EP0948257A1 - Imidazoles a substitution triaryle, compositions renfermant de tels composes et modes d'utilisation - Google Patents

Imidazoles a substitution triaryle, compositions renfermant de tels composes et modes d'utilisation

Info

Publication number
EP0948257A1
EP0948257A1 EP97948342A EP97948342A EP0948257A1 EP 0948257 A1 EP0948257 A1 EP 0948257A1 EP 97948342 A EP97948342 A EP 97948342A EP 97948342 A EP97948342 A EP 97948342A EP 0948257 A1 EP0948257 A1 EP 0948257A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
independently selected
substituted
groups independently
naphthyl
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP97948342A
Other languages
German (de)
English (en)
Other versions
EP0948257A4 (fr
Inventor
Linda L. Chang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
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 GBGB9702823.7A external-priority patent/GB9702823D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP0948257A1 publication Critical patent/EP0948257A1/fr
Publication of EP0948257A4 publication Critical patent/EP0948257A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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

Definitions

  • IL-1 IL-1
  • rheumatoid arthritis rheumatoid arthritis
  • osteoarthritis endotoxemia
  • toxic shock syndrome other acute or chronic inflammatory diseases, such as the inflammatory reaction induced by endotoxin or inflammatory bowel disease
  • tuberculosis atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis and acute synovitis.
  • allograft rejections fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS related complex (ARC), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis and pyresis.
  • AIDS cachexia secondary to infection or malignancy
  • AIDS related complex ARC
  • keloid formation scar tissue formation, Crohn's disease, ulcerative colitis and pyresis.
  • compositions which comprise a compound of formula I in combination with a pharmaceutically acceptable carrier.
  • R 1 is 4-pyridyl, 4-pyrimidinyl, 4-quinolyl or pyridazinyl, each of which is unsubstituted or substituted with one or two substituents each of which is independently selected from the group consisting of
  • Ci-io alkyl (2) R5, and
  • Rl i or R8 and R9 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR12;
  • RlO and R20 is each independently selected from hydrogen and Ci-4 alkyl;
  • Rn is (1) Cl-10 alkyl,
  • Ci-4 alkyl wherein the substituents may be halo, C1-3 alkoxy, amino, or carboxy
  • aryl C 1-4 alkyl wherein the substituents may be halo, C1-3 alkoxy, amino, or carboxy, or
  • Rl8 and R19 are independently selected from
  • Rl is 4-pyridyl, 4-pyrimidinyl or 4-quinolyl
  • 1-naphthyl optionally substituted with up to 5 groups independently selected from Ci-io alkyl, R5, and Ci-io alkyl substituted with up to 5 groups independently selected from R5, (6) 2-naphthyl, optionally substituted with up to 5 groups independently selected from Ci-io alkyl, R5, and Ci-io alkyl substituted with up to 5 groups independently selected from R5, (7) heteroaryl, optionally substituted with up to 5 groups independently selected from Ci-io alkyl, R5, and Ci-io alkyl substituted with up to 5 groups independently selected from R5,
  • Aryl refers to aromatic rings wherein all ring atoms are carbon, including phenyl and naphthyl.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids/bases and organic acids/bases.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins such as
  • the compounds of formula I can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of disease states in mammals, which are exacerbated or caused by excessive or unregulated cytokine production, more specifically IL-1, IL-6, IL-8 or TNF production, by such mammal's cells, such as but not limited to monocytes and/or macrophages.
  • the compounds of formula I are also useful in treating diseases characterized by excessive IL-8 activity.
  • diseases characterized by excessive IL-8 activity.
  • diseases include psoriasis, inflammatory bowel disease, asthma, cardiac and renal reperfusion injury, adult respiratory distress syndrome, thrombosis and glomerulonephritis.
  • the invention includes a method of treating psoriasis, inflammatory bowel disease, asthma, cardiac and renal reperfusion injury, adult respiratory distress syndrome, thrombosis and glomerulonephritis, in a mammal in need of such treatment which comprises administering to said mammal a compound of formula I in an amount which is effective for treating said disease or condition.
  • the active compounds of the present invention may be orally administered as a pharmaceutical composition, for example, with an inert diluent, or with an assimilable edible carrier, or they may be enclosed in hard or soft shell capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet.
  • these active compounds may be incorporated with excipients and used in the form of tablets, pills, capsules, ampules, sachets, elixirs, suspensions, syrups, and the like.
  • Such compositions and preparations should contain at least 0.1 percent of active compound.
  • the percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit.
  • the amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
  • the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • Liquids include solutions, suspensions and emulsions. Solids include powders, poultices and the like. Semi-solids include creams, ointments, gels and the like. Drops according to the present invention may comprise sterile aqueous or oil solutions or suspensions, and may be prepared by dissolving the active ingredient in a suitable aqueous solution, optionally including a bactericidal and/or fungicidal agent and/or any other suitable preservative, and optionally including a surface active agent.
  • Lotions according to the present invention include those suitable for application to the skin or eye.
  • An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops.
  • Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
  • Step B 4'-Ethyl-4-biphenyl 4-pyridyl-t-butyldimethylsilyloxymethyl ketone
  • Step C 4-Benzoyl-2-(4-chlorophenyD- 1 -methoxymethyl-5-(4- pyridyDimidazole To a cooled solution of 2-(4-chlorophenyl)-l-methoxymethyl-5-
  • Step D 2-( -Chlorophenyl)-4-(4'-methoxybiphenyl-4-ylV5-f4- pyridyPimidazole
  • BIOLOGICAL ASSAYS The ability of compounds of the present invention to inhibit the binding of glucagon and the synthesis or the activity of cytokines can be determined by the following in vitro assays.
  • the box is incubated for 60 min. at 22 °C on a shaker at 275 rpm.
  • the wells are filtered over pre-soaked (0.5% polyethylimine(PEI)) GF/C filtermat using an Innotech Harvester or Tomtec Harvester with four washes of ice-cold 20 mM Tris, pH 7.8 buffer.
  • Count filters in Gamma- scintillation counter. Lipopolysaccharide mediated production of cytokines
  • IL-l ⁇ standards are prepared from purified recombinant IL-l ⁇ produced from E. coli.. The highest concentration begins at 10 ng/mL followed by 11 two-fold serial dilution's. For detection of IL-l ⁇ from cell culture supernatants or blood plasma, 10 - 25 mL of supernatant is added to each test well with 75 - 90 mL of PBS Tween.
  • Peroxidase activity was determined using TMB peroxidase substrate kit (Kirkegaard and Perry) with quantitation of color intensity on a 96-well plate Molecular Devices spectrophotometer set to determine absorbance at 450 nM. Samples are evaluated using a standard curve of absorbance versus concentration. Four-parameter logistics analysis generally is used to fit data and obtain concentrations of unknown compounds.

