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

Dérivés de la pyridazinone inhibiteurs de cytokines Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
pyridazinone
nmr
substituted
dmso
Prior art date
Application number
PCT/JP2005/018901
Other languages
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.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
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

Links

Classifications

    • 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

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)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AU2004905844 2004-10-08
AU2004905844A AU2004905844A0 (en) 2004-10-08 Pyridazinone Derivatives

Publications (1)

Publication Number Publication Date
WO2006038734A1 true WO2006038734A1 (fr) 2006-04-13

Family

ID=35708974

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2005/018901 WO2006038734A1 (fr) 2004-10-08 2005-10-07 Dérivés de la pyridazinone inhibiteurs de cytokines

Country Status (1)

Country Link
WO (1) WO2006038734A1 (fr)

Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007026950A1 (fr) * 2005-09-01 2007-03-08 Astellas Pharma Inc. Nouveaux composes
WO2007040208A1 (fr) * 2005-10-03 2007-04-12 Ono Pharmaceutical Co., Ltd. Composé hétérocyclique azoté et application pharmaceutique de celui-ci
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
WO2010084152A1 (fr) 2009-01-21 2010-07-29 Basilea Pharmaceutica Ag Nouveaux antibiotiques bicycliques
US20100204209A1 (en) * 2007-05-31 2010-08-12 Boehringer Ingelheim International Gmbh CCR2 Receptor Antagonists and Uses Thereof
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
WO2011073378A1 (fr) 2009-12-18 2011-06-23 Basilea Pharmaceutica Ag Antibiotiques tricycliques
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
AU2012203026B2 (en) * 2008-03-21 2014-06-12 Novartis Ag Novel heterocyclic compounds and uses thereof
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
US8865732B2 (en) 2008-03-21 2014-10-21 Novartis Ag Heterocyclic compounds and uses thereof
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
US9855271B2 (en) 2013-07-31 2018-01-02 Zenith Epigenetics Ltd. Quinazolinones as bromodomain inhibitors
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
US10233195B2 (en) 2014-04-02 2019-03-19 Intermune, Inc. Anti-fibrotic pyridinones
US10231953B2 (en) 2014-12-17 2019-03-19 Zenith Epigenetics Ltd. Inhibitors of bromodomains
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

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995013067A1 (fr) * 1993-11-08 1995-05-18 Smithkline Beecham Corporation Oxazoles pour le traitement de maladies induites par la cytokine
WO1995018128A1 (fr) * 1993-12-29 1995-07-06 Fujisawa Pharmaceutical Co., Ltd. Compose pyrazolopyridine antagoniste de l'adenosine
WO2001040230A1 (fr) * 1999-12-02 2001-06-07 Fujisawa Pharmaceutical Co., Ltd. Pyrazolopyrazines et leur utilisation comme antagonistes vis-a-vis de l'adenosine
WO2003015776A1 (fr) * 2001-08-13 2003-02-27 Janssen Pharmaceutica N.V. Derives de thiazolyl 2,4,5-trisubstitue et activite anti-inflammatoire associee
WO2003039451A2 (fr) * 2001-11-08 2003-05-15 Fujisawa Pharmaceutical Co., Ltd. Derive de thiazole et utilisation pharmaceutique
WO2003059891A1 (fr) * 2002-01-18 2003-07-24 Pharmacia Corporation Pyridazinones substituees inhibant la map kinase p38
WO2003097062A1 (fr) * 2002-05-13 2003-11-27 Merck & Co., Inc. Imidazopyridines phenyle substituees et benzimidazoles phenyle substitues

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995013067A1 (fr) * 1993-11-08 1995-05-18 Smithkline Beecham Corporation Oxazoles pour le traitement de maladies induites par la cytokine
WO1995018128A1 (fr) * 1993-12-29 1995-07-06 Fujisawa Pharmaceutical Co., Ltd. Compose pyrazolopyridine antagoniste de l'adenosine
WO2001040230A1 (fr) * 1999-12-02 2001-06-07 Fujisawa Pharmaceutical Co., Ltd. Pyrazolopyrazines et leur utilisation comme antagonistes vis-a-vis de l'adenosine
WO2003015776A1 (fr) * 2001-08-13 2003-02-27 Janssen Pharmaceutica N.V. Derives de thiazolyl 2,4,5-trisubstitue et activite anti-inflammatoire associee
WO2003039451A2 (fr) * 2001-11-08 2003-05-15 Fujisawa Pharmaceutical Co., Ltd. Derive de thiazole et utilisation pharmaceutique
WO2003059891A1 (fr) * 2002-01-18 2003-07-24 Pharmacia Corporation Pyridazinones substituees inhibant la map kinase p38
WO2003097062A1 (fr) * 2002-05-13 2003-11-27 Merck & Co., Inc. Imidazopyridines phenyle substituees et benzimidazoles phenyle substitues

