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WO2017164705A1 - Nouveau dérivé de pyridine, son procédé de préparation, et composition pharmaceutique pour prévenir ou traiter une maladie liée à fgfr contenant ledit dérivé comme principe actif - Google Patents

Nouveau dérivé de pyridine, son procédé de préparation, et composition pharmaceutique pour prévenir ou traiter une maladie liée à fgfr contenant ledit dérivé comme principe actif Download PDF

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Publication number
WO2017164705A1
WO2017164705A1 PCT/KR2017/003226 KR2017003226W WO2017164705A1 WO 2017164705 A1 WO2017164705 A1 WO 2017164705A1 KR 2017003226 W KR2017003226 W KR 2017003226W WO 2017164705 A1 WO2017164705 A1 WO 2017164705A1
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Prior art keywords
substituted
cancer
unsubstituted
methyl
carboxamide
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Ceased
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PCT/KR2017/003226
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English (en)
Korean (ko)
Inventor
최환근
안성민
손정범
김남두
김소영
강석용
류희윤
김현경
배재현
김성환
손영진
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Industry Academic Cooperation Foundation of Gachon University
Daegu Gyeongbuk Medical Innovation Foundation
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Industry Academic Cooperation Foundation of Gachon University
Daegu Gyeongbuk Medical Innovation Foundation
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Publication of WO2017164705A1 publication Critical patent/WO2017164705A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to a novel pyridine derivative, a method for producing the same, and a pharmaceutical composition for preventing or treating a fibroblast growth factor receptor (FGFR) related disease containing the same as an active ingredient.
  • FGFR fibroblast growth factor receptor
  • Fibroblast growth factor receptor (FGFR) tyrosine kinase consists of about 800 amino acids and contains three immunoglobulin (Ig) -like domains (D1, D2, D3). There are four subtypes FGFR1, FGFR2, FGFR3, and FGFR4 as the type 5 receptor trocine kinases.
  • Fibroblast growth factor and its receptors (FGFR) form part of a unique and diverse signaling system that plays a major role in various physiological processes, including various aspects of embryonic development and adult pathophysiology. FGFs are known to stimulate broad cell functions, including migration, proliferation, differentiation and survival through binding to FGFR.
  • carcinomas e.g., bladder, breast, cervix, colorectal, endometrium, stomach, head and neck, kidney, liver, lung, ovary, prostate
  • carcinomas e.g., bladder, breast, cervix, colorectal, endometrium, stomach, head and neck, kidney, liver, lung, ovary, prostate
  • hematopoietic malignancies e.g.
  • multiple myeloma, chronic lymphocytic lymphoma, adult T cell leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, myeloproliferative neoplasms and Waldenstrom's Macroglubulinemia, glioblastoma, melanoma and rhabdomyomas This is known to occur, FGFR gene fusion occurs in several types of cancer, and it is known to promote the proliferation of cancer cells by activating FGFR signal transduction, efforts to develop drugs targeting FGFR for the purpose of treating cancer Has been.
  • the present inventors can effectively inhibit FGFR, and while trying to develop drugs for treating diseases such as cancer and tumor therefrom, the compound according to the present invention can effectively inhibit FGFR, After confirming that the growth can be effectively inhibited, the present invention was found to be useful for diseases such as cancer and tumors when used as a pharmaceutical composition containing the same as an active ingredient.
  • An object of the present invention is to provide a compound useful as an active ingredient of a pharmaceutical composition for the prevention or treatment of fibroblast growth factor receptor (FGFR) -related diseases.
  • FGFR fibroblast growth factor receptor
  • Another object of the present invention is to provide a method for preparing the compound.
  • Still another object of the present invention is to provide a pharmaceutical composition for preventing or treating a fibroblast growth factor receptor (FGFR) related disease containing the compound as an active ingredient.
  • FGFR fibroblast growth factor receptor
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer containing the compound as an active ingredient.
  • Another object of the present invention to provide a health functional food for the prevention or improvement of FGFR (Fibroblast growth factor receptor) -related diseases containing the compound as an active ingredient.
