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.

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