WO2008020606A1

WO2008020606A1 - Antiangiogenic agent

Info

Publication number: WO2008020606A1
Application number: PCT/JP2007/065932
Authority: WO
Inventors: Yukimasa Shiotsu; Hiroshi Umehara
Original assignee: Kyowa Hakko Kirin Co., Ltd.
Priority date: 2006-08-16
Filing date: 2007-08-16
Publication date: 2008-02-21
Also published as: JPWO2008020606A1

Abstract

An antiangiogenic agent comprising an indazole derivative represented by the formula (I) [wherein R1 represents a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group] or a pharmacologically acceptable salt thereof as an active ingredient; an inhibitor of a kinase involved in angiogenesis, comprising an indazole derivative represented by the formula (I) or a pharmacologically acceptable salt thereof as an active ingredient; a therapeutic agent for a disease associated with angiogenesis, comprising an indazole derivative represented by the formula (I) or a pharmacologically acceptable salt thereof as an active ingredient. (I)

Description

Specification

Angiogenesis inhibitor

Technical field

[0001] 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.

Background art

[0002] 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)]. Factors that promote tumor angiogenesis include vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and jfll platelet derived growth factor. PDG F), Angiopoietin (ANG), Ephrin (EPH), and the like. These factors promote the proliferation of vascular endothelial cells, fibroblasts, stromal cells, etc. by binding to their receptors [Nature Review Cancer, Volume 3, Page 401 (2003 Year)].

[0003] 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). VEGFR3, also known as fms-like tyrosine kinase 4 (FLT4), plays an important role in the growth and invasion of the lymphatic vessels and is important for lymphatic growth and lymph node metastasis and leukemia drug resistance Demonstrate [Nature's Medicine, 7, 199 (2001); Blood, 99, 2179 (2002)]. 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 (FGFR), 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. Four subtypes of FGFR1 to FGFR4 are known for FGFR. These FGFRs play an important role in fibroblast cell proliferation and differentiation [Expert Opinion on Therapeutic Targets], 6, 469 (2002) ]. In the tumor environment, fibroblasts surround the tumor and are thought to play an important role in tumor growth [Cell, 100, 57 (2000)]. On the other hand, about 25% of multiple myeloma, FGFR3 gene overexpression is caused by chromosomal translocation, as a result of examination in patient specimens [Blood, Vol. 92, p. 3025] (1998)]. In addition, 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)]. In addition, 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)]. In addition, 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.) [Expert Opinion on Therapeutic Targets, 6, 469 (2002); Nature, 411, 355 (2 001)]. Therefore, FGFR inhibitors are thought to be useful as therapeutic agents for various cancers. [0005] In addition, it is thought that angiogenesis is promoted through the intracellular signal pathway by the binding of Platelet derived growth factor receptor (PDGF) [Nature Review Cancer (Nature Review Cancer), 3, pp. 401 (2003)] Two subtypes of PDGFR a and PDGFR / 3 are known in PDGFR, and pericytes or vascular smooth muscle cells become vascular endothelial cells due to their activation. [Nature's Medicine (Mature Medicine), 7, 199 (2001); Blood, 99, 2179 (2002)], and PDGFR mutations become cancerous [Nature's Review You Cancer (Nature Review Cancer), 4, 718 (2004)] The above-mentioned sunitinib has PDGFR inhibitory activity, and PDGFR inhibitor is a cancer. It is thought to be useful as a therapeutic agent.

[0006] In addition, 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. Has been reported to be involved in angiogenesis, neuroplasticity, blood coagulation, and morphogenesis [Nature Review Molecul ar Cell Biology, 6, 462 (2005) ].

[0007] Various compounds are known as indazole derivatives!

1-12 and a nonpatent literature 1 reference).

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, ρ · 957-959

Disclosure of the invention

Problems to be solved by the invention

[0008] 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.

Means for solving the problem

The present invention relates to the following (1) to (54).

a) Equation ω

[0010] [Chemical 1]

(Wherein R ¹ represents a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group) and an angiogenesis containing an indazole derivative represented by the formula or a pharmaceutically acceptable salt thereof as an active ingredient. Inhibitor.

(2) Formula (la)

[Chemical 2]

[In the formula, 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, substituted or unsubstituted lower alkanol, substituted or unsubstituted aryl, substituted or A substituted heteroaroyl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted lower alkylsulfonyl or a substituted or unsubstituted arylolsulfonyl), or a pharmacologically An angiogenesis inhibitor comprising an acceptable salt as an active ingredient.

(3) The angiogenesis according to (2), wherein R ² is CONR ^4a R ^4b (wherein R ^4a and R ^4b are as defined above), and R ³ is a hydrogen atom. Inhibitor.

(4) 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 The angiogenesis inhibitor according to (2) above, which is an atom.

(5) The description in (2), wherein R ² is NR ^5a R ^5b (wherein R ^5a and R ^5b are as defined above), and R ³ is a substituted or unsubstituted lower alkoxy. Angiogenesis inhibitors.

