WO2021075691A1 - Dérivé de pyrimidine, son procédé de préparation, et composition pharmaceutique pour prévenir ou traiter le cancer, le comprenant en tant que composant actif - Google Patents

Dérivé de pyrimidine, son procédé de préparation, et composition pharmaceutique pour prévenir ou traiter le cancer, le comprenant en tant que composant actif Download PDF

Info

Publication number
WO2021075691A1
WO2021075691A1 PCT/KR2020/010657 KR2020010657W WO2021075691A1 WO 2021075691 A1 WO2021075691 A1 WO 2021075691A1 KR 2020010657 W KR2020010657 W KR 2020010657W WO 2021075691 A1 WO2021075691 A1 WO 2021075691A1
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
amino
egfr
phenyl
formula
Prior art date
Application number
PCT/KR2020/010657
Other languages
English (en)
Korean (ko)
Inventor
이광호
조병철
두기랄라크리시나바부
최길돈
윤지연
박채원
채종학
정명은
Original Assignee
한국화학연구원
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 한국화학연구원 filed Critical 한국화학연구원
Publication of WO2021075691A1 publication Critical patent/WO2021075691A1/fr

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/308—Foods, ingredients or supplements having a functional effect on health having an effect on cancer prevention

Definitions

  • the present invention relates to a pharmaceutical composition for preventing or treating cancer, and specifically to a pharmaceutical composition for preventing or treating cancer containing a pyrimidine derivative as an active ingredient.
  • Cancer incidence is related to changes in various environmental factors including chemicals, radiation, and viruses, oncogenes, tumor suppressor genes, and genes related to apoptosis and DNA repair.
  • a new treatment, targeted chemotherapy became possible.
  • Targeted therapies are generally made to target molecules characteristic of cancer cells to exert their effects, and molecular targets are cancer cell signal transduction pathways, angiogenesis, and interstitial cells. They are genes related to (matrix), cell cycle regulator, and apoptosis.
  • Currently used as important target therapeutics in treatment include tyrosine kinase inhibitors, signaling pathway inhibitors, and angiogenesis inhibitors.
  • EGFR epidermal growth factor receptor
  • a receptor tyrosine kinase of the erbB family is a non-small cell lung cancer. It is abnormally activated in many epithelial cell tumors, including NSCLC, breast cancer, glioma, squamous cell carcinoma of the head and neck, colon cancer, rectal carcinoma, head and neck cancer, gastric cancer, and prostate cancer. It has been known that activation causes continuous cell proliferation, invasion of surrounding tissues, distant metastasis, and blood vessel formation, and increases cell survival.
  • the EGFR is one of the ErbB tyrosine kinase receptors family (EGFR, HER-2, ErbB-3, ErbB-4), an extracelluar ligand-binding domain and a tyrosine kinase region It is a transmembrane tyrosine kinase that has an intracellular domain including (tyrosine kinase domain).
  • PI3K phosphatidylinositol 3-kinase
  • EGFR is overexpressed in more than half of non-small cell lung cancer (NSCLC), and many studies have been conducted as a target of treatment.
  • EGFR TKI tyrosine kinase inhibitor
  • representative drugs include gefitinib (IRESSATM), erlotinib (TARCEVATM), and lapatinib (TYKERBTM, TYVERBTM).
  • the EGFR mutation is largely classified into a sensitizing mutation and a resistant mutation.
  • the deletion of exon 19 and the L858R point mutation of exon 21 are the most important sensitive mutations. %, and exon 19 del mutations are known to be more sensitive to TKI.
  • the T790M point mutation of exon 20 is the most important resistance mutation and is known to be found in more than 50% of acquired resistance patients (Clin Cancer Res 2006;12:6494-6501.).
  • Somatic mutations identified so far include in-frame deletions within exon 19 or insertions in exon 20, as well as point mutations in which a single nucleic acid residue is modified in the expressed protein (e.g., L858R, G719S, G719C, G719A, L861Q) ( Fukuoka et al. JCO 2003; Kris et al JAMA 2003 and Shepherd et al NEJM 2004).
  • EGFR mutations EGFR_del19 or EGFR_L858R
  • their therapeutic drugs Iressa and Taseba
  • Iressa and Taseba their therapeutic drugs
  • Iressa and Taseba their therapeutic drugs
  • this is the main cause of actual drug resistance.
  • the first generation EGFR inhibitor is used for an average of 10 months, the acquired resistance of the T790M mutation located at the gatekeeper of the EGFR kinase occurs, and the first generation EGFR inhibitors do not take effect.
  • EGFR_del19_T790M or EGFR_L858R_T790M double mutation occurs, preventing the existing treatment from showing efficacy.
  • EGFR Exon20insertion mutations There is a wide variety of EGFR Exon20insertion mutations, including EGFR D770delinsGY, EGFR H773_V774insH, EGFR Y764_V765insHH, EGFR D770insASV and EGFR D770_N771insSVD.
  • the pyrimidine derivatives according to the present invention exhibit relatively low inhibition against wild-type EGFR, while exhibiting high inhibitory ability against EGFR mutations, thereby preventing cancer.
  • the present invention was completed by finding that it can be usefully used for treatment.
  • Another object of the present invention is to provide a method for preparing the pyrimidine derivative.
  • Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of cancer containing the pyrimidine derivative, isomers thereof, or pharmaceutically acceptable salts thereof as an active ingredient.
  • Another object of the present invention is to provide a health functional food composition for preventing or improving cancer containing the pyrimidine derivative, isomers thereof, or pharmaceutically acceptable salts thereof as an active ingredient.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating diseases related to EGFR mutations containing the pyrimidine derivative, isomers thereof, or pharmaceutically acceptable salts thereof as an active ingredient.
  • R is -OR a or -NR b1 R b2 ,
  • R a is -(CH 2 ) m -NR b1 R b2 , where m is 1 to 3,
