WO2011077502A1 - Composé de dihydrothiéno[2,3-e]indazole - Google Patents

Composé de dihydrothiéno[2,3-e]indazole Download PDF

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WO2011077502A1
WO2011077502A1 PCT/JP2009/071205 JP2009071205W WO2011077502A1 WO 2011077502 A1 WO2011077502 A1 WO 2011077502A1 JP 2009071205 W JP2009071205 W JP 2009071205W WO 2011077502 A1 WO2011077502 A1 WO 2011077502A1
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group
optionally substituted
substituted
alkyl group
alkyl
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PCT/JP2009/071205
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Japanese (ja)
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裕保 高橋
弘美 樋口
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杏林製薬株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to dihydrothieno [2,3-e] indazole compounds, pharmaceutical compositions containing them, and their use in preventing or treating diseases.
  • I ⁇ B kinase (sometimes abbreviated as IKK in the present specification) is a kinase complex having a molecular weight of 900 kilodaltons or more that phosphorylates I ⁇ B.
  • the complex includes kinase subunits IKK- ⁇ (IKK-1), IKK- ⁇ (IKK-2), regulatory subunit IKK- ⁇ (NEMO), and the like.
  • IKK is known to make an important contribution as a factor in the signal transduction system of NF- ⁇ B, which is a transcription factor.
  • NF- ⁇ B normally binds to the inhibitory protein I ⁇ B and exists in the cytoplasm as an inactive form.
  • NF- ⁇ B released with the degradation of I ⁇ B translocates into the nucleus and activates transcription of the target gene.
  • Tumor necrosis factor (TNF ⁇ ) inflammatory cytokines such as IL-1 and IL-6 Cell adhesion factor such as ICAM-1 (Intercellular Adhesion Molecule-1); and production of enzymes such as cyclooxygenase COX2 (Cyclooxygenase-2) and inducible NO synthase (inducible nitrite oxyoxide synthase).
  • TNF ⁇ Tumor necrosis factor
  • COX2 Cyclooxygenase-2
  • inducible NO synthase inducible nitrite oxyoxide synthase
  • IKK is known to activate NF- ⁇ B also by phosphorylating NF- ⁇ B subunits and histones.
  • IKK inhibitors suppress the activation of NF- ⁇ B, and inflammatory cytokines such as tumor necrosis factor (TNF ⁇ ) and IL-1, IL-6; cell adhesion factors such as ICAM-1; and cyclooxygenase COX2, By suppressing the production of inducible NO synthase and other enzymes, autoimmune diseases (eg, rheumatoid arthritis, systemic lupus erythematosus, systemic scleroderma, Crohn's disease, ulcerative colitis) and inflammatory diseases (eg , Osteoarthritis, atherosclerosis, atopic dermatitis, chronic obstructive pulmonary disease, endotoxin shock, sepsis, inflammatory bowel disease), is expected to be useful as a preventive or therapeutic agent for ischemic disease, etc.
  • autoimmune diseases eg
  • NF- ⁇ B functions as an anti-apoptotic factor and growth factor in cancer cells
  • an IKK inhibitor that suppresses the activation of NF- ⁇ B is expected to be useful as a preventive or therapeutic agent for cancer. Is done.
  • IKK inhibitors are expected to be useful as immunosuppressants.
  • Patent Document 1 thiophene derivatives
  • Patent Document 2 pyridine derivatives
  • Patent Document 3 urea derivatives
  • Patent Document 3 A naphthothiophene derivative (see Patent Documents 4 and 5) has been reported as a tricyclic compound. It has been reported that the substituent on the thiophene ring can be substituted with an equivalent of a carboxamide group or a ureido group (see Patent Documents 6 to 10).
  • Patent Documents 11 to 30 describe kinase inhibitors that are thiophene derivatives, there are no compounds having a tricyclic structure.
  • An object of the present invention is to provide a novel compound for use as an active ingredient in a preventive or therapeutic agent for a disease involving NF- ⁇ B and TNF ⁇ , which has an excellent inhibitory effect on I ⁇ B kinase and further suppresses TNF ⁇ production. It is.
  • the present invention includes the following inventions.
  • R 1 is a cyano group, —C ( ⁇ O) R 3 , —CO 2 R 3 , —C ( ⁇ O) NR 3 R 4 , —C ( ⁇ O) NHC ( ⁇ NH) R 3 , —C ( ⁇ O) NHC ( ⁇ NH) NR 3 R 4 , —C ( ⁇ O) NHC ( ⁇ O) R 3 , —C ( ⁇ O) NHC ( ⁇ O) NR 3 R 4 , —C ( ⁇ S) NR 3 R 4 , —SO 2 —R 3 , —S ( ⁇ O) R 3 , —SO 3 R 3 , —SO 2 NR 3 R 4 , —P ( ⁇ O) (OR 3 ) OR 4 , —NR 3 R 4 , —NHC ( ⁇ O) NR 3 R 4 , —NHC ( ⁇ O) R 5 , —NHC ( ⁇ S)
  • R 3 , R 4 , R 17 and R 18 are the same or different and are a hydrogen atom, a phenyl group, a heterocyclic group or a C1-C8 alkyl group
  • R 5 is an optionally substituted phenyl group, an optionally substituted heterocyclic group or an optionally substituted C1-C8 alkyl group
  • R 6 represents a hydrogen atom, an optionally substituted heterocyclic group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted sulfamoyl group, or an optionally substituted R 6.
  • Rf represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted carbamoyl C1-C6 alkyl group, an optionally substituted halogeno C1-C6 alkyl group, or an optionally substituted ( C3-C6 cycloalkyl) C1-C6 alkyl group, C3-C6 cycloalkyl group which may be substituted, C1-C6 alkoxycarbonyl group which may be substituted, C1-C6 alkylcarbonyl group which may be substituted An optionally substituted C1-C6 alkoxy C1-C6 alkyl group, an optionally substituted phenyloxy C1-C6 alkyl group, an optionally substituted C1-C6 alkoxycarbonyl C1-C6 alkyl group, or a substituted An optionally substituted phenylsulfonyl C2-C6 alkyl group, Rh is an optionally substituted phenyl
  • R 5 R 11 represents —NR 17 R 18 , —NHC ( ⁇ O) NR 17 R 18 or R 10 when R 10 is a cyano group, —C ( ⁇ O) NR 3 R 4 or —C ( ⁇ S) NR 3 R 4
  • Rc is a hydrogen atom, an optionally substituted phenyl group, an optionally substituted furyl group, an optionally substituted thienyl group, an optionally substituted imidazolyl group, an optionally substituted pyridyl group, An optionally substituted pyranyl group, an optionally substituted pyrrolyl group, an optionally substituted pyrazolyl group, an optionally substituted thiazolyl group, an optionally substituted isothiazolyl group, an optionally substituted Good oxazolyl group, optionally substituted isoxazolyl group, optionally substituted pyrazinyl group, optionally substituted pyrimidinyl group, optionally substituted pyridazinyl group, optionally substituted indolyl group, substituted Optionally substituted quinolidinyl group, optionally substituted quinolyl group, optionally substituted benzofuranyl , An optionally substituted isobenzofuranyl group, an optionally substitute
  • Rf ′ represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted carbamoyl C1-C6 alkyl group, an optionally substituted halogeno C1-C6 alkyl group, or an optionally substituted (C3-C6 cycloalkyl) C1-C6 alkyl group, C3-C6 cycloalkyl group which may be substituted, C1-C6 alkoxycarbonyl group which may be substituted, C1-C6 alkylcarbonyl which may be substituted A group, an optionally substituted C1-C6 alkoxy C1-C6 alkyl group, an optionally substituted phenyloxy C1-C6 alkyl group, an optionally substituted C1-C6 alkoxycarbonyl C1-C6 alkyl group, or An optionally substituted phenylsulfonyl C2-C6 alkyl group, The substituent of the optionally substituted C1
  • Rg is a hydrogen atom, methyl group, ethyl group, propyl group, isopropyl group, pentyl group, isopentyl group, 1-methylbutyl group, 1-ethylpropyl group, butyl group, isobutyl group, tert-butyl group, sec-butyl group Hexyl group, heptyl group, octyl group, trifluoromethyl group, 2,2,2-trifluoroethyl group or trimethylsilylmethyl group, 2-methoxyethyl group, 2-phenyloxyethyl group, 2-phenylsulfonylethyl group, Cyclopentyl group, cyclopentylmethyl group, cyclohexylmethyl group, cyclobutylmethyl group, 2-cyclohexylethyl group, 1-pyrrolidinylcarbonylmethyl group, N-methyl-N-phenylcarbamoylmethyl group, N
  • Rh ′ is —Za—Ar;
  • Ar is an optionally substituted phenyl group, an optionally substituted 2-furyl group, an optionally substituted 3-furyl group, an optionally substituted 2-thienyl group, an optionally substituted A good 3-thienyl group, an optionally substituted 1-imidazolyl group, an optionally substituted 2-imidazolyl group, an optionally substituted 4-imidazolyl group, an optionally substituted 2-pyridyl group, 3-pyridyl group which may be substituted, 4-pyridyl group which may be substituted, pyranyl group which may be substituted, pyrrolyl group which may be substituted, pyrazolyl group which may be substituted, substituted Optionally substituted thiazolyl group, optionally substituted isothiazolyl group, optionally substituted oxazolyl group, optionally substituted isoxazolyl group, substituted An optionally substituted pyrazinyl group, an optional
  • the alkylene group is a halogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C1-C6 alkoxy group, or an optionally substituted C1.
