WO2020256477A1 - 암 세포 성장을 억제하는 피리미딘 유도체 및 이의 의약 용도 - Google Patents
암 세포 성장을 억제하는 피리미딘 유도체 및 이의 의약 용도 Download PDFInfo
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- WO2020256477A1 WO2020256477A1 PCT/KR2020/007982 KR2020007982W WO2020256477A1 WO 2020256477 A1 WO2020256477 A1 WO 2020256477A1 KR 2020007982 W KR2020007982 W KR 2020007982W WO 2020256477 A1 WO2020256477 A1 WO 2020256477A1
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- Prior art keywords
- amino
- phenyl
- pyrimidin
- dimethylamino
- methyl
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- KPUXYKMAEDAWET-UHFFFAOYSA-N CC(C)(C)OC(Nc(c(OC)c1)cc([N+]([O-])=O)c1F)=O Chemical compound CC(C)(C)OC(Nc(c(OC)c1)cc([N+]([O-])=O)c1F)=O KPUXYKMAEDAWET-UHFFFAOYSA-N 0.000 description 1
- 0 CC(C)Nc(cc(c(*)c1)Nc(nc2Nc3ccccc3N(C)S(C)(=O)=O)nc3c2[s]cc3)c1N(C)CCN(C)C Chemical compound CC(C)Nc(cc(c(*)c1)Nc(nc2Nc3ccccc3N(C)S(C)(=O)=O)nc3c2[s]cc3)c1N(C)CCN(C)C 0.000 description 1
- FEXDJZXXTPBFON-UHFFFAOYSA-N CC(C)Nc(cc(c(OC)c1)Nc(nc2)nc(Nc(cccc3)c3N(C)S(C)(=O)=O)c2Cl)c1N(C)CCN(C)C Chemical compound CC(C)Nc(cc(c(OC)c1)Nc(nc2)nc(Nc(cccc3)c3N(C)S(C)(=O)=O)c2Cl)c1N(C)CCN(C)C FEXDJZXXTPBFON-UHFFFAOYSA-N 0.000 description 1
- SBPOGWLERRUQGV-UHFFFAOYSA-N CC(C)Nc(cc(c(OC)c1)Nc(nc2Nc3ccccc3N(C)S(C)(=O)=O)nc3c2[s]cc3)c1N(CC1)CCC1N(C)C Chemical compound CC(C)Nc(cc(c(OC)c1)Nc(nc2Nc3ccccc3N(C)S(C)(=O)=O)nc3c2[s]cc3)c1N(CC1)CCC1N(C)C SBPOGWLERRUQGV-UHFFFAOYSA-N 0.000 description 1
- FYSIGSQCZXQTIH-UHFFFAOYSA-N COc(c(N)c1)cc(F)c1[N+]([O-])=O Chemical compound COc(c(N)c1)cc(F)c1[N+]([O-])=O FYSIGSQCZXQTIH-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- 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
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07D403/12—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 linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to a pyrimidine derivative compound effective in inhibiting the growth of cancer cells, and an anticancer use thereof.
- EGFR epidermal growth factor receptor
- EGFR epidermal growth factor receptor
- Gefitnib, Erlotinib, Osimertinib, and the like have been used as kinase inhibitors.
- lung cancer caused by the epithelial growth factor receptor exon 20 insertion mutation accounts for 5% of the total mutation, and various epithelial growth factor receptor inhibitors (EGFR inhibitors) have been evaluated for its treatment.
- EGFR EXON 20 Insertion mutation epithelial growth factor receptor exon 20 Insertion mutation
- EGFR inhibitors epithelial growth factor receptor inhibitors
- a problem to be solved by the present invention is to provide a compound useful in the treatment of lung cancer, particularly, lung cancer exhibiting epithelial cell growth factor receptor mutation characteristics, and a pharmaceutical use of these compounds.
- the present invention provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof.
