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WO2010104307A2 - Compositions pharmaceutiques pour traiter ou prévenir des maladies causées par la translocation de gsk3 du noyau cellulaire au cytoplasme, contenant des composés inhibant la translocation de gsk3 du noyau cellulaire au cytoplasme - Google Patents

Compositions pharmaceutiques pour traiter ou prévenir des maladies causées par la translocation de gsk3 du noyau cellulaire au cytoplasme, contenant des composés inhibant la translocation de gsk3 du noyau cellulaire au cytoplasme Download PDF

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WO2010104307A2
WO2010104307A2 PCT/KR2010/001446 KR2010001446W WO2010104307A2 WO 2010104307 A2 WO2010104307 A2 WO 2010104307A2 KR 2010001446 W KR2010001446 W KR 2010001446W WO 2010104307 A2 WO2010104307 A2 WO 2010104307A2
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unsubstituted
substituted
alkyl
methyl
ethyl
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WO2010104307A3 (fr
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육종인
김현실
김남희
노경태
김수연
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주식회사 메디젠텍
사단법인 분자설계연구소
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a pharmaceutical composition for treating or preventing a disease caused by GSK3 migration from a cell nucleus to a cytoplasm containing a compound that inhibits the migration of GSK3 from the nucleus to the cytoplasm, and more particularly, to the cytoplasm in the nucleus.
  • the present invention relates to a pharmaceutical composition for inhibiting the growth or metastasis of cancer cells and a pharmaceutical composition for treating immunological diseases, which contain a novel compound that inhibits the migration of GSK3 to the stratum.
  • Glycogen synthase kinase-3 (GSK3) is a serine / threonine kinase and has a molecular weight of about 47 kD and phosphorylates 50 proteins.
  • GSK3 has two isoforms, GSK3 ⁇ and GSK3 ⁇ , and these genes are known to be very similar and very similar in function (Double BW & Woodgett. JR, J. Cell Sci ., 116: 1175, 2003). .
  • GSK3 has numerous proteins, especially ⁇ -catenin or (1) in the course of (1) onset, (2) cancer development and progression, and (3) development of immune and chronic inflammatory diseases such as rheumatoid arthritis or It regulates the phosphorylation of proteins such as snail.
  • abnormality in signaling systems such as Wnt signaling promotes the development and progression of various diseases by increasing the half-life by inhibiting the phosphorylation of cancer-causing and metastatic activators such as ⁇ -catenin and snail by GSK3.
  • substances that promote the activity of GSK3 in cells or in the nucleus may be helpful in suppressing disease occurrence and progression by Wnt signaling.
  • increasing the activity of GSK3 can reduce the inhibition of GSK3 in the nucleus by Wnt signaling and effectively inhibit the onset and progression of many diseases caused by Wnt signaling.
  • the Axin gene has two isoforms, Axin1 and Axin2 (conductin).
  • the Axin1 and Axin2 genes are known to regulate protein phosphorylation through different transcriptional regulation processes.
  • the Axin gene acts as a negative regulator of Wnt signaling by promoting the phosphorylation of ⁇ -catenin by GSK3 and reducing its half-life (US Patent 2001 / 0052137A1).
  • FRAT-1 and FRAT-2 genes that bind to GSK3 to perform the nuclear export function of GSK3.
  • FRAT was found to be a GSK3 inhibitor, unlike Axin, which is known to promote ⁇ -catenin phosphorylation (Ciani, L. et al., J. Cell Biol ., 164: 243, 2004; Yost, C. et al. , Cell , 93: 1031, 1998), and GSK3 has different binding points and binding forms.
  • knock-out of either the Axin-1 or Axin-2 gene does not normally occur (Chia, IV & Costatini, F., Mol.
  • FRAT-1, -2, -3 can be knocked out in the normal development (van Amerongen, R. et al., Genes De ., 19: 425, 2005) FRAT It is not yet clear what role genes play in Wnt signaling.
  • the present inventors have made diligent efforts to develop new compounds for treating diseases caused by a decrease in GSK3 concentration in the nucleus, resulting in novel compounds that inhibit GSK3 migration from the nucleus to the cytoplasm, and the compounds in the nucleus.
  • the present invention has been found to be useful in treating various diseases caused by decreasing GSK3 concentration.
  • the main object of the present invention is to provide a novel compound of formula (3) which inhibits GSK3 migration from the nucleus to the cytoplasm by binding to Axin.
  • Another object of the present invention to provide a pharmaceutical composition for the treatment or prevention of diseases caused by GSK3 migration from the cell nucleus to the cytoplasm containing the compound as an active ingredient.
  • Still another object of the present invention is to provide a pharmaceutical composition for inhibiting growth or metastasis of cancer cells containing the compound as an active ingredient.
  • Still another object of the present invention is to provide a pharmaceutical composition for treating an immunological disease containing the compound as an active ingredient.
  • the present invention provides a method for treating diseases caused by GSK3 migration from the cell nucleus to the cytoplasm containing the compound represented by the following formula (3), a pharmaceutically acceptable salt, prodrug, or isomer thereof as an active ingredient.
  • a pharmaceutically acceptable salt, prodrug, or isomer thereof as an active ingredient.
