1H, m), 8.16 (1H, d, J = 8.4 Hz), 10.25 (1H, s), 12.37 (1H, s) 5-Chloro-N-(2,6-difluorophenyl)-4-fluoro-2-hydroxybenzamide (NIC-99)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.05 (1H, d, J = 10.8 Hz), 7.23 (2H, t, J = 8.4 Hz), 7.39-7.48 (1H, m), 8.16 ( 1H, d, J = 8.4 Hz), 10.25 (1H, s), 12.37 (1H, s)
5-Chloro-4-fluoro-N-(2-fluoro-4-(trifluoromethyl)phenyl)-2-hydroxybenzamide (NIC-100)
1H-NMR (400 MHz, DMSO-d6) δ: 6.85 (1H, d, J = 10.8 Hz), 7.60 (1H, d, J = 8.0 Hz), 7.77 (1H, dd, J = 9.2, 1.6 Hz), 8.01 (1H, d, J = 9.2 Hz), 8.58 (1H, t, J = 8. 0 Hz), 11.84 (1H, s) 5-Chloro-4-fluoro-N-(2-fluoro-4-(trifluoromethyl)phenyl)-2-hydroxybenzamide (NIC-100)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 6.85 (1H, d, J = 10.8 Hz), 7.60 (1H, d, J = 8.0 Hz), 7.77 (1H, dd, J = 9.2, 1.6 Hz), 8.01 (1H, d, J = 9.2 Hz), 8.58 (1H, t, J = 8.0 Hz), 11.84 (1H, s)
N-(2-Bromo-4-(trifluoromethyl)phenyl)-5-chloro-4-fluoro-2-hydroxybenzamide (NIC-101)
1H-NMR (400 MHz, DMSO-d6) δ: 7.01 (1H, d, J = 10.8 Hz), 7.81 (1H, dd, J = 8.8, 2.0 Hz), 8.10 (1H, d, J = 2.0 Hz), 8.11 (1H, d, J = 8.8 Hz), 8.63 (1H, d, J = 8. 8 Hz), 10.92 (1H, s) N-(2-Bromo-4-(trifluoromethyl)phenyl)-5-chloro-4-fluoro-2-hydroxybenzamide (NIC-101)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 7.01 (1H, d, J = 10.8 Hz), 7.81 (1H, dd, J = 8.8, 2.0 Hz), 8.10 (1H, d, J = 2.0 Hz), 8.11 (1H, d, J = 8.8 Hz), 8.63 (1H, d, J = 8.8 Hz), 10.92 (1H, s)
5-Chloro-4-fluoro-2-hydroxy-N-(2-iodo-4-(trifluoromethyl)phenyl)benzamide (NIC-102)
1H-NMR (500 MHz, DMSO-d6) δ: 7.04 (1H, d, J = 10.5 Hz), 7.81 (1H, dd, J = 9.0, 2.0 Hz), 8.13 (1H, d, J = 9.0 Hz), 8.24 (1H, d, J = 2.0 Hz), 8.37 (1H, d, J = 9. 0 Hz), 10.63 (1H, s) 5-Chloro-4-fluoro-2-hydroxy-N-(2-iodo-4-(trifluoromethyl)phenyl)benzamide (NIC-102)
1 H-NMR (500 MHz, DMSO-d 6 ) δ: 7.04 (1H, d, J = 10.5 Hz), 7.81 (1H, dd, J = 9.0, 2.0 Hz), 8.13 (1H, d, J = 9.0 Hz), 8.24 (1H, d, J = 2.0 Hz), 8.37 (1H, d, J = 9.0 Hz), 10.63 (1H, s)
5-Chloro-4-fluoro-2-hydroxy-N-(2,4,6-trifluorophenyl)benzamide) (NIC-103)
1H-NMR (400 MHz, DMSO-d6) δ: 7.05 (1H, d, J = 10.8 Hz), 7.30-7.40 (2H, m), 8.13 (1H, d, J = 8.8 Hz), 10.16 (1H, s) 5-Chloro-4-fluoro-2-hydroxy-N-(2,4,6-trifluorophenyl)benzamide) (NIC-103)
1H-NMR (400 MHz, DMSO-d6) δ: 7.05 (1H, d, J = 10.8 Hz), 7.30-7.40 (2H, m), 8.13 (1H, d, J = 8.8 Hz), 10.16 (1H, s)
5-Chloro-4-fluoro-2-hydroxy-N-(3,4,5-trifluorophenyl)benzamide) (NIC-104)
1H-NMR (400 MHz, DMSO-d6) δ: 7.01 (1H, d, J = 10.8 Hz), 7.66 (2H, dd, J = 10.0, 6.4 Hz), 7.98 (1H, d, J = 8.8 Hz), 10.52 (1H, s). 5-Chloro-4-fluoro-2-hydroxy-N-(3,4,5-trifluorophenyl)benzamide) (NIC-104)
1H-NMR (400 MHz, DMSO-d6) δ: 7.01 (1H, d, J = 10.8 Hz), 7.66 (2H, dd, J = 10.0, 6.4 Hz), 7.98 (1H, d, J = 8.8 Hz) , 10.52 (1H, s).
5-Chloro-4-fluoro-2-hydroxy-N-(2,4,6-trichlorophenyl)benzamide) (NIC-105)
1H-NMR (500 MHz, DMSO-d6) δ: 7.06 (1H, d, J = 10.5 Hz), 7.84 (2H, d), 8.17 (1H, d, J = 9.0 Hz), 10.46 (1H, s) 5-Chloro-4-fluoro-2-hydroxy-N-(2,4,6-trichlorophenyl)benzamide) (NIC-105)
1H-NMR (500 MHz, DMSO-d6) δ: 7.06 (1H, d, J = 10.5 Hz), 7.84 (2H, d), 8.17 (1H, d, J = 9.0 Hz), 10.46 (1H, s)
5-Chloro-N-(2-chloro-5-nitrophenyl)-4-fluoro-2-hydroxybenzamide (NIC-106)
1H-NMR (400 MHz, DMSO-d6) δ: 7.01 (1H, d, J = 10.8 Hz), 7.87 (1H, d, J = 9.2 Hz), 8.01 (1H, dd, J = 8.8, 2.8 Hz), 8.11 (1H, d, J = 8.8 Hz), 10.52 (1H, s) 5-Chloro-N-(2-chloro-5-nitrophenyl)-4-fluoro-2-hydroxybenzamide (NIC-106)
1H-NMR (400 MHz, DMSO-d6) δ: 7.01 (1H, d, J = 10.8 Hz), 7.87 (1H, d, J = 9.2 Hz), 8.01 (1H, dd, J = 8.8, 2.8 Hz) , 8.11 (1H, d, J = 8.8 Hz), 10.52 (1H, s)
5-Chloro-N-(2-chloro-4,6-difluorophenyl)-4-fluoro-2-hydroxybenzamide) (NIC-107) 1H-NMR (400 MHz, DMSO-d6) δ: 7.05 (1H, d, J = 10.4 Hz), 7.47-7.57 (2H, m), 8.15 (1H, d, J = 8.0 Hz), 10.24 (1H, s) 5-Chloro-N-(2-chloro-4,6-difluorophenyl)-4-fluoro-2-hydroxybenzamide) (NIC-107) 1H-NMR (400 MHz, DMSO-d6) δ: 7.05 (1H, d, J = 10.4 Hz), 7.47-7.57 (2H, m), 8.15 (1H, d, J = 8.0 Hz), 10.24 (1H, s)
5-Chloro-N-(3-chloro-2-fluorophenyl)-4-fluoro-2-hydroxybenzamide) (NIC-108)
1H-NMR (400 MHz, DMSO-d6) δ: 7.01 (1H, d, J = 10.4 Hz), 7.25 (1H, dt, J = 7.6, 2.8 Hz), 7.39 (1H, dt, J = 6.8, 1.2 Hz), 8.06 (1H, d, J = 6.8 Hz), 8.11 (1H, d, J = 9.2 Hz), 10.62 (1H, s) 5-Chloro-N-(3-chloro-2-fluorophenyl)-4-fluoro-2-hydroxybenzamide) (NIC-108)
1H-NMR (400 MHz, DMSO-d6) δ: 7.01 (1H, d, J = 10.4 Hz), 7.25 (1H, dt, J = 7.6, 2.8 Hz), 7.39 (1H, dt, J = 6.8, 1.2 Hz), 8.06 (1H, d, J = 6.8 Hz), 8.11 (1H, d, J = 9.2 Hz), 10.62 (1H, s)
5-Chloro-N-(3,4-difluorophenyl)-4-fluoro-2-hydroxybenzamide) (NIC-109)
1H-NMR (400 MHz, DMSO-d6) δ: 7.01 (1H, d, J = 10.8 Hz), 7.39-7.50 (2H, m), 7.80-7.90 (1H, m), 8.06 (1H, d, J = 6.8 Hz), 8.05 (1H, d, J = 8.8 Hz), 10.47 (1H, s) 5-Chloro-N-(3,4-difluorophenyl)-4-fluoro-2-hydroxybenzamide) (NIC-109)
1H-NMR (400 MHz, DMSO-d6) δ: 7.01 (1H, d, J = 10.8 Hz), 7.39-7.50 (2H, m), 7.80-7.90 (1H, m), 8.06 (1H, d, J = 6.8 Hz), 8.05 (1H, d, J = 8.8 Hz), 10.47 (1H, s)
5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxy-4-iodobenzamide (NIC-110)
1H-NMR (400 MHz, DMSO-d6) δ: 7.60 (1H, s), 8.01 (1H, s), 8.29 (1H, dd, J = 9.6, 2.8 Hz), 8.43 (1H, d, J = 2.8 Hz), 8.79 (1H, d, J = 9.6 Hz), 11.19 (1H, s) 5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxy-4-iodobenzamide (NIC-110)
1H-NMR (400 MHz, DMSO-d6) δ: 7.60 (1H, s), 8.01 (1H, s), 8.29 (1H, dd, J = 9.6, 2.8 Hz), 8.43 (1H, d, J = 2.8 Hz), 8.79 (1H, d, J = 9.6 Hz), 11.19 (1H, s)
N-(2-Chloro-4-nitrophenyl)-4-cyano-2-hydroxybenzamide (NIC-111)
1H-NMR (400 MHz, DMSO-d6) δ: 7.38 (1H, d, J = 1.6 Hz), 7.43 (1H, dd, J = 8.4, 1.6 Hz), 8.16 (1H, d, J = 8.4 Hz), 8.30 (1H, dd, J = 9.2, 2.8 Hz), 8.44 (1H, d, J = 2.8 Hz),8.18 (1H, d, J = 9.2 Hz) 11.49 (1H, s) N-(2-Chloro-4-nitrophenyl)-4-cyano-2-hydroxybenzamide (NIC-111)
1H-NMR (400 MHz, DMSO-d6) δ: 7.38 (1H, d, J = 1.6 Hz), 7.43 (1H, dd, J = 8.4, 1.6 Hz), 8.16 (1H, d, J = 8.4 Hz) , 8.30 (1H, dd, J = 9.2, 2.8 Hz), 8.44 (1H, d, J = 2.8 Hz), 8.18 (1H, d, J = 9.2 Hz) 11.49 (1H, s)
N-(2-Chloro-4-nitrophenyl)-2-hydroxy-4-(methylsulfonyl)benzamide (NIC-112)
1H-NMR (500 MHz, DMSO-d6) δ: 3.25 (3H, s), 7.53-7.58 (2H, m), 8.25 (1H, d, J = 9.0 Hz), 8.31 (1H, dd, J = 9.0, 2.5 Hz), 8.45 (1H, d, J = 2.5 Hz), 8.82 (1H, d, J = 9.0 Hz), 11.34 (1H, s) N-(2-Chloro-4-nitrophenyl)-2-hydroxy-4-(methylsulfonyl)benzamide (NIC-112)
1H-NMR (500 MHz, DMSO-d6) δ: 3.25 (3H, s), 7.53-7.58 (2H, m), 8.25 (1H, d, J = 9.0 Hz), 8.31 (1H, dd, J = 9.0 , 2.5 Hz), 8.45 (1H, d, J = 2.5 Hz), 8.82 (1H, d, J = 9.0 Hz), 11.34 (1H, s)
N-(2-bromo-4-(trifluoromethyl)phenyl)-4-fluoro-2-hydroxybenzamide (NIC-119)
1H-NMR (500 MHz, DMSO-d6) δ: 10.94 (1H, s), 8.65 (1H, d, J = 9.0 Hz), 8.13-8.08 (2H, m), 7.80 (1H, dd, J= 9.0, 2.0 Hz), 6,87 (1H, dt, J= 9.0, 2.0 Hz), 6,82 (1H, dd, J= 9.0, 2.0 Hz). N-(2-bromo-4-(trifluoromethyl)phenyl)-4-fluoro-2-hydroxybenzamide (NIC-119)
1 H-NMR (500 MHz, DMSO-d 6 ) δ: 10.94 (1H, s), 8.65 (1H, d, J = 9.0 Hz), 8.13-8.08 (2H, m), 7.80 (1H, dd, J = 9.0, 2.0 Hz), 6,87 (1H, dt, J= 9.0, 2.0 Hz), 6,82 (1H, dd, J= 9.0, 2.0 Hz).
N-(2-bromo-4-(trifluoromethyl)phenyl)-4-chloro-2-hydroxybenzamide (NIC-120)
1H-NMR (500 MHz, DMSO-d6) δ: 10.95 (1H, s), 8.66 (1H, d, J = 8.5 Hz), 8.09 (1H, d, J = 1.5 Hz), 8.03 (1H, d, J = 8.5 Hz), 7.80 (1H, dd, J = 8.5, 1.5 Hz), 7.12-7.08 (2H, m). N-(2-bromo-4-(trifluoromethyl)phenyl)-4-chloro-2-hydroxybenzamide (NIC-120)
1 H-NMR (500 MHz, DMSO-d 6 ) δ: 10.95 (1H, s), 8.66 (1H, d, J = 8.5 Hz), 8.09 (1H, d, J = 1.5 Hz), 8.03 (1H, d, J = 8.5 Hz), 7.80 (1H, dd, J = 8.5, 1.5 Hz), 7.12-7.08 (2H, m).
5-chloro-4-fluoro-2-hydroxy-N-(4-nitrophenyl)benzamide (NIC-121)
1H-NMR (400 MHz, DMSO-d6) δ: 10.84 (1H, s), 8.26 (2H, d, J = 9.2 Hz), 8.01 (1H, d, J = 9.2 Hz), 7.96 (1H, d, J =10.4 Hz), 7.00 (1H, d, J = 11.2 Hz). 5-chloro-4-fluoro-2-hydroxy-N-(4-nitrophenyl)benzamide (NIC-121)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.84 (1H, s), 8.26 (2H, d, J = 9.2 Hz), 8.01 (1H, d, J = 9.2 Hz), 7.96 (1H, d, J =10.4 Hz), 7.00 (1H, d, J = 11.2 Hz).
4-fluoro-2-hydroxy-N-(4-(trifluoromethyl)phenyl)benzamide (NIC-122)
1H-NMR (400 MHz, DMSO-d6) δ: 10.57 (1H, s), 7.97 (1H, dd, J = 8.8, 6.8 Hz), 7.92 (2H, d, J = 8.8 Hz), 6.84 (1H, dd, J = 8.4, 2.4 Hz), 6.80 (1H, dd, J = 8.4, 2.4 Hz). 4-fluoro-2-hydroxy-N-(4-(trifluoromethyl)phenyl)benzamide (NIC-122)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.57 (1H, s), 7.97 (1H, dd, J = 8.8, 6.8 Hz), 7.92 (2H, d, J = 8.8 Hz), 6.84 ( 1H, dd, J = 8.4, 2.4 Hz), 6.80 (1H, dd, J = 8.4, 2.4 Hz).
4-chloro-2-hydroxy-N-(4-(trifluoromethyl)phenyl)benzamide (NIC-123)
1H-NMR (400 MHz, DMSO-d6) δ: 11.84 (1H, s), 10.59 (1H, s), 7.92 (1H, d, J = 8.8 Hz), 7.87 (1H, d, J = 8.8 Hz), 7.72 (1H, d, J = 8.8 Hz), 7.06-7.00 (2H, m). 4-chloro-2-hydroxy-N-(4-(trifluoromethyl)phenyl)benzamide (NIC-123)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 11.84 (1H, s), 10.59 (1H, s), 7.92 (1H, d, J = 8.8 Hz), 7.87 (1H, d, J = 8.8 Hz), 7.72 (1H, d, J = 8.8 Hz), 7.06-7.00 (2H, m).
2-hydroxy-4-methyl-N-(4-(trifluoromethyl)phenyl)benzamide (NIC-124)
1H-NMR (400 MHz, DMSO-d6) δ: 11.67 (1H, s), 10.56 (1H, s), 7.93 (2H, d, J = 8.4 Hz), 7.86 (1H, d, J = 8.4 Hz), 7.72 (2H, d, J = 8.4 Hz), 6.81-6.78 (2H, m), 2.29 (3H, s). 2-hydroxy-4-methyl-N-(4-(trifluoromethyl)phenyl)benzamide (NIC-124)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 11.67 (1H, s), 10.56 (1H, s), 7.93 (2H, d, J = 8.4 Hz), 7.86 (1H, d, J = 8.4 Hz), 7.72 (2H, d, J = 8.4 Hz), 6.81-6.78 (2H, m), 2.29 (3H, s).
N-(2-bromo-4-(trifluoromethyl)phenyl)-2-hydroxy-4-methylbenzamide (NIC-125)
1H-NMR (400 MHz, DMSO-d6) δ: 11.06 (1H, s), 8.68 (1H, d, J = 8.4 Hz), 8.09 (1H, d, J = 2.4 Hz), 7.92 (1H, d, J = 8.4 Hz), 7.79 (1H, dd, J = 8.4, 1.2 Hz), 6.85 (1H, s), 6.83 (1H, d, J = 8.0 Hz), 2.29 (3H, s). N-(2-bromo-4-(trifluoromethyl)phenyl)-2-hydroxy-4-methylbenzamide (NIC-125)
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 11.06 (1H, s), 8.68 (1H, d, J = 8.4 Hz), 8.09 (1H, d, J = 2.4 Hz), 7.92 (1H, d, J = 8.4 Hz), 7.79 (1H, dd, J = 8.4, 1.2 Hz), 6.85 (1H, s), 6.83 (1H, d, J = 8.0 Hz), 2.29 (3H, s).
5-chloro-2-hydroxy-4-methyl-N-(4-(trifluoromethyl)phenyl)benzamide (NIC-126)
1H-NMR (500 MHz, DMSO-d6) δ: 11.72 (1H, s), 10.60 (1H, s), 7.94 (1H, s), 7.92 (2H, d, J = 8.5 Hz), 7.13 (2H, d, J= 8.5 Hz), 6.98 (1H, s), 2.31 (3H, s). 5-chloro-2-hydroxy-4-methyl-N-(4-(trifluoromethyl)phenyl)benzamide (NIC-126)
1 H-NMR (500 MHz, DMSO-d 6 ) δ: 11.72 (1H, s), 10.60 (1H, s), 7.94 (1H, s), 7.92 (2H, d, J = 8.5 Hz), 7.13 ( 2H, d, J = 8.5 Hz), 6.98 (1H, s), 2.31 (3H, s).
N-(2-bromo-4-(trifluoromethyl)phenyl)-5-chloro-2-hydroxy-4-methylbenzamide (NIC-127)
1H-NMR (500 MHz, DMSO-d6) δ: 11.00 (1H, s), 8.65 (1H, d, J = 9.0 Hz), 8.09 (1H, d, J = 2.0 Hz), 7.95 (1H, s), 7.80 (1H, dd, J = 9.0, 2.0 Hz), 7.01 (1H, s), 2.31 (3H, s). N-(2-bromo-4-(trifluoromethyl)phenyl)-5-chloro-2-hydroxy-4-methylbenzamide (NIC-127)
1 H-NMR (500 MHz, DMSO-d 6 ) δ: 11.00 (1H, s), 8.65 (1H, d, J = 9.0 Hz), 8.09 (1H, d, J = 2.0 Hz), 7.95 (1H, s), 7.80 (1H, dd, J = 9.0, 2.0 Hz), 7.01 (1H, s), 2.31 (3H, s).
4-chloro-2-hydroxy-5-methyl-N-(4-(trifluoromethyl)phenyl)benzamide (NIC-128)
1H-NMR (500 MHz, DMSO-d6) δ: 11.57 (1H, s), 10.57 (1H, s), 7.93 (2H, d, J = 8.0 Hz), 7.83 (1H, s), 7.73 (2H, d, J= 8.0 Hz), 7.06 (1H, s), 2.29 (3H, s). 4-chloro-2-hydroxy-5-methyl-N-(4-(trifluoromethyl)phenyl)benzamide (NIC-128)
1 H-NMR (500 MHz, DMSO-d 6 ) δ: 11.57 (1H, s), 10.57 (1H, s), 7.93 (2H, d, J = 8.0 Hz), 7.83 (1H, s), 7.73 ( 2H, d, J = 8.0 Hz), 7.06 (1H, s), 2.29 (3H, s).
N-(2-bromo-4-(trifluoromethyl)phenyl)-4-chloro-2-hydroxy-5-methylbenzamide (NIC-129)
1H-NMR (500 MHz, DMSO-d6) δ: 12.33 (1H, s), 10.97 (1H, s), 8.67 (1H, d, J = 9.0 Hz), 8.09 (1H, d, J = 1.5 Hz), 7.97 (1H, s), 7.81 (1H, dd, J= 9.0, 1.5 Hz), 7.10 (1H, s), 2.49 (3H, s). N-(2-bromo-4-(trifluoromethyl)phenyl)-4-chloro-2-hydroxy-5-methylbenzamide (NIC-129)
1 H-NMR (500 MHz, DMSO-d 6 ) δ: 12.33 (1H, s), 10.97 (1H, s), 8.67 (1H, d, J = 9.0 Hz), 8.09 (1H, d, J = 1.5 Hz), 7.97 (1H, s), 7.81 (1H, dd, J = 9.0, 1.5 Hz), 7.10 (1H, s), 2.49 (3H, s).
２．NIC-113-115の合成 2. Synthesis of NIC-113-115
　Ar雰囲気下、NIC-42, NIC-51またはNIC-101 (0.50 mmol) のエタノール (3 mL) 溶液に対して、室温にて2-アミノエタノール (0.04 mL, 0.60 mmol) を加えた後、60 ℃で2時間撹拌した。放冷後、ロータリーエバポレーターを用いて溶媒を留去し、得られた固体をジクロロメタン (1 mL x 3) を用いて洗浄することによって目的とするNIC-113-115をそれぞれ得た。 Under Ar atmosphere, add 2-aminoethanol (0.04 mL, 0.60 mmol) to ethanol (3 mL) solution of NIC-42, NIC-51 or NIC-101 (0.50 mmol) at room temperature, and °C for 2 hours. After allowing to cool, the solvent was distilled off using a rotary evaporator, and the resulting solid was washed with dichloromethane (1 mL x 3) to obtain the target NIC-113-115, respectively.