- W is oxygen or NH
- X and Y are independently of each other CH, oxygen or nitrogen,
- Z 1 and Z 2 independently of each other do not exist when X or Y is oxygen, and when X or Y is not oxygen, they are composed of C1 to C4 alkyl or carbon and are connected to each other to pentagonal with X and Y, Forming a hexagonal or hexagonal ring,
- R 1 is C1 to C4 alkyl
- R 2 is hydrogen or C1 to C4 alkyl
- R 3 and R 4 are independently of each other hydrogen, halogen, OH, OMe, OEt, CN, CF 3 , C1 to C4 alkyl, or linked to each other to form a pentagonal or hexagonal (fused to phenyl) heteroaryl ring.
- R 5 is hydrogen, halogen, OH, OMe, OEt, CN, CF 3 , or C1 to C4 alkyl,
- R 6 and R 7 are independently of each other hydrogen, halogen, OH, OMe, OEt, CN, CF 3 , COOH, COO-C 1-4 alkyl, COO-C 1-5 cycloalkyl, C1 to C4 alkyl, or Are connected to each other to form a pentagonal or hexagonal heteroaryl ring,
- R 8 is hydrogen, halogen, OH, OMe, OEt, CN, CF 3 , or C1 to C4 alkyl,
- R 10 has no substituent or hydrogen, halogen, C1 to C4 alkyl, OH, OMe, OEt, CN, CF 3 , NMe 2 , piperazine, piperazine, morpholine, or C1 substituted with C1 to C3 alkyl To C3 alkyl substituted morpholine.
- the present inventors have confirmed that the novel compounds according to the present invention are effective in the treatment of lung cancer, particularly lung cancer in which epithelial cell growth factor receptor mutations appear.
- the compounds of the present invention are useful for the treatment of lung cancer having cancer cells exhibiting epidermal growth factor receptor exon 20 insertion mutation (Epidermal growth factor receptor, EGFR EXON20 Insertion mutation) characteristics among lung cancer.
- alkyl refers to a saturated linear or branched, saturated, linear or branched, non-cyclic hydrocarbon having 1 to 10 carbon atoms (when the number of carbon atoms is not particularly limited). “Lower alkyl” means straight or branched alkyl having 1 to 4 carbon atoms.
- saturated straight-chain alkyls are -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl and -n- Decyl, while saturated branched alkyl is -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, isopentyl, 2-methylhexyl, 3-methylbutyl, 2-methylpentyl, 3- Methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5- Me
- cycloalkyl refers to a monocyclic or polycyclic saturated ring having carbon and hydrogen atoms and not having multiple carbon-carbon bonds.
- cycloalkyl groups include, but are not limited to (C 3 -C 7 )cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl).
- cycloalkyl is (C 3 -C 5 )cycloalkyl.
- the cycloalkyl is cyclopropyl.
- the cycloalkyl group is a monocyclic or bicyclic ring (ring).
- C 1-6 alkyl means alkyl having 1 to 6 carbon atoms.
- halogen and “halo” as used herein mean fluorine, chlorine, bromine or iodine.
- aryl refers to a carbocyclic aromatic group containing 5 to 10 ring atoms. Representative examples include phenyl, tolyl, xylyl, naphthyl, tetrahydronaphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, etc. Including, but not limited to.
- the carbocyclic aromatic group may be optionally substituted.
- heteroaryl has at least one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur, and includes 5 to 10 carbon atoms including mono- and bicyclic ring systems. It is a member of an aromatic heterocycle ring.
- heteroaryls include triazolyl, tetrazolyl, oxadiazolyl, pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl ( benzoxazolyl), imidazolyl, benzimidazolyl, thiazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, tria Genyl, cinnolinyl, phthalazinyl, quinazolinyl, pyrimidyl, oxetanyl, azepinyl, piperazinyl, morpholinyl, dioxanyl, thietanyl and oxazolyl
- the compound represented by Formula 1 may be used in the form of a salt derived from an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid.
- an inorganic or organic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid.
- Glutaric acid fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfuric acid It may be used in the form of a salt derived by one or more acids selected from the group consisting of folic acid, toluenesulfonic acid, and the like.
