WO2009096435A1 - Dérivés hétérocycliques condensés et leurs utilisations - Google Patents

Dérivés hétérocycliques condensés et leurs utilisations Download PDF

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WO2009096435A1
WO2009096435A1 PCT/JP2009/051383 JP2009051383W WO2009096435A1 WO 2009096435 A1 WO2009096435 A1 WO 2009096435A1 JP 2009051383 W JP2009051383 W JP 2009051383W WO 2009096435 A1 WO2009096435 A1 WO 2009096435A1
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alkyl
optionally
mmol
compound
pyridazin
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PCT/JP2009/051383
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Japanese (ja)
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Naoki Miyamoto
Shigemitsu Matsumoto
Shinichi Imamura
Takaharu Hirayama
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Takeda Pharmaceutical Company Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to fused heterocyclic derivatives and uses thereof, and more particularly to imidazopyridazine derivatives having strong kinase inhibitory activity and useful for cancer prevention and treatment and uses thereof.
  • VEGF Vascular endothelial growth factor
  • VEGFR vascular endothelial growth factor receptor
  • HGF hepatocyte growth factor
  • c-Met vascular endothelial cells
  • HGF hepatocyte growth factor
  • c-Met is highly expressed in various cancers (such as colorectal cancer, stomach cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, prostate cancer, etc.), and is clearly involved in the growth and survival of cancer cells.
  • Non-Patent Document 5 a tumor cell invasion / metastasis
  • c-Met inhibition is thought to be effective in preventing cancer invasion / metastasis. .
  • Examples of compounds that inhibit kinases including VEGFR and c-Met include phthalazine derivatives (see, for example, Patent Document 1), pyrrole-substituted 2-indolinone derivatives (see, for example, Patent Document 2), and quinazoline derivatives (for example, Patent Document).
  • Patent Document 4 ⁇ -carboxyaryl-substituted diphenylurea derivatives
  • Patent Document 4 quinoline derivatives and / or quinazoline derivatives
  • Patent Documents 5 7, and 13
  • nitrogen-containing aromatic ring derivatives for example, Patents
  • Patent Document 8 pyrazole-substituted indole derivatives
  • Patent Document 9 pyrrolopyridine and / or pyrrolopyrimidine derivatives
  • imidazopyridazine derivatives see, for example, Patent Document 10
  • imidazopyridine, Triazolopyridine, benzothiazole And / or thiazolopyridine derivatives is known (Patent Document 11 reference) and the like.
  • Patent Document 12 describes imidazopyridazine derivatives as antidiabetic agents.
  • Kinase inhibitors with excellent affinity for kinases, excellent drug efficacy, pharmacokinetics, solubility, interaction with other drugs, safety and stability can be expected to have excellent therapeutic effects. .
  • none of them has been found to be excellent in affinity for kinases and sufficiently satisfactory in terms of drug efficacy, pharmacokinetics, solubility, interaction with other pharmaceuticals, safety and stability. Therefore, development of a compound having excellent kinase inhibitory activity and sufficiently satisfactory as a pharmaceutical is eagerly desired. Accordingly, an object of the present invention is to provide a compound having excellent kinase inhibitory activity, low toxicity and sufficiently satisfactory as a pharmaceutical product.
  • X represents N or CR 1 (R 1 represents a hydrogen atom, a halogen atom or C 1-6 alkyl); Y represents N or CR 2 (R 2 represents a hydrogen atom, a halogen atom or C 1-6 alkyl); R 3 represents a hydrogen atom, a halogen atom or C 1-6 alkyl; R 4 represents a hydrogen atom, a halogen atom or C 1-6 alkyl; R 5 represents a hydrogen atom; R 60 is (1) a C 6-10 arylamino optionally having C 1-6 alkyl, optionally substituted by 1 to 3 halogen atoms, (2) C 7-12 aralkyl-carbonylamino, (3) C 7-12 aralkyloxy, (4) (a) (i ) C 1-6 alkoxy, and (ii) C 1-6 alkyl - which may have a substituent group selected from a carbonyl C 1-6 alkyl, (b) C 6-10 aryl, (c
  • R 5 and R 60 may together form a fused heterocycle;
  • Z represents O or S.
  • the following 4 compounds are excluded.
  • X represents N or CR 1 (R 1 represents a hydrogen atom, a halogen atom or C 1-6 alkyl); Y represents N or CR 2 (R 2 represents a hydrogen atom, a halogen atom or C 1-6 alkyl); R 3 represents a hydrogen atom, a halogen atom or C 1-6 alkyl; R 4 represents a hydrogen atom, a halogen atom or C 1-6 alkyl; R 5 represents a hydrogen atom; R 6 is (1) C 6-10 arylamino optionally having C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms, (2) C 7-12 aralkyl-carbonylamino, (3) C 7-12 aralkyloxy, (4) (a) (i ) C 1-6 alkoxy, and (ii) C 1-6 alkyl - which may have a substituent group selected from a carbonyl C 1-6 alkyl, (b) C 6-10 aryl, (c) o
  • R 5 and R 6 may be taken together to form a fused heterocycle;
  • Z represents O or S.
  • the following 4 compounds are excluded: (1) N- [4-( ⁇ 2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl ⁇ oxy) phenyl] -5-methyl-1-phenyl-1H-pyrazole -3-carboxamide; (2) N- [4-( ⁇ 2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl ⁇ oxy) phenyl] -3-methyl-1-phenyl-1H-pyrazole -5-carboxamide; (3) N- [4-( ⁇ 2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl ⁇ oxy) phenyl] -1,3-dimethyl
  • X is N or CR 1 ′ (R 1 ′ represents a hydrogen atom, a fluorine atom, a chlorine atom or methyl);
  • Y is N or CR 2 ′ (R 2 ′ represents a hydrogen atom, a fluorine atom, a chlorine atom or methyl);
  • R 3 is a hydrogen atom or a halogen atom;
  • R 4 is a hydrogen atom or a halogen atom;
  • R 5 is a hydrogen atom;
  • R 6 is (1) C 6-10 arylamino optionally having C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms, (2) C 7-12 aralkyloxy, (3) (a) C 1-6 alkyl, (b) a C 6-10 aryl optionally having 1
  • the compounds of the present invention have a strong inhibitory effect on kinases such as vascular endothelial growth factor receptor, hepatocyte growth factor receptor, platelet-derived growth factor receptor and the like, and also have a strong anti-angiogenic effect, and thus are clinically useful for cancer Prophylactic / therapeutic agents, cancer growth inhibitors, and cancer invasion / metastasis inhibitors can be provided. Furthermore, the compound of the present invention can provide a clinically useful prophylactic / therapeutic agent in applications other than cancer such as rheumatoid arthritis and diabetic retinopathy. It is also excellent in terms of interaction with pharmaceuticals, safety, and stability.
  • halogen atom represents a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • C 1-6 alkyl means, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neopentyl, hexyl, isohexyl. Indicates.
  • C 6-10 arylamino refers to, for example, phenylamino and naphthylamino.
  • C 7-12 aralkyl-carbonylamino refers to, for example, benzylcarbonylamino, phenethylcarbonylamino, naphthylmethylcarbonylamino.
  • C 7-12 aralkyloxy refers to, for example, benzyloxy, phenethyloxy, naphthylmethyloxy.
  • C 1-6 alkoxy means, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy.
  • C 1-6 alkyl-carbonyl means, for example, acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl, hexyl. Indicates carbonyl.
  • C 6-10 aryl means, for example, phenyl or naphthyl.
  • the “nitrogen-containing 5-membered ring group” contains 1 to 4 nitrogen atoms in addition to carbon atoms as ring-constituting atoms, and further oxygen and sulfur atoms (the sulfur atoms are oxidized).
  • a non-aromatic nitrogen-containing 5-membered cyclic group eg, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl
  • a 5-membered aromatic group which may contain 1 or 2 heteroatoms selected from A nitrogen-containing heterocyclic group (eg, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl);
  • the “5-membered aromatic heterocyclic group” means a hetero atom selected from an oxygen atom, a sulfur atom (the sulfur atom may be oxidized) and a nitrogen atom in addition to a carbon atom as a ring constituent atom.
  • a 5-membered aromatic heterocyclic group containing 1 to 4 atoms eg, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl
  • the “nitrogen-containing 6-membered ring group” contains 1 to 4 nitrogen atoms in addition to carbon atoms as ring-constituting atoms, and further oxygen atoms and sulfur atoms (the sulfur atoms are oxidized).
  • a non-aromatic nitrogen-containing 6-membered cyclic group eg, dihydropyridyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl
  • an aromatic nitrogen-containing 6-membered group which may contain 1 or 2 heteroatoms selected from A cyclic group (eg, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl) is shown.
  • the “oxidized nitrogen-containing 6-membered cyclic group” represented by “optionally oxidized nitrogen-containing 6-membered cyclic group” is a group in which the nitrogen-containing 6-membered cyclic group is oxidized ( Example pyridyl oxide).
  • C 6-10 aryl-carbamoyl-C 1-6 alkyl means, for example, phenylcarbamoylmethyl, 1-methyl-1- (phenylcarbamoyl) ethyl.
  • C 7-12 aralkyl refers to, for example, benzyl, phenethyl, and naphthylmethyl.
  • C 6-10 aryl-carbonyl means, for example, benzoyl or naphthylcarbonyl.
  • C 6-10 aryl-carbonylamino refers to, for example, benzoylamino.
  • C 3-6 cycloalkyl means, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • C 1-6 alkylthio refers to methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio.
  • C 1-6 alkoxy-carbonyl means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl Represents hexyloxycarbonyl.
  • the “aromatic heterocyclic group” means a hetero atom selected from an oxygen atom, a sulfur atom (the sulfur atom may be oxidized) and a nitrogen atom in addition to a carbon atom as a ring constituent atom.
  • 5 to 7-membered monocyclic aromatic heterocyclic group containing 1 to 4 eg, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl
  • a group formed by condensation of rings corresponding to a 5- to 7-membered monocyclic aromatic heterocyclic group, or a ring corresponding to a 5- to 7-membered monocyclic aromatic heterocyclic group and a benzene ring are condensed.
  • quinolyl quinolyl
  • the “6-membered heterocycle” formed by R 7 and R 8 together with —NR 7 R 8 is a ring corresponding to the nitrogen-containing 6-membered ring group (eg, piperidine, morpholine). , Thiomorpholine).
  • the “fused heterocycle” formed by R 5 and R 60 or R 5 and R 6 together refers to the ring corresponding to the nitrogen-containing 6-membered ring group and the aromatic heterocyclic group.
  • X represents N or CR 1 (R 1 represents a hydrogen atom, a halogen atom or C 1-6 alkyl).
  • R 1 is preferably a hydrogen atom, a fluorine atom, a chlorine atom or methyl.
  • X is preferably N or CR 1 ′ (R 1 ′ represents a hydrogen atom, a fluorine atom, a chlorine atom or methyl).
  • Y represents N or CR 2 (R 2 represents a hydrogen atom, a halogen atom or C 1-6 alkyl).
  • R 2 is preferably a hydrogen atom, a fluorine atom, a chlorine atom or methyl.
  • Y is preferably N or CR 2 ′ (R 2 ′ represents a hydrogen atom, a fluorine atom, a chlorine atom or methyl).
  • R 3 represents a hydrogen atom, a halogen atom or C 1-6 alkyl.
  • R 3 is preferably a hydrogen atom or a halogen atom (particularly a fluorine atom).
  • R 4 represents a hydrogen atom, a halogen atom or C 1-6 alkyl.
  • R 4 is preferably a hydrogen atom or a halogen atom (particularly a fluorine atom).
  • R 5 represents a hydrogen atom.
