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WO1999051580A1 - Inhibiteurs de type pyrazole de la production de cytokine - Google Patents

Inhibiteurs de type pyrazole de la production de cytokine Download PDF

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Publication number
WO1999051580A1
WO1999051580A1 PCT/US1999/007766 US9907766W WO9951580A1 WO 1999051580 A1 WO1999051580 A1 WO 1999051580A1 US 9907766 W US9907766 W US 9907766W WO 9951580 A1 WO9951580 A1 WO 9951580A1
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Prior art keywords
trifluoromethyl
pyrazol
bis
phenyl
fifteen carbons
Prior art date
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Ceased
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PCT/US1999/007766
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English (en)
Inventor
Nwe Y. Ba Maung
Anwer Basha
Stevan W. Djuric
Earl J. Gubbins
Jay R. Luly
Noah P. Tu
David J. Madar
Usha Warrior
Paul E. Wiedeman
Xun Zhou
Frank L. Wagenaar
Richard J. Sciotti
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Abbott Laboratories
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Abbott Laboratories
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Priority to EP99915341A priority Critical patent/EP1068187A1/fr
Priority to AU33879/99A priority patent/AU3387999A/en
Priority to JP2000542301A priority patent/JP2002510679A/ja
Priority to CA002327185A priority patent/CA2327185A1/fr
Publication of WO1999051580A1 publication Critical patent/WO1999051580A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/16—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C07D403/10—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 linked by a carbon chain containing aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur 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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic 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
    • C07D413/10—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 linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D417/10—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 linked by a carbon chain containing aromatic 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
    • C07D417/14—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
    • 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

