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WO2008053812A1 - Dérivé de cyanopyridine et son utilisation médicale - Google Patents

Dérivé de cyanopyridine et son utilisation médicale Download PDF

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Publication number
WO2008053812A1
WO2008053812A1 PCT/JP2007/070950 JP2007070950W WO2008053812A1 WO 2008053812 A1 WO2008053812 A1 WO 2008053812A1 JP 2007070950 W JP2007070950 W JP 2007070950W WO 2008053812 A1 WO2008053812 A1 WO 2008053812A1
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Prior art keywords
substituted
optionally substituted
alkyl
general formula
iii
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PCT/JP2007/070950
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English (en)
Japanese (ja)
Inventor
Masahiko Morioka
Hiroshi Ikegami
Makoto Sakiyama
Shinsuke Ooike
Masayuki Hayashi
Yasuhiro Fujino
Daisuke Abe
Hideo Tomozane
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Mitsubishi Tanabe Pharma Corporation
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Publication of WO2008053812A1 publication Critical patent/WO2008053812A1/fr

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    • 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
    • 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
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel cyanopyridine derivative and a pharmaceutical comprising the same as an active ingredient.
  • Protein kinases are considered to be important drug targets along with GPCRs (G protein-coupled receptors). Abnormal activation of protein kinases has been associated with a number of diseases involving abnormal cell growth. For example, inflammatory and proliferative diseases, so-called tumors, rheumatoid arthritis, heart diseases, neurological diseases, psoriasis, asthma, hyperproliferation such as intravascular smooth muscle proliferation of stenosis or restenosis after angioplasty Obstacles. Protein kinase abnormalities are said to be directly and indirectly related to 400 human diseases. Therefore, if the activity of protein kinase can be manipulated, various diseases can be effectively treated. Power to do S There are only a few compounds on the market as pharmaceuticals (Non-patent Document 1).
  • Mitochondrial protein kinases phosphorylate various proteins at specific timings and locations to promote accurate cell division, but once their control is disrupted, there are a variety of chromosomes, including chromosome distribution. Abnormalities occur in mitotic events, resulting in large phenotypic changes in cells.
  • mitotic protein kinases is Aurora kinase.
  • O Bite lakinase is a highly conserved serine / threonine kinase that is
  • Non-patent document 4 Non-patent document 5, Non-patent document 6, Non-patent document 7, Non-patent document 8, Non-patent document 9 and Non-patent document Patent Document 10
  • Non-Patent Document 11 The fact that experimentally overexpressed Aurora 2 kinase in normal cells revealed that the cells showed signs of canceration.
  • Patent Document 1 treatment of human tumor cell lines with antisense oligonucleotide suppresses the expression of Aurora 2 kinase and suppresses cell proliferation. This is because it is possible to suppress the abnormal growth of cells by inhibiting the activity of Aurora 2 kinase, and it is considered useful for the treatment of many diseases accompanied by abnormal growth of cells such as cancer. It is done.
  • Patent Literature 2 Low molecular weight compounds that inhibit Aurora 2 kinase have been reported in patents!
  • Patent Literature 2 Patent Literature 3
  • Patent Literature 4 Patent Literature 5
  • Patent Literature 6 Patent Literature 7
  • Non-Patent Literature 12 Non-Patent Literature 13
  • Non-Patent Literature 14 may be mentioned.