  • X is C ⁇ O, C ⁇ S or SO 2 ;
  • Y is a covalent bond or NH
  • R 3 , R 4 and R 5 are each independently hydrogen, halogen,-(CH 2 ) n -CN,-(CH 2 ) n -NO 2 ,-(CH 2 ) n -C (O) OH,-( CH 2 ) n -C (O) H,-(CH 2 ) n -OH,-(CH 2 ) n -NH 2 ,-(CH 2 ) n -C (O) NH 2 ,-(CH 2 ) n Substituted or unsubstituted alkyl including -O-alkyl, methyl, ethyl and isopropyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl including phenyl, imidazolyl, thiazolyl, Substituted or non-containing, including pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl
  • c and d are each independently 0, 1, 2 or 3;
  • a and b are each independently 0, 1, 2, 3, 4, 5 or 6;
  • a 1 is a covalent bond, single or polysubstituted or unsubstituted alkyl including isopropyl, phenyl, furanyl, pyrazolyl, triazolyl, thiophenyl, pyridinyl, , Pyrimidinyl, pyrazinyl, pyrrolyl, tetrazolyl, oxazolyl, isoxazolyl, oxdiazolyl, thienyl, thiadiazolyl, benzimidazolyl, imidazolyl, indolyl, indazolyl, benzoisothia Single or polysubstituted or unsubstituted aryl or heteroaryl single or bicyclic rings comprising zolyl and benzofuranyl, substituted or unsubstituted heteroarylalkyl comprising thiophenylethyl, piperidinyl, pipera Genyl, pyridaziny
  • a 2 is hydrogen, halogen,-(CR 1 R 2 ) n -CN,-(CR 1 R 2 ) n -NO 2 ,-(CR 1 R 2 ) n -C (O) OH,-(CR 1 R 2 ) n -C (O) H,-(CR 1 R 2 ) n -OH,-(CR 1 R 2 ) n -C (O) N (R 1 ) R 2 ,-(CR 1 R 2 ) nN (R 1 ) R 2 ,-(CR 1 R 2 ) n -O-alkyl,-(CR 1 R 2 ) n -S-alkyl,-(CR 1 R 2 ) n -C (O) -alkyl,- (CR 1 R 2 ) n -C (O) O-alkyl,-(CR 1 R 2 ) n -OC (O) -alkyl,-(CR 1 R 2 ) n -C (O)
  • R 1 and R 2 are each independently hydrogen, halogen,-(CH 2 ) n -CN,-(CH 2 ) n -NO 2 ,-(CH 2 ) n -C (O) OH,-(CH 2 ) n- C (O) H,-(CH 2 ) n -OH,-(CH 2 ) n -NH 2 ,-(CH 2 ) n -C (O) NH 2 ,-(CH 2 ) n -O-alkyl Substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted amino;
  • a 21 is a covalent bond, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,-(CR 1 R 2 ) n -C (O)-,-(CR 1 R 2 ) n -C (O) O-,-(CR 1 R 2 ) n -OC (O)-,-(CR 1 R 2 ) n -C (O) N (R 1 )-,-( CR 1 R 2 ) n -N (R 1 ) C (O)-,-(CR 1 R 2 ) n -OC (O) N (R 1 )-,-(CR 1 R 2 ) n -N (R 1 ) C (O) O-,-(CR 1 R 2 ) n -O-alkyl,-(CR 1 R 2 ) n -S-alkyl, or-(CR 1 R 2 ) n -SO
  • a 22 is a substituted or unsubstituted non-aromatic ring including hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or morpholinyl;
  • T 1 is a covalent bond,-(CR 1 R 2 ) n -C (O)-,-(CR 1 R 2 ) n -C (O) O-,-(CR 1 R 2 ) n -OC (O) -,-(CR 1 R 2 ) n -C (O) N (R 1 )-,-(CR 1 R 2 ) n -N (R 1 ) C (O)-,-(CR 1 R 2 ) n -OC (O) N (R 1 )-,-(CR 1 R 2 ) n -N (R 1 ) C (O) O-,-(CR 1 R 2 ) n -O-alkyl,-(CR 1 R 2 ) n -S-alkyl,-(CR 1 R 2 ) n -SO 2- , substituted or unsubstituted alkyl, phenyl, methylphenyl, pyridinylethynylphenyl,
  • T 11 is a covalent bond, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,-(CR 1 R 2 ) n -C (O)-,-(CR 1 R 2 ) n -C (O) O-,-(CR 1 R 2 ) n -OC (O)-,-(CR 1 R 2 ) n -C (O) N (R 1 )-,-( CR 1 R 2 ) n -N (R 1 ) C (O)-,-(CR 1 R 2 ) n -OC (O) N (R 1 )-,-(CR 1 R 2 ) n -N (R 1 ) C (O) O-,-(CR 1 R 2 ) n -O-alkyl,-(CR 1 R 2 ) n -S-alkyl, or-(CR 1 R 2 ) n -SO
  • T 12 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl including pyridinyl, or substituted or unsubstituted non-aromatic rings;
  • T 2 is hydrogen, halogen, (CR 1 R 2 ) n -CN,-(CR 1 R 2 ) n -NO 2 ,-(CR 1 R 2 ) n -C (O) OH,-(CR 1 R 2 ) n -C (O) H,-(CR 1 R 2 ) n -OH,-(CR 1 R 2 ) n -C (O) N (R 1 ) R 2 ,-(CR 1 R 2 ) n- O-alkyl,-(CR 1 R 2 ) n -N (R 1 ) R 2 ,-(CR 1 R 2 ) n -S-alkyl,-(CR 1 R 2 ) n -C (O) -alkyl, -(CR 1 R 2 ) n -C (O) O-alkyl,-(CR 1 R 2 ) n -OC (O) -alkyl,-(CR 1 R 2 ) n -C (O
  • the present invention also provides a pharmaceutical composition for inhibiting the growth or metastasis of cancer cells containing the compound represented by Formula 3, a pharmaceutically acceptable salt, prodrug, or isomer thereof as an active ingredient.
  • FIG. 1 is a schematic diagram showing the activation of ⁇ -catenin, increased Axin2 expression, and GSK3 regulation in the nucleus by Wnt signaling.
  • Figure 2 is a schematic diagram of the process of concentration control of nuclear GSK3 by nuclear signaling by Wnt signaling.
  • FIG. 3 is a schematic diagram of the binding structure of Axin and GSK3.
  • alkyl refers to a saturated straight or branched ratio having 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, most preferably 1 to 4 carbon atoms.
  • -Means a cyclic hydrocarbon.
  • saturated straight chain alkyls include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl and -n-decyl, and saturated branched alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, tert-butyl, -isopentyl, 2- Methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-d
  • Alkyl groups may be unsubstituted or substituted. Alkyl groups can be specified as having a certain number of carbon atoms. For example, an alkyl group having 1 to 8 carbon atoms may be specified as a C1-C8 alkyl group, while an alkyl group having 1 to 6 carbon atoms may be specified as a C1-C6 alkyl group.
  • the symbol “-” denotes the point of attachment to the rest of the molecule, wherein one of the hydrogens of the alkyl group is associated with an aryl group. It is substituted with a bond.
  • — (C 1 -C 2 alkyl) aryl includes groups such as —CH 2 Ph, —CH 2 CH 2 Ph and —CH (Ph) CH 3 .
  • alkenyl refers to unsaturated straight or branched non-cyclic hydrocarbons having 2 to 20 carbon atoms and one or more carbon-carbon double bonds. Preferably alkenyl has 2 to 10 carbon atoms.
  • Exemplary straight-chain alkenyls include, but are not limited to, -but-3-ene, -hex-4-ene and -oct-1-ene.
  • Exemplary branched alkenyls include, but are not limited to, 2-methyl-but-2-ene, -1-methyl-hex-4-ene and -4-ethyl-oct-1-ene Can be.
  • Alkenyl groups may be substituted or unsubstituted.
