WO2008020606A1 - Agent anti-angiogénique - Google Patents

Agent anti-angiogénique Download PDF

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Publication number
WO2008020606A1
WO2008020606A1 PCT/JP2007/065932 JP2007065932W WO2008020606A1 WO 2008020606 A1 WO2008020606 A1 WO 2008020606A1 JP 2007065932 W JP2007065932 W JP 2007065932W WO 2008020606 A1 WO2008020606 A1 WO 2008020606A1
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substituted
unsubstituted
angiogenesis
acceptable salt
growth factor
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PCT/JP2007/065932
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English (en)
Japanese (ja)
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Yukimasa Shiotsu
Hiroshi Umehara
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Kyowa Hakko Kirin Co., Ltd.
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Priority to JP2008529873A priority Critical patent/JPWO2008020606A1/ja
Publication of WO2008020606A1 publication Critical patent/WO2008020606A1/fr

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    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to an angiogenesis inhibitor and the like containing an indazole derivative or a pharmacologically acceptable salt thereof as an active ingredient.
  • Angiogenesis is also involved in the regeneration of tissues in the active adults [Nature Review Cancer, Vol. 2, 727 (2002)] In the pathological state, angiogenesis is deeply involved in the formation or promotion of solid tumor growth or metastasis, diabetic retinopathy and rheumatoid arthritis. Angiogenesis also plays a very important role in the process of tumor development and growth, and the tumor itself releases factors that promote angiogenesis, resulting in vascular endothelial cells, fibroblasts, stromal cells, lymphatic vessels. Tumor environment has been constructed by drawing around the tumor [Cell, 100, 57 (2000)].
  • VEGF vascular endothelial growth factor
  • FGF fibroblast growth factor
  • PDG F Angiopoietin
  • EPH Ephrin
  • Vascula r endothelial growth factor receptor (ViiGFR), a receptor-type protein tyrosine kinase, is activated by dimerization by binding to its efcoViiG, It is an enzyme that phosphorylates various proteins that are intracellular substrates VEGFR has three known subtypes, VEGFR1 to VEGFR3, and these VEGFRs play an important role in cell proliferation and differentiation of vascular endothelial cells.
  • VEGFR1 is also known as fins-like tyrosine kinase 1 (FLT1) and VEGFR2 is also known as kinase insert domain-containing rec tor (KDR).
  • FLT1 fins-like tyrosine kinase 1
  • KDR kinase insert domain-containing rec tor
  • VEGFR3 also known as fms-like tyrosine kinase 4 (FLT4)
  • FLT4 fms-like tyrosine kinase 4
  • Sunitinib a drug that inhibits FLT1 and KDR, has been shown to be effective as a new stake cancer agent in kidney cancer, and V EGFR inhibitors are considered to be useful as cancer treatments.
  • Fibroblast growth factor receptor a receptor protein tyrosine kinase, is activated by dimerization by the binding of its ligand, FGF, and is an intracellular substrate. It is an enzyme that phosphorylates various proteins.
  • FGF ligand
  • FGFR4 Fibroblast growth factor receptor
  • FGFRs play an important role in fibroblast cell proliferation and differentiation [Expert Opinion on Therapeutic Targets], 6, 469 (2002) ].
  • fibroblasts surround the tumor and are thought to play an important role in tumor growth [Cell, 100, 57 (2000)].
  • FGFR3 gene overexpression is caused by chromosomal translocation, as a result of examination in patient specimens [Blood, Vol. 92, p. 3025] (1998)].
  • FGF expression is high in the bone marrow of patients with multiple myeloma, and activation of FGFR signal is considered to occur in multiple myeloma cells expressing FGFR3 [Blood, Vol. 101, 2775 (2003)].
  • FGFR3 active mutations are known in multiple myeloma cell lines and patient specimens, and such constitutive activation leads to infinite proliferation of cells by transmitting cell proliferation signals, resulting in multiple It is thought to be an important cause of myeloma [Blood, 97, 729 (2001)].
  • FGF or FGFR overexpression and active type mutations other than multiple myeloma for example, pituitary tumor, myeloproliferative disease, renal cancer, bladder cancer, colon cancer, head and neck cancer, skin cancer
  • Gastric cancer, non-Hodgkin lymphoma, brain tumor, breast cancer, ovarian cancer, etc. Gastric cancer, non-Hodgkin lymphoma, brain tumor, breast cancer, ovarian cancer, etc.
  • FGFR inhibitors are thought to be useful as therapeutic agents for various cancers.
  • PDGF Platelet derived growth factor receptor
  • the ephrin receptor has 16 types of subtypes, A1 to A10 and B1 to B6, and phosphorylates various proteins in the cell by the binding of its ligand EPH.