2-Hydroxyethanaminium 4-chloro-2-((2-chloro-4-nitrophenyl)carbamoyl)-5-fluorophenolate (NIC-113)
1H-NMR (400 MHz, DMSO-d6) δ: 2.84 (2H, d, J = 5.6 Hz), 3.55 (2H, br), 5.12 (1H, br), 6.25 (1H, d, J = 13.6 Hz), 7.57 (3H, br), 7.72 (1H, d, J = 10.4 Hz), 8.16 (1H, dd, J = 9.2, 2.8 Hz), 8.28 (1H, d, J = 2.8 Hz), 8.94 (1H, d, J = 9.2 Hz). 2-Hydroxyethanaminium 4-chloro-2-((2-chloro-4-nitrophenyl)carbamoyl)-5-fluorophenolate (NIC-113)
1H-NMR (400 MHz, DMSO-d6) δ: 2.84 (2H, d, J = 5.6 Hz), 3.55 (2H, br), 5.12 (1H, br), 6.25 (1H, d, J = 13.6 Hz) , 7.57 (3H, br), 7.72 (1H, d, J = 10.4 Hz), 8.16 (1H, dd, J = 9.2, 2.8 Hz), 8.28 (1H, d, J = 2.8 Hz), 8.94 (1H, d, J = 9.2 Hz).
2-Hydroxyethanaminium 4,5-dichloro-2-((4'-nitro-[1,1'-biphenyl]-4-yl)carbamoyl)phenolate (NIC-114)
1H-NMR (400 MHz, DMSO-d6) δ: 2.60 (2H, d, J = 5.2 Hz), 3.38 (2H, br), 6.54 (1H, s), 7.74 (1H, s), 7.76 (2H, d, J = 8.8 Hz), 7.79 (2H, d, J = 8.8 Hz), 7.95 (2H, d, J = 8.8 Hz), 8.26 (2H, d, J = 8.8 Hz). 2-Hydroxyethanaminium 4,5-dichloro-2-((4'-nitro-[1,1'-biphenyl]-4-yl)carbamoyl)phenolate (NIC-114)
1H-NMR (400 MHz, DMSO-d6) δ: 2.60 (2H, d, J = 5.2 Hz), 3.38 (2H, br), 6.54 (1H, s), 7.74 (1H, s), 7.76 (2H, d, J = 8.8 Hz), 7.79 (2H, d, J = 8.8 Hz), 7.95 (2H, d, J = 8.8 Hz), 8.26 (2H, d, J = 8.8 Hz).
2-Hydroxyethanaminium 2-((2-bromo-4-(trifluoromethyl)phenyl)carbamoyl)-4-chloro-5-fluorophenolate (NIC-115)
1H-NMR (400 MHz, DMSO-d6) δ: 2.68 (2H, d, J = 5.6 Hz), 3.38 (2H, br), 6.22 (1H, d, J = 13.6 Hz), 7.65 (1H, dd, J = 8.8, 1.6 Hz), 7.71 (1H, d, J = 10.8 Hz), 7.91 (1H, d, J = 1.6 Hz), 8.81 (1H, d, J = 8.8 Hz). 2-Hydroxyethanaminium 2-((2-bromo-4-(trifluoromethyl)phenyl)carbamoyl)-4-chloro-5-fluorophenolate (NIC-115)
1H-NMR (400 MHz, DMSO-d6) δ: 2.68 (2H, d, J = 5.6 Hz), 3.38 (2H, br), 6.22 (1H, d, J = 13.6 Hz), 7.65 (1H, dd, J = 8.8, 1.6 Hz), 7.71 (1H, d, J = 10.8 Hz), 7.91 (1H, d, J = 1.6 Hz), 8.81 (1H, d, J = 8.8 Hz).
３．栄養欠乏培地中でのヒト膵臓がん由来細胞株PANC-1に対するin vitro細胞傷害活性評価
　がん細胞は低栄養・低酸素といった極限状態におかれると、エネルギー代謝を変えることで生存する特有の耐性機構を示す。特に、PANC-1のようなヒト膵臓がん細胞は、このような耐性を獲得しており、低栄養・低酸素といった厳しい環境下においても長期間の生存が可能となっている。したがって、がん細胞の栄養飢餓耐性を解除する化合物（antiausterity agent）は、新たな抗がん剤探索の標的となる。そこで、合成されたN-化合物の栄養欠乏培地中におけるPANC-1に対する細胞傷害活性をin vitroで評価した。具体的には、以下のようにして試験した。
　PANC-1（RBRC-RCB2095）ヒト膵臓がん細胞株は、理研BRC細胞バンクから購入し、10％FBSを補充した標準的なDMEMで維持し、5％CO2と95％空気の加湿雰囲気下、37℃で保存した。ヒト膵臓がん細胞を96ウェルプレート（1.5×104細胞/ウェル）に播種し、新鮮なDMEMを用いて、5% CO2および95%空気の下、37℃で24時間培養した。細胞をPBSで2回洗浄した後、培地を栄養豊富な培地（DMEM）または栄養欠乏培地（NDM）で表１および２に記載の被験化合物、並びにN-113～115を連続的に希釈した試験サンプル培地に変更した。各試験プレートは、コントロールとブランクを含んでいた。
　NDMの組成は以下の通りであった。0.1 mg L-1 Fe（NO3）3（9 H2O），265 mg L-1 CaCl2（2 H2O），400 mg L-1 KCl，200 mg L-1 MgSO4（7 H2O），6400 mg L-1 NaCl，700 mg L-1 NaHCO3，125 mg L-1 NaH2PO4，15 mg L-1フェノールレッド，25 mM L-1 HEPES緩衝液（pH 7.4），MEMビタミン液（Life Technologies, Inc）, 最終的なpHは10％のNaHCO3水溶液で7.4に調整した。
　PANC-1をDMEMおよびNDM中の各試験化合物と24時間インキュベートした後、PBSで2回洗浄し、10％WST-8細胞計数キット溶液を含む100μLのDMEMに交換した。3時間インキュベートした後、EnSpireマルチモードプレートリーダー（PerkinElmer, Inc.、Waltham, MA, USA）で450nmにおける吸光度を測定し、細胞生存率を求めた。細胞生存率は、3つのウェルの平均値から以下の式を用いて算出した。 3. In vitro cytotoxic activity evaluation against human pancreatic cancer-derived cell line PANC-1 in nutrient-deficient medium Indicate a resistance mechanism. In particular, human pancreatic cancer cells such as PANC-1 have acquired such resistance and are able to survive for a long period of time even in harsh environments such as low nutrition and low oxygen. Therefore, antiausterity agents that release resistance to nutrient starvation in cancer cells are targets for searching for new anticancer drugs. Therefore, we evaluated the cytotoxic activity of synthesized N-compounds against PANC-1 in nutrient-deficient medium in vitro. Specifically, the test was performed as follows.
PANC-1 (RBRC-RCB2095) human pancreatic cancer cell line was purchased from the Riken BRC Cell Bank and maintained in standard DMEM supplemented with 10% FBS under a humidified atmosphere of 5% CO and 95% air. , and stored at 37 °C. Human pancreatic cancer cells were seeded in 96-well plates (1.5×10 4 cells/well) and cultured with fresh DMEM for 24 hours at 37° C. under 5% CO 2 and 95% air. After washing the cells twice with PBS, the medium was serially diluted in nutrient-rich medium (DMEM) or nutrient-deficient medium (NDM) for the test compounds listed in Tables 1 and 2, and N-113-115. Changed to sample medium. Each test plate included controls and blanks.
The composition of NDM was as follows. 0.1 mg L-1 Fe( NO3 ) 3 ( 9H2O ), 265 mg L-1 CaCl2 ( 2H2O ), 400 mg L-1 KCl, 200 mg L-1 MgSO4 (7H2O ) O), 6400 mg L-1 NaCl, 700 mg L-1 NaHCO3 , 125 mg L-1 NaH2PO4 , 15 mg L-1 phenol red , 25 mM L-1 HEPES buffer (pH 7.4), MEM Vitamin solution (Life Technologies, Inc), final pH adjusted to 7.4 with 10% NaHCO 3 aqueous solution.
PANC-1 was incubated with each test compound in DMEM and NDM for 24 hours, then washed twice with PBS and replaced with 100 μL of DMEM containing 10% WST-8 cell counting kit solution. After incubation for 3 hours, absorbance at 450 nm was measured with an EnSpire multimode plate reader (PerkinElmer, Inc., Waltham, Mass., USA) to determine cell viability. Cell viability was calculated from the average value of 3 wells using the following formula.
Cellviability(%)=[Abs(test sample)-Abs(blank)/Abs(control)-Abs(blank)]x100 Cellviability(%)=[Abs (test sample) -Abs (blank) /Abs (control) -Abs (blank) ]x100
＜結果＞
　N-化合物は、膵臓がん由来細胞に対する細胞傷害活性を示した（表１および２）。中でも、化合物N-42、N-48、N-50、N-51、N-54、N-56、N-68、N-81、N-101、N-110およびN-115は栄養飢餓選択的50%細胞阻害濃度（PC50）値が、それぞれ16nM、16nM、8nM、8nM、10nM、10nM、12nM、5nM、<5nM、<5nMおよび3nMと特に強力な細胞傷害活性を示した。また、化合物N-120、N-127およびN-129もPC50値が、それぞれ4.3nM、0.46nM、0.48nMと特に強力な細胞傷害活性を示した。
　また、表３に示すように、N-101のカリウム塩またはナトリウム塩は、NDMにおけるニクロサミドの300倍を超える栄養飢餓選択的細胞毒性を有し、特に強力な細胞傷害活性を示した。 <Results>
N-compounds exhibited cytotoxic activity against pancreatic cancer-derived cells (Tables 1 and 2). Among them, compounds N-42, N-48, N-50, N-51, N-54, N-56, N-68, N-81, N-101, N-110 and N-115 were selected for nutrient starvation The target 50% cell inhibitory concentration (PC 50 ) values were 16 nM, 16 nM, 8 nM, 8 nM, 10 nM, 10 nM, 12 nM, 5 nM, <5 nM, <5 nM and 3 nM, respectively, showing particularly strong cytotoxic activity. Compounds N-120, N-127 and N-129 also exhibited particularly strong cytotoxic activity with PC 50 values of 4.3 nM, 0.46 nM and 0.48 nM, respectively.
In addition, as shown in Table 3, the potassium or sodium salts of N-101 had more than 300-fold more nutrient-starvation selective cytotoxicity than niclosamide in NDM, and exhibited particularly potent cytotoxic activity.
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000015
　上記のとおり、フェニルベンズアミド誘導体であるN-化合物は、NDM培養下のPANC-1に対して強力な細胞傷害活性を示した。フェニルベンズアミド誘導体は、anti-austerity agentとして有用であることが示された。 As mentioned above, the N-compound, which is a phenylbenzamide derivative, showed strong cytotoxic activity against PANC-1 under NDM culture. Phenylbenzamide derivatives have been shown to be useful as anti-austerity agents.
４．栄養豊富培地（DMEM）培養下のPANC-1に対する転移阻害活性の評価
　膵臓腫瘍は転移性の高い腫瘍である。転移は、原発性腫瘍細胞が血管系を通って、成長するのに十分な栄養分がある遠くの臓器に移動し、二次的な腫瘍を形成することで起こる。このプロセスは、膵臓がん患者の罹患率が高く、寿命が短いことの一部の原因となっている。そこで、PANC-1ヒト膵臓腫瘍細胞の遊走に対するN-42の影響を定量的リアルタイム腫瘍遊走アッセイを用いて検討した。
　PANC-1細胞懸濁液70μl（3×105 cells/mL）を35mm μ-dishのCulture-Insert 2 Wellの各ウェルに播種し、37℃、5% CO2で24時間以上インキュベートして細胞を接着させた。その後、Culture-Insert 2ウェルを滅菌したピンセットで静かに取り除き、細胞層をPBSで洗浄した。μ-DishにDMEM単独（コントロール）または試験化合物（N-42）を含むDMEMを2mL入れ、CO2インキュベーター内に設置したCytoSMARTデバイスに載せた。
　コントロールと、DMEMを用いた通常の栄養豊富な条件でN-42を表示濃度で処理したPANC-1細胞について、並行して実験を行った。細胞をCytoSMARTデバイス上で48時間培養し、15分ごとにリアルタイム画像を撮影した。画像は15分ごとに自動的に撮影された。ImageJを用いて、各経過時間における画像の開創面積はImageJソフトウェアを用いて算出し、データはGraphPad Prism 7を用いて処理した。各群について合計193枚の画像を撮影した。 4. Evaluation of metastasis inhibitory activity against PANC-1 under nutrient-rich medium (DMEM) culture Pancreatic tumors are highly metastatic tumors. Metastasis occurs when primary tumor cells migrate through the vasculature to distant organs that have sufficient nutrients to grow and form secondary tumors. This process is partly responsible for the high morbidity and short life span of pancreatic cancer patients. Therefore, we investigated the effect of N-42 on the migration of PANC-1 human pancreatic tumor cells using a quantitative real-time tumor migration assay.
Seed 70 μl of PANC-1 cell suspension (3×10 5 cells/mL) into each well of Culture-Insert 2 Well of 35 mm μ-dish, and incubate at 37°C, 5% CO 2 for at least 24 hours to remove cells. was glued. Culture-Insert 2 wells were then gently removed with sterile forceps, and the cell layer was washed with PBS. A μ-Dish was filled with 2 mL of DMEM alone (control) or DMEM with test compound (N-42) and placed on the CytoSMART device placed in a CO 2 incubator.
Parallel experiments were performed on control and PANC-1 cells treated with N-42 at the indicated concentrations in normal nutrient-rich conditions with DMEM. Cells were cultured on the CytoSMART device for 48 hours and real-time images were taken every 15 minutes. Images were taken automatically every 15 minutes. Using ImageJ, the retraction area of the images at each elapsed time was calculated using ImageJ software, and the data were processed using GraphPad Prism 7. A total of 193 images were taken for each group.
＜結果＞
　N-化合物のがん細胞転移能に対する活性を検討すべく、DMEM培養下のPANC-1に対する転移阻害活性の評価を行った結果撮影された写真を図１Ａに、ImageJソフトウェアを用いて算出された開創面積の経時変化を図１Ｂに示す。
　コントロール細胞は、より高い移動速度を示した。48時間後、コントロールの創傷面積は、最初の創傷面積の100％まで創傷閉鎖を示した。化合物N-42を5，10，20，40μMの濃度で処理したところ、濃度依存的にPANC-1腫瘍細胞の移動が抑制され、T0での初期の傷の面積と比較して約25％，50％，75％，98％の傷の面積になった。これらの結果から、化合物N-42はPANC-1腫瘍細胞の移動を強力に阻害することが示唆された。 <Results>
In order to examine the activity of N-compounds on cancer cell metastasis, metastasis inhibitory activity against PANC-1 under DMEM culture was evaluated. FIG. 1B shows changes in the retraction area over time.
Control cells showed a higher migration rate. After 48 hours, the control wound area showed wound closure to 100% of the initial wound area. Treatment with compound N-42 at concentrations of 5, 10, 20, and 40 µM inhibited migration of PANC-1 tumor cells in a concentration-dependent manner, and reduced the initial wound area by about 25% and 25%, respectively. The wound area was 50%, 75%, and 98%. These results suggested that compound N-42 potently inhibited migration of PANC-1 tumor cells.
５．ヌードマウスにおけるMIA PaCa-2腫瘍の増殖に対するN-化合物およびGemcitabineの併用効果
　in vitro検討において強力な阻害活性を示したN-42、N-51の抗腫瘍効果について、in vivo抗腫瘍効果を検討した。5週齢の雄BALB/cヌードマウス（CAnN, Cg-Fixbk<nu>/CrlCrlJ 5Wオス）を1週間、動物舎で馴化させた。MIA PaCa-2腫瘍細胞（10,000,000 細胞s/200 mL PBS）を全マウスの左右の脇腹に皮下注射した。腫瘍細胞接種後4日目に、マウス（n＝8／群）を以下のの5群に無作為に分けた。
(i)対照群
(ii)低用量N化合物投与群（10mg/kg/日;5回/週）
(iii)高用量N化合物投与群 (30mg/kg/日; 5回/週）
(iv)Gemcitabine(GEM)投与群（150mg/kg/週; 1回/週）
(v)併用群[Gemcitabine150mg/kg/週; 1回/週　＋　N-42化合物、30mg/kg/日, 5回/週]  5. Combined effect of N-compound and Gemcitabine on MIA PaCa-2 tumor growth in nude mice. bottom. Five-week-old male BALB/c nude mice (CAnN, Cg-Fixbk<nu>/CrlCrlJ 5W males) were acclimated in the animal house for one week. MIA PaCa-2 tumor cells (10,000,000 cells/200 mL PBS) were injected subcutaneously into the left and right flanks of all mice. Four days after tumor cell inoculation, mice (n=8/group) were randomly divided into the following five groups.
(i) control group
(ii) Low-dose N compound administration group (10 mg/kg/day; 5 times/week)
(iii) High dose N compound administration group (30mg/kg/day; 5 times/week)
(iv) Gemcitabine (GEM) administration group (150mg/kg/week; once/week)
(v) Combination group [Gemcitabine 150 mg/kg/week; once/week + N-42 compound, 30 mg/kg/day, 5 times/week]
　N-化合物および／またはGemcitabine(処理群)またはPBS(対照群)をマウスの腹腔内に注射した。すべてのマウスは、固形の食物と水を自由に摂取できる状態とした。体重と腫瘍の大きさを週に2回、以下の計算式を用いて測定した。 Mice were injected intraperitoneally with N-compounds and/or Gemcitabine (treatment group) or PBS (control group). All mice had free access to solid food and water. Body weight and tumor size were measured twice weekly using the following formula.
推定腫瘍体積（週2回の測定）＝（π×長さ×幅2）／6 Estimated tumor volume (measured twice weekly) = (π x length x width2 )/6
＜結果＞
　結果を図２（N-51）および図３（N-42）に示す。また、実験開始29日目に摘出した腫瘍の写真を図４に示す。N-42、N-51を単独で投与した群では、顕著な腫瘍サイズおよび重量の抑制効果が示された。その効果は濃度依存的であった。Gemcitabineと、N-42またはN-51とを併用した群でも、顕著な腫瘍サイズおよび重量の抑制効果が示された。これにより、N-51およびN-42の単独投与、並びに、N-51とGemcitabineとの併用、および、N-42とGemcitabineとの併用の全てが、抗がん活性を有することが示された。特に、N-51またはN-42とGemcitabineとを併用することにより、それぞれの化合物を単独で投与するよりも、より優れた効果が認められた。一方、N-42およびN-51は、マウス体重増加に影響せず、生育への副作用は認められなかった。 <Results>
