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WO2006038734A1 - Dérivés de la pyridazinone inhibiteurs de cytokines - Google Patents

Dérivés de la pyridazinone inhibiteurs de cytokines Download PDF

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Publication number
WO2006038734A1
WO2006038734A1 PCT/JP2005/018901 JP2005018901W WO2006038734A1 WO 2006038734 A1 WO2006038734 A1 WO 2006038734A1 JP 2005018901 W JP2005018901 W JP 2005018901W WO 2006038734 A1 WO2006038734 A1 WO 2006038734A1
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Prior art keywords
alkyl
pyridazinone
nmr
substituted
dmso
Prior art date
Application number
PCT/JP2005/018901
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English (en)
Inventor
Hitoshi Yamazaki
Chiyoshi Kasahara
Shinji Shigenaga
Koichi Higuchi
Hidekazu Mizuhara
Minoru Yasuda
Masaharu Yokomoto
Keiji Misumi
Tomohiko Kinoshita
Kimiko Katayama
Original Assignee
Astellas Pharma Inc.
Wakunaga Pharmaceutical Co., Ltd.
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Publication date
Priority claimed from AU2004905844A external-priority patent/AU2004905844A0/en
Application filed by Astellas Pharma Inc., Wakunaga Pharmaceutical Co., Ltd. filed Critical Astellas Pharma Inc.
Publication of WO2006038734A1 publication Critical patent/WO2006038734A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to a pyridazinone derivative and a salt thereof, which are useful as medicaments.
  • Rheumatoid arthritis is a systemic inflammatory disease which causes mainly in the arthrosynovia.
  • Methotrexate MTX
  • DMARD disease-modified anti-rheumatic drugs
  • the anti-RA drugs in the next generation are expected to overcome these problems, that is to be an orally small-molecule drug, which blocks or modulates selectively the function of these cytokines.
  • p38 ⁇ mitogen activated protein kinase belongs to intracellular phosphorylation kinase participating in production and/or functional expression of the cytokine (TNF, IL-I, IL-6), and it is reported that
  • p38 ⁇ MAPK is activated in the arthrosynovia of RA patients thereby cytokines are produced excessively, so that p38oc MAPK has been attracted as a target of anti-RA drug.
  • the present invention relates to a pyridazinone derivative and a pharmaceutically acceptable salt thereof, which are useful as medicaments; a pharmaceutical composition comprising, as an active ingredient, said pyridazinone derivative or a pharmaceutically acceptable salt thereof; a use of said pyridazinone derivative or a pharmaceutically acceptable salt thereof as a medicament; and a method for using said pyridazinone derivative or a pharmaceutically acceptable salt thereof for therapeutic purposes, which comprises administering said pyridazinone derivative or a pharmaceutically acceptable salt thereof to a human being or an animal.
  • the pyridazinone derivatives and a salt thereof are inhibitors of cytokines' production or their transduction,
  • analgesic in particular anti-RA agent, drug for pain and other conditions t associated with inflammation, drug for Crohn's disease, drug for inflammatory bowel disease, drug for psoriasis, or the like.
