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WO2009139576A2 - Dérivés de pyridine substitués avec de nouveaux benzoxazoles ou des sels pharmaceutiquement acceptables de ces composés, procédé de préparation de ces composés et compositions pharmaceutiques contenant ces composés comme principes actifs destinées à la prévention et au traitement d'une maladie à croissance cellulaire anormale - Google Patents

Dérivés de pyridine substitués avec de nouveaux benzoxazoles ou des sels pharmaceutiquement acceptables de ces composés, procédé de préparation de ces composés et compositions pharmaceutiques contenant ces composés comme principes actifs destinées à la prévention et au traitement d'une maladie à croissance cellulaire anormale Download PDF

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Publication number
WO2009139576A2
WO2009139576A2 PCT/KR2009/002536 KR2009002536W WO2009139576A2 WO 2009139576 A2 WO2009139576 A2 WO 2009139576A2 KR 2009002536 W KR2009002536 W KR 2009002536W WO 2009139576 A2 WO2009139576 A2 WO 2009139576A2
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cancer
formula
compound
substituted
pharmaceutically acceptable
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Korean (ko)
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WO2009139576A3 (fr
Inventor
류재욱
고종성
이정옥
이종국
정희정
조성윤
하재두
한선영
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Korea Research Institute of Chemical Technology KRICT
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Korea Research Institute of Chemical Technology KRICT
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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 novel pyridine derivative substituted with benzoxazole or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition for preventing and treating aberrant cell growth disease containing the same as an active ingredient.
  • Protein kinases are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins.
  • the protein kinases play an important role in the growth factor signal transduction that causes cell growth, differentiation and proliferation, and thus the activity of protein kinases affects almost all aspects of cell life.
  • Protein kinases can be classified into tyrosine kinases (TK) and serine-threonine kinases (STK).
  • TK tyrosine kinases
  • STK serine-threonine kinases
  • tyrosine kinases are cell surface proteins that, when bound to growth factor ligands, convert the growth factor receptors into active form and interact with proteins on the inner surface of the cell membrane, causing phosphorylation on tyrosine residues of these receptors and other proteins.
  • growth factor receptors are cell surface proteins that, when bound to growth factor ligands, convert the growth factor receptors into active form and interact with proteins on the inner surface of the cell membrane, causing phosphorylation on tyrosine residues of these receptors and other proteins.
  • complexes with various cytoplasmic signaling molecules are formed inside cells, resulting in numerous cellular reactions such as cell growth, differentiation and proliferation, and expression of metabolic effects on extracellular microenvironments (Schleessinger and Ullrich, Neuron. 1992 9, 303-391).
  • RTK receptor tyrosine kinase
  • Subtype receptor tyrosine kinases such as those previously termed 19 or more "HER RTKs" are known, and such HER RTKs include epidermal growth factor receptors (EGFR), HER2, HER3, HER4 and the like.
  • the receptor tyrosine kinase consists of an extracellular glycosylated ligand binding domain, a transmembrane domain and an intracellular cytoplasmic domain capable of phosphorylating tyrosine residues on proteins.
  • the receptor tyrosine kinase subfamily also consists of insulin receptor (IR), insulin like growth I receptor (IGF-1R) and insulin receptor related receptor (IRR).
  • IR and IGF-IR interact with insulin, IGF-I and IGF-II, resulting in heterologous doses of two ⁇ subunits and two completely extracellular glycosylated ⁇ subunits that cross the cell membrane and contain a kinase domain Forms a heterotetramer.
  • the receptor tyrosine kinase subfamily includes PDGFR ⁇ , PDGFR ⁇ , CSFIR, c-Kit and c-Fms, which are termed platelet induced growth factor receptors (PDGFR).
  • PDGFR platelet induced growth factor receptors
  • the receptor consists of a glycosylated extracellular domain consisting of a variable immunoglobulin-like loop and an intracellular domain. Due to its similarity to the PDGFR subfamily, fetal liver kinase (Flk) receptor subfamily belonging to the PDGFR group is known.
  • the Flk subfamily is a kinase insert domain-receptor fetal liver kinase-1 (KDR / Flk-1), Flk-1R, Flk-1, Fms-like tyrosine kinase 1 or 3 (Flt-1 or Flt-3) and the like. Is done.
