WO2018056621A1 - Nouveau dérivé de pyrimidine imidazolyle, son procédé de préparation et une composition pharmaceutique le contenant en tant que principe actif pour prévenir ou traiter le cancer - Google Patents

Nouveau dérivé de pyrimidine imidazolyle, son procédé de préparation et une composition pharmaceutique le contenant en tant que principe actif pour prévenir ou traiter le cancer Download PDF

Info

Publication number
WO2018056621A1
WO2018056621A1 PCT/KR2017/009908 KR2017009908W WO2018056621A1 WO 2018056621 A1 WO2018056621 A1 WO 2018056621A1 KR 2017009908 W KR2017009908 W KR 2017009908W WO 2018056621 A1 WO2018056621 A1 WO 2018056621A1
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
imidazol
amine
phenyl
substituted
Prior art date
Application number
PCT/KR2017/009908
Other languages
English (en)
Korean (ko)
Inventor
최환근
고은화
손정범
조중희
김남두
김현경
Original Assignee
재단법인 대구경북첨단의료산업진흥재단
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 재단법인 대구경북첨단의료산업진흥재단 filed Critical 재단법인 대구경북첨단의료산업진흥재단
Publication of WO2018056621A1 publication Critical patent/WO2018056621A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/495—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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • the present invention relates to a novel imidazolyl pyrimidine derivative, a preparation method thereof and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient.
  • HCC Human hepatocellular carcinoma
  • TGF- ⁇ 1 Transforming growth factor beta-1 (TGF- ⁇ 1) strongly inhibits human hepatocellular carcinoma (HCC) cell growth. In particular, it promotes cell growth in non-epithelial cells, such as fibroblasts and stellate cells, while in rodents and by cell death or cell cycle arrest. It inhibits cell growth in both human hepatocellular carcinoma (HCC) cells.
  • HCC human hepatocellular carcinoma
  • Induction of apoptosis by TGF- ⁇ 1 in human hepatocellular carcinoma (HCC) cells is mediated by dephosphorylation of cdc2 Tyr15 (active form of cdc2), ie, reduction in cdc2 phosphorylation.
  • the cdc2 activity is induced by Wee1 kinase downregulation, and cdc2 activity by decreasing Tyr15 phosphorylation is very important for TGF- ⁇ 1-induced apoptosis in human hepatocellular carcinoma (HCC) cells.
  • a decrease in Wee1 kinase expression is observed after TGF- ⁇ 1 treatment, and cdc2 phosphorylation is regulated by Wee1 kinase. From this, it can be said that TGF- ⁇ 1-mediated apoptosis is induced in the Wee1 / cdc2 axis.
  • Wee1 kinase In surgically excised samples, Wee1 kinase is overexpressed in human hepatocellular carcinoma (HCC), but kinase expression is not observed in non-cancerous tissues including cirrhotic tissue. Overexpression of Wee1 kinase has been reported in other tumor types, including brain tumors and leukemia (Non-Patent Document 1, Harris PS et al., (2014) Integrated genomic analysis identifies the mitotic checkpoint kinase WEE1 as a novel therapeutic target in medulloblastoma Mol Cancer 13: 72). In brain tumors, Wee1 kinase expression is upregulated only in tumor cells, and elevated kinases play an important role in cancer cell survival.
  • HCC human hepatocellular carcinoma
  • Wee1 kinase is a negative regulator of cdc2. Since TGF- ⁇ 1 is a multifunctional cytokine, it is not a practical therapeutic alternative. Wee1 kinase negatively regulates the G2 / M phase by inhibiting the early stages of mitosis before DNA damage is repaired, thereby preventing premature mitotic entry and subsequent cell death. It is considered. Certain inhibitors or siRNAs may be used to inhibit Wee1 kinase to induce apoptosis in human hepatocellular carcinoma (HCC) cells.
  • HCC human hepatocellular carcinoma
  • Wee1 kinase inhibitors may be new therapeutic strategies and alternatives emerging in Wee1 kinase-overexpressing carcinomas such as human hepatocellular carcinoma (HCC), and these types of inhibitors may present a realistic therapeutic alternative to advanced solid cancers. Can be.
  • HCC human hepatocellular carcinoma
  • the present inventors while studying a compound that inhibits Wee1 kinase, the imidazolyl pyrimidine derivative, optical isomer or pharmaceutically acceptable salt thereof according to the present invention is remarkably excellent in the inhibitory effect of Wee1 kinase,
  • the present invention has been completed and found to be useful as a prophylactic or therapeutic agent for Wee1 kinase related diseases such as liver cancer.
  • Another object of the present invention is to provide a method for preparing the imidazolyl pyrimidine derivative.