  • FGFR Fibroblast growth factor receptor
  • the present invention provides a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  • R 1 is hydrogen, unsubstituted or substituted 6-10 cyclic aryl, N, O and S unsubstituted or substituted 5-10 cyclic heteroaryl containing one or more heteroatoms selected from the group consisting of, or -(CH 2 ) n -R 3 ,
  • the substituted 6-10-membered aryl and 5-10-membered heteroaryl are independently selected from the group consisting of C 1-3 straight or branched alkyl, C 1-3 straight or branched alkoxy and N, O and S At least one substituent selected from the group consisting of unsubstituted or substituted 5-6 hexacyclic heterocycloalkyl containing 1-3 hetero atoms is substituted, wherein the substituted 5-6 hexacyclic heterocycloalkyl is Substituted with C 1-3 straight or branched alkyl,
  • R 3 is a 5-6 hexacyclic unsubstituted or substituted heterocycloalkyl including at least one hetero atom selected from the group consisting of N, O and S, wherein the substituted heterocycloalkyl is C 1-3 At least one substituent selected from the group consisting of linear or branched alkyl and oxo groups is substituted, wherein n is an integer of 1-3;
  • R 2 is hydrogen, —XR 4 or —NR 5 R 6 ,
  • X is O or S
  • R 4 is 5- to 6-membered unsubstituted ring containing 1 to 3 heteroatoms selected from the group consisting of C 1-5 straight or branched alkyl unsubstituted or substituted with methoxy or N, O and S; Heterocycloalkyl,
  • R 5 and R 6 are each independently -H or substituted or unsubstituted C 1-5 straight or branched alkyl, substituted or unsubstituted C 1-5 straight or branched alkoxy, unsubstituted or substituted 6- Unsubstituted or substituted 5-10 cyclic heteroaryl, unsubstituted or substituted 3-10 cyclic cycloalkyl containing one or more heteroatoms selected from the group consisting of 10 cyclic aryl, N, O and S, Or unsubstituted or substituted 5-6 hexaheterocycloalkyl containing 1-3 hetero atoms selected from the group consisting of N, O and S, or R 5 and R 6 together are unsubstituted or substituted 4 Form a 10-membered ring or an unsubstituted or substituted 5-10-membered heterocycloalkyl ring containing one or more heteroatoms selected from the group consisting of N, O and S,
  • At least one substituent selected from the group consisting of alkylamino, C 1-3 alkyl or C 1-3 alkoxy is substituted.
  • It provides a method for producing a compound represented by the formula (1) comprising the step (step 3) of preparing a compound represented by the formula (1) from the compound represented by the formula (6) prepared in step 2.
  • R 1 and R 2 are the same as defined in Chemical Formula 1, respectively.
  • the present invention provides a pharmaceutical composition for preventing or treating a disease related to Fibroblast growth factor receptor (FGFR) containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • FGFR Fibroblast growth factor receptor
  • the present invention also provides a pharmaceutical composition for preventing or treating cancer containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a health functional food for preventing or improving cancer containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • novel pyridine derivatives, optical isomers thereof and pharmaceutically acceptable salts thereof according to the present invention can effectively inhibit Fibroblast growth factor receptor (FGFR), which is useful for the prevention or treatment of FGFR related diseases, preferably cancer. have.