  • Patent Document 1 JP 2002-95479 A
  • Patent Document 2 Pamphlet of International Publication No. 2001-21595
  • Patent Document 3 Pamphlet of International Publication No. 2002-22601
  • Patent Document 4 International Publication No. 2002-66461 Pamphlet
  • Patent Document 5 Pamphlet of International Publication No. 2003-55491
  • Patent Document 6 International Publication No. 2005-013996 Pamphlet
  • Patent Document 7 US Patent Application Publication No. 2005-0256102
  • Non-patent literature l Irena Melnikova et al., Nature Reviews / Drug Discovery, 3 993-994, 2004
  • Non-Patent Document 2 David M. Glover et al., Cell, 81 95-105, 1995
  • Non-patent literature 3 Daniela Berdnik et al., Current Biology, 12 640-647, 2002
  • Non-patent literature 4 Hongyi Zhou et al., Nature Genetics, 20 189-193, 1998
  • Non-patent literature 5 Takuji Tanaka et al. Cancer Research, 59, 2041-2044, 1999
  • Non-Patent Document 6 C. Sakakura et al., British Journal of Cancer, 84, 824-831, 2001
  • Non-Patent Document 7 Subrata Sen et al., Journal of the National Cancer Institute, 94, 1320-1329, 2002
  • Non-Patent Document 8 Donghui Li et al., Clinical Cancer Research, Vol. 9, 991-997, 2003
  • Non-patent Document 9 Yung-Ming Jeng et al., Clinical Cancer Research, Vol. 206, 2065-2071, 20 04
  • Non-Patent Document 10 Sangeeta Rojanala et al., Molecular Cancer Therapeutics Vol.3, No.4, 451-457, 2004
  • Non-patent literature l l James R. Bischoi3 ⁇ 4, EMBO Journal, 17 3052-3065, 1998
  • Non-patent literature 12 Elizabeth A. Harrington et al., Nature Medicine 10 3 262-267, 2 004
  • Non-patent document 13 Nicolas Keen et al., Nature Reviews Cancer 4, 927-936, 2004
  • Non-patent document 14 Daniele Faucelli et al., J. Med. Chem. 48, 3080-3084, 2005 Disclosure of the invention
  • An object of the present invention is to provide a novel cyanopyridine derivative and a medicine containing the same as an active ingredient.
  • the gist of the present invention is as follows.
  • R 1 represents the general formula (II) or the general formula (III).
  • ir, R 3 ′, R 5 and R 5 ′ are the same or different and each represents a hydrogen atom, a halogen atom or an optionally substituted alkyl. Alternatively, R 3 and R 3 ′ or R 5 and R 5 ′ may be joined together to form an oxo.
  • X represents NR 6 or a sulfur atom.
  • R 6 represents a hydrogen atom or substituted! /, May! /, Alkyl.
  • Y represents an oxygen atom or a sulfur atom.
  • n represents an integer of 1 to 5
  • m represents an integer of 0 to 4.
  • R 4 is a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted aryl, a substituted Represents! /, May! /, An aromatic heterocycle, substituted les, may! /, Alkoxycarbonyl, or an optionally substituted non-aromatic heterocycle.
  • R 4 is a hydrogen atom, an optionally substituted alkyl, an optionally substituted aralkyl, an optionally substituted pyridylcarbonyl, an optionally substituted May be substituted, may be substituted! /, Urea or substituted! /, May! /, Czzia.
  • R 4 is a hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, substituted Is! /, May! /, Aromatic heterocycle, substituted les, may! /, Alkoxycarbonyl or substituted! /, May! /, Non-aromatic heterocycles.
  • R 4 is a hydrogen atom, an optionally substituted alkyl, an optionally substituted aralkyl, an optionally substituted pyridylcarbonyl, or a substituted! /, Mayo! /, Asil, substituted! /, Mayo! /, Urea or substituted! /, Mayo! /, Tow. )
  • R 2 represents a hydrogen atom, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted hydroxy.
  • Rilalkyl, optionally substituted rubamoyl, optionally substituted alkanoylamino, substituted, may! /, Alkylamino or amino.
  • R 2 ′ represents a hydrogen atom or substituted! /, May! /, Alkyl.
  • R 2 and R 2 ′ may be joined together to form an optionally substituted ring.
  • R x represents TR 8 .
  • T represents a valence bond or an alkylene chain
  • R 8 represents a hydrogen atom, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted, an aromatic heterocyclic ring. Or substituted !, may! /, Represents a non-aromatic heterocycle.
  • R 7 represents a hydrogen atom, an optionally substituted alkyl or a halogen atom.
  • R X and R 7 may be taken together to form an optionally substituted ring.
  • a pharmaceutically acceptable salt, hydrate, water adduct or solvate thereof may be taken together.
  • T represents a valence bond
  • R 8 represents an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted, an aromatic heterocycle or a substituted !, may! /, Non-aromatic heterocycle ,
  • R 4 is substituted with a hydrogen atom, Optionally substituted alkyl, substituted, aryl, or substituted! /, May! /, Represents an aromatic heterocycle,
  • R 4 may be substituted, may be! /, Alkyl or substituted /! Or even! /, A syranopyridine derivative, a pharmaceutically acceptable salt, hydrate, water adduct or solvate thereof according to (1), which represents aralkyl.
