WO2005118543A1 - Inhibiteur des kinases et utilisation de cet inhibiteur - Google Patents

Inhibiteur des kinases et utilisation de cet inhibiteur Download PDF

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WO2005118543A1
WO2005118543A1 PCT/JP2005/010120 JP2005010120W WO2005118543A1 WO 2005118543 A1 WO2005118543 A1 WO 2005118543A1 JP 2005010120 W JP2005010120 W JP 2005010120W WO 2005118543 A1 WO2005118543 A1 WO 2005118543A1
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group
substituent
compound
inhibitor
hydrocarbon group
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PCT/JP2005/010120
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English (en)
Japanese (ja)
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Toshio Yoshizawa
Kazuyuki Ohmoto
Koji Ogawa
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Ono Pharmaceutical Co., Ltd.
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Publication of WO2005118543A1 publication Critical patent/WO2005118543A1/fr

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Definitions

  • the present invention relates to kinase inhibitors useful as pharmaceuticals, particularly c Jun N-terminal kinase (c
  • Adenosine triphosphate (ATP) power Amino acid residues such as phosphate to tyrosine, serine, threonine, or histidine on proteins.
  • These protein kinases are involved in cell division, cell differentiation, cell death (apoptosis), changes in cell motility and cytoskeletal structure, regulation of DNA replication, transcription, splicing and translation, endoplasmic reticulum and Golgi apparatus membrane and cell Wide range of protein transport to the outer space, nuclear import and export of proteins, metabolic reactions, etc.! ⁇ Indispensable for cell function.
  • Eukaryotic protein kinases are based on structural and functional characteristics.
  • AGC groups For example, cyclic nucleotide-dependent and phosphorylated lipid-dependent proteins such as PKA, PKG, and PKC
  • CaMK group for example, Ca 2+ Z calmodulin kinase such as CaMK
  • CMGC group for example, cyclin-dependent protein kinase such as CDK, MAPK, GSK-3
  • PTK group For example, protein tyrosine kinases such as SRC, EGFR, etc .
  • Others For example, it is classified into 5 groups such as other kinases such as MEK, Raf, TGFR, LIMK, etc.
  • the AGC and CaMK groups include serine Z threonine residues near arginine and lysine, and C A group of MGCs phosphorylate the serine Z threonine residue of the proline rich domain.
  • the PTK group phosphorylates tyrosine residues. It is known that the PTK group has a “receptor type”, which is a receptor for cell growth factor, and a “non-receptor type”, which is representative of oncogene products contained in RNA tumor viruses.
  • kinases can phosphorylate serine Z threonine or tyrosine residues, and some kinases phosphorylate both serine Z threonine and tyrosine residues. If you can do that, it is sometimes called dual-specificity kinase.
  • PTKs protein tyrosine kinases
  • Receptor type is sometimes referred to as receptor ostium synthase (RTK).
  • Growth factors such as epidermal growth factor (EGF)
  • EGF epidermal growth factor
  • EGFR epidermal growth factor receptor
  • EGFR has also been implicated as a factor in the growth of epithelial cysts in polycystic kidney [Du, J., Amer. J. Physiol., 269 (2 Pt 1), 487 (1995); Nauta , J., Pediatric Res., 37 (6), 755 (1995); Gattone, VH, Developmental Biology, 169 (2), 504 (1995); Wilson, PD, Eur. J. Cell Biol, 61 (1). , 131 (1993)].
  • FGFR a receptor for fibroblast growth factor (FGF), flk 1ZKDR and fit-1, receptors for endothelial cell growth factor (VEGF), and platelet-derived growth factor (PDGF) Receptors such as PDGFR are also classified as RTKs.
  • FGF fibroblast growth factor
  • VEGF endothelial cell growth factor
  • PDGF platelet-derived growth factor
  • RTKs New blood vessels for tumor growth
  • angiogenesis a process known as angiogenesis
  • FGF and VEGF are known to stimulate angiogenesis.
  • tie-1 and tie-2 have been reported to be involved in angiogenesis [Sato, TN, Nature, 376, 70 (1995)].
  • RTKs include colon stimulating factor receptor, nerve growth factor receptor (trkA, trkB and trkC), insulin receptor, insulin-like growth factor receptor, hepatocyte growth factor receptor and erythropoietin-producing hepatocytes ( EP H) is known.
  • non-receptor type protein tyrosine kinases are present in the cytoplasm and cell nucleus and are involved in various signal pathways.
  • the important molecules are thought to be the eight Src families, Src, Fyn, Lyn, Yes, Lck, Fgr, Hck and Blk [Schwartzberg, PL, Oncogene, 17, 1463 (1998)].
  • Src activity is upregulated in breast, colon ( ⁇ 90%), spleen (> 90%) and liver (> 90%) tumors, and Src antisense is It has also been shown to inhibit cell growth [Staley, CA, Cell Growth Differentiation, 8, 269 (1997)].
  • antisense of Src has also been shown to reduce angiogenesis [Ellis, LM, J. Biol. Chem., 273, 1052 (1998)].
  • Src has been reported to be involved in the function of osteoclasts [Soriano, P., Cell, 64, 693 (1991); Boyce, B.F "J. Clin., Invest. , 90, 1 622 (1992); Missbach, M., Bone, 24, 437 (1999)].
  • Lck and ZAP-70 are molecules that are mainly expressed in T cells and natural killer ( ⁇ ) cells, and that these “non-receptor type” protein tyrosine kinases are important for the immune system. Suggested [Myers, M., Current Pharm. Design, 3, 4 73 (1997)].
  • mitogen is a protein kinase that phosphorylates serine Z threonine residue.
  • MAP -activated protein
  • the MAP kinase group consists of two strains, stress-activated protein kinase (SAPK) and mitogen-activated protein kinase (M APK). These kinases are involved in cellular responses to a variety of stimuli, including growth factors, chemicals, osmotic stress, radiation, bacterial infection, and various cytokins.
  • MAP kinases are activated by being phosphorylated twice by upstream kinases such as Thr and Tyr forces of the Thr-Xaa-Tyr motif MAP kinase kinases MEKs (MKKs).
  • MEKs are activated by the upstream, more than 30 known MAP kinase kinase kinases.
  • 12 different MAP kinase molecules have been identified in mammalian cells, RU
  • the most studied MAP kinases in mammalian cells are ERKlZ2, p38 (SAPK2), and c-Jun N-terminal kinase (JNK).
  • Cyclin-dependent kinases such as cdc2Z cyclin B, cdk2Z cyclin A, cdk2Z cyclin E and cdk4Z cyclin D are serine Z threonine kinases that control cell division of mammalian cells. It has been reported that activation of these kinases is frequently observed in human tumor cells [Garrett, MD, Current Opin. Genetics DeveL, 9, 104 (1999); Webster, KR, Exp. Opin. . Invest. Drugs, 7, 865 (1998)
  • Protein kinases 8, B and C are also important serine Z threonine kinases. Each of these kinases may also be referred to as PKA / cyclic AMP-dependent protein kinase, PKB / Akt, PKC, and the like.
  • protein phosphorylation abnormalities are widely known to be involved in the pathogenesis of many diseases, for example, cancer, and immune, neurological and metabolic disorders.
  • RTKs such as EGFR and PDGFR
  • tyrosine kinases that constitutively produce active forms are known to exist in many cancer cells [Druker, Nat. Med. ., 2, 561 (1996)].
  • protein serine / threon kinase gene deficiencies are associated with myotonic dystrophy and several diseases, such as cancer, and Aln's disease (Sanpei, Biochem. Biophvs. Res. Com mun., 212, 341 (1995); Sperber, Neurosci. Lett., 197, 149 (1995); Grammas, Neuro biol. Aging, 16, 563 (1995); Govoni, Ann. NY Acad. Sci., 777, 332 (1996)].
  • a protein kinase inhibitor is considered to be useful for the treatment of the above-mentioned diseases caused by abnormal protein phosphorylation.
  • protein kinases particularly MAP kinase is involved in various immune and inflammatory responses, so that a drug that inhibits its activation may be a therapeutic agent for a wide variety of diseases.
  • JNK a type of MAP kinase
  • c Jun is a component of the transcription factor AP-1, and its N-terminus is known to be specifically phosphorylated by JNK.
  • compounds that inhibit the activity of JNK include metabolic diseases (eg, diabetes (type I diabetes, type II diabetes (insulin-resistant diabetes, insulin-lowering diabetes)), hyperlipidemia, Other insulin-resistant diseases, etc.), inflammatory diseases (eg, rhinitis, pharyngitis, bronchitis, pneumonia, pleurisy, bronchial asthma, chronic emphysema, pulmonary fibrosis, inflammatory bowel disease, acute splenitis, chronic knee inflammation) , Adult respiratory distress syndrome, chronic thyroiditis, autoimmune gastritis, etc.), scleroderma, deep lupus erythematosus, Graves' disease, autoimmune neutropenia, thrombocytopenia, myasthenia gravis, Multiple myeloma, acute myeloblastic leukemia, chronic sarcoma, chronic myeloid leukemia Disease, metastatic melanoma, positron sarcoma, wasting disease
  • metabolic diseases
  • Ar an and Ar bh each represent an aromatic group which may have a substituent, and the BaH ring may have a substituent.
  • the x aH and Y aH are the same or different and each is a bond or oxygen atom or the like
  • R aH and R bH are the same or different and each is a halogen
  • a compound represented by an atom or a hydrocarbon group, and ReH represents a hydroxy group, a carboxyl group, or the like (however, symbols in the group are extracted only where necessary) is useful as a JNK inhibitor. There is a description (see Patent Document 1).
  • R Q is a hydrogen atom, a force containing C 16 alkyl, C 1-6 alkyl alkoxy, C 1-6 alkylamino, or the like, or a base composed of these
  • R 1Q is a hydrogen atom
  • a group containing or consisting of halogen, nitro, etc. is selected from the group consisting of n
  • n Q represents an integer of 0 to 3.
  • JNK inhibitory activity especially JNK2 or NK3 inhibitory activity, and are cerebral ischemic disease or central nervous system disease It is described as being useful for the treatment of (see Patent Document 2).
  • Patent Document 1 JP 2003-137785 A
  • Patent Document 2 International Publication No.03Z091249 pamphlet
  • a kinase inhibitor which is useful as a preventive and / or therapeutic agent for various diseases including metabolic diseases and inflammatory diseases and has excellent effects, long-lasting properties and oral absorbability, and especially JNK inhibitor There is an eager need for drug development.
  • the present inventors have conducted intensive studies to find compounds that can serve as therapeutic agents for various diseases by suppressing the kinase activity of JNK, and as a result, the compound represented by the general formula (I)
  • the present inventors have found that they have an inhibitory action, particularly a JNK inhibitory action, and completed the present invention.
  • the present invention provides:
  • A is an amino group which may have a substituent
  • ring A 1 represents a nitrogen-containing heterocyclic group which may have a substituent.
  • D represents a substituent
  • a C 1-4 alkylene group may be represented by E Represents a protected !, may! /, An amino group which may have a hydroxyl group or a substituent.
  • Ring A 1 is a compound of according to claim 2, wherein a nitrogen-containing heterocyclic ring containing an additional at least one nitrogen atom in addition to nitrogen atom may also be titled substituted.
  • a ring A 1 is a substituted group, it is also good ⁇ piperazine or pyrazole compound of the range 3 wherein claims.
  • R 1A and R 3A each independently represent a hydrogen atom or a C 18 aliphatic hydrocarbon group which may have a substituent, and R 1G has a substituent, and also I represents the unsaturated ring-shaped hydrocarbon group or substituted! / ⁇ be due! ⁇ monocyclic or bicyclic unsaturated heterocyclic group,
  • R 5A is optionally substituted C1-8 aliphatic hydrocarbon group, having a substituent! / ⁇ May be! / ⁇ Having cyclic hydrocarbon group and a substituent! / ⁇ May be!