  • the pyridazinone derivative or a salt thereof of the present invention can be shown by the following formula (I) :
  • R 1 is lower alkyl substituted with hydroxy, hydroxycyclo(lower)alkyl or cyclo(lower)alkyl; or • aryl optionally substituted with substituent(s) selected from the group consisting of lower alkyl, aryloxy, halo(lower)alkyl, hydroxy(lower)alkyl, lower alkanoyl, halogen and lower alkoxy;
  • R 2 is aryl or thienyl, each of which may be sutstituted with substitutent(s) selected from the group consisting of halogen, halo(lower)alkyl, lower, alkyl and lower alkoxy;
  • R 3 is hydrogen or lower alkyl;
  • A is O or S;
  • R 4 is halogen; amino optionally substituted with lower alkyl, hydroxy(lower)alkyl, lower alkanoyl, lower alkoxycarbonyl, lower alkylamino(lower)alkyl, di(lower)alkylamino(lower)alkyl, hydroxycyclo(lower)alkyl, piperidyl, lower alkoxycarbonylpiperidyl or lower alkylsulfonylpiperidyl; or a group of the formula: wherein
  • R 7 is hydrogen, hydroxy, halogen, lower alkyl, lower alkylamino, di(lower)alkylamino, N-lower alkanoyl-N-lower alkylamino,
  • R 7 and R 8 are taken together to form lower alkylene
  • X is CH 2 , NH, N(CH 3 ) or O; and n is 0 or 1; and
  • R 5 is hydrogen, lower alkyl or hydroxyl(lower)alkyl
  • R 6 is hydrogen; amino optionally substituted with lower alkyl, lower alkoxy(lower)alkyl, morpholino- (lower) alkyl, aryl, cyclo(lower)alkyl, lower alkoxycarbonyl(lower)alkyl or hydroxy(lower)alkyl; piperazinyl or N-lower alkoxycarbonylpiperazinyl; or R 5 andR 6 are taken together to form a group of the formula:
  • R 1 is lower alkyl substituted with hydroxycyclo(lower)alkyl; or aryl optionally substituted with substituent(s) selected from the group consisting of lower alkyl, aryloxy, halo(lower)alkyl, hydroxy(lower)alkyl, lower alkanoyl, halogen and lower alkoxy when
  • R2 is aryl which may be substituted with substituent(s) selected from the group consisting of halogen, halo(lower)alkyl, lower alkyl and lower alkoxy) ; or
  • R 1 is lower alkyl substituted with hydroxycyclo(lower)- alkyl; or aryl optionally substituted with substituent(s) selected from the group consisting of lower alkyl, aryloxy, halo(lower)alkyl, hydroxy(lower)alkyl, lower alkanoyl, halogen and lower alkoxy when
  • R 2 is aryl which may be substituted with substituent(s) selected from the group consisting of halogen, halo(lower)alkyl, lower alkyl and lower alkoxy, and R 4 is amino optionally substituted with lower alkyl, lower alkanoyl or lower alkoxycarbonyl
  • R 4 is amino optionally substituted with lower alkyl, lower alkanoyl or lower alkoxycarbonyl
  • R 1 is (Cl-C4)alkyl substituted with hydroxycyclo(C5-C8)alkyl; or phenyl optionally substituted with (C1-C4)alkyl or (Cl-C4)alkoxy;
  • R 2 is phenyl optionally substituted with substituent(s) selected from the group consisting of (C1-C4)alkyl and halogen;
  • R 3 is hydrogen or (Cl-C4)alkyl;
  • R 5 is hydrogen, (Cl-C4)alkyl or hydroxy(Cl-C4)alkyl;
  • R 6 is amino substituted with (Cl-C4)alkyl which may be substituted with (Cl-C4)alkoxy; morpholino; phenyl; cyclo(C5-C8)alkyl or hydroxy(C1-C4)alky1; or a salt thereof.
  • R 1 is phenyl substituted with (Cl-C4)alkyl or (C1-C4) alkoxy;
  • R 2 is phenyl substituted with halogen; and R 3 is hydrogen or (Cl-C4)alkyl; R 6 is amino substituted with (Cl-C4)alkyl; or a salt thereof.
  • R 3 is hydrogen or (Cl-C4)alkyl; R 6 is amino substituted with (Cl-C4)alkyl; or a salt thereof.
  • R 1 is (Cl-C4)alkyl substituted with hydroxycyclo(C5-C8)alkyl; or phenyl optionally substituted with (Cl-C4)alkyl;
  • R 2 is phenyl optionally substituted with substituent(s) selected from the group consisting of lower alkyl and halogen;
  • R 3 is hydrogen or (C1-C4)alkyl;
  • A is O or S; and
  • R 4 is halogen; amino optionally substituted with hydroxy(C1-C4)alkyl, hydroxycyclo(Cl-C4)alkyl, piperidyl, (Cl-C4)alkoxycarbonylpiperidyl or
  • R 7 is hydrogen, hydroxy, (Cl-C4)alkyl
  • R 1 is phenyl substituted with (Cl-C4)alkyl
  • R 2 is phenyl substituted with (C1-C4)alkyl or ⁇ halogen
  • R 3 is hydrogen or (Cl-C4)alkyl; and R 4 is a group of the formula:
  • R 7 is hydrogen, hydroxy, methyl, methylamino or dimethylamino; and R 8 is hydrogen; or R 7 and R 8 are taken together to form methylene or ethylene;
  • X is CH 2 , NH, N(CH 3 ) or O; and n is 0 or 1; or a salt thereof.