  • R 60 is (1) a C 6-10 arylamino optionally having C 1-6 alkyl, optionally substituted by 1 to 3 halogen atoms, (2) C 7-12 aralkyl-carbonylamino, (3) C 7-12 aralkyloxy, (4) (a) (i ) C 1-6 alkoxy, and (ii) C 1-6 alkyl - which may have a substituent group selected from a carbonyl C 1-6 alkyl, (b) C 6-10 aryl, (c) oxo, (d) hydroxy, and (e) a nitrogen-containing 5-membered cyclic group optionally having 1 to 4 substituents selected from C 1-6 alkoxy, (5) (a) C 1-6 alkyl, (b) a C 6-10 aryl optionally having 1 to 3 halogen atoms or C 1-6 alkyl, (c) oxo, (d) 1 to 3 C 1-6 alkyl optionally having 5 membered aromatic heterocyclic group, and (
  • R 6 is (1) C 6-10 arylamino optionally having C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms, (2) C 7-12 aralkyl-carbonylamino, (3) C 7-12 aralkyloxy, (4) (a) (i ) C 1-6 alkoxy, and (ii) C 1-6 alkyl - which may have a substituent group selected from a carbonyl C 1-6 alkyl, (b) C 6-10 aryl, (c) oxo, (d) hydroxy, and (e) a nitrogen-containing 5-membered cyclic group optionally having 1 to 3 substituents selected from C 1-6 alkoxy, (5) (a) C 1-6 alkyl, (b) C 6-10 aryl optionally having 1 to 3 halogen atoms or C 1-6 alkyl, (c) oxo, (d) a 5-membered aromatic heterocyclic group optionally having 1 to 3 C 1-6 alkyls, and (e)
  • R 6 (1) C 6-10 arylamino (eg, optionally having C 1-6 alkyl (eg, methyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine)) Phenylamino), (2) C 7-12 aralkyl-carbonylamino (eg, benzylcarbonylamino), (3) C 7-12 aralkyloxy (eg, benzyloxy), (4) (a) (i) C 1-6 alkoxy (eg, methoxy), and (ii) C 1-6 alkyl-carbonyl (eg, acetyl) C 1-6 alkyl (eg, methyl, ethyl), which may have a substituent selected from (b) C 6-10 aryl (eg, phenyl), (c) oxo, (d) hydroxy, and (e) C 1-6 alkoxy (eg, methoxy)
  • a nitrogen-containing 5-membered cyclic group for example,
  • R 6 is (1) phenylamino optionally having trifluoromethyl, (2) benzylcarbonylamino, (3) benzyloxy, (4) (a) C 1-6 alkyl (eg, methyl, ethyl) optionally having a substituent selected from methoxy and acetyl, (b) phenyl, (c) oxo, (d) hydroxy, and (e) a nitrogen-containing 5-membered ring group (eg, pyrazolyl, pyrrolidinyl, dihydropyrazolyl) optionally having 1 to 3 substituents selected from methoxy, (5) (a) methyl or ethyl, (b) phenyl optionally having 1 to 3 fluorine atoms or methyl, (c) oxo, (d) a 5-membered aromatic heterocyclic group (eg, thiazolyl) optionally having 1 to 3 methyl groups, and (e) 1 to
  • a nitrogen-containing 6-membered cyclic group (eg, dihydropyridyl) which may be oxidized, (4) C 6-10 aryl-carbamoyl-C 1-6 alkyl (eg, phenylcarbamoylmethyl, 1-methyl-1- (phenylcarbamoyl) methyl, 1-methyl-1- (phenylcarbamoyl) ethyl), (5) benzyl or (6) Benzoyl, carboxyl or formula —CONR 7 ′ R 8 ′ (Wherein R 7 ′ is (a) C 1-6 alkyl optionally having furyl (eg, methyl, ethyl, propyl, isopropyl, tert-butyl), (b) C 3-6 cycloalkyl (eg, cyclopropyl, cyclopentyl, cyclohexyl) optionally having C 1-6 alkyl (eg, methyl, tert-butyl
  • Z represents O or S.
  • compound (I) include the following: [Compound A]
  • X is N or CR 1 ′ (R 1 ′ represents a hydrogen atom, a fluorine atom, a chlorine atom or methyl);
  • Y is N or CR 2 ′ (R 2 ′ represents a hydrogen atom, a fluorine atom, a chlorine atom or methyl);
  • R 3 is a hydrogen atom or a halogen atom (eg, fluorine atom);
  • R 4 is a hydrogen atom or a halogen atom (eg, fluorine atom);
  • R 5 is a hydrogen atom;
  • R 6 is (1) phenylamino optionally having trifluoromethyl, (2) benzylcarbonylamino, (3) benzyloxy, (4) (a) C 1-6 alkyl (eg, methyl, ethyl) optionally having a substituent selected from methoxy and acetyl, (b) phenyl, (c
  • X is N or CR 1 ′ (R 1 ′ represents a hydrogen atom, a fluorine atom, a chlorine atom or methyl); Y is N or CR 2 ′ (R 2 ′ represents a hydrogen atom, a fluorine atom, a chlorine atom or methyl); R 3 is a hydrogen atom or a fluorine atom; R 4 is a hydrogen atom or a fluorine atom; R 5 is a hydrogen atom; R 6 is (1) phenylamino optionally having trifluoromethyl, (2) benzyloxy, (3) (a) methyl, (b) phenyl optionally having 1 to 3 fluorine atoms or methyl, (c) oxo, (d) optionally having 1 to 3 methyl groups, a 5-membered aromatic heterocyclic group (eg, thiazolyl), and (e) having 1 to 3 substituents selected from epoxy.
  • R 3 is a hydrogen atom or a fluorine atom
  • a nitrogen-containing 6-membered cyclic group (eg, dihydropyridyl) which may be oxidized, (4) C 6-10 aryl-carbamoyl-C 1-6 alkyl (eg, phenylcarbamoylmethyl, 1-methyl-1- (phenylcarbamoyl) methyl, 1-methyl-1- (phenylcarbamoyl) ethyl), (5) benzyl or (6) (a) benzoyl, (b) Carboxyl, or (c) Formula —CONR 7 ′ R 8 ′ (Wherein R 7 ′ is (a) C 1-6 alkyl optionally having furyl (eg, methyl, ethyl, propyl, isopropyl, tert-butyl), (b) C 3-6 cycloalkyl (eg, cyclopropyl, cyclopentyl, cyclohexyl) optionally having C 1-6 alkyl (eg,
  • X is N or CR 1 ′ (R 1 ′ represents a hydrogen atom, a fluorine atom, a chlorine atom or methyl); Y is N or CR 2 ′ (R 2 ′ represents a hydrogen atom, a fluorine atom, a chlorine atom or methyl); R 3 is a hydrogen atom or a fluorine atom; R 4 is a hydrogen atom or a fluorine atom; R 5 is a hydrogen atom; R 6 is (1) phenylamino optionally having trifluoromethyl, (2) benzyloxy, (3) (a) methyl or ethyl, (b) phenyl optionally having 1 to 3 fluorine atoms or methyl, (c) oxo, (d) a 5-membered aromatic heterocyclic group (eg, thiazolyl) optionally having 1 to 3 methyl groups, and (e) 1 to 3 substituents selected from epoxy Well, a nitrogen-containing
  • examples of such a salt include a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a basic or acidic amino acid, and the like.
  • examples include salts.
  • the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
  • Preferable examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzyl.
  • Examples include salts with ethylenediamine and the like.
  • Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • salt with organic acid examples include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene Examples thereof include salts with sulfonic acid, p-toluenesulfonic acid and the like.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Is mentioned. Of these, pharmaceutically acceptable salts are preferred.
  • inorganic salts such as alkali metal salts (eg, sodium salts, potassium salts, etc.), alkaline earth metal salts (eg, calcium salts, magnesium salts, etc.), ammonium salts
  • a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid
  • organic acids such as acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
  • Compound (I) can be obtained, for example, by a method represented by the following reaction formula or a method analogous thereto.
  • the compound in a formula also includes the case where the salt is formed, as such a salt, the thing similar to the salt in the compound (I) illustrated above etc. is used, for example.
  • the compound obtained in each step can be used in the next reaction as a reaction solution or as a crude product, but can be isolated from the reaction mixture according to a conventional method, such as recrystallization, distillation, chromatography, etc. It can be easily purified by separation means.
  • a schematic diagram of the reaction formula is shown below, and each symbol of the compound in the schematic diagram has the same meaning as described above.
  • Halogen atom refers to fluorine, chlorine, bromine and iodine.
  • the “optionally substituted alkylsulfonyl” is substituted with a substituent selected from a halogen atom, an optionally halogenated C 1-6 alkyl (eg, methyl, ethyl, trifluoromethyl) and nitro.
  • C 1-6 alkylsulfonyl eg, methylsulfonyl, ethylsulfonyl, etc. which may be optionally represented.
  • the “optionally substituted alkylsulfonyloxy” is substituted with a substituent selected from a halogen atom, an optionally halogenated C 1-6 alkyl (eg, methyl, ethyl, trifluoromethyl) and nitro.
  • C 1-6 alkylsulfonyloxy eg, methylsulfonyloxy, ethylsulfonyloxy and the like
  • the “optionally substituted arylsulfonyloxy” is substituted with a substituent selected from a halogen atom, an optionally halogenated C 1-6 alkyl (eg, methyl, ethyl, trifluoromethyl) and nitro.
  • C 6-14 arylsulfonyloxy (eg, phenylsulfonyloxy and the like) which may be optionally represented.
  • the “optionally substituted aryloxy” is substituted with a substituent selected from a halogen atom, an optionally halogenated C 1-6 alkyl (eg, methyl, ethyl, trifluoromethyl) and nitro.
  • C 6-14 aryloxy eg, phenyloxy etc.
  • the “optionally substituted alkoxy” is substituted with a substituent selected from a halogen atom, an optionally halogenated C 1-6 alkyl (eg, methyl, ethyl, trifluoromethyl) and nitro.
  • C 1-6 alkoxy eg, methoxy, ethoxy, etc.).
  • L 1 represents a leaving group
  • R 0 represents R 60 or R 6.
  • Other symbols are as defined above.
  • a halogen atom an optionally substituted alkylsulfonyl, an optionally substituted alkylsulfonyloxy, an optionally substituted arylsulfonyloxy and the like are used.
  • Step 1-1 Compound (I) can be produced by reacting compound (II) with compound (III) in the presence of a base.
  • Compound (III) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound (II).
  • As the base an inorganic base, an organic base, or the like is used.
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds.
  • alcohols such as methanol, ethanol, 2-propanol, 2-methyl-2-propanol, diethyl ether, tetrahydrofuran, 1,4-dioxane, 1
  • Ethers such as 2-dimethoxyethane
  • hydrocarbons such as benzene, toluene, cyclohexane and hexane
  • esters such as ethyl acetate and butyl acetate
  • ketones such as acetone and methyl ethyl ketone
  • N N-dimethylformamide
  • Amides such as N-dimethylacetamide and 1-methyl-2-pyrrolidone
  • halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane
  • reaction time varies depending on the reagent and solvent to be used, it is generally 1 min to 200 hr, preferably 10 min to 100 hr.
  • reaction temperature varies depending on the reagent and solvent to be used, it is generally ⁇ 100 to 250 ° C., preferably ⁇ 78 to 200 ° C.
  • the reaction may be carried out using a microwave reactor.
  • Step 2-1 Compound (V) can be produced by reacting compound (II) with compound (IV) in the presence of a base.
  • Compound (IV) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound (II).
  • the base those similar to the base exemplified in Reaction Scheme 1 can be used.
  • the base is used in an amount of 1 to 30 equivalents, preferably 1 to 10 equivalents, relative to compound (II).
  • Step 2-2 Compound (VII) can be produced by reducing the nitro group of compound (V). The reduction of nitro can be carried out according to a method known per se, for example, the method described in the 4th edition Experimental Chemistry Course, Vol. 20, 279-280 or the like, or a method analogous thereto.
  • Step 2-3 Compound (VII) can also be produced by reacting Compound (II) with Compound (VI) in the presence of a base.
  • Compound (VI) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound (II).
  • the base those similar to the base exemplified in Reaction Scheme 1 can be used.
  • the base is used in an amount of 1 to 30 equivalents, preferably 1 to 10 equivalents, relative to compound (II).
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • the solvent the same solvents as those exemplified in Reaction Scheme 1 can be used.
  • the reaction time is usually 1 minute to 200 hours, preferably 10 minutes to 100 hours.
  • Step 2-4 Compound (I-1) can be produced by reacting Compound (VII) with Compound (VIII) in the presence of a condensing agent.
  • Compound (VIII) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound (VII).
  • condensing agent examples include 1-ethyl-1- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1,3-dicyclohexylcarbodiimide, diethyl cyanophosphate, diphenylphosphoryl azide, 1,1′-carbonyldiimidazole, benzoate Triazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate, O— ( 7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate and the like can be used.
  • condensation accelerator for example, 1-hydroxybenzotriazole, N-hydroxysuccinimide, etc.
  • condensation accelerators are used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound (VII).
  • the reaction may proceed more smoothly by adding a base.
  • the base those similar to the base exemplified in Reaction Scheme 1 can be used.
  • the base is used in an amount of 0.01 to 10 equivalents, preferably 0.03 to 5 equivalents, relative to compound (VII). This reaction is advantageously performed using a solvent inert to the reaction.
  • the same solvents as those exemplified in Reaction Scheme 1 can be used.
  • the reaction time is usually 1 minute to 200 hours, preferably 10 minutes to 100 hours.
  • the reaction temperature is generally ⁇ 100 to 250 ° C., preferably ⁇ 78 to 200 ° C.
  • Compound (I-1) can also be produced by reacting compound (VII) with compound (IX).
  • Compound (IX) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound (VII).
  • the base may be used in an amount of 0.01 to 10 equivalents, preferably 0.03 to 5 equivalents, relative to compound (VII).
  • As the base those similar to the base exemplified in Reaction Scheme 1 can be used.
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • the solvent the same solvents as those exemplified in Reaction Scheme 1 can be used.
  • the reaction time is usually 1 minute to 200 hours, preferably 10 minutes to 100 hours.
  • the reaction temperature is generally ⁇ 100 to 250 ° C., preferably ⁇ 78 to 200 ° C.
  • R 6A is (a) C 1-6 alkyl optionally having a 5-membered aromatic heterocyclic group, and (b) C 3-6 optionally having C 1-6 alkyl.
  • Step 3-1 Compound (I-2) can be produced by reacting compound (VII) with a monohalide of compound (X) in an appropriate solvent (eg, N, N-dimethylacetamide, etc.). .
  • the monohalide of compound (X) can be produced by reacting compound (X) with thionyl chloride in the presence of a base (for example, triethylamine) in an appropriate solvent (for example, tetrahydrofuran).
  • Step 3-2 Compound (I-3) can be produced by condensing compound (I-2) and compound (XI) by the same method as in Step 2-4.
  • Step 4-1 Compound (I-4) can be produced by reacting compound (VII) with isocyanate derivative (XII).
  • the isocyanate derivative (XII) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound (VII).
