WO2010036910A1 - Protection cardiaque par administration d'un activateur de protéine kinase activée par amp - Google Patents

Protection cardiaque par administration d'un activateur de protéine kinase activée par amp Download PDF

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WO2010036910A1
WO2010036910A1 PCT/US2009/058405 US2009058405W WO2010036910A1 WO 2010036910 A1 WO2010036910 A1 WO 2010036910A1 US 2009058405 W US2009058405 W US 2009058405W WO 2010036910 A1 WO2010036910 A1 WO 2010036910A1
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optionally substituted
group
alkyl
atom
compound
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PCT/US2009/058405
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Yoshikazu Ohta
Sarah S. Bacus
Scott A. Shell
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Yoshikazu Ohta
Bacus Sarah S
Shell Scott A
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Publication of WO2010036910A1 publication Critical patent/WO2010036910A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2063—Proteins, e.g. gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to protection of a mammal's heart with a Compound (T), a salt thereof, or a prodrug thereof, wherein the Compound (T) is represented by the formula:
  • A is an optionally substituted aryl group or an optionally substituted heteroaryl group
  • X 1 is -NR ⁇ Y 1 -, -O-, -S-, -SO-, -SO 2 - or -CHR 3 - wherein R 3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R is optionally bonded to a carbon atom or a hetero atom on the aryl group or the 5 heteroaryl group represented by A to form an optionally substituted ring structure
  • R 3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R is optionally bonded to a carbon atom or a hetero atom on the aryl group or the 5 heteroaryl group represented by A to form an optionally substituted ring structure
  • Y 1 is a single bond or an optionally substituted CM alkylene or an optionally substituted -O-
  • R is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, and R is a hydrogen atom or an optionally substituted o group bonded via a carbon atom or a sulfur atom, or
  • R and R 2 are optionally bonded to form an optionally substituted ring structure, provided that compounds represented by formulas
  • AMP-activated protein kinase for preparing a corresponding pharmaceutical composition.
  • the gene of cell growth factor and growth factor receptor is called a proto-oncogene and plays a key role in the pathology of human tumor.
  • the epithelial cell growth factor receptor family i o includes EGFR, HER2, HER3 and HER4, which are type I receptor type tyrosine kinases. These ErbB family members express in various cell groups, and are deeply involved in the control of the growth and differentiation of cells and the control of suppression of cell death (apoptosis suppression). For example, high expression of EGFR and HER2, and homeostatic activation of receptors are empirically known to transform cells. is It is also known that high expression and simultaneous expression of each of these receptors are poor prognostic factors in various cancer patients.
  • receptors are bound with many peptide ligands such as EGF, TGF ⁇ and the like, and binding of the ligand promotes homo- or heterodimerization of the receptors. This induces increase of kinase activity from self-phosphorylation or transphosphorylation of the receptors, and causes 0 activation of downstream signaling pathway (MAPK, Akt) via a protein bound with a particular phosphorylated tyrosine residue. This is the mechanism of the receptor activity of the above- mentioned cell growth, differentiation, cell death suppression and the like, which is considered to be responsible for the high expression of receptor in cancer and malignant degeneration of cancer due to topical increase in the ligand concentration. In recent years, clinical use of a humanized anti-HER2 antibody (Trastuzumab) against trastuzumab.
  • HER2 highly expressing breast cancer clinical trial of anti-EGFR antibody and clinical trials of several low molecular weight receptor enzyme inhibitors have demonstrated a potential of these drugs against HER2 or EGFR for therapeutic drugs for cancer. While these drugs show a tumor growth inhibitory action in clinical and non-clinical trials, they are known to induce inhibition of receptor enzyme activity and suppression of downstream signaling pathway. Therefore, a compound inhibiting EGFR or HER2 kinase, or inhibiting activation of EGFR or HER2 kinase is effective as a therapeutic drug for cancer.
  • fused heterocyclic compounds e.g., WO97/13771, WO98/02437, WO00/44728
  • quinazoline derivatives e.g., WO02/02552, WO01/98277, WO03/049740, WO03/050108
  • thienopyrimidine derivatives e.g., WO03/053446
  • aromatic azole derivatives e.g., WO98/03648, WO01/77107, WO03/031442
  • pyrrolo[3,2-d]pyrimidine derivatives the following compounds are known as compounds having a cell growth inhibitory activity (Khim.-Farm. Zh L , 1982, 16, 1338-1343; Collect. Czech. Chem. Commun., 2003, 68, 779-791).
  • pyrazolo[4,3-d]pyrimidine derivatives 3,5,7-trisubstituted pyrazolo[4,3- d]pyrimidine derivatives are known as compounds having a CDK inhibitory action, a cell growth inhibitory action and/or an apoptosis inducing action (EP-A- 1348707), and 3- isopropylpyrazolo[4,3-d]pyrimidine derivatives are known as compounds having a CDKl/ cyclin B inhibitory activity (Bioorganic & Medicinal Chemistry Letters, 2003, 13, 2989-2992). Furthermore, o synthesis of 3 -methylpyrazolo[4,3-d]pyrirnidine derivatives has been reported (The Journal of
  • the present invention protects heart of mammals from damages casued by cardiotoxic materials such as anti-cancer drugs, particularly, compounds having kinase inhibitory activities.
  • Such damages can include damages caused by other cardio toxic materials, free radicals, oxidation, specially, ⁇ -oxidation of fatty acid, chemotherapy, radiation to radio active materials, TNF ⁇ , other i o cytokines, cardiomyopathy, ischemic injury(ischemia), hypoxia, obesity, lipidemia, low-density lipoprotein (LDL), other lipid accumulation, glucose deprivation, starvation, heart transplant, statins, HMG-CoA reductase inhibitors, and other stresses to the heart.
  • cardiotoxic materials such as anti-cancer drugs, particularly, compounds having kinase inhibitory activities.
  • Such damages can include damages caused by other cardio toxic materials, free radicals, oxidation, specially, ⁇ -oxidation of fatty acid, chemotherapy, radiation to radio active materials, TNF ⁇ , other i o cytokines, cardiomy
  • the present invention relates to a method to protect heart of a mammal by administering a compound having activation acitivites of AMP-activated protein kinase, its salt or prodrug to a 15 mammal, i.e., AMPK (5'-adenosine monophosphate-activated protein kinase) activator, a pharmaceutical composition that protects heart of a mammal containing such as an AMPK activator, use of the AMPK activator for preparing a pharmaceutical composition that protects heart of a mammal, a method to activate the AMPK by administering to a mammal a compound having activation activities of the AMPK including its salt and prodrug, a pharmaceutical composition to 0 activate the AMPK that includes at least one compound having activation activities of the AMPK, and use of the compound that activates the AMPK for preparing a pharmaceutical composition.
  • AMPK (5'-adenosine monophosphate-activated protein kinase)
  • This heart protection in this invention includes not only prevention of damage to the heart of a mammal but also treatment of such damage that may have occurred in the heart. Accordingly, the present invention provides the following.
  • a method for protecting heart of a mammal in need thereof comprising administering to the mammal an effective amount of at least one of Compound (T), a salt thereof, or a prodrug thereof, wherein the Compound (T) is represented by the formula:
  • A is an optionally substituted aryl group or an optionally substituted heteroaryl group
  • X 1 is -NR ⁇ Y 1 -, -O-, -S-, -SO-, -SO 2 - or -CHR 3 - wherein R is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R 3 is optionally bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A to form an optionally substituted ring structure, and
  • Y 1 is a single bond or an optionally substituted C ⁇ alkylene or an optionally substituted -O-
  • R 1 is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, and R is a hydrogen atom or an optionally substituted group bonded via a carbon atom or a sulfur atom, or
  • R and R are optionally bonded to form an optionally substituted ring structure, provided that compounds represented by formulas are excluded.
  • [2] The method for protecting heart of a mammal in need thereof according to [1] above, which protects the heart from damages caused by a cardiotoxic material, free radicals, oxidation, ⁇ - 5 oxidation of fatty acid, chemotherapy, radiation to radio active materials, TNF ⁇ , other cytokines, cardiomyopathy, ischemia, hypoxia, obesity, lipidemia, low-density lipoprotein (LDL), other lipid accumulation, glucose deprivation, starvation, heart transplant, statins, and HMG-CoA reductase inhibitors.
  • a cardiotoxic material free radicals, oxidation, ⁇ - 5 oxidation of fatty acid, chemotherapy, radiation to radio active materials, TNF ⁇ , other cytokines, cardiomyopathy, ischemia, hypoxia, obesity, lipidemia, low-density lipoprotein (LDL), other lipid accumulation, glucose deprivation, starvation, heart transplant, statins, and HMG-CoA reductase inhibitors.
  • R is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom,
  • R ⁇ is an optionally substituted group bonded via a carbon atom or a sulfur atom, or R la and R 23 , or R 2a and R 3a are optionally bonded to form an optionally substituted ring structure,
  • R 3a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or
  • R 3a is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure
  • B a is an optionally substituted benzene ring
  • C a is an optionally substituted C 6-18 aryl group, or a salt thereof.
  • a method for protecting heart of a mammal comprising administering to the mammal an effective amount of N- ⁇ 2-[4-( ⁇ 3-chloro-4-[3- (trMuorome1hyl)phenoxy]phenyl ⁇ ammo)-5H-pvrrolo[3,2-d]pyrimidin-5-yl]e1hyl ⁇ methylbutanamide, a salt thereof, or a prodrug thereof.
  • a pharmaceutical composition for protecting heart of a mammal in need thereof comprising at least one of Compound (T), a salt thereof, or a prodrug thereof in a therapeutically effective amount wherein the Compound (T) is represented by the formula: wherein W is C(R 1 ) or N,
  • A is an optionally substituted aryl group or an optionally substituted heteroaryl group
  • X 1 is -NR 3 -Y ! -, -O-, -S-, -SO-, -SO 2 - or -CHR 3 - wherein R 3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or
  • R 3 is optionally bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A to form an optionally substituted ring structure
  • Y 1 is a single bond or an optionally substituted Cu alkylene or an optionally substituted -O-
  • R 1 is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom
  • R 2 is a hydrogen atom or an optionally substituted group bonded via a carbon atom or a sulfur atom, or
  • R and R are optionally bonded to form an optionally substituted ring structure, provided that compounds represented by formulas
  • R la is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom,
  • R ⁇ 2a is an optionally substituted group bonded via a carbon atom or a sulfur atom, or
  • R la and R 28 , or R 2 * 1 and R 3a are optionally bonded to form an optionally substituted ring structure
  • R ,3a a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or
  • R >3a is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure
  • B a is an optionally substituted benzene ring
  • C a is an optionally substituted C 6-18 aryl group, or a salt thereof.
  • a pharmaceutical composition for protecting heart of a mammal in need thereof comprising N- ⁇ 2-[4-( ⁇ 3-cMoro4-[3-(trifluoromethyl)phenoxy]phenyl ⁇ amino)-5H-pyrrolo[3,2-d]pyrimidin-5- yl]ethyl ⁇ -3-hydroxy-3-methylbutanamide, a salt thereof, or a prodrug thereof in a therapeutically effective amount.
  • A is an optionally substituted aryl group or an optionally substituted heteroaryl group
  • X 1 is -NR ⁇ Y 1 -, -O-, -S-, -SO-, -SO 2 - or -CHR 3 - wherein R 3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or
  • R 3 is optionally bonded to a carbon atom or a hetero atom on the aryl group or the i o heteroaryl group represented by A to form an optionally substituted ring structure, and
  • Y 1 is a single bond or an optionally substituted CM alkylene or an optionally substituted -O-
  • R 1 is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom
  • R 2 is a hydrogen atom or an optionally substituted 15 group bonded via a carbon atom or a sulfur atom, or
  • R 1 and R 2 , or R 2 and R 3 are optionally bonded to form an optionally substituted ring structure, provided that compounds represented by formulas are excluded.