  • the object compound (I) and a salt thereof of the present invention can be prepared by the following processes.
  • Process 1
  • R 1 , R 2 , R 3 , R 7 , R 8 , A, X and n are defined above;
  • Hal is a halogen atom
  • R 4 a is amino optionally substituted with lower alkyl, hydroxyl(lower)alkyl, lower alkanoyl, lower alkoxycarbonyl, lower alkylamino(lower)alkyl, di(lower)alkylamino(lower)alkyl, hydroxycyclo(lower)alkyl, piperidyl, lower alkoxycarbonylpiperidyl or lower alkylsulfonylpiperidyl; or a group of the formula:
  • R 7 is hydrogen, hydroxy, halogen, lower alkyl, ' . lower alkylamino, di(lower)alkylamino,
  • N-lower alkanoyl-N-lower alkylamino N-lower alkoxycarbonyl-N-lower alkylamino; lower alkanoyloxy or -N + (CH 3 J 2 O " and R 8 is hydrogen; or
  • R 7 and R 8 are taken together to form lower alkylene;
  • X is CH 2 , NH, N(CH 3 ) or O; and n is 0 or 1;
  • R 6 a is amino optionally substituted with lower alkyl, lower alkoxy(lower)alkyl, morpholino(lower)alkyl, aryl, cyclo(lower)alkyl, lower alkoxycarbonyl- (lower)alkyl, piperazinyl or N-lower alkoxycarbonylpiperazinyl;
  • m is an integer of 1 to 4; and
  • R X a is aryl optionally substituted with substituent(s) selected from the group consisting of lower alkyl, aryloxy, halo(lower)alkyl, hydroxy(lower)alky1, lower alkanoyl, halogen and lower alkoxy.
  • the object compound (I) and a salt thereof can be prepared, for example, according to the procedures as illustrated in Examples in the present specification or in amanner similar thereto.
  • the starting compounds can be prepared, for example, according to the procedures as illustrated in Preparations in the present specification or in amanner similar thereto.
  • the object compound (I) and a salt thereof can be prepared according to the methods as shown in Preparations or Examples, or in a manner similar thereto.
  • solvating form of the compound (I) e.g. hydrate, ethanolate, etc.
  • any form of the crystal of the compound (I) are included within the scope of the present invention.
  • the compound (I) and other compounds may include one or more stereoisomer(s) such as optical isomer(s) and geometrical isomer(s) due to asymmetric carbon atom(s) and double bond(s), and all of such isomers and mixtures thereof are included within the scope of this invention.
  • radiolabelled derivatives of compound (I) which are suitable for biological studies, are included within the scope of the present invention.
  • Suitable salts of the object compound (I) are conventional pharmaceutically acceptable ones and include a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earthmetal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N' -dibenzylethylenediamine salt, etc.), an organic acid salt (e.g.
  • a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earthmetal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N' -dibenzy
  • All starting materials and product compounds may be salts.
  • the compounds of above processes can be converted to salts according to a conventional method.
  • lower alkyl and lower alkyl moiety in the terms "halo(lower)alkyl", “N-lower alkanoyl-N-lower alkylamino", “N-lower alkoxycarbonyl-N-lower alkylamino", “lower alkoxycarbonyl(lower)alkyl” , “hydroxy(lower)alkyl”, “lower alkylamino”,
  • di(lower)alkylamino may include straight or branched ones such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl or the like, in which the preferred one may be (C1-C4) alkyl and the more preferred one may be methyl, ethyl, isopropyl or isobutyl.
  • Suitable "cyclo(lower)alkyl” and cyclo(lower)alkyl moiety in the term “hydroxycyclo(lower)alkyl” may be cyclo(C3-C8)alkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or the like, in which the preferred one may be cyclo(C5-C8)alkyl and themore preferred onemaybe cyclohexyl or cycloheptyl.
  • Sutible "lower alkylene” maybe (Cl-C ⁇ )alkylene such as methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene, ethylethylene or the like, in which the preferred one is methylene or ethylene.
  • Suitable "aryl” and aryl moiety in the term “aryloxy” may be phenyl, naphthyl, indenyl, anthryl, or the like, in which the preferred one may be (C6-C10) aryl, and the more preferred one may be phenyl or tolyl.