  • Mono- or bicyclic unsaturated heterocyclic group having 1 to 2 substituents selected from the group consisting of a carbamoyl group, —CO— (optionally substituted C 1— 8 aliphatic hydrocarbon groups),-
  • R 7A and R 9A each independently represent a hydrogen atom, a CO atom (optionally having a substituent !, a 3- to 15-membered monocyclic or bicyclic unsaturated heterocyclic group).
  • Optionally substituted C May represent an aliphatic hydrocarbon group of 18 or form a cyclic hydrocarbon together with the carbon atom to which they are attached, and R 11 may have a substituent, 8 represents an aliphatic hydrocarbon group or a cyclic hydrocarbon group which may have a substituent, wherein R 11 is the same or different at the substitutable position and z is 0
  • R 5B represents —CO— (a cyclic hydrocarbon group which may have a substituent) or CO (a 3- to 15-membered group which may have a substituent)
  • R 12 is an optionally substituted C 1-8 aliphatic hydrocarbon group, and is a substituted or unsubstituted V; It represents a cyclic hydrocarbon group or a 3- to 15-membered monocyclic or bicyclic heterocyclic group having a substituent, and the other symbols have the same meanings as described above.
  • a pharmaceutical composition comprising a compound represented by the general formula (I) according to claim 1, a salt thereof, a solvate thereof, or a prodrug thereof.
  • composition according to claim 8 which is a kinase inhibitor.
  • kinase is c Jun N-terminal kinase.
  • composition according to claim 10 which is c-Jun N-terminal kinase JNK1.
  • composition according to claim 8 which is an agent for preventing and / or treating c-Jun N-terminal kinase-related disease.
  • c-Jun N-terminal kinase-related disease potency The pharmaceutical composition according to claim 12, which is a metabolic disease or an inflammatory disease.
  • composition according to claim 13, wherein the metabolic disease is diabetes.
  • a compound represented by the general formula (I) according to claim 1 a salt thereof, a solvate thereof, or a prodrug thereof, and an MTP inhibitor, an HMG-CoA reductase inhibitor, or a squalene synthetase inhibitor.
  • Fibrate Fibrate, ACAT inhibitor, 5-lipoxygenase inhibitor, cholesterol absorption inhibitor, bile acid absorption inhibitor, ileal Na + Z bile acid cotransporter inhibitor, LDL receptor activator, LDL receptor expression Potentiator, lipase inhibitor, probucol, nicotinic acid, sulfonylurea hypoglycemic, biguanide, a darcosidase inhibitor, rapid-acting insulin secretagogue, insulin, DPP4 inhibitor, PTP1B inhibitor, 13 3 Adrenergic receptor agonist, PPAR agonist, PPA A medicament comprising a combination of at least one selected from the group consisting of an R antagonist and a drug for treating diabetic complications.
  • a compound represented by the general formula (I) according to claim 1 a salt thereof, a solvate thereof, or a prothromer thereof for producing a prophylactic and / or therapeutic agent for c-Jun N-terminal kinase-related disease.
  • a salt thereof, a solvate thereof, or a prothromer thereof for producing a prophylactic and / or therapeutic agent for c-Jun N-terminal kinase-related disease.
  • the "substituent" in the "optionally substituted or optionally substituted amino” represented by A is, for example, an optionally substituted hydrocarbon group or an optionally substituted hydrocarbon group. And an optionally substituted heterocyclic group and a substituted or unsubstituted amino group, and a substituted and unsubstituted carbamoyl group.
  • hydrocarbon group includes, for example, a linear or branched aliphatic hydrocarbon group, a cyclic hydrocarbon group, or a cyclic hydrocarbon group, an aliphatic hydrocarbon group, and a cyclic hydrocarbon group.
  • Examples of the “linear or branched aliphatic hydrocarbon group” include “C1-8 aliphatic hydrocarbon group” and the like, and “C1-8 aliphatic hydrocarbon group”.
  • Examples include C18 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, etc., for example, butyl, probel, butenyl, pentenyl C2-8 alkenyl groups such as hexenyl, heptenyl, octenyl, butadenyl, butadienyl, pentadieninole, hexadeninole, heptadenoline, otatageneole, hexaterinele, heptatrilele, otatatrile, etc.
  • the "cyclic hydrocarbon” includes “unsaturated cyclic hydrocarbon” or “saturated cyclic hydrocarbon”. No. Examples of “saturated cyclic hydrocarbon” include, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane, cyclododecane, cyclotridodecane, cyclotetradecane, cyclopentadecane And cycloalkanes such as perhydropentalene, perhydroazulene, perhydroindene, perhydronaphthalene, perhydroheptalene, spiro [4.4] nonane, spiro [4.5] decane, spiro [5.5] ] Undekan, bicyclo [2.2.1] hept-down, bicyclo
  • unsaturated cyclic hydrocarbon for example, cyclopentene, cyclohexene, cycloheptene, cyclootaten, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, and other cycloanolekens such as benzene, azulene, naphthalene, Aromatic hydrocarbons such as phenanthrene, anthracene, etc .; , bicyclo [2.2.1] to the descriptor one 2 E down, bicyclo [3.1.1] Heputa 2 E down, bicyclo [2.2.2] Okuta "3 15-membered, such as one 2-E down not Saturated hydrocarbon "and the like.
  • cyclic hydrocarbon group aliphatic hydrocarbon group examples include those in which the above “cyclic hydrocarbon group” and “aliphatic hydrocarbon group” are bonded, such as benzyl, phenylethyl, and phenylpropyl.
  • C16-16 aralkyl group such as phenyl, butyl, naphthalene 1-ylmethyl and the like, for example, C8-16 aralkyl such as 3-phenyl 2-probel, 2- (2 naphthyl vinyl), 4-cyclobutyl 1-butyl and the like.
  • Groups such as (C3-8 cycloalkyl)-(C1-4 alkyl) groups such as cyclopropylmethyl, cyclohexinolemethinole, cyclohexinolethine, cyclohexinolepropinole, 1-methylinole 1 cyclohexylmethyl, etc., for example, 3-cyclo And a (C3-8 cycloalkenyl)-(C1-4 alkyl) group such as hexylmethyl.
  • cyclic hydrocarbon group-cyclic hydrocarbon group examples include those in which the above “cyclic hydrocarbon group” and “cyclic hydrocarbon group” are bonded, and examples thereof include 2-phenyl and 3-phenyl. -Phenyl, 4-phenyl, 2-phenylcyclopropyl and the like.
  • heterocycle refers to a monocyclic, bicyclic, tricyclic or tetracyclic ring which may contain 1 to 7 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Represents a cyclic heterocyclic ring.
  • heterocycle for example, "3- to 15-membered or 3- to 18-membered unsaturated monocyclic, bicyclic, tricyclic or tetracyclic heterocycle", "3- to 15-membered or 3- to 18-membered saturated monocyclic, Bicyclic, tricyclic or tetracyclic compound rings ”and the like.
  • the “3-15 membered or 3-18 membered unsaturated monocyclic, bicyclic, tricyclic or tetracyclic heterocyclic ring” for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine , Pyridazine, triazine, furan, thiophene, oxazonole, isoxazole, thiazole, isothiazole, furazane, oxaziazole, thiadiazole and other aromatic monocyclic heterocycles such as indole, isoindole, benzofuran, isobenzofuran, benzothiane Shenfen, isobenzothienfen, indazonole, quinoline, isoquinoline, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinno
  • the “3-15 membered or 3-18 membered saturated monocyclic, bicyclic, tricyclic or tetracyclic heterocyclic ring” includes, for example, aziridine, azetidine, pyrrolidine, imidazolidin, triazolidine, tetrazolidine, virazolidine, Peridine, piperazine, nohydropyrimidine, perhydropyridazine, perhydroazepine, perhydrodiazepine, perhydroazosin, xylan, xetane, tetrahydrofuran, tetrahydropyran, perhydrooxy Sepin, thiirane, chetan, tetrahydrothiophene, tetrahydrothiopyran, perhydrochepin, tetrahydrooxazole (oxazolidine), tetrahydroisoxazole (isosazozolidine), tetrahydrothiazole (thiazolidine),
  • hydrocarbon group and “heterocycle” as “substituents” in the “substituted or optionally substituted amino group” represented by ⁇ are the aforementioned “hydrocarbon group” and “heterocycle”, respectively. Represents the same meaning as.
  • the “hydrocarbon group” and “heterocyclic group” may be substituted at any of the substitutable positions with 1 to 5 arbitrary substituents. Examples of the "substituent” include (1) a hydrocarbon group optionally having a substituent, (2) a heterocyclic group optionally having a substituent, and (3) a heterocyclic group optionally having a substituent.
  • An amino group (4) a C14 alkylsulfol group such as methylsulfol and ethylsulfol, (5) a phenylsulfol group, and (6) a fluorine, chlorine, bromine, iodine, etc. (7) carboxyl group, (8) cyano group, (9) nitro group, (10) oxo group, (11) oxo group, (12) hydroxyl group optionally having a protecting group, 13) having a protecting group, may be a mercapto group, (14) having a substituent!
  • / May be, a carbamoyl group, (15) having an optionally substituted sulfamoyl group;
  • Groups, (16) alkoxycarbyl groups for example, C16 alkoxycarbol groups such as methoxycarbol, ethoxycarbol, tert-butoxycarbol, etc.)
  • (17) sulfo group one SOH
  • (18) sulfino group (19) phosphono group
  • C16 acyl groups such as formyl, acetyl, propionyl and butyryl.
  • hydrocarbon group in “(1) having a substituent! / May be a hydrocarbon group” has the same meaning as described above.
  • the “hydrocarbon group” may be substituted with 1 to 5 identical or different substituents selected from Group 1 below;
  • Group 1 a hydrocarbon group which may have a substituent (for example, a halogen atom, a hydroxyl group, a methoxy group, a trifluoromethyl group, a trifluoromethoxy group, an acetyloxy group, etc.), a substituent (for example, a hydrocarbon group) , A halogen atom, a hydroxyl group, a trifluoromethyl group, a trifluoromethoxy group, an acetyloxy group, etc.), an amino group, a sulfo group, a halogen atom, a carboxyl group, a cyano group, and a nitro group.
  • a substituent for example, a halogen atom, a hydroxyl group, a methoxy group, a trifluoromethyl group, a trifluoromethoxy group, an acetyloxy group, etc.
  • a substituent for example, a hydrocarbon group
  • Heterocycle in the above “(2) Substituent! / ⁇ may be / Heterocyclic group” has the same meaning as described above. This “heterocyclic group” may be substituted with the same or different 1 to 5 substituents selected from Group 1 described above.
  • the “substituent” in “(3) Substituent! / Polyaminoamino” includes, for example, a substituent! / Examples include a heterocyclic group and the like having a group and a substituent.
  • the “having a substituent, a hydrocarbon group” and the “having a substituent, a heterocyclic group” are each the above-mentioned “(1) having a substituent! They have the same meanings as "a hydrocarbon group” and "(2) having a substituent! /, A heterocyclic group”.
  • Protecting group in "(12) Having a protecting group! / ⁇ ⁇ hydroxyl group” or "(13) Having a protecting group! / ⁇ ⁇ ! / ⁇ Mercapto group”
  • Examples thereof include a hydrocarbon group which may have a substituent.
  • the “hydrocarbon group which may have a substituent (s)” has the same meaning as the “(1) hydrocarbon group which may have a substituent (s)”.
  • Examples of the hydroxyl group having a protecting group include C1-6 alkoxy such as methoxy, ethoxy, propoxy, butoxy and cyclohexyloxy, and phenoxy.
  • Examples of the mercapto group having a protecting group include C1 groups such as methylthio, ethylthio, propylthio, and butylthio. 6 alkylthio or phenylthio and the like.
  • Examples thereof include piperidine 1-ylcarbol, pyrrolidine 1-ylcarbonyl, piperazine 1-ylcarbonyl, morpholine-4-ylcarbol, and the like.