  • R 8 is substituted! /, May! /, C alkyl, substituted! /, May! /, Phenyl, substituted
  • R 4 is substituted! /, Maybe! /, C alkyl, substituted! /, Mayo! /, Phenyl, substituted les, may! /, Pyridyl or substituted! /, May! /, Pyrimidyl
  • R 1 is represented by the general formula (II) (n represents 1) or general formula ( III) (m represents 0)
  • R 4 represents an optionally substituted C alkyl or an optionally substituted C aralkyl.
  • a substance selected from the group consisting of a cyanopyridine derivative represented by the general formula (I), a pharmaceutically acceptable salt, hydrate, water adduct and solvate thereof is used as an active ingredient. It is possible to provide a medicine.
  • halogen atom eg, fluorine, chlorine, bromine, iodine
  • C alkyl methyl
  • Norebonyl (methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), force norebamoyl, mono- or di-C alkyl one strength ruvamoyl (methylcarbamoyl,
  • “optionally substituted” means 1 to 5 (preferably 1 to 3) substituents at positions that can be substituted by any of the above-described substituents, unless otherwise specified. It is meant to include those with In addition, when there are a plurality of substituents, the types of the substituents may be the same or different! /, Or! /.
  • Examples of the "norogen atom" represented by R 3 ', R 5 and R 5 include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and a fluorine atom is particularly preferred.
  • Examples of the alkyl in the "optionally substituted alkyl" represented by R 3 , R 3 ', R 5 and R 5 include C alkyl (eg, methyl, ethyl, propyl, isopropyl).
  • Straight chain or branched chain C alkyl such as pill, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl, and C cyclic alkyl such as cyclopropyl).
  • it is C alkyl (eg, methyl, ethyl, propyl, isopropyl).
  • examples of the substituent include the same substituents as those described above.
  • Examples of the alkyl in the "optionally substituted alkyl” represented by R 6 include the same as the alkyl in the above “optionally substituted alkyl", and in particular, C alkyl ( Examples, methyl, ethyl, propyl) are preferred.
  • the alkyl is
  • alkyl in "substituted! /, May! /, Alkyl” represented by R 4 are the same as those in the “optionally substituted alkyl” represented by the above, and in particular, C alkyl (eg, methyl, ethyl, propyl, isopropyl, tert-butyl) is
  • examples of the substituent include those similar to the above-mentioned substituent, and preferably a halogen atom, hydroxy, C alkoxy, amino and
  • alkenyl in the "optionally substituted alkenyl" represented by R 4 examples include C alkenyl such as bull. The alkenyl is substituted
  • examples of the substituent include the same substituents as those described above.
  • Examples of the "substituted! /, May! /, Aryl" represented by R 4 include C aryl such as phenyl, 1-naphthyl, 2-naphthyl, and the like, and is preferably phenyl.
  • the phenyl is
  • substituents include those similar to the above-mentioned substituent, and preferred are a halogen atom, cyano and C alkanoylamino.
  • Aromatic heterocycle represented by R 4 is, for example, selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom Containing 1 or 2 heteroatoms;!
  • the alkoxy power norlevonyl in "optionally substituted alkoxycarbonyl" represented by R 4 includes, for example, C alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and the like.
  • the alkoxy power includes, for example, C alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and the like.
  • examples of the substituent include those similar to the above-described substituent.
  • a non-aromatic heterocyclic ring in "substituted! /, May! /, Non-aromatic heterocyclic ring” represented by R 4 examples thereof include 5- to 7-membered non-aromatic complex rings such as piperidyl, piperazil, morpholinyl and the like.
  • examples of the substituent include the same as the above-described substituent.
  • the aralkyl in “substituted! /, Mayo! /, Aralkyl” represented by R 4 is “substituted! /, May! /, Ariel” or “ Substituted! /, May! / Is a group formed by linking an “aryl” or “aromatic heterocycle” of an aromatic heterocyclic ring to a C alkyl,
  • C aralkyl such as benzyl, phenethyl, pyridino remetinole, pyridylethyl, etc.
  • examples of the substituent include the same as the above-described substituent.
  • acyl in the “optionally substituted acyl” represented by R 4 examples include C alkanoyl such as acetyl and bivaloyl. The isil is replaced
  • examples of the substituent include the same substituents as those described above.