The results are shown in Figure 2 (N-51) and Figure 3 (N-42). In addition, FIG. 4 shows a photograph of the tumor excised on the 29th day after the start of the experiment. Groups administered with N-42 and N-51 alone showed significant tumor size and weight suppression effects. The effect was concentration dependent. The group that combined Gemcitabine with N-42 or N-51 also showed significant tumor size and weight suppression effects. This indicated that the administration of N-51 and N-42 alone, and the combination of N-51 and Gemcitabine, and the combination of N-42 and Gemcitabine all had anticancer activity. . In particular, the combined use of N-51 or N-42 and Gemcitabine was found to be more effective than the administration of each compound alone. On the other hand, N-42 and N-51 had no effect on mouse body weight gain, and no side effects on growth were observed.
６．N-化合物の作用により変動する分子種の検討
　N-化合物の機能をさらに検討した。0.5 mMフェニルメチルスルホニルフルオリド（PMSF）（pH 7.4）、cOmplete（商標）プロテアーゼ阻害剤カクテル（Roche、マンハイム、ドイツ）を含むRIPAバッファー（和光純薬、大阪、日本）を使用して、細胞から抽出したタンパク質サンプルを、2x Laemmliサンプルバッファー（Bio-Rad、Hercules、カリフォルニア、米国）中、100℃で5分間加熱した。等量のタンパク質を8～15％のアクリルアミドゲル上でSDS-ポリアクリルアミドゲル電気泳動にかけた。続いて、ゲルをImmobilon-P転写ポリフッ化ビニリデン膜（Millipore Corp, Bedford, MA, USA）に転写した。メンブレンを直ちにブロッキングバッファー［10mM Tris, 100mM NaCl, 0.1% Tween 20, pH7.5を含むTBS-Tween（TBS-T）バッファー中に5%脱脂粉乳を含む］に室温で1時間浸し、次にTBS-Tバッファーで30分洗浄した後、市販の適切な特異的一次抗体と4℃で一晩インキュベートした。その後、TBS-Tバッファーで30分洗浄した後、二次抗体（DakoCytomation, Glostrup, Denmark）と室温で1時間インキュベートし、さらにTBS-Tバッファーで40分洗浄した後、ImageQuant LAS 4000を用いて強化化学発光溶液（Bio-Rad, Hercules, CA, USA）でバンドを検出した。 6. Investigation of molecular species changed by the action of N-compounds We further investigated the functions of N-compounds. Cells were isolated using RIPA buffer (Wako Pure Chemical Industries, Osaka, Japan) containing 0.5 mM phenylmethylsulfonyl fluoride (PMSF) (pH 7.4), cOmplete™ protease inhibitor cocktail (Roche, Mannheim, Germany). Extracted protein samples were heated at 100° C. for 5 minutes in 2× Laemmli sample buffer (Bio-Rad, Hercules, CA, USA). Equal amounts of protein were subjected to SDS-polyacrylamide gel electrophoresis on 8-15% acrylamide gels. The gel was subsequently transferred to an Immobilon-P transfer polyvinylidene fluoride membrane (Millipore Corp, Bedford, Mass., USA). The membrane was immediately immersed in blocking buffer [5% non-fat dry milk in TBS-Tween (TBS-T) buffer containing 10 mM Tris, 100 mM NaCl, 0.1% Tween 20, pH 7.5] for 1 hour at room temperature, followed by TBS. After washing with -T buffer for 30 minutes, they were incubated overnight at 4°C with appropriate specific primary antibodies commercially available. Then washed with TBS-T buffer for 30 minutes, incubated with secondary antibody (DakoCytomation, Glostrup, Denmark) for 1 hour at room temperature, washed with TBS-T buffer for 40 minutes and enhanced using ImageQuant LAS 4000. Bands were detected with a chemiluminescent solution (Bio-Rad, Hercules, Calif., USA).
＜結果＞
　結果を図５および図６に示す。N-42、またはN-51処置細胞では、栄養飢餓条件下で、濃度依存的にpAKt、pmTOR、SOX-2、c-MYC、OCT-4の減少が認められたすなわち、フェニルベンズアミド誘導体は、栄養飢餓条件下で、Akt/mTOR活性化を阻害した。 <Results>
The results are shown in FIGS. 5 and 6. FIG. In N-42 or N-51 treated cells, concentration-dependent decreases in pAKt, pmTOR, SOX-2, c-MYC, and OCT-4 were observed under nutrient starvation conditions. It inhibited Akt/mTOR activation under nutrient starvation conditions.
　セリン/スレオニンキナーゼAkt（プロテインキナーゼBとも呼ばれる）は、細胞シグナル伝達における中心的役割を果たし、これらのシグナル伝達の異常はがんおよび糖尿病から神経変性に至る広範囲の疾患に影響を及ぼす。
　また、mTORは、PI3K関連プロテインキナーゼ（PIKK）ファミリーのメンバーで、増殖因子経路のシグナルを伝播する機能を持ち、それによって細胞の成長、増殖、および生存をサポートする。さまざまながんにおいて、上方制御されているmTORシグナル伝達が検出されている。mTORは、２種類のタンパク質複合体mTORC1およびmTORC2のコア触媒ユニットで、mTORC1複合体は、ラパマイシン感受性で、mTOR、Raptor、およびmLST8から構成される。mTORC1は、細胞の成長および増殖を制御する。翻訳、リボソーム生合成、オートファジー、グルコース代謝、低酸素に対する細胞反応、および転移等のさまざまな腫瘍細胞特異的なプロセスを含むその他の生物学的プロセスもmTORC1によって制御される。 The serine/threonine kinase Akt (also called protein kinase B) plays a central role in cell signaling, and abnormalities in these signaling affect a wide range of diseases from cancer and diabetes to neurodegeneration.
mTOR is also a member of the PI3K-related protein kinase (PIKK) family and functions to propagate growth factor pathway signals, thereby supporting cell growth, proliferation, and survival. Upregulated mTOR signaling has been detected in various cancers. mTOR is the core catalytic unit of two protein complexes, mTORC1 and mTORC2, the mTORC1 complex is rapamycin-sensitive and consists of mTOR, Raptor, and mLST8. mTORC1 controls cell growth and proliferation. Other biological processes are also regulated by mTORC1, including various tumor cell-specific processes such as translation, ribosome biogenesis, autophagy, glucose metabolism, cellular response to hypoxia, and metastasis.
　がん細胞は一般に不規則かつ急速に増殖し、多くの場合、脆弱で無秩序に血管系が形成されるためグルコース欠乏や低酸素、その他栄養素の不足等ストレスの多い微小環境にさらされている。しかしながら、がん細胞はエネルギー代謝を調節して、低栄養・低酸素供給のような苛酷な条件に耐える固有の能力を示す。オートファジーは、その一機構と考えられる。本結果から、N-化合物がオートファジーを阻害するanti-austerity agentであり、新規抗がん剤として有用であることが見出された。 Cancer cells generally grow irregularly and rapidly, and often have fragile and disorganized vasculature that expose them to a stressful microenvironment such as glucose deprivation, hypoxia, and other nutrient deficiencies. However, cancer cells exhibit an inherent ability to regulate energy metabolism and withstand harsh conditions such as low nutrition and low oxygen supply. Autophagy is thought to be one such mechanism. From these results, it was found that N-compounds are anti-austerity agents that inhibit autophagy and are useful as novel anticancer agents.
　また、フェニルベンズアミド誘導体は、栄養飢餓条件下で、SOX2、c-MYC、OCT-4を阻害した。がん幹細胞は、自己複製能と、多分化能を有し、少数の細胞からでも高率にがんを形成する強い造腫瘍能を有する細胞である。がん幹細胞は、がんの治療抵抗性、再発・転移と深く結び付いているとも考えられる。SOX2、c-MYC、OCT-4はがん細胞の脱分化を促進し、幹細胞性を付与することが知られる。フェニルベンズアミド誘導体は、がん細胞の脱分化を促進し、幹細胞性を付与を阻害し、がんの治療抵抗性、再発・転移の抑制に有用であることが示された。特に、本発明に用いられる化合物は、SOX2、c-MYC、OCT-4を阻害することによって、がんの治療抵抗性、すなわち、膵臓がんに対してほとんど耐性を示すことなく、優れた効果をもたらすことが示唆された。 In addition, phenylbenzamide derivatives inhibited SOX2, c-MYC, and OCT-4 under nutrient starvation conditions. Cancer stem cells are cells that have self-renewal ability, multipotency, and strong tumorigenic ability to form cancer at a high rate even from a small number of cells. Cancer stem cells are also thought to be deeply associated with treatment resistance, recurrence, and metastasis of cancer. SOX2, c-MYC, and OCT-4 are known to promote dedifferentiation of cancer cells and confer stemness. Phenylbenzamide derivatives were shown to promote dedifferentiation of cancer cells, inhibit conferment of stemness, and be useful for treatment resistance of cancer and suppression of recurrence and metastasis. In particular, the compound used in the present invention inhibits SOX2, c-MYC, and OCT-4, thereby exhibiting excellent efficacy against cancer treatment resistance, that is, pancreatic cancer, without showing almost any resistance. It was suggested that
７．同所移植モデルにおけるN-化合物の効果
　in vitroおよびin vivoにおけるN-化合物の優れた抗腫瘍効果をさらに検証すべく、ヌードマウスにおける同所移植モデルにN-化合物を投与してその効果を確認した。
　5週齢の雄ヌードマウス（CAnN、Cg-Foxn1 <nu> / CrlCrlJ 5W、Charles Rivers）は、日本のNinox Lab Supply Co.,Ltdから購入した。マウスは、温度25℃、12時間の明暗サイクルで、45～50％の相対湿度である、病原微生物freeの環境で飼育され、1週間飼育環境に馴化させた。
　MIA PaCa-2異種移植片を有するドナーマウスを、同所移植の3～4週間前に調製した。概略としては、図７に示す通り、単細胞懸濁液（0.2mlのPBS中の1×107細胞）をマウスの背側腹部領域に皮下注射した（n=5）。腫瘍を3～4週間増殖させた。腫瘍が1.0～1.5cm3のサイズに増殖したときに、ドナーマウスは同所移植のための腫瘍採取の準備が整ったとした。
　移植日にドナーマウスを頸椎脱臼により屠殺し、腫瘍を単離し、約10mgのブロックに切断した。腫瘍ブロックを0℃でマトリゲル（Corning、354234）で覆った。固形腫瘍移植のため、マウスをイソフルラン下で麻酔した。マウスの腹部の左上腋窩領域に縦方向1cmの小さな皮膚切開を行い、腹膜を開いて膵臓を露出させた。4-0吸収性外科用縫合糸（Bicryl Rapid、VR426、Johnson＆Johnson）を使用して、腫瘍ブロックの一塊を膵頭に移植した。膵臓を腹腔に静かに戻し、6-0吸収性外科用縫合糸を使用して外科的開口部を閉じた。すべての手術は無菌環境で行った。細菌感染を防ぐため、エンロフロキサシン（5mg/kg）を手術前日と手術後2日間の計3回、腹腔内に投与した。次に、マウスをランダムに8匹/群に分けた。薬物投与は異所性モデルと同様に行った。体重を週に2回測定し、最終的な腫瘍データをエンドポイント（29日目）で取得した。CO2麻酔下でマウスを屠殺し、開腹して腫瘍を回収し秤量した。 7. Effects of N-compounds in orthotopic transplantation models To further verify the excellent anti-tumor effects of N-compounds in vitro and in vivo, we administered N-compounds to an orthotopic transplantation model in nude mice and confirmed their effects. bottom.
Five-week-old male nude mice (CAnN, Cg-Foxn1<nu>/CrlCrlJ 5W, Charles Rivers) were purchased from Ninox Lab Supply Co., Ltd., Japan. Mice were housed in a pathogen-free environment with a temperature of 25° C., a 12-hour light-dark cycle, and a relative humidity of 45-50%, and were acclimated to the housing environment for 1 week.
Donor mice with MIA PaCa-2 xenografts were prepared 3-4 weeks prior to orthotopic transplantation. Briefly, a single cell suspension (1×10 7 cells in 0.2 ml PBS) was injected subcutaneously into the dorsal flank area of mice (n=5) as shown in FIG. Tumors were allowed to grow for 3-4 weeks. Donor mice were ready for tumor harvest for orthotopic implantation when tumors grew to a size of 1.0-1.5 cm 3 .
Donor mice were sacrificed by cervical dislocation on the day of implantation and tumors were isolated and cut into approximately 10 mg blocks. Tumor blocks were overlaid with Matrigel (Corning, 354234) at 0°C. Mice were anesthetized under isoflurane for solid tumor implantation. A small 1 cm longitudinal skin incision was made in the upper left axillary region of the abdomen of the mouse and the peritoneum was opened to expose the pancreas. A mass of tumor block was implanted into the pancreatic head using 4-0 absorbable surgical sutures (Bicryl Rapid, VR426, Johnson & Johnson). The pancreas was gently placed back into the abdominal cavity and the surgical opening was closed using 6-0 absorbable surgical sutures. All surgeries were performed in a sterile environment. To prevent bacterial infection, enrofloxacin (5 mg/kg) was administered intraperitoneally three times, one day before surgery and two days after surgery. Mice were then randomly divided into 8/group. Drug administration was performed as in the ectopic model. Body weights were measured twice weekly and final tumor data were obtained at endpoint (Day 29). Mice were sacrificed under CO2 anesthesia and the tumors were harvested and weighed by laparotomy.
＜結果＞
　結果を図８～１０に示す。ヌードマウスの膵臓にMIA PaCa-2腫瘍を移植すると、体重減少、皮膚の黒ずみ、脊椎骨の骨格が現れ、胃が膨らむことから、重度の悪液質と腹水が生じていた。体重減少や皮膚の変色等の悪液質症状は、腫瘍移植から10日後以降に現れ始めた。GEM投与マウスにおいても、同様に体重の著しい減少と悪液質症状を呈した。一方で、N-42単剤投与群およびN-42とGEMとの併用投与群では、悪液質の症状は見られなかった。対照群の体重は、治療群に比べて有意に低かった。腫瘍の湿潤重量および腫瘍の大きさも、対照群に比べて有意に小さいことが示された。 <Results>
The results are shown in Figures 8-10. Transplantation of MIA PaCa-2 tumors into the pancreas of nude mice resulted in weight loss, darkened skin, a vertebral skeleton, and a swollen stomach, resulting in severe cachexia and ascites. Cachectic symptoms such as weight loss and skin discoloration began to appear after 10 days after tumor implantation. GEM-treated mice also showed significant weight loss and cachectic symptoms. On the other hand, no symptoms of cachexia were observed in the N-42 monotherapy group and the combined administration group of N-42 and GEM. Body weight in the control group was significantly lower than in the treatment group. Tumor wet weight and tumor size were also shown to be significantly smaller than in the control group.
８．アラビアゴムを用いた担がんマウス薬効試験
　N-42化合物およびGemcitabine（東京化成工業、G0544）の必要量（マウス体重による）とアラビアゴム0.5gをメノウ乳鉢でよくすり混ぜ、PBS少量を加えて練りこみ粘調に整えた。残りPBSを少量ずつ加えて粘調な薬液をのばし、最終的にPBS5mlになるよう調製した（Gemcitabine調整薬液濃度：3mg/0.2ml、N-42高用量調整薬液濃度： 3mg/1.0mL、N-42低用量調整薬液濃度：1mg/1.0mL)。薬物の入らない対照溶液は、同様にアラビアゴムを乳鉢で調製し、10%(w/v)溶液とした。調製した薬液は4℃冷蔵保存した。
　凍結MIAPaca2細胞全量を15mLの滅菌チューブに移し、37℃に温めておいた培地（DMEM(High Glucose, Wako 043-30085) + 10%FBS 20 ml）5mLを静かに加えた。遠心分離(3000rpm, 5 min, 37℃)後、上澄みを除去し、37℃に温めておいた培地5mLを静かに加え、細胞が単離するように混ぜた。細胞数をカウント後、T-25 フラスコに移し、CO2インキュベーター内で培養した(37℃ , 5%C02)。24時間後の細胞状態を観察し、さらに4日間培養した。その後、直径150mm、（底面積152cm2)のディッシュに移して継代を続けた。 8. Efficacy test using gum arabic in tumor-bearing mice Necessary amounts of N-42 compound and Gemcitabine (Tokyo Kasei Kogyo, G0544) (according to mouse body weight) and 0.5 g of gum arabic were thoroughly mixed in an agate mortar, and a small amount of PBS was added and kneaded. It was adjusted to a thick consistency. The remaining PBS was added little by little to spread the viscous drug solution, and the final volume was adjusted to 5 ml of PBS (Gemcitabine adjusted drug solution concentration: 3 mg/0.2 ml, N-42 high dose adjusted drug solution concentration: 3 mg/1.0 mL, N- 42 Low-dose adjustment liquid concentration: 1mg/1.0mL). A drug-free control solution was similarly prepared with gum arabic in a mortar to give a 10% (w/v) solution. The prepared drug solution was refrigerated at 4°C.
