WO2010150927A1 - Composition pharmaceutique pour la prévention et le traitement de maladies cancéreuses, comprenant des dérivés de benzamide - Google Patents

Composition pharmaceutique pour la prévention et le traitement de maladies cancéreuses, comprenant des dérivés de benzamide Download PDF

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WO2010150927A1
WO2010150927A1 PCT/KR2009/003420 KR2009003420W WO2010150927A1 WO 2010150927 A1 WO2010150927 A1 WO 2010150927A1 KR 2009003420 W KR2009003420 W KR 2009003420W WO 2010150927 A1 WO2010150927 A1 WO 2010150927A1
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group
alkyl
substituted
pharmaceutical composition
alkoxy
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Mi-Jung Lim
Hyun-Jung Kwak
Man-Young Cha
Sang-Rak Choi
Sun-Gwan Hwang
Kyung-Chul Cho
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SK Inc
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SK Holdings Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a pharmaceutical composition for prevention and treatment of cancer diseases, and more particularly, to a pharmaceutical composition for prevention and treatment of cancer diseases such as colorectal cancer comprising benzamide derivatives or pharmaceutically available salts thereof as active components.
  • Cancer is a disease that is defined as uncontrolled proliferation and abnormal cell spreading, and is an incurable disease that takes the second place next to unexpected accidents.
  • the cancer diseases have appeared as social and economic problems due to continuous increases in cancer incidence and early cancer outbreaks.
  • the outbreak causes of cancer are mainly divided into extrinsic factors (smoking, chemical drugs, radiations, etc.) and intrinsic factors (genetic mutations, hormones, immune conditions, etc.). These factors have been known to act together, or act sequentially to initiate or promote carcinogenesis.
  • Many genes (oncogenes or tumor suppressor genes) affecting the induction of cancer have been known, and the cancer induced by radical accumulation of genetic mutants induces abnormal cell growth. Finally, the proliferated cancer cells move to other human tissues or organs.
  • Single nucleotide polymorphism may cause errors in signaling pathways since the SNP affects the signaling pathways that require normal roles of a target gene.
  • one representative example of the signaling pathways includes a Wnt/ ⁇ -catenin signaling pathway.
  • the Wnt signaling pathway is directly associated with the anticancer activities, and is recognized as the most general characteristics of human malignancy.
  • Wnt is a group of highly conserved proteins that are associated with the differentiation, growth, maturation and movement of cells. It was known that these proteins maintain homeostasis in adult tissues during a germinating period of cells, and regulate the growth, morphology and motility of cells (Mark L. Johnson et al., 2006; Janssens N. et al., 2006).
  • Typical Wnt signal transduction stabilizes ⁇ -catenin proteins by the control of protein kinases, thus to induces the migration into the cell nucleus and the transcriptional activities. It was reported that these transcriptional activities are induced by transcription factors including a group of Lef1/Tcf (Moon RT et al., 2002; Reya T and Clevers H, 2005; Wodarz A and Nusse R, 1998).
  • glycogen-synthase kinase-3 ⁇ forms a complex together with adenomatous polyposis coli (APC) and Axin proteins (a scaffolding protein complex) to induce the phosphorylation of a main regulator ⁇ -catenin.
  • APC adenomatous polyposis coli
  • Axin proteins a scaffolding protein complex
  • Wnt activates a transducer protein, Dvl (Dishevelled), to suppress the activities of GSK-3 ⁇ .
  • Dvl Dishevelled
  • the suppression of the GSK activities results in the accumulation of ⁇ -catenin in the cytoplasm, and the accumulated ⁇ -catenin migrates into the nucleus and binds to a variety of transcription factors to induce the expression of target genes.
  • Representative target genes associated with the Wnt signal transduction include a large number of oncogenes such as matrix metalloproteinases (MMP, for example, MMP2, MMP3, MMP7 and MMP9), cyclin D1, Cox-2, c-myc, c-jun, Fra-1 and VEGFR, which are all associated with the outbreak and invasion of cancer.