  • FGFR Fibroblast growth factor receptor
  • the present invention provides a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  • R 1 is hydrogen, unsubstituted or substituted 6-10 cyclic aryl, N, O and S unsubstituted or substituted 5-10 cyclic heteroaryl containing one or more heteroatoms selected from the group consisting of, or -(CH 2 ) n -R 3 ,
  • the substituted 6-10 cyclic aryl or 5-10 hexacyclic heteroaryl is selected from the group consisting of C 1-3 straight or branched alkyl, C 1-3 straight or branched alkoxy and N, O and S. At least one substituent selected from the group consisting of unsubstituted or substituted 5-6 hexacyclic heterocycloalkyl containing -3 hetero atoms is substituted, wherein the substituted 5-6 hexacyclic heterocycloalkyl is C 1 Is substituted with -3 straight or branched alkyl,
  • R 3 is a 5-6 hexacyclic unsubstituted or substituted heterocycloalkyl including at least one hetero atom selected from the group consisting of N, O and S, wherein the substituted heterocycloalkyl is C 1-3 At least one substituent selected from the group consisting of linear or branched alkyl and oxo groups is substituted, wherein n is an integer of 1-3;
  • R 2 is hydrogen, —XR 4 or —NR 5 R 6 ,
  • X is O or S
  • R 4 is 5- to 6-membered unsubstituted ring containing 1 to 3 heteroatoms selected from the group consisting of C 1-5 straight or branched alkyl unsubstituted or substituted with methoxy or N, O and S; Heterocycloalkyl,
  • R 5 and R 6 are each independently -H or substituted or unsubstituted C 1-5 straight or branched alkyl, substituted or unsubstituted C 1-5 straight or branched alkoxy, unsubstituted or substituted 6- Unsubstituted or substituted 5-10 cyclic heteroaryl, unsubstituted or substituted 3-10 cyclic cycloalkyl containing one or more heteroatoms selected from the group consisting of 10 cyclic aryl, N, O and S, Or unsubstituted or substituted 5-6 hexaheterocycloalkyl containing 1-3 hetero atoms selected from the group consisting of N, O and S, or R 5 and R 6 together are unsubstituted or substituted 4 Form a 10-membered ring or an unsubstituted or substituted 5-10-membered heterocycloalkyl ring containing one or more heteroatoms selected from the group consisting of N, O and S,
  • substituted alkyl, substituted alkoxy, substituted aryl, substituted heteroaryl, substituted cycloalkyl, substituted heterocycloalkyl, substituted ring or substituted heterocycloalkyl ring is halogen, diC 1-3 At least one substituent selected from the group consisting of alkylamino, C 1-3 alkyl or C 1-3 alkoxy is substituted.
  • R 1 is hydrogen, unsubstituted or substituted 6-8 cyclic aryl, N, O and S unsubstituted or substituted 5-8 hexacyclic heteroaryl containing one or more heteroatoms selected from the group consisting of, or -(CH 2 ) n -R 3 ,
  • the substituted 6-8 cyclic aryl or 5-8 hexacyclic heteroaryl is selected from the group consisting of C 1-3 straight or branched alkyl, C 1-3 straight or branched alkoxy and N, O and S. At least one substituent selected from the group consisting of unsubstituted or substituted 5-6 hexacyclic heterocycloalkyl containing -3 hetero atoms is substituted, wherein the substituted 5-6 hexacyclic heterocycloalkyl is C 1 Is substituted with -3 straight or branched alkyl,
  • R 3 is a 5-6 hexacyclic unsubstituted or substituted heterocycloalkyl including at least one hetero atom selected from the group consisting of N, O and S, wherein the substituted heterocycloalkyl is C 1-3 At least one substituent selected from the group consisting of linear or branched alkyl and oxo groups is substituted, wherein n is an integer of 1-3;
  • R 2 is hydrogen, —XR 4 or —NR 5 R 6 ,
  • X is O or S
  • R 4 is C 1-5 straight or branched alkyl substituted or unsubstituted with methoxy
  • R 5 and R 6 are each independently -H or substituted or unsubstituted C 1-5 straight or branched alkyl, substituted or unsubstituted C 1-5 straight or branched alkoxy, unsubstituted or substituted 6- Unsubstituted or substituted 5-8 cyclic heteroaryl, unsubstituted or substituted 3-8 cyclic cycloalkyl containing one or more heteroatoms selected from the group consisting of octacyclic aryl, N, O and S, Or unsubstituted or substituted 5-8 cyclic heterocycloalkyl comprising 1-3 hetero atoms selected from the group consisting of N, O and S, or R 5 and R 6 together are unsubstituted or substituted 4 To form an -8-membered ring or an unsubstituted or substituted 5-8-membered heterocycloalkyl ring containing one or more heteroatoms selected from the group consisting of N, O and S,
  • substituted alkyl, substituted alkoxy, substituted aryl, substituted heteroaryl, substituted cycloalkyl, substituted heterocycloalkyl, substituted ring or substituted heterocycloalkyl ring is halogen, dimethylamino, C 1 At least one substituent selected from the group consisting of -3 alkyl or C 1-3 alkoxy is substituted.
