WO2005012258A1 - タンパク質キナーゼ阻害剤 - Google Patents
タンパク質キナーゼ阻害剤 Download PDFInfo
- Publication number
- WO2005012258A1 WO2005012258A1 PCT/JP2004/011300 JP2004011300W WO2005012258A1 WO 2005012258 A1 WO2005012258 A1 WO 2005012258A1 JP 2004011300 W JP2004011300 W JP 2004011300W WO 2005012258 A1 WO2005012258 A1 WO 2005012258A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cancer
- substituted
- acceptable salt
- pharmaceutically acceptable
- indazole derivative
- Prior art date
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- 239000003909 protein kinase inhibitor Substances 0.000 title claims description 32
- 229940043355 kinase inhibitor Drugs 0.000 title claims description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 177
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 54
- 239000004480 active ingredient Substances 0.000 claims abstract description 30
- 108010055717 JNK Mitogen-Activated Protein Kinases Proteins 0.000 claims abstract description 25
- 102000001253 Protein Kinase Human genes 0.000 claims abstract description 19
- 108060006633 protein kinase Proteins 0.000 claims abstract description 16
- 239000003112 inhibitor Substances 0.000 claims abstract description 9
- 206010028980 Neoplasm Diseases 0.000 claims description 168
- 150000002473 indoazoles Chemical class 0.000 claims description 147
- -1 nitro, hydroxy, carbonyl Chemical group 0.000 claims description 134
- 201000011510 cancer Diseases 0.000 claims description 129
- 238000000034 method Methods 0.000 claims description 105
- 125000000217 alkyl group Chemical group 0.000 claims description 80
- 125000001424 substituent group Chemical group 0.000 claims description 78
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- 238000004519 manufacturing process Methods 0.000 claims description 60
- 229940124597 therapeutic agent Drugs 0.000 claims description 60
- 125000003545 alkoxy group Chemical group 0.000 claims description 53
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 44
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 42
- 125000003118 aryl group Chemical group 0.000 claims description 31
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- 125000003710 aryl alkyl group Chemical group 0.000 claims description 23
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 23
- 239000007787 solid Substances 0.000 claims description 23
- 230000002401 inhibitory effect Effects 0.000 claims description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 14
- 125000000304 alkynyl group Chemical group 0.000 claims description 13
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- 125000003342 alkenyl group Chemical group 0.000 claims description 11
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 5
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 238000006467 substitution reaction Methods 0.000 claims description 5
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
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- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
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- 125000003107 substituted aryl group Chemical group 0.000 abstract description 10
- 125000003453 indazolyl group Chemical class N1N=C(C2=C1C=CC=C2)* 0.000 abstract 1
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- 238000000668 atmospheric pressure chemical ionisation mass spectrometry Methods 0.000 description 30
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- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229960004025 sodium salicylate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 1
- JUJBNYBVVQSIOU-UHFFFAOYSA-M sodium;4-[2-(4-iodophenyl)-3-(4-nitrophenyl)tetrazol-2-ium-5-yl]benzene-1,3-disulfonate Chemical compound [Na+].C1=CC([N+](=O)[O-])=CC=C1N1[N+](C=2C=CC(I)=CC=2)=NC(C=2C(=CC(=CC=2)S([O-])(=O)=O)S([O-])(=O)=O)=N1 JUJBNYBVVQSIOU-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005942 tetrahydropyridyl group Chemical group 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- POXSDSRWVJZWCN-UHFFFAOYSA-N triphenylphosphanium;iodide Chemical compound I.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 POXSDSRWVJZWCN-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- 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
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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 a protein kinase inhibitor and the like containing an indazole derivative or a pharmacologically acceptable salt thereof as an active ingredient.
- Fms like tyrosine kinase 3 is a receptor-type protein tyrosine kinase (PTK) belonging to the platelet-induced growth factor receptor (PDGFR) family, and its ligand, Fit -3
- PTK platelet-induced growth factor receptor
- Fit -3 This enzyme is activated by dimerization through the binding of ligands and phosphorylates various proteins as intracellular substrates, and is involved in cell growth and differentiation.
- Fit-3 or Flk-2 Fetal liver kinase-2 plays an important role in the proliferation of hematopoietic stem cells [Cell], Vol. 65, p. 1143 ( 1991)].
- F11-3 is constantly activated by amino acid point mutations in the kinase region of Fit-3 [Blood, 97, 2434 (2001)]. . Constitutive activation based on these Flt-3 mutations is thought to be an important cause of leukemia by transmitting cell proliferation signals and causing infinite proliferation of cells.
- the mutations in Fit-3 include insertion of a repetitive sequence of tyrosine residues in the 'region near the cell membrane, changes in the length of the region near the cell membrane, and amino acids in the kinase region of Flt_3.
- cytokine-dependent cell lines such as 32D cells
- FH-3 inhibitors are considered to be useful as therapeutic agents for various cancers including leukemia.
- staurosporine has been widely known as a kinase inhibitor [Biochemical & Biophysical Research Communications], 135, 397 (1986).
- staurosporine non-selectively inhibits a large number of kinases, and is known to cause death when administered to animals such as mice.
- imatinib which was researched and developed as a selective kinase inhibitor, has low toxicity and high clinical efficacy in chronic leukemia patients by selectively inhibiting Abl kinase [New ⁇ London Jars-Nare Ob Metzin (New England Journal of Medicine), 345, 645 (2002)].
- Quinazoline derivatives and the like are known as Flt-3 inhibitors (W002 / 036587).
- As the indazole derivative various compounds are known. Soedinenii), 7, 957-959 (1978)].
- R 15A is a hydrogen atom, nitro, NR 15A1 R 15A2
- R 15Al and R 15A2 are the same or different and are a hydrogen atom, substituted or unsubstituted lower alkyl, lower alkanol (the lower alkanol)
- R 16A represents a hydrogen atom, etc.
- Substituents Q 1 , Q 2 and on the substituted phenyl are the same or different and are each a hydrogen atom, Halogen, hydroxy, nitro, nitroso, carboxy, lower alkyl having 1 to 6 carbons, lower alkoxy having 1 to 6 carbons, lower alkoxycarbonyl having 1 to 6 carbons, NR 17A1 R 2 (wherein R i and R 17A2 has the same meaning as R 15Al and R 15A2 ) or 0 (CH 2 ) nd NR 17A3 R 17A4 (where nd represents an integer of 1 to 6, R m3 and RI 7A4 represent the R 15Al and represent a R 15A2 synonymous), become any two Gar ⁇ of QQ 2 and Q 3 - 0 (CR 17A5 R l7A6) 0- ( wherein two oxygen atoms of the terminal, R s and R 6 are the same or different and represent a hydrogen atom or a lower alkyl having 1 to 6 carbon atoms, or
- R 2D represents methoxy or nitro
- An object of the present invention is to provide a protein kinase inhibitor or the like containing an indazole derivative or a pharmacologically acceptable salt thereof as an active ingredient.
- the present invention relates to the following (1) to (97).
- R 1 represents a substituted or unsubstituted aryl or a substituted or unsubstituted complex ring group
- a pharmacologically acceptable salt thereof as an active ingredient Protein kinase inhibitors except C-jun N-terminal kinase.
- R 24 is C0NR 24a R 24b (wherein R 24a and R 24b are the same or different and are hydrogen atoms, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted Aralkyl or a substituted or unsubstituted heterocyclic group Or R 24a and R 24b together with an adjacent nitrogen atom form a substituted or unsubstituted heterocyclic group) or NR 24c R 24d , wherein R 24e is a substituted or unsubstituted Represents a lower alkylsulfonyl or a substituted or unsubstituted arylsulfonyl, and R 24d represents a hydrogen atom or a substituted or unsubstituted lower alkyl.
- R 25 is a hydrogen atom, 'halogen, cyano, nitro, hydroxy, carboxy, lower alkoxycarbonyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkanoyl,
- R 25a and R 25b are the same or different and are each a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl or substituted Or an unsubstituted heterocyclic group, or R 25a and R 25b together with an adjacent nitrogen atom form a substituted or unsubstituted heterocyclic group) or NR 25e R 25d (wherein R 25e And R 25d are the same or different and are a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkanol, substituted or unsubstituted aryloyl, substituted or unsubstituted heteroaroyl, A substituted or unsubstituted aralkyl, a substituted or unsubstituted lower alkylsulfonyl or a substituted or unsub
- R 24 is NR 24e R 24d (wherein, R 24e and R 24d are each as defined above), and R 25 is a substituted or unsubstituted lower alkoxy.
- -Protein kinase inhibitors except jun N-terminal kinase (c-jun N-terminal kinase).
- Protein kinase inhibitors except N-terminal kinase).
- (6) The protein kinase inhibitor according to any one of (1) to (5), wherein the protein kinase is humus-like tyrosine kinase 3.
- a cancer therapeutic agent comprising the indazole derivative or the pharmaceutically acceptable salt thereof according to (1) as an active ingredient.
- Hematopoietic tumors breast cancer, uterine body cancer, uterine face cancer, prostate cancer, bladder cancer, kidney cancer, stomach cancer, esophagus cancer, liver cancer, biliary tract, colon cancer, rectal cancer, ⁇ cancer
- the cancer therapeutic agent according to the above (7) which is a cancer caused by lung cancer, oral cancer, osteosarcoma, melanomas or brain tumor.
