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WO2019107993A1 - Nouveau composé utilisé en tant qu'inhibiteur de la liaison de la protéine p34 à nedd4-1 et utilisation associée - Google Patents

Nouveau composé utilisé en tant qu'inhibiteur de la liaison de la protéine p34 à nedd4-1 et utilisation associée Download PDF

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WO2019107993A1
WO2019107993A1 PCT/KR2018/015013 KR2018015013W WO2019107993A1 WO 2019107993 A1 WO2019107993 A1 WO 2019107993A1 KR 2018015013 W KR2018015013 W KR 2018015013W WO 2019107993 A1 WO2019107993 A1 WO 2019107993A1
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carbon atoms
cancer
substituted
unsubstituted
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김두섭
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(주)인핸스드바이오
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel compound and its use, and more particularly, to a novel compound having a binding inhibitory effect of p34 protein and NEDD4-1 protein, or a pharmaceutically acceptable salt or solvate thereof, ≪ / RTI > and their use.
  • Cancer is one of the greatest threats to human health, a disease that occurs when cells undergo a series of mutagenic processes that multiply and are immortalized in an unlimited, unregulated way.
  • the causes of cancer are environmental or external factors such as chemicals, viruses, bacteria, and ionizing radiation, and internal factors such as congenital mutations (Klaunig & Kamendulis, Annu Rev Pharmacol Toxicol., 44: 239-267, 2004 ).
  • treatments such as surgery, radiation therapy, and chemotherapy, but the side effects are becoming a serious problem.
  • life is terminated without any special treatment.
  • the death rate for colorectal cancer is 15.4% per 100,000 cancer patients.
  • the incidence of colorectal cancer per 100,000 population is increasing from 21.8% to 50.3%.
  • expression of PTEN decreases when colon cancer develops and metastasis progresses, and the role of PTEN in this process is very important. Taking this into consideration, it can be said that PTEN needs to be used as an endpoint in the development of anticancer drugs. Activation of PTEN inhibits the cell cycle and induces apoptosis.
  • tumor growth is inhibited when PTEN is overexpressed in an animal model derived from a colon cancer cell line.
  • the overexpression of PTEN in the animal models derived from the colorectal cancer cell lines SW480 and HT29 indicates that tumor growth is remarkably inhibited.
  • PTEN expression which is a tumor suppressor in PI3K / PTEN signal transduction in colorectal cancer, is rarely expressed in colorectal cancer, and 75.4% of patients with liver metastases have almost no expression of PTEN Year survival rate has been reported to decrease significantly.
  • One of the objects of the present invention is to provide a compound capable of selectively and effectively inhibiting the binding of p34 protein and NEDD4-1 protein, or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a pharmaceutical composition comprising the compound as an active ingredient.
  • Another object of the present invention is to provide a pharmaceutical composition capable of preventing or treating various diseases mediated by selectively and effectively inhibiting the binding of p34 protein and NEDD4-1 protein by including the above compound as an active ingredient do.
  • the present invention provides a compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof:
  • n is an integer of 1 to 10
  • X 1 and X 4 are the same or different and are each independently selected from the group consisting of S, O, N (R 2 ) and C (R 3 ) (R 4 )
  • X 2 and X 3 are each independently N or C (R 5 ), at least one is N,
  • L 1 and L 2 are the same or different and each independently represents a single bond, a carbonyl group, an unsubstituted or substituted alkylene group having 1 to 10 carbon atoms or an unsubstituted or substituted arylene group having 6 to 30 carbon atoms,
  • Ar 1 and Ar 2 are the same or different and each independently represents an unsubstituted or substituted C 6 -C 30 aryl group, an unsubstituted or substituted C 6 -C 30 aralkyl group, an unsubstituted or substituted C 3 -C 30 A substituted or unsubstituted heteroaryl group, an unsubstituted or substituted C 6 -C 30 heteroarylalkyl group, an unsubstituted or substituted C 3 -C 40 cycloalkyl group, and an unsubstituted or substituted C 3 -C 40 heterocycloalkyl group And,
  • R 1 to R 5 are the same or different from each other and each independently represents hydrogen, deuterium, a hydroxyl group, an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 30 carbon atoms, An aralkyl group having 7 to 30 carbon atoms and an aryl group having 6 to 30 carbon atoms and may be bonded to adjacent groups to form a substituted or unsubstituted ring,
  • the substituted alkylene group, the substituted arylene group, the substituted aryl group, the substituted aralkyl group, the substituted heteroaryl group, the substituted heteroarylalkyl group, the substituted cycloalkyl group, and the substituted heterocycloalkyl group are each independently hydrogen, deuterium A halogen atom, a hydroxy group, an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 30 carbon atoms, an alkynyl group having 2 to 24 carbon atoms, an aralkyl group having 7 to 30 carbon atoms , An aryl group having 6 to 30 carbon atoms, a heteroaryl group having 6 to 30 carbon atoms, a heteroaralkyl group having 3 to 30 carbon atoms, an alkoxy group having 1 to 30 carbon atoms, an alkylamino group having 1 to 30 carbon atoms, an
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, wherein said medicament is for the prevention or treatment of a disease mediated by the simultaneous expression of p34 and NEDD4-1 Purpose.