  • R b1 and R b2 are each independently hydrogen or unsubstituted or straight or branched chain C 1-6 alkyl substituted with NR c1 R c2 , or R b1 and R b2 are N, O together with the nitrogen to which they are attached. And to form an unsubstituted or straight or branched chain C 1-6 alkyl containing one or more heteroatoms selected from the group consisting of S or a 5 to 7 membered heterocycloalkyl substituted with NR c1 R c2,
  • R c1 and R c2 are each independently hydrogen or straight or branched chain C 1-6 alkyl, or, R c1 and R c2 are selected from the group consisting of N, O and S together with the nitrogen to which they are attached. 5 to 7 membered heterocycloalkyl substituted with unsubstituted or straight or branched C 1-6 alkyl containing one or more atoms.
  • R is as defined in Chemical Formula 1.
  • a pharmaceutical composition for preventing or treating cancer containing the compound represented by Chemical Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a health functional food for preventing or improving cancer containing the compound represented by Formula 1, isomers thereof, or pharmaceutically acceptable salts thereof as an active ingredient.
  • a pharmaceutical composition for preventing or treating diseases related to EGFR mutations containing the compound represented by Formula 1, isomers thereof, or pharmaceutically acceptable salts thereof as an active ingredient.
  • cancer or EGFR comprising administering to a subject in need a pharmaceutical composition or a dietary supplement composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient It provides a method of preventing or treating mutation-related diseases.
  • a pharmaceutical composition or a dietary supplement composition containing a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof in the prevention or treatment of cancer or EGFR mutation-related diseases Provides.
  • the pyrimidine derivative according to the present invention exhibits a relatively weak inhibitory effect on EGFR activity against wild-type EGFR, and exhibits a high inhibitory ability against EGFR mutations, so it can be usefully used in the treatment of cancer in which EGFR mutations have occurred.
  • 1 is a graph showing the results of measuring the cell growth inhibitory ability of the existing EGFR TKI (tyrosine kinase inhibitor) drug osimertinib against the Ba/F3 EGFR exon20 insertion mutation.
  • EGFR TKI tyrosine kinase inhibitor
  • Example 2 is a graph showing the results of measuring the cell growth inhibitory ability of the compound represented by Example 1 against the Ba/F3 EGFR exon20 insertion mutation.
  • the present invention provides a compound represented by the following formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof.
  • R is -OR a or -NR b1 R b2 ,
  • R a is -(CH 2 ) m -NR b1 R b2 , where m is 1 to 3,
  • R b1 and R b2 are each independently hydrogen or unsubstituted or straight or branched chain C 1-6 alkyl substituted with NR c1 R c2 , or R b1 and R b2 are N, O together with the nitrogen to which they are attached. And to form an unsubstituted or straight or branched chain C 1-6 alkyl containing one or more heteroatoms selected from the group consisting of S or a 5 to 7 membered heterocycloalkyl substituted with NR c1 R c2,
  • R c1 and R c2 are each independently hydrogen or straight or branched chain C 1-6 alkyl, or, R c1 and R c2 are selected from the group consisting of N, O and S together with the nitrogen to which they are attached. 5 to 7 membered heterocycloalkyl substituted with unsubstituted or straight or branched C 1-6 alkyl containing one or more atoms.
  • R is , , , , , , or Can be
  • Examples of the compound represented by Formula 1 according to the present invention include the following compounds:
  • the compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., 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, etc., acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, and the like.
  • pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, i.
  • the acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate formed by dissolving the derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and adding an organic or inorganic acid It can be prepared by filtration and drying, or it can be prepared by distilling a solvent and an excess of acid under reduced pressure and then drying to crystallize under an organic solvent.
  • an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc.
  • a pharmaceutically acceptable metal salt can be made using a base.
  • the alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved 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.
  • the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg, silver nitrate).
  • the present invention includes not only the compound represented by Formula 1 and its pharmaceutically acceptable salts, but also solvates, isomers, hydrates, etc. that may be prepared therefrom.
  • solvate refers to a compound of the present invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces.
  • Preferred solvents therefor include volatile, non-toxic, and/or suitable solvents for administration to humans. In this case, when the solvent is water, it is referred to as "hydrate”.
  • isomers refers to a compound of the present invention or a salt thereof having the same chemical formula or molecular formula, but structurally or sterically different.
  • isomers include structural isomers such as tautomers, R or S isomers having an asymmetric carbon center, stereoisomers such as geometric isomers (trans, cis), and optical isomers. All these isomers and mixtures thereof are also included within the scope of the present invention.
  • It provides a method for preparing a compound represented by Formula 1, comprising the step of preparing a compound represented by Formula 1 by reacting a compound represented by Formula 2 with a compound represented by Formula 3.
  • R is as defined in Chemical Formula 1.