- compound of the present invention as used herein is meant to include not only the compounds of Formula 1, but also clathrates, hydrates, solvates, or polymorphs thereof.
- compound of the present invention is meant to include a pharmaceutically acceptable salt of the compound of the present invention, unless a pharmaceutically acceptable salt thereof is mentioned.
- the compounds of the present invention are stereoisomerically pure compounds (e.g., substantially free of other stereoisomers (e.g., 85% ee or more, 90% ee or more, 95% ee or more, 97% ee or more, or 99% ee or more)).
- the compound of Formula 1 or a salt thereof according to the present invention is tautomeric isomers and/or stereoisomers (e.g., geometrical isomers and conformational isomers), their separated isomers And mixtures each are also included in the scope of the compounds of the present invention.
- the compound of the present invention or a salt thereof has an asymmetric carbon in the structure, their optically active compounds and racemic mixtures are also included in the scope of the compound of the present invention.
- polymorph refers to a solid crystalline form of the compound of the present invention or a complex thereof. Different polymorphs of the same compound exhibit different physical, chemical and/or spectral properties. Differences in terms of physical properties include, but are limited to, stability (e.g., thermal or light stability), compressibility and density (important for formulation and product manufacturing), and dissolution rate (which may affect bioavailability). It doesn't work. Differences in stability can be attributed to changes in chemical reactivity (e.g., differential oxidation, which discolors more rapidly when composed of one polymorph than when composed of another polymorph) or mechanical characteristics (e.g., kinematically.
- stability e.g., thermal or light stability
- compressibility and density important for formulation and product manufacturing
- dissolution rate which may affect bioavailability
- the stored tablet fragments are thermodynamically converted to a more stable polymorph) or both (a tablet of one polymorph is more susceptible to degradation at high humidity).
- Other physical properties of polymorphs can influence their processing. For example, one polymorph may be more likely to form a solvate than another polymorph, for example due to its shape or size distribution of the particles, or may be more difficult to filter or wash.
- solvent compound refers to a compound of the present invention or a pharmaceutically acceptable salt thereof comprising a stoichiometric or non-stoichiometric amount of a solvent bound by force between non-covalent molecules.
- Preferred solvents are volatile, non-toxic and can be administered in very small amounts to humans.
- hydrate refers to a compound of the present invention or a pharmaceutically acceptable salt thereof containing a stoichiometric or non-stoichiometric amount of water bound by force between non-covalent molecules. .
- clathrate refers to a compound of the present invention in the form of a crystal lattice including a space (eg, a channel) confining guest molecules (eg, solvent or water). Or its salt.
- purified means that when separated, the separated body is 90% or more pure, in one embodiment 95% or more pure, in another embodiment 99% or more pure, and In other examples, it means 99.9% or more pure.
- treatment includes eradication, removal, modification, or control of primary, localized or metastatic cancer tissue; It minimizes or delays the spread of cancer.
- Non-limiting, examples of the compounds according to the invention include the following compounds and pharmaceutically acceptable salts thereof.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of the compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention, and a pharmaceutically acceptable carrier.
- an "effective amount” refers to the destruction, modification, control or removal of primary, localized or metastatic cancer cells or cancerous tissues; Slowing or minimizing the spread of cancer; Or an amount of a compound of the invention sufficient to provide a therapeutic benefit in the treatment or management of cancer, neoplastic disease, or tumor. "Effective amount” also refers to an amount of a compound of the invention sufficient to cause cancer or neoplastic cell death. “Effective amount” also refers to an amount sufficient to inhibit or reduce the activity of lung cancer cells, either in vitro or in vivo.
- the present invention is to treat a disease or condition comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof.
- a method is provided, wherein the disease or condition is lung cancer.
- the subject is a human.
- the lung cancer is lung cancer exhibiting epidermal growth factor receptor (EGFR) mutation characteristics.
- the lung cancer is lung cancer having cancer cells that exhibit epithelial growth factor receptor exon 20 insertion mutation (EGFR EXON 20 Insertion mutation) characteristics.