  • EPH ligand
  • Patent Document 1 Japanese Patent Laid-Open No. 2-32059
  • Patent Document 2 Pamphlet of International Publication No. 01/53268
  • Patent Document 3 International Publication No. 02/10137 Pamphlet
  • Patent Document 4 Pamphlet of International Publication No. 01/02369
  • Patent Document 5 Pamphlet of International Publication No. 02/083648
  • Patent Document 6 Pamphlet of International Publication No. 03/101968
  • Patent Document 7 International Publication No. 2004/094388 Pamphlet
  • Patent Document 8 International Publication No. 2004/050088 Pamphlet
  • Patent Document 9 International Publication No. 2005/0137171 Pamphlet
  • Patent Document 10 International Publication No. 2005/012257 Pamphlet
  • Patent Document 11 Pamphlet of International Publication No. 2005/012258
  • Patent Document 12 International Publication No. 2005/094823 Pamphlet
  • Non-Patent Document 1 Kimiya 'Geterotsik licheskikh Soedinenii', 1978, Vol. 7, ⁇ ⁇ 957-959
  • An object of the present invention is to provide an angiogenesis inhibitor containing an indazole derivative or a pharmacologically acceptable salt thereof as an active ingredient.
  • the present invention relates to the following (1) to (54).
  • R 1 represents a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group
  • Inhibitor a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group
  • R 2 is CONR 4a R 4b (wherein R 4a and R 4b are the same or different and represent a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted aryl, a substituted Or a force representing an unsubstituted aralkyl or a substituted or unsubstituted heterocyclic group, or R 4a and R 4b together with the adjacent nitrogen atom to form a substituted or unsubstituted heterocyclic group) or NR 5a R 5b (wherein R 5a represents a substituted or unsubstituted lower alkylsulfonyl or a substituted or unsubstituted arylolsulfonyl, R 5b represents a hydrogen atom or a substituted or unsubstituted lower alkyl),
  • R 3 is a hydrogen atom, halogen, cyano, nitro, hydroxy, carboxy, lower alkoxy group sulfonyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkanol, CONR 6a R 6b (Wherein R 6a and R 6b are the same or different and each represents a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, or a substituted or unsubstituted heterocyclic group; Or R 6a and R 6b together with the adjacent nitrogen atom form a substituted or unsubstituted heterocyclic group) or NR 7a R 7b (wherein R 7a and R 7b are the same or Differently from a hydrogen atom, substituted or unsubstituted lower alkyl
  • R 2 is CONR 4e R 4d (wherein R 4e and R 4d together with the adjacent nitrogen atom form a substituted or unsubstituted heterocyclic group), and R 3 is hydrogen
  • R 8a , R 8b and R 8e are the same or different, and are a hydrogen atom, halogen, nitro, nitroso, carboxy, siryl substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkanol.
  • R 8a , R 8b and R is NR 9e R 9d (wherein R 9e and R 9d are the same or different and represent a hydrogen atom or a substituted or unsubstituted lower alkanol, Or an angiogenesis inhibitor according to (7) above, wherein R and R 9d together with the adjacent nitrogen atom form a substituted or unsubstituted heterocyclic group).
  • angiogenesis inhibitor comprising as an active ingredient an indazole derivative represented by the formula or a pharmacologically acceptable salt thereof.
  • an angiogenesis inhibitor comprising as an active ingredient an indazole derivative represented by the formula or a pharmaceutically acceptable salt thereof.
  • R u is a substituted or unsubstituted heterocyclic group
  • substituted heterocyclic group are the same or different and have 1 to 3 substituents of oxo, formyl, carboxy, lower alkoxy groups
  • Luponyl substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy
  • CONR 12a R 12b (wherein R 12a and R 12b are the same or different and are a hydrogen atom or a substituted or unsubstituted lower alkyl.
  • NR 13a R 13b (wherein R 13a and R 13b are the same or different and each represents a hydrogen atom, lower alkanol, lower alkoxycarbonyl, aralkyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted Of aryl, substituted or unsubstituted aroyl or substituted or unsubstituted heterocyclic group) or -0 (CR 14a R 14b ) 0- (formula
  • R 14a and R 14b are the same or different and each represents a hydrogen atom or lower alkyl, n represents 2 or 3, and the two oxygen atoms at the ends are the same carbon atom on the heterocyclic group in the substituted heterocyclic group
  • An indazole derivative represented by the above formula or a pharmaceutically acceptable salt thereof as an active ingredient is the same or different and each represents a hydrogen atom or lower alkyl, n represents 2 or 3, and the two oxygen atoms at the ends are the same carbon atom on the heterocyclic group in the substituted heterocyclic group
  • An indazole derivative represented by the above formula or a pharmaceutically acceptable salt thereof as an active ingredient is an indazole derivative represented by the above formula or a pharmaceutically acceptable salt thereof as an active ingredient.
  • An inhibitor of a kinase involved in angiogenesis comprising the indazole derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (16) as an active ingredient.
  • VAGFR Vascular Endothelial Growth Factor Receptor
  • VEGFR1 vascular endothelial growth factor receptor 1
  • FLT1 fins_like tyrosine kinase 1
  • VEG R2 Vascular Endothelial Growth Factor Receptor 2
  • K DR kinase insert domain-containing receptor
  • a therapeutic agent for a disease associated with angiogenesis comprising the indazole derivative according to any one of (1) to (16) or a pharmacologically acceptable salt thereof as an active ingredient.
  • a therapeutic agent for rheumatism comprising the indazole derivative or the pharmacologically acceptable salt thereof according to any one of (1) to (16) as an active ingredient.
  • An anticancer agent comprising the indazole derivative or the pharmacologically acceptable salt thereof according to any one of (1) to (16) as an active ingredient.