  • step 1 is a step of preparing a compound represented by Formula 1 by reacting a compound represented by Formula 2 with a compound represented by Formula 3. Specifically, this is a step in which the compound represented by Formula 1 is formed by reacting the halogen of the compound represented by Formula 2 with the primary amine of the compound represented by Formula 3.
  • the reaction of Scheme 1 is not particularly limited as long as it is a condition capable of forming an amine bond by combining a halogen and an amine.
  • an acid condition was used, and trifluoroacetic acid (TFA) was used as the acid, but the present invention is not limited thereto.
  • the concentration of the acid may be 1 N, but is not limited thereto.
  • the solvent usable in Reaction Scheme 1 is not particularly limited, but lower alcohols including isopropanol, methanol, ethanol, propanol and butanol; Tetrahydrofuran (THF); Dioxane; Ether solvents including ethyl ether and 1,2-dimethoxyethane; Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methylene chloride, dichloroethane, water, acetonase sulfonate, toluene sulfonate, chlorobenzene sulfonate, xylene sulfonate, ethyl acetate, phenyl acetate, phenyl propionate , Phenylbutyrate, Cycrate, lactate, hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, na
  • reaction temperature in Scheme 1 may be 80° C. to 95° C., but is not limited thereto, and the reaction temperature may be appropriately adjusted according to the degree to which the reaction proceeds.
  • reaction time in Scheme 1 may be 10 minutes to 24 hours, but is not limited thereto, and the reaction time may be appropriately adjusted according to the degree to which the reaction proceeds.
  • the present invention provides a pharmaceutical composition for preventing or treating cancer containing the compound represented by Formula 1, isomers thereof, or pharmaceutically acceptable salts thereof as an active ingredient.
  • the cancer is pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, cleft lip cancer, mycological sarcoma, acute myeloid leukemia, acute lymphocytic leukemia, basal cell Cancer, ovarian epithelial cancer, ovarian germ cell carcinoma, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colon cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, barter bulge cancer, bladder cancer, Peritoneal cancer, parathyroid cancer, adrenal cancer, non-sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer
  • the EGFR mutations are EGFR del19, EGFR L858R, EGFR del19/T790M, EGFR L858R/T790M, EGFR del19/T790M/C797S, EGFR L858R/T790M/C797S, EGFR D770delinsGY, EGFR H773_V774ins D770ASH, EGFR EGFR and EGFR D770ASH, EGFR and EGFR D770ASH, EGFR, and EGFR del19/T790M_EGFR L858R/T790M It may be one or more selected from the group consisting of.
  • the compound represented by Formula 1 of the present invention exhibits a relatively weak inhibitory effect on EGFR activity against wild-type EGFR, while selectively exhibiting a high inhibitory ability against EGFR mutations, and in particular, exhibits a high inhibitory ability against EGFR del19/T790M, a double mutation. (See Experimental Example 1 and Table 2).
  • the compound represented by Formula 1 of the present invention exhibits a selectively high cell growth inhibitory ability against EGFR mutations in Ba/F3 cell lines.
  • the existing EGFR against triple mutations EGFR del19/T790M/C797S or EGFR L858R/T790M/C797S Since it exhibits a higher cell growth inhibitory ability than Osimertinib, which is a tyrosine kinase inhibitor (TKI) drug, it can be seen that it exhibits superior anticancer effects than osimertinib (see Experimental Example 2, Table 3 and Table 4).
  • TKI tyrosine kinase inhibitor
  • Example 1 compound of the present invention selectively shows high cell growth inhibitory ability against EGFR mutations in Ba/F3 cell lines, specifically EGFR D770delinsGY, EGFR H773_V774insH, EGFR Y764_V765insHH, EGFR D770insASV or EGFR D770_N771insSVD Since it exhibits a higher cell growth inhibitory ability than mertinib, it can be seen that it exhibits superior anticancer effects than osimertinib (see Experimental Example 3 and Table 5).
  • the compound represented by Formula 1 according to the present invention exhibits high inhibitory ability against EGFR mutations, EGFR del19, EGFR L858R, EGFR del19/T790M, EGFR L858R/T790M, EGFR del19/T790M/C797S, EGFR L858R/ T790M/C797S, EGFR D770delinsGY, EGFR H773_V774insH, EGFR Y764_V765insHH, EGFR D770insASV, EGFR D770_N771insSVD can be usefully used in the treatment of cancers expressing EGFR mutations.
  • the inhibitory ability against T790M/C797S is remarkably excellent, it can be usefully used in the treatment of cancers expressing EGFR del19/T790M/C797S or EGFR L858R/T790M/C797S.
  • the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various oral and parenteral formulations upon clinical administration.
  • formulation it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants that are usually used.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and these solid preparations include at least one excipient in one or more compounds, such as starch, calcium carbonate, sucrose, or lactose ( lactose), gelatin, etc.
  • lubricants such as magnesium stearate and talc are also used.
  • Liquid preparations for oral administration include suspensions, liquid solutions, emulsions, syrups, etc., but may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to water and liquid paraffin, which are commonly used simple diluents. have.
  • Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, and emulsions.
  • the non-aqueous solvent and the suspension solvent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used.
  • a pharmaceutical composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient can be administered parenterally, and parenteral administration is by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. It depends on how to do it.
  • the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is mixed in water together with a stabilizer or buffer to prepare a solution or suspension, and the ampoule or vial unit dosage form It can be manufactured with.