  • MMP matrix metalloproteinases
  • cyclin D1 Cox-2
  • c-myc c-jun
  • Fra-1 and VEGFR VEGFR
  • the mutations of various regulators for example, APC, Axin, ⁇ -catenin, etc.
  • the mutations of APC or ⁇ -catenin have been found in a large number of cancer diseases (liver cancer, prostate cancer, ovarian cancer and stomach cancer).
  • cytotoxic drugs Most of cytotoxic drugs have been used are used as the therapeutic agents for treating cancer disease to treat cancer. However, these cytotoxic drugs adversely affect the quality of patients lives due to their sever side effects, and have their limits such as the unexpectedly low treatment effects on advanced tumor such as recurring or metastatic cancer diseases. Therefore, there is an urgent demand for development of new drugs that show beneficial effects on progressive cancers and may relieve side effects by improvement of the cancer cell selectivity and specificity.
  • a molecular target drug, EGFR inhibitor, or a VEGFR inhibitor, Avastin which is recently on the market, has been used along with the cytotoxic drugs.
  • Wnt signaling molecules have been recognized to be a good target to screen drugs. Accordingly, there are many attempts to find compounds (activators or inhibitors) that can control the Wnt signaling molecules, and to develop new drugs.
  • the present inventors have made ardent attempts to solve the above-mentioned problems, and found that benzamide derivatives and their pharmaceutically available salts, which act as antagonists that have the effect of suppressing the Wnt/ ⁇ -catenin signaling pathway, show an anticancer effect. Therefore, the present invention was completed on the basis of the above facts.
  • the present invention is designed to solve some of the problems of the prior art, and therefore it is an object of the present invention to provide a pharmaceutical composition having the effect of prevention and treatment of cancer diseases since the pharmaceutical composition comprises benzamide derivatives or their pharmaceutically available salts as active components.
  • a pharmaceutical composition for prevention and treatment of cancer including benzamide derivatives represented by the following formula 1, or pharmaceutically available salts thereof as active components:
  • A is -(CH 2 ) 0 - or -(NR 4 )-
  • B is -(CH 2 ) 0 - or -(NH)n(NHR 5 )-
  • n is an integer of 0 and 1
  • R 4 and R 5 are same or different, and each of the R 4 and R 5 is a group represented by hydrogen or alkyl
  • R 1 and R 2 are same or different, and each of R 1 and R 2 is selected from the group consisting of hydrogen; alkyl group; alkyl group substituted with alkynyl alkoxy, cycloalkyl or aryl; and aryl group substituted with alkyl, alkynyl alkoxy, cycloalkyl or aryl, or
  • R 1 and R 2 form a pyrrolidine, morpoline, piperidine or piperazine ring together with adjacent N, wherein
  • At least one hydrogen in the pyrrolidine, morpoline, piperidine or piperazine ring may be substituted with alkyl group; alkynyl- or alkoxy-substituted alkyl group; aryl group; aryl group substituted with alkyl, alkynyl or alkoxy; carboxy group; or carbamoyl group, or may be fused with other aryl group, and
  • R 3 is selected from the group consisting of hydrogen, alkyl, aryl-substituted alkyl group, aryl group, aryl group substituted with halo, alkoxy, carboalkoxy, carbamoyl, cyano, hydroxyl, nitro or thio, heteroaryl group, and heteroaryl group substituted with alkyl, halo, alkoxy, carboalkoxy or aryl group.
  • benzamide derivatives may be presented by the following formula 2:
  • R 1 , R 2 , R 3 and R 5 are defined in the same manner as described above.
  • benzamide derivatives may be represented by the following formula 3:
  • X is CH 2 -, O, S, NR 7 R 8 ,
  • R 3 and R 5 are defined in the same manner as described above,
  • R 6 is selected from the group consisting of hydrogen, alkyl group, alkynyl- or alkoxy-substituted alkyl group, phenyl group, and substituted phenyl group, or forms a fused ring together with the other substituted ring,
  • R 7 and R 8 are same or different, and each of R 7 and R 8 is selected from the group consisting of hydrogen, alkyl group, alkynyl-, hydroxyl- or alkoxy-substituted alkyl group, hydroxyl, carboxyalkoxy and carbamoyl group.