- An antitumor agent comprising the indazole derivative or the pharmaceutically acceptable salt thereof according to the above (1) as an active ingredient.
- a method for treating cancer comprising a step of administering an effective amount of the indazole derivative or the pharmaceutically acceptable salt thereof according to (1).
- a cancer due to hematopoietic tumor, breast cancer, endometrial cancer, uterine facial cancer, prostate which comprises a step of administering an effective amount of the indazole derivative or the pharmaceutically acceptable salt thereof according to (1).
- a method for treating a tumor comprising a step of administering an effective amount of the indazole derivative or the pharmaceutically acceptable salt thereof according to (1).
- a method for treating a solid tumor comprising a step of administering an effective amount of the indazole derivative or the pharmaceutically acceptable salt thereof according to (1).
- R 2 , R 3 and R 4 are the same or different and each represents a hydrogen atom, a halogen, a nitro, a nitroso, a propyloxy, a cyano, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkyl, Noyl, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted aryl, NR 5 R 6 (wherein R 5 and R 6 are the same or different and are a hydrogen atom, substituted or unsubstituted lower alkyl, Substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted Aroiru,
- R 2 , R 5a and R 6a have the same meanings as described above), respectively, or a pharmaceutically acceptable salt thereof.
- R 2 and R 7a are as defined above
- a pharmacologically acceptable salt thereof provided that when R 2 is a hydrogen atom, R 7a is methyl Or not 2- (dimethylamino) ethyl].
- Protein kinase inhibitors except (c-jun N-terminal kinase).
- a medicament comprising the indazole derivative according to any of (32) to (38) or a pharmacologically acceptable salt thereof as an active ingredient.
- a therapeutic agent for cancer comprising the indazole derivative or the pharmacologically acceptable salt thereof according to any of (32) to (38) as an active ingredient.
- An antitumor agent comprising, as an active ingredient, the indazole derivative or the pharmacologically acceptable salt thereof according to any of (32) to (38).
- a method for treating cancer comprising a step of administering an effective amount of the indazole derivative or the pharmaceutically acceptable salt thereof according to any of (32) to (38).
- a cancer or breast cancer caused by a hematopoietic tumor comprising a step of administering an effective amount of the indazole derivative or the pharmacologically acceptable salt thereof according to any of (32) to (38).
- (62) A method for treating leukemia, myeloma or lymphoma, comprising a step of administering an effective amount of the indazole derivative or the pharmaceutically acceptable salt thereof according to any of (32) to (38).
- a method for treating solid cancer comprising a step of administering an effective amount of the indazole derivative or the pharmaceutically acceptable salt thereof according to any of (32) to (38).
- R 8 is a substituted or unsubstituted heterocyclic group
- substituted heterocyclic group may be the same or different and have 1 to 3 substituents, such as oxo, formyl, carbonyl, lower alkoxycarbonyl, ⁇ Le, a substituted or unsubstituted lower alkyl, in a substituent if Ku is unsubstituted lower alkoxy, C0NR 9 R ie (wherein, R g and R l ° is lower hydrogen atom or a substituted or unsubstituted become identical or different alkyl), NR "R 12
- R 11 and R 12 are the same or different and are each a hydrogen atom, lower alkanol, lower alkoxyl propyl, aralkyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylo or a substituted or unsubstituted heterocyclic group) or - 0 (CR 13 R 14) n 0- (wherein, R 13 and R 14 represents a hydrogen atom or a lower alkyl the same or different, n represents 2 Or 3 and the two terminal oxygen atoms are bonded to the same carbon atom on the heterocyclic group in the substituted heterocyclic group).] Or an indazole derivative represented by Acceptable salts.
- Protein kinase inhibitors except (c-jun N-terminal kinase).
- a medicament comprising the indazole derivative or the pharmaceutically acceptable salt thereof according to any one of (67) to (69) as an active ingredient.
- a therapeutic agent for cancer comprising as an active ingredient the indazole derivative or the pharmaceutically acceptable salt thereof according to any one of (67) to (69).
- Cancer is caused by hematopoietic tumors, breast cancer, endometrial cancer, uterine facial cancer, prostate cancer, bladder cancer, kidney cancer, stomach cancer, esophagus cancer, liver cancer, biliary tract, colon cancer, rectal cancer, ⁇ cancer (73)
- the therapeutic agent for cancer according to the above (73) which is a cancer caused by lung cancer, oral and neck cancer, osteosarcoma, melanoma or brain tumor. '
- An antitumor agent comprising, as an active ingredient, the indazole derivative or the pharmacologically acceptable salt thereof according to any of (67) to (69).
- a method for inhibiting humus-like tyrosin kinase 3, comprising a step of administering an effective amount of the indazole derivative or the pharmaceutically acceptable salt thereof according to any of (67) to (69). .
- a method for treating cancer comprising a step of administering an effective amount of the indazole derivative or the pharmaceutically acceptable salt thereof according to any of (67) to (69).
- a cancer caused by a hematopoietic tumor comprising a step of administering an effective amount of the indazole derivative or the pharmaceutically acceptable salt thereof according to any of (67) to (69).
- Breast cancer, endometrial cancer, uterine malignant cancer, prostate cancer, bladder cancer, renal cancer, bladder cancer, esophageal cancer, liver cancer, biliary tract cancer, colorectal cancer, rectum cancer, ⁇ cancer, lung cancer, oral cancer, osteosarcoma, Rano A method for treating cancer caused by a tumor or a brain tumor.
- a method for treating solid cancer comprising a step of administering an effective amount of the indazole derivative or the pharmaceutically acceptable salt thereof according to any of (67) to (69). .
- a method for treating a tumor comprising a step of administering an effective amount of the indazole derivative or the pharmaceutically acceptable salt thereof according to any of (67) to (69).
- Examples of 0 halogen include fluorine, chlorine, bromine, and iodine atoms.
- Lower alkyl, lower alkoxy, lower alkoxyl propyl, lower alkoxycarbonylamino, lower alkoxycarbonyl-substituted lower alkyl and lower alkyl moiety of lower alkylsulfonyl include, for example, straight chain having 1 to 10 carbon atoms. , Branched, cyclic, or a combination thereof, and more specifically,
- (ii-a) straight-chain or branched lower alkyl includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, /?-pentyl, neopentyl , -Hexyl ,? -Heptyl ', -octyl, ⁇ -nonyl, / 7-decyl, and the like.
- cyclic lower alkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, Cyclodecyl, noradamantyl, adamantyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.3.0] octyl, bicyclo [3.3.1] nonyl and the like Can be
- Examples of the lower alkyl composed of a combination of a linear or branched chain and a cyclic group include cyclopropylmethyl, cyclopentylmethyl, cyclooctylethyl and the like.
- the alkylene moiety of the lower alkoxycarbonyl-substituted lower alkyl and aralkyl has the same meaning as the above-mentioned linear or branched lower alkyl (ii-a) obtained by removing one hydrogen atom.
- Examples of the lower alkenyl include a straight-chain or branched alkenyl having 2 to 10 carbon atoms, and more specifically, vinyl, aryl, 1-propenyl, tributenyl, 3- Butenyl, 2-pentenyl, 4-pentenyl, 2_hexenyl, 5-hexenyl, 2-decenyl, 9-decenyl and the like.
- Lower alkynyl includes, for example, straight-chain or branched alkynyl having 2 to 10 carbon atoms, and more specifically ethynyl, 2-propenyl, 3-butynyl, 4-pentynyl and 5- Xinyl, 9-decinyl and the like.
- the aryl moiety in aryl, aralkyl, arylo, aryloamino and arylsulfonyl is, for example, a monocyclic or condensed aryl having two or more condensed rings, more specifically having a ring-forming carbon atom number.
- aryls such as phenyl, naphthyl, indenyl, and anthranil.
- Examples of the lower alkanoyl include alkanols having 1 to 8 carbon atoms, which are linear, branched, cyclic or a combination thereof, more specifically formyl, acetyl, propionyl, butyryl, isobutyryl, parelli , Isovaleryl, bivaloyl, hexanoyl, heptanyl, octanol, cyclopropylpropionyl, cyclobutylcarbonyl, cyclopropylcarbonyl, cyclopropylmethylcarbonyl, cyclohexylcarbonyl, 1-methylcyclopropylcarbonyl, cycloheptyl And carbonyl.
- Examples of the heterocyclic group include an aromatic heterocyclic group and an alicyclic heterocyclic group. .
- the aromatic heterocyclic group examples include a monocyclic or a condensed aromatic heterocyclic group in which two or more rings are condensed and are included in the aromatic heterocyclic group.
- the type and number of the hetero atoms are not particularly limited, but may include one or more hetero atoms selected from the group consisting of, for example, a nitrogen atom, a sulfur atom, and an oxygen atom.
- Aromatic heterocyclic groups having 5 to U atoms for example, furyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxaziazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, indolinyl, indolinyl, indolinyl Benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, phthala Dinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, purinyl, coumarinyl and the like.
- Examples of the alicyclic heterocyclic group include a monocyclic or a condensed alicyclic heterocyclic group in which two or more rings are condensed, and are included in the alicyclic heterocyclic group.