  • a method for inhibiting angiogenesis comprising a step of administering an effective amount of the indazole derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (16).
  • a method for inhibiting a kinase involved in angiogenesis comprising a step of administering an effective amount of the indazole derivative or the pharmacologically acceptable salt thereof according to any one of (1) to (16).
  • the kinase that is involved in angiogenesis is a fibroblast growth factor receptor (30) The described inhibition method.
  • a method for treating a disease associated with angiogenesis comprising a step of administering an effective amount of the indazole derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (16).
  • a method for treating rheumatism comprising a step of administering an effective amount of the indazole derivative or the pharmacologically acceptable salt thereof according to any one of (1) to (16).
  • a method for treating cancer comprising a step of administering an effective amount of the indazole derivative or the pharmacologically acceptable salt thereof according to any one of (1) to (16).
  • renal cancer comprising a step of administering an effective amount of the indazole derivative or the pharmacologically acceptable salt thereof according to any one of (1) to (16) A method for treating cancer selected from cancer, prostate cancer and ovarian cancer.
  • the present invention provides an angiogenesis inhibitor and the like containing an indazole derivative or a pharmacologically acceptable salt thereof as an active ingredient.
  • Fig. 1 is a view showing the intensity of a CD31 positive portion in a tumor.
  • the test used two mice in each group, and two microscopic images were obtained from each mouse.
  • Each graph represents the average of the two CD positive parts of each mouse.
  • the vertical axis represents the sum total of CD31 positive parts quantified by ImageJ software.
  • Halogen includes fluorine, chlorine, bromine and iodine atoms.
  • Lower alkyl, lower alkoxy, lower alkoxycarbonyl, lower alkoxy force examples of the lower alkyl moiety of noreblonamino, lower alkoxycarbonyl-substituted lower alkyl, and lower alkylsulfonyl include, for example, alkyl having 1 to 10 carbon atoms, linear, branched, cyclic, or a combination thereof. In fact
  • (ii-a) linear or branched lower alkyl includes, for example, methyl, ethyl, n-propinole, isopropyl, n-butynole, isobutyl, sec-butyl, tert-butyl, n_pentinole, neopentyl, n-hexyl, n-heptyl, n-octyl, n_nonyl, n_decyl, etc.
  • Examples of (ii-b) cyclic lower alkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, noradamantyl, adamantyl, bicyclo [2.2.1] heptyl, bicyclo [2 ⁇ 2.2] octyl, bicyclo [3.3.0] octinore, bicyclo [3.3.1] nonyl and the like.
  • the lower alkyl comprising a combination of linear or branched and cyclic is as follows.
  • the lower alkoxycarbonyl-substituted lower alkyl and the alkylene part of the aralkyl are the same as those obtained by removing one hydrogen atom from the linear or branched lower alkyl (ii-a).
  • Lower alkenyl includes, for example, straight-chain or branched alkenyl having 2 to 10 carbon atoms, and more specifically, bur, allyl, 1-propenyl, 1-butyr, 3- Examples include butenyl, 2-pentenyl, 4-pentenyl, 2-hexenyl, 5-hexenyl, 2-decenyl and 9-decenyl.
  • Examples of (V) lower alkynyl include straight chain or branched chain anolequinyl having 2 to 10 carbon atoms, and more specifically, ethur, 2-probule, 3-butul, 4-pentur, 5-hexul, 9-decynyl and the like.
  • aryl moiety in aryl, alanolequinole, aroinore, aroylamino and allylsulfonyl is, for example, monocyclic or a condensed arylene in which two or more rings are condensed, more specifically, a ring-constituting carbon atom.
  • aryl, eg phenyl, naphth Examples include chill, indul, anthranyl and the like.
  • alkanoyl for example, an alkanol composed of straight, branched, cyclic, or a combination thereof having 1 to 8 carbon atoms, more specifically formyl, acetyl, propionyl, butyrinole, isobutyryl, Norelinore, isovaleryl, pivalol, hexanoyl, heptanol, otatanol, cyclopropylcarbonyl, cyclobutylcarboninole
  • Cyclopentinorecanenopononole Cyclopentinorecanenopononole, cyclopropinoremethinorecanenopononole, cyclohexenorenorebonyl, 1-methylcyclopropylcarbonyl, cycloheptylcarbonyl and the like.
  • heterocyclic group examples include an aromatic heterocyclic group and an alicyclic heterocyclic group.
  • the (viii-a) aromatic heterocyclic group includes, for example, a monocyclic or a condensed aromatic heterocyclic group in which two or more rings are condensed, and is included in the aromatic heterocyclic group
  • the type and number of heteroatoms to be selected are not particularly limited.
  • the heteroatom may contain one or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom.
  • Aromatic heterocyclic groups having 5 to 14 ring atoms such as furyl, chenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazo'linole, pyridinore, pyrajinole, pyrimidinole, pyridazinole, tridinole , Indolinol, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinole, isoquinolyl, phthalazi Le, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, purinyl, coumarinyl and the like.
  • the (viii-b) alicyclic heterocyclic group includes, for example, a monocyclic or a condensed alicyclic heterocyclic group in which two or more rings are condensed, and the like.
  • the type and number of heteroatoms contained in the group are not particularly limited.