  • benzamide derivatives may be represented by the following formula 4:
  • R 1 , R 2 , R 3, and R 5 are defined in the same manner as described above.
  • the residue R 3 may be heteroaryl selected from the group consisting of thiazole; oxadiazole; benzothiazole; and rings thereof in which at least one hydrogen substituted with alkyl, halo, alkoxy, carboalkoxy, aryl or heteroaryl.
  • benzamide derivatives may be represented by the following formula 5:
  • benzamide derivatives may be represented by the following formula 5:
  • R 1, R 2 , and R 4 are defined in the same manner as described above, and
  • R 3 is selected from the group consisting of aryl group, alkyl-substituted alkyl group, aryl group substituted with aryl, halo, alkyl, alkoxy, carboalkoxy, carbamoyl, cyano, hydroxyl, nitro or thio, heteroaryl group, and heteroaryl group substituted with alkyl, halo, alkoxy, carboalkoxy or aryl group.
  • the residue R 3 may be heteroaryl selected from the group consisting of thiazole; oxadiazole; benzothiazole; and rings thereof in which at least one hydrogen substituted with alkyl, halo, alkoxy, carboalkoxy, aryl or heteroaryl.
  • the pharmaceutical composition according to one exemplary embodiment of the present invention may be useful to prevent or treat a variety of cancer diseases such as colorectal cancer (CRC) since the pharmaceutical composition is associated with the cell growth inhibition and the tumor growth retardation, including the suppression of the Wnt signaling pathway.
  • CRC colorectal cancer
  • FIG. 1 shows an effect of a pharmaceutical composition according to one exemplary embodiment of the present invention on Tcf-4 activities.
  • FIG. 2 shows the body weight change after the administration of the pharmaceutical composition according to one exemplary embodiment of the present invention.
  • FIG. 3 shows the tumor volume changes after the administration of the pharmaceutical composition according to one exemplary embodiment of the present invention.
  • Alkyl group has 1 to 10 carbon atoms and may be composed of linear or branched saturated or unsaturated hydrocarbon.
  • Cycloalkyl group has a 3 to 12-membered ring structure comprising saturated or partially unsaturated hydrocarbon, and may include 0 to 5 heteroatoms such as oxygens, sulfur, nitrogen and the like.
  • the ring structure is a 3 to 12-membered single ring or fused ring compound.
  • cycloalkyl group examples include, but are not particularly limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohehexyl, cycloheptyl, cyclooctyl, morpholinyl, homomorpholinyl, thiomorpholinyl, homothiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, pyrrolidiny, pyrrolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyr
  • Aryl group include both aromatic group composed of 5 to 15-membered single-ring or fused-ring unsaturated hydrocarbons and heteroaromatic group containing 1 to 5 heteroatoms such as oxygen, sulfur, nitrogen and the like.
  • aryl group examples include, but are not particularly limited to, phenyl, 1-naphtyl, 2-naphtyl, pyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, pyrazinyl, isoindolyl, isoquinolyl, qunazolinyl, quinoxalinyl, phthalazinyl, imidazolinyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl, cinn
  • Halo is the general term for fluoro, chloro, bromo and iodo.
  • the benzamide derivatives according to one exemplary embodiment of the present invention pharmaceutically available acids or base addition salts, and stereochemical isomers of the compounds of the Formulas 1 to 5.
  • the base addition salts include any salts that maintain the activities of parent compounds and does not induce undesirable effects in objects to be administered, but the present invention is not particularly limited thereto.
  • These salts comprise inorganic salts and organic salts, and preferably include the following acids.