(6) The angiogenesis inhibitor according to (2), wherein R ² is NR ^5a R ^5b (wherein R ^5a and R ^5b are as defined above), and R ³ is a hydrogen atom. (7) Formula (lb)

[0014] [Chemical 3]

[In the formula, 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. , Substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted aryl, NR ^9a R ^9b (wherein R and R are the same or different, 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 alkanol, substituted or unsubstituted aryl, substituted or unsubstituted aryleno, substituted or unsubstituted complex ring group or a substituted or unsubstituted to represent Teroaroiru or nitrogen atom to which R and R ^9b are adjacent, During together such connexion to form a substituted or unsubstituted heterocyclic group) or OR ^1Q (wherein, R ^1Q is a hydrogen atom, a substituted or unsubstituted lower alk kill, a substituted or unsubstituted Ariru, substituted or unsubstituted An indazole derivative represented by the following formula: or an pharmacologically acceptable salt thereof as an active ingredient.

[0016] (8) The angiogenesis according to (7), wherein at least one of R ^8a , R ^8b and R is NR ^9a R ^9b (wherein R ^9a and R ^9b are as defined above), Inhibitor.

(9) at least one of 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).

(10) The angiogenesis inhibitor according to (7), wherein at least one of R ^8a , R ^8b and R is OR ^1Q (wherein R ^1Q has the same ^{meaning as} described above). (11) The angiogenesis inhibitor according to (7), wherein at least one of R ^8a , R ^8b and R is OR ^1Qa (wherein R ^1Qa represents a substituted or unsubstituted lower alkyl).

(12) Formula (Ib-1)

[0017] [Chemical 4]

(Wherein R ^8a , R ^9e and R ^9d have the same ^{meanings as} described above), or an angiogenesis inhibitor comprising as an active ingredient an indazole derivative represented by the formula or a pharmacologically acceptable salt thereof.

(13) Formula (Ib-2)

[Chemical 5]

(Wherein R ^8a and R ^{1 <) a} are as defined above), an angiogenesis inhibitor comprising as an active ingredient an indazole derivative represented by the formula or a pharmaceutically acceptable salt thereof.

(14) Formula (Ic)

[Chemical 6]

[0020] wherein R ^u is a substituted or unsubstituted heterocyclic group [substituents in the 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

In n, 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.

[0021] (15) The angiogenesis inhibitor according to the above (14), wherein the substituent in the substituted heterocyclic group is ami-oxo, lower alkoxy, lower alkoxycarbonylamino, aroylamino, or lower alkoxycarbonyl-substituted lower alkyl.

(16) The angiogenesis inhibitor according to the above (14), wherein R ^U is 3-pyridyl.

(17) 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.

(18) The inhibitor according to (17), wherein the kinase involved in angiogenesis is Vascular Endothelial Growth Factor Receptor (VEGFR).

(19) The inhibitor according to (17), wherein the kinase involved in angiogenesis is vascular endothelial growth factor receptor 1 (VEGFR1); fins_like tyrosine kinase 1 (FLT1)].

[0022] (20) The above (17), wherein the kinase involved in angiogenesis is Vascular Endothelial Growth Factor Receptor 2 (VEG R2); kinase insert domain-containing receptor (K DR)] The described inhibitors.

(21) The inhibitor according to (17), wherein the kinase involved in angiogenesis is Vascular Endothelial Growth Factor Receptor 3 (VEGFR3); fins_like tyrosine kinase 4 (FLT4)].

(22) Kinase involved in angiogenesis is fibroblast growth factor receptor The inhibitor according to (17), which is h factor receptor (FGFR).

(23) The inhibitor according to the above (17), wherein the kinase involved in angiogenesis is a platelet derived growth factor receptor (PDGFR).

(24) The inhibitor according to the above (17), wherein the kinase involved in angiogenesis is an Ephrin receptor.

[0023] (25) 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.

(26) 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.

(27) 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.

(28) Renal cancer, colorectal cancer, breast cancer, brain tumor, head and neck cancer, prostate, containing 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 cancer selected from cancer and ovarian cancer.

[0024] (29) 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).

(30) 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).

(31) The inhibition method according to the above (30), wherein the kinase involved in angiogenesis is a vascular endothelial growth factor receptor.

(32) The method according to (30), wherein the kinase involved in angiogenesis is vascular endothelial growth factor receptor 1.

(33) The inhibition method according to the above (30), wherein the kinase involved in angiogenesis is vascular endothelial growth factor receptor 2.

(34) The method according to the above (30), wherein the kinase involved in angiogenesis is vascular endothelial growth factor receptor 3.

(35) The kinase that is involved in angiogenesis is a fibroblast growth factor receptor (30) The described inhibition method.

[0025] (36) The inhibition method according to the above (30), wherein the kinase involved in angiogenesis is a platelet-derived growth factor receptor.

(37) The method for inhibiting according to the above (30), wherein the kinase involved in angiogenesis is an ephrin receptor.

(38) 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).

(39) 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).

(40) 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).

(41) renal cancer, colorectal cancer, breast cancer, brain tumor, head and neck, 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.

[0026] (42) Use of the indazole derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (16) for the production of an angiogenesis inhibitor.