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
COLLETTI, STEVEN L. ET AL: "Hybrid-Designed Inhibitors of p38 MAP Kinase Utilizing N-Arylpyridazinones", JOURNAL OF MEDICINAL CHEMISTRY , 46(3), 349-352 CODEN: JMCMAR; ISSN: 0022-2623, 2003, XP002269334 *

Cited By (78)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10010536B2 (en) 2005-05-10 2018-07-03 Intermune, Inc. Method of modulating stress-activated protein kinase system
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
US7968572B2 (en) 2005-10-03 2011-06-28 Ono Pharmaceuticals Co., Ltd. Nitrogen-containing heterocyclic compound and pharmaceutical application thereof
WO2007040208A1 (fr) * 2005-10-03 2007-04-12 Ono Pharmaceutical Co., Ltd. Composé hétérocyclique azoté et application pharmaceutique de celui-ci
WO2007084391A3 (fr) * 2006-01-18 2008-03-20 Amgen Inc Composes thiazole et procedes d'utilisation
US7514566B2 (en) 2006-01-18 2009-04-07 Amgen, Inc. Thiazole compounds and methods of use
AU2007207743B2 (en) * 2006-01-18 2010-07-08 Amgen Inc. Thiazole compounds as protein kinase B (PKB) inhibitors
US8084479B2 (en) 2006-01-18 2011-12-27 Amgen Inc. Thiazole compounds and methods of use
US8653262B2 (en) * 2007-05-31 2014-02-18 Boehringer Ingelheim International Gmbh CCR2 receptor antagonists and uses thereof
US20100204209A1 (en) * 2007-05-31 2010-08-12 Boehringer Ingelheim International Gmbh CCR2 Receptor Antagonists and Uses Thereof
US7919504B2 (en) 2007-07-17 2011-04-05 Amgen Inc. Thiadiazole modulators of PKB
US7897619B2 (en) 2007-07-17 2011-03-01 Amgen Inc. Heterocyclic modulators of PKB
US8865732B2 (en) 2008-03-21 2014-10-21 Novartis Ag Heterocyclic compounds and uses thereof
AU2012203026B2 (en) * 2008-03-21 2014-06-12 Novartis Ag Novel heterocyclic compounds and uses thereof
USRE47142E1 (en) 2008-06-03 2018-11-27 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
US9290450B2 (en) 2008-06-03 2016-03-22 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
US8969347B2 (en) 2008-06-03 2015-03-03 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
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
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
US9067951B2 (en) 2008-12-19 2015-06-30 Boehringer Ingelheim International Gmbh Process and intermediates for the production of CCR2 antagonists
WO2010084152A1 (fr) 2009-01-21 2010-07-29 Basilea Pharmaceutica Ag Nouveaux antibiotiques bicycliques
US8716280B2 (en) 2009-01-21 2014-05-06 Basilea Pharmaceutica Ag Bicyclic antibiotics
US8927542B2 (en) 2009-01-21 2015-01-06 Basilea Pharmaceutica Ag Bicyclic antibiotics
US9133219B2 (en) 2009-01-21 2015-09-15 Basilea Pharmaceutica Ag Bicyclic antibiotics
US10196402B2 (en) 2009-12-17 2019-02-05 Centrexion Therapeutics Corporation CCR2 receptor antagonists and uses thereof
US9670222B2 (en) 2009-12-17 2017-06-06 Centrexion Therapeutics Corporation CCR2 receptor antagonists and uses thereof
US8765949B2 (en) 2009-12-17 2014-07-01 Boehringer Ingelheim International Gmbh CCR2 receptor antagonists and uses thereof
US11731981B2 (en) 2009-12-17 2023-08-22 Centrexion Therapeutics Corporation CCR2 receptor antagonists and uses thereof
US11046706B2 (en) 2009-12-17 2021-06-29 Centrexion Therapeutics Corporation CCR2 receptor antagonists and uses thereof
WO2011073378A1 (fr) 2009-12-18 2011-06-23 Basilea Pharmaceutica Ag Antibiotiques tricycliques
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
US8841313B2 (en) 2010-05-17 2014-09-23 Boehringer Ingelheim International Gmbh CCR2 antagonists and uses thereof
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
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