  • R 1 is -H, , , , , or ego
  • R 2 is -H, , , , , , , , , , , , , , , , , , , , or to be.
  • Preferred 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 as the salt, 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, 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, acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, glutaric acid, benzoic acid, citric acid, lactic acid, glulic, unsubstituted or substituted with at least one halogen selected from the group consisting of F, Cl, Br and I Obtained from organic acids such as choline acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like.
  • Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, eye Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suve Latex, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chloro
  • the acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate produced by dissolving a derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and adding an organic or inorganic acid.
  • an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and adding an organic or inorganic acid.
  • the solvent may be prepared by filtration and drying, or the solvent and excess acid may be distilled under reduced pressure, dried, and then crystallized under an organic solvent.
  • Bases can also be used to make pharmaceutically acceptable metal salts.
  • Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt.
  • Corresponding salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg silver nitrate).
  • the present invention includes not only the compound represented by Formula 1 and pharmaceutically acceptable salts thereof, but also solvates, optical isomers, hydrates, and the like that can be prepared therefrom.
  • It provides a method for producing a compound represented by the formula (1) comprising the step (step 3) of preparing a compound represented by the formula (1) from the compound represented by the formula (6) prepared in step 2.
  • R 1 and R 2 are independently the same as defined in Chemical Formula 1.
  • Step 1 is a step of preparing a compound represented by Chemical Formula 4 by reacting the compound represented by Chemical Formula 2 with the compound represented by Chemical Formula 3.
  • H 2 O, ethanol, tetrahydrofuran (THF), methylene chloride, toluene, acetonitrile, etc. may be used as the solvent usable in the above step, and preferably H 2 O or tetrahydrofuran (THF) may be used.
  • reaction temperature in the step is preferably carried out between the boiling point of the solvent at 0 °C, the reaction time is not particularly limited, it is preferable to react for 0.5-20 hours.
  • Step 2 is a compound represented by Chemical Formula 6 by reacting the compound represented by Chemical Formula 4 prepared in Step 1 with the compound represented by Chemical Formula 5 Manufacturing step.
  • dimethylformamide (DMF) dimethylformamide
  • water methanol, ethanol, tetrahydrofuran (THF), methylene chloride, toluene, acetonitrile and the like
  • DMF dimethylformamide
  • reaction temperature in the step is preferably carried out between the boiling point of the solvent at 0 °C, the reaction time is not particularly limited, it is preferable to react for 0.5-30 hours.
  • Step 3 is a step of preparing a compound represented by Formula 1 from the compound represented by Formula 6 prepared in Step 2.
  • dimethylformamide (DMF) dimethylformamide
  • water methanol, ethanol, tetrahydrofuran (THF), methylene chloride, toluene, acetonitrile and the like
  • DMF dimethylformamide
  • reaction temperature in the step is preferably carried out between the boiling point of the solvent at 0 °C, the reaction time is not particularly limited, it is preferable to react for 0.5-30 hours.
  • a compound of the present invention may be prepared in a form in which a Suzuki reaction is omitted in the method of Scheme 1, as in Scheme 2 below. Can be prepared.
  • R 1 and R 2 are as defined in the formula (1).
  • the present invention provides a pharmaceutical composition for preventing or treating a disease related to Fibroblast growth factor receptor (FGFR) containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • FGFR Fibroblast growth factor receptor
  • the fibroblast growth factor receptor (FGFR) -related disease is not limited to the following, but refers to any disease that can be expressed from a phenomenon other than normal activity such as abnormality, modification, overexpression of FGFR enzyme, and the like.