(43) Use of the indazole derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (16) for the manufacture of an inhibitor of a kinase involved in angiogenesis.

(44) The use according to the above (43), wherein the kinase involved in angiogenesis is a vascular endothelial growth factor receptor.

(45) The use according to the above (43), wherein the kinase involved in angiogenesis is vascular endothelial growth factor receptor 1.

(46) The use according to the above (43), wherein the kinase involved in angiogenesis is vascular endothelial growth factor receptor 2.

(47) The use according to the above (43), wherein the kinase involved in angiogenesis is vascular endothelial growth factor receptor 3.

(48) The above-mentioned (43), wherein the kinase involved in angiogenesis is a fibroblast growth factor receptor. Use of description.

(49) The use according to the above (43), wherein the kinase involved in angiogenesis is a platelet-derived growth factor receptor.

(50) The use according to the above (43), wherein the kinase involved in angiogenesis is an ephrin receptor.

[0027] (51) Use of the indazole derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (16) for the manufacture of a therapeutic agent for a disease involving angiogenesis.

(52) Use of the indazole derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (16) for the manufacture of a therapeutic agent for rheumatism.

(53) Use of the indazole derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (16) for the production of an anticancer agent.

(54) Indazole according to any one of (1) to (16) above for the manufacture of a therapeutic agent for cancer selected from renal cancer, colon cancer, breast cancer, brain tumor, head and neck cancer, prostate cancer and ovarian cancer Use of derivatives or pharmacologically acceptable salts thereof.

The invention's effect

[0028] The present invention provides an angiogenesis inhibitor and the like containing an indazole derivative or a pharmacologically acceptable salt thereof as an active ingredient.

Brief Description of Drawings

[0029] [Fig. 1] 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.

BEST MODE FOR CARRYING OUT THE INVENTION

[0030] Hereinafter, the compounds represented by the formulas (I), (la), (lb), (lb-1), (lb-2) and (Ic) are respectively converted to compounds (1), (la) , (lb), (lb-1), (Ib-2) and (Ic). The same applies to the compounds of other formula numbers.

In the definition of each group of formula (1), (la), (lb), (lb-1), (Ib-2) and (Ic),

(i) Halogen includes fluorine, chlorine, bromine and iodine atoms.

(ii) 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.

(ii-c) The lower alkyl comprising a combination of linear or branched and cyclic is as follows.

(iii) 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).

(iv) 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.

(vi) The 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. 6 to 14 aryl, eg phenyl, naphth Examples include chill, indul, anthranyl and the like.

(vii) As the lower 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, cyclopropinoremethinorecanenopononole, cyclohexenorenorebonyl, 1-methylcyclopropylcarbonyl, cycloheptylcarbonyl and the like.

(viii) Examples of the heterocyclic group include an aromatic heterocyclic group and an alicyclic heterocyclic group.

[0032] 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. For example, 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.

[0033] 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. For example, the heteroatom may contain one or more heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen atoms. For example, pyrrolidinyl, 2,5-dioxopyrrolidinyl, thiazolidinyl, oxazolidinyl, piperidyl, 1,2-dihydropyridyl, piperazil, homopiperadul, morpholinyl, thiomorpholinyl, virazolinyl, oxazolinyl, dioxolanyl, Tetrahydrobiranyl, tetrahydrothiopyrael, tetrahydrofuryl, tetrahydroquinolyl, tetrahydroisoquinolinole, tetrahydroquinoxalini , O Kuta tetrahydroquinolyl, dihydro India linoleate, 1,3-Jiokisoi And soindolinyl.

(ix) Examples of the heterocyclic group formed together with the adjacent nitrogen atom 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.

The heteroaryl moiety in (X) heteroaroyl is the same as the aromatic heterocyclic group (viii-a).

(Xi) 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,

(xi-a) hydroxy,

(xi-b) lower alkoxy,

(xi-c) Oxo,

(xi-d) canolepoxy,

(xi-e) lower alkoxycarbonyl,

(xi-f) heteroaroyl,

(xi-g) arylsulfonyl,

(xi-h) substituted or unsubstituted aryl (substituents in the substituted aryl are carboxy, lower alkoxy, lower alkoxycarbonyl, etc.),

(xi-i) substituted or unsubstituted heterocyclic group (the substituent in the substituted heterocyclic group is carboxy, lower alkoxy, lower alkoxycarbonyl, etc.),

[0035] (x) CONR ^15a R ^15b (wherein 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, arolenole, substituted or unsubstituted, having 1 to 3 substituents. 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.}

(X k) NR ^16a R ^16b (wherein R ^16a and R ^16b have the same ^{meanings as} R ^15a and R ^15b , respectively), (xi-1) a lower alkanoinoreamino,

(xHn) N-lower alkanoyl-N-lower alkylamino and the like.

In the definition (xi) of the substituent in the substituted lower alkyl, substituted lower alkoxy, substituted lower alkenyl, substituted lower alkynyl, substituted lower alkanol, substituted lower alkoxycarbonyl, and substituted lower alkylsulfonyl, 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), and the alkylene part of aralkyl is as defined above (iii). And the 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. Is as defined in (vii) above, and 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).