  • the composition may be sterilized and/or contain adjuvants such as preservatives, stabilizers, hydrating agents or emulsification accelerators, salts and/or buffers for controlling osmotic pressure, and other therapeutically useful substances, which are conventional methods of mixing and granulation. It can be formulated according to the method of painting or coating.
  • Formulations for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, and troches. , Dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants (such as silica, talc, stearic acid and magnesium or calcium salts thereof and/or polyethylene glycol). Tablets may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and in some cases boron such as starch, agar, alginic acid or sodium salt thereof. It may contain release or boiling mixtures and/or absorbents, colorants, flavoring agents, and sweetening agents.
  • a binder such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine,
  • the present invention provides a health functional food for the prevention or improvement of cancer containing the compound represented by Chemical Formula 1, its isomer, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the cancer is pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, cleft lip cancer, mycosis fungoides, acute myelogenous leukemia, acute lymphocytic leukemia, basal cell cancer, Ovarian epithelial cancer, ovarian germ cell carcinoma, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colon cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, barter bulge cancer, bladder cancer, peritoneal cancer , Parathyroid cancer, adrenal cancer, non-sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer,
  • the compound represented by Formula 1 according to the present invention is a health functional food composition for the prevention or improvement of cancer, in particular, cancer in which EGFR mutation is expressed, by showing a high inhibitory ability against EGFR mutation. Can be added to.
  • the compound represented by Formula 1 according to the present invention may be added to food as it is or may be used together with other foods or food ingredients, and may be appropriately used according to a conventional method.
  • the mixing amount of the active ingredient may be appropriately determined depending on the purpose of use (for prevention or improvement).
  • the amount of the compound in the health food may be added in an amount of 0.1 to 90 parts by weight of the total food weight.
  • the amount may be less than the above range, and there is no problem in terms of safety, so the active ingredient may be used in an amount above the above range.
  • the health functional beverage composition of the present invention is not particularly limited to other ingredients other than containing the compound as an essential ingredient in the indicated ratio, and may contain various flavoring agents or natural carbohydrates, etc. as additional ingredients, as in ordinary beverages.
  • natural carbohydrates include monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose, and the like; And polysaccharides, for example, common sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring agents tacmatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.)
  • synthetic flavoring agents sacharin, aspartame, etc.
  • the proportion of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 g of the composition of the present invention.
  • the compound represented by Chemical Formula 1 according to the present invention is a variety of nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavors and natural flavoring agents, coloring agents and heavy weight agents (cheese, chocolate, etc.), pects. Acids and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonates used in carbonated beverages, and the like.
  • the compound represented by Chemical Formula 1 of the present invention may contain flesh for the manufacture of natural fruit juice and fruit juice beverages and vegetable beverages.
  • the present invention provides a pharmaceutical composition for preventing or treating diseases related to EGFR mutations containing the compound represented by Formula 1, isomers thereof, or pharmaceutically acceptable salts thereof as an active ingredient.
  • the EGFR mutation-related disease may be at least one selected from the group consisting of cancer, psoriasis, eczema, atherosclerosis, stomatous rash, dry skin, chronic diarrhea, liver cirrhosis, myocardial fibrosis, and chronic renal failure.
  • the present invention is a cancer or EGFR mutation-related disease comprising the step of administering to a subject in need a pharmaceutical composition or a dietary supplement composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient It provides a method of preventing or treating.
  • the present invention provides a use of a pharmaceutical composition or a health functional food composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof in the prevention or treatment of cancer or EGFR mutation-related diseases. .
  • N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)methanesulfonamide was prepared through the method represented by Scheme 2 below.
  • the organic layer was washed with water, brine, dried over Na 2 SO 4 and evaporated under reduced pressure.
  • the obtained crude was dissolved in methanol (50 mL), K 2 CO 3 (2.0 g) was added, and stirred for 12 hours. The stirred liquid was evaporated under reduced pressure. Subsequently, the obtained stock solution was diluted with H 2 O (100 mL) and extracted with DCM (100 mL). The aqueous layer was separated, acidified with 1N HCl (pH ⁇ 5-4), and extracted with DCM.
  • the product stock solution was purified by flash silica chromatography, and was eluted with DCM containing 1 to 10% MeOH. The pure fractions were evaporated and dried to obtain 4-fluoro-2-methoxy-5-nitroaniline (4.5 g, 76% yield, yellow solid).
  • Step 2 Preparation of tert-butyl (4-fluoro-2-methoxy-5-nitrophenyl) carbamate