  • lower alkoxy and lower alkoxy moiety in the terms “lower alkoxycarbonyl(lower)alkyl", “N-lower alkoxycarbonyl-N-lower alkylamino", “N-lower alkoxycarbonylpiperazinyl” , “lower alkoxycarbonyl", “lower alkoxy(lower)alkyl” may include straight or branched ones such as methoxy, ethoxy, propoxy, isopropoxy, methylpropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy or the like, in which the preferred one may be (Cl-C4)alkoxy and the more preferred one may be methoxy or ethoxy.
  • Suitable "lower alkanoyl” and lower alkanoyl moiety in the term "N-lower alkanoyl-N-lower alkylamino" may be formyl, acetyl, propionyl, butyryl, isobutyryl, isovaleryl, pivaloyl, hexanoyl and the like, in which the preferred one is formyl or acetyl.
  • Suitable "lower alkoxycarbonyl” and lower alkoxycarbonyl moiety in the terms “lower alkoxycarbonyl- (lower)alky” , “N-lower alkoxycarbonyl-N-lower alkylamino” and “N-lower alkoxycarbonylpiperazinyl” may be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, and the like, in which the preferred one is ethoxycarbonyl or tert-butoxycarbonyl.
  • Suitable “lower alkylamino(lower)alkyl” maybe lower alkyl substituted with lower alkylamino.
  • Suitable “di(lower)alkylamino(lower)alkyl” may be lower alkyl substituted with di(lower)alkylamino, the "di(lower)alkyl” in which may be the same or different.
  • Suitable examples of the "lower alkylamino" are methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, isobutylamino, pentylamino, hexylamino, and the like, in which the preferred one may be methylamino.
  • di(lower)alkylamino Suitable examples of the "di(lower)alkylamino" are dimethylamino, methyl(ethyl)amino, diethylamino, ethyl(propyl)amino and dipropylamino, or the like, inwhich the preferred one may be dimethylamino.
  • Suitable "halogen” may be fluoro, chloro, bromo and iodo.
  • Suitable "halo(lower)alkyl” may be lower alkyl substitutedwith one or more halogens such as chloromethyl, dichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentachloroethyl or the like, inwhich the preferred one may be trifluoromethyl.
  • the substitute(s) on aryl for R 1 and R 2 may be plural and in such case the substitute(s) may be the same or different.
  • the object compound (I) of the present invention is inhibitors of cytokines' production or their transduction andpossesses thevarious pharmacological actions as stated before.
  • Test method Inhibition of TNF-a production in THP-I cells [I] Test method
  • THP-I cells a human monocytic cell line, were maintained in RPMI 1640 (Sigma R8758) supplemented with
  • LPS LPS
  • lO ⁇ g/mL final Sigma L-4005, from E.coli serotype 055:B5
  • test compound 0.1% DMSO vehicle
  • the cell mixture was incubated for 20 hours in a humidified incubator at 37°C, 5% CO 2 .
  • the culture supernatants were harvested and TNF-a levels, from LPS stimulated cells in the presence of 100 nM test compound was calculated compared with control cells stimulated in the presence of 0.1% DMSO.
  • the pyridazinone compound (I) and a salt thereof of this invention are useful as inhibitors of cytokines' production or their transduction, and through inhibiting
  • the p38 ⁇ MAPK they possess pharmacological actions such as analgesic action, anti-inflammatory, anti arthritis mutilans action, or the like, and for the prevention and/or the treatment of pain, rheumatoid arthritis, other conditions associated with inflammation, Crohn's disease, inflammatory bowel disease, drug for psoriasis, or the like.
  • the pharmaceutical composition of this invention can be used in the form of a pharmaceutical preparation, for example, in a solid, semisolid or liquid form, which contains the pyridazinone compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for rectal, pulmonary (nasal or buccal inhalation) , nasal, ocular, external (topical), oral or parenteral (including subcutaneous, intravenous and intramuscular) administrations or insufflation.
  • a pharmaceutical preparation for example, in a solid, semisolid or liquid form, which contains the pyridazinone compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for rectal, pulmonary (nasal or buccal inhalation) , nasal, ocular, external (topical), oral or parenteral (including subcutaneous, intravenous and intramuscular) administrations or insufflation.
  • the active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, troches, capsules, suppositories, creams, ointments, aerosols, powders for insufflation, solutions, emulsions, suspensions, and any other form suitable for use.