  • the disease is selected from tumor cells (e. G., Breast, colon and colon carcinoma).
  • tumor cells e. G., Breast, colon and colon carcinoma.
  • novel compounds according to the present invention can selectively or simultaneously inhibit various diseases mediated by the coexpression of p34 and NEDD4-1. Therefore, the novel derivatives according to the present invention can be usefully used for the treatment or prevention of tumor cells (for example, breast, colon and colon carcinoma).
  • tumor cells for example, breast, colon and colon carcinoma.
  • FIG. 1 is a graph comparing the growth of a tumor of a mouse group administered with p34 activity inhibitor and a control group by subcutaneously injecting SW620, a human colon cancer cell line, into a Balb / c nude mouse to form a xenograft tumor.
  • FIG. 2 shows the expression of PTEN and NEDD4-1 in the mouse group treated with p34 activity inhibitor and the control group by subcutaneously injecting SW620, a human colon cancer cell line, into Balb / c nude mice to form xenograft tumors This is a comparative photograph.
  • FIG. 3 is a graph comparing the growth of a tumor of a mouse group administered with p34 activity inhibitor and a control group by subcutaneously injecting SW620, a human colon cancer cell line, into a Balb / c nude mouse to form xenograft tumors.
  • 4a to 4d are graphs showing the results of performing NMR titration to determine the site of NEDD4-1 protein binding to p34.
  • &quot means fluorine, chlorine, bromine or iodine or both.
  • " alkyl " refers to saturated, straight or branched hydrocarbon radicals represented by C n H 2n + 1 , specifically between 1 and 6, refers to saturated, straight or branched hydrocarbon radicals containing between 8, 1 to 10, or between 1 and 20 carbon atoms.
  • these radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, octyl radicals.
  • " alkenyl " refers to monovalent groups derived from unsaturated, linear, or branched hydrocarbon moieties having at least one carbon-carbon double bond, refers to an unsaturated, straight chain or branched monovalent group comprising between 2 and 6, between 2 and 8, between 2 and 10, or between 2 and 20 carbon atoms. Examples thereof include, but are not limited to, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, and octenyl radicals.
  • " cycloalkyl " refers to a monovalent radical derived from a monocyclic or polycyclic saturated or partially unsaturated carbocyclic ring compound.
  • examples of C3-C8-cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, and cyclooctyl;
  • Examples of C3-C12-cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl.
  • Monovalent radicals derived from monocyclic or polycyclic carbocyclic ring compounds having at least one carbon-carbon double bond by the removal of a single hydrogen atom are also contemplated.
  • groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl, cyclooctenyl, and the like.
  • " cycloalkenyl " refers to a partially unsaturated carbocyclic ring containing 3 to 6 carbon atoms and having a carbon-carbon double bond in the ring .
  • examples of such groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and the like.
  • &quot refers to a mono- or poly-cyclic carbocyclic ring system having one or more fused or non-fused aromatic rings, including, but not limited to, Phenyl, naphthyl, tetrahydronaphthyl, indenyl, indenyl, and the like.
  • " heterocycloalkyl " includes saturated or partially unsaturated 3-10 membered rings containing one or more heteroatoms selected from N, O and S, Quot; means a monocyclic or polycyclic substituent of < / RTI >
  • monocyclic heterocycloalkyl include, but are not limited to, piperidinyl, morpholinyl, thiamorpholinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperazinyl, and similar groups. It is not.
  • " heteroaryl " refers to a monocyclic or bicyclic 5- to 12-membered ring containing one or more heteroatoms selected from O, N and S, refers to an aromatic group that is more than a click.