Definitions

  • the present invention relates to organic compounds and compositions that are cytokine synthesis inhibitors, processes for making such compounds, synthetic intermediates employed in these processes, and methods for inhibiting cytokine production in a mammal.
  • Therapeutic control of the immune system is the goal of many approaches toward the treatment of autoimmune diseases that differ in organ specific involvement, pathogenic cofactors, response to treatment and prognosis. They range from diseases with "spontaneous" onset such as rheumatoid arthritis to rejection reactions after allograft organ transplantation.
  • Interleukin 2 IL-2
  • IL-2 Interleukin 2
  • B cells B cells
  • activated macrophages NK cells
  • LAK cells LAK cells
  • the central importance of IL-2 in initiating adaptive immune responses such as the rejection of tissue grafts is well-illustrated by drugs that are most commonly used to suppress undesirable effects such as the rejection of tissue grafts.
  • the drugs cyclosporin A and FK506 inhibit IL-2 production by disrupting signalling initiated through the T-cell receptor.
  • the drug rapamycin also inhibits signalling through the T cell receptor. Cyclosporin A and rapamycin act synergistically to inhibit immune responses by preventing the IL-2 driven clonal expansion of T cells (Brazelton and Morris, Current Opinion in Immunology 8,, 710 (1996)).
  • IL-2 is a key orchestrator of the immune response such as rheumatoid arthritis, atopic dermatitis, psoriasis and the rejection of tissue grafts.
  • Interleukin-5 IL-5
  • Interleukin-4 IL-4
  • IL-5 has selective biologic effects on eosinophils and their precursors and may regulate selective accumulation of these cells in the asthmatic bronchial mucosa.
  • IL-4 is an essential co-factor for IgE switching in B-lymphocytes and is therefore likely to be involved in situations where there is inappropriate IgE synthesis.
  • Compounds of this invention inhibit the production of both IL-4 and IL-5 and can be expected to exhibit efficacy in atopic diseases where the aforementioned cytokines play a prominent role in disease pathophysiology.
  • R l and R3 are : independently selected from
  • R7 and Rs are independently selected from
  • alkoxycarbonyl where the alkyl part is one to fifteen carbons
  • alkoxycarbonyl where the alkyl part is one to fifteen carbons and is substituted with 1 or 2 substituents selected from the group consisting of aryl
  • R9 is selected from
  • Z is nitrogen or carbon
  • R 2 is absent or is selected from
  • R7' and R 8 ' together with the nitrogen to which they are attached form a ring selected from
  • Q is aryl or heterocycle where, when Q is phenyl, the phenyl is 2-, 3-, or 4- substituted by E relative to the position of attachment of the pyrazole or 1,2,4-triazole ring to the phenyl ring;
  • R4 and R5 are independently selected from (1) hydrogen,
  • alkenyl of two to fifteen carbons (i) alkenyl of two to fifteen carbons, (ii) alkoxy of one to fifteen carbons, (iii) thioalkoxy of one to fifteen carbons, (iv) alkynyl of two to fifteen carbons, and (v) aryl,
  • Rc, RD > and RE are independently selected from hydrogen, alkanoyl where the alkyl part is one to fifteen carbons, alkanoyloxy where the alkyl part is one to fifteen carbons, alkoxy of one to fifteen carbons, thioalkoxy of one to fifteen carbons, alkoxy of one to fifteen carbons substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of halo , perfluoroalkyl of one to fifteen carbons, perfluoroalkoxy of one to fifteen carbons,
  • alkyl part is one to fifteen carbons, alkoxy of one to fifteen carbons, thioalkoxy of one to fifteen carbons, 5 alkoxy of one to fifteen carbons substituted with
  • substituents independently selected from 25 alkyl of one to fifteen carbons, perfluoroalkyl of one to fifteen carbons, alkoxy of one to fifteen carbons, thioalkoxy of one to fifteen carbons, halo, 30 -NR ⁇ C(O)NR ⁇ R z ,
  • alkanoyl where the alkyl part is one to fifteen carbons
  • alkanoyloxy where the alkyl part is one to fifteen
  • R E provided that when Rj and R 3 are both perfluoroalkyl of one carbon, Z is carbon, R 2 is hydrogen, Q is phenyl that is 4-substituted by E relative to the position of attachment of the pyrazole ring to the phenyl group, R4 and R5 are hydrogen, E is -L3-B, L is -N(R7)C(X)-, R7 is hydrogen, X is oxygen, and RA, RB, RD > and RE are hydrogen, Re is other than chloro, and (g) heterocycle where the heterocycle can be optionally substituted with 1 ,
  • alkanoyl where the alkyl part is one to fifteen carbons
  • alkanoyloxy where the alkyl part is one to fifteen carbons
  • alkoxy of one to fifteen carbons alkoxy of one to fifteen carbons substituted with 1, 2, 3,
  • substituents selected from the group consisting of halo, thioalkoxy of one to fifteen carbons, perfluoroalkyl of one to fifteen carbons, perfluoroalkoxy of one to fifteen carbons, -N 3 , -NO 2 ,
  • alkanoyl where the alkyl part is one to fifteen carbons
  • alkanoyloxy where the alkyl part is one to fifteen carbons
  • the present invention also relates to a method of inhibiting
  • Interleukin-2, Interleukin-4, and Interleukin-5 production in a mammal comprising administering a therapeutically effective amount of a compound of Formula I.
  • the present invention also relates to a method of treating immunologically-mediated diseases in a mammal comprising administering a therapeutically effective amount of a compound of Formula I.
  • the present invention relates to pharmaceutical compositions which comprise a therapeutically effective amount of a compound of Formula I in combination with a pharmaceutically acceptable carrier.
  • Compounds of the invention include but are not limited to N-[4-[3,5-bis(trifluoromethyl)-lH-pyrazol-l-yl]phenyl]cyclopro ⁇ anecarboxamide,
  • N-[4-[3,5-bis(trifluoromethyl)-lH-pyrazol- -yl]phenyl]-4-iodobenzamide N-[4-[3,5-bis(trifluoromethyl)-lH-pyrazol- -yl]phenyl]-3-chloropropan amide, N-[4-[3,5-bis(trif ⁇ uoromethyl)-lH-pyrazol- -yl]phenyl]-4-methoxybenzamide,
  • N-(4-(5-chloro-3-(trifluoromethyl)- IH-pyrazol- 1 -yl)phenyl)-3-fluoroisonicotinamide N-(4-(5-bromo-3-(trifluoromethyl)-l H-pyrazol- l-yl)phenyl)-3-fluoroisonicotinamide, 3-fluoro-N-(4-(5-nitro-3-(trifluoromethyl)-lH-pyrazol-l-yl)phenyl)isonicotinamide, N-(4-(5-bromo-3-(trifluoromethyl)-lH-pyrazol-l-yl)phenyl)-4-methyl-l,2,3-thiadiazole- 5-carboxamide,
  • alkanoyl refers to an alkyl group attached to the parent molecular group through a carbonyl group.
  • alkanoyloxy refers to an alkanoyl group attached to the parent molecular group through an oxygen atom.
  • alkenyl refers to a monovalent straight or branched chain group derived from a hydrocarbon of two to fifteen carbons having at least one carbon-carbon double bond.
  • the alkenyl groups of this invention can be optionally substituted.
  • alkenylene refers to a divalent straight or branched chain group derived from a hydrocarbon of two to fifteen carbons having at least one carbon-carbon double bond.
  • alkoxy refers to an alkyl group attached to the parent molecular group through an oxygen atom.
  • alkyl refers to a monovalent straight or branched chain group derived from an saturated hydrocarbon of one to fifteen carbons.
  • the alkyl groups of this invention can be optionally substituted.
  • alkylene refers to a divalent group derived from a straight or branched chain saturated hydrocarbon of one to fifteen carbons.
  • alkynyl refers to a monovalent straight or branched chain group derived from a hydrocarbon of one to fifteen carbons having at least one carbon-carbon triple bond.
  • the alkynyl groups of this invention can be optionally substituted.
  • alkynylene refers to a divalent group derived from a straight or branched
  • amino refers to -NH 2 .
  • amino protecting group refers to groups intended to protect an amino group against undersirable reactions during synthetic procedures. Commonly used amino protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis,” (John Wiley & Sons, New York (1981)), which is hereby inco ⁇ orated by reference. Preferred N- protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and allylcarbonyloxy (Alloc).