  • MET As a family of tyrosine kinase growth factor receptors, MET is named c-Met and is believed to play a role in primary tumor growth and metastasis as human hepatocyte growth factor receptor tyrosine kinase (hHGFR) (Plowman et al., DN & P, 1994, 7, 6, 334-339).
  • hHGFR human hepatocyte growth factor receptor tyrosine kinase
  • nonreceptor tyrosine kinases In addition to receptor tyrosine kinases, there is a specific family of complete intracellular TKs called nonreceptor tyrosine kinases or cellular tyrosine kinases (CTKs).
  • CTKs cellular tyrosine kinases
  • the non-receptor tyrosine kinase contains no extracellular and transmembrane domains and consists of the Src, Frk, Btk, Csk Abl, Zap70, Fes, Fak, Jak and Ack subfamily.
  • Src subfamily includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, AUR1 (Aurora-B), AUR2 (Aurora-A), AUR3 (Aurora-C), Yrk, etc. (Bolen, Oncogene. 1993, 8, 2025-2031).
  • Pathogenic diseases associated with receptor tyrosine kinases and non-receptor tyrosine kinases include psoriasis, cirrhosis, diabetes, angiogenesis, recurrent stenosis, ophthalmic diseases, rheumatoid arthritis, autoimmune diseases, atherosclerosis, kidney disorders and the like.
  • receptor tyrosine kinases such as Bcr-Abl, EGFR, and VEGFR have been studied as a good anticancer target, and anticancer agents such as Gleevec and Iresa have been developed and marketed.
  • HGFR Hepatocyte Growth Factor Receptor
  • HGF / SF hepatocyte growth factor / scatter factor
  • c-Met is overexpressed or activated in many human cancers, including lung cancer, gastric cancer, skin cancer, kidney cancer, rectal cancer, and pancreatic cancer, accompanied by tumor formation, increased cell motility and invasive tumor progression, and metastasis (JG Christensen et. al., Cancer Letters, 2005, 225, 1-26; WG Jiang et al., Critical Reviews in Oncology / Hematology, 2005, 53, 35-69).
  • c-Met and its ligand, HGF are expressed in many tissues, but are normally limited to cells of epithelial and mesenchymal origin, respectively.
  • HGF / SF is an angiogenesis factor and c-Met signaling in epithelial cells induces cellular responses (proliferation, motility, invasiveness, etc.) that are essential for angiogenesis.
  • c-Met and its ligand, HGF are co-expressed at increased levels in various human cancers.
  • receptors and ligands are usually expressed by different cell types, c-Met signaling is most commonly regulated by tumor-stroma interactions.
  • c-Met and / or HGF / SF are associated with disease progression in different types of cancer (lungs, colon, breast, prostate, liver, pancreas, brain, kidney, ovary, stomach, skin, bone, etc.)
  • Overexpression of c-Met or HGF / SF has been found to correlate with poor prognosis and disease outcome in many major human cancers including lung, liver, stomach and breast.
  • c-Met has been reported to be directly related to cancers without successful treatment such as pancreatic cancer, glioma and hepatocellular carcinoma, and lung cancer caused by ERBB3 signaling system activation due to overexpression of c-Met is Gefitinib (Gefitinib; It has been reported to be resistant to Irresa (JA Engelman, K. Zejnullahu et. Al. Science, 2007, 316, 1039-1043).
  • HGF / SF binds to the extracellular domain of c-Met to activate c-Met, and activation of c-Met is tyrosine phosphorylation and downstream via Gab1 and Grb2-mediated PI3-kinase and Ras / MAPK activation, respectively. Signaling to induce cell motility and proliferation.
  • c-Met has been shown to interact with other proteins leading to receptor activation, transformation and invasion, and c-Met also has an extracellular matrix (ECM) such as ⁇ 6 ⁇ 4 integrin (laminin) that forms focal adhesion.
  • ECM extracellular matrix
  • laminin ⁇ 6 ⁇ 4 integrin
  • pyridine derivatives substituted with benzoxazole having excellent inhibitory activity against protein kinases are useful for the treatment of abnormal cell growth, such as protein kinases such as c-Met. Since the present invention has an inhibitory effect on the present invention, the present invention has been found to be useful for the prevention and treatment of abnormal cell growth diseases.
  • Another object of the present invention is to provide a method for preparing a pyridine derivative or pharmaceutically acceptable salt thereof substituted with novel benzoxazole.