  • Two substituents of "(15) having a substituent! /, Or a sulfamoyl group" may be combined with an adjacent nitrogen atom to form a heterocyclic ring (for example, piperidine, pyrrolidine, morpholine, etc.
  • Specific examples which may form a nitrogen-containing heterocycle include piperidine 1-ylsulfonyl, pyrrolidine 1-ylsulfonyl, piperazine 1-ylsulfonyl, and morpholine-4-ylsulfol.
  • the complex ring formed by the substituent of the sulfamoyl group or the sulfamoyl group together with the adjacent nitrogen atom may be substituted with a substituent selected from the group 1.
  • substituted or may be an amino group represented by A "a substituted or may be an amino group” or " As the “substituent” in the “carbamoyl group”, a hydrocarbon group and the like, which may be substituted with a substituent selected from the group 1 described above, may be mentioned.
  • the "substituent" in the "substituted or may be an amino group” represented by A is preferably a substituted or may have a hydrocarbon group or a substituted group. And a heterocyclic group.
  • nitrogen-containing heterocyclic group for ring A 1, for example, in addition to the title nitrogen atom, is et to the nitrogen atom, an oxygen atom, a sulfur nuclear 1-6 heteroatom selected Represents a monocyclic, bicyclic, tricyclic or tetracyclic heterocyclic ring which may contain Examples of the “nitrogen-containing heterocyclic ring” include “3- to 15-membered or 3- to 18-membered nitrogen-containing unsaturated monocyclic, bicyclic, tricyclic or tetracyclic heterocyclic ring”, “3 to 15-membered or 3 to 18-membered” Nitrogen-containing saturated monocyclic, bicyclic, tricyclic or tetracyclic heterocycles ”and the like.
  • Examples of the “3- to 15-membered or 3- to 18-membered nitrogen-containing unsaturated monocyclic, bicyclic, tricyclic or tetracyclic heterocycle” include pyrrole, imidazole, triazole, tetrazole, pyrazole, azepine and diazepine.
  • Examples of the "3-15 membered or 3-18 membered nitrogen-containing saturated monocyclic, bicyclic, tricyclic or tetracyclic heterocyclic ring” include, for example, aziridine, azetidine, pyrrolidine, imidazolidine, triazolidine, tetrazolidine, virazolidine, Peridine, piperazine, perhydropyrimidine, perhydride Mouth pyridazine, perhydroazepine, perhydrodiazepine, perhydroazosin, tetrahydroxazole (oxazolidine), tetrahydroisoxazole (isoxazolidine), tetrahydrothiazole (thiazolidine), tetrahydroisothiazole (isothiazolidine) ), Tetrahydrofurazan, tetrahydrooxaziazol (oxaziazolidine), tetrahydrooxazine, tetrahydroo
  • This “nitrogen-containing heterocycle” may be substituted with 1 to 5 optional substituents.
  • the “substituent” includes, for example, a substituted or unsubstituted hydrocarbon group or a substituted or unsubstituted V heterocycle.
  • the “having a substituent, or a hydrocarbon group” and the “having a substituent, a heterocyclic ring” are each represented by the above “having a substituent,” The same meanings as “substituted or may be a hydrocarbon group” and “substituted or may be a heterocyclic ring” as substituents of the “amino group” are given.
  • ring A 1 further comprises at least one nitrogen atom other than the indicated nitrogen atom.
  • nitrogen atom other than the indicated nitrogen atom.
  • Specific examples include piperazine and pyrazole.
  • the "substituent" in the "substituted or C1-C4 alkylene group” represented by D is the "substituted or represented by A" It has the same meaning as the substituent of the hydrocarbon group as the substituent of the "amino group".
  • Preferable examples of the “substituent” of the C1-4 alkylene group include a hydrocarbon group, an oxo group, and a hydroxyl group which may be substituted with a substituent selected from the group 1.
  • the C14 alkylene group may be substituted at any position with a substituent. When there are two or more substituents, each substituent may be the same or different. Two arbitrarily selected substituents may form a ring together with adjacent carbon atoms.
  • the ring formed is preferably the ring exemplified as the above “cyclic hydrocarbon”.
  • the C 1-4 alkylene group which may have a substituent of D is preferably an ethylene group.
  • substituents of the ethylene group together with an adjacent carbon atom form a ring, examples of the ring formed include:
  • the hydroxyl group represented by E may be protected by a protecting group.
  • protecting group include an optionally substituted hydrocarbon group.
  • the “hydrocarbon group” has the same meaning as described above, and may be substituted with a halogen atom, a hydroxyl group, a C 1-4 alkoxy group (eg, methoxy, ethoxy, propoxy, butoxy, etc.).
  • substituted or may be an amino group represented by E preferably a substituted or may have a hydrocarbon group or a substituted group And then, Carbamo Yl group.
  • E is preferably a hydroxyl group or an amino group having one substituent.
  • R 1 R 2 , R 3 and R 4 are each independently substituted with a hydrogen atom or a substituent selected from the group 1, and may represent a hydrocarbon group;
  • a la represents a nitrogen-containing complex ring which may have a substituent and further contains at least one nitrogen atom in addition to the indicated nitrogen atom), or a compound represented by the general formula (I 2)
  • R 6 , R 7 , R ° and R 9 each independently represent a hydrogen atom, a hydrocarbon group optionally substituted with a substituent selected from the aforementioned group 1, or a hydroxyl group
  • R 6 and R 7 , or R 8 and R 9 taken together to represent an oxo group, or R 6 , R 7 , R 8 and R 9 arbitrarily selected two are adjacent
  • R 5 may have a substituent, may have a substituent, may have a hydrocarbon group or may have a substituent, and may have a substituent.
  • the other symbols have the same meanings as described above.).
  • the substituent represented by R 5 may have a substituent, may have a hydrocarbon group or may have a substituent, and may have a substituent.
  • As the “optionally / optionally substituted hydrocarbon group” represented by R 5 for example, (for example, (substituted with a group selected from the group 1!), A hydrocarbon group or May be substituted with a group selected from the group 1, Elementary ring group) A carbonyl group is exemplified. Specific examples include a 1,3-oxazole-5-ylcarboxy group (provided that “oxazole” may be substituted with one or two substituents selected from Group 1) and the like.
  • R 1A and R dA each independently represent a hydrogen atom or a C 18 aliphatic hydrocarbon group which may have a substituent, and R 1G has a substituent.
  • R 1G has a substituent.
  • R 5A is a C1-8 aliphatic hydrocarbon group which may have a substituent, may have a substituent, or may have a cyclic hydrocarbon group and a substituent.
  • R 7A and R 9A each independently represent a hydrogen atom, a C 1-8 aliphatic hydrocarbon group which may have a substituent, or a cyclic hydrocarbon group together with a carbon atom to which they are bonded hydrogen
  • R 5B is —CO— (a cyclic hydrocarbon group which may have a substituent)) or —CO (which may have a substituent and is a 3- to 15-membered monocyclic ring Or a bicyclic unsaturated heterocyclic group), and R 12 is a C1-8 aliphatic hydrocarbon group which may have a substituent, or an unsaturated cyclic hydrocarbon group which may have a substituent.
  • a hydrogen group, or a substituted or unsubstituted, 3-15 membered monocyclic or bicyclic heterocyclic group, and the other symbols have the same meanings as described above.
  • R 1C> may have an unsaturated cyclic hydrocarbon group which may have a substituent, or may have a substituent, and the substituent of the monocyclic or bicyclic unsaturated heterocyclic ring may be It has the same meaning as the substituent of the "hydrocarbon group" as the "substituent” in the "amino group” having the "substituent group” for A.
  • the unsaturated cyclic hydrocarbon group having a substituent in R 1C> is preferably, for example, benzene, preferably having a substituent.
  • the monocyclic or bicyclic unsaturated heterocyclic group which may have a substituent in R 1G is preferably, for example, a substituted or unsubstituted pyridine.
  • R 11 have a substituent R 11, O be, C1- 8 aliphatic hydrocarbon group or preferably fluorine as a substituent a good cyclic hydrocarbon group which may have a substituent, a chlorine , A bromine, a halogen atom such as iodine, an alkoxycarbol group (for example, a C1-6 alkoxycarbol group such as methoxycarbol, ethoxycarbol, tert-butoxycarbol, etc.), a nitro group, or an oxo group Groups.
  • R 5B is preferably CO (substituted or monocyclic unsaturated heterocyclic group), and particularly preferably —CO (oxazole which may be substituted) It is.
  • R 12 a substituent! /, It also includes a benzene.
  • R 12 O be, C1- 8 aliphatic hydrocarbon group, substituted! /, Even, have a unsaturated cyclic hydrocarbon group or a substituted group
  • a substituent of the 3- to 15-membered monocyclic or bicyclic heterocyclic group a halogen atom such as fluorine, chlorine, bromine or iodine, or an alkoxycarbol group (for example, methoxycarboxy) is preferable.
  • C1-6 alkoxycarbol groups such as benzyl, ethoxycarbol and tert-butoxycarbol), nitro group and oxo group.
  • the alkyl group, the alkyl group, the alkyl group, the alkoxy group, the alkylthio group, the alkylene group, the alkylene group and the alkylene group include straight-chain and branched-chain ones.
  • the compound represented by the general formula (I) is converted into a salt by a known method.
  • a salt a pharmacologically acceptable salt is preferred.
  • Examples of the salt include an alkali metal salt, an alkaline earth metal salt, an ammonium salt, an amine salt, an acid addition salt and the like.
  • the salt is preferably a water-soluble salt.
  • Suitable salts include salts of alkali metals (such as potassium and sodium), salts of alkaline earth metals (such as calcium and magnesium), ammonium salts, and pharmaceutically acceptable organic amines (tetramethylammonium).
  • alkali metals such as potassium and sodium
  • alkaline earth metals such as calcium and magnesium
  • ammonium salts such as calcium and magnesium
  • pharmaceutically acceptable organic amines tetramethylammonium
  • Pem triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) aminomethane, Lysine, arginine, N-methyl-D-glucamine, etc.).
  • the acid addition salt is preferably water-soluble.
  • Suitable acid addition salts include, for example, inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, or acetate, lactate, tartrate, and the like.
  • Organic salts such as benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, and dalconate.
  • the solvate is preferably non-toxic and water-soluble. Suitable solvates include, for example, solvates such as water, alcoholic solvents (eg, ethanol, etc.).
  • the salts also include quaternary ammonium salts.
  • the quaternary ammonium salt refers to a compound in which the nitrogen atom of the compound of the present invention has been quaternized by a group.
  • the R group represents a Cl-8 alkyl group or a Cl-8 alkyl group substituted by a phenyl group.
  • the compound of the present invention can be converted to N-oxide by any method.
  • N-oxide means that the nitrogen atom of the compound of the present invention is oxidized.
  • a prodrug of the compound of the present invention refers to a compound that is converted into the compound of the present invention by a reaction with an enzyme, gastric acid, or the like in a living body.
  • a prodrug of the compound of the present invention when the compound of the present invention has an amino group, a compound in which the amino group is acylated, alkylated, or phosphorylated (eg, the amino group of the compound of the present invention is eicosanoylated, alanylated, Pentylaminocarboxylation, (5-methyl 2-oxo-1,3-dioxolen-14-yl) methoxycarbonylation, tetrahydrofuration, pyrrolidylmethylation, bivaloyloxymethylation, acetoxymethylation, tert
  • the compound of the present invention has a hydroxyl group
  • a compound in which the hydroxyl group is acylated, alkylated, phosphorylated, or borated
  • the prodrug of the compound of the present invention may be either a hydrate or a non-hydrate.
  • prodrugs of the compound represented by the general formula (I) are described in Hirokawa Shoten, 1990, “Development of Pharmaceuticals,” Vol. 7, “Molecular Design,” pp. 163-198, under general physiological conditions as described below.
  • the compound may be changed to the compound represented by the formula (I).
  • the compound represented by the general formula (I) may be labeled with an isotope (eg, 3 H, "C, 35 S, 1251, etc.).