  • auxiliary, stabilizing agents, thickening agents, coloring agents and perfumes may be used where necessary.
  • the pyridazinone compound (I) or a pharmaceutically acceptable salt thereof is included in a pharmaceutical composition in an amount sufficient to produce.the desired aforesaid pharmaceutical effect upon the process or condition of diseases.
  • the composition For applying the composition to a human being or an animal, it is preferable to apply it by intravenous, intramuscular, pulmonary or oral administration, or insufflation. While the dosage of therapeutically effective amount of the pyridazinone compound (I) varies depending on .the age and condition of each individual patient to be treated, in the case of intravenous administration, a daily dose of 0.01 - 100 mg of the pyridazinone compound (I) per kg weight of a human being or an animal, in the case of intramuscular administration, a daily dose of 0.1 - 100 mg of the pyridazinone compound (I) per kg weight of a human being or an animal, and in case of oral administration, a daily dose of 0.5 - 100 mg of the pyridazinone compound (I) per kg weight of a human being or an animal is generally given for the prevention and/or treatment of the aforesaid diseases.
  • Example 1 A mixture of 1- (2-phenylpyrazolo[1,5-a]pyridin-3 ⁇ yl)ethanone (1.0Og) and glyoxylic acid monohydrate (l:56g)in 1,2-dimethoxyethane (3ml) was refluxed for 15h. The mixture was concentrated in vacuo and taken up EtOAc (5ml) and water (4ml) . The aqueous layer was extracted with EtOAc (3ml) . The combined organic layer were washed with water (3ml) and concentrated in vacuo to give an oil.
  • Example 25 To a solution of 6- [2-amino ⁇ 4 ⁇ (4-fluorophenyl) ⁇ 1,3- thiazol-5-yl] -2-[ (1-hydroxycyclohexyl)methyl] -3(2H) - pyridazinone (200mg) in pyridine (1.58g) was added ethyl chloroformate (190mg) at room temperature. After 12h, the mixture was concentrated and triturated with water to give a crude solid (170mg) . The solid was dissolved in EtOAc and washed with IN HCl, sat. NaHCO 3 and brine, dried and evaporated in vacuo.
  • Example 52 A mixture of 2- [ (1-hydroxycyclohexyl)methyl] -6-(2- phenylpyrazolo[1,5-a]pyridin-3-yl) -3(2H)-pyridazinone (200mg) and palladium hydroxide (lOOmg, 20% wt. on carbon) in EtOH (20ml) was stirred for lday under the pressure of 3atm of hydrogen. After filtration of catalyst through the celite pad, the filtrate was concentrated in vacuo and crystallized from EtOH (2ml) and hexane (ImI) .
  • Example 79 To a suspension of 2- [3-[2- [3-(dimethylamino)-1- pyrrolidinyl] -4-(4-fluorophenyl) -1,3-thiazol-5-yl] -6- oxo-l(6H)-pyridazinyl]benzaldehyde (41mg) in THF (2ml) was added a solution of NaBH 4 (6.3mg) in H 2 O (0.3ml) at room temperature. After stirring for 2h, the mixture became clear solution and was quenched with cone. HCl (pH 3) . After Ih with stirring, the mixture was made alkaline with sat. NaHCO 3 and extracted with EtOAc.
  • Example 80 tert-Butyl 4- ⁇ 3- (4-fluorophenyl)-4- [1-(2-methylphenyl) - 6-oxo-l,6-dihydro-3-pyridazinyl] -lH-pyrazol-5-yl ⁇ -l- piperazinecarboxylate (48mg) was dissolved in 4N hydrogen chloride in dioxane (ImI) and methanol (0.5ml), and stirred for 2h at room temperature.
  • Example 86 A mixture of 6- [l-bromo-2-(2,4-difluorophenyl)-2- oxoethyl]-2-(2-methylphenyl)-3(2H)-pyridazinone (3.7g) and tert-butyl [1-(aminocarbonyl)-3-pyrrolidinyl] - methylcarbamate (3.8g) in xylene (21 ml) was stirred at 140 °C for 5h. After cooling to room temperature, the reaction mixture was diluted with H 2 O (50ml) and extracted with EtOAc (50ml) two times. The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by columnchromatography on SiO 2 (eluent: CH 2 Cl2/Me0H 100:1-100:2-10:1) to give tert-butyl
  • Example 91 6- ⁇ 3-(2,4-Difluorophenyl)-5- [ (3-hydroxypropyl)amino] - lH-pyrazol-4-yl ⁇ -2-(2-methylphenyl) -3(2H) -pyridazinone was obtained in a similar manner to that of the above Preparations or Examples from 6- [l-bromo-2-(2,4- difluorophenyl)-2-oxoethyl]-2-(2-methylphenyl) -3(2H) - pyridazinone.