  • Still another object of the present invention is to provide a pharmaceutical composition for preventing and treating aberrant cell growth disease, containing a pyridine derivative substituted with novel benzoxazole or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a pyridine derivative substituted with novel benzoxazole or a pharmaceutically acceptable salt thereof, a method for preparing the same and a pharmaceutical composition for preventing and treating aberrant cell growth disease containing the same as an active ingredient. to provide.
  • novel benzoxazole-substituted pyridine derivatives or pharmaceutically acceptable salts thereof according to the present invention exhibit excellent inhibitory activity against protein kinases, which are useful for the treatment of aberrant cell growth diseases, for example c-Met. Since it shows an excellent inhibitory effect on, it can be usefully used for the prevention and treatment of abnormal cell growth diseases.
  • the present invention provides a pyridine derivative or pharmaceutically acceptable salt thereof substituted with benzoxazole represented by the following formula (1).
  • A is , Unsubstituted or substituted C 3 -C 8 cycloalkyl, or unsubstituted or substituted quinoline,
  • X is N, O or CH;
  • R 1 and R 2 are each hydrogen, unsubstituted or substituted C 3 ⁇ C 8 cycloalkyl, C 5 -C 8 aryl, C 5 ⁇ C 8 aryl C 3 ⁇ C 8 cycloalkyl, C 3 ⁇ C 8 heterocycloalkyl Alkyl or ego;
  • R 3 is unsubstituted or substituted C 1 to C 6 straight or branched alkyl, C 1 to C 6 alkoxy, C 3 to C 8 cycloalkyl, C 5 to C 8 aryl, C 5 to C 8 aryl C 3 to C 8 cycloalkyl or C 3 to C 8 heterocycloalkyl;
  • the A is , , , Unsubstituted or substituted quinoline, or unsubstituted or substituted isoquinoline,
  • R 1 and R 2 are each hydrogen, unsubstituted or substituted C 5 to C 6 cycloalkyl, C 5 to C 6 aryl, C 5 to C 6 aryl C 5 to C 6 cycloalkyl, C 5 to C 6 heterocycloalkyl or ego;
  • R 3 is unsubstituted or substituted C 1 -C 6 straight or branched alkyl, C 1 -C 6 alkoxy, C 5 to C 6 cycloalkyl, C 5 to C 6 aryl, C 5 to C 6 aryl C 5 to C 6 cycloalkyl or C 5 to C 6 heterocycloalkyl.
  • A is , , , 3-quinoline or 4-isoquinoline
  • R 1 and R 2 are each hydrogen, And It is selected from the group consisting of.
  • Pyridine derivatives substituted with benzoxazole represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and acid salts formed by pharmaceutically acceptable free acid are useful as salts.
  • the expression pharmaceutically acceptable salt is a concentration that has a relatively nontoxic and harmless effect on the patient and that any side effects due to the salt do not degrade the beneficial efficacy of the base compound of formula 1, or Means inorganic addition salts.
  • These salts may include inorganic acids and organic acids as free acids, hydrochloric acid, bromic acid, nitric acid, sulfuric acid, perchloric acid, phosphoric acid, and the like, and citric acid, acetic acid, lactic acid, maleic acid, and fumarine as organic acids.
  • Acids Gluconic Acid, Methanesulfonic Acid, Glyconic Acid, Succinic Acid, Tartaric Acid, Galluturonic Acid, Embonic Acid, Glutamic Acid, Aspartic Acid, Oxalic Acid, (D) or (L) Malic Acid, Maleic Acid, Methanesulphonic Acid, Ethene Sulfuric Acid Phonic acid, 4-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid or malonic acid and the like can be used.
  • These salts also include alkali metal salts (sodium salts, potassium salts, and the like), alkaline earth metal salts (calcium salts, magnesium salts, and the like) and the like.
  • acid addition salts include acetates, aspartates, benzates, besylates, bicarbonates / carbonates, bisulfates / sulfates, borates, camsylates, citrates, edisylates, ecylates, formates, fumarates, Gluceptate, Gluconate, Glucuronate, Hexafluorophosphate, Hibenzate, Hydrochloride / Chloride, Hydrobromide / Bromide, Hydroiodide / Iodide, Isetionate, Lactate, Maleate, Mali Eate, malonate, mesylate, methyl sulfate, naphthylate, 2-naphsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccha Laterate, stearate, succinate, tartrate, cit
  • the pyridine derivative substituted with benzoxazole represented by Formula 1 of the present invention includes not only pharmaceutically acceptable salts, but also all salts, isomers, hydrates, and solvates that can be prepared by conventional methods. .