  • Another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of Wee1 kinase-related diseases containing the imidazolyl pyrimidine derivative, optical isomer thereof or pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a nutraceutical composition for preventing or ameliorating Wee1 kinase-related diseases containing the imidazolyl pyrimidine derivative, its optical isomer, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
  • X is hydrogen, halogen, unsubstituted or substituted C 1-3 straight chain or C 3 branched alkyl
  • the substituted straight or branched chain alkyl may be substituted with halogen
  • R 1 and R 2 are each independently unsubstituted or substituted C 1-5 straight chain or C 3-5 branched alkoxy
  • the substituted straight or branched chain alkoxy may be substituted with dimethylamino
  • R 3 is unsubstituted or substituted 5 to 10 atoms, including -NR 4 R 5 , unsubstituted or substituted C 6-10 cycloalkyl, or at least one hetero atom selected from the group consisting of N, O, S Heterocycloalkyl,
  • R 4 and R 5 are each independently unsubstituted or substituted C 1-5 linear or C 3-5 branched alkyl, and the substituted straight or branched alkyl may be substituted with dimethylamino There is,
  • the substituted cycloalkyl or substituted heterocycloalkyl is selected from the group consisting of C 1-10 straight or C 3-10 branched alkyl, halogen, amino, C 1-3 alkylcarbonyl or N, O, S Optionally substituted with 5 to 10 atoms of unsubstituted or substituted hetero cycloalkyl containing one or more hetero atoms selected,
  • substituted hetero cycloalkyl may be substituted with C 1-5 straight chain or C 3-5 branched alkyl).
  • Step 2 Preparing a compound represented by Chemical Formula 1 by reacting the compound represented by Chemical Formula 3 prepared in Step 1 with the compound represented by Chemical Formula 4 (step 2); Provide the manufacturing method:
  • X, R 1 , R 2 and R 3 are the same as defined in the compound represented by Formula 1).
  • the present invention provides a pharmaceutical composition for preventing or treating a Wee1 kinase related disease containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a health functional food composition for preventing or ameliorating Wee1 kinase-related diseases containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Imidazolyl pyrimidine derivatives, optical isomers thereof or pharmaceutically acceptable salts thereof according to the present invention are excellent in inhibiting the cell proliferation of hepatic cancer cell lines as well as the activity of Wee1 kinase.
  • Solid cancers such as vaginal carcinoma, vulvar carcinoma, prostate cancer, bladder cancer, kidney cancer, ureter cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system tumor liver cancer, etc., preferably can be used as a pharmaceutical composition for the prevention or treatment of liver cancer .
  • the present invention provides a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
  • X is hydrogen, halogen, unsubstituted or substituted C 1-3 straight chain or C 3 branched alkyl
  • the substituted straight or branched chain alkyl may be substituted with halogen
  • R 1 and R 2 are each independently unsubstituted or substituted C 1-5 straight chain or C 3-5 branched alkoxy
  • the substituted straight or branched chain alkoxy may be substituted with dimethylamino
  • R 3 is unsubstituted or substituted 5 to 10 atoms, including -NR 4 R 5 , unsubstituted or substituted C 6-10 cycloalkyl, or at least one hetero atom selected from the group consisting of N, O, S Heterocycloalkyl,
  • R 4 and R 5 are each independently unsubstituted or substituted C 1-5 linear or C 3-5 branched alkyl, and the substituted straight or branched alkyl may be substituted with dimethylamino There is,
  • the substituted cycloalkyl or substituted heterocycloalkyl is selected from the group consisting of C 1-10 straight or C 3-10 branched alkyl, halogen, amino, C 1-3 alkylcarbonyl or N, O, S Optionally substituted with 5 to 10 atoms of unsubstituted or substituted hetero cycloalkyl containing one or more hetero atoms selected,
  • substituted hetero cycloalkyl may be substituted with C 1-5 straight chain or C 3-5 branched alkyl).
  • R 3 is , , , , , or ego,
  • Preferred examples of the compound represented by Formula 1 according to the present invention include the following compounds.
  • the compound represented by the formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt
  • the acid addition salt formed by the pharmaceutically acceptable free acid is useful as the salt.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes.
  • Non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids and the like, and organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like.
  • Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, eye Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suve Latex, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chloride
  • the acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate produced by dissolving a derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile and adding an organic or inorganic acid.
  • the solvent may be prepared by filtration and drying, or the solvent and excess acid may be distilled under reduced pressure, dried, and then crystallized under an organic solvent.
  • Bases can also be used to make pharmaceutically acceptable metal salts.
  • Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt.
  • Corresponding salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg silver nitrate).
  • the present invention includes not only the compound represented by Formula 1 and pharmaceutically acceptable salts thereof, but also solvates, stereoisomers, hydrates, and the like that can be prepared therefrom.
  • Step 2 Preparing a compound represented by Chemical Formula 1 by reacting the compound represented by Chemical Formula 3 prepared in Step 1 with the compound represented by Chemical Formula 4 (step 2); Provide the manufacturing method:
  • X, R 1 , R 2 and R 3 are the same as defined in the compound represented by Formula 1).
  • Step 1 of Scheme 1 is a step of preparing a compound represented by Formula 3 from the compound represented by Formula 2.
  • step 1 may be understood as a reaction for introducing an imidazole substituent, and there is no particular limitation, but the reaction temperature may be preferably performed at 40 to 90 ° C., and the reaction time may be performed for 5 to 20 hours. Can be.
  • tetrahydrofuran THF
  • Dioxane Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Lower alcohols including methanol, ethanol, propanol and butanol; Dimethylformamide (DMF), Dimethylsulfoxide (DMSO), Dichloromethane (DCM), Dichloroethane, Water, Acetonazenesulfonate, Toluenesulfonate, Chlorobenzenesulfonate, Xylenesulfonate, Phenyl acetate, Phenylpropionate , Phenylbutyrate, citrate, lactate, ⁇ -hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and
  • Step 2 of Scheme 1 is a step of preparing a compound represented by Formula 1 by reacting the compound represented by Formula 4 from the compound represented by Formula 3 .
  • step 2 may be understood as a reaction for introducing an aniline derivative, and there is no particular limitation, but after addition of imidazolyl pyrimidine derivative, aniline derivative and K 2 CO 3 , Pd 2 (dab 3 ) and
  • the compound of the present invention may be prepared by adding Xphos to react, the reaction temperature may be preferably performed at 60-100 ° C., and the reaction time may be performed for 5 to 20 hours.
  • step 2 H 2 O, ethanol, sec-BuOH, tetrahydrofuran (THF), dichloromethane, toluene, acetonitrile, dimethylformamide and the like and mixtures thereof may be used. Preference is given to using -BuOH.
  • the present invention also provides a pharmaceutical composition for preventing or treating a disease related to Wee1 kinase containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the Wee1 kinase-related disease is solid cancer
  • the solid cancer is liver cancer, lung cancer, colon cancer, gastric cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, anal muscle cancer.
  • Fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, prostate cancer, bladder cancer, kidney cancer, ureter cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system tumor, etc. preferably liver cancer.
  • the present invention provides a health functional food composition for preventing or ameliorating a disease caused by Wee1 kinase overactivity containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. do.
  • the present invention comprises the step of administering a compound represented by the formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof to a subject in need thereof, preventing the disease caused by Wee1 kinase overactivity Or provide a method of treatment.
  • the subject in need thereof refers to a patient having a disease caused by Wee1 kinase overactivity.