  • Alkenyl groups can be specified as having a certain number of carbon atoms. For example, alkenyl groups having 2 to 8 carbon atoms can be specified as C 2 -C 8 alkenyl groups, while alkenyl groups with 2 to 6 carbon atoms can be specified as C 2 -C 6 alkenyl groups.
  • alkynyl refers to an alkyl group wherein one or more carbon-carbon single bonds are replaced with the same number of carbon-carbon triple bonds. Alkynyl groups must contain two or more carbon atoms and can be substituted or unsubstituted. Alkynyl groups can be specified as having a certain number of carbon atoms. For example, an alkynyl group having 2 to 8 carbon atoms may be specified as a C 2 -C 8 alkynyl group, while an alkynyl group having 2 to 6 carbon atoms may be specified as a C 2 -C 6 alkynyl group.
  • oxo means a ⁇ O group.
  • hydroxy and hydroxyl refer to an -OH group.
  • hydroxyalkyl as used herein, means an alkyl group wherein at least one hydrogen is substituted with a hydroxyl group.
  • hydroxyalkenyl as used herein refers to an alkenyl group in which one or more hydrogens are substituted with hydroxyl groups.
  • hydroxyalkynyl as used herein refers to an alkynyl group in which one or more hydrogens are substituted with a hydroxyl group.
  • Alkoxy means the structure of formula —O-alkyl, wherein alkyl has the meanings described above.
  • Haloalkoxy means an alkoxy group wherein at least one hydrogen is replaced with a halogen atom.
  • Hydroxyalkoxy means an alkoxy key in which at least one hydrogen is substituted with a hydroxy group.
  • Alkylsulfonyl refers to the structure of the formula -S (O) 2 -alkyl.
  • Amino refers to the group —NH 2 .
  • Alkylamino and dialkylamino refer to the structures of the formula -NH-alkyl and -N (alkyl) alkyl, respectively, wherein alkyl is as defined above.
  • the alkyl groups in the dialkylamino groups can be the same or different.
  • Alkylsulfonyl amino refers to the structure of the formula -NHS (O) 2 -alkyl.
  • Carbocyclic ring system and “carbocyclic” refer to ring systems in which all ring members are carbon atoms. Carbocyclic ring systems typically contain 3 to 14 ring atoms. Carbocyclic ring systems may be aromatic or non-aromatic. Carbocyclic ring systems include cycloalkyl rings and may also include fused ring systems. Examples of fused ring carbocyclic ring systems include, but are not limited to, decalin, norbornane, tetrahydronaphthalene, naphthalene, indene and adamantane. Ring atoms in the carbocyclic ring system may be substituted or unsubstituted.
  • heterocyclic ring refers to a carbocyclic ring system in which one or more ring atoms is a heteroatom such as N, O, S or Si.
  • the heterocyclic ring system includes 1 to 4 hetero atoms.
  • the hetero atom is selected from N, O or S.
  • Heterocyclic ring systems can include one ring or a fused ring system.
  • the heterocyclic ring system may comprise two six membered rings fused to each other, or may comprise one five membered ring and one six membered ring fused to each other.
  • Heterocyclic ring systems can be aromatic or non-aromatic, and can be unsaturated, partially unsaturated or saturated. Ring atoms in the heterocyclic ring system may be substituted or unsubstituted.
  • aryl refers to a carbocyclic ring or ring system containing 6 to 14 ring atoms in which at least one ring is aromatic.
  • the ring atoms of the carbocyclic aryl group are all carbon atoms.
  • Aryl groups include mono-, bi- and tricyclic groups, as well as benzo-fused carbocyclic moieties such as, but not limited to, 5,6,7,8-tetrahydronaphthyl and the like.
  • the aryl group is a monocyclic ring or bicyclic ring.
  • aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, phenanthrenyl and naphthyl.
  • the aryl group can be unsubstituted or substituted.
  • heteroaryl means an aryl group in which one or more, but not all, ring carbon atoms in any ring that is aromatic or non-aromatic is substituted with a hetero atom.
  • pyridine is a heteroaryl group, such as a compound in which benzene is fused to a non-aromatic ring containing one or more hetero atoms.
  • exemplary hetero atoms are N, O, S and Si.
  • the hetero atom is N, O or S.
  • Heteroaryl groups can be unsubstituted or substituted.
  • Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3- Pyrazolyl, 5-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-iso Sazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furanyl, 3-furanyl, dibenzofuryl, 2-thienyl (2 -Thiophenyl), 3-thienyl (3-thiophenyl), 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidiny
  • Non-limiting examples of other heteroaryl groups include pyridyl, indazolyl, isoquinolinyl, thiazolopyridinyl, benzothiazolonyl, dihydroquinolinonyl, benzoisoxazolyl, benzooxazoloyl, indolinonyl, Benzoimidazolonyl, phthalazinyl, naphthyridinyl, thienopyridinyl, benzodioxolyl, isoindolinonyl, quinazolinyl or cinnaolinyl.
  • cycloalkyl refers to an unsaturated or saturated hydrocarbon that forms one or more rings having 3 to 20 ring carbon atoms, and in some embodiments 3 to 10, 3 to 8 or 3 to 6 ring carbon atoms do.
  • the ring in the cycloalkyl group is non-aromatic. Cycloalkyl groups can be unsubstituted or substituted.
  • a compound of the present invention may be optionally substituted with one or more substituents, such as those generally exemplified above or exemplified by certain classes, subclasses and species of the present invention.
  • substituents such as those generally exemplified above or exemplified by certain classes, subclasses and species of the present invention.
  • substituted refers to the substitution of a hydrogen radical in a given structure with a radical of a specified substituent, whether or not preceded by "optionally”.
  • an optionally substituted group may have a substituent at each substitutable position of the group, and if more than one position in any given structure may be substituted with more than one substituent selected from the specified group, such substituents May be the same or different at all positions.
  • Combinations of substituents contemplated in the present invention are preferably combinations which lead to the formation of stable or chemically suitable compounds.
  • "for inhibiting the growth or metastasis of cancer cells” means “anticancer”. That is, it means the action of inhibiting or killing the proliferation of cancer cells and the action of inhibiting or blocking the metastasis of cancer cells, and means both prevention and treatment of cancer.
  • prevention refers to any action that inhibits cancer formation or delays the onset of administration of the composition
  • treatment refers to any action that improves or advantageously changes the symptoms of the disease by administration of the composition. It means.
  • treatment includes (i) preventing the disease, disorder or symptom in a mammal that may be susceptible to disease, disorder and / or symptom but cannot yet be diagnosed with it; (ii) inhibiting a disease, disorder or symptom, ie, arresting their onset; And (iii) alleviating a disease, disorder or symptom, ie, causing regression of one or more of the disease, disorder and / or symptoms, or signs thereof.