The total amount of frozen MIAPaca2 cells was transferred to a 15 mL sterile tube, and 5 mL of medium (DMEM (High Glucose, Wako 043-30085) + 10% FBS 20 ml) warmed to 37°C was gently added. After centrifugation (3000 rpm, 5 min, 37° C.), the supernatant was removed and 5 mL of medium warmed to 37° C. was gently added and mixed to isolate the cells. After counting the number of cells, the cells were transferred to a T-25 flask and cultured in a CO 2 incubator (37°C, 5% CO 2 ). After 24 hours, the cells were observed and cultured for another 4 days. Thereafter, the cells were transferred to a dish with a diameter of 150 mm (bottom area of 152 cm 2 ) and subculture was continued.
　凍結細胞を解凍し、培養開始後3週目以降に200μl PBS中に1x107 cellsを懸濁させた。1×107 cells/mouse(1×107 cells/200μL/head)を25GX1’'注射針をつけた1mlシリンジを用いて脇腹皮下移植（マウス1匹あたり1か所）した。移植後3日目に化合物投与を開始した。移植3日後の平均腫瘍体積200mm3であった。Gemcitabineは、週1回の腹腔内投与(IP）(150 mg/Kg/week)を合計4回投与した。N-42は、週5回の腹腔内投与(IP) ｛高用量(150mg/Kg/week)または低用量(50mg/Kg/week)｝を、合計20回投与した。N-42高用量＋Gemcitabine投与群においては、Gemcitabine投与後にN-42を投与した。
　各群10匹とし、以下の5群で実験を行った（動物数合計50)。
(1) 陰性対照群（10％アラビアゴム溶液）
(2) Gemcitabine投与群
(3) NIC-42高用量投与群
(4) NIC-42低用量投与群
(5) NIC-42高用量＋Gemcitabine投与群 Frozen cells were thawed, and 1×10 7 cells were suspended in 200 μl PBS after 3 weeks from the start of culture. 1×10 7 cells/mouse (1×10 7 cells/200 μL/head) were subcutaneously transplanted to the flank (1 site per mouse) using a 1 ml syringe with a 25GX1″ injection needle. Compound administration was initiated 3 days after transplantation. The mean tumor volume was 200 mm 3 3 days after transplantation. Gemcitabine was administered weekly intraperitoneally (IP) (150 mg/Kg/week) for a total of 4 doses. N-42 was administered intraperitoneally (IP) {high dose (150 mg/Kg/week) or low dose (50 mg/Kg/week)} five times a week for a total of 20 doses. In the N-42 high dose + Gemcitabine administration group, N-42 was administered after administration of Gemcitabine.
Each group had 10 animals, and experiments were conducted in the following 5 groups (total number of animals: 50).
(1) Negative control group (10% gum arabic solution)
(2) Gemcitabine administration group
(3) NIC-42 high dose group
(4) NIC-42 low-dose administration group
(5) NIC-42 high dose + Gemcitabine administration group
　デジタルノギスを用いて腫瘍サイズ（推定）測定を週2回実施した。腫瘍サイズは以下の式を用いて計算した。
（腫瘍サイズ）＝（3.14×長さ×幅2）×1/6
　また、腫瘍移植部位の状態がわかるような写真を週1回イソフルラン吸入麻酔下で撮影した。
　投与開始29 日目にサンプリングし腫瘍の写真を撮影し、腫瘍重量を測定した。 Tumor size (estimated) measurements were performed twice weekly using digital calipers. Tumor size was calculated using the following formula.
(tumor size) = (3.14 x length x width2 ) x 1/6
In addition, photographs were taken once a week under isoflurane inhalation anesthesia so that the state of the tumor-implanted site could be seen.
Samples were taken on day 29 after the start of administration, tumors were photographed, and tumor weights were measured.
＜結果＞
　腫瘍サイズの経時変化を図１１に示す。N-42の高用量投与群（N-42(H)）、低用量投与群（N-42(L)）、Gemcitabine投与群（GEM）、N-42とGemcitabineの併用群は、いずれもコントロール（Cont）と比較して腫瘍抑制効果を示した。特に、N-42とGemcitabineの併用群は、N-42の高用量投与群（N-42(H)）、Gemcitabine投与群（GEM）の単独投与と比較して、相乗効果を示した。 <Results>
FIG. 11 shows changes in tumor size over time. N-42 high-dose administration group (N-42(H)), low-dose administration group (N-42(L)), Gemcitabine administration group (GEM), N-42 and Gemcitabine combination group were all controls. showed a tumor suppressive effect compared with (Cont). In particular, the combined N-42 and Gemcitabine group showed a synergistic effect compared to the high-dose N-42 administration group (N-42(H)) and the Gemcitabine administration group (GEM) alone.
９．低栄養・低酸素環境下でのヒト膵臓がん由来細胞株PANC-1に対するN-化合物のin vitro細胞傷害活性評価
　上述の通り、腫瘍の微小環境は、低栄養のみならず酸素欠乏（低酸素）の利用可能性によっても特徴づけられる。よって、グルコースと血清を取り除いた培地中のN-化合物の効果を低酸素（3％O2）および正常酸素（20％O2）の条件下で評価して比較した。本実験ではグルコースを含まないDMEM（Fujifilm、042-3225）を使用した。DMEM中のPANC-1細胞（2×104細胞/100μL/ウェル）を96ウェルプレートに播種し、細胞接着のために24時間培養した。次に、細胞をダルベッコのリン酸緩衝生理食塩水（PBS）で2回洗浄した後、段階希釈した各N-化合物（N-113、N-114、または115）または比較対象としてゲムシタビンを含むグルコース欠乏培地（グルコースと血清を含まないDMEM）と培地交換し（各サンプルにつき2枚のプレート）、低酸素インキュベーター(3%O2)（低酸素培養群）または正常酸素インキュベーター（20％O2）（低酸素培養群）内で24時間培養した。培養後、培地を、10％WST-8細胞計数キット溶液を含む100μLのDMEMと交換した。3時間インキュベーションした後、450nmにおける吸光度を測定し、細胞生存率を求めた。細胞生存率は、次の式を使用して3つのウェルの平均値から計算した。 9. Evaluation of in vitro cytotoxic activity of N-compounds against human pancreatic cancer-derived cell line PANC-1 under low-nutrient and low-oxygen environment. ) is also characterized by the availability of Therefore, the effects of N-compounds in media depleted of glucose and serum were evaluated and compared under hypoxic (3% O 2 ) and normoxic (20% O 2 ) conditions. DMEM without glucose (Fujifilm, 042-3225) was used in this experiment. PANC-1 cells (2×10 4 cells/100 μL/well) in DMEM were seeded in 96-well plates and cultured for 24 hours for cell attachment. Cells were then washed twice with Dulbecco's phosphate-buffered saline (PBS) followed by serial dilutions of each N-compound (N-113, N-114, or 115) or glucose with gemcitabine as a comparator. Replace medium (two plates for each sample) with depleted medium (DMEM without glucose and serum) and place in hypoxic incubator (3% O 2 ) (hypoxic culture group) or normoxic incubator (20% O 2 ). (hypoxic culture group) and cultured for 24 hours. After incubation, the medium was replaced with 100 μL of DMEM containing 10% WST-8 cell counting kit solution. After incubation for 3 hours, absorbance at 450 nm was measured to determine cell viability. Cell viability was calculated from the mean of triplicate wells using the following formula:
細胞生存率(%)=[Abs(test sample)-Abs(blank)/Abs(control)-Abs(blank)]x100 Cell viability (%) = [Abs (test sample) -Abs (blank) /Abs (control) -Abs (blank) ]x100
＜結果＞
　結果を図１２に示す。N-化合物は、栄養素欠乏に加えて酸素が欠乏した腫瘍微小環境を模倣した条件下でより高い感度を示した。ゲムシタビンは、このような腫瘍微小環境模倣条件下（グルコースおよび酸素欠乏）でPANC-1細胞に対して高い耐性[IC50（24時間）>100μM]を示したが、N-113、N-114、およびN-115は、グルコースおよび酸素欠乏状態で30 nM、111 nM、および0.9nMのPC50値を示した。よって、低栄養かつ低酸素条件下において、N-化合物はゲムシタビンの約10,000倍強いことが示された。 <Results>
The results are shown in FIG. N-compounds showed greater sensitivity under conditions mimicking the tumor microenvironment with nutrient deprivation plus oxygen deprivation. Gemcitabine was highly resistant [IC50 (24 h) >100 μM] against PANC-1 cells under such tumor microenvironment-mimicking conditions (glucose and oxygen deprivation), whereas N-113, N-114, and N-115 exhibited PC50 values of 30 nM, 111 nM, and 0.9 nM under glucose and oxygen deprivation conditions. Thus, N-compounds were shown to be approximately 10,000 times more potent than gemcitabine under low-nutrient and hypoxic conditions.
１０．N-化合物の抗がん剤としての使用とGEMとの併用による同所性膵臓腫瘍モデルでの抗腫瘍効果と生存率の改善
　N-化合物の抗がん剤としての有効性は、免疫正常C57Bl/6マウスを用いた同所性膵臓腫瘍モデルで評価された。マウスにN-42、GEM、またはN-42とGEMの併用投与を行い、エンドポイント試験および全体試験に供した。
　本発明の実験プロトコール（図１３）では、まずKPCYマウス膵臓がん細胞を皮下接種し、宿主BALB/c-nuマウスで2～3週間増殖させた。移植日に、宿主BALB/c-nuマウスの腫瘍を摘出し、約15mgの大きさの小片に切断した。この腫瘍の小片を、外科手術によってC57Bl/6レシピエントマウスの膵臓に移植した。手術後3日目にマウスを無作為に割り付け、3日目からN-42、GEM、または2つの薬剤の併用投与を行った。
　エンドポイント試験では、16日目にマウスを犠牲にし、生存試験では、すべてのマウスが死亡するまで薬剤の投与が継続された。マウスの全生存期間は、Kaplan-Meier生存プロットを用いて決定し、Log-rank検定により解析した。 10. Use of N-compounds as anticancer agents and combination with GEM improves antitumor efficacy and survival in an orthotopic pancreatic tumor model It was evaluated in an orthotopic pancreatic tumor model using /6 mice. Mice were administered N-42, GEM, or a combination of N-42 and GEM and subjected to endpoint and global studies.
In our experimental protocol (FIG. 13), KPCY mouse pancreatic cancer cells were first inoculated subcutaneously and grown in host BALB/c-nu mice for 2-3 weeks. On the day of implantation, tumors in host BALB/c-nu mice were excised and cut into pieces approximately 15 mg in size. Small pieces of this tumor were surgically implanted into the pancreas of C57B1/6 recipient mice. Mice were randomly assigned on day 3 after surgery and received N-42, GEM, or a combination of the two drugs from day 3 onwards.
For endpoint studies, mice were sacrificed on day 16, and for survival studies, drug administration continued until all mice died. Overall mouse survival was determined using Kaplan-Meier survival plots and analyzed by the Log-rank test.
＜結果＞
　エンドポイント試験の結果を図１４に示す。その結果、対照群の平均腫瘍重量が最も高く、N-42群は平均腫瘍重量が有意に低いことが示された。N-42とGEMの組み合わせでは、平均腫瘍重量が最も低く、他のすべてのグループと比較して有意に低い値を示した。これは、同所性腫瘍の成長を減少させるN-42およびGEMとの組み合わせの強い抗腫瘍活性を実証するものである。
　エンドポイント試験の結果、N-42の単剤投与は同所腫瘍の成長を有意に抑制した。N-42とGEMを併用した場合、非常に強い抗腫瘍活性が認められ、統計学的に有意な腫瘍増殖の減少が見られた。群間でマウスの体重に明らかな変化はなかった。 <Results>
Results of the endpoint study are shown in FIG. The results showed that the control group had the highest mean tumor weight and the N-42 group had a significantly lower mean tumor weight. The combination of N-42 and GEM had the lowest mean tumor weight, significantly lower than all other groups. This demonstrates the strong anti-tumor activity of the combination with N-42 and GEM in reducing orthotopic tumor growth.
End-point studies showed that single-agent N-42 significantly inhibited orthotopic tumor growth. When N-42 and GEM were combined, very strong anti-tumor activity was observed and a statistically significant reduction in tumor growth was observed. There was no apparent change in body weight of mice between groups.
　全生存試験の結果を図１５に示す。その結果、Kaplan-Meier生存プロットで示され、Log-rank検定で分析されるように、N-化合物が、膵臓腫瘍を有する免疫正常C57Bl/6マウスにおいて有意な全生存率を示した。同所性膵臓腫瘍モデルにおいて、対照群の生存期間中央値は28.5日、N-42で処置したマウスの生存期間中央値は41日、N-42とGEMの併用で処置したマウスの生存期間中央値は55.5日であった。これらの結果は、N-化合物が全生存率を向上させ、N-化合物およびGEMとの併用が膵臓癌の有効な治療薬となる可能性を示している。 The results of the overall survival study are shown in Figure 15. As a result, the N-compound showed significant overall survival in immune-normal C57B1/6 mice bearing pancreatic tumors, as shown by Kaplan-Meier survival plots and analyzed by the Log-rank test. In an orthotopic pancreatic tumor model, the median survival of the control group was 28.5 days, the median survival of mice treated with N-42 was 41 days, and the median survival of mice treated with the combination of N-42 and GEM The value was 55.5 days. These results indicate that N-compounds improve overall survival and that the combination of N-compounds and GEM may be effective therapeutic agents for pancreatic cancer.
＜考察＞
　本発明は、既存の抗がん剤とは全く異なるスクリーニングで見出したものである。すなわち、栄養の豊富な状態では毒性をほとんど示さず、栄養飢餓状態においてのみがん細胞に毒性を示す極めてユニークな化合物である複数のフェニルベンズアミド誘導体が見出された。これは、まさしく抗がん剤特有の深刻な副作用を回避することができることを示している。また、フェニルベンズアミド誘導体は、がんの増殖や栄養飢餓耐性等の主要機構に関する複数のキナーゼを阻害する。したがって、膵臓がんのみならず、耐性を示す膵臓がんやがん全般に効果を奏すると考えられる。
　一方、がん細胞では、栄養飢餓状態であればある程、増殖能、転移能さらには悪性度が高いことが明らかになりつつある。これは、がん幹細胞に密接に関わっていると考えられ、事実栄養飢餓状態においてはがん幹細胞の発現が著しく増大している。がん幹細胞を効果的に死滅させなければ、やがてがんの再発を招くことになり極めて深刻である。本発明は、がん微小環境、すなわち栄養飢餓状態における細胞毒性に特に焦点を当てたアプローチであり、このがん幹細胞にも効果を発揮する可能性が極めて高いことに加え、複数の作用機序によって、がん細胞を効果的に死滅させることができる画期的薬剤の提案である。さらに、本発明に用いられる化合物とともに、他の抗がん剤、特に膵臓がんの場合、Gemcitabineを多剤併用すると、単独投与に比べさらに優れた腫瘍効果を示す。 <Discussion>
The present invention was discovered through screening that is completely different from existing anticancer agents. In other words, several phenylbenzamide derivatives were discovered, which are extremely unique compounds that exhibit little toxicity to cancer cells under nutrient-rich conditions and exhibit toxicity to cancer cells only under nutrient-starved conditions. This indicates that serious side effects peculiar to anticancer drugs can be avoided. Phenylbenzamide derivatives also inhibit multiple kinases involved in key mechanisms such as cancer growth and resistance to nutrient starvation. Therefore, it is thought to be effective not only against pancreatic cancer but also against pancreatic cancer showing resistance and cancer in general.
On the other hand, it is becoming clear that in cancer cells, the more they are in a state of nutritional starvation, the higher their proliferative ability, metastatic ability, and malignancy. This is considered to be closely related to cancer stem cells, and in fact, the expression of cancer stem cells is significantly increased under conditions of nutritional starvation. If cancer stem cells are not effectively killed, the cancer will eventually recur, which is extremely serious. The present invention is an approach that specifically focuses on cytotoxicity in the cancer microenvironment, i.e., nutrient starvation, and is very likely to be effective in this cancer stem cell as well. This is a proposal for an epoch-making drug that can effectively kill cancer cells by Furthermore, in combination with the compounds used in the present invention, other anticancer agents, especially in the case of pancreatic cancer, combined use of multiple agents with Gemcitabine exhibits superior tumor effects compared to single administration.
　本発明は、がん治療用医薬組成物として用いることができる。 The present invention can be used as a pharmaceutical composition for cancer treatment.