  • Example 94 To a solution of 6- ⁇ 2- [3-(dimethylamino) -1-pyrrolidinyl]- 4-(4-fluorophenyl) -1,3-thiazol-5-yl ⁇ -2-(2-methylphenyl) -3(2H)-pyridazinone (80mg) in CH2C12 (ImI) was added mCPBA (37.7mg) and the mixture was stirred at ambient temperature for 30 min. The reaction mixture was washed with a mixture of sat.MaHCO3 and brine, 5% Na2S2O3, water and brine, successively.
  • 6- ⁇ 4-(2,4-Difluorophenyl)-2-[4-(dimethylamino)-1- piperidinyl] -1,3-oxazol-5-yl ⁇ -2-(2-methylphenyl) -3(2H) - pyridazinone was obtained in a conventional manner from 6- ⁇ 4-(2,4-Difluorophenyl) -2-[4- (methylamino) -1- piperidinyl] -1,3-oxazol-5-yl ⁇ -2-(2-methylphenyl)-3(2H)- pyridazinone

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Abstract

La présente invention a pour objet un dérivé de pyridazinone de formule (I) ci-après : où ; qui peut être employé en tant que médicament pour le traitement de maladies provoquées par les cytokines.
PCT/JP2005/018901 2004-10-08 2005-10-07 Dérivés de la pyridazinone inhibiteurs de cytokines WO2006038734A1 (fr)

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AU2004905844A AU2004905844A0 (en) 2004-10-08 Pyridazinone Derivatives

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WO2007084391A3 (fr) * 2006-01-18 2008-03-20 Amgen Inc Composes thiazole et procedes d'utilisation
WO2010064769A1 (fr) * 2008-12-05 2010-06-10 한국화학연구원 Dérivé de 2-pipérazino-4,5-disubstitué-1,3-thiazole et son procédé de préparation, et agent thérapeutique le contenant en tant qu'ingrédient actif pour les maladies liées à une inflammation par l'activité du
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US7897619B2 (en) 2007-07-17 2011-03-01 Amgen Inc. Heterocyclic modulators of PKB
US7919504B2 (en) 2007-07-17 2011-04-05 Amgen Inc. Thiadiazole modulators of PKB
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WO2012171860A1 (fr) 2011-06-17 2012-12-20 Basilea Pharmaceutica Ag Antibiotiques tricycliques
WO2013050437A1 (fr) 2011-10-06 2013-04-11 Bayer Intellectual Property Gmbh Hétérocyclylpyridinylpyrazole et hétérocyclylpyrimidinylpyrazole utilisés comme fongicides
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US8765949B2 (en) 2009-12-17 2014-07-01 Boehringer Ingelheim International Gmbh CCR2 receptor antagonists and uses thereof
US8835440B2 (en) 2008-12-19 2014-09-16 Boehringer Ingelheim International Gmbh Cyclic pyrimidin-4-carboxamides as CCR2 receptor antagonists for treatment of inflammation, asthma and COPD
US8841313B2 (en) 2010-05-17 2014-09-23 Boehringer Ingelheim International Gmbh CCR2 antagonists and uses thereof
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US8877745B2 (en) 2010-05-12 2014-11-04 Boehringer Ingelheim International Gmbh CCR2 receptor antagonists, method for producing the same, and use thereof as medicaments
US8946218B2 (en) 2010-05-12 2015-02-03 Boehringer Ingelheim International Gmbh CCR2 receptor antagonists, method for producing the same, and use thereof as medicaments
US8962656B2 (en) 2010-06-01 2015-02-24 Boehringer Ingelheim International Gmbh CCR2 antagonists
US8969347B2 (en) 2008-06-03 2015-03-03 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
US9018212B2 (en) 2010-05-25 2015-04-28 Boehringer Ingelheim International Gmbh Pyridazine carboxamides as CCR2 receptor antagonists
