WO2019235894A1 - Composition pour la prévention ou le traitement du cancer solide comprenant un composé inhibant la liaison de aimp2-dx2 et de k-ras et nouveau composé inhibant la liaison de aimp2-dx2 et k-ras - Google Patents

Composition pour la prévention ou le traitement du cancer solide comprenant un composé inhibant la liaison de aimp2-dx2 et de k-ras et nouveau composé inhibant la liaison de aimp2-dx2 et k-ras Download PDF

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WO2019235894A1
WO2019235894A1 PCT/KR2019/006910 KR2019006910W WO2019235894A1 WO 2019235894 A1 WO2019235894 A1 WO 2019235894A1 KR 2019006910 W KR2019006910 W KR 2019006910W WO 2019235894 A1 WO2019235894 A1 WO 2019235894A1
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methyl
amino
pyrrole
thieno
dione
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PCT/KR2019/006910
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English (en)
Korean (ko)
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권남훈
김성훈
한균희
한정민
이철호
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재단법인 의약바이오컨버젼스연구단
연세대학교 산학협력단
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Publication of WO2019235894A1 publication Critical patent/WO2019235894A1/fr

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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
    • A61K31/495—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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a composition for preventing or treating solid cancer comprising a compound that inhibits the binding of AIMP2-DX2 and K-Ras and a novel compound that inhibits the binding of AIMP2-DX2 and K-Ras.
  • Ras protein formed by the Ras gene has a molecular weight of 21 kDa, which is specifically expressed in eukaryotic cells. In all animal cells, there are three types of Ras proteins, H-Ras, K-Ras and N-Ras. Ras proteins are activated in response to external stimuli that activate tyrosine kinase receptors. When autophosphorylation of tyrosine kinase receptors occurs by external stimulation, Grb2, an adapter protein that connects a signal protein to an activated receptor, calls for SOS protein to form a complex.
  • SOS proteins are linked to activated receptors, resulting in a GDP / GTP exchange of inactive Ras GDP bound to the surrounding plasma membrane, which activates Ras.
  • Activated Ras plays a role in regulating cell proliferation and differentiation by activating various signaling processes such as the Raf-MAP kinase pathway.
  • Cancer cells are constantly dividing and proliferating, and reports in several articles suggest a model for cancer proliferation and metastasis from experimental animal models.
  • cancer cells caused by K-Ras a carcinogenic gene
  • K-Ras in normal tissues regulates cell growth and differentiation, but cancer cells are affected by tumor microenvironmental factors around tumor cells and become abnormal due to rapid division and activation of abnormal division and maintenance pathways. It is proposed to acquire and ultimately cause cancer to recur.
  • AIMP2 aminoacyl-tRNA synthetase-interacting multifunctional protein 2
  • ARS aminoacyl-tRNA synthetase
  • AIMP2 is known to have a function of enhancing TGF- ⁇ signaling through direct interaction with Smad2 / 3 as a novel cancer suppressor, in addition to the essential function constituting the ARS complex.
  • TNF- ⁇ and DNA damage signals promote cell death through binding to TRAF-2 and P53, respectively.
  • AIMP2-DX2 a variant of exon 2 deficient in AIMP2, is expressed in various cancer cell lines and tissues such as lung cancer, liver cancer, skin cancer, breast cancer, kidney cancer, and osteosarcoma.
  • transforming normal cells to overexpress AIMP2-DX2 inhibits AIMP2 activity, such as preventing wild-type (WT) AIMP2 from moving to the nucleus, increases c-myc expression, and promotes cell growth. Etc. It has been shown to cause dysfunction of TGF- ⁇ signaling. This suggests that there is a close relationship between AIMP2-DX2 and cancer development and progression.
  • AIMP2-DX2 which is closely related to the differentiation and proliferation of cancer cells, directly binds to K-Ras, stabilizes K-Ras protein, and consequently plays a crucial role in the survival and differentiation of cancer cells.
  • the present inventors have made diligent efforts to find compounds exhibiting excellent anticancer activity in solid cancers overexpressing AIMP2-DX2 by directly inhibiting the binding of AIMP2-DX2 and K-Ras.
  • the present invention has been found to be excellent in such activity and exhibits very good cancer cell growth inhibitory effect and cytotoxicity in solid cancers overexpressing AIMP2-DX2.