  • -C6 alkylcarbonyl group, optionally substituted C1-C6 alkoxycarbonyl group, optionally substituted carbamoyl group or optionally substituted amino group may be substituted by 1 to 4,
  • the substituent of Ar is a halogen atom, an optionally substituted C1-C8 alkyl group, a trifluoromethyl group, a cyano group, a nitro group, an optionally substituted amino group, an optionally substituted carbamoyl group, A hydroxy group, a trimethylsilyl group, an optionally substituted C3-C6 cycloalkyl group, an optionally substituted C1-C6 alkoxy group, an optionally substituted phenyloxy group, an optionally substituted phenyl group, An optionally
  • Ri represents benzyl group, phenethyl group, 1-phenylethyl group, 2-fluorobenzyl group, 3-fluorobenzyl group, 4-fluorobenzyl group, 2,3-difluorobenzyl group, 2,4-difluorobenzyl.
  • Rj ′ is an optionally substituted phenyl group, an optionally substituted 2-furyl group, an optionally substituted 3-furyl group, an optionally substituted 2-thienyl group, an optionally substituted A good 3-thienyl group, an optionally substituted 1-imidazolyl group, an optionally substituted 2-imidazolyl group, an optionally substituted 4-imidazolyl group, an optionally substituted 2-pyridyl group, 3-pyridyl group which may be substituted, 4-pyridyl group which may be substituted, pyranyl group which may be substituted, pyrrolyl group which may be substituted, pyrazolyl group which may be substituted, substituted A thiazolyl group which may be substituted, an isothiazolyl group which may be substituted, an oxazolyl group which may be substituted, an isoxazolyl group which may be substituted, An optionally substituted pyrazinyl group, an optionally substituted
  • Rk is 2-bromophenyl group, 2-chlorophenyl group, 2-methylphenyl, 2,6-dichlorophenyl group, 2-chloro-4-methylphenyl group, 2-fluorophenyl group, 4-fluorophenyl group, 3,5 -Difluorophenyl group, 2-ethylphenyl group, 2-trifluoromethylphenyl group, 2-ethoxycarbonylphenyl group, 2-carboxyphenyl group, 2- (N, N-dimethylcarbamoyl) phenyl group, 2-nitrophenyl group 2-dimethylaminophenyl group, 4-dimethylaminophenyl group, 2-chloro-6-methylphenyl group, 2-chloro-4-methylphenyl group, 2-pyridyl group, 3-pyridyl group, pyrazinyl group, 3- Methylpyridin-2-yl group, 5- (4-methylpiperazin-1-yl) carbonyl group
  • Rl ′ is —Zb—NR 13 R 14 ;
  • R 13 and R 14 are the same or different and each may be an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C6 cycloalkyl group, or an optionally substituted (C3-C6 cycloalkyl).
  • Ro represents 2-dimethylaminoethyl group, 2- (N-cyclohexyl-N-methylamino) ethyl group, 2- (N-methyl-N-phenylamino) ethyl group, 2- (N-benzyl-N-methylamino) ) Ethyl group, 2- [N- (2-methoxyethyl) -N-methylamino] ethyl group, 2- (N-benzyl-N-methylamino) -1,1-dimethylethyl group, 2- (N, N-dibenzylamino) ethyl group, 2- (N-benzyl-N-ethylamino) ethyl group, 2- (N-benzyl-N-methylamino) -2-methylpropyl group, 2- (N-benzyl- Nn-propylamino) ethyl group, 2- (N-benzyl-N-methylamino)
  • Ring A is an optionally substituted pyrrolidinyl group, an optionally substituted pyrrolinyl group, an optionally substituted imidazolinyl group, an optionally substituted imidazolidinyl group, an optionally substituted pyrazolidinyl group, Optionally substituted morpholinyl group, optionally substituted thiomorpholinyl group, optionally substituted pyrazolinyl group, optionally substituted piperidyl group, optionally substituted piperazinyl group, optionally substituted A good tetrahydropyranyl group, an optionally substituted isoindolinyl group or an optionally substituted indolinyl group; R 15 and R 16 are the same or different and each may be an optionally substituted C1-C8 alkyl group, an optionally substituted amino group, an optionally substituted phenyl C1-C6 alkyl group, a halogen atom, a substituted An optionally substituted phenyl group, an
  • Rq represents 2-morpholinoethyl group, 2-piperidinoethyl group, 3-piperidinopropyl group, 2- (1-pyrrolidinyl) ethyl group, 4-tetrahydropyranylmethyl group, 2- (3-pyrroline -1-yl) ethyl group, 2- (1-indolinyl) ethyl group, 2- (2-isoindolinyl) ethyl group, 1-methylpiperidin-4-ylmethyl group, 2- (4-methylpiperidino) ethyl group, 2- (4-methyl-1-piperazinyl) ethyl group, 2- (4-dimethylaminopiperidino) ethyl group, 1-benzyl-2-pyrrolidinylmethyl group, 1-neopentyl-2-pyrrolidinylmethyl group, (R) -1-benzyl-2-pyrrolidinylmethyl group, (S) -1-benzyl-2-pyrrolidin
  • Rr is a hydrogen atom
  • Rs is a hydrogen atom, methyl group, ethyl group, isopropyl group, methoxymethyl group, cyclopropyl group, trifluoromethyl group, phenyl group, benzyl group, phenethyl group, 2-methyl-1-propenyl group, styryl group, 2 -Furyl group, 3-furyl group, 5-phenyl-2-furyl group, 2,5-dimethyl-3-furyl group, 2-methyl-3-furyl group, 4,5-dimethyl-2-furyl group, 2 -Thienyl group, 3-thienyl group, 2,5-dichloro-3-thienyl group, 2,5-dimethyl-4-oxazolyl group, 5-isoxazolyl group, 5-methyl-4-isoxazolyl group, 5-phenyl-4 -Isoxazolyl group, 5-methyl-3-isoxazolyl group, 1,5-d
  • a pharmaceutical composition comprising the compound according to any of [18] or [18] or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a therapeutic agent for inflammatory diseases wherein the active ingredient is a compound according to any one of [1] to [18] or a pharmaceutically acceptable salt thereof.
  • [24] [1] A method for treating an inflammatory disease, comprising administering an effective amount of the compound according to any one of [18] to [18] or a pharmaceutically acceptable salt thereof.
  • the heterocyclic group includes, for example, a 4- to 10-membered, preferably 4- to 8-membered non-aromatic group containing 1, 2 or 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom.
  • An aromatic heterocyclic group or an aromatic heterocyclic group is included. These may be further condensed with a benzene ring.