  • the acids include, but are not particularly limited to, acetic acid, nitric acid, aspartic acid, sulfonic acid, sulfuric acid, maleic acid, glutamic acid, formic acid, succinic acid, phosphoric acid, phthalic acid, tannic acid, tartaric acid, hydrobromic acid, propionic acid, benzenesulfonic acid, benzoic acid, stearic acid, esyl acid, lactic acid, bicarbonic acid, busulfuric acid, bitartaric acid, oxalic acid, butyric acid, calcium edentate acid, camsylic acid, carbonic acid, chlorobenzoic acid, citric acid, edetic acid, toluenesulfonic acid, edisylic acid, esylic acid, fumaric acid, gluceptic acid, pamoic acid, gluconic acid, glycollylarsanilic acid, methylnitric acid, hydrochloric acid,
  • the basic slats include, for example, ammonium salts, alkaline metal or alkaline earth metal salts, particularly lithium, sodium, potassium, magnesium and calcium salts, salts containing an organic base, for example, bezatin, N-methyl-D-glucamine, hydrabamin salts, and salts containing an amino acid, for example, arginine, lysine and the like.
  • salt form may be converted into free salt form by treatment with suitable bases or acids.
  • the preferred salt of the benzamide derivatives of the present invention is benzo[1,3]-dioxole-5-carboxylic acid[4-(4-methoxy-phenylsulfamoyl)-phenyl]-amide.
  • the present invention provides a method for prevention or treatment of cancer using as the active components the benzamide derivatives or their pharmaceutically available salts represented by Formulas 1 to 5, wherein the benzamide derivatives or their pharmaceutically available salts show the anticancer activity since they have the effect of suppressing the Wnt/ ⁇ -catenin signaling pathway.
  • the pharmaceutical composition according to one exemplary embodiment of the present invention may be useful to prevent and treat a variety of cancer diseases.
  • the cancer diseases may include, but are not particularly limited to, colorectal cancer, breast cancer, liver cancer, prostate cancer, ovarian cancer, stomach cancer, etc.
  • the cancer disease is colorectal cancer.
  • the compounds of the present invention may be prepared by a variety of synthesis or para-synthesis technologies. Suitable starting materials are known in the art, or may be prepared by the known synthesis methods or be commercially purchased. Therefore, it should be understood that other equivalents and modifications of the synthetic pathway may be made by those skilled in the art in order to use other starting materials or selective reagents, and reaction conditions (for example, temperature, solvents and the like) may be suitably changed in order to realize the desired equivalents and modifications. Additionally, it may be recognized by those skilled in the art that protective groups may be required to prepare any of the compounds, and the reaction conditions suitable for the selected protective groups are also widely known. Therefore, it should be understood that the methods and exemplas proposed herein are just preferable examples for the purpose of illustrations only, not intended to limit the scope of the invention.
  • n is an integer of 0 or 1
  • R 1 and R 2 are same or different, and each of R 1 and R 2 is selected from the group consisting of hydrogen; alkyl group; alkyl group substituted with alkynyl alkoxy, cycloalkyl or aryl; and aryl group substituted with alkyl, alkynyl alkoxy, cycloalkyl or aryl, or
  • R 1 and R 2 form a pyrrolidine, morpoline, piperidine or piperazine ring together with adjacent N, wherein
  • At least one hydrogen in the pyrrolidine, morpoline, piperidine or piperazine ring may be substituted with alkyl group; alkynyl- or alkoxy-substituted alkyl group; aryl group; aryl group substituted with alkyl, alkynyl or alkoxy; carboxy group; or carbamoyl group, or may be fused with other aryl group, and
  • R 3 is selected from the group consisting of hydrogen, alkyl, aryl-substituted alkyl group, aryl group, aryl group substituted with halo, alkoxy, carboalkoxy, carbamoyl, cyano, hydroxyl, nitro or thio, heteroaryl group, and heteroaryl group substituted with alkyl, halo, alkoxy, carboalkoxy or aryl group,
  • R 5 is a group represented by hydrogen or alkyl
  • X is a group activated by halo, methansulfonyl, phenylsulfonyl, alkoxy and the like.
  • the Scheme 1 is a coupling reaction used to prepare the compound represented by the Formula 4. More particularly, the intermediate (1) activated by alkoxy may be, for example, refluxed with stirring at the presence of the intermediate (2) and an ethanol solvent to obtain benzamide derivatives of Formula 4.