  • R la is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom,
  • R 2a is an optionally substituted group bonded via a carbon atom or a sulfur atom, or
  • R la and R ⁇ 5 or R ⁇ and R 3a are optionally bonded to form an optionally substituted ring structure
  • R 3a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or
  • R a is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure
  • B a is an optionally substituted benzene ring
  • C a is an optionally substituted C 6-18 aryl group, or a salt thereof.
  • a method for activating an AMP-activated protein kinase comprising administering to a mammal in need thereof an effective amount of at least one of Compound (T), a salt thereof, or a prodrug thereof, wherein the Compound (T) is represented by a formula:
  • W is C(R 1 ) or N
  • A is an optionally substituted aryl group or an optionally substituted heteroaryl group
  • X 1 is -NR 3 - Y 1 -, -O, -S-, -SO-, -SO 2 - or -CHR 3 - wherein R 3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R 3 is optionally bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A to form an optionally substituted ring structure, and Y 1 is a single bond or an optionally substituted CM alkylene or an optionally substituted -O-
  • R 1 is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom
  • R 2 is a hydrogen atom or an optionally substituted group bonded via a carbon atom or a sulfur atom, or R 1 and R 2 , or R 2 and R 3 are optionally bonded to form an optionally substituted ring structure, provided that compounds represented by formulas
  • R > la a is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom,
  • R is an optionally substituted group bonded via a carbon atom or a sulfur atom, or ⁇ la a a_.nd R >2a , or rR>2a 3a
  • R a . , nd R are optionally bonded to form an optionally substituted ring structure
  • R 3a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or
  • R a is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure
  • B a is an optionally substituted benzene ring
  • C a is an optionally substituted C 6-18 aryl group, or a salt thereof.
  • a method for activating an AMP-activated protein kinase comprising administering to a mammal in need thereof an effective amount of N- ⁇ 2-[4-( ⁇ 3-chloro-4-[3- (1rifluoromethyl)phenoxy]phenyl ⁇ amm ⁇ methylbutanamide, a salt thereof, or a prodrug thereof.
  • a pharmaceutical composition for activating an AMP-activated protein kinase comprising at least one of Compound (J), a salt thereof, or a prodrug thereof in a therapeutically effective amount, wherein the Compound (T) is represented by a formula:
  • W is C(R 1 ) or N
  • A is an optionally substituted aryl group or an optionally substituted heteroaryl group
  • X 1 is -NR ⁇ Y 1 -, -O-, -S-, -SO-, -SO 2 - or -CHR 3 - wherein R is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R is optionally bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A to form an optionally substituted ring structure
  • R is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R is optionally bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A to form an optionally substituted ring structure
  • Y 1 is a single bond or an optionally substituted C 1-4 alkylene or an optionally substituted -O-
  • R 1 is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom
  • R 2 is a hydrogen atom or an optionally substituted group bonded via a carbon atom or a sulfur atom, or
  • R 1 and R 2 , or R 2 and R 3 are optionally bonded to form an optionally substituted ring structure, provided that compounds represented by formulas
  • R la is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom,
  • R 2 * 1 is an optionally substituted group bonded via a carbon atom or a sulfur atom, or R la and R 28 , or R ⁇ and R 3a are optionally bonded to form an optionally substituted ring structure, R 3a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or
  • R3a is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure
  • B a is an optionally substituted benzene ring
  • 5 C a is an optionally substituted C 6-18 aryl group, or a salt thereof.
  • a pharmaceutical composition for activating an AMP-activated protein kinase comprising N- ⁇ 2-[4-( ⁇ 3-cMoro-4-[3-(trifluorome&yl)ph yl]ethyl ⁇ -3-hydroxy-3-methylbutanamide, a salt thereof, or a prodrug thereof in a therapeutically effective amount.
  • i o A use of at least one of Compound (T), a salt thereof, or a prodrug thereof for preparing a pharmaceutical composition for activating an AMP-activated protein kinase, wherein the
  • W is C(R 1 ) or N, is A is an optionally substituted aryl group or an optionally substituted heteroaryl group,
  • X 1 is -NR ⁇ Y 1 -, -O-, -S-, -SO-, -SO 2 - or -CHR 3 - wherein R is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R 3 is optionally bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A to form an optionally substituted ring structure, and 0 Y 1 is a single bond or an optionally substituted Cn alkylene or an optionally substituted -O- (Q- 4 alkylene)-,
  • R is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, and R is a hydrogen atom or an optionally substituted group bonded via a carbon atom or a sulfur atom, or
  • R 1 and R 2 , or R 2 and R 3 are optionally bonded to form an optionally substituted ring structure, provided that compounds represented by formulas
  • R is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom
  • R 28 is an optionally substituted group bonded via a carbon atom or a sul&r atom, or
  • R la and R 23 , or R 28 and R 3a are optionally bonded to form an optionally substituted ring
  • R a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or
  • R 3a is optionally bonded to a carbon atom of the adjacent phenyl group to form an
  • B a is an optionally substituted benzene ring
  • C a is an optionally substituted C 6-I8 aryl group, or a salt thereof.
  • FIG 1 shows photographs of Human primary miocardiocytes treated with the compound
  • Figure 2 shows photographs of Human primary miocardiocytes treated with the compound of the present invention and comparative compounds and blotted using various antibodies.
  • Figure 3 shows photographs of Human primary miocardiocytes treated with the compound of the present invention and comparative compounds and blotted using various antibodies.
  • Figure 4 shows photographs of Human cardiac miocardiocytes treated with the compound of the present invention and comparative compounds in vitro, and lipids in the cells are stained.
  • Figure 5 shows photographs of rat cardiac miocardiocytes treated with the compound of the present invention and a comparative compound in vivo and blotted with various antibodies.
  • Figure 6 shows photographs of rat cardiac miocardiocytes treated with the compound of the 5 present invention and comparative compounds in vivo, and lipids in the cells are stained.
  • the present invention protects the heart of mammals from damage by using compounds having kinase inhibitory activities, especially, compounds having tyrosine kinase 5 inhibitory activities, and more specifically, compounds having EGFR/ HER2 (which is also referred to as ErbB2) tyrosine kinase inhibitory activities.
  • Cells of the myocardium of a mammal have the ability to regulate metabolism and control uptake and production of energy sources such as glucose and fatty acid.
  • Compounds that induce inhibition of receptor enzyme activity and suppress the downstream signaling pathway often show o cardiotoxicity.
  • the inhibition of phosphorylation in the signaling pathway affects that signaling pathway and causes alterations in fatty acid metabolism, which may lead to organ toxicity, including cardiotoxicity.
  • the alterations in fatty acid metabolism are not only caused by the cardio- toxic materials but also caused by free radicals, oxidation, specially, ⁇ -oxidation of fatty acid, chemotherapy, radiation to radio active materials, TNF ⁇ , other cytokines, ischemia, hypoxia,5 obesity, lipidemia, other lipid accumulation, glucose deprivation, starvation, low-density lipoprotein (LDL), heart transplant, statins, and HMG-CoA reductase inhibitors.
  • AMP activated protein kinase is known as an enzyme that promotes phosphorylation reactions in downstream and inactivates acetyl-CoA carboxylase (ACC) and 3- hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase, HMGR). Therefore, it is thought o that the activated AMPK switches cardiac cells from a state of consuming ATP and synthesizing fatty acid, cholesterol, and protein, etc. to a state of producing ATP and oxidizing fatty acid, i.e., consuming fatty acid and prevents cardiotoxic damages from a mammal. In addition, it is known that the activity of the AMPK is significantly increased at the end of ischemia, and remains elevated throughout reperfusion.
  • the present inventors have conducted intensive studies and found that the heart of mammals can be protected with an AMP-activated protein kinase (AMPK) activator, a salt thereof, or a prodrug thereof.
  • AMPK AMP-activated protein kinase
  • the method for heart protection in this invention is to protect the heart of a mammal by administering at least a compound that is an AMPK activator, a salt thereof, or a prodrug thereof to a mammal.
  • the invention also is directed to a heart protecting pharmaceutical composition that includes at least an AMPK activator, a salt thereof, or a prodrug thereof that can be administered to a mammal to protect the heart of the mammal and to the use of the AMPK activator, a salt thereof, or a prodrug thereof for the preparation of the pharmaceutical composition.
  • Such pharmaceutical composition may contain other active ingredients, for example, hormonal therapeutic agents, anticancer agents, anthracyclines, anti-depressants, calcium channel blockers, beta-blockers, and the like.
  • the AMPK activator, a salt thereof, or a prodrug thereof may be administered to a mammal to protect the heart in combination with drugs including the other active ingredients as listed above and/or other drugs than those including the ingredients listed above, simultaneously or separately, and non-drug therapies can be combined with administring the AMPK activator, a salt thereof, or a prodrug thereof.
  • the heart protection in this invention protects the heart of mammals from damage to the heart such as damages caused by cardiotoxic materials, cardiomyopathy, ischemic injury, hypoxia, glucose deprivation, starvation, and the like.
  • This protection includes not only prevention of damage to the heart of a mammal, but also treatment of such damage that may have occurred in the heart.
  • the AMPK activator may be the AMPK activator compound itself, salt thereof, or a prodrug thereof.
  • the AMPK activator is preferably at least one of a tyrosine kinase inhibitor, a serine kinase inhibitor, threonine kinase inhibitor, salt thereof, and a prodrug thereof.
  • the tyrosine kinase inhibitor may be an ErbB 1 and ErbB2 tyrosine kinase inhibitor, salt thereof, or a prodrug thereof.