  • the heteroatom may contain one or more heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen atoms.
  • heterocyclic group formed together with the adjacent nitrogen atom examples include, for example, a 5-membered or 6-membered monocyclic heterocyclic group containing at least one nitrogen atom (the monocyclic heterocyclic ring).
  • the group may contain other nitrogen, oxygen or sulfur atoms), a bicyclic or tricyclic fused ring with 3 to 8 members and a condensed heterocyclic ring containing at least one nitrogen atom Group (the condensed heterocyclic group may contain other nitrogen atom, oxygen atom or sulfur atom) and the like, and more specifically, pyrrolidinyl, piperidyl-containing piperazil, monoreforino, thiomol.
  • Examples include holino, homopiperidino, homopiperadur, tetrahydropyridyl, tetrahydroquinolyl, tetrahydroisoquinolyl and the like.
  • heteroaryl moiety in (X) heteroaroyl is the same as the aromatic heterocyclic group (viii-a).
  • Substituents in substituted lower alkyl, substituted lower alkoxy, substituted lower alkenyl, substituted lower alkynyl, substituted lower alkanol, substituted lower alkoxycarbonyl and substituted lower alkylsulfonyl are the same or different, for example, substituted Number 1-3,
  • R 15a and R 15b are the same or different and are each a hydrogen atom or a substituted or unsubstituted lower alkyl
  • the substituent in the substituted lower alkyl is, for example, Halogen, hydroxy, oxo, nitro, cyan, carboxy, lower alkanol, lower alkoxycarbonyl, aroyl, substituted or unsubstituted lower alkoxy having 1 to 3 substitutions (substituents in the substituted lower alkoxy are, for example, 1 to 3 substitutions)
  • R 15a and R 15b together with the adjacent nitrogen atom are substituted or unsubstituted heterocyclic groups [with the adjacent nitrogen atom
  • Substituents in the substituted heterocyclic group thus formed are, for example, halogen, hydroxy, oxo, nitro, cyano, carboxy, lower alkanol, lower alkoxycarbonyl, aralkyl, arol
  • Lower alkyl (the substituent in the substituted lower alkyl is, for example, hydroxy having 1 to 3 substituents), Substituted or unsubstituted lower alkoxy (substituent in the substituted lower alkoxy is, for example, hydroxy having 1 to 3 substituents), etc. ⁇
  • the halogen is the above (i)
  • the lower alkyl part of lower alkyl, lower alkoxy, lower alkoxycarbonyl, and N-lower alkanoleno-N-lower alkylamino is as defined above (ii)
  • the alkylene part of aralkyl is as defined above (iii).
  • aryl moiety in aryl, aralkyl, aryl and arylsulfonyl is as defined in (vi) above, and the lower alkanoyl moiety of lower alkanoyl, lower alkanoylamino and N-lower alkanoyl-N-lower alkylamino.
  • the heterocyclic group is as defined in (viii) above.
  • the heterocyclic group formed together with the adjacent nitrogen atom has the same meaning as the above (ix), and the heteroaryl has the same meaning as the above (X).
  • Substituents in substituted heterocyclic groups formed together with substituted aryl, substituted aryl, substituted aralkyl, substituted arylsulfonyl, substituted heteroaroyl, substituted heterocyclic groups and adjacent nitrogen atoms include The same or different, for example 1 to 3 substitutions, (xiHa) Norogen,
  • substituted aryl substituted or unsubstituted or unsubstituted aryl
  • substituted aryl include, for example, halogen, hydroxy, nitro, carboxy-substituted, lower alkanol, lower alkoxycarbonyl, aralkyl, aroyl, substituted, Unsubstituted lower alkynole (the substituent in the substituted lower alkyl is, for example, hydroxy having 1 to 3 substituents), substituted or unsubstituted lower alkoxy (the substituent in the substituted lower alkoxy is, for example, substituted 1 ⁇ 3 hydroxy and the like)],
  • R 17a and R 17b are the same or different and each represents a hydrogen atom, a lower alkenylsulfonyl, a substituted or unsubstituted lower alkyl.
  • a substituted or unsubstituted lower alkenyl [the substituent in the substituted lower alkenyl has the same meaning as the above (xi)], a substituted or unsubstituted lower alkynyl [substitution in the substituted lower alkynyl].
  • the group is as defined in the above (xi)], a substituted or unsubstituted lower alkoxy [the substituent in the substituted lower alkoxy is as defined in the above (xi)], a substituted or unsubstituted lower alkanol [the group The substituents in the substituted lower alkanol are as defined in the above (xi)], substituted or unsubstituted aryl
  • substituents in the substituted aryl include halogen having 1 to 3 substituents, hydroxy, nitro, cyan, carboxy, lower alkanol, lower alkoxycarbonyl, aralkyl, aryl, substituted or unsubstituted lower alkyl (the substituted lower alkyl).