  • 0.01 to 10 equivalents, preferably 0.01 to 3 equivalents of a base may be used.
  • the base those similar to the base exemplified in Reaction Scheme 1 can be used. This reaction is advantageously performed using a solvent inert to the reaction.
  • the solvent the same solvents as those exemplified in Reaction Scheme 1 can be used.
  • the reaction time is usually 1 minute to 200 hours, preferably 10 minutes to 100 hours.
  • the reaction temperature is generally ⁇ 100 to 250 ° C., preferably ⁇ 78 to 200 ° C.
  • Compound (I) can also be produced by the method shown in Reaction Scheme 5.
  • Compound (I-5) is encompassed in compound (I). (Reaction Formula 5)
  • Step 5-1 Compound (I-5) can be produced by reacting compound (VII) with acyl thiocyanate derivative (XIII).
  • the acyl thiocyanate derivative (XIII) is used in an amount of 0.1 to 10 equivalents, preferably 0.5 to 5 equivalents, relative to compound (VII).
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • the solvent the same solvents as those exemplified in Reaction Scheme 1 can be used.
  • the reaction time is usually 1 minute to 200 hours, preferably 10 minutes to 100 hours.
  • the reaction temperature is generally ⁇ 100 to 250 ° C., preferably ⁇ 78 to 200 ° C.
  • reaction formula 6 The compound (II) represented by the reaction formulas 1 and 2 can be produced by, for example, the method represented by the following reaction formula or a method analogous thereto. (Reaction Formula 6)
  • Step 6-1 Compound (XVI) can be produced by reacting compound (XIV) with acetylcarbamic acid derivative (XV).
  • the acetylcarbamic acid derivative (XV) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 5 equivalents, relative to compound (XIV).
  • the base may be used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 5 equivalents, relative to compound (XIV).
  • an inorganic base or an organic base is used as the base.
  • Step 6-2 Compound (XVII) can be produced by treating compound (XVI) with a base or acid.
  • the base include sodium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide and the like.
  • the base is used in an amount of 0.01 to 10 equivalents, preferably 0.03 to 5 equivalents, relative to compound (XVI).
  • the acid examples include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, trifluoroacetic acid and the like.
  • the acid is used in an amount of 0.1 to 20 equivalents, preferably 0.3 to 10 equivalents, relative to compound (XVI).
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • the solvent the same solvents as those exemplified in Reaction Scheme 1 can be used.
  • Step 6-3 Compound (II) can be produced by reacting compound (XVII) with compound (XVIII).
  • Compound (XVIII) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound (XVII).
  • the base may be used in an amount of 0.01 to 10 equivalents, preferably 0.03 to 5 equivalents, relative to compound (XVII).
  • the base those similar to the base exemplified in Reaction Scheme 1 can be used.
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • the solvent the same solvents as those exemplified in Reaction Scheme 1 can be used.
  • the reaction time is usually 1 minute to 200 hours, preferably 10 minutes to 100 hours.
  • the reaction temperature is generally ⁇ 100 to 250 ° C., preferably ⁇ 78 to 200 ° C.
  • Step 7-1 Compound (XXI) can be produced by reacting compound (XIX) with compound (XX).
  • Compound (XX) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound (XIX).
  • the base may be used in an amount of 0.01 to 10 equivalents relative to compound (XIX).
  • the base those similar to the base exemplified in Reaction Scheme 1 can be used. This reaction is advantageously performed using a solvent inert to the reaction.
  • Step 7-2 Compound (II) can be produced by reacting compound (XXI) with compound (XIV).
  • Compound (XXI) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 5 equivalents, relative to compound (XIV).
  • the base may be used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 5 equivalents, relative to compound (XIV).
  • an inorganic base or an organic base is used as the base.
  • Undec-7-ene pyridine, 4- (dimethylamino) pyridine, N, N-dimethylaniline and the like. This reaction is advantageously performed using a solvent inert to the reaction.
  • the solvent the same solvents as those exemplified in Reaction Scheme 1 can be used.
  • the reaction time is usually 1 minute to 200 hours, preferably 10 minutes to 100 hours.
  • the reaction temperature is generally ⁇ 100 to 250 ° C., preferably ⁇ 78 to 200 ° C.
  • Compound (II) can also be produced by sequentially performing Step 7-1 and Step 7-2 without isolating and purifying Compound (XXI).
  • Step 8-1 Compound (V) can be produced by reacting compound (XXII) with compound (XXIII) in the presence of a base.
  • Compound (XXIII) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound (XXII).
  • As the base those similar to the base exemplified in Reaction Scheme 1 can be used.
  • the base is used in the amount of 1 to 30 equivalents, preferably 1 to 10 equivalents, relative to compound (XXII).
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • the solvent the same solvents as those exemplified in Reaction Scheme 1 can be used.
  • the reaction time is usually 1 minute to 200 hours, preferably 10 minutes to 100 hours.
  • the reaction temperature is generally ⁇ 100 to 250 ° C., preferably ⁇ 78 to 200 ° C.
  • Reaction Scheme 8 Compound (XXII) represented by Reaction Scheme 8 can be produced, for example, by the method represented by the following Reaction Formula or a method analogous thereto. (Reaction Formula 9)
  • Step 9-1 Compound (XXIV) can be produced by reacting compound (XVII) with sodium methoxide in an appropriate solvent (eg, methanol).
  • Step 9-2 Compound (XXV) can be produced by reacting compound (XXIV) with compound (XVIII) by the same method as in Step 6-3.
  • Step 9-3 Compound (XXII) can be produced by reacting compound (XXV) with sodium ethanethiolate in a suitable solvent (eg, N, N-dimethylformamide and the like).
  • a suitable solvent eg, N, N-dimethylformamide and the like.
  • Step 10-1 Compound (I-6) can be produced by reacting compound (VII) with compound (XXVI) in the same manner as in Step 2-4.
  • Step 10-2 Compound (I-7) can be produced by reacting compound (I-6) with triethyl orthoformate and acetic acid in a suitable solvent (eg, ethanol, tetrahydrofuran, etc.).
  • a suitable solvent eg, ethanol, tetrahydrofuran, etc.
  • a compound within the scope of the present invention can also be produced by applying means known per se to compound (I) to further introduce substituents or convert functional groups.
  • substituent conversion known general methods are used. For example, conversion to carboxy by hydrolysis of ester, conversion to carbamoyl by amidation of carboxy, conversion to hydroxymethyl by reduction of carboxy, reduction of carbonyl or alkyl To alcohol by rehydration, reductive amination of carbonyl, oximation of carbonyl, acylation / urealation / sulfonylation / alkylation of amino, substitution / amination of active halogen with amine, amination by reduction of nitro , Hydroxy alkylation, hydroxy substitution / amination.
  • a protective group is introduced into the reactive substituent in advance by a publicly known means as necessary.
  • the protecting group can be removed by means known per se to produce a compound within the scope of the present invention.
  • the raw material compound or intermediate has an amino group, carboxyl group or hydroxyl group as a substituent, these groups may be protected with a protecting group generally used in peptide chemistry or the like.
  • the target compound can be obtained by removing the protecting group as necessary after the reaction.
  • Examples of the protecting group for amino group include formyl group, C 1-6 alkyl-carbonyl group, C 1-6 alkoxy-carbonyl group, benzoyl group, C 7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), C 7-14 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), trityl group, phthaloyl group, N, N-dimethylaminomethylene group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, Dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl groups (eg, 1-allyl) and the like.
  • C 7-10 aralkyl-carbonyl group eg, benzylcarbonyl
  • These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C 1-6 alkoxy group and a nitro group.
  • the protecting group for the carboxyl group include a C 1-6 alkyl group, a C 7-11 aralkyl group (eg, benzyl), a phenyl group, a trityl group, a substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl groups (eg, 1-allyl) and the like.
  • hydroxyl protecting group examples include C 1-6 alkyl group, phenyl group, trityl group, C 7-10 aralkyl group (eg, benzyl), formyl group, C 1-6 alkyl-carbonyl group, benzoyl group, C 7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert- Butyldiethylsilyl), C 2-6 alkenyl groups (eg, 1-allyl) and the like.
  • C 1-6 alkyl group eg, phenyl group, trityl group, C 7-10 aralkyl group (eg, benzyl), formyl group, C 1-6 alkyl
  • These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group or a nitro group.
  • substituents selected from a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group or a nitro group.
  • Examples of the method for removing the protecting group include methods known per se, such as the method described in “Protective Groups in Organic Synthesis”, edited by John Wiley and Sons (1980).
  • the method used or the reduction method is used.
  • Compound (I) can be isolated and purified by known means such as phase transfer, concentration, solvent extraction, fractionation, liquid conversion, crystallization, recrystallization, chromatography and the like.
  • compound (I) When compound (I) is obtained as a free compound, it can be converted to the target salt by a method known per se or a method analogous thereto, and conversely when it is obtained as a salt, it is known per se. It can be converted into a free form or other desired salt by the method or a method analogous thereto.
  • Compound (I) may be used as a prodrug.
  • a prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc.
  • a compound in which the amino of the compound (I) is acylated, alkylated or phosphorylated for example, the amino of the compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, ( 5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.); compounds ( Compounds wherein the hydroxyl of I) is acylated, alkylated, phosphorylated, borated (eg, hydroxyl of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, Dimethylaminomethylcarbonylated compounds, etc.
  • prodrug of compound (I) changes to compound (I) under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Drugs”, Volume 7, Molecular Design, pages 163 to 198. There may be.
  • any one of the isomers and a mixture are included in the compound (I).
  • the optical isomer resolved from the racemate is also encompassed in compound (I).
  • Each of these isomers can be obtained as a single product by a known synthesis method or separation method (concentration, solvent extraction, column chromatography, recrystallization, etc.).
  • Compound (I) may be a crystal, and it is included in compound (I) regardless of whether the crystal form is a single crystal form or a crystal form mixture. Crystals can be produced by crystallization by applying a crystallization method known per se. Compound (I) may be a co-crystal. Compound (I) may be a solvate (eg, hydrate etc.) or non-solvate (eg non-hydrate etc.), both of which are encompassed in compound (I). The Compounds labeled with isotopes (eg, 2 H, 3 H, 14 C, 35 S, 125 I, etc.) are also encompassed in compound (I). Further, compound (I) may be a deuterium converter.
  • Compound (I) or a prodrug thereof (may be abbreviated as “the compound of the present invention” in the present specification) has, for example, an activity of inhibiting its phosphorylation against the phosphorylation action of a kinase.
  • the kinase includes not only a substance having a phosphorylation action as a whole, but also a substance having a phosphorylation action on its part, and the phosphorylation action of a kinase is a phosphorylation action on self and It includes both effects of phosphorylation on other substances.
  • vascular endothelial growth factor receptor examples include vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), Raf, c-Met and the like.
  • VEGFR vascular endothelial growth factor receptor
  • VGFR1 vascular endothelial growth factor receptor 1
  • VGFR2 vascular endothelial growth factor receptor 2
  • VGFR3 vascular endothelial growth factor receptor 3
  • vascular endothelial growth factor receptor 2 is preferable.
  • Examples of the platelet-derived growth factor receptor include platelet-derived growth factor receptor ⁇ (PDGFR ⁇ ), platelet-derived growth factor receptor ⁇ (PDGFR ⁇ ), and the like.
  • Examples of Raf include A-Raf, B-Raf, C-Raf and the like.
  • the kinase is preferably vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor (PDGFR), Raf, or c-Met.
  • kinases include TIE2, fibroblast growth factor receptor (FGFR), stem cell factor receptor (c-Kit), Aurora, CDK, MEK, Akt, ERK, MAPK, Src, epidermal growth factor receptor ( EGFR), epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor 4 (HER4), Abl, Fgr, Fms, Flt3, Ron, Ret, Eph and the like.
  • FGFR fibroblast growth factor receptor
  • c-Kit stem cell factor receptor
  • Aurora CDK
  • MEK Akt
  • ERK MAPK
  • Src epidermal growth factor receptor
  • EGFR epidermal growth factor receptor 2
  • HER4 epidermal growth factor receptor 4
  • Abl Fgr, Fms, Flt3, Ron, Ret, Eph and the like.
  • the vascular endothelial growth factor receptor 2 (VEGFR2) inhibitory activity of the compound of the present invention is in accordance with Test Example 1
  • the vascular endothelial cell growth inhibitory activity is in accordance with Test Example 2
  • hepatocyte growth factor receptor vascular endothelial growth factor receptor 2 (C-Met) inhibitory activity
  • C-Met C-Met inhibitory activity
  • human gastric cancer cell MKN45 growth inhibitory activity according to Test Example 4 can be measured according to Test Example 5.
  • the compound of the present invention exhibits a strong inhibitory activity especially against the vascular endothelial growth factor receptor (VEGFR), among which the selectivity for the vascular endothelial growth factor receptor 2 (VEGFR2, KDR, Flk-1) is high, It also shows strong kinase inhibitory activity against VEGFR1, PDGFR, and Raf.
  • the compound of the present invention exhibits a strong inhibitory action on hepatocyte growth factor receptor (c-Met).
  • the compound of the present invention has a medicinal effect, pharmacokinetics (absorbability, distribution, metabolism, excretion, etc.), solubility (water solubility, etc.), interaction with other pharmaceuticals, safety (acute toxicity, chronic toxicity, Genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity, etc.) and stability (chemical stability, stability to enzymes, etc.) are also excellent and useful as pharmaceuticals.