  • Wee1 kinase negatively regulates the G2 / M phase by inhibiting the early stages of mitosis before DNA damage is repaired, thus premature mitotic entry and subsequent cell death. It is believed to prevent.
  • Example compound 1-21 according to the present invention was found to have excellent inhibitory activity of Wee1 kinase In particular, it was shown to effectively inhibit the activity of Wee1 kinase at very low concentrations of 1 ⁇ M or less (see Table 2 of Experimental Example 1).
  • Example compound 1-21 according to the present invention of Hep3B and Huh7 cells It has been shown to inhibit cell proliferation at low concentrations and to effectively inhibit cell proliferation at very low concentrations of ⁇ M units (see Table 3 of Experimental Example 2).
  • the imidazolyl pyrimidine derivatives, optical isomers thereof or pharmaceutically acceptable salts thereof according to the present invention are excellent in the activity of Wee1 kinase, as well as in inhibiting the cell proliferation of cancer cell lines, preferably liver cancer cell lines, Wee1. It can be usefully used as a pharmaceutical composition for the prophylaxis or treatment of kinase related diseases, for example, the aforementioned solid cancer, preferably liver cancer.
  • the compound represented by the formula (1) according to the present invention can be administered in various oral and parenteral dosage forms at the time of clinical administration, when formulated, commonly used fillers, extenders, binders, wetting agents, disintegrants, surfactants It is prepared using diluents or excipients.
  • Solid form preparations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, which form at least one excipient such as starch, calcium carbonate, water, or the like. It is prepared by mixing cross, lactose or gelatin. In addition to simple excipients, lubricants such as magnesium styrate talc are also used.
  • Liquid preparations for oral administration include suspensions, solvents, emulsions or syrups, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Can be.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like.
  • non-aqueous solvent and the suspension solvent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.
  • base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used.
  • the effective dosage of the compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and is generally about 0.001-100 mg / kg / day, preferably Preferably 0.01-35 mg / kg / day. Based on an adult patient weighing 70 kg, it is generally 0.07-7000 mg / day, preferably 0.7-2500 mg / day, once a day at regular intervals according to the judgment of the doctor or pharmacist. Multiple doses may be administered.
  • UV detector 254nm
  • UV detector 254nm
  • UV detector 254nm
  • step 2 4 -(1H-imidazol-1-yl))-5- Iodo -N- (4- (4- Methylpiperazine Preparation of -1-yl) phenyl) pyrimidin-2-amine
  • Example 1 except that 3- (3- (dimethylamino) propoxy) aniline was used in place of 4- (4-methylpiperazin-1-yl) aniline used in Step 2 of Example 1 In the same manner as in the title compound was prepared.
  • Example 1 1- (4-amino-2-methoxyphenyl) -N, N-dimethylpiperidine- in place of 4- (4-methylpiperazin-1-yl) aniline used in step 2 of Example 1 above
  • a target compound was prepared in the same manner as in Example 1, except that 4-amine was used.
  • Example 1 except that 2,4-dichloro-5-trifluoromethylpyrimidine was used in place of 2,4-dichloro-5-iodopyrimidine used in Step 1 of Example 1 In the same manner to prepare the target compound.
  • Examples 1-21 compounds according to the present invention were added at concentrations of 1 ⁇ M or less, more than 1 ⁇ M to 10 ⁇ M or less, more than 10 ⁇ M to 100 ⁇ M and more than 100 ⁇ M, and then reacted in a 30 ° C. incubator for 1 hour. After the reaction was completed, the same amount of Kinase-Glo (Promega, Madison, WI) solution was added for 1 hour and the detection solution was added for 10 minutes at room temperature. The IC 50 value of the kinase was calculated by measuring the amount of luciferase using a microplate enzyme-linked immunosorbent assay reader (Bio-Tek). The results are shown in Table 2 below.
  • Example Wee1 (IC 50 , ⁇ M) One 0.068 2 0.343 3 0.213 4 0.426 5 0.256 6 0.0078 7 0.345 8 0.289 9 0.458 10 37.45 11 17.19 12 > 50 13 4.51 14 0.035 15 1.32 16 0.656 17 0.515 18 1.32 19 0.346 20 0.339 21 1.207
  • Example Compound 1-21 according to the present invention can excellently inhibit Wee1 kinase at an nM unit concentration of 1 ⁇ M or less.