  • heterocyclic group examples include pyrrolidinyl group, pyrrolinyl group, imidazolinyl group, imidazolidinyl group, pyrazolidinyl group, morpholinyl group (for example, morpholino group), thiomorpholinyl group (for example, thiomorpholino group), pyrazolinyl group, piperidyl group (For example, piperidino group), piperazinyl group, indolinyl group, isoindolinyl group, azetidinyl group, azepanyl group, azocanyl group, and other non-aromatic heterocyclic groups, as well as furyl group (2- or 3-furyl group), thienyl group ( 2- or 3-thienyl group), imidazolyl group (1-, 2- or 4-imidazolyl group), pyridyl group (2-, 3- or 4-pyridyl group), pyranyl group, pyrrolyl group, imi
  • Examples of the substituent of the substituted phenyl group and the substituted heterocyclic group include a halogen atom, phenyl group, substituted phenyl group, heterocyclic group, substituted heterocyclic group, C1-C8 alkyl group, substituted C1-C8 alkyl group, phenyl C1-C6 Alkyl group (for example, benzyl group), substituted phenyl C1-C6 alkyl group, C2-C6 alkenyl group, substituted C2-C6 alkenyl group, C2-C6 alkynyl group, substituted C2-C6 alkynyl group, C1-C6 alkoxy group, substituted C1-C6 alkoxy group, C3-C6 cycloalkyl group, substituted C3-C6 cycloalkyl group, nitro group, cyano group, hydroxy group, oxy group, amino group, substituted amino group (for example, dimethylamino group), C1-C6
  • substituted phenyl group and the substituted heterocyclic group include 2-bromophenyl group, 2-chlorophenyl group, 4-chlorophenyl group, 2,6-dichlorophenyl group, 2-chloro-4-methylphenyl group, 2-fluoro Phenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 4-tert-butylphenyl group, 3,5-difluorophenyl group, 2,4-difluorophenyl group, 2,5-difluorophenyl group, 2,6 -Difluorophenyl group, 3,4-difluorophenyl group, 2-methylphenyl group, 4-methylphenyl group, 2-ethylphenyl group, 2-trifluoromethylphenyl group, 3-trifluoromethylphenyl group, 4-triphenyl Fluoromethylphenyl group, 2-ethoxycarbonylphenyl group, 2-carboxyphenyl
  • the C1-C8 alkyl group and the C1-C6 alkyl group are each 1-8 and 1-6, preferably 1-4, more preferably 1 alone or as part of another group.
  • the substituted C1-C8 alkyl group preferably refers to a C1-C8 alkyl group having 1 to 3 substituents.
  • substituent for the C1-C8 alkyl group include a nitro group, an amino group, a carbamoyl group, a cyano group, a hydroxy group, and a trimethylsilyl group.
  • Specific examples of the substituted C1-C8 alkyl group include a trimethylsilylmethyl group.
  • the halogeno C1-C6 alkyl group refers to a linear or branched alkyl group in which 1 to 3 hydrogen atoms of the above alkyl group are substituted with a halogen atom.
  • Specific examples include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, and a 2,2,2-trifluoroethyl group.
  • the substituted halogeno C1-C6 alkyl group preferably refers to a halogeno C1-C6 alkyl group having 1 to 3 substituents.
  • the (C3-C6 cycloalkyl) C1-C6 alkyl group refers to a linear or branched alkyl group having 1 to 6 carbon atoms substituted with a C3-C6 cycloalkyl group.
  • Specific examples include a cyclohexylmethyl group, a cyclohexylethyl group, a cyclopentylmethyl group, and a cyclobutylmethyl group.
  • the substituted (C3-C6 cycloalkyl) C1-C6 alkyl group preferably refers to a (C3-C6 cycloalkyl) C1-C6 alkyl group having 1 to 3 substituents.
  • a phenyl C1-C6 alkyl group refers to a linear or branched alkyl group having 1 to 6 carbon atoms substituted with a phenyl group, and specifically includes a benzyl group, a phenethyl group, 1 -Phenylethyl group.
  • substituted phenyl C1-C6 alkyl group examples include 2-fluorobenzyl group, 3-fluorobenzyl group, 4-fluorobenzyl group, 2,3-difluorobenzyl group, 2,4-difluorobenzyl group, 2,5 -Difluorobenzyl group, 2,6-difluorobenzyl group, 3,4-difluorobenzyl group, 3,5-difluorobenzyl group, 2-chlorobenzyl group, 3-chlorobenzyl group, 4-chlorobenzyl group, 2,6 -Dichlorobenzyl group, 3,4-dichlorobenzyl group, 2-chloro-4-fluorobenzyl group, 2-chloro-5-fluorobenzyl group, 2-chloro-6-fluorobenzyl group, 4-chloro-2-fluoro Benzyl group, 2-iodobenzyl group, 2-bromobenzyl group, 4-fluoro
  • the heterocyclic C1-C6 alkyl group refers to a linear or branched alkyl group having 1 to 6 carbon atoms substituted with a heterocyclic ring, and includes a pyridyl C1-C6 alkyl group, a thiazolyl C1-C6 alkyl group, and an isoxazolyl C1.
  • -C6 alkyl group imidazolyl C1-C6 alkyl group, aromatic heterocyclic C1-C6 alkyl group such as pyrazolyl C1-C6 alkyl group, and morpholinyl C1-C6 alkyl group, piperidyl C1-C6 alkyl group, piperazinyl C1-C6 alkyl
  • Non-aromatic heterocyclic C1-C6 alkyl group such as pyrrolidinyl C1-C6 alkyl group, tetrahydropyranyl C1-C6 alkyl group, pyrrolinyl C1-C6 alkyl group, indolinyl C1-C6 alkyl group, isoindolinyl C1-C6 alkyl group, etc.
  • the substituted heterocyclic C1-C6 alkyl group preferably refers to a heterocyclic C1-C6 alkyl group having 1 to 3 substituents, including a substituted pyridyl C1-C6 alkyl group, a substituted thiazolyl C1-C6 alkyl group, and a substituted isoxazolyl C1.
  • a substituted aromatic heterocyclic C1-C6 alkyl group such as a -C6 alkyl group, a substituted imidazolyl C1-C6 alkyl group, a substituted pyrazolyl C1-C6 alkyl group, a substituted morpholinyl C1-C6 alkyl group, a substituted piperidyl C1-C6 alkyl group, Substituted piperazinyl C1-C6 alkyl group, substituted pyrrolidinyl C1-C6 alkyl group, substituted tetrahydropyranyl C1-C6 alkyl group, substituted pyrrolinyl C1-C6 alkyl group, substituted indolinyl C1-C6 alkyl group, substituted isoindolinyl C1-C6 alkyl group, etc.
  • Substitution of non-aromatic And a heterocyclic C1-C6 alkyl group examples include a halogen atom, a nitro group, an amino group, a substituted amino group (eg, dimethylamino group), a carbamoyl group, a substituted carbamoyl group, a cyano group, a hydroxy group, and a trimethylsilyl group.
  • C1-C8 alkyl group substituted C1-C8 alkyl group, phenyl C1-C6 alkyl group (for example, benzyl group), C3-C6 cycloalkyl group, C1-C6 alkoxy group, substituted C1-C6 alkoxy group, phenyloxy group .
  • 3- (2-chloro) pyridylmethyl group 3- (4-chloro) pyridylmethyl group, 2-methylthiazol-4-ylmethyl group, 5-methylisoxazol-3-ylmethyl group, 1- Methylimidazol-5-ylmethyl group, 1-benzylimidazol-2-ylmethyl group, 1-methylpiperidin-4-ylmethyl group, 2- (4-methylpiperidino) ethyl group, 2- (4-methyl-1-piperazinyl) ethyl Group, 2- (4-dimethylaminopiperidino) ethyl group, 1-benzyl-2-pyrrolidinylmethyl group, 1-neopentyl-2-pyrrolidinylmethyl group, (R) -1-benzyl-2- Pyrrolidinylmethyl group, (S) -1-benzyl-2-pyrrolidinylmethyl group, 1- (2-chlorobenzyl) -2-pyrrolidinylmethyl group,
  • the C1-C6 alkoxy C1-C6 alkyl group refers to a linear or branched alkyl group having 1 to 6 carbon atoms substituted with a C1-C6 alkoxy group, specifically, a methoxymethyl group, 2 -Methoxyethyl group.
  • the substituted C1-C6 alkoxy C1-C6 alkyl group preferably means a C1-C6 alkoxy C1-C6 alkyl group having 1 to 3 substituents.
  • the substituted phenyloxy C1-C6 alkyl group preferably means a phenyloxy C2-C6 alkyl group having 1 to 3 substituents.
  • the phenylsulfonyl C2-C6 alkyl group refers to a linear or branched alkyl group having 1 to 6 carbon atoms substituted with a phenylsulfonyl group, and specifically includes a 2-phenylsulfonylethyl group. .
  • the substituted phenylsulfonyl C2-C6 alkyl group preferably means a phenylsulfonyl C2-C6 alkyl group having 1 to 3 substituents.
  • the substituted amino C2-C6 alkyl group refers to a linear or branched alkyl group having 2 to 6 carbon atoms substituted with a substituted amino group, and specifically includes the following structures.