  • prevention also specifically refers to the ability of a compound or composition of the invention to prevent such a disease in a mammal diagnosed with or at risk of developing the disease identified herein. The term also includes preventing further progression of the disease in a mammal already suffering from or having signs of the disease.
  • containing as an active ingredient is meant to contain a “therapeutically effective amount” or “prophylactically effective amount” of the compound represented by the formula (3) according to the present invention, a pharmaceutically acceptable salt, prodrug or isomer thereof.
  • a “therapeutically effective amount” is a compound of the invention sufficient to provide an advantage in the treatment or prevention of a symptom or disease, such as cancer, to delay or minimize a symptom associated with the symptom or disease, or to treat or ameliorate a disease or cause thereof. Or the amount of a prodrug thereof.
  • a therapeutically effective amount means an amount sufficient to provide a therapeutic benefit in vivo.
  • prophylactically effective amount refers to an amount of a compound of the present invention or other active ingredient sufficient to prevent a symptom or disease, such as cancer, or recurrence or metastasis of the cancer.
  • a prophylactically effective amount refers to an amount sufficient to prevent the initial disease, or recurrence or spread of the disease.
  • the term “preferably” includes non-toxic amounts that improve overall prophylaxis or enhance or synergize with the prophylactic efficacy of another prophylactic or therapeutic agent.
  • the term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic and organic acids and bases.
  • the compound of formula 3 is a base, any suitable method available in the art, for example, treatment of the free base with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or the like, or organic acids such as acetic acid, male Acids, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid such as glucuronic acid or galacturonic acid, alpha-hydroxy acid such as citric acid or tartaric acid, amino acids such as aspartic acid Or by treating with glutamic acid, aromatic acid such as benzoic acid or cinnamic acid, sulfonic acid such as p-toluenesulfonic
  • any suitable method is preferred, for example, by treating the free acid with an inorganic or organic base such as an amine (primary, secondary or tertiary), alkali metal hydroxide or alkaline earth metal hydroxide and the like.
  • Phase acceptable salts can be prepared.
  • suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine and piperazine, and sodium, calcium, Inorganic salts derived from potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • the salt can be contacted with a base or an acid in a conventional manner and the parent compound can be isolated to regenerate the neutral form of the compound from the salt.
  • the parent form of the compound differs from some physical properties, such as various salt forms, solubility in polar solvents, for the purposes of the present invention, the salt is equivalent to the parent form of the compound.
  • prodrug means any chemical that is converted to various therapeutically effective chemicals after administration.
  • Prodrugs of the compounds described herein are compounds that readily change chemically under physiological conditions to provide the compounds of the present invention.
  • Prodrugs may also be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, when a prodrug is present with a suitable enzyme or chemical reagent in a transdermal package reservoir, it may be slowly converted to a compound of the present invention.
  • Prodrugs are often useful because, in some cases, they may be easier to administer than the parent drug. For example, prodrugs are available in vivo by oral administration, while parent drugs are not.
  • Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent drug.
  • Various prodrug derivatives such as derivatives based on hydrolytic or oxidative activation of prodrugs, are known in the art.
  • Non-limiting examples of prodrugs will be compounds of the invention that are administered as esters ("prodrugs"), but then metabolically hydrolyzed with an active substance called carboxylic acid. Further examples include peptidyl derivatives of the compounds.
  • the compounds of the present invention may contain one or more asymmetric centers and may therefore exist in racemic and racemic mixtures, scalemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. have. All such isomeric forms of these compounds are expressly included in the present invention.
  • optically pure or “stereoisomericly pure” means a composition comprising one stereoisomer of a compound and substantially free of other stereoisomers of that compound.
  • a stereoisomerically pure compound having one chiral center will be substantially free of the opposite enantiomers of the compound.
  • a typical stereoisomerically pure compound is greater than about 80 weight percent of one isomer of the compound, less than about 20 weight percent of the other stereoisomer of the compound, more preferably greater than about 90 weight percent of one stereoisomer of the compound, Less than about 10 weight percent of stereoisomers, even more preferably more than about 95 weight percent of one stereoisomer of the compound, less than about 5 weight percent of the other stereoisomers of the compound, most preferably about 97 weight of one stereoisomer of the compound Greater than weight percent and less than about 3 weight percent of other stereoisomers of the compound.
  • the present invention encompasses the use of stereoisomericly pure forms of such compounds as well as the use of mixtures of these forms.
  • mixtures comprising the same or non-equivalent amounts of enantiomers of certain compounds of the invention can be used in the methods and compositions of the invention.
  • isomers can be synthesized asymmetrically or cleaved using standard techniques such as chiral columns or chiral splitting agents (see, eg, Jacques, J., et al, Enantiomers, Racemates and Resolution (Wiley-lnterscience). , New York, 1981); Wilen, SH, et al.
  • Some compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are within the scope of the present invention.
  • GSK3 tau protein kinase (TPK I), FA factor (Factor A) kinase, kinase FA and ATP-citrate lyase kinase (ACLK).
  • Glycogen synthase kinase 3 present in two isotypes, GSK3 ⁇ and GSK3 ⁇ , is a proline-associated serine / threonine kinase originally identified as an enzyme that phosphorylates glycogen synthase.
  • GSK3 is a glycogen synthase, phosphatase inhibitor I-2, type II subunit of cAMP-dependent protein kinase, G-subunit of phosphatase-1, acetyl coenzyme A carboxylase, myelin basic protein, microtubule- Related protein, neurofibrillary protein, M-CAM cell adhesion molecule, nerve growth factor receptor, c-Jun transcription factor, JunD transcription factor, c-Myb transcription factor, c-Myc transcription factor, L-Myc transcription factor, adenomatous It has been demonstrated to phosphorylate many proteins in vitro, such as polyposis tumor suppressor protein, tau protein and ⁇ -catenin.
  • the various proteins described above that can be phosphorylated by GSK3 mean that GSK3 is involved in a number of metabolic and regulatory processes in the cell.