  • the compound of the present invention represented by the general formula (I) is described in a known manner, for example, in Comprehensive Organic Transformations: A uuiae to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999).
  • the method can be produced by appropriately improving the method described above, a method according to the method, a method shown in Examples, and the like, and using them in combination.
  • the compound represented by the general formula (I) has the general formula (II)
  • a P has the same meaning as A. However, carbo contained in the group represented by A Xyl, hydroxyl, amino and mercapto groups shall be protected where protection is required. ) And a compound of the general formula (III)
  • X is a leaving group (e.g., halogen atom, p-toluenesulfonyloxy - Ruokishi group, methanesulfonyl - Ruokishi groups, trifluoperazine Ruo Russia methanesulfonyl - represents a Ruokishi group)
  • D P and EP respectively
  • D And E have the same meaning as above, provided that the carboxy, hydroxyl, amino and mercapto groups contained in the groups represented by D and E are protected if necessary.
  • the compound can be produced by subjecting the compound to be subjected to an alkylation reaction and, if necessary, to a deprotection reaction.
  • This alkylation reaction may be carried out according to the method described in Bioorg. Med. Chem. Lett., 2000, 10 (29), 2375-2377 or a method analogous thereto, or, for example, an organic solvent (eg, benzene, Aromatic hydrocarbons such as toluene and xylene, for example, hydrogenated hydrocarbons such as dichloromethane and chloroform, and saturated hydrocarbons such as hexane, heptane and cyclohexane, for example, acetyl ether, tetrahydrofuran, Ethers such as dioxane, for example, ketones such as acetone and methylethylketone, for example, -tolyls such as acetonitrile, for example, sulfoxides such as dimethylsulfoxide, for example, N, N dimethylformamide, dimethylacetamide, Acid amides such as 3 dimethyl-2 imidazolidinone, for example
  • a base for example, hydrogen
  • Hydrides of alkali metals or alkaline earth metals such as sodium hydride and potassium hydride, for example, alkyl lithiums such as butyllithium, sec-butyllithium and t-butyllithium, and alkali metal such as sodium methoxide and sodium ethoxide
  • Alkoxides such as inorganic bases such as alkali metals such as metal sodium and metal potassium, such as carbonates such as cesium carbonate, sodium carbonate and potassium carbonate, such as triethylamine, tributylamine, N, N diisopropylethylamine, N-methylmorpholine Alkylamines such as N, N dimethyla- Emissions, lutidine, collidine, 4 (Jimechiruamino) aromatic such as pyridine Zoku
  • the deprotection reaction of the protecting group is carried out by a method known per se, for example, the method described in TW Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999 or a method analogous thereto.
  • deprotection reactions of protecting groups for carboxy, hydroxyl, amino or mercapto groups are well known, and include, for example, (1) alkaline hydrolysis, (2) acidic
  • the deprotection reaction by alkali hydrolysis is carried out, for example, in an organic solvent (methanol, tetrahydrofuran, dioxane, etc.) in an alkali metal hydroxide (sodium hydroxide, potassium hydroxide, water). Lithium oxide, etc.), alkaline earth metal hydroxides (barium hydroxide, hydroxide hydroxide, etc.) or carbonates (sodium carbonate, potassium carbonate, etc.) or their aqueous solutions or mixtures thereof. Performed at a temperature of 40 ° C.
  • the deprotection reaction under acid conditions is carried out, for example, by using an organic acid (acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosyl) in an organic solvent (dichloromethane, chloroform, dioxane, ethyl acetate, alcohol, etc.). Acid) or an inorganic acid (hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (hydrogen bromide Z acetic acid, etc.) at a temperature of 0 to 100 ° C.
  • organic acid acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosyl
  • an organic solvent diichloromethane, chloroform, dioxane, ethyl acetate, alcohol, etc.
  • Acid or an inorganic acid (hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (hydrogen bromide Z acetic acid, etc.) at
  • Deprotection reactions by hydrogenolysis include, for example, solvent (ether (tetrahydrofuran, dioxane, dimethoxyethane, getyl ether, etc.), alcohol (methanol, ethanol, etc.), benzene (benzene, toluene, etc.) ), Ketones (acetone, methylethylketone, etc.), nitriles (acetonitrile, etc.), amides (dimethylformamide, etc.), water, ethyl acetate, acetic acid or a mixed solvent of two or more thereof, and a catalyst (palladium) —Carbon, Noji
  • the reaction is carried out at a temperature of 0 to 200 ° C. in the presence of gem black, palladium hydroxide, platinum oxide, Raney nickel, etc., in a hydrogen atmosphere under normal pressure or caro pressure or in the presence of ammonium formate.
  • the deprotection reaction of the silyl group is carried out, for example, in a water-miscible organic solvent (tetrahydrofuran, acetonitrile, etc.) at a temperature of 0 to 40 ° C. using tetrabutylammonium-dimethyl fluoride.
  • a water-miscible organic solvent tetrahydrofuran, acetonitrile, etc.
  • the deprotection reaction using a metal is carried out, for example, by the presence of zinc powder in an acidic solvent (acetic acid, a buffer solution of pH 4.2 to 7.2 or a mixture thereof and an organic solvent such as tetrahydrofuran). Below, it is carried out at a temperature of 0 to 40 ° C. while applying ultrasonic waves if necessary.
  • an acidic solvent acetic acid, a buffer solution of pH 4.2 to 7.2 or a mixture thereof and an organic solvent such as tetrahydrofuran.
  • the deprotection reaction using a metal complex includes, for example, an organic solvent (dichloromethane, dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, ethanol, etc.), water or a mixed solvent thereof, a trapping reagent (triptytin hydride, Triethylsilane, dimedone, morpholine, getylamine, pyrrolidine, etc.), organic acids (acetic acid, formic acid, 2-ethylhexanoic acid, etc.) and Z or organic acid salts (sodium 2-ethylhexanoate, 2-ethylhexanoic acid) Metal complex (tetrakistriphenylphosphine palladium (0)) in the presence or absence of a phosphine-based reagent (such as triphenylphosphine) in the presence or absence of potassium
  • the target compound of the present invention can be easily produced by using and separating these deprotection reactions.
  • Examples of the carboxy-protecting group include a methyl group, an ethyl group, an aryl group, a t-butyl group, a trichloroethyl group, a benzyl (Bn) group, and a funacyl group.
  • Examples of the hydroxyl-protecting group include a methyl group, a trityl group, a methoxymethyl (MOM) group, a 1-ethoxyxethyl (EE) group, a methoxyethoxymethyl (MEM) group, and a 2-tetrahydrovinyl (THP) group.
  • TMS Trimethylsilyl
  • TES triethylsilyl
  • TDMS t-butyldimethylsilyl
  • TDPS t-butyldiphenylsilyl
  • acetyl Ac
  • pivaloyl benzoyl
  • benzyl (Bn ) Group p-methoxybenzyl group, aryloxy group (Alloc) group, 2,2,2-trichloromouth ethoxycarbon (Troc) group, etc.
  • the Examples of the protecting group for the amino group include benzyloxycarbyl group, t-butoxycarbol group, aryloxycarbol (Alloc) group, 1-methyl-11- (4-biphenyl) ethoxycarboyl. -(Bpoc) group, trifluoroacetyl group, 9-fluoro-methoxycarbonyl group, benzyl (Bn) group, p-methoxybenzyl group, benzyloxymethyl (BOM) group, 2- (trimethylsilyl) ethoxy And a methyl (SEM) group.
  • Examples of the mercapto-protecting group include a benzyl group, a methoxybenzyl group, a methoxymethyl (MOM) group, a 2-tetrahydrovinyl (THP) group, a diphenylmethyl group, and an acetyl (Ac) group.
  • the protecting group for a carboxy group, a hydroxyl group, an amino group or a mercapto group is not particularly limited as long as it is a group other than those described above that can be easily and selectively eliminated. For example, those described in T. W. ureene, Protective uroups in Organic Synthesis, Wiley, New Yor, 1999 are used.
  • A is substituted and may be piperazine, that is, the general formula (Ia)
  • R 1 (nP have the same meanings as R 1 (n. However, the carboxy group contained in the group represented by R 1 (n, hydroxyl, amino and mercapto groups require protection In such cases, the compound is protected and the other symbols have the same meanings as described above), and a compound represented by the general formula (V)
  • the alkylidation reaction can be carried out in the same manner as described above.
  • R 1C> 2 is a hydrocarbon group which may be substituted with a substituent selected from Group 1, and other symbols have the same meanings as described above.
  • R 1C 2P has the same meaning as R 1C> 2 .
  • the carboxy group, hydroxyl group, amino group and mercapto group contained in the group represented by R 1C> 2 shall be protected if necessary.
  • the ureation reaction is known, and for example, a base (eg, pyridine, triethylamine, diisopropylethylamine, etc.) is present in an organic solvent (eg, dichloromethane, dichloroethane, tetrahydrofuran, N, N dimethylformamide, etc.).
  • a base eg, pyridine, triethylamine, diisopropylethylamine, etc.
  • organic solvent eg, dichloromethane, dichloroethane, tetrahydrofuran, N, N dimethylformamide, etc.
  • the compound can be produced by subjecting the compound to the following reaction and, if necessary, to deprotection of a protecting group. it can.
  • This reaction is known, and is carried out, for example, in an organic solvent (tetrahydrofuran, N, N dimethylformamide or the like) in the presence of triphosgene using a base (triethylamine or the like) at 0 to 40 ° C.
  • a base triethylamine or the like
  • an organic solvent methylene chloride, N, N dimethylformamide
  • CDI 1,1′-carbolbis-1H-imidazole
  • R 1 is a substituent (this “substituent” is a “hydrocarbon group” as a substituent of the “amino group which may have a substituent” represented by E) And the other symbols have the same meanings as described above.)
  • R 1G3P has the same meaning as R 1G3.
  • protection is when the carboxy group contained in the group represented by R 1G3, hydroxyl, amino and mercapto groups are protected as necessary
  • amido-dani reaction is known, for example, (1) a method using an acid halide,
  • the method using an acid or a compound is, for example, a method in which a carboxylic acid is converted into an acid halide (oxalyl chloride, oxalyl chloride, or the like) in an organic solvent (e.g., And thionyl chloride) at ⁇ 20 ° C to reflux temperature, and the resulting acid and chloride are reacted in the presence of a base (pyridine, triethylamine, dimethylamine, dimethylaminopyridine, diisopropylethylamine, etc.).
  • a base pyridine, triethylamine, dimethylamine, dimethylaminopyridine, diisopropylethylamine, etc.
  • the reaction is carried out at a temperature of 0 to 40 ° C in an organic solvent (eg, chloroform, dichloromethane, getyl ether, tetrahydrofuran, etc.).
  • an organic solvent eg, chloroform, dichloromethane, getyl ether, tetrahydrofuran, etc.
  • the obtained acid peroxide is reacted with an amine at 0 to 40 ° C. in an organic solvent (dioxane, tetrahydrofuran, etc.) using an aqueous alkali solution (aqueous sodium bicarbonate or sodium hydroxide solution). You can do it. Further, a commercially available acid halide may be used.
  • a carboxylic acid is dissolved in an organic solvent (eg, chloroform, dichloromethane, dimethyl ether, tetrahydrofuran) or in the absence of a solvent, and a base (pyridine, triethylamine) is used.
  • an organic solvent eg, chloroform, dichloromethane, dimethyl ether, tetrahydrofuran
  • a base pyridine, triethylamine
  • Amide dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.
  • acid nolide pivaloyl chloride, tosyl chloride, mesyl chloride, etc.
  • acid derivative ethyl ethyl chloroformate, isobutyl chloroformate, etc.
  • organic solvent e.g., chloroform, dichloromethane, methyl ether, tetrahydrofuran
  • a condensing agent for example, a carboxylic acid and an amine are reacted with a base (pyridine) in an organic solvent (eg, chloroform, dichloromethane, dimethylformamide, dimethyl ether, tetrahydrofuran) or without a solvent.