  • the carbamoyl C1-C6 alkyl group refers to a linear or branched alkyl group having 1 to 6 carbon atoms substituted with a carbamoyl group, and specifically includes a carbamoylmethyl group.
  • the substituted carbamoyl C1-C6 alkyl group refers to a linear or branched alkyl group having 1 to 6 carbon atoms substituted with a substituted carbamoyl group, specifically, a 1-pyrrolidinylcarbonylmethyl group, Examples include N-methyl-N-phenylcarbamoylmethyl group, N-ethylcarbamoylmethyl group, and 1- (N-benzylcarbamoyl) -1-methylethyl group.
  • the C1-C6 alkoxycarbonyl C1-C6 alkyl group refers to a linear or branched alkyl group having 1 to 6 carbon atoms substituted with a C1-C6 alkoxycarbonyl group
  • the C6 alkoxycarbonyl C1-C6 alkyl group preferably means a C1-C6 alkoxycarbonyl C1-C6 alkyl group having 1 to 3 substituents. Specific examples include a (1-ethoxycarbonyl-1-methyl) ethyl group.
  • a C1-C6 alkoxy group is a straight-chain or branched alkoxy group having 1 to 6 carbon atoms (in other words, a C1-C6 alkyloxy group).
  • Specific examples include a methoxy group, an ethoxy group, and a butoxy group.
  • the substituted C1-C6 alkoxy group preferably refers to a C1-C6 alkoxy group having 1 to 3 substituents.
  • substituent of the substituted C1-C6 alkoxy group include a halogen atom, a nitro group, an amino group, a protected amino group (eg, Boc amino group), a cyano group, a hydroxy group, a C1-C8 alkyl group, and a C1-C6 alkoxy group.
  • a phenyloxy group (phenoxy group) is represented by —O-phenyl, alone or as part of another group, and a substituted phenyloxy group has a phenyl group in the phenyloxy group having a substituent.
  • substituents include a substituent of the above substituted phenyl group, such as a halogen atom and a C1-C6 alkoxy group.
  • examples of the substituted amino group, substituted carbamoyl group, substituted sulfamoyl group and substituted sulfonamido group include a hydrogen atom, a heterocyclic group, a substituted heterocyclic group, a C1-C8 alkyl group, and a substituted C1-C8 alkyl group.
  • substituents are taken together with the adjacent nitrogen atom to form a ring (preferably an optionally substituted 5- to 10-membered, preferably 5- or 6-membered heterocyclic group such as a non-aromatic heterocyclic ring or Aromatic heterocycles) are also included.
  • substituted amino group include the following structures.
  • substituted carbamoyl group examples include the following structures.
  • substituted sulfonamide group examples include the following structures.
  • halogen atom means fluorine, chlorine, bromine or iodine.
  • a C2-C6 alkenyl group alone or as part of another group, has 2 to 6, preferably 2 to 3 carbon atoms, and has at least 1, preferably 1 A straight-chain or branched hydrocarbon group having a carbon-carbon double bond.
  • Specific examples include an ethenyl group, a propenyl group, an isopropenyl group, and a butenyl group.
  • the substituted C2-C6 alkenyl group preferably refers to a C2-C6 alkenyl group having 1 to 3 substituents.
  • substituents include a halogen atom, nitro group, amino group, substituted amino group, cyano group, hydroxy group, C1-C6 alkoxy group, carbamoyl group, C1-C8 alkyl group, phenyl group, substituted phenyl group, and heterocyclic ring.
  • Group, substituted heterocyclic group and the like include 2-methyl-1-propenyl group and styryl group.
  • a C2-C6 alkynyl group contains 2 to 6, preferably 2 to 3 carbon atoms, and has at least 1, preferably 1 carbon.
  • Specific examples include acetylenyl, 1-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 1-hexynyl, acetylenyl-1-propynyl-1-butynyl and the like.
  • Substituted C2-C6 alkynyl preferably refers to a C2-C6 alkynyl group having 1 to 3 substituents.
  • substituents include a halogen atom, nitro group, amino group, substituted amino group, cyano group, hydroxy group, C1-C8 alkyl group, C1-C6 alkoxy group, acetamide group, phenyl group, substituted phenyl group, and heterocyclic ring. Group, substituted heterocyclic group and the like.
  • the (C3-C6) cycloalkyl group refers to a 3- to 6-membered saturated cyclic hydrocarbon group. Specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
  • the substituted (C3-C6) cycloalkyl group preferably refers to a (C3-C6) cycloalkyl group having 1 to 3 substituents.
  • substituents include a halogen atom, a nitro group, an amino group, a protected amino group (for example, a Boc amino group), a cyano group, a hydroxy group, a C1-C8 alkyl group, a C1-C6 alkoxy group, a carbamoyl group, and a phenyl group.
  • C1-C6 alkoxycarbonyl group examples include a methoxycarbonyl group, an ethoxycarbonyl group, and a tert-butoxycarbonyl group.
  • the substituted C1-C6 alkoxycarbonyl group preferably refers to a C1-C6 alkoxycarbonyl group having 1 to 3 substituents.
  • C1-C6 alkylcarbonyl group examples include a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, and an isovaleryl group.
  • the substituted C1-C6 alkylcarbonyl group preferably refers to a C1-C6 alkylcarbonyl group having 1 to 3 substituents.
  • an acyloxy group means a linear or branched acyloxy group having 1 to 7 carbon atoms, and the acyl moiety may be cyclic or contain an aromatic group. Examples thereof include an acetoxy group, a propionyloxy group, an isopropionyloxy group, a cyclohexylenyloxy group, and a benzoyloxy group.
  • the substituted acyloxy group preferably refers to an acyloxy group having 1 to 3 substituents.
  • a phenylsulfonyl group is represented by —SO 2 -phenyl, and specifically includes a phenylsulfonyl group.
  • the substituted phenylsulfonyl group preferably refers to a phenylsulfonyl group having 1 to 3 substituents. Specific examples include 4-fluorophenylsulfonyl group and 2-nitrophenylsulfonyl group.
  • the pharmaceutically acceptable salt of the compound represented by the general formula (1) means a non-toxic salt of the compound (1).
  • examples of such salts include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.
  • salt with organic base examples include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine and the like.
  • salt with inorganic acid examples include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • the salt with organic acid include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- And salts with toluenesulfonic acid.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like.
  • salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
  • the compound (1) may be an anhydride or a solvate.
  • the solvate of the compound (1) is also included in the compound (1) of the present invention.
  • the solvent is not particularly limited as long as it does not interfere with the biological activity of the solute (compound (1) or a salt thereof).
  • suitable solvents include water, methanol, ethanol and acetic acid.
  • the solvent is water.
  • Physiologically functional derivatives of the compound (1) are also included in the compound (1) of the present invention.
  • Physiologically functional derivative means any pharmaceutically acceptable derivative of compound (1), for example an ester or amide, which gives compound (1) or an active metabolite thereof when administered to a mammal. To do.
  • Such derivatives will be apparent to those skilled in the art without undue experimentation by reference to the teachings of Burger's Medicinal Chemistry And Drug Drug Discovery, 5th Edition, Vol. 1: Principles and Practice.
  • the compound of the present invention has an excellent I ⁇ B kinase inhibitory action, and includes mammals (eg, primates such as humans and monkeys, rodents such as mice, rats and rabbits, pets such as dogs and cats, and cattle, It can be used as an active ingredient of a pharmaceutical composition (preventive and / or therapeutic agent) for preventing or treating various diseases in livestock such as horses and pigs).
  • a pharmaceutical composition preventive and / or therapeutic agent
  • the compound of the present invention has a selective I ⁇ B kinase inhibitory action, it has low toxicity (for example, acute toxicity, chronic toxicity, cardiotoxicity, carcinogenicity, genotoxicity) and few side effects.
  • examples of the I ⁇ B kinase include IKK ⁇ (IKK-1), IKK ⁇ (IKK-2), and the regulatory subunit IKK ⁇ (NEMO).
  • the compound of the present invention also has an NF- ⁇ B inhibitory (transcription inhibitory) action, a TNF- ⁇ inhibitory (production inhibitory) action, and the like.
  • the compound of the present invention inhibits IKK and inhibits the function of NF- ⁇ B, it is effective as a prophylactic and / or therapeutic agent for diseases involving NF- ⁇ B.