US9675593B2 (en) 2012-10-02 2017-06-13 Intermune, Inc. Anti-fibrotic pyridinones
US10898474B2 (en) 2012-10-02 2021-01-26 Intermune, Inc. Anti-fibrotic pyridinones
US10376497B2 (en) 2012-10-02 2019-08-13 Intermune, Inc. Anti-fibrotic pyridinones
AU2013365926B2 (en) * 2012-12-21 2018-08-16 Zenith Epigenetics Ltd. Novel heterocyclic compounds as bromodomain inhibitors
US9598367B2 (en) 2012-12-21 2017-03-21 Zenith Epigenetics Ltd. Heterocyclic compounds as bromodomain 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
EP2935253A4 (fr) * 2012-12-21 2016-04-27 Zenith Epigenetics Corp Nouveaux composés hétérocycliques en tant qu'inhibiteurs de bromodomaine
US9861637B2 (en) 2012-12-21 2018-01-09 Zenith Epigenetics Ltd. Heterocyclic compounds as bromodomain inhibitors
AU2013365926B9 (en) * 2012-12-21 2019-01-17 Zenith Epigenetics Ltd. Novel heterocyclic compounds as bromodomain inhibitors
US10709712B2 (en) 2013-03-14 2020-07-14 Novartis Ag Biaryl amide compounds as kinase inhibitors
US9242969B2 (en) 2013-03-14 2016-01-26 Novartis Ag Biaryl amide compounds as kinase inhibitors
US9694016B2 (en) 2013-03-14 2017-07-04 Novartis Ag Biaryl amide compounds as kinase inhibitors
US10245267B2 (en) 2013-03-14 2019-04-02 Novartis Ag Biaryl amide compounds as kinase inhibitors
US10363257B2 (en) 2013-06-21 2019-07-30 Zenith Epigenetics Ltd. Bicyclic bromodomain inhibitors
US11446306B2 (en) 2013-06-21 2022-09-20 Zenith Epigenetics Ltd. Bicyclic bromodomain inhibitors
US10010556B2 (en) 2013-06-21 2018-07-03 Zenith Epigenetics Ltd. Bicyclic bromodomain inhibitors
US11026926B2 (en) 2013-06-21 2021-06-08 Zenith Epigenetics Ltd. Substituted bicyclic compounds as bromodomain inhibitors
US10772892B2 (en) 2013-06-21 2020-09-15 Zenith Epigenetics Ltd. Bicyclic bromodomain inhibitors
US9663520B2 (en) 2013-06-21 2017-05-30 Zenith Epigenetics Ltd. Bicyclic bromodomain inhibitors
US10500209B2 (en) 2013-07-31 2019-12-10 Zenith Epigenetics Ltd. Quinazolinones as bromodomain inhibitors
US9855271B2 (en) 2013-07-31 2018-01-02 Zenith Epigenetics Ltd. Quinazolinones as bromodomain inhibitors
US10233195B2 (en) 2014-04-02 2019-03-19 Intermune, Inc. Anti-fibrotic pyridinones
US10544161B2 (en) 2014-04-02 2020-01-28 Intermune, Inc. Anti-fibrotic pyridinones
US9809610B2 (en) 2014-09-12 2017-11-07 Novartis Ag Compounds and compositions as kinase inhibitors
US9573969B2 (en) 2014-09-12 2017-02-21 Novartis Ag Compounds and compositions as kinase inhibitors
US10179125B2 (en) 2014-12-01 2019-01-15 Zenith Epigenetics Ltd. Substituted pyridines as bromodomain inhibitors
US10710992B2 (en) 2014-12-01 2020-07-14 Zenith Epigenetics Ltd. Substituted pyridinones as bromodomain inhibitors
WO2016092375A1 (fr) * 2014-12-11 2016-06-16 Zenith Epigenetics Corp. Hétérocycles substitués à titre d'inhibiteurs de bromodomaines
CN107207474A (zh) * 2014-12-11 2017-09-26 齐尼思表观遗传学有限公司 被取代的杂环作为溴结构域抑制剂
CN107207474B (zh) * 2014-12-11 2021-05-07 恒翼生物医药科技(上海)有限公司 被取代的杂环作为溴结构域抑制剂
US10292968B2 (en) 2014-12-11 2019-05-21 Zenith Epigenetics Ltd. Substituted heterocycles as bromodomain inhibitors
US10231953B2 (en) 2014-12-17 2019-03-19 Zenith Epigenetics Ltd. Inhibitors of bromodomains
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
US11147814B2 (en) 2015-07-02 2021-10-19 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
US10568885B2 (en) 2015-07-02 2020-02-25 Centrexion Therapeutics Corporation (4-((3R,4R)-3-methoxytetrahydro-pyran-4-ylamino)piperidin-1-y1)(5-methyl-6-(((2R,6S)-6-(p-tolyl)tetrahydro-2H-pyran-2-citrate
US10633379B2 (en) 2016-04-15 2020-04-28 Abbvie Inc. Bromodomain inhibitors