  • Examples of compounds that are the AMPK activator and can be administered to a mammal to protect the heart in this method may be represented by the following formula (T) [1], a salt thereof, or a prodrug thereof [2] (sometimes collectively to be referred to as compound (I) in the present specification) as described in WO 2005-118588 and US 7,507,740:
  • A is an optionally substituted aryl group or an optionally substituted heteroaryl group
  • X 1 is -NF ⁇ Y 1 -, -O-, -S-, -SO-, -SO 2 - or -CHR 3 - wherein R 3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R 3 is optionally bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A to form an optionally substituted ring structure
  • R 3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R 3 is optionally bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A to form an optionally substituted ring structure
  • Y 1 is a single bond or an optionally substituted C ⁇ alkylene or an optionally substituted -0-(CM alkylene)-, R 1 is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, and R 2 is a hydrogen atom or an optionally substituted group bonded via a carbon atom or a sulfur atom, or
  • R 1 and R 2 , or R 2 and R 3 are optionally bonded to form an optionally substituted ring structure, provided that the compounds represented by the formulas
  • the compound (T) may be [3] the compound of the above-mentioned compound (T) [1], wherein W is C(R 1 ),
  • A is an aryl group substituted by a group of the formula -Y 2 -B and optionally further substituted, wherein Y 2 is a single bond, o -O-, -0-(C 1-3 alkylene)-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C 3-8 cycloalkyl group, a carbamoyl group, aureido group, a C 6-18 aryl-carbonyl group or a C 6-18 aryl-Cw alkyl- carbonyl group, each of which is optionally substituted,
  • R is a group of the formula -X -R wherein X 2 is a single bond, -NH- or -O-, and R 4 is a hydrogen atom, a cyano group, or a C 1-8 alkyl group, a C 2-8 alkenyl group, a C 2-8 alkynyl group, a carbamoyl group, a C 1-8 alkyl-carbonyl group, a C 3-8 cycloalkyl group, a C 6-18 aryl group, a C 6-18 aryl-Cw alkyl group, a C 6-18 aryl-carbonyl group, a C 6-18 aryl-Cw alkyl-carbonyl group, a heterocyclic group, aheterocycle-Cw alkyl group, a heterocycle-carbonyl group or a heterocycle-Cw alkyl-carbonyl group, each of which is optionally substituted
  • R 2 is a hydrogen atom or a C 1-8 alkyl group, a C 2-8 alkenyl group, a C 2-8 alkynyl group, a carbamoyl group, a C 1-8 alkyl-carbonyl group, a C 1-8 alkylsulfonyl group, a C 3-8 cycloalkyl group, a C 6-18 aryl group, a C 6-18 aryl-C ⁇ alkyl group, a C 6-18 aryl-carbonyl group, a C 6-18 aryl-C ⁇ alkyl-carbonyl group, a C 6-18 aryl-sulfonyl group, a heterocyclic group, aheterocycle-C M alkyl group, aheterocycle-carbonyl group or aheterocycle- 5 CM alkyl-carbonyl group, each of which is optionally substituted, [7]
  • A is an aryl group substituted by a group of the formula -Y -B and optionally further substituted, wherein Y is a single bond, i o -O-, -0-(C 1-3 alkylene)-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C 3-8 cycloalkyl group, a carbamoyl group, a ureido group, a C 6-18 aryl-carbonyl group or a C 6-18 aryl-C 1-4 alkyl- carbonyl group, each of which is optionally substituted;
  • R 1 is a group of the formula -X 2 -R wherein X 2 is a single bond, -NH- or -O-, and R 4 is a- hydrogen atom, a cyano group, or a C 1-8 alkyl group, a C 2-8 alkeny
  • R 2 is a hydrogen atom or a C 1-8 alkyl group, a C 2-8 alkenyl group, a C 2-8 alkynyl group, a carbamoyl 0 group, a C 1-8 alkyl-carbonyl group, a C 1-8 alkylsulfonyl group, a C 3-8 cycloalkyl group, a C 6-18 aryl group, a C 6-18 aryl-C ⁇ alkyl group, a C 6-18 aryl-carbonyl group, a C 6-18 aryl-Cw alkyl-carbonyl group, a heterocyclic group, aheterocycle-C ⁇ alkyl group, aheterocycle-carbonyl group or a heterocycle-Ci 4 alkyl-carbonyl group, each of which is optionally substituted;
  • R 2 is a hydrogen atom or a C 1-8 alkyl group, a C 2-8 alkenyl group, a C 2-8 alky
  • C 6-18 aryl group a C 6-18 aryl-Cw alkyl group, a C 6-18 aryl-carbonyl group, a C 6-18 aryl-C ⁇ alkyl- carbonyl group, a C 6-18 aryl-sulfonyl group, a heterocyclic group, aheterocycle-Ci- 4 alkyl group, a heterocycle-carbonyl group or a heterocycle-C ⁇ alkyl-carbonyl group, each of which is optionally substituted; and
  • X is -NR - wherein R is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group
  • B is an aryl group, a heterocyclic group, a C 3-8 cycloalkyl group, a carbamoyl group, a ureido group, a C 6-18 aryl-carbonyl group or a C 6-18 aryl-C ⁇ alkyl- carbonyl group, each of which is optionally substituted,
  • R is a hydrogen atom or a C 1-8 alkyl i o group, a C 2-8 alkenyl group, a C 2-8 alkynyl group, a carbamoyl group, a C 1-8 alkyl-carbonyl group, a C 1-8 alkylsulfonyl group, a C 3-8 cycloalkyl group, a C 6-18 aryl group, a C 6-18 aryl-Cw alkyl group, a C 6-18 aryl-carbonyl group, a C 6-18 aryl-Cw alkyl-carbonyl group, a C 6-18 aryl-sulfonyl group, a heterocyclic group, aheterocycle-C ⁇ alkyl group, aheterocycle-carbonyl group or aheterocycle- C 1-4 alkyl-carbonyl group, each of which is optionally substituted, 15
  • R 3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group
  • R is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group
  • A is an aryl group substituted by a group of the formula -Y -B and optionally further substituted, 0 wherein Y 2 is a single bond, -O-, -0-(C 1-3 alkylene)-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C 3-8 cycloalkyl group, a carbamoyl group, a ureido group, a C 6-18 aryl-carbonyl group or a C 6-18 aryl-C ⁇ alkyl-carbonyl group, each of which is optionally substituted;
  • R is a hydrogen atom or a Ci -8 alkyl group, a C 2-8 alkenyl group, a C 2-8 alkynyl group, a carbamoyl group, a C 1-8 alkyl-carbonyl group, a C 1-8 alkylsulfonyl group, a C 3-8 cycloalkyl group, a C 6-18 aryl group, a C 6-18 aryl-Q.
  • A is an aryl group substituted by a group of the formula -Y -B and optionally further substituted, wherein Y 2 is a single bond, -O-, -0-(C 1-3 alkylene)-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C 3-8 cycloalkyl group, a carbamoyl group, a ureido group, a C 6-18 aryl-carbonyl group or a C 6-18 aryl-C ⁇ alkyl-carbonyl group, each of which is optionally substituted; and R and R are bonded to form an optionally substituted ring structure,
  • heterocycle-C ⁇ alkyl preferably, 5- to 8-membered heterocycle-Q- 4 alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like
  • heterocycle-C ⁇ alkyl preferably, 5- to 8-membered heterocycle-Q- 4 alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like
  • heterocycle-C M alkyl preferably, 5- to 8-membered heterocycle-Cn alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like
  • heterocycle-C M alkyl preferably, 5- to 8-membered heterocycle-Cn alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like
  • heterocycle-C M alkyl preferably, 5- to 8-membered heterocycle-C ⁇ alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like
  • heterocycle-C M alkyl preferably, 5- to 8-membered heterocycle-C ⁇ alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like
  • heterocycle-Ci 4 alkyl preferably, 5- to 8-membered heterocycle-C ⁇ alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like
  • heterocycle-Ci 4 alkyl preferably, 5- to 8-membered heterocycle-C ⁇ alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like
  • R 1 is (i) a hydrogen atom, (ii) a cyano group, or
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C 14 alkyl, optionally oxidized C 14 alkylthio, -CO-CM alkyl, - CO-O-C 14 alkyl, -CO-NH-C 14 alkyl,
  • n is an integer of 1 to 4
  • R 6 and R 7 are the same or different and each is a hydrogen atom or a C 14 alkyl group
  • R is a hydrogen atom or a C 14 alkyl group
  • R is a hydrogen atom or a Cw alkyl group; or, R and R 2 are optionally bonded to form
  • R and R are optionally bonded to form C 24 alkylene optionally substituted by an imino group.
  • R is a C 1-8 alkyl group, a C 2-8 alkenyl group or a C 2-8 alkynyl group (particularly C 1-8 alkyl group), each of which is optionally substituted by substituent(s) selected from
  • heterocyclic group is a 5- 5 to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C 14 alkyl, optionally oxidized C 14 alkylthio, -CO-C 14 alkyl, -
  • n is an integer of 1 to 4
  • R and R are the same or different and each is a hydrogen atom or a C 14 alkyl group
  • R 8 is a hydrogen atom or a C 14 alkyl group
  • A is a C 6-18 aryl group substituted by substituent(s) selected from (i) aphenyloxy group substituted by 1 to 5 substituents selected from
  • heterocycle-Cn alkyl preferably, 5- to 8-membered heterocycle-C ⁇ alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like
  • heterocycle-Cn alkyl preferably, 5- to 8-membered heterocycle-C ⁇ alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like
  • heterocycle-C ⁇ alkyl preferably, 5- to 8-membered heterocycle-C ⁇ alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like
  • heterocycle-C ⁇ alkyl preferably, 5- to 8-membered heterocycle-C ⁇ alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like
  • heterocycle-C ⁇ alkyl preferably, 5- to 8-membered heterocycle-Cw alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like
  • heterocycle-C ⁇ alkyl preferably, 5- to 8-membered heterocycle-Cw alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like
  • heterocycle-C M alkyl preferably, 5- to 8-membered heterocycle-C ⁇ alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like
  • heterocycle-C M alkyl preferably, 5- to 8-membered heterocycle-C ⁇ alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like
  • R is a C 1-8 alkyl group, a C 2-8 alkenyl group or a C 2-8 alkynyl group, each of which is substituted by substituent(s) selected from
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C 14 alkyl, optionally oxidized C 14 alkylthio, -CO-C 14 alkyl, -
  • n is an integer of 1 to 4, R and R are the same or different and each is a hydrogen atom or a C 14 alkyl group, R 8 is a hydrogen atom or a C 14 alkyl group, and (CH 2 ) n is optionally substituted by C 14 alkyl or hydroxy);
  • R 3 is a hydrogen atom or a C 1-6 alkyl group
  • R 1 and R 2 are optionally bonded to form
  • R and R are optionally bonded to form C 24 alkylene, particularly preferably, R 2 is a C 1-8 alkyl group, a C 2-8 alkenyl group or a C 2-8 alkynyl group (particularly, a C 1-8 alkyl group), each of which is substituted by substituent(s) selected from