  • the compound of the present invention is a kinase inhibitor, preferably a vascular endothelial growth factor receptor, for mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human etc.). It is useful as a (VEGFR) inhibitor, a platelet derived growth factor receptor (PDGFR) inhibitor, a Raf inhibitor, more preferably a vascular endothelial growth factor receptor 2 (VEGFR2, KDR, Flk-1) inhibitor.
  • the compounds of the present invention are useful as angiogenesis inhibitors and vascular endothelial cell growth inhibitors.
  • the compounds of the present invention can be affected by vascular endothelial growth factors such as cancer (eg, colon cancer (eg, familial colon cancer, hereditary nonpolyposis colon cancer, gastrointestinal stromal tumor, etc.) , Lung cancer (eg, non-small cell lung cancer, small cell lung cancer, malignant mesothelioma, etc.), mesothelioma, pancreatic cancer (eg, pancreatic duct cancer, etc.), gastric cancer (eg, papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous epithelium) Cancer), breast cancer (eg, invasive ductal carcinoma, non-invasive ductal carcinoma, inflammatory breast cancer, etc.), ovarian cancer (eg, epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, ovary Low-grade tumors), prostate cancer (eg, hormone-dependent prostate cancer, hormone-independent prostate
  • the compounds of the present invention are effective against patients with lung cancer, colon cancer, ovarian cancer, prostate cancer, and kidney cancer. Further, the compound of the present invention exhibits a cancer invasion / metastasis suppression action based on a strong c-Met inhibitory action.
  • the compound of the present invention can be administered orally or parenterally as it is or in combination with a pharmacologically acceptable carrier.
  • dosage forms for oral administration of the compound of the present invention include tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules (including soft capsules and microcapsules), and syrups.
  • dosage forms for parenteral administration include injections, infusions, drops, suppositories, and the like.
  • an appropriate base eg, butyric acid polymer, glycolic acid polymer, butyric acid-glycolic acid copolymer, a mixture of butyric acid polymer and glycolic acid polymer, polyglycerol fatty acid ester, etc. It is also effective to make a combined sustained-release preparation.
  • the compound of the present invention when the compound of the present invention is produced into tablets, it can be produced by containing excipients, binders, disintegrants, lubricants, etc., and when produced into pills and granules. , Excipients, binders, disintegrants and the like.
  • excipients, binders, disintegrants and the like when producing powders and capsules, excipients, etc., when producing syrups, sweeteners, etc., when producing emulsions or suspensions, suspending agents, surfactants It can be produced by containing an emulsifier and the like.
  • excipients include lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium bicarbonate, calcium phosphate, calcium sulfate and the like.
  • binder examples include 5 to 10% by weight starch paste solution, 10 to 20% by weight gum arabic solution or gelatin solution, 1 to 5% by weight tragacanth solution, carboxymethyl cellulose solution, sodium alginate solution, glycerin and the like.
  • disintegrant include starch and calcium carbonate.
  • the lubricant include magnesium stearate, stearic acid, calcium stearate, purified talc and the like.
  • sweeteners include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, simple syrup and the like.
  • surfactant include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, polyoxyl 40 stearate and the like.
  • suspending agent include gum arabic, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose, bentonite and the like.
  • emulsifiers include gum arabic, tragacanth, gelatin, polysorbate 80 and the like.
  • intravenous injections In addition to intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, intravenous infusions and the like are included as injections, and iontophoretic transdermal agents and the like are included as sustained-release preparations.
  • Such an injection is prepared by a method known per se, that is, by dissolving, suspending or emulsifying the compound of the present invention in a sterile aqueous or oily liquid.
  • Aqueous solutions for injection include isotonic solutions (eg, D-sorbitol, D-mannitol, sodium chloride, etc.) containing physiological saline, glucose and other adjuvants, and suitable solubilizing agents such as You may use together with alcohol (for example, ethanol), polyalcohol (for example, propylene glycol, polyethylene glycol), a nonionic surfactant (for example, polysorbate 80, HCO-50), etc.
  • the oily liquid include sesame oil and soybean oil.
  • benzyl benzoate As a solubilizing agent, benzyl benzoate, benzyl alcohol and the like may be used in combination. Buffers (eg, phosphate buffer, sodium acetate buffer), soothing agents (eg, benzalkonium chloride, procaine hydrochloride, etc.), stabilizers (eg, human serum albumin, polyethylene glycol, etc.), preservatives (For example, benzyl alcohol, phenol, etc.) may be blended.
  • the prepared injection solution is usually filled in an ampoule.
  • the content of the compound of the present invention in the preparation of the present invention varies depending on the form of the preparation, but is generally about 0.01 to 100% by weight, preferably about 2 to 85% by weight, based on the whole preparation, Preferably, it is about 5 to 70% by weight.
  • the content of the additive in the preparation of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.9% by weight, preferably about 10 to 90% by weight, based on the whole preparation.
  • the compound of the present invention can be safely used with stable, low toxicity.
  • the daily dose varies depending on the patient's condition and body weight, the type of compound, the route of administration, etc.
  • the daily dose for an adult (body weight of about 60 kg) Is about 1 to 1000 mg, preferably about 3 to 300 mg, more preferably about 10 to 200 mg as an active ingredient (compound of the present invention), and these can be administered once or divided into 2 to 3 times. .
  • the compound of the present invention When the compound of the present invention is administered parenterally, it is usually administered in the form of a liquid (for example, an injection).
  • a liquid for example, an injection.
  • the single dose varies depending on the administration subject, target organ, symptom, administration method and the like, but is usually about 0.01 to about 100 mg per kg body weight, preferably about 0.01 in the form of injection. It is convenient to administer from about 50 mg, more preferably from about 0.01 to about 20 mg by intravenous injection.
  • the compound of the present invention can be used in combination with other drugs.
  • the compounds of the present invention can be used in combination with drugs such as hormone therapeutic agents, chemotherapeutic agents, immunotherapeutic agents or drugs that inhibit the action of cell growth factors and their receptors.
  • drugs such as hormone therapeutic agents, chemotherapeutic agents, immunotherapeutic agents or drugs that inhibit the action of cell growth factors and their receptors.
  • a drug that can be used in combination with the compound of the present invention is abbreviated as a concomitant drug.
  • ⁇ hormone therapeutic agent '' examples include phosfestol, diethylstilbestrol, chlorotrianicene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, gestrinone, mepartricin, Raloxifene, olmeroxifene, levormeroxifene, antiestrogens (eg, tamoxifen citrate, toremifene citrate, etc.), pill formulations, mepithiostan, testrolactone, aminoglutethimide, LH-RH agonists (eg, goserelin acetate, Buserelin, leuprorelin, etc.), droloxifene, epithiostanol, ethinyl estradiol sulfonate, aromatase inhibitor (eg, fadrozo
  • chemotherapeutic agent for example, alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents and the like are used.
  • alkylating agent examples include nitrogen mustard, nitrogen mustard hydrochloride-N-oxide, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carbocon, improsulfan tosylate, busulfan, nimustine hydrochloride, mitoblonitol, Faran, dacarbazine, ranimustine, estramustine phosphate sodium, triethylenemelamine, carmustine, lomustine, streptozocin, piprobroman, etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambermuthine, dibrospine hydrochloride, fotemustine hydrochloride Predonimustine, pumitepa, ribomustine, temozolomide, treosulphane, trophosphamide Zinostatin Lamar, ado
  • antimetabolite examples include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, pemetrexed, enositabine, cytarabine, cytarabine okphosphatate, ancitabine hydrochloride, 5-FU drugs (eg, fluorouracil, tegafur, UFT, doxyfluridine, carmofur, galocitabine, emiteful, capecitabine, etc.), aminopterin, nerzarabine, leucovorin calcium, tabloid, butosine, folinate calcium, levofolinate calcium, cladribine, emitefur, fludarabine, gemcitabine pendant, hydroxycarbamide pendant , Idoxyuridine, mitoguazone, thiazofurin, ambamustine, bendamustine and those DDS formulation or the like is used.
  • 5-FU drugs eg, fluorouracil, tegafur, UFT,
  • anticancer antibiotic examples include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride , Neocartinostatin, misramycin, sarcomycin, carcinophylline, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride and their DDS preparations.
  • plant-derived anticancer agent for example, etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, vinorelbine and their DDS preparations are used.
  • Examples of the “immunotherapy agent (BRM)” include picibanil, krestin, schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, corynebacteria Umparbum, levamisole, polysaccharide K, procodazole, anti-CTLA4 antibody and the like are used.
  • the “cell growth factor” in the “drug that inhibits the action of the cell growth factor and its receptor” may be any substance that promotes cell growth, and usually has a molecular weight of 20,000 or less.
  • Examples of peptides include factors that exert an action at a low concentration by binding to a receptor.
  • EGF epidermal growth factor
  • IGF insulin, IGF (insulin-like growth factor) -1, IGF-2, etc.
  • FGF fibroblast growth factor
  • Other cell growth factors eg, CSF (erythropoietin), EPO (erythropoietin), IL-2 (interleukin-2) , NGF (near growth factor), PDGF (platelet-derived growth factor), TGF ⁇ (transforming growth factor ⁇ ), HGF (hepatocyte growth factor, thor factor).
  • the “cell growth factor receptor” may be any receptor capable of binding to the above-mentioned cell growth factor. Specifically, EGF receptor, heregulin receptor (HER3, etc.) Insulin receptor, IGF receptor-1, IGF receptor-2, FGF receptor-1 or FGF receptor-2, VEGF receptor, angiopoietin receptor (Tie2, etc.), PDGF receptor and the like are used.
  • “Agents that inhibit the action of cell growth factors and their receptors” include EGF inhibitors, TGF ⁇ inhibitors, heregulin inhibitors, insulin inhibitors, IGF inhibitors, FGF inhibitors, KGF inhibitors, CSF inhibitors, EPO inhibitor, IL-2 inhibitor, NGF inhibitor, PDGF inhibitor, TGF ⁇ inhibitor, HGF inhibitor, VEGF inhibitor, angiopoietin inhibitor, EGF receptor inhibitor, HER2 inhibitor, HER4 inhibitor, insulin receptor Body, IGF-1 receptor inhibitor, IGF-2 receptor inhibitor, FGF receptor-1 inhibitor, FGF receptor-2 inhibitor, FGF receptor-3 inhibitor, FGF receptor-4 inhibitor , VEGF receptor inhibitor, Tie-2 inhibitor, PDGF receptor inhibitor, Abl inhibitor, Raf inhibitor, FLT3 inhibitor, c-Kit inhibitor, Src Inhibitor, PKC inhibitor, Trk inhibitor, Ret inhibitor, mTOR inhibitor, Aurora inhibitor, PLK inhibitor, MEK (MEK1 / 2) inhibitor, c-Met inhibitor, CDK inhibitor, Akt inhibitor, An ER
  • anti-VEGF antibody Bevacizumab etc.
  • anti-HER2 antibody Trastuzumab, Pertuzumab etc.
  • anti-EGFR antibody Cetuximab, Panitumab, Matusumumab, Nimotozumab etc.
  • anti-VEGFR antibody Ehtitinb
  • anti-HGFb antibody EHtibb
  • Gefitinib Gefitinib
  • Sorafenib Sunitinib
  • Dasatinib Lapatinib, Vatalanib
  • the compound of the present invention By combining the compound of the present invention and a concomitant drug, (1) The dose can be reduced compared to when the compound of the present invention or the concomitant drug is administered alone. (2) Depending on the patient's symptoms (mild, severe, etc.), a drug to be used in combination with the compound of the present invention can be selected. (3) The treatment period can be set longer. (4) The therapeutic effect can be sustained. (5) By using the compound of the present invention in combination with a concomitant drug, excellent effects such as a synergistic effect can be obtained.
  • the concomitant drug of the present invention the administration time of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be administered simultaneously to the administration subject, with a time difference. May also be administered.
  • the dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
  • Examples of the dosage form when the compound of the present invention is used in combination with the concomitant drug include, for example, (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the concomitant drug, and (2) Simultaneous administration of the two preparations obtained by separately formulating the compound and the concomitant drug by the same route of administration, (3) Two preparations obtained by separately formulating the compound of the present invention and the concomitant drug Administration at the same administration route with a time difference, (4) simultaneous administration of two different preparations obtained by separately formulating the compound of the present invention and a concomitant drug by different administration routes, (5) Administration of two types of preparations obtained by separately formulating the compound and the concomitant drug at different time intervals in different administration routes (for example, administration in the order of the compound of the present invention ⁇ the concomitant drug, or in the reverse order) Administration).
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the mixing ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like.
  • the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention.
  • the concomitant drug of the present invention has low toxicity.
  • the compound of the present invention or (and) the above concomitant drug is mixed with a pharmacologically acceptable carrier according to a method known per se, for example, a pharmaceutical composition such as a tablet.
  • a pharmaceutical composition such as a tablet.
  • a pharmaceutical composition such as a tablet.
  • powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release preparations, etc., orally or parenterally (eg, Topical, rectal, intravenous administration, etc.) can be safely administered.
  • the injection can be administered intravenously, intramuscularly, subcutaneously, or into an organ, or directly to the lesion.
  • the pharmacologically acceptable carrier that may be used for the production of the concomitant drug of the present invention is the same as the pharmacologically acceptable carrier that may be used for the production of the pharmaceutical of the present invention described above. Is given. Further, if necessary, an appropriate amount of additives such as preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like that may be used in the production of the medicament of the present invention described above may be appropriately used. it can.