  • aryl refers to a mono- or bicyclic carbocyclic ring system having at least one aromatic ring that can be optionally substituted.
  • the aryl group can be fused to a cyclohexane, cyclohexene, cyclopentane or cyclopentene ring in which case the aryl group can be attached through the ring to which it is attached or through the aromatic ring itself.
  • carboxy protecting group refers to a carboxylic acid protecting ester or amide group typically employed to block or protect the carboxylic acid functionality while the reactions involving other functional sites of the compound are performed.
  • Carboxy protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis". Additionally, a carboxy protecting group can be used as a prodrug whereby the carboxy protecting group can be readily cleaved in vivo, for example by enzymatic hydrolysis, to release the biologically active parent.
  • Such carboxy protecting groups are well-known to those skilled in the art, having been extensively used in the protection of carboxyl groups in the penicillin and cephalosporin fields as described in U.S. Pat. Nos. 3,840,556 and 3,719,667 which are hereby inco ⁇ orated by reference.
  • cycloalkenyl refers to a monovalent cyclic or bicyclic hydrocarbon of three to fifteen carbons having at least one carbon-carbon double bond.
  • the cycloalkenyl groups of this invention can be optionally substituted.
  • cycloalkyl refers to a monovalent saturated cyclic or bicyclic hydrocarbon of three to fifteen carbons.
  • the cycloalkyl groups of this invention can be optionally substituted.
  • halo refers to F, CI, Br, or I.
  • heterocycle or “heterocyclic” refer to a 4-, 5-, 6- or 7-membered ring containing one, two or three heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur.
  • the 4- and 5-membered rings have 0, 1 , or 2 double bonds and the 6- and 7-membered rings have 0, 1, 2, or 3 double bonds.
  • the nitrogen and sulfur atoms can be optionally oxidized, and the nitrogen atom can be optionally quaternized.
  • heterocycle also includes bicyclic, tricyclic, and tetracyclic groups in which a heterocyclic ring is fused to one or two rings selected from an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring or another monocyclic heterocyclic ring.
  • Heterocycles of this type can be attached through the ring to which they are fused or through the heterocyclic ring itself.
  • Heterocycles include, but are not limited to, acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, mo ⁇ holinyl, oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazol
  • Heterocyclics also include bridged bicyclic groups where a monocyclic heterocyclic group is bridged by an alkylene group such as H ® N H and the like.
  • Heterocyclics also include compounds of the formula Y* ° where X* is selected from -CH 2 -, -CH 2 O- and -O-,and Y* is selected from
  • hydroxyl refers to -OH.
  • hydroxyl protecting group refers to a protecting ester or ether group typically employed to block or protect the hydroxyl group while reactions involving other functional sites of the compound are performed. Hydroxyl protecting groups are disclosed in Greene, “Protective Groups In Organic Synthesis,” (John Wiley & Sons, New York (1981)).
  • perfluoroalkyl refers to an alkyl group wherein all of the hydrogens have been substituted with fluorides.
  • pharmaceutically acceptable prodrugs refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower mammals without undue
  • prodrug refers to compounds which are rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood.
  • a thorough discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems, “ Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., "Bioreversible Carriers in Drug Design,” American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby inco ⁇ orated by reference.
  • thioalkoxy refers to an alkyl group attached to the parent molecular group through a sulfur atom.
  • Stereoisomers include enantiomers and diastereomers.
  • Individual stereoisomers of compounds of the present invention can be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art.
  • Geometric isomers may also exist in the compounds of the present invention.
  • the present invention contemplates the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or disposition of substituents around a ring.
  • Substituents around a carbon-carbon double bond are designated as being in the Z or E configuration where the term “Z” refers to substituents on the same side of the carbon-carbon double bond and the term “E” refers to substituents on opposite sides of the carbon-carbon double bond.
  • Compounds of the present invention can exist as rotamers. Rotamers are formed from hinderance around an amide bond to provide 2 or more distinct compounds which can be separated by means well-known to those skilled in the art.
  • Human peripheral blood mononuclear cells were cultured in RPMI 1640 medium supplemented with 10 ⁇ g/ml gentamicin, 50 uM 2-mercaptoethanol, IX MEM non-essential amino acids (Sigma Chemical Co., St. Louis, MO), 100 U/ml sodium penicillin G, 100 ⁇ g/ml streptomycin sulfate, 2 mM L-glutamine, 1 mM sodium pyruvate (Life Technologies, Grand Island, NY) and 10% fetal bovine serum (Hyclone, Logan, UT) at 37 °C with 5% CO2-
  • Cells at the interface from each Histopaque tube were removed and mixed with 5 ml of D-PBS. Each cell suspension was diluted to 50 ml with D-PBS, mixed and centrifuged at 400 X G for 15 minutes at room temperature. After most of the supernatant was removed, cells were resuspended to 40 ml with D-PBS per tube (2 tubes per donor). Cells were centrifuged at 400 X G for 10 minutes at room temperature. Pellets were resuspended in 10 ml of supplemented RPMI 1640 and cell number determined with a Coulter counter. Cells were diluted to a concentration of 0.5 X 10 ⁇ cells per mL.
  • test compounds were added to appropriate wells on 96-well tissue culture plates (Corning Glass Works, Corning, NY) in 20 ⁇ l of supplemented RPMI 1640. Human peripheral blood mononuclear cells were added to each well in 100 ⁇ l volumes (final cell concentration equal to 50,000 cells per well). After 15 minutes, 100 ⁇ l of 5 ⁇ g/ml concanavalin-A (Sigma Chemical Co., St. Louis, MO) in supplemented RPMI 1640 was added to a final concentration of 2.5 ⁇ g/ml. Plates were incubated for 3 days at 37° C with 5% CO 2 . On day 3, plates were pulsed with 0.5 ⁇ Ci/well tritiated thymidine (New England Nuclear, Boston, MA). After 6 hours, plates were harvested
  • PBMC peripheral blood mononuclear cells
  • Tissue culture supernatant at various dilutions were added in triplicate at 100 ⁇ l/well. Plates were incubated for 2 hours at room temperature and washed 4 times with wash buffer. 100 ⁇ l of rabbit anti-human IL-2 (10 ⁇ g/ml, Genzyme) was added and incubated for 1 hour at room temperature. The incubation was followed by 4 washes and subsequent addition of 100 ⁇ l of 1 :2000 dilution of alkaline phosphatase-conjugated goat anti-rabbit F(ab')2 (Biosource International). After 1 hour the plates were washed 4 times and 100 ⁇ l of pNPP (Southern Biotech or Sigma) at 1 mg/ml in buffer was added.
  • pNPP Pacificn Biotech or Sigma
  • Human T cells (HUT 78) were cultured to lxl0 6 /mL in RPMI 1640 medium containing 10% fetal calf
  • IL-4 and IL-5 ELISA's were performed according to standard procedures. Inhibition was calculated relative to cytokine levels produced from control stimulated cells not treated with compound.
  • the compounds are useful for inhibiting cytokine (IL-2, IL-4 and IL-5) production and cellular proliferation in stimulated human T cell lines or human peripheral blood mononuclear cells and therefore have utility in the treatment of diseases that are prevented by or ameliorated with cytokine inhibitors.
  • cytokine IL-2, IL-4 and IL-5
  • the compounds of the invention possess immunomodulatory activity in mammals, especially humans.
  • immunosuppressants the compounds of the present invention are useful for the treatment and