  • Example 1 compound has an iodo (I) substituent at the pyrimidine 5 position
  • Example 15-20 compounds at the pyrimidine 5 position Hydrogen, methyl, fluoro, chloro, bromo, or trifluoromethyl has substituents.
  • Wee1 kinase inhibitory activity is remarkably changed. That is, in the case of having the iodo (I) substituent at the pyrimidine 5 position as in the compound of Example 1 of the present invention, it has a Wee1 kinase inhibitory activity of up to about 20 times that of the above-described Example 15-20 compound.
  • Example 7 compound when the Example 7 compound is compared with the Example 21 compound, the Example 7 compound according to the present invention has an iodo (I) substituent at the pyrimidine 5 position, which is about 4 times higher than that of the Example 21 compound. It can be confirmed that it has Wee1 kinase inhibitory activity.
  • I iodo
  • the imidazolyl pyrimidine derivatives, optical isomers thereof or pharmaceutically acceptable salts thereof according to the present invention exhibit excellent inhibitory activity of Wee1 kinase and therefore are used for the prevention or treatment of diseases related to Wee1 kinase, for example, liver cancer. It can be usefully used as a pharmaceutical composition.
  • Hep3B cells manufactured by ATCC
  • Huh7 cells Huh7 cells which are liver cancer cell lines
  • ATCC American Type Culture Collection
  • 1-14 compounds were dissolved in concentrations of 1 ⁇ M or less, 1 ⁇ M or more and 10 ⁇ M or less, 10 ⁇ M or more and 100 ⁇ M or less and 100 ⁇ M or more, and then replaced with a well plate containing cells and incubated for 72 hours.
  • MTS (3,-(4, 5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazolium salt, Promega) solution
  • GI 50 was calculated by measuring absorbance at a wavelength of 490 nm using a microplate ELISA reader (Bio-Tek). The results are shown in Table 3 below.
  • A is 1 ⁇ M or less
  • B is greater than 1 ⁇ M and less than or equal to 10 ⁇ M
  • C is greater than 10 ⁇ M and less than or equal to 100 ⁇ M.
  • Example Compounds 1-14 according to the present invention were shown to inhibit cell proliferation of Hep3B and Huh7 cells, which are liver cancer cell lines, at micromolar concentrations.
  • Examples 1, 3 and 6 have been shown to effectively inhibit Hep3B and Huh7 cell proliferation, which are liver cancer cell lines, at very low concentrations of 10 ⁇ M or less.
  • imidazolyl pyrimidine derivatives, optical isomers thereof or pharmaceutically acceptable salts thereof according to the present invention can effectively inhibit the activity of Wee1 kinase, and can also inhibit the cell proliferation of liver cancer cell lines. It may be usefully used as a pharmaceutical composition for preventing or treating liver cancer.
  • the derivative according to the present invention can be formulated in various forms according to the purpose. Examples of preparations for the compositions of the present invention are illustrated below.
  • tablets were prepared by tableting according to a conventional method for producing tablets.
  • the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.
  • Imidazolyl pyrimidine derivatives, optical isomers thereof or pharmaceutically acceptable salts thereof according to the present invention are excellent in inhibiting the cell proliferation of hepatic cancer cell lines as well as the activity of Wee1 kinase.
  • It is useful as a pharmaceutical composition for the prevention or treatment of solid cancers preferably hepatocellular carcinoma, vulvar carcinoma, prostate cancer, bladder cancer, kidney cancer, ureter cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system tumor liver cancer and the like.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nutrition Science (AREA)
  • Engineering & Computer Science (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Mycology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un nouveau dérivé de pyrimidine imidazolyle, son procédé de préparation et une composition pharmaceutique le contenant en tant que principe actif pour prévenir ou traiter le cancer.
PCT/KR2017/009908 2016-09-23 2017-09-08 Nouveau dérivé de pyrimidine imidazolyle, son procédé de préparation et une composition pharmaceutique le contenant en tant que principe actif pour prévenir ou traiter le cancer WO2018056621A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2016-0121847 2016-09-23
KR1020160121847A KR102030886B1 (ko) 2016-09-23 2016-09-23 신규한 이미다졸일 피리미딘 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물