[0037] (xii) 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,

(xiHD) Nitro,

(xii-c) nitroso,

(xii-d) canolepoxy,

_(X ii- _e) a substituted or unsubstituted lower alkyl [the substituent in the substituted lower alkyl has the same meaning as above (xi)],

(xii-f) substituted or unsubstituted lower alkenyl [the substituent in the substituted lower alkenyl has the same meaning as the above (xi)],

(xii-g) substituted or unsubstituted lower alkynyl [the substituent in the substituted lower alkynyl has the same meaning as the above (xi)],

(xii-h) substituted or unsubstituted lower alkoxycarbonyl [the substituent in the substituted lower alkoxycarbonyl is as defined above (xi)],

(xii-i) substituted or unsubstituted lower alkanoyl [the substituent in the substituted lower alkanol is as defined in the above (xi)],

(xii-j) substituted or unsubstituted aryl [substituents in the 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)],

(xiH NR ^17a R ^17b (wherein 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 Examples of the substituent 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 [Substituents in the substituted 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 the substituted heterocyclic group are, for example, halogen, hydroxy, nitro, cyan, carboxy, lower alkanoyl, lower alkoxycarbonyl, aralkyl, aroyl, substituted or unsubstituted, having 1 to 3 substituents. Lower alkyl (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, 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 [Substituent in the substituted heterocyclic group formed together with the adjacent nitrogen atom 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 alkoxy group, a lower alkanol group, and an N-lower alkanol group. -N-lower alkylamino, etc.), substituted or unsubstituted alicyclic heterocyclic carbonyl (the substituted alicyclic heterocyclic carbonyl includes, for example, a halogen having 1 to 3 substituents, hydroxy, Are oxo, lower alkyl, lower alkoxy, etc.)]

(Xi 1) CONR ^18a R ^18b (wherein R ^18a and R ^18b have the same ^{meanings as} R ^17a and R ^17b , respectively),

(xii-m) OR ¹⁹ wherein 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 [Substituents in the substituted aryl 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 substituent in the substituted heterocyclic group is, for example, a halogen of 1 to 3 substituents, hydroxy, nitro (B) substituted carboxy, lower alkanoyl, lower alkanoyl, lower alkoxycarbonyl, aralkyl, aroyl, substituted or unsubstituted lower alkyl (substituent in the substituted lower alkyl is, for example, hydroxy having 1 to 3 substituents), substituted Or an unsubstituted lower alkoxy (the substituent in the substituted lower alkoxy is, for example, hydroxy having 1 to 3 substituents)], etc.},

(xiHi) Heteraroinole,

(xii-o) substituted or unsubstituted alicyclic heterocyclic carbonyl (the substituent in the substituted alicyclic heterocyclic carbonyl is, for example, halogen having 1 to 3 substituents, hydroxy, oxo, lower alkyl, lower alkoxy) Etc.).

[0040] In addition to the above (xii_a) to (xii-o), 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.

(xii-p) oxo

(xii-q) -O (CR ^20a R ^20b ) O- (wherein R ² ° ^a and R ² ° ^b are the same or different and represent a hydrogen atom or na

Represents lower alkyl, na represents 2 or 3, and 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)

Substituted aryl, substituted aryl, substituted aralkyl, substituted arylsulfonyl, substituted Definition of Substituent in Substituted Cyclocyclic Group Formed together with Loaroyl, Substituted Heterocyclic Group and Adjacent Nitrogen Atom In (xii), 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), and the aryl moiety of the aryleno, aroyl and aralkyl has the same meaning as the above (vi), and the lower alkanoyl, lower alkanoylamino and N- The lower alkanoyl part of the lower alkanoyl-N-lower alkylamino is as defined in the above (vii), and 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).

[0041] 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. Examples of 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. Examples of organic amine addition salts include addition salts such as morpholine and piperidine. Examples of amino acid addition salts include lysine, glycine, and phenylalanine. Addition salts are mentioned.

[0042] Salts of compounds (I), (la), (lb), (lb-1), (lb-2) and (Ic) were obtained! /, In some cases, 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.

[0043] 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.

In addition, 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.

[0044] 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.

[0045] 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. In the table, Me represents methyl.

[0046] [Table 1-1]

[0047] [Table 1-2] Table 1-2

Next, the pharmacological action of compound ω will be described in test examples.

Test, Test Example 1: KDR IV.

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 (ρΗ7 · 5), 0.01% Tween—20 2 mmol / L DTT 250 nmol / L biotin-labeled Lyn substrate peptide, 40 mmol / L magnesium chloride, 10 μmol / 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. After completion of the reaction, the well was washed with wash buffer (50 mmol / L Tris- It was washed with HCl (ρΗ5 · 5), 150 mmol / L NaCl, 0.02% Tween-20), and blocked with one blocking buffer (wash buffer with 0.1% BSA applied P). After blocking, 100 L of diluted Horseradish peroxidase (HRP) -labeled anti-phosphotyrosine antibody PY20 (Santa Cruz Biotechnology) was reacted at room temperature for 30 minutes. After washing the well to remove unreacted antibodies, 100 TMB solution (MOSS) was added and allowed to react for 30 minutes at room temperature. The HRP reaction was stopped by adding 100 mol of 0.1 mol / L sulfuric acid, and the absorbance at 450 nm was measured with a microphone plate reader.