  • FGFR-related diseases include cancer, where the compounds of the present invention, the optical isomers thereof and acceptable salts thereof, may be responsible for the activity of FGFR when it results from aberrant activity of FGFR in connection with cell proliferation of cancer cells. It can be effectively suppressed in molar units and can be usefully used for the prevention or treatment of diseases referred to as the above-mentioned FGFR-related diseases.
  • the present invention also provides a pharmaceutical composition for preventing or treating cancer containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound may be characterized by preventing or treating cancer by inhibiting Fibroblast growth factor receptor (FGFR), the cancer may be colon cancer, liver cancer, stomach cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, Uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, anal muscle cancer, colon cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, prostate cancer, bladder cancer, kidney cancer, ureter cancer One or two or more selected from the group consisting of renal cell carcinoma, renal pelvic carcinoma central nervous system tumor and leukemia.
  • FGFR Fibroblast growth factor receptor
  • the present invention provides a health functional food for preventing or improving cancer containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound may be characterized in that it inhibits Fibroblast growth factor receptor (FGFR) to prevent or improve cancer
  • the cancer is colon cancer, liver cancer, gastric cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, Uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, anal muscle cancer, colon cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, prostate cancer, bladder cancer, kidney cancer, ureter cancer
  • the compound represented by Formula 1 according to the present invention may be administered in various oral and parenteral formulations during clinical administration, and when formulated, the commonly used fillers, extenders, binders, humectants, disintegrating agents, surfactants, and the like. Prepared using diluents or excipients.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, troches and the like, which solid preparations contain at least one excipient such as starch, calcium carbonate, water, or the like. It is prepared by mixing cross, lactose or gelatin. In addition to simple excipients, lubricants such as magnesium styrate talc are also used.
  • Liquid preparations for oral administration include suspensions, solvents, emulsions or syrups, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Can be.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like.
  • non-aqueous solvent and the suspension solvent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.
  • base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used.
  • the effective dosage of the compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and is generally about 0.001-100 mg / kg / day, preferably Preferably 0.01-35 mg / kg / day. Based on an adult patient weighing 70 kg, it is generally 0.07-7000 mg / day, preferably 0.7-2500 mg / day, once a day at regular intervals according to the judgment of the doctor or pharmacist. Multiple doses may be administered.
  • the example compound of the present invention has inhibitory activity against FGFR 4, nanomolar units It can be seen that it has a good inhibitory activity of the compounds according to the present invention, as well as FGFR-related diseases, cancers derived therefrom, for example, colon cancer, liver cancer, gastric cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, tofu or Cervical cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, anal muscle cancer, colon cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, prostate cancer, bladder cancer, kidney cancer, urinary tract Cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system tumor, and the distal potential of leukemia or solid tumor can be usefully used for the prevention and treatment of cancer (experi).
  • the compound according to the present invention specifically evaluated the effect of inhibiting cancer cell proliferation through the inhibition of extracellular signal-regulated kinase activity, as a result of experiments on the human liver cancer cell line Huh-7 cell line, the embodiment of the present invention
  • Compounds have been shown to effectively inhibit cancer cell proliferation in human cancer cell line Huh7, and not only FGFR related diseases, but also cancers derived therefrom, such as colon cancer, liver cancer, gastric cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or Cervical cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, anal muscle cancer, colon cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, prostate cancer, bladder cancer, kidney cancer, urinary tract It can be usefully used for the prevention and treatment of cancer, renal cell carcinoma, renal pelvic carcinoma central nervous system tumor and cancer that is distal dislocation of leukemia or solid tumor
  • Step 1 ethyl 2-((2- ( tert - Butoxycarbonylamino )ethyl)( Methylamino Manufacture of Acetate
  • Step 2 Preparation of ethyl 2-((2-aminoethyl) (methyl) amino) acetate
  • step 3 6 - Bromo -7- ( Dimethoxymethyl ) -1,2,3,4- Tetrahydro -1,8- Naphthyridine Produce
  • step 2 The compound (12 g, 57.6 mmol) prepared in step 2 was dissolved in acetonitrile (192 ml), and N-bromosuccinimide (NBS) (10.77 g, 60.5 mmol) was slowly added at room temperature. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The reaction residue obtained above was extracted with diethyl ether and ice water, and then the combined organic layers were washed with brine, dried over sodium sulfate, concentrated under reduced pressure and purified by MPLC to give the title compound as a yellow solid (11 g, 66%) was obtained.