- the present invention provides a pharmaceutical use, characterized in that the compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention is used as an active ingredient.
- the pharmaceutical use of the present invention is for the treatment or prophylaxis of a disease or condition described herein.
- the present invention is a pharmaceutical for the treatment or prevention of lung cancer, particularly epithelial cell growth factor receptor mutation-expressing lung cancer, characterized in that it comprises a compound according to the present invention or a pharmaceutically acceptable salt thereof as an active ingredient
- the composition is provided.
- the compound of the present invention or a pharmaceutically acceptable salt thereof is generally administered in a therapeutically effective amount.
- the compounds of the present invention may be administered by any suitable route in the form of a pharmaceutical composition suitable for this route, and in an effective dosage for the intended treatment.
- Effective dosages are generally about 0.0001 to about 200 mg/kg body weight/day, preferably about 0.001 to about 100 mg/kg/day, in single or divided doses. Depending on the age, species, and disease or condition to be treated, dosage levels below the lower limit of this range may be suitable. In other cases, still larger dosages can be used without harmful side effects. Larger dosages can be divided into several smaller dosages, for administration throughout the day. Methods for determining an appropriate dosage are well known in the art to which the present invention pertains, for example, Remington: The Science and Practice of Pharmacy, Mack Publishing Co., 20th ed., 2000 can be used.
- the compound described herein or a pharmaceutically acceptable salt thereof may be administered in various ways as follows.
- the compound of the present invention can be administered orally, and the oral cavity is a concept including swallowing.
- oral administration the compounds of the present invention can enter the gastrointestinal tract or be absorbed directly from the mouth into the bloodstream, for example, buccal or sublingual administration.
- compositions for oral administration may be in the form of solid, liquid, gel, or powder, and may have formulations such as tablets, lozenges, capsules, granules, powders, etc. .
- compositions for oral administration may optionally be enteric coated, and exhibit delayed or sustained release through enteric coating. That is, the composition for oral administration according to the present invention may be a formulation having an immediate or modified release pattern.
- Liquid formulations may include solutions, syrups and suspensions, and such liquid compositions may be contained within soft or hard capsules.
- Such formulations may contain a pharmaceutically acceptable carrier, such as water, ethanol, polyethylene glycol, cellulose, or oil.
- the formulation may also contain one or more emulsifying and/or suspending agents.
- the amount of the active ingredient drug may be present in about 0.05% to about 95% by weight, more generally from about 2% to about 50% by weight of the formulation, based on the total weight of the tablet.
- the tablet may contain a disintegrant comprising from about 0.5% to about 35% by weight, more generally from about 2% to about 25% by weight of the formulation.
- the disintegrant may include lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or a mixture thereof, but is not limited thereto.
- Suitable lubricants included to prepare tablets may be present in an amount of about 0.1% to about 5% by weight, such as talc, silicon dioxide, stearic acid, calcium, zinc or magnesium stearate, sodium stearyl fumarate, etc. Although it can be used as a lubricant, the present invention is not limited to the types of these additives.
- Gelatin polyethylene glycol, sugar, gum, starch, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, etc. can be used as a binder for manufacturing tablets.
- suitable diluents for preparing tablets mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, starch, microcrystalline cellulose, etc. may be used, but the present invention is not limited to the types of these additives. .
- the solubilizing agent that may be included in the tablet may be used in an amount of about 0.1% to about 3% by weight based on the total weight of the tablet, for example, polysorbate, sodium lauryl sulfate, sodium dodecyl sulfate, propylene carbonate, Diethylene glycol monoethyl ether, dimethylisosorbide, polyoxyethylene glycolated natural or hydrogenated castor oil, HCOR TM (Nikkol), oleyl ester, Gelucire TM , caprylic/caprylic acid mono/ Although diglyceride, sorbitan fatty acid ester, sorbitol HS TM and the like can be used in the pharmaceutical composition according to the present invention, the present invention is not limited to the specific types of such solubilizing agents.