  • immune-mediated diseases such as the resistance to transplantation of organs or tissue such as heart, kidney, liver, medulla ossium, skin, cornea, lung, pancreas, intestinum ***, limb, muscle, nerves, duodenum, small-bowel, pancreatic-islet-cell, and the like; graft- versus-host diseases brought about by medulla ossium transplantation; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, allergic encephalomyelitis, glomerulonephritis, and the like.
  • Further uses include the treatment and prophylaxis of inflammatory and hype ⁇ roliferative skin diseases and cutaneous manifestations of immunologically-mediated illnesses, such as psoriasis, atopic dermatitis, contact dermatitis and further eczematous dermatitises, seborrhoeis dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, lupus erythematosus, acne and alopecia areata; various eye diseases (autoimmune and otherwise) such as keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, he ⁇ etic keratitis, conical cornea, dystrophia epithelialis corneae, corneal leukoma
  • reversible obstructive airway disease which includes conditions such as asthma (for example, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma), particularly chronic or inveterate asthma (for example, late asthma and airway hyper-responsiveness), bronchitis, allergic rhinitis, and the like are targeted by compounds of this invention.
  • asthma for example, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma
  • chronic or inveterate asthma for example, late asthma and airway hyper-responsiveness
  • bronchitis allergic rhinitis
  • Inflammation of mucosa and blood vessels such as gastric ulcers, vascular damage caused by ischemic diseases and thrombosis.
  • hype ⁇ roliferative vascular diseases such as intimal smooth muscle cell hype ⁇ lasia, restenosis and vascular occlusion, particularly following biologically- or mechanically- mediated vascular injury, could be treated or prevented by the compounds of the invention.
  • treatable conditions include but are not limited to ischemic bowel diseases, inflammatory bowel diseases, necrotizing enterocolitis, intestinal inflammations/allergies such as Coeliac diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis; nervous diseases such as multiple myositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis and radiculopathy; endocrine diseases such as hyperthyroidism and Basedow's disease; hematic diseases such as pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic pu ⁇ ura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia and anerythroplasia; bone diseases such as osteoporosis; respiratory diseases such as sarcoidosis, fibroid lung and idiopathic intersti
  • -56- photoallergic sensitivity and cutaneous T cell lymphoma cutaneous T cell lymphoma
  • circulatory diseases such as arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa and myocardosis; collagen diseases such as scleroderma, Wegener's granuloma and Sjogren's syndrome; adiposis; eosinophilic fasciitis; periodontal disease such as lesions of gingiva, periodontium, alveolar bone and substantia ossea dentis; nephrotic syndrome such as glomerulonephritis; male pattern aleopecia or alopecia senilis by preventing epilation or providing hair germination and/or promoting hair generation and hair growth; muscular dystrophy; Pyoderma and Sezary's syndrome; Addison's disease; active oxygen-mediated diseases, as for example organ injury such as ischemia-reperfusion injury of organs (such as heart,
  • the compounds of the invention are useful for the treatment and prevention of hepatic disease such as immunogenic diseases (for example, chronic autoimmune liver diseases such as autoimmune hepatitis, primary biliary cirrhosis and sclerosing cholangitis), partial liver resection, acute liver necrosis (e.g.
  • chemotherapeutic effect such as cytomegalo
  • the present invention also provides pharmaceutical compositions that comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers.
  • the pharmaceutical compositions can be specially formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally , intracisternally, intravaginally, intraperitoneally or topically (such as powders, ointments or drops), bucally or as an oral or nasal spray.
  • parenteral administration refers to modes of administration that include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
  • compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged abso ⁇ tion of the injectable pharmaceutical form can be brought about by the inclusion of agents (such as aluminum monostearate and gelatin) that delay abso ⁇ tion .
  • agents such as aluminum monostearate and gelatin
  • the abso ⁇ tion of the drug in order to prolong the effect of the drug, it is desirable to slow the abso ⁇ tion of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amo ⁇ hous material with poor water solubility. The rate of abso ⁇ tion of the drug then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed
  • -58- abso ⁇ tion of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter or by inco ⁇ orating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) abso ⁇ tion accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h)
  • compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols, and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally or in delayed fashion. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • the active compounds may also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • the compounds of the present invention may be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids.
  • pharmaceutically acceptable salt is meant those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well-known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1 et seq.
  • the salts may be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable acid.
  • Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate.
  • the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates
  • long chain halides such as decyl
  • Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • suitable bases such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.
  • inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzo
  • the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth and mixtures thereof.
  • Compositions for rectal or vaginal administration are preferably suppositories that can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax that are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like.
  • the preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic.
  • immunosuppressant agents within the scope of this invention include, but are not limited to, IMURAN® (azathioprine sodium), brequinar sodium, SPANIDIN® (gusperimus trihydrochloride, also known as deoxyspergualin), mizoribine (also known as bredinin), CELLCEPT® (mycophenolate mofetil), Cyclosporin A in its various formulations (NEORAL®, SANDIMMUNE®, and generic formulations), PROGRAF® (tacrolimus, also known as FK-506), RAPAMUNE® (sirolimus also known as rapamycin), and leflunomide (also known as HWA-486), glucocorticoids, such as prednisolone and its derivatives, antibody therapies such as orthoclone (OKT3) and Zenapax®, and antithymyocyte globulins, such as thym
  • Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants that can be required.
  • Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention can be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated.
  • dosage levels of about 1 to about 50, more preferably of about 5 to about 20 mg, of active compound per kilogram of body weight per day when administered orally to a mammalian patient.
  • the effective daily dose can be divided into multiple doses for pu ⁇ oses of administration, e.g. two to four separate doses per day.
  • THF for tetrahydrofuran
  • DMF for N,N-dimethylformamide
  • DMSO for dimethylsulfoxide
  • Boc for tert-butylcarbonyloxy
  • DCC for dicyclohexylcarbodiimide
  • EDC for l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • HBTU for O- benzotriazol-yl-N,N,N'N'-tetramethyluronium hexafluorophosphate
  • DMAP for 4- dimethylaminopyridine.