- hetero atoms are not particularly limited, but may include, for example, one or two or more hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom, and more specifically,
- heterocyclic group formed together with the adjacent nitrogen atom for example, a 5- or 6-membered monocyclic heterocyclic group containing at least one nitrogen atom (the monocyclic heterocyclic group May contain other nitrogen, oxygen or sulfur atoms.
- a condensed heterocyclic group containing at least one nitrogen atom which is a bicyclic or tricyclic condensed 3- to 8-membered ring (the condensed heterocyclic group is other nitrogen atom, oxygen atom or May contain a sulfur atom).
- pyrrolidinyl pi'peridino, piperazinyl, morpholino, thiomorpholino, homopiperidino, homopiperazinyl, tetrahydropyridyl, tetrahydroquinolyl, tetrahydroisoquinolyl And the like.
- heteroaryl moiety in the heteroaryl is the aromatic heterocyclic group
- Substituted lower alkyl, substituted lower alkoxy, substituted lower alkenyl, substituted lower alkynyl, substituted lower alkanol, substituted lower alkoxycarbonyl, and substituted lower alkylsulfonyl may have the same or different substituents, e.g. 3,
- R 19a and R are the same or different and each is a hydrogen atom or substituted or unsubstituted lower alkyl (substituents in the substituted lower alkyl are, for example, Halogen, hydroxy, oxo ', nitro, cyano, carboxy, lower alkanol, lower alkoxyl propyl, a.
- (xii-j) a substituted or unsubstituted aryl
- the substituent in the substituted aryl is, for example, halogen having 1 to 3 substituents, hydroxy, nitro, cyano, carboxy, lower alkanol, lower alkoxyl arponyl, aralkyl, aralkyl Aryl, substituted or unsubstituted lower alkyl (substituents in the substituted lower alkyl are, for example, hydroxy having 1 to 3 substituents), substituted or unsubstituted lower alkoxy (substituents in the substituted lower alkoxy are , For example, hydroxy having 1 to 3 substitutions), etc.],
- R 21a and R 21b are the same or different and each represents a hydrogen atom, a lower alkylsulfonyl, a substituted or unsubstituted lower alkyl [substituents in the substituted lower alkyl, xi)], substituted or unsubstituted lower alkenyl [substituents in the substituted lower alkenyl are the same as those in the above (xi)], substituted or unsubstituted lower alkynyl [substituted lower alkynyl
- the substituent is the same as defined in the above (xi)], a substituted or unsubstituted lower alkoxy [The substituent in the substituted lower alkoxy is the same as the above (xi)], a substituted or unsubstituted lower alkanol [ The substituent in the substituted lower alkanol has the same meaning as the above (xi)], substituted or un
- substituted lower alkyl substituted or unsubstituted lower alkoxy (substituents in the substituted lower alkoxy are, for example, 1 to 3 substituents) Or a substituted or unsubstituted arylo.
- the substituent in the substituted arylo is, for example, halogen having 1 to 3 substituents, hydroxy, nitro, cyano, alkoxy, lower alkanoyl, lower alkoxy.
- substituted or unsubstituted heterocyclic group [Examples of the substituent in the substituted heterocyclic group include halogen having 1 to 3 substituents, hydroxy, nitro, cyano, propyloxy, and lower alkanoyl.
- Substituted or unsubstituted lower alkyl substituted or unsubstituted lower alkyl (substituents in the substituted lower alkyl are, for example, hydroxy having 1 to 3 substituents), substituted or unsubstituted lower.
- Alkoxy the substituent in the substituted lower alkoxy is, for example, hydroxy having 1 to 3 substituents
- Substituent in the substituted heterocyclic group are connexion formed such together with R 21 a and connexion substituted or unsubstituted Hajime Tamaki together with the nitrogen atom to which R 21b is adjacent [said adjacent nitrogen atom such as substituted Halogen, amino, nitro, hydroxy, oxo, cyano, carboxy, lower alkoxycarbonyl, aralkyl, aroyl, heteroaroyl, substituted or unsubstituted lower alkyl of the formulas 1 to 3 (substituents in the substituted lower alkyl are, for example, Substituted or unsubstituted lower alkoxy (substituents having 1 to 3 substituents such as hydroxy and lower alkoxy) (substituents in the substituted lower alkoxy are, for example, 1 to 3 substituted hydroxy and lower alkoxy) A substituted or unsubstituted lower alkanol (substituents in the substituted lower alkanol
- R 22 is a hydrogen atom, substituted or unsubstituted lower alkyl [substituents in the substituted lower alkyl are the same as defined in the above (xi)], substituted or unsubstituted aryl.
- Substituents in the substituted aryl include, for example, halogen having 1 to 3 substituents, hydroxy, nitro, cyano, alkoxy, lower alkanol, lower alkoxyl propyl, aralkyl, aroyl, substituted or unsubstituted lower alkyl (such as Substituents in the substituted lower alkyl are, for example, hydroxy having 1 to 3 substitutions), substituted or unsubstituted penta-alkoxy (substituents in the substituted lower alkoxy are, for example, hydroxy having 1 to 3 substitutions) Or a substituted or unsubstituted heterocyclic group [The substituent in the substituted heterocyclic group is, for example, a halogenated group having 1 to 3 substituents.
- Substituted or unsubstituted alicyclic heterocyclic carbonyl substituted or unsubstituted alicyclic heterocyclic carbonyl (substituents in the substituted alicyclic heterocyclic carbonyl include, for example, octogen, hydroxy, oxo, lower alkyl, lower alkoxy having 1 to 3 substituents) Etc.).
- Substituents in the substituted heterocyclic group and the substituted heterocyclic group formed together with the adjacent nitrogen atom are, in addition to (xii-a) to (xii-0) described above, (xii-p) or (Xi i- q). (xii-p) oxo
- lower alkenyl has the same meaning as in the above (iv)
- J lower alkynyl has the same meaning as in the above (V)
- aryl, aroyl and the aryl moiety of aralkyl have the same meaning as in the above (vi).
- the heterocyclic group has the same meaning as in the above (viii)
- the alicyclic heterocyclic group in the alicyclic heterocyclic carbonyl has the same meaning as the above (viii-b).
- the heterocyclic group formed together with the nitrogen atom is as defined in the above (ix), and heteroaroyl is as defined in the above (X).
- the pharmacologically acceptable salts of the compounds (I), (la), (II) and (III) include, for example, pharmacologically acceptable acid addition salts, metal salts, ammonium salts, and organic amines. Addition salts, amino acid addition salts and the like can be mentioned. Acid addition salts include inorganic acid salts such as hydrochloride, sulfate, phosphate, etc., acetate, maleate, fumarate, tartrate, citrate, lactate, aspartate, glutamate, etc.
- Metal salts include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, aluminum salts, zinc salts, and the like.
- Ammonium salts include ammonium salts , Tetramethylammonium, and the like; organic amine addition salts include morpholine and piperidine; and amino acid addition salts include lysine and glycine. , Phenylalanine and the like.
- reaction steps described below structural formulas, Me in the table or the like, Et, 'Pr,' Pr , l Bu, Ph, Ac, Bz, Boc each methyl, Echiru, propyl, isopropyl, tert- heptyl, phenyl , Acetyl, benzoyl, -butoxycarpanol.
- the definition of each group in the reaction steps described below has the same meaning as the definition of each group described above, unless otherwise specified.
- Compound (II) can be produced according to the following reaction steps.
- Compound (II) can be prepared by a known method [eg, The Journal, Ob Organ 'U. Org. Chem.], 52, 19 (1987); Canadian Journal The compound (A) obtained according to the method of Chemical Chemistry, Vol. 51, p. 792 (1973)] can be produced by the following steps.
- the compound (A) is reacted with the compound (B) in a solvent such as methanol, ethanol, tetrahydrofuran (THF), or -dimethylformamide (DMF), or a mixed solvent thereof in the presence of a base to give the compound (B).
- a solvent such as methanol, ethanol, tetrahydrofuran (THF), or -dimethylformamide (DMF), or a mixed solvent thereof in the presence of a base to give the compound (B).
- THF tetrahydrofuran
- DMF -dimethylformamide
- the base potassium carbonate, potassium //-butoxide, sodium hydride and the like are used.
- the compound (B) and the base are each used in an amount of 1 to 10 equivalents relative to the compound (A).
- the reaction is usually carried out at a temperature between (! ⁇ 100 ° C) and is completed in 1-72 hours.
- the compound (Ula) having a specific functional group at R 2 , R 3 and R 4 can be obtained according to Production method 1 or a known method (for example, JP-A-2-32059). It can also be produced from the compound (C) having another functional group at R 3 and R 4 by the following steps. '
- R 2a , R 3a , R 4a , R 2 ⁇ R 3b and R 4b each represent a group defined in each of the following steps 2-1 to 2-3. However, each of the following steps 2-1 And unless otherwise defined, R 2a , R 3a , R 4a , R 2b , R 3b and R 4b have the same meanings as R 2 , R 3 and R 4 , respectively.
- step 2-1 at least one of R 2a , R 3a and R 4a represents carboxy, and at least one of R 2b , R 3b and R 4b is a lower alkoxycarbonyl. Represents)
- Compound (Ila) is hydrolyzed in water or a mixed solvent of water and methanol, ethanol, THF, etc. in the presence of a base such as sodium hydroxide or an acid such as hydrochloric acid to give compound (Ila). Obtainable.