- the compounds of the present invention can be administered directly into the bloodstream, muscle, or intestines.
- Suitable methods for parenteral administration include intravenous, intra-muscular, subcutaneous intraarterial, intraperitoneal, intrathecal, intracranial injection, etc. Include.
- Suitable devices for parenteral administration include injectors (including needles and needleless syringes) and infusion methods.
- compositions for parenteral administration may be formulations having an immediate or modified release pattern, and the modified release pattern may be a delayed or sustained release pattern.
- parenteral formulations are liquid compositions, and such liquid compositions are aqueous solutions containing the pharmaceutical ingredients, salts, buffers, isotonic agents, and the like according to the present invention.
- Parenteral formulations can also be prepared in dried form (eg, lyophilized) or as sterile non-aqueous solutions. These formulations can be used with a suitable vehicle such as sterile water. Solubility-enhancing agents can also be used in the preparation of parenteral solutions.
- the compounds of the present invention can be administered topically, dermal or transdermally.
- Formulations for this topical administration include lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches and the like.
- Pharmaceutically acceptable carriers for topical administration formulations may include water, alcohol, mineral oil, glycerin, polyethylene glycol, and the like. Local administration can also be performed by electroporation, iontophoresis, phonophoresis, and the like.
- compositions for topical administration may be formulations with an immediate or modified release pattern, and the modified release pattern may be a delayed or sustained release pattern.
- the present invention provides a novel pymiridine derivative compound having cancer cell inhibitory activity and a pharmaceutically acceptable salt thereof.
- the pyrimidine derivative or a pharmaceutically acceptable salt thereof according to the present invention can effectively inhibit the growth of cancer cells expressing epithelial growth factor receptor mutations, particularly cancer cells present in lung cancer. Accordingly, the compounds according to the present invention and pharmaceutically acceptable salts thereof are useful for treating lung cancer.
- Reaction Formula 4 structure B1 (50mg, 0.178mmol) was dissolved in isopropyl alcohol (3mL), and then A1 (71mg, 0.205mmol) and PTSA (48.8mg, 0.257mmol) were added at room temperature, and stirred at 90 °C for 12 hours. I did.
- the solvent was removed by distillation under reduced pressure, followed by extraction with water and 10% MeOH/DCM. The organic layer was separated, dried, and distilled under reduced pressure to obtain compound 1 in a crude state. Purified pure compound 1 (60mg, 58%) was obtained by tube chromatography.
- Step-1 N -methyl- N Synthesis of -(2-nitrophenyl)methanesulfonamide
- Step-2 N -(2-aminophenyl)- N -Synthesis of methylmethanesulfonamide
- N -methyl- N- (2-nitrophenyl)methanesulfonamide (1.0 equivalent) was dissolved in methanol and ethyl acetate (1:1), and 10% palladium/charcoal (0.2 equivalent) was added. Stir for 2 hours under hydrogen. After completion of the reaction, the resultant was filtered using Celite and the filtrate was evaporated under reduced pressure. Ethyl ether and pentane were used to solidify and filter to obtain a target compound. It was used in the next reaction without separation.
- N- (2-aminophenyl) -N -methylmethanesulfonamide (1.0 equivalent) is dissolved in isopropyl alcohol and 2,4,5-trichloropyrimidine (1.1 equivalent) and N,N-diisopropylethylamine (2.5 eq) was added at room temperature. Stir at 80° C. overnight. After completion of the reaction, it was evaporated under reduced pressure and extracted using water and dichloromethane. The organic layer was washed with 2N hydrochloric acid. The organic layer was evaporated under reduced pressure and subjected to column chromatography to obtain a target compound. (50% hexane/ethyl acetate)
- Step-4 N-(2-((6-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfone Synthesis of amide
- the pyrimidine derivative (1.0 equivalent) was dissolved in isopropyl alcohol, and the aniline derivative (1.0 equivalent) and methanesulfonyl acid (1.3 equivalent) were added at room temperature. Stir at 80° C. overnight. After completion of the reaction, the solvent was removed by evaporation under reduced pressure, and extraction was performed using a mixture of water and 10% methanol/dichloromethane. The organic layer was evaporated under reduced pressure and subjected to column chromatography to obtain a target compound. (50% hexane/ethyl acetate)
- Step-5 N-(2-((6-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-4 Synthesis of -yl)amino)phenyl)-N-methylmethanesulfonamide
- N-(2-((6-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (1.0 equivalent ) was dissolved in acetonitrile, and potassium carbonate (3.0 equivalent) and amine chain (1.2 equivalent) were added at room temperature. The mixture was refluxed and stirred overnight. After completion of the reaction, the temperature was lowered to room temperature and filtered. The filtrate was evaporated under reduced pressure to obtain a target compound. It was used in the next reaction without separation.