  • the obtained stock solution was purified using column chromatography in which the eluent was hexanes/ethyl acetate (7:3), and tert-butyl (4-fluoro-2-methoxy -5-nitrophenyl)carbamate (4.0 g, 58% yield, yellow solid) was obtained.
  • N-(5-amino-2((2-(dimethylamino)ethyl(methyl)amino)-4-methoxyphenyl)acrylamide was prepared through the method represented by Scheme 4 below.
  • Step 1 Preparation of tert-butyl (4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)carbamate
  • the tert-butyl (4-fluoro-2-methoxy-5-nitrophenyl) carbamate (300 mg, 1.04 mmol) prepared in Preparation Example 1-2 was dissolved in DMF (5 mL) and added to the stirred solution.
  • N 1 ,N 1 ,N 2 -Trimethylethane-1,2-diamine (106 mg, 1.04 mmol) and cesium carbonate (183 mg, 1.56 mmol) were added at room temperature.
  • the reaction mixture was stirred at 70° C. overnight. Thereafter, the reaction mixture was cooled to room temperature and quenched with ice water.
  • Step 2 Preparation of tert-butyl(5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)carbamate
  • Step 3 Preparation of tert-butyl (5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)carbamate
  • Step 4 Preparation of N-(5-amino-2((2-(dimethylamino)ethyl(methyl)amino)-4-methoxyphenyl)acrylamide
  • Step 4 of Preparation Example 1-3 except that tert-butyl (5-acrylamido-2-methoxy-4-morpholinophenyl) carbamate prepared in Preparation Example 4-1 was used as a precursor. According to the following, N-(5-amino-4-methoxy-2-morpholinophenyl)acrylamide was prepared.
  • Steps 1 to 3 of Preparation Example 1-3 except that N-methyl-2-morpholinoethan-1-amine was used instead of N 1 ,N 1 ,N 2 -trimethylethane-1,2-diamine According to the following, tert-butyl (5-acrylamido-2-methoxy-4-(methyl(2-morpholinoethyl)amino)phenyl)carbamate (69% yield) was prepared.
  • N-5-((5-chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino-2-((2- (Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide was prepared in the same manner as shown in Scheme 5 below.
  • N-(5-amino-2((2-(dimethylamino)ethyl(methyl)amino)-4-methoxyphenyl)acrylic prepared in Preparation Example 1-3 above in a solution dissolved in (30 mL) and stirred Amide (71.5 mg, 0.3 mmol) was added at room temperature The reaction tube was sealed with a Teflon-lined cap, and the reaction mixture was stirred overnight at 90° C.
  • the pyrimidine derivative compound according to the present invention N-(5-((5-chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-2-(4 -(Dimethylamino)piperidin-1-yl)-4-methoxyphenyl)acrylamide, prepared in Preparation Example 2-2, N-(5-amino-2-(4-(dimethylamino)pi) It was prepared according to Example 1, except that peridin-1-yl)-4-methoxyphenyl)acrylamide was used (yield 27%).
  • N-(5-((5-chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy -2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide was prepared in Preparation Example 3-2. It was prepared according to Example 1, except that oxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide was used (yield 30%).
  • the pyrimidine derivative compound according to the present invention N-(5-((5-chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy -2-morpholinophenyl)acrylamide, except that the N-(5-amino-4-methoxy-2-morpholinophenyl)acrylamide prepared in Preparation Example 4-2 was used. It was prepared according to Example 1 (yield 31%).
  • the pyrimidine derivative compound according to the present invention N-(5-((5-chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy -2-(4-methylpiperazin-1-yl)phenyl)acrylamide, prepared in Preparation Example 5-2, N-(5-amino-4-methoxy-2-(4-methylpiperazine-) It was prepared according to Example 1, except that 1-yl)phenyl)acrylamide was used (yield 41%).
  • the pyrimidine derivative compound according to the present invention N-(5-((5-chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-2-(2 -(Dimethylamino)ethoxy)-4-methoxyphenyl)acrylamide, prepared in Preparation Example 6-2, N-(5-amino-2-(2-(dimethylamino)ethoxy)-4- It was prepared according to Example 1 except for methoxyphenyl)acrylamide (yield 29%).
  • N-(5-((5-chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy -2-(methyl(2-morpholinoethyl)amino)phenyl)acrylamide was prepared in Preparation Example 7-2 above. N-(5-amino-4-methoxy-2-(2-morpholino) It was prepared according to Example 1, except that ethoxy)phenyl)acrylamide was used (yield 22%).
  • N-(5-((5-chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy -2-(Methyl(2-(4-methylpiperazin-1-yl)ethyl)amino)phenyl)acrylamide was prepared in Preparation Example 8-2 above N-(5-amino-4-methoxy- It was prepared according to Example 1, except that 2-(methyl(2-(4-methylpiperazin-1-yl)ethyl)amino)phenyl)acrylamide was used (yield 27%).
  • the pyrimidine derivative compound according to the present invention N-(5-((5-chloro-4-((2-(methylsulfonamido)phenyl)amido)pyrimidin-2-yl)amino)-4-me N-(5-amino-4-methoxy-2-(methyl(2-morpholino) prepared in Preparation Example 9-2) of oxy-2-(2-morpholinoethoxy)phenyl)acrylamide It was prepared according to Example 1, except that ethyl) amino) phenyl) acrylamide was used (yield 26%).
  • the activity measurement for wild-type and EGFR mutant enzymes for the compounds of the present invention was tested as follows using the HTRF system sold by Cisbio. EGFR wild-type and EGFR del19/T790M mutant enzymes were used by purchasing a recombinant protein provided by Carna Biosciences.
  • the composition of the assay buffer used for the activity measurement was 50 mM Tris-HCl pH 7.5, 100 mM NaCl, 7.5 mM MgCl 2 , 3 mM KCl, 0.01% Tween 20, 0.1% BSA, and 1 mM DTT.
  • the enzyme reaction was carried out using a peptide substrate labeled with 50 mM ATP and 0.5 mM biotin.
  • the analysis of the EGFR activity inhibitory effect of the compound was performed according to the following analytical reaction recipe.
  • Component 1 4 mL of EGFR wild-type or mutant enzyme
  • Component 3 4 mL ATP and biotin-labeled peptide