  • an object of the present invention is to provide a pharmaceutical composition for preventing or treating solid cancer, comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • R 1 is C 1 -C 6 alkyl unsubstituted or substituted with C 2 -C 10 hetero aryl including at least one hetero atom selected from the group consisting of N, O and S; C1-C6 alkyl substituted with C6-C12 aryl unsubstituted or substituted with C1-C6 alkoxy; Thiophene unsubstituted or substituted with C1-C6 alkyl; Furan; Pyrrole; Thiazole; C3-C7 cycloalkyl; Or C6-C12 aryl unsubstituted or substituted with one or more selected from the group consisting of C1-C6 alkoxy, C1-C6 alkylamino, amino, C1-C6 alkyl, hydroxy and halogen,
  • R 2 is hydrogen; Straight or branched C1-C6 alkyl; C1-C6 alkoxycarbonyl; Thiophene; Or C1-C6 alkoxy, hydroxy, linear or branched C1-C6 alkyl, heterosubstituted or unsubstituted with C2-C10 heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S.
  • C6-C12 aryl unsubstituted or substituted with one or more selected from the group consisting of cycloalkyloxy and halogen
  • R 3 is hydrogen; Cyano; C1-C6 alkoxy; C1-C6 alkoxycarbonyl; Aminocarbonyl; C3-C10 alkoxycarbonylalkyl; C3-C10 heterocycloalkyl comprising at least one hetero atom selected from the group consisting of N, O and S; Thiophene; C2-C10 hetero aryl unsubstituted or substituted with straight or branched C1-C6 alkyl or C3-C10 cycloalkyl; C1-C6 alkyl; C1-C6 alkyl substituted with C6-C12 aryl unsubstituted or substituted with hydroxy or C1-C6 alkoxy; C6-C12 aryl substituted with unsubstituted C1-C6 alkoxy; C6-C12 aryl unsubstituted or substituted with one or more selected from the group consisting of hydroxy, nitro, halogen and cyano; or Is
  • R 4 is C 1 -C 6 alkylamino unsubstituted or substituted with one or more selected from the group consisting of C 1 -C 6 alkylamino, hydroxy, C 1 -C 6 alkoxy, cyano and halogen; C2-C10 heterocycloalkyl unsubstituted or substituted with one or more selected from the group consisting of C1-C6 aminoalkyl, C2-C10 alkylaminoalkyl and C2-C6 alkylcarbonyl; Amino; C2-C6 alkenylamino; C2-C6 alkynylamino; C2-C10 spiroheterocycloalkyl; And benzylamino is one or more selected from the group consisting of
  • N is an integer of 1 to 5.
  • Another object of the present invention is 1-[[6-[(4-fluorophenyl) -2- (2-furyl) -5-methyl-thieno [2,3-d] pyrimidin-4-yl] amino ] -3-methyl-pyrrole-2,5-dione;
  • Another object of the present invention to provide a use of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof for the preparation of a preventive or therapeutic agent for solid cancer.
  • Another object of the present invention to provide a method for treating solid cancer, comprising administering to a subject in need thereof an effective amount of a composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. will be.
  • the present invention provides a pharmaceutical composition for preventing or treating solid cancer comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating solid cancer, comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating solid cancer, consisting essentially of the compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
  • R 1 is C 1 -C 6 alkyl unsubstituted or substituted with C 2 -C 10 hetero aryl including at least one hetero atom selected from the group consisting of N, O and S; C1-C6 alkyl substituted with C6-C12 aryl unsubstituted or substituted with C1-C6 alkoxy; Thiophene unsubstituted or substituted with C1-C6 alkyl; Furan; Pyrrole; Thiazole; C3-C7 cycloalkyl; Or C6-C12 aryl unsubstituted or substituted with one or more selected from the group consisting of C1-C6 alkoxy, C1-C6 alkyl amino, amino, C1-C6 alkyl, hydroxy and halogen,
  • R 2 is hydrogen; Straight or branched C1-C6 alkyl; C1-C6 alkoxycarbonyl; Thiophene; Or C 1 -C 6 alkoxy, hydroxy, straight or branched C 1 -C 6 alkyl unsubstituted or substituted with C 2 -C 10 heterocycloalkyl containing one or more hetero atoms selected from the group consisting of N, O and S; , C6-C12 aryl unsubstituted or substituted with one or more selected from the group consisting of heterocycloalkyloxy and halogen,