  • alkyl in the "substituted! /, May! /, Alkyl" represented by R 2 include those similar to the “alkyl” represented by the above, and in particular, C alkyl (eg, methyl ,
  • alkoxy in "substituted! /, May! /, Alkoxy" represented by R 2 include C alkoxy such as methoxy, ethoxy, isopropoxy and the like.
  • the alkoxy is
  • alkylthio in the “substituted! /, May! /, Alkylthio” represented by R 2 include those in which the alkyl moiety is the same as the “alkyl” represented by R 3 , for example, And C alkylthio such as methylthio, ethylthio, propylthio, isopropylthio, cyclopropylthio, and butylthio.
  • the alkylthio is substituted
  • hydroxyalkyl in the "optionally substituted hydroxyalkyl" represented by R 2 examples include hydroxy C alkyl such as hydroxymethyl and hydroxyethyl.
  • R 2 “Substituted! /, May! /, Rubamoyl” represented by R 2 includes rubamoyl, mono- or di-C alkyl rubamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.)
  • alkanoylamino in the "substituted! /, Mayo! /, Alkanoylamino" represented by R 2 include C alkanoylamino and the like such as acetylamino and bivalloamino.
  • examples of the substituent include those similar to the above-described substituent.
  • alkylamino in "substituted! /, May! /, Alkylamino" represented by R 2 may be either mono- or di-alkylamino, such as methylamino, ethylamino, isopropylamino, dimethylamino. , Jetilamino etc.
  • alkylamino examples include the same substituents as those described above.
  • alkyl which may be substituted represented by R 2
  • R 3 ' is replaced! /
  • I be! / Alkyl include the same.
  • the ring in the "optionally substituted ring" formed by R 2 and R 2 'together is particularly preferably a 5- to 10-membered monocyclic or bicyclic ring such as a benzene ring , Pyridine ring, pyrimidine ring
  • alkylene chain represented by T is, for example, a C 4 linear or branched saturated hydrocarbon.
  • Divalent group derived from silicon specifically, C-alkyl such as methylene, ethylene, propylene, etc.
  • Examples of the alkyl in the "substituted! /, May! /, Alkyl" represented by R 8 include the same as the alkyl in the "optionally substituted alkyl” represented by the above.
  • C alkynoles such as methyl, ethyl, propyl, isopropyl, cyclopropyl, etc.
  • examples of the substituent include the same ones as the above-mentioned substituent, preferably a halogen atom and a 5- to 7-membered cyclic group.
  • aromatic heterocyclic ring in the “ring” examples include the same, and preferred are pyridyl, chenyl, and benzodioxol.
  • substituent examples include those similar to the above-mentioned substituent, and preferably C alkyl.
  • the non-aromatic heterocycle in the "substituted! /, May! /, Non-aromatic heterocycle" represented by R 8 includes a nitrogen atom, a sulfur atom and an oxygen atom in addition to the carbon atom. 1 to 2 of 1 to 2 heteroatoms selected from 5 to; 10-membered monocyclic or bicyclic non-aromatic heterocycles (eg piperidinole, piperazil, pyrrolidinyl, monomorpholinole, thiomorpholinyl) Etc.), preferably piperidyl.
  • substituent include those similar to the above-mentioned substituent, preferably carboxyl and C
  • Examples of the alkyl in the "substituted! /, May! /, Alkyl" represented by R 7 include the same as the alkyl in the "optionally substituted alkyl” represented by the above. In particular, C alkyl (eg, methyl etc.) is preferred. When the alkyl is substituted
  • examples of the substituent include the same substituents as those described above.
  • Nono androgenic atom represented by R 7 is, include those similar to the “Nono androgenic atom” represented by R 3, in particular, a fluorine atom, a chlorine atom is preferable.
  • the ring in the “optionally substituted ring” formed by R x and R 7 being joined together includes 5
  • -7 membered ring is mentioned, for example, a cyclopentane ring, a cyclohexane ring, etc. are mentioned.
  • substituents include the same substituents as those described above.
  • Examples of the pharmaceutically acceptable salt in the compound of the general formula (I) include acid addition salts with inorganic acids or organic acids.
  • compositions of general formula (I) include water adducts, hydrates and solutions. These water adducts, hydrates and solvates are also encompassed by the present invention as they may exist as solvates.