  • disease caused by GSK3 migration from the nucleus to the cytoplasm refers to diseases mediated through GSK3, such as cancer, diabetes, Niemann Pick's disease type C, Bipolar disorder (particularly manic depression), Alzheimer's disease, FTDP-17 (frontal temporal dementia associated with Parkinson's disease), cortico-basal degeneration, progressive supranuclear palsy, multiple system atrophy ), Pick's disease, dementia Pugilistica, AIDS associated dementia, dementia, stroke, Guam parkinsonism-dementia complex, Parkinson syndrome after brain inflammation (postencephalic Parkinsonism), frontal lobe degeneration, argyrophilic grains disease, depression, Schizophrenia, Huntington's disease, myotonic dystrophy (myotonic dystrophy), subacute sclerotizing panencephalitis, prion disease, Down syndrome, allergic or asthma, multiple sclerosis, rheumatoid arthritis, arteriosclerosis, inflammatory bowel disease Disease
  • the compound according to the present invention inhibits the GSK3 function by inhibiting the movement of GSK3 from the cell nucleus to the cytoplasm, It can be useful for preventing and treating diseases. It can also be used to inhibit sperm movement and thus can be used as a male contraceptive. In particular, the compounds of the present invention are useful for the prevention or treatment of cancer.
  • the signaling mechanism proposed by the present invention suggests a new therapeutic effect and concept of the ⁇ -catenin targeted therapeutic agent that has been developed or developed in the future.
  • As a method of inhibiting the activity of ⁇ -catenin it is known to inhibit the ⁇ -catenin transcriptional regulation by competitively binding to ⁇ -catenin transcription complexes, that is, LEF / TCF, CBP300 and the like. In this case, most of the drugs developed so far have been expected to induce apoptosis of cells by targeting ⁇ -catenin.
  • Wnt signaling system Genetic mutations or other abnormalities of the Wnt signaling system have been observed, so the Wnt signaling system is considered to be very important in the development of cancer, but the specific regulatory mechanisms for Wnt signaling are not well known. However, the genetic abnormalities of Wnt signaling activate the ⁇ -catenin gene in common and the cancer development process proceeds.
  • Wnt signaling reduces the expression of E-cadherin, increases the expression of ⁇ -catenin and Snail, and invades growth and metastasis of cancer cells.
  • Snail phosphorylation control process by ⁇ -catenin is as shown in FIG. Briefly, the expression of Axin is increased by ⁇ -catenin, and Axin binds to GSK3 inside the nucleus and transfers GSK3 into the cytoplasm. This increases the expression of Snail and metastasis of cancer cells occurs.
  • 2 is a schematic diagram illustrating the GSK3 concentration control process in the nucleus by Wnt signaling.
  • the activation of ⁇ -catenin gene induces Axin2 gene expression, and the Axin2 gene binds to GSK3 present in the cell nucleus to perform the nuclear export function of GSK3, thereby reducing the concentration of GSK3 in the nucleus.
  • the expression of the Snail gene which is phosphorylated and degraded by GSK3, is increased.
  • increased expression of the Snail gene by Wnt signaling induces invasive growth and metastasis of cancer cells, and clinically causes continuous recurrence and distant metastasis.
  • FIG. 3 shows the binding structure of Axin and GSK3, it can be seen that Axin binds to GSK3 by the Axin-derived peptide fragment (370-390 amino acid sequence of hAxin2) (Dajani et al., EMBO J. , 22: 494, 2003).
  • the Axin and FRAT proteins have ⁇ -helix structure, and the intermediate hydrophobic residues bind to the groove structure of GSK3, and the compound that can competitively bind to inhibit the nuclear export function of GSK3 by Axin or FRAT.
  • Axin1 and Axin2 have very similar structures and similar functions to transfer GSK3 into the cytoplasm inside the nucleus.
  • Axin1 and Axin2 appear to have the same function, ie very similar structure, by replacing Axin1 and Axin2 during development (Chia, IV & Cos tantini, F., Mol. Cell Biol). ., 25: 4371, 2005).
  • the present inventors have confirmed that the induction of Axin1 or Axin2 expression in cells after numerous trials and errors rapidly decreases the expression of GSK3 in the cell nucleus and consequently strongly increases the expression of the Snail protein, which is phosphorylated and degraded by GSK3.
  • the present invention has a fundamentally different concept from the development of various compounds for inhibiting existing phosphatase. That is, the compound described in the present invention is fundamentally different from the conventional phosphatase inhibition in that it increases the GSK3 kinase activity inside the cell nucleus by inhibiting the nuclear export function of GSK3 by Axin, rather than inhibiting the kinase domain. The concept is different.
  • the present inventors first analyzed the X-ray structure of GSK3-Axin2 to develop a new inhibitor that inhibits the binding of GSK3 and Axin2, and through this, the structural and functional pharmacophore of Axin2 binding to GSK3 Obtained new information on On the basis of this, 55 compounds of the final product obtained through various stages of organic chemical reaction were obtained, and their structure was confirmed through NMR and Mass experiment equipment. The compounds with high fitness scores were selected for the pharmacophore, and the expected pharmacological activity of the selected compounds was predicted through docking studies. The actual pharmacological activity of the compounds was confirmed by in vitro screeening experiments.
  • the present invention provides a composition for inhibiting GSK3 migration from the nucleus to the cytoplasm comprising a compound represented by the following formula (3), a pharmaceutically acceptable salt, a prodrug, or an isomer thereof, that is, from the nucleus to the cytoplasm
  • a pharmaceutical composition for treating or preventing a disease caused by GSK3 migration comprising a compound represented by the following formula (3), a pharmaceutically acceptable salt, a prodrug, or an isomer thereof, that is, from the nucleus to the cytoplasm
  • X is C ⁇ O, C ⁇ S or SO 2 ;
  • Y is a covalent bond or NH
  • R 3 , R 4 and R 5 are each independently hydrogen, halogen,-(CH 2 ) n -CN,-(CH 2 ) n -NO 2 ,-(CH 2 ) n -C (O) OH,-( CH 2 ) n -C (O) H,-(CH 2 ) n -OH,-(CH 2 ) n -NH 2 ,-(CH 2 ) n -C (O) NH 2 ,-(CH2) n- Substituted or unsubstituted alkyl including O-alkyl, methyl, ethyl and isopropyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl including phenyl, imidazolyl, thiazolyl, Substituted or non-containing, including pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, pyr
  • c and d are each independently 0, 1, 2 or 3;
  • a and b are each independently 0, 1, 2, 3, 4, 5 or 6;
  • n is an integer of 0 or more, preferably 0, 1, 2, 3, 4, 5 or 6.
  • a 1 is a covalent bond, meaning that A 1 is a covalent bond, meaning that N or carbon is A 2 covalently bonded according to a and c.