- Step-6 N-(2-((6-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino) Synthesis of phenyl)-N-methylmethanesulfonamide
- Step-7 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((6-((2-(N-methylmethylsulfonamido)phenyl) Synthesis of )amino)pyrimidin-4-yl)amino)phenyl)acrylamide
- the cells build a stable group into a 1 X 10 4 cell to the 96 well plate overnight incubation were treated with the dose dependent of one embodiment of the compound after. After 72 hours, the MTT reagent was added and after 3 hours, a stop buffer (10% SDS) was added. After 24 hours of incubation, reading at 595nm was performed to analyze the results, and the IC 50 value was calculated at the concentration where each compound inhibited cell growth by 50%.
- the results are shown in Table 1 below as A, B, C, and D.
- A means IC 50 ⁇ 100nM
- C means IC 50 300-1,000nM
- D means IC 50 >1,000nM.
- Osimertinib was used as a control drug.
- the compounds according to the present invention showed excellent activity in the lung cancer cell line expressing the epithelial growth factor receptor exon 20 insertion mutation.
- the activities of the compounds of Examples 10-17 were more excellent.
- the activity of the control drug osimertinib was relatively weak.
- the present invention proposes a novel pyrimidine derivative capable of treating lung cancer expressing an epithelial growth factor receptor exon 20 insertion mutation.
Abstract
Description
실시예 | EXON 20 Insertion (NPG) Ba/F3 Cell |
1 | C |
2 | C |
3 | C |
4 | C |
5 | C |
6 | C |
7 | B |
8 | B |
9 | B |
10 | A |
11 | A |
12 | A |
13 | A |
14 | A |
15 | A |
16 | A |
17 | A |
오시머티닙 | C |
Claims (6)
- 하기 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염.[화학식 1]상기 화학식 1에서,A, B, D, E, 및 G는 A=N, B=C, D=C, E=C, 및 G=N의 조합이거나, 또는 A=N, B=C, D=N, E=C, 및 G=C의 조합이고,W는 산소 또는 NH이고,X및 Y는 서로 독립적으로 CH, 산소 또는 질소이고,Z 1 및 Z 2는 서로 독립적으로 C1 내지 C4의 알킬, 또는 탄소로 이루어지며 서로 연결되어 X 및 Y와 함께 5각, 6각, 또는 7각 고리를 형성하고,Z 1 및 Z 2는 서로 독립적으로 X 또는 Y가 산소일 경우 존재하지 않으며, X 또는 Y가 산소가 아닐 경우 C1 내지 C4의 알킬, 또는 탄소로 이루어지며 서로 연결되어 X 및 Y와 함께 5각, 6각, 또는 7각 고리를 형성하고,R 1은 C1 내지 C4의 알킬이고,R 2는 수소 또는 C1 내지 C4의 알킬이고,R 3 및 R 4는 서로 독립적으로 수소, 할로겐, OH, OMe, OEt, CN, CF 3, C1 내지 C4의 알킬, 또는 서로 연결되어 5각 또는 6각의 헤테로아릴 고리를 형성하고,R 5는 수소, 할로겐, OH, OMe, OEt, CN, CF 3, 또는 C1 내지 C4의 알킬이고,R 6 및 R 7은 서로 독립적으로 수소, 할로겐, OH, OMe, OEt, CN, CF 3, COOH, COO-C 1-4 알킬, COO-C 1-5 사이클로알킬, C1 내지 C4의 알킬, 또는 서로 연결되어 5각 또는 6각의 헤테로아릴 고리를 형성하고,R 8은 수소, 할로겐, OH, OMe, OEt, CN, CF 3, 또는 C1 내지 C4의 알킬이고,R 9은 -C(O)-CH=CH 2 또는 C1 내지 C4의 알킬이고,R 10은 치환기가 없거나, 수소, 할로겐, C1 내지 C4의 알킬, OH, OMe, OEt, CN, CF 3, NMe 2, 피페라진, C1 내지 C3의 알킬로 치환된 피페라진, 모르폴린, 또는 C1 내지 C3의 알킬로 치환된 모르폴린임.