  • R 1 is defined in the same manner as described above,
  • R 4 is a group represented by hydrogen or alkyl
  • R 3 is selected from the group consisting of hydrogen, alkyl, aryl-substituted alkyl group, aryl group, aryl group substituted with halo, alkoxy, carboalkoxy, carbamoyl, cyano, hydroxyl, nitro or thio, heteroaryl group, and heteroaryl group substituted with alkyl, halo, alkoxy, carboalkoxy or aryl group, and
  • X is a group activated by halo, methansulfonyl, phenylsulfonyl, alkoxy and the like.
  • the Scheme 2 is a coupling reaction used to prepare the compound represented by the Formula 5. More particularly, the activated intermediate (4) may be, for example, refluxed with stirring at the presence of the amine intermediate (3) and an acetonitrile solvent to obtain benzamide derivatives of Formula 5.
  • a pharmaceutical composition suitable for pharmaceutical use comprising at least one compound of the present invention and pharmaceutically available carrier, excipients or diluents is provided.
  • composition is intended to comprise any products that are directly or indirectly obtained from a combination of certain amounts of certain components, as well as products comprising (when necessary, certain amounts of) the certain components.
  • pharmaceutically available means that the carrier or excipient is compatible with the other components of the formulations, and is not toxic to its receptors.
  • carriers may be selected according to the kinds of the formulations to be prepared, and the pharmaceutical composition may be formulated by mixing the carriers with the active components, benzamide derivatives, at a suitable ratio.
  • the pharmaceutical composition of the present invention may be parenterally, locally, orally or topically administered for therapeutic treatment.
  • various aqueous vehicles such as water, buffer, 0.04% saline and 0.3% glycol may be used for the pharmaceutical composition, and the pharmaceutical composition may also comprise other proteins, such as albumin, lipoproteins globulins, which reinforce the stability of the pharmaceutical composition.
  • the pharmaceutical composition may be sterilized by widely known sterilization techniques. Solutions may be packaged for the future use, and filtered and dry-frozen under an aseptic condition. In this case, the dry-frozen products are mixed with a sterile solution prior to the administration.
  • oral compositions include an inert diluent or an edible vehicle.
  • the compositions may be sealed in a gelatin capsule or be compressed into tablets.
  • the active compound is mixed with an excipient, and may be used in the form of a tablet, a troche or a capsule.
  • Conventional pharmaceutical carriers may be used to prepare the oral composition.
  • water, glycol, oil, alcohol and the like may be used as the carrier in the case of the oral liquid formulations such as suspensions, syrups, elixirs and solutions, and starch, sugar, kaoline, a lubricating agent, a bonding agent, a disintegrating agent may be used in the case of the solid formulations such as powders, pills, capsules and tablets.
  • the tablets and capsules may be delivered in the most convenient manner, and the tablets and pills are more preferably formulated into enteric agents.
  • conventional sterile water may be used as the carrier, and include other components such as a solution adjuvant.
  • Injectable formulations for example, sterile injectable aqueous or oily suspensions may be prepared with a suitable component such as powders, a wetting agent or a suspending agent according to the known technologies.
  • the solvent that may be used herein includes water, a Ringer's solution and an isotonic NaCl solution, and a sterile fixed oil may also be generally used as the solvent or the suspension medium. Any non-pungent fixed oils comprising mono or di-glycerides may be use to this purpose, and fatty acids such as oleic acid may also be used for preparation of the injectable formulations.
  • a therapeutically effective amount of the pharmaceutical composition according to the present invention may be determined by experience by subjecting a target compound to a known in vivo and in vitro model system for diseases to be treated.
  • the term "therapeutically effective amount” means an amount of an active component that is suitable to relieve or lower symptoms of diseases in need of treatment, or to reduce or delay clinical markers or symptoms of diseases in need of prevention.
  • a daily dose of the active component is preferably in a range of 0.1 to 100 mg per 1kg of body weight.
  • a specific dose level of the active component for certain patients may be varied according to certain compounds used, the weight, sex, health, diet of patients, the time and routes of administration of drugs, the methods of administration, the excretion rate, the admixture of drugs and the severity of diseases.
  • the benzamide derivatives may be used to formulate effective pharmaceutical compositions into the form of their prodrugs.