  • the compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
  • the content of the compound of the present invention in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, based on the whole preparation. More preferably, it is about 0.5 to 20% by weight.
  • the content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 90% by weight, preferably about 0.1 to 50% by weight, more preferably based on the whole preparation. About 0.5 to 20% by weight.
  • the content of the additive in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation. Further, when the compound of the present invention and the concomitant drug are formulated separately, the same content may be used.
  • the compound of the present invention or the concomitant drug includes a dispersant (eg, Tween 80 (manufactured by Atlas Powder, USA), HCO 60 (manufactured by Nikko Chemicals), polyethylene glycol, carboxymethylcellulose, sodium alginate, hydroxypropylmethylcellulose.
  • a dispersant eg, Tween 80 (manufactured by Atlas Powder, USA), HCO 60 (manufactured by Nikko Chemicals), polyethylene glycol, carboxymethylcellulose, sodium alginate, hydroxypropylmethylcellulose.
  • solubilizers eg, glycerin, ethanol, etc.
  • buffers eg, Phosphoric acid and alkali metal salts thereof, citric acid and alkali metal salts thereof, isotonic agents (eg, sodium chloride, potassium chloride, mannitol, sorbitol, glucose, etc.), pH regulators (eg, hydrochloric acid, sodium hydroxide) Etc.), preservatives (eg, ethyl paraoxybenzoate, benzoic acid, Ruparaben, propylparaben, benzyl alcohol, etc.), solubilizers (eg, concentrated glycerin, meglumine, etc.), solubilizers (eg, propylene glycol, sucrose, etc.), soothing agents (eg
  • an excipient eg, lactose, sucrose, starch, etc.
  • a disintegrant eg, starch, calcium carbonate, etc.
  • a binder eg, Starch, gum arabic, carboxymethyl cellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose, etc.
  • lubricant eg, talc, magnesium stearate, polyethylene glycol 6000, etc.
  • an oral preparation can be obtained by coating by a method known per se.
  • Examples of the coating agent used for coating include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (manufactured by Rohm, Germany, methacrylic acid / acrylic acid copolymer) and pigments (eg, Bengala, titanium dioxide, etc.) are used.
  • the preparation for oral administration may be either an immediate release preparation or a sustained release preparation.
  • the compound of the present invention or the concomitant drug is mixed with an oily base, an aqueous base or an aqueous gel base to give an oily or aqueous solid, semisolid or liquid suppository.
  • oily base include glycerides of higher fatty acids (eg, cacao butter, witepsols (manufactured by Dynamite Nobel, Germany)), glycerides of medium chain fatty acids [eg, miglyols (manufactured by Dynamite Nobel, Germany)] Etc.], or vegetable oils (eg, sesame oil, soybean oil, cottonseed oil, etc.).
  • the aqueous base include polyethylene glycols and propylene glycol.
  • the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers, acrylic acid polymers, and the like.
  • sustained-release preparation examples include sustained-release microcapsules.
  • the sustained-release microcapsule is produced according to a method known per se, for example, the method shown in the following [2].
  • the compound of the present invention is preferably molded into a preparation for oral administration such as a solid preparation (eg, powder, granule, tablet, capsule) or into a preparation for rectal administration such as a suppository. Particularly preferred are preparations for oral administration.
  • a preparation for oral administration such as a solid preparation (eg, powder, granule, tablet, capsule) or into a preparation for rectal administration such as a suppository.
  • preparations for oral administration are particularly preferred.
  • the concomitant drug can be in the above-mentioned dosage form depending on the type of drug.
  • injection and preparation thereof An injection prepared by dissolving the compound of the present invention or the concomitant drug in water is preferable.
  • the injection may contain benzoate and / or salicylate.
  • the injection is obtained by dissolving both the compound of the present invention or the concomitant drug and, optionally, a benzoate and / or salicylate in water.
  • benzoic acid and salicylic acid salts include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts, meglumine salts, and salts with other organic bases such as trometamol. It is done.
  • the concentration of the compound of the present invention or the concomitant drug in the injection is 0.5 to 50 w / v%, preferably about 3 to 20 w / v%.
  • the concentration of benzoate or / and salicylate is about 0.5 to 50 w / v%, preferably about 3 to 20 w / v%.
  • the present injection includes additives generally used in injections, such as stabilizers (eg, ascorbic acid, sodium pyrosulfite), surfactants (eg, polysorbate 80, macrogol, etc.), acceptable Solvent (eg, glycerin, ethanol, etc.), buffer (eg, phosphoric acid and its alkali metal salts, citric acid and its alkali metal salts, etc.), isotonic agents (eg, sodium chloride, potassium chloride, etc.), dispersing agents (Eg, hydroxypropylmethylcellulose, dextrin), pH adjuster (eg, hydrochloric acid, sodium hydroxide, etc.), preservative (eg, ethyl paraoxybenzoate, benzoic acid, etc.), solubilizer (eg, concentrated glycerin, meglumine, etc.) , Solubilizers (eg, propylene glycol, sucrose, etc.), soothing agents (eg, glucose, benzyl alcohol, etc.),
  • the injection may be adjusted to pH 2 to 12, preferably pH 2.5 to 8.0 by adding a pH adjusting agent.
  • An injection is obtained by dissolving both the compound of the present invention or the concomitant drug and optionally a benzoate and / or salicylate, and if necessary, the above additives in water. These dissolutions may be performed in any order, and can be appropriately performed in the same manner as in the conventional method for producing an injection.
  • the aqueous solution for injection is preferably heated, and can be provided as an injection by performing, for example, filtration sterilization, high-pressure heat sterilization, or the like, as in a normal injection.
  • the aqueous solution for injection is preferably sterilized by high-pressure heat at a temperature of 100 to 121 ° C. for 5 to 30 minutes. Furthermore, it is good also as a formulation which provided the antibacterial property of the solution so that it could be used as a multi-dose administration formulation.
  • Sustained-release preparation or immediate-release preparation and preparation thereof Sustained-release preparation comprising a core containing the compound of the present invention or a concomitant drug optionally coated with a coating agent such as a water-insoluble substance or a swellable polymer Is preferred.
  • a coating agent such as a water-insoluble substance or a swellable polymer
  • a once-daily administration type sustained-release preparation for oral administration is preferred.
  • water-insoluble substances used in the coating agent include cellulose ethers such as ethyl cellulose and butyl cellulose, cellulose esters such as cellulose acetate and cellulose propionate, polyvinyl esters such as polyvinyl acetate and polyvinyl butyrate, and acrylic acid.
  • cellulose ethers such as ethyl cellulose and butyl cellulose
  • cellulose esters such as cellulose acetate and cellulose propionate
  • polyvinyl esters such as polyvinyl acetate and polyvinyl butyrate
  • acrylic acid acrylic acid
  • swellable polymer a polymer having an acidic dissociation group and exhibiting pH-dependent swelling is preferable. Swelling is small in an acidic region such as the stomach, and swelling is large in a neutral region such as the small intestine and large intestine.
  • a polymer having an acidic dissociation group is preferred.
  • the polymer having an acidic dissociable group and exhibiting pH-dependent swelling include, for example, Carbomer 934P, 940, 941, 974P, 980, 1342, polycarbophil, calcium polycarbophil, and the like. (Calcium polycarbophil) (all of which are manufactured by BF Goodrich), Hibiswako 103, 104, 105, 304 (all of which are manufactured by Wako Pure Chemical Industries, Ltd.), etc.
  • the film agent used in the sustained release preparation may further contain a hydrophilic substance.
  • the hydrophilic substance include polysaccharides that may have a sulfate group such as pullulan, dextrin, and alkali metal alginate, hydroxyalkyl or carboxyalkyl such as hydroxypropylcellulose, hydroxypropylmethylcellulose, and carboxymethylcellulose sodium.
  • examples thereof include polysaccharides, methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, and polyethylene glycol.
  • the content of the water-insoluble substance in the coating agent of the sustained-release preparation is about 30 to about 90% (w / w), preferably about 35 to about 80% (w / w), more preferably about 40 to about 75. % (W / w) and the swellable polymer content is from about 3 to about 30% (w / w), preferably from about 3 to about 15% (w / w).
  • the coating agent may further contain a hydrophilic substance, in which case the content of the hydrophilic substance in the coating agent is about 50% (w / w) or less, preferably about 5 to about 40% (w / w). More preferably, it is about 5 to about 35% (w / w).
  • the above% (w / w) represents the weight% with respect to the coating agent composition obtained by removing the solvent (eg, water, lower alcohol such as methanol, ethanol, etc.) from the coating agent solution.
  • the sustained-release preparation is prepared by preparing a core containing a drug as exemplified below, and then coating the obtained core with a film agent solution in which a water-insoluble substance or a swellable polymer is dissolved by heating or dissolved or dispersed in a solvent. Manufactured by coating.
  • nucleus containing a drug coated with a film agent is not particularly limited, but is preferably formed into a granular shape such as a granule or a fine granule.
  • the average particle size is preferably about 150 to about 2,000 ⁇ m, more preferably about 500 to about 1,400 ⁇ m.
  • the preparation of the nucleus can be carried out by a usual production method. For example, suitable excipients, binders, disintegrants, lubricants, anti-aggregation agents, lubricants, stabilizers, etc.
  • the drug content of the nucleus is about 0.5 to about 95% (w / w), preferably about 5.0 to about 80% (w / w), more preferably about 30 to about 70% (w / w) It is.
  • excipients contained in the core include saccharides such as sucrose, lactose, mannitol, glucose, starch, crystalline cellulose, calcium phosphate, corn starch and the like. Of these, crystalline cellulose and corn starch are preferable.
  • binder for example, polyvinyl alcohol, hydroxypropyl cellulose, polyethylene glycol, polyvinyl pyrrolidone, pluronic F68, gum arabic, gelatin, starch and the like are used.
  • disintegrant for example, carboxymethylcellulose calcium (ECG505), croscarmellose sodium (Ac-Di-Sol), cross-linked polyvinyl pyrrolidone (crospovidone), low substituted hydroxypropylcellulose (L-HPC) and the like are used. . Of these, hydroxypropylcellulose, polyvinylpyrrolidone, and low-substituted hydroxypropylcellulose are preferable.
  • talc magnesium stearate and an inorganic salt thereof, and polyethylene glycol or the like as a lubricant
  • polyethylene glycol or the like polyethylene glycol or the like
  • acids such as tartaric acid, citric acid, succinic acid, fumaric acid and maleic acid are used.
  • the core is a drug while spraying a binder dissolved in an appropriate solvent such as water, lower alcohol (eg, methanol, ethanol, etc.) on an inert carrier particle that becomes the center of the core.
  • an appropriate solvent such as water, lower alcohol (eg, methanol, ethanol, etc.)
  • it can also be prepared by a rolling granulation method, a pan coating method, a fluidized bed coating method or a melt granulation method in which a mixture of this and an excipient, a lubricant or the like is added little by little.
  • the inert carrier particles for example, those made of sucrose, lactose, starch, crystalline cellulose, waxes can be used, and those having an average particle size of about 100 ⁇ m to about 1,500 ⁇ m are preferable.
  • the surface of the nucleus may be coated with a protective agent.
  • the protective agent for example, the hydrophilic substance, the water-insoluble substance, or the like is used.
  • the protective agent is preferably a polysaccharide having polyethylene glycol or hydroxyalkyl or carboxyalkyl, more preferably hydroxypropylmethylcellulose or hydroxypropylcellulose.
  • the protective agent may contain an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, maleic acid or a lubricant such as talc as a stabilizer.
  • the coating amount is about 1 to about 15% (w / w), preferably about 1 to about 10% (w / w), more preferably about 2 to about 8% of the core ( w / w).
  • the protective agent can be coated by a normal coating method, and specifically, the protective agent can be coated by spraying the nucleus by, for example, a fluidized bed coating method or a pan coating method.
  • the core obtained in the above I is coated with a coating agent solution in which the water-insoluble substance, the pH-dependent swelling polymer, and the hydrophilic substance are dissolved by heating or dissolved or dispersed in a solvent.
  • a sustained-release preparation is produced.
  • the coating method using the core coating solution include a spray coating method.
  • the composition ratio of the water-insoluble substance, the swellable polymer, or the hydrophilic substance in the coating agent solution is appropriately selected so that the content of each component in the film is the above content.
  • the coating amount of the coating agent is about 1 to about 90% (w / w), preferably about 5 to about 50% (w / w) with respect to the core (excluding the coating amount of the protective agent), more preferably About 5 to about 35% (w / w).
  • water or an organic solvent can be used alone or a mixture of the two can be used.
  • the mixing ratio of water and organic solvent (water / organic solvent: weight ratio) in the case of using the mixed liquid can be varied in the range of 1 to 100%, preferably 1 to about 30%.
  • the organic solvent is not particularly limited as long as it dissolves water-insoluble substances.
  • lower alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and n-butyl alcohol, lower alkanones such as acetone, acetonitrile, chloroform , Methylene chloride and the like are used. Of these, lower alcohols are preferred, and ethyl alcohol and isopropyl alcohol are particularly preferred.
  • Water and a mixed solution of water and an organic solvent are preferably used as a solvent for the film agent.
  • an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, maleic acid, etc. may be added to the coating agent solution to stabilize the coating agent solution.