  • a base pyridine
  • organic solvent eg, chloroform, dichloromethane, dimethylformamide, dimethyl ether, tetrahydrofuran
  • condensing agents (1,3-dicyclohexynolephenolic olepositimide (DCC), 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide) (EDC), 1,1, -carbodiimidazole (CDI), 2-chloro- 1-methylpyridi-dimethodine, 1-propanephosphonic acid cyclic anhydride ⁇ P
  • the reaction is carried out at ⁇ 40 ° C.
  • All of the reactions (1), (2) and (3) are desirably performed under an inert gas (argon, nitrogen, etc.) atmosphere under anhydrous conditions.
  • inert gas argon, nitrogen, etc.
  • the compound used as a starting material or a reagent may be a compound known per se, or a method described in the above or a known method (column f, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard And the method described in Larock, John Wiley & Sons Inc, 1999).
  • a method described in the above or a known method for example, among the compounds represented by the general formula ( ⁇ ), Le) pidazine (CAS.No.2252-63-3), 4, -piperazinoacetophenone (CAS.No.
  • reaction involving heating can be performed using a water bath, an oil bath, a sand bath, or a microwave, as will be apparent to those skilled in the art.
  • a solid-phase-supported reagent supported on a high-molecular polymer eg, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, or the like
  • a high-molecular polymer eg, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, or the like
  • a reaction product is purified by a conventional purification means, for example, distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion It can be purified by a method such as exchange resin, scavenger resin or column chromatography or washing and recrystallization. Purification may be performed for each reaction or may be performed after completion of several reactions. [Pharmacological activity]
  • the vehicle used to administer the compound represented by the general formula (I) to an animal may be any as long as it can suspend or dissolve the compound in a safe and administrable state.
  • the vehicle used for administration to methinoresenololose, canoleboxy methinoresenololose, hydroxypropinoresenorelose, hydroxypropyl methylcellulose, propylene glycol, polyethylene glycol, sugar, sugar alcohol, edible oil, distilled water, physiological water Salt water and a mixture thereof can be appropriately selected and used.
  • Ii Insulin resistance in a diabetes model using ⁇ mice B Investigation of good effects Male KKAyZTa Jcl mice are received at the age of 8 weeks and then reared in individual cages for about one week. During the pre-breeding period and during the test period, the animals are allowed to freely ingest solid feed and tap water from water bottles. On the day of the experiment (Day O), the body weight is measured, and the tail vein strength is measured using a microcapillary blood sample, and then the blood glucose level is measured. Groups are divided by the randomized stratification method using blood glucose as an index, and 5 animals are assigned to each group, and medication is started.
  • Administration can be carried out, for example, by suspending or dissolving the test drug in the above-described medium, and then parenterally administering subcutaneously using a force or a syringe that forcibly administers orally using a probe. It is preferable to administer the vehicle alone to the control group.
  • the dose and the number of times of administration can be appropriately increased or decreased depending on the effect of the test drug. For example, it is preferable to administer about 0.1 to 100 mgZkg body weight once to three times a day every day.
  • body weight, food consumption, blood glucose level, plasma triglyceride, insulin level, liver weight, etc. can be used. Can be measured after spending.
  • pioglitazone which is generally used as a control drug, can be administered, for example, by orally administering 50 mg Zkg body weight once a day to increase body weight, decrease blood glucose level, decrease insulin level, etc. Can be shown to be effective.
  • LPS lipopolysaccharide
  • 055 B5
  • Difco lipopolysaccharide
  • Administer intraperitoneally 5 patients in each group).
  • the control group receives vehicle alone (5 cases).
  • blood is collected from the abdominal vena cava with ether under anesthesia and centrifuged (12,000 rpm, 3 minutes, 4 ° C) to obtain a plasma sample.
  • Store the obtained plasma sample at 80 ° C until use.
  • TNF-a in plasma can be quantified using a commercially available ELISA kit (for example, R & D: # MTA00, etc.).
  • a test drug suspended or dissolved in the above-mentioned medium is administered (preferably by oral administration, etc.), and 2 hours later, lipopolysaccharide (LPS, 055: B5, Difco) is weighed at 10 gZkg.
  • LPS lipopolysaccharide
  • the control group receives vehicle alone (5 cases).
  • 90 minutes after LPS treatment, under anesthesia with ether blood is collected from the abdominal vena cava by adding blood, and centrifuged (12,000 rpm, 3 minutes, 4 ° C) to obtain a plasma sample. Store the obtained plasma sample at -80 ° C until use.
  • TNF-a in plasma can be quantified using a commercially available ELISA kit (eg, Genzyme ZTechne: # 10516 etc.).
  • the toxicity of the compound represented by the general formula (I) is extremely low, and it is safe enough for use as a medicine.
  • the compound represented by the general formula (I), a salt thereof or a solvate thereof, or a prodrug thereof may be abbreviated as the compound of the present invention
  • may be a mammal for example, a human, non-human animal, For example, it has excellent kinase (particularly JNK) inhibitory activity against monkeys, sheep, horses, horses, dogs, cats, rabbits, rats, mice, etc .
  • Jun-related diseases such as metabolic diseases (eg, diabetes (type I diabetes, type II diabetes (insulin-resistant diabetes, insulin-lowering diabetes)), hyperlipidemia, and other insulin-resistant diseases
  • Inflammatory diseases eg, rhinitis, pharyngitis, bronchitis, lungs
  • Inflammation pleurisy, bronchial asthma, chronic emphysema, pulmonary fibrosis, inflammatory bowel disease, acute splenitis, chronic knee inflammation, adult respiratory distress syndrome, chronic thyroiditis, autoimmune gastritis, etc
  • the compound of the present invention can be used to produce TNF- ⁇ in mammals (eg, humans, non-human animals such as monkeys, sheep, pests, pomas, canines, cats, pawns, rats, mice, etc.).
  • TNF- ⁇ -mediated diseases such as inflammatory diseases [eg, diabetic complications (eg, retinopathy, nephropathy, neuropathy, macrovascular disorders, etc.), inflammation, dermatitis, atopic Dermatitis, hepatitis, nephritis, glomerulonephritis, spleenitis, psoriasis, gout, Addison's disease, arthritis (eg, rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, synovium Inflammation), inflammatory eye disease, inflammatory lung disease (e.g., chronic pneumonia, silicosis, pulmonary sarcoidosis,
  • inflammatory diseases e.
  • kinase-related diseases JNK-related diseases, c Jun-related diseases, and TNF- ⁇ -mediated diseases are not limited to the above-listed diseases, and diseases for which their involvement is suggested, and their involvement will be discovered in the future. All diseases.
  • the compound of the present invention can provide an eosinophil infiltration inhibitory action based on a kinase inhibitory action, a JNK inhibitory action and a TNF- ⁇ production inhibitory action. By this action, the compound of the present invention can also be used as a nasal congestion improving agent.
  • the compound of the present invention is a disease involving infiltration of eosinophils, for example, chronic juniper, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, irritable pneumonitis, eczema, herpetic dermatitis, psoriasis, Prevention and / or treatment of eosinophilic pneumonia (PIE syndrome), chronic obstructive pulmonary disease (COPD), asthma, contact dermatitis, pruritus, dry dermatitis, acute juvenile rash, prurigo etc. It can also be used as a closure improving agent.
  • PIE syndrome chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • JNK1, JNK2, JNK3 JNK1, JNK2, JNK3
  • JNK1 for example, the enzyme system described in the examples below, dissociation of IC values in JNKl ⁇ JNK2, JNKliJNK3, and PioNK1, 2, 3
  • JNK1 for example, the enzyme system described in the examples below, dissociation of IC values in JNKl ⁇ JNK2, JNKliJNK3, and PioNK1, 2, 3
  • the IC values for JNK1 and other enzyme activities are determined.
  • the compound of the present invention In order to use the compound of the present invention for the above purpose, it is generally administered as a pharmaceutical composition systemically or locally, orally or parenterally. [0151] Since the compound of the present invention is safe and has low toxicity, it can be used in mammals (for example, humans, non-human animals, for example, monkeys, higgs, puppies, pomas, dogs, cats, puppies, rats, mice, etc.). ) Can be administered.
  • the dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc. Usually, the dosage is in the range of lmg to lOOOOmg per adult, once a day, and several times a day. It is administered orally or parenterally (preferably intravenously) several times as often as once a day in a dose of 0.1 mg to 100 mg per adult per day. It is continuously administered intravenously within a period of time to 24 hours.
  • the compound of the present invention is mixed as it is or with a pharmacologically acceptable carrier according to a means known per se generally used in a method for producing a pharmaceutical preparation.
  • a pharmaceutical preparation such as a release preparation, it can be safely administered orally or parenterally (eg, topically, rectally, intravenously, etc.).
  • the content of the compound of the present invention in the vigorous preparation is about 0.01% to about 100% by weight, preferably about 0.1% to about 50% by weight, more preferably about 0.1% by weight of the whole preparation. 5% to about 20% by weight.
  • the compound of the present invention used in the production of these pharmaceutical preparations is not limited to a substance that is substantially pure and a single substance, but may include impurities (for example, by-products derived from the production process, solvents, Raw materials, or degradation products, etc.) as long as the drug substance is acceptable.
  • impurities for example, by-products derived from the production process, solvents, Raw materials, or degradation products, etc.
  • Pharmacologically acceptable carriers used in the production of these pharmaceutical preparations include various organic or inorganic carrier substances commonly used as preparation materials, such as excipients in solid preparations, lubricants and the like. Examples include powders, binders and disintegrants, or solvents in liquids, solubilizers, emulsifying or suspending agents, isotonic agents, buffers and soothing agents. Further, if necessary, usual additives such as preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts. [0157] Examples of the solid preparation for oral administration for oral administration include tablets, pills, capsules, powders, and granules.
  • Capsules include hard capsules and soft capsules.
  • the one or more active ingredients may be as such or excipients (eg, ratatose, mannitol, glucose, microcrystalline cellulose, starch, corn starch, light caffeic anhydride, etc.).
  • Binders eg, hydroxypropylcellulose, polybutylpyrrolidone, magnesium aluminate metasilicate, crystalline cellulose, sucrose, D-mantol, dextrin, hydroxypropylmethylcellulose, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose)
  • Disintegrants eg, calcium cellulose glycolate, starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, L-hydroxypropyl cellulose
  • lubricants e.g., magnesium stearate, calcium stearate, are mixed talc, colloidal silica and the like
  • a coating agent eg, sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.
  • a coating agent eg, sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.
  • You may also use capsules made of absorbable substances such as gelatin! ,.
  • liquid preparation for oral administration examples include pharmaceutically acceptable solutions, suspensions, emulsions, syrups, elixirs and the like.
  • viscous solutions one or more active substances are dissolved, suspended or emulsified using commonly used diluents (eg, purified water, ethanol or a mixture thereof).
  • the solution may further contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffer and the like.
  • injections for parenteral administration include all injections and also include drops. For example, injections into muscle, subcutaneous injections, intradermal injections, intraarterial injections, intravenous injections, intraperitoneal injections, spinal injections, Intravenous infusions and the like can be mentioned.
  • Injections for parenteral administration include solutions, suspensions, emulsions, and solid injections used by dissolving or suspending in a solvent before use. Injectables are used by dissolving, suspending or emulsifying one or more active substances in a solvent.
  • solvents examples thereof include distilled water for injection, physiological saline, macrogol, vegetable oils (eg, sesame oil, corn oil, olive oil, etc.), alcohols such as propylene glycol, polyethylene glycol, and ethanol, and combinations thereof. Is used.
  • the injection may further contain a stabilizing agent (for example, D sorbitol, D mannitol, L alanine, ascorbic acid, albumin, inositol, sodium dalconate, sodium thioglycolate, polyoxyethylene hydrogenated castor oil, etc.)
  • a stabilizing agent for example, D sorbitol, D mannitol, L alanine, ascorbic acid, albumin, inositol, sodium dalconate, sodium thioglycolate, polyoxyethylene hydrogenated castor oil, etc.