- the acid or base is used in 0.1 to 10 equivalents relative to compound (C).
- the reaction is usually carried out at a temperature between 20 and 100 t and is complete in 1 to 24 hours.
- step 2-2 at least one of R 2a , R 3a and R 4a represents amino, and at least one of R 2b , R 3b and R 4b represents nitro
- the compound (C) is treated with a reducing agent such as tin or iron in a solvent such as water or ethanol or a mixed solvent thereof or in the absence of an acid in the presence of an acid such as concentrated hydrochloric acid or acetic acid, or In a solvent such as methanol, ethanol, THF, DMF or a mixed solvent thereof, in the presence of a catalyst such as palladium carbon, platinum dioxide, Raney nickel or the like, in a hydrogen atmosphere, or in the presence of a hydrogen donor such as hydrazine hydrate or asimonium formate By subjecting the compound to a reduction reaction, the compound (Ila) can be obtained.
- a reducing agent such as tin or iron in a solvent such as water or ethanol or a mixed solvent thereof or in the absence of an acid in the presence of an acid such as concentrated hydrochloric acid or acetic acid, or In a solvent such as methanol, ethanol, THF, DMF or a mixed solvent thereof, in the presence of a
- R 2a , R 3a and R 4a is NHC0R 24 (where R 24 is a substituted or unsubstituted lower alkyl, a substituted or unsubstituted aryl or Represents a teloaryl), and at least one of R 2b , R 3b and R 4b represents amino.
- lower alkyl and aryl are the same as defined in (ii) and (vi), respectively, and heteroaryl is defined as (vi iia) in the definition of the aromatic heterocyclic group.
- the substituent in the substituted lower alkyl has the same meaning as the above (xi), and the substituent in the substituted aryl has the same meaning as the above (xii).
- Compound (C) is converted to dichloromethane, THF, 1,4-dioxane, DMF, N-methylpi Or a mixed solvent thereof in a solvent such as piperidone, Toryechiruamin, pyridinium Jin, 4-dimethyl ⁇ amino pyridine, poly Biel pyridine, 4_ Moruhorinomechi Le polystyrene, 4- piperidinocarbonyl presence of a base such as polystyrene, R 24 C0C1 (wherein, R 24 has the same meaning as defined above) compound (VIII) or (R 24 C0) 2 0 (wherein, R 24 is as defined above) represented by compounds represented by the (IX) Reaction, or dicyclohexylcarpoimide, tolethyl-3- (3-dimethylaminopropyl) carpoimide hydrochloride, polymer-bound-1-technyl-3- (3-dimethylaminopropyl) carpoimi
- the base, compound (VIII) or compound (IX), condensing agent, activator and compound (X) are each used in an amount of 1 to 20 equivalents relative to compound (C).
- the reaction is usually carried out at a temperature between -20 and 80 ° C and is completed in 30 minutes to 24 hours.
- the compound (II) having a desired functional group at a desired position can be obtained by appropriately combining and carrying out the above methods.
- Compound (I) can be synthesized according to the method for producing compound (II) described above or according to a known method, or can be obtained by purchasing a commercial product.
- Compound (III) can be produced according to the method for producing compound (II) described above.
- the isolation and purification of the product in the above production method can be carried out by appropriately combining the methods used in ordinary organic synthesis, for example, filtration, extraction, washing, drying, concentration, crystallization, various types of chromatography, and the like. .
- the intermediate can be subjected to the next reaction without purification.
- Compound (I) includes isomers such as positional isomers, geometric isomers or optical isomers However, the possible isomers and mixtures of the isomers in any ratio may be used as protein kinase inhibitors except for the C-jun N-terminal kinase of the present invention. it can. '
- the compounds (II) and (III) may have isomers such as positional isomers, geometric isomers, or optical isomers, and the possible isomers and mixtures of the isomers in any ratio are described in the present invention. Is included.
- salts of the compounds (I), (II) and (III) when it is desired to obtain the salts of the compounds (I), (II) and (III), when the compounds (I), (II) and (III) are obtained in the form of a salt, they may be purified as they are, and When obtained in free form, compounds (I), (II) and (III) may be dissolved or suspended in an appropriate solvent, and an acid or a base may be added to form a salt.
- Compounds (I), (II) and (III) and their pharmacologically acceptable salts may be present in the form of adducts with water or various solvents. Included in the present invention. '
- compound (I) examples include, for example, compound 2, compounds 60 to 78, and specific examples of compound (II) include, for example, compound 1, compounds 3 to 20, and compounds _28 to 59.
- Specific examples of the compound (III) include, for example, compounds 21 to 27 (Tables 1 to 4).
- Test Example 1 Proliferation inhibitory activity against leukemia cell lines and solid cancer cell lines in which kinase activation has been reported due to Fit-3 mutation or another mechanism of action
- the cell growth inhibition rate of the test compound against the human acute myeloid leukemia cell lines MV-4-11, ML-1, and the human chronic myeloid leukemia cell line K562 was measured by the following method.
- Roswell ParkMemorial Institute's Medium containing 10% fetal bovine serum (Gibco, Cat. No. 10437-028) and penicillin / streptomycin (1: 1) (Gibco, Cat. No. 15140-122) for each cell culture (RPMI) 1640 medium (Gibco, catalog number 11875-093) was used.
- 7.5X10 solids / mL Inoculate 80 L of the prepared MV-4-11 cells (2.5-10 4 cells for ML-1 cells and K562 cells) into a TC MICROWELL 96U plate (Nalgene Nunc, catalog number 163320) at 37 ° C. For 4 hours in a 5% CO 2 incubator.
- a well to which only 80 L of RPMI medium was added was also prepared as a blank.
- MV-4-11 cells, ML-1 cells, and K562 cells add a test compound solution in dimethyl sulfoxide (DMS0) adjusted to a final concentration of 3.16 ⁇ mol / L or 10 mol / L. il was added.
- DMS0 dimethyl sulfoxide
- 20 L of DMS0 was added so that the final concentration was 0.1%.
- the cells were cultured at 37 C for 72 hours in a 5% carbon dioxide gas incubator.
- the cell growth inhibition rate of the test compound against the human colon cancer cell line Colo205 was measured by the following method.
- Cell cultures include Roswel 1 Park Memorial Institute's containing 10% fetal bovine serum (Gibco, Cat. No. 10437-028) and penicillin / streptomycin (1: 1) (Gibco, Cat. No. 15140-122).
- Medium (RPMI) 1640 medium (Gibco, catalog number 11875-093) was used.
- Colo205 cells prepared at 1.25X10 4 cells / mL were seeded in 80 L each on a TC MICROWELL 96F plate (Nalgene Nunc, catalog number 167008), and cultured at 37X for 4 hours in a CO2 incubator. . A well to which only 80 L of RPMI medium was added was also prepared as a blank.
- Table 5 shows the results. Table 5 shows that the compounds of the present invention show effective growth inhibitory activity against leukemia cell lines and solid cancer cell lines in which kinase activation is reported by Fit-3 mutation or another mechanism of action. You can see that. Table 5
- the Flt-3 inhibitory activity was measured by the following method.
- Fit-3 was prepared by infecting insect cells with a baculovirus expressing a protein in which GST (daltathione S-transferase) was fused to the N-terminal of the intracellular domain (583-953 amino acids) of human Fit-3.
- 96-L plate FIA-PLATE BLACK 96-well FALT-BOTTOM HIGH BINDING, GRAY ⁇ ", Cat. No. 655077
- Neutroavidin Pierce, Catalog No. 31000
- 61GT0BAA was immobilized, blocked with 0.25% gelatin, and used as a plate for kinase reaction measurement.
- the final concentration was GST-fused Flt-3 (100 iig / V), Tris ⁇ CI (H 7.5) (20 mmol / L),] S Guriseruhosufue one bets (5 mmol / L), DTT (Di thiothrei tol) (1 mmol / L), Na 3 V0 4 (0.1 mmol / L), MgCl 2 (10 mmol / L), MnCl 2 (10 mmol / L), ATP (10 Mmol / L), BSA (Bovine Serum Albumin) (0.1%), DMS0 (0.1%), test compound (10 (mol / L) to the kinase reaction plate at a volume of 60 xL.
- the reaction was stopped by adding 50 L of an aqueous solution of 25 mL / L of ethylenediaminetetraacetic acid After the reaction, the plate was washed with TBS-T [10 mmol / L Tris-CI (pH 7.5). ), 150 mmol / L NaCK 0.053 ⁇ 4 Tween 20 (Bio-Rad, Cat.No. 170-6531)], and then react with anti-phosphotyrosine anti-phosphotyrosine antibody and wash 4 times with TBS-T.
- TBS-T 10 mmol / L Tris-CI (pH 7.5).
- 150 mmol / L NaCK 0.053 ⁇ 4 Tween 20 Bio-Rad, Cat.No. 170-6531
- the compound (I), (la), (II), (III) or a pharmacologically acceptable salt thereof can be used as it is or in various pharmaceutical forms depending on its pharmacological action, administration purpose and the like. it can.
- the pharmaceutical composition of the present invention comprises a pharmacologically acceptable amount of the compound (I), (la), (II), (III) or a pharmaceutically acceptable salt thereof in an effective amount as an active ingredient. It can be manufactured by uniformly mixing with a carrier.