Similar Documents

Publication Publication Date Title
WO2006038734A1 (fr) Dérivés de la pyridazinone inhibiteurs de cytokines
US11390618B2 (en) Inhibitors of cyclin-dependent kinases
US7019005B2 (en) 3 (5)-heteroaryl substituted pyrazoles as p38 kinase inhibitors
AU755498B2 (en) 3(5)-heteroaryl substituted pyrazoles as p38 kinase inhibitors
CA2672373C (fr) Derives de la nicotinamide en tant qu'inhibiteurs de h-pgds et leur utilisation dans le traitement de maladies liees aux prostaglandines d2
JP4679509B2 (ja) ２，３，６−置換−４−ピリミドン誘導体
US20100113445A1 (en) Chemical Compounds
JP5432249B2 (ja) 新規なヘテロアリールカルボキシアミド誘導体
JP2023501253A (ja) Ｐａｒｐ７阻害剤としてのピリダジノン
CA3085561A1 (fr) Azines triazoles d'acide cyclohexyle utilisees en tant qu'antagonistes de lpa
AU2006262441A1 (en) Piperidine derivatives useful as histamine H3 antagonists
RU2425826C2 (ru) СОЕДИНЕНИЯ И КОМПОЗИЦИИ В КАЧЕСТВЕ ИНГИБИТОРОВ ITPKb
EA018709B1 (ru) Пиридоновые агонисты сопряженного с g-белком рецептора gpr119
JP2008525408A (ja) 早産、月経困難症および子宮内膜症の処置用のオキトシン受容体アンタゴニストとしての１，６−置換（３ｒ，６ｒ）−３−（２，３−ジヒドロ−１ｈ−インデン−２−イル）−２，５−ピペラジンジオン誘導体
JP2012507512A (ja) アミロイドβのモジュレーター
TW201336825A (zh) 雙環芳基及雜芳基化合物之鈉通道抑制劑
CA2736955A1 (fr) Composes multiheteroaryles servant d'inhibiteurs de la h-pgds, ainsi que leur utilisation dans le traitement des maladies induites par la prostaglandine d2
US20170233371A1 (en) Rorc2 inhibitors and methods of use thereof
AU2014212193A1 (en) Flap modulators
AU771344B2 (en) Novel diphenyl-piperidine derivate
JPWO2012036278A1 (ja) グリシントランスポーター阻害物質
WO2015152367A1 (fr) Dérivé cyclique oxo-hétérocyclique
US20050043315A1 (en) Aminopyrimidine compounds, processes for their preparation and pharmaceutical compositions containing them
AU2011305667A1 (en) Oxadiazole inhibitors of leukotriene production
TW202028188A (zh) 新穎胺基-嘧啶酮基-哌啶基衍生物、其製備之方法及包含其之醫藥組合物

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KP KR KZ LC LK LR LS LT LU LV LY MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 05793104

Country of ref document: EP

Kind code of ref document: A1