  • Auxiliaries eg, glutamic acid, aspartic acid, polysorbate 80®, polyethylene glycol, propylene glycol, D mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate , Sodium citrate, etc.
  • emulsifying or suspending agents for example, surfactants (for example, steary
  • a sterile solid preparation for example, a lyophilized product
  • Freeze-drying can be performed by a method known per se. Generally, after freezing at a temperature of -25 ° C or less, while keeping the vacuum in the drying cabinet at about 13.3Pa or less, raise the shelf temperature until it reaches 25 ° C to 40 ° C. Drying is preferred.
  • compositions for parenteral administration include topical solutions, ointments, salves, inhalants, sprays, suppositories containing one or more active substances and prescribed in a conventional manner. And a pessary for vaginal administration.
  • Sprays may be used in addition to commonly used diluents, such as buffering agents, which provide isotonicity with stabilizers such as sodium bisulfite, for example, sodium chloride, sodium citrate or citric acid. It may contain a suitable isotonic agent.
  • the compound of the present invention comprises (1) complementation and / or enhancement of the prophylactic and Z or therapeutic effects of the compound, (2) improvement of kinetic 'absorption of the compound, reduction of the dose, and Z or (3 )
  • the compound may be administered as a concomitant drug in combination with another drug for the purpose of, for example, reducing the side effects of the compound.
  • the compound of the present invention may be combined and administered as a concomitant drug for the reduction and the reduction of Z or (3) side effects.
  • the concomitant drug of the compound of the present invention and the concomitant drug may be administered in the form of a combination preparation in which both components are combined in one preparation, or may be in the form of administration as separate preparations. When administered as separate preparations, simultaneous administration and administration at different times are included. The administration at a time difference may be performed by administering the compound of the present invention first and then administering the concomitant drug later, or administering the concomitant drug first and then administering the compound of the present invention later. The method of administration may be the same or different. Diseases in which the compound of the present invention and the concomitant drug exert a prophylactic and / or Z- or therapeutic effect are not particularly limited.
  • the weight ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the compound of the present invention and the concomitant drug is not particularly limited.
  • the concomitant drug is not limited to a low-molecular compound, and may be a high-molecular protein, polypeptide, polynucleotide (DNA, RNA, gene), antisense, decoy, antibody, vaccine, or the like.
  • the dose of the concomitant drug can be appropriately determined based on the clinically used dose.
  • the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the age and weight of the administration subject, administration method, administration time, target disease, symptom, combination, and the like.
  • the compound of the present invention The concomitant drug may be used in an amount of 0.01 to 100 parts by weight per part by weight.
  • the concomitant drug may be administered in the same or different groups as described below, and optionally one or more of them may be administered in an appropriate ratio and in an appropriate combination.
  • Concomitant drugs that complement and / or enhance the prophylactic and / or therapeutic effects of the compounds of the present invention include those that have been found to date as well as those that will be discovered in the future based on the mechanism described above. included. Examples of concomitant drugs that can be used in combination with the compound of the present invention include the following.
  • Examples of the concomitant drug for complementing and / or enhancing the prophylactic and / or Z or therapeutic effects of the compound of the present invention on arthritis and the like include, for example, steroid drugs, elastase inhibitors, cannapinoid 2 receptor stimulants, Prostaglandins, prostaglandin synthase inhibitors, phosphodiesterase inhibitors, meta-oral proteinase inhibitors, adhesion molecule inhibitors, anti-cytointensity protein preparations (e.g., anti-TNF- ⁇ preparations, anti-IL-1 preparations, Anti-IL 6 preparations), anti-cytopotency drugs, immunomodulators, disease-modifying anti-rheumatic drugs, non-steroidal anti-inflammatory drugs, cj un N-terminal kinase inhibitors and the like.
  • steroid drugs elastase inhibitors
  • cannapinoid 2 receptor stimulants include, for example, steroid drugs, elastase inhibitors, cannapinoid 2 receptor
  • Examples of the concomitant drug for complementing and / or enhancing the effect of the compound of the present invention on, for example, inflammatory bowel disease and the like, for example, for inflammatory bowel disease include steroid drugs, elastase inhibitors, and cannapinoid 2 receptor Stimulants, prostaglandins, prostaglandin synthase inhibitors, phosphodiesterase inhibitors, meta-oral proteinase inhibitors, adhesion molecule inhibitors, anti-cytopotency protein preparations, anti-cytopotency drugs, immunomodulators, Leukotriene receptor antagonist, anticholinergic, 5-lipoxygenase inhibitor, nitric oxide synthase inhibitor, interleukin-8 antagonist, poly (ADP) -ribose polymerase inhibitor, mitochondrial benzodiazepine Receptor agonist, antioxidant, local anesthetic, gastrointestinal ulcer, protective factor potentiator, mesalazine, sala Zosulfaviridine and the like.
  • Examples of the concomitant drug for complementing and / or enhancing the effect of the compound of the present invention on, for example, prophylactic and Z or therapeutic effects against respiratory diseases and the like include steroid drugs, elastase inhibitors, and cannapinoid 2 receptors.
  • Stimulants prostaglandins, prostaglandin synthase inhibitors, phosphodiesterase inhibitors, meta-oral proteinase inhibitors Harmful drugs, adhesion molecule inhibitors, leukotriene receptor antagonists, anticholinergics, thromboxane A2 receptor antagonists, thromboxane synthase inhibitors, ⁇ 2-adrenergic receptor stimulants, xanthin derivatives, expectorants, antibiotics And antihistamines, anti-cytotoxic proteins, anti-cytotoxic drugs, forskolin preparations, mediator release inhibitors and the like.
  • Examples of the concomitant drug for complementing and / or enhancing the preventive and / or therapeutic effects of the compound of the present invention on hyperlipidemia and the like include, for example, MTP (Microsomal Triglyceride Transfer Protein) inhibitor, HMG — Co A reductase inhibitor, squalene synthetase inhibitor, fibrate-based drug (fibric acid derivative), ACAT (acyl CoA: cholesterol O-acyltransferase) inhibitor, 5-lipoxygenase inhibitor, cholesterol absorption inhibitor, bile acid absorption inhibitors, ileal Na + Z bile acid co transportation Okukarada (ileal Na + / bile acid transporter ; IBAT) inhibitor, LDL receptor activator, LDL receptor expression-enhancing drug, a lipase inhibitor, probucol formulation And nicotinic acid preparations, and other drugs for treating anti-hypercholesterolemia.
  • MTP Mericrosomal Triglyceride Transfer Protein
  • the compound of the present invention complements the prophylactic and Z or therapeutic effects of, for example, diabetes (type I diabetes, type II diabetes (insulin-resistant diabetes mellitus, insulin-secreting diabetes)), diabetic complications and the like.
  • Z or concomitant drugs for potentiation include, for example, sulfourea hypoglycemic drugs, biguanide drugs, a-dalcosidase inhibitors, fast-acting insulin secretagogues, insulin drugs, DPP (dipeptidyl) Peptidase) 4 inhibitors, PTP1B inhibitors, ⁇ 3 adrenergic receptor agonists, PPAR (eg, PPAR, PPARy, PPAR ⁇ , etc.) agonists, and diabetic complication therapeutic agents.
  • sulfourea hypoglycemic drugs biguanide drugs, a-dalcosidase inhibitors, fast-acting insulin secretagogues, insulin drugs, DPP (dipeptidyl) P
  • Examples of the inhibitors include BMS-201038, BMS-212122, BMS-200150, GW-328713, R-103757 and the like.
  • Examples of the HMG-CoA reductase inhibitor include atorvastatin, flupastatin, oral pastatin, pitapatin, pravastatin, rospastatin, simpastatin and the like.
  • Examples of the ACAT inhibitor include F-12511, F-1394, CI-1011, melinamide, FCE27677, RP73163 and the like.
  • Examples of the squalene synthetase inhibitor include TAK-475 and the like.
  • fibrate preparations include gemfibrozil, clofibrate, b ezafibrate, fenofibrate and the like.
  • examples of the cholesterol absorption inhibitor include SCH48461 and the like.
  • examples of bile acid absorption inhibitors include cholestyra mine, cholestagel and the like.
  • Examples of LDL receptor activity drugs and LDL receptor expression enhancers include MD-700, LY295427 and the like.
  • lipase inhibitor include orlistat.
  • Examples of the sulfolurea hypoglycemic agent include acetohexamide, dalibenclamide, daliclazide, glycloviramide, chlorpropamide, tolazamide, tolptamide, glimepiride and the like.
  • Examples of biguanide-based preparations include pformin hydrochloride and metformin hydrochloride.
  • Examples of the a-dalcosidase inhibitor include acarbose, voglibose, and the like.
  • Examples of fast-acting insulin secretagogues include nateglinide, repaglinide and the like.
  • Examples of the DPP4 inhibitor include NVP—DPP728A and the like.
  • Examples of ⁇ 3 adrenergic receptor agonists include AJ9677, L750355, CP331648, etc. in column f.
  • PPAR agonists include pioglitazone, troglitazone, rosiglitazone, JTT-501 and the like.
  • Examples of the drug for treating diabetic complications include epalrestat.
  • steroid drugs include clobetasol propionate, diflorazone acetate, fluocinonide, mometasone furoate, betamethasone dipropionate, betamethasone propionate butyrate, betamethasone valerate, difluprednate, diflucortron valerate, and amsino -D, halcino -d, dexamethasone, dexamethasone propionate, dexamethasone valerate, dexamethasone acetate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyrate, deprodone propionate, prednisolone valerate, fluocinolone acetate, propionate Beclomethasone, triamcinolone acetate, flumethasone pivalate, alclomethasone propionate, clobetasone butyrate, prednisolone, fludroqui Cortide,
  • Examples of elastase inhibitors include ONO-5046, ONO-6818, MR-889, PBI-1101, EPI-HNE-4, R-665, ZD-0892, ZD-8321, GW-311616, DMP- 777, L-659286, L-658758, L-680833, L-683845, AE-3763.
  • Examples of prostaglandins include PG receptor agonists, PG receptor antagonists and the like. Examples of the PG receptor include PGE receptor (EP1, EP2, EP3, EP4), PGD receptor (DP, CRTH2), PGF receptor (FP), PGI receptor (IP), TX receptor (TP) And the like.
  • prostaglandin synthase inhibitors include, for example, salazosulfapyridine, mesalazine, osalazine, 4-aminosalicylic acid, JTE-522, auranofin, carpuprofen, difenpyramide, flunoxaprofen, flurbiprofen, Dexamethasin, ketoprofen, lornoxicam, loxoprofen, meloxicam, oxaprozin, persalmide, piploxen, piroxicam, piroxicam betadettas, piloxicam cinnamate, tropine indomethacinate, zaltoprofen, planoprofen and the like.
  • Examples of phosphodiesterase inhibitors include PDE4 inhibitors rolipram, cilomilast (trade name: Arif Mouth), Bayl9—8004, NIK—616, roflumilast (BY—217), sipamphylline (BRL—61063), and achizolam (CP— 80633), SCH-3511591, YM-976, V-11294A, PD-168787, D-4396, IC-485 and the like, or PDE5 inhibitor sildenafil and the like.
  • Examples of the adhesion molecule inhibitor include an antagonist such as ⁇ 4 integrin.
  • Anti-TNF- ⁇ preparations also include, for example, antibodies to TNF-a, soluble TNF- ⁇ receptor, antibodies to TNF- ⁇ receptor, soluble TNF- ⁇ binding protein, and the like. For example, infliximab, etanercept, and the like are included.
  • Anti-IL-1 preparations also include, for example, antibodies to IL-1, soluble IL1 receptor, IL1Ra, antibodies to IL1 receptor, and anakinra, for example.
  • Anti-IL-6 preparations also include, for example, antibodies to IL-6, soluble IL-6 receptor, antibodies to IL-6 receptor, and, for example, MRA and the like. I can get lost.