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Abstract

La présente invention concerne des composés représentés par la formule (I) convenant pour le traitement de maladies pour lesquelles les inhibiteurs de production de l'interleukine 2, de l'interleukine 4 ou de l'interleukine 5 ont un effet préventif ou bénéfique.
PCT/US1999/007766 1998-04-08 1999-04-08 Inhibiteurs de type pyrazole de la production de cytokine Ceased WO1999051580A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP99915341A EP1068187A1 (fr) 1998-04-08 1999-04-08 Inhibiteurs de type pyrazole de la production de cytokine
AU33879/99A AU3387999A (en) 1998-04-08 1999-04-08 Pyrazole inhibitors of cytokine production
JP2000542301A JP2002510679A (ja) 1998-04-08 1999-04-08 ピラゾールサイトカイン産生阻害剤
CA002327185A CA2327185A1 (fr) 1998-04-08 1999-04-08 Inhibiteurs de type pyrazole de la production de cytokine

Applications Claiming Priority (2)

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US5699698A 1998-04-08 1998-04-08
US09/056,996 1998-04-08

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WO1999051580A1 true WO1999051580A1 (fr) 1999-10-14

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Cited By (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001072740A1 (fr) * 2000-03-23 2001-10-04 Boehringer Ingelheim Pharmaceuticals, Inc. Triazoles 1-(4-aminophenyl) substitues et leur utilisation comme agents anti-inflammatoires
EP1101759A4 (fr) * 1998-07-31 2001-12-12 Nippon Soda Co Composes phenylazole, procede de production desdits composes et medicaments pour le traitement de l'hyperlipidemie
WO2002006273A1 (fr) * 2000-07-13 2002-01-24 Boehringer Ingelheim Pharmaceuticals, Inc. 1-(4-aminophenyl) indoles substitues et leur utilisation comme anti-inflammatoires
EP1024138A4 (fr) * 1997-10-13 2002-02-06 Yamanouchi Pharma Co Ltd Derives de pyrazole
EP1176140A4 (fr) * 1999-02-10 2002-07-31 Mitsubishi Pharma Corp Composes amide et leur utilisation medicinale
EP1273580A1 (fr) * 2001-07-05 2003-01-08 Pfizer Products Inc. Sulfonyl heteroaryl triazoles comme agent anti-inflammatoire et analgetique
WO2003002555A1 (fr) * 2001-06-29 2003-01-09 Boehringer Ingelheim Pharmaceuticals Inc. Procede d'utilisation d'inhibiteurs d'hydrolase epoxyde solubles
JP2003528070A (ja) * 2000-03-22 2003-09-24 イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニー 殺虫性アントラニルアミド類
WO2004002948A1 (fr) * 2001-05-16 2004-01-08 Mitsubishi Pharma Corporation Compose amide et utilisation medicinale de ce compose
WO2004022055A1 (fr) * 2002-09-09 2004-03-18 Amgen Inc. Derives de 1, 4, 5-substitue 1, 2-dihydro-pyrazol-3-one et 3-alcoxy-1h-pyrazole, tnf-alpha et agents reduisant l'interleukine dans le traitement des inflammations
WO2004048367A1 (fr) * 2002-11-26 2004-06-10 Cj Corporation Derive de 1,2,4-triazole, procede de preparation de celui-ci et composition pharmaceutique renfermant celui-ci
US6927230B2 (en) 2001-11-09 2005-08-09 Fujisawa Pharmaceutical Co., Ltd. Triazole derivatives
WO2005090333A1 (fr) * 2004-03-09 2005-09-29 Boehringer Ingelheim Pharmaceuticals, Inc. 3-'4-heterocyclyl -1,2,3,-triazol-1-yl-n-aryl-benzamides en tant qu'inhibiteurs de la production de cytokines pour le traitement de maladies inflammatoires
US7078419B2 (en) 2003-03-10 2006-07-18 Boehringer Ingelheim Pharmaceuticals, Inc. Cytokine inhibitors
US7132546B2 (en) 2000-12-22 2006-11-07 Ishihara Sangyo Kaisha, Ltd. Aniline derivatives or salts thereof and cytokine production inhibitors containing the same
US7141585B2 (en) 2000-07-07 2006-11-28 Agouron Pharmaceuticals, Inc. Pyrazole derivatives
US7285545B2 (en) 2004-05-03 2007-10-23 Boehringer Ingelheim Pharmaceuticals, Inc. Cytokine inhibitors
JP2007530594A (ja) * 2004-03-25 2007-11-01 シンタ ファーマシューティカルズ コーポレーション 炎症及び免疫に関連する用途に用いられるアクリロニトリル誘導体
WO2007067836A3 (fr) * 2005-12-05 2007-11-15 Boehringer Ingelheim Int Composes de pyrazole substitues utiles en tant qu'inhibiteurs d'epoxyde hydrolase soluble
US7309710B2 (en) 2002-08-27 2007-12-18 Astellas Pharma Inc. Crystals
AU2006225221B2 (en) * 2000-03-24 2008-11-20 Euro-Celtique S.A. Aryl substituted pyrazoles, triazoles and tetrazoles, and the use thereof
US7485657B2 (en) 2004-05-12 2009-02-03 Boehringer Ingelheim Pharmaceuticals, Inc. Anti-cytokine heterocyclic compounds
EP1845081A4 (fr) * 2005-02-01 2009-03-25 Takeda Pharmaceutical Composé amide
US7511042B2 (en) 2003-12-03 2009-03-31 Boehringer Ingelheim Pharmaceuticals, Inc. Triazole compounds
US7531560B2 (en) 2004-11-10 2009-05-12 Boehringer Ingelheim Pharmaceuticals, Inc. Anti-cytokine heterocyclic compounds
US7622471B2 (en) 2003-02-07 2009-11-24 Daiichi Pharmaceutical Co., Ltd. Pyrazole derivatives having a pyridazine and pyridine functionality
US7671058B2 (en) 2006-06-21 2010-03-02 Institute Of Medicinal Molecular Design, Inc. N-(3,4-disubstituted phenyl) salicylamide derivatives
US8263657B2 (en) * 2000-12-18 2012-09-11 Institute Of Medicinal Molecular Design, Inc. Inhibitors against the production and release of inflammatory cytokines
US8410144B2 (en) 2009-03-31 2013-04-02 Arqule, Inc. Substituted indolo-pyridinone compounds
US8546403B2 (en) 2010-04-27 2013-10-01 Calcimedica, Inc. Compounds that modulate intracellular calcium
WO2013164773A1 (fr) * 2012-05-02 2013-11-07 Lupin Limited Composés substitués de pyrazole en tant que modulateurs de crac
US8754219B2 (en) 2010-04-27 2014-06-17 Calcimedica, Inc. Compounds that modulate intracellular calcium
US8835468B2 (en) 2007-06-22 2014-09-16 Chemocentryx, Inc. N-(2-(hetaryl)aryl)arylsulfonamides and n-(2-(hetaryl)hetaryl) arylsulfonamides
US9079891B2 (en) 2010-08-27 2015-07-14 Calcimedica, Inc. Compounds that modulate intracellular calcium
US9512116B2 (en) 2012-10-12 2016-12-06 Calcimedica, Inc. Compounds that modulate intracellular calcium
WO2017102014A1 (fr) * 2015-12-17 2017-06-22 Universite D'aix-Marseille Dérivés de thiophène propénamide utilisés comme inhibiteurs de flavivirus et leur utilisation
US9856240B2 (en) 2011-10-19 2018-01-02 Calcimedica, Inc. Compounds that modulate intracellular calcium
US20180235959A1 (en) 2015-08-07 2018-08-23 Calcimedica, Inc. Use of crac channel inhibitors for the treatment of stroke and traumatic brain injury
US10106529B2 (en) 2011-06-10 2018-10-23 Calcimedia, Inc. Compounds that modulate intracellular calcium
US10703722B2 (en) 2010-04-27 2020-07-07 Calcimedica, Inc. Compounds that modulate intracellular calcium
US10821109B1 (en) 2015-02-27 2020-11-03 Calcimedica, Inc. Pyrazine-containing compound
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
CN115093373A (zh) * 2022-08-24 2022-09-23 江苏省中国科学院植物研究所 一种1,5-二取代-3-氟烷基-1,2,4-三氮唑化合物及其制备方法和应用