- 제1항에 있어서, 상기 화합물은N-(2-((5-염화-2-((4-((2-(디메틸아미노)에틸)(메틸)아미노)-5-(이소프로필아미노)-2-메톡시페닐)아미노)피리딘-4-yl)아미노)페닐)-N-메틸설폰산아마이드,N-(2-((2-((4-((2-(다이메틸아미노)에틸)(메틸)아미노)-5-(이소프로필아미노)-2-메톡시페닐)아미노)싸이에노[3,2-d]피리미딘-4-일)아미노)페닐)-N-메틸메탄설폰아마이드,N-(2-((2-((4-(4-(다이메틸아미노)피페리딘-1-일)-5-(이소프로필아미노)-2-메톡시페닐)아미노)싸이에노[3,2-d]피리미딘-4-일)아미노)페닐)-N-메톡시메탄설폰아마이드,N-(2-((2-((5-(이소프로필아미노)-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)싸이에노[3,2-d]피리미딘-4-일)아미노)페닐)-N-메틸메탄설폰아마이드,N-(2-((5-클로로-2-((5-(이소프로필아미노)-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)-N-메틸메탄설폰아마이드,N-(2-((5-클로로-2-((4-(4-(다이메틸아미노)피페리딘-1-일)-5-(이소프로필아미노)-2-메톡시페닐)아미노)피리미딘-4-일)아미노)페닐-N-메틸메탄설폰아마이드,N-(4-메톡시-5-((4-((2-(N-메틸메틸설폰아미도)페닐)아미노)싸이에노[3,2-d]피리미딘-2-일)아미노)-2-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아크릴아마이드,N-(2-((2-(다이메틸아미노)에틸)(메틸)아미노)-4-메톡시-5-((4-((2-(N-메틸메틸설폰아미도)페닐)아미노)싸이에노[3,2-d]피리미딘-2-일)아미노)페닐)아크릴아마니드,N-(2-(4-(다이메틸아미노)피페리딘-1-일)-4-메톡시-5-((4-((2-(N-메틸메틸설폰아미도)페닐)아미노)싸이에노[3,2-d]피리미딘-2-일)아미노)페닐)아크릴아마이드,N-(5-((5-클로로-4-((2-(메틸설폰아미도)페닐)아미노)피리미딘-2-일)아미노)-2-((2-(다이메틸아미노)에틸)(메틸)아미노)-4-메톡시페닐)아크릴아마이드,N-(5-((5-클로로-4-((5-(N-메틸메틸설폰아미도)퀴녹살린-6-일)아미노)피리미딘-2-일)아미노)-2-((2-(다이메틸아미노)에틸)(메틸)아미노)-4-메톡시페닐)아크릴아마이드,N-(5-((5-클로로-4-((5-(메틸설폰아미도)퀴녹살린-6-일)아미노)피리미딘-2-일)아미노)-2-((2-(다이메틸아미노)에틸)(메틸)아미노)-4-메톡시페닐)아크릴아마이드,N-(5-((5-클로로-4-((5-플루오로-2-(N-메틸메틸설폰아미도)페닐)아미노)피리미딘-2-일)아미노)-2-((2-(다이메틸아미노)에틸)(메틸)아미노)-4-메톡시페닐)아크릴아마이드,N-(5-((5-클로로-4-((5-플루오로-2-(메틸설폰아미도)페닐)아미노)피리미딘-2-일)아미노)-2-((2-(다이메틸아미노)에틸)(메틸)아미노)-4-메톡시페닐)아크릴아마이드,이소프로필 2-((5-아크릴아미도-4-((2-(디메틸아미노)에틸)(메틸)아미노)-2-메톡시페닐)아미노)-4-((2-(N-메틸메틸설폰아미도)페닐)아미노)피리미딘-5-카로복실레이트,사이클로프로필 2-((5-아크릴아미도-4-((2-(디메틸아미노)에틸)(메틸)아미노)-2-메톡시페닐)아미노)-4-((2-(N-메틸메틸설폰아미도)페닐)아미노)피리미딘-5-카로복실레이트, 또는N-(2-((2-(다이메틸아미노)에틸)(메틸)아미노)-4-메톡시-5-((6-((2-(N-메틸메틸설폰아미도)페닐)아미노) 피리미딘-4-일)아미노)페닐)아크릴아마이드인화합물 또는 이의 약학적으로 허용 가능한 염.
- 제1항 또는 제2항의 화합물 또는 이의 약학적으로 허용 가능한 염, 및 약학적으로 허용 가능한 담체를 포함하는 조성물.
- 유효 성분으로 제1항 또는 제2항의 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 것을 특징으로 하는 폐암의 치료 또는 예방용 약학 조성물.