- the carrier may take a wide variety of forms depending on the form of preparation desired for administration.
- These pharmaceutical compositions are desirably in a unit dosage form suitable for oral or parenteral administration, such as injection.
- excipients such as lactose and mannitol; disintegrants such as starch; lubricants such as magnesium stearate; binders such as polyvinyl alcohol and hydroxypropyl cellulose; sucrose fatty acid esters; A surfactant such as a fatty acid ester may be used according to a conventional method. Tablets containing 1 to 200 mg of active ingredient per tablet are preferred.
- solubilizers such as sodium benzoate, sodium salicylate, urethane, salt, glucose And the like.
- Preservatives such as phenol, cresol, hydroxybenzoate, chlorobutanol, and antioxidants such as ascorbic acid and sodium pyrosulfite may be used in a conventional manner.
- Compound (I), (la), (II), (III) or a pharmaceutically acceptable salt thereof can be administered orally or parenterally as an injection, etc., and its effective dose
- the number of administrations varies depending on the administration form, age, weight, and symptoms of the patient, but it is usually preferable to administer 0.01 to 100 mg / kg per day.
- 1-Indazole-3-carboxylic acid (45.2 g, 279 mmol) was suspended in TH.F (500 mL) and obtained according to a known method [eg, Synthesis, 1992, p. 285].
- 1-Hydroxybenzotriazol dimethylammonium salt (55.7 g, 308 mmol)
- 1-ethyl-3- (3-dimethylaminopropyl) rubodiimide hydrochloride 58.9 g, 307 mmol
- step 5 of Example 1 (1-indazole-3-ylmethyl) triphenylphosphonium iodide (1.00 g, 1.92 mmol), (2-ethylethylethoxy) benzaldehyde hydrochloride (0.25 g) , 0.97 mmol) and potassium carbonate (0.80 g, 5.79 mmol) to obtain the free base of compound 6, and then treat with a 4 mol / L hydrogen chloride / ethyl acetate solution according to step 2 of Example 2. As a result, compound 6 (0.11 g, 31%) was obtained.
- Step 5 of Example 1 (1-indazole-3-ylmethyl) triphenylphosphonium iodide (1.00 g, 1.92 mmol), (2-piberidinoethoxy) benzaldehyde hydrochloride (0.26 g, 0.96 mmol) and potassium carbonate (0.80 g, 5.79 mmol) to give the free base of compound 8, and then treat it with a 4 mol / L hydrogen chloride / ethyl acetate solution according to step 2 of Example 2 to obtain the compound. 8 (0.10 g, 273 ⁇ 4) was obtained.
- Step 5 of Example 1 (1-indazol-3-ylmethyl) triphenylphosphonium iodide (1.00 g, 1.92 mmol), (3-piperidinopropoxy) benzaldehyde hydrochloride (0.28 g, 0.98 mmol) and potassium carbonate (0.80 g, 5.79 mmol) to give the free base of compound 9, followed by treatment with a mol / L hydrogen chloride / ethyl acetate solution according to step 2 of Example 2. Compound 9 (0.11 g, 27 °) was obtained. '
- Step 5 of Example 1 (1) -indazole-3-ylmethyl) triphenylphosphonium (5.00 g, 9.61 mmol), ⁇ nitrobenzaldehyde (1.45 g, 9.60 mmol) and carbonic acid From potassium (3.98 g, 28.8 mmol), 3_ [2- (4-nitrophenyl) vinyl] -1-indazole (1.12 g, 44%) was obtained.
- step 5 of Example 1 (1_indazol-3-ylmethyl) triphenylphosphonium iodide (2.50 g, 4.80 mmol) and terephthalaldehyde monomethyl acetal (1.00 g, 4.80 (2.00 mmol, 14.5 mmol) in the presence of potassium carbonate. (2.00 g, 14.5 mmol), and then treated with) -toluenesulfonic acid monohydrate (0.04 g, 0.20 mmol) in acetone to give Compound 16. (0,08 g, 73 ⁇ 4) was obtained.
- Step 5 of Example 1 (1-indazole-3-ylmethyl) triphenylphosphonium iodide (0.51 g, 0.97 mmol), ⁇ (2-dimethylaminoethoxy) benzaldehyde (0.13 g, 0.67 mmol) and potassium carbonate (0.43 g, 3.09 mmol) to give the free base of compound 18.
- the compound 18 was treated with a 4 mol / L hydrogen chloride / ethyl acetate solution according to step 2 of Example 2 to give compound 18. (0.19 g, 833 ⁇ 4) was obtained.
- Example 21 () -3_ [2_ (3-pyridyl) vinyl] -1-indazole (Compound 21) According to Step 5 of Example 1, iodide (1-indazole-3-ylmethyl) triphenylphospho Compound 21 (2.12 g, 503 ⁇ 4) was obtained from dimethyl (10.0 g, 19.2 mmol), 3-pyridinecarboxaldehyde (1.80 mL, 19.0 mmol) and potassium carbonate (7.96 g, 57.6 mmol).
- Step 5 of Example 1 (1-indazole-3-ylmethyl) triphenylphosphonium iodide (0.34 g, 0.64 mmol), 4- (2-dimethylaminoethoxy) -3-methoxybenzaldehyde
- the free base of compound 28 was obtained from hydrochloride (0.17 g, 0.64 mmol) and lithium carbonate (0.27 mg, 1.93 mmol).
- Step 2 of Example 2 a 4 mol / L hydrogen chloride monoethyl acetate solution was prepared. Processing by As a result, compound 28 (0.19 g, 78 °) was obtained.
- step 1 of Example 29 vanillin (10.0 g, 65.7 mmol), potassium carbonate (27.2 g, 197 mmol) and 2-morpholinoethyl chloride hydrochloride (14.7 g, 79.0 mmol) gave 3 -Methoxy-4- (2-morpholinoethoxy) benzaldehyde hydrochloride (17.3 g, 87%) was obtained.
- Step 2 of Example 29 3-methoxy-4- (2-morpholinoethoxy) benzaldehyde hydrochloride (0.50 g, 1.66 mmol) obtained in Step 1, iodide (1-indazol-3-ylmethyl)
- the free base of compound 36 was obtained from triphenylphosphonium (0.82 g, 1.58 mmol) and potassium carbonate (0.63 g, 4.56 mmol).
- 4 mol / L hydrogen chloride-acetic acid Compound 30 (0.25 g, 37%) was obtained by treating with ethyl acetate solution (4.0 mL, 16.0 mmol).
- Step 2 of Example 29 4_ (3-morpholinopropoxy) benzaldehyde (0.51 g, 2.04 mmol) obtained in Step 1 and iodide (1-idazole-3-ylmethyl) triphenylphosphonide Compound (1.00 g, 1.92 mmol) and potassium carbonate (0.56 g, 4.08 mmol) gave Compound 31 (0.13 g, 18%).
- Step 1 of Example 29 4-hydroxy-3-nitrobenzaldehyde (6.37 g, 38.1 mmol), potassium carbonate (15.8 g, 114 mmol) and 2-morpholinoethyl chloride hydrochloride (7.09 g, 38.1 mmol) to obtain a crude product
- Step 2 of Example 2 4- (2-morpholino) -3-nitrobenzaldehyde hydrochloride was treated with a 4 mol / L hydrogen chloride / ethyl acetate solution (10. OmL, 40.0 mmol). (6.07 g, 503 ⁇ 4).
- Step 2 of Example 29 4_ (2-morpholino) -3_ditobenzaldehyde hydrochloride (0.32 g, 1.02 mmol) obtained in Step 1 and iodide (1-indazole-3) were obtained.
- Step 1 of Example 29 a crude product was obtained from vanillin (1.27 g, 8.35 mmol), potassium carbonate (1.92 g, 13.9 mmol) and 3-morpholinopropyl chloride (1.21 g, 7.42 bandol). And then 4 mol / L chloride according to Step 2 of Example 2. Treatment with ethyl monoacetate hydrogen solution (4.0 mL, 16.0 mmol) gave 3-methoxy-4- (3-morpholinopropoxy) benzaldehyde hydrochloride (1.15 g, 56%).
- Step 1 of Example 29 3_bromo-4-hydroxybenzaldehyde (14.3 g, 71.0 mmol) obtained in Step 1, potassium carbonate (20.0 g, 145 mmol), and 2-morpho'linoletyl chloride From hydrochloride (13.5 g, 72.6 mmol), 3-bromo-4- (2-morpholinoethoxy) benzaldehyde (10.9 g, 49%) was obtained.
- Step 2 of Example 32 3_bromo-4-'(2_morpholinoethoxy) benzaldehyde (2.76 g, 8.78 mmol) obtained in Step 2, potassium carbonate (0.20 g, J. 5 mmol) and Compound 34 (1.23 g, 59%) was obtained from (1-indazole-3-ylmethyl) triphenylphosphonium iodide (2.54 g, 4.88 mmol).
- Benzoyl chloride (O.lO mL, 0.86 mmol) and pyridine were added to a dichloromethane (2.00 mL) solution of dimethyl acetal (0.21 g, 0.70 mmol) of 3-amino_4_ (2-morpholinoethoxy) benzaldehyde obtained in Step 2.