Claims (19)

  1. 　下記式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩を有効成分として含有する、医薬組成物：
    Figure JPOXMLDOC01-appb-C000001
     
    　式中、
    　Ｒ１は、水素、ヒドロキシ、炭素数１～１０のカルボン酸エステル、または炭素数１～４のアルコキシを示し、
    　Ｒ２～Ｒ４は、それぞれ独立に、水素、電子供与性基または電子吸引性基を示し、
    　Ｒ５は、水素、ヒドロキシ、炭素数１～１０のカルボン酸エステル、炭素数１～４のアルコキシ、またはＲ６と結合し形成した環を示し、
    　Ｒ６は、水素、またはＲ５と結合し形成した環を示し、
    　Ｒ７およびＲ１１は、それぞれ独立に、水素、またはハロゲンを示し、
    　Ｒ８～Ｒ１０は、それぞれ独立に、水素、電子供与性基または電子吸引性基を示し、
    　ＸおよびＹは、それぞれ独立に、炭素、または窒素であり、
    　Ｒ２～Ｒ４およびＲ８～Ｒ１０の少なくとも１つは電子吸引性基である。     A pharmaceutical composition containing a compound represented by the following formula (I) or a pharmacologically acceptable salt thereof as an active ingredient:
    Figure JPOXMLDOC01-appb-C000001