  • the operation in the case of coating by spray coating can be carried out by a normal coating method, specifically, by coating the core with a film agent solution, for example, by a fluidized bed coating method, pan coating method or the like. can do. If necessary, plasticize glycerin fatty acid ester, hydrogenated castor oil, triethyl citrate, cetyl alcohol, stearyl alcohol, etc., using talc, titanium oxide, magnesium stearate, calcium stearate, light anhydrous silicic acid as a lubricant. You may add as an agent. After coating with a coating agent, an antistatic agent such as talc may be mixed as necessary.
  • the immediate-release preparation may be liquid (solution, suspension, emulsion, etc.) or solid (particles, pills, tablets, etc.).
  • a parenterally administered agent such as an orally administered agent and an injectable agent is used, and an orally administered agent is preferable.
  • the immediate-release preparation usually contains a carrier, an additive or an excipient (hereinafter sometimes abbreviated as an excipient) commonly used in the pharmaceutical field in addition to the drug as the active ingredient.
  • the excipient used is not particularly limited as long as it is an excipient commonly used as a pharmaceutical excipient.
  • excipients for oral solid preparations include lactose, starch, corn starch, crystalline cellulose (Asahi Kasei Co., Ltd., Avicel PH101, etc.), powdered sugar, granulated sugar, mannitol, light anhydrous silicic acid, magnesium carbonate, carbonate Calcium, L-cysteine and the like can be mentioned, preferably corn starch and mannitol.
  • excipients can be used alone or in combination of two or more.
  • the content of the excipient is, for example, about 4.5 to about 99.4 w / w%, preferably about 20 to about 98.5 w / w%, more preferably about 30, relative to the total amount of the immediate-release preparation. Or about 97 w / w%.
  • the content of the drug in the immediate release preparation can be appropriately selected from the range of about 0.5 to about 95 w / w%, preferably about 1 to about 60 w / w%, based on the total amount of the immediate release preparation.
  • the immediate-release preparation When the immediate-release preparation is an oral solid preparation, it usually contains a disintegrant in addition to the above components.
  • disintegrants include carboxymethylcellulose calcium (manufactured by Gotoku Pharmaceutical Co., ECG-505), croscarmellose sodium (for example, Asahi Kasei Co., Ltd., Akizol), crospovidone (for example, BASF Corp., Kollidon CL ), Low-substituted hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd.), carboxymethyl starch (manufactured by Matsutani Chemical Co., Ltd.), sodium carboxymethyl starch (manufactured by Kimura Sangyo Co., Ltd., Protab), partially pregelatinized starch (Asahi Kasei ( Co., Ltd., PCS), etc.
  • disintegrants are used, for example, those that disintegrate granules by contacting with water, absorbing water, swelling, or creating channels between the active ingredient constituting the core and excipients. Can be used. These disintegrants can be used alone or in combination of two or more. The amount of the disintegrant is appropriately selected depending on the type and amount of the drug to be used, the design of the releasable preparation, and the like. For example, about 0.05 to about 30 w / w%, Preferably, it is about 0.5 to about 15 w / w%.
  • an additive commonly used in the solid preparation may be further included as desired.
  • additives include binders (for example, sucrose, gelatin, gum arabic powder, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, pullulan, dextrin, etc.), lubricants ( For example, polyethylene glycol, magnesium stearate, talc, light anhydrous silicic acid (for example, Aerosil (manufactured by Nippon Aerosil)), surfactant (for example, anionic surfactant such as sodium alkyl sulfate, polyoxyethylene fatty acid ester and poly Non-ionic surfactants such as oxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, etc.), colorants (eg tar dyes, caramel, bengara, titanium oxide, riboflavins),
  • binder hydroxypropylcellulose, polyethylene glycol, polyvinylpyrrolidone and the like are preferably used.
  • the immediate-release preparation can be prepared by mixing the above-mentioned components, further kneading and molding if necessary, based on a normal preparation manufacturing technique.
  • the above mixing is performed by a generally used method, for example, mixing, kneading and the like.
  • a vertical granulator when the immediate-release preparation is formed into particles, a vertical granulator, a universal kneader (manufactured by Hata Iron Works), by a method similar to the preparation method of the core of the sustained-release preparation, It can be prepared by mixing using a fluidized bed granulator FD-5S (manufactured by POWREC) or the like and then granulating by a wet extrusion granulation method, a fluidized bed granulation method or the like.
  • FD-5S manufactured by POWREC
  • the immediate-release preparation and the sustained-release preparation thus obtained are administered as they are or as appropriate, together with preparation excipients, etc., separately according to a conventional method, and then simultaneously or in combination with an arbitrary administration interval.
  • both of them may be formulated into a single oral preparation (eg, granules, fine granules, tablets, capsules, etc.) as they are or as appropriate together with formulation excipients.
  • Both preparations may be produced into granules or fine granules and filled in the same capsule or the like to prepare a preparation for oral administration.
  • Sublingual tablet, buccal or intraoral quick disintegrating agent and preparation thereof may be a solid preparation such as a tablet, or an oral mucosal patch (film) It may be.
  • a preparation containing the compound of the present invention or the concomitant drug and an excipient is preferable. Further, it may contain auxiliary agents such as a lubricant, an isotonic agent, a hydrophilic carrier, a water-dispersible polymer, and a stabilizer.
  • ⁇ -cyclodextrin or ⁇ -cyclodextrin derivatives may be contained in order to facilitate absorption and increase bioavailability.
  • Examples of the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, and light anhydrous silicic acid.
  • Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like, and magnesium stearate and colloidal silica are particularly preferable.
  • Examples of the isotonic agent include sodium chloride, glucose, fructose, mannitol, sorbitol, lactose, saccharose, glycerin, urea and the like, and mannitol is particularly preferable.
  • hydrophilic carrier examples include swellable hydrophilic carriers such as crystalline cellulose, ethyl cellulose, cross-linkable polyvinyl pyrrolidone, light anhydrous silicic acid, silicic acid, dicalcium phosphate, calcium carbonate, and particularly crystalline cellulose (eg, microcrystalline cellulose, etc. ) Is preferred.
  • swellable hydrophilic carriers such as crystalline cellulose, ethyl cellulose, cross-linkable polyvinyl pyrrolidone, light anhydrous silicic acid, silicic acid, dicalcium phosphate, calcium carbonate, and particularly crystalline cellulose (eg, microcrystalline cellulose, etc. ) Is preferred.
  • water-dispersible polymers examples include gums (eg, tragacanth gum, acacia gum, guar gum), alginates (eg, sodium alginate), cellulose derivatives (eg, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose), Gelatin, water-soluble starch, polyacrylic acid (eg, carbomer), polymethacrylic acid, polyvinyl alcohol, polyethylene glycol, polyvinyl pyrrolidone, polycarbophil, ascorbic acid, palmitate, etc., hydroxypropyl methylcellulose, polyacrylic acid, Alginate, gelatin, carboxymethylcellulose, polyvinylpyrrolidone, polyethylene glycol and the like are preferable.
  • gums eg, tragacanth gum, acacia gum, guar gum
  • alginates eg, sodium alginate
  • cellulose derivatives eg, methylcellulose, carboxymethylcellulose, hydroxy
  • Hydroxypropyl methylcellulose is particularly preferable.
  • the stabilizer include cysteine, thiosorbitol, tartaric acid, citric acid, sodium carbonate, ascorbic acid, glycine, sodium sulfite and the like, and citric acid and ascorbic acid are particularly preferable.
  • a sublingual tablet, buccal or intraoral quick disintegrating agent can be produced by mixing the compound of the present invention or the concomitant drug and an excipient by a method known per se.
  • auxiliary agents such as the above-mentioned lubricants, tonicity agents, hydrophilic carriers, water-dispersible polymers, stabilizers, colorants, sweeteners, preservatives and the like may be mixed as desired.
  • a sublingual tablet, a buccal tablet or an intraoral quick disintegrating tablet is obtained by compression tableting.
  • it may be produced by humidifying and wetting with a solvent such as water or alcohol as necessary before and after the tableting molding process, and drying after molding.
  • Bioadhesive polymers eg, polycarbophil, carbopol, etc. are added to increase the adhesion of the film to the mucosal lining of the oral cavity and to contain glycols such as polyethylene glycol and propylene glycol to give the film moderate elasticity.
  • Casting is performed by pouring the solution onto a non-adhesive surface, spreading it to a uniform thickness (preferably about 10 to 1000 microns) with an application tool such as a doctor blade, and then drying the solution to form a film. Achieved.
  • the film thus formed may be dried at room temperature or under heating and cut to a desired surface area.
  • Preferred intraoral quick disintegrating agents include solid rapid diffusion administration comprising a network of a compound of the present invention or a concomitant drug and a water-soluble or water-diffusible carrier that is inactive with the compound of the present invention or the concomitant drug.
  • Agents. The network is obtained by sublimating a solvent from the solid composition composed of a solution of the compound of the present invention or the concomitant drug in a suitable solvent.
  • composition of the intraoral quick disintegrating agent preferably contains a matrix forming agent and a secondary component.
  • Examples of the matrix forming agent include gelatins, dextrins, and animal or vegetable proteins such as soybean, wheat and psyllium seed proteins; gums such as gum arabic, guar gum, agar and xanthan; Examples include sugars, alginic acids, carboxymethylcelluloses, carrageenans, dextrans, pectins, synthetic polymers such as polyvinylpyrrolidone, gelatin-gum arabic complex, and the like.
  • sugars such as mannitol, dextrose, lactose, galactose and trehalose; cyclic saccharides such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicate; glycine, L-alanine, L-aspartic acid, L- Examples include amino acids having 2 to 12 carbon atoms such as glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and L-phenylalanine.
  • One or more of the matrix forming agents can be introduced into a solution or suspension before solidification.
  • a matrix forming agent may be present in addition to the surfactant, or may be present with the surfactant excluded.
  • the matrix-forming agent can help maintain the diffusion state of the compound of the invention or the concomitant drug in the solution or suspension.
  • Suitable colorants include red, black and yellow iron oxides and FD & C dyes such as FD & C Blue 2 and FD & C Red 40 from Ellis & Everald.
  • Suitable flavors include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavor and combinations thereof.
  • Suitable pH adjusting agents include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and maleic acid.
  • Suitable sweeteners include aspartame, acesulfame K, thaumatin and the like.
  • Suitable taste masking agents include sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbate materials, and microencapsulated apomorphine.
  • the preparation usually contains about 0.1 to about 50% by weight, preferably about 0.1 to about 30% by weight of a compound of the present invention or a concomitant drug, and is about 1 to about 60 minutes, preferably about 1
  • a preparation capable of dissolving 90% or more of the compound of the present invention or the concomitant drug (in water) between about 2 minutes and about 15 minutes, more preferably between about 2 minutes and about 5 minutes (in the above sublingual tablets) , Buccals, etc.) and intraoral fast disintegrating agents that disintegrate within 1 to 60 seconds, preferably within 1 to 30 seconds, more preferably within 1 to 10 seconds after being placed in the oral cavity are preferred.
  • the content of the above-mentioned excipient in the whole preparation is about 10 to about 99% by weight, preferably about 30 to about 90% by weight.
  • the content of ⁇ -cyclodextrin or ⁇ -cyclodextrin derivative in the whole preparation is 0 to about 30% by weight.
  • the content of the lubricant in the whole preparation is about 0.01 to about 10% by weight, preferably about 1 to about 5% by weight.
  • the content of the tonicity agent in the whole preparation is about 0.1 to about 90% by weight, preferably about 10 to about 70% by weight.
  • the content of the hydrophilic carrier in the whole preparation is about 0.1 to about 50% by weight, preferably about 10 to about 30% by weight.
  • the content of the water-dispersible polymer in the whole preparation is about 0.1 to about 30% by weight, preferably about 10 to about 25% by weight.
  • the content of the stabilizer in the whole preparation is about 0.1 to about 10% by weight, preferably about 1 to about 5% by weight.
  • the above-mentioned preparation may further contain additives such as a coloring agent, a sweetening agent, and a preservative as necessary.
  • the dose of the concomitant drug of the present invention varies depending on the type, age, weight, symptom, dosage form, administration method, administration period, etc. of the compound of the present invention.
  • the compound of the present invention and the concomitant drug are each about 0.01 to about 1000 mg / kg body weight, preferably about 0.01 to about 100 mg / kg body weight, more preferably about 0.1 to about 100 mg / kg per day.
  • the dosage varies depending on various conditions. Therefore, a dosage smaller than the dosage may be sufficient, or the dosage may need to be administered beyond the range.
  • the amount of the concomitant drug can be set as long as side effects do not become a problem.
  • the daily dose as a concomitant drug varies depending on the degree of symptoms, age of the subject, sex, body weight, sensitivity difference, timing of administration, interval, nature of pharmaceutical preparation, formulation, type, type of active ingredient, etc. Although it is not limited, the amount of the drug is usually about 0.001 to 2000 mg, preferably about 0.01 to 500 mg, more preferably about 0.1 to 100 mg per kg body weight of the patient by oral administration. The dose is usually divided into 1 to 4 times a day.
  • the compound of the present invention and the concomitant drug may be administered at the same time, but after the concomitant drug is administered first, the compound of the present invention may be administered.
  • the compound of the present invention may be administered first, followed by administration of the concomitant drug.
  • the time difference varies depending on the active ingredient to be administered, dosage form, and administration method.
  • the concomitant drug when administered first, within 1 minute to 3 days after administering the concomitant drug, preferably A method of administering the compound of the present invention within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour is mentioned.