  • Examples of monocyclic heteroaryl include thiazolyl, oxazolyl, thiophenyl, furanyl, pyrroyl, imidazolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridine Pyridazinyl, pyrimidinyl, pyrazinyl, and similar groups, but are not limited thereto.
  • bicyclic heteroaryl examples include, but are not limited to, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, Isoquinolinyl, purine, furopyridinyl and similar groups, but is not limited thereto.
  • non-aromatic condensed heterocyclic ring &quot refers to a heterocyclic ring having two or more rings condensed with each other and containing heteroatoms selected from N, O and S in addition to carbon as a ring- refers to a group having a non-aromacity (e.g., having 5 to 10 nucleus atoms).
  • non-aromatic fused heterocyclic rings include, but are not limited to, benzo [d] [1,3] dioxole and the like.
  • n is an integer of 1 to 10
  • X 1 and X 4 are the same or different and are each independently selected from the group consisting of S, O, N (R 2 ) and C (R 3 ) (R 4 )
  • X 2 and X 3 are each independently N or C (R 5 ), at least one is N,
  • L 1 and L 2 are the same or different and each independently represents a single bond, a carbonyl group, an unsubstituted or substituted alkylene group having 1 to 10 carbon atoms or an unsubstituted or substituted arylene group having 6 to 30 carbon atoms,
  • Ar 1 and Ar 2 are the same or different and each independently represents an unsubstituted or substituted C 6 -C 30 aryl group, an unsubstituted or substituted C 6 -C 30 aralkyl group, an unsubstituted or substituted C 3 -C 30 A substituted or unsubstituted heteroaryl group, an unsubstituted or substituted C 6 -C 30 heteroarylalkyl group, an unsubstituted or substituted C 3 -C 40 cycloalkyl group, and an unsubstituted or substituted C 3 -C 40 heterocycloalkyl group And,
  • R 1 to R 5 are the same or different from each other and each independently represents hydrogen, deuterium, a hydroxyl group, an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 30 carbon atoms, An aralkyl group having 7 to 30 carbon atoms and an aryl group having 6 to 30 carbon atoms and may be bonded to adjacent groups to form a substituted or unsubstituted ring,
  • the substituted alkylene group, the substituted arylene group, the substituted aryl group, the substituted aralkyl group, the substituted heteroaryl group, the substituted heteroarylalkyl group, the substituted cycloalkyl group, and the substituted heterocycloalkyl group are each independently hydrogen, deuterium A halogen atom, a hydroxy group, an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 30 carbon atoms, an alkynyl group having 2 to 24 carbon atoms, an aralkyl group having 7 to 30 carbon atoms , An aryl group having 6 to 30 carbon atoms, a heteroaryl group having 6 to 30 carbon atoms, a heteroaralkyl group having 3 to 30 carbon atoms, an alkoxy group having 1 to 30 carbon atoms, an alkylamino group having 1 to 30 carbon atoms, an
  • Ar 1 may be a compound represented by the following formula (2):
  • n is an integer of 0 to 2
  • X 5 is selected from the group consisting of N (R 6), S, O and C (R 7) (R 8 ),
  • R 6 to R 8 are the same or different from each other and each independently represent a hydrogen atom, a hydrogen atom, a cyano group, a nitro group, a halogen group, a hydroxy group, an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 1 to 20 carbon atoms, An alkenyl group having 2 to 24 carbon atoms, an aralkyl group having 7 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms, a heteroaryl group having 6 to 30 carbon atoms, a heteroaralkyl group having 3 to 30 carbon atoms, An alkoxy group, an alkylamino group having 1 to 30 carbon atoms, an arylamino group having 6 to 30 carbon atoms, an aralkylamino group having 6 to 30 carbon atoms, a heteroarylamino group having 6 to 30 carbon atoms, an alkylsilyl group having 1 to 30 carbon atoms,
  • Ar 2 may be selected from the group consisting of compounds represented by the following formulas (3) to (5):
  • o is an integer from 0 to 4,
  • p and q are the same as or different from each other, each independently an integer of 0 to 2,
  • X 6 , X 9 and X 10 are the same or different and are each independently selected from the group consisting of N, O, S and C (R 11 )
  • X 7 and X 8 are the same or different and are each independently selected from the group consisting of N (R 12 ), O, S and C (R 13 ) (R 14 )
  • R 9 to R 14 are the same or different from each other and each independently represents hydrogen, deuterium, cyano group, nitro group, halogen group, hydroxyl group, alkyl group having 1 to 30 carbon atoms, cycloalkyl group having 1 to 20 carbon atoms, An alkenyl group having 2 to 24 carbon atoms, an aralkyl group having 7 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms, a heteroaryl group having 6 to 30 carbon atoms, a heteroaralkyl group having 3 to 30 carbon atoms, An alkoxy group, an alkylamino group having 1 to 30 carbon atoms, an arylamino group having 6 to 30 carbon atoms, an aralkylamino group having 6 to 30 carbon atoms, a heteroarylamino group having 6 to 30 carbon atoms, an alkylsilyl group having 1 to 30 carbon atoms, A cycloalkyl group having 3 to 40 carbon atoms
  • L 2 is a single bond, and adjacent R 1 and Ar 2 may bond to each other to form a condensed ring.