  • Diseases involving NF- ⁇ B include, for example, diabetic complications, obesity, osteoporosis, cachexia (eg, cancer cachexia, tuberculosis cachexia, diabetic cachexia, hematological cachexia, endocrine secretion) Disease cachexia, infectious cachexia or cachexia due to acquired immune deficiency syndrome), fatty liver, hypertension, polycystic ovary syndrome, kidney disease (eg, diabetic nephropathy, glomerulonephritis, glomerulosclerosis) , Nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease), muscular dystrophy, myocardial infarction, angina pectoris, cerebrovascular disorders (eg, cerebral infarction, stroke), insulin resistance syndrome, syndrome X, metabolic syndrome (type 2 diabetes)
  • the required dose will of course vary depending on the mode of administration, the particular condition being treated and the desired effect. In general, a daily dose of about 0.03 to 2.5 mg / kg body weight is preferred.
  • the indicated daily dose in mammals such as humans ranges from about 0.5 mg to about 100 mg, preferably administered in divided doses or in delayed form, no more than 4 times daily.
  • Suitable unit dosage forms for oral administration contain about 1-50 mg of active ingredient.
  • the compounds of the invention may be administered by any conventional route, in particular enterally, for example orally, for example in tablet or capsule form, or parenterally, for example in injectable solution or suspension form, topically.
  • it can be administered in the form of a lotion, gel, ointment or cream, or in the form of a nasal or suppository.
  • a pharmaceutical composition comprising a free form or pharmaceutically acceptable salt form of a compound of the invention together with at least one pharmaceutically acceptable carrier or diluent is conventionally used by mixing with a pharmaceutically acceptable carrier or diluent.
  • the compound of the present invention can be used in combination with drugs (hereinafter abbreviated as concomitant drugs) such as glucocorticoid agents, immunosuppressive agents, antibacterial agents, and 5ASA preparations.
  • drugs hereinafter abbreviated as concomitant drugs
  • the combination is not particularly limited, and (1) a combination of the compound of the present invention and a glucocorticoid agent, (2) a combination of the compound of the present invention and an immunosuppressant, and (3) a combination of the compound of the present invention and an antibacterial agent.
  • a combination of the compound of the present invention and a 5ASA preparation is included.
  • the administration timing of the compound of the present invention and the concomitant drug is not limited, and these may be administered simultaneously to the administration subject, or may be administered with a time difference.
  • the compound of the present invention and the concomitant drug may be administered as two types of preparations containing each active ingredient, or may be administered as a single preparation containing both active ingredients.
  • the dose of the concomitant drug can be appropriately selected 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 administration subject, administration route, target disease, symptom, combination and the like.
  • the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention.
  • the combination of the above (1) includes a combination of the compound of the present invention and at least one glucocorticoid agent selected from the group consisting of prednisolone, methylprednisolone, dexamethasone, betamethasone, and cilazapril.
  • the combination of the above (2) includes a combination of the compound of the present invention and at least one immunosuppressive agent selected from the group consisting of cyclosporine, tacrolimus, azathioprine, methotrexate, mizoribine and the like.
  • the combination of (3) above includes a combination of the compound of the present invention and at least one antibacterial agent selected from the group consisting of metronidazole, ciprofloxacin, tetracycline, amoxicillin and the like.
  • the combination of the above (4) includes a combination of the compound of the present invention and at least one 5ASA preparation selected from the group consisting of mesalazine, salazosulfapyridine and the like.
  • the compound of the present invention By combining the compound of the present invention and a concomitant drug, (1) Compared with the case where the compound of the present invention or the concomitant drug is administered alone, the dose of the compound of the present invention and / or the concomitant drug can be reduced. (2) By selecting a concomitant drug having a mechanism of action different from that of the compound of the present invention, the therapeutic effect can be sustained. (3) By using the compound of the present invention and a concomitant drug in combination, excellent effects such as a synergistic effect can be obtained.
  • Compound (10) can be synthesized by reacting compound (9) with a carboxylic acid derivative represented by RbC ( ⁇ O) R ′ in a solvent in the presence of a base. Further, after reacting compound (9) with a carboxylic acid derivative represented by RbC ( ⁇ O) R ′ in the presence of a base in a solvent, compound (11) can be isolated without isolating compound (10). It can also be used for synthesis.
  • R ′ is a halogen atom, an optionally substituted C1-C6 alkoxy group, an optionally substituted C1-C6 alkoxycarbonyl group, or an optionally substituted acyloxy group. Specifically, A chlorine atom, an ethoxy group, an ethoxycarbonyl group, and an acetoxy group are mentioned.
  • RbC ( ⁇ O) R ′ include formic acid methyl ester, formic acid ethyl ester, acetyl chloride, propionyl chloride, phenylacetyl chloride, hydrocinnamoyl chloride, isobutyryl chloride, cyclopropanecarbonyl chloride, benzoyl chloride, 2 -Furoyl chloride, methoxyacetyl chloride, ethyl trifluoroacetate, 2-thiophenecarbonyl chloride, isoxazole-5-carbonyl chloride, 3-furoyl chloride, 3-thiophenecarbonyl chloride, 3,3-dimethylacryloyl chloride, 5- Phenyl-2-furoyl chloride, 5-phenyl-4-isoxazolecarbonyl chloride, 2,5-dimethylfuran-3-carbonyl chloride, 1,5-dimethyl-1H-pyrazo -3-carbonyl chloride, 5-methylisoxazo
  • the solvent examples include tetrahydrofuran, ethanol, methanol, toluene and the like
  • specific examples of the base include sodium hydride, hexamethyldisilazane lithium salt and the like.
  • the reaction temperature is from ⁇ 78 ° C. to the boiling point of the solvent.
  • Compound (12) can be synthesized by reacting compound (11) with an alkyl halide, alkyl halide hydrochloride, alkyl methanesulfonate, alkyl tosylate or the like in the presence of a base in a solvent.
  • alkyl halide or alkyl halide hydrochloride examples include methyl iodide, n-propyl bromide, 2- (4-fluorophenyl) ethyl bromide, benzyl bromide, 4-fluorobenzyl bromide, 3- (chloromethyl) pyridine hydrochloride Salt, 4- (bromomethyl) pyridine hydrobromide, 4-nitrobenzyl bromide, 2-fluorobenzyl bromide, 2-chlorobenzyl bromide, 3-fluorobenzyl bromide, 3-chlorobenzyl bromide, 4-chlorobenzyl bromide, 4-methyl Benzyl bromide, 4-tert-butylbenzyl bromide, 3-trifluoromethylbenzyl bromide, 4-trifluoromethylbenzyl bromide, 2,4-difluorobenzyl bromide, 2,5- Fluorobenzyl bromide, 2,6-d
  • alkyl methanesulfonate examples include 1-benzyl-2-pyrrolidinylmethyl methanesulfonate, (S) -1-benzyl-2-pyrrolidinylmethyl methanesulfonate, and (R) -1-benzyl-2-pyrrole. Examples thereof include dinylmethyl methanesulfonate and 1-benzylpyrrolidin-3-ylmethanesulfonate.
  • the reaction temperature is -78 ° C to the boiling point of the solvent, preferably 0 ° C to the boiling point of the solvent.
  • both isomers of the compound (12) can be separated by silica gel column chromatography or the like.
  • Compound (13a) can be synthesized by reacting compound (12) in a solvent in the presence of an acid.
  • compound (13b) can be synthesized by reacting compound (11) in a solvent in the presence of an acid.
  • the solvent include acetone
  • specific examples of the acid include 0.1 to 6 mol / L hydrochloric acid, preferably 1 mol / L hydrochloric acid.
  • the reaction temperature is from room temperature to the boiling point of the solvent.
  • Ra ′ represents an optionally substituted phenyl C1-C6 alkyl group, or an optionally substituted phenyl group, and R 3 ′ and R 4 ′ are substituted.
  • Compound (12b) can be synthesized by reacting compound (12a) in a solvent in the presence of Pd—C under a hydrogen atmosphere.
  • the solvent include methanol, ethanol, ethyl acetate and the like, and the reaction temperature is from ⁇ 78 ° C. to the boiling point of the solvent, preferably from room temperature to the boiling point of the solvent.
  • Compound (12c) can be synthesized by reacting compound (12b) with an aldehyde in the presence of a reducing agent in a solvent.
  • the reaction temperature is from ⁇ 78 ° C. to the boiling point of the solvent, preferably from room temperature to the boiling point of the solvent.
  • Compound (13c) can be synthesized by reacting compound (12c) in a solvent in the presence of an acid.