[0049] 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.

Compounds 4, 6, 7, 8, 9, 10, and 11 showed a KDR inhibitory activity of 90% or more at a concentration of 1 mol / L. From this result, it can be seen that compound (I) exhibits an effective KDR inhibitory activity.

[0050] Test example 2: FLT1 阳.

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 (ρΗ7 · 5), 0.01% Tween—20, 2 mmol / L DTT, 250 nmol / L biotin labeled Lyn substrate peptide, 20 mmol / L magnesium chloride, 10 μmol / 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. After completion of the reaction, the well was washed with wash buffer (50 mmol / L Tris-HC1 (ρΗ7 · 5), 150 mmol / L NaCl, 0.02% Tween-20). The buffer was blocked with 0.1% BSA applied force P). After blocking, 100 diluted HRP-labeled anti-phosphotyrosine antibody PY20 (Santa Cruz Biotechnology) was reacted at room temperature for 30 minutes. After washing the well to remove unreacted antibodies, 100 TMB solution (MOSS) was added and allowed to react for 5 minutes at room temperature. The HRP reaction was stopped by adding 100 mol of 0.1 mol / L sulfuric acid, and the absorbance at 450 nm was measured with a microplate reader.

[0051] 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.

Compounds 4, 6, 7, 8, 9, 10 and 11 showed an FLT1 inhibitory activity of 80% or more at a concentration of 1 mol / L. From this result, it can be seen that compound (I) exhibits an effective FLT1 inhibitory activity.

[0052] 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 μL, 15 mmol / L Tris-HCl (ρΗ7.5), 0.01% Tween-20, 2 mmol / L DTT, 250 nmol / L biotin labeled Lyn substrate peptide, 20 mmol / L magnesium chloride, 10 μmol / L ATP, 1% dimethyl sulfoxide (DMSO), 1 mol / L Was performed for 1 hour at room temperature in a streptavidin-coated microplate (Perkin Elma). After completion of the reaction, the well was washed with a wash buffer (50 mmol / L Tris-HCl (ρΗ7 · 5), 150 mmol / L NaCl, 0.02% Tween-20), and a blocking buffer (Wood). Blocked with 0.1% BSA in the wash buffer with an addition force P). After completion of blocking, 100 diluted HRP-labeled anti-phosphotyrosine antibody PY20 (Santa Cruz Biotechnology) was reacted at room temperature for 30 minutes. After washing the well to remove unreacted antibodies, 100 TMB solution (MOSS) was added and reacted at room temperature for 5 minutes. The HRP reaction was stopped by adding 100 L of 0.1 mol / L sulfuric acid, and the absorbance at 450 nm was measured with a microplate reader.

[0053] 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.

Compounds 4, 6, 7, 8, 9, 10, and 11 showed FGFR1 inhibitory activity of 70% or more at a concentration of 1 mol / L. From this result, it can be seen that compound (I) exhibits an effective FGFR1 inhibitory activity.

[0054] Test Example 4: FGFR2 inhibitory activity

The following method was used to measure the inhibitory activity against FGFR2.

FGFR2 protein (carna bioscience) with a final reaction volume of 40 ng, 100 ng / mL, 15 mmol / L Tris—HCl (ρΗ7 · 5), 0.01% Tween-20, 2 mmol / L DTT, 250 nm ol / L biotin-labeled Gastrin peptide, 20 mmol / L magnesium chloride, 10 μmol / 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). After completion of the reaction, the well was washed with wash buffer (50 mmol / L Tris-HC1 (ρΗ7 · 5), 150 mmol / L NaCl, 0.02% Tween-20). The buffer was blocked with 0.1% BSA applied force P). After blocking, 100 diluted HRP-labeled anti-phosphotyrosine antibody PY20 (Santa Cruz Biotechnology) was reacted at room temperature for 30 minutes. After washing the well to remove unreacted antibodies, 100 TMB solution (MOSS) was added and allowed to react for 5 minutes at room temperature. The HRP reaction was stopped by adding 100 mol of 0.1 mol / L sulfuric acid, and the absorbance at 450 nm was measured with a microplate reader.

[0055] Taking the measured value of the control when ATP was added as 100% and the measured value when ATP was not added as 0%, the relative activity (%) of the kinase activity with the test compound added was calculated. The subtracted value was defined as the FGFR2 inhibition rate (%) of the test compound.

Compounds 4, 6, 7, 8, 9, 10, and 11 showed FGFR2 inhibitory activity of 80% or more at a concentration of 1 mol / L. From this result, it can be seen that compound (I) exhibits an effective FGFR1 inhibitory activity.