  • NBS N-bromosuccinimide
  • step 4 2 -( Dimethoxymethyl ) -5,6,7,8- Tetrahydro -1,8- Naphthyridine -3- Carbaldehyde Produce
  • Methyllithium (1.6 M in ether, 16.3 ml, 26.1 mmol) was slowly added dropwise at -78 ° C to a solution of the compound (7.5 g, 26.1 mmol) prepared in Step 3 in tetrahydrofuran (200 ml). After stirring the reaction mixture for 5 minutes, n-butyllithium (1.6 M in hexane, 18 ml, 28.7 mmol) was slowly added dropwise. After the mixture was stirred for 20 minutes, tetrahydrofuran (50 ml) was added at -78 ° C.
  • N-butyllithium (1.6 M in hexane, 24.5 ml, 39.0 mmol) was added sequentially, and the reaction mixture was stirred for 20 minutes. Then n-butyllithium (1.6 M in hexane, 3.3 ml, 5.2 mmol) was added and the reaction mixture was stirred at -78 ° C for 10 minutes. Dimethylformamide (1.05 ml, 18.6 mmol) was added and the reaction mixture was stirred at ⁇ 78 ° C. for 45 minutes, then the temperature was slowly raised to room temperature. The reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain the target compound.
  • step 5 1 -((2-( Dimethoxymethyl ) -5,6,7,8- Tetrahydro -1,8- Naphthyridine Preparation of -3-yl) methyl) -4-methylpiperazin-2-one
  • the reaction mixture was warmed to room temperature and neutralized with saturated aqueous sodium bicarbonate solution.
  • the reaction was extracted with dichloromethane, and the combined organic layers were dried over sodium sulfate, concentrated under reduced pressure, and purified by MPLC to obtain the target compound (1 g, 57%).
  • step 1 4 - Nitrophenyl 6- Bromo -7- ( Dimethoxymethyl ) -3,4- Dehydro -1,8- Naphthyridine Preparation of -1 (2H) -carboxylate
  • step 2 6 - Bromo -7- ( Dimethoxymethyl ) -N- (4-((2- Methoxyethyl ) Amino) -5- Nitropyridine Preparation of 2-Nyl) -3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide
  • step 3 7 -( Dimethoxymethyl ) -N- (4- (2- Methoxyethylamino ) -5- Nitropyridine Preparation of 2-yl) -6- (thiazol-5-yl) -3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide
  • step 4 7 - Formyl -N- (4-((2- Methoxyethyl ) Amino) -5- Nitropyridine -2- day) -6- ( Thiazole Preparation of -5-yl) -3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide
  • N 4 - (2- methoxy-ethyl) -5-nitropyridin-2,4-diamine in place of N 4 - (2- (dimethylamino) ethyl) -5-nitro The desired compound was prepared in a similar manner to Example 1, except that pyridine-2,4-diamine was used.
  • N 4 - N 4 in place of 5-nitropyridine-2,4-diamine (2-methoxyethyl) - (1-methyl -1H- pyrazol-4-yl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaboro, using) -5-nitropyridine-2,4-diamine and used in step 3 of Example 1 above.