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006022442A1 (fr) * 2004-08-24 2006-03-02 Santen Pharmaceutical Co., Ltd. Nouveaux derives d’amides heterocycliques ayant une activite d’inhibition de la dihydroorotate deshydrogenase
BRPI0706610A2 (pt) * 2006-01-18 2011-04-05 Siena Biotech Spa moduladores de receptores alfa 7 nicotìnico acetilcolina e usos terapêuticos destes
WO2009055917A1 (fr) * 2007-11-02 2009-05-07 Methylgene Inc. Inhibiteurs de l'histone déacétylase

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992001684A1 (fr) * 1990-07-24 1992-02-06 Pfizer Inc. Derives de 3-(1-pyrazoyle substitue)-2-oxindole
EP0644198A1 (fr) * 1993-06-03 1995-03-22 Sterling Winthrop Inc. Alpha-hétéroaryloxyméthyl cétones comme inhibiteurs d'enzyme convertissant l'interleukine-1 bêta
WO1995015316A1 (fr) * 1993-11-30 1995-06-08 G. D. Searle & Co. Benzenesulfonamides de pyrazolyle substitues destines au traitement des inflammations
WO1995015317A1 (fr) * 1993-11-30 1995-06-08 G.D. Searle & Co. Composes du 1,4,5-triphenyle pyrazolyle destines au traitement des inflammations et des troubles lies aux inflammations
WO1995033751A1 (fr) * 1994-06-08 1995-12-14 Sanofi Winthrop, Inc. INHIBITEURS AU LACTAME BICYCLIQUE DE L'ENZYME DE CONVERSION DE L'INTERLEUKINE-1-$g(b)
WO1999019303A1 (fr) * 1997-10-13 1999-04-22 Yamanouchi Pharmaceutical Co., Ltd. Derives de pyrazole
WO1999023091A1 (fr) * 1997-11-03 1999-05-14 Boehringer Ingelheim Pharmaceuticals, Inc. Composes heterocycliques aromatiques convenant comme anti-inflammatoires

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992001684A1 (fr) * 1990-07-24 1992-02-06 Pfizer Inc. Derives de 3-(1-pyrazoyle substitue)-2-oxindole
EP0644198A1 (fr) * 1993-06-03 1995-03-22 Sterling Winthrop Inc. Alpha-hétéroaryloxyméthyl cétones comme inhibiteurs d'enzyme convertissant l'interleukine-1 bêta
US5585357A (en) * 1993-06-03 1996-12-17 Sanofi Winthrop Inc. Heteroaryloxymethyl ketones as interleukin-1βconverting enzyme inhibitors
WO1995015316A1 (fr) * 1993-11-30 1995-06-08 G. D. Searle & Co. Benzenesulfonamides de pyrazolyle substitues destines au traitement des inflammations
WO1995015317A1 (fr) * 1993-11-30 1995-06-08 G.D. Searle & Co. Composes du 1,4,5-triphenyle pyrazolyle destines au traitement des inflammations et des troubles lies aux inflammations
WO1995033751A1 (fr) * 1994-06-08 1995-12-14 Sanofi Winthrop, Inc. INHIBITEURS AU LACTAME BICYCLIQUE DE L'ENZYME DE CONVERSION DE L'INTERLEUKINE-1-$g(b)
WO1999019303A1 (fr) * 1997-10-13 1999-04-22 Yamanouchi Pharmaceutical Co., Ltd. Derives de pyrazole
WO1999023091A1 (fr) * 1997-11-03 1999-05-14 Boehringer Ingelheim Pharmaceuticals, Inc. Composes heterocycliques aromatiques convenant comme anti-inflammatoires

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
TSUJI, KIYOSHI ET AL: "Studies on anti- inflammatory agents. IV. Synthesis and pharmacological properties of 1,5-diarylpyrazoles and related derivatives", CHEM. PHARM. BULL. (1997), 45(6), 987-995, XP002112608 *
TSUJI, KIYOSHI ET AL: "Studies on anti- inflammatory agents. V. Synthesis and pharmacological properties of 3-(difluoromethyl)-1-(4-methoxyphenyl)- 5-[4-(methylsulfinyl)phenyl]pyrazole and related compounds", CHEM. PHARM. BULL. (1997), 45(9), 1475-1481, XP002112607 *