  • the solvent include acetone
  • specific examples of the acid include 0.1 to 6 mol / L hydrochloric acid, preferably 1 mol / L hydrochloric acid.
  • the reaction temperature is from room temperature to the boiling point of the solvent.
  • Compound (12) can be synthesized by reacting compound (10) with a hydrazine derivative in a solvent.
  • the solvent include methanol.
  • Specific examples of the hydrazine derivative include hydrazine, hydrazine hydrate, ethyl hydrazine, 2,2,2-trifluoroethyl hydrazine, cyclohexyl hydrazine, 4-fluorophenylhydrazine. 3,5-difluorophenylhydrazine, 2-hydrazinopyridine, methylhydrazine, (2-hydroxy) ethylhydrazine, tert-butylhydrazine.
  • the reaction temperature is from ⁇ 78 ° C. to the boiling point of the solvent, preferably from room temperature to the boiling point of the solvent.
  • Compound (13a) can be synthesized by reacting compound (12) in a solvent in the presence of an acid.
  • the solvent include acetone
  • specific examples of the acid include 0.1 to 6 mol / L hydrochloric acid, preferably 1 mol / L hydrochloric acid.
  • the reaction temperature is from room temperature to the boiling point of the solvent.
  • R 5 ′ is a trialkylsilyl group
  • R 8 ′ and R 9 ′ are optionally substituted C1-C8 alkyl groups
  • Ra and Rb are as described above
  • Compound (14) can be synthesized by reacting compound (9) with an alkyl halide in the presence of a base in a solvent.
  • the solvent include tetrahydrofuran and diethyl ether.
  • Specific examples of the base include hexamethyldisilazane lithium salt and sodium amide.
  • Specific examples of the alkyl halide include methyl iodide.
  • the reaction temperature is from ⁇ 78 ° C. to the boiling point of the solvent, preferably from room temperature to the boiling point of the solvent.
  • Compound (15) can be synthesized by reacting compound (14) with a trialkylsilyl halide in the presence of a base in a solvent.
  • the solvent include tetrahydrofuran
  • specific examples of the base include hexamethyldisilazane lithium salt
  • specific examples of the trialkylsilyl halide include trimethylsilyl chloride.
  • the reaction temperature is from ⁇ 78 ° C. to the boiling point of the solvent.
  • Compound (10a) can be synthesized by reacting compound (15) with a carboxylic acid derivative represented by RbC ( ⁇ O) X ′ in the presence of a base in a solvent.
  • X ′ of the carboxylic acid derivative represented by RbC ( ⁇ O) X ′ is a halogen atom, Specifically, a chlorine atom is mentioned.
  • Compound (11a) can be synthesized by reacting compound (10a) with hydrazine or hydrazine hydrate in a solvent.
  • the reaction temperature is from ⁇ 78 ° C. to the boiling point of the solvent, preferably from room temperature to the boiling point of the solvent.
  • Compound (12d) can be synthesized by reacting compound (11a) with an alkyl halide in the presence of a base in a solvent.
  • the reaction temperature is from ⁇ 78 ° C. to the boiling point of the solvent, preferably from room temperature to the boiling point of the solvent.
  • Compound (13d) can be synthesized by reacting compound (12d) in a solvent in the presence of an acid.
  • compound (13e) can be synthesized by reacting compound (11a) in a solvent in the presence of an acid.
  • the solvent include acetone
  • specific examples of the acid include 0.1 to 6 mol / L hydrochloric acid, preferably 1 mol / L hydrochloric acid.
  • the reaction temperature is from room temperature to the boiling point of the solvent.
  • R 3 ′′ and R 4 ′′ represent a ring together with a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted phenylsulfonyl group, or an adjacent nitrogen atom.
  • PG represents a protecting group
  • Ra ′ is an optionally substituted C1-C8 alkyl group, a C1-C8 alkyl group, an optionally substituted phenylsulfonyl group, an optionally substituted phenyl C1-C6 alkyl group Or an optionally substituted phenyl group, and Rb is as described above
  • Compound (12f) can be synthesized by reacting compound (12e) with mesyl chloride in a solvent.
  • secondary amines include pyrrolidine, piperidine, 3-pyrroline, N-benzyl-N-methylamine, N-methyl-N-phenylamine, N-benzyl-Nn-propylamine, N-benzyl- N-isopropylamine, N- (4-chlorobenzyl) -N-methylamine, N-methyl-N- (2-pyridylmethyl) amine, N-cyclohexylmethyl-N-methylamine, N- (4-fluorobenzyl ) -N-methylamine, Nn-butyl-N-methylamine, N- (2,4-difluorobenzyl) -N-methylamine, N- (2-fluorobenzyl) -N-methylamine .
  • Compound (12h) can be synthesized by reacting compound (12e) with an amine in a solvent under Mitsunobu conditions.
  • Mitsunobu conditions include diethyl azodicarboxylate and triphenylphosphine
  • specific examples of the solvent include tetrahydrofuran.
  • Specific examples of the amine include N-methyl-N- (2-nitrophenylsulfonyl) amine.
  • Compound (12i) can be synthesized by reacting compound (12f) with a primary amine in a solvent.
  • the reaction temperature is from ⁇ 78 ° C. to the boiling point of the solvent, preferably from room temperature to the boiling point of the solvent.
  • Compound (12i) can be synthesized by deprotecting compound (12h) in a solvent.
  • PG is a 2-nitrophenylsulfonyl group
  • it can be synthesized by reacting in the presence of thiophenol and a base.
  • the solvent include N, N-dimethylformamide and the like
  • specific examples of the base include potassium carbonate and the like.
  • Compound (12g) can be synthesized by reacting compound (12i) with alkyl halide, alkyl halide hydrochloride, phenylsulfonyl chloride or alkylmethane sulfonate in the presence of a base.
  • alkyl halide or alkyl halide hydrochloride include 1-bromopropane and the like
  • specific examples of the solvent include N, N-dimethylformamide and the like
  • specific examples of the base include N, N— And diisopropylethylamine.
  • the reaction temperature is from ⁇ 78 ° C. to the boiling point of the solvent, preferably from room temperature to the boiling point of the solvent.
  • Compound (13f) can be synthesized by reacting compound (12g) in a solvent in the presence of an acid.
  • the solvent include acetone
  • specific examples of the acid include 0.1 to 6 mol / L hydrochloric acid, preferably 1 mol / L hydrochloric acid.
  • the reaction temperature is from room temperature to the boiling point of the solvent.
  • Compound (12j) can be synthesized by reacting compound (12i) in a solvent in the presence of a base.
  • a solvent include methanol and ethanol
  • specific examples of the base include 0.1 to 6 mol / L sodium hydroxide, preferably 1 mol / L sodium hydroxide.
  • the reaction temperature is from room temperature to the boiling point of the solvent.
  • Compound (12k) can be synthesized by reacting compound (12j) with various amines in the presence of a condensing agent in a solvent.
  • a condensing agent include WSC (water-soluble carbodiimide), N, N-dimethyl-4-aminopyridine, oxalyl chloride, and the like.
  • WSC water-soluble carbodiimide
  • N, N-dimethyl-4-aminopyridine oxalyl chloride
  • Specific examples of the solvent include N, N-dimethylformamide, dichloromethane and the like.
  • Compound (13g) can be synthesized by reacting compound (12k) in a solvent in the presence of an acid.
  • the solvent include acetone
  • specific examples of the acid include 0.1 to 6 mol / L hydrochloric acid, preferably 1 mol / L hydrochloric acid.
  • the reaction temperature is from room temperature to the boiling point of the solvent.
  • Compound (13h) can be synthesized by reacting compound (12l) in a solvent in the presence of an acid.
  • the solvent include acetone
  • specific examples of the acid include 0.1 to 6 mol / L hydrochloric acid, preferably 1 mol / L hydrochloric acid.
  • the reaction temperature is from room temperature to the boiling point of the solvent.
  • R 5 ′ ′′ is an optionally substituted C1-C8 alkyl group or an optionally substituted C1-C6 alkylcarbonyl group, and Ra ′, Rb, R 3 ′′ and R 4 '' Is as described above]
  • Compound (12n) can be synthesized by reacting compound (12j) with a carboxylic acid derivative represented by R 5 ′ ′′ C ( ⁇ O) X ′ in the presence of a base in a solvent.
  • X ′ in R 5 ′ ′′ C ( ⁇ O) X ′ is a halogen atom, and specifically includes a chlorine atom.