  • step 1 4 - Nitrophenyl 7- ( Dimethoxymethyl ) -3,4- Dihydro -1,8- Naphthyridine Preparation of -1 (2H) -carboxylate
  • step 2 7 -( Dimethoxymethyl ) -N- (5- Nitropyridine -2-yl) -3,4- Dehydro -1,8- Naphthyridine Preparation of -1 (2H) -Carboxamide
  • step 3 7 - Formyl -N- (5- Nitropyridine Preparation of 2-Nyl) -3,4-dihydro-1,8-naphthyridine-1 (2H) -carboxamide
  • Example 9 was carried out in the same manner as in Example 9, except that 4- (ethylthio) -5-nitropyridin-2-amine was used instead of 5-nitropyridin-2-amine. To prepare the target compound.
  • Example 13 except that 4-morpholino-5-nitropyridin-2-amine was used in place of 4- (ethylthio) -5-nitropyridin-2-amine used in Example 13. Similarly, the desired compound was prepared.
  • Example 13 Except for using 5-nitro-4- (piperidin-1-yl) pyridin-2-amine in place of 4- (ethylthio) -5-nitropyridin-2-amine used in Example 13, In the same manner as in Example 13, to prepare a target compound.
  • Example 4 except that N 4 -cyclohexyl-5-nitropyridine-2,4-diamine was used in place of 4- (ethylthio) -5-nitropyridin-2-amine used in Example 13. Proceed similarly to 13 to prepare the target compound.
  • Example 13 Except for using N 4- (2-methoxyethyl) -5-nitropyridine-2,4-diamine in place of 4- (ethylthio) -5-nitropyridin-2-amine used in Example 13. And the target compound was prepared in the same manner as in Example 13.
  • Example 13 except that N 4 -ethyl-5-nitropyridin-2,4-diamine was used in place of the 4- (ethylthio) -5-nitropyridin-2-amine used in Example 13. Was carried out similarly to prepare the desired compound.
  • Example 13 In place of 4- (ethyl-thio) -5-nitropyridin-2-amine used in Example 13 N 4 - except for using (4-methoxyphenyl) -5-nitropyridine-2,4-diamine And the target compound was prepared in the same manner as in Example 13.
  • Example 13 N 4- (2- (dimethylamino) ethyl) -5-nitropyridine-2,4-diamine in place of 4- (ethylthio) -5-nitropyridin-2-amine used in Example 13 A target compound was prepared in the same manner as in Example 13 except for the above.
  • Example 13 4- (ethyl-thio) used in the 5-nitropyridin-2-amine in place of N 4 - (3-chloro-4-fluorophenyl) -5-nitropyridine-2,4-diamine
  • a target compound was prepared in the same manner as in Example 13 except that was used.
  • Example constitutional formula Example constitutional formula One 12 2 13 3 14 4 15 5 16 6 17 7 18 8 19 9 20 10 21 11 22
  • FGFR 4 enzymatic activity of the compound according to the present invention was performed by Reaction Biology, and the results are shown in Table 2 below.
  • Example compound according to the present invention inhibits FGFR 4 at a nanomolar unit concentration.
  • the compound according to the present invention can effectively inhibit FGFR, thereby preventing FGFR-related diseases, such as cancer and It can be usefully used for treatment.
  • the Huh-7 cells, plant to be 3 ⁇ 10 3/80 ⁇ l / well in 96-well plates are attached for a day.
  • 20 ⁇ l / well of the culture medium containing 9 concentrations (0.0015-10 ⁇ M) of Example compound and DMSO control, which were serially diluted in multiples of 3, were added in 20 ⁇ l / well and the final concentration was 0-10 ⁇ M, followed by 37 ° C CO 2 Incubate for 72 hours in the incubator.
  • 50 ⁇ l of CellTiter-Glo solution is added to each well, orbital shaken for 2 minutes and left in the absence of light for 10 minutes.
  • Example compound of the present invention inhibits the proliferation of Huh-7 which is a human liver cancer cell line.
  • the compound according to the present invention can inhibit the proliferation of cancer cells in units of uM or less, usefully as a pharmaceutical composition for the prevention and treatment of cancer diseases, for example liver cancer. Can be used.
  • novel pyridine derivatives, optical isomers thereof and pharmaceutically acceptable salts thereof according to the present invention can effectively inhibit Fibroblast growth factor receptor (FGFR), which is useful for the prevention or treatment of FGFR related diseases, preferably cancer. have.