  • R 3 is hydrogen; Cyano; C1-C6 alkoxy; C1-C6 alkoxycarbonyl; Aminocarbonyl; C3-C10 alkoxycarbonylalkyl; C3-C10 heterocycloalkyl comprising at least one hetero atom selected from the group consisting of N, O and S; Thiophene; C2-C10 hetero aryl unsubstituted or substituted with straight or branched C1-C6 alkyl or C3-C10 cycloalkyl; C1-C6 alkyl; C1-C6 alkyl substituted with hydroxy or C6-C12 aryl unsubstituted or substituted with C1-C6 alkoxy; C6-C12 aryl substituted with unsubstituted C1-C6 alkoxy; C6-C12 aryl unsubstituted or substituted with one or more selected from the group consisting of hydroxy, nitro, halogen and cyano; or Is
  • R 4 is C 1 -C 6 alkylamino unsubstituted or substituted with one or more selected from the group consisting of C 1 -C 6 alkylamino, hydroxy, C 1 -C 6 alkoxy, cyano and halogen; C2-C10 heterocycloalkyl unsubstituted or substituted with one or more selected from the group consisting of C1-C6 aminoalkyl, C2-C10 alkylaminoalkyl and C2-C6 alkylcarbonyl; Amino; C2-C6 alkenylamino; C2-C6 alkynylamino; C2-C10 spiroheterocycloalkyl; And benzylamino is one or more selected from the group consisting of
  • N is an integer of 1 to 5.
  • the present invention provides 1-[[6-[(4-fluorophenyl) -2- (2-furyl) -5-methyl-thieno [2,3-d] pyrimidine -4-yl] amino] -3-methyl-pyrrole-2,5-dione;
  • the present invention provides a use of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof for the manufacture of a preparation for preventing or treating solid cancer.
  • the present invention provides a method for treating solid cancer comprising administering to a subject in need thereof an effective amount of a composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. Provide a method.
  • the present invention provides a pharmaceutical composition for preventing or treating solid cancer, comprising the compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating solid cancer, comprising the compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating solid cancer, consisting essentially of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:
  • R 1 is C 1 -C 6 alkyl unsubstituted or substituted with C 2 -C 10 hetero aryl including at least one hetero atom selected from the group consisting of N, O and S; C1-C6 alkyl substituted with C6-C12 aryl unsubstituted or substituted with C1-C6 alkoxy; Thiophene unsubstituted or substituted with C1-C6 alkyl; Furan; Pyrrole; Thiazole; C3-C7 cycloalkyl; Or C6-C12 aryl unsubstituted or substituted with one or more selected from the group consisting of C1-C6 alkoxy, C1-C6 alkyl amino, amino, C1-C6 alkyl, hydroxy and halogen,
  • R 2 is hydrogen; Straight or branched C1-C6 alkyl; C1-C6 alkoxycarbonyl; Thiophene; Or C1-C6 alkoxy, hydroxy, linear or branched C1-C6 alkyl, heterosubstituted or unsubstituted with C2-C10 heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S.
  • C6-C12 aryl unsubstituted or substituted with one or more selected from the group consisting of cycloalkyloxy and halogen
  • R 3 is hydrogen; Cyano; C1-C6 alkoxy; C1-C6 alkoxycarbonyl; Aminocarbonyl; C3-C10 alkoxycarbonylalkyl; C3-C10 heterocycloalkyl comprising at least one hetero atom selected from the group consisting of N, O and S; Thiophene; C2-C10 hetero aryl unsubstituted or substituted with straight or branched C1-C6 alkyl or C3-C10 cycloalkyl; C1-C6 alkyl; C1-C6 alkyl substituted with hydroxy or C6-C12 aryl unsubstituted or substituted with C1-C6 alkoxy; C6-C12 aryl substituted with unsubstituted C1-C6 alkoxy; C6-C12 aryl unsubstituted or substituted with one or more selected from the group consisting of hydroxy, nitro, halogen and cyano; or Is
  • R 4 is C1-C6 alkylamino unsubstituted or substituted with one or more selected from the group consisting of C1-C6 alkylamino, hydroxy, C 1 -C6 alkoxy, cyano and halogen; C2-C10 heterocycloalkyl unsubstituted or substituted with one or more selected from the group consisting of C1-C6 aminoalkyl, C2-C10 alkylaminoalkyl and C2-C6 alkylcarbonyl; Amino; C2-C6 alkenylamino; C2-C6 alkynylamino; C2-C10 spiroheterocycloalkyl; And benzylamino is one or more selected from the group consisting of
  • N is an integer of 1 to 5.