- 제4항에 있어서, 상기 폐암은 상피세포 성장인자 수용체 변이 발현 폐암인, 폐암의 치료 또는 예방용 약학 조성물.
- 제4항에 있어서, 상기 변이는 엑손 20 삽입 변이인, 폐암의 치료 또는 예방용 약학 조성물.
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WO2022208454A1 (en) * | 2021-04-02 | 2022-10-06 | Bridge Biotherapeutics, Inc. | N2-phenylpyrimidine-2,4-diamine compounds, and preparation methods and methods of use thereof |
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CA3228333A1 (en) * | 2021-08-05 | 2023-02-09 | Korea Research Institute Of Chemical Technology | Pyrimidine derivative, method for preparing same, and pharmaceutical composition for preventing or treating cancer comprising same as active ingredient |
KR102611488B1 (ko) * | 2021-08-05 | 2023-12-11 | 한국화학연구원 | 피리미딘 유도체, 이의 제조방법 및 이를 유효성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물 |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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CN113717156A (zh) * | 2020-05-25 | 2021-11-30 | 南京红云生物科技有限公司 | Egfr抑制剂、其制备方法及用途 |
WO2021238827A1 (zh) * | 2020-05-25 | 2021-12-02 | 南京红云生物科技有限公司 | Egfr抑制剂、其制备方法及用途 |
CN113717156B (zh) * | 2020-05-25 | 2023-05-09 | 南京红云生物科技有限公司 | Egfr抑制剂、其制备方法及用途 |
WO2022208454A1 (en) * | 2021-04-02 | 2022-10-06 | Bridge Biotherapeutics, Inc. | N2-phenylpyrimidine-2,4-diamine compounds, and preparation methods and methods of use thereof |
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EP3988542A4 (en) | 2023-06-28 |
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AU2020296620B2 (en) | 2023-07-13 |
BR112021025764A2 (pt) | 2022-02-01 |
AU2020296620A1 (en) | 2022-02-17 |
CA3143919A1 (en) | 2020-12-24 |
JP7330546B6 (ja) | 2024-02-21 |
MX2021015543A (es) | 2022-04-25 |
US20220227781A1 (en) | 2022-07-21 |
JP2022538014A (ja) | 2022-08-31 |
JP7330546B2 (ja) | 2023-08-22 |
EP3988542A1 (en) | 2022-04-27 |
CN114008028A (zh) | 2022-02-01 |
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