- '(0 ⁇ 10 mL, 1.24 mmol) was added and the mixture was stirred at room temperature for 10 hours.
- the reaction solution was added with 3 mo 1 / L hydrochloric acid (3.00 mL), stirred at room temperature for 20 minutes, neutralized with saturated aqueous sodium hydrogen carbonate (50 ml), and extracted with ethyl acetate (50 mLX3).
- Step 2 of Example 32 3-benzoylamino-4- (2-morpholinoethoxy) benzaldehyde (0.24 g, 0.69 mmol) obtained in Step 3, iodide (1-indazol-3-ylmethyl) Compound 35 (0.11 g, 33%) was obtained from triphenylphosphonium (0.36 g, 0.69 mmol) and potassium carbonate (0.19 g, '1.38 mmol).
- step 1 of Example 29 4-hydroxybenzaldehyde (0.60 g, 4.91 mol), lithium carbonate (2.00 g, 14.5 ol) and-(2-chloroethyl) thiomorpholine obtained in step 1 (1.20 g) , 7.27 mmol) to give 4- (2-thiomorpholinoethoxy) benzaldehyde hydrochloride by treating with a 4 mol / L hydrogen chloride / ethyl acetate solution according to Step 2 of Example 2.
- Step 4 of Example 1 4_ (2-thiomorpholinoethoxy) benzaldehyde hydrochloride (1.00 g, 3.48 mmol) obtained in Step 2, iodinated (1-indazole-3-ylmethyl) Compound 36 (0.03 g, 3%) was obtained from refenylphosphonium (1.81 g, 3.48 mmol) and potassium carbonate (1.44 g, 10.4 mmol).
- Step 4 of Example 1 #-(4-formylphenoxy) acetylmorpholine (0.30 g, 1.20 mmol) obtained in Step 2, iodinated (1-indazol-3-ylmethyl) ) Compound 37 (0.24 g, 56%) was obtained from triphenylphosphonium (0.75 g, 1.44 mmol) and lithium carbonate- (0.50 g, 3.62 mmol).
- Step 5 of Example 1 3-hydroxy-4- (2-morpholinoethoxy) benzaldehyde (0.31 g, 1.23 mmol) obtained in Step 1, iodide (1-indazole-3-ylmethyl) ) Compound 39 (0.04 g, 153 ⁇ 4) was obtained from triphenylphosphonium (0.40 g, 0.77 mmol) and potassium carbonate (0.15 g, 1.09 mmol).
- Step 5 of Example 1 -(4-formyl-2-methoxyphenoxy) acetylmorpholine (0.85 g, 3.23 mmol) obtained in Step 1, iodide (1-indazole-3-ylmethyl) Compound 40 (0.11 g, 123 ⁇ 4) was obtained from triphenylphosphonium (2.00 g, 3.85 mmol) and potassium carbonate (1.34 g, 9.70 mmol).
- Step 5 of Example 1 3-methoxy-4- (4-pyridyloxy) benzaldehyde (0.27 g, 1.37 mmol) obtained in Step 1, iodide (1-indazole-3-ylmethyl)
- the free base of Compound 41 was obtained from triphenylphosphonium (0.85 g, 1.63 mmol) and potassium carbonate (0.57 g, 4.10 mmol).
- 4 mol / L hydrogen chloride monoacetic acid was used.
- Compound 41 (0.33 g, 64%) was obtained by treating with ethyl acetate.
- Step 3 of Example 35 a dimethyl acetal form of the 3-amino-4- (2-morpholinoethoxy) benzaldehyde obtained in Step 2 of Example 35 (0.31 g, 1.05 marl ol), acetic anhydride ( 0.50 mL, 5.30 band01) and pyridine (O.lO mL, 1.24 mmol) gave _ [5-formyl-2- (2-morpholinoethoxy) phenyl] acetamide (0.28 g, 91%). '
- Step 5 of Example 1 -[5-formyl-2- (2-morpholinoethoxy) phenyl] acetamide (0.22 g, 0.75 mmol ') obtained in Step 1 was prepared according to the procedure described in Step 1 of Example 1.
- Compound 42 (0.15 g, 50%) was obtained from (-methyl) triphenylphosphonium (0.34 g, 0.65 mmol) and potassium carbonate (0.18 g, 1.30 mmol).
- Step 37 of Example 37 4-hydroxy-3-methylbenzaldehyde (0.50 g, 3.67 mmol), ⁇ chloroacetylmorpholine (0.90 g, 5.55 mmol) obtained in Step 1 of Example 37, and carbonic acid From potassium (1.52 g, 11.0 ol),-(4-formyl-2-methylphenoxy) azetylmorpholine (0.50 g, 52%) was obtained.
- Step 5 of Example 1 #-(4-formyl-2-methylphenoxy) acetylmorpholine (0.50 g, 1.90 mmol) obtained in Step 1, iodinated (1-indazole-3-) Compound 43 (0.16 g, 22%) was obtained from (methyl) triphenylphosphonium (1.19 g, 2.29 mmol) and potassium carbonate (0.79 g, 5.70 mmol).
- Step 2 of Example 37 vanillin (1.00 g, 6.57 mmol), ⁇ dimethylchloroacetamide obtained in Step 1 (1.20 g, 9.88 ol) and potassium carbonate (3.40 g, 24.6 mmol) , -Dimethyl- (4-formyl-2-methoxyphenoxy) acetoamide (0.16 g, 10%) was obtained.
- Step 5 of Example 1 -dimethyl- (4-formyl_2-methoxyphenoxy) acetamide (0.16 g, 0.68 mmol) obtained in Step 2 and iodide (1-indazole-3- Compound 44 (0.14 g, 60%) was obtained from (methyl) triphenylphosphonium (0.42 g, 0.81 mmol) and potassium carbonate (0.28 g, 2.03 mmol).
- Step 1 DMF (0.20 mL, 2.58 mmol) was added to thionyl chloride (6.00 mL, 82.3 mmol), and the mixture was stirred at 45 ° C for 15 minutes.
- Picolinic acid (2.00 g, 16.3 mmol) was added to the reaction solution, and the mixture was stirred at 45 ° C for 45 minutes and further at 80 ° C for 3 days.
- chloroform and baking soda were added to the residue for extraction, and the organic layer was washed with saturated saline. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 4-chloropicolinic acid (2.78 g).
- the 4-chloropicolinic acid (2.78 g, 17.7 mmol) obtained in step 1 was dissolved in THF (50 mL), and methylamine hydrochloride (2.41 g, 35.7 mmol), trihydroxybenzotriazo monoluohydrate ( 3.61 g, 26.7 mmol) and triethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (5.13 g, 26.'8 mmol) were added, and the mixture was stirred at room temperature for 2 hours.
- Step 1 of Example 41 vanillin (0.45 g, 2.94 mmol), methyl-4-clopicolinic acid amide (0.50 g, 2.94 mmol) obtained in Step 2, and 4-dimethylaminopyridine (0.26 g) were used. g, 2.13 mmol) to give -methyl-4- (4-formyl-2-methoxyphenoxy) picolinamide (0.05 g, 6%).
- Step 2 of Example 44 4-hydroxy-3-methylbenzaldehyde (0.50 g, 3.67 mmol), ⁇ dimethylclomouth acetoamide (0.75 g, 6.13 mmol) obtained in Step 1 of Example 44, and carbonic acid V, -Dimethyl- (4-formyl-2-methylphenoxy) acetoamide (0.86 g, quantitative) was obtained from the potato (1.52 g, 11.0 mmol).
- Step 5 of Example 1 ⁇ dimethyl_ (4-formyl-2methylphenoxy) acetamide (0.68 g, 3.89 mmol), iodide (1-indazol-3-ylmethyl) obtained in Step 1 according to Step 5 of Example 1
- Compound 46 (0.52 g, 40%) was obtained from triphenylphosphonium (2.40 g, 4.62 mmol) and potassium carbonate (1.61 g, 11.7 mmol).
- Step 5 of Example 1 3-cyano-4-'(2'-morpholinoethoxy) benzaldehyde (0.24 g, 0.91 mmol) obtained in Step 1, iodide (1-indazole ⁇ 3-ylmethyl) ) Compound 47 (0.11 g, 333 ⁇ 4) was obtained from triphenylphosphonium (0.45 g, 0.87 mmol) and potassium carbonate (0.25 g, 1.82 mmol).
- Step 5 of Example 1 4- (4-acetylpiperazine-1-ylcarbonyl) methoxy-3-methylbenzaldehyde obtained in Step 1 (0.19 g, 0.64 mmol), iodide (1-indazole) Compound 49 (0.029 g, 16%) was obtained from (-3-ylmethyl) triphenylphosphonium (0.22 g, 0.43 mmol). And potassium carbonate (0.27 g, 1.9 mmol).
- Example 53 3- ⁇ 2- [4- (Piperazin_1-yl) phenyl] vinyl ⁇ -1-indazole hydrochloride (Compound 53)
- Compound 52 (2.78 g, 8.37 mmol) was dissolved in methanol (100 mL), 10% hydrogen chloride-methanol solution (20 mL) was added, and the mixture was heated with stirring at 60 for 3 hours.