    During the ceremony,
    R 1 represents hydrogen, hydroxy, carboxylic acid ester having 1 to 10 carbon atoms, or alkoxy having 1 to 4 carbon atoms,
    R 2 to R 4 each independently represent hydrogen, an electron-donating group or an electron-withdrawing group,
    R 5 represents hydrogen, hydroxy, carboxylic acid ester having 1 to 10 carbon atoms, alkoxy having 1 to 4 carbon atoms, or a ring formed by combining with R 6 ,
    R 6 represents hydrogen or a ring formed by combining with R 5 ,
    R 7 and R 11 each independently represent hydrogen or halogen,
    R 8 to R 10 each independently represent hydrogen, an electron-donating group or an electron-withdrawing group,
    X and Y are each independently carbon or nitrogen;
    At least one of R 2 -R 4 and R 8 -R 10 is an electron withdrawing group.
  2. 　前記Ｒ９が、電子吸引性基である、請求項１に記載の医薬組成物。 2. The pharmaceutical composition of Claim 1, wherein said R9 is an electron-withdrawing group.
  3. 　前記Ｒ２およびＲ３の少なくとも１つが、電子供与性基または電子吸引性基である、請求項１または２に記載の医薬組成物。 3. The pharmaceutical composition according to claim 1 or 2, wherein at least one of said R2 and R3 is an electron-donating group or an electron-withdrawing group.
  4. 　前記電子吸引性基が、ハロゲン、炭素数１～４のハロゲン化アルキル、炭素数１～１０のカルボン酸エステル、炭素数１～４のアシル、シアノ（－ＣＮ）、ニトロ（－ＮＯ2）、炭素数１～４のアルキルチオ（－ＳＲ；Ｒはアルキルを示す）、炭素数１～４のアルキルスルフィニル（－ＳＯＲ；Ｒはアルキルを示す）、炭素数１～４のアルキルスルホニル（－ＳＯ２Ｒ；Ｒはアルキルを示す）；またはこれらの電子吸引性基を置換基として有するアリールまたはヘテロアリールである、請求項１～３のいずれか１項に記載の医薬組成物。 the electron withdrawing group is halogen, halogenated alkyl having 1 to 4 carbon atoms, carboxylic acid ester having 1 to 10 carbon atoms, acyl having 1 to 4 carbon atoms, cyano (--CN), nitro (--NO 2 ), C 1-4 alkylthio (-SR; R represents alkyl), C 1-4 alkylsulfinyl (-SOR; R represents alkyl), C 1-4 alkylsulfonyl (-SO 2 R ; R represents alkyl); or aryl or heteroaryl having these electron-withdrawing groups as substituents.
  5. 　前記電子供与性基がヒドロキシ、炭素数１～４のアルキル、炭素数１～４のアルコキシ、またはアミノである、請求項１～４のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 4, wherein the electron-donating group is hydroxy, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or amino.
  6. 　栄養飢餓状態の腫瘍細胞を選択的に死滅させるための、請求項１～５のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 5, for selectively killing nutrient-starved tumor cells.
  7. 　抗がん用である、請求項１～６のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 6, which is for anticancer use.
  8. 　前記がんが、膵臓がんである、請求項７に記載の医薬組成物。 The pharmaceutical composition according to claim 7, wherein the cancer is pancreatic cancer.
  9. 　前記膵臓がんが、式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩以外の抗がん化合物に対して耐性を示す膵臓がんである、請求項８に記載の医薬組成物。 The pharmaceutical composition according to claim 8, wherein the pancreatic cancer is resistant to an anticancer compound other than the compound represented by formula (I) or a pharmacologically acceptable salt thereof. thing.
  10. 　がん幹細胞の発生抑制用、または、がん幹細胞の殺傷用である、請求項１～９のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 9, which is for suppressing the development of cancer stem cells or for killing cancer stem cells.
  11. 　さらに、式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩以外の抗がん化合物を含有する、請求項１～１０のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 10, further comprising an anticancer compound other than the compound represented by formula (I) or a pharmacologically acceptable salt thereof.
  12. 　式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩以外の抗がん化合物と併用投与されるように用いられるための、請求項１～１１のいずれか１項に記載の医薬組成物。 12. The method according to any one of claims 1 to 11, for use in combination administration with an anticancer compound other than a compound represented by formula (I) or a pharmacologically acceptable salt thereof. pharmaceutical composition.
  13. 　前記式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩以外の抗がん化合物が、代謝拮抗薬である、請求項９、１１または１２のいずれか１項に記載の医薬組成物。 13. The medicament according to any one of claims 9, 11 or 12, wherein the anticancer compound other than the compound represented by formula (I) or a pharmacologically acceptable salt thereof is an antimetabolite. Composition.
  14. 　前記代謝拮抗薬が、ゲムシタビンである、請求項１３に記載の医薬組成物。 The pharmaceutical composition according to claim 13, wherein the antimetabolite is gemcitabine.
  15. 　下記式（Ｉ）’で示される化合物、またはその薬理学的に許容可能な塩：
    Figure JPOXMLDOC01-appb-C000002
     