  • Enzymatic reaction starts by mixing component 1 and component 2 first, and then adding component 3 to it. After 2 hours reaction at 37°C, 10 mL of a measurement solution consisting of streptavidin-XL665 and europium-labeled anti-phosphotyrosine antibody provided by Cisbio was added to the enzyme reaction solution and reacted at room temperature for 1 hour. Finally, the ratio of fluorescence values at 615 nm and 665 nm is calculated using Perkin-Elmer's Envision equipment, and the enzyme activity is quantitatively measured and the inhibitory ability of the compound is confirmed. The measured values measured at the concentrations of the seven compounds were analyzed using the Prism program (version 5.01, Graphpad Software, Inc.), and the IC 50 value, an index of the inhibitory ability of the compound, was calculated.
  • All the compounds of the present invention exhibit a relatively weak EGFR activity inhibitory effect against wild-type EGFR, and selectively exhibit high inhibitory ability against EGFR mutations, which is similar to the case of osimertinib, a conventional EGFR tyrosine kinase inhibitor (TKI) drug. Similar things were confirmed.
  • TKI EGFR tyrosine kinase inhibitor
  • the pyrimidine derivative compound according to the present invention can effectively inhibit the EGFR mutation, and thus can be usefully used as a pharmaceutical composition for preventing or treating cancer.
  • the /C797S mutant cell line was used by purchasing a cell line provided by Crown Bioscience.
  • the /C797S mutant cell line was cultured in an RPMI containing 10% FBS and 1% penicillin-streptomycin with 1 ug of puromycine in an incubator at 37°C and 5% CO 2.
  • 2500 cells/90 ⁇ L were cultured by passage in a 96 well cell culture plate, and after 24 hours, the compound represented by Formula 1 was treated with 0, 0.01, 0.03, 0.1, 0.3, 1, 3, 10 ( ⁇ M). After the reaction for 72 hours, the plate treated with the compound was allowed to stand at room temperature for 30 minutes, and then 100 ⁇ L of the reagent was further treated and shaking at room temperature for 10 minutes. Finally, the ratio of the fluorescence value at 570 nm is calculated using an equipment, and the quantitative measurement is performed, and the ability of the compound to inhibit cell growth is confirmed. The measured values measured at the concentrations of the 8 compounds were analyzed using the Prism program (version 5.01, Graphpad Software, Inc.), and the IC 50 value, an indicator of the cell growth inhibitory ability of the compound, was calculated.
  • All the compounds of the present invention exhibited relatively weak inhibitory effect against wild-type EGFR in Ba/F3 cell lines, and selectively against EGFR mutations including triple mutations EGFR del19/T790M/C797S, EGFR L858R/T790M/C797S. It showed high cell growth inhibitory ability, and was found to be particularly superior to the case of osimertinib, an existing EGFR TKI drug.
  • the pyrimidine derivative compound according to the present invention can effectively inhibit the EGFR mutation, and thus can be usefully used as a pharmaceutical composition for preventing or treating cancer.
  • Example 1 In order to confirm the ability of the compound represented by Example 1 according to the present invention to inhibit cell growth against the Ba/F3 EGFR exon20 insertion mutation in the Ba/F3 cell line, the following experiment was performed. The results are shown in Table 5 below.
  • the activity measurement of the mutant Ba/F3 EGFR cell line for the compound of the present invention was tested as follows using the CellTiter-Glo system sold by Promega.
  • CellTiter-Glo assay is a method to check cell viability by measuring ATP present in cells in the cell culture state.
  • Ba/F3 EGFR D770delinsGY, H773_V774insH, Y764_V765insHH, V769_D770insASV, D770_N771insSVD mutant cell lines were purchased and used in Pasi A Janne laboratory of Dana-Farber Cancer Institute.
  • Ba/F3 D770delinsGY, H773_V774insH, Y764_V765insHH, V769_D770insASV, D770_N771insSVD mutant cell lines were cultured in an incubator at 37° C., 5% CO 2 by adding 1 ⁇ g/ml of puromycine to RPMI containing 10% FBS and 1% penicillin-streptomycin.
  • Ba/F3 EGFR V769_D770insASV IC 50 ( ⁇ M) Ba/F3 EGFR D770delinsGY IC 50 ( ⁇ M) Ba/F3 EGFR H773_V774insH IC 50 ( ⁇ M) Ba/F3 EGFR Y764_V765insHH IC 50 ( ⁇ M) Ba/F3 EGFR D770_N771insSVD IC 50 ( ⁇ M) Osimertinib 0.124 0.159 0.191 0.136 0.149 Example 1 0.026 0.021 0.06 0.029 0.027
  • the compound represented by Example 1 according to the present invention exhibits high cell growth inhibitory ability against Ba/F3 EGFR exon20 insertion mutations in Ba/F3 cell lines, which is the case of osimertinib, an existing EGFR tyrosine kinase inhibitor (TKI) drug. It was confirmed that it is more excellent.
  • TKI EGFR tyrosine kinase inhibitor
  • the pyrimidine derivative compound according to the present invention can effectively inhibit the EGFR mutation, and thus can be usefully used as a pharmaceutical composition for preventing or treating cancer.
  • the above ingredients were mixed and filled in an airtight cloth to prepare a powder.
  • tablets were prepared by tableting according to a conventional tablet preparation method.
  • a gelatin capsule was filled according to a conventional capsule preparation method to prepare a capsule.
  • injections were prepared by containing the above ingredients in the indicated amount.
  • the ingredients suitable for health food are mixed and formulated as a preferred formulation example, but the mixing ratio may be arbitrarily modified.
  • the resulting solution After mixing the above ingredients according to a conventional health drink manufacturing method, after stirring and heating at 85° C. for about 1 hour, the resulting solution is filtered and obtained in a sterilized container, sealed and sterilized, and then stored in a refrigerator. It was used in preparation.
  • composition ratio is a mixture of ingredients suitable for a relatively preferred beverage in a preferred embodiment, but the mixing ratio may be arbitrarily modified according to regional and ethnic preferences such as the demand class, the country of demand, and the purpose of use.