[0056] 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 (ρΗ7.5), 0.01% Tween-20, 2 mmol / L DTT, 250 nm ol / L biotin labeled Lyn substrate peptide, 20 mmol / L manganese chloride, 10 μmol / 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. After completion of the reaction, the well was washed with wash buffer (50 mmol / L Tris-HC1 (ρΗ7 · 5), 150 mmol / L NaCl, 0.02% Tween-20). The buffer was blocked with 0.1% BSA applied force P). After blocking, 100 diluted HRP-labeled anti-phosphotyrosine antibody PY20 (Santa Cruz Biotechnology) was reacted at room temperature for 30 minutes. Washing the well to remove unreacted antibodies Thereafter, 100 L of TMB solution (MOSS) was added and reacted at room temperature for 5 minutes. The HRP reaction was stopped by adding 100 mol of 0.1 mol / L sulfuric acid, and the absorbance at 450 nm was measured with a microplate reader.

[0057] Taking the measured value of the control when ATP was added as 100% and the measured value when no ATP was added as 0%, the relative activity (%) of the kinase activity with the test compound added was calculated. The subtracted value was defined as the FGFR3 inhibition rate (%) of the test compound.

Compounds 4, 6, 7, 8, 9, 10, and 11 showed FGFR3 inhibitory activity of 90% or more at a concentration of 1 mol / L. From this result, it can be seen that compound (I) exhibits an effective FGFR3 inhibitory activity.

[0058] Test Example 6: CD31 lowering action

In Test Example 6, compound 9 was used as the test compound.

(i) Tumor cell subcutaneous transplantation into mice

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. At the same time, in order to inhibit the function of NK cells and increase the engraftment rate in SCID mice, 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. The next day, 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.

(ii) Test compound administration and tumor recovery

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.

[0059] (iii) CD31 staining

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. After washing with PBS, sealed with VECTERSHIELD mountain medium, observed under a microscope (Leica DM IRBE objective lens 10X, eyepiece 10X), and attached digital camera (Leica DFC 300FX objective lens 10X, camera port 0.63) X). The obtained image was imageJ software (Ver. L.38j; National Institute of Health), and the CD31 positive area was digitized.

(iv) Results and discussion

The results are shown in Figure 1. In the control group, a CD31 positive portion was observed, whereas in the compound 9 administration group, a decrease in the CD31 positive portion was observed. As a result of quantifying the area of the CD31 positive region using ImageJ software, it was confirmed that the compound 9 administration group decreased to about half! From this result, it was found that Compound 9 has a CD31 lowering action, suggesting that Compound (I) is effective in the treatment of diseases such as cancer and rheumatism.

[0060] 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. Can be produced by uniformly mixing a pharmaceutically acceptable carrier with a pharmaceutically acceptable carrier. 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.

[0061] For the preparation of tablets, for example, 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.

[0062] In the preparation of injections, 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 In addition, 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.

[0063] 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.

Example 1

[0064] Formulation Example 1: Tablet

A tablet having the following composition is prepared by a conventional method.

Mix 250 g of Compound 4, 1598.5 g of mannitol, 100 g of sodium starch glycolate, 10 g of light anhydrous caustic acid, 40 g of magnesium stearate and 1.5 g of yellow iron sesquioxide in a conventional manner. Using this mixture, tableting is carried out with a tableting machine (Purepress Correct-12, manufactured by Kikusui Co., Ltd.) having a punch with a diameter of 8 mm to obtain tablets (containing 25 mg of active ingredient per tablet). Formula Compound 4 25 mg

Mannito nore 159.85 mg

Starch sodium glycolate 10 mg

Light anhydrous anhydrous 1 mg Magnesium stearate 4 mg

Yellow ferric oxide 0.15 mg

200 mg

Example 2

Formulation Example 2: Injection

An injection having the following composition is prepared by a conventional method.

Add 1 g of compound 6 and 5 g of D-mannitol to distilled water for injection, mix, add hydrochloric acid and aqueous sodium hydroxide solution to adjust the pH to 6, then add the whole volume with distilled water for injection. To 1000 mL. The resulting mixture is aseptically filled in 2 mL glass vials to give an injection (containing 2 mg of active ingredient per vial).

Formulation Compound 6 2 mg

D-mannito nore 10 mg

Hydrochloric acid

Sodium hydroxide aqueous solution

¾ltffi¾¾¾7k ¾ quantity

2.00 mL

Industrial applicability

The present invention provides an angiogenesis inhibitor and the like containing an indazole derivative or a pharmacologically acceptable salt thereof as an active ingredient.

Claims

The scope of the claims

[1] Equation ω

[Chemical 7]

[2] Formula (la)

[Chemical 8]

[Wherein 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, substituted or unsubstituted Aralkyl or a force representing a substituted or unsubstituted heterocyclic group, or R ^4a and R ^4b together with the adjacent nitrogen atom form a substituted or unsubstituted heterocyclic group) or NR ^5a R ^5b ( In the formula, R ^5a represents substituted or unsubstituted lower alkylsulfonyl or substituted or unsubstituted arylolsulfonyl, and R ^5b represents a hydrogen atom or 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 (In the formula, R ^6a and R ^6b are the same. Or 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 are adjacent to each other Together with the nitrogen atom to form a substituted or unsubstituted heterocyclic group) or NR ^7a R ^7b (wherein R ^7a and R ^7b are the same or different, a hydrogen atom, a substituted or unsubstituted lower alkyl, Substituted or unsubstituted lower alkanoyl, substituted or unsubstituted aryloyl, substituted or unsubstituted heteroaroyl, substituted or unsubstituted aralkyl, substituted or unsubstituted lower alkylsulfonyl or substituted or unsubstituted arylolsulfonyl. An indazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient. Angiogenesis inhibitors.