- the solvent was distilled off from the reaction solution under reduced pressure, and the residue was crystallized from acetone and ethyl acetate to obtain Compound 53 (3.16 g, 100%).
- Step 3 of Example 57 () -3- ⁇ 2 -_ [4- (4-(/ er / _butoxycarbonyl) pidazine-1-yl) -3- obtained in Step 2
- Compound 59 (29 mg, 6.7%) was obtained from ditrophenyl] vinyl ⁇ -1-indazole (0.61 g, 1.4 mmol), concentrated hydrochloric acid (10 mL) and tin (0.48 g, 4.0 mmol).
- Example 61 compound 15 (0.50 g, 1.89 mmol), getylamine (0.29 niL, 2.80 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carposimid hydrochloride (0.51 g, 2.67 ol ol) ))
- acetic acid 5 mL
- 4 mol / L hydrogen chloride / ethyl acetate solution (1.00 mL
- the resulting precipitate was collected by filtration to give Compound 62 (0.11 g, 18%).
- Example 63 4- ⁇ 4- [2- (1-'indazol-3-yl) vinyl] benzoyl ⁇ pyrazine-1-carboxylic acid 1,1-dimethylethyl ester (Compound 63)
- Example 61 compound 15 (0.50 g, 1.89 mmol), 4-(/ er-butoxycarbonyl) pidazine (0.53 g, 2.84 mmol), trihydroxybenzotriazole monohydrate (0.33 g , 2.17 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carposimide hydrochloride (0.51 g, 2.66 mmol) to give compound 63 (0.27 g, 333 ⁇ 4).
- Example 61 compound 64 (0.40 g, 0.95 mmol), formic acid (0.03 mL), 1-hydroxybenzotriazo mono-hydrate (0.27 g, 1.96 mmol) and 1-ethyl_3- ( Compound 65 (0.34 g, 99%) was obtained from (3-dimethylaminopropyl) carpozimid hydrochloride (0.17 g, 0.90 mmol).
- Example 61 compound 15 (500 mg, 1.89 mmol), 1-piperazine carboxylic acid ethyl ester (0.42 mL, 2.84 mmol), trihydroxybenzotriazole hydrate (332 mg, 2.46 mmol), tritoxin Compound 66 (346 mg, 453 ⁇ 4) was obtained from ethyl_3- (3-dimethylaminopropyl) carboimide hydrochloride (510 mg, 2.67 mmol) and ⁇ methylmorpholine (0.42 mL, 3.82 mmol).
- Example 61 compound 15 (477 mg, 1.81 mmol), 4- (isonicotinyl) pidazine dihydrochloride (617 mg, 2.71 mmol), 1-hydroxybenzotriazole hydrate (332 mg , 2.46 mmol), triethyl-3_ (3-dimethylaminopropyl) carbodiimide hydrochloride (510 mg, 2.67 mmol) and ⁇ methylmorpholine (1.00 mL, 9.55 mmol) to give compound 67 (108 mg, 13%).
- dihydrochloride of compound 64 400 mg, 1.09. Bandol
- methoxyacetic acid 0.069 mL, 0.896 mmol
- 1-hydroxybenzotriazole-hydrate 173 mg, 1.28 mmol
- Compound 69 225 mg, 62%) was obtained from, triethyl_3- (3-dimethylaminopropyl) carbodiimide hydrochloride (265 mg, 1.38 mmol) and -methylmorpholine (0.40, mL, 3.64 mmol).
- Example 61 compound 15 (500 mg, 1.89 mmol), piperazine-2-amine (284 mg, 2.83 mmol), 1-hydroxybenzotriazo monoluohydrate (332 mg, 2.46 mmol) ), Triethyl_3_ (3-dimethylaminopropyl) carbodiimide hydrochloride (510 mg, 2.67 mmol) and -methylmorpholine (850 mL, 7.73 mmol) to give compound 70 (309 mg, 60%).
- Example 61 compound 15 (800 mg, 2.66 t ol), (pyrrolidine-3-yl) rubbamate-butyl ester (1.00 g, 5.32 mmol), trihydroxy benzotriazo monohydrate (470 mg) , 3.46 mmol), triethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (720 mg, 3.72 mmol) and N_methylmorpholine (0.58 mL, 5.32 mmol) were converted to methanol. (5.00 mL), 4 mol / L hydrogen chloride-methanol solution (2.00 mL) was added, and the mixture was heated under reflux at 60 ° C for 1 hour. The reaction solution was concentrated under reduced pressure, and crystallized from acetone to obtain Compound 71 (398 mg, 38%).
- Example 72 (-() _ 1_ ⁇ 4- [2- (1-Indazol-3-yl) vinyl] benzoyl ⁇ -4_ (pyrrolidine-3-ylcarbonyl) pidazine hydrochloride (Compound 72) Compound 64 (300 mg, 0.90 mmol), pyrrolidine-1,3-dicarboxylic acid tri-butyl ester (162 mg, 0.76 mmol), 1-hydroxybenzotriazo monohydrate (133 mg) according to Example 61 , 0.99 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (204 mg, 1.06 mmol) and N-methylmorpholine (0.17 mL, 1.52 mmol).
- dihydrochloride of compound 64 (100 mg, 0.25 mmol), N- ⁇ tert-butoxycarbonyl) -L-proline (53 mg, 0.25 mmol), trihydroxybenzotriazo mono-hydrate (43 mg, 0.33 mmol), 1-ethyl-3- (3-dimethyla
- the product obtained from (Minopropyl) carposimide hydrochloride (66 mg, 0.35 mmol) and -methylmorpholine (0.06 mL, 0.50 mmol) was dissolved in methanol (2.00 mL), and 4 mol / L hydrogen chloride-methanol solution ( (1.50 mL) and heated to reflux at 60 ° C for 30 minutes.
- the reaction solution was concentrated under reduced pressure, and the residue was extracted with saturated aqueous sodium hydrogen carbonate and ethyl acetate.
- the obtained crude product was crystallized from acetone to give compound 76 (21 mg, 20%).
- Example 61 the dihydrochloride of compound 64 (200 mg, 0.49 marl), trimethyl piperidine-4-carboxylic acid (70 mg, 0.49 mmol), 1-hydroxybenzotriazole hydrate (86 mg, 0.64 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (132 mg, 0.69 mmol) and ⁇ methylmorpholine (0.10 mL, 0.98 mmol) to give compound 77 (0.02 mg, 93 ⁇ 4).
- trimethyl piperidine-4-carboxylic acid 70 mg, 0.49 mmol
- 1-hydroxybenzotriazole hydrate 86 mg, 0.64 mmol
- 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 132 mg, 0.69 mmol
- ⁇ methylmorpholine (0.10 mL, 0.98 mmol
- the reaction solution was concentrated under reduced pressure, and a saturated aqueous potassium carbonate solution and ethyl acetate were added to the residue for extraction.
- the obtained crude product was crystallized from ethyl acetate to obtain Compound 78 (435 rag, 66%).
- Example 79 Formulation example (tablet)
- a tablet consisting of the following composition is prepared by a conventional method.
- a protein kinase inhibitor or the like containing an indazole derivative or a pharmacologically acceptable salt thereof as an active ingredient is provided.