  • the raw material for producing the compound of the present invention represented by the general formula (I) is represented by the general formula (IV) (in the general formula (IV), L represents a fluorine atom, a chlorine atom or a bromine atom). 2,6-dihaguchi-3-cyanobilidine derivatives are used.
  • This starting compound can be produced by a known method (J. Org. Chem. Vol. 25 p560, JP-A-49-62477, Bioorg. Med. Chem. Lett. 11 (2001). ) ⁇ 475, J.Org.Chem.44 (1979) p2693) 0 or the corresponding ⁇ -ketoester is reacted with 2-cyanoacetamide in the presence of DBU (diazabicyclo [5,4,0] undecene), The precipitate can be easily synthesized by heat treatment with phenylphosphonic dichloride.
  • DBU diazabicyclo [5,4,0] undecene
  • reaction 1 the compound of general formula (IV) and the 3-aminobiazole derivative are placed in a suitable solvent at room temperature or under heating in the presence of a base to obtain a compound of formula (V).
  • This force S is possible.
  • the reaction proceeds thermally by increasing the reaction temperature, whereby compound (V) can be obtained.
  • the above base is not particularly limited as long as it is a substance for accelerating the reaction, metal alkoxide such as tertiary amine, potassium tert-butoxide, diazabicyclo [5,4,0] un Examples thereof include amidines such as decene, metal hydrides such as guanidine and sodium hydride, metal fluorides such as potassium fluoride, and solids carrying metal fluorides.
  • metal alkoxide such as tertiary amine, potassium tert-butoxide, diazabicyclo [5,4,0] un
  • amidines such as decene
  • metal hydrides such as guanidine and sodium hydride
  • metal fluorides such as potassium fluoride
  • solids carrying metal fluorides solids carrying metal fluorides.
  • tertiary amine triethylamine, Huech base
  • the amount of the base to be added is usually 0.;! To 30 equivalents, preferably 1 to 10 equivalents based on the compound.
  • the solvent used in the reaction is not limited as long as it does not inhibit this reaction. Mentioning oxan, N, N-dimethylformamide (hereinafter referred to as DMF).
  • the reaction temperature of this reaction is usually 20 ° C to 200 ° C, preferably 80 ° C to 150 ° C.
  • reaction time varies depending on the temperature or the type of solvent and is usually 30 minutes to 8 hours.
  • Examples of the protecting group include trityl, benzyloxymethyl, ethoxymethyl, and benzyloxycarbonyl.
  • the target product of each reaction can be collected from the reaction mixture according to a conventional method. For example, by concentrating the reaction mixture, or if solids are present, the solids are removed by appropriate filtration, and then the liquid is crystallized by adding it to basic or neutral water for crystallization. Things are obtained. If the target product does not crystallize, wash it with an organic solvent immiscible with water, such as ethyl acetate or black mouth form, separate the organic layer containing the target product, dry it over anhydrous magnesium sulfate, etc., and then evaporate the solvent. It is obtained by doing.
  • an organic solvent immiscible with water such as ethyl acetate or black mouth form
  • the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation, washing with a solvent, or chromatography.
  • the compound of formula (I) can be obtained by heating the compound of general formula (V) and the amine derivative or thiol derivative in the presence of a base in an appropriate solvent.
  • the reaction can be accelerated thermally by increasing the reaction temperature, thereby obtaining the compound (I).
  • the base is not particularly limited as long as it is a substance for accelerating the reaction, metal alkoxide such as tertiary amine, potassium tert-butoxide, diazabicyclo [5,4,0] undecene, etc.
  • metal alkoxide such as tertiary amine, potassium tert-butoxide, diazabicyclo [5,4,0] undecene, etc.
  • metal hydrides such as amidine, guanidine, sodium hydride, sodium hydrogen carbonate, and the like. In particular, sodium hydrogen carbonate is preferable.
  • the amount of the base to be added is usually 0.;! To 30 equivalents, preferably 1 to 10 equivalents.
  • the solvent used in the reaction is not limited as long as it does not inhibit this reaction, but preferably THF, DMSO, 1,4-dioxane, DMF and the like can be mentioned.
  • the reaction temperature of this reaction is usually 60 ° C to 200 ° C, preferably 80 ° C to 150 ° C.
  • reaction time varies depending on the temperature or the type of solvent, and is usually 1 to 100 hours.
  • the target product of each reaction can be collected from the reaction mixture according to a conventional method.