Publications (1)

Publication Number Publication Date
WO2018056621A1 true WO2018056621A1 (fr) 2018-03-29

Family

ID=61689897

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2017/009908 WO2018056621A1 (fr) 2016-09-23 2017-09-08 Nouveau dérivé de pyrimidine imidazolyle, son procédé de préparation et une composition pharmaceutique le contenant en tant que principe actif pour prévenir ou traiter le cancer

Country Status (2)

Country Link
KR (1) KR102030886B1 (fr)
WO (1) WO2018056621A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110041302A (zh) * 2019-03-01 2019-07-23 南方医科大学 2-氨基-4-取代吡啶衍生物及其合成方法和应用
US11332473B2 (en) 2019-04-09 2022-05-17 Nuvation Bio Inc. Substituted pyrazolo[3,4-d]pyrimidines as Wee1 inhibitors

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022216097A1 (fr) * 2021-04-08 2022-10-13 주식회사 스탠다임 Nouvel inhibiteur de lrrk2

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003011836A1 (fr) * 2001-08-01 2003-02-13 Merck & Co., Inc. Inhibiteurs de tyrosine kinase
WO2005040154A1 (fr) * 2003-10-17 2005-05-06 F. Hoffmann-La Roche Ag Nouveaux derives d'imidazole et leur utilisation comme agents pharmaceutiques
WO2005075461A1 (fr) * 2004-02-03 2005-08-18 Astrazeneca Ab Imidazolo-5-yl-2-anilinopyrimidines utilises en tant qu'agents inhibiteurs de la proliferation cellulaire
CN104788427A (zh) * 2015-02-05 2015-07-22 上海泓博智源医药技术有限公司 3-(2-嘧啶氨基)苯基丙烯酰胺类化合物及其应用
US20160102076A1 (en) * 2014-10-13 2016-04-14 Yuhan Corporation Compounds and compositions for modulating egfr mutant kinase activities

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20100021321A (ko) * 2008-08-14 2010-02-24 일양약품주식회사 Ν-페닐-2-피리미딘-아민 유도체의 제조방법

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003011836A1 (fr) * 2001-08-01 2003-02-13 Merck & Co., Inc. Inhibiteurs de tyrosine kinase
WO2005040154A1 (fr) * 2003-10-17 2005-05-06 F. Hoffmann-La Roche Ag Nouveaux derives d'imidazole et leur utilisation comme agents pharmaceutiques
WO2005075461A1 (fr) * 2004-02-03 2005-08-18 Astrazeneca Ab Imidazolo-5-yl-2-anilinopyrimidines utilises en tant qu'agents inhibiteurs de la proliferation cellulaire
US20160102076A1 (en) * 2014-10-13 2016-04-14 Yuhan Corporation Compounds and compositions for modulating egfr mutant kinase activities
CN104788427A (zh) * 2015-02-05 2015-07-22 上海泓博智源医药技术有限公司 3-(2-嘧啶氨基)苯基丙烯酰胺类化合物及其应用

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110041302A (zh) * 2019-03-01 2019-07-23 南方医科大学 2-氨基-4-取代吡啶衍生物及其合成方法和应用
CN110041302B (zh) * 2019-03-01 2021-11-30 南方医科大学 2-氨基-4-取代吡啶衍生物及其合成方法和应用
US11332473B2 (en) 2019-04-09 2022-05-17 Nuvation Bio Inc. Substituted pyrazolo[3,4-d]pyrimidines as Wee1 inhibitors

Also Published As

Publication number Publication date
KR20180032784A (ko) 2018-04-02
KR102030886B1 (ko) 2019-10-10