Cited By (73)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7285554B2 (en) 1997-10-13 2007-10-23 Astellas Pharma Inc. Pyrazole derivative
US6958339B2 (en) 1997-10-13 2005-10-25 Astellas Pharma Inc. Pyrazole derivative
EP1024138A4 (fr) * 1997-10-13 2002-02-06 Yamanouchi Pharma Co Ltd Derives de pyrazole
US6348480B1 (en) 1997-10-13 2002-02-19 Yamanouchi Pharmaceutical Co., Ltd. Pharmaceutical compound comprising a pyrazole derivative and methods of using the same for the treatment of calcium release-activated calcium channel associated diseases
US7247635B2 (en) 1997-10-13 2007-07-24 Astellas Pharma Inc. Pyrazole derivative
EP1101759A4 (fr) * 1998-07-31 2001-12-12 Nippon Soda Co Composes phenylazole, procede de production desdits composes et medicaments pour le traitement de l'hyperlipidemie
EP1176140A4 (fr) * 1999-02-10 2002-07-31 Mitsubishi Pharma Corp Composes amide et leur utilisation medicinale
JP2003528070A (ja) * 2000-03-22 2003-09-24 イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニー 殺虫性アントラニルアミド類
JP4828073B2 (ja) * 2000-03-22 2011-11-30 イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニー 殺虫性アントラニルアミド類
WO2001072740A1 (fr) * 2000-03-23 2001-10-04 Boehringer Ingelheim Pharmaceuticals, Inc. Triazoles 1-(4-aminophenyl) substitues et leur utilisation comme agents anti-inflammatoires
US6451820B1 (en) 2000-03-23 2002-09-17 Boehringer Ingelheim Pharmaceuticals, Inc. Substituted 1-(4-aminophenly)triazoles and their use as anti-inflammatory agents
AU2006225221B2 (en) * 2000-03-24 2008-11-20 Euro-Celtique S.A. Aryl substituted pyrazoles, triazoles and tetrazoles, and the use thereof
US7141585B2 (en) 2000-07-07 2006-11-28 Agouron Pharmaceuticals, Inc. Pyrazole derivatives
WO2002006273A1 (fr) * 2000-07-13 2002-01-24 Boehringer Ingelheim Pharmaceuticals, Inc. 1-(4-aminophenyl) indoles substitues et leur utilisation comme anti-inflammatoires
US8263657B2 (en) * 2000-12-18 2012-09-11 Institute Of Medicinal Molecular Design, Inc. Inhibitors against the production and release of inflammatory cytokines
US7132546B2 (en) 2000-12-22 2006-11-07 Ishihara Sangyo Kaisha, Ltd. Aniline derivatives or salts thereof and cytokine production inhibitors containing the same
WO2004002948A1 (fr) * 2001-05-16 2004-01-08 Mitsubishi Pharma Corporation Compose amide et utilisation medicinale de ce compose
US6831082B2 (en) 2001-06-29 2004-12-14 Boehringer Ingelheim Pharmaceuticals, Inc. Method of using soluble epoxide hydrolase inhibitors
WO2003002555A1 (fr) * 2001-06-29 2003-01-09 Boehringer Ingelheim Pharmaceuticals Inc. Procede d'utilisation d'inhibiteurs d'hydrolase epoxyde solubles
US6753332B2 (en) 2001-07-05 2004-06-22 Pfizer, Inc. Sulfonyl heteroaryl triazoles as anti-inflammatory/analgesic agents
US6875779B2 (en) 2001-07-05 2005-04-05 Pfizer Inc. Sulfonyl heteroaryl triazoles as anti-inflammatory/analgesic agents
EP1273580A1 (fr) * 2001-07-05 2003-01-08 Pfizer Products Inc. Sulfonyl heteroaryl triazoles comme agent anti-inflammatoire et analgetique
US6927230B2 (en) 2001-11-09 2005-08-09 Fujisawa Pharmaceutical Co., Ltd. Triazole derivatives
US7309710B2 (en) 2002-08-27 2007-12-18 Astellas Pharma Inc. Crystals
AU2003273295B2 (en) * 2002-09-09 2007-03-22 Amgen Inc. 1, 4, 5-substituted 1, 2-dihydro-pyrazol-3-one derivatives as TNF-alpha and interleukin lowering agents for the treatment of inflammation
WO2004022055A1 (fr) * 2002-09-09 2004-03-18 Amgen Inc. Derives de 1, 4, 5-substitue 1, 2-dihydro-pyrazol-3-one et 3-alcoxy-1h-pyrazole, tnf-alpha et agents reduisant l'interleukine dans le traitement des inflammations
WO2004048367A1 (fr) * 2002-11-26 2004-06-10 Cj Corporation Derive de 1,2,4-triazole, procede de preparation de celui-ci et composition pharmaceutique renfermant celui-ci
CN1324023C (zh) * 2002-11-26 2007-07-04 Cj株式会社 1,2,4－三唑衍生物、其制备方法和含有所述化合物的药物组合物
US7622471B2 (en) 2003-02-07 2009-11-24 Daiichi Pharmaceutical Co., Ltd. Pyrazole derivatives having a pyridazine and pyridine functionality
US7078419B2 (en) 2003-03-10 2006-07-18 Boehringer Ingelheim Pharmaceuticals, Inc. Cytokine inhibitors
US7511042B2 (en) 2003-12-03 2009-03-31 Boehringer Ingelheim Pharmaceuticals, Inc. Triazole compounds
US7514458B2 (en) 2004-03-09 2009-04-07 Boehringer Ingelheim Pharmaceuticals, Inc. Anti-cytokine heterocyclic compounds
US7214802B2 (en) 2004-03-09 2007-05-08 Boehringer Ingelheim Pharmaceuticals, Inc. Anti-cytokine heterocyclic compounds
EP1887003A1 (fr) * 2004-03-09 2008-02-13 Boehringer Ingelheim Pharmaceuticals, Inc. 3-[4-heterocyclyl -1,2,3-triazol-1-yl]-n-aryl-benzamides comme inhibiteurs de la production de cytokines utiles pour le traitement de maladies inflammatoires chroniques