  • composition according to the present invention may further comprise other components that do not suppress the functions of an active component or assist the functions of the active component, and may be formulated into the other various forms known in the art.
  • the composition according to the present invention may further comprise anticancer drugs known in the art.
  • the compound used herein was purchased from Chemdiv (Cat No. C502-0586).
  • the compound used herein was purchased from Chemdiv (Cat No. C502-0643).
  • the compound used herein was purchased from Chemdiv (Cat No. C502-0559).
  • the compound used herein was purchased from Chemdiv (Cat No. C502-0515).
  • the compound used herein was purchased from Chemdiv (Cat No. C502-0290).
  • the compound used herein was purchased from the Chemdiv (Cat No. C502-0066).
  • the compound used herein was purchased from Life Chemical (Cat No. F0642-0594).
  • the compound used herein was purchased from Chemdiv (Cat No. C502-0571).
  • the compound used herein was purchased from Chemdiv (Cat No. C079-0047).
  • the compound used herein was purchased from Chemdiv (Cat No. C079-0139).
  • the compound used herein was purchased from Chemdiv (Cat No. C059-0001).
  • the compound used herein was purchased from Chemdiv (Cat No. 3331-4726).
  • the compound used herein was purchased from Chemdiv (Cat No. 2884-3651).
  • a plasmid which comprises a binding site of a Tcf/Lef transcription regulator protein to which 5 ⁇ -catenins bind, and a marker protein, firefly luciferase, expressed under the control of the Tcf/Lef transcription regulator protein, was introduced into cells to prepare a transformed cell line (PCT/KR2006/005837).
  • a Wnt-conditioning medium is a culture solution obtained by incubating a cell line CRL2647 (ATCC) expressing Wnt3a for 2 days, and collecting and filtering the cell-cultured medium.
  • the negative control used herein used a cell line treated only with a normal culture solution, and the positive control used a cell line treated only with a Wnt-conditioned medium.
  • An inhibitory rate of the Wnt signal transduction is calculated as represented by the following Equation 1.
  • a reporter plasmid (TOP-Flash) containing a Tcf-4 binding site or a reporter plasmid (FOP-Flash) (Korinek V. et al, 1997) containing a mutant Tcf-4 binding site and 0.1 ⁇ g of Renilla Luciferase reporter plasmid pRLTK (promega) for correcting the transfection were introduced into a HCT116 cell line in which the Wnt signaling pathway was activated, by using Lipofectamin 2000 (Invitrogen), and incubated for 18 hours. Then, the transfected HCT116 cells were treated with the compounds for 18 hours, and the changes in expression of a marker gene by the Tcf-4 promoter were than measured using a Dual-Glo Luciferase kit (Promega).
  • FIG. 1 The experimental results were shown in FIG. 1.
  • the two plasmids were instantly co-expressed in the HCT116 cells, and their expression rates were compared to that of the TOP-Flash that was not treated with the compounds.
  • the expression rate of the TOP-Flash was set to 100 %.
  • the expression rate of the TOP-Flash was reduced in a dose-dependent manner by the treatment with Compounds 3 and 4, but there is no effect of reducing the expression of FOP-Flash plasmid by the treatment with the compounds when the FOP-Flash plasmid was introduced into the HCT116 cells.
  • each cell line was divided at a concentration of 1 10 4 into a 96 well plate, and incubated for 24 hours.
  • the cell lines were treated, respectively, with 6 decreasing concentrations (50.0, 16.7, 5.6, 1.9, 0.6 and 0.2 uM) of the serially diluted compounds.
  • a GI 50 concentration where a concentration of a drug is required to reduce growth by 50% was determined using a CellTiter-Glo Cell Viability Assay kit (Promega).
  • a GI 50 value was determined by the following Equation 2.
  • GI 50 [(Ti-Tz)]/Tz*100 (if, Ti ⁇ Tz)
  • An HCT116 cell line was incubated in a DMEM culture solution under a standard culture condition (5% CO 2 , 37°C, 100% relative moisture).
  • the DMEM culture solution was supplemented with penicillin-streptomycin (100 Units/mL) and 10% fetal bovine serum inactivated by thermal treatment.