Similar Documents

Publication Publication Date Title
WO2019112344A1 (fr) Nouveau dérivé de pyrimidine ayant pour effet d'inhiber la croissance de cellules cancéreuses, et composition pharmaceutique contenant celui-ci
WO2018230934A1 (fr) Dérivé de n2,n4-diphénylpyrimidine-2,4-diamine, son procédé de préparation, et composition pharmaceutique le contenant comme principe actif pour la prévention ou le traitement du cancer
WO2021075691A1 (fr) Dérivé de pyrimidine, son procédé de préparation, et composition pharmaceutique pour prévenir ou traiter le cancer, le comprenant en tant que composant actif
WO2018139903A1 (fr) Composé pyrimidine et son utilisation pharmaceutique
WO2017026718A1 (fr) Nouveau composé 3-(isoxazol-3-yl)-pyrazolo[3,4-d]pyrimidin-4-amine, qui est un inhibiteur de la kinase ret
WO2017188694A1 (fr) Composé hétéroaryle comprenant de l'azote et son utilisation
WO2020171499A1 (fr) Nouveau dérivé de pyrido[3,4-d]pyrimidin-8-one ayant une activité inhibitrice de protéine kinase, et composition pharmaceutique pour prévenir, soulager ou traiter le cancer, comprenant celui-ci
WO2018004258A1 (fr) Nouveau dérivé hétérocyclique et son utilisation
WO2018155947A1 (fr) Composition pharmaceutique comprenant un composé apte à traverser la barrière hémato-encéphalique en tant que principe actif pour prévenir ou traiter le cancer du cerveau
WO2018088749A1 (fr) Nouveau composé de pyrimidine, son procédé de préparation et composition pharmaceutique le contenant en tant que principe actif pour la prévention ou le traitement du cancer et des maladies inflammatoires
WO2014109530A1 (fr) Dérivé 2-(phényléthynyl)thiéno[3,4-b]pyrazine, et composition pharmaceutique comprenant ce dérivé et destinée à la prévention ou au traitement du cancer
WO2018056621A1 (fr) Nouveau dérivé de pyrimidine imidazolyle, son procédé de préparation et une composition pharmaceutique le contenant en tant que principe actif pour prévenir ou traiter le cancer
WO2020036386A1 (fr) Dérivé d'isoindolin-1-one, procédé de préparation de celui-ci, et composition pharmaceutique le contenant en tant que composant actif pour la prévention ou le traitement du cancer
WO2017176040A1 (fr) Composé hétérocyclique décomposant une protéine ras et utilisations correspondantes
WO2016093554A2 (fr) Nouveau dérivé de 4-(aryl)-n-(2-alkoxythiéno[3,2-b]pyrazin-3-yl)-pipérazine-1-carboxamide et effet antiprolifératif de celui-ci
WO2021096112A1 (fr) Dérivé de composé pyrrolopyrimidine, pyrrolopyridine et d'indazole, et composition pharmaceutique thérapeutique le contenant
WO2011049274A1 (fr) Dérivés d'imidazole et compositions pour le traitement d'un mélanome
WO2016006975A2 (fr) Nouveaux dérivés imidazotriazinone ou imidazopyrazinone et leur utilisation
WO2016006974A2 (fr) Nouveaux dérivés triazolopyrimidinone ou triazolopyridinone et leur utilisation
WO2010032986A2 (fr) Nouveaux dérivés de 5-(4-aminophenyl)-isoquinoline, leurs sels pharmaceutiquement acceptables, procédé de production associé et composition contenant les dérivés comme principe actif pour la prophylaxie et le traitement d'états pathologiques induits par l'hyperactivité de la kinase raf
WO2021101268A1 (fr) Dérivé de benzamide, son procédé de préparation, et composition pharmaceutique le comprenant en tant que principe actif pour la prévention ou le traitement du cancer
WO2017164705A1 (fr) Nouveau dérivé de pyridine, son procédé de préparation, et composition pharmaceutique pour prévenir ou traiter une maladie liée à fgfr contenant ledit dérivé comme principe actif
WO2021040422A1 (fr) Nouveau dérivé de pyrimido[4,5-d]pyrimidine-2-one ayant une activité inhibitrice de protéine kinase
WO2021080346A1 (fr) Nouveau dérivé de pyridinyltriazine ayant une activité inhibitrice de la protéine kinase, et composition pharmaceutique pour la prévention, l'amélioration ou le traitement du cancer le comprenant
WO2019098785A1 (fr) Dérivé de 7-amino-1h-indole-5-carboxamide et utilisation correspondante

Legal Events

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

Ref document number: 17853335

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17853335

Country of ref document: EP

Kind code of ref document: A1