Landscapes

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

Abstract

La présente invention concerne un dérivé de pyrimidine, un procédé de préparation de celui-ci, et une composition pharmaceutique pour prévenir ou traiter le cancer, comprenant le dérivé de pyrimidine en tant que composant actif, le dérivé présentant un effet inhibiteur relativement faible sur l'activité de l'EGFR par rapport à l'EGFR de type sauvage tout en présentant un effet inhibiteur élevé vis-à-vis des mutations de l'EGFR, et peut ainsi être utilisé de manière efficace pour le traitement du cancer ayant des mutations de l'EGFR.
PCT/KR2020/010657 2019-10-18 2020-08-12 Dérivé de pyrimidine, son procédé de préparation, et composition pharmaceutique pour prévenir ou traiter le cancer, le comprenant en tant que composant actif WO2021075691A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2019-0130157 2019-10-18
KR1020190130157A KR102383200B1 (ko) 2019-10-18 2019-10-18 피리미딘 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물

Publications (1)

Publication Number Publication Date
WO2021075691A1 true WO2021075691A1 (fr) 2021-04-22

Family

ID=75537846

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2020/010657 WO2021075691A1 (fr) 2019-10-18 2020-08-12 Dérivé de pyrimidine, son procédé de préparation, et composition pharmaceutique pour prévenir ou traiter le cancer, le comprenant en tant que composant actif

Country Status (2)

Country Link
KR (1) KR102383200B1 (fr)
WO (1) WO2021075691A1 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4371983A1 (fr) * 2021-07-13 2024-05-22 Korea Research Institute of Chemical Technology Nouveaux dérivés de pyrimidine-2,4-diamine, leur procédé de préparation et composition pharmaceutique les contenant en tant que principe actif pour la prévention ou le traitement du cancer
CA3228333A1 (fr) * 2021-08-05 2023-02-09 Korea Research Institute Of Chemical Technology Derive de pyrimidine, son procede de preparation et composition pharmaceutique pour prevenir ou traiter le cancer le comprenant en tant que principe actif
KR102611488B1 (ko) * 2021-08-05 2023-12-11 한국화학연구원 피리미딘 유도체, 이의 제조방법 및 이를 유효성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물
WO2023063751A1 (fr) * 2021-10-15 2023-04-20 제이투에이치바이오텍 주식회사 Composés inhibant les kinases de mutation alk et/ou egfr et leur utilisation médicale
WO2023163527A1 (fr) * 2022-02-23 2023-08-31 주식회사 카나프테라퓨틱스 Nouveau composé ayant une activité inhibitrice contre la tyrosine kinase du récepteur du facteur de croissance épidermique, et ses utilisations
KR102524856B1 (ko) * 2022-06-23 2023-04-24 주식회사 카나프테라퓨틱스 표피 성장인자 수용체 티로신 키나제에 대한 억제 활성을 갖는 신규 화합물 및 이의 용도