  • carboxylic acid derivative represented by R 5 ′ ′′ C ( ⁇ O) X ′ include isobutyl chlorocarbonate and the like.
  • Specific examples of the base include N-methylmorpholine and the like, and specific examples of the solvent include tetrahydrofuran and the like.
  • Compound (12o) can be synthesized by reacting compound (12n) in a solvent in the presence of a reducing agent.
  • a solvent include diethyl ether, tetrahydrofuran and the like
  • specific examples of the reducing agent include sodium borohydride, lithium aluminum hydride and the like.
  • the reaction temperature is from ⁇ 78 ° C. to the boiling point of the solvent, preferably from room temperature to the boiling point of the solvent.
  • Compound (12p) can be synthesized by reacting compound (12o) with an oxidizing agent in a solvent.
  • the oxidizing agent include Dess-Martin periodinane.
  • Specific examples of the solvent include dichloromethane and the like.
  • the reaction temperature is from ⁇ 78 ° C. to the boiling point of the solvent, preferably from room temperature to the boiling point of the solvent.
  • Compound (12q) can be synthesized by reacting compound (12p) with an amine in the presence of a reducing agent in a solvent.
  • a reducing agent include triacetoxy sodium borohydride and the like.
  • the reaction temperature is from ⁇ 78 ° C. to the boiling point of the solvent, preferably from room temperature to the boiling point of the solvent.
  • Compound (13i) can be synthesized by reacting compound (12q) in a solvent in the presence of an acid.
  • the solvent include acetone
  • specific examples of the acid include 0.1 to 6 mol / L hydrochloric acid, preferably 1 mol / L hydrochloric acid.
  • the reaction temperature is from room temperature to the boiling point of the solvent.
  • PG represents a protecting group
  • Ra ′′ represents an optionally substituted C1-C8 alkyl group, an optionally substituted amino C1-C6 alkyl group, an optionally substituted heterocyclic ring C1- A C6 alkyl group or an optionally substituted heterocyclic group
  • R 15 ′ is an optionally substituted C1-C8 alkyl group or an optionally substituted phenyl C1-C6 alkyl group
  • Rb is as defined above.
  • Compound (12s) can be synthesized by reacting compound (12r) in a solvent in the presence of Pd—C in a hydrogen atmosphere when PG is a benzyl group or a benzyloxycarbonyl group.
  • Specific examples of the solvent include methanol and ethanol.
  • the reaction temperature is from ⁇ 78 ° C. to the boiling point of the solvent, preferably from room temperature to the boiling point of the solvent.
  • Compound (12s) can be synthesized by reacting compound (12r) with thiophenol in the presence of a base in a solvent when PG is a 2-nitrophenylsulfonyl group.
  • a solvent include N, N-dimethylformamide and the like
  • specific examples of the base include potassium carbonate and the like.
  • the reaction temperature is from ⁇ 78 ° C. to the boiling point of the solvent, preferably from room temperature to the boiling point of the solvent.
  • Compound (12t) can be synthesized by reacting compound (12s) with an alkyl halide in a solvent.
  • alkyl halides include iodomethane.
  • Compound (13j) can be synthesized by reacting compound (12t) in a solvent in the presence of an acid.
  • the solvent include acetone
  • specific examples of the acid include 0.1 to 6 mol / L hydrochloric acid, preferably 1 mol / L hydrochloric acid.
  • the reaction temperature is from room temperature to the boiling point of the solvent.
  • R5 ′′ ′′ is an optionally substituted phenyl group or an optionally substituted C1-C8 alkyl group, and Ra ′ and Rb are as described above]
  • Compound (12u) can be synthesized by reacting compound (12e) with an alkyl halide in the presence of a base in a solvent or by reacting with phenol under Mitsunobu conditions.
  • the solvent include tetrahydrofuran and the like
  • specific examples of the alkyl halide include iodomethane and the like.
  • Specific examples of the base include sodium hydride and the like, and the reaction temperature is from ⁇ 78 ° C. to the boiling point of the solvent, preferably from room temperature to the boiling point of the solvent.
  • Specific examples of Mitsunobu conditions include a combination of diethyl azodicarboxylate and triphenylphosphine.
  • Compound (13k) can be synthesized by reacting compound (12u) in a solvent in the presence of an acid.
  • the solvent include acetone and the like
  • specific examples of the acid include 0.1 to 6 mol / L hydrochloric acid, preferably 1 mol / L hydrochloric acid.
  • the reaction temperature is from room temperature to the boiling point of the solvent.
  • Compound (16) and compound (20) can be synthesized by reacting compounds (13a) to (13k) [hereinafter referred to as compound (13)] with malononitrile, sulfur and a base in a solvent.
  • Compound (16) and Compound (20) can be separated by purification.
  • Compound (17) can be synthesized by reacting compound (16) in concentrated sulfuric acid.
  • compound (21) can be synthesized by reacting compound (20) in concentrated sulfuric acid.
  • This reaction can be carried out without solvent, and the reaction temperature is from room temperature to the boiling point of the solvent.
  • the reaction time is 1 hour to 4 days.
  • Compound (17) and Compound (21) can be separated by purification.
  • compound (22) can be synthesized by reacting compound (21) with sodium cyanate or potassium cyanate in a solvent in the presence of an acid.
  • the reaction temperature is from ⁇ 78 ° C. to the boiling point of the solvent, preferably from room temperature to the boiling point of the solvent.
  • the reaction time is 1 to 24 hours.
  • Compound (19a) is produced together with compound (18) when acetic acid is used as a solvent, and can be separated from compound (18) by purification.
  • compound (23a) is produced together with compound (22) when acetic acid is used as a solvent, and can be separated from compound (22) by purification.
  • compound (19b) is produced together with compound (18) when toluene is used as a solvent, and can be separated from compound (18) by purification.
  • compound (23b) is produced together with compound (22) when toluene is used as a solvent, and can be separated from compound (22) by purification.
  • Compound (18) and Compound (22) can be separated by purification.
  • the solvent include methanol, ethanol and the like
  • specific examples of the base include 0.1 to 6 mol / L sodium hydroxide, preferably 1 mol / L sodium hydroxide.
  • the reaction temperature is from room temperature to the boiling point of the solvent.
  • R 6 ′ is an optionally substituted C1-C8 alkyl group or an optionally substituted phenyl C1-C6 alkyl group.
  • Compound (24) can be synthesized by reacting compound (17) with a carboxylic acid derivative represented by R 6 'COY' in a solvent.
  • compound (25) can be synthesized by reacting compound (21) with a carboxylic acid derivative in a solvent.
  • the solvent include pyridine
  • Y ′ of R 6 'COY' is a halogen atom or an optionally substituted acyloxy group, specifically, a chlorine atom, an acetoxy group or a benzoxy group.
  • Specific examples of the carboxylic acid derivative represented by R 6 'COY' include benzoyl chloride and acetic anhydride.
  • the reaction temperature is from ⁇ 78 ° C. to the boiling point of the solvent, preferably from room temperature to the boiling point of the solvent.
  • the reaction time is 1 to 24 hours.
  • Rb, R 8 and R 9 are as defined above, and R 7 ′ is an optionally substituted C1-C8 alkyl group or an optionally substituted phenyl C1-C6 alkyl group]
  • Compound (26) can be synthesized by reacting compound (16 ′) or compound (20 ′) with a carboxylic acid derivative represented by R 7 'COZ' in a solvent.
  • R 7 'COZ' is a halogen atom or an optionally substituted acyloxy group, and specifically includes a chlorine atom and an acetoxy group.
  • carboxylic acid derivative represented by R 7 'COZ' include benzoyl chloride and acetic anhydride, preferably 2 equivalents or more based on compound (16 ') or compound (20').
  • the reaction temperature is from ⁇ 78 ° C. to the boiling point of the solvent, preferably from room temperature to the boiling point of the solvent.
  • the reaction time is 1 hour to 3 days.
  • Compound (28) can be synthesized by reacting compound (26) in a solvent in the presence of a base.
  • a specific example of the base is preferably 1 mol / L sodium hydroxide, and a specific example of the solvent is methanol.
  • Compound (27) can be synthesized by reacting compound (16 ′) or compound (20 ′) with a carboxylic acid derivative represented by R 7 'COZ' in a solvent.
  • carboxylic acid derivative represented by R 7 'COZ' include acetyl chloride, and preferably 1 to 2 equivalents are used relative to compound (16 ') or compound (20').