  • the substituent in is, 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), etc. ],
  • Substituted or unsubstituted aroyl are, for example, halogen, hydroxy, nitro, carboxy-substituted, lower alkanoyl, lower alkoxycarbonyl, aralkyl, aroyl, substituted or unsubstituted, substituted 1 to 3 Lower alkynole (the substituent in the substituted lower alkyl is Substituted or unsubstituted lower alkoxy (substituent in the substituted lower alkoxy is, for example, hydroxy having 1 to 3 substituents) or the like] or substituted or non-substituted Substituted heterocyclic group [Substituents in
  • Lower alkyl substituted or unsubstituted lower alkoxy (substituent in the substituted lower alkoxy is, for example, having 1 to 3 substituents) Or the like, or R 1 and R are substituted or non-bonded together with the adjacent nitrogen atom.
  • Substituted heterocyclic group is, for example, halogen having 1 to 3 substituents, amidonitro, hydroxy, oxo, cyan, canolepoxy , Lower alkoxycarbonyl, aranolyl, alloy, heteroaroyl, substituted or unsubstituted lower alkyl (substituents in the substituted lower alkyl are, for example, hydroxy having 1 to 3 substituents, lower alkoxy, etc.), substituted Is an unsubstituted lower alkoxy (substituent in the substituted lower alkoxy is, for example, hydroxy having 1 to 3 substituents, lower alkoxy, etc.), a substituted or unsubstituted lower alkyl group (substituent in the substituted lower alkanol) Is, for example, an amino-substituted hydroxyl group having 1 to 3 substitutions, a lower al
  • substituted or unsubstituted alicyclic heterocyclic carbonyl includes, for example, a halogen having 1 to 3 substituents, hydroxy, Are oxo, lower alkyl, lower alkoxy, etc.
  • R 19 is a hydrogen atom, a substituted or unsubstituted lower alkyl [the substituent in the substituted lower alkyl has the same meaning as in the above (xi)], a substituted or unsubstituted alkyl Reel
  • substituted or unsubstituted alkyl Reel include, for example, halogen having 1 to 3 substituents, hydroxy, nitro, cyano, carboxy, lower alkanol, lower alkoxycarbonyl, aralkylenoyl, aroyl, substituted or unsubstituted lower alkyl (including Substituents in substituted lower alkyl are, for example, hydroxy having 1 to 3 substituents, and substituted or unsubstituted lower alkoxy (substituents in the substituted lower alkoxy are, for example, hydroxy having 1 to 3 substituents) Or a substituted or unsubstituted heterocyclic group [the substitution or a substituted or
  • the substituents in the substituted heterocyclic group formed together with the substituted heterocyclic group and the adjacent nitrogen atom include the following (xii-p) or (Xii-q) may also be used.
  • na represents 2 or 3
  • the two oxygen atoms at the ends are identical on the heterocyclic group in the substituted heterocyclic group or a substituted heterocyclic group formed together with the adjacent nitrogen atom To carbon atoms
  • halogen is as defined in (i) above, and lower alkyl, lower alkoxy , Lower alkoxycarbonyl, N-lower alkanoyl-N-lower alkylamino, and lower alkyl moiety of lower alkylsulfonyl are as defined in (ii) above, and the alkylene moiety of aralkyl is as defined in (iii) above.
  • Alkenyl has the same meaning as the above (iv)
  • lower alkynyl has the same meaning as the above (V)
  • the aryl moiety of the aryleno, aroyl and aralkyl has the same meaning as the above (vi)
  • the lower alkanoyl part of the lower alkanoyl-N-lower alkylamino is as defined in the above (vii)
  • the heterocyclic group is as defined in the above (viii).
  • the alicyclic heterocyclic group moiety in the alicyclic heterocyclic force luponyl has the same meaning as the above (viii-b), and the heterocyclic group formed together with the adjacent nitrogen atom is the same as the above (ix). Heteroyl is synonymous with the above (X).
  • the pharmacologically acceptable salts of the compounds (1), (la), (lb), (lb-1), (Ib_2) and (Ic) include, for example, pharmacologically acceptable acids.
  • examples include addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like.
  • Acid addition salts include inorganic acid salts such as hydrochloride, sulfate, and phosphate, organic salts such as acetate, maleate, fumarate, tartrate, citrate, lactate, aspartate, and glutamate.
  • 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, and zinc salts.
  • Ammonium salts include Examples include salts such as ammonium and tetramethylammonium.
  • organic amine addition salts include addition salts such as morpholine and piperidine.
  • amino acid addition salts include lysine, glycine, and phenylalanine. Addition salts are mentioned.
  • Salts of compounds (I), (la), (lb), (lb-1), (lb-2) and (Ic) were obtained! /,
  • compound (1), ( la), (lb), (lb-1), (Ib-2) and (Ic) can be purified as they are in the salt form, or in a suitable solvent if they are obtained in the free form.
  • Compounds (1), (la), (lb), (lb -1), (Ib-2) and (Ic) may be dissolved or suspended, and an acid or a base may be added to form a salt.
  • Compounds (I), (la), (lb), (lb-1), (Ib_2) and (Ic) include positional isomers, geometrical isomers. Alternatively, possible isomers such as optical isomers, and mixtures of the isomers in an extremely high ratio can be used as the angiogenesis inhibitor of the present invention.
  • compounds (1), (la), (lb), (lb-1), (Ib-2) and (Ic) and their pharmacologically acceptable salts are added with water or various solvents. Forces that may exist in the form of products, and their adducts can also be used as the angiogenesis inhibitor of the present invention.