  • the reaction mixture is concentrated, and if a solid is present, the solid is removed by filtration as appropriate, and then the liquid is added to water for crystallization to obtain the desired product.
  • the target product does not crystallize, wash it with an organic solvent immiscible with water, such as ethyl acetate or chloroform, separate the organic layer containing the target product, dry it over anhydrous magnesium sulfate, etc. It is obtained by leaving.
  • the thus-produced cyanopyridine derivative of the general formula (I) of the present invention is appropriately subjected to known separation and purification means, for example, means such as concentration, extraction, chromatography, reprecipitation, recrystallization and the like. By applying, it can be collected as having an arbitrary purity.
  • the salt, hydrate, water adduct and solvate of the cyanopyridine derivative represented by the general formula (I) can be produced from the cyanopyridine derivative by a known method.
  • the compound of the general formula (I) obtained by the above method, or a pharmaceutically acceptable salt, hydrate, water adduct and solvate thereof have anticancer activity, and Or it is useful as a therapeutic agent.
  • the compound of the present invention, optical isomers thereof or pharmaceutically acceptable salts thereof can be safely used with low toxicity.
  • the dosage can be appropriately determined depending on conditions such as the patient's age, health condition, weight, etc., and if there are drugs to be administered at the same time, conditions such as the type and frequency of administration, or the nature of the desired effect. .
  • the daily dose of active ingredient is 0.5 to 300 mg / kg body weight, usually;! To 30 mg / kg body weight, and can be administered one or more times per day.
  • a pharmaceutical composition containing the above active ingredient and one or more pharmaceutically acceptable excipients for preparation is prepared and administered. It is preferable.
  • Examples of the pharmaceutical composition suitable for oral administration include tablets, capsules, powders, liquids, elixirs and the like.
  • Examples of the pharmaceutical composition suitable for parenteral administration include liquids.
  • a sterilized liquid pharmaceutical composition such as a suspending agent can be exemplified.
  • the type of pharmaceutically acceptable pharmaceutical additive used for the preparation of the pharmaceutical composition is not particularly limited, and an appropriate pharmaceutical additive is selected depending on the form of various pharmaceutical compositions. Is possible.
  • the additive for the preparation may be either solid or liquid.
  • a solid carrier or a liquid carrier can be used.
  • an ordinary gelatin type capsule can be used.
  • the active ingredient can be tableted with one or two or more pharmaceutical additives, or without using pharmaceutical additives, or can be prepared and packaged as a powder.
  • These capsules, tablets and powders can generally contain 5 to 95% by weight, preferably 5 to 90% by weight, of the active ingredient relative to the total weight of the formulation, and the dosage unit form is 5 to 500 mg. Preferably, it contains 25 to 250 mg of active ingredient.
  • the liquid carrier water, oils of animal or vegetable origin such as petroleum, peanut oil, soybean oil, mineral oil, sesame oil or synthetic oils are used.
  • TMS tetramethylsilane
  • the primer sequences used for the PCR reaction were SEQ ID NO: 1 (5, -GGA ATT CCA TAT GGA CCG ATC TAA AGA AAA CTG-3,) and SEQ ID NO: 2 (5,-GGG GGG CTC GAG AGA CTG TTT G CT AGC TGA TTC -3 ').
  • the amplified Aurora 2-kinase-encoding gene was introduced into the E. coli expression vector pET32a (Novagen) to prepare a recombinant. Recombinants are described in Ambrook et al., “Molecular Cloning-Experimental Manual, Second Edition (1989 Cold Spring Harbor Laboratory press)” and Ausubel et al., “Current Protocols in Molecular Biology, (1999 John Wiley and Sons In c.) ”You can get power S.
  • E. coli strain for aurora 2 kinase large expression was cultured in an LB medium containing Ampicilin ⁇ O g / ml). Incubate Aurora 2 kinase after 1 hour shaking culture at 37 ° C for this purpose, the culture temperature was set to 25 ° C., a final concentration of 0. ImM IPTG (SIGMA) was added, and the cells were cultured with shaking at 25 ° C. for 24 hours. Thereafter, the culture solution was centrifuged at 7000 rpm for 10 minutes, and the cells were collected.