  • Single or polysubstituted or unsubstituted alkyl including isopropyl, Phenyl, furanyl, pyrazolyl, triazolyl, thiophenyl, pyridinyl, , Pyrimidinyl, pyrazinyl, pyrrolyl, tetrazolyl, oxazolyl, isoxazolyl, oxdiazolyl, thienyl, thiadiazolyl, benzimidazolyl, imidazolyl, indolyl, indazolyl, benzoisothia Single or polysubstituted or unsubstituted aryl or heteroaryl single or bicyclic rings including zolyl and benzofuranyl, substituted or unsubstituted heteroarylalky
  • a 2 is hydrogen, halogen,-(CR 1 R 2 ) n -CN,-(CR 1 R 2 ) n -NO 2 ,-(CR 1 R 2 ) n -C (O) OH,-(CR 1 R 2 ) n -C (O) H,-(CR 1 R 2 ) n -OH,-(CR 1 R 2 ) n -C (O) N (R 1 ) R 2 ,-(CR 1 R 2 ) n -N (R 1 ) R 2 ,-(CR 1 R 2 ) n -O-alkyl,-(CR 1 R 2 ) n -S-alkyl,-(CR 1 R 2 ) n -C (O) -alkyl ,-(CR 1 R 2 ) n -C (O) O-alkyl,-(CR 1 R 2 ) n -OC (O) -alkyl,-(CR 1 R 2 ) n -C
  • R 1 and R 2 are each independently hydrogen, halogen,-(CH 2 ) n -CN,-(CH 2 ) n -NO 2 ,-(CH 2 ) n -C (O) OH,-(CH 2 ) n- C (O) H,-(CH 2 ) n -OH,-(CH 2 ) n -NH 2, -(CH 2 ) n -C (O) NH 2 ,-(CH 2 ) nO-alkyl, Substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted amino;
  • a 21 is a covalent bond, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,-(CR 1 R 2 ) n -C (O)-,-(CR 1 R 2 ) n -C (O) O-,-(CR 1 R 2 ) n -OC (O)-,-(CR 1 R 2 ) n -C (O) N (R 1 )-,-( CR 1 R 2 ) n -N (R 1 ) C (O)-,-(CR 1 R 2 ) n -OC (O) N (R 1 )-,-(CR 1 R 2 ) n -N (R 1 ) C (O) O-,-(CR 1 R 2 ) n -O-alkyl,-(CR 1 R 2 ) n -S-alkyl, or-(CR 1 R 2 ) n -SO
  • a 22 is a substituted or unsubstituted non-aromatic ring including hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or morpholinyl;
  • T 1 is a covalent bond,-(CR 1 R 2 ) n -C (O)-,-(CR 1 R 2 ) n -C (O) O-,-(CR 1 R 2 ) n -OC (O) -,-(CR 1 R 2 ) n -C (O) N (R 1 )-,-(CR 1 R 2 ) n -N (R 1 ) C (O)-,-(CR 1 R 2 ) n -OC (O) N (R 1 )-,-(CR 1 R 2 ) n -N (R 1 ) C (O) O-,-(CR 1 R 2 ) n -O-alkyl,-(CR 1 R 2 ) n -S-alkyl,-(CR 1 R 2 ) n -SO 2- , substituted or unsubstituted alkyl, phenyl, methylphenyl, pyridinylethynylphenyl,
  • T 11 is a covalent bond, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,-(CR 1 R 2 ) n -C (O)-,-(CR 1 R 2 ) n -C (O) O-,-(CR 1 R 2 ) n -OC (O)-,-(CR 1 R 2 ) n -C (O) N (R 1 )-,-( CR 1 R 2 ) n -N (R 1 ) C (O)-,-(CR 1 R 2 ) n -OC (O) N (R 1 )-,-(CR 1 R 2 ) n -N (R 1 ) C (O) O-,-(CR 1 R 2 ) n -O-alkyl,-(CR 1 R 2 ) n -S-alkyl, or-(CR 1 R 2 ) n -SO
  • T 12 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl including pyridinyl, or substituted or unsubstituted non-aromatic rings;
  • T 2 is hydrogen, halogen, (CR 1 R 2 ) n -CN,-(CR 1 R 2 ) n -NO 2 ,-(CR 1 R 2 ) n -C (O) OH,-(CR 1 R 2 ) n -C (O) H,-(CR 1 R 2 ) n -OH,-(CR 1 R 2 ) n -C (O) N (R 1 ) R 2 ,-(CR 1 R 2 ) n- O-alkyl,-(CR 1 R 2 ) n -N (R 1 ) R 2 ,-(CR 1 R 2 ) n -S-alkyl,-(CR 1 R 2 ) n -C (O) -alkyl, -(CR 1 R 2 ) n -C (O) O-alkyl,-(CR 1 R 2 ) n -OC (O) -alkyl,-(CR 1 R 2 ) n -C (O
  • X may be C ⁇ O
  • Y may be a covalent bond or NH
  • Y is a covalent bond
  • T 1 and T 2 are each independently mono or polysubstituted or unsubstituted non-aromatic ring, mono or polysubstituted or unsubstituted aryl Or heteroaryl single or bicyclic rings.
  • the mono- or polysubstituted or unsubstituted non-aromatic rings are morpholinyl, dimethylmorpholinyl, , , , , Piperidinyl, piperazinyl, tetrahydrofuranyl, pyrrolidinyl or pyrazolidinyl.
  • the single or polysubstituted or unsubstituted aryl or heteroaryl single or bicyclic ring is phenyl, methylphenyl, hydroxyphenyl, methoxyphenyl, dimethoxyphenyl, methylmethoxy Phenyl, fluorophenyl, difluorophenyl, trifluorophenyl, chlorophenyl, dichlorophenyl, furanyl, methylfuranyl, pyrazolyl, dimethylpyrazolyl, pyridinyl, imidazolyl, thiophenyl, , , , Pyrrolyl, triazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, isoxazolyl, oxazolyl, oxdiazolyl, thienyl, thiazolyl, thiadizolyl, benzimidazolyl, indoly
  • the compound may be a compound according to the following examples.