  • the reaction temperature is from ⁇ 78 ° C. to the boiling point of the solvent, preferably from room temperature to the boiling point of the solvent.
  • the reaction time is 1 to 24 hours.
  • Compound (32) can be synthesized by reacting compound (31) with phosphorus oxychloride and N, N-dimethylformamide in a solvent.
  • a specific example of the solvent is dichloromethane.
  • the reaction temperature is from ⁇ 78 ° C. to the boiling point of the solvent, preferably from room temperature to the boiling point of the solvent.
  • the reaction time is 1 to 24 hours.
  • a specific example of the solvent is ethanol, and a specific example of the base is sodium acetate.
  • the reaction temperature is from ⁇ 78 ° C. to the boiling point of the solvent, preferably from room temperature to the boiling point of the solvent.
  • the reaction time is 1 to 24 hours.
  • Compound (35) can be synthesized by reacting compound (34) with 2-mercaptoacetamide in a solvent in the presence of a base.
  • Specific examples of the solvent include ethanol, and specific examples of the base include sodium methylate.
  • the reaction temperature is from ⁇ 78 ° C. to the boiling point of the solvent, preferably from room temperature to the boiling point of the solvent.
  • the reaction time is 1 to 24 hours. It can also be synthesized using a microwave reactor.
  • reaction mixture was cooled to room temperature, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to obtain 571 mg of the title compound as a regioisomer mixture.
  • the solid was dissolved in N, N-dimethylformamide (3 mL), pyridine (3 mL) and acetic anhydride (3 mL) were added, and the mixture was stirred for 1 hour. Water was added to the reaction solution, and the precipitated crystals were collected by filtration. The solid collected by filtration was dissolved in methanol (5 mL), 1 mol / L sodium hydroxide (0.5 mL) was added, and the mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure, 1 mol / L hydrochloric acid was added, and the precipitated crystals were collected by filtration and dried under reduced pressure to give 150 mg of the title compound.
  • the solvent was concentrated under reduced pressure, ethyl acetate / hexane was added to the residue, the precipitated solid was dissolved in methanol (5 mL), 1 mol / L sodium hydroxide (0.5 mL) was added, and the mixture was stirred for 10 minutes.
  • the reaction mixture was concentrated under reduced pressure, 1 mol / L hydrochloric acid was added, and the mixture was extracted with a mixed solution of ethyl acetate and tetrahydrofuran.
  • the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
  • the solvent was concentrated under reduced pressure to obtain 165 mg of the title compound.
  • PBS Phosphate Buffered Saline
  • PBS-T Phosphate Buffered Saline
  • IKK- ⁇ inhibitory activity IC 50 value was calculated as follows. The absorbance value of the culture supernatant treated with DMSO was taken as 100% IKK inhibitory activity, and the IKK- ⁇ inhibitory activity at each concentration of the test compound was determined. From the concentration between two sandwiched points showing a 50% production rate, a linear line was obtained, and an IC 50 value was calculated.
  • yy 1 (y 2 -y 1 ) / (Log (x 2 ) -Log (x 1 )) * (Log (x) -Log (x 1 )) y 1 : Inhibition rate when the inhibition rate is 50% or less x 1 : Concentration at that time y 2 : Suppression rate when the suppression rate is 50% or more x 2 : Concentration at that time Test Example 2 Measurement of TNF- ⁇ inhibitory activity THP-1 diluted in RPMI 1640 medium (Sigma) containing 10% inactivated fetal bovine serum and penicillin (100 units / mL) / streptomycin (100 ⁇ g / mL) (Invitrogen) 198 ⁇ L of cells (ATCC) was seeded in a 96-well plate at 2 ⁇ 10 5 cells / well.
  • test compound 2 ⁇ L was added to each 96-well plate, cultured at 37 ° C. for 1 hour in a carbon dioxide incubator, and then LPS (Sigma) was added to a final concentration of 1 ⁇ g / mL.
  • LPS Sigma
  • the resulting mixture was cultured at 37 ° C. for 6 hours in a carbon dioxide incubator and then centrifuged at 3000 rpm for 3 minutes.
  • the TNF- ⁇ concentration in the resulting supernatant was measured using an ELISA method.
  • the TNF- ⁇ concentration in the DMSO-treated culture supernatant was defined as a TNF- ⁇ production rate of 100% (0% inhibition rate), and the TNF- ⁇ inhibition rate at each concentration of the test compound was determined.
  • a concentration-dependent TNF- ⁇ production inhibitory action was observed, a primary straight line was obtained from the concentration between two sandwiching points showing a 50% inhibition rate, and an IC 50 value was calculated.
  • yy 1 (y 2 -y 1 ) / (Log (x 2 ) -Log (x 1 )) * (Log (x) -Log (x 1 )) y 1 : Inhibition rate when the inhibition rate is 50% or less x 1 : Concentration at that time y 2 : Suppression rate when the suppression rate is 50% or more x 2 : Concentration at that time Test Example 3 Measurement of In vivo Blood TNF ⁇ Inhibitory Activity Test compounds were orally administered to 6-7 week old female DBA / 2 mice 60 minutes before LPS administration. Sixty minutes later, 1 ⁇ g of LPS was intraperitoneally administered. Blood was collected from the tail vein 90 minutes after LPS administration (50-100 ⁇ L).
  • This compound group significantly suppressed the area of colonic injury at a lower dose than the existing drug salazosulfapyridine.

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Abstract

La présente invention concerne un nouveau composé présentant une excellente activité inhibitrice d'IκB kinase et une activité inhibitrice dans la production de TNFα, utilisé comme principe actif pour un agent de prévention ou de traitement de maladies associées à NF-κB et TNFα. En particulier, l'invention concerne un nouveau composé de dihydrothiéno[2,3-e]indazole de formule (1). De manière spécifique également, la présente invention concerne une composition pharmaceutique contenant le composé de dihydrothiéno[2,3-e]indazole, et l'utilisation de composé de dihydrothiéno[2,3-e]indazole pour la prévention ou le traitement de maladies.
PCT/JP2009/071205 2009-12-21 2009-12-21 Composé de dihydrothiéno[2,3-e]indazole WO2011077502A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2269990A1 (fr) * 2008-03-25 2011-01-05 Takeda Pharmaceutical Company Limited Composé hétérocyclique
JP2016539979A (ja) * 2013-12-09 2016-12-22 ユーシービー バイオファルマ エスピーアールエル Ｔｎｆ活性のモジュレーターとしてのイミダゾピリジン誘導体

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001085686A2 (fr) * 2000-05-09 2001-11-15 Cephalon, Inc. Nouveaux composes multicycliques et leur utilisation
WO2003029242A1 (fr) * 2001-10-04 2003-04-10 Smithkline Beecham Corporation Inhibiteurs du facteur de transcription nf-$g(k)b
WO2003086309A2 (fr) * 2002-04-11 2003-10-23 Smithkline Beecham Corporation Inhibiteurs de nf-?b
WO2004009582A1 (fr) * 2002-07-19 2004-01-29 Pharmacia Corporation Composes de thiophene carboxamide substitues utilises pour traiter une inflammation
WO2006055268A2 (fr) * 2004-10-27 2006-05-26 Bayer Pharmaceuticals Corporation Nouvelles pyrimidothienoindazoles

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001085686A2 (fr) * 2000-05-09 2001-11-15 Cephalon, Inc. Nouveaux composes multicycliques et leur utilisation
WO2003029242A1 (fr) * 2001-10-04 2003-04-10 Smithkline Beecham Corporation Inhibiteurs du facteur de transcription nf-$g(k)b
WO2003086309A2 (fr) * 2002-04-11 2003-10-23 Smithkline Beecham Corporation Inhibiteurs de nf-?b
WO2004009582A1 (fr) * 2002-07-19 2004-01-29 Pharmacia Corporation Composes de thiophene carboxamide substitues utilises pour traiter une inflammation
WO2006055268A2 (fr) * 2004-10-27 2006-05-26 Bayer Pharmaceuticals Corporation Nouvelles pyrimidothienoindazoles

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2269990A1 (fr) * 2008-03-25 2011-01-05 Takeda Pharmaceutical Company Limited Composé hétérocyclique
EP2269990A4 (fr) * 2008-03-25 2012-04-18 Takeda Pharmaceutical Composé hétérocyclique
JP2016539979A (ja) * 2013-12-09 2016-12-22 ユーシービー バイオファルマ エスピーアールエル Ｔｎｆ活性のモジュレーターとしてのイミダゾピリジン誘導体

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