  • R 1 is thiophene unsubstituted or substituted with methyl; Benzene unsubstituted or substituted with one or more selected from the group consisting of methoxy, dimethylamino, amino, methyl, hydroxy and fluoro; Furan; Pyrrole; Thiazole; Cyclo propane; Cyclopentane; Or methyl substituted with one or more selected from the group consisting of benzene, thiophene and methoxybenzene.
  • R 2 is hydrogen; C1-C2 alkyl; Ethoxycarbonyl; Thiophene; Or benzene unsubstituted or substituted with one or more selected from the group consisting of methoxy, hydroxy, methyl, morpholinoethoxy, piperazinylethoxy, piperidyloxy and fluoro.
  • R 3 is hydrogen; Methoxycarbonyl; Methoxy; Thiophene; Aminocarbonyl; Ethoxycarbonylethyl; Cyano; Ethoxycarbonyl; Morpholino; methyl; t-butyloxadiazolyl; Cyclohexyloxadiazolyl; Methyloxadiazolyl; Hydroxybenzyl; Methoxybenzyl; Or methoxy, hydroxy, nitro, aminoethoxy, (diethylamino) ethoxy, pyrrolidinylethoxy, (dimethylamino) ethoxy, (isopentylamino) ethoxy, (benzylamino) ethoxy, ( Piperidyl) ethoxy, morpholinoethoxy, (methyl (propyl) amino) ethoxy, thiomorpholinoethoxy, ((aminoethyl) piperazinyl) ethoxy, ((aminoethyl)
  • the compound of Formula 1 may be selected from the group consisting of the following compounds:
  • the compound represented by Formula 1 of the present invention may be prepared as a pharmaceutically acceptable salt or solvate according to a conventional method in the art.
  • an acid addition salt formed by a pharmaceutically acceptable free acid is useful.
  • Acid addition salts are prepared by conventional methods, for example by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equivalent molar amounts of the compound and acid or alcohol (eg, glycol monomethyl ether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.
  • organic acids and inorganic acids may be used as the free acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. may be used as the inorganic acid, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, Maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid ( gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid, and the like. It doesn't work.
  • 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 then evaporating and drying the filtrate.
  • the metal salt it is particularly suitable to prepare sodium, potassium or calcium salts, but is not limited thereto.
  • Corresponding silver salts may also be obtained by reacting alkali or alkaline earth metal salts with a suitable silver salt (eg, silver nitrate).
  • a suitable silver salt eg, silver nitrate
  • Pharmaceutically acceptable salts of the compounds of formula 1 of the present invention include salts of acidic or basic groups which may be present in compounds of formula 1 unless otherwise indicated.
  • pharmaceutically acceptable salts may include sodium, calcium and potassium salts of the hydroxy group
  • other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfates, hydrogen sulphates, phosphates, hydrogen phosphates, Dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts and the like. It can be manufactured through the manufacturing process.
  • the compound of Formula 1 since the compound of Formula 1 has an asymmetric center, it may exist in different enantiomeric forms, and all optical isomers and R or S type stereoisomers of the compound of Formula 1 and mixtures thereof are also included within the scope of the present invention.
  • the present invention encompasses the use of racemates, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof, and includes methods or processes for the separation of isomers known in the art.
  • the compound of Formula 1 or a pharmaceutically acceptable salt thereof is very excellent in inhibiting the binding of AIMP2-DX2 and K-Ras, K-Ras protein in cancer cells It was judged that the effect of reducing the level of and suppressing the development and progression of cancer could be considered.
  • the solid cancer is preferably colon cancer, colon cancer, lung cancer, liver cancer, stomach cancer, esophageal cancer, pancreatic cancer, gallbladder cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, cervical cancer, endometrial cancer, chorionic cancer, ovarian cancer, breast cancer , Thyroid cancer, brain cancer, head and neck cancer, and malignant melanoma.
  • the compound of Formula 1 since the compound of Formula 1 exhibits an activity that directly inhibits the binding of AIMP2-DX2 and K-Ras, the compound of Formula 1 may exhibit an excellent therapeutic effect against solid cancers overexpressing AIMP2-DX2.
  • the pharmaceutical composition according to the present invention may contain the compound of Formula 1 or a pharmaceutically acceptable salt thereof alone or may further contain one or more pharmaceutically acceptable carriers, excipients or diluents.