  • the condensed ring formed by combining R 1 and Ar 2 with each other is a compound represented by the following formula 6:
  • r is an integer of 1 to 4,
  • X 8 , R 10 and p are as defined in formula (4).
  • the compound of Formula 1 may be selected from the group consisting of the following compounds, but not limited thereto:
  • the compound of formula 1 according to the present invention can be prepared by a method represented by the following schemes 1 to 8:
  • the intermediate compound (2) containing a carboxylic acid group is synthesized by reacting a commercially available oxadiazole compound (1) as a starting material with chloroacetic acid and coupling reaction with various amines (3) to obtain the final compound (4) were synthesized.
  • the compound of formula (I) according to the present invention may be prepared in the form of a pharmaceutically acceptable salt to which an inorganic acid or an organic acid is added.
  • Preferred salts thereof include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, , Pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, , Salicylic acid, methanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid.
  • the pharmaceutically acceptable salt according to the present invention is prepared by dissolving the compound of the formula (1) in an organic solvent such as acetone, methanol, ethanol, acetonitrile or the like, adding crystals precipitated by adding an organic acid or an inorganic acid, can do. Or by reducing the solvent or excess acid in a reaction mixture to which acid has been added and drying the residue, or by adding a different organic solvent to the precipitated salt.
  • an organic solvent such as acetone, methanol, ethanol, acetonitrile or the like
  • the compounds of formula (I) according to the invention, or pharmaceutically acceptable salts thereof, may be in the form of hydrates or solvates, and such compounds are also included in the present invention.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof according to the present invention can effectively inhibit protein kinase.
  • the compounds of the present invention can effectively prevent or treat diseases mediated by the coexpression of p34 and NEDD4-1. That is, binding to a part of the p34 protein and binding to a part of the NEDD4-1 protein can inhibit binding of the p34 protein and the NEDD4-1 protein.
  • the disease may be selected from, but not limited to, metastatic growth of the tumor.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof can effectively prevent or treat cancer or tumor, and further effectively inhibit the metastasis of cancer cells.
  • the cancer is selected from the group consisting of liver cancer, hepatocellular carcinoma, thyroid cancer, colorectal cancer, testicular cancer, bone cancer, oral cancer, basal cell carcinoma, cancer of the head and neck, colorectal cancer, bladder cancer, ovarian cancer, ovarian cancer, brain tumor, gallbladder carcinoma, biliary tract cancer, esophageal cancer, glioma, glioblastoma, renal cancer, malignant melanoma, gastric cancer, pancreatic cancer, gastric cancer, Breast cancer, sarcoma, pharynx carcinoma, uterine cancer, cervical cancer, prostate cancer, rectal cancer, pancreatic cancer, Lung cancer, colorectal cancer, colon cancer, and other solid tumors. It is selected from the group, but is not limited to this.
  • the compound of formula 1 or a pharmaceutically acceptable salt thereof can effectively prevent or treat the carcinoma mediated by the simultaneous expression of p34 and NEDD4-1.
  • the carcinoma can be selected from the group consisting of lung, liver, bile duct, gastrointestinal tract, head and neck, pancreas, prostate, cervix, breast, colon and colon.
  • the compound of the formula (1) according to the present invention or a pharmaceutically acceptable salt thereof and the like can be administered to a specimen to prevent or treat the above-mentioned diseases.