  • Diseases involving angiogenesis include, for example, cancer [eg, breast cancer, endometrial cancer, cervical cancer, prostate cancer, bladder cancer, kidney cancer, stomach cancer, esophageal cancer, liver cancer, biliary tract cancer, colon cancer ( Rectal cancer, colon cancer), spleen cancer, lung cancer, head and neck cancer, osteosarcoma, melanoma, brain tumor, cancer caused by hematopoietic tumor (eg leukemia, myeloma, lymphoma, etc.)], diabetic retinopathy, chronic Rheumatoid arthritis and the like.
  • cancer eg, breast cancer, endometrial cancer, cervical cancer, prostate cancer, bladder cancer, kidney cancer, stomach cancer, esophageal cancer, liver cancer, biliary tract cancer, colon cancer ( Rectal cancer, colon cancer), spleen cancer, lung cancer, head and neck cancer, osteosarcoma, melanoma, brain tumor, cancer caused by hematopoietic tumor (eg
  • Examples of kinases involved in angiogenesis include VEGFR1-3, FGFR1-4, PDGFRa, PDGFR / 3, ephrin receptor A1-A10, ephrin receptor B1-B6, and Tie2.
  • Compounds (1), (la), (lb), (lb-1), (Ib-2) and (Ic) used in the invention are synthesized by the method described in, for example, W 02005/012257, WO2005 / 012258 be able to.
  • Examples of the compounds (1), (la), (lb), (lb-1), (Ib-2) and (Ic) used in the present invention include the compounds shown in Table 1.
  • Me represents methyl.
  • KDR inhibitory activity was measured by the following method.
  • KDR protein (carna bioscience) with a final reaction volume of 40 ng and a final concentration of 50 ng / mL, 15 mmol / L Tris—HCl ( ⁇ 7 ⁇ 5), 0.01% Tween—20 2 mmol / L DTT 250 nmol / L biotin-labeled Lyn substrate peptide, 40 mmol / L magnesium chloride, 10 ⁇ mol / L AT P 1% dimethyl sulfoxide (DMSO), prepared as 1 mol / L test compound for enzyme reaction was performed in a streptavidin-coated microplate (Perkin Elma company) at room temperature for 3 hours.
  • DMSO dimethyl sulfoxide
  • the relative activity (%) of the kinase activity to which the test compound was added was calculated from the control value when ATP was added as 100% and the measurement value without addition of ATP as 0%.
  • the subtracted value was defined as the KDR inhibition rate (%) of the test compound.
  • Test example 2 FLT1 ⁇ .
  • FLT1 inhibitory activity was measured by the following method.
  • FLT1 protein (carna bioscience) with a final reaction volume of 40 HL and a final concentration of 50 ng / mL, 15 mmol / L Tris—HCl ( ⁇ 7 ⁇ 5), 0.01% Tween—20, 2 mmol / L DTT, 250 nmol / L biotin labeled Lyn substrate peptide, 20 mmol / L magnesium chloride, 10 ⁇ mol / L ATP, 1% dimethyl sulfoxide (DMSO), 1 mol / L
  • Elementary reaction was carried out in a streptavidin-coated microplate (Perkin Elma Co.) well at room temperature for 2 hours.
  • the control measured value when ATP was added was 100%, and the measured value when ATP was not added was 0%.
  • the relative activity (%) of the kinase activity to which the test compound was added was calculated, and the value obtained by subtracting the value from 100 was taken as the FLT1 inhibition rate (%) of the test compound.
  • Test Example 3 FGFR1 inhibitory activity
  • FGFR1 inhibitory activity was measured by the following method.
  • FGFR1 protein (Carna Bioscience), final concentration of 40 ng / mL, reaction volume of 40 ⁇ L, 15 mmol / L Tris-HCl ( ⁇ 7.5), 0.01% Tween-20, 2 mmol / L DTT, 250 nmol / L biotin labeled Lyn substrate peptide, 20 mmol / L magnesium chloride, 10 ⁇ mol / L ATP, 1% dimethyl sulfoxide (DMSO), 1 mol / L was performed for 1 hour at room temperature in a streptavidin-coated microplate (Perkin Elma).
  • Relative activity (%) of the kinase activity with the test compound added was calculated from the 100% control value when ATP was added and 0% when no ATP was added. The subtracted value was defined as the FGFR1 inhibition rate (%) of the test compound.
  • Test Example 4 FGFR2 inhibitory activity
  • FGFR2 protein (carna bioscience) with a final reaction volume of 40 ng, 100 ng / mL, 15 mmol / L Tris—HCl ( ⁇ 7 ⁇ 5), 0.01% Tween-20, 2 mmol / L DTT, 250 nm ol / L biotin-labeled Gastrin peptide, 20 mmol / L magnesium chloride, 10 ⁇ mol / L ATP, 1% dimethyl sulfoxide (DMSO), prepared to be 1 mol / L test compound, and the enzyme reaction is streptavidin This was performed at room temperature for 1 hour in the well of a coated microplate (Perkin Elma).
  • Test Example 5 FGFR3 IV.
  • FGFR3 inhibitory activity was measured by the following method.