  • immunomodulator examples include methotrexate, cyclosporin, ascomycin, leflunomide, bucillamine, salazosulfaviridin, azathioprine, tacrolimus, cyclophosphamide and the like.
  • Disease-modifying antirheumatic drugs include, for example, gold thioglucose, sodium gold thiomalate, auranofin, cloquinine, actalit, D ⁇ -silamine preparation, oral benzaritni sodium, bucillamine, hydroxychloroquine, salazosulfapyridine And the like.
  • Non-steroidal anti-inflammatory drugs include, for example, sazapyrine, sodium salicylate, aspirin, aspirin, dialuminate, diflu-sal, indomethacin, suprofen, ⁇ fenamate, dimethylisopropylazulene, bufexamac, fuerbinac, diclofenac, tolmetin sodium , Crinolyl, fenbufen, napmetone, proglumetacin, indomethacin pharmacin, acemetacin, maleic acid proglumetacin, ampfenac sodium, mofuezolac, etodolac, ibuprofen, ibuprofen piconol, naproxen, funorerbiprofen, Norelbiprofen Axetil, Ketoprofen, Fenoprofen calcium, Thiaprofen, Oxaprozin, Pranoprofen, Loki Soprofen sodium, alum
  • leukotriene receptor antagonists examples include pranlukast hydrate, montelukast, zafirlukast, seratrodast, MCC—847, KCA—757, CS—615, YM—158, L—740515, CP—195494, and LM—1484. , RS-635, A-93178, S-36496, BIIL-284, ONO-4057, etc.
  • Anticholinergic agents include, for example, palladium bromide, oxitropium bromide, pium pium bromide, cimetropium bromide, temiverine, pium pium bromide, revatropate (UK-112166) and the like.
  • Examples of the local anesthetic include ***e hydrochloride, procaine hydrochloride, lidocaine, dibucaine hydrochloride, tetracaine hydrochloride and the like.
  • Protective factor enhancers include, for example, sucralfate, ardioxa, teprenone, cetraxate hydrochloride, ornoprost And the like.
  • Examples of the thromboxane A2 receptor antagonist include seratrodast, ramatroban, domitroban calcium hydrate, KT-2-962, and the like.
  • Examples of the thromboxane synthase inhibitor include ozadarel hydrochloride, ozadarel sodium, imitrodast sodium and the like.
  • ⁇ 2-adrenergic receptor stimulants include phenoterol hydrobromide, salbutamol sulfate, terbutaline sulfate, formoterol fumarate, salmeterol xinafoate, isoproterenol sulfate, orciprenaline sulfate, chlorprenaline sulfate, epinephrine, Trimethoquinol hydrochloride, hexoprenaline mesyl sulfate, proforcerol hydrochloride, lobbuterol hydrochloride, lobbuterol, pyrbuterol hydrochloride, clenbuterol hydrochloride, mabuterol hydrochloride, ritodrine hydrochloride, bambuterol hydrochloride, doxamine hydrochloride, meradrine tartrate, AR-C68397, revo Salbutamol, formoterol, KUR-1246, KUL-7211,
  • xanthine derivative examples include aminophylline, theophylline, doxophylline, sipamphyrin, diprofylline and the like.
  • Ammo Yuaukiyosei sodium bicarbonate, bromhexine hydrochloride, carbocysteine, ambroquinol hydrochloride, ambroxol hydrochloride sustained release agent, methyl cysteine hydrochloride, acetyl cysteine, L-ethyl cysteine hydrochloride, Tyloxapol and the like.
  • Antibiotics include, for example, cefuroxime sodium, meropenem trihydrate, netinoremycin sulfate, sisomycin sulfate, ceftibutene, PA-1806, IB-367, tobramycin, PA-1420, doxorubicin, astromycin sulfate And cefetametopivoxil hydrochloride.
  • Antibiotics for inhalation include, for example, PA-1806, IB-367, tobramycin, PA-1420, doxorubicin, astromycin sulfate, cefetametopivoxil hydrochloride and the like.
  • Antihistamines include, for example, ketotifen fumarate, mequitazine, azelastine hydrochloride, oxatomide, terfenadine, emedastine fumarate, epinastine hydrochloride, astemizole, ebastine, cetirizine hydrochloride, bepotastine, fexofenadine, oral latadine, Det's mouth latadine, olopatadine hydrochloride, TAK-427, ZCR-2060, NIP-530, mometasoneph mouth, mizolastine, BP-294, andlast, auranofin, atarivastin and the like.
  • Anti-cytokine drugs include all non-protein preparations that block the action of cytoforce, such as MAP kinase inhibitors, genes Modulators, cytoinhibitors, TNF-a converting enzyme inhibitors, IL- ⁇ converting enzyme inhibitors, IL-6 antagonists, IL-8 antagonists, chemokine antagonists, gene therapeutics, antisense And the like.
  • cytoforce such as MAP kinase inhibitors, genes Modulators, cytoinhibitors, TNF-a converting enzyme inhibitors, IL- ⁇ converting enzyme inhibitors, IL-6 antagonists, IL-8 antagonists, chemokine antagonists, gene therapeutics, antisense And the like.
  • MAP kinase inhibitor include PD-98059 and the like.
  • the gene modulator include inhibitors of molecules related to signal transduction such as NF- ⁇ B, IKK-1, IKK-2, and AP-1.
  • Examples of the cytoforce in production inhibitor include sublatast tosylate (trade name IPD), T-614, SR-31747, sonatimod and the like.
  • Examples of chemokine antagonists include ONO-4128.
  • Examples of gene therapy drugs include gene therapy aimed at enhancing the expression of anti-inflammatory genes such as interleukin 4, interleukin 10, soluble IL 1 receptor, and soluble TNF- ⁇ receptor. Drugs and the like.
  • Examples of the mediator release inhibitor include tralast, sodium cromoglycate, amlexanox, revilinast, ibudilast, dazanolast, and dimilolast potassium.
  • Jun N-terminal kinase inhibitor examples include the conjugates described in WOOO / 35906, WOOO / 35909, WOOO / 35921, WO00 / 64872 or WO00 / 75118.
  • the dose of the compound of the present invention or the concomitant drug can be reduced as compared with a case where the compound is administered alone;
  • the compound of the present invention and the concomitant drug can be selected according to the symptoms (mild, severe, etc.) of the compound.
  • the treatment period can be reduced by selecting a concomitant drug having a different mechanism of action from the compound of the present invention.
  • Selection of a concomitant drug having a different mechanism of action from the compound of the present invention can maintain the therapeutic effect; (5) Combination of the compound of the present invention and the concomitant drug By doing so, excellent effects such as a synergistic effect can be obtained.
  • rhabdomyolysis may occur as a side effect when a fibrate-based drug and an HMG-CoA reductase inhibitor are used in combination. May reduce the incidence and extent of rhabdomyolysis.
  • the use of the compound of the present invention in combination with a concomitant drug is referred to as “the concomitant drug of the present invention”.
  • the administration time of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention or the pharmaceutical composition thereof and the concomitant drug or the pharmaceutical composition thereof are simultaneously administered to a subject to be administered. It may be administered at an interval or at different times.
  • the dose of the concomitant drug can be appropriately selected depending on the administration subject, administration route, disease, combination and the like according to the clinically used dose.
  • the administration form of the concomitant drug of the present invention is not particularly limited, as long as the compound of the present invention and the concomitant drug are combined in vivo.
  • Such administration forms include, for example, (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the concomitant drug, and (2) separate preparation of the compound of the present invention and the concomitant drug. (3) Simultaneous administration of the two preparations obtained in the same administration route, and (3) a time lag between the two preparations obtained by separately formulating the compound of the present invention and the concomitant drug by the same administration route.
  • the compound of the present invention and Z or a concomitant drug are used directly or in pharmacology according to a method known per se generally used in a method for producing a pharmaceutical preparation.
  • Solid carriers eg, tablets (including dragees, film-coated tablets), powders, pills, granules, capsules, etc.
  • liquids for internal use liquids for external use
  • pharmaceutical preparations such as injections, suppositories and sustained-release preparations, they can be safely administered orally or parenterally (eg, topically, rectally, intravenously, etc.).
  • Pharmaceutically acceptable carriers used in the production of these pharmaceutical preparations include various organic or inorganic carrier substances commonly used as preparation materials, such as excipients in solid preparations, lubricants and the like. Examples include solubilisers, binders and disintegrants, or solvents in liquids, solubilizers, emulsifying or suspending agents, isotonic agents, buffers and soothing agents. If necessary, conventional additives such as preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.
  • excipient examples include ratatose, mannitol, glucose, and microcrystalline cellulose.
  • binder examples include hydroxypropylcellulose, polyvinylpyrrolidone, magnesium aluminate metasilicate, crystalline cellulose, sucrose, D-mantol, dextrin, hydroxypropylmethylcellulose, starch, sucrose, gelatin, methylcellulose And sodium carboxymethyl cellulose.
  • Disintegrators include, for example, cellulose glycolate, starch, carboxymethylcellulose, carboxymethylcellulose calcium, sodium carboxymethyl starch, L-hydroxypropylcellulose and the like.
  • Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • Examples of the solvent include distilled water for injection, physiological saline, macrogol, vegetable oils (eg, sesame oil, corn oil, olive oil, etc.), alcohols such as propylene glycol, polyethylene glycol, ethanol and the like, and combinations thereof. Is mentioned.
  • Examples of the stabilizer include D-sorbitol, D-mantol, L-alanine, ascorbic acid, albumin, inositol, sodium dalconate, sodium thioglycolate, polyoxyethylene hydrogenated castor oil, and the like.
  • solubilizing agent examples include glutamic acid, aspartic acid, polysorbate 80 (registered trademark), polyethylene glycol, propylene glycol, D-mantole, benzyl benzoate, ethanol, trisaminomethane, cholesterol, and triethanolamine. , Sodium carbonate, sodium citrate and the like.
  • emulsifying or suspending agents examples include surfactants (eg, stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalco-pum chloride, benzetium chloride, monostearin) Glycerin acid), hydrophilic polymers (eg, polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethinoresenorelose, hydroxyethinoresenorelose, hydroxypropinoresenorelose, etc.) and the like. It is.
  • the soothing agent examples include benzyl alcohol and the like.
  • Examples of the tonicity agent include glucose, D-sorbitol, sodium salt, glycerin, D-mantol and the like.
  • Examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate.
  • Preservatives include, for example, norahydroxybenzoic esters, chlorobutanol, benzyl alcohol, phenethyl alcohol , Dehydroacetic acid, sorbic acid and the like.
  • Examples of the antioxidant include sulfite, ascorbic acid, a -tocopherol and the like.
  • the compounding ratio of the compound of the present invention in the concomitant preparation of the present invention may vary depending on the form of the preparation. Usually, about 0.01% to about 100% by weight, preferably about 0.1% by weight based on the whole preparation. % To about 50% by weight, more preferably about 0.5% to about 20% by weight.
  • the compounding ratio of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01% to about 100% by weight, preferably about 0.1% to about 100% by weight, based on the whole preparation. 50% by weight, more preferably from about 0.5% to about 20% by weight.
  • the content of additives such as a carrier in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 1% to about 99.99% by weight, preferably about 10% by weight based on the whole preparation. About 90% by weight. The same content may be used when the compound of the present invention and the concomitant drug are separately formulated.
  • a tablet is prepared by granulating a drug as it is or by adding an excipient, a binder, a disintegrant or other appropriate additives, and mixing them uniformly to obtain granules by an appropriate method.
  • a tablet is prepared by granulating a drug as it is or by adding an excipient, a binder, a disintegrant or other appropriate additives, and mixing them uniformly to obtain granules by an appropriate method.
  • the granules can be produced as they are or by adding an appropriate additive to the granules and mixing them uniformly, followed by compression molding.
  • Such tablets may optionally contain a coloring agent, a flavoring agent, and the like.
  • the coating can be applied with an appropriate coating agent.