  • Pharmaceutically acceptable carriers may further include, for example, carriers for oral administration or carriers for parenteral administration.
  • Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like.
  • carriers for parenteral administration may include water, suitable oils, saline, aqueous glucose and glycols, and the like, and may further include stabilizers and preservatives.
  • Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid.
  • Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol.
  • Other pharmaceutically acceptable carriers may be referred to those known in the art.
  • the pharmaceutical composition of the present invention can be administered to any mammal, including humans.
  • it can be administered orally or parenterally.
  • Parenteral administration methods include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intradural, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual or rectal administration.
  • the pharmaceutical composition of the present invention can be prepared in an injectable formulation and administered by lightly pricking the skin with a 30 gauge thin needle or by applying it directly to the skin.
  • composition of the present invention may be formulated into a preparation for oral or parenteral administration according to the route of administration as described above.
  • compositions of the present invention may be formulated using methods known in the art as powders, granules, tablets, pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions and the like.
  • oral formulations can be obtained by tablets or dragees by combining the active ingredients with solid excipients and then grinding them, adding suitable auxiliaries and processing them into granule mixtures.
  • excipients examples include sugars, including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol and maltitol and starch, cellulose, including starch, corn starch, wheat starch, rice starch and potato starch, and the like. Fillers such as cellulose, gelatin, polyvinylpyrrolidone, and the like, including methyl cellulose, sodium carboxymethylcellulose, hydroxypropylmethyl-cellulose, and the like. In addition, crosslinked polyvinylpyrrolidone, agar, alginic acid or sodium alginate and the like may optionally be added as a disintegrant. Furthermore, the pharmaceutical composition of the present invention may further include an anticoagulant, a lubricant, a humectant, a perfume, an emulsifier, a preservative, and the like.
  • Formulations for parenteral administration may be formulated by methods known in the art in the form of injections, creams, lotions, external ointments, oils, humectants, gels, aerosols and nasal inhalants. These formulations are described in prescriptions generally known in all pharmaceutical chemistries.
  • the total effective amount of the pharmaceutical composition of the present invention may be administered to a patient in a single dose and may be administered by a fractionated treatment protocol which is administered in multiple doses for a long time.
  • the pharmaceutical composition of the present invention may vary the content of the active ingredient depending on the extent of the disease.
  • the total dose of the pharmaceutical composition of the present invention may be about 0.01 ug to 1,000 mg, most preferably 0.1 ug to 100 mg per kg of patient body weight per day.
  • the dosage of the pharmaceutical composition of the present invention is effective for the patient in consideration of various factors such as the age, weight, health condition, sex, severity of the disease, diet and excretion rate, as well as the route and frequency of treatment.
  • the pharmaceutical composition according to the present invention is not particularly limited to its formulation, route of administration and method of administration as long as the effect of the present invention is shown.
  • the term 'treatment' refers generically to ameliorating symptoms related to solid cancer, which may preferably include curing, substantially preventing, or ameliorating a solid cancer overexpressing AIMP2-DX2. And alleviating, healing or preventing one or most of the symptoms resulting from these solid cancers.
  • the present invention is also a novel compound that inhibits the binding of AIMP2-DX2 and K-Ras,
  • the present invention also provides the use of a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof for the preparation of a preventive or therapeutic agent for solid cancer.
  • the present invention provides a method for treating solid cancer, comprising administering to a subject in need thereof an effective amount of a composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the term 'effective amount' of the present invention when administered to an individual, refers to an amount of improving, treating, preventing, detecting, diagnosing, or inhibiting or reducing a solid cancer.
  • the 'individual' refers to an animal, preferably a mammal. It may be an animal, especially a human, and may be cells, tissues, organs and the like derived from the animal. The subject may be a patient in need of the effect.
  • treatment' of the present invention refers generically to ameliorating the symptoms of solid or solid cancer, which may include curing, substantially preventing, or ameliorating the solid cancer, one symptom resulting from solid cancer. Or alleviate, cure, or prevent most of the symptoms.
  • the term 'comprising' of the present invention is used in the same way as 'containing' or 'featured' and does not exclude additional component elements or method steps not mentioned in the composition or method. .
  • the term 'consisting of' means to exclude additional elements, steps or components, etc., unless otherwise noted.
  • the term “essentially consisting of” means within the scope of a composition or method, including the component elements or steps described, as well as the component elements or steps that do not substantially affect its basic properties, and the like.