  • FGFR3 protein (carna bioscience) with a final reaction volume of 40 ⁇ L, 7.5 ng / mL, 15 mmol / L Tris—HCl ( ⁇ 7.5), 0.01% Tween-20, 2 mmol / L DTT, 250 nm ol / L biotin labeled Lyn substrate peptide, 20 mmol / L manganese chloride, 10 ⁇ mol / L ATP, 1% dimethyl sulfoxide (DMSO), 1 mol / L test compound,
  • the enzyme reaction was carried out in a streptavidin-coated microplate (Perkin Elma Co.) well for 3 hours at room temperature.
  • Test Example 6 CD31 lowering action
  • test Example 6 compound 9 was used as the test compound.
  • SCID mice (5 weeks old, male, CLEA Japan) ventral subcutaneous heman multiple myeloma cells (NCI-H929 cells, ATCC) were transplanted. Two SCID mice were used in each group (control group, test compound administration group). In order to facilitate the transplantation of tumor cells and the measurement of tumor volume, the area around the transplanted area was shaved with an electric clipper the day before cell transplantation.
  • anti-asharo GM1 antibody (Wako Pure Chemical Industries) was dissolved in 1 mL of distilled water for injection (Otsuka Pharmaceutical Factory) (10 mg After dilution with phosphate-buf fered saline (PBS, Invitrogen) to 3 mg / mL, 1.0 mL tuberculin for thermosyringe (26 G1 / 2 injection needle) was injected into the abdominal cavity of SCID mice at 0.3 mg / mL. It was administered by mouse.
  • PBS phosphate-buf fered saline
  • NCI-H929 cells were transplanted at 5 ⁇ 10 6 cells / mouse in the 1.0 mL tuberculin Terumo syringe (26 G1 / 2 injection needle) subcutaneously on the ventral side of SCID mice. Administration of the test compound was started 10 days after transplantation.
  • test compound For administration of the test compound, a 1.0 mL tuberculin Terumo syringe (without a needle) equipped with an EO-sterilized DISPOSABLE oral sonde (Fuchigami Instrument, Kyoto) for mice was used. Compound 9 was orally administered at a dose of 50 mg / kg twice daily for 2.5 consecutive days (bid X 2.5). The control group was administered with a 0.5 w / v% methylcellulose 400 solution (Wako Pure Chemical Industries, Ltd.) as the administration solvent. One hour after the end of administration, the tumor was removed and divided into 2 parts, and one of them was divided into OCT compounds (sac Embedded in Latish Tech) and frozen in liquid nitrogen. The frozen block was stored in a -80 ° C freezer and used for the following experiments.
  • OCT compounds sin Embedded in Latish Tech
  • Sections sliced into 6 ⁇ m were fixed with ice-cooled methanol for 10 minutes. After fixation, the cells were washed with PBS, and further washed with Wash Buffer (1% BSA, 0.05% sodium azide, 0.02% EDTA in PBS) (5 minutes ⁇ 2). After washing, S g / mL of anti_CD31 antibody was reacted at room temperature for 1 hour. After the reaction, it was washed with a wash buffer, and then reacted with a secondary antibody (Alexa Fluor (registered trademark) 4888 goat anti-rat IgG (H + L); diluted 1/200) for 1 hour at room temperature.
  • a secondary antibody Alexa Fluor (registered trademark) 4888 goat anti-rat IgG (H + L); diluted 1/200
  • Compounds (1), (la), (lb), (lb-1), (Ib_2) and (Ic) or pharmacologically acceptable salts thereof are used for their pharmacological action, administration purpose, etc. It can be used as it is or in various pharmaceutical forms.
  • the pharmaceutical composition of the present invention comprises an effective amount of compound (1), (la), (lb), (Ib_l), (Ib-2) and (Ic) or a pharmacologically acceptable amount thereof.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are preferably in unit dosage forms suitable for oral or parenteral administration such as injection.
  • excipients such as lactose and mannitol, disintegrants such as starch, lubricants such as magnesium stearate, polybutyl alcohol, hydroxypropyl
  • a binder such as cellulose and a surfactant such as sucrose fatty acid ester and sorbite fatty acid ester may be used in accordance with a conventional method. Tablets containing 1 to 200 mg of active ingredient per tablet are preferred.
  • water physiological saline
  • olive oil vegetable oils such as peanut oil
  • solvents such as ethyl oleate and propylene glycol
  • solubilizers such as sodium benzoate, sodium salicylate, urethane, salt
  • an isotonic agent such as glucose, a preservative such as phenol, talesol, p-hydroxybenzoic acid ester and chlorobutanol
  • an antioxidant such as ascorbic acid and sodium pyrosulfite may be used in a conventional manner.
  • Compounds (1), (la), (lb), (lb-1), (Ib_2) and (Ic) or pharmacologically acceptable salts thereof are non-oral or non-injectable Although it can be administered orally, the effective dose and frequency of administration vary depending on the dosage form, patient age, body weight, symptoms, etc., but it is usually preferable to administer 0.01-100 mg / kg per day.
  • Compound 1 Compound 2, Compound 3, Compound 4, Compound 5, Compound 7, Compound 8, Compound 9, Compound 9, Compound 10, Compound 12, Compound 13, and Compound 14 used in the present invention are examples of WO 2005/012258, respectively.
  • 5, 2, 22, 38, 54, 69, 70, 64, 74, 59, 51 and 29 can be synthesized.