  • Injectables are prepared by dissolving, suspending, or emulsifying a certain amount of the drug in an aqueous solvent, water for injection, physiological saline, Ringer's solution, etc. Alternatively, a quantity of the medicinal product can be prepared in a sealed container for injection.
  • the carrier used in the preparation for oral administration for example, substances commonly used in the field of preparations such as starch, mannitol, crystalline cellulose, sodium carboxymethylcellulose and the like are used.
  • As the carrier used for the preparation for injection for example, distilled water, physiological saline, glucose solution, infusion solution and the like are used.
  • additives generally used in preparations can be appropriately added.
  • the dose of the concomitant drug of the present invention varies depending on the age, body weight, symptom, therapeutic effect, administration method, treatment time, and the like.
  • 1 force is orally administered several times in a single dose. It is administered parenterally several times (preferably intravenously) or continuously administered intravenously in the range of 1 hour to 24 hours a day.
  • the dose varies depending on various conditions, so that a dose smaller than the above dose may be sufficient, or may be required beyond the range.
  • the concomitant drug can be used in any amount as long as side effects do not become a problem and the object of the present invention can be achieved.
  • the daily dosage of the concomitant drug varies depending on the severity of symptoms, age, sex, weight, sensitivity difference, timing of administration, interval of administration, nature of pharmaceutical preparation, preparation, type, type of active ingredient, etc. There is no particular limitation.
  • the concomitant drug may be administered at the same time.
  • the compound of the present invention may be administered after the concomitant drug is administered first, or the compound of the present invention may be administered first. Administration may be followed by concomitant medication.
  • the administration is carried out with a time difference, the time difference varies depending on the active ingredient to be administered, the dosage form and the administration method.
  • the concomitant drug is administered first, it is preferably within 1 minute to 3 days after administration of the concomitant drug.
  • the method includes administering the compound of the present invention within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour.
  • the concomitant drug is administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour after administering the compound of the present invention. Method and the like.
  • the kinase inhibitor of the present invention comprising a compound represented by the general formula (I), a salt thereof, a solvate thereof, or a prodrug thereof, inhibits kinases, particularly JNK, and inhibits TNF- Since it also inhibits ⁇ production and has low toxicity, it can prevent and prevent metabolic diseases such as diabetes (particularly insulin-resistant diabetes), hyperlipidemia, and inflammatory diseases such as rheumatoid arthritis. Or, it is very useful as a therapeutic agent.
  • the solvent in kakkoko shown at the point of separation by chromatography and in TLC indicates the elution solvent or developing solvent used, and the ratio indicates the volume ratio.
  • NMR data are-NMR data.
  • the katakana shown in the NMR section indicates the solvent used for the measurement.
  • Solution A 0.1% trifluoroacetic acid aqueous solution
  • Solution B 0.1% trifluoroacetic acid-acetonitrile solution
  • the name of the compound used in the present specification is generally a computer program for naming according to the rules of IUPAC, ACD / Name (registered trademark, manufactured by Advanced Chemistry Development Inc.) or ACD. / Name This is a name using a batch (registered trademark, manufactured by Advanced Chemistry Development Inc.) or according to the IUPAC nomenclature.
  • ACD / Name registered trademark, manufactured by Advanced Chemistry Development Inc.
  • ACD registered trademark, manufactured by Advanced Chemistry Development Inc.
  • Example 2 The same operation as in Example 1 was performed using a corresponding halogenated compound instead of 2-bromopyridine to obtain the following compound of the present invention.
  • JNK1 Upstate Biotechnology # 14-327
  • JNK2 Upstate Biotechnology # 14-329
  • Tris-HC1 pH7.5
  • 5 mM ⁇ -glycerate phosphate 2 mM Dithiothreitol
  • O.lmM Na VO 10mM
  • kinase buffer 5 L containing the compound of the present invention was added, and the mixture was incubated at room temperature for 20 minutes.
  • a substrate mixture prepared using a kinase buffer [Piotinylated ATF2 ( 5 ⁇ g / mL) (Upstate Biotechnology # 14-4 32), adenosine triphosphate (for measuring JNK1 activity: 2 ⁇ mo // for measuring JNK2 activity: 5 mol / L) (Cell Signaling Technology # 9804), anti-phosphorylated ATF2 antibody (20-fold dilution) ( Cell Signaling Technology # 9221L)] was added, and the enzyme reaction was performed at 30 ° C for 30 minutes.
  • a kinase buffer [Piotinylated ATF2 ( 5 ⁇ g / mL) (Upstate Biotechnology # 14-4 32), adenosine triphosphate (for measuring JNK1 activity: 2 ⁇ mo // for measuring JNK2 activity: 5 mol
  • the enzyme reaction was stopped by adding 5 L of Hepes buffer (pH 7.4) containing 0.25% serum albumin (BSA) and 100 mM EDTA.
  • BSA serum albumin
  • the amount of the complex of phosphorylated ATF2 and anti-phosphorylated ATF2 produced by this reaction was measured using Alpha Screen TM Rabbit Detection Kit (Packard # 6760607).
  • the compounds of the present invention all had 50% or more of JNK enzyme inhibitory activity at 10 ⁇ mol ZL.
  • the IC values of the compounds prepared in Examples 1 (22), 2, and 2 (1) for JNK1 were 0.25 ⁇ mol / L, 0.47 ⁇ mol / L, and 0.3, respectively.
  • N- (l ⁇ [5-tert-butyl-3 (trifluoromethyl) 1H pyrazole-1 yl] methyl ⁇ butyl) N, monophenyl (100 g), carboxymethylcellulose potassium (20. Og), magnesium stearate (10. Og) and microcrystalline cellulose (87 Og) were mixed by a conventional method and tabletted to obtain 10,000 tablets containing 10 mg of the active ingredient in one tablet.
  • the compound represented by the general formula (I), a salt thereof or a solvate thereof, or a prodrug thereof has a kinase, particularly c Jun N-terminal kinase inhibitory activity, and has diabetes (type I diabetes, type II diabetes (insulin resistance)). It is useful as a medicament because it can be used as a prophylactic and / or therapeutic agent for metabolic diseases such as sexual diabetes mellitus and insulin-lowering diabetes mellitus)), hyperlipidemia and inflammatory diseases such as rheumatoid arthritis.

Abstract

Composé représenté par la formule générale (I) : A-D-E (I) [dans laquelle A représente un groupe aminé éventuellement substitué ou un groupe représenté par la formule (II) (dans lequel le noyau A1 représente un groupe hétérocyclique azoté éventuellement substitué) ; D représente un groupe alkylène en C1 à C4 éventuellement substitué ; et E représente un groupe hydroxy éventuellement protégé ou un groupe aminé éventuellement substitué] ; sel ou solvate du composé ; ou promédicament de n’importe lequel de ces composés. Ces composés ont une activité inhibitrice contre les kinases, en particulier la kinase à extrémité terminale N c-Jun, et sont donc utiles en tant qu’agent de prévention et/ou thérapeutique pour les maladies métaboliques telles que les diabètes (diabètes de type I, diabètes de type II (diabètes insulino-résistants, et les diabètes provoqués par une déficience de la sécrétion d’insuline)) et l’hyperlipémie et les maladies inflammatoires telles que l’arthrite rhumatoïde chronique.
PCT/JP2005/010120 2004-06-03 2005-06-02 Inhibiteur des kinases et utilisation de cet inhibiteur WO2005118543A1 (fr)

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US8940726B2 (en) 2012-12-21 2015-01-27 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US8993555B2 (en) 2012-12-21 2015-03-31 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US9221794B2 (en) 2012-12-21 2015-12-29 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US9365555B2 (en) 2012-12-21 2016-06-14 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US10517849B2 (en) 2016-10-26 2019-12-31 Constellation Pharmaceuticals, Inc. LSD1 inhibitors and medical uses thereof
US10526287B2 (en) 2015-04-23 2020-01-07 Constellation Pharmaceuticals, Inc. LSD1 inhibitors and uses thereof
US10653693B2 (en) 2014-08-04 2020-05-19 Epizyme, Inc. PRMT5 inhibitors and uses thereof

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JPS61254563A (ja) * 1985-04-30 1986-11-12 アルツナイミッテルベルク、ドレスデン、ゲゼルシャフト、ミット、ベシュレンクテル、ハフツング 新規な３−シアン−ピリジン、その製造方法およびその薬学的応用
JPS62169768A (ja) * 1986-01-20 1987-07-25 ドムペ・フアルマセウテイチ・ソシエタ・ペル・アツイオ−ニ 薬理学的に活性なアルキロ−ル誘導体
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JPH11106398A (ja) * 1997-10-01 1999-04-20 Morinaga Milk Ind Co Ltd ペプチド誘導体および抗真菌剤
JP2002516854A (ja) * 1998-05-29 2002-06-11 アストラゼネカ アクチボラグ ピルビン酸デヒドロゲナーゼ活性を高めるための化合物の使用
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WO2002046184A1 (fr) * 2000-12-05 2002-06-13 Vertex Pharmaceuticals Incorporated Inhibiteurs de kinases c-jun n-terminales (jnk) et d'autres proteines kinases
WO2002051442A1 (fr) * 2000-12-26 2002-07-04 Takeda Chemical Industries, Ltd. Co-prescriptions
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WO2002092573A2 (fr) * 2001-05-16 2002-11-21 Vertex Pharmaceuticals Incorporated Inhibiteurs de src et autres proteine kinases
WO2003004488A1 (fr) * 2001-07-03 2003-01-16 Chiron Corporation Composes d'indazole benzimidazole utilises comme inhibiteurs de tyrosine et de serine/threonine kinase
JP2003506375A (ja) * 1999-07-30 2003-02-18 ノバルティス アクチエンゲゼルシャフト チロシンタンパク質キナーゼｓｙｋのプリン誘導体阻害剤
JP2003507329A (ja) * 1999-08-12 2003-02-25 フアルマシア・イタリア・エツセ・ピー・アー ３（５）−アミノ−ピラゾール誘導体、それらの製造方法および抗腫瘍薬としてのそれらの使用
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JP2003517447A (ja) * 1998-11-06 2003-05-27 ビーエーエスエフ アクチェンゲゼルシャフト 三環式ピラゾール誘導体
JP2003176273A (ja) * 1999-02-10 2003-06-24 Mitsubishi Pharma Corp アミド化合物およびその医薬としての用途
JP2003523340A (ja) * 2000-02-15 2003-08-05 スージェン・インコーポレーテッド ピロール置換２−インドリノン蛋白質キナーゼ阻害剤
WO2003068754A1 (fr) * 2002-02-13 2003-08-21 Astrazeneca Ab Derives d'indazole therapeutiques a substitution
JP2003525278A (ja) * 2000-03-01 2003-08-26 アストラゼネカ アクチボラグ 抗新生物薬剤としての２，４−ジ（ヘテロ−）アリールアミノ（−オキシ）−５−置換ピリミジン
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WO2004080973A1 (fr) * 2003-03-07 2004-09-23 Abbott Laboratories Inhibiteurs de pyrazole kinase fusionnee tricyclique et tetracyclique
WO2004080980A1 (fr) * 2003-03-14 2004-09-23 Novartis Ag 2,4-di(phenylamino)pyrimidines utilisees pour traiter des maladies neoplasiques, des troubles inflammatoires et des troubles du systeme immunitaire
WO2004110375A2 (fr) * 2003-06-06 2004-12-23 Merck & Co., Inc. Polytherapie permettant de traiter le diabete
WO2005018624A2 (fr) * 2003-08-22 2005-03-03 Boehringer Ingelheim Pharmaceuticals, Inc. Procedes pour traiter la bronchopneumopathie chronique obstructive et l'hypertension pulmonaire
WO2005021519A2 (fr) * 2003-08-28 2005-03-10 Novartis Ag Composes organiques
WO2005034869A2 (fr) * 2003-10-08 2005-04-21 Irm Llc Composes et compositions convenant comme inhibiteurs de proteine-kinases
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