  • Example 8 (Compound 9): Butyl 2- (2,6-difluorophenylsulfonamido) acetate
  • Example 9 (Compound 10): 1-((5-methylfuran-2-yl) methyl) -3- (2,3,4-trifluorophenyl) urea
  • Example 21 N-ethyl-N- (2- (ethyl (methyl) amino) ethyl) -6- (5-oxo-1,4-diazepan-1-yl) nicotinamide
  • Example 42 (Compound 66): 2- (5- (5,6-dihydro-4H-cyclopenta [b] thiophen-2-yl) -2-oxo-1,3,4-oxadiazole- 3 (2H) -yl) -N-isopropylacetamide
  • Example 44 (Compound 68): 1- (4-chlorophenyl) -N- (2- (6-oxo-3- (thiophen-2-yl) pyridazine-1 (6H) -yl) ethyl) cyclo Propanecarboxamide
  • Example 50 (Compound 127): N- (2- (1H-1,2,4-triazol-1-yl) propyl) -4- (1H-pyrazol-1-yl) -3- (pyridine- 3-ylethynyl) benzamide
  • Example 51 3-ethyl-1,4-dimethyl-N- (1- (pyridin-3-yl) -2- (thiophen-3-yl) ethyl) -1H-pyrazole-5 Carboxamide
  • Example 54 (Compound 153): 1- (pyridin-2-ylmethyl) -N- (1- (thiazol-2-yl) -2- (thiophen-3-yl) ethyl) piperidine-4 Carboxamide
  • Example 55 (Compound 154): 1- (2- (1- (3-methylpyridin-2-yl) -2- (thiophen-3-yl) ethylamino) -2-oxoethyl) piperidine- 4-carboxamide
  • the compound is 1- (4-butoxyphenyl) -3- (5- (diethylamino) pentan-2-yl) urea, N- (2-hydroxyethyl) -N, 4-di Isopropylbenzenesulfonamide, 1- (4-methoxy-2-methylphenyl) -3- (thiophen-2-ylmethyl) thiourea, N-ethyl-N- (2- (ethyl (methyl) amino) ethyl ) -6- (5-oxo-1,4-diazepan-1-yl) nicotinamide, N- (2- (3- (2-ethylhexyloxy) propylamino) -2-oxoethyl) furan- 2-carboxamide, N-((3,4-difluorophenyl) (1-methyl-1H-imidazol-2-yl) methyl) -2- (4-hydroxyphenyl) acetamide, N
  • the compounds according to the present invention may be readily available from commercial compound library vendors such as LeadQuest, Asinex, or the like, and may be readily synthesized by those skilled in the art in combination with known synthetic mechanisms.
  • the compounds inhibit the nuclear export function of GSK3 by binding GSK3 competitively with Axin. That is, the compounds according to the present invention inhibit GSK3 migration from the cell nucleus to the cytoplasm by binding to Axin, thereby promoting intracellular activity of GSK, or inhibiting or maintaining and increasing GSK3 concentration or activity decrease in the cell nucleus. It is useful for the treatment of diseases caused by decreasing GSK3 concentration.
  • the "diseases caused by GSK3 migration from the nucleus to the cytoplasm” include diseases mediated through GSK3, such as cancer, diabetes, Niemann Pick's disease type C, bipolar disorders (especially Manic depression), Alzheimer's disease, FTDP-17 (frontal temporal dementia associated with Parkinson's disease), cortico-basal degeneration, progressive supranuclear palsy, multiple system atrophy, peak disease (Pick's disease), dementia Pugilistica, AIDS associated dementia, dementia, stroke, Guam parkinsonism-dementia complex, postencephalic Parkinsonism , Frontal lobe degeneration, argyrophilic grains disease, depression, Schizophrenia, Huntington's disease, myotonic dystrophy ), Subacute sclerotizing panencephalitis, prion disease, Down syndrome, allergic or asthma, multiple sclerosis, rheumatoid arthritis, arteriosclerosis, inflammatory bowel disease, inflammatory bowel disease, baldness Among such skin diseases,
  • the compound of formula 3 or a pharmaceutically acceptable salt, prodrug, or isomer thereof can be used as a medicament.
  • the compounds can be used to prepare a medicament for treating or preventing diseases caused by GSK3 migration from the cell nucleus to the cytoplasm. More particularly, the compounds can be used to prepare a medicament for treating or preventing immune diseases, including arthritis, and cancer.
  • the pharmaceutical composition for inhibiting the growth or metastasis of cancer cells containing the compound represented by the formula (3), a pharmaceutically acceptable salt, prodrug or isomer thereof as an active ingredient and the treatment of immune diseases It relates to a pharmaceutical composition.
  • the composition is the compound compound 2 to 13, 15 to 17, 19 to 21, 23, 26, 29, 31 to 34, 36 to 38, 43, 44, 47 to 49, 51, 53, 54, 56 , 58, 62 to 64, 66 to 69, 83, 121, 123, 124, 127, 133, 134, 148, 153, 154.
  • the compounds according to the present invention can be usefully used to inhibit the development and progression of autoimmune and degenerative diseases such as rheumatoid arthritis as well as metastasis of cancer cells promoted by Wnt signal transduction.
  • the compounds according to the invention can be used by themselves or in the form of pharmaceutically acceptable acid addition salts or salts of metal complexes such as zinc, iron and the like.
  • the acid addition salt may be selected from the group consisting of hydrogen chloride, hydrogen bromide, sulfate, phosphate, maleate, acetic salt, citralate, benzoate, succinate, dried salt, ascorbate and tartalate. It is preferable.
  • compositions containing a compound according to the invention as an active ingredient may contain a pharmaceutically acceptable excipient or matrix according to conventional administration methods, dosage forms and therapeutic purposes. Mixing and dilution with a phosphorus carrier or encapsulation in a carrier in the form of a container is preferred. It can also be used in combination with other medicines that are beneficial for the treatment of other bone defects. At this time, the preparation of a physiologically acceptable protein composition having a desired pH, isotonicity, stability and the like can be used within the conventional technical scope in the field of the present invention.
  • the matrix is a biodegradable and chemical substance such as calcium sulfate, tricalcium phosphate, hydroxyapatite, polylactic acid, or polyanhydride, depending on biocompatibility, biodegradability, mechanical properties, cosmetic appearance and contact properties; Biodegradable and biological substances such as bone or skin collagen, other pure proteins or matrix components of cells; Non-biodegradable and chemical materials such as sintered hydroxyapatite, bioglass, aluminate or other ceramics; Preference is given to using combinations of the foregoing materials such as polylactic acid, hydroxyapatite, collagen and tricalcium phosphate.
  • the present invention is not limited to the carrier.
  • Excipients in the present invention are lactose, dextrose, sucrose, sorbitol, mannitol, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, magnesium styrate, water, methylhydroxy Benzoate (methylhydroxybenzoate), propylhydroxybenzoate (propylhydroxybenzoate), talc (talc), mineral oil and the like can be used.
  • the compound of formula 3 may be used in other conventional drugs used to treat cancer, such as platinum coordination compounds such as cisplatin or carboplatin; Taxane compounds such as paclitaxel or docetaxel; Camptothecin compounds such as irinotecan or topotecan; Anti-tumor vinca alkaloids such as vinblastine, vincristine or vinorelbine; Anti-tumor nucleoside derivatives such as 5-fluorouracil, gemcitabine or capecitabine; Nitrogen mustard or nitrosourea alkylating agents such as cyclophosphamide, chlorambucil, carmustine or romustine; Anti-tumor anthracycline derivatives such as daunorubicin, doxorubicin or idarubicin; HER2 antibodies such as trastuzumab; And anti-tumor grapephytotoxin derivatives such as etoposide or ten
  • the present invention also relates to a combination of a compound of formula 3 and another agent capable of preventing or treating cancer.