[3] R ² is CONR ^4a R ^4b (wherein, R ^4a and R ^4b are the same meanings as defined above, respectively), and angiogenesis inhibitor according to claim 2 wherein R ³ is a hydrogen atom.

[4] R ² is CONR ^{4 4d} (wherein R ^4e and R ^4d together with the adjacent nitrogen atom form a substituted or unsubstituted heterocyclic group), and R ³ is a hydrogen atom The angiogenesis inhibitor according to claim 2.

[5] The R ² is NR ^5a R ^5b (wherein R ^5a and R ^5b are as defined above), and R ³ is a substituted or unsubstituted lower alkoxy. Angiogenesis inhibitors.

6. The angiogenesis inhibitor according to claim 2, wherein R ² is NR ^5a R ^5b (wherein R ^5a and R ^5b are as defined above), and R ³ is a hydrogen atom.

[7] Expression (lb)

[Wherein R ^8a , R ^8b and R ^8e are the same or different and each represents a hydrogen atom, halogen, utro, nitroso, carboxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkanol, substituted or Unsubstituted lower alkoxycarbonyl, substituted or unsubstituted Substituted aryl, NR ^9a R ^9b (wherein R ^9a and R ^9b are the same or different and represent a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted lower group, Represents alkynyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkanol, substituted or unsubstituted aryl, substituted or unsubstituted arylenore, substituted or unsubstituted heterocyclic group or substituted or unsubstituted heteroaroyl. Or R 1 and R ^9b together with the adjacent nitrogen atom form a substituted or unsubstituted heterocyclic group) or OR ^1Q (where R ^1Q is a hydrogen atom, substituted or unsubstituted lower alkyl, Represents a substituted or unsubstituted aryl, substituted or unsubstituted aryl or substituted or unsubstituted heterocyclic group) Ndazoru derivative or angiogenesis inhibitor containing a pharmacologically acceptable salt thereof as an active ingredient.

[8] The angiogenesis inhibitor according to claim 7, wherein at least one of R ^8a , R ^8b and R is NR ^9a R ^9b (wherein R ^9a and R ^9b are as defined above).

[9] At least one of R ^8a , R ^8b and R is NR ^{9 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 R And R ^9d together with the adjacent nitrogen atom forms a substituted or unsubstituted heterocyclic group).

[10] The angiogenesis inhibitor according to claim 7, wherein at least one of R ^8a , R ^8b and R is OR ^1Q (wherein R ^1Q is as defined above).

[11] The angiogenesis inhibitor according to claim 7, wherein at least one of R ^8a , R ^8b and R is OR ^1Qa (wherein R ^1Qa represents a substituted or unsubstituted lower alkyl).

[12] Formula (Ib-1)

[Chemical 10]

(Wherein R ^8a , R ^9e and R ^9d are as defined above) Or the angiogenesis inhibitor which contains the salt accept | permitted pharmacologically as an active ingredient. Formula (lb-2)

[Chemical 11]

An angiogenesis inhibitor comprising an indazole derivative represented by the formula (wherein R and R are as defined above) or a pharmacologically acceptable salt thereof as an active ingredient. Formula (Ic)

[Chemical 12]

{Wherein the substituents in R ^u is a substituted or unsubstituted Hajime Tamaki [the substituent heterocyclic group are the same or different 1 to 3 substituents, Okiso, formyl, carboxy, lower alkoxy force Ruponiru, 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 each represents 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 aryl, substituted Or an unsubstituted aroyl or a substituted or unsubstituted heterocyclic group) or -0 (CR ^14a R ^14b ) 0- (formula

In n, 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. [15] The angiogenesis inhibitor according to [14], wherein the substituent in the substituted heterocyclic group is ami-oxo, lower alkoxy, lower alkoxy group, sulfonylamino, aroylamino, or lower alkoxy group, sulfonyl substituted lower alkyl.

16. The angiogenesis inhibitor according to claim 14, wherein R ^U is 3-pyridyl.

[17] An inhibitor of a kinase involved in angiogenesis, comprising the indazole derivative according to any one of claims 1 to 16 or a pharmacologically acceptable salt thereof as an active ingredient.

18. The inhibitor according to claim 17, wherein the kinase involved in angiogenesis is vascular endothelial growth factor receptor (VEGFR).

[19] The inhibitor according to claim 17, wherein the kinase involved in angiogenesis is vascular endothelial growth factor receptor 1 [Vascular endothelial growth factor receptor 1 (VEGFRl); fms_like tyrosine kinase 1 (FLT1)].

[20] Kinase involved in angiogenesis is vascular endothelial growth factor receptor 2 (VEG R2); kinase insert domain-containing receptor (KDR)

18. The inhibitor according to claim 17, wherein

[21] The inhibitor according to claim 17, wherein the kinase involved in angiogenesis is vascular endothelial growth factor receptor 3 (VEGFR3); fms_like tyrosine kinase 4 (FLT4)].