Abstract

Les 2,4-diaryl-5-pyridylimidazoles sont des antagonistes du glucagon et des inhibiteurs de la biosynthèse et/ou de l'action du TNF-α et d'IL-1. Ces composés bloquent l'action du glucagon au niveau de son récepteur et réduisent par conséquent le taux du glucose dans le plasma. Les présents imidazoles sont également des inhibiteurs du TNF-α et de IL-1. Les composés selon l'invention peuvent être utilisés pour le traitement des maladies liées au glucagon ou à la cytokine. Les maladies liées à la cytokine correspondent à des maladies ou états dans lesquels on observe une production excessive et non régulée d'une ou plusieurs cytokines. L'interleukine-1 (IL-1) et le facteur de nécrose des tumeurs ( TNF) sont des cytokines produites par diverses cellules qui interviennent dans l'immunorégulation et dans d'autres états physiologiques tels que l'inflammation.
EP97948342A 1996-11-20 1997-11-17 Imidazoles a substitution triaryle, compositions renfermant de tels composes et modes d'utilisation Withdrawn EP0948257A4 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US3146796P 1996-11-20 1996-11-20
US31467P 1996-11-20
GBGB9702823.7A GB9702823D0 (en) 1997-02-12 1997-02-12 Triayl substituted imidazoles, compositions containing such compounds and methods of use
GB9702823 1997-02-12
PCT/US1997/021019 WO1998021957A1 (fr) 1996-11-20 1997-11-17 Imidazoles a substitution triaryle, compositions renfermant de tels composes et modes d'utilisation

Publications (2)

Publication Number Publication Date
EP0948257A1 true EP0948257A1 (fr) 1999-10-13
EP0948257A4 EP0948257A4 (fr) 1999-12-29

Family

ID=26310972

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97948342A Withdrawn EP0948257A4 (fr) 1996-11-20 1997-11-17 Imidazoles a substitution triaryle, compositions renfermant de tels composes et modes d'utilisation

Country Status (5)

Country Link
EP (1) EP0948257A4 (fr)
JP (1) JP2001504490A (fr)
AU (1) AU728760B2 (fr)
CA (1) CA2271963A1 (fr)
WO (1) WO1998021957A1 (fr)