  • the combination can be used as a medicament.
  • the present invention also relates to a product containing (a) Formula (3) and (b) another agent capable of preventing or treating cancer as a combination formulation for simultaneous, separate or continuous use in the prevention or treatment of cancer.
  • Different drugs may be combined in a single formulation with a pharmaceutically acceptable carrier.
  • the compound of formula 3 may be used in other conventional drugs used to treat inflammatory diseases, such as steroids, cyclooxygenase-2 inhibitors, nonsteroidal-anti-inflammatory drugs, TNF - ⁇ antibodies, for example acetyl salicylic acid, bufexamac, diclofenac potassium, sulindac, diclofenac sodium, ketorolac tromethamol, tolmethine, ibuprofen, naproxen, naproxen sodium, triaprofenic acid, flubiprofen, mefenamic acid , Niflumic acid, meclofenamate, indomethacin, proglumetacin, ketoprofen, nabumethone, paracetamol, pyroxhamm, tenoxycam, nimesulide, phenylbutazone, tramadol, beclomethasone Dipropionate, betamethasone, beclomethasone Dipropionate, betamethasone, beclomethas
  • the present invention also relates to a combination of a compound of formula 3, a pharmaceutically acceptable salt, a prodrug thereof, or another isomer which is capable of preventing or treating isomers and inflammatory diseases.
  • the combination can be used as a medicament.
  • the invention also provides a combination formulation for use simultaneously, separately or continuously in the prevention or treatment of an inflammatory disease, comprising: (a) a compound of formula 3, a pharmaceutically acceptable salt, a prodrug, or an isomer thereof; and (b
  • the present invention relates to a product containing another agent capable of preventing or treating an inflammatory disease. Different drugs may be combined in a single formulation with a pharmaceutically acceptable carrier.
  • the present invention provides methods for treating or preventing mammals, including humans suffering from diseases caused by GSK3 migration from the cell nucleus to the cytoplasm, more particularly immune diseases including cancer, arthritis, Alzheimer's disease, Methods of treating or preventing diabetes, particularly type 2 diabetes, or bipolar disorder are provided.
  • the method comprises administering to a mammal, including a human, an effective amount of a compound of Formula 3 or a pharmaceutically acceptable salt, prodrug, or isomer thereof.
  • the pharmaceutical composition containing the compound according to the present invention can be prepared in a variety of formulations, it is preferable to use injectable or capsulated in a viscous form for injection into the site where the therapeutic effect is expected.
  • the dosage of the composition according to the present invention can be adjusted in consideration of the type of carrier such as the excipient or matrix used, the treatment site of the patient, the age, sex and diet of the patient, the severity of infection, the time of administration and other clinical factors.
  • a conventionally known effective amount can be administered continuously or dividedly, in consideration of weight, to observe the therapeutic effect and to determine further administration.
  • Axin2-His cDNA was obtained by PCR amplification in A549 cells and amplified at the HindIII and BamHI sites of the pcDNA3.1-hyg (+) (invitrogen) vector.
  • Axin2-His cDNA was prepared and amplified in E. coli DH5 ⁇ to obtain pcDNA3.1-Axin2-His expression vector.
  • pcDNA3.1-Axin2-His expression vector After transfection of the episomal Axin2-His expression vector, pcDNA3.1-Axin2-His expression vector, to MCF7 cells (ATCC HTB-26), 200 ⁇ g / ml of hygromycin (hygromycin) ) was treated to obtain Axin2-His overexpressing cells.
  • Triton X-100 lysis buffer was added to the obtained Axin2-His overexpressing cells to obtain cell lysate.
  • 1000 ⁇ l of Triton X-100 lysis buffer was added to 20 ⁇ l of beads, and the procedure of precipitation for 1 minute at 2000 rpm was repeated three times.
  • 10 ⁇ M of the cell lysate and compounds 5, 23, 26, 29, 33, 69, 83, and 148 were added to the neutralized bead, and Triton X The total volume was adjusted to 1000 ⁇ l with -100 lysis buffer. After shaking for 5 hours at 4 °C, it was precipitated at 2000 rpm for 1 minute.
  • the primary antibodies were anti-conductin (Sigma) and anti-GSK3 ⁇ (BD Bioscience), and the protein expression level was horseradish peroxidase (HRP) -conjugated secondary antibody and enhanced chemiluminescence (ECL) detection kit ( Intron, Korea) was used to sensitize the x-ray film.
  • HRP horseradish peroxidase
  • ECL enhanced chemiluminescence
  • the present invention has an effect of providing a composition for inhibiting the development and progression of a disease caused by the GSK3 migration from the cell nucleus to the cytoplasm, which occurs due to the decrease in GSK3 concentration in the nucleus.
  • the compounds according to the present invention are useful for the treatment or prevention of various diseases caused by a decrease in the GSK3 concentration in the nucleus by inhibiting the nuclear export function of GSK3 by Axin and increasing the GSK3 concentration in the nucleus.

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Abstract

La présente invention concerne des compositions pharmaceutiques pour traiter ou prévenir des maladies causées par la translocation de GSK3 du noyau cellulaire au cytoplasme, contenant des composés inhibant la translocation de GSK3 du noyau cellulaire au cytoplasme. Plus particulièrement, la présente invention concerne des compositions pharmaceutiques destinées à inhiber la croissance ou la métastase de cellules cancéreuses ainsi que des compositions pharmaceutiques destinées à traiter des maladies autoimmunes, contenant de nouveaux composés inhibant la translocation de GSK3 du noyau cellulaire au cytoplasme. La présente invention permet d'obtenir des compositions empêchant l'apparition et la progression de maladies causées par une réduction de la concentration de GSK3 dans le noyau et par la translocation de GSK du noyau cellulaire au cytoplasme. Les composés selon la présente invention inhibent la fonction d'exportation nucléaire de GSK3 assurée par l'axine et augmentent la concentration de GSK3 dans le noyau, d'où leur utilité pour traiter ou prévenir une pluralité de maladies causées par une réduction de la concentration de GSK3 dans le noyau.
PCT/KR2010/001446 2009-03-07 2010-03-08 Compositions pharmaceutiques pour traiter ou prévenir des maladies causées par la translocation de gsk3 du noyau cellulaire au cytoplasme, contenant des composés inhibant la translocation de gsk3 du noyau cellulaire au cytoplasme WO2010104307A2 (fr)

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