  • Compound represented by the formula (1) according to the present invention by inhibiting the binding of AIMP2-DX2 and K-Ras lowers the level of K-Ras protein in cancer cells and is very excellent in inhibiting the development and progression of cancer, AIMP2 It can be very useful for the prevention or treatment of solid cancer overexpressing DX2.
  • R 1 , R 2 and R 3 in Scheme 1 are as defined in Chemical Formula 1.
  • Scheme 1 shows a process for preparing a thienopyrimidine compound (8a-8k) using a ketone compound which can be easily obtained commercially or prepared in a general manner.
  • ethyl 2-aminothiophen-3-carboxylate and commercially available ketones or aldehydes are dissolved in ethanol or dimethylamide solvent, sulfur is added, morpholine, triethylamine, piperidine, etc.
  • Compound (3a-3e) was prepared by Gewald reaction using a base of. At this time, the reaction temperature was performed by heating to about 60 °C.
  • compound (6a-6k) was prepared by refluxing the compound (5a-5k) prepared in the second step in a phosphorus oxychloride solution.
  • the chloro compound (6a-6k) obtained in the third step is dissolved in an organic solvent such as tetrahydrofuran and then reacted while slowly adding hydrazine hydrate to prepare a hydrazine compound (7a-7k).
  • the reaction temperature at this time is preferably carried out under reflux.
  • the hydrazine compound (7a-7k) obtained in the fourth step was dissolved in a chloroform solvent, citraconic anhydride was added and the final derivative (8a-8k) was prepared through reflux.
  • Compounds 3c and 3e were purchased from Tokyo chemical industry (TCI) and used.
  • Example 1-1 1-[[6- (4- Fluorophenyl ) -2- (2- Furyl ) -5- methyl - Thieno [2,3-d] pyrimidine -4-yl] amino] -3-methyl-pyrrole-2, 5-dione (8a)
  • Example 1-7 1-[[6- (4- Fluorophenyl )-2- (1 ⁇ ⁇ H ⁇ -pyrrole-2-yl) thieno [2, 3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2, 5-dione (8 g)
  • Example 1-8 1-[[6- (4- Fluorophenyl ) -2-thiazol-5-yl- Thieno [2,3-d] pyrimidine -4-yl] amino] -3- methyl -Pyrrole-2, 5-dione (8h)
  • Example IUPAC Name 1-12 1-[[5- (4-methoxyphenyl) -2- (2-thienyl) thieno [2, 3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2, 5 -Dione; hydrochloride 1-13 1-[[5- (4-hydroxyphenyl) -2- (2-thienyl) thieno [2, 3-d] pyrimidin-4-yl] amino] -3-methyl-pyrrole-2, 5 -Dione; Hydrochloride 1-14 3-methyl-1-[[5- (p-tolyl) -2- (2-thienyl) thieno [2, 3-d] pyrimidin-4-yl] amino] pyrrole-2, 5-dione; Hydrochloride 1-15 3-methyl-1-[[5-methyl-2- (2-thienyl) thieno [2, 3-d] pyrimidin-4-yl] amino] pyrrole-2, 5-dione; Hydrochloride
  • CHO-K cells (ATCC) were cultured in RPMI-1640 (Hyclone, GE lifesciences) medium containing 10% FBS (Fetal bovine serum, Hyclone, GE lifesciences), 1% penicillin (Hyclone, GE lifesciences). Each cell was incubated under conditions of 5% CO 2 , 37 ° C.
  • AIMP2-DX2 and Kras genes were cloned into pBiT1.1-N [TK / LgBiT] Vector and pBiT2.1-N [TK / SmBiT] vectors, respectively, and transformed into CHO-K cells using Turibofect (Thermo scientific). Infection was performed.
  • each of the compounds of Examples 1-1 to 1-98 dissolved in DMSO in serum-free medium was diluted, and the prepared cells were incubated at a concentration of 3 ⁇ M for 4 hours.