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US6613942B1 (en) 1997-07-01 2003-09-02 Novo Nordisk A/S Glucagon antagonists/inverse agonists
US6436966B1 (en) 1997-10-27 2002-08-20 Takeda Chemical Ind., Ltd. Adenosine A3 receptor antagonists
CA2346665A1 (fr) 1998-10-07 2000-04-13 Smithkline Beecham Corporation Nouveau traitement pour la gestion des accidents vasculaires cerebraux
US6503949B1 (en) 1999-05-17 2003-01-07 Noro Nordisk A/S Glucagon antagonists/inverse agonists
US6808902B1 (en) 1999-11-12 2004-10-26 Amgen Inc. Process for correction of a disulfide misfold in IL-1Ra Fc fusion molecules
JP2003520226A (ja) 2000-01-21 2003-07-02 ノバルティス アクチエンゲゼルシャフト ジペプチジルペプチダーゼ−ｉｖ阻害剤および抗糖尿病薬剤を含む組合せ物
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US6821960B2 (en) 2000-11-17 2004-11-23 Noyo Nordisk Pharmaceuticals, Inc. Glucagon antagonists/inverse agonists
US6706744B2 (en) 2000-11-17 2004-03-16 Novo Nordisk A/S Glucagon antagonists/inverse agonists
CA2451955C (fr) 2001-06-26 2015-09-29 Abgenix, Inc. Anticorps opgl
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US6762318B2 (en) 2001-12-03 2004-07-13 Novo Nordisk A/S Glucagon antagonists
US6881746B2 (en) 2001-12-03 2005-04-19 Novo Nordick A/S Glucagon antagonists/inverse agonists
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WO2004063192A1 (fr) * 2003-01-10 2004-07-29 Pharmacopeia Drug Discovery, Inc. Derives de d'imidazolyl pyrimidine utilises comme modulateurs du recepteur de il-8
AU2004210127B2 (en) 2003-01-27 2009-10-01 Merck Sharp & Dohme Corp. Substituted pyrazoles, compositions containing such compounds and methods of use
US20070060584A1 (en) * 2003-04-18 2007-03-15 Chakravarty Prasun K Biaryl substituted thiazoles, oxazoles and imidazoles as sodium channel blockers
CN1897936A (zh) 2003-12-19 2007-01-17 默克公司 环状胍、含有这种化合物的组合物及其使用方法
ES2306165T3 (es) 2004-06-04 2008-11-01 MERCK & CO., INC. Derivados de pirazol, composiciones que contienen dichos compuestos y procedimientos de uso.
CA2572745A1 (fr) 2004-07-07 2006-02-16 Teresa Beeson Derives de pyrazole amide, compositions contenant de tels composes et procedes d'utilisation
ATE468853T1 (de) * 2004-07-22 2010-06-15 Merck Sharp & Dohme Substituierte pyrazole, derartige verbindungen enthaltende zusammensetzungen und verfahren zu ihrer verwendung
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US7803951B2 (en) 2005-03-30 2010-09-28 Merck Sharp & Dohme Corp. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use
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PE20070458A1 (es) 2005-09-14 2007-07-05 Takeda Pharmaceutical Composicion farmaceutica que comprende 2-[[6-(3r)-3-amino-1-piperidinil]-3,4-dihidro-3-metil-2,4-dioxo-1(2h)-pirimidinil]metil]-benzonitrilo como inhibidor de dipeptidil peptidasa
TW200745031A (en) 2005-10-13 2007-12-16 Merck & Co Inc Acyl indoles, compositions containing such compounds and methods of use
CA2645639A1 (fr) 2006-03-23 2007-10-04 Merck & Co. Inc. Composes antagonistes du recepteur du glucagon, compositions contenant de tels composes et procedes d'utilisation
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EP3065736B1 (fr) 2013-11-04 2018-11-14 Merck Sharp & Dohme Corp. Composés antagonistes du récepteur du glucagon, compositions correspodantes et méthodes d'utilisation
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US3929807A (en) * 1971-05-10 1975-12-30 Ciba Geigy Corp 2-Substituted-4(5)-(aryl)-5(4)-(2,3 or -4-pyridyl)-imidazoles
WO1993014081A1 (fr) * 1992-01-13 1993-07-22 Smithkline Beecham Corporation Derives imidazole et leur utilisation comme inhibiteurs de cytokine
WO1995003297A1 (fr) * 1993-07-21 1995-02-02 Smithkline Beecham Corporation Imidazoles actives contre les maladies transmises par la cytokine
WO1996018626A1 (fr) * 1994-12-13 1996-06-20 F. Hoffmann-La Roche Ag Derives imidazoles utilises comme inhibiteurs de la proteine kinase, notamment de la tyrosine kinase du recepteur du facteur de croissance de l'epiderme (egf-r)

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Publication number Priority date Publication date Assignee Title
US3772441A (en) * 1970-11-16 1973-11-13 Pfizer Anti-inflammatory imidazoles
US3929807A (en) * 1971-05-10 1975-12-30 Ciba Geigy Corp 2-Substituted-4(5)-(aryl)-5(4)-(2,3 or -4-pyridyl)-imidazoles
WO1993014081A1 (fr) * 1992-01-13 1993-07-22 Smithkline Beecham Corporation Derives imidazole et leur utilisation comme inhibiteurs de cytokine
WO1995003297A1 (fr) * 1993-07-21 1995-02-02 Smithkline Beecham Corporation Imidazoles actives contre les maladies transmises par la cytokine
WO1996018626A1 (fr) * 1994-12-13 1996-06-20 F. Hoffmann-La Roche Ag Derives imidazoles utilises comme inhibiteurs de la proteine kinase, notamment de la tyrosine kinase du recepteur du facteur de croissance de l'epiderme (egf-r)

Non-Patent Citations (1)

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Title
See also references of WO9821957A1 *

Also Published As

Publication number Publication date
EP0948257A4 (fr) 1999-12-29
WO1998021957A1 (fr) 1998-05-28
AU728760B2 (en) 2001-01-18
CA2271963A1 (fr) 1998-05-28
JP2001504490A (ja) 2001-04-03
AU5442798A (en) 1998-06-10

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