  • the dosage of the compound of formula (I) is usually 0.1 to 2,000 mg per day on a weight basis of 70 kg as an active ingredient to a human, although the dosage thereof may vary depending on the subject to be treated, the severity of the disease or condition, , Preferably from 1 to 1,000 mg per day, or via an oral or parenteral route, with an on / off schedule of one to four times per day. In some cases, doses less than the above-mentioned ranges may be more suitable, more doses may be used without causing harmful side effects, and more doses may be dispensed with several smaller doses per day do.
  • the pharmaceutical composition according to the present invention may be formulated according to a conventional method and may be formulated into various oral dosage forms such as tablets, pills, powders, capsules, syrups, emulsions and microemulsions, or by intramuscular, intravenous or subcutaneous administration Can be prepared in parenteral dosage forms.
  • the carrier to be used examples include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, Calcium, gelatin, talc, surfactants, suspending agents, emulsifying agents, diluents and the like.
  • the carrier includes water, saline solution, glucose aqueous solution, pseudosugar solution, alcohol, glycol, ether (e.g. polyethylene glycol 400), oil, fatty acid, Glyceride, a surfactant, a suspending agent, an emulsifying agent and the like can be used.
  • DIPEA diisopropylethylamine
  • Example 3 The compounds of Examples 3 to 6 were synthesized in the same manner except for the amine used in Example 1, and the results are shown in Table 1. (5-2,3-dimethyl-1H-indol-5-yl) -1,3,4-oxadiazol-2-yl) acetic acid obtained in Preparation Example 1 instead of 2- The compound of Example 2 was synthesized using 2- ⁇ 5- (1H-indol-5-yl) -1,3,4-oxadiazol-2-yl ⁇ acetic acid obtained in 2 .
  • the inhibitory activity of the compound against p34 and NEDD4-1 was evaluated using the p34 protein and the NEDD4-1 protein based on HTRF technology developed by CISBio. This assay measures the FRET (fluorescence resonance energy transfer) signal in the presence of Terbium-labeled Anti-FLAG antibody and d2-labeled Anti-6XHis antibody. Experiments were performed in 384-well plates, 1X PBS pH 7.4, 0.1% BSA and 2% DMSO.
  • Example 1 45.8
  • Example 2 65.8
  • Example 3 59.4
  • Example 4 54.6
  • Example 6 46.6 control 0
  • Test Example 2 Evaluation of activity by inducing PTEN reactivation of p34 activity inhibitor
  • the human colon cancer cell line, SW620 was treated with 5 uM of p34 activity inhibitor for 48 hours.
  • the cell lysate was collected and immunoprecipitated with PTEN antibody.
  • reaction buffer 100 mM tris-HCl pH 8.0, 10 mM DTT
  • Solution for 30 minutes at room temperature, and the PTEN lipid phosphatase activity was measured at CD650 nm.
  • the activity of the phospholipase by PTEN reactivation of the compound was calculated as%. The results are shown in Table 3 below.
  • Example 1 Compound_ID PTEN activity (relative fold @ 5? N) Example 1 1.8 Example 2 1.0 Example 3 2.1 Example 4 2.2 Example 5 2.2 Example 6 1.8 control 1.0
  • Test Example 3 Evaluation of tumor growth inhibitory activity in xenograft mouse animal model of p34 activity inhibitor
  • Human colon cancer cell line SW620 was injected subcutaneously into Balb / c nude mice to form xenograft tumors. Tumor size was monitored every 3 days and the size of the tumor was continuously monitored by oral administration of p34 activity inhibitor daily (the control group was administered only the solvent) with 0 day when the tumor size reached 100 mm 3 .
  • Fig. 1 and Fig. 3 tumor growth was significantly reduced in the mouse group to which the p34 activity inhibitor was administered, as compared with the control group.
  • PTEN expression was increased and NEDD4-1 expression was decreased in the group to which p34 activity inhibitor was administered.
  • Test Example 4 Identification of the binding site of NEDD4-1 binding to p34
  • NMR titration was performed to determine the site of NEDD4-1 protein binding to p34.
  • 0.5 mM recombinant 14 N-labeled NEDD4-1 WW1 domain and 0.8 mM unlabed p34 protein were prepared.
  • Two proteins are 137 mM NaCl, 2.7 mM KCl, 8.1 mM Na 2 HPO 4 and 1.5 mM KH 2 PO 4, It was prepared by dissolving in PBS buffer for the pH 7.4 in 10% D 2 O .
  • Unlabed p34 increased the concentration of 14 N-labeled NEDD4-1 ratios with the WW1 domain to 1: 0. 1: 0.25, and 1: 0.5, respectively.