  • a test compound was dissolved in dimethyl sulfoxide (DMSO) to a final concentration of 10 ⁇ M.
  • Cells (3x10 7 ) were incubated with/without the test compound for 24 hours.
  • the incubated cells were lysed by treatment with a high concentration of salt. Then, the resultant cell suspension was centrifuged at 12,000 rpm for 10 minutes to collect a supernatant.
  • the collected cytoplasm solution was electrophoresized in a 10% PAGE gel, and probed with cyclin D1 and survivin antibodies (Cell signaling).
  • Cell signaling The probing procedure was performed using a chemiluminescence system (ECL, Amersham).
  • ECL chemiluminescence system
  • an actin protein was used as the control. The results are listed in the following Table 3.
  • cyclin D1 and survivin are used as a cell growth inhibitor and a cell death inhibitor, respectively, and play an important role in the proliferation of cancer cells.
  • Table 3 it was revealed that when the HCT116 cells were treated with the compounds, the expression of the cyclin D1 and survivin known as the target gene of ⁇ -catenin is reduced to a high extent. That is, the expression of the cyclin D1 gene was reduced by the minimum of 19.8% (Compound 10) to the maximum of 64.9% (Compound 7), and the expression of the survivin gene was reduced by the minimum of 30.5% (Compound 10) to the maximum of 98.1% (Compound 3).
  • Balb/c nude mice (15-16 g, 6 weeks old, female) were prepared and adapted in a clean room for more than 1 week, and then used for assays.
  • 0.3 ml of an HCT 116 cancer cell line per mouse was subcutaneously injected via an axilla region between the right shoulder and walls of the chest to induce the tumorigenesis.
  • the test compounds were peritoneally administered once a day at a dose of 50mg/10ml/kg by a day before the closing day (day 20).
  • Irinotecan used as the positive control was repeatedly administered peritoneally once a week at a dose of 50mg/10ml/kg.
  • mice The changes in body weight of the mice were measured three times a week during the test period to determine the toxicity of drugs such as reduction of mouse body weight caused by the administration of the drugs.
  • the tumor volume was measured in 3 directions using a verier caliper, and then represented by the following Equation 3.
  • Tumor volume (length ⁇ width ⁇ height)/2
  • mice When the compound was repeatedly administered peritoneally into the human colorectal cancer cell line (HCT-116)-engrafted nude mice at a dose of 50 mg/kg, the specific general symptoms and the statistically significant body weight changes were not observed during the administration period, and the died mice were observed but the death of the mice was considered to be derived from the growth of tumor rather than the administration of drugs.
  • HCT-116 human colorectal cancer cell line
  • Compounds 3, 5, 6 and 8 have the effect of effectively suppressing the growth of tumor in the anticancer animal model without the changes in the body weight of the mice.

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

Abstract

L'invention porte sur une composition pharmaceutique pour la prévention et le traitement de maladies cancéreuses, comprenant des dérivés de benzamide. La composition pharmaceutique comprend des dérivés de benzamide représentés par la formule suivante 1, telle qu'indiquée dans la spécification, ou des sels pharmaceutiquement acceptables de ceux-ci. Il en résulte que la composition pharmaceutique peut être utile pour prévenir ou traiter une pluralité de maladies cancéreuses telles qu'un cancer colorectal (CRC), étant donné que la composition pharmaceutique est associée à l'inhibition de la croissance cellulaire et au retard de la croissance tumorale, comprenant la suppression de la voie de signalisation Wnt.