  • the concomitant drug is administered within 1 minute to 1 day after administration of the compound of the present invention, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour. A method is mentioned.
  • a concomitant drug molded into an orally administered preparation is orally administered, and about 0.005 of the compound of the present invention formed into an orally administered preparation after about 15 minutes.
  • the compound of the present invention or the concomitant drug of the present invention can be used in combination with non-drug therapy.
  • the compound of the present invention or the concomitant drug of the present invention includes, for example, (1) surgery, (2) pressor chemotherapy using angiotensin II, (3) gene therapy, (4) hyperthermia, (5 It can also be combined with non-drug therapies such as)) cryotherapy, (6) laser ablation, and (7) radiation therapy.
  • treatment with the compound of the present invention or the concomitant drug of the present invention and supportive therapy [(i) antibiotics for concurrent occurrence of various infectious diseases (for example, ⁇ -lactams such as pansporin, macrolides such as clarithromycin, etc. ), (Ii) high calorie infusion for improving nutritional disorders, amino acid preparations, administration of multivitamins, (iii) morphine for pain relief, (iv) nausea, vomiting, loss of appetite, diarrhea, leukocytes Reduction, thrombocytopenia, hemoglobin concentration reduction, hair loss, liver damage, kidney damage, DIC, administration of drugs to improve side effects such as fever, and (v) administration of drugs to suppress multidrug resistance of cancer, etc.] Can also be combined.
  • antibiotics for concurrent occurrence of various infectious diseases for example, ⁇ -lactams such as pansporin, macrolides such as clarithromycin, etc.
  • high calorie infusion for improving nutritional disorders, amino acid preparations, administration of multivitamins
  • the compound of the present invention or the combination of the present invention is administered orally (including sustained release), intravenous (including bolus, infusion, inclusion body), subcutaneous and intramuscular injection (including bolus, infusion, sustained release), transdermal, intratumoral and proximal administration.
  • the timing of administering the compound of the present invention or the concomitant drug of the present invention before surgery or the like can be administered once, for example, about 30 minutes to 24 hours before surgery or the like.
  • the administration can be divided into 1 to 3 cycles before about 3 to 6 months.
  • cancer tissue can be reduced, so that surgery and the like are facilitated.
  • the compound of the present invention or the concomitant drug of the present invention When the compound of the present invention or the concomitant drug of the present invention is administered after surgery or the like, it can be repeatedly administered, for example, in units of several weeks to 3 months, about 30 minutes to 24 hours after surgery. Thus, by administering the compound of the present invention or the concomitant drug of the present invention after surgery or the like, the effect of surgery or the like can be enhanced.
  • Ionization method Electron impact ionization method (Electron Spray Ionization: ESI positive and negative ion peaks are detected) The percentage value of the peak area detected at UV of the corresponding product peak at 220 nm was taken as the purity of the compound.
  • preparative HPLC was performed as follows. Preparative HPLC instrument: Gilson high-throughput purification system Column: YMC Combiprep Hydrosphere C18 S-5 5 ⁇ m, 12 nM.
  • a formulation additive eg, lactose, corn starch, magnesium stearate, microcrystalline cellulose
  • JP 14th revised Japanese Pharmacopoeia
  • a product conforming to the Pharmaceutical Additives Standard 2003 is used.
  • Oxalyl chloride (28 mL, 321 mmol) was added dropwise to a suspension of 2-chloroacetamide (25 g, 267 mmol) in 1,2-dichloroethane (125 mL) at 0 ° C. After refluxing for 3 hours, the mixture was cooled to 0 ° C., tert-butyl alcohol / 1,2-dichloroethane (75 mL, 1/1) was added, and the mixture was stirred for 20 minutes. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with 1,2-dichloroethane.
  • N- (6-methoxyimidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxamide (6650 mg, 29 mmol) in N, N-dimethylformamide (100 mL) was added to sodium ethanethiolate (6020 mg). , 58 mmol) and the mixture was stirred at 140 ° C. for 5 h. After evaporating the solvent under reduced pressure, ethyl acetate / tetrahydrofuran, saturated brine and 6N aqueous hydrochloric acid were added to the residue, and the aqueous layer was extracted 4 times with ethyl acetate / tetrahydrofuran.
  • N- (6-hydroxyimidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxamide (350 mg, 1.6 mmol), 2-bromo-5-nitropyridine (490 mg, 2.4 mmol), cesium carbonate ( A mixture of 1320 mg, 4.0 mmol) and dimethyl sulfoxide (4 mL) was stirred at 70 ° C. for 3 hours. Ethyl acetate / tetrahydrofuran and saturated aqueous sodium hydrogen carbonate solution were added to the mixture, and the aqueous layer was extracted 4 times with ethyl acetate / tetrahydrofuran.
  • N- (6-Chloroimidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxamide (4.16 g, 18 mmol), 6-aminopyridin-3-ol (2.7 g, 24 mmol), cesium carbonate ( 14.3 g, 44 mmol) and dimethyl sulfoxide (40 mL) were stirred at 100 ° C. for 15 hours.
  • Ethyl acetate / tetrahydrofuran and saturated aqueous sodium hydrogen carbonate solution were added to the mixture, and the aqueous layer was extracted 4 times with ethyl acetate / tetrahydrofuran.
  • 6-chloropyridazine-3-amine (100 mg, 0.772 mmol), N- (2-chloroacetyl) cyclopropanecarboxamide (212 mg, 1.31 mmol), disodium hydrogen phosphate (273 mg, 1.92 mmol), N, N-dimethylacetamide (1 mL) was charged, heated to 100 ° C. and stirred for 4 hours. After adding water (2 mL) at the same temperature, the mixture was cooled to room temperature and stirred for 1 hour. The crystals were collected by filtration, washed with water (1 mL), and dried under reduced pressure to give the title compound (88 mg, 0.372 mmol) as brown crystals.
  • 6-chloropyridazine-3-amine (100 mg, 0.772 mmol), N- (2-bromoacetyl) cyclopropanecarboxamide (270 mg, 1.34 mmol), disodium hydrogen phosphate (273 mg, 1.92 mmol), N, N-dimethylacetamide (1 mL) was charged, heated to 85 ° C. and stirred for 2 hours. After adding water (2 mL) at the same temperature, the mixture was cooled to room temperature and stirred for 0.5 hour. The crystals were collected by filtration, washed with water (1 mL), and dried under reduced pressure to give the title compound (169 mg, 0.714 mmol) as brown crystals.
  • Cyclopropanecarboxamide (790 g, 9.28 mol) was dissolved in N, N-dimethylacetamide (3.0 L). Under ice-cooling, bromoacetyl bromide (1400 g, 6.94 mol) and N, N-dimethylacetamide (0.6 L) were sequentially added, and the mixture was heated to 60 ° C. and stirred for 1 hour. After cooling with ice, tripotassium phosphate (1480 g, 6.97 mol), 6-chloropyridazine-3-amine (600 g, 4.63 mol), N, N-dimethylacetamide (1.2 L) were added in that order, and then 80 Heated to ° C. and stirred for 2 hours.
  • the extract was dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure.
  • the obtained residue was dissolved in tetrahydrofuran (1 mL) and methanol (0.3 mL), lithium hydroxide monohydrate (26.9 mg, 0.641 mmol) was added, and the mixture was stirred at room temperature for 4 hr.
  • the reaction mixture was concentrated, 1N hydrochloric acid (1 mL) and ethyl acetate were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine.
  • 6-Ethyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carbonitrile (395 mg, 1.76 mmol) was dissolved in concentrated sulfuric acid (0.4 mL) and water (0.4 mL) and dissolved at 120 ° C. The mixture was heated and stirred for 7 hours. 1N sodium hydroxide was added to the reaction solution to form a basic solution, and then washed with ethyl acetate. 1N Hydrochloric acid was added to the aqueous layer to make an acidic solution, and the mixture was extracted 3 times with ethyl acetate, and the organic layer was washed with saturated brine.
  • Trifluoromethanesulfonic anhydride is added to a solution of 6- (4-fluorophenyl) -5-methylpyridine-2-carbonitrile (16.76 g, 79 mmol) and sodium percarbonate (24.8 g, 158 mmmol) in acetonitrile (200 mL).
  • the product (66.8 g, 237 mmol) was added dropwise at 0 ° C., stirred at 0 ° C. for 1 hour, and further stirred at room temperature overnight.
  • Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate.
  • N- [6- (4-aminophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide 200 mg, 0.647 mmol
  • N, N-dimethylacetamide 4.0 mL
  • 1 -(Phenylcarbonyl) cyclopropanecarboxylic acid 185 mg, 0.970 mmol
  • O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (369 mg) , 0.970 mmol)
  • N, N-diisopropylethylamine 169 ⁇ L, 0.970 mmol
  • Example 21 N- (6- ⁇ 2-fluoro-4-[(phenylacetyl) amino] phenoxy ⁇ imidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxamide (Example 21-1) and N- [6 -(2-Fluoro-4- ⁇ [(phenylacetyl) carbamothioyl] amino ⁇ phenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (Example 21-2)
  • N- [6- (4-amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclo Propane carboxamide 200 mg, 0.611 mmol was added and stirred at room temperature for 15 hours.
  • the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, The solvent was distilled off under reduced pressure.
  • the obtained solid was dissolved in ethyl acetate, and the organic layer was washed with 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title compound (121 mg, 38% ) Was obtained as a white solid.
  • the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, The solvent was distilled off under reduced pressure.
  • the obtained white powder was dissolved in tetrahydrofuran and ethyl acetate, washed with 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure.
  • N- [6- (4-amino-3-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide 100 mg, 0.31 mmol
  • N, N-dimethylacetamide 0.5 mL
  • Ethyl acetate was added to the resulting reaction solution, and the mixture was extracted twice with 1N sodium hydroxide. The extract was acidified with 1N hydrochloric acid, and the precipitate was filtered to obtain a white powder.
  • N- [6- (4-amino-3-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide 100 mg, 0.306 mmol
  • N, N -A dimethylacetamide 0.5 mL
  • Ethyl acetate was added to the resulting reaction solution, and the mixture was extracted twice with 1N sodium hydroxide.
  • the extract was acidified with 1N hydrochloric acid, and extracted three times with ethyl acetate.
  • the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • Tetrahydrofuran, ethyl acetate and 1N sodium hydroxide (5 mL) were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, The solvent was distilled off under reduced pressure.
  • the obtained white powder was washed with ethyl acetate to give the title compound (175 mg, 73%) as a white powder.
  • the same operation as in Example 28 was carried out using diisopropylethylamine (201 ⁇ L, 1.4 mmol) and N, N-dimethylformamide (2.0 mL) to obtain the title compound (210 mg, 68%) as a white powder.
  • N- [6- (4-Amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (200 mg, 0.611 mmol), 1-methyl-2-oxo-1, 2-dihydropyridine-3-carboxylic acid (112 mg, 0.733 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (279 mg, 0.733 mmol), N, N-diisopropylethylamine (211 ⁇ L, 1.22 mmol), N, N-dimethylformamide (2.0 mL), and the same operation as in Example 28 was carried out to give the title compound (204 mg, 72% ) Was obtained as a white powder.
  • N- [6- (4-Amino-2-methylphenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (80 mg, 0.247 mmol), 2-oxo-1-phenyl-1, 2-dihydropyridine-3-carboxylic acid (69 mg, 0.321 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (122 mg, 0.320 mmol), N, N-diisopropylethylamine (85 ⁇ L, 0.494 mmol), N, N-dimethylformamide (1.0 mL), and the same operation as in Example 28 was carried out to give the title compound (90 mg, 70% ) Was obtained as a white powder.
  • N- [6- (4-Amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide 200 mg, 0.611 mmol
  • 1-[(phenylcarbonyl) amino] cyclo Propanecarboxylic acid 150 mg, 0.733 mmol
  • O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (279 mg, 0.733 mmol)
  • N , N-diisopropylethylamine (211 ⁇ L, 1.22 mmol) and N, N-dimethylformamide 2.0 mL
  • N- [6- (4-Amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (187 mg, 0.544 mmol), 2-oxo-1-phenylpiperidine-3 -Carboxylic acid (143 mg, 0.652 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (310 mg, 0.815 mmol), N , N-Diisopropylethylamine (187 ⁇ L, 1.09 mmol) and N, N-dimethylformamide (2 mL) were used in the same manner as in Example 28 to give the title compound (150 mg, 52%) as a white powder.
  • 6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (84 mg, 0.367 mmol), N- [6- (4-amino-2-fluorophenoxy) imidazo [1,2 -b] pyridazin-2-yl] cyclopropanecarboxamide (100 mg, 0.306 mmol) in N, N-dimethylformamide (1 mL) and N, N-diisopropylethylamine (105 ⁇ L, 0.612 mmol) and O- ( 7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (140 mg, 0.368 mmol) was added, and the mixture was stirred at room temperature for 6 hours.
  • 6-Phenylpyridine-2-carboxylic acid 1-oxide (79 mg, 0.367 mmol), N- [6- (4-amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclo
  • propanecarboxamide 100 mg, 0.306 mmol
  • N, N-dimethylformamide (1 mL)
  • N, N-diisopropylethylamine 105 ⁇ L, 0.612 mmol
  • O- (7-azabenzotriazol-1-yl) -1,1,3,3-Tetramethyluronium hexafluorophosphate 140 mg, 0.368 mmol
  • the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • the obtained pale yellow powder was washed with ethyl acetate and filtered to give the title compound (150 mg, 7%) as a pale yellow powder.