[22] The inhibitor according to claim 17, wherein the kinase involved in angiogenesis is a fibroblast growth factor receptor (FGFR).

[23] The inhibitor according to claim 17, wherein the kinase involved in angiogenesis is a platelet derived growth factor receptor (PDGFR).

24. The inhibitor according to claim 17, wherein the kinase involved in angiogenesis is an ephrin receptor.

[25] A therapeutic agent for a disease involving angiogenesis, comprising the indazole derivative according to any one of claims 1 to 16 or a pharmacologically acceptable salt thereof as an active ingredient.

[26] A therapeutic agent for rheumatism comprising the indazole derivative according to any one of claims 1 to 16 or a pharmacologically acceptable salt thereof as an active ingredient.

[27] The indazole derivative or the pharmacologically acceptable product thereof according to any one of claims 1 to 16 The anticancer agent which contains the salt made as an active ingredient.

[28] Renal cancer, colorectal cancer, breast cancer, brain tumor, head and neck cancer, prostate cancer, which contains the indazole derivative according to any one of claims 1 to 16 or a pharmacologically acceptable salt thereof as an active ingredient A therapeutic agent for cancer selected from ovarian cancer.

[29] A method for inhibiting 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].

[30] A method for inhibiting a kinase involved in angiogenesis, comprising a step of administering an effective amount of the indazole derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 16;

31. The inhibition method according to claim 30, wherein the kinase involved in angiogenesis is vascular endothelial growth factor receptor (VEGFR).

[32] The method according to claim 30, wherein the kinase involved in angiogenesis is vascular endothelial growth factor receptor 1 [Vascular endothelial growth factor receptor 1 (VEGFRl); fms_like tyrosine kinase 1 (FLT1)].

[33] Kinase involved in angiogenesis is vascular endothelial growth factor receptor 2 (VEG R2); kinase insert domain-containing receptor (DR)

The inhibition method according to claim 30, wherein

[34] The method according to claim 30, wherein the kinase involved in angiogenesis is vascular endothelial growth factor receptor 3 [Vascular endothelial growth factor receptor 3 (VEGFR3); fms_like tyrosine kinase 4 (FLT4)].

35. The inhibition method according to claim 30, wherein the kinase involved in angiogenesis is fibroblast growth factor receptor (FGFR).

[36] The inhibition method according to [30], wherein the kinase involved in angiogenesis is a platelet derived growth factor receptor (PDGFR).

[37] The method of inhibiting according to [30], wherein the kinase involved in angiogenesis is an ephrin receptor.

[38] A method for treating a disease involving angiogenesis, comprising a step of administering an effective amount of the indazole derivative or the pharmacologically acceptable salt thereof according to any one of claims 1 to 16; [39] 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 claims 1 to 16;

[40] 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 claims 1 to 16;

[41] Renal cancer, colon cancer, breast cancer, brain tumor, head and neck cancer, comprising a step of administering an effective amount of the indazole derivative or pharmacologically acceptable salt thereof according to any one of claims 1 to 16; A method for treating cancer selected from prostate cancer and ovarian cancer.

[42] Use of the indazole derivative or the pharmaceutically acceptable salt thereof according to any one of claims;! To 16 for the production of an angiogenesis inhibitor.

[43] Use of the indazole derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 16 for the manufacture of an inhibitor of a kinase involved in angiogenesis.

[44] The use according to claim 43, wherein the kinase involved in angiogenesis is a vascular endothelial growth factor receptor (VEGFR).

[45] The use according to claim 43, wherein the kinase involved in angiogenesis is vascular endothelial growth factor receptor 1 [Vascular endothelial growth factor receptor 1 (VEGFRl); fms_like tyrosine kinase 1 (FLT1)].

[46] Vascular endothelial growth factor receptor 2 (VEG R2); kinase insert domain-containing receptor (KDR)

44. Use according to claim 43, wherein

[47] The use according to claim 43, wherein the kinase involved in angiogenesis is vascular endothelial growth factor receptor 3 (VEGFR3); fms_like tyrosine kinase 4 (FLT4)].

[48] The use according to claim 43, wherein the kinase involved in angiogenesis is a fibroblast growth factor receptor (FGFR).

[49] The use according to claim 43, wherein the kinase involved in angiogenesis is a platelet-derived growth factor receptor (PDGFR).

[50] The use according to claim 43, wherein the kinase involved in angiogenesis is an Ephrin receptor. [51] Use of the indazole derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 16 for the manufacture of a therapeutic agent for a disease involving angiogenesis.

[52] Use of the indazole derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16 for the manufacture of a therapeutic agent for rheumatism.

[53] Use of the indazole derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 16 for the manufacture of an anticancer agent.

[54] The indazole derivative according to any one of claims 1 to 16 for producing a therapeutic agent for cancer selected from renal cancer, colon cancer, breast cancer, brain tumor, head and neck cancer, prostate cancer and ovarian cancer Is the use of a pharmacologically acceptable salt thereof.