  • SIGMA ImM IPTG
  • the collected bacterial cells were treated with 36 ml of lysis buffer [50 mM Tris pH6.8, 150 mM NaCl, 20 mM ⁇ -Glycerophosphate, 0.3 mM Na V0, 50 mM NaF, 2 mM PMSF (phenylmethyl fluoride)
  • Each well contains an enzyme reaction buffer (200 mM Tris-HCl (pH 7.0), lOOmM MgCl 2) (1.5 ⁇ 1), 50 mM dithiothreitol (1.5 1), ImM peptide substrate [LRRASLG] (1 ⁇ 5 ⁇ 1), water (2.5 1), and DMSO solution with compound added (1.5 ⁇ 1) were added.
  • an enzyme reaction buffer 200 mM Tris-HCl (pH 7.0), lOOmM MgCl 2) (1.5 ⁇ 1), 50 mM dithiothreitol (1.5 1), ImM peptide substrate [LRRASLG] (1 ⁇ 5 ⁇ 1), water (2.5 1), and DMSO solution with compound added (1.5 ⁇ 1) were added.
  • Aurora 2 kinase (lmg / ml, 1.5 1) diluted in enzyme diluent [50 mM Tris_HCl (pH 6.8), 200 mM NaCl, 50% glycerol, lmg / ml BSA] Added to all but wells. Enzyme Diluent 1.51 without Aurora 2 kinase was added to the “Blank” well. To the “total” well, DMSO solution containing no compound was added 1.5 H 1 calorie.
  • a cancer therapeutic agent comprising as an active ingredient a substance selected from the group consisting of a novel cyanopyridine derivative, a pharmaceutically acceptable salt, hydrate, water adduct and solvate thereof. it can.

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Abstract

Bien que plusieurs substances inhibant la kinase Aurora 2 aient été signalées, on n'en a pas encore trouvé une ayant une activité biologique suffisante pour traiter des maladies. La présente invention concerne donc un inhibiteur de la kinase Aurora 2 utilisable pour traiter des maladies de prolifération cellulaire dont le type est le cancer. L'invention concerne un composé de cyanopyridine représenté par la formule générale (I) ci-dessous, un sel ou un hydrate de celui-ci pharmaceutiquement acceptable, un produit d'addition d'eau ou un solvate du même ayant un puissant effet cancérostatique.
PCT/JP2007/070950 2006-10-27 2007-10-26 Dérivé de cyanopyridine et son utilisation médicale WO2008053812A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015141095A1 (fr) * 2014-03-19 2015-09-24 富士フイルム株式会社 Compose, composition de pigment, encre d'impression a jet d'encre, procede d'impression a jet d'encre, catouche d'imprimante a jet d'encre, et materiau imprime par jet d'encre

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002066461A1 (fr) * 2000-12-21 2002-08-29 Vertex Pharmaceuticals Incorporated Composes de pyrazole utilises comme inhibiteurs de la proteine kinase
WO2006082392A1 (fr) * 2005-02-04 2006-08-10 Astrazeneca Ab Dérivés de pyrazolylaminopyridine employés en tant qu'inhibiteurs de kinase
WO2006118231A1 (fr) * 2005-04-28 2006-11-09 Mitsubishi Tanabe Pharma Corporation Dérivé de cyanopyridine et emploi dudit dérivé au titre de médicament

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002066461A1 (fr) * 2000-12-21 2002-08-29 Vertex Pharmaceuticals Incorporated Composes de pyrazole utilises comme inhibiteurs de la proteine kinase
WO2006082392A1 (fr) * 2005-02-04 2006-08-10 Astrazeneca Ab Dérivés de pyrazolylaminopyridine employés en tant qu'inhibiteurs de kinase
WO2006118231A1 (fr) * 2005-04-28 2006-11-09 Mitsubishi Tanabe Pharma Corporation Dérivé de cyanopyridine et emploi dudit dérivé au titre de médicament

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015141095A1 (fr) * 2014-03-19 2015-09-24 富士フイルム株式会社 Compose, composition de pigment, encre d'impression a jet d'encre, procede d'impression a jet d'encre, catouche d'imprimante a jet d'encre, et materiau imprime par jet d'encre
JP2015178576A (ja) * 2014-03-19 2015-10-08 富士フイルム株式会社 化合物、着色組成物、インクジェット記録用インク、インクジェット記録方法、インクジェットプリンタカートリッジ、及びインクジェット記録物

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