  • the addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound of Formula 1 in a water miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile and adding an excess of an organic acid or an inorganic acid. It can be prepared by adding an acidic aqueous solution of and then precipitating or crystallizing. The solvent or excess acid may then be evaporated and dried in this mixture to obtain an addition salt or the precipitated salt may be prepared by suction filtration.
  • a water miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile
  • Isomers herein means compounds of the present invention or salts thereof having the same chemical formula or molecular formula, but which are optically or sterically different, and such isomers and mixtures thereof are also included within the scope of the present invention.
  • the present invention provides a method for preparing a pyridine derivative or pharmaceutically acceptable salt thereof substituted with benzoxazole represented by Chemical Formula 1.
  • the compound of Formula 1 according to the present invention may be prepared by a method as shown in Schemes 1 to 5 below.
  • the deprotection reaction of the compound of Chemical Formula 4 prepared in Step 1 may be prepared by a process comprising the step of preparing the compound of Chemical Formula 1 (step 2).
  • n is an integer of 1-3
  • formula 1a is a derivative of formula 1 or a pharmaceutically acceptable salt thereof
  • NaOt-Bu sodium tert-butoxide
  • BINAP 2,2'-bis (diphenylphosphino) -1,1 'binaptyl
  • Pd 2 dpa 3 tris (dibenzylideneacetone) ipalladium (0)
  • TFA trifluoroacetic acid do
  • Deprotection of the compound of Chemical Formula 5 prepared in Step 1 may be prepared by a method comprising the step of preparing a compound of Chemical Formula 1c (Step 2).
  • R 3 is as defined in Formula 1, n is an integer of 1-3, Formulas 1b and 1c are derivatives of Formula 1 or a pharmaceutically acceptable salt thereof, and EDAC: 1- (3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride, Et 3 N: triethylamine, TFA means trifluoroacetic acid)
  • Deprotection of the compound of Chemical Formula 8 prepared in Step 2 may be prepared by a manufacturing method comprising the step of preparing a compound of Chemical Formula 1d (step 3).
  • R 3 is as defined in Formula 1, n is an integer of 1-3, Formula 1d is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof, and EDAC, Et 3 N and TFA are as defined in Scheme 2 above. same)
  • Deprotection of the compound of Chemical Formula 11 prepared in Step 1 may be prepared by a manufacturing method comprising the step of preparing a compound of Chemical Formula 1e (Step 2).
  • A is as defined in formula 1, n is an integer of 1-3, formula 1e is a derivative of formula 1 or a pharmaceutically acceptable salt thereof)
  • Step 3 It may be prepared by a manufacturing method comprising the step (step 3) of preparing a compound of Formula 1e by deprotecting the compound of Formula 11 prepared in Step 2.
  • A is as defined in formula 1, n is an integer of 1-3, formula 1e is a derivative of formula 1 or a pharmaceutically acceptable salt thereof)
  • the present invention also provides a pharmaceutical composition for the prevention and treatment of aberrant cell growth diseases containing a pyridine derivative substituted with benzoxazole represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a method for treating aberrant cell growth disease comprising administering a pyridine derivative substituted with benzoxazole represented by Formula 1 or a pharmaceutically acceptable salt thereof to a patient in need of a therapeutically effective amount. Provide treatment.
  • the abnormal cell growth disease is lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, perianal cancer, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrium Cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocyte lymphoma, Bladder cancer, kidney or ureter cancer, renal cell cancer, renal cancer, central nervous system (CNS) tumor, primary CNS lymphoma, spinal cord tumor, brain stem glioma, pituitary adenoma, and the like are preferred.
  • CNS central nervous system
  • the abnormal cell growth disease is preferably psoriasis, benign prostatic hypertrophy or retinopathy.
  • the abnormal cell growth disease is preferably a benign proliferative disease
  • the benign proliferative disease is preferably fibroadenoma, sclerotic gland disease, papilloma and the like.
  • a pyridine derivative substituted with benzoxazole represented by Formula 1 or a pharmaceutically acceptable salt, solvate and hydrate thereof may inhibit protein kinase of c-Met.