  • Compounds 6 and 11 are synthesized according to Examples 13 and 158 of WO2005 / 012257, respectively. be able to.
  • a tablet having the following composition is prepared by a conventional method.
  • An injection having the following composition is prepared by a conventional method.
  • the present invention provides an angiogenesis inhibitor and the like containing an indazole derivative or a pharmacologically acceptable salt thereof as an active ingredient.

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Abstract

La présente invention concerne un agent anti-angiogénique comprenant un dérivé d'indazole représenté par la formule (I) [dans laquelle R1 représente un groupe aryle substitué ou non substitué ou un groupe hétérocyclique substitué ou non substitué] ou un sel pharmacologiquement acceptable de celui-ci en tant que matière active ; un inhibiteur d'une kinase impliquée dans l'angiogenèse, comprenant un dérivé d'indazole représenté par la formule (I) ou un sel pharmacologiquement acceptable de celui-ci en tant que matière active ; un agent thérapeutique pour une maladie associée à l'angiogenèse, comprenant un dérivé d'indazole représenté par la formule (I) ou un sel pharmacologiquement acceptable de celui-ci en tant que matière active. (I)
PCT/JP2007/065932 2006-08-16 2007-08-16 Agent anti-angiogénique WO2008020606A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008114812A1 (fr) * 2007-03-19 2008-09-25 Kyowa Hakko Kirin Co., Ltd. Inhibiteur de jak
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
JP2020506675A (ja) * 2017-01-05 2020-03-05 へリックス バイオファーマ コープ． Ｖｅｇｆｒ−２抗体

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WO2005012258A1 (fr) * 2003-07-30 2005-02-10 Kyowa Hakko Kogyo Co., Ltd. Inhibiteur de la proteine kinase
WO2005012257A1 (fr) * 2003-07-30 2005-02-10 Kyowa Hakko Kogyo Co., Ltd. Derives indazole
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JP2006515589A (ja) * 2002-12-19 2006-06-01 ファイザー・インク 眼疾患の治療に有用なプロテインキナーゼ阻害剤としての２−（１ｈ−インダゾール−６−イルアミノ）−ベンズアミド化合物
WO2006080450A1 (fr) * 2005-01-27 2006-08-03 Kyowa Hakko Kogyo Co., Ltd. Inhibiteur d’igf-1r
WO2006118257A1 (fr) * 2005-04-28 2006-11-09 Kyowa Hakko Kogyo Co., Ltd. Méthode de synthèse d'un sel d'indazole-3-ylméthylphosphonium
JP2007051082A (ja) * 2005-08-17 2007-03-01 Kyowa Hakko Kogyo Co Ltd インダゾール−３−イルメチルホスホン酸誘導体及びその製造法
WO2007056075A2 (fr) * 2005-11-02 2007-05-18 Targegen, Inc. Inhibiteurs heteroaromatiques a six chainons diriges contre des mutations de kinases resistantes
WO2007058626A1 (fr) * 2005-11-16 2007-05-24 S*Bio Pte Ltd Composes d'indazole

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Publication number Priority date Publication date Assignee Title
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
US20050009876A1 (en) * 2000-07-31 2005-01-13 Bhagwat Shripad S. Indazole compounds, compositions thereof and methods of treatment therewith
JP2006501217A (ja) * 2002-08-12 2006-01-12 スージェン・インコーポレーテッド 新規キナーゼ阻害剤としての３−ピロリル−ピリドピラゾールおよび３−ピロリル−インダゾール
JP2006515589A (ja) * 2002-12-19 2006-06-01 ファイザー・インク 眼疾患の治療に有用なプロテインキナーゼ阻害剤としての２−（１ｈ−インダゾール−６−イルアミノ）−ベンズアミド化合物
WO2005012257A1 (fr) * 2003-07-30 2005-02-10 Kyowa Hakko Kogyo Co., Ltd. Derives indazole
WO2005012258A1 (fr) * 2003-07-30 2005-02-10 Kyowa Hakko Kogyo Co., Ltd. Inhibiteur de la proteine kinase
WO2006080450A1 (fr) * 2005-01-27 2006-08-03 Kyowa Hakko Kogyo Co., Ltd. Inhibiteur d’igf-1r
WO2006118257A1 (fr) * 2005-04-28 2006-11-09 Kyowa Hakko Kogyo Co., Ltd. Méthode de synthèse d'un sel d'indazole-3-ylméthylphosphonium
JP2007051082A (ja) * 2005-08-17 2007-03-01 Kyowa Hakko Kogyo Co Ltd インダゾール−３−イルメチルホスホン酸誘導体及びその製造法
WO2007056075A2 (fr) * 2005-11-02 2007-05-18 Targegen, Inc. Inhibiteurs heteroaromatiques a six chainons diriges contre des mutations de kinases resistantes
WO2007058626A1 (fr) * 2005-11-16 2007-05-24 S*Bio Pte Ltd Composes d'indazole

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008114812A1 (fr) * 2007-03-19 2008-09-25 Kyowa Hakko Kirin Co., Ltd. Inhibiteur de jak
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
JP2020506675A (ja) * 2017-01-05 2020-03-05 へリックス バイオファーマ コープ． Ｖｅｇｆｒ−２抗体

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