  • Examples 60 to 123 shown in Tables 1 to 8 were produced in the same manner as in Example 59.
  • N- [6- (4-Amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (100 mg, 0.306 mmol), 1- (2-methylphenyl) -2 -Oxo-1,2-dihydropyridine-3-carboxylic acid (84 mg, 0.367 mmol), N, N-dimethylformamide (1 mL), N, N-diisopropylethylamine (105 ⁇ L, 0.612 mmol), O- (7 -Azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (151 mg, 0.398 mmol) was used for the same operation as in Example 124, and the title compound (134 mg, 81%) was obtained as a white solid.
  • a medicament containing the compound of the present invention as an active ingredient can be produced, for example, according to the following formulation.
  • Tablet (1) Compound obtained in Example 1 40 mg (2) Lactose 58mg (3) Corn starch 18mg (4) Microcrystalline cellulose 3.5mg (5) Magnesium stearate 0.5mg 1 tablet 120mg After mixing 2/3 of (1), (2), (3), (4) and 1/2 of (5), granulate. The remaining (4) and (5) are added to the granules and pressed into tablets.
  • VEGFR2 Human Vascular Endothelial Growth Factor Receptor 2
  • VEGFR2 cDNA Library Human Humana
  • PCR was carried out using as a template.
  • the primer used for PCR is based on the VEGFR2 gene base sequence (Genbank Accession AF035121) information, and the flag tag is added to the base sequence encoding the VEGFR2 intracellular domain (2671-4374 in Genbank Access AF035121) at the N-terminus of the protein.
  • VEGFR2-U 5'-AATTAAGTCGACATGGACTACAAGGATGACGATGACAAGAAGCGGGCCAATGGAGGGGAACTGAAGACA-3 '(SEQ ID NO: 1)
  • VEGFR2-L 5'-AATTAAGCATGCTTAAACAGGAGGAGAGCTCAGTGTGGTCCC-3 '(SEQ ID NO: 2)
  • the base sequence of primer VEGFR2-U is shown in SEQ ID NO: 1 in the sequence listing
  • the base sequence of primer VEGFR2-L is shown in SEQ ID NO: 2 in the sequence listing.
  • the PCR reaction was performed using a KOD-plus kit (manufactured by TOYOBO).
  • the obtained PCR product was electrophoresed on an agarose gel (1%), and a DNA fragment amplified by PCR was recovered from the gel and then digested with restriction enzymes Sal I and Sph I.
  • the restriction enzyme-treated DNA was electrophoresed on an agarose gel (1%), and the resulting DNA fragment was recovered, ligated to the plasmid pFASTBAC1 (manufactured by Invitrogen) digested with restriction enzymes Sal I and Sph I, and the expression plasmid pFB- VEGFR2 was produced.
  • baculovirus virus stock BAC-VEGFR2 was prepared using a BAC-TO-BAC Baculovirus Expression System (manufactured by Invitrogen).
  • Vascular Endothelial Growth Factor Receptor 2 Intracellular Domain Protein SF-21 cells were treated with 10% fetal bovine serum (trace), 50 mg / L Gentamin (Invitrogen), 0.1% Pluronic F-68 ( Inoculated at 1 ⁇ 10 6 cells / mL in 1 L of Sf-900IISFM medium (Invitrogen) containing Invitrogen), and cultured with shaking at 27 ° C. and 100 rpm using a 2 L Erlenmeyer flask. After 24 hours of culture, 13.4 mL of recombinant baculovirus BAC-VEGFR2 was added, and further cultured for 3 days.
  • VEGFR2 Vascular Endothelial Growth Factor Receptor 2
  • the culture solution was centrifuged at 2,000 rpm for 5 minutes to obtain virus-infected cells.
  • the infected cells were washed with phosphate physiological buffer (Invitrogen), centrifuged under the same conditions, and the cells were stored at -80 ° C.
  • the cryopreserved cells were thawed in ice and suspended in 30 mL of buffer A (20% Glycerol, 50 mM Tris buffer (pH 7.4) containing 0.15 M NaCl) supplemented with Complete Protease Inhibitor (manufactured by Boehringer). Thereafter, crushing was performed three times using a Polytron homogenizer (manufactured by Kinematica) under the conditions of 20,000 rpm and 30 seconds.
  • the crushed liquid was clarified by centrifugation at 40,000 rpm for 30 minutes, and further filtered using a 0.45 ⁇ m filter.
  • the filtrate was passed through a column packed with 4 mL of Anti-FLAG M2 Affinity Gel (manufactured by Sigma) at a flow rate of about 0.5 mL / min.
  • the column was washed with buffer A and then eluted with buffer A containing 100 ⁇ g / mL FLAG peptide.
  • the eluate was concentrated with Vivaspin 20 (manufactured by Viva Science) having a molecular weight cut off of 30K.
  • the buffer solution was exchanged with a NAP TM 25 column (manufactured by Amersham Bioscience) in which the concentrated solution was equilibrated with buffer A. Fractions containing the VEGFR2 intracellular domain protein were collected, added with glycerol to a final concentration of 50%, and stored frozen at ⁇ 80 ° C.
  • Test Example 1 Measurement of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Kinase Inhibitory Activity Test compounds dissolved in dimethyl sulfoxide (DMSO) were mixed with a buffer solution (50 mM Tris-HCl (pH 7.5), 5 mM MgCl 2 , 5 mM MnCl 2 , Diluted with 2 mM dithiothreitol, 0.01% Tween-20).
  • DMSO dimethyl sulfoxide
  • the reaction solution was left for 16 hours at 25 ° C., were counted using a plate reader Fusion (Fusion TM) (Perkin Elmer).
  • the count of the solution reacted without adding the compound was taken as “control”
  • the count of the solution without adding the compound and ATP was taken as “blank”.
  • the inhibition rate at 1 ⁇ M of the compounds of Examples 6, 27, 35, 36, 47, 54, 55, 126 and 128 was 80% or more.
  • Test Example 2 Growth Inhibition Test of Vascular Endothelial Cells
  • Human umbilical vein-derived vascular endothelial cells (HUVEC, purchased from Kurabo Industries) were obtained at 37 ° C. in a 5% carbon dioxide incubator with 3% fetal calf serum and 2.5 ng / mL basic fiber.
  • the cells were cultured in a vascular endothelial cell medium (manufactured by Invitrogen) containing blast growth factor.
  • HUVEC suspended in the vascular endothelial cell medium containing 3% fetal bovine serum was seeded in a 96-well flat-bottom plate at 50 ⁇ L (3,000 cells).
  • vascular endothelial growth factor 120 ng / mL vascular endothelial growth factor (VEGF) were dissolved in vascular endothelial cell medium containing 3% fetal calf serum, and 50 ⁇ L of each well was added. After culturing for 5 days, 10 ⁇ L of Cell counting kit-8 reagent (manufactured by Dojin Chemical) was added to each well and reacted in a 37 ° C., 5% carbon dioxide incubator for 2-3 hours. Absorbance at 450 nm was measured with a microtiter plate reader to measure cell growth inhibitory activity.
  • VEGF vascular endothelial growth factor
  • Test Example 3 Measurement of Hepatocyte Growth Factor Receptor (c-Met) Kinase Inhibitory Activity
  • DMSO dimethyl sulfoxide
  • 5 mM MgCl 2 5 mM MnCl 2 Diluted with 2 mM dithiothreitol (0.01% Tween-20).
  • 5 ⁇ L of this compound solution contains 2.5 ng / mL c-Met intracellular domain protein (Millipore) and 250 ng / mL biotinylated polypeptide biotinyl-poly-Glu: Tyr (4: 1) (CIS bio International). 10 ⁇ L of buffer was added.
  • the reaction solution was left for 16 hours at 25 ° C., were counted using a plate reader Fusion (Fusion TM) (Perkin Elmer).
  • the count of the solution reacted without adding the compound was taken as “control”
  • the count of the solution without adding the compound and ATP was taken as “blank”.
  • the inhibition rate at 1 ⁇ M of the compounds of Examples 6, 27, 35, 36, 47, 54, 55, 126 and 128 was 80% or more.
  • test substance concentration IC 50 value
  • IC 50 value the test substance concentration at which growth was inhibited by 50% was calculated by GraphPad Prism non-linear regression analysis [Sigma dose response (variable slope)].
  • the human gastric cancer cell line MKN45 growth inhibition rate (%) of the test compound was calculated by the following formula. Dimethyl sulfoxide was added to the positive control (100% growth) instead of the test substance. A large excess (10 ⁇ M) of Reference Example 52 (compound described in Entry 104 of WO2005 / 030140), which is a known c-Met inhibitor, was added to the negative control (0% growth) instead of the test substance.
  • Inhibition rate (%) (1 ⁇ (absorbance when test compound is added ⁇ absorbance of negative control) ⁇ (absorbance of positive control ⁇ absorbance of negative control)) ⁇ 100
  • the inhibition rate at 1 ⁇ M of the compounds of Examples 6, 27, 35, 36, 47, 54, 55, 126 and 128 was 80% or more.
  • the IC 50 values of the compounds of Examples 6, 27, 35, 36, 47, 54, 55, 126 and 128 were 1 ⁇ M or less.
  • Test Example 5 Antitumor Test Cancer cells are cultured in a culture solution containing 10% fetal bovine serum in a 37 ° C., 5% carbon dioxide incubator. The cells are isolated by trypsin / EDTA treatment, washed with HBSS (HANK's Balanced Solution), and then adjusted to a cell density of 5 ⁇ 10 7 cells / mL with HBSS. 0.1 mL (5 ⁇ 10 6 cells) of this cell suspension is injected subcutaneously into the abdomen of a 6-week-old female nude mouse (BALB / c nu / nu, manufactured by CLEA Japan) and transplanted.
  • HBSS HANK's Balanced Solution
  • the compound of the present invention exhibits an excellent inhibitory action on kinases such as vascular endothelial growth factor receptor and hepatocyte growth factor receptor, it is related to the action of vascular endothelial growth factor and hepatocyte growth factor in vivo.
  • a clinically useful prophylactic / therapeutic agent for a disease for example, cancer
  • the compound of the present invention is also useful as a pharmaceutical because it is excellent in terms of drug efficacy, pharmacokinetics, solubility, interaction with other pharmaceuticals, safety, and stability.

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Abstract

Cette invention porte sur des composés représentés par la Formule et des sels de ceux-ci, ainsi que sur des médicaments qui sont des inhibiteurs de kinases et des agents de prévention/traitement du cancer qui comprennent lesdits composés ou sur des promédicaments de ceux-ci. [Dans la formule, chaque référence a la même signification que dans le corps principal de la description.]
PCT/JP2009/051383 2008-01-29 2009-01-28 Dérivés hétérocycliques condensés et leurs utilisations WO2009096435A1 (fr)

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US20110046169A1 (en) * 2008-05-08 2011-02-24 Takeda Pharmaceutical Company Limited Fused heterocyclic derivatives and use thereof
US8232294B2 (en) 2009-03-21 2012-07-31 Ning Xi Amino ester derivatives, sailts thereof and methods of use
US8293897B2 (en) 2008-10-14 2012-10-23 Ning Xi Compounds comprising a spiro-ring and methods of use
US9133162B2 (en) 2011-02-28 2015-09-15 Sunshine Lake Pharma Co., Ltd. Substituted quinoline compounds and methods of use
JP2016520617A (ja) * 2013-05-30 2016-07-14 カラ ファーマシューティカルズ インコーポレイテッド 新規の化合物及びその使用
CN107325048A (zh) * 2009-08-07 2017-11-07 埃克塞里艾克西斯公司 使用c‑Met调节剂的方法
CN109879827A (zh) * 2019-03-30 2019-06-14 陕西理工大学 一种新型吲唑类衍生物及其应用
CN110467616A (zh) * 2019-07-01 2019-11-19 江西科技师范大学 含杂芳基取代哒嗪酮结构的三唑并吡嗪类化合物的制备及应用
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CN107325048A (zh) * 2009-08-07 2017-11-07 埃克塞里艾克西斯公司 使用c‑Met调节剂的方法
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US9598400B2 (en) 2011-02-28 2017-03-21 Calitor Sciences, Llc Substituted quinoline compounds and methods of use
US9133162B2 (en) 2011-02-28 2015-09-15 Sunshine Lake Pharma Co., Ltd. Substituted quinoline compounds and methods of use
JP2016520617A (ja) * 2013-05-30 2016-07-14 カラ ファーマシューティカルズ インコーポレイテッド 新規の化合物及びその使用
CN109879827A (zh) * 2019-03-30 2019-06-14 陕西理工大学 一种新型吲唑类衍生物及其应用
CN109879827B (zh) * 2019-03-30 2022-05-31 陕西理工大学 一种吲唑类衍生物及其应用
CN110467616A (zh) * 2019-07-01 2019-11-19 江西科技师范大学 含杂芳基取代哒嗪酮结构的三唑并吡嗪类化合物的制备及应用
EP4005637A4 (fr) * 2019-07-29 2023-07-19 Takeda Pharmaceutical Company Limited Composé hétérocyclique
WO2023125803A1 (fr) * 2021-12-29 2023-07-06 北京鞍石生物科技有限责任公司 Composé d'oxyde d'azote hétéroaromatique, son procédé de préparation et son utilisation

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