    　式中、
    　Ｒ１’は、水素、ヒドロキシ、炭素数１～１０のカルボン酸エステル、または炭素数１～４のアルコキシを示し、
    　Ｒ２’～Ｒ４’は、それぞれ独立に、水素、電子供与性基または電子吸引性基を示し、
    　Ｒ５’は、水素、ヒドロキシ、炭素数１～１０のカルボン酸エステル、炭素数１～４のアルコキシ、またはＲ６’と結合し形成した環を示し、
    　Ｒ６’は、水素、またはＲ５’と結合し形成した環を示し、
    　Ｒ７’およびＲ１１’は、それぞれ独立に、水素、またはハロゲンを示し、
    　Ｒ８’およびＲ１０’は、それぞれ独立に、水素、または電子吸引性基を示し、
    　Ｒ９’は、電子吸引性基を示し、
    　Ｘ’およびＹ’は、それぞれ独立に、炭素、または窒素であり、
    　Ｒ９’がヒドロキシである場合、Ｒ２’はアルコキシ以外であり、
    　Ｒ９’がシアノまたはニトロである場合、Ｒ２’は塩素以外である。     A compound represented by the following formula (I)', or a pharmacologically acceptable salt thereof:
    Figure JPOXMLDOC01-appb-C000002

    During the ceremony,
    R 1 ' represents hydrogen, hydroxy, carboxylic acid ester having 1 to 10 carbon atoms, or alkoxy having 1 to 4 carbon atoms,
    R 2 ' to R 4 ' each independently represent hydrogen, an electron-donating group or an electron-withdrawing group,
    R 5 ' represents hydrogen, hydroxy, carboxylic acid ester having 1 to 10 carbon atoms, alkoxy having 1 to 4 carbon atoms, or a ring formed by combining with R 6 ',
    R 6 ' represents hydrogen or a ring formed by combining with R 5 ',
    R 7 ' and R 11 ' each independently represent hydrogen or halogen,
    R 8 ' and R 10 ' each independently represent hydrogen or an electron-withdrawing group,
    R 9 ' represents an electron-withdrawing group,
    X' and Y' are each independently carbon or nitrogen;
    when R 9 ' is hydroxy, then R 2 ' is other than alkoxy;
    When R 9 ' is cyano or nitro, R 2 ' is other than chlorine.
  16. 　前記電子吸引性基が、ハロゲン、炭素数１～４のハロゲン化アルキル、炭素数１～１０のカルボン酸エステル、炭素数１～４のアシル、シアノ（－ＣＮ）、ニトロ（－ＮＯ2）、炭素数１～４のアルキルチオ（－ＳＲ；Ｒはアルキルを示す）、炭素数１～４のアルキルスルフィニル（－ＳＯＲ；Ｒはアルキルを示す）、炭素数１～４のアルキルスルホニル（－ＳＯ２Ｒ；Ｒはアルキルを示す）；またはこれらの電子吸引性基を置換基として有するアリールまたはヘテロアリールである、請求項１５に記載の化合物、またはその薬理学的に許容可能な塩。 the electron withdrawing group is halogen, halogenated alkyl having 1 to 4 carbon atoms, carboxylic acid ester having 1 to 10 carbon atoms, acyl having 1 to 4 carbon atoms, cyano (--CN), nitro (--NO 2 ), C 1-4 alkylthio (-SR; R represents alkyl), C 1-4 alkylsulfinyl (-SOR; R represents alkyl), C 1-4 alkylsulfonyl (-SO 2 R R represents alkyl); or aryl or heteroaryl having these electron-withdrawing groups as substituents, or a pharmaceutically acceptable salt thereof according to claim 15.
  17. 　前記電子供与性基がヒドロキシ、炭素数１～４のアルキル、炭素数１～４のアルコキシ、またはアミノである、請求項１５または１６に記載の化合物、またはその薬理学的に許容可能な塩。 The compound according to claim 15 or 16, or a pharmacologically acceptable salt thereof, wherein the electron-donating group is hydroxy, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or amino.
  18. 　請求項１５～１７のいずれか１項に記載の化合物、またはその薬理学的に許容可能な塩の、栄養飢餓状態の腫瘍細胞を選択的に死滅させる抗がん剤としての使用。 Use of the compound according to any one of claims 15 to 17, or a pharmacologically acceptable salt thereof, as an anticancer agent that selectively kills nutrient-starved tumor cells.
  19. 　請求項１５～１７のいずれか１項に記載の化合物、またはその薬理学的に許容可能な塩の、がん幹細胞の発生を抑制させる、または、がん幹細胞を殺傷させる抗がん剤としての使用。 The compound according to any one of claims 15 to 17, or a pharmacologically acceptable salt thereof, as an anticancer agent that suppresses the development of cancer stem cells or kills cancer stem cells use.
PCT/JP2023/003580 2022-02-03 2023-02-03 Novel pharmaceutical composition WO2023149548A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2022015848 2022-02-03
JP2022-015848 2022-02-03