  • FGFR Fibroblast growth factor receptor

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Abstract

La présente invention concerne un nouveau dérivé de pyridine, son procédé de préparation, et une composition pharmaceutique qui le contient en tant que principe actif et qui est destinée à prévenir ou à traiter une maladie liée au récepteur du facteur de croissance des fibroblastes (FGFR). Un nouveau dérivé de pyridine selon la présente invention, un isomère optique de celui-ci, et un sel pharmaceutiquement acceptable du dérivé de pyridine peuvent efficacement inhiber un récepteur du facteur de croissance des fibroblastes (FGFR), et donc une maladie liée au récepteur FGFR, ils ont de préférence un effet utile sur la prévention et le traitement du cancer.
PCT/KR2017/003226 2016-03-24 2017-03-24 Nouveau dérivé de pyridine, son procédé de préparation, et composition pharmaceutique pour prévenir ou traiter une maladie liée à fgfr contenant ledit dérivé comme principe actif Ceased WO2017164705A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3498707A4 (fr) * 2016-08-12 2020-04-08 Jiangsu Hansoh Pharmaceutical Group Co., Ltd. Inhibiteur de fgfr4, son procédé de préparation et son utilisation
WO2020257527A1 (fr) * 2019-06-21 2020-12-24 Terns, Inc. Composés pour inhiber fgfr4

Citations (4)

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Publication number Priority date Publication date Assignee Title
US5663181A (en) * 1993-06-25 1997-09-02 Laboratoires Upsa Naphthyridine derivatives, their methods of preparation and pharmaceutical compositions in which they are present, useful especially as antiproliferative drugs
KR20110046514A (ko) * 2008-07-31 2011-05-04 제넨테크, 인크. 피리미딘 화합물, 조성물 및 사용 방법
WO2013061080A1 (fr) * 2011-10-28 2013-05-02 Astex Therapeutics Limited Pyridopyrazines anti-cancéreuses par l'inhibition de kinases de fgfr
WO2015059668A1 (fr) * 2013-10-25 2015-04-30 Novartis Ag Dérivés pyridyle bicycliques à anneaux fusionnés utilisés en tant qu'inhibiteurs de fgfr4

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5663181A (en) * 1993-06-25 1997-09-02 Laboratoires Upsa Naphthyridine derivatives, their methods of preparation and pharmaceutical compositions in which they are present, useful especially as antiproliferative drugs
KR20110046514A (ko) * 2008-07-31 2011-05-04 제넨테크, 인크. 피리미딘 화합물, 조성물 및 사용 방법
WO2013061080A1 (fr) * 2011-10-28 2013-05-02 Astex Therapeutics Limited Pyridopyrazines anti-cancéreuses par l'inhibition de kinases de fgfr
WO2015059668A1 (fr) * 2013-10-25 2015-04-30 Novartis Ag Dérivés pyridyle bicycliques à anneaux fusionnés utilisés en tant qu'inhibiteurs de fgfr4

Non-Patent Citations (1)

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Title
HIERRO, C.: "Fibroblast Growth Factor (FGF) receptor/FGF inhibitors: novel targets and strategies for optimization of response of solid tumors", SEMINARS IN ONCOLOGY, vol. 42, no. 6, 2015, pages 801 - 819 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3498707A4 (fr) * 2016-08-12 2020-04-08 Jiangsu Hansoh Pharmaceutical Group Co., Ltd. Inhibiteur de fgfr4, son procédé de préparation et son utilisation
WO2020257527A1 (fr) * 2019-06-21 2020-12-24 Terns, Inc. Composés pour inhiber fgfr4
CN114144176A (zh) * 2019-06-21 2022-03-04 拓臻制药公司 用于抑制fgfr4的化合物
EP3986405A4 (fr) * 2019-06-21 2023-06-14 Terns Pharmaceuticals, Inc. Composés pour inhiber fgfr4

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