US9108958B2 (en) 2011-07-15 2015-08-18 Boehringer Ingelheim International Gmbh Selective CCR2 antagonists
US9242969B2 (en) 2013-03-14 2016-01-26 Novartis Ag Biaryl amide compounds as kinase inhibitors
JP2016507496A (ja) * 2012-12-21 2016-03-10 ゼニス・エピジェネティクス・コーポレイションＺｅｎｉｔｈ Ｅｐｉｇｅｎｅｔｉｃｓ Ｃｏｒｐ． ブロモドメイン阻害剤としての新規複素環式化合物
US9296741B2 (en) 2011-12-30 2016-03-29 Abbvie Inc. Bromodomain inhibitors
US9359379B2 (en) 2012-10-02 2016-06-07 Intermune, Inc. Anti-fibrotic pyridinones
WO2016092375A1 (fr) * 2014-12-11 2016-06-16 Zenith Epigenetics Corp. Hétérocycles substitués à titre d'inhibiteurs de bromodomaines
US9527816B2 (en) 2005-05-10 2016-12-27 Intermune, Inc. Method of modulating stress-activated protein kinase system
US9573969B2 (en) 2014-09-12 2017-02-21 Novartis Ag Compounds and compositions as kinase inhibitors
US9663520B2 (en) 2013-06-21 2017-05-30 Zenith Epigenetics Ltd. Bicyclic bromodomain inhibitors
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US10179125B2 (en) 2014-12-01 2019-01-15 Zenith Epigenetics Ltd. Substituted pyridines as bromodomain inhibitors
US10213428B2 (en) 2015-07-02 2019-02-26 Centrexion Therapeutics Corporation (4-((3R,4R)-3-methoxytetrahydro-pyran-4-ylamino)piperidin-1-yl)(5-methyl-6-(((2R,6S)-6-(p-tolyl)tetrahydro-2H-pyran-2-yl)methylamino)pyrimidin-4-yl)methanone citrate
US10231953B2 (en) 2014-12-17 2019-03-19 Zenith Epigenetics Ltd. Inhibitors of bromodomains
US10233195B2 (en) 2014-04-02 2019-03-19 Intermune, Inc. Anti-fibrotic pyridinones
US10633379B2 (en) 2016-04-15 2020-04-28 Abbvie Inc. Bromodomain inhibitors
US10710992B2 (en) 2014-12-01 2020-07-14 Zenith Epigenetics Ltd. Substituted pyridinones as bromodomain inhibitors
US11026926B2 (en) 2013-06-21 2021-06-08 Zenith Epigenetics Ltd. Substituted bicyclic compounds as bromodomain inhibitors
US12011449B2 (en) 2016-09-19 2024-06-18 Novartis Ag Therapeutic combinations comprising a c-RAF inhibitor
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US12247071B2 (en) 2016-12-21 2025-03-11 Amgen Inc. Anti-TNF alpha antibody formulations

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US9527816B2 (en) 2005-05-10 2016-12-27 Intermune, Inc. Method of modulating stress-activated protein kinase system
JP2009507758A (ja) * 2005-09-01 2009-02-26 アステラス製薬株式会社 疼痛の治療に用いられるピリダジノン誘導体
WO2007026950A1 (fr) * 2005-09-01 2007-03-08 Astellas Pharma Inc. Nouveaux composes
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AU2007207743B2 (en) * 2006-01-18 2010-07-08 Amgen Inc. Thiazole compounds as protein kinase B (PKB) inhibitors
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US9018212B2 (en) 2010-05-25 2015-04-28 Boehringer Ingelheim International Gmbh Pyridazine carboxamides as CCR2 receptor antagonists
US8962656B2 (en) 2010-06-01 2015-02-24 Boehringer Ingelheim International Gmbh CCR2 antagonists
WO2012171860A1 (fr) 2011-06-17 2012-12-20 Basilea Pharmaceutica Ag Antibiotiques tricycliques
US9108958B2 (en) 2011-07-15 2015-08-18 Boehringer Ingelheim International Gmbh Selective CCR2 antagonists
WO2013050437A1 (fr) 2011-10-06 2013-04-11 Bayer Intellectual Property Gmbh Hétérocyclylpyridinylpyrazole et hétérocyclylpyrimidinylpyrazole utilisés comme fongicides
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