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105503827A (zh) * 2014-10-11 2016-04-20 上海翰森生物医药科技有限公司 Egfr抑制剂及其制备方法和用途
CN106187915A (zh) * 2015-05-27 2016-12-07 上海翰森生物医药科技有限公司 具有alk与egfr双重活性的抑制剂及其制备方法和应用
WO2017101803A1 (fr) * 2015-12-15 2017-06-22 合肥中科普瑞昇生物医药科技有限公司 Nouveau double inhibiteur de egfr et de alk
KR20170118681A (ko) * 2014-10-11 2017-10-25 상하이 한서 바이오메디컬 컴퍼니 리미티드 Ｅｇｆｒ 억제제, 및 이의 제조 및 적용
KR20190108079A (ko) * 2018-03-13 2019-09-23 보로노이바이오 주식회사 2,4,5-치환된 피리미딘 유도체, 이의 제조방법 및 이를 유효성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105503827A (zh) * 2014-10-11 2016-04-20 上海翰森生物医药科技有限公司 Egfr抑制剂及其制备方法和用途
KR20170118681A (ko) * 2014-10-11 2017-10-25 상하이 한서 바이오메디컬 컴퍼니 리미티드 Ｅｇｆｒ 억제제, 및 이의 제조 및 적용
CN106187915A (zh) * 2015-05-27 2016-12-07 上海翰森生物医药科技有限公司 具有alk与egfr双重活性的抑制剂及其制备方法和应用
WO2017101803A1 (fr) * 2015-12-15 2017-06-22 合肥中科普瑞昇生物医药科技有限公司 Nouveau double inhibiteur de egfr et de alk
KR20190108079A (ko) * 2018-03-13 2019-09-23 보로노이바이오 주식회사 2,4,5-치환된 피리미딘 유도체, 이의 제조방법 및 이를 유효성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물

Also Published As

Publication number Publication date
KR102383200B1 (ko) 2022-04-06
KR20210046914A (ko) 2021-04-29

Similar Documents

Publication Publication Date Title
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
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
WO2019112344A1 (fr) Nouveau dérivé de pyrimidine ayant pour effet d'inhiber la croissance de cellules cancéreuses, et composition pharmaceutique contenant celui-ci
WO2018139903A1 (fr) Composé pyrimidine et son utilisation pharmaceutique
WO2018012907A1 (fr) Nouveaux dérivés de quinazolinone inhibant la pi3k et composition pharmaceutique en contenant
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
WO2009125923A2 (fr) Nouveaux dérivés de bispyridyl carboxamide d'acide indole carboxylique, leurs sels pharmaceutiquement acceptables, procédé de préparation et composition les contenant en tant d'ingrédient actif
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
WO2017142325A1 (fr) Nouveau composé thiophène substitué en 2,3,5 utilisé en tant qu'inhibiteur de la protéine kinase
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
WO2018004258A1 (fr) Nouveau dérivé hétérocyclique et son utilisation
WO2020149715A1 (fr) Dérivé de pyrrolopyridine et son utilisation dans la prévention et le traitement d'une maladie liée à la protéine kinase
WO2021145521A1 (fr) Dérivé de pyrido[3,4-d]pyrimidine et composition pharmaceutique thérapeutique le comprenant
WO2021125803A1 (fr) Nouveau dérivé de pyrimidine et utilisation correspondante
WO2018004213A1 (fr) Nouveau composé ayant une activité inhibitrice de smo et composition comprenant celui-ci en tant qu'ingrédient actif pour prévenir ou traiter le cancer
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
WO2020040582A1 (fr) Nouveau dérivé de benzopyrane ou sel pharmaceutiquement acceptable de celui-ci et composition pharmaceutique le comprenant en tant que principe actif
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
AU2017256488B2 (en) Quinazoline derivative or its salt and pharmaceutical composition comprising the same
WO2022234965A1 (fr) Dérivé hétéroaryle, son procédé de préparation et composition pharmaceutique le comprenant en tant que principe actif
WO2023287130A1 (fr) Nouveaux dérivés de pyrimidine-2,4-diamine, leur procédé de préparation et composition pharmaceutique les contenant en tant que principe actif pour la prévention ou le 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
WO2018021826A1 (fr) Nouveau dérivé de pyrimidine-2,4-diamine et composition pharmaceutique pour la prévention ou le traitement du cancer contenant celui-ci comme ingrédient actif
WO2021096112A1 (fr) Dérivé de composé pyrrolopyrimidine, pyrrolopyridine et d'indazole, et composition pharmaceutique thérapeutique le contenant
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

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: 20876928

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: 20876928

Country of ref document: EP

Kind code of ref document: A1