  • c-Met is a hepatocyte growth factor (HGF / SF) receptor that is being studied as an anticancer agent, and many anticancer agents targeting it have been reported (JG Christensen, J. Burrows et al., Cancer Letters, 2005). , 225, 1-26; WO 2004/076412; WO 2006/021881 A; WO 2006/021886; WO 2007/064797).
  • HGF / SF hepatocyte growth factor
  • c-Met is overexpressed or activated in many human cancers, including lung cancer, gastric cancer, skin cancer, kidney cancer, rectal cancer, and pancreatic cancer, accompanied by tumor formation, increased cell motility and invasive tumor progression, and metastasis (JG Christensen et. al., Cancer Letters, 2005, 225, 1-26; WG Jiang et al., Critical Reviews in Oncology / Hematology, 2005, 53, 35-69).
  • c-Met and its ligand, HGF are expressed in many tissues, but are normally limited to cells of epithelial and mesenchymal origin, respectively.
  • HGF / SF is an angiogenesis factor and c-Met signaling in epithelial cells induces cellular responses (proliferation, motility, invasiveness, etc.) that are essential for angiogenesis.
  • c-Met and its ligand, HGF are co-expressed at increased levels in various human cancers.
  • receptors and ligands are usually expressed by different cell types, c-Met signaling is most commonly regulated by tumor-stroma interactions.
  • c-Met has been observed in various human cancers with gene amplification, mutations and rearrangements. Classes with germline mutations that activate c-Met kinase are susceptible to multiple kidney tumors and tumors of other tissues.
  • c-Met and / or HGF / SF are associated with disease progression in different types of cancer (lungs, colon, breast, prostate, liver, pancreas, brain, kidney, ovary, stomach, skin, bone, etc.)
  • Overexpression of c-Met or HGF / SF has been found to correlate with poor prognosis and disease outcome in many major human cancers including lung, liver, stomach and breast.
  • c-Met has been reported to be directly related to cancers without successful treatment such as pancreatic cancer, glioma and hepatocellular carcinoma, and lung cancer caused by ERBB3 signaling system activation due to overexpression of c-Met is Gefitinib (Gefitinib; It has been reported to be resistant to Irresa (JA Engelman, K. Zejnullahu et. Al. Science, 2007, 316, 1039-043).
  • the derivative of Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention showed the result that the IC50 had a c-Met kinase inhibitory activity of 20 ⁇ M or less in the c-Met kinase activity experiment.
  • the pharmaceutical composition containing a pyridine derivative substituted with benzoxazole according to the present invention or a pharmaceutical salt thereof as an active ingredient can be usefully used to treat various cancers described above derived from the expression of c-Met.
  • the compound of the present invention may be administered in various oral and parenteral dosage forms for clinical administration, and when formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc., which are commonly used, may be used. Are manufactured.
  • Solid form preparations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, which form at least one excipient such as starch, calcium carbonate, water, or the like. It is prepared by mixing cross, lactose or gelatin. In addition to simple excipients, lubricants such as magnesium styrate talc are also used.
  • Liquid preparations for oral administration include suspensions, solvents, emulsions or syrups, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Can be.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like.
  • non-aqueous solvent and the suspension solvent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.
  • base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used.
  • the effective dosage of the compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and is generally about 0.001-100 mg / kg / day, preferably Preferably 0.01-35 mg / kg / day. Based on an adult patient weighing 70 kg, it is generally 0.07-7000 mg / day, preferably 0.7-2500 mg / day, once a day at regular intervals according to the judgment of the doctor or pharmacist. Multiple doses may be administered.
  • Step 1 Preparation of tert-butyl-3-benzoxazolyl-5- (4- (4-tert-butoxycarbonylpiperazin-1-yl) pyridin-2-amine
  • Step 2 Preparation of the tritrifluoroacetic acid salt of 3-benzoxazolyl-5- (4- (piperazin-1-yl)) pyridin-2-amine
  • the target compound was prepared in the same manner as in Example 4, except that 3-methoxypropionic acid was used instead of 1- (tert-butoxycarbonyl) -4-piperidinecarboxylic acid used in Example 4. (3-benzoxazolyl-5- ⁇ 4- (methoxypropanol) piperazin-1-yl ⁇ pyridin-2-amine) was obtained (15 mg, 75%).