  • All NMR experiments were performed with Bruker DRX 850 MHz and the results were analyzed by XWINNMR program and NMRpipe / NMRDraw software.
  • Figures 4a-4d illustrate the molecular interaction and backbone dynamics of the WW1 domain of NEDD4-1 after interaction with p34SEI-1.
  • Figure 4a is a superposition of the 2D 1H-15N HSQC spectrum of the 15N WW1 domain of NEDD4-1 (Red) titrated with increasing concentrations of unlabeled p34SEI-1 (1e120).
  • Figure 4b is an enlargement of the overlapping 1H-15N HSQC spectrum of the WW1 domain of NEDD4-1 titrated with increasing concentrations of unlabeled p34SEI-1 (1e120).
  • the asterisk [*] denotes residues that have disappeared due to peak broadening.
  • FIG. 4c shows the average heteronuclear NOE value for the NEDD4-1 WW1 domain and the corresponding secondary structure (shown on the panel) as a result of the 1H-15N heteronuclear NOE experiment.
  • FIG. 4D is a depiction of a sausage form showing the dynamic region of the NEDD4-1 WW1 domain (SWISS-MODEL).

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un nouveau composé présentant un effet inhibiteur sur la liaison de la protéine p34 à la protéine NEDD4-1. L'invention concerne également une composition pharmaceutique contenant ledit composé comme principe actif, cette composition pouvant être utilisée efficacement dans le traitement et/ou la prévention du cancer.
PCT/KR2018/015013 2017-11-30 2018-11-29 Nouveau composé utilisé en tant qu'inhibiteur de la liaison de la protéine p34 à nedd4-1 et utilisation associée WO2019107993A1 (fr)

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KR10-2017-0162753 2017-11-30
KR1020170162753A KR20190063746A (ko) 2017-11-30 2017-11-30 p34 단백질 및 NEDD4-1 단백질의 결합 억제제로서의 신규 화합물 및 이의 용도

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WO2019107993A1 true WO2019107993A1 (fr) 2019-06-06

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CN113512032B (zh) * 2021-04-05 2023-08-04 合肥工业大学 一种噁二唑硫醚衍生物及其制备方法和应用

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WO2011094708A2 (fr) * 2010-01-29 2011-08-04 Dana-Farber Cancer Institute, Inc Petites molécules pour la modulation de mcl-1 et procédés de modulation de la mort cellulaire, la division cellulaire, la différenciation cellulaire et procédés de traitement de troubles
WO2014157965A1 (fr) * 2013-03-27 2014-10-02 재단법인 아산사회복지재단 Composition pour le traitement ou l'inhibition de la métastase de cancers qui comprend un inhibiteur de l'expression de p34 ou un inhibiteur de l'activité p34 comme principe actif
US20170020858A1 (en) * 2005-05-09 2017-01-26 Hydra Biosciences, Inc. Compounds for modulating trpv3 function

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US20170020858A1 (en) * 2005-05-09 2017-01-26 Hydra Biosciences, Inc. Compounds for modulating trpv3 function
WO2011094708A2 (fr) * 2010-01-29 2011-08-04 Dana-Farber Cancer Institute, Inc Petites molécules pour la modulation de mcl-1 et procédés de modulation de la mort cellulaire, la division cellulaire, la différenciation cellulaire et procédés de traitement de troubles
WO2014157965A1 (fr) * 2013-03-27 2014-10-02 재단법인 아산사회복지재단 Composition pour le traitement ou l'inhibition de la métastase de cancers qui comprend un inhibiteur de l'expression de p34 ou un inhibiteur de l'activité p34 comme principe actif

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ABDELAZEEM, A. H. ET AL.: "Novel Diphenylthiazole Derivatives with Multi-target Mechanism: Synthesis, Docking Study, Anticancer and Anti-inflammatory Activities", BIOORGANIC CHEMISTRY, vol. 75, 12 September 2017 (2017-09-12), pages 127 - 138, XP085278654, doi:10.1016/j.bioorg.2017.09.009 *
SHIRINZADEH, H. ET AL.: "Novel Indole-based Melatonin Analogues Substituted with Triazole, Thiadiazole and Carbothioamides: Studies on Their Antioxidant, Chemopreventive and Cytotoxic Activities", JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, vol. 31, no. 6, December 2016 (2016-12-01), pages 1312 - 1321, XP055618830 *

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