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C 1-4 alkyl, optionally oxidized C 14 alkylthio, -CO-C 14 alkyl, - CO-NH-C 14 alkyl, -CONH 2 , -SO 2 -C 14 alkyl, -SO 2 -NH-C 14 alkyl, -SO 2 NH 2 and the like), i o wherein n is an integer of 1 to 4, R and R are the same or different and each is a hydrogen atom or a C 14 alkyl group, and R is a hydrogen atom or a C 14 alkyl group,
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C 14 alkyl, optionally oxidized C 14 alkylthio, -CO-C 14 alkyl, -
  • n is an integer of 1 to 4
  • R 8 is a hydrogen atom or a C 14 alkyl group
  • (CH 2 ) n is optionally substituted by C 14 alkyl, (in) a C 2 - 8 alkenyl group optionally substituted by hydroxy, or
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C 14 alkyl, optionally oxidized CM alkylthio, -CO-CM alkyl, - CO-NH-C 14 alkyl, -CONH 2 , -SO 2 -C 14 alkyl, -SO 2 -NH-C 14 alkyl, -SO 2 NH 2 and the like), wherein n is an integer of 1 to 4, and R 8 is a hydrogen atom or a C 14 alkyl group,
  • W is CR 1 ;
  • A is a phenyloxy-C 6-18 aryl group wherein the phenyloxy moiety is optionally substituted by 1 to 5 substituents selected from
  • heterocycle-C 14 alkyl preferably, 5- to 8-membered heterocycle-C 14 alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like), (v) optionally halogenated C 14 alkyloxy,
  • X is -NR 3 - wherein R 3 is a hydrogen atom or a Cw alkyl group
  • R 2 is (i) a hydrogen atom or
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by i o substituent(s) selected from hydroxy, C 14 alkyl, optionally oxidized C 14 alkylthio, -CO-C 14 alkyl, -
  • n is an integer of 1 to 4
  • R and R are the same or different and each is a hydrogen atom or a C 14 alkyl group
  • R 8 is a hydrogen atom or a C 14 alkyl group
  • (CH 2 ) n is optionally substituted by 15 optionally halogenated C 14 alkyl or hydroxy, and when n is not less than 2, a subset -CH 2 CH 2 - of
  • R and R are optionally bonded to form
  • R and R are optionally bonded to form C 24 alkylene optionally substituted by an imino group, 0 particularly preferably, R ⁇ is a C 1-8 alkyl group, a C 2-8 alkenyl group or a C 2-8 alkynyl group (particularly, C 1-8 alkyl group), each of which is optionally substituted by substituent(s) selected (a) hydroxy,
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an 0 oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C 14 alkyl, optionally oxidized C 14 alkylthio, -CO-C 14 alkyl, -
  • n is an integer of 1 to 4
  • R 6 and R 7 are the same or different and each is a hydrogen atom or a CM alkyl group
  • R 8 is a hydrogen atom or a CM alkyl group
  • A is phenyl-C 1-3 ⁇ kyhxy-C ⁇ -is aryl group wherein the phenyl moiety is optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated C 14 alkyl and cyano, and the C 6-18 aryl moiety is optionally further substituted by 1 to 4 substituents selected from halogen, CM alkyl optionally having hydroxy and CM alkyloxy;
  • X 1 is -NR 3 - wherein R is a hydrogen atom or
  • n is an integer of 1 to 4
  • R 6 and R 7 are the same or different and each is a hydrogen atom or a C 14 alkyl group
  • R 8 is a hydrogen atom or a C 14 alkyl group
  • n is not less than 2
  • n is an integer of 1 to 4
  • R 8 is a hydrogen atom or a Q 4 alkyl group, or
  • R 2 is (i) a hydrogen atom, ( ⁇ ) a C 1-8 aUkyl group optionally substituted by substituent(s) selected from
  • n is an integer of 1 to 4
  • R 6 and R 7 are the same or different and each is a hydrogen atom or a CM alkyl group
  • R 8 is a hydrogen atom or a Cw alkyl group
  • CM alkoxy-carbonyl (c) CM alkoxy-carbonyl, (d) 5- to 8-membered heterocycle-carbonyl having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which optionally has substituent(s) selected from hydroxy and C 1-4 alkyl, and
  • R and R are optionally bonded to form C 24 alkylene
  • A is a 5- to 8-membered heterocycleoxy-C 6 - 18 aryl group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, wherein the heterocycleoxy moiety is optionally substituted by 1 to 5 substituents selected from
  • X is -NR - wherein R is a hydrogen atom or a C 1 ⁇ alkyl group; R 1 is (i) a hydrogen atom,
  • R 2 is (i) a hydrogen atom, (ii) a C 14 alkyl group optionally substituted by substituent(s) selected from
  • R 2 and R are optionally bonded to form C 24 alkylene
  • A is 5- to 8-memberedheterocycle-C 1-3 alkyloxy-Ce- ⁇ s aryl group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom wherein the C 6-18 aryl moiety is optionally further substituted by halogen;
  • X is -NR 3 - wherein R is a hydrogen atom or a C 1-6 alkyl group; 0 R 1 is (i) a hydrogen atom or
  • R 2 is (i) a hydrogen atom, ( ⁇ ) Ci 4 atkyl optionally substituted by substituent(s) selected from
  • W is N
  • A is a phenyloxy-C 6 . 18 aryl group wherein the phenyloxy moiety is optionally substituted by 1 to 5 substituents selected from optionally halogenated CM alkyl and cyano, and the C 6-18 aryl moiety is optionally further substituted by 1 to 4 substituents selected from halogen and CM alkyl;
  • X is -NR - wherein R is a hydrogen atom or a Cw alkyl group; and R 2 is (i) a hydrogen atom or
  • CM alkyl group optionally substituted by -O-(CH 2 ) n -OH wherein n is an integer of 1 to 4,
  • F a compound (T) wherein W is N;
  • A is a phenyl-C 1-3 alkyloxy-C 6-1 8 aryl group wherein the phenyl moiety is optionally substituted by 1 to 5 substituents selected from halogen and cyano, and the C 64 8 aryl moiety is optionally further substituted by 1 to 4 substituents selected from halogen and C 14 alkyl;
  • X is -NR 3 - wherein R 3 is a hydrogen atom or a C 1 ⁇ alkyl group
  • R 2 is (i) a hydrogen atom, 5 (ii) a CM alkyl group optionally substituted by 1 to 5 substituents selected from the group consisting of
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom
  • n is an integer of 1 to 4
  • R 8 is a hydrogen atom or a C 14 alkyl group, 15 (iii) a C 6-18 aryl group optionally substituted by C 14 alkyl optionally substituted by substituent(s) selected from hydroxy, -NR 8 -(CH 2 )n-OH, -NR 8 -(CH 2 ) n -heterocyclic group (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom) and -NR 8 -(CH 2 ) n -SO 2 -C 14 alkyl, or
  • W is CH
  • A is a C 6-18 aryl group optionally substituted by substituent(s) selected from
  • a 5- to 8-membered heterocycle-carbonyl group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom preferably, a 5- to 8-membered cyclic amino- carbonyl group optionally having 1 or 2 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom
  • a carbamoyl group optionally substituted by C 6-18 aryl-Cw alkyl
  • X 1 is -NR 3 - wherein R 3 is a hydrogen atom or a C 1-6 alkyl group; and R 2 is a hydrogen atom, or
  • A is (i) a C 6-1S aryl group or (if) a 5- to 8- membered heteroaryl group containing, as an atom (ring atom) constituting a ring system, 1 to 4 hetero atoms selected from an oxygen atom, an optionally oxidized sulfur atom and a nitrogen atom
  • CM alkyl preferably, an oxygen atom, a sulfur atom and a nitrogen atom
  • substituents selected from halogen, optionally halogenated CM alkyl, hydroxy, optionally halogenated CM alkyloxy, C 14 alkyloxymethyl, hydroxy-C M alkyl, C 1 ⁇ alkyl-carbonyl, carboxy, CM alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, CM alkyl- carbonylamino, Q 4 alkoxy-carbonylarnino, CM alkylsulfonylamino and a group of the formula - Y 2 -B, wherein Y 2 is a single bond, -O-, -0-(C 1-3 alkylene)-, -NH- or -S-, B is
  • (A) (i) a C 6-18 aryl group, ( ⁇ ) a 5- to 8-membered heteroaryl group containing, as an atom (ring atom) constituting a ring system, 1 to 4 hetero atoms selected from an oxygen atom, an optionally oxidized sulfur atom and a nitrogen atom (preferably, an oxygen atom, a sulfur atom and a nitrogen atom) or a saturated or unsaturated aliphatic heterocyclic group, ( ⁇ i) a C 3-8 cycloalkyl group, (iv) a carbamoyl group, (v) a C 6-18 aryl-carbonyl group or (vi) a C 6-18 aryl-C ⁇ alkyl-carbonyl group, each of which is optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated CM alkyl, hydroxy, optionally halogenated Q 4 alkyloxy, CM alkyloxymethyl, hydroxy-C ⁇ alkyl,
  • ureido group T optionally having 1 or 2 C 1-8 alkyl group(s) optionally substituted by substituent(s) selected from substituent group T, wherein the ureido group has two substituents, and they optionally form, together with the adjacent nitrogen atom, a 3- to 8-membered saturated or unsaturated aliphatic heterocyclic group optionally substituted by substituent(s) selected from substituent group T, wherein the substituent group T is a group consisting of
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom
  • Q is hydroxy, carboxy, cyano, nitro, -NR 6 R 7 , -CONR 6 R 7 , -OCONH 2 or -SO 2 NR 6 R 7 ,
  • Z 2 is -0-, -CO-, -C(OH)R 8 -, -C(-N-0R 8 )-, -S-, -SO-, -SO 2 -, -NR 8 -, -N(COR 8 )-, -N(CO 2 R 9 )-, -
  • (CH 2 ) m and (CH 2 ) n are optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated C 14 alkyl and hydroxy, and when m or n is not less than 2, a subset -
  • R and R are the same or different and each is a hydrogen atom or a CM alkyl group, or R and R form, together with a nitrogen atom, a 3- to 8-membered saturated or unsaturated aliphatic heterocyclic group optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated CM alkyl, hydroxy, optionally halogenated CM alkyloxy, C ⁇ alkyloxyrnethyl, hydroxy CM alkyl, C 1-4 alkyl-carbonyl, carboxy, CM alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, CM alkyl-carbonylamino, CM alkoxy-carbonylamino and CM alkylsulfonylamino, R is a hydrogen atom or
  • R 1 is (i) a hydrogen atom or ( ⁇ ) a group represented by the formula -X -R , wherein X 2 is a single bond, -NH- or -O-, and R is (i) a hydrogen atom, (ii) a cyano group, ( ⁇ i) a C 1-8 alkyl group, a C 2-8 alkenyl group, a C 2-8 alkynyl group, a C 1-8 alkyl-carbonyl group, a C 3-8 cycloalkyl group, a C 6-18 aryl group, a C 6-18 aryl-Cn alkyl group, a C 6-18 aryl-carbonyl group, a C 6-18 aryl-Cw alkyl-carbonyl group, a heterocyclic group (e.g., a 5- to 8-memberedheteroaryl group containing, as an atom (ring atom) constituting a ring system, 1 to 4 hetero atoms selected from
  • a carbamoyl group optionally having 1 or 2 C 1-8 alkyl group(s) optionally substituted by substituent(s) selected from substituent group T, wherein the carbamoyl group has two substituents, and they optionally form, together with the adjacent nitrogen atom, a 3- to 8-membered saturated or an unsaturated aliphatic heterocyclic group, which is optionally substituted by substituent(s) selected from substituent group T, or R 1 and R 2 , or R 2 and R 3 are optionally bonded to form a saturated or unsaturated 4- to 8-membered heterocycle optionally substituted by 1 to 5 substituents selected from substituent group T.