  • Example 4 Except for using phenyl acetic acid instead of 1- (tert-butoxycarbonyl) -4-piperidinecarboxylic acid used in Example 4 was carried out in the same manner as in Example 4 to obtain the target compound (3- Benzoxazolyl-5- ⁇ 4- (benzylcarbonyl) piperazin-1-yl ⁇ pyridin-2-amine) was obtained (15 mg, 50%).
  • Example 4 Except for using isovaleric acid instead of 1- (tert-butoxycarbonyl) -4-piperidinecarboxylic acid used in Example 4, the method was carried out in the same manner as in Example 4, -Benzoxazolyl-5- ⁇ 4- (2-methyl-propylcarbonyl) piperazin-1-yl ⁇ pyridin-2-amine) was obtained (13 mg, 45%).
  • the target compound trifluoroacetic acid salt of 3-benzoxazolyl-5- ⁇ 3-piperidin-4-ylcarbonyl) piperazin-1-yl ⁇ pyridin-2-amine
  • the target compound trifluoroacetic acid salt of 3-benzoxazolyl-5- ⁇ 3-piperidin-4-ylcarbonyl
  • piperazin-1-yl ⁇ pyridin-2-amine was obtained. Obtained (25 mg, 48.5%).
  • Example 13 Except for using 3-bromoquinoline used in Example 13, except that 4-bromoisoquinoline was used in the same manner as in Example 13 to the target compound (3-benzoxazolyl-5- (4-isoquinoline 1) trifluoroacetic acid salt of pyridin-2-amine) (25 mg, 73%).
  • DELFIA Dissociation Enhanced Lanthanide Fluoro Immuno Assay
  • TRF time-resolved fluorescence
  • Europium-containing anti-phosphotyrosine antibody was diluted 1: 2,500, added to 100 ⁇ l per well, incubated under shaking, and washed 1 time with PBS-T buffer (PBS 0.05% Tween20).
  • Enhancement solution (100 mL) was added and shaken for 5 minutes, then read in a wavelength range of 615/665 nm with a Wallac Envision 2103 instrument.
  • the IC 50 of the test compound which carried out the experiment was determined by two data sets and was obtained using Prism (version 5.01, GraphPad) software.
  • the IC 50 of this compound which reduces c-Met kinase enzyme activity by 50% is shown in Table 1 below.
  • the IC 50 of the compounds according to the present invention (Examples 4 to 6, 8 to 12) was measured at 20 ⁇ M or less, from which the pyridine derivatives or pharmaceutics thereof substituted with benzoxazoles according to the present invention. It can be seen that the acceptable salt has an excellent inhibitory effect on c-Met kinase.
  • the airtight cloth was filled to prepare a powder.
  • tablets were prepared by tableting according to a conventional method for producing tablets.
  • the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.
  • the solution was filled into a 5 ml Type I ampoule made of clear glass, encapsulated under an upper grid of air by dissolving the glass and sterilized by autoclaving at 120 ° C. for at least 15 minutes to prepare an injection solution.

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Abstract

La présente invention concerne des dérivés de pyridine substitués avec de nouveaux benzoxazoles ou des sels pharmaceutiquement acceptables de ces composés, un procédé de préparation de ces composés et des compositions pharmaceutiques contenant ces composés comme principes actifs destinées à la prévention et au traitement d'une maladie à croissance cellulaire anormale. La présente invention présente d'excellents effets inhibiteurs pour une variété de protéine kinases qui conviennent pour traiter une maladie à croissance cellulaire anormale, par exemple C-Met, et peut ainsi être utilisée avec profit dans la prévention et le traitement d'une maladie à croissance cellulaire anormale.
PCT/KR2009/002536 2008-05-14 2009-05-13 Dérivés de pyridine substitués avec de nouveaux benzoxazoles ou des sels pharmaceutiquement acceptables de ces composés, procédé de préparation de ces composés et compositions pharmaceutiques contenant ces composés comme principes actifs destinées à la prévention et au traitement d'une maladie à croissance cellulaire anormale Ceased WO2009139576A2 (fr)

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KR1020080044485A KR101034351B1 (ko) 2008-05-14 2008-05-14 신규 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의약학적으로 허용가능한 염, 이의 제조방법 및 이를유효성분으로 함유하는 이상세포 성장 질환의 예방 및치료용 약학적 조성물
KR10-2008-0044485 2008-05-14

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