PCT/KR2009/003420 2009-06-25 2009-06-25 Composition pharmaceutique pour la prévention et le traitement de maladies cancéreuses, comprenant des dérivés de benzamide Ceased WO2010150927A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2014173904A1 (fr) * 2013-04-22 2014-10-30 Vib Vzw Composé à activité antibactérienne
JP2021521175A (ja) * 2018-04-12 2021-08-26 パーデュー・リサーチ・ファウンデーションＰｕｒｄｕｅ Ｒｅｓｅａｒｃｈ Ｆｏｕｎｄａｔｉｏｎ ベンズアミド抗菌剤
WO2023182958A1 (fr) * 2022-03-24 2023-09-28 T.C. Ankara Universitesi Rektorlugu Sels de n'-(benzo[d]thiazole-2-yl)-4-bromobenzohydrazide pour le traitement du myélome multiple et leur procédé de synthèse
US12036286B2 (en) 2021-03-18 2024-07-16 Seagen Inc. Selective drug release from internalized conjugates of biologically active compounds
US12612396B1 (en) 2024-11-20 2026-04-28 Dewpoint Therapeutics, Inc. Modulators of beta catenin and uses thereof

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WO2001097786A2 (fr) * 2000-06-21 2001-12-27 F. Hoffmann-La Roche Ag Derives de benzothiazole
WO2004041813A1 (fr) * 2002-10-30 2004-05-21 Vertex Pharmaceuticals Incorporated Compositions utiles en tant qu'inhibiteurs de rock et d'autres proteines kinases
WO2004078115A2 (fr) * 2003-02-28 2004-09-16 Viropharma, Incorporated Composes de benzothiazole, compositions et procedes pour le traitement et la prophylaxie des infections par rotavirus et des maladies associees
WO2005033288A2 (fr) * 2003-09-29 2005-04-14 The Johns Hopkins University Antagonistes de la voie hedgehog
WO2005037845A1 (fr) * 2003-10-17 2005-04-28 Rigel Pharmaceuticals, Inc. Compositions de benzothiazole et de thiazole'5,5-b!pyridine et leur utilisation comme inhibiteurs de l'ubiquitine ligase
WO2007008541A2 (fr) * 2005-07-08 2007-01-18 Kalypsys, Inc. Modificateurs d'absorption de cholesterol cellulaire

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WO2001097786A2 (fr) * 2000-06-21 2001-12-27 F. Hoffmann-La Roche Ag Derives de benzothiazole
WO2004041813A1 (fr) * 2002-10-30 2004-05-21 Vertex Pharmaceuticals Incorporated Compositions utiles en tant qu'inhibiteurs de rock et d'autres proteines kinases
WO2004078115A2 (fr) * 2003-02-28 2004-09-16 Viropharma, Incorporated Composes de benzothiazole, compositions et procedes pour le traitement et la prophylaxie des infections par rotavirus et des maladies associees
WO2005033288A2 (fr) * 2003-09-29 2005-04-14 The Johns Hopkins University Antagonistes de la voie hedgehog
WO2005037845A1 (fr) * 2003-10-17 2005-04-28 Rigel Pharmaceuticals, Inc. Compositions de benzothiazole et de thiazole'5,5-b!pyridine et leur utilisation comme inhibiteurs de l'ubiquitine ligase
WO2007008541A2 (fr) * 2005-07-08 2007-01-18 Kalypsys, Inc. Modificateurs d'absorption de cholesterol cellulaire

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014173904A1 (fr) * 2013-04-22 2014-10-30 Vib Vzw Composé à activité antibactérienne
JP2021521175A (ja) * 2018-04-12 2021-08-26 パーデュー・リサーチ・ファウンデーションＰｕｒｄｕｅ Ｒｅｓｅａｒｃｈ Ｆｏｕｎｄａｔｉｏｎ ベンズアミド抗菌剤
JP7357934B2 (ja) 2018-04-12 2023-10-10 パーデュー・リサーチ・ファウンデーション ベンズアミド抗菌剤
US12459936B2 (en) 2018-04-12 2025-11-04 Purdue Research Foundation Benzamide antibacterial agents
US12036286B2 (en) 2021-03-18 2024-07-16 Seagen Inc. Selective drug release from internalized conjugates of biologically active compounds
WO2023182958A1 (fr) * 2022-03-24 2023-09-28 T.C. Ankara Universitesi Rektorlugu Sels de n'-(benzo[d]thiazole-2-yl)-4-bromobenzohydrazide pour le traitement du myélome multiple et leur procédé de synthèse
US12612396B1 (en) 2024-11-20 2026-04-28 Dewpoint Therapeutics, Inc. Modulators of beta catenin and uses thereof

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