  • the compound (I) that is an AMPK activator and to be at least one of compounds administered to a mammal to protect heart in this method may be a compound (Ia) represented by the following formula [20], a salt thereof, or a prodrug thereof [21] (sometimes collectively to be referred to as compound (fa) in the present specification):
  • R a is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom,
  • R a is an optionally substituted group bonded via a carbon atom or a sulfur atom, or R a and R 2 * 1 , or R 2 * 1 and R 3a are optionally bonded to form an optionally substituted ring structure, R 3a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R 3a is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure, B a is an optionally substituted benzene ring, and C a is an optionally substituted C 6-18 aryl group, 5 [22] a compound of the compound (Ta) [20], wherein
  • Q is hydroxy, carboxy, cyano, nitro, -NR 6 R 7 , -CONR 6 R 7 , -OCONH 2 or -SO 2 NR 6 R 7 ,
  • R 6 and R 7 are the same or different and each is a hydrogen atom or a CM alkyl group, or R 6 and R 7 are bonded to form, together with a nitrogen atom, a 3- to 8-membered saturated or unsaturated aliphatic heterocyclic group,
  • R 8 is a hydrogen atom or a C 1-4 alkyl group
  • R 9 is a CM alkyl group
  • B a is a benzene ring optionally substituted by 1 to 4 substituents selected from halogen, C 1 ⁇ alkyl, hydroxy-Ci4 alkyl and Q 4 alkyloxy;
  • C a is a phenyl group optionally substituted by 1 to 5 substituents selected from
  • heterocycle-Q- 4 alkyl preferably, 5- to 8-membered heterocycle-C ⁇ alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like
  • R is a Q-8 alkyl group, a C 2-8 alkenyl group or a C 2-8 alkynyl group, each of which is optionally substituted by substituent(s) selected from (a) hydroxy,
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C 14 alkyl, optionally oxidized C 14 alkylthio, -CO-C 14 alkyl, -
  • n is an integer of 1 to 4
  • R and R are the same or different and each is a hydrogen atom or a C 14 alkyl group
  • R 8 is a hydrogen atom or a C 14 alkyl group
  • R 3a is a hydrogen atom or a C 1-6 alkyl group; or R la and R 211 are optionally bonded to form
  • R 211 and R 3a are optionally bonded to form C 24 alkylene optionally substituted by an imino group, i o particularly preferably, R 28 is a C 1-8 alkyl group, a C 2-8 alkenyl group or a C 2-8 alkynyl group (particularly, a C 1-8 alkyl group), each of which is optionally substituted by substituent(s) selected from
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C 14 alkyl, optionally oxidized C 14 alkylthio, -CO-C 14 alkyl,
  • n is an integer of 1 to 4
  • R 6 and R 7 are the same or different and each is a hydrogen atom or a C 14 alkyl group
  • R is a hydrogen atom or a C 14 alkyl group
  • B a is a benzene ring optionally substituted by 1 to 4 substituents selected from halogen and optionally halogenated C 14 alkyl;
  • C a is a phenyl group substituted by 1 to 5 substituents selected from
  • heterocycle-C 14 alkyl preferably, 5- to 8-membered heterocycle-C ⁇ alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like
  • R a is a hydrogen atom
  • R ⁇ is a C 1-8 alkyl group, a C 2-8 alkenyl group or a C 2-8 alkynyl group, each of which is substituted by substituent(s) selected from (a) hydroxy,
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C 14 alkyl, optionally oxidized C 14 alkylthio, -CO-C 14 alkyl, -
  • R la and R 2a are optionally bonded to form
  • R ⁇ and R 3a are optionally bonded to form C 24 alkylene, particularly preferably, R 2 * 1 is a C 1-8 alkyl group, a C 2-8 alkenyl group or a C 2-8 alkynyl group (particularly, a C 1-8 alkyl group), each, of which is substituted by substituent(s) selected from 5 (a) hydroxy,
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C 14 alkyl, optionally oxidized C 14 alkylthio, -CO-C 14 alkyl, -
  • R 2a is (i) a C 5-8 alkyl group substituted by hydroxy
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by o substituent(s) selected from hydroxy, C 14 alkyl, optionally oxidized C 14 alkylthio, -CO-C 14 alkyl, -
  • n is an integer of 1 to 4
  • R is a hydrogen atom or a Ci 4 alkyl group
  • (CH 2 ) n is optionally substituted by Ci 4 alkyl or hydroxy, (i ⁇ ) a C 2-8 alkenyl group optionally substituted by hydroxy, or (iv) a C 2-8 alkynyl group optionally substituted by hydroxy, particularly preferably, R 2a is (i) a C 5-8 alkyl group substituted by hydroxy, ( ⁇ ) a C 1-8 alkyl group substituted by substituent(s) selected from 5 (a) halogenated CM alkyloxy,
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, CM atkyl, optionally oxidized C 14 alkylthio, -CO-C 1-4 alkyl, -
  • n is an integer of 1 to 4
  • R is a hydrogen atom or a C 14 alkyl group, (i ⁇ ) a C 2-8 alkenyl group optionally substituted by hydroxy, or
  • R a is (i) a hydrogen atom or
  • R 4 is (i) a hydrogen atom
  • a C 1-8 alkyl group (i ⁇ ) a C 1-8 alkyl group, a C 2-8 alkenyl group, a C 2-8 alkynyl group, a C 1-8 alkyl-carbonyl group, a C 3-8 cycloalkyl group, a C 6-18 aryl group, a C 6-18 aryl-C 14 alkyl group, a C 6-18 aryl-carbonyl group, a C 6-18 aryl-C 14 alkyl-carbonyl group, a heterocyclic group (e.g., a 5- to 8-membered heteroaryl group containing, as an atom (ring atom) constituting a ring system, 1 to 4 hetero atoms selected from an oxygen atom, an optionally oxidized sulfur atom and a nitrogen atom (preferably, an oxygen atom, a sulfur atom and a nitrogen atom) or a saturated or unsaturated aliphatic heterocyclic group), a heterocycle-Q. 4 alky
  • R 2 * 1 is (i) a hydrogen atom, (ii) a C 1-8 alkyl group, a C 2-8 alkenyl group, a C 2-8 alkynyl group, a C 1-8 alkyl-carbonyl group, a C 1-8 alkylsulfonyl group, a C 3-8 cycloalkyl group, a C 6-18 aryl group, a C 6-18 aryl-Q- 4 alkyl group, a C 6-1 S aryl-carbonyl group, a
  • a carbamoyl group optionally having 1 or 2 C 1-8 alkyl group(s) optionally substituted by substituent(s) selected from substituent group T, wherein the carbamoyl group has two substituents, and they optionally form, together with the adjacent nitrogen atom, a 3- to 8-membered saturated or an unsaturated aliphatic heterocyclic group, which is optionally substituted by substituent(s) selected from substituent group T, or
  • R la and R ⁇ , or R 2a and R 3a are optionally bonded to form a saturated or unsaturated 4- to 8- membered heterocycle optionally substituted by 1 to 5 substituents selected from substituent group
  • R a is (i) a hydrogen atom, or
  • R 3a is optionally bonded to a carbon atom of the adjacent phenyl group to form a saturated or unsaturated 4- to 8-membered nitrogen-containing heterocycle, which is optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, CM alkyloxy, CM alkyl-carbonyl, carboxy, CM alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, CM alkyl-carbonylamino, CM alkoxy- i o carbonylamino and CM alkylsulfonylamino,
  • B a is a benzene ring optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated CM alkyl, hydroxy, optionally halogenated CM alkyloxy, CM alkyloxymethyl, hydroxy-C M alkyl, CM alkyl-carbonyl, carboxy, CM alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, CM alkyl-carbonylamino, CM alkoxy-carbonylamino and CM
  • C a is a C 6-18 aryl group optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated CM alkyl, hydroxy, optionally halogenated CM alkyloxy, CM alkyloxymethyl, hydroxy-C M alkyl, CM alkyl-carbonyl, carboxy, CM alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, CM alkyl-carbonylamino, CM alkoxy-carbonylamino and CM 0 alkylsulfonylamino.
  • substituents selected from halogen, optionally halogenated CM alkyl, hydroxy, optionally halogenated CM alkyloxy, CM alkyloxymethyl, hydroxy-C M alkyl, CM alkyl-carbonyl, carboxy, CM alkoxy-carbonyl, cyano, carbamoyl, sul
  • the compound (Ia) that is an AMPK activator and to be at least one of compounds administered to a mammal to protect heart in this method may be a compound (Ia') represented by the following formula [27], a salt thereof, or a prodrug thereof [28] (sometimes collectively to be referred to as compound (Ta') in the present specification):
  • R la is a hydrogen atom
  • R ,2a is a Cw alkyl group substituted by a group represented by -NR 6a -CO-(CH 2 ) n -S ⁇ 2 -optionally halogenated C ⁇ alkyl wherein n is an integer of 1 to 4, R 6a is a hydrogen atom or a C ⁇ alkyl group, and -(CH 2 ) n - is optionally substituted by C ⁇ alkyl, ° R 3a is a hydrogen atom or a Cw alkyl group,
  • R 4a is a halogen atom or a Cw alkyl group
  • R 5a is a halogen atom or a C 1-6 alkyl group
  • X a is a hydrogen atom or a halogen atom, or a salt thereof, provided that N- [2-(4- ⁇ [3 -chloro-4-(3 -chlorophenoxy)phenyl] amino ⁇ -5H-pyrrolo[3 ,2-d]pyrimidin-
  • the "aryl” in the “aryl group” and the substituents includes a monocyclic aryl group and a fused polycyclic aryl group.
  • aryl group for example, a C 6-18 aryl group can be mentioned.
  • C 6-18 aryl group for example, phenyl, biphenylyl, naphthyl, anthryl, phenanthryl and acenaphthylenyl can be mentioned.
  • heterocyclic group for example, a 5- to 8-membered heteroaryl group or a saturated or unsaturated 5 aliphatic heterocyclic group containing, as an atom (ring atom) constituting a ring system, one or more (preferably 1 to 4, more preferably 1 or 2) hetero atoms selected from an oxygen atom, an optionally oxidized sulfur atom and a nitrogen atom and the like (preferably, an oxygen atom, a sulfur atom and a nitrogen atom etc.) can be mentioned.
  • aliphatic hydrocarbon i o group a linear or branched aliphatic hydrocarbon group having 1 to 15 carbon atom (preferably, 1 to 8 carbon atom) can be mentioned.
  • aliphatic hydrocarbon group for example, a C 1-8 alkyl group, a C 2-8 alkenyl group, a C 2-8 alkynyl group, a C 3-8 cycloalkyl group and the like can be mentioned.
  • an 15 aromatic monocyclic heterocyclic group e.g., 5- or 6-membered aromatic monocyclic heterocyclic group such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, l,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like) and an aromatic fused heterocyclic group (e.g., 5- or 6-membered aromatic monocyclic heterocyclic group such as fu
  • aromatic fused heterocyclic group a heterocycle wherein the aforementioned 5- or 6-membered aromatic monocyclic heterocyclic group is fused with a benzene ring and a heterocycle wherein the same or different two heterocycles of the aforementioned 5- or 6-membered aromatic monocyclic heterocyclic group are fused are preferable.
  • aliphatic heterocyclic group i o for example, a 3- to 8-membered (preferably 5- or 6-membered) saturated or unsaturated (preferably saturated) aliphatic heterocyclic group such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomo ⁇ holinyl, piperazinyl, dihydro-l,2,4-oxadiazolyl and the like, and the like, and the like can be mentioned.
  • oxiranyl azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiom
  • C 1-8 alkyl group for is example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t- pentyl, neopentyl, n-hexyl, i-hexyl, n-heptyl and n-octyl and the like can be mentioned, with preference given to a C 1 ⁇ alkyl group.
  • C 1 ⁇ alkyl group for example, methyl, ethyl, n-propyl, i-propyl, n-butyl and i- butyl can be mentioned.
  • C 2-8 alkenyl group for example, vinyl, (1- or 2-)propenyl, (1-, 2- or 3-)butenyl, pentenyl, octenyl and (l,3-)butadienyl can be mentioned, with preference given to a C 2 ⁇ alkenyl group.
  • C 2-8 alkynyl group for example, ethynyl, (1- or 2-)propynyl, (1-, 2- or 3-)butynyl, pentynyl and octynyl can be mentioned, with preference given to a C 24 alkynyl group.
  • C 3 . 8 cycloalkyl group for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl can be 5 mentioned, with preference given to a C 3 ⁇ cycloalkyl group.
  • CM alkylene for example, methylene, ethylene, trimethylene, tetramethylene and propylene and the hike can be mentioned.
  • -0-(CM alkylene)- for example, -OCH 2 -, -OCH 2 CH 2 -, -O(CH 2 ) 3 -, -O(CH 2 ) 4 -, -OCH(CH 3 )-, -OC(CH 3 ) 2 -, i o -OCH(CH 3 )CH 2 -, -OCH 2 CH(CH 3 )-, -OC(CH 3 ) 2 CH 2 - and -OCH 2 C(CH 3 ) 2 - and the like can be mentioned.
  • C 6-18 aryl-carbonyl group for example, benzoyl, naphthoyl, anthrylcarbonyl, phenanthrylcarbonyl and acenaphthylenylcarbonyl and the like can be mentioned.
  • C 6-18 aryl-C ⁇ alkyl-carbonyl group for example, benzylcarbonyl, 3-phenylpropionyl, 2-phenylpropionyl, 4-phenylbutyryl and 5-phenylpentanoyl and the like can be mentioned.
  • halogen fluorine, chlorine, bromine and iodine can be mentioned.
  • halogen fluorine, chlorine, bromine and iodine
  • a 5- to 8-membered cyclic amino-carbonyl group optionally having 1 or 2 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom is preferable, for example, pyrrolidin-1-ylcarbonyl, piperidin-1- ylcarbonyl, piperazin-1-ylcarbonyl, morpholin-4-ylcarbonyl, thiomorpholin-4-ylcarbonyl and the like can be mentioned.