EA011634B1 (ru) * 2004-03-09 2009-04-28 Бёрингер Ингельхайм Фармасьютиклз, Инк. 3-[4-гетероциклил-1,2,3-триазол-1-ил]-n-арилбензамиды в качестве ингибиторов продуцирования цитокинов, предназначенные для лечения хронических воспалительных заболеваний
WO2005090333A1 (fr) * 2004-03-09 2005-09-29 Boehringer Ingelheim Pharmaceuticals, Inc. 3-'4-heterocyclyl -1,2,3,-triazol-1-yl-n-aryl-benzamides en tant qu'inhibiteurs de la production de cytokines pour le traitement de maladies inflammatoires
JP2007530594A (ja) * 2004-03-25 2007-11-01 シンタ ファーマシューティカルズ コーポレーション 炎症及び免疫に関連する用途に用いられるアクリロニトリル誘導体
US7592332B2 (en) 2004-05-03 2009-09-22 Boehringer Ingelheim Pharmaceuticals, Inc. Cytokine inhibitors
US7285545B2 (en) 2004-05-03 2007-10-23 Boehringer Ingelheim Pharmaceuticals, Inc. Cytokine inhibitors
US7485657B2 (en) 2004-05-12 2009-02-03 Boehringer Ingelheim Pharmaceuticals, Inc. Anti-cytokine heterocyclic compounds
US7531560B2 (en) 2004-11-10 2009-05-12 Boehringer Ingelheim Pharmaceuticals, Inc. Anti-cytokine heterocyclic compounds
EP1845081A4 (fr) * 2005-02-01 2009-03-25 Takeda Pharmaceutical Composé amide
WO2007067836A3 (fr) * 2005-12-05 2007-11-15 Boehringer Ingelheim Int Composes de pyrazole substitues utiles en tant qu'inhibiteurs d'epoxyde hydrolase soluble
US7671058B2 (en) 2006-06-21 2010-03-02 Institute Of Medicinal Molecular Design, Inc. N-(3,4-disubstituted phenyl) salicylamide derivatives
US9409909B2 (en) 2007-06-22 2016-08-09 Chemocentryx, Inc. N-(2-(hetaryl)aryl)arylsulfonamides and N-(2-(hetaryl)hetaryl)arylsulfonamides
US8835468B2 (en) 2007-06-22 2014-09-16 Chemocentryx, Inc. N-(2-(hetaryl)aryl)arylsulfonamides and n-(2-(hetaryl)hetaryl) arylsulfonamides
US8410144B2 (en) 2009-03-31 2013-04-02 Arqule, Inc. Substituted indolo-pyridinone compounds
US9120751B2 (en) 2010-04-27 2015-09-01 Calcimedica, Inc. Compounds that modulate intracellular calcium
US8546403B2 (en) 2010-04-27 2013-10-01 Calcimedica, Inc. Compounds that modulate intracellular calcium
US8980629B2 (en) 2010-04-27 2015-03-17 Calcimedica, Inc. Compounds that modulate intracellular calcium
US8754219B2 (en) 2010-04-27 2014-06-17 Calcimedica, Inc. Compounds that modulate intracellular calcium
US9090612B2 (en) 2010-04-27 2015-07-28 Calcimedica, Inc. Compounds that modulate intracellular calcium
US11905248B2 (en) 2010-04-27 2024-02-20 Calcimedica, Inc. Compounds that modulate intracellular calcium
US9353099B2 (en) 2010-04-27 2016-05-31 Calcimedica, Inc. Compounds that modulate intracellular calcium
US10703722B2 (en) 2010-04-27 2020-07-07 Calcimedica, Inc. Compounds that modulate intracellular calcium
US9079891B2 (en) 2010-08-27 2015-07-14 Calcimedica, Inc. Compounds that modulate intracellular calcium
US10336738B2 (en) 2010-08-27 2019-07-02 Calcimedica, Inc. Compounds that modulate intracellular calcium
US10106529B2 (en) 2011-06-10 2018-10-23 Calcimedia, Inc. Compounds that modulate intracellular calcium
US9856240B2 (en) 2011-10-19 2018-01-02 Calcimedica, Inc. Compounds that modulate intracellular calcium
US9409898B2 (en) 2012-05-02 2016-08-09 Lupin Limited Substituted pyrazole compounds as CRAC modulators
WO2013164773A1 (fr) * 2012-05-02 2013-11-07 Lupin Limited Composés substitués de pyrazole en tant que modulateurs de crac
AU2013255441B2 (en) * 2012-05-02 2017-11-09 Lupin Limited Substituted pyrazole compounds as CRAC modulators
US9512116B2 (en) 2012-10-12 2016-12-06 Calcimedica, Inc. Compounds that modulate intracellular calcium
US11013737B2 (en) 2015-02-27 2021-05-25 Calcimedia, Inc. Pyrazine-containing compound
US10821109B1 (en) 2015-02-27 2020-11-03 Calcimedica, Inc. Pyrazine-containing compound
US11311535B2 (en) 2015-02-27 2022-04-26 Calcimedica, Inc. Pancreatitis treatment
US11439639B2 (en) 2015-02-27 2022-09-13 Calcimedica, Inc. Pyrazine-containing compound
US11752148B2 (en) 2015-02-27 2023-09-12 Calcimedica, Inc. Pyrazine-containing compound
US10478435B2 (en) 2015-08-07 2019-11-19 Calcimedica, Inc. Use of CRAC channel inhibitors for the treatment of stroke and traumatic brain injury
US20180235959A1 (en) 2015-08-07 2018-08-23 Calcimedica, Inc. Use of crac channel inhibitors for the treatment of stroke and traumatic brain injury
WO2017102014A1 (fr) * 2015-12-17 2017-06-22 Universite D'aix-Marseille Dérivés de thiophène propénamide utilisés comme inhibiteurs de flavivirus et leur utilisation
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
CN115093373A (zh) * 2022-08-24 2022-09-23 江苏省中国科学院植物研究所 一种1,5-二取代-3-氟烷基-1,2,4-三氮唑化合物及其制备方法和应用

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