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Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002518951A CA2518951A1 (en) | 2003-07-30 | 2004-07-30 | Protein kinase inhibitors |
EP04771303A EP1650194A4 (en) | 2003-07-30 | 2004-07-30 | INHIBITOR OF PROTEIN KINASE |
JP2005512593A JP4363530B2 (ja) | 2003-07-30 | 2004-07-30 | タンパク質キナーゼ阻害剤 |
AU2004260759A AU2004260759B2 (en) | 2003-07-30 | 2004-07-30 | Protein kinase inhibitors |
US10/548,592 US20060281789A1 (en) | 2003-07-30 | 2004-07-30 | Protein kinase inhibitors |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2003-203509 | 2003-07-30 | ||
JP2003203509 | 2003-07-30 |
Publications (1)
Publication Number | Publication Date |
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WO2005012258A1 true WO2005012258A1 (ja) | 2005-02-10 |
Family
ID=34113615
Family Applications (1)
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---|---|---|---|
PCT/JP2004/011300 WO2005012258A1 (ja) | 2003-07-30 | 2004-07-30 | タンパク質キナーゼ阻害剤 |
Country Status (6)
Country | Link |
---|---|
US (1) | US20060281789A1 (ja) |
EP (1) | EP1650194A4 (ja) |
JP (1) | JP4363530B2 (ja) |
AU (1) | AU2004260759B2 (ja) |
CA (1) | CA2518951A1 (ja) |
WO (1) | WO2005012258A1 (ja) |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005094823A1 (ja) * | 2004-03-30 | 2005-10-13 | Kyowa Hakko Kogyo Co., Ltd. | Flt-3阻害剤 |
WO2006080450A1 (ja) * | 2005-01-27 | 2006-08-03 | Kyowa Hakko Kogyo Co., Ltd. | Igf-1r阻害剤 |
WO2008001886A1 (fr) | 2006-06-30 | 2008-01-03 | Kyowa Hakko Kirin Co., Ltd. | Inhibiteur d'aurora |
WO2008001885A1 (fr) | 2006-06-30 | 2008-01-03 | Kyowa Hakko Kirin Co., Ltd. | INHIBITEUR DE KINASE Abl |
WO2008020606A1 (fr) * | 2006-08-16 | 2008-02-21 | Kyowa Hakko Kirin Co., Ltd. | Agent anti-angiogénique |
WO2008108386A1 (ja) | 2007-03-05 | 2008-09-12 | Kyowa Hakko Kirin Co., Ltd. | 医薬組成物 |
WO2008111441A1 (ja) | 2007-03-05 | 2008-09-18 | Kyowa Hakko Kirin Co., Ltd. | 医薬組成物 |
WO2008114812A1 (ja) * | 2007-03-19 | 2008-09-25 | Kyowa Hakko Kirin Co., Ltd. | Jak阻害剤 |
JP4975616B2 (ja) * | 2005-04-28 | 2012-07-11 | 協和発酵キリン株式会社 | インダゾール−3−イルメチルホスホニウム塩の製造法 |
CN103804298A (zh) * | 2012-11-09 | 2014-05-21 | 韩冰 | 一类治疗青光眼的化合物及其用途 |
CN103816157A (zh) * | 2012-11-16 | 2014-05-28 | 常辉 | 一类治疗溃疡性结肠炎的化合物及其用途 |
WO2018151126A1 (ja) * | 2017-02-14 | 2018-08-23 | 富士フイルム株式会社 | インダゾール化合物の製造方法およびインダゾール化合物 |
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EP2308866A1 (de) | 2009-10-09 | 2011-04-13 | Bayer CropScience AG | Phenylpyri(mi)dinylpyrazole und ihre Verwendung als Fungizide |
WO2012175513A1 (en) | 2011-06-20 | 2012-12-27 | Bayer Intellectual Property Gmbh | Thienylpyri(mi)dinylpyrazole |
KR20140072177A (ko) | 2011-10-06 | 2014-06-12 | 바이엘 인텔렉쳐 프로퍼티 게엠베하 | 헤테로사이클릴피리(미)디닐피라졸 |
KR20140080522A (ko) | 2011-10-06 | 2014-06-30 | 바이엘 인텔렉쳐 프로퍼티 게엠베하 | 살진균제로서의 헤테로시클릴피리(미)디닐피라졸 |
GB201511382D0 (en) | 2015-06-29 | 2015-08-12 | Imp Innovations Ltd | Novel compounds and their use in therapy |
CN106220587B (zh) * | 2016-08-15 | 2018-05-18 | 辽宁中医药大学 | 马齿苋中两种生物碱化合物及其提取分离方法 |
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JPH0232059A (ja) * | 1988-07-18 | 1990-02-01 | Kyowa Hakko Kogyo Co Ltd | インダゾール誘導体 |
WO2002010137A2 (en) * | 2000-07-31 | 2002-02-07 | Signal Pharmaceuticals, Inc. | Indazole derivatives as jnk inhibitors |
JP2003503481A (ja) * | 1999-07-02 | 2003-01-28 | アゴウロン・ファーマスーティカルス・インコーポレーテッド | インダゾール及びプロテインキナーゼ阻害のためのその使用 |
JP2003520273A (ja) * | 2000-01-18 | 2003-07-02 | アゴウロン・ファーマスーティカルス・インコーポレーテッド | インダゾール化合物、医薬組成物及び細胞増殖を誘発又は阻害する方法 |
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JP2570424B2 (ja) * | 1989-06-29 | 1997-01-08 | 日本電気株式会社 | 半導体受光素子 |
US6632815B2 (en) * | 1999-09-17 | 2003-10-14 | Millennium Pharmaceuticals, Inc. | Inhibitors of factor Xa |
US7238853B2 (en) * | 2000-07-14 | 2007-07-03 | Unicrop Ltd | Molecular mechanisms for gene containment in plants |
US7211594B2 (en) * | 2000-07-31 | 2007-05-01 | Signal Pharmaceuticals, Llc | Indazole compounds and compositions thereof as JNK inhibitors and for the treatment of diseases associated therewith |
US20050009876A1 (en) * | 2000-07-31 | 2005-01-13 | Bhagwat Shripad S. | Indazole compounds, compositions thereof and methods of treatment therewith |
ATE449763T1 (de) * | 2001-04-16 | 2009-12-15 | Eisai R&D Man Co Ltd | 1h-indazolverbindungen die jnk hemmen |
AU2003241925A1 (en) * | 2002-05-31 | 2003-12-19 | Eisai R&D Management Co., Ltd. | Pyrazole compound and medicinal composition containing the same |
AU2003289287A1 (en) * | 2002-12-03 | 2004-06-23 | Kyowa Hakko Kogyo Co., Ltd. | Jnk inhibitor |
-
2004
- 2004-07-30 JP JP2005512593A patent/JP4363530B2/ja not_active Expired - Fee Related
- 2004-07-30 AU AU2004260759A patent/AU2004260759B2/en not_active Ceased
- 2004-07-30 EP EP04771303A patent/EP1650194A4/en not_active Withdrawn
- 2004-07-30 CA CA002518951A patent/CA2518951A1/en not_active Abandoned
- 2004-07-30 US US10/548,592 patent/US20060281789A1/en not_active Abandoned
- 2004-07-30 WO PCT/JP2004/011300 patent/WO2005012258A1/ja active Application Filing
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JPH0232059A (ja) * | 1988-07-18 | 1990-02-01 | Kyowa Hakko Kogyo Co Ltd | インダゾール誘導体 |
JP2003503481A (ja) * | 1999-07-02 | 2003-01-28 | アゴウロン・ファーマスーティカルス・インコーポレーテッド | インダゾール及びプロテインキナーゼ阻害のためのその使用 |
JP2003520273A (ja) * | 2000-01-18 | 2003-07-02 | アゴウロン・ファーマスーティカルス・インコーポレーテッド | インダゾール化合物、医薬組成物及び細胞増殖を誘発又は阻害する方法 |
WO2002010137A2 (en) * | 2000-07-31 | 2002-02-07 | Signal Pharmaceuticals, Inc. | Indazole derivatives as jnk inhibitors |
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Cited By (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005094823A1 (ja) * | 2004-03-30 | 2005-10-13 | Kyowa Hakko Kogyo Co., Ltd. | Flt-3阻害剤 |
US7605272B2 (en) | 2005-01-27 | 2009-10-20 | Kyowa Hakko Kirin Co., Ltd. | IGF-1R inhibitor |
WO2006080450A1 (ja) * | 2005-01-27 | 2006-08-03 | Kyowa Hakko Kogyo Co., Ltd. | Igf-1r阻害剤 |
AU2006209712B2 (en) * | 2005-01-27 | 2011-06-09 | Kyowa Hakko Kirin Co., Ltd. | IGF-1R inhibitor |
JP4975616B2 (ja) * | 2005-04-28 | 2012-07-11 | 協和発酵キリン株式会社 | インダゾール−3−イルメチルホスホニウム塩の製造法 |
WO2008001886A1 (fr) | 2006-06-30 | 2008-01-03 | Kyowa Hakko Kirin Co., Ltd. | Inhibiteur d'aurora |
WO2008001885A1 (fr) | 2006-06-30 | 2008-01-03 | Kyowa Hakko Kirin Co., Ltd. | INHIBITEUR DE KINASE Abl |
WO2008020606A1 (fr) * | 2006-08-16 | 2008-02-21 | Kyowa Hakko Kirin Co., Ltd. | Agent anti-angiogénique |
WO2008111441A1 (ja) | 2007-03-05 | 2008-09-18 | Kyowa Hakko Kirin Co., Ltd. | 医薬組成物 |
WO2008108386A1 (ja) | 2007-03-05 | 2008-09-12 | Kyowa Hakko Kirin Co., Ltd. | 医薬組成物 |
EP2543390A1 (en) | 2007-03-05 | 2013-01-09 | Kyowa Hakko Kirin Co., Ltd. | Pharmaceutical composition |
WO2008114812A1 (ja) * | 2007-03-19 | 2008-09-25 | Kyowa Hakko Kirin Co., Ltd. | Jak阻害剤 |
CN103804298A (zh) * | 2012-11-09 | 2014-05-21 | 韩冰 | 一类治疗青光眼的化合物及其用途 |
CN103816157A (zh) * | 2012-11-16 | 2014-05-28 | 常辉 | 一类治疗溃疡性结肠炎的化合物及其用途 |
WO2018151126A1 (ja) * | 2017-02-14 | 2018-08-23 | 富士フイルム株式会社 | インダゾール化合物の製造方法およびインダゾール化合物 |
JPWO2018151126A1 (ja) * | 2017-02-14 | 2019-11-14 | 富士フイルム株式会社 | インダゾール化合物の製造方法およびインダゾール化合物 |
US10689358B2 (en) | 2017-02-14 | 2020-06-23 | Fujifilm Corporation | Method for producing indazole compound, and indazole compound |
Also Published As
Publication number | Publication date |
---|---|
EP1650194A1 (en) | 2006-04-26 |
JPWO2005012258A1 (ja) | 2006-09-14 |
EP1650194A4 (en) | 2008-10-01 |
JP4363530B2 (ja) | 2009-11-11 |
US20060281789A1 (en) | 2006-12-14 |
AU2004260759A1 (en) | 2005-02-10 |
CA2518951A1 (en) | 2005-02-10 |
AU2004260759B2 (en) | 2010-04-22 |
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