Publications (1)

Publication Number Publication Date
WO2023149548A1 true WO2023149548A1 (en) 2023-08-10

Family

ID=87552610

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2023/003580 WO2023149548A1 (en) 2022-02-03 2023-02-03 Novel pharmaceutical composition

Country Status (1)

Country Link
WO (1) WO2023149548A1 (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004022525A1 (en) * 2002-09-05 2004-03-18 Neurosearch A/S Amide derivatives and their use as chloride channel blockers
JP2011511806A (en) * 2008-02-07 2011-04-14 マサチューセッツ・アイ・アンド・イア・インファーマリー Compounds that enhance Atoh1 expression
WO2019074747A1 (en) * 2017-10-09 2019-04-18 Merck Sharp & Dohme Corp. Novel substituted cyclobutylbenzene compounds as indoleamine 2,3-dioxygenase (ido) inhibitors
JP2021536458A (en) * 2018-09-04 2021-12-27 マジェンタ セラピューティクス インコーポレイテッドMagenta Therapeutics, Inc. Aryl Hydrocarbon Receptor Antagonists and Usage

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004022525A1 (en) * 2002-09-05 2004-03-18 Neurosearch A/S Amide derivatives and their use as chloride channel blockers
JP2011511806A (en) * 2008-02-07 2011-04-14 マサチューセッツ・アイ・アンド・イア・インファーマリー Compounds that enhance Atoh1 expression
WO2019074747A1 (en) * 2017-10-09 2019-04-18 Merck Sharp & Dohme Corp. Novel substituted cyclobutylbenzene compounds as indoleamine 2,3-dioxygenase (ido) inhibitors
JP2021536458A (en) * 2018-09-04 2021-12-27 マジェンタ セラピューティクス インコーポレイテッドMagenta Therapeutics, Inc. Aryl Hydrocarbon Receptor Antagonists and Usage

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
KAUSHAL JYOTI, BHATIA RAKESH, KANCHAN RANJANA, RAUT PRATIMA, MALLAPRAGADA SURYA, LY QUAN, BATRA SURINDER, RACHAGANI SATYANARAYANA: "Repurposing Niclosamide for Targeting Pancreatic Cancer by Inhibiting Hh/Gli Non-Canonical Axis of Gsk3β", DEPARTMENT OF BIOCHEMISTRY AND MOLECULAR BIOLOGY, UNIVERSITY OF NEBRASKA MEDICAL CENTER, OMAHA, NE 68198, USA, vol. 13, no. 13, pages 3105, XP093082542, DOI: 10.3390/cancers13133105 *
LI ZHONG, XU JIMIN, LANG YUEKUN, FAN XIAOYU, KUO LILI, D’BRANT LIANNA, HU SAIYANG, SAMRAT SUBODH KUMAR, TRUDEAU NICOLE, THARAPPEL : "JMX0207, a Niclosamide Derivative with Improved Pharmacokinetics, Suppresses Zika Virus Infection Both In Vitro and In Vivo", ACS INFECTIOUS DISEASES, AMERICAN CHEMICAL SOCIETY, US, vol. 6, no. 10, 9 October 2020 (2020-10-09), US , pages 2616 - 2628, XP093082548, ISSN: 2373-8227, DOI: 10.1021/acsinfecdis.0c00217 *
TANG, ZHONGHAI, ACUÑA, ULYANA MUÑOZ, FERNANDES, NELSON FREITAS, CHETTIAR, SOMSUNDARAM: "Structure–Activity Relationship of Niclosamide Derivatives", ANTICANCER RESEARCH, INTERNATIONAL INSTITUTE OF ANTICANCER RESEARCH, GR, vol. 37, no. 6, 29 May 2017 (2017-05-29), GR , pages 2839 - 2843, XP093082547, ISSN: 0250-7005, DOI: 10.21873/anticanres.11635 *

Similar Documents

Publication Publication Date Title
TWI812581B (en) Kinase modulation, and indications therefor
RU2316326C2 (en) Method and composition for cancer disease treatment, tosylate and pharmaceutically acceptable salts of n-(4-chloro-3-(trifluoromethyl)phenyl)-n&#39;-(4-(2-(n-methylcarbamoyl)-4-pyridyloxy)phenyl)urea
TW201601727A (en) Methods for the treatment of solid tumors
JP2009538317A (en) Drug combinations using substituted diarylureas for cancer treatment
KR102634247B1 (en) Drug combinations to treat multiple myeloma
AU2016213972A1 (en) Combinations of IRS/Stat3 dual modulators and anti-cancer agents for treating cancer
JP6381523B2 (en) Administration regimen of PI-3 kinase inhibitor
WO2012012454A1 (en) Methods of treating metastatic breast cancer with 4-iodo-3-nitrobenzamide and irinotecan
JP2016528162A (en) Use of eribulin and lenvatinib as combination therapy for the treatment of cancer
JP2015536986A (en) Combination therapy
WO2010031265A1 (en) Pharmaceutical composition for the treatment of proliferative diseases
JP6768682B2 (en) Apirimodo for use in the treatment of melanoma
JP2018138570A (en) Use of amg 900 for treatment of cancer
WO2014201111A1 (en) Treatment of mtor hyperactive related diseases and disorders
BRPI0620242A2 (en) combination comprising combretastatin and anti-cancer agents
TW201130830A (en) Combined treatment of pancreatic cancer with gemcitabine and masitinib
US20170112865A1 (en) Treatment for melanoma
CA3017552A1 (en) Combination therapy for proliferative diseases
JP2012526772A (en) Combination of phosphoinositide 3-kinase inhibitor and antidiabetic compound
WO2023149548A1 (en) Novel pharmaceutical composition
JP2022534742A (en) Method for treating cholangiocarcinoma
WO2020236668A1 (en) Leukadherin-1 alone or in combination for use in the treatment of cancer
US11124489B2 (en) EPAC antagonists
JP2019519573A (en) Methods for treating cancer
US20220409582A1 (en) Combination therapies comprising panobinostat for the treatment of cholangiocarcinoma

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23749864

Country of ref document: EP

Kind code of ref document: A1