  • Example Inhibition rate of AIMP2-DX2 and K-Ras binding (%, 3 ⁇ M) Example Inhibitory effect (%) Example Inhibitory effect (%) Example Inhibitory effect (%) Example Inhibitory effect (%) 1-1 99.0 1-34 93.6 1-67 94.2 1-2 99.7 1-35 97.7 1-68 97.0 1-3 93.6 1-36 96.2 1-69 96.8 1-4 99.4 1-37 91.3 1-70 85.0 1-5 99.5 1-38 88.1 1-71 95.0 1-6 99.2 1-39 95.3 1-72 97.2 1-7 99.1 1-40 99.1 1-73 94.8 1-8 85.6 1-41 94.5 1-74 91.4 1-9 91.3 1-42 99.6 1-75 93.3 1-10 95.2 1-43 99.1 1-76 97.4 1-11 88.9 1-44 96.3 1-77 97.6 1-12 98.6 1-45 94.6 1-78 98.8 1-13 92.4 1-46 98.9 1-79 95.7 1-14 98.4 1-47 99.8 1-80 90.1 1-15 93
  • Example Inhibitory effect of AIMP2-DX2 and K-Ras Coupling (IC50)
  • Example Inhibitory effect IC50 ( ⁇ M)
  • Example Inhibitory effect IC50 ( ⁇ M)
  • Example Inhibitory effect IC50 ( ⁇ M) 1-1 0.0442 1-34 0.6081 1-69 1.3470 1-2 0.4553 1-35 0.9573 1-71 1.6950 1-3 0.7273 1-36 2.2630 1-72 2.1120 1-4 0.8518 1-37 1.7130 1-73 1.9440 1-5 0.6081 1-38 1.7730 1-74 2.0260 1-6 0.5412 1-39 1.2980 1-75 1.7640 1-7 0.8384 1-40 1.3050 1-76 1.9890 1-8 2.618 1-41 1.0140 1-77 1.0650 1-9 0.2482 1-42 0.3020 1-78 3.1590 1-10 1.6170 1-43 0.2538 1-79 1.5350 1-11 2.5400 1-44 0.8180 1-80 0.9617 1-12 0.2726 1-45 1.0530 1-81 1.4430 1-13 0.4862 1-46 0.4298
  • AIMP2-DX2 which is closely related to the differentiation and proliferation of cancer cells, directly binds to K-Ras to stabilize K-Ras protein and consequently plays a critical role in the survival and differentiation of cancer cells.
  • the compounds according to the present invention have a very good effect of directly inhibiting the binding of AIMP2-DX2 and K-Ras, lowering the level of K-Ras protein in cancer cells It can be judged that it may have an effect of suppressing the development and progression of cancer.
  • Compound represented by the formula (1) according to the present invention by inhibiting the binding of AIMP2-DX2 and K-Ras lowers the level of K-Ras protein in cancer cells and is very excellent in inhibiting the development and progression of cancer, AIMP2 It can be very useful for the prevention or treatment of solid cancer overexpressing DX2, so the industrial applicability is excellent.

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Abstract

La présente invention concerne une composition pour prévenir ou traiter un cancer solide comprenant un composé inhibant la liaison de AIMP2-DX2 et de K-Ras et un nouveau composé inhibant la liaison de AIMP2-DX2 et K-Ras. Le composé représenté par la formule 1 selon la présente invention inhibe la liaison de AIMP2-DX2 et de K-Ras, ayant ainsi des effets très supérieurs d'abaissement du niveau de protéine K-Ras dans des cellules cancéreuses et d'inhibition de l'apparition et de la progression du cancer. Ainsi, le composé peut être très utile pour la prévention ou le traitement du cancer solide surexprimant AIMP2-DX2.
PCT/KR2019/006910 2018-06-08 2019-06-07 Composition pour la prévention ou le traitement du cancer solide comprenant un composé inhibant la liaison de aimp2-dx2 et de k-ras et nouveau composé inhibant la liaison de aimp2-dx2 et k-ras WO2019235894A1 (fr)

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KR10-2018-0066351 2018-06-08
KR1020180066351A KR20190139640A (ko) 2018-06-08 2018-06-08 AIMP2-DX2와 K-Ras의 결합을 저해하는 화합물을 포함하는 고형암 예방 또는 치료용 조성물 및 AIMP2-DX2와 K-Ras의 결합을 저해하는 신규 화합물

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Cited By (1)

* Cited by examiner, † Cited by third party
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WO2022219172A1 (fr) * 2021-04-15 2022-10-20 Novelyeast Bv Inhibiteurs de l'absorption du glucose utilisés dans le traitement du cancer et d'autres maladies

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022219172A1 (fr) * 2021-04-15 2022-10-20 Novelyeast Bv Inhibiteurs de l'absorption du glucose utilisés dans le traitement du cancer et d'autres maladies

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