  • aryl group for A, a C 6-18 aryl group is preferable, and phenyl is more preferable.
  • the "aryl group” is optionally substituted by a group of the formula -Y -B, wherein Y is a single bond, -O-, -0-(C 1-3 alkylene)- (preferably -OCH 2 -), -NH- or -S-, and B is an aryl group, a heterocyclic group, a C 3-8 cycloalkyl group, a carbamoyl group, a ureido group, a C 6-18 aryl-carbonyl group or a C 6-18 aryl-Ci 4 alkyl-carbonyl group, each of which is optionally substituted.
  • Y a single bond, -O- or -OCH 2 - is preferable, and -O- or -OCH 2 - is more preferable.
  • aryl group for B, a C 6-18 aryl group is preferable, and phenyl is more preferable.
  • heterocyclic group for B, the aforementioned “5 or 6-membered aromatic monocyclic heterocyclic group” is preferable, and pyridyl is more preferable.
  • the "aryl group”, “heterocyclic group”, “C 6-18 aryl-carbonyl group” or “C 6-18 aryl-C ⁇ alkyl-carbonyl group” for B may have, for example, 1 to 5, the same or different substituents selected from halogen, optionally halogenated C ⁇ alkyl, hydroxy, optionally halogenated C M alkyloxy, C 1 ⁇ alkyloxymethyl, hydroxy-Cw alkyl, C 1-4 alkyl-carbonyl, carboxy, C 1 ⁇ alkoxy- carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C 14 alkyl-carbonylamino, CM alkoxy- carbonylamino and C 1 ⁇ alkylsulfonylamino, at any substitutable position(s).
  • the "aryl group” for A may have, besides a group of the above-mentioned formula -Y -B, 1 to 5, the same or different substituents at any substitutable position(s).
  • substituents similar to those exemplified for "aryl group” or “heterocyclic group” for B can be mentioned.
  • aliphatic hydrocarbon group for R , a C 1-8 alkyl group, a C 2-8 alkenyl group, a C 2-8 alkynyl group and a C 3-8 cycloalkyl group are preferable.
  • the "aliphatic hydrocarbon group" for R is optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, C 14 alkyloxy, C 14 alkyl-carbonyl, carboxy, CM alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C 14 alkyl-carbonylamino, C 14 alkoxy-carbonylamino and Cj 4 alkylsulfonylamino.
  • C 1-4 alkylene and "-0-(C 14 alkylene)-" for Y 1 are optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, C 14 alkyloxy, C 14 alkyl-carbonyl, carboxy, C 14 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C 14 alkyl-carbonylamino, C 14 alkoxy- carbonylamino and C 14 alkylsulfonylamino.
  • substituents selected from halogen, hydroxy, C 14 alkyloxy, C 14 alkyl-carbonyl, carboxy, C 14 alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C 14 alkyl-carbonylamino, C 14 alkoxy- carbonylamino and C 14 alkylsulfonylamino.
  • a group of the formula -X -R can be mentioned, wherein X is a single bond, -NH- or -O-, and R is a hydrogen atom, a cyano group, or a C 1-8 alkyl group, a C 2-8 alkenyl group, a C 2-8 alkynyl group, a carbamoyl group, a C 1-8 alkyl-carbonyl group, a C 3-8 cycloalkyl group, a C 6-18 aryl group, a C 6-18 aryl-C 14 alkyl group, a C 6-18 aryl-carbonyl group, a C 6-18 aryl-C 14 alkyl-carbonyl group, a heterocyclic group, aheterocycle-C 14 alkyl group, aheterocycle-carbonyl group or a heterocycle-C 14 al
  • C 1-8 alkyl group "C 2-8 alkenyl group”, “C 2-8 alkynyl group”, “C 1-8 alkyl-carbonyl group”, “C 3-8 cycloalkyl group”, “C 6-18 aryl group”, “C 6-18 aryl-C 14 alkyl group”, “C 6-18 aryl- carbonyl group”, “C 6-18 aryl-C 14 alkyl-carbonyl group”, “heterocyclic group", “heterocycle-C M alkyl group”, “heterocycle-carbonyl group” and “heterocycle-C ⁇ alkyl-carbonyl group” are, for example, optionally substituted by one or more (preferably 1 to 5, more preferably 1 to 3) substituent(s) selected from (a) halogen,
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom
  • substituent group T (1) -(CH ⁇ m -Z ⁇ H ⁇ n -Z ⁇ H ⁇ n -Z ⁇ C M alkyl (hereinafter to be sometimes to be referred to as substituent group T).
  • m is an integer of 0 to 4
  • n is an integer of 1 to 4
  • Q is hydroxy, carboxy, cyano, nitro, -NR 6 R 7 , -CONR 6 R 7 or -SO 2 NR 6 R 7
  • R and R are the same or different and each is a hydrogen atom or CM alkyl, or R 6 and R 7 form a ring together with a nitrogen atom.
  • R 8 is a hydrogen atom or Q 4 alkyl and R 9 is C 1 4 alkyl.
  • R 6 and R 7 form a ring together with a nitrogen atom
  • a nitrogen-containing heterocyclic group for example, a 3 to 8-membered (preferably 5 or 6-membered) saturated or unsaturated (preferably saturated) aliphatic heterocyclic group such as azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, heptamethyleneimino, morpholinyl, thiomorphoUnyl, piperazinyl, homopiperazinyl and the like, and the like can be mentioned.
  • R a hydrogen atom or a C 1-8 alkyl group, a C 2-8 alkenyl group, a C 6-18 aryl group or heterocyclic group, each of which is optionally substituted is preferable.
  • C 648 aryl group phenyl is preferable.
  • heterocyclic group for R 4 , the aforementioned “5 or 6- membered aromatic monocyclic heterocyclic group” is preferable, and furyl is preferable.
  • Ci-4 alkyl-carbonyl group each of which is optionally substituted, can be mentioned.
  • the "Q- 8 alkyl group”, “C 2-8 alkenyl group”, “C 2-8 alkynyl group”, “C 1-8 alkyl-carbonyl group”, “C 1-8 alkylsulfonyl group”, “C 3-8 cycloalkyl group”, “C 6-18 aryl group”, “C 6-18 aryl-C ⁇ alkyl group”, “C 6-18 aryl-carbonyl group”, “C 6-18 aryl-C ⁇ alkyl-carbonyl group”, “C 6-18 aryl-sulfonyl group”, "heterocyclic group", “heterocycle-C ⁇ alkyl group”, “heterocycle-carbonyl group” and 5 "heterocycle-C ⁇ alkyl-carbonyl group” are optionally substituted by, for example, one or more (preferably 1 to 5, more preferably 1 to 3) substituents selected from the above-menti
  • R 2 a hydrogen atom or a C 1-8 alkyl group, a C 6-18 aryl group, a C 6-18 aryl-C ⁇ alkyl group, a C 6-18 aryl-carbonyl group, a C 6-18 aryl-sulfonyl group or heterocycle-Cw alkyl group, each of i o which is optionally substituted, is preferable.
  • phenyl is preferable.
  • C 6-18 aryl-Cw alkyl group for R
  • benzyl is preferable.
  • C 6-18 aryl-carbonyl group for R
  • benzoyl is preferable.
  • C 6-18 aryl-sulfonyl group for R 2 , phenylsulfonyl is preferable.
  • heterocyclic group or “heterocycle-” of “heterocycle-C ⁇ alkyl group”, “heterocycle-carbonyl group” and “heterocycle- 15 Q 4 alkyl-carbonyl group” for R 2
  • the aforementioned "5 or 6-membered aromatic monocyclic heterocyclic group” or the aforementioned “aliphatic heterocyclic group” is preferable, and furyl or tetrahydrofuryl is preferable.
  • a group represented by R may have, when R and R form a ring together with a nitrogen atom, the "ring” optionally further has 1 to 5 (preferably 1 to 3) the same or 0 different substituents.
  • substituents similar to those exemplified for "aryl group” or “heterocyclic group” for B can be mentioned.
  • the aforementioned “carbamoyl group” and “ureido group” optionally have 1 or 2 optionally substituted C 1-8 alkyl group(s).
  • the “carbamoyl group” and “ureido group” may have two substituents and they may form an optionally substituted ring, together with the adjacent nitrogen atom.
  • rings similar to those formed by R 6 and R 7 together with a nitrogen atom as exemplified above can be mentioned.
  • carbamoyl, C 1-8 alkylcarbamoyl, di(C 1-8 alkyl)carbamoyl, C 6-18 aryl-C ⁇ alkylcarbamoyl, azetidin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, piperazin-1-ylcarbonyl, morpholin-4-ylcarbonyl, thiomorpholin-4- ylcarbonyl, (C ⁇ alkyl)piperidin-l-ylcarbonyl, (C 6-18 aryl-Cw alkyl)piperidin-l-ylcarbonyl and the like can be mentioned.
  • ureido 3-(C 1-8 alkyl)ureido, 3,3-di(C 1-8 alkyl)ureido, 3-(C 6-18 aryl-C ⁇ alkyl)ureido, azetidine-1-ylcarbonylarnino, pyrrolidin-1- ylcarbonylamino, piperidin-1-ylcarbonylamino, piperazin-1-ylcarbonylamino, rnorpholin-4- ylcarbonylamino, thiomo ⁇ holin-4-ylcarbonylamino, (CM alkyl)piperidin- 1 -ylcarbonylamino, (C 6 . I8 aryl-Q- 4 alkyl)piperidin-l -ylcarbonylamino and the like can be mentioned.
  • ring structure of the optionally substituted ring structure formed by R 3 bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A
  • a saturated or unsaturated (preferably saturated) 4- to 8-membered (preferably 5- or 6-membered) nitrogen- containing heterocycle can be mentioned.
  • the "ring structure” may have 1 to 5 (preferably 1 to 3, more preferably 1 or 2) the same or different substituents at any substitutable position(s).
  • substituents similar to those exemplified for "aryl group” or “heterocyclic group” for B can be mentioned.
  • ring structure of the optionally substituted ring structure formed by R 1 and R 2 bonded to each other, a saturated or unsaturated (preferably saturated) 4- to 8-membered (preferably 5- or 6-membered) heterocycle can be mentioned.
  • R and R 2 are bonded to form an optionally substituted ring structure, for example,
  • ring structure of the optionally substituted ring structure formed by R 2 and R 3 bonded to each other, a saturated or unsaturated (preferably saturated) 4- to 8-membered (preferably 5- to 7-membered) heterocycle can be mentioned.
  • R 2 and R 3 are bonded to form an optionally substituted ring structure, for example,
  • R 1 and R 2 , or R 2 and R 3 bonded to each other may have 1 to 5 (preferably 1 to 3, more
  • compound (T) is represented by the following formula (TB) or (IC):
  • the compound (I) the following compound (Ia) and the like are preferably
  • R la is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom
  • R 2 * 1 is an optionally substituted group bonded via a carbon atom or a sulfur atom, or
  • R a and R , or R 28 and R 3a are optionally bonded to form an optionally substituted ring structure
  • R 3a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R 3a is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure
  • B a is an optionally substituted benzene ring
  • C a is an optionally substituted C 6-18 aryl group, or a salt thereof.
  • substituent of the "optionally substituted benzene ring" for B a for example, 1 to 5, the same or different substituents selected from halogen, optionally halogenated CM alkyl, hydroxy, optionally halogenated Q 4 alkyloxy, Q 4 alkyloxymethyl, hydroxy-C ⁇ alkyl, C 1 ⁇ alkyl-carbonyl, carboxy, C 1 ⁇ alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C 1-4 alkyl- carbonylamino, C 1 ⁇ alkoxy-carbonylamino and C 1-4 alkylsulfonylamino can be used.
  • C 6-18 aryl group of the "optionally substituted C 6-18 aryl group” for C a for example, phenyl, biphenylyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like can be used, with preference given to a phenyl group.
  • substituted C 6-18 aryl group for C a those similar to the substituents of the "optionally substituted benzene ring" for B a can be used.
  • a C 1-8 alkyl group a C 2-8 alkenyl group, a C 2-8 alkynyl group, a carbamoyl group, a C 1-8 alkyl-carbonyl group, a C 1-8 alkylsulfonyl group, a C 3-8 cycloalkyl group, a C 6-18 aryl group, a C 6-18 aryl-Ci 4 alkyl group, a C 6-I8 aryl-carbonyl group, a C 6-18 aryl-C ⁇ alkyl-carbonyl group, a C 6-18 aryl-sulfonyl group, a heterocyclic group, a heterocycle-Q- 4 alkyl group, a heterocycle-carbonyl group or a heterocycle-C ⁇ alkyl-carbonyl group, each of which is optionally substituted by 1 to 5 substituents selected from
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom
  • R and R are the same or different and each is a hydrogen atom or a C 1-4 alkyl group, or R and R are bonded to form, together with a nitrogen atom, a 3- to 8-membered saturated or unsaturated aliphatic heterocyclic group,
  • R is a hydrogen atom or CM alkyl, and R is CM alkyl, is preferable.
  • compound (Ia) a compound wherein
  • B a is a benzene ring optionally substituted by 1 to 4 substituents selected ftom halogen, C 1-4 alkyl, hydroxy-Ci 4 alkyl and CM alkyloxy;
  • C a is a phenyl group optionally substituted by 1 to 5 substituents selected from (i) halogen, (ii) i o optionally halogenated CM alkyl, (iii) hydroxy-C ⁇ alkyl, (iv) heterocycle-C ⁇ alkyl (preferably, 5- to 8-membered heterocycle-Ci- 4 alkyl, said 5- to 8-membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like), (v) optionally halogenated CM alkyloxy, (vi) CM alkyl-carbonyl,
  • R 2a is a Ci- 8 alkyl group, a C 2 -g alkenyl group or a C 2 .g alkynyl group, each of which is optionally substituted by substituent(s) selected from
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C 14 alkyl, optionally oxidized C 14 alkylthio, -CO-C 14 alkyl, - 0 CO-O-C 14 alkyl, -CO-NH-C 14 alkyl,
  • n is an integer of 1 to 4
  • R 6 and R 7 are the same or different and each is a hydrogen atom or a C 14 alkyl group
  • R is a hydrogen atom or a C 14 alkyl group
  • R 3a is a hydrogen atom or a Cw alkyl group; or R la and R 2 * are optionally bonded to form
  • R 2 * 1 and R 3a are optionally bonded to form C 24 alkylene optionally substituted by an irnino group is preferable.
  • R 8 a hydrogen atom, methyl, ethyl and the like are preferable, and a hydrogen atom is particularly preferable.
  • R a C 1-8 alkyl group, a C 2-8 alkenyl group or a C 2-8 alkynyl group, each of which is optionally substituted by substituent(s) selected from
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by i o substituent(s) selected from hydroxy, C 14 alkyl, optionally oxidized C 14 alkylthio, -CO-C 14 alkyl, -
  • R and R are the same or different and each is a hydrogen atom or a C 14 alkyl group
  • R 8 is a hydrogen atom or a C 14 alkyl group
  • R 8 a hydrogen atom, methyl, ethyl and the like are preferable, and a hydrogen atom is particularly preferable.
  • B a is a benzene ring optionally substituted by 1 to 4 substituents selected from halogen and optionally halogenated C 14 alkyl;
  • 0 C a is a phenyl group substituted by 1 to 5 substituents selected from (i) halogen, (ii) optionally halogenated C 14 alkyl, (Mi) hydroxy-C 14 alkyl, (iv) heterocycle-C 14 alkyl (preferably, 5- to 8- membered heterocycle-C 14 alkyl, said 5- to 8-membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like), (v) optionally halogenated C 14 alkyloxy, (vi) cyano, and (vii) carbamoyl optionally substituted by C 1-8 alkyl;
  • R la is a hydrogen atom;
  • R ⁇ is a C 1-8 alkyl group, a C 2-8 alkenyl group or a C 2-8 alkynyl group, each of which is substituted by substituent(s) selected from
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an i o oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C 14 alkyl, optionally oxidized C 14 alkylthio, -CO-C 1-4 alkyl, -
  • n is an integer of 1 to 4
  • R and R 7 are the same or different and each is a hydrogen atom or a C 14 alkyl group
  • R 8 is a hydrogen atom or a C 14 alkyl group
  • (CH 2 ) n is optionally substituted 15 by C 14 alkyl or hydroxy
  • R 3a is a hydrogen atom or a C 1 ⁇ alkyl group
  • R la and R 28 are optionally bonded to form
  • R 2 * 1 and R 3a are optionally bonded to form C 24 alkylene, is preferable.
  • R 28 a C 1-8 alkyl group, a C 2-8 alkenyl group or a C 2-8 alkynyl group (particularly, a C 1-8 alkyl group), each of which is substituted by substituent(s) selected from (a) hydroxy,
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C 14 alkyl, optionally oxidized CM alkylthio, -CO-C 14 alkyl, - CO-NH-C 14 alkyl, -CONH 2 , -SO 2 -C 14 alkyl, -SO 2 -NH-C 14 alkyl, -SO 2 NH 2 and the like), wherein n is an integer of 1 to 4, R and R are the same or different and each is a hydrogen atom or a C 14 alkyl group, R is a hydrogen atom or a C 14 alkyl group, is preferable.
  • R 2 * 1 (i) a C 5 - S alkyl group
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, Ci 4 alkyl, optionally oxidized C 14 alkylthio, -CO-C 14 alkyl, - is CO-NH-Ci 4 alkyl, -CONH 2 , -SO 2 -C 14 alkyl, -SO 2 -NH-C 14 alkyl, -SO 2 NH 2 and the like), wherein n is an integer of 1 to 4, R 8 is a hydrogen atom or a C 14 alkyl group, and (CH 2 ) n is optionally substituted by C 14 alkyl or hydroxy, (i ⁇ ) a C 2-8 alkenyl group optionally substituted by hydroxy, or (iv)
  • heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, CM alkyl, optionally oxidized C ⁇ alkylthio, -CO-CM alkyl, - CO-NH-C 14 alkyl, -CONH 2 , -SO 2 -C 14 alkyl, -SO 2 -NH-Ci 4 alkyl, -SO 2 NH 2 and the like), wherein n is an integer of 1 to 4, and R is a hydrogen atom or a Ci 4 alkyl group, (i ⁇ ) a C 2-8 alkenyl group optionally substituted by hydroxy, or
  • a C 2-8 alkynyl group optionally substituted by hydroxy is preferable, and as R , a hydrogen atom, methyl, ethyl and the like are preferable, and a hydrogen atom is particularly preferable.
  • compound (T) preferred is a compound wherein A is an aryl group substituted by a group of the formula -Y -B and optionally further substituted, wherein Y is a single bond, -0-, -OCH 2 -, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C 3-8 cycloalkyl group, a i o carbamoyl group, a ureido group, a C 6-I8 aryl-carbonyl group or a C 6-18 aryl-C 14 alkyl-carbonyl group, each of which is optionally substituted.
  • compound (T) a compound wherein W is C(R 1 ); A is an aryl group substituted by a group of the formula -Y -B, and optionally further substituted, wherein Y is a single bond, -0-, -OCH 2 -, -NH- or -S-, and B is an aryl group, a heterocyclic group,
  • R 1 is a group of the formula -X 2 -R 4 wherein X 2 is a single bond, -NH- or -0-, and R 4 is hydrogen atom or a C 1-8 alkyl group, a C 2-8 alkenyl group, a C 2-8 alkynyl group, a carbamoyl group, a C 1-8 alkyl-carbonyl group, a C 3-8 cycloalkyl group, a C 6-I8 aryl group, a C 6-I8 aryl-Ci 4 alkyl group, a C 6-I8 0 aryl-carbonyl group, a C 6-I8 aryl-Ci 4 alkyl-carbonyl group, a heterocyclic group, a heterocycle-C 14 alkyl group, a heterocycle-carbonyl group or aheterocycle-Ci 4 alkyl-carbonyl group, each of which is optionally substituted;
  • R 2 is hydrogen atom or a Ci -8 alkyl group, a C 2-8 alkenyl group, a C 2-8 alkynyl group, a carbamoyl group, a C 1-8 alkyl-carbonyl group, a C 1-8 alkylsulfonyl group, a C 3-8 cycloalkyl group, a C 6-18 aryl group, a C 6-18 aryl-C ⁇ alkyl group, a C 6-18 aryl-carbonyl group, a C 6-18 aryl-Cw alkyl-carbonyl group, a C 6-18 aryl-sulfonyl group, a heterocyclic group, aheterocycle-C ⁇ alkyl group, a heterocycle-carbonyl group or aheterocycle-C M alkyl-carbonyl group, each of which is optionally 5 substituted; and
  • X 1 is -NR 3 - wherein R 3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group can be mentioned.
  • compound (T) a compound wherein W is N;
  • X 1 is -NR 3 - wherein R 3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbono group;
  • A is an aryl group substituted by a group of the formula -Y -B and optionally further substituted wherein Y 2 is a single bond, -O-, -OCH 2 -, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C 3-8 cycloalkyl group, a carbamoyl group, a ureido group, a C 6-18 aryl-carbonyl group or a C 6-18 aryl-Cw alkyl-carbonyl group, each of which is optionally substituted; and s R is a hydrogen atom or a C 1-8 alkyl group, a C 2-8 alkenyl group, a C 2-8 alkynyl group, a carbamoyl group, a C 1-8 alkyl-carbonyl group, a C 1-8 alkylsulfonyl group, a C 3-8 cycloalkyl group, a C 6-18
  • A is an aryl group substituted by a group of the formula -Y 2 -B and optionally further substituted wherein Y 2 is a single bond, -O-, -OCH 2 -, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C 3-8 cycloalkyl group, a carbamoyl group, a ureido group, a C 6-18 aryl-carbonyl group or a C 6-18 aryl-Ci 4 alkyl-carbonyl group, each of which is optionally substituted; and R 2 and R 3 are bonded to form an optionally substituted ring structure can be mentioned.
  • a compound that is an AMPK activator and to be administered to a mammal to protect heart thereof in this method may be N- ⁇ 2-[4-( ⁇ 3-chloro-4-[3-(trifluoromethyl)phenoxy] phenyl ⁇ ammo)-5H-py ⁇ olo[3,2-d]pyrirmdin-5-yl]ethyl ⁇ -3-hydroxy-3-methylbutanara thereof, or a prodrug thereof.
  • compound (T), compound (Ia), compound (Ia'), or N- ⁇ 2-[4-( ⁇ 3-chloro-4-[3- (1rmuorome1hyl)phenoxy] phenyl ⁇ arr ⁇ methylbutanamide has an isomer such as optical isomer, stereoisomer, positional isomer, rotational isomer and the like, any isomers and mixtures of the compound are encompassed in compound (T), compound (Ia), compound (Ia'), orN- ⁇ 2-[4-( ⁇ 3-chloro-4-[3-(rrifluoromethyl)phenoxy] phenyl ⁇ amino)-5H-pyrrolo[3,2-d]pyrirr ⁇ din-5 ⁇ yl]e ⁇ respectively.
  • the optical isomer when the compound has an optical isomer, an optical isomer separated from aracemate, the optical isomer is also encompassed in compound (T), compound (Ia), compound (Ia'), or N- ⁇ 2-[4-( ⁇ 3-chloro-4-[3-(trifluoromethyl)phenoxy] phenyl ⁇ amino)-5H- pyi ⁇ olo[3,2-d]pyrrrnidin-5-yl]e1hyl ⁇ -3-hydroxy-3-me1hylbutanamide, respectively.
  • These isomers can be obtained as independent products by a synthesis means or a separation means (concentration, solvent extraction, column chromatography, recrystallization and the lrke) known per se.
  • the compound may be a crystal, and both a single crystal and crystal mixtures, which are encompassed in the compound (T), compound (Ia), compound (Ta'), or N- ⁇ 2-[4-( ⁇ 3-chloro-4-[3-
  • the crystals can be produced by crystallization according to crystallization methods knom ⁇ er se.
  • the compound may be a solvate (e.g., hydrate etc.) or a non-solvate, both of which are encompassed in the compound (T), compound (Ta), compound (Ia'), orN- ⁇ 2-[4-( ⁇ 3-chloro-4-[3- (trifluoromethyl)phenoxy] phenyl ⁇ amino)-5H-pyrrolo[3 ,2-d]pyrirnidin-5-yl]ethyl ⁇ -3 -hydroxy-3 - methylbutanamide, respectively.
  • the compound labeled with an isotope (e.g., 3 H, 14 C, 35 S, 125 I and the like) is also encompassed in the compound (T), compound (Ta), compound (Ia'), or N- ⁇ 2 ⁇ [4 ⁇ ( ⁇ 3-chloro-4-[3- (tr ⁇ luorome1hyl)phenoxy] phenyl ⁇ ammo)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl ⁇ -3-hydroxy-3- methylbutanamide, respectively.
  • an isotope e.g., 3 H, 14 C, 35 S, 125 I and the like
  • salts of the compounds represented by the compound (T), compound (Ta), compound (Ia'), mdN- ⁇ 2-[4-( ⁇ 3-cMoro4-[3-(trifiuorome1hyl)phenoxy] phenyl ⁇ amino)-5H-pyrrolo[3,2- d]pvrirr ⁇ dm-5-yl]ethyl ⁇ -3-hydroxy-3-methylbutanamide for example, metal salt, ammonium salt, salts with organic base, salts with inorganic acid, salts with organic acid, salts with basic or acidic amino acid and the like can be mentioned.
  • the metal salt for example, alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt, barium salt and the like; aluminum salt and the hike can be mentioned.
  • the salts with organic base for example, salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolarnine, triethanolamine, tromethamine [rris(hydroxymethyl)methylamine], t-butylamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine and the like can be mentioned.
  • salts with inorganic acid for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like can be mentioned.
  • the salts with organic acid for example, salts with formic acid, acetic acid, trifiuoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like can be mentioned.
  • salts with basic amino acid for example, salts with 5 arginine, lysine, ornithine and the like can be mentioned, and as preferable examples of the salts with acidic amino acid, for example, salts with aspartic acid, glutamic acid and the like can be mentioned.
  • inorganic salts such as alkali metal salts (e.g., sodium salt, o potassium salt etc.), alkaline earth metal salts (e.g., calcium salt, magnesium salt, barium salt etc.) and the like, ammonium salt and the like
  • a compound contains a basic functional group
  • salts with inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like
  • organic acid such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic 5 acid, p-toluenesulfonic acid and the like
  • organic acid such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic 5 acid, p-toluenesulf
  • a prodrug of the compounds represented by the compound (T), compound (Ia), compound (Ia'), and N- ⁇ 2-[4-( ⁇ 3-chloro-4-[3-(trifluoromethyl)phenoxy] phenyl ⁇ amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethyl ⁇ -3-hydroxy-3-methylbutanamide, or a salt thereof means a compound that is converted to the o compound in this invention with a reaction due to an enzyme, an gastric acid, etc. under the physiological condition in the living body, that is, a compound that is converted to the compound in this invention with oxidation, reduction, hydrolysis, etc.
  • a prodrug for the compound in this invention may be a compound obtained by subjecting an amino group in the compound in this invention to an acylation, alkylation or phosphorylation (e.g., a compound obtained by subjecting an amino group in the compound in this invention to an eicosanoylation, danylation, pentylaminocarbonylation, (5-methyl-2-oxo-l,3- ⁇ loxolen-4-yl)me1hoxycarbonylation, 5 tetrahydroruranylation, pyrrolidylmethylation, pivaloyloxymethylation and tert-butylation, etc.); a compound obtained by subjecting a hydroxy group in the compound in this invention to an acylation, alkylation, phosphorylation or boration (e.g., a compound obtained by subjecting an hydroxy group in the compound in this invention to an acet
  • a prodrug for the compound in this invention may also be one which is converted into the compound in this invention under a physiological condition, such as those described in IYAKUHIN 0 no KAIHATSU (Development of Pharmaceuticals ⁇ , Vol. 7, Design of Molecules, p.163-198, Published by HIROKAWA SHOTEN (1990).
  • the compound in this invention which is the AMPK activator and activates the AMPK, also possesses tyrosine kinase-inhibiting activity and can be used for the prophylaxis or treatment of tyrosine kinase-dependent diseases in mammals.
  • Tyrosine kinase-dependent diseases include diseases characterized by increased cell proliferation due to abnormal tyrosine kinase enzyme activity.
  • compounds that have the tyrosine kinase-inhibiting activity and may trap transcriptional activators in the nucleus, and these tyrosine kinase inhibitors affect transcription of genes.
  • the compound in this invention does not affect such protein export of the transcriptional activators from nucleus and does not affect the gene transcription.
  • the compound in this invention specifically inhibits EGFR and ErbB2 receptor tyrosine kinase and is therefore also useful as a therapeutic agent for suppressing the growth of ErbB2 and/or EGFRkinase-expressing cancer, or a preventive agent for preventing the transition of hormone-dependent cancer to hormone- independent cancer.
  • the compound in this invention is useful in a pharmaceutical composition because it shows low toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity and the like), high water solubility, and is superior in stability, pharmacokinetics (absorption, distribution, metabolism, excretion and the like) and efficacy expression. Accordingly, the compound in this invention can be safely used in a pharmaceutical composition not only for protection of the heart of mammals but also for the prophylaxis or treatment of diseases due to abnormal cell proliferation such as various cancers, atherosclerosis, angiogenesis, and viral diseases, and cardiovascular diseases associated with abnormal tyrosine kinase enzyme activity such as restenosis, (HTV infection etc.).
  • diseases due to abnormal cell proliferation such as various cancers, atherosclerosis, angiogenesis, and viral diseases, and cardiovascular diseases associated with abnormal tyrosine kinase enzyme activity such as restenosis, (HTV infection etc.).
  • the pharmaceutical composition for heart protection for a mammal contains at least one of the compound (1), preferably, at least one of the compound (Ia) or compound (Ia'), orN- ⁇ 2-[4-( ⁇ 3-chloro-4-[3-(trifiuoromethyl) phenoxy]phenyl ⁇ amino)-5H- pvrrolo[3,2-d]pyrimidin-5-yl]ethyl ⁇ -3-hydrox ⁇ a salt thereof, or a prodrug thereof.
  • the pharmaceutical composition can be used in admixture with a commonly known pharmaceutically acceptable carrier etc. in mammals (e.g., humans, horses, bovines, dogs, cats, rats, mice, rabbits, pigs, monkeys, and the like).
  • said pharmaceutical composition may contain other active ingredients, e.g., the following hormonal therapeutic agents, anticancer agent (e.g., chemotherapeutic agents, immunotherapeutic agents, or pharmaceutical agents inhibiting the action of cell growth factors or cell growth factor receptors), and the like.
  • active ingredients e.g., the following hormonal therapeutic agents, anticancer agent (e.g., chemotherapeutic agents, immunotherapeutic agents, or pharmaceutical agents inhibiting the action of cell growth factors or cell growth factor receptors), and the like.
  • the compound in this invention i o can be administered orally in the form of, for example, tablets, capsules (including soft capsules and microcapsules), powders, granules and the like, or parenterally in the form of injections, suppositories, pellets and the like.
  • parenteral administration route include intravenous, intramuscular, subcutaneous, intra-tissue, intranasal, intradermal, instillation, intracerebral, intrarectal, intravaginal, intraperitoneal, intratumoral, juxtaposition of tumor and
  • the dose of the compound in this invention varies depending on the route of administration, a type of a mammal, a type of a heart damages from which the heart is protected, other existing diseases, symptoms, a form of the compound in this invention to be administered, etc.
  • a human patient body weight 40 to

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Abstract

La présente invention porte sur un procédé de protection du cœur d'un mammifère par l'administration à un mammifère d'un activateur de protéine kinase activée par AMP comprenant son sel ou un promédicament, une composition pharmaceutique contenant au moins l'activateur AMPK pour une protection cardiaque, l'utilisation de l'activateur AMPK pour préparer la composition pharmaceutique pour la protection cardiaque, un procédé d'activation de l'AMPK par administration à un mammifère d'un composé ayant une activité consistant à activer l'AMPK comprenant son sel ou un promédicament, une composition pharmaceutique destinée à activer l'AMPK qui comprend au moins le composé ayant une activité consistant à activer l'AMPK, et l'utilisation du composé ayant une activité consistant à activer l'AMPK pour préparer la composition pharmaceutique.
PCT/US2009/058405 2008-09-26 2009-09-25 Protection cardiaque par administration d'un activateur de protéine kinase activée par amp WO2010036910A1 (fr)

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WO2014139388A1 (fr) * 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Nouveaux dérivés d'indole utiles en tant qu'agents antidiabétiques
US8889730B2 (en) 2012-04-10 2014-11-18 Pfizer Inc. Indole and indazole compounds that activate AMPK
US9394285B2 (en) 2013-03-15 2016-07-19 Pfizer Inc. Indole and indazole compounds that activate AMPK
JP2016531119A (ja) * 2013-07-31 2016-10-06 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ Ｂｔｋの阻害剤としてのピリジン、ピリミジン及びピラジンならびにその使用
WO2024048809A1 (fr) * 2022-08-31 2024-03-07 보로노이 주식회사 Dérivé hétéroaryle contenant n, composition pharmaceutique le comprenant et utilisation associée

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WO2007101191A2 (fr) * 2006-02-27 2007-09-07 Targeted Molecular Diagnostics, Llc Compositions et procédés permettant de réduire la graisse cellulaire et de prédire la toxicité cardiaque lors d'un traitement avec des inhibiteurs de tyrosine kinases
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8889730B2 (en) 2012-04-10 2014-11-18 Pfizer Inc. Indole and indazole compounds that activate AMPK
WO2014139388A1 (fr) * 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Nouveaux dérivés d'indole utiles en tant qu'agents antidiabétiques
US9650375B2 (en) 2013-03-14 2017-05-16 Merck Sharp & Dohme Corp. Indole derivatives useful as anti-diabetic agents
US9394285B2 (en) 2013-03-15 2016-07-19 Pfizer Inc. Indole and indazole compounds that activate AMPK
JP2016531119A (ja) * 2013-07-31 2016-10-06 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ Ｂｔｋの阻害剤としてのピリジン、ピリミジン及びピラジンならびにその使用
WO2024048809A1 (fr) * 2022-08-31 2024-03-07 보로노이 주식회사 Dérivé hétéroaryle contenant n, composition